Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[O:12]=[C:13]1[N:17]([CH2:18][C@@H:19]2[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[C:16](=O)[CH2:15][NH:14]1>O1CCCC1>[OH:24][C@H:22]1[CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])[C@H:19]([CH2:18][N:17]2[CH:16]=[CH:15][NH:14][C:13]2=[O:12])[CH2:23]1
Reactant: O=C1CNC(=O)N1C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1Cn1cc[nH]c1=O
Reaction time: 12 h
Yield: 4.2 %

Procedure:
To a suspension of sodium borohydr-ide (6.03 g) in tetrahydrofuran (270 ml) was added boron trifluoride etherate (72 ml) at 0° C. under stirring. After stirring for 10 minutes, to the suspension was added a solution of (2S,4R)-2-(2,4-dioxoimidazolidin-3-yl)methyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (27.3 g) obtained in Preparation 10 in tetrahydrofuran (140 ml) and the mixture was stirred for 14 hours at ambient temperature. This reaction mixture was evaporated in vacuo and to the residue was added a solution of conc. hydrochloric acid (31 ml) in methanol (400 ml). After standing for 12 hours at ambient temperature, the solution was evaporated in vacuo and the resulting residue was poured into saturated aqueous sodium hydrogen carbonate (450 ml). The aqueous layer was extracted three times with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (200 ml) and evaporated in vacuo. The resulting residue was chromatographed on silica gel (600 ml) eluting with a mixture of methanol and dichloromethane (5:95, V/V) to give (2 S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxo-4-imidazolin-1-yl)methyl pyrrolidine (1.11 g).
Reaction SMILES: C(Br)C1C=CC=CC=1.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][NH:35][C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:22][C:23]1[N:24]=[C:25]([N:33]2[CH2:37][CH2:36][N:35]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([O:11][C:10]([F:21])([F:20])[F:9])=[CH:13][CH:14]=3)[C:34]2=[O:38])[S:26][C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)nc1C
Yield: 90 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with 4-(trifluoromethoxy)benzyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 90% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.32 (d, J=8.7 Hz, 2H), 7.18 (d, J=8.7 Hz, 2H), 4.48 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 4.08 (t, J=7.8 Hz, 2H), 3.46 (t, J=7.8 Hz, 2H), 2.60 (s, 3H), 1.32 (t, J=7.2 Hz, 3H); MS (ES+) m/z 430.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21]N(C)[CH2:19][CH2:18]2)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(O)(=O)/C=C\C(O)=O>>[CH3:1][C:2]1([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:21][CH2:22]2)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CN1CCN(CCC2(C)OCCc3c2[nH]c2ccccc32)CC1
Agent: O=C(O)/C=C\C(=O)O
Product: CC1(CCN2CCCC2)OCCc2c1[nH]c1ccccc21

Procedure:
1-methyl-1-[2-(4-methyl-1-piperazinyl)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (CDC13) δ1.47 (3H), 2.58 (3H), 3.87 (t,2H), [m.p. of corresponding maleic acid addition salt (i.e. dimaleate), 208° - 210° C.], respectively.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([N+:20]([O-])=O)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1>CO.C(O)(=O)C.[Pt]>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(COc2ccc(N)c3ccccc23)ccn1
Yield: 94.5 %

Procedure:
A solution of 2-Amino-4-[(4-nitronaphthalen-1-yloxy)methyl]pyridine (3) (4.50 g, 15.24 mmol) in methanol (200 mL) and glacial acetic acid (200 mL) was passed through a Thales ‘H-cube’ flow reactor (2 mL min−1, 40° C., 55 mm 10% Pt/C Cat-Cart®, full H2) and the volatiles were then removed in vacuo. The crude product was subjected to SCX capture and release eluting with 1% ammonia in MeOH solution and the solvent was removed in vacuo to give 2-amino-4-[(4-aminonaphthalen-1-yloxy)methyl]pyridine (4) (3.82 g, 94%) as a mauve solid: m/z 266 (M+H)+ (ES+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[C:4]([CH3:12])[CH:3]=1.[N:13]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:18][CH2:17][CH:16]([O:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:6]([N:31]2[CH2:32][CH2:33][CH:28]([N:13]3[CH2:14][CH2:15][CH:16]([O:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:18]3)[CH2:29][CH2:30]2)=[O:8])=[C:9]([CH3:11])[CH:10]=1
Reactant: O=C(OC1CCN(C2CCNCC2)CC1)c1ccccc1
Reactant: Cc1cc(Br)cc(C)c1C(=O)O
Product: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC(OC(=O)c3ccccc3)CC2)CC1

