Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5])C.[Li+].[OH-].[CH3:18]O.O>>[CH3:1][O:3][C:4]([C:6]1[N:7]([CH3:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Reactant: CO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc2ccc(Br)cc2n1C

Procedure:
6-Bromo-1-methyl-1H-indole-2-carboxylic acid methyl ester was prepared by N-methylation of 6-bromo-1H-indole-2-carboxylic acid ethyl ester using the procedure described in Example 13 for N-methylation of indole carboxylic acid esters. Ester hydrolysis was performed with LiOH (4 equ.) in methanol-water 4:1, 12 h at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was acidified to pH˜2-3 with 2N HCl and extracted in ethyl acetate. The organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 95% of 6-bromo-1-methyl-1H-indole-2-carboxylic acid [(1S,2R)-2-cyanomethyl-carbamoyl)-cyclohexyl]-amide; m/z 253.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:23]2)=[N:19][CH:20]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:24]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[N:23]2)=[N:19][CH:20]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cn2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
After a mixture of ethyl 3-[1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]propionate (930 mg), 1N sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (830 mg, yield: 94%). This was recrystallized from acetone-hexane. Melting point: 175–176° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:11]([N:8]1[N:9]=[C:10]2[C:2]([C:31]3[S:30][CH:29]=[CH:33][CH:32]=3)=[CH:3][CH:4]=[C:5]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[C:6]2=[N:7]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCn1nc2c(Br)ccc(Br)c2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCn1nc2c(-c3cccs3)ccc(-c3cccs3)c2n1

