Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>O1CCCC1>[CH3:35][S:36]([O:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)(=[O:38])=[O:37]
Reactant: OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 84.0 g of N-triphenylmethyl-4-piperidinemethanol and 36.2 ml of triethylamine in 420 ml of dried tetrahydrofuran, 18.3 ml of methanesulfonyl chloride was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 5.5 hours. The reaction mixture was added with waiter and extracted with diethyl ether. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting residue was added with a mixture of isopropanol and methanol, and the precipitated crystals were collected by filtration and washed with methanol to give 90.4 g of colorless crystals. Recrystallization from a mixture of methylene chloride and methanol gave colorless prisms having the melting point of from 129.5 to 134° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:39][CH:38]=1>>[CH3:34][O:33][C:31]([CH:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:22]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:12]=2[O:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:39][CH:38]=3)=[CH:3][CH:4]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:23])[CH2:26]1)=[O:32]
Reactant: ClCc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(Oc4ccccc4)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)-4-(3-{4-[(4-phenoxybenzyl)oxy]phenyl}propoxy)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-phenoxybenzene.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:10]([OH:28])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.[F:55][C:56]([F:70])([F:69])[C:57]1[CH:58]=[C:59]([CH:62]=[C:63]([C:65]([F:68])([F:67])[F:66])[CH:64]=1)[CH2:60]Br>>[CH2:1]([N:8]1[C@@H:13]2[C@:14]([F:27])([C:16]3[N:20]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[N:19]=[N:18][N:17]=3)[CH2:15][C@@:9]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:10]([O:28][CH2:60][C:59]1[CH:62]=[C:63]([C:65]([F:67])([F:68])[F:66])[CH:64]=[C:57]([C:56]([F:55])([F:69])[F:70])[CH:58]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: COCCOCn1nnnc1[C@]1(F)C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
(1R*,2R*,5S*,6S*)-8-benzyl-6-fluoro-6-[1-(2-methoxyethoxymethyl)-1H-tetrazol-5-yl]-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 45; 205 mg, 0.44 mmol) was added to a stirred mixture of sodium hydride (60% in oil, 60 mg, 1.5 mmol, washed twice with iso-hexane) in THF (2 ml) followed by 18-crown-6 (40 mg, 1.5 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (0.4 ml, 2.16 mmol) at room temperature. The reaction mixture was warm up to reflux and stirred at room temperature overnight, then quenched with saturated aqueous NH4Cl and extracted into diethyl ether. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 10-70%) to give the title compound (303 mg, 97%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].Cl.[CH2:24]([O:26][NH2:27])[CH3:25].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[CH2:24]([O:26][NH:27][C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4])[CH3:25]
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Reactant: CCON
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (165.0 mg, 0.40 mmol) and O-ethylhydroxylamine hydrochloride (78.1 mg, 0.80 mmol, 2.0 eq) in anhydrous THF (9.4 mL) at 0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.2 mmol, 3.0 eq). After stirring at room temperature for 16 h, additional O-ethylhydroxylamine hydrochloride (234.3 mg, 2.40 mmol, 3.0 eq) and lithium hexamethyldisilazide (1M in THF, 3.6 mL, 3.6 mmol, 9.0 eq) were added at 0° C., and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate (5 mL) and diluted with ethyl acetate (50 mL). The organic layer was isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 45% to 100%, ethyl acetate in hexane, followed by gradient 0 to 15% methanol in ethyl acetate) to give an oil. Crystallization from DCM—ether—hexane afforded the title compound as a yellow solid (33.7 mg, 19.1%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.86 (s, 1H), 10.38 (s, 1H), 8.82 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.73 (d, J=10.4 Hz, 1H), 7.44 (d, 8.4 Hz, 1H), 6.57 (t, J=8.4 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.18 (t, J=6.8 Hz, 3H); LCMS (method D2): RT=1.24 min, [M+H]+=442.
Reaction SMILES: C(O[C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[Na].[C:31]([O:35][CH3:36])(=[O:34])[CH2:32][SH:33]>CO>[CH3:36][O:35][C:31]([CH2:32][S:33][C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:34]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CS
Agent: [Na]
Solvent: CO
Product: COC(=O)CS[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1.93 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 100 ml of methanol is added a solution of 0.64 g of methyl thioglycolate sodium salt with stirring under ice-cooling. After 1 hour, the solvent is distilled off and the residue is dissolved in ethyl acetate. The solution is washed with water, then the solvent is distilled off, and the residue is purified by silica gel column-chromatography (methylene chloride:ethyl acetate=11:1) to give 1.38 g of (3R4R)-4-methoxycarbonylmethylthio-3-tritylamino-2-oxoazetidine (A) and 0.92 g of the corresponding (3R,4S)-isomer (B)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:36][CH:37]5[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: CN1CCC(N)CC1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCN(C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 77.8 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (j), starting with 0.3 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.348 g of 4-amino-1-methylpiperidine instead of the cyclopropylamine used in example 34 stage (j). After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluents), 0.28 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(1-methylpiperidin-4-yl)amine is obtained with the following characteristics:
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([C:7]1[CH:8]=[C:9]([C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:6])[CH3:5].Cl>CCO>[CH3:17][C:14]([C:11]1[CH:10]=[C:9]([CH:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[OH:19])[CH:8]=[C:7]([C:4]([CH3:3])([CH3:5])[CH3:6])[C:12]=1[OH:13])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(C(O)c2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 1.5 h