Procedure:
In analogy to the procedures described for intermediates 3B, 3C, 1, 4B and for example 1, the title compound has been prepared by the following reaction sequence: i) 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester [Lawrence, L.; Rigby, A.; Sanganee, H.; Springthorpe, B. PCT Int. Appl. (2001), WO 2001077101 A1] was reacted with benzoyl chloride to give 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester; ii) 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester was reacted with trifluoroacetic acid to give benzoic acid [1,4′]bipiperidinyl-4-yl ester; iii) 4-bromo-2,6-dimethyl-benzoic acid was converted into its acid chloride and reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester to give benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester; iv) benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester was saponified to give (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone; v) Suzuki reaction of (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone with 3-trifluoromethyl-phenyl boronic acid gave the title compound as light brown solid. MS: 461.3 (MH+).
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2.[CH3:20][S:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:23])=[O:22]>>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][S:21]([CH3:20])(=[O:23])=[O:22])[C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: COc1ccc2c(c1)CCc1ccccc1C2=CBr
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: COc1ccc2c(c1)CCc1ccccc1C2=Cc1ccccc1NS(C)(=O)=O

Procedure:
Following the procedures essentially as described in Example 219, below, and using 5-bromomethylene-2-methoxy-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (E/Z mixture, 100 mg, 0.32 mmol) with 4-methanesulfonylaminophenylboronic acid (75 mg, 0.35 mmol) to give 35 mg (27%) of an E/Z mixture of the title compound. MS (ES) 406 (M+1), 404 (M−1). HPLC shows 53% of the E isomer and 44% of the Z isomer.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[N:8][CH:7]=[CH:6][CH:5]=1.I[CH:21]([CH3:23])[CH3:22]>O.CC(O)C>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH2:7][N:8]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccnc1)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CC(C)N1C=C(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)C=CC1
Temperature: 0 °C
Reaction time: 96 h
Yield: 78.3 %

Procedure:
Boc-D-Pal (4.0 g, 17.7 mmol) and Ag2O (8.0 g, 34.4 mmol) in 22 ml water was stirred at room temperature for 4 hours. The reaction vessel was cooled to 0° C., and 2-iodopropane (20.4 g, 120 mmol) in 40 ml 2-propanol was added. After addition was complete, the mixture was allowed to warm to room temperature and stirred for 4 days. Additional Ag2O (2 g) and 2-iodopropane (2 g) were added after 24 hours and again after 48 hours. The mixture was filtered, and the precipitate was washed with ethanol (2×15 ml). The filtrate was evaporated to yield 4.3 g of a yellow oil. Crystallization from ethanol/ethyl acetate gave light yellow crystals (3.0 g); Yield: 63%; m.p. 182–185° C.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:32])([CH3:31])[O:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C:18](=[O:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][C:2]([Si:5]([CH3:32])([CH3:31])[O:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([C:17]([CH3:30])([CH3:29])[C@@H:18]([OH:28])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])([CH3:3])[CH3:4]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H]2[C@@H]3CC=C4C(C)(C)[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
ix)—A solution of compound 9 (39.4 g) in dry tetrahydrofuran (400 ml) was added dropwise to an ice-cooled suspension of lithium aluminium hydride (9.81 g) in tetrahydrofuran (490 ml). The mixture was stirred at room temperature for 1 h. The reaction was cooled to 0° C., and then quenched with a saturated aqueous solution of sodium sulfate. The reaction mixture was filtered over celite and the filtrate concentrated under reduced pressure to give (3β,20S)-20-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4,4-dimethylpregn-5-en-3-ol (compound 10: 38.9 g), which was used in the following step without further purification.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([NH:22][C:23](=[O:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]4[CH2:34][CH2:33][CH2:32][NH:31]4)[CH:25]=3)=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:43]([C:45]1[CH:46]=[C:47]([N:51]=[C:52]=[O:53])[CH:48]=[CH:49][CH:50]=1)#[N:44].[N-]=C=O>CN(C=O)C>[CH2:2]([O:9][C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([NH:22][C:23](=[O:35])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]4[CH2:34][CH2:33][CH2:32][N:31]4[C:52](=[O:53])[NH:51][C:47]4[CH:48]=[CH:49][CH:50]=[C:45]([C:43]#[N:44])[CH:46]=4)[CH:25]=3)=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2)c1cccc(C2CCCN2)c1
Reactant: N#Cc1cccc(N=C=O)c1
Agent: Cl
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cccc(NC(=O)N2CCCC2c2cccc(C(=O)Nc3ccc4c(c3)CN(C(=O)OCc3ccccc3)CC4)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.1 %

