Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[C:14]([O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[N:13]=1)=[O:11])([CH2:7][CH3:8])[CH2:5][CH3:6].O.[OH-].[Li+].[OH-].[Na+]>C1COCC1.O>[CH:18]1([C:15]2[CH:16]=[CH:17][C:12]([C:10]([NH:9][C:4]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]([OH:28])=[O:2])=[O:11])=[N:13][C:14]=2[O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[CH2:20][CH2:19]1
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)OC
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
Methyl 2-(5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamido)-2-ethylbutanoate (60 mg, 154 μmol, Example 233) and lithium hydroxide hydrate (7.74 mg, 184 μmol) were dissolved in a mixture of THF (600 μL) and water (150 μL). The reaction mixture was stirred for 48 h at ambient temp. Additional sodium hydroxide (24.6 mg, 614 μmol) was added and stirring was continued at 70° C. for additional 3 d. The mixture was poured onto ice water/brine/1N HCl (25 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with ice water/brine (25 mL) and dried over Na2SO4. Concentration in vacuo afforded the title compound (49 mg, 85%) as a light yellow waxy solid. MS: 375.3 [M−H]−.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[C:12]1[NH:16][N:15]([CH3:17])[C:14](=[O:18])[CH:13]=1.Cl[CH:20]([F:22])[F:21]>O.O1CCOCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([CH3:11])=[CH:6][C:5]=1[C:12]1[CH:13]=[C:14]([O:18][CH:20]([F:22])[F:21])[N:15]([CH3:17])[N:16]=1
Reactant: Cc1cc(-c2cc(=O)n(C)[nH]2)c(Cl)cc1Cl
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(Cl)cc1Cl

Procedure:
28.8 g (720 mmol) of sodium hydroxide dissolved in 240 ml of water were added to a solution of 37 g (144 mmol) of 5-(2,4-dichloro-5-methylphenyl)-1,2-dihydro-2-methyl-3H-pyrazol-3-one in 390 ml of dioxane. Chlorodifluoromethane was subsequently passed in at 60-65° C. in the course of 4 hours, whereupon the reaction solution was stirred into 1 l of water. It was then extracted using methyl tert-butyl ether. The organic phase was dried over magnesium sulfate, filtered and then concentrated. The crude product was purified by means of column chromatography on silica gel (eluent: diethyl ether). Yield: 35.1 g.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)[CH3:12])=[O:7].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH2:10][CH:11]([CH:13]1[CH2:18][CH2:17][C:16]2([O:28][CH:15]2[CH2:14]1)[CH3:19])[CH3:12])=[O:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=CCC(C(C)CCOC(=O)c2ccco2)CC1
Solvent: ClCCl
Product: CC(CCOC(=O)c1ccco1)C1CCC2(C)OC2C1

Procedure:
The procedure of Example 1 was followed for the epoxidation of 5.2g (0.02 mole) of furoic acid, 3-(4-methyl-3-cyclohexenyl)butyl ester using 4.2g (0.02 mole) of 85% m-chloroperbenzoic acid in 150 ml of methylene chloride. Obtained following distillation was 3.7g of pure furoic acid, 3-(3,4-epoxy-4-methylcyclohexyl)butyl ester as a clear, colorless liquid with a boiling point of 156°-161°C. (0.10mm). (See Table I).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:39])[CH2:34][CH2:35][C:36](O)=[O:37])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH3:42].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33](=[O:39])[CH2:34][CH2:35][C:36]([NH:46][CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:47])=[O:37])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCC(=O)N1C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.6 %