Procedure:
Over a 25-minute period NaBH4 (1.89 g, 0.05 mole) is added to a solution of 3.1 g (0.01 mole) of [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]phenylmethanone (C. D. Cook, JOC, 1960, p. 1429) in 50 mL absolute EtOH while maintaining the temperature at 10°-15° C. The reaction mixture is then allowed to come to room temperature for 1.5 hours. The reaction mixture is cooled to 0° and 4N HCl (12 mL) is slowly added. The white precipitate is filtered off and washed with H2. It is taken up in Et2O and washed with saturated NaHCO3. After drying over Na2SO4 the Et2O is evaporated to dryness yielding an analytically pure olive-colored product, 2.9 g (93%), m.p. 117°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[N:7](S(C)(=O)=O)[C:6]([C:19]([OH:29])([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:5]2.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]([F:13])([F:14])[F:12])[NH:7][C:6]([C:19]([OH:29])([CH2:27][CH3:28])[CH2:20][S:21][CH2:22][C:23]([F:25])([F:24])[F:26])=[CH:5]2
Reactant: CCC(O)(CSCC(F)(F)F)c1cc2cc(Cl)c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CCC(O)(CSCC(F)(F)F)c1cc2cc(Cl)c(C(F)(F)F)cc2[nH]1

Procedure:
This compound was prepared using the standard de-protection procedure from, as described in General Procedures Example B, reacting 2-(5-chloro-1-methanesulfonyl-6-trifluoromethyl-1H-indol-2-yl)-1-(2,2,2-trifluoro-ethylsulfanyl) -butan-2-ol (0.24 g, 0.50 mmol) and using 4N sodium hydroxide as a base (0.37 mL, 0.50 mmol) to yield the title compound as a yellow sticky oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH3:16][O:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C>>[CH3:16][O:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13]
Reactant: COCCNCCOC
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: COCCN(CCOC)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 89.1 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.82 g, 6.26 mmol), bis(2-methoxyethyl)amine (830 mg, 6.26 mmol) and triethylamine(1.7mL, 12.52 mmol) were reacted to form the desired product (2.16 g, 89%). LC-MS (m/z) 387.2 (M+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])[CH2:2][CH3:3].[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=1[NH:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCNc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CNOC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCCNc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 56.8 %

Procedure:
2-Propylamino-4-(trifluoromethyl)benzoic acid (147 mg, 0.594 mmol) in CH2Cl2 was reacted with N,O-dimethylhydroxy amine (82 mg), NMM (0.2 ml) and DMTMM (222 mg) at room temperature overnight. The reaction mixture was quenched by adding H2O (3 ml). The reaction solvent was removed under reduced pressure. Water (30 ml) was added to the resulting residue, which was extracted with ethylacetate (30 ml×3). The combined organic layer was washed with sat. NaHCO3 solution (30 ml), 1N HCl aqueous solution (30 ml) and brine (30 ml), and then dried over MgSO4. The filterate was concentrated in vacuo. The residue was purified with column chromatography to yield the title compound (98 mg, 57%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[C:9]1[CH3:19]>ClCCl>[CH3:7][N:8]1[C:9]([CH3:19])=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:12]1[C:1](=[O:5])[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(-c2ccccc2)cn1C
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)c(C(=O)C(=O)Cl)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
Oxalyl chloride (19.5 mL, 0.21 mol) was added slowly to a 0° C. solution of 1,2-dimethyl-4-phenyl-pyrrole (30.5 g, 0.178 mol) in dry dichloromethane (150 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was removed in vacuo to afford 2-(1,5-dimethyl-3-phenyl-pyrrol-2-yl)-2-oxo-acetyl chloride (46 g, 99%) as a brown oil.
Reaction SMILES: [CH2:1]=[O:2].[C:3]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(=O)(O)[O-].[Na+].CS(C)=O>[C:10]([O:12][CH3:13])(=[O:11])[CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:1][OH:2]
Reactant: C=O
Reactant: COC(=O)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccccc1
Reaction time: 0.67 h
Yield: 65.6 %