Procedure:
To a solution of 7-(3-pyrrolidin-2-yl-benzoylamino)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester HCl (238 mg, 0.387 mmol) in DMF (5 mL) add Et3N (0.082 mL, 0.581 mmol) followed by 3-cyanophenyl isocyanate (69 mg, 0.464 mmol). Stir the solution at room temperature for 48 h. LCMS analysis indicates the presence of starting material. Add more isocyanate (69 mg, 0.464 mmol) and stir the reaction at room temperature 24 h more. Quench the reaction with sat. NH4Cl (100 mL) and extract with EtOAc (2×150 mL). Wash the organic layers with water (100 mL), dry (Na2SO4) and concentrate to an oil. Purify the crude product by silica gel chromatography eluting with 10% to 75% EtOAc/hexane to afford 186 mg 7-{3-[1-(3-cyanophenylcarbamoyl)-pyrrolidin-2-yl]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a solid foam.
Reaction SMILES: Cl[C:2]1[C:15]2[O:14][CH2:13][CH:12]3[N:7]([CH2:8][CH2:9][O:10][CH2:11]3)[C:6]=2[N:5]=[C:4]([Cl:16])[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[Cl:16][C:4]1[N:3]=[C:2]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:15]2[O:14][CH2:13][CH:12]3[N:7]([C:6]=2[N:5]=1)[CH2:8][CH2:9][O:10][CH2:11]3
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2c(n1)N1CCOCC1CO2
Solvent: CCN(CC)CC
Product: Clc1nc(N2CCOCC2)c2c(n1)N1CCOCC1CO2
Temperature: 140 °C
Yield: 37.9 %

Procedure:
A mixture of 1,3-dichloro-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triaza-phenanthrene (100 mg, 0.38 mmol), morpholine (80 μL, 0.92 mmol) and triethylamine (70 μL, 0.50 mmol) in IMS (5 mL) was heated at 140° C. for 25 mins in a microwave reactor, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 10 to 15 to 25% ethyl acetate in pentane) affording 3-Chloro-1-morpholin-4-yl-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triaza-phenanthrene (45 mg, 38%). LCMS (method A): RT=2.92 min, [M+H]+=313. 1H NMR (400 MHz, CDCl3): δ 4.37 (1H, dd, J=13.2, 3.0 Hz), 4.19 (1H, dd, J=10.8, 3.3 Hz), 3.99 (1H, dd, J=11.1, 3.9 Hz), 3.88 (1H, dd, J=10.8, 3.2 Hz), 3.80 (dd, J=11.1, 8.4 Hz), 3.75 (4H, m), 3.66-3.53 (6H, m), 3.24 (1H, t, J=11.1 Hz), 3.00 (1H, m).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][S:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]OS(C)(=O)=O)(=[O:8])=[O:7].C(O)C>O>[CH3:5][S:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])(=[O:8])=[O:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCOCCOCCOCCOS(C)(=O)=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-]
Yield: 47.1 %

Procedure:
Sodium azide (1.0 g) is added to a solution of tetraethyleneglycol dimethanesulphonate (5.25 g, 15 mmol), obtained according to A. W. Chwabacher et al. (J. Org. Chem. 1998, 65(5), 1717), in 18 mL of 95° ethanol. The reaction mixture is taken to reflux for 24 hours. Then the solvent is evaporated off, the reaction crude is added to 100 mL of salt water and extracted with ether 3×100 mL. The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column using a gradient of AcOEt in hexane (1/1 to 3/1) as eluents. 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl mono-methanesulphonate 47 (2.10 g, 47%) is obtained, which is used directly in the following stage.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:8])[CH2:3][CH2:2]1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>C(#N)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][N:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:8])[CH2:3][CH2:2]1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccccn1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CN1CCC(C(=O)c2ccccn2)CC1
Temperature: 80 °C
Yield: 80.1 %

