Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH2:36][CH2:35][CH2:34][NH:33]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:33]1[CH2:34][CH2:35][CH2:36][CH:32]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(C2CCCN2)nc1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCC2c2ccccn2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(pyridin-2-yl)pyrrolidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.98 minutes; C26H23Cl2N5O2 (508.41); mass spectrum: (M−H)−=507/509/511 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4].N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CO>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:8][CH2:7][N:6]1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[C:16]([Cl:22])[C:15]=1[CH3:23])=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 107.3 %

Procedure:
A cooled (0° C.) solution of compound 55A (510.1 mg, 1.51 mmol) and imidazole (516 mg, 7.58 mmol) in dry DMF (2.6 mL) was treated with 97% tert-butyldimethylsilyl chloride (572 mg, 3.68 mmol), stirred at 0° C. for 5 min then at rt for 24 h. Methanol (3.5 mL) was added and the solution stirred at rt for another 24 h. The mixture was partitioned between 10% citric acid (5.3 mL) and EtOAc (3×50 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting syrup was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (732.3 mg, 100%) as a white solid, mp 123-125° C. HPLC: 3.38 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=9.30 min (98.6%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 452 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:5]=[CH:4][NH:3]1.[C:21]([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH3:21][N:3]1[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][C:2]1=[O:1]
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1CCc1cc[nH]c(=O)c1
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccc(CCN2C(=O)c3ccccc3C2=O)cc1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.1 %

Procedure:
A mixture of 2-(2-(2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (300 mg, 1.1 mmol) CH3I (1.0 g, 7 mmol) and K2CO3 (700 mg, 5 mmol) in 30 mL of DCM and 10 mL of DMF was stirred at room temperature for 3 days. 30 mL of DCM was added. The mixture was washed with H2O (3×30 mL), dried over anhydrous sodium sulfate, concentrated under reduce pressure to give 2-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)isoindoline-1,3-dione (230 mg, 73%) as a white solid. LC-MS: 283 [M+H]+, tR=1.29 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[NH2:20]>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[NH:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: COc1ccc(N)cc1OC
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: COc1ccc(Nc2cc(C)nc(-c3ccccn3)n2)cc1OC

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 3,4-dimethoxyaniline (61.2 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid (108 mg, 84%). 1H NMR (CDCl3): 8.63 (d, J=4.2 Hz, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.65 (t, J=1.5 Hz, 1H), 7.18 (m, 2 H), 6.7 (s, 1H), 6.71 (s, 2H), 6.28 (s, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[CH:26]=[C:25]([CH2:30]O)[CH:24]=[CH:23]4)=[N:16][CH:17]=2)=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([CH2:30][N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:26]=4)[CH:21]=3)=[N:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: C1CCNC1
Reactant: OCc1ccc2cc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Clc1ccc(-c2ccc(C#Cc3ccc4cc(CN5CCCC5)ccc4c3)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
58 μL (0.80 mmol) thionyl chloride are added at 0° C. to a solution of 148 mg (0.40 mmol) {6-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-naphthalen-2-yl}-methanol in 5 mL DCM. The solution is heated to RT and stirred for 1 h at this temperature. The reaction mixture is diluted with 30 mL DCM, combined with ice water, made alkaline with saturated NaHCO3 solution and the organic phase is washed with water. The organic phase is dried over MgSO4 and filtered. 0.10 mL (1.20 mmol) pyrrolidine are added to the filtrate, which is stirred for 2 h at RT and for 1 h at 40° C. The solvent is eliminated i.vac. and the purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH/NH3 5:1:0.1).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:3](=[O:10])[N:4]([CH2:8][CH3:9])[CH:5]=[CH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: CCn1ccnc(Br)c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCn1ccnc(-c2ccc(Cl)cc2)c1=O
Yield: 47.6 %

