Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([N:14]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].FC(F)(F)C(O)=O>ClCCl>[F:35][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([N:14]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:26][CH:27]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: CC(C)(C)OC(=O)c1ccc(N(Cc2cccnc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(N(Cc2cccnc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.6 %

Procedure:
A solution consisting of 1.75 g (3.44 mmol) of tert-butyl N-(3,4-bis-difluoromethoxyphenyl)-N-(3-pyridylmethyl)-4-aminobenzoate, 33.5 mL of dichloromethane and 8.4 mL of trifluoroacetic acid was stirred at room temperature for 5 hours. The solution was washed with 50 mL of H2O. Then 50 mL of H2O was added and the pH adjusted to 6 by the addition of 10% aqueous NaOH. The combined aqueous layers were extracted with 2×50 mL of dichloromethane. The combined dichloromethane extracts were evaporated and the remaining material was purified by flash chromatography over SiO2 using 10% MeOH in CH2Cl2 as eluant. The material was triturated with CH3CN to yield 1.09 g (73% yield) of the title compound as a white crystalline powder. [MW 436.359; ESMS m/z (M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([NH2:22])=[C:17]([NH2:23])[CH:16]=1.C(N(CC)CC)C>ClCCl>[NH2:23][C:17]1[CH:16]=[C:15]([Cl:14])[C:20]([Cl:21])=[CH:19][C:18]=1[NH:22][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C#N)ccc1C(=O)Cl
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C(=O)Nc1cc(Cl)c(Cl)cc1N
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A solution of 2-methoxy-4-cyanobenzoyl chloride (2 g, 10 mmol) in dichloromethane (20 ml) was added dropwise in 1 h to a solution of 4,5-dichlorophenylendiamine (3.54 g, 20 mmol) and triethylamine (10.1 g=13.9 ml, 100 mmol) in dichloromethane (20 ml). Stirring was continued for additional two hours. The solvent was removed under vacuum and the residue was triturated with water (50 ml), filtered and dried at 50° C. under vacuum. The solid was suspended in diethyl ether (150 ml), stirred for 1 h, filtered and dried under vacuum to give 2.9 g of N-(2-amino-4,5-dichlorophenyl)-2-methoxy-4-cyanobenzamide (yield 43%), mp>250° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15](=[O:53])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]=2[CH2:48][CH2:49][OH:50])=[CH:18][C:17]=1[O:51][CH3:52]>ClCCl>[CH3:13][O:14][C:15](=[O:53])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]=2[CH2:48][CH2:49][O:50][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][C:17]=1[O:51][CH3:52]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
MeSO2Cl (0.03 mL, 0.39 mmol) and Et3N (0.07 mL, 0.48 mmol) were added to a solution of the alcohol from step 5 (0.11 g, 0.19 mmol) in dichloromethane (8 mL) at 0° C. Reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred an additional hour. Reaction solution was concentrated by rotary evaporation. Obtained 0.123 g of 4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoic acid methyl ester in quantitative yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Cl[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23](C(C)=C)[C:22]1=[O:33].C(=O)(O)[O-].[Na+].N>O1CCCC1.CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:33])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: C=C(C)n1c(=O)n(CCCCCl)c2ccccc21
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCCCN1CCC(c2c[nH]c3ccccc23)CC1
Reaction time: 2 h

Procedure:
A mixture consisting of 3.0 gm of 4-(3-indolyl)-piperidine, 4.0 gm of 1-(4-chloro-butyl)-3-isopropenylbenzimidazolone, 1.3 gm of sodium bicarbonate, 30 ml of dimethyl-formamide and 30 ml of tetrahydrofuran was refluxed for 16 hours. Thereafter, the reaction mixture was poured into a mixture of ice and ammonia, the aqueous mixture was extracted with ethyl acetate, and the extract solution was washed with water, dried and evaporated to dryness in vacuo. The residue was dissolved in ether, etheric hydrogen chloride was added to the solution, and the precipitate formed thereby was collected by filtration, dried and dissolved in 100 ml of ethanol. The resulting solution was cooled, 16 ml of concentrated sulfuric acid were carefully added while stirring, and the mixture was allowed to stand at 20° C. for two hours, whereupon it was poured into a mixture of ice and ammonia. The precipitate formed thereby was collected by filtration and recrystallized from ethanol, yielding 3.2 gm (55% of theory) of the compound of the formula ##STR13## having a melting point of 196° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:12]([OH:21])=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:10][C:11]1[C:12]([OH:21])=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][C:16]=1[O:17][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccc(I)cc2)c(Cl)c1O
Reaction time: 18 h
Yield: 29.5 %