Procedure:
4,7-Dibromo-2-dodecylbenzotriazole (100 mg, 0.224 mmol), and tributyl(thiophen-2-yl)stannane were dissolved in anhydrous THF (100 ml) and dichlorobis (triphenylphosphine)-palladium(II) (50 mg, 0.045 mmol) was added at room temperature. The mixture was refluxed for 12 hours under argon atmosphere. Solvent was evaporated under vacuum and the crude product was purified by column chromatography on silica gel to obtain 75 mg (74%) TBT. 1H NMR (400 MHz, CDCl3, δ): 8.01 (d, J=5.6 Hz, 2H), 7.52 (s, 2H), 7.28 (d, J=6.0 Hz, 2H), 7.09 (t, JA=8.8 Hz, JB=4.8, 2H), 4.60 (t, J=7.0 Hz, 2H), 2.10 (m, 2H), 1.38-1.15 (m, 18H), 0.80 (t, J=6.9 Hz, 3H); 13C NMR (100 MHz, DMSO-d6, δ): 142.4, 140.2, 128.4, 127.3, 125.8, 123.9, 123.0, 57.1, 32.2, 30.3, 29.9, 29.8, 29.7, 29.6, 29.5, 29.3, 26.9, 22.9, 14.4. MS (m/z): 451 [M+]
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9]([OH:11])=[O:10].Cl[C:16]1[C:25]2[C:20](=[C:21]([C:26]3[N:30]=[C:29]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH:38]([CH3:40])[CH3:39])=[C:33]([Cl:41])[CH:32]=4)[O:28][N:27]=3)[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1>C(Cl)Cl>[Cl:41][C:33]1[CH:32]=[C:31]([C:29]2[O:28][N:27]=[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[CH:19]=[CH:18][N:17]=[C:16]4[N:7]3[CH2:14][CH2:13][CH2:12][C@H:8]3[C:9]([OH:11])=[O:10])[N:30]=2)[CH:36]=[CH:35][C:34]=1[O:37][CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(Cl)nccc34)no2)cc1Cl
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCC[C@H]5C(=O)O)nccc34)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
A mixture of sodium hydride (60%; 9.99 mg, 0.250 mmol), dimethyl sulfoxide (DMSO) (2 ml) and proline (36.0 mg, 0.312 mmol) were stirred at room temp under nitrogen for 1 hour. 1-Chloro-5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)isoquinoline (D7; 50 mg, 0.125 mmol) was added and the reaction mixture was heated at 120° C. under nitrogen for 3 hr. The cooled reaction mixture was loaded onto an SCX column. The column was washed with methanol and then eluted using 2M methanolic ammonia. The appropriate fractions were combined and the solvent was removed in vacuo to give an orange oil which was dissolved in DCM and washed with water. The organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo to give the title compound as an orange solid (40 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:14]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:15]3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CS(O[CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[Cl:1][C:2]1[C:10]2[N:9]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:8]([C:11]([N:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:14]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:15]3)=[O:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCCOS(C)(=O)=O
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3c(Cl)cccc3[nH]2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21
Temperature: 70 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-{[(4-chloro-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (1.7 g) and 4-methoxybutyl methanesulfonate (754 mg) were dissolved in DMA (50 ml), cesium carbonate (1.7 g) was added, and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was poured into ice water (100 ml), and the mixture was extracted twice with ethyl acetate (100 ml). The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a less polar fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced is pressure to give 1-tert-butyl 3-methyl (3R,5S)-5-[{[7-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (200 mg).
Reaction SMILES: C[Si](Cl)(C)C.[C:6]([O:10][C:11](=[O:14])[CH2:12]Br)([CH3:9])([CH3:8])[CH3:7].[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[C:21]([C:25](=[O:28])[CH2:26][CH3:27])[CH:20]=[CH:19][N:18]=1>C(OCC)C.O1CCCC1.[Zn]>[C:6]([O:10][C:11](=[O:14])[CH2:12][C:25]([C:21]1[CH:20]=[CH:19][N:18]=[C:17]([O:16][CH3:15])[C:22]=1[O:23][CH3:24])([OH:28])[CH2:26][CH3:27])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCC(=O)c1ccnc(OC)c1OC
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
To a mixture of zinc (23.1 g; 353.9 mmol) in anhydrous diethyl ether (400 mL) was added trimethylsilyl chloride (0.5 mL). The mixture was stirred for 15 minutes at room temperature and refluxed. Bromoacetic acid tert-butyl ester (56.5 g, 290.0 mmol) was added dropwise and the reaction continued refluxing for an additional 1 hour. The mixture was then cooled to room temperature and cannulated to a solution of 1-(2,3-dimethoxy-pyridin-4-yl)-propan-1-one (13.8 g; 70.8 mmol) in anhydrous tetrahydrofuran (300 mL). The reaction was stirred for 16 hours at room temperature and quenched with saturated ammonium chloride solution. The aqueous layer was extracted with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure and purified by chromatography (SiO2; 2-10% ethyl acetate/hexane) to give the product 3-(2,3-dimethoxy-pyridin-4-yl)-3-hydroxy-pentanoic acid tert-butyl ester (6) (16.0 g).
Reaction SMILES: CC(O[C:5]1[C:9](=[O:10])[C:7](=[O:8])[C:6]=1[O:11][CH:12]([CH3:14])[CH3:13])C.[Sn:15]([Si](C)(C)C)([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH3:14][CH:12]([O:11][C:6]1[C:7](=[O:8])[C:9](=[O:10])[C:5]=1[Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13]
Reactant: CCCC[Sn](CCCC)(CCCC)[Si](C)(C)C
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reaction time: 2 h
Yield: 67 %

Procedure:
A solution of 0.052M n-Bu4N+CN- in tetrahydrofuran (7.69 mL, 0.4 mmol) was added dropwise to a stirred solution at -20° C. of diisopropyl squarate (3.96 g, 0.020 mol) and n-Bu3SnSi(CH3)3 (7.27 g, 0.020 mol) in tetrahydrofuran (154 mL). Stirring was continued at -20° C. for 2 hrs. The solution was concentrated and the residue chromatographed on SiO2 with diethyl etherhexane (10:90) to afford the title compound (5.75 g, 67% yield) as a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[C:1]1([N:7]2[C:11]([NH2:12])=[C:10]([C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=3)[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)nn1-c1ccccc1
Reactant: O=C1CCCCC1
Product: Nc1c(C2=CCCCC2)c(-c2ccccc2)nn1-c1ccccc1

