Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][S:10]/[C:9]/2=[N:13]\[H])=[CH:4][CH:3]=1.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][S:10]/[C:9]/2=[N:13]\[C:15]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[O:16])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: [H]/N=C1\SCCN1c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(/N=C1\SCCN1c1ccc(Cl)cc1)n1ccnc1

Procedure:
(2Z)-3-(4-Chlorophenyl)-1,3-thiazolidin-2-imine (233 mg, 1.095 mmol, Example 24A) and carbonyldiimidazole (195 mg, 1.205 mmol) in dry tetrahydrofuran were heated at 65° C. After 14 hours the reaction mixture cooled down, diluted with 75 mL of dichloromethane, and washed successively with sodium bicarbonate (50 mL) water and brine (50 mL), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].[CH2:20]=O>C(O)=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:20])[C:12]([CH3:19])([CH3:18])[CH2:11]2)[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: Cc1cc(C2CC(C)(C)NC(C)(C)C2)cc(C)c1O
Reactant: C=O
Solvent: O=CO
Product: Cc1cc(C2CC(C)(C)N(C)C(C)(C)C2)cc(C)c1O

Procedure:
3.0 Parts by weight of 4-(3',5'-dimethyl-4'-hydroxyphenyl)-2,2,6,6-tetramethylpiperidine was dissolved in formic acid and treated with 1.0 part by weight of formaldehyde on a steam bath. After heating for 12 hours the solution was cooled and basified in aqueous solution. The basification liquor was extracted into ether, the ethereal layer dried with magnesium sulphate and evaporated under reduced pressure. Crystallisation of the residue from petroleum (b.p. 80°-100°) have 1.9 parts by weight of product melting at 144°-6°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH:19][CH3:20])=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH2:16])=[NH:15])[CH:9]=2)=[CH:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:17]([NH:19][CH3:20])=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[NH:16][CH:6]=[C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:15]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: CNC(=O)c1nc(-c2cccc(C(=N)N)c2)cnc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1nc(-c2cccc(-c3nc(-c4ccccc4)c[nH]3)c2)cnc1N
Temperature: 70 °C
Yield: 62.6 %

Procedure:
To a stirred solution of 3-amino-6-{3-[amino(imino)methyl]phenyl}-N-methylpyrazine-2-carboxamide (0.13 6 mg, 0.5 mmol) in DMF (5 mL) was added bronoacetophenone (0.11 g, 0.55 mmol ) followed by K2CO3 (0.276 g). The resulting mixture was heated at 70 ° C. for 0.5 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL). The extract was washed with brine, dried (Na2SO4), and concentrated. The product was purified by hplc to provide 3-amino-N-methyl-6-[3-(4-phenyl-1H-imidazol-2-yl)phenyl]pyrazine-2-carboxamide (58 mg): 1H NMR (400 MHz; DMSO-d6): 8.94 (s, 1H); 8.82 (m, 1H); 8.62 (s, 1H); 8.2 (d, 1H); 8.04 (d, 1H); 7.9-7.78 (m, 3H); 7.58 (t, 1H); 7.38 (m, 2H); 7.24 (t, 1H); 2.82 (d, 3H); MS (EI) for C21H18N6O: 371 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12]C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>O1CCCC1.CN(C)C=O.ClCCl.O>[Si:30]([O:12][CH2:10][C:9]1[CH:14]=[CH:15][N:16]=[C:7]([NH:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH:8]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: COC(=O)c1ccnc(Nc2nccs2)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(Nc2nccs2)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A stirred suspension of methyl 2-(thiazol-2-ylamino)isonicotinate (14.17 g, 60.23 mmol) in tetrahydrofuran (385 mL) was treated with lithium aluminum hydride (2.51 g, 66.25 mmol) at 23° C. The reaction was stirred at 23° C. for 1 hour then sodium hydroxide (5N, 20 mL) was added to the mixture which was stirred again for 2 more hours. The solid was filtered and washed with tetrahydrofuran and water. The combined washings and filtrate were concentrated to give the crude alcohol (11.17 g). The crude alcohol was dissolved in N,N-dimethylformamide (150 mL) and the resulting solution was treated with imidazole (6.60 g, 97.01 mmol) and tert-butyldimethylsilyl chloride (12.19 g, 80.84 mmol) at 23° C. The reaction was stirred for 1 hour, tert-butyldimethylsilyl chloride (6.0 g) was added again and the reaction stirred for 30 more minutes. N,N-Dimethylformamide was added and the residue was taken into dichloromethane/water/saturated ammonium chloride. The organic phase was separated and the aqueous phase was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (Biotage, 0% to 70% ethyl acetate in hexanes) to give the title material (10.55 g, 61% two steps). 1H NMR (400 MHz, CDCl3) δ (ppm): 0.15 (6H, s), 0.98 (9H, s), 4.76 (2H, s), 6.81 (1H, br d, J=5.05 Hz), 6.84 (1H, d, J=3.54 Hz), 6.95 (1H, s), 7.48 (1H, d, J=3.54 Hz), 8.30 (1H, br d, J=5.31 Hz), 9.79 (1H, s). LC/MS (M+H)+: 322. HPLC ret. time (Condition A): 1.800 min.
Reaction SMILES: Cl.C(N(CC)[C:5]([CH:7]1[CH2:15][CH2:14][C:10]2[N:11]=[CH:12][NH:13][C:9]=2[CH2:8]1)=[O:6])C.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].C([O-])(=O)/C=C/C([O-])=O>O>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:5]([CH:7]2[CH2:15][CH2:14][C:10]3[N:11]=[CH:12][NH:13][C:9]=3[CH2:8]2)=[O:6])=[CH:20]1
Reactant: CCN(CC)C(=O)C1CCc2nc[nH]c2C1
Reactant: Cn1ccc2ccccc21
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1cc(C(=O)C2CCc3nc[nH]c3C2)c2ccccc21
Temperature: 80 °C
Yield: 29.4 %