Procedure:
A nitrogen purged 500 mL three-neck flask was charged with sodium bicarbonate (1.05 g; 0.013 mole), paraformaldehyde (17.37 g; 0.55 mole) and dimethyl sulfoxide (100 mL). Methyl phenylacetate (75.09 g; 0.5 mole) was added and rinsed in with dimethylsulfoxide (50 mL). The slurry was stirred magnetically and the temperature rose from 22° C. to 34° C. over 40 minutes. The temperature remained at 33°-35° C. for about one hour, after which the temperature was raised to 45°-46° C. and held for 12 hours. The reaction mixture was allowed to cool with stirring for about seven hours. A solution of tartaric acid (1.88 g) in dimethylsulfoxide (6 mL) was added, and the solvent was distilled at pot temperature 45° C. to 88° C. at 0.25 mm Hg. The distillate g) was retained. The pale yellow oily residue (97.79 g) which contained a small amount of white solid(sodium hydrogen tartrate) was filtered, then fractionally distilled to give a main cut (59.1 g) of methyl tropate b.p. 106°-112° C. (0.2 mm. Hg).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH3:10])=[O:4].C([Li])CCC.[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[C:21]1[CH:28]=[CH:27][C:24](C#N)=[CH:23][CH:22]=1>O1CCCC1>[O:16]1[CH2:20][CH2:19][O:18][CH:17]1[C:21]1[CH:28]=[CH:27][C:24]([C:1]2[NH:2][C:3](=[O:4])[C:5]3[CH:9]=[CH:8][S:7][C:6]=3[CH:10]=2)=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(C2OCCO2)cc1
Reactant: CNC(=O)c1ccsc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(C3OCCO3)cc2)cc2sccc12
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 17.5 %

Procedure:
To a solution of N-methyl-2-methylthiophene-3-carboxamide (18.5 g) in tetrahydrofuran (350 ml) was dropwise added 2.5M n-butyl lithium (100 ml) at −70° C. The resulting solution was stirred at −70° C. for 1.5 hr, followed by the addition of a solution of 4-(1,3-dioxolan-2-yl)benzonitrile (20.9 g) in tetrahydrofuran (100 ml) at once. After the dry ice/acetone bath was removed, the reaction mixture was back to room temperature. Three hours later, an aqueous solution of saturated ammonium chloride was added thereto, and the organic layer was separated, washed with water and dried. The filtrate was concentrated, and the resulting solid was washed with ethyl acetate, tetrahydrofuran/ether and n-hexane in this order. The resulting solid was then dried, to give the title compound as white crystals (6.24 g, yield; 31.7%).
Reaction SMILES: C(O)(=O)C.C(O[CH:8](OCC)[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=1)C.[ClH:24].[OH:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[OH:35])[CH2:29][CH2:30][NH2:31]>Cl.O>[ClH:24].[S:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH:8]2[C:32]3[C:28](=[CH:27][C:26]([OH:25])=[C:34]([OH:35])[CH:33]=3)[CH2:29][CH2:30][NH:31]2)=[CH:16][CH:15]=1)(=[O:19])(=[O:20])[NH2:18]
Reactant: CCOC(COc1ccc(S(N)(=O)=O)cc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(OCC2NCCc3cc(O)c(O)cc32)cc1
Temperature: 110 °C
Yield: 73.5 %

