Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](Cl)=[O:12])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[NH:28][C:25]2[S:26][CH:27]=[C:23]([S:22][CH3:21])[N:24]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Reactant: CSc1csc(N)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1csc(NC(=O)c2cccc(OC(C)=O)c2)n1
Temperature: 25 °C
Yield: 121.4 %

Procedure:
Into a solution of 511 (0.815 g, 4.10 mmol) and dry THF (25.0 mL) was added triethylamine (0.572 mL, 4.10 mmol), followed by a solution of the 508 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL). The reaction was stirred at room temperature. After stirring overnight, the reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed once with water, three times with saturated aqueous. sodium bicarbonate solution, and once with brine. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo to give crude 85 (1.28 g, >100%) as a red foam. The crude product was dissolved in dichloromethane. Silica gel was added to the dichloromethane solution and the suspension was concentrated in vacuo. The residue was loaded on top of a 90 g silica gel cartridge and eluted down the column using a solution of 20% ethyl acetate in hexane. Appropriate fractions of the major product were combined and concentrated in vacuo to give 85 (0.614 g, 58%) as a tan solid. This material was used in the next step without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][S:12][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:19]([S:28][CH3:29])[NH:18][N:17]=2)=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(O)(=O)C>[OH:8][CH2:9][C:10]1[S:11][S:12][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:19]([S:28][CH3:29])[NH:18][N:17]=2)=[CH:14][CH:15]=1
Reactant: CSN1NN=C(C2=CC=C(CO[Si](C)(C)C(C)(C)C)SS2)N1c1ccc(O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CSN1NN=C(C2=CC=C(CO)SS2)N1c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a stirred solution of the 3-[(tert-butyldimethylsilyloxy)methyl]-6-[methylthio-[1-(4-hydroxyphenyl)-tetrazol-5-yl]]-1,2-dithiin obtained above (440 mg, 0.94 mmol) in 4 mL of THF was added a solution of 7 mL of 1M tetrabutylammonium fluoride in THF and 4 mL of acetic acid. The reaction mixture was stirred for 1 h at 0° C. until TLC analysis showed the reaction to be complete, then concentrated in vacuo. The residue was partitioned between 60 mL of water and 90 mL ethyl acetate. The organic phase was washed with dilute aqueous sodium bicarbonate, water, dried over sodium sulfate, and then concentrated to a small volume. The residue was purified by flash chromatography (ethyl acetate-hexane, 1:3) to yield 265 mg (79.8%) of the title compound as yellow crystals, mp 130°-131° C.; 1H-NMR (CD3OD) δ7.36 (d, J=9.2, 2 H), 6.97 (d, J=9.2, 2 H), 6.47 (d, J=6.0, 1 H), 6.34 (d, J=6.4, 1 H) 4.24 (s 2 H), 4.15 (s, 2 H); 1H-NMR (DMSO-d6):10.26 (s, 1 H, phenol OH), 7.41 (d, 2 H, J=8.8), 6.97 (d, 2 H, J=8.8), 6.52 (d, 1 H, J=6.0), 6.35 (d, 1 H, J=6.0), 5.39 (t, 1 H, J=5.2), 4.30 (s, 2 H), 4.06 (d, 2 H, J=5.2); 13C--NMR (CD3OD) δ160.99, 154.90, 138.09, 130.34, 129.49 127.42, 126.05, 125.77, 117.29, 64.67, 40.01; 1H-NMR NOESY showed an interaction between aromatic and dithiin rings protons. MS (+FAB) 353.5 (MH+); IR (KBr) 3378.7 (OH); 3135 (OH)cm-1. HMBC (DMSO-d6) shows a long range correlation between the protons at 4.30 ppm and the carbon at 154.90 ppm. Anal. calcd for C13H12N4O2S3 :C, 44.30; H, 3.43; N, 15.90; S, 27.29. Found:C, 44.68; H, 3.37; N, 16.24; S, 27.23.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.Cl[C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:21])[C:11]=1O>COCCOC.ClCCl>[O:20]=[C:19]1[C:10]2[N:1]=[C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]3[C:11]=2[C:12](=[O:21])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]1=2
Reactant: O=C1C(O)=C(Cl)C(=O)c2ccccc21
Reactant: Cc1ccc(N)nc1
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccc2nc3c(n2c1)C(=O)c1ccccc1C3=O
Yield: 16.9 %

