Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=3[Cl:20])[N:10]=2)[CH:7]=1.O.O.Cl[Sn]Cl>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([CH:14]=[CH:13][C:12]=3[Cl:20])[NH2:17])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(-c2cn3cc(Br)cnc3n2)c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)c(-c2cn3cc(Br)cnc3n2)c1
Temperature: 75 °C
Reaction time: 12 h
Yield: 28.4 %

Procedure:
To a suspension of 6-bromo-2-(2-chloro-5-nitrophenyl)imidazo[1,2-a]pyrimidine (1-3) (10 g, 28.28 mmol, 1.00 equiv) in ethanol (100 ml) was added SnCl2.2H2O (12.7 g) and stirred for 12 h at 75° C. The solvent was removed under vacuum and the residue was diluted with water. The pH value of the mixture was adjusted to 8-9 with sodium bicarbonate (sat.). The solids were collected by filtration and applied onto a silica gel column with ethyl acetate/petroleum ether (2/1) to give 2.6 g (28%) of 3-[6-bromoimidazo[1,2-a]pyrimidin-2-yl]-4-chloroaniline (1-4) as a light yellow solid. 1H-NMR: (d6-DMSO, 400 MHz): 9.37 (d, J=2.4 Hz, 1H), 8.63 (d, J=2.4 Hz, 1H), 8.47 (s, 1H), 7.56 (d, J=2.8 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.59 (dd, J=8.4, 2.8 Hz, 1H), 5.44 (s, 2H). EI, m/z): MS (M+H)+=325
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccc3ccccc3c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccc3ccccc3c2)cc1
Yield: 0 %

Procedure:
2-(4-nitrophenylthio)naphthalene (9.2 moles, 2.6 g) was dissolved in 50 ml ethanol and 20 ml ethyl acetate and hydrogenated for 16 hrs at room temperature over 1.0 g 5% Pd/C. The solution was filtered through celite and concentrated to yield 2-(4-aminophenylthio)naphthalene 1.1 g, 47%.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([CH2:37][O:38][CH3:39])[CH:34]=[C:33]([F:40])[C:32]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:47]([C:45]3[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:32]4[C:31]([F:30])=[CH:36][C:35]([CH2:37][O:38][CH3:39])=[CH:34][C:33]=4[F:40])[N:46]=3)=[O:48])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (256 mg, 0.633 mmol), 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (188 mg, 0.633 mmol), HATU (481 mg, 1.26 mmol) in DMF (1 mL) and DIPEA (0.330 mL, 1.90 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water and then extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to yield 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate as an intermediate.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 86 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 86% of theory, C29H31N5O3 (497.6) Rf value: 0.11 (silica gel; dichloromethane/ethanol=4:1) ##EQU40##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[S:8][CH2:7]1.Cl.[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C(#N)C>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4([CH2:15][CH2:14][CH2:13][CH2:12]4)[S:8][CH2:7]3)[CH2:30][CH2:31]2)=[N:18]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1N(CCCCBr)CSC12CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: O=C1N(CCCCN2CCN(c3nsc4ccccc34)CC2)CSC12CCCC2
Yield: 33.9 %

Procedure:
A mixture of 3-(4-bromobutyl)-1-thia-3-azaspiro[4.4]-nonan-4-one (4.50 g), 1-(1,2-benzisothiazol-3-yl)piperazine hydrochloride (4.33 g), K2CO3 (7.45 g) and NaI (560 mg), in acetonitrile (220 ml) was heated at 65° C. for 14.5 hours and the product was processed in substantially the same manner as in Example 10 to afford 2.25 g of crystals, m.p. 200-203° C.
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=3)[N:15]=2)[CH2:7]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CC#N>[F:23][C:24]1[CH:29]=[C:28]([CH:27]=[CH:26][CH:25]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][N:18]=3)[N:15]=2)[CH2:7]1
Reactant: Oc1cccc(F)c1
Reactant: CS(=O)(=O)OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Fc1cccc(OC2CN(c3ccc4nnc(C(F)(F)F)n4n3)C2)c1

