Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[C:11]([NH2:21])(=[O:20])/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH:21][C:11](=[O:20])/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(Br)cc1
Reactant: NC(=O)/C=C/c1ccccc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(NC(=O)/C=C/c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 98 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), 4-dimethylamino-1-bromobenzene (201 mg, 1.00 mmol), trans-cinnamamide (178 mg, 1.21 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %) and toluene (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 23 h. The resulting bright yellow suspension was allowed to reach room temperature and then filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate-dichloromethane 1:1. The filtrate was concentrated, the residue was dissolved in 10 mL of dichloromethane and purified by flash chromatography on silica gel (2×20 cm, ethyl acetate-dichloromethane 1:4, 15 mL fractions). Fractions 10-20 provided 261 mg (98% yield) of the desired product as a bright yellow solid.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].O>CN(C)C=O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Ic1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
3-Iodo-1H-pyrrolo[2,3-b]pyridine 36 (2.00 g, 8.20 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (60% dispersion in mineral oil, 390 mg, 9.8 mmol) was added. After 20 minutes, triisopropylsilyl chloride (1.74 mL, 8.20 mmol) was added dropwise. After 1.5 hours, the reaction was poured into water and extracted with ethyl acetate, washed with saturated sodium bicarbonate and brine. The organic portions were dried over anhydrous sodium sulfate and concentrated. Purification by silica gel chromatography, 0-25% gradient ethyl acetate hexane gave compound 37 as a white solid (3.224 g, 98.2%). 1H-NMR was consistent with the desired compound.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:33]=[CH:32][C:31](=[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C>[C:25]([C:29]1[CH:33]=[CH:32][CH:31]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)C1=CC(C(c2ccccc2)(c2ccccc2)c2cccc3c2Cc2ccccc2-3)C=C1
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 0.76 g of fluorene (4.57 mmol) was dissolved in 40 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 3.1 ml of a n-butyl lithium/hexane solution (1.57M: 4.87 mmol) was gradually added dropwise in an ice bath and stirred at room temperature for over night. The solvent was distilled off under reduced pressure and thereby a reddish-orange solid was obtained. To the solid, a solution prepared by dissolving 2.40 g of 2-tert-butyl-6,6-diphenyl fulvene (8.38 mmol) in 150 ml of dehydrated diethyl ether was added and stirred under reflux for 7 days. The reaction mixture was added to 150 ml of a hydrochloric acid aqueous solution (2%) and then diethyl ether was added therein to separate an organic phase. The organic phase was washed with water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate and the drying agent was filtered off. The solvent was distilled off under reduced pressure from the filtrate and thereby orange brown oil was obtained. The oil was re-crystallized using hexane and thereby the aimed compound was obtained in an amount of 1.03 g (2.28 mmol) as a pale yellow solid. The solid further was purified with a chromatography using 100 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure and thereby the aimed compound was obtained in an amount of 0.370 g (0.817 mmol) as a yellow solid (yield: 67%).
Reaction SMILES: OC1C=C[C:5]2[CH2:6][CH2:7][CH:8]3[C:13]([C:4]=2C=1)=[N:12][N:11](C1C=CC(O)=CC=1)[C:10](=[O:21])[CH2:9]3.[OH-].[Na+].CN(C)CCCCl>CN(C)C=O>[N:12]1[NH:11][C:10](=[O:21])[CH:9]=[C:8]2[C:13]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: O=C1CC2CCc3ccc(O)cc3C2=NN1c1ccc(O)cc1
Agent: CN(C)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=c1cc2ccccc2n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 60 ml of dried dimethylformamide is added 5 g of 9-hydroxy-2-(4-hydroxyphenyl)-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one, and thereto is added 1.6 g of 60% sodium hydroxide. After the mixture is stirred at room temperature for 1 hour, 5 g of 3-dimethylaminopropyl chloride is added thereto. The mixture is stirred under heating at 60°-70° C. for 14 hours. After the completion of the reaction, the solvent is distilled off and the residue is extracted with chloroform. The extract is washed with water and dried over anhydrous magnesium sulfate. Thereafter, the solvent is distilled off. The obtained oily substance (7.8 g) is subjected to column chromatography to give 5.2 g of 2-[4-(3-dimethylaminopropoxy)phenyl]-9-(3-dimethylaminopropoxy)-4,4a,5,6-tetrahydrobenzoh]cinnolin-3(2H)-one as an oily substance.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:8]=[N:7]1)C.[OH-].[Na+]>CO.O>[OH2:3].[OH:17][C:13]1[CH:12]=[C:11]([C:9]2[N:8]=[N:7][N:6]([CH2:5][C:4]([OH:18])=[O:3])[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)Cn1cc(-c2cccc(O)c2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cn1cc(-c2cccc(O)c2)nn1
Reaction time: 24 h
Yield: 99 %