Procedure:
0.55 g (5.08 mmol) of 2-amino-5-methylpyridine is added to a suspension of 0.45 g (2.16 mmol) of 3-chloro-1,4-dihydro-1,4-dioxo-2-hydroxynaphthalene in 15 mL of 1,2-dimethoxyethane. The reaction medium is brought to reflux for 21 h. After complete cooling, it is diluted with 120 mL of dichloromethane. The organic phase is washed successively with a saturated solution of sodium hydrogen carbonate and sodium chloride, then dried on sodium sulfate and evaporated under reduced pressure. The raw product obtained is purified on a medium-pressure column (support: silica; eluent: dichloromethane/heptane/ethyl acetate, 68/40/2) to produce 0.096 g of 6,11-dihydro-6,11-dioxo-2-methyl-naphtho[2',3':4,5]imidazo[1,2-a]pyridine in the form of yellow crystals after decoloration with animal black.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][CH2:18][C:12]2=[C:11]2[C:7]=1[C:8]([C:28](=[O:32])[C:29]([NH2:31])=[O:30])=[C:9]([CH2:26][CH3:27])[N:10]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Li+]>O1CCCC1.CO>[NH2:31][C:29](=[O:30])[C:28]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:18][CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:33])=[O:2])[N:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]=1[CH2:26][CH3:27])=[O:32]
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)cc3c(c2n1Cc1ccccc1)CCCC3
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCCC3
Yield: 88.2 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-1-benzyl-2-ethyl-6,7,8,9-tetrahydro-1H-benz[g]indol-4-yl]oxy]acetic acid methyl ester (150 mg, 0.334 mmol) in 3:1 tetrahydrofuran/methanol (4 mL) was treated with 1 M lithium hydroxide solution (1 mL) at room temperature for 1 h. The reaction mixture was concentrated in vacuo to one half the original volume and treated with 1 M hydrochloric acid (1 mL). The resulting suspension was diluted with water (5 mL), stirred, and the precipitate collected via vacuum filtration. This material was washed with water and dried to provide 128 mg (88%) of the title compound as a yellow solid: mp 222-225° C. 1H NMR (DMSO-d6) δ 7.72 (bs, 1H), 7.33 (m, 0.4H), 6.87 (d, J=7.3 Hz, 2H), 6.23 (s, 1H), 5.65 (s, 2H), 4.56 (s, 2H), 2.87 (m, 2H), 2.72 (m, 4H), 1.59 (m, 4H), 1.07 (t, J=7.3 Hz, 3H); MS ES+ m/e 435 (p+1); IR (CHCl3, cm−1) 3507, 3472, 3393, 2938, 1759, 1640.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][CH2:14][CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[F:31])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[F:31][C:25]1[C:26]([F:30])=[CH:27][CH:28]=[CH:29][C:24]=1[CH:15]([CH2:14][NH:13][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CCOC(=O)CCCC(CN)c1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCC(CNCc1ccc(OC)cc1OC)c1cccc(F)c1F
Reaction time: 0.5 h