Procedure:
A stirred partial solution of 6-[3-(methanesulfonyloxy)azetidin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (169 mg, 0.5 mmol), 3-fluorophenol (112 mg, 1.5 mmol) and potassium carbonate (207 mg, 1.5 mmol) in DMF (3 mL) was heated at 100° C. for 24 hours. The reaction mixture was filtered and the product was isolated by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-[3-(3-fluorophenoxy)azetidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (58 mg, 33%) as a solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][OH:34]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:34][CH2:33][CH2:32][NH2:31])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1Oc1c(Cl)ncnc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: NCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)ncnc1OCCN

Procedure:
According to Example 4b) 1.13 g 4-tert.-butyl-N-[6-chloro-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide was reacted with 2-amino-ethanol to give 1.08 g 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxy-phenoxy)-4-pyrimidinyl]-benzene sulfonamide. LC-MS: tR=3.81 min, [M−1]−=471.41
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][S:22][C:23]([NH:25][CH3:26])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1.CN=C=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][S:22][C:23]([NH:25][CH:26]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1
Reactant: CNC(=O)SC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Agent: CN=C=O
Product: O=C(NC1CCCC1)SC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 73 was prepared in the manner of compound 22 by substituting cyclopentyl isocyanate for methyl isocyanate [MS 465.2 (M+1)].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](OC(C)(C)C)=[O:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([O:14][CH2:15][CH2:16][OH:17])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COC1CCN(c2ccc(Br)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOC1CCN(c2ccc(Br)cc2)CC1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a stirred solution of tert-butyl 2-(1-(4-bromophenyl)piperidin-4-yloxy)acetate (3.08 g, 8.3 mmol) in THF (20 mL) at −10° C. under nitrogen was added lithium aluminum hydride (0.57 g, 15 mmol). After 2 hours, the reaction mixture was quenched by sequential addition of water (0.6 mL), 15 percent aqueous sodium hydroxide solution (1.8 mL) and water (0.6 mL). The resulting mixture was filtered and concentrated under vacuum to provide the crude 2-(1-(4-bromophenyl) piperidin-4-yloxy)ethanol 2.16 g. MS (m/z): 302 (M+2)+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].C([Mg]Br)C.[C:18]([NH:28][CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([C:36](Cl)=[O:37])[CH2:32][CH2:31]1)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[NH4+].[Cl-].Cl>C(Cl)Cl.[Cl-].[Cl-].[Zn+2].C(Cl)Cl.CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:7]([C:36]([C@H:33]3[CH2:32][CH2:31][C@H:30]([CH2:29][NH:28][C:18]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])[CH2:35][CH2:34]3)=[O:37])=[CH:8][NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)Cl)CC1)OCc1ccccc1
Agent: CC[Mg]Br
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccc2[nH]cc(C(=O)[C@H]3CC[C@H](CNC(=O)OCc4ccccc4)CC3)c12
Reaction time: 0.08 h