Procedure:
A mixture of 0.27 g (1.05 mmol) of N,N-diethyl 4,5,6,7-tetrahydrobenzimidazole-5-carboxamide hydrochloride, 0.16 ml (1.25 mmol) of 1-methylindole, and 0.15 ml (1.65 mmol) of phosphorus oxychloride was heated at 80° C. for 2 hours while stirring. 30 ml of water were added thereto, and the mixture was rendered basic with a 1N sodium hydroxide aqueous solution, followed by extracting with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol/aqueous ammonia=10:1:0.1 by volume) and preparative thin layer chromatography (developing solvent: dichloromethane/methanol/aqueous ammonia=10:1:0.1 by volume) to obtain 20 mg of a foaming substance. To the product was added 10 mg of fumaric acid to convert it to a fumarate. Recrystallization from ethyl acetate/methanol (10:1 by volume) gave 10 mg of 5-[(1-methylindol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1)#[N:2].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.O>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([CH:6]2[CH2:7][CH2:8][C:3]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:1]#[N:2])[CH2:4][CH2:5]2)[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CC1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: N#CC1(c2ccccc2)CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
35.0 g of 4-cyano-4-phenylcyclohexanone (0.176 mol), (prepared as disclosed in J. Amer. Chem. Soc. 74, (1972) 773) were dissolved with 31 g of 1-benzylpiperazine (0.176 mol) and 21 g of acetic acid in 200 ml of ethanol and, at room temperature, a solution of 12.5 g of sodium cyanoborohydride (0.19 mol) was slowly added dropwise. The mixture was stirred overnight, and then water was added and the mixture was extracted with dichloromethane. Drying and removal of the solvent by distillation resulted in a residue of 46.6 g (76%) of oil.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.C(#N)C.[F-].[K+].F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[CH:16]=1>C(OCC)C>[Cl:23][C:17]1[CH:16]=[C:15]([O:7][CH:3]2[CH2:4][CH2:5][CH2:6][CH:1]([OH:8])[CH2:2]2)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: OC1CCCC(O)C1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1ccc(OC2CCCC(O)C2)cc1Cl
Yield: 8.7 %

Procedure:
1,3-Cyclohexanediol (116 mg, 1.0 mmole) was added to a flame dried round bottom flask under nitrogen. The flask was then charged with 5 mL of dry acetonitrile, 26 mg of potassium fluoride on alumina (0.1 mmol), and 4-fluoro-2-chloro-benzonitrile (155 mg, 1.0 mmole) and heated at reflux for 16 h. Diethyl ether (15 ml) was added to the reaction mixture, which was then extracted with water (2×), dried (MgSO4) and concentrated. Purification using a chromatotron, eluting with 10% EtOAc/hex (ethylacetate and hexane) provided 22 mg of the title compound. GC/MS: 251 (M/Z for C13H14ClNO2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[S:24]([NH2:27])(=[O:26])=[O:25])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(/C=C/S(NC2C=C3C(CCC3)=CC=2S(N)(=O)=O)(=O)=O)C=CC=1Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][S:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]3[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[S:24]([NH2:27])(=[O:26])=[O:25])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NS(=O)(=O)c1c(NS(=O)(=O)/C=C/c2ccc(Cl)c(Cl)c2)ccc2c1CCC2
Agent: NS(=O)(=O)c1cc2c(cc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1)CCC2
Product: NS(=O)(=O)c1c(NS(=O)(=O)CCc2ccc(Cl)c(Cl)c2)ccc2c1CCC2
Yield: 20 %

