Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.Cl[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])(=[O:32])=[O:31])[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>CS(C)=O>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[S:30]([C:26]1[N:25]=[C:24]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:29]=[CH:28][CH:27]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(c1cccc(Cl)n1)c1ccccc1F
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3cccc(S(=O)(=O)c4ccccc4F)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A RBF was charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.6 g, 2 mmol), 2-chloro-6-(2-fluorophenylsulfonyl)pyridine (0.400 g, 1 mmol), 2M sodium carbonate (1 mL, 2 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.2 g, 0.2 mmol), and dioxane (8 mL). The flask was heated in a pre-heated (95° C.) heat bath while stirring under inert atmosphere overnight. The mixture was cooled, diluted with DMSO and filtered. The crude was purified by reverse-phase HPLC to provide N-(6-(6-(2-fluorophenylsulfonyl)pyridin-2-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 428. Calculated exact mass for C20H14FN3O3S3: 427. 1H NMR (400 MHz, DMSO-d6): 8.49 (s, 1H), 8.20-8.36 (m, 2H), 8.08-8.19 (m, 2H), 7.95 (d, J=7.5 Hz, 1H), 7.79-7.88 (m, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.56 (m, 1H), 7.44 (m, 1H), 2.21 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([Cl:16])=[O:6])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cccc(C)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cccc(C)c1C(=O)Cl
Reaction time: 15 h

Procedure:
A solution of 2-ethyl-6-methylbenzoic acid (49 mg, 0.30 mmol) in dichloromethane (3 mL) containing DMF (1 drop) was treated with oxalyl chloride (0.14 mL, 1.6 mmol) and the mixture was stirred for 15 h. The mixture was concentrated, azeotroping with toluene to remove traces of oxalyl chloride and the residue was used directly in the next step.
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.[CH3:19][C:20](OC(C)=O)=[O:21].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:2]1[C:6]2([CH2:7][CH2:8][NH:9][CH2:10][CH2:11]2)[CH2:5][CH2:4][N:3]1[C:20](=[O:21])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC2(CCNCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
A stirred solution of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate hydrochloride (400 mg, 1.445 mmol) in DCM (5 mL) was treated with TEA (0.604 mL, 4.34 mmol), followed by Ac2O (0.164 mL, 1.734 mmol), stirred at room temperature for 2 h. To this reaction mixture was added TFA (2.115 mL, 27.5 mmol) and stirred at room temperature for h. Concentrated under reduced pressure to obtain crude material which purified by SCX cartridge, loading with MeOH, washed with additional MeOH. Product was recovered eluting with 2M NH3 in MeOH. Solvent evaporation gave 1-(2,8-diazaspiro[4.5]decan-2-yl)ethanone (165 mg)
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:36])[C:12]([CH:14]([C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:43]([OH:46])(=[S:45])[CH3:44]>>[CH2:8]([O:10][C:11](=[O:36])[CH:12]([CH2:13][S:45][C:43](=[O:46])[CH3:44])[CH:14]([C:22]1[CH:23]=[N:24][C:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:26][CH:27]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:9]
Reactant: CC(O)=S
Reactant: C=C(C(=O)OCC)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CSC(C)=O)C(Cc1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 45 °C
Yield: 65 %

Procedure:
Triethylamine (0.096 g, 0.95 mmol) was added to a solution of 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-phenyl-ethyl]-acrylic acid ethyl ester (0.34 g, 0.86 mmol) in thioacetic acid (3.5 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 (CH2Cl2/ethyl acetate, 1:0→100:5) to give 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-4-phenyl-butyric acid ethyl ester (0.264 g, 65%).
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH:6]=[CH:7][CH2:8]2)[CH2:3][NH:2]1.[CH:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[CH2:11].C(O)(=O)C>CO>[N:15]1[CH:16]=[CH:17][C:12]([CH2:10][CH2:11][N:2]2[CH2:3][C@H:4]3[C@H:9]([CH2:8][CH:7]=[CH:6][CH2:5]3)[CH2:1]2)=[CH:13][CH:14]=1
Reactant: C=Cc1ccncc1
Reactant: C1=CC[C@H]2CNC[C@H]2C1
Solvent: CO
Solvent: CC(=O)O
Product: C1=CC[C@H]2CN(CCc3ccncc3)C[C@H]2C1