Procedure:
To a solution of indole-4-carboxylic acid methyl ester (2.33 g, 13.3 mmol) in CH2Cl2 (25 mL) was added ethylmagnesium bromide (3M in ether, 4.4 mL, 13.2 mmol). The reaction mixture was stirred for five minutes and ZnCl2 (1M in ether, 40 mL, 40 mmol) was added and the cloudy, brown suspension was stirred for 15 minutes. A solution of trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carbonyl chloride (4.36 g, 14.1 mmol), prepared as in step 2, in CH2Cl2 (20 mL) was added and the reaction mixture was stirred for three hours. The reaction mixture was poured into a separatory funnel containing saturated aqueous NH4Cl which left a green-brown gum. The gum was broken up by trituration with aqueous 1M HCl and CH2Cl2 /methanol and added to the separatory funnel. The layers were separated and the organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. Chromatography on silica gel (1%, then 3% methanol/CH2Cl2) gave 3-[(trans-4-(N-carbobenzyloxy)aminomethylcyclohex-1-yl)carbonyl]indole-4-carboxylic acid methyl ester (2.83 g, 48%) as a tan foam.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([S:18][CH2:19][CH:20]=[CH2:21])[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([S:18][CH2:19][CH:20]=[CH2:21])[S:15]1)=[O:11]
Reactant: C=CCSc1nc(O)ns1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCSc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.5 ml of triethylamine and 5 ml of methyl isocyanate were added to a solution of 13.9 g of 3-hydroxy-5-allylthio-1,2,4-thiadiazole in 150 ml of tetrahydrofuran and the mixture was stirred at 20° C for 2 hours and was concentrated to dryness under reduced pressure. The residue was empasted with ethyl ether and was vacuum filtered and dried to obtain 15.9 g of 2-(N-methylcarbamoyl)-5-allylthio-1,2,4-thiadiazole-3-one melting at 110° C.
Reaction SMILES: CS(C)=O.CO.C(=O)=O.C(Cl)(=O)C(Cl)=O.[C:16]([N:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:22]([CH2:31][C:32]([NH:34][CH:35]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:36]([OH:41])[C:37]([F:40])([F:39])[F:38])=[O:33])[C:21](=[O:49])[CH:20]1[CH:50]([CH3:52])[CH3:51])(=[O:18])[CH3:17]>C(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[C:16]([N:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:22]([CH2:31][C:32]([NH:34][CH:35]([CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[O:33])[C:21](=[O:49])[CH:20]1[CH:50]([CH3:52])[CH3:51])(=[O:18])[CH3:17]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)NC(Cc2ccccc2)C(O)C(F)(F)F)C(=O)C1C(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)NC(Cc2ccccc2)C(=O)C(F)(F)F)C(=O)C1C(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of dimethyl sulfoxide (0.26 ml) in anhydrous methylene chloride (4.0 ml) is cooled with methanol/dry ice, oxalyl chloride (0.16 ml) is added to the solution, and the mixture is stirred for 10 minutes. To the mixture is added a solution of (2RS,3RS)-3-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-hydroxy-4-phenyl-1,1,1-trifluorobutane (0.75 ml, Compound No. 2-1) in anhydrous methylene chloride (3.0 ml). The temperature is raised to 0° C., triethylamine (0.75 ml) is added thereto, and the whole is stirred for one hour. Ethyl acetate is added to the reaction mixture, the whole is washed with a saturated aqueous ammonium chloride solution and saturated brine successively, and the organic layer is dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (154 mg).
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH2:13]([S:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14]>>[CH2:13]([S:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]=[CH:9][C:8]2[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=2)=[CH:18][CH:17]=1)[CH3:14]
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: CCSc1ccc(N)cc1
Product: CCSc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 4-ethylthioaniline as starting materials, the title compound was obtained as a yellow powder (yield 56%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].Cl>COCCOCCOC>[Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH:5]=[O:6]
Reactant: O=C(Cl)c1cccc(Cl)c1O
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: COCCOCCOC
Product: O=Cc1cccc(Cl)c1O
Temperature: -70 °C
Yield: 14.9 %

Procedure:
3-Chloro-2-hydroxybenzoylchloride (8.7 mmol) was dissolved in diglyme (10 ml) and cooled to -70° C. under argon. Lithium tritertbutoxyaluminohydride (0.5M, 34.8 ml 17.4 mmol) was added via syringe keeping the temperature below -60° C. The reaction was stirred at -60° C. for 2% hours. The reaction mixture was poured onto ice, acidified with concentrated HCl and extracted with ethyl acetate (2×). The organic phases were combined, dried over MgSO4 and evaporated. Flash chromatography (eluant: CH2Cl2 /hexanes) gave the title product (0.2 g, 1.3 mmol). MS (CI+) (M+NH4)+ 174
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][C:32](O)=[O:33])[C:6]=2[CH:35]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][C:32]([N:55]3[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]3)=[O:33])[C:6]=2[CH:35]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)O)c3cc(Cl)ccc32)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCC(=O)N3CCN(C)CC3)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 7-chloro-5-carboxymethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.3 g) in dichloromethane (10 ml) is added with stirring N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.2 g) under ice-cooling, and the mixture is stirred at room temperature for 15 minutes. Subsequently, to the mixture are added with stirring N-methylpiperazine (0.09 ml) and triethylamine (0.17 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-[(4-methyl-1-piperazinyl)carbonylmethoxy]-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.23 g) as colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)N2CCN(C)CC2)ccc1Br
Reaction time: 8 h
Yield: 33.6 %