Procedure:
2,4-Dimethoxybenzaldehyde was added to a solution of ethyl 6-amino-5-(2,3-difluorophenyl)hexanoate (4.73 g, 17.5 mmol) in methanol (75 mL). Acetic acid was added until the pH of the reaction mixture reached pH 5. After 30 min, sodium cyanoborohydride (1.69 g, 26.9 mmol) was added. After 1 h, the mixture was diluted with ethyl acetate and saturated aqueous sodium carbonate. The mixture was extracted with ethyl acetate and the organic extracts were washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→95% dichloromethane/(10% ammonium hydroxide/methanol)] gave the title compound (7.3 g). MS 422.1 (M+1).
Reaction SMILES: [F:1][C:2]([O:6][C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[C:3]([F:5])[F:4].[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl.[N+:25]([C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[O-:31])([O-:27])=[O:26].[Na+]>CN(C)C=O>[F:4][C:3]([F:5])([O:31][C:30]1[CH:29]=[C:28]([N+:25]([O-:27])=[O:26])[CH:34]=[CH:33][CH:32]=1)[C:2]([F:1])([Cl:17])[O:6][C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:10])([F:11])[F:12]
Reactant: O=[N+]([O-])c1cccc([O-])c1
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OC(F)(F)C(F)(Cl)OC(F)(F)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
To a mixture of 19.3 g (0.072 mol) of perfluoropropyl perfluorovinyl ether and 16.3 g (0.069 mol) of hexachloroethane in 25 mL of dimethylformamide (DMF) at about 0° C. under argon was added 6.85 g (0.043 mol) of solid sodium 3-nitrophenoxide over 14 min. The solid was rinsed into the flask with an additional 15 mL of DMF. The mixture was allowed to warm to room temperature and stirred for about 3 days. It was then poured into ice water containing 5 mL of concentrated hydrochloric acid and extracted with 2×100 mL of ether. The combined ether extracts were washed with 2×50 mL of water and dried over anhydrous magnesium sulfate. The solution was concentrated on a rotary evaporator and then distilled in a Kugelrohr apparatus. After removing lower boiling materials, the product was distilled at a bath temperature of 85°-95° C. and 0.5 mm pressure to give 16.6 g (89%) of 3-(perfluoro-2-chloro-3-oxahexyloxy)nitrobenzene as a clear oil; 1H NMR (δ, CDCl3) 7.63 (m, 2H), 8.10 (s, 1H), 8.23 (m, 1H); 19F NMR (δ, CDCl3) -79.8 (1F), -81.6 (3F), -85.2 (AB quartet with fine structure, 2F); -87.3 (2F), -130.4 (2F). Anal. Calcd for C11H4ClF10NO4 : C, 30.05; H, 0.92; N, 3.12; Cl, 8.06; F, 43.22. Found: C, 29.79; H, 0.82; N, 3.54; Cl, 8.39; F, 40.19.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]3[C:12]([CH2:13][C:14]([OH:16])=O)=[C:11]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:10]=[C:7]3[N:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:25][NH2:26]>O1CCCC1>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]3[C:12]([CH2:13][C:14]([NH:26][CH3:25])=[O:16])=[C:11]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:10]=[C:7]3[N:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CN
Reactant: Cn1c2cc(Cl)ccc2n2c(CC(=O)O)c(-c3ccccc3)nc12
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccccc2)nc2n(C)c3cc(Cl)ccc3n12
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A suspension of 1.7 g (0.005 mol) of 7-chloro-9-methyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran, 1.3 g (0.008 mol) of N,N'-carbonyldiimidazole are added thereto and the mixture is stirred at 40° C. for 2 h. The solution obtained is treated with an excess of dry gaseous methylamine and stirred for 72 h. The solvent is evaporated under reduced pressure. The residue is treated with 50 ml of water. The insoluble matter is separated by filtration, washed with water and then dried. 1.66 g of solid are obtained which are purified by silica gel chromatography, eluting with a dichloromethane/methanol 95/5 mixture. The product is recrystallized from an N,N-dimethylformamide/water 75/25 mixture and then dried. 1.27 g of solid are obtained. Melting point: 274°-275° C.
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[Cl:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][C:7]([Cl:13])([NH:15][NH2:16])[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: NN
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Solvent: O
Solvent: CCO
Product: NNC1(Cl)C=Cc2nc(Cl)cnc2C1

Procedure:
A mixture consisting of 23 g. (0.10 mole) of 2,3,6-trichloroquinoxaline and 11 g. (0.22 mole) of hydrazine hydrate in 500 ml. of ethanol was stirred at room temperature (~20° C.) overnight (~16 hours). The precipitate which formed was separated by filtration and washed with ethanol to ultimately afford 22.2 g. (97%) of pure 2,6-dichloro-3-hydrazinoquinoxaline, m.p. <250° C. Mass Spectrum: m/e, 228 (P).
Reaction SMILES: O.O.O.O.O.O.[S:7]([O-:11])([O-])(=[O:9])=S.[Na+].[Na+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl.[Cl:26]Cl>C(O)(=O)C>[C:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][S:7]([Cl:26])(=[O:11])=[O:9])([O:15][CH3:14])=[O:25]
Reactant: ClCl
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)c1ccccc1CCl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1CS(=O)(=O)Cl
Reaction time: 5 h
Yield: 83 %