Procedure:
To a solution of compound piperidin-4-yl-pyridin-2-yl-methanone (170 mg, 0.894 mmol) in 10 mL acetonitrile was added ethyl bromoacetate (0.13 mL, 1.12 mmol) and triethylamine (362 mg, 3.57 mmol). The reaction was heated at 80° C. for 16 hour. The combined organic layers were concentrated under vacuum to afford an orange oily solid. The residue was chromatographed on silica gel (gradient: methanol/dichloromethane; 0:1 to 1:9 over 20 minutes) to afford the title compound as a white solid (198 mg). 1H NMR (400 MHz, CDC3) δ 8.68 (d, J=4.0 Hz, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.89 (t, J=9.0 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 4.33-4.27 (m, 2H), 3.92 (s, 2H), 3.70-3.72 (m, 2H), 3.59-3.53 (m, 2H), 2.34-2.28 (m, 4H), 1.34 (t, J=7.1 Hz, 3H). MS m/z ES+=276.8 (M+H), retention time 0.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:19]([C:20]([NH2:22])=[O:21])=[C:12]3[CH2:13][NH:14][C:15]4([CH2:18][CH2:17]4)[CH2:16][N:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.O>[C:23]([NH:27][C:28]([N:14]1[C:15]2([CH2:18][CH2:17]2)[CH2:16][N:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[C:19]([C:20]([NH2:22])=[O:21])=[C:12]2[CH2:13]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)N=C=O
Reactant: NC(=O)c1c(-c2ccc(F)c(Cl)c2)nn2c1CNC1(CC1)C2
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2CC12CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 25.3 %

Procedure:
To a solution of Intermediate 350H (30 mg, 0.094 mmol) in THF (2 mL) was added TEA (0.026 mL, 0.187 mmol) and tert-butyl isocyanate (0.022 mL, 0.187 mmol) and the resulting solution was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and the filtrate concentrated. The crude product was purified by preparative HPLC to afford Compound 350 as an off-white solid (10 mg, 25%). HPLC retention times 9.363 min. and 13.023 min. (Methods A and F respectively). MS(ES): m/z=420 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.85 (dd, J=7.31, 2.16 Hz, 1H), 7.68 (ddd, J=8.63, 4.80, 2.20 Hz, 1H), 7.45 (t, J=9 Hz, 1H), 7.30 (br. s, 1H), 7.16 (br. s, 1H), 4.78 (br. s, 2H), 4.10 (br. s, 2H), 1.26 (s, 9H), 1.09 (s, 4H).
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[CH3:15][O:16][C:17]1([O:28][CH3:29])[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.Cl[C:31]([O:33][CH3:34])=[O:32]>C1COCC1>[CH3:15][O:16][C:17]1([O:28][CH3:29])[CH2:22][CH2:21][C:20]([C:31]([O:33][CH3:34])=[O:32])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C1CCC(OC)(OC)CC1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OC)CCC(OC)(OC)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 92.6 %

Procedure:
To a −78° C. solution of iPr2NEt (3.95 mL, 27.7 mmol) in THF (50 mL) was added n-BuLi (17.3 mL of a 1.6 M solution in hexanes; 27.7 mmol) was added. After 15 min, ethyl 4,4-dimethoxycyclohexane-carboxylate (4.0 g, 18.50 mmol) was added and the reaction mixture was stirred at −78° C. for 1 h. Methyl chloroformate (2.87 mL, 37.0 mmol) was added and the reaction mixture was warmed to rt. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (100 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude oil was chromatographed (SiO2; continuous gradient from 0 to 20% EtOAc:hexanes) to afford the title compound (4.7 g, 93% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 4.21 (q, J=7.1 Hz, 2H), 3.75 (s, 3H), 3.19 (s, 6H), 2.16-2.05 (m, 4H), 1.79-1.69 (m, 4H), 1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:12]1(O)[CH2:19][CH2:18]C[CH2:16][CH2:15][CH2:14][CH2:13]1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].C(OCC)(=O)C>[CH:1]1([O:2][C:3](=[O:11])[C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OC1CCCCCCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Product: O=C(OC1CCCCCCC1)c1ccc(O)cc1
Temperature: 180 °C
Yield: 12.6 %