Procedure:
It is obtained by essentially following the procedure of example 1, reacting 1,3-diphenyl-5-pyrazolamine (1 mole) with cyclohexanone (1.1 mole) at a temperature of about 80° C. for about 4 hours. M.p. 115°-117° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=O.C[O-].[Na+]>CN(C)C=O.CO>[C:1]1([CH2:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([O:12][CH3:17])=[S:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(=S)c1cccnc1Cc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=S)c1cccnc1Cc1ccccc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A solution of 18.3 g (75 mmol) of 2-phenylmethylthionicotinic acid and 16.2 g (100 mmol) of carbonyldiimidazole in 250 mL of dry dimethylformamide was stirred at room temperature for 2 hours. The solution was cooled to 0° and 25 mL of 4M sodium methoxide in methanol was added. After warming to room temperature the solution was partitioned between ether and water and the aqueous layer was washed with two portions of ether. The ether extracts were washed with brine, dried over MgSO4, and concentrated. The residue was crystallized from ether-hexane to afford 17.4 g (89%) of fine white needles, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1O[CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13].ClC1C2C(=CC=CC=2)C=CC=1SC[CH2:37][NH:38]CC1C=CC=CN=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[CH:23]=[CH:22][CH:21]=[CH:37][N:38]=1)(=[O:14])=[O:13]
Reactant: Clc1c(SCCNCc2ccccn2)ccc2ccccc12
Reactant: O=S(=O)(CCNCc1ccco1)c1ccc2ccccc2c1Cl
Product: O=S(=O)(CCNCc1ccccn1)c1ccc2ccccc2c1Cl
Yield: 78 %

Procedure:
Prepared as described for compound 25 from 2-[(1-chloronaphthalen-2-yl)sulfanyl]-N-(pyridin-2-ylmethyl)ethanamine in 78% yield as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@H:20]([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:31])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:31])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCc3ccccc3)C(=O)N12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 10 mL round-bottomed flask, (1S,9S)-tert-butyl 9-(benzyloxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (1.3 g, 3.01 mmol) was combined with CH2Cl2 (5 ml) to give a colorless solution. TFA (3.53 g, 2.38 ml, 31.0 mmol) was added and stirred at room temperature for 5 hr. The crude reaction mixture was concentrated in vacuo and redissolved in EtOAc (10 ml). It was evaporated to afford (1S,9S)-9-(benzyloxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid as a foaming solid (1.0 g, 88.4%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[O:31][CH3:32]>>[CH3:32][O:31][C:25]1[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: COc1ccc(C)cc1Br
Product: COc1ccc(C)cc1N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 2-bromo-4-methylanisole. Light yellow solid. MS (ESI): 435.3 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Rh]>[C:1]([O:5][C:6]([N:8]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Agent: [Rh]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CC(=O)O)C1CCCCC1