Procedure:
A mixture of 0.64 g of cis-3a,4,7,7a-tetrahydroisoindoline, 0.6 mL of 4-vinylpyridine, 0.4 mL of acetic acid and 10 mL of methanol was heated under reflux for 16 hours. Removal of the solvent and short-path distillation of the residue (160° bath temperature, 0.002 mm) gave 0.74 g. of cis-2-(4-pyridylethyl)-3a,4,7,7a-tetrahydropyridine. 1H NMR (in CDCl3) δ8.5 (d, 2H); 7.1 (d, 2H); 5.8 (m, 2H); 3.0 (m, 2H); 2.7-2.8(m, 4H); 2.4 (m, 2H); 2.2-2.3 (m, 4H) and 1.9 (d, 2H). The dihydrochloride hemi-hydrate had an indefinite melting point after crystallization from 2-propanol.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][C:26]1([CH3:44])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]2[CH2:30][C:29]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])([CH:37]=O)[CH2:28][C:27]1=2.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:37][C:29]1([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:28][C:27]2[C:26]([CH3:25])([CH3:44])[CH2:34][CH2:33][C:32]([CH3:36])([CH3:35])[C:31]=2[CH2:30]1
Reactant: CCCCCC1(C=O)CC2=C(C1)C(C)(C)CCC2(C)C
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCC1(C=C(Br)Br)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4.9 g of carbon tetrabromide were dissolved in 75 ml of methylene chloride and treated dropwise with a solution of 7.7 g of triphenylphosphine in 80 ml of methylene chloride at a temperature of −20° C. The slightly orange solution was stirred at 0° C. for 15 minutes, then treated with a solution of 2 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbaldehyde in 20 ml of methylene chloride. the reaction mixture was stirred at room temperature for 2 hours, then poured on ice/water and diluted aqueous sodium bicarbonate solution and extracted with methylene chloride. The yellow oil which was received after drying of the organic phase and evaporation of the solvent, was further purified with flash chromatography (silica gel, hexane/ethyl acetate=20:1) to give 2-(2,2-dibromo-vinyl)-4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene as a slightly yellow oil.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:14])C(OCC)=O)=[O:5])C.S(=O)(=O)(O)O>C(O)(=O)C.O>[N+:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][CH2:6][C:4]([OH:5])=[O:3])=[CH:20][CH:19]=1)([O-:23])=[O:22]
Reactant: CCOC(=O)C(CC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCC(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of ethyl 2-ethoxycarbonyl-4-(4-nitrophenyl)-4-oxobutyrate (6.2 g, 19 mmol) and sulphuric acid (1.0 g) in acetic acid:water (4:1, 50 ml) was stirred at reflux for 4 hours, then concentrated in vacuo to small volume. Dilution with water (100 ml) gave a precipitate which was filtered and dried at 50° C. under vacuum. Purification by chromatography on silica gel eluting with methanol:methylene chloride (3:97) and filtration of the resulting solid from diethyl ether containing a small percentage of methanol gave, after drying under high vacuum, 4-(4-nitrophenyl)-4-oxobutyric acid (2.1 g). 1NMR (DMSO-d6, 300 MHz) δ: 2.62 (t, J=6 Hz, 2H, CH2), 3.33 (t, J=6 Hz, 2H, CH2), 8.22 (d, J=8.5 Hz, 2H, Ar), 8.36 (d, J=8.5 Hz, 2H, Ar), 12.22 (s, 1H, CO2H). Anal. Calculated for C10H9NO5 : C, 53.82; H, 4.06; N, 6.28. Found: C, 53.65; H, 4.02; N, 6.21.
Reaction SMILES: [OH:1][C@@H:2]([CH2:10][O:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][CH2:4][O:5][S:6]([CH3:9])(=[O:8])=[O:7].N1C=CN=C1.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:25]([O:1][C@@H:2]([CH2:10][O:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:3][CH2:4][O:5][S:6]([CH3:9])(=[O:8])=[O:7])([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)OCC[C@@H](O)COS(C)(=O)=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](O[C@H](CCOS(C)(=O)=O)COS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of methanesulfonic acid (R)-3-hydroxy-4-methanesulfonyloxy-butyl ester (7.5 g) obtained in Step 1 in N,N-dimethylformamide (30 mL) were added imidazole (2.9 g) and tert-butylchlorodiphenylsilane (10.3 mL) under ice-cooling, followed by stirring the reaction mixture at room temperature for 12 hours. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:2 to 1:1) to give methanesulfonic acid (R)-3-(tert-butyldiphenylsilanyloxy)-4-methanesulfonyloxy-butyl ester (11.4 g).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH3:16])[NH:9][C:10]=1[C:11]#[N:12])(=[O:5])[CH3:4].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.[Cl-].[Na+]>CN(C)C(=O)C>[C:3]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH2:15][CH3:16])[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:21][CH:20]=2)[C:10]=1[C:11]#[N:12])(=[O:5])[CH3:4]
Reactant: CCCCc1nc(C(C)=O)c(C#N)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.5 %