Procedure:
To 200 mg (0.98 mM) of 3-bromo-1-ethylpyrazin-2(1H)-one and 57 mg (0.05 mM) of palladium tetrakis triphenylphosphine in 4 ml of toluene were added, under nitrogen, 231.0 mg (1.48 mM) of 4-chlorophenylboronic acid and 2.9 ml of 2M sodium carbonate aqueous solution The mixture was stirred for 3 h at reflux under nitrogen atmosphere, and then at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was separated, dried, over anhydrous sodium sulfate, and concentrated. The compound was purified through a silica plug, eluting with dichloromethane, which afforded 110 mg of 3-(4-chlorophenyl)-1-ethylpyrazin-2(1H)-one as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:35][O:36][CH:37]1[CH2:40][NH:39][CH2:38]1>CN1C(=O)CCC1>[CH3:35][O:36][CH:37]1[CH2:40][N:39]([C:2]2[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=2)[C:5]([NH:7][C:8]2[S:9][C:10]3[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=3[N:12]=2)=[O:6])[CH2:38]1
Reactant: COC1CNC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CC(OC)C4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-mopholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-methoxy-azetidine hydrochloride in NMP. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)([Cl:18])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:18][C:16]([N:12]1[CH2:13][CH2:14][N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:11]1=[O:15])=[O:17]
Reactant: O=C1NCCN1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N1CCN(S(=O)(=O)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 80 parts by weight of 1-benzenesulphonyl-2-oxo-imidazolidine, 69 parts by weight of phosgene, 31.6 parts by weight of pyridine and 350 parts by volume of dichloromethane, brought together at 0°C, was stirred overnight at room temperature and subsequently evaporated to dryness. Thereafter the material was suspended in 500 parts by volume of ice water and filtered off, the residue was taken up in 500 parts by volume of dichloromethane, the solution was dried over MgSO4, filtered and again evaporated to dryness, and the residue was recrystallized from acetone/petroleum ether.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[Cl:15][CH:16]([C:22]([CH3:24])=O)[C:17](OCC)=[O:18]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:22]([CH3:24])[C:16]([Cl:15])=[C:17]([OH:18])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Solvent: CC(=O)O
Product: Cc1nc2nc(SCc3ccccc3)nn2c(O)c1Cl
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A solution of 16 g (77 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 10.6 g (77 mmol) of ethyl 2-chloroacetoacetate in 150 ml of glacial acetic acid was heated at 100° C. for 17 hours. Upon cooling to room temperature the solid which separated was collected by filtration. The filtrate was diluted with ice water to separate an additional quantity of solid. The solids were combined and dried to yield 14.0 g (60%) of the desired product as a solid, m.p. 258°-260° C. IR and 1H NMR were in agreement with the assigned structure.
Reaction SMILES: [C:1]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][OH:21])=[O:19])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(NC(=O)CCCCC(O)=[O:39])CCCCCCCCC.OO>CS(O)(=O)=O>[CH2:1]([NH:12][C:13](=[O:39])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][OH:21])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)NCCCCCC(=O)OO
Reactant: CCCCCCCCCCNC(=O)CCCCC(=O)O
Agent: CS(=O)(=O)O
Agent: OO
Product: CCCCCCCCCCNC(=O)CCCCC(=O)OO
Temperature: -15 °C

Procedure:
6-Decylamino-6-oxoperoxycaproic acid was prepared according to the procedure described in Example I for N-decanoyl-6-aminoperoxycaproic acid. Thus, the methyl ester of 6-decylamino-6-oxocaproic acid (29.9 g, 0.10 mol), hydrogen peroxide (17.0 g, 0.50 mol), and 98% methanesulfonic acid (60 mL) were reacted at room temperature for 2 hrs., the reaction mixture poured over ice, and the peroxyacid extracted into 125 mL of 60° C. ethyl acetate. The aqueous layer was discarded and the warm ethyl acetate solution was washed with two 100 mL portions of water. The ethyl acetate solution was transferred to a 250 mL Erlenmeyer flask (rinsed with 25 mL ethyl acetate), reheated to 60° C., and then cooled to -15° C. The crystals of N-decylamino-6-oxoperoxycaproic acid were collected by filtration, washed twice with 50 mL of ice-cold ethyl acetate and air dried. Yield was 21.6 g having peroxyacid AvO of 4.49% (theoretical Yield=30.1 g of 5.32% AvO), and mp 77°-85° C.
Reaction SMILES: C(O)=O.[CH:4]([NH2:6])=O.[NH2:7][C:8]1[NH:9][C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[CH:11][C:12]=1[C:13](OCC)=[O:14]>CN(C)C=O>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([C:10]2[NH:9][C:8]3[N:7]=[CH:4][N:6]=[C:13]([OH:14])[C:12]=3[CH:11]=2)=[CH:19][CH:20]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)[nH]c1N
Reactant: NC=O
Solvent: CN(C)C=O
Solvent: O=CO
Product: Oc1ncnc2[nH]c(-c3ccc(OCc4ccccc4)cc3)cc12
Temperature: 140 °C
Reaction time: 48 h

