Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:22]([N:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[O:23])[CH:21]=1)[C:15]([O:17]C)=[O:16].O.[OH-].[Li+]>O1CCCC1.C(OCC)(=O)C.O1CCCC1.CO.O.C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:28][N:24]([CH2:25][CH2:26][CH3:27])[C:22]([C:20]1[CH:19]=[C:14]([CH:13]=[C:12]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH:21]=1)[C:15]([OH:17])=[O:16])=[O:23]
Reactant: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of oxazole (330 mg, 4.8 mmol) in tetrahydrofuran (4 mL) is added n-butyllithium (1.6 M in hexanes, 3.3 mL, 5.3 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 14.5 mL, 14.5 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is added a solution of methyl 3-iodo-5-{[methyl(propyl)amino]carbonyl}benzoate (1.6 g, 4.5 mmol) in anhydrous tetrahydrofuran (3 mL) followed by palladium(0)tetrakis(triphenylphosphine) (221 mg, 0.19 mmol). The reaction mixture is heated at reflux for 2 h. The reaction mixture is cooled, diluted with ethyl acetate, washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 60% ethyl acetate/hexane) provides a solid. The solid is redissolved in 1:1:1 tetrahydrofuran/methanol/water (9 mL), and lithium hydroxide monohydrate (311 mg, 7.4 mmol) is added and stirred 2 h at room temperature. The reaction is diluted in chloroform and washed with 1N hydrochloric acid (aq), water, and brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give the title compound. ESI MS m/z 287.3 [M−H]−.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)CC)C.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>CO.CCOCC>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccccc1
Agent: CS(=O)(=O)On1nnc2ccccc21
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of benzoic acid (2.5 g) and triethylamine (5.6 ml) in methanol (5.0 ml) and anhydrous ether (30 ml) is added 1-methanesulfonyloxy-1,2,3-benzotriazole (4.3 g) under cooling. The mixture is stirred for 1 hour and then allowed to stand overnight. The reaction mixture is extracted with ether, and the extract is washed with water, an aqueous sodium hydrogen carbonate and water in order, dried over anhydrous magnesium sulfate and then the solvent is distilled off to give methyl benzoate (2.1 g) as an oily substance.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[Cl:18])=S.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:7]=[C:5]1[NH:4][CH2:3][CH2:2][NH:1]1
Reactant: NCCNC(=S)Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cc(Cl)c(N=C2NCCN2)c(Cl)c1
Reaction time: 24 h

Procedure:
The thiourea (7) (0.28 g, 0.91 mmole) was suspended in 10 mL of t-butanol and potassium t-butoxide (0.10 g, 0.91 mmole) was then added. The yellow mixture was heated at reflux where the color changed to orange, then slowly back to yellow and accompanied by the precipitation of a solid. Heating was continued for approximately 24 hours, and the solvent was then removed on a rotary evaporator. The residue was partitioned between 1M HCl and ethyl acetate and the aqueous phase was brought to pH 8-9 with 1N NaOH. The resulting yellow solid was collected by filtration, washed successively with water and hexane, and then air dried to provide 0.10 g (40%) of nitroclonidine contaminated by a trace of a higher R1 impurity by TLC.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:18]1OCCOCCOCCOCCOC1.IC>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C1COCCOCCOCCOCCO1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 278 mg, 6.96 mmol) was suspended in THF (5 mL) and cooled to 0° C. trans-tert-Butoxy-N-(4-hydroxycyclohexyl) carboxamide (1 g, 4.64 mmol) and 15-crown-5 (0.965 mL, 4.88 mmol) were added and the reaction mixture was stirred at 0° C. for about 30 minutes. Iodomethane (0.289 mL, 4.64 mmol) was added and the reaction stirred at 0° C. for about 1 hour after which the LCMS showed it was complete. The reaction was quenched with methanol, the solvents removed in vacuo and the crude purified by column chromatography (SiO2, 8:2 n-hexanes/ethyl acetate) to afford 642 mg of the methyl ether. ES-MS: 230 (M+1).
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:8]=[C:9]([CH:13]=[C:14](N)[C:15]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3]1.N1(C2C=C(C=C(S(Cl)(=O)=O)C=2OC2C=CC=CC=2)C(O)=O)CCCC1.N1(C2C=C(C=C([S:70](=[O:73])(=[O:72])[NH2:71])C=2OC2C=CC=CC=2)C(O)=O)CCCC1>>[N:2]1([CH:7]2[C:15]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([S:70](=[O:73])(=[O:72])[NH2:71])[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: Cl
Agent: O=C(O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(=O)(=O)Cl)c1
Product: NS(=O)(=O)C1(Oc2ccccc2)C=CC(C(=O)O)=CC1N1CCCC1