Procedure:
A mixture of 350 mg of the crude 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid obtained in Example 9 (1), 101 mg of glycine ethyl ester hydrochloride, 45 mg of HOBt, 73 mg of triethylamine and 5 ml of dichloromethane was mixed with 190 mg of WSC hydrochloride and stirred at room temperature for 2 days. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-ethyl acetate) to obtain 315 mg of ethyl ({4-[(3R,4S)-3-({(tert-butoxycarbonyl) [(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoyl}amino)acetate as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:11]=[C:10]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2nc(Cl)nc3cc(OC)c(OC)cc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol) and 4-methoxyaniline (49 mg, 0.386 mmol) by a procedure similar to Example 1b and was isolated as white powder (10 mg, 10%). 1H NMR (CDCl3): 8.10 (s, 1H), 7.70-7.68 (m, 2H), 7.23 (s, 1H), 6.96-6.94 (m, 2H), 4.07 (s, 3H), 3.99 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:14]=[CH:13][C:12]=1[Cl:26])=[O:10].O>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([OH:30])=[O:29])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:14]=[CH:13][C:12]=1[Cl:26])=[O:10]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)c(Cl)c1
Yield: 45.9 %

Procedure:
A solution of ethyl (3-chloro-4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetate (72 mg, 0.15 mmol) in acetic acid (3 ml) and 2M HCl (3 ml) was heated at 90° C. for 2 hours. On cooling water was added and the mixture filtered. The resulting solid was dried in vac oven, then triturated with ether to afford the title compound as an off-white solid (32 mg). MS (ES+) m/z 464 [M+H]+ (C24H2035Cl3NO4). 1H-NMR (400 MHz, d6-DMSO) δ 3.63 (2H, s), 5.20 (2H, s), 7.17 (1H, dd, J 8.8, J 2.8), 7.25-7.60 (10H, m), 10.18 (1H, s), 12.5 (1H, s).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH2:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(O)CCCC>>[CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13]([NH:29][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCN
Reactant: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(Cl)nc12
Solvent: CCCCCO
Product: CCCCCCCNc1nc(NCc2ccccc2)c2[nH]nc(C(C)C)c2n1
Yield: 60 %

Procedure:
The mixture 85.6 mg of 7-benzylamino-5-chloro-3-isopropylpyrazolo[4,3-d]pyrimidine XVI, 0.21 mL of heptyl amine and 1 mL of pentanol was heated at 125° C. for 12 hours. The reaction mixture was evaporated to dryness in vacuo and then chromatographed on silica gel. The mixture of chloroform/acetone/heptane (1:1:1) was used as a mobile phase. Yield=60%; white syrupy; MS (ES+): 381.0 (100%, M+H+). 1H-NMR (300 MHz, CDCl3): 0.86 t (3H, J=6.6 Hz), 1.22-1.36 m (12H), 1.56 m (2H), 1.64 m (2H), 3.12 sept (1H, J=7.1 Hz), 3.41 d (2H, J=5.2 Hz), 4.79 bs (2H), 7.19-7.35 m (5H), 7.60 s (1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[CH3:22][C:23]1[O:24][C:25]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)=[C:26]([CH3:28])[N:27]=1>>[CH3:22][C:23]1[O:24][C:25]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:2]3[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)[N:3]=3)=[CH:31][CH:30]=2)=[C:26]([CH3:28])[N:27]=1
Reactant: Cc1nc(C)c(-c2ccc(N)cc2)o1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: Cc1nc(C)c(-c2ccc(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)cc2)o1
Yield: 51.2 %