Procedure:
A mixture of water (50 ml) and 29.5 g of sodium thiosulfate pentahydrate was added to o-(chloromethyl)benzoic acid methyl ester 20 g, and stirred for 5 hours at 50˜55° C. 300 ml of acetic acid was added and then excess of chlorine gas for 3 hours was infused, while maintaining the internal temperature of reactor at 5˜10° C. The reaction mixture was further stirred for 1 hour at the same temperature. Excess of chlorine gas was removed via infusion of nitrogen gas and with the addition of ice water (300 ml), stirred for 30 minutes. A solid, so formed, was filtered with a cold water and dried to afford 22.4 g of desired compound (yield 83%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:10][CH2:11][OH:12].C(N(C(C)C)C(C)C)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:12][CH2:11][CH2:10][CH2:9][C@@H:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)c1ccccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCCOS(C)(=O)=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a solution of (S)-tert-butyl 1-(2-bromophenyl)-4-hydroxybutylcarbamate (compound 5; 59.4 mmol, 20.44 g) in dry methylene chloride (500 mL) cooled in an ice bath was added N-ethyldiisopropylamine (119 mmol, 15.35 g) followed by the slow addition of methane sulfonyl chloride (60.0 mmol, 6.87 g) under nitrogen maintaining the reaction temperature below 5° C. Once the addition was complete the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and left to stir for two days. The reaction mixture was evaporated at 45° C. under vacuum and residue taken up in methylene chloride (500 mL) washed with 0.5% citric acid, dried over magnesium sulfate with activated charcoal, filtered through a bed of dicalite and evaporated to give a slightly oily solid which was triturated with heptane to give (S)-4-(2-bromophenyl)-4-(tert-butoxycarbonylamino)butyl methanesulfonate 23.25 g) as a pale brown solid, MS (ES): m/z [M+H]+ 422 and 424.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.BrC1C=CC(N2CCC(=O)CC2)=CC=1.N1C[CH2:35][O:34][CH2:33]C1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:16][CH2:35][O:34][CH2:33][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CN(C)C1CCN(c2ccc(Br)cc2)CC1
Reactant: C1COCCN1
Agent: O=C1CCN(c2ccc(Br)cc2)CC1
Product: Brc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Yield: 97 %

Procedure:
The title compound was synthesized according to the synthesis of 1-(4-bromophenyl)-N,N-dimethylpiperidin-4-amine, except reacting 1-(4-bromophenyl)piperidin-4-one (500 mg, 1.97 mmol) with morpholine (0.21 mL, 2.36 mmol) for 25 h to give the title compound as a yellow solid (620 mg, 97%). 1H NMR (400 MHz, MeOD) δ 7.31 (d, J=8.2 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 3.87-3.67 (m, 6H), 2.71 (t, J=12.5 Hz, 2H), 2.67-2.62 (m, 4H), 2.37-2.36 (m, 1H), 2.04-1.97 (m, 2H), 1.72-1.56 (m, 2H); MS ESI 325.2 [M+H]+, calcd for [C15H21BrN2O+H]+ 325.08.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:20]=[CH:19][C:7]([CH:8]([OH:18])[C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)[CH3:3].COC.[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:25]O.O1CCCC1>CS(O)(=O)=O.CN(C)C(=N)N(C)C.CCCCCC>[CH3:17][N:15]([CH3:16])[C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:7]2[CH:19]=[CH:20][C:4]([N:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=2)[O:18][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CO
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Agent: CN(C)C(=N)N(C)C
Agent: COC
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)COC(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1

Procedure:
A solution of 4,4'-bis(N,N-dimethylamino)benzhydrol, methyl ether (11.0 g, 0.039 mole), ethyl glycolate 4.04 g, 0.039 mole), 70 ml of tetrahydrofuran, 230 ml of n-hexane and one drop of methanesulfonic acid was refluxed for 2 hours. On completion of the reaction, 2 drops of tetramethylguanidine was added to discharge the blue color. The reaction mixture was filtered hot and the filtrate was cooled. An oily layer formed which was removed and stripped free of solvent; the remaining filtrate was also stripped, leaving an oil. Both samples of oil were combined and chilled. A waxy solid formed which, on repeated trituration with petroleum ether, gave a white solid. Recrystallization from a mixture of petroleum ether/acetone gave a white solid, mp 63°-67.5° C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:20]([NH2:22])[CH3:21].C(O)(=O)C.[C-:27]#[N:28].[K+]>CO>[CH:1]([N:14]1[CH2:17][C:16]([NH:22][CH2:20][CH3:21])([C:27]#[N:28])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCN
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 1-benzhydrylazetidin-3-one (9.5 g, 40 mmol) in methanol (30 ml) was added ethylamine hydrochloride (4.2 g, 52 mmol) and then acetic acid (3.0 ml, 52 mmol) at room temperature. After stirring for 15 minutes, solid KCN (3.4 g, 52 mmol) was added and the homogeneous mixture was heated at 60° C., overnight. The reaction was cooled and then concentrated, in vacuo. The residue was then extracted from saturated aqueous sodium bicarbonate with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford I-(13A-9)d as a colorless solid (11.7 g, quantitative): +ES MS (M+1) 292.2; 1H NMR (400 MHz, CD3OD) δ 7.42 (d, J=7.5 Hz, 4H), 7.26 (t, J=7.5 Hz, 4H), 7.17 (t, J=7.3 Hz, 2H), 4.47 (s, 1H), 3.54 (d, J=8.3 Hz, 2H), 3.25 (d, J=8.3 Hz, 2H), 2.61 (s, J=7.2 Hz, 2H), 1.11 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[Mg].[CH2:11]([N:18]1[CH2:26][C:25]2([C:27]([O:29][CH3:30])=[O:28])[CH:20]([C:21](=[O:37])[CH2:22][CH2:23][CH:24]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:11]([N:18]1[CH2:26][C:25]2([C:27]([O:29][CH3:30])=[O:28])[CH:20]([C:21]([OH:37])([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=3)[CH2:22][CH2:23][CH:24]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(Br)cc1C
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C)c(C)c1)CCC2c1ccccc1
Temperature: -7 °C
Reaction time: 4 h