Procedure:
The hydrochloride of the 3-(1-pyrrolidinyl)-4-phenoxy-5-aminobenzoic acid in converted in the manner described in Example 35 over the 3-(1-pyrrolidinyl)-4-phenoxy-5-chlorosulphonyl-benzoic acid into the desired 3-(1-pyrrolidinyl)-4-phenoxy-5-sulphamylbenzoic acid melting at 225°-226° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[C:13]1([NH:12][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1ccc2ccccc2c1
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: O
Product: c1ccc(Nc2ccc3ccccc3c2)cc1
Reaction time: 5 h
Yield: 95 %

Procedure:
288 parts of β-naphthol, 220 parts of aniline and 6 parts of diphenyl phosphite are mixed and fused at 130° C. At 190° C internal temperature, the reaction commences, with elimination of water. After 5 hours, the internal temperature has reached 235° C and 36 parts of water have distilled off. Thereafter, 416 parts of N-phenyl-β-naphthylamine, of melting point 100° - 102° C, distil, passing over at 230° C/15 mm Hg. This corresponds to a yield of 95% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O.Cl.C(=O)=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(Br)ccc1Cl
Reaction time: 8 h
Yield: 100 %

Procedure:
8.00 kg 2-chloro-5-bromobenzoic acid was suspended in 80.00 L methylene chloride (KF of methylene chloride<0.1% H2O) and 0.02 L of DMF added at 20° C. 5.18 Kg oxalyl chloride were slowly added and the internal temperature maintained below 25° C. The addition was slightly exothermic; gas evolution of HCl and CO2 occurred. The reaction was run at 20-25° C. overnight; a clear solution was obtained. The mixture was concentrated in vacuum to an oily residue and degased at 40° C. in vacuum. Yield of 2-chloro-5-bromobenzoic acid chloride: 8.63 kg (33.98 mol, yield 100.0%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[CH3:9].[OH-:10].[K+].O>C(O)COCCO>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Cc1c(Cl)cccc1Cl
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: Cc1c(O)cccc1Cl

Procedure:
16.1 g (0.1 mol) of 2,6-dichlorotoluene and 19.8 g (0.3 mol) of potassium hydroxide (85%) are heated in 30 ml of diethylene glycol at a bath temperature of 190° C. for 18 hours. The water released by the reaction is distilled off. After cooling, the reaction mixture is stirred with 100 ml of water until a solution is obtained and extracted three times with 50 ml of dichloromethane. The aqueous phase is admixed with 35 ml of 30% hydrochloric acid and extracted three times with 70 ml of dichloromethane. The organic phases are dried over sodium sulphate and concentrated under reduced pressure. 3-Chloro-2-methylphenol is obtained as a solid (12.4 g, content by HPLC: 83%, 72% of theory).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12.Cl[Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:11]=[CH:12][C:5]=12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)ccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
Sodium hydride (8.37 g, 209 mmol; 60% oil dispersion) was slowly added to 4-bromo-1H-pyrrolo[2,3-b]pyridine (33.0 g, 167 mmol) in THF (500 mL) at 0° C. The reaction was stirred for 15 minutes. Chlorotriisopropylsilane (38.7 g, 201 mmol) was then added in one portion. The suspension was warmed to room temperature and stirred for 30 minutes. The suspension was then cooled to about 0-5° C. and quenched with saturated aqueous NH4Cl (about 200 mL). The aqueous phase was extracted with hexanes (3×300 mL), and the combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexanes to yield 4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (50 g, 84% yield) as an oil, which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 1H), 7.34 (d, 1H), 7.22 (d, Hz, 2H), 6.59 (d, 1H), 1.88-1.80 (m, 3H), 1.11 (d, 18H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].OC1N=CC=CC=1C(O)=O.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5](=[O:12])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: COC(=O)c1cc(Br)cnc1O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 60.1 %