Procedure:
Using in analogous manner the procedure described in example 1e), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (95 mg, 0.3 mmol) was reacted with 4-(2,4-dimethyl-oxazol-5-yl)-phenylamine (56 mg, 0.3 mmol) to give the title compound as light yellow solid (72 mg, 51%). MS ISP (m/e): 469.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.20, 7.78, 7.75 and 7.63 (4 d, 4×2H), 7.31 (s, 2H), 3.93 (s, 1H), 2.53 (s, 3H), 1.61 (s, 6H).
Reaction SMILES: O=[C:2]1[CH2:11][C:10]2[CH:9]=[C:8]([C:12]#[N:13])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.BrC1C=C2C(CCC(=O)C2)=CC=1.[CH2:26]([NH2:29])[CH:27]=[CH2:28].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[CH2:26]([NH:29][CH:2]1[CH2:11][C:10]2[CH:9]=[C:8]([C:12]#[N:13])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1)[CH:27]=[CH2:28]
Reactant: N#Cc1ccc2c(c1)CC(=O)CC2
Reactant: C=CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C1CCc2ccc(Br)cc2C1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=CCNC1CCc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 7-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [prepared from commercially available 7-bromo-2-tetralone following a similar procedure as described in WO2004/071389A2](500 mg, 2.9 mmol) in 20 mL of anhydrous DCM was added 3 drops of HOAc, allylamine (330 mg, 5.8 mmol) and NaBH(OAc)3 (2.46 g, 12 mmol), and the mixture was stirred at RT under nitrogen for 48 hours. DCM was added and the mixture was washed with saturated NaCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give 7-(Allylamino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9].O>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cnn2cccc2c1Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cnn2cccc2c1Cl
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Dissolved ethyl 4-chloropyrrolo[1,2-b]pyridazine-3-carboxylate (Preparation 2 from Step 5B, 2 g, 8.90 mmol) in THF (12 mL) and added water (2 mL) followed by monohydrated lithium hydroxide (0.747 g, 17.81 mmol) and the resulting yellow mixture was sonicated to give a fine dispersion followed by heating to 55° C. and stirring vigorously for one hour. After removing the organics under vacuum, the resulting residue was dissolved in ˜50 mL of water and 6 N aqueous HCl added until acidic giving a yellow slurry of the product. The product was extracted with ethyl acetate, washed with brine, dried over Na2SO4, decanted and conc. in vacuo to afford 1.8 g (˜quant.) of a yellow solid as the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][C:8]([N:17]([CH3:19])[CH3:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C1([O:26][C:27](=O)[NH:28][CH2:29][CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)C=CC=CC=1>O1CCOCC1>[CH3:18][N:17]([CH3:19])[C:8]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6][CH:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:28][CH2:29][CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)=[O:26])[CH2:10][CH2:9]1
Reactant: CN(C)C1(c2ccccc2)CCC(CCCN)CC1
Reactant: O=C(NCCc1c[nH]c2ccccc12)Oc1ccccc1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CCCNC(=O)NCCc2c[nH]c3ccccc23)CC1
Yield: 17.8 %

Procedure:
The mixture of [4-(3-aminopropyl)-1-phenyl-cyclohexyl]-dimethylamine (380 mg, 1.46 mmole) was added to a solution of [2-(1H-indol-3-yl)ethyl]carbamic acid phenyl ester (409 mg, 1.46 mmole) in dioxane (10 ml). The batch was then refluxed for 12 h. Working up was performed by removing the dioxane by distillation and combining the residue with water (10 ml). The batch was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The combined EE extracts were washed with 1M NaOH (5 ml) and dried with Na2SO4. The solvent was removed by distillation under a vacuum. The residue was the diastereoisomeric mixture of 1-[3-(4-dimethylamino-4-phenyl-cyclohexyl)-propyl]-3-[2-(1H-indol-3-yl)-ethyl]-urea, which was separated and purified by flash chromatography on silica gel (70 g). Methanol/EE (3:1, 1500 ml; 1:1, 500 ml; and 1:2, 1000 ml) was used as eluent. The more nonpolar diastereoisomer of 1-[3-(4-dimethylamino-4-phenyl-cyclohexyl)-propyl]-3-[2-(1H-indol-3-yl)-ethyl]-urea (Example 35, 95 mg, m.p. 126° C., 15%) and the more polar diastereoisomer of 1-[3-(4-dimethylamino-4-phenyl-cyclohexyl)-propyl]-3-[2-(1H-indol-3-yl)-ethyl]-urea (Example 36, 116 mg, m.p. 57° C., 18%) were isolated in this manner.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(C#N)[CH3:6])C.S(=O)(=O)(O)O.C(O)(=O)C.[OH-].[Na+]>O>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:15]3[C:10](=[C:9]([CH:5]([CH3:6])[C:4]([OH:26])=[O:3])[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:12][N:13]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(C)(C#N)c1cccc2c(-c3ccc(Cl)cc3)nccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C(=O)O)c1cccc2c(-c3ccc(Cl)cc3)nccc12