Procedure:
Ethyl[4-(3-Hydroxyphenyl)-1H-1,2,3-triazol-1-yl]acetate (Preparation 291, 27.2 g, 0.110 mol) was dissolved in methanol (200 mL), and a solution of NaOH (4.84 g, 121 mmol) in water (40 mL) was added. The solution was kept at room temperature for 24 hours. Methanol was evaporated in vacuo, water (120 mL) was added, and the solution was refluxed with activated charcoal. The mixture was filtered, and 11 M HCl was added to the filtrate. The mixture was dissolved by addition of water (120 mL) and cooled to carry out the crystallization. The crystals were filtered, washed with water (2×25 mL), and evaporated to dryness to afford the title compound as brown crystals (mp 186.3-188.7° C.) in 99.0% yield 23.9 g. MS m/z 218 [M−H]−
Reaction SMILES: C(OC(=O)[N:7]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])=[CH:13][CH:12]=1)(C)(C)C.[ClH:32].COC1CCCC1>>[ClH:32].[CH:28]1([CH2:27][NH:7][C@@H:8]2[CH2:10][C@H:9]2[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:26])=[CH:13][CH:12]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N2Cc3ccccc3C2=O)cc1
Agent: Cl
Solvent: COC1CCCC1
Product: O=C1c2ccccc2CN1c1ccc([C@@H]2C[C@H]2NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl(cyclopropylmethyl){trans-2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]cyclopropyl}carbamate (123.7 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (1.5 mL), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure. The residue was recrystallized from methanol/diisopropyl ether to give the title compound (76.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([O:12][CH2:34][C:31]2[CH:32]=[CH:33][CH:28]=[CH:29][CH:30]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(Cc1ccc(Br)cc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(Cc1ccc(Br)cc1)C(=O)OCc1ccccc1
Reaction time: 60 h
Yield: 7.1 %

Procedure:
A suspension of 3-(4-bromo-phenyl)-2-(tert-butoxycarbonylamino-methyl)-propionic acid (496 mg, 1.385 mmol), K2CO3 (383 mg, 2.77 mmol) and BnBr (0.493 ml, 4.15 mmol) in DMF (3 ml) was allowed to stir under nitrogen for 60 hours. The reaction mixture was cooled, and brine was added. The product was extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 50:50) and then purified by RP-HPLC (XBridge Prep Phenyl OBD, H2O (0.1% NH4OH)/CH3CN) to give benzyl 2-(4-bromobenzyl)-3-(tert-butoxycarbonylamino)propanoate (44 mg); Retention time=1.67 minutes (condition B); MS (ES+)=348.0 (m-Boc+2).
Reaction SMILES: C([O:7][CH2:8][CH2:9][C@H:10]1[C@H:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:12]([CH2:24][CH3:25])([CH2:22][CH3:23])[O:11]1)(=O)C(C)(C)C.C[O-].[Na+]>CO.CCOC(C)=O>[CH2:15]([C@@H:14]1[O:13][C:12]([CH2:22][CH3:23])([CH2:24][CH3:25])[O:11][C@H:10]1[CH2:9][CH2:8][OH:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC1(CC)O[C@@H](CCOC(=O)C(C)(C)C)[C@H](Cc2ccccc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC1(CC)O[C@@H](CCO)[C@H](Cc2ccccc2)O1
Temperature: 45 °C
Reaction time: 14 h
Yield: 92.3 %

Procedure:
To a stirred solution of (2-((4S,5S)-5-benzyl-2,2-diethyl-1,3-dioxolan-4-yl)ethyl pivalate (Preparation example 246, 1.0 g, 2.87 mmol) in MeOH (10 mL) was added NaOMe (0.47 g, 8.61 mmol) and then warm to 45° C. The mixture was stirred for 14 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (0.7 g, 80˜95%);
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=O)[C:5](=[O:13])[C:4]2[CH:14]=[CH:15][O:16][C:3]1=2.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:8]([C:6]2[C:5](=[O:13])[C:4]3[CH:14]=[CH:15][O:16][C:3]=3[N:2]([CH3:1])[CH:7]=2)=[O:10])=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cn(C)c2occc2c1=O
Reactant: NCc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2ccoc21
Temperature: 190 °C
Yield: 68 %