Procedure:
Add 1-bromomethyl-4-iodo-benzene (10.00 g, 33.7 mmol) to a solution of 1-(3-chloro-2,4-dihydroxy-phenyl)-ethanone (7.92 g, 42.4 mmol) and cesium carbonate (16.6 g, 50.9 mmol) in dimethylformamide (250 mL) and stir. After 18 hours, pour reaction into water and extract with ethyl acetate. Combine organic layers and wash with 2N NaOH. Dry with sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography eluting with a gradient of ethyl acetate:hexanes to yield the title product as a tan solid (4.00 g, 23%): 1H NMR (DMSO-d6) δ 2.62 (s, 3H), 5.33 (s, 2H), 6.87 (d, 1H), 7.27 (d, 2H), 7.78 (d, 2H), 7.94 (d, 1H), 13.13 (s, 1H).
Reaction SMILES: Br[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[CH:8][C:4]=2[S:5][C:6]=1[CH3:7].C([Li])CCC.[C:20](=[O:22])=[O:21].C1(C)C=CC=CC=1>CCOCC>[OH:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([C:20]([OH:22])=[O:21])=[C:6]([CH3:7])[S:5][C:4]=2[CH:8]=1
Reactant: Cc1sc2cc(CCO)ccc2c1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1sc2cc(CCO)ccc2c1C(=O)O

Procedure:
Successive treatment of 3-bromo-6-(2-hydroxyethyl)-2-methylbenzo[b]thiophene with n-butyl lithium in ether followed by carbon dioxide according to the method of Example 11(ii) gave 6-(2-hydroxyethyl)-2-methylbenzo[b]thiophene-3-carboxylic acid, m.p. 166°-169° C. (from toluene).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=5)[C:17]4=[O:27])=[CH:12][C:11]=3[F:28])[CH2:6]2)[O:4][CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[CH2:34]OS(C)(=O)=O>>[O:4]1[C:5]2([CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:34][C@H:30]6[CH2:31][CH2:32][CH2:33][O:29]6)[CH:22]=5)[C:17]4=[O:27])=[CH:12][C:11]=3[F:28])[CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CS(=O)(=O)OC[C@H]1CCCO1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CCC3(C2)OCCO3)c(F)c1
Product: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(N2CCC3(C2)OCCO3)c(F)c1

Procedure:
2-[4-(1,4-Dioxa-7-aza-spiro[4.4]non-7-yl)-3-fluorophenyl]-6-hydroxy-2H-isoquinolin-1-one was reacted with (R)-methanesulfonic acid tetrahydrofuran-2-ylmethyl ester according to Method K1. In this way the product was obtained with molecular weight 466.19 (C26H27FN2O5); MS (ESI): 467 (M+H+).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([OH:27])=[C:11]([C:28](OCC)=[O:29])[C:10]1=[O:33].[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[O:34]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][N:9]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=2)[C:12]([OH:27])=[C:11]([C:28]([NH:39][CH2:38][CH2:37][O:36][CH3:35])=[O:29])[C:10]1=[O:33]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCS2(=O)=O)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCS2(=O)=O)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(1, 1-dioxido-2-isothiazolidinyl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.24 (s, 1 H), 8.58 (s, 1 H), 7.86 (s, 1 H), 7.24 (m, 2 H), 7.01 (t, J=8.6 Hz, 2 H), 4.42 (t, J=7.0 Hz, 2 H), 4.12 (s, 2 H), 3.65 (m, 2 H), 3.59 (m, 2 H), 3.42 (s, 3 H), 3.36 (t, J=6.9 Hz, 2 H), 3.26 (t, J=6.7 Hz, 2 H), 3.07 (t, J=7.5 Hz, 2 H), 2.24 (m, 2 H); HRMS C24H27FN4O6S (M+H)+ calcd 519.1635, found 519.1718.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][C@H:9]1[CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN.O>CCO>[NH2:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N2C(=O)c3ccccc3C2=O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a stirred solution of N-[cis-1-tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy) methyl-4-pyrrolidinyl]phthalimide (1.60 g, 2.74 mmol) in EtOH (8 ml) was added NH2NH2·H2O(206 mg, 4.11 mmol) at room temperature. The reaction mixture was stirred at 70 for 1 hr. The mixture was concentrated in vacuo. The resulting solid was filtered off, and washed with CHCl3. The filtrate was concentrated in vacuo. The resulting solid was filtered off, and washed with CHCl3. The filtrate was concentrated in vacuo to give cis-4-amino-1-tert-butoxycarbonyl-(2S)-(tert-butyl diphenylsilyloxy)methylpyrrolidine (1.3 g, quant) as a pale yellow oil. The crude product was used to the subsequent reaction without further purification. 1H-NMR (CDCl3) δ1.06 (s, 9H), 1.30 and 1.45 (each s, total 9H), 1.59 (m, 1H), 1.85 (m, 1H), 2.94 (m, 1H), 3.44 (m, 1H), 3.78-4.07 (m, 4H), 7.36-7.41 (m, 6H), 7.51-7.65 (m, 4H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]=[O:11])[C:4]=2[O:3][CH2:2]1.[Li][CH3:13]>C1COCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH:10]([OH:11])[CH3:13])[C:4]=2[O:3][CH2:2]1
Reactant: [Li]C
Reactant: O=Cc1cccc2c1OCO2
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a chilled (−78° C.) solution of 10 g of benzo[1,3]dioxole4-carbaldehyde in 200 mL of THF was added by addition funnel 43.7 mL of a 1.6M MeLi solution in diethyl ether. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was monitored by TLC. The mixture was then cooled to −78° C. and quenched with saturated aqueous ammonium chloride and concentrated in vacuo. The residue was extracted with EtOAc. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 11 g of 1-benzo[1,3]dioxol-4-ylethanol as a brown oil that crystallized upon standing.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([CH:7]1[CH2:20][C:11]2[S:12][C:13]([C:15](OCC)=[NH:16])=[CH:14][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH3:3].[NH3:21]>CCO>[ClH:1].[C:15]([C:13]1[S:12][C:11]2[CH2:20][CH:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:8][CH2:9][C:10]=2[CH:14]=1)(=[NH:16])[NH2:21]
Reactant: CCOC(=N)c1cc2c(s1)CC(C(=O)OCC)CC2
Reactant: N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CCc2cc(C(=N)N)sc2C1