Procedure:
Ethyl-2-[1-(4-chlorophenyl)isoquinolin-5-yl]-2-cyanopropionate (1.0 g) was heated over an oil bath at 150° C. together with 2 ml of conc. sulfuric acid, 4 ml of acetic acid and 2 ml of water. After the reaction, the reaction mixture was poured into water. The pH of the mixture was adjusted to 4 with a 1 N aqueous solution of sodium hydroxide. The crystals that precipitated were extracted with dichloromethane, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from dichloromethane-hexane to afford 2-[1-(4-chlorophenyl)isoquinolin-5-yl]propionic acid as colorless prisms having a melting point of 199.5° to 202.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:19])(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1OCc1ccccc1
Reactant: N
Product: NS(=O)(=O)c1ccccc1OCc1ccccc1

Procedure:
To 148 ml of concentrated hydrochloric acid and 45 ml of acetic acid, maintained at <10°, was added 39.2 g of 2-(benzyloxy)aniline [See Berichte, 58, 79 (1925)]. White solid formed. Sufficient additional acetic acid was added to render the mixture stirrable. While temperature was 0° to 3°, a solution of 28 g of sodium nitrite in 75 ml of water was dripped into it. The mixture was kept at 5° to 10° for 15 minutes, then added to a mixture of 5.2 g of cuprous chloride, 37 ml of sulfur dioxide and 211 ml of acetic acid at 3°. Next, 290 ml of butyl chloride was added and the mixture allowed to warm to ambient temperature. After 16 hours, the mixture was diluted with water and the organic layer washed with water and dilute sodium bicarbonate solution until the washings were basic. The mixture was then dried (MgSO4) and evaporated to an oil (A). The effervescing aqueous portion (from which the butyl chloride solution had been removed) was depositing an oil; it was then treated portionwise with sodium bisulfite over several hours. After about 16 hours the oil was extracted into butyl chloride and the butyl chloride solution washed, dried and evaporated, providing an oil (B). Oils A and B are 2-(benzyloxy)benzenesulfonyl chloride. To oils A and B was added an excess of concentrated aqueous ammonia, the mixture was swirled and a white solid was observed. The solid was filtered off and extracted with hot butyl chloride; upon cooling, the extract precipitated 2-(benzyloxy)benzenesulfonamide as a white solid, m.p. 127°-129°.
Reaction SMILES: Cl.Cl.C(NNCC)C.O1CC[N:12]([CH2:15][CH:16]([N+:24]([O-:26])=[O:25])[CH2:17][N:18]2CCO[CH2:20][CH2:19]2)[CH2:11][CH2:10]1>CO.C1(C)C=CC=CC=1>[N+:24]([CH:16]1[CH2:15][N:12]([CH2:11][CH3:10])[N:18]([CH2:19][CH3:20])[CH2:17]1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])C(CN1CCOCC1)CN1CCOCC1
Agent: CCNNCC
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN1CC([N+](=O)[O-])CN1CC

Procedure:
A stirred solution of 4.03 g. (0.025 moles) of 1,2-diethyl hydrazine dihydrochloride and 6.72 g. (0.026 moles) of 1,3-dimorpholino-2-nitropropane in a mixture of 28 ml of methanol and 16 ml of toluene was heated at reflux for 3 hours. The solvents were evaporated under reduced pressure and the residue was re-suspended in toluene. The solid (mostly morpholine hydrochloride) was removed by filtration, leaving a solution of the title compound in toluene. Evaporation of the toluene gave an oil weighing 5.1 g., the free base of the title compound with minor impurity. Column chromatography on Florisil, eluting with toluene, gave pure title compound which was obtained as an oil by evaporation of toluene under reduced pressure. The product was characterized as follows: Infra Red (CHCl3, microns) 6.46 (S), 6.94 (M), 7.27 (S) and 9.82 (M); Nuclear Magnetic Resonance (CDCL3,δ)=5.18 (m, 1H), 3.16-3.75 with weight center at 3.47 (m, 4H), 2.56 (q, 7.7HZ, 4H), 1.07 (t, 7.7 HZ, 6H); Mass Spec: M+ 173.
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=O)([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[CH3:29]>N1C=CC=CC=1>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:11](=[O:13])[CH2:10][N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])=[CH:24][C:23]=1[CH3:29]
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Reactant: Cc1cc(N)ccc1Br
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)CN(CC(=O)O)CC(=O)O)ccc1Br
Temperature: 100 °C
Yield: 54.9 %