Procedure:
2.3 cm3 of 4-bromo-ortho-xylene and 0.42 g of magnesium turnings in a mixture of 20 cm3 of diethyl ether and 20 cm3 of tetrahydrofuran were heated at reflux for one hour. After cooling to a temperature in the region of -7° C., a solution of 3.11 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 20 cm3 of diethyl ether was added over 25 minutes. The reaction mixture was stirred for four hours at a temperature in the region of 25° C. and then hydrolysed by 50 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with 25 cm3 of ethyl acetate. The organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, 1.995 g of methyl (3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(3,4-dimethylphenyl)-4-phenyl-octahydroisoindole-3a-carboxylate were obtained, the characteristic of which compound, used as it was in the following stage, was as follows:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.ClC(Cl)(O[C:15](=[O:21])OC(Cl)(Cl)Cl)Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.ClCCl>[N:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:15]([N:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)=[O:21])[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCC(c2ccncc2)CC1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 112.8 %

Procedure:
0.12 g of 1,2,3,4-tetrahydroquinoline, 9 ml of dichloromethane and 0.16 ml of triethylamine are placed in a 50 ml round-bottomed flask under nitrogen atmosphere. 0.09 g of triphosgene is added at 0° C. and then the reaction mixture is left stirring at ambient temperature for 18 h. 0.147 g of 4-(piperidin-4-yl)pyridine is subsequently added and the reaction mixture is stirred for 60 h and then refluxed for 12 h. 20 ml of a saturated aqueous sodium hydrogencarbonate solution are added and then the aqueous phase is extracted three times with dichloromethane. The organic phases are combined and dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol 95/5 mixture. 0.11 g of 1-[(4-(pyridin-4-yl)piperidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoline is obtained.
Reaction SMILES: CCCCC.[H-].[Na+].[NH2:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:14])=[C:11]([OH:26])[CH:10]=1.Cl[CH2:28][CH2:29][CH2:30][C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32]>CN(C=O)C.[Cl-].[Na+].O>[NH2:8][C:9]1[C:24]([Cl:25])=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[O:14])=[C:11]([O:26][CH2:28][CH2:29][CH2:30][C:31]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])=[O:32])[CH:10]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CCN(CC)C(=O)CCCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCCC(=O)N(CC)CC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.8 %

Procedure:
To a well-stirred suspension of pentane-washed sodium hydride (0.52 g of 60%, 3 mmole) in 3 ml dry DMF was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.43 g, 12 mmoles) (prepared as in Example 53). To this was added 10 ml of DMF and the mixture was stirred at ambient temperature for 45 minutes then warmed to about 50° C. for 15 minutes whereupon 4-chloro-N,N-diethylbutyramide (1.92 g, 11 mmoles) was added. The mixture was then stirred at 60°-70° C. for 6 hours, at room temperature for 2 days and then at 60-70° C. for a further 4 hours. After cooling, the mixture was poured into 400 ml of brine and extracted with methylene chloride (4×100 ml). After combining, the organic phase was washed two times with 100 ml of 10% aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil (3.75 g). This was purified by flash chromatography on silica gel to give 1.64 g of the title compound as an oil.