Procedure:
6-Ethoxycarbonyl-2-(1-ethoxy-1-iminomethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene hydrochloride (1.51 g), 2.7 N ethanol solution of ammonia (1.41 ml) and EtOH (5 ml) was stirred at reflux for 4 hours. After evaporation, the resulting oil was purified by chromatography on silica gel (CHCl3 -MeOH as eluent), and subsequently washed with Et2O to give 2-amidino-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene hydrochloride (1.20 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[N:8]=2)[CH2:3][CH2:2]1.[N:31]([O-])=O.[Na+].O>C(O)(=O)C>[NH2:31][C:12]1[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[N:8][C:9]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[N:10][C:11]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: c1ccc(N2CCN(c3nc(N4CCOCC4)cc(N4CCOCC4)n3)CC2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(N2CCOCC2)nc(N2CCN(c3ccccc3)CC2)nc1N1CCOCC1
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. 4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine (3.0 g, 7.31 mmol) was dissolved in acetic acid (20 ml), an aqueous solution (1 ml) of sodium nitrite (605 mg, 8.78 mmol) was dripped in under water cooling, and agitation was done for 30 minutes at room temperature. After adjusting the pH to approximately 4.0 with a 2N NaOH aqueous solution, extraction was carried out 2 times using dichloromethane. After washing with water, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. The residue was dissolved in a methanol (40 ml)-ethyl acetate (40 ml) mixture solvent, 300 mg of Pd/C was added, and catalytic hydrogenation was done for 2 hours under atmospheric pressure. The Pd/C was filtered using celite, and the filtered liquid was distilled away under reduced pressure. The residue was washed with ether, and 1.63 g (52% yield) of 5-amino-4,6-dimorpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 63 are shown below.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[C:10](/[CH:11]=[C:12]2\[CH2:13][N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15][CH2:16][CH:17]\2O)=[N:9][N:8]=[N:7]1)=[O:4].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>ClCCl>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[C:38]([S:40][CH:17]1[CH2:16][CH2:15][NH:14][CH2:13]/[C:12]/1=[CH:11]\[C:10]1[N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]=[N:8][N:9]=1)(=[O:41])[CH3:39]
Reactant: CC(O)=S
Reactant: COC(=O)Cn1nnnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1nnnc1/C=C1\CNCCC1SC(C)=O
Yield: 27 %

Procedure:
Following a procedure similar to that described in Example 150-(e), (E)-3-{[1-(methoxycarbonylmethyl)-1H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (1.5 g) was subjected to the reaction with thioacetic acid and N,N-dimethylformamide dineopentyl acetal. The product was purified by silica gel chromatography to afford (E)-4-(acetylsulfanyl)-3-{([1-(methoxycarbonylmethyl)-1H-tetrazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (980 mg). This product was similarly treated with trifluoroacetic acid in dichloromethane, and the resulting product was purified by silica gel chromatography using dichloromethane and methanol (20:1) as an eluent to afford the title compound (342 mg, overall yield: 27%) as a yellow amorphous solid.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].CC(C)=O.Br[CH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>O>[Cl:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([CH:19]=1)[CH2:13][S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CSCc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.7 %