Procedure:
0.192 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to a solution of 0.843 g of 4-acetyl-2-butylimidazole-5-carbonitrile [prepared as described in Preparation 24(i)] in 17 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 20 minutes. 1.68 g of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate was then added, and the resulting mixture was stirred at 55° C. for 2.5 hours. At the end of this time, an aqueous solution of sodium chloride was added to the mixture, which was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting oily residue was purified by column chromatography through silica gel, using 4:1 and 2:1 by volume mixtures of hexane and ethyl acetate as the eluent, to afford 1.14 g of the title compound as a viscous oil.
Reaction SMILES: N(C1C=C(S(N=C=O)(=O)=O)C=CC=1)=C=O.NC1N=C(OC)C=C(C)N=1.[N:26]([C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([NH:41][C:42]2[N:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([CH3:50])[N:43]=2)=[O:40])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1)=[C:27]=[O:28].[CH3:51][CH:52]([OH:54])[CH3:53]>C(Cl)Cl>[CH3:49][O:48][C:46]1[CH:45]=[C:44]([CH3:50])[N:43]=[C:42]([NH:41][C:39]([NH:38][S:35]([C:31]2[CH:30]=[C:29]([NH:26][C:27](=[O:28])[O:54][CH:52]([CH3:53])[CH3:51])[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:36])=[O:40])[N:47]=1
Reactant: CC(C)O
Reactant: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc(N=C=O)c2)n1
Agent: COc1cc(C)nc(N)n1
Agent: O=C=Nc1cccc(S(=O)(=O)N=C=O)c1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc(NC(=O)OC(C)C)c2)n1

Procedure:
To an anhydrous solution of 2.3 g of m-isocyanatobenzenesulfonyl isocyanate in 50 ml of methylene chloride was added in small portions 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine. Efficient stirring was maintained during the addition and for three additional hours. The intermediate thus obtained, 3-isocyanato-N-[(4-methoxy-6-methylpyrimidin-2-yl)aminocarbonyl]benzenesulfonamide, was reacted further by adding one gram of 2-propanol and stirring the resultant mixture for an additional sixteen hours. Filtration of the reaction mixture and evaporation of the filtrate yielded the desired product melting at 173°-180°.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC(=O)[NH:27][CH2:28][CH2:29][N:30]([C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=1)[CH3:31])(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([N:30]([CH2:29][CH2:28][NH2:27])[CH3:31])=[CH:33][N:34]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(CCNC(=O)OC(C)(C)C)c1ccc(N)nc1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N(C)CCN)cn3)nc2n1C1CCCC1
Yield: 34.8 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.68 mmol) and {2-[(6-amino-pyridin-3-yl)-methyl-amino]-ethyl}-carbamic acid tert-butyl ester (200 mg, 0.75 mmol), followed by deprotection using General Procedure A to give 2-{5-[(2-amino-ethyl)-methyl-amino]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 34%). MS (ESI) m/z 423.4 (M+H)+
Reaction SMILES: [Na].C[O:3][C:4]([C@H:6]1[C@H:10]([C:11]([O:13]C)=[O:12])[O:9][C:8]([CH:28]([Br:30])[CH3:29])([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[C:21]=3[Br:25])[CH:16]=2)[O:7]1)=[O:5]>O.CO>[Br:30][C@H:28]([C:8]1([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[C:21]=3[Br:25])[CH:16]=2)[O:9][C@@H:10]([C:11]([OH:13])=[O:12])[C@H:6]([C:4]([OH:5])=[O:3])[O:7]1)[CH3:29]
Reactant: COC(=O)[C@@H]1OC(c2ccc3c(Br)c(OC)ccc3c2)(C(C)Br)O[C@H]1C(=O)OC
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(C3([C@H](C)Br)O[C@@H](C(=O)O)[C@H](C(=O)O)O3)ccc2c1Br
Reaction time: 2 h