Procedure:
The title compound was synthesized as described for Example 226 in 20% yield, starting from a mixture of (E)-5-(2-(3,4-dichlorophenyl)vinylsulfonamido)-2,3-dihydro-1H-indene-4-sulfonamide compound and (E)-6-(2-(3,4-dichlorophenyl)vinylsulfonamido)-2,3-dihydro-1H-indene-5-sulfonamide (1:1). Purification by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][OH:29].C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)(Cl)Cl.CO>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][O:29][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: CN(C)CCO
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(OCCN(C)C)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 24 h
Yield: 24.5 %

Procedure:
A mixture of 5-bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.078 g, 0.2 mmol), 2-dimethylamino-ethanol (0.04 mL, 0.4 mmol), Pd(OAc)2 (0.001 g, 0.004 mmol), and Cs2CO3 (0.130 g, 0.4 mmol) in toluene (3 mL) was stirred at 100° C. for 24 h. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 5-(2-dimethylamino-ethoxy)-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.020 g, 25%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.32 (s, 6H), 2.70 (m, 5H), 4.06 (t, 2H), 4.18 (s, 2H), 4.74 (s, 2H), 6.70 (d, 2H), 7.15-7.37 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][C:8]([CH3:13])=[CH:9][C:10](Cl)=[O:11]>CCOCC>[CH3:7][C:8]([CH3:13])=[CH:9][C:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:11]
Reactant: CC(C)=CC(=O)Cl
Reactant: C1COCCN1
Solvent: CCOCC
Product: CC(C)=CC(=O)N1CCOCC1
Temperature: 0 °C

Procedure:
Morpholine (2 equivalents) is added to a well-stirred ice-cooled solution in dry ether of 3,3-dimethylacryloyl chloride (1 equivalent) and when addition is complete, the mixture is warmed for a few minutes. the mixture is then cooled, filtered, the solvent removed and the residue recrystallized from 60-80 petrol to give 3,3-dimethylacryloyl morpholine m.pt. 52°-4°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[OH-:10].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([OH:10])[N:3]=1
Reactant: Nc1nc(Cl)nc(Cl)n1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(O)nc(Cl)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Amino-4,6-dichloro-s-triazine 16.5 g, 0.1 mol) was suspended in 250 mL of water containing sodium hydroxide (4.4 g,0.11 mol), and the mixture was stirred at room temperature for 15 h. The mixture was filtered to remove 5.0 g of unreacted starting material before the cooled (0°-5° C.), clear, colorless filtrate was neutralized (pH 6.8-7.0) with glacial acetic acid. The white solid that separated was collected, washed with cold water (5×25 mL), and dried. It was crystallized from hot water to yield 7.5 g (73.4%, based on the recovery of the starting material): mp>320° C. (lit. mp 300° C.); UVλmax (pH 1)225 nm (ε=7400); UVλmax (pH 7) 250 nm (ε=4600); UVλmax (pH 11) 247 nm (ε=3600). Anal. (C3H3CIN4O, 146.54) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[CH3:35][O:34][N:33]([CH3:32])[C:16]([CH:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:15][CH2:14]1)=[O:18]
Reactant: O=C(O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A suspension of 1-(4-nitrophenyl)piperidine-4-carboxylic acid (0.76 g, 3.0 mmol) in dichloromethane (15 mL) is cooled to 0° C. in an ice-water bath. Carbonyldiimidazole (0.59 g, 3.6 mmol) is added and the mixture is allowed to warm to room temperature. An additional volume of dichloromethane (10 mL) is added and the mixture continued to stir for 30 minutes before the addition of N,O-dimethylhydroxylamine hydrochloride (0.73 g, 7.5 mmol). After stirring overnight, the reaction mixture is filtered. The insoluble material is washed with diethyl ether, and the combined filtrate is washed with 5% aqueous potassium hydrogen carbonate solution, water, and saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide as a bright yellow powder (0.84 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC(=O)c1cccc(F)c1N
Product: NC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-benzamide was prepared from 2-Amino-3-fluoro-benzamide and 2,4,5 Trichloropyrimidine in an analogous manner to Example 1230a. Product was isolated as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([Cl:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.N1C=CN=C1.[C:24]([Si:28]([CH3:31])([CH3:30])Cl)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C.O>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([O:14][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:31])[CH3:30])[CH:8]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cc(O)cc(Cl)c2)n1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(N)n(-c2cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c2)n1
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of Intermediate 62b (615 mg, 2.31 mmol) and imidazole (189 mg, 2.78 mmol) in DMF (4.5 mL) was added tert-butyl dimethylchlorosilane (384 mg, 2.55 mmol). The solution was stirred for 2 h then added tert-butyl dimethylchlorosilane (192 mg, 1.28 mmol). After 1.5 h, the solution was diluted with water and extracted with EtOAc. The combined organics were dried and concentrated in vacuo to give the title compound (831 mg, 94%). LCMS (Method 3): Rt 5.21 min, m/z 380 [MH+].
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:43])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]=3[C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[CH3:14])=CC=1)([O-])=O.Cl.[F:46][CH2:47][CH2:48][NH2:49]>N1C=CC=CC=1>[CH2:28]([O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:49][CH2:48][CH2:47][F:46])[CH3:14])=[O:43])[C:18]2[CH:42]=[CH:41][CH:40]=[CH:39][C:19]=2[C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]1=2)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCCF
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: C[C@H](OC(=O)NCCF)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Carbonic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester (80 mg, 0.13 mmol), 2-fluoroethylamine hydrochloride (40 mg, 0.40 mmol) and pyridine (2 ml) were stirred in a sealed tube for 18 h at ambient temperature. After evaporation of the volatile components under reduced pressure, the residue was taken up in water/ethyl acetate, the phases separated and the organic layer extracted 5-times with saturated aqueous sodium carbonate, twice with 10% citric acid and once with saturated aqueous sodium chloride. After drying over magnesium sulphate and evaporation of the solvent, the title compound is obtained as white solid (>98%). MS: n/e=520(M+H+).
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C-:11]#[N:12].[Na+]>CO.O>[CH:1]([CH:3]([C:11]#[N:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CC(C#N)c1ccccc1
Yield: 71 %