Procedure:
A mixture of ethyl 7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxylate (Preparation 9, 1.00 g) and 4-chlorobenzylamine (5.5 mL) was heated to 190° C. for 1 h. The reaction mixture was allowed to cool for several minutes and toluene (50 mL) was added. The resulting off-white solid was filtered and recrystallized from ethyl acetate to yield 0.979 g (68%) of the title compound as a pale yellow solid. Physical characteristics. M.p. 197-205° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.62, 8.59, 7.92, 7.41-7.33, 7.06, 4.55, 3.94; 13C NMR (100 MHz, CDCl3) δ 174.0, 164.8, 153.4, 141.4, 140.5, 137.3, 132.8, 128.9, 128.7, 116.7, 114.2, 107.9, 42.6, 37.7; MS (ESI+) m/z 317 (M+H)+.
Reaction SMILES: [OH2:1].O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Cl([O-])=O.[Na+].CC(=CC)C.[C:20]([NH:24][C:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:43]([CH2:44][CH2:45][C@:28]12[CH3:29])[C@:41]1([CH3:42])[C:36]([CH:37]=[C:38]([CH:46]=[O:47])[CH2:39][CH2:40]1)=[CH:35][CH2:34]3)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O.C(O)(C)(C)C>[C:20]([NH:24][C:25]([C@H:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:43]([CH2:44][CH2:45][C@:28]12[CH3:29])[C@:41]1([CH3:42])[C:36]([CH:37]=[C:38]([C:46]([OH:1])=[O:47])[CH2:39][CH2:40]1)=[CH:35][CH2:34]3)=[O:26])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O
Agent: CC=C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h

Procedure:
600 mg of sodium phosphate dihydrate and 1.2 g of sodium chlorite were added, in that order, at room temperature to a mixture of 7.5 ml of t-butanol, 2.0 ml of water and 1 ml of 2-methyl-2-butene containing 400 mg of N-t-butyl-3-formylandrosta-3,5-diene-17β-carboxamide (prepared as described in Preparation 6). The reaction mixture was then stirred for 15 minutes. At the end of this time, the reaction mixture was quenched by pouring it into a ice-cooled aqueous solution of sodium thiosulfate; it was then made acidic by the addition of 1N aqueous hydrochloric acid, and extracted with ethyl acetate three times. The combined organic extracts were washed with water and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was crystallized by the addition of diethyl ether, to give 225 mg of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5](C(=O)C)[CH2:4][CH2:3]1.[OH-].[Na+].O>C(O)C>[S:2]1(=[O:16])(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC(=O)N1CCS(=O)(=O)c2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=S1(=O)CCNCc2ccccc21
Yield: 76.6 %

Procedure:
To a solution of 1-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)ethanone (240 g, 1.0 mol) in ethanol (1.0 L) was added sodium hydroxide (200 g, 5.0 mol) and water (700 mL). The mixture was refluxed overnight and then concentrated in vacuo. The residue was extracted by ethyl acetate (1500 mL×4). The combined organic layers were extracted by hydrochloric acid (2000 mL, 3 N). The acidic aqueous layer was washed with ethyl acetate (1500 mL×2), then basified with a saturated aqueous solution of sodium bicarbonate to pH>7, and extracted with ethyl acetate (1500 mL×4). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford 151 g of 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (yield was 76%), MS obsd. (ESI+) [(M+H)+] 198, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, J=1.2, 7.6 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 4.04 (s, 2H), 3.32-3.30 (m, 2H), 3.30-3.25 (m, 2H), 2.64 (s, 1H).
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=3)=[CH:25][CH:24]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[ClH:38]>>[ClH:38].[ClH:38].[N+:35]([C:31]1[CH:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([CH:8]([C:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[CH2:9][N:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)=[CH:28][CH:27]=2)[CH:34]=[CH:33][CH:32]=1)([O-:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(-c3cccc([N+](=O)[O-])c3)cc2)C2(O)CCCCC2)CC1
Agent: Cl
Product: O=[N+]([O-])c1cccc(-c2ccc(C(CN3CCNCC3)C3(O)CCCCC3)cc2)c1