Procedure:
22.82 g (0.15 mol) p-hydroxybenzoic acid methyl ester, 38.47 g (0.30 mol) cyclooctanol and 26 mg (0.1 mmol) tetraisopropyl orthotitanate are placed under argon in a round-bottom flask with distillation bridge. The mixture is stirred and heated to 180° C. within 45 minutes. The pressure is reduced to 800 mbar and over the further course of distillation to 650 mbar. After a further 15 minutes the pressure is increased to 900 mbar and the reaction mixture stirred for a further 2 hours, during which time methanol continues to be removed by distillation. A further 9.62 g (0.075 mol) cyclooctanol and 2 drops of tetraisopropyl orthotitanate are added to the reaction solution and stirred for a further 4 hours at 180° C. It is allowed to cool and the residue is dissolved in 100 ml ethyl acetate and washed repeatedly with distilled water. The organic phase is concentrated to small volume. The crude product is purified by column chromatography (silica gel 60, 0040-0.063 mm, Merck) with an n-hexane/acetone mixture (3:1). The product obtained is freed from adhering cyclooctanol under high vacuum. The white crystalline residue is recrystallised in acetone. 4.70 g (12%) of colourless crystals are obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[Cl:11][CH2:12][C:13]([C:8]1[S:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:10][CH:9]=1)=[O:14]
Reactant: O=C(Cl)CCl
Reactant: ClCCCCc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)c1ccc(CCCCCl)s1
Yield: 90.7 %

Procedure:
To a solution of 23 g of 2-(4-chlorobutyl)thiophene and 17.9 g of chloroacetyl chloride in 250 ml of dichloromethane is added a small portion of 21 g of aluminum chloride under cooling at 0°-5° C. and with stirring. After stirring under cooling with ice for 2 hours, the resultant mixture is poured into water and the organic layer is separated. The water layer is extracted with chloroform and the extract is combined with the organic layer. The combined organic layer is washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give 30 g of 2-chloroacetyl-5-(4-chlorobutyl)thiophene as a brown oil. To a solution of the oil in 300 ml of ethanol is added 11 g of thiourea, and refluxed on a water bath for 2 hours. After the solvent is concentrated under reduced pressure, water is added to the residue and the precipitated crystalline hydrochloride is collected by filtration. To a suspension of the crystals in a mixture of water and ethyl acetate is added sodium hydrogencarbonate until the mixture is made alkaline. The organic layer is separated, washed with water and dried over magnesium sulfate. After the is distilled off under reduced pressure, the residue is recrystallized from ethanol to give 2-amino-4-[5-(4-chlorobutyl)-2-thienyl] thiazole as pale yellow crystals, melting at 99°-100° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[O:10][CH2:9]1)[CH:2]=[CH2:3].[NH2:15][CH2:16][CH2:17][C:18]1[NH:19][C:20]2[CH:26]=[C:25]([C:27]3[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=3)[CH:24]=[CH:23][C:21]=2[N:22]=1>>[CH2:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:10])[CH2:9][NH:15][CH2:16][CH2:17][C:18]1[NH:19][C:20]2[CH:26]=[C:25]([C:27]3[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=3)[CH:24]=[CH:23][C:21]=2[N:22]=1)[CH:2]=[CH2:3]
Reactant: CC1CC(=O)NN=C1c1ccc2nc(CCN)[nH]c2c1
Reactant: C=CCc1ccccc1OCC1CO1
Product: C=CCc1ccccc1OCC(O)CNCCc1nc2ccc(C3=NNC(=O)CC3C)cc2[nH]1

Procedure:
Prepared analogously to Example 1 from 1-(2-allylphenoxy)-2,3-epoxypropane and 6-[2-(2-aminoethyl)benzimidazol-5-yl]-4,5-dihydro-5-methyl-3(2H)- pyridazinone.