Procedure:
A slurry of 9.56 g of nitrilotriacetic acid in 80 ml of dry pyridine (dried over molecular sieves) is heated to 55° C. Acetic anhydride (7.66 g) is added and the solution is heated to 100° C. After heating for 0.5 hour, the solution is cooled to 55° C. and 9.30 g of 4-bromo-3-methylaniline is added with a 5 ml pyridine rinse. The solution is heated at 100° C. for 1.0 hour. The reaction is cooled and rotary evaporated to a pasty solid which is dissolved in 120 ml of aqueous ammonium hydroxide (30 ml concentrated ammonium hydroxide/90 ml distilled water). The clear brown solution is extracted with two 100 ml portions of methylene chloride and neutralized to pH 3 with 35 ml of concentrated HCl. The white solid is filtered, washed with three 25 ml portions of cold distilled water, and dried under vacuum for 2.75 hours at 60° C. The crude product (12.9 g) is recrystallized from 360 ml of 50% ethanol to give 9.85 g of product, melting point 206.5°-209.0° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:10]([OH:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH2:43]Cl)[CH:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:10]([O:24][CH2:43][C:35]2[CH:34]=[C:33]([O:32][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1cc(OCc2ccccc2)c2ccccc2c1
Reactant: CCCC1CN(Cc2ccccc2)CC(O)C1c1ccc(F)cc1
Product: CCCC1CN(Cc2ccccc2)CC(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Example 62(h), by alkylating (3RS,4RS,5SR)-1-benzyl-4-(4-fluoro-phenyl)-5-propyl-piperidin-3-ol with 1-benzyloxy-3-chloromethyl-naphthalene there was obtained (3RS,4RS,5SR)-1-benzyl-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(4-fluoro-phenyl)-5-propyl-piperidine as a yellow resin, MS (ISP): 574 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][NH2:26])=[CH:16]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][NH:26][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:16]1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: NCCc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccccc12)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (0.23 g, 1.25 mmol), 2-(1H-Indol-3-yl)ethylamine (0.20 g, 1.25 mmol), 1-hydroxybenzotriazole (0.18 g, 1.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.26 g, 1.37 mmol), and triethylamine (0.7 mL, 4.99 mmol) in DMF (12 mL) was stirred at room temp overnight. The reaction mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provide the title compound as yellow solid.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:25]([CH2:26][NH:27][CH2:28][CH3:29])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:9]=1)[CH3:4].C(N(C(C)C)CC)(C)C.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:30])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16]2[C:25]([CH2:26][N:27]([C:43]([CH:40]3[CH2:42][CH2:41]3)=[O:44])[CH2:28][CH3:29])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)[CH:9]=1)[CH3:4]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc2ccccc2nc1-c1cc(CC(=O)OCC)ccc1OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(OC)c(-c2nc3ccccc3cc2CN(CC)C(=O)C2CC2)c1
Reaction time: 0.08 h

Procedure:
[3-(3-Ethylaminomethyl-quinolin-2-yl)-4-methoxy-phenyl]-acetic acid ethyl ester, dihydrochloride (0.40 g, 0.89 mmol) and diisopropylethylamine (1.0 mL, 5.74 mmol) were combined in CH2Cl2 (5 mL) and stirred for 5 minutes. Cyclopropanecarbonyl chloride (0.09 mL, 0.99 mmol) was added, and the reaction was stirred at room temperature until no starting material was seen by analytical LCMS. The mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (0-75% EtOAc in hexanes) to give the title compound.