Procedure:
After adding 84 ml of formic acid, 338 ml of formamide and 169 ml of dimethylformamide to 56.7 g of the ethyl 2-amino-5-(4-benzyloxyphenyl)-1H-pyrrole-3-carboxylate synthesized in Production Example 153-1, the mixture was stirred at 140° C. for 48 hours and then allowed to stand at room temperature for 24 hours. The precipitated solid was filtered out and dried under reduced pressure to obtain 41 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28]Cl)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28][O:1][C:2]2[C:11]3[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:13])[C:3]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:22][CH2:21]1
Reactant: Cc1cccc2c(O)c(-c3ccccc3)c(=O)oc12
Reactant: CC(CCl)CN1CCOCC1
Product: Cc1cccc2c(OCC(C)CN3CCOCC3)c(-c3ccccc3)c(=O)oc12
Yield: 65 %

Procedure:
Prepared according to the method of Example 8 from 4-hydroxy-8-methyl-3-phenyl-coumarin and 3-morpholino-2-methyl-1-chloropropane. An oil is obtained which cannot be crystallised. Yield 65%.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH2:40])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([NH:40][C:2]3[N:20]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
179 c) 4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 1.625 mmol) and 4-(3-Amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.803 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (90.0 mg, 0.165 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.70 g, 79%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.6 Hz, 1H), 8.24 (d, J=8.3 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.4 Hz, 1H), 7.32 (s, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.05-6.99 (m, 2H), 6.89 (s, 1H), 6.59 (d, J=8.2 Hz, 1H), 3.63-3.58 (m, 4H), 3.22-3.17 (m, 4H), 3.10 (s, 3H), 1.50 (s, 9H). MS=549 (MH)+.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@:24]([CH3:30])([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Li+]>O1CCCC1>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:41])[C:16]([N:18]2[CH2:32][CH2:31][C@:21]3([NH:25][C@@:24]([CH2:26][OH:27])([CH3:30])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=2[CH3:40])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC(=O)[C@]1(C)CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.6 %

Procedure:
To a solution of methyl (2S,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-2-methyl-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 45, 72.9 mg, 0.118 mmol) in Tetrahydrofuran (THF) (2.5 ml) at 0° C. lithium borohydride (0.174 ml, 0.354 mmol) was added and the reaction mixture was stirred at room temperature and under nitrogen atmosphere for 3 days. Volatiles were evaporated in vacuo and the residue was dissolved in Methanol (2 ml)/HCl 1 N in water (3 ml). After 1 h stirring combined solvents were evaporated in vacuo. The residue was dissolved in Ethyl acetate (4 ml) and washed with NaHCO3 sat. sol. 2×3 ml. Organic phase was dried and evaporated and the residue was purified by flash chromatography on silica gel using a Biotage SNAP 10 g as column and Dichloromethane/Methanol 95:5 as eluent affording the title compound (39.8 mg, 0.068 mmol, y=57.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:13]3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>O1CCCC1>[NH:1]([C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][N:12]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:13]3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)[C:26]([CH3:27])=[O:28]
Reactant: Nc1ccc(C(=O)N2CC3CC(CN(Cc4ccccc4)C3)C2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)N2CC3CC(CN(Cc4ccccc4)C3)C2)cc1
Reaction time: 8 h

Procedure:
80.2 g (0.24 mole) of 3-(4-aminobenzoyl)-7-benzyl-3,7-diazabicyclo[3.3.1]nonane (cf. European Pat. No. 62,199) were dissolved in 500 ml anhydrous tetrahydrofuran and cooled with ice. 23.5 g (0.3 mole) of acetyl chloride, dissolved in 50 ml of tetrahydrofuran, were added dropwise, followed by 48.6 g (0.48 mole) of triethylamine at room temperature. The entire mixture was stirred overnight and then evaporated down under reduced pressure. The residue was taken up in water and the solution was extracted 3 times with methylene chloride. The combined organic phases were washed with water, dried and evaporated down under reduced pressure. Yield: 78.1 g, mp.: 208° C.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C@@H:3]([N:5]([CH2:9][CH2:10][C:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([OH:15])[CH2:12][CH:13]=[CH2:14])[C:6](=O)[O-:7])[CH3:4].[H-].[Na+]>C1COCC1>[CH2:12]([C:11]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:15][C:6](=[O:7])[N:5]([C@H:3]([C:2]([CH3:24])([CH3:23])[CH3:1])[CH3:4])[CH2:9][CH2:10]1)[CH:13]=[CH2:14]
Reactant: C=CCC(O)(CCN(C(=O)[O-])[C@@H](C)C(C)(C)C)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Reaction time: 8 h