Procedure:
Mercapto-acetic acid (1.39 ml, 20 mmol) was dissolved in a 3.3 molar aqueous solution of sodium hydroxide (12 ml, 40 mmol) and cooled in an ice bath, before an acetone (50 ml) solution of 2-Bromomethyl-4-chloro-1-nitro-benzene (T. J. McCord et al, J. Het. Chem. 1972, 119–122)(5 g, 20 mmol) was added slowly. The resulting solution was stirred for 20 hours at room temperature before being diluted with water (50 ml) and extracted with dichloromethane (25 ml). The aqueous phase was made acidic with acetic acid and extracted with dichloromethane (2×25 ml). The combined organics were washed with brine, dried (MgSO4), filtered and evaporated to give the title product as an off-white foam (3.65 g).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C([Mg]Cl)(C)C.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.ClCCl.[Cl-].[NH4+]>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][C:8]=3[OH:11])[O:1][CH2:2][CH2:3][CH2:4]4)[C:25]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Oc1ccc2c(c1)OCCC2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)OCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
To a cooled (0° C.) solution of chroman-7-ol (Cube, R. V., et al., Bioorg. Med. Chem. Lett. (2005), 15(9):2389-93) (0.55 g, 3.66 mmol) in tetrahydrofuran (11 mL) under nitrogen was added isopropylmagnesium chloride (2.4 mL, 2 M in tetrahydrofuran, 4.8 mmol). The resulting solution was stirred at 0° C. for 30 min. A suspension of 1-(diphenylmethyl)indoline-2,3-dione (1.16 g, 3.70 mmol) in dichloromethane (4 mL) was added. The reaction was stirred at 0° C. for 10 min, then warmed to ambient temperature and stirred for 15.5 h. The reaction was diluted with saturated ammonium chloride solution (10 mL) and the organic solvents were removed under reduced pressure. The residual mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×25 mL). The combined organic solution was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography with hexanes/ethyl acetate (7:3) to afford 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-3,4-dihydro-2H-chromen-6-yl)-1,3-dihydro-2H-indol-2-one (1.37 g, 81%) as a light yellow solid: mp 204-206° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.90 (s, 1H), 7.49 (dd, J=5.6, 3.2 Hz, 1H), 7.38-7.23 (m, 10H), 7.12-7.06 (m, 2H), 6.95 (s, 1H), 6.52-6.47 (m, 3H), 4.23 (s, 1H), 4.121 (dd, J=5.7, 4.5 Hz, 2H), 2.53 (t, J=6.3 Hz, 2H), 1.95-1.87 (m, 2H); MS (ES+) m/z 486.1 (M+23).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=2)[CH:9]1[CH2:21][CH2:22][CH2:23][CH3:24])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][C@@H:59]([CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=1>C(Cl)Cl>[CH2:21]([CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[C:12]([C:18]([NH:58][C@@H:59]([CH2:73][C:74]3[CH:75]=[C:76]([F:81])[CH:77]=[C:78]([F:80])[CH:79]=3)[C@H:60]([OH:72])[CH2:61][NH:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][CH3:71])[CH:65]=3)=[O:20])[CH:11]=2)[CH2:16][CH2:17][NH:8]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC1c2cc(C(=O)O)ccc2CCN1C(=O)OC(C)(C)C
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC1NCCc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-1-butyl-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid (205 mg, 0.61 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol) in methylene chloride (4.0 mL) was added HBTU (233 mg, 0.61 mmol) and the reaction mixture stirred for 0.5 h. To this was added a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (250 mg, 0.61 mmol) in methylene chloride (4.0 mL) containing N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 95:5 chloroform/methanol) gave the desired amide product. The amide was then dissolved in dioxane (5.0 mL) to which was added hydrochloric acid (20 mL, 4.0 M dioxanes, 80 mmol) and the reaction mixture stirred overnight. The reaction mixture was then concentrated to dryness and purified by flash column chromatography (silica, 90:6:3:1 ethyl acetate/chloroform/methanol/ammonium hydroxide) to yield a colorless oil. The oil was partitioned between 3:1 chloroform/2-propanol, washed with water, and saturated sodium chloride. The organic layer was then dried (sodium sulfate), filtered, and concentrated to yield a white solid. The solid was dried under high vacuum at 45° C. in the presence of P2O5 to yield 1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxamide(140 mg) characterized as a mixture of diastereomers: mp 121-124° C.; ESI MS m/z 550 [M+H]+.