Procedure:
A solution of sodium hydroxyde (5.32 g, 0.133 mol) in water (70 ml) was added dropwise in 1 hour, under stirring, to a solution of the diastereoisomer 3 (35.4 g, 0.0665 mol) in methanol (250 ml) at 20° C. The reaction mixture was kept at 20° C. for 2 hours; then methanol was removed under reduced pressure mantaining the initial volume of the solution by addition of water. The aqueous solution, so obtained, was extracted with dichloromethane, acidified with conc HCl to pH 1, and extracted with diethylether (3×100 ml). The combined organic extracts were washed with water, anhydrified over sodium sulfate, filtered, and concentrated in vacuo. Crystallization of the residue from dichloromethane gave the pure 2-(1(S)-bromoethyl)-2-(5-bromo-6-methoxy-2-naphthyl)-1,3-dioxolane-4(R),5(R)-dicarboxylic acid (diastereoisomer 7).
Reaction SMILES: I[C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl:11][CH2:12][C:13](N(OC)C)=[O:14]>C1COCC1>[Cl:11][CH2:12][C:13]([C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])=[O:14]
Reactant: CON(C)C(=O)CCl
Reactant: Cc1c(I)cccc1C#N
Solvent: C1CCOC1
Product: Cc1c(C#N)cccc1C(=O)CCl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-iodo-2-methylbenzonitrile (7.71 g, 31.7 mmol) and 2-chloro-N-methoxy-N-methylacetamide (6.55 g, 47.6 mmol) in THF (100 mL) at −78° C. was added n-butylithium (2.5 M in hexanes, 14.0 mL, 34.9 mmol) dropwise. After complete addition, the mixture was stirred 15 min. at −78° C., then quenched with the dropwise addition of 1 N HCl. The mixture was partitioned between EtOAc/water and the layers separated. The aqueous was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried (magnesium sulfate), filtered and concentrated. Recrystallization of the resulting residue from hexanes provided 3-(2-chloroacetyl)-2-methylbenzonitrile: 1H NMR (500 MHz, CDCl3), δ 7.76 (m, 2H), 7.41 (m, 1H), 4.55 (s, 2H), 2.68 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[C:11]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:25]CCOCCOC.C[O-].[Na+]>CO>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:13]([CH3:22])[N:12]=[C:11]1[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOCCOC
Reactant: Cc1nc(Br)n(COCc2ccccc2)c1Sc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(O)n(COCc2ccccc2)c1Sc1ccccc1

Procedure:
To a mixture of 15 mg of 1-benzyloxymethyl-2-bromo-4-methyl-5-phenylthioimidazole (I-20) (0.04 mmol), obtained in Example 20, and 3 ml of 2-methoxyethyl ether is added 1 ml of 1M sodium methoxide solution in methanol, and the resultant mixture is heated at 130° C. for 5 hours. After evaporating the 2-methoxyethyl ether, the residue is chromatographed on a column of silica gel, eluting with 3% methanol/methylene chloride. The crude product is recrystallized from ethyl acetate/isopropyl ether to give 9 mg of the product (I-28). Yield, 71%; mp. 147°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.O1CCCC1.[CH3:25][NH2:26]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:26][CH3:25])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: CN
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1