Procedure:
4.5 g of methyl 5-bromo-2-hydroxynicotinate synthesized by a known method from 2-hydroxynicotinic acid, and 4.7 g of phenylboronic acid were dissolved in 200 ml of tetrahydrofuran. To the mixture were added 705 mg of copper acetate and 1 ml of pyridine, followed by stirring at room temperature for 3 nights in a flow of air. Aqueous ammonia was added to the reaction solution, and the solution was extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue obtained as a solid was washed with diethyl ether, to obtain 3.59 g of 5-bromo-3-methoxycarbonyl-1-phenyl-1,2-dihydropyridin-2-one as white crystals. 3.2 g of the product was dissolved in 100 ml of dimethylformamide, to which 7.7 g of tri-N-butyl-(2-pyridyl)tin [CAS No. 59020-10-9] and 240 mg of tetrakistriphenylphosphine palladium were added, followed by stirring at 110° C. for 3 hours in nitrogen atmosphere. After cooling to room temperature, the reaction solution was poured into water, extracted with ethyl acetate. Then, the extract was successively washed with water and brine, dried over anhydrous magnesium sulfate, and then filtered through NH silica gel and silica gel. Then, the filtrate was evaporated, and the resulting precipitates were washed with ether and hexane, and dried, to give 1.59 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][NH:10][CH3:11]>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]([CH3:11])[CH3:9])=[N:3][CH:4]=1
Reactant: CNC
Reactant: Brc1ccc(Br)nc1
Solvent: C1CCOC1
Product: CN(C)c1ccc(Br)cn1
Yield: 86 %

Procedure:
A solution of 2,5-dibromopyridine (11.84 g, 50.0 mmol) in 2.0 M solution of dimethylamine in tetrahydrofuran (100 mL) in a sealed tube was heated at 120° C. for 12 hours. The reaction was quenched with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 10-15% ethyl acetate/hexane) to provide the title compound (8.67 g, 86% yield): 1H NMR (CDCl3) 8.16 (d, 1H), 7.49 (dd, 1H), 6.41 (d, 1H), 3.05 (s, 6H); ES-MS m/z 201 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26]([C@@H:28]2[O:30][C@H:29]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:45][CH3:46])=[C:42]([Cl:44])[CH:43]=2)[C:5](=[O:6])[NH:4][CH2:3]1.Br.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)(=O)C>[CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:30][CH:29]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:45][CH3:46])=[C:42]([Cl:44])[CH:43]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@@H]3O[C@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: Br
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)[C@@H]3O[C@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Solvent: COCCOC
Solvent: CC(=O)O
Product: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl

Procedure:
A solution of 7 mg of Cryptophycin 38 in 1 mL of dimethoxyethane was treated with 10 μL of 30% HBr in acetic acid at 50° C. for 18 hours. The mixture was brought to the ambient temperature and stirred with 20 mg of powdered dry potassium carbonate for 3 hours. The solution was filtered, the solvent evaporated and the residue subjected to HPLC on an Econosil silica column (250×10 mm, 5μ, 1:1 ethylacetate/hexane, 3 mL/min) to obtain 3.3 mg of crypptophycin 71 (tR 49.6 min) and 2.8 mg of cryptophycin 72 (tR 46 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([O:28]CC)=[O:27])=[CH:4][CH:3]=1.FC1C=CC(C2C3C(=CC=CC=3)C(C3C=CC4OCOC=4C=3)=C2C(OCC)=O)=CC=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(F)cc1
Solvent: CCO
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl (1RS,2RS,3SR)-1-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(4-fluorophenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (40 mg, 0.10 mmol) in EtOH (3 ml) was added 10% palladium on activated carbon (45 mg). The resulting suspension was stirred under an atmosphere of H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (40 mg, 100%), which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(C)C=CC=CC=1>C1C=CC=CC=1>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
83.1 g (1 mol) of 1,2,5,6-tetrahydropyridine are dissolved in 300 ml of benzene. 83 g of sodium bicarbonate are introduced into this solution and the mixture is cooled to 0° under a nitrogen atmosphere and, at this temperature, treated dropwise in the course of one hour with 332 ml of a 50% strength solution of benzyl chloroformate in toluene (1 mol). The reaction mixture is stirred at 0° for a further 21/2 hours and then poured into 1.5 liters of ice-water. The benzene phase is separated off and the aqueous phase is extracted by shaking 3 times with 250 ml of methylene chloride; subsequently the combined organic phases are washed with 1 N hydrochloric acid and then with a saturated solution of sodium chloride, dried over sodium sulphate and evaporated under a water pump vacuum. The oily residue is distilled under a high vacuum and gives 1-carbobenzyloxy-1,2,5,6-tetrahydropyridine with a boiling point of 102°-113°/0.01 mm Hg.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.CCOCC>[N:1]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6]1
Reactant: C1=CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 1,2,3,6-tetrahydropyridine (5.0 g, 60.15 mmol) and triethylamine (16.77 mL, 2 equiv) in CH2Cl2 (50 mL) was cooled to 0° C. (ice/water bath), Benzyl chloroformate (9.7 mL, 1.1 equiv) was added slowly. After 30 min, the reaction mixture was allowed to warm slowly to rt and stirred for 4 h. LC-MS showed the reaction was complete. The mixture was diluted with ether (300 mL), washed with 5% aq HCl (2×50 mL), satd aq NaHCO3 (40 mL) and brine (40 mL), and dried over Na2SO4. After concentration, benzyl 5,6-dihydropyridine-1(2H)-carboxylate (9.93 g, 78% yield) was left. LC-MS (3 min) tR=1.74 min., m/z 218 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reaction time: 2 h