Procedure:
To a solution of (S)-3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-hydroxyhex-5-enyl)carba mate (2.2 g, 6.27 mmol) in dry THF (25 mL) was added NaH (752 mg, 18.80 mmol) at 0° C. under N2, and the mixture was stirred at it overnight. The reaction was quenched with water, and the mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude product, which was purified by chromatography to give two isomers of 6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1([NH:21][C:22]([C:24]2[C:32]3[CH:31]=[C:30]([C:33]4[C:38]([F:39])=[CH:37][N:36]=[C:35](Cl)[N:34]=4)[S:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)=[O:23])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH:17][C:35]2[N:34]=[C:33]([C:30]3[S:29][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([C:22](=[O:23])[NH:21][CH:18]5[CH2:19][CH2:20]5)[C:32]=4[CH:31]=3)[C:38]([F:39])=[CH:37][N:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3F)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(CCCNc2ncc(F)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 80.4 %

Procedure:
4-(3-Aminopropyl)-piperidine-1-carboxylic acid tert-butyl ester (0.557 g, 2.30 mmol) is added to a stirred suspension of 2-(2-chloro-5-fluoropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.400 g, 1.15 mmol) and diisopropylethylamine (0.60 mL, 3.5 mmol) in anhydrous 1,4-dioxane (8 mL) at room temperature under nitrogen. The resultant mixture is heated in an oil bath at 95° C. for 34 hours. At room temperature the mixture is concentrated and chromatographed on silica gel, eluting with CH3OH in dichloromethane: 0-2%, to give 4-{3-[4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-5-fluoropyrimidin-2-ylamino]-propyl}-piperidine-1-carboxylic acid tert-butyl ester (0.512 g) as a solid.
Reaction SMILES: [C:1]1([C:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]1([C:7](=[N:17][OH:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C(Cc1ccccc1)c1ccccc1
Yield: 94.7 %

Procedure:
A solution of deoxybenzoin (407.4 g, 2.076 mol) in 2 L of absolute ethanol and 600 mL of water was treated with hydroxylamine hydrochloride (288 g, 4.15 mol) and sodium acetate trihydrate (564 g, 4.15 mol). The solution was then warmed to reflux for 2 hours. The reaction mixture was then diluted with 1000 mL of 30% aqueous ethanol and allowed to cool to room temperature whereupon crystals of pure oxime formed which were isolated by filtration and air dried to afford 415.4 g, 95%, mp 94°-96° C. of pure deoxybenzoin oxime.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[NH:5][NH:4][C:3]1=[O:8].[H-].[Na+].[CH2:11]=[CH:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][N:2]1[C:6](=[O:7])[NH:5][N:4]([CH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:3]1=[O:8]
Reactant: Cn1c(=O)[nH][nH]c1=O
Reactant: C=CC(=O)CCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC(=O)CCn1[nH]c(=O)n(C)c1=O
Temperature: 0 °C
Reaction time: 48 h
Yield: 54.3 %

Procedure:
To a solution of 4-methyl-1,2,4-triazolidine-3,5-dione (5.75 g, 0.05 mol) in dry dimethylformamide (40 ml) stirred at 75° under a nitrogen atmosphere was added portionwise sodium hydride (1.575 g, 0.055 mol, as an 80% dispersion in mineral oil) and the resultant solution stirred at 75° for 0.5 hr. To this solution was added oct-1-en-3-one (6.57 g, 0.055 mol) dropwise in dimethylformamide (20 ml) and the solution heated with stirring for 48 hr at 75°. The reaction mixture was then cooled, taken up in ethyl acetate (100 ml) and poured into ice-cold 5 N aqueous hydrochloric acid (200 ml). The aqueous layer was separated and extracted with ethyl acetate (4×100 ml). The combined extracts were washed with 5 N aqueous hydrochloric acid, water and then brine, then dried (Na2SO4), filtered and the solvent removed by evaporation in vacuo, to leave a gum (6.55 g). This was chromatographed on silica gel (Merck, Kieselgel 60) with a packing ratio of 1:20 with chloroform as eluant, to afford the triazolidine-3,5-dione (4.61 g) as a gum, which later solidified. (In subsequent preparations the crude material from the reaction mixture could be triturated with hexane to induced crystallisation), m.p. 76°-8°.