Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:15][NH:16][O:17][CH2:18][C:19]([OH:21])=[O:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:16]([CH3:15])[O:17][CH2:18][C:19]([OH:21])=[O:20])=[S:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNOCC(=O)O
Reactant: CC(C)(C)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(OCC(=O)O)C(=S)Nc1ccc(C(C)(C)C)cc1
Yield: 100.4 %

Procedure:
A mixture of 4-tert-butylphenyl-isothiocyanate (10.8 g), N-methyl aminooxy acetic acid hydrochloride (8.0 g), triethylamine (14 g) and chloroform (300 mL) was heated at reflux for three hours, then evaporated to dryness. The residue was treated with 2N HCl (300 mL) and the mixture was stirred for fifteen minutes. The solid was collected by filtration, washed with water and dried to give (16.8 g) of [[[[(4-tert-butylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid. 1H-NMR (DMSO-d6; 300 Mhz) δ13.5 (br s, 1H), 10.48 (s, 1H), 7.48-7.32 (m, 4H), 4.62 (s, 2H), 3.52 (s, 3H), and 1.28 ppm (s, 9H). The acid (14.8 g) was dissolved in benzene (200 mL). Phosphorus pentachloride (10.4 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (600 mL) and washed with sodium bicarbonate saturated solution (2×400 mL) then with water (400 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel (40% methylene chloride in hexane). The title compound (9.1 g) was obtained as a solid, m.p. 168-170° C. Mass spectrum (El, M.+) m/z 276. 1H-NMR (DMSO-d6; 400 MHz) δ7.45 (d, 2H), 7.09 (d, 2H), 5.06 (s, 2H), 3.68 (s, 3H), and 1.30 ppm (s, 9H).
Reaction SMILES: C([C:3]1(CC)[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)[N:5](C(N[C@H](CCC)C2C=CC(C)=CC=2)=O)[C:4]1=[O:30])C.[P:33]([O:40]CC)([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36].C(OCC)(=O)C>CCCCCC>[CH2:35]([O:34][P:33]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:6]2[NH:5][C:4](=[O:30])[CH2:3]2)=[CH:13][CH:12]=1)([O:37][CH2:38][CH3:39])=[O:40])[CH3:36]
Reactant: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(CBr)cc1)c1ccc(C)cc1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOP(=O)(Cc1ccc(OC2CC(=O)N2)cc1)OCC
Temperature: 90 °C

Procedure:
A mixture of (4S)-3,3-diethyl-1-[(R)-α-n-propyl-(4-methyl)-benzylaminocarbonyl]-4-[4-(bromomethyl)phenoxy]-azetidin-2-one (362 mg, 0.72 mmol) and triethyl phosphite (1.4 mL, 8.2 mmol) was heated for 2 hours at 90° C. The crude product mixture was subjected to flash chromatography on silica gel using initially 25% ethyl acetate in hexane and subsequently 33% ethyl acetate in hexane as the mobile phase. (4S)-3,3-Diethyl-1-[(R)-α-n-propyl(4-methyl)-benzylaminocarbonyl)]-4-[4-(diethoxyphosphinylmethyl)-phenoxy]-azetidin-2-one was obtained as colorless oil; yield 371 mg, 92%; Fast atom bombardment mass spectrum (FAB MS): m/z 559 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8]1[C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].O.Cl>CCCCCC>[CH:6]([C:8]1([C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1=[O:14])=[CH:8][CH2:9][CH3:10]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: CCC=CC1(C(=O)OCC)CCCCC1=O
Temperature: 25 °C
Yield: 186.4 %

Procedure:
Sodium hydride, 60% in mineral oil (8,3 g, 200 mmol) was washed with 2 portions of hexane and then dried under an N2 flow. This was suspended in dimethylformamide and ethyl 2-cyclohexanonecarboxylate (34.1 g, 200 mmol) was added slowly under N2 (note the foaming and exotherm), with cooling with a 25° C. water bath. After complete addition, the mixture was stirred at 25° C. for ~1 hour and the treagents added. The stirring mixture was heated to 50° C. for 18 hours (overnight). The reaction was then cooled to room temperature. The entire mixture was poured into water, neutralized with dilute HCl and extracted with two portions of 1:1 ether-hexane The combined organics were then washed with two portions of water followed by saturated brine, then dried over MgSO4, filtered and stripped giving 41.8 g of an impure mixture of products. Purification of the product by chromatography (silica gel, 5% methyl t-butyl ether/90% hexane) gave 28.4 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:26][OH:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:27][CH2:26][C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][N:22]=2)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Reactant: Cc1cccnc1CO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cccnc1COc1nc(N)nc(-c2ccccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[C:7]([B:8](C2C(F)=C(F)C(F)=C(F)C=2F)[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34].[OH2:35]>CCCCCCC.C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([B:8]([C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])[OH:35])=[C:6]([F:31])[C:5]([F:32])=[C:4]([F:33])[C:3]=1[F:34]
Reactant: Fc1c(F)c(F)c(B(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: OB(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 5 h

Procedure:
20 g (39 mmol) of tris(pentafluorophenyl)borane are suspended in 150 ml of heptane and, under reflux, a solution of 1.8 ml (97.5 mmol) of water in 40 ml of toluene is then added over a period of 30 minutes. The mixture is subsequently stirred for another five hours under reflux. The solution is subsequently cooled to 0° C. Over a period of 30 minutes, the product precipitates as a white solid. The product is isolated and washed three times with 50 ml each time of pentane and subsequently dried in an oil pump vacuum. This gives 11.5 g (80%) of colorless bis(pentafluorophenyl)hydroxyborane. The boroxin content is 10%. 1H-NMR(C6D6, 400 MHz): −133.1 (m, 4 F, o-B(C6F5)2), −147.9 (m, 2 F, p-B(C6F5)2), −161.1 (m, 4 F, m-B(C6F5)2) ppm.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:28]=[CH:27][C:7]2[N:8]=[C:9]([NH:17][C:18]3[C:23]([Cl:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=3[Cl:26])[C:10]3[CH:11]=[CH:12][NH:13][C:14](=[O:16])[C:15]=3[C:6]=2[CH:5]=1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[Br:3][C:4]1[CH:28]=[CH:27][C:7]2[N:8]=[C:9]([N:17]([C:18]3[C:19]([Cl:26])=[CH:20][C:21]([F:25])=[CH:22][C:23]=3[Cl:24])[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:10]3[CH:11]=[CH:12][N:13]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:14](=[O:16])[C:15]=3[C:6]=2[CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]ccc2c(Nc3c(Cl)cc(F)cc3