Procedure:
A solution of 63.2 g. (0.2 mol) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one in 1.7 l. of tetrahydrofuran and 400 ml. of benzene was saturated with methylamine. A solution of 45.5 g. of titanium tetrachloride in 400 ml. of benzene was added slowly with ice cooling. After addition was complete, the reaction mixture was stirred and refluxed for 2 hours. It was then partitioned between water and methylene chloride. The organic layer was dried over sodium sulfate and evaporated. Crystallization from methylene chloride/hexane yielded 7-bromo-2-methylamino-5-(2-pyridyl)-3H-1,4-benzodiazepine, having a melting point of 208°-214°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[CH3:14][N:15]1CCCC1=O.[Cu]C#N>CCOC(C)=O.O.[NH4+].[OH-]>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:14]#[N:15])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(C#N)c1
Temperature: 190 °C
Reaction time: 1 h

Procedure:
To a mixture of of (3-bromo-phenyl)-acetic Acid ethyl ester (15.3 g, 62.9 mmol) and 1-methyl-2-pyrrolidinone (125 mL) was added copper (I) cyanide (8.46 g, 94.4 mmol). The reaction mixture was stirred in an oil bath at 190° C. for 1 h. The reaction was cooled to room temperature and was diluted with EtOAc and 2:1 H2O/NH4OH. The mixture was stirred for 10 minutes and was filtered through Celite. The aqueous layer was washed with EtOAc (2×). The organic solution was washed with 2:1 H2O/NH4OH until the aqueous extracts were no longer blue. The organic solution was dried over MgSO4, filtered and concentrated to afford (3-cyano-phenyl)-acetic Acid ethyl ester (11.95 g). 1H NMR (400 MHz, CDCl3) δ 7.51-7.58 (m, 3H), 7.43 (t, 1H), 4.16 (q, 2H), 3.63 (s, 2H), 1.25 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:9][N:8]=2)[CH:7]=1
Reactant: C[C@H]1COCCN1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nnc2ccc(F)cn12
Temperature: 55 °C
Yield: 28.8 %

Procedure:
To an ice cold solution of Intermediate 139a (574 mg, 2.26 mmol) in THF (23.0 mL) was added sequentially triphenylphosphine (1.18 g, 4.52 mmol), triethylamine (1.26 mL, 9.04 mmol) and hexachloroethane (1.07 g, 4.52 mmol). The cooling bath was removed and the reaction was heated to 55° C. overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The residue was concentrated in vacuo and then re-submitted to the above reaction conditions overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (154 mg, 29%). 1H NMR (300 MHz, CDCl3); 0.94 (3H, d, J=6.3 Hz), 3.13 (1H, dt, J=12.2, 3.1 Hz), 3.32 (1H, ddd, J=12.4, 9.5, 3.2 Hz), 3.49 (1H, dd, J=11.1, 8.6 Hz), 3.56-3.68 (1H, m), 3.84 (1H, ddd, J=12.1, 9.4, 2.7 Hz), 3.92-4.01 (2H, m), 7.16 (1H, ddd, J=9.9, 7.5, 2.3 Hz), 7.68 (1H, ddd, J=10.0, 4.8, 0.8 Hz), 7.85 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13].Cl>N1C=CC=CC=1>[CH3:11][S:12]([NH:7][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc([N+](=O)[O-])c1

Procedure:
To a solution of 2.76 g. (0.02 mol) of m-nitroaniline in 5 ml. of pyridine cooled to 0° C. is added 1.6 ml. (0.02 mol) of methanesulfonyl chloride dropwise and the mixture is stirred at room temperature for two hours. The reaction mixture is decomposed by addition of dilute hydrochloric acid and ice, and dried to give m-(methylsulfonamido)-nitrobenzene, m.p. 237° C. The latter, 1.08 g. (0.005 mol), is dissolved in 100 ml. of ethanol, 300 mg. of 10% palladium-on-carbon is added and the mixture is hydrogenated in a Parr shaker. After hydrogen uptake has ceased, the catalyst is filtered off leaving the product, 3-methylsulfonamidoaniline, in solution. To this solution (100 ml. ethanol) is added 1.08 g. (0.005 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and the solution is refluxed for one hour. The reaction mixture is concentrated and filtered to yield 5-acetyl-4-hydroxy-3-[1-(3-methylsulfonamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 196° C.