Procedure:
To a mixture of acetic acid (23 ml), water (6.6 ml) and concentrated hydrochloric acid (15 drops) was added (4-sulfamoylphenoxy)acetaldehyde diethyl acetal (2.3 g), and the mixture was heated for 20 minutes at 110°C. To the solution was added 3,4-dihydroxyphenethylamine hydrochloride (1.2 g), and the mixture was heated for 3.5 hours at the same temperature. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was crystallized by adding acetone, and the crystals were recrystallized from a mixed solvent of methanol and acetone to give 1-(4-sulfamoylphenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.8 g), mp 270°C (dec.).
Reaction SMILES: [CH2:1]([N:8]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22](=[O:40])[N:23]([C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]3)[CH:24]([CH3:26])[CH3:25])[C:19]([CH3:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:44])([C:41](O)=[O:42])[C:12]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C>O1CCCC1>[CH2:1]([N:8]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([N:23]([CH:24]([CH3:25])[CH3:26])[C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:28]3)=[O:40])[C:19]([CH3:21])=[CH:20][C:15]=2[O:14][C:13]([CH2:41][OH:42])([CH3:44])[C:12]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN(Cc1ccccc1)Cc1ccccc1)C(=O)C(C)(C(=O)O)O2
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN(Cc1ccccc1)Cc1ccccc1)C(=O)C(C)(CO)O2
Reaction time: 1 h
Yield: 84.4 %

Procedure:
Under nitrogen atmosphere, the mixture was cooled with ice-bath, and to a solution of the obtained 4-[2-(dibenzylamino)ethyl]-2,7-dimethyl-6-{[(3R)-1-{[(2-methyl-2-propanyl)oxy]carbonyl}-3-piperidinyl](2-propanyl)carbamoyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (27.2 g) in tetrahydrofuran (75 ml) were added triethylamine (5.8 g) and chloroformic acid isobutyl ester (6.2 g), and the mixture was stirred for one hour. The precipitated salt was filtered, and the filtrate was added dropwise into a suspension of sodium borohydride (2.9 g) in tetrahydrofuran-ethanol (50 ml-50 ml) under ice-cooling. The mixture was stirred for one hour, and thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 2-methyl-2-propanyl (3R)-3-[({4-[2-(dibenzylamino)ethyl]-2-(hydroxymethyl)-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(2-propanyl)amino]-1-piperidinecarboxylate (22.5 g).
Reaction SMILES: S(N)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=O)=O.C[C:13]([OH:15])=[O:14]>[Zn]>[C:4]12([C:13]([OH:15])=[O:14])[CH2:8][CH:7]([CH2:9][CH2:10]1)[CH:6]=[CH:5]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)O
Agent: [Zn]
Product: O=C(O)C12C=CC(CC1)C2
Yield: 96.8 %

Procedure:
Compound 4 (27.0 g; 0.062 mole) and Zn° (16.2 g; 0.249 mol) were combined in HOAc (100 ml) and heated to reflux for one half hour. The reaction mixture was cooled and filtered through Celite®. The filtrate was concentrated and the residue suspended in H2O, whereupon the oil crystallized. The solid was filtered, washed with H2O and suction dried to yield 18.4 g (96.8%) of Compound 5 as a white solid.
Reaction SMILES: [C:1]([CH:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][N:16]=2)[NH:11][C:10]1=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O>C(#N)C>[C:1]([CH:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][N:16]=2)[N:11]([C:20]([NH2:21])=[O:26])[C:10]1=[O:19])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Nc2cc(Cl)cnc2C1C(=O)c1ccccc1
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2ccccc2)c2ncc(Cl)cc21

Procedure:
The title compound was prepared from 3-benzoyl-6-chloro-4-azaoxindole (Example 14) according to the procedure of Example 2C, using 3-benzoyl-6-chloro-4-azaoxindole (500 mg, 1.83 mmol), N-chlorosulfonyl isocyanate (0.24 mL), 2.76 mmol) and acetonitrile (20 mL). The crude product was recrystallized from acetonitrile/chloroform. Yield: 121 mg (21%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=1.Cl[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: ClCCOc1ccccc1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCOc1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a flask was added 7.2 g. (0.150 mole) of a 50% oil dispersion of sodium hydride. After washing the sodium hydride several times with hexane to remove the mineral oil, 18.9 g. (0.125 mole) of 4-chlorobenzyl cyanide in 50 ml of dry DMF was added dropwise at 0° C. Upon completion of the addition, the reaction was stirred for one hour while warming to room temperature, then 20.0 g. (0.128 mole) of 1-chloro-2-phenoxyethane was added dropwise at 15° C. over a 30 minute period. The stirred reaction was allowed to warm to room temperature and was complete in two hours. The reaction mixture was diluted with 300 ml. of water and extracted three times with 100 ml. portions of methylene chloride. The combined extracts were washed with dilute hydrochloric acid and water followed by drying using sodium sulfate. Upon removal of the solvent, 33 g. of the crude 2-(4-chlorophenyl)-4-phenoxybutanenitrile was obtained (96% yield).