Procedure:
In an analogous manner to Example 135, step 4, 1-[1-(3′-nitro-1,1′-biphenyl-4-yl)-2-piperazin-1-yethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(3′-nitro-1,1′-biphenyl-4-yl)ethyl]piperazine-1-carboxylate. MS (ES) m/z 410.3 ([M+H]+); HRMS: calcd for C24H31N3O3.2.00 HCl, 481.1899; found (ESI), 410.2452.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[OH:15][C@@H:16]([CH3:30])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([S:18]([CH2:17][C@@H:16]([OH:15])[CH3:30])(=[O:20])=[O:19])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C[C@H](O)CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: C[C@H](O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
150 mg of (S)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (S)-methyl 4-(2-hydroxypropylthio)benzoate. 650 mg of (S)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 350 mg of (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (S)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[O:4]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=O)[CH3:20])=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O.[OH-].[Na+].C(O)C>[O:4]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[N:2][OH:3])[CH3:20])=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NO
Reactant: CC(=O)CCc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCc1ccc(Oc2ccccc2)cc1)=NO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Over about 30 minutes, a freshly prepared solution of 15.3 g (0.22 mole) of hydroxylamine hydrochloride in 100 ml of water and 200 ml of 1N sodium hydroxide solution is added dropwise at room temperature to a solution of 48 g (0.2 mole) of 4-(4-phenoxyphenyl)-2-butanone*) in 500 ml of ethanol. Subsequently, the mixture is heated for 1.5 hours at reflux temperature and then stirred for 16 hours at room temperature. The ethanol is distilled off in a water jet vacuum and the residue is extracted repeatedly with ether. The combined ethereal phases are washed repeatedly with water and dried over sodium sulfate and the ther is distilled off entirely. The crude oxime is chromatographed over silica gel (eluant: a 1:1 mixture of diethyl ether and n-hexane). The resultant 4-(4-phenoxyphenyl)-2-butanone oxime melts at 80°-82° C. after recrystallisation in a mixture of diethyl ether and n-hexane.
Reaction SMILES: Cl[C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26]>CN1CCCC1=O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH:26][C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: COC(=O)CCc1nc(Cl)c2c3c(sc2n1)CCCC3
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1nc(NCc2ccc(OC)c(Cl)c2)c2c3c(sc2n1)CCCC3
Yield: 95.4 %

Procedure:
1.9 g of methyl 3-(4-chloro-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidin-2-yl)propionate [obtainable by cyclization of methyl 2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate with methyl 3-cyanopropionate and subsequent chlorination with phosphorus oxychloride/dimethylamine] and 2.3 g of 3-chloro-4-methoxybenzylamine (“A”) in 20 ml of N-methylpyrrolidone are stirred at 110° for 5 hours. The solvent is removed and worked up in the customary manner. 2.6 g of methyl 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno-[2,3-d]pyrimidin-2-yl]propionate are obtained as a colourless oil.
Reaction SMILES: [Na].S([C:6]1[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH:9]=[C:10]([CH:15]=1)C(OC)=O)(O)(=O)=O>>[C:16]([O:18][CH3:19])(=[O:17])[C:15]1[CH:6]=[CH:7][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)O)c1
Agent: [Na]
Product: COC(=O)c1ccc(C(=O)OC)cc1

Procedure:
3.79 g Sodium salt of dimethyl 5-sulfoisophthalate.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([O:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1>[Pd].C(O)C>[CH3:13][C:12]1[C:7]([CH3:6])=[CH:8][C:9]([NH2:16])=[C:10]([O:14][CH3:15])[CH:11]=1
Reactant: COc1cc(C)c(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C)c(C)cc1N
Reaction time: 5 h
Yield: 82 %

Procedure:
Tetrahydrofuran(100 ml) and ethanol(40 ml) were added into 4,5-dimethyl-2-nitroanisole(7.80 g, 0.043 mol) and then added 10% Pd/activated carbon(0.57 g) slowly, hydrogenated for 5 hrs. The reaction was completed by the same way with the above and the resulting product was purified by column chromatography to obtain the titled compound.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19].N1CCCCC1.Cl>N1C=CC=CC=1>[O:1]([C:8]1[N:13]=[CH:12][C:11]([CH:14]=[CH:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(Oc2ccccc2)nc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C

Procedure:
5 g (25.1 mmol) of 6-phenoxy-pyridine-3-carbaldehyde were dissolved in 50 ml of pyridine, and 3.134 g (30.1 mmol) of malonic acid and 213 mg (2.5 mmol) of piperidine were added. The reaction mixture was boiled under reflux for 6 h. After cooling to room temperature, it was poured into a mixture of ice and concentrated hydrochloric acid. The precipitated product was isolated by filtration. Yield: 5.66 g.
Reaction SMILES: C[O-].[Na+].[N:4]1([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][NH:22][C:23](=[O:29])[CH2:24][S:25][C:26](=O)[CH3:27])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ClCC[CH2:33][OH:34].O>CO>[N:4]1([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18]/[CH:19]=[CH:20]\[CH2:21][NH:22][C:23](=[O:29])[CH2:24][S:25][CH2:26][CH2:27][CH2:33][OH:34])[CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCCCl
Reactant: CC(=O)SCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(CSCCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reaction time: 0.33 h
Yield: 81 %

Procedure:
5 ml of a methanolic solution containing 0.26 g of a 28% w/v sodium methoxide solution were added, whilst ice-cooling, to a solution of 0.50 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(acetylthio)acetamide [prepared as described in step (b) above] in 5 ml of methanol, and the resulting solution was stirred for 20 minutes. At the end of this time, a solution of 0.11 ml of 3-chloro-1-propanol in 5 ml of methanol, was added, and the reaction mixture was heated under reflux for 5 hours. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.42 g (yield 81%) of the title compound as an oil.