Procedure:
Under a nitrogen atmosphere, 5% rhodium/alumina (3.00 g) is added to a solution of DL-N-tert-butoxycarbonylphenylglycine in ethanol (80 ml). The atmosphere is replaced with pressurized hydrogen (4.0 kgf/cm2) and stirred for ten days. The 5% rhodium/alumina is filtered out. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the titled reference compound (25.0 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]2[CH:11]=1.[I:12]N1C(=O)CCC1=O.C(#N)C>C(Cl)Cl>[I:12][C:11]1[N:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cn2c(C)cccc2n1
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nc2cccc(C)n2c1I
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,5-dimethylimidazo[1,2-a]pyridine (0.5 g, 3.4 mmol), N-iodosuccinimide (770 mg, 3.4 mmol) and ACN (5 ml) is stirred at RT for 45 minutes. The mixture is diluted with DCM and extracted with an aqueous solution sodium thiosulfate. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 775 mg (83%). HPLC-MS: M+H=273; tR=1.02 min (METHOD—1).
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2].[NH:15]1[CH:19]=[C:18]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=3[N:23]=[CH:24][N:25]=2)[CH:17]=[N:16]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:17]=[N:16]2)[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 417.2 g, 2.15 mol, 1.05 equiv) and 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 645 g, 2.04 mol) in acetonitrile (4.9 L) was added DBU (30.5 mL, 0.204 mol, 0.1 equiv) drop wise at room temperature. The resulting reaction mixture was then stirred at room temperature for 3 h. After about 1 h, a clear, brown solution was obtained. When LCMS showed that no starting material remained, silica gel (SiO2, 1 Kg) was added and the mixture was concentrated to dryness under reduced pressure. This material, which contains the crude desired product (15), was then loaded onto a pre-packed silica column (SiO2, 2.5 Kg) and the column was eluted with 60-80% of ethyl acetate/heptane. The fractions containing the pure desired product (15) were combined and concentrated under reduced pressure to give the desired product as thick oil which was then stirred in heptane at room temperature until crystallization occurred. The solids were collected by filtration and washed with heptane to afford tert-butyl 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (15, 1014.9 g, 1039.7 g theoretical, 97.6% yield) as white solids. For 15: 1H NMR (DMSO-d6, 300 MHz) δ 8.93 (s, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 7.80 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.50 (d, 2H, J=9.3 Hz), 4.21 (d, 2H, J=9.3 Hz), 3.66 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 1.40 (s, 9H), 0.82 (t, 2H, J=8.1 Hz), −0.12 (s, 9H) ppm; C25H35N7O3Si (MW, 509.68), LCMS (EI) m/e 510 (M−+H) and 532 (M++Na).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:35])[C:12]([CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:42]([OH:45])(=[S:44])[CH3:43]>>[CH2:8]([O:10][C:11](=[O:35])[CH:12]([CH2:13][S:44][C:42](=[O:45])[CH3:43])[CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:9]
Reactant: C=C(C(=O)OCC)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: CC(O)=S
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 45 °C
Yield: 73 %

Procedure:
Triethylamine (0.105 g, 1.04 mmol) was added to a solution of 2-[(6tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-acrylic acid ethyl ester (0.36 g, 0.94 mmol) in thioacetic acid (4 mL) at 0° C. under argon. The mixture was heated at 45° C. for 24 h. Ethyl acetate was added and the organic phase was washed with aqueous saturated sodium bicarbonate and brine and dried. After filtration and evaporation in vacuo the crude product was purified by flash chromatography (toluene/ethyl acetate, 1:0→5:1) to give 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-3-phenyl-propionic acid ethyl ester (0.314 g, 73%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:5]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:3]=1.[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:12]1([CH2:11][NH:10][C:6]2[C:7]([C:8]#[N:9])=[C:2]([N:28]3[CH2:29][CH2:30][CH:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[N:3]=[C:4]([NH:15][CH2:16][CH2:17][OH:18])[N:5]=2)[CH2:14][CH2:13]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCC2CC2)nc(NCCO)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-6-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 41b) was treated with 4-phenyl-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield the 4-(cyclopropylmethyl-amino)-2-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:20]C(=O)C1C=CC=CC=1)=[N:9]2.C1CCN2C(=NCCC2)CC1>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH2:20])=[N:9]2
Reactant: CO[C@H]1CC[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccccc2F)C1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CO[C@H]1CC[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)C1
Temperature: 25 °C

Procedure:
(±)-N-[(4aR*,7S*,8aS*)-8a-(2-Fluorophenyl)-7-methoxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]benzamide obtained in Preparation Example 57-(7) (268 mg) was dissolved in methanol (8 mL). Then, DBU (202 μL, specific gravity: 1.018 g/cm3) was added, and the mixture was stirred with heating under reflux for four hours and 15 minutes. Then, the reaction solution was stirred at 64° C. for 13 hours and 30 minutes. Thereafter, the reaction solution was stirred with heating under reflux for nine hours and 30 minutes. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (150 mg).