Procedure:
To a solution of 4-bromo-3-methylbenzoyl chloride (0.5 g, 2 mmol) in toluene (6 mL) was added N-methylpiperazine (0.5 mL, 4 mmol, 2 equiv.). The resulting mixture was stirred overnight, The precipitate was filtered and the filtrate was concentrated under reduced pressure. The residue was taken into ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, concentrated under reduced pressure to give 0.2 g (34% yield) of intermediate 11.
Reaction SMILES: [OH-].[Na+].O.[CH3:4][C:5](=[CH:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH3:16])[C:12]1([CH3:18])[CH3:17])[C:6](=[O:8])[CH3:7].[CH3:19]Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[CH3:4][C:5]([CH3:19])([CH:9]=[CH:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH3:16])[C:12]1([CH3:17])[CH3:18])[C:6](=[O:8])[CH3:7]
Reactant: CCl
Reactant: CC(=O)C(C)=CCC1CCC(C)C1(C)C
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C(C)(C)C=CC1CCC(C)C1(C)C
Reaction time: 20 h

Procedure:
To a rapidly stirred mixture of 400 g of NaOH, 400 g of H2O and 400 ml of toluene are added 8 g of tricaprylmethylammonium chloride (Aliquat 336), then 70 g of 3-methyl-5-(2,2,3-trimethyl-cyclopent-1-yl)-pent-3-en-2-one (0.34 moles) at room temperature. At the end of the addition methyl chloride is injected over~20 hours. The temperature reaches 30° C. The reaction is monitored by GC. After 20 hours the alkylation is finished and the reaction mass is poured into ice. The resulting mixture is extracted with ether. The organic phase is washed with H2O and the solvents are removed by evaporation. The distillation of the crude product using a Widmer column leads to 38 g of pure ketone (purity: 96%, GC).
Reaction SMILES: B.[CH2:2]([C:5]1([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:3]=[CH2:4].[OH-:19].[Na+].OO>O1CCCC1.C(OCC)C.O>[Si:12]([O:11][C:5]1([CH2:2][CH2:3][CH2:4][OH:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: C=CCC1(O[Si](C)(C)C(C)(C)C)CCCCC1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1(CCCO)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A solution of borane in tetrahydrofuran (1 M, 15.7 mL, 15.7 mmol) was added to a solution of [(1-allylcyclohexyl)oxy](tert-butyl)dimethylsilane (8.00 g, 31.4 mmol) in tetrahydrofuran. After 2 h, water (5 mL) was added dropwise, followed by 3 M NaOH (6 mL), followed by dropwise addition of 30% aqueous hydrogen peroxide (6 mL). The mixture was stirred at rt for 1 h, then was diluted with diethyl ether (100 mL) and water (70 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×35 mL). The combined organic layers were washed with brine (90 mL), dried over MgSO4, filtered, and concentrated to yield a colorless oil that was purified using HPFC (silica gel, gradient elution with 2-30% ethyl acetate/hexanes) to afford pure 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-ol (6.80 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:10][C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11]
Reactant: COc1cccc(C(C)=O)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of 1-(3-methoxyphenyl)ethanone (5.5 mL, 40 mmol) in chloroform (100 mL) was added dropwise a solution of bromine (2.05 mL, 40 mmol) in chloroform (20 mL). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was diluted in methylene chloride (50 mL) and washed with water (2×25 mL). The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure. Purification by column cromatography using methylene chloride as eluent gave the title compound (8.44 g. 84%) as oil.