Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=C[CH2:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH2:18][CH2:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:17]>ClCCl>[CH3:3][N:4]1[C@@H:21]2[CH2:22][C:9]3[CH:10]=[CH:11][C:12]([OH:24])=[C:13]4[O:14][C@H:15]5[C:16]([CH:18]=[CH:19][C@:20]2([OH:23])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:17]
Reactant: C=CCN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Solvent: ClCCl
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)C=C[C@@]3(O)[C@H]1C5
Temperature: 20 °C
Yield: 89.5 %

Procedure:
Into a 5 L reactor equipped with an overhead stirrer and reflux condenser was dissolved N,N-dimethyl barbituric acid (32.56 g, 208.5 mmol) and tetrakis(triphenylphosphine)palladium[0](20.36 g, 17.6 mmol) in dichloromethane (1.5 L). The mixture was stirred at a temperature of about 20° C. Into the mixture was charged naloxone (110.90 g, 338.8 mmol) as a suspension in dichloromethane (1 L). The resulting reaction mixture was stirred at 38° C. for 16 hours. The mixture was cooled to a temperature of about 20° C. and the solids were filtered off under reduced pressure. The solids were washed with dichloromethane (5 L) followed by washing with water (2.5 L). The solids were dissolved into a 10:1 mixture of water:concentrated sulfuric acid at 40° C. The heated aqueous solution was washed with dichloromethane (0.5 L) and then basified to a pH of 9.05 with 28% ammonium hydroxide. The resulting solids were filtered and dried under reduced pressure at 100° C. for 20 hours to provide noroxymorphone as a white solid (87.12 g, 303.2 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]3[O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:7][CH:6]=2)=[O:42])=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccc(Cl)cc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 4-chlorobenzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(4-chloro-benzoyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 616 (M+H)+.
Reaction SMILES: [Br:1][C:2]([Br:16])([Br:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](O)=[O:10])(=[O:5])=[O:4].S(Cl)([Cl:19])=O>CN(C)C=O>[Br:1][C:2]([Br:16])([Br:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([Cl:19])=[O:10])(=[O:5])=[O:4]
Reactant: O=C(O)c1cccc(S(=O)(=O)C(Br)(Br)Br)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(S(=O)(=O)C(Br)(Br)Br)c1
Yield: 94 %

Procedure:
To 375 g (0.86 mole) of 3-tribromomethanesulfonyl benzoic acid were added 1 ml of dimethylformamide and 500 ml of thionyl chloride and the mixture was refluxed for one hour. The reaction mixture was filtered and 3000 ml of hexane was added to the filtrate to precipitate crystals. The crystals were recovered by filtration and dried to obtain 366 g of 3-tribromomethanesulfonyl benzoylchloride (yield 94%, white crystals).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccccc2C(=O)O)cc1
Yield: 76 %