Procedure:
12.2 g of commercially available vinylbenzyl chloride (a mixture of 60% of a meta-isomer and 40% of a para-isomer) were reacted with 5 g of NaCN in a mixed solvent of methanol/water=12.2 g/5 g at 64° C. for 12 hours. A reaction product solution was filtered, and the solvent was then distilled off, followed by distillation under reduced pressure, thereby obtaining 8.1 g of vinylbenzyl cyanide (yield 71%).
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.OC1[C:13]([C:21]#[N:22])=[C:14](C)[N:15]([CH2:17][C:18]#[CH:19])[CH:16]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:5]([C:6]1[C:13]([C:21]#[N:22])=[CH:14][N:15]([CH2:17][C:18]#[CH:19])[CH:16]=1)=[O:9]
Reactant: C#CCn1cc(O)c(C#N)c1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCn1cc(C#N)c(C=O)c1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
18 ml of a molar solution of dimethylsulfoxide in methylene chloride were introduced dropwise at -60° C. into 9.5 ml of a molar solution of oxalyl chloride in methylene chloride and the mixture was stirred at -60° C. for 5 minutes. Then, at -60° C., a solution of 724 g of 4-hydroxy-methyl-1-(2-propynyl)-1H-pyrrole-3-carbonitrile was added dropwise and the mixture was stirred at -60° C. for 5 hours, after which, still at -60° C., 25 ml of a molar solution of triethylamine in methylene chloride were added dropwise. The mixture was stirred at -60° C. for 30 minutes and the reaction mixture was allowed to return to ambient temperature. Water was added and the mixture was stirred and decanted. The organic phase was washed with a saturated aqueous solution of sodium chloride and concentrated to dryness by distilling under reduced pressure. The residue was chromatographed over silica and was eluted with a mixture of hexane and ethyl acetate (1-1) to obtain 702 mg of 4-formyl-1-(2-propynyl)-1H-pyrrol-3-carbonitrile melting at 114° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:16](I)[CH3:17]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:16][CH3:17])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(S)cc1Br
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
To a mixture of 3-bromo-4-fluorobenzenethiol (2.07 g, 10 mmol) and K2CO3 (4.14 g, 30 mmol) in acetone (20 mL) was added EtI (3.12 g, 20 mmol). The mixture was stirred at room temperature for 12 h, filtered, and the volatile components were removed under vacuum to give the title compound (2.34 g) as light yellow oil which was carried on without purification. 1H NMR (CDCl3, 400 MHz): δ 7.54 (dd, J1=6.4 Hz, J2=2.4 Hz, 1H), 7.26-7.25 (m, 1H), 7.05 (t, J=8.4 Hz, 1H), 2.91 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].C1COCC1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1F>CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[O:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2Br)C1
Reaction time: 1 h

Procedure:
To a solution of Boc-3-hydroxyazetidine (1.50 g, 8.67 mmol) in DMF (9.1 mL) was added 1 M potassium tert-butoxide in THF (9.96 mL, 9.96 mmol) followed by 1-bromo-2,4-difluorobenzene (2.50 g, 13.0 mmol). After a period of 1 h at 50° C., the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (15% ethyl acetate in hexane) to provide the title compound as a white solid.