Procedure:
A mixture of 4-(4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (11) (18.9 mmol), 10% palladium-on-carbon (600 mg), ethanol (100 mL), and ethyl acetate (100 mL) is hydrogenated at room temperature and 40 psi for 2 hrs. The mixture is filtered through celite, washing with ethyl acetate (2×100 mL), and concentrated in vacuo to give 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (12) as a brown oil.
Reaction SMILES: CSC.B.[CH:5]([N:18]1[CH2:21][C:20]2([CH2:26][NH:25][C:24](=O)[CH2:23][O:22]2)[CH2:19]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CO.CNCCNC>C1COCC1>[CH:5]([N:18]1[CH2:21][C:20]2([CH2:26][NH:25][CH2:24][CH2:23][O:22]2)[CH2:19]1)([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1COC2(CN1)CN(C(c1ccccc1)c1ccccc1)C2
Agent: B
Agent: CNCCNC
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: c1ccc(C(c2ccccc2)N2CC3(CNCCO3)C2)cc1
Temperature: 25 °C

Procedure:
Borane methyl sulfide complex (2M in THF, 10.7 mL) was added to a solution of 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonan-7-one (example 33, step e) (2 g) in dry THF (40 mL) and the resultant solution was stirred at 70° C. under nitrogen for 50 minutes. The mixture was cooled to room temperature and treated dropwise with methanol (40 mL) followed by N1,N2-dimethylethane-1,2-diamine (3.43 g). The mixture was heated at 70° C. for 6 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 1% triethylamine and 5% methanol in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.35 g.
Reaction SMILES: [OH-].[Na+].[CH3:3][S:4][C:5]([NH2:7])=[NH:6].OS(O)(=O)=O.C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C(O)C>[CH3:3][S:4][C:5]1[N:7]=[C:16]([OH:15])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][N:6]=1
Reactant: CSC(=N)N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cnc(SC)nc1O
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a 4N sodium hydroxide solution (200 mL) was added S-methylisothioureasulfate (55.6 g, 0.2 mol), and after stirring for 30 min, at room temperature a solution of diethyl ethoxymethylenemalonate (80.8 mL, 0.35 mol) in ethanol (100 mL) was dropwise added slowly over 1 h. After stirring for 18 h, the precipitated crystals were collected by filtration, washed several times with cold ethanol and the obtained crystals were added to 1N hydrochloric acid (300 mL). The mixture was stirred for 30 min and the precipitated crystals were collected by filtration, washed several times with cold water and dried with heating under vacuum to give the title compound (26 g, 61%) as crystals.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[C:19]1(=O)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>C(O)C.[C].[Pd]>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: O=C1CCC(=O)CC1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 89.2 %

Procedure:
261 mg of 4-(4-trifluoromethoxyphenoxy)piperidine, 224 mg of 1,4-cyclohexanedione and 4 mg of 10% palladium-carbon were heated in ethanol and reacted at 70° C. to 80° C. for 9 hours. After the completion of the reaction, the resultant was separated by silica gel column chromatography (n-hexane:ethyl acetate=3:1) and 315 mg of 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine was obtained (yield 89%).