Procedure:
A mixture of 52 g (0.33 mole) of 2-chlorobenzoic acid, 82 g (0.66 mole) of 4-methoxyaniline, 46 g (0.33 mole) of potassium carbonate, 5 g (0.025 mole) of cupric acetate and 150 ml of dimethylformamide was heated at reflux for two hours. The reaction mixture was cooled, 300 ml of water added and the mixture filtered. The filtrate was acidified with 50 ml of 6N hydrochloric acid, and the resulting solid was collected by filtration and recrystallized from acetonitrile to give 61 g of 2-(4-methoxyphenylamino)benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[Br:17]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[C:5]([Br:17])=[C:4]([CH3:16])[N:3]=1
Reactant: Cc1cc(N[C@H]2CC[C@H](O)CC2)nc(N)n1
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClC(Cl)Cl
Product: Cc1nc(N)nc(N[C@H]2CC[C@H](O)CC2)c1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (trans-4-(2-amino-6-methylpyrimidin-4-ylamino)cyclohexanol (1.33 g, 5.98 mmol) in chloroform (15 mL) was added N-bromosuccinamide (1.08 g, 6.04 mmol). After stirring at room temperature for 1.5 hr, the solution was concentrated. The residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-5%) to afford the title compound (1.14 g, 63%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:40][CH2:41][N:42]([CH3:44])[CH3:43].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 40 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (19 mg, 0.04 mmol) in dry DMF (1 mL) was added sodium hydride (8 mg, 0.18 mmol) at 0° C. under nitrogen. After 1 h at 0° C., 2-chloro-N,N-dimethylethanamine.hydrochloride (18 mg, 0.12 mmol) was added and the resulting mixture was stirred for an additional 5 h at 40° C. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel chromatography (gradient 0 to 3% MeOH in dichloromethane) to give the title compound (7 mg, 32%). 1H NMR (500 MHz, CDCl3): 7.38 (1H, s), 7.31-7.24 (7H,m), 7.20-7.18 (2H,m), 5.01 (1H, br s), 4.88 (2H, s), 4.08 (2H,t), 2.60 (2H, t), 2.55-2.25 (4H, m), 2.33 (6H, s), 2.09-2.01 (1H, m), 1.85-1.76 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:16][C:17]1[C:22]2[NH:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Br:16][C:17]1[C:22]2[N:23]([C:2]3[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]4[CH2:14][CH2:13]4)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=3)[CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)OCCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCOc3cc(OC)cc(Br)c32)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone (67.9 mg, 0.275 mmol) and 5-bromo-7-methoxy-3,4-dihydro-2H-1,4-benzoxazine (67 mg, 0.275 mmol) were combined in THF (1.4 mL). The mixture was cooled to 0° C. and was treated with NaHMDS (302 μL, 0.302 mmol, 1 M in THF). The cooling bath was removed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into a separatory funnel containing saturated NaHCO3 and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (10% EtOAc→30% EtOAc in hexanes) to afford a brown oil. 1H NMR (300 MHz, CDCl3): δ 6.73 (d, J=1.5 Hz, 1H), 6.70 (s, 1H), 6.45 (d, J=1.3 Hz, 1H), 4.31-4.00 (m, 5H), 3.75 (s, 3H), 1.89-1.74 (m, 2H), 1.05-1.02 (m, 1H), 0.93 (t, J=7.3 Hz, 3H), 0.90-0.75 (m, 1H), 0.52-0.49 (m, 2H), 0.35-0.25 (m, 1H); HRMS (ESI) m/z 453.0459 [M+, calcd for C19H21N3O3BrCl 453.0455].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[C:13]([CH3:25])[C:12]=2[C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:32]N1C(=O)CCC1=O>>[Br:32][CH2:25][C:13]1[C:12]([C:26](=[O:31])[CH2:27][CH:28]([CH3:29])[CH3:30])=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(-c2c(C(=O)CC(C)C)c(C)nc3cc(OC)c(OC)cc23)cc1OC
Product: COc1ccc(-c2c(C(=O)CC(C)C)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC

Procedure:
According to the same manner as that described in Reference Example 5, 4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxy-2-methylquinoline was brominated with N-bromo-succinimide (NBS) to give 2-bromomethyl-4-(3,4-dimethoxyphenyl)-3-isovaleryl-6,7-dimethoxyquinoline. This compound was recrystallized from ethyl acetate - hexane to give colorless prisms. mp. 159°-161° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:11](=[O:12])[C:10]2[CH:13]=[C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[S:15][C:9]=2[N:8]([CH2:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:24][C:23]=2[F:37])[C:7]1=[O:38].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[O:38]=[C:7]1[N:8]([CH2:21][C:22]2[C:27]([F:28])=[CH:26][C:25]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:24][C:23]=2[F:37])[C:9]2[S:15][C:14]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=2[C:11](=[O:12])[NH:6]1
Reactant: COc1ccc(Cn2c(=O)c3cc(CC(F)(F)F)sc3n(Cc3c(F)cc(-c4ccccc4C#N)cc3F)c2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(CC(F)(F)F)sc32)c(F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of 4′-{[3-(2,4-dimethoxybenzyl)-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′,5′-difluorobiphenyl-2-carbonitrile (1.71 g) and trifluoroacetic acid (20 mL) was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (20 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (20 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (1.3 g, 100%).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:47][O:48][C:49]([NH:51][C@H:52]([C:56](O)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:47][O:48][C:49]([NH:51][C@H:52]([C:56]([N:2]1[CH:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:4][C:5]2([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[CH2:1]1)=[O:57])[CH:53]([CH3:54])[CH3:55])=[O:50]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of 8-(1,1-dimethylethyl) 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (131) (150 mg, 0.48 mmol), HATU (183 mg, 0.48 mmol) and N-[(methyloxy)carbonyl]-L-valine (93 mg, 0.53 mmol) in anhydrous CH2Cl2 (4 mL) was added Hunig's base (0.17 mL, 0.96 mmol) and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was concentrated in vacuo and purified by silica gel chromatography eluting with 15-80% hexanes/EtOAc to afford the title compound as a pale yellow oil (125 mg, 55% yield).
Reaction SMILES: [CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][CH:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[H][H]>C(O)(=O)C.[Pd].O>[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]4[O:22][C@H:6]5[C:7]([CH2:9][CH2:10][C@:11]2([OH:23])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8]
Reactant: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 5 °C
Yield: 91.8 %

Procedure:
72.50 kg of 14-Hydroxycodeinone is dissolved in 10% aqueous solution of acetic acid, 5% Pd/C catalyst is added, and the mixture is hydrogenated under overpressure of electrolytic hydrogen 104 to 106 kPa at temperatures 30 to 35° C. The reaction mixture is diluted with 200 l of water, filtered, the filtrate is cooled down to 5° C. and Oxycodone base is precipitated by adjusting pH with an addition of an ethanolic solution of ammonia to the value 9.2. The suspension is centrifuged, Oxycodone is washed with water and dried at 70 to 80° C. At least 67 kg (92%, purity 98.5%) of Oxycodone is obtained.
Reaction SMILES: Cl.N1C=CC=CC=1.C([O:10][C:11]1[C:16]2[S:17][C:18]3[C:23]([C:24]4([CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)C.[OH-].[Na+]>O>[OH:10][C:11]1[C:16]2[S:17][C:18]3[C:23]([C:24]4([CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[C:15]=2[CH:14]=[CH:13][CH:12]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: CCOc1cccc2c1Sc1ccccc1C21CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: CN1CCC2(CC1)c1ccccc1Sc1c(O)cccc12
Temperature: 210 °C

Procedure:
To a melt of pyridine hydrochloride (19 g.) at 160° C. is added 4-ethoxy-1'-methylthioxanthene-9-spiro-4'-piperidine (1.3 g.). The stirred mixture is heated to 210° C. for 30 minutes and then cooled, diluted with water and made alkaline with aqueous sodium hydroxide solution. A small amount of solid material is removed by filtration and the filtrate is acidified with concentrated hydrochloric acid followed by neutralisation with sodium bicarbonate and extraction with chloroform. The chloroform extract is evaporated to dryness and the residual yellow gum crystallised from aqueous ethanol to give 4-hydroxy-1'-methylthioxanthene-9-spiro-4'-piperidine, m.p. 180°-182° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:7]=1.[H-].[Na+].[CH3:26][N:27]=[C:28]=[S:29]>CN(C)C=O>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[N:7]=[C:3]([NH:2][C:28]([NH:27][CH3:26])=[S:29])[S:4][C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: CN=C=S
Reactant: COc1ccc(-c2nc(N)sc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=S)Nc1nc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2-amino-4,5-bis(4-methoxyphenyl)thiazole hydrochloride (1.00 g) in N,N-dimethylformamide (5 ml) was added dropwise to a suspension of sodium hydride (60% dispersion in mineral oil) (0.13 g) in N,N-dimethylformamide (5 ml) at 0° C. for 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes. After methyl isothiocyanate (2.19 ml) was added dropwise to the reaction mixture, the reaction mixture was stirred at 80° C. for 5.5 hours. After allowing to cool to room temperature, the resulting precipitates were collected by filtration, washed with diisopropyl ether and diethyl ether to give 4,5-bis(4-methoxyphenyl)2-(3-methylthioureido)thiazole (0.81 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12]O>>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1
Reactant: CO
Reactant: Nc1cccc(CC(=O)O)c1
Product: COC(=O)Cc1cccc(N)c1

Procedure:
3-Aminophenylacetic acid (5 g, 33.1 mmol) was esterified with MeOH using Method B to give the title compound
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]2[N+:16]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2].[H][H]>C(O)C.O1CCCC1.[Ni]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH2:16])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20])[CH3:2]
Reactant: CCOc1cc([C@@H]2CC=CC[C@@H]2[N+](=O)[O-])ccc1OC
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc([C@@H]2CCCC[C@@H]2N)ccc1OC

Procedure:
40.0 g of (+/−)-cis-2-ethoxy-1-methoxy-4-(2-nitro-cyclohex-4-enyl)benzene (compound C1) are dissolved in 1000 ml of ethanol and 500 ml of tetrahydrofuran, treated with 10 g of Raney nickel and hydrogenated at a hydrogen pressure of 100 bar for 4 days in an autoclave. After filtration and removal of the solvent in vacuo, 35.9 g of the title compound are obtained as a solidifying oil.
Reaction SMILES: N1C2C(CCCC2)C[CH2:3][CH2:2]1.[CH3:11][C:12]1([CH3:23])[CH2:21][CH:20]([CH3:22])[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:13]1.ICC>>[CH2:2]([N:13]1[CH:14]2[CH:19]([CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:20]([CH3:22])[CH2:21][C:12]1([CH3:23])[CH3:11])[CH3:3]
Reactant: CC1CC(C)(C)NC2CCCCC12
Reactant: C1CCC2NCCCC2C1
Solvent: CCI
Product: CCN1C2CCCCC2C(C)CC1(C)C
Temperature: 105 °C
Reaction time: 3 h

Procedure:
1-ethyl-2,2,4-trimethyl decahydroquinoline was prepared by the reaction of the intermediate saturated decahydroquinoline with the alkyl halide. 36.3 grams (0.2 mole) of 2,2,4-trimethyl decahydroquinoline of about 76% cis structure was placed into a reactor vessel equipped for heating and agitation. 15.6 grams (0.1 mole) of iodoethane was added dropwise to the reactor vessel. The mix was heated to 105° C. while stirring for 3 hours. A thick slurry formed which was filtered out and washed wih acetone. The acetone wash liquid was then concentrated and distilled using a 3 inch Vigreaux column to yield 7.1 grams of a product boiling at 58° - 60° C. at 0.25 mm Hg. The NMR spectra of the product was consistent with the desired product, 1-ethyl-2,2,4-trimethyl decahydroquinoline. Calculated carbon, hydrogen, nitrogen content for the formula C14H27N is 80.31% carbon, 13.00% hydrogen, and 6.69% nitrogen while the measured contents were 79.93% carbon, 13.54% hydrogen, and 6.35% nitrogen respectively.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][C@@H:23]3[C:28]([NH:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[O:29])(=[O:21])=[O:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:3]([O:2][C:1]([N:25]1[CH2:26][CH2:27][N:22]([S:19]([C:17]2[S:18][C:14]([C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)=[CH:15][CH:16]=2)(=[O:21])=[O:20])[C@@H:23]([C:28]([NH:30][O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)=[O:29])[CH2:24]1)=[O:5])[CH3:4]
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccc(F)cc2)s1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(-c3ccc(F)cc3)s2)[C@@H](C(=O)NOC2CCCCO2)C1
Yield: 82.1 %

Procedure:
A solution of ethyl chlorocarbonate (42 mg) in CHCl3 (1 ml) was added dropwise to a solution of (2R)-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (150 mg) and triethylamine (39 mg) in CHCl3 (2 ml) with cooling on an ice bath. The reaction mixture was stirred at said temperature for 30 minutes and the reaction was quenched by adding 3-(N,N-dimethylamino)propylamine (0.5 ml). The mixture was concentrated in vacuo, and the residue was partitioned between AcOEt and 5% aqueous citric acid. The organic layer was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over MgSO4, and concentrated in vacuo. The residue was purified by SiO2 column chromatography eluted with AcOEt in hexane gradually from 40% to 60%, to give 142 mg of (2R)-4-ethoxycarbonyl-1-[5-(4-fluorophenyl)thiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:3]1=2.O.NN>C(O)C.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:3]2[N:2]([CH3:1])[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[CH:10]=1
Reactant: CN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1C(=O)CCCc2cc(N)ccc21
Temperature: 25 °C

Procedure:
1-Methyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (185 mg, 0.84 mmol) was dissolved in ethanol (3.5 ml). 10% palladium on carbon (50 mg) and hydrazine hydrate (1 ml) were then added, and the mixture was heated to reflux for 2 hours. After cooling to room temperature, the mixture was then filtered through Celite and concentrated to give 7-Amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one as a clear oil, 166 mg. 1H NMR (400 MHz, DMSO-d6) δ 6.92-6.97 (m, 1H), 6.42-6.50 (m, 1H), 6.40 (s, 1H), 5.13 (s, 2H), 3.10 (s, 3H), 1.90-2.16 (m, 6H); MS (m/e) 221 (M+1).
Reaction SMILES: O[C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][C:20]1[C:29]([NH2:30])=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:31][CH2:32][CH3:33])[CH:21]=1.C(O)C>CN(C)C=O>[CH2:32]([O:31][C:22]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][C:29]2[C:20]([CH:21]=1)=[N:19][C:11]1[C:2](=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([OH:13])=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]3=1)[N:30]=2)[CH3:33]
Reactant: CCOC(=O)C1=C(O)C(=O)c2ccccc2C1=O
Reactant: CCOc1cc(N)c(N)cc1C(=O)OC
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ccccc2c2nc3cc(OCC)c(C(=O)OC)cc3nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 895 mg of ethyl 3-hydroxy-1,4-dihydro1,4-dioxo-2-naphthoate in 10 ml of N,N-dimethylformamide was added 620 mg of N,N'-carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours. To the mixture was added the crude methyl 4,5-diamino-2-ethoxybenzoate in 10 ml of N,N-dimethyl-formamide under ice cooling, and the mixture was stirred at room temperature overnight. To the reaction solution was added 200 ml of ethanol, and then the resulting precipitate was collected by filtration and recrystallized from chloroform - ethanol to give the title compound, m.p. 270°-273° C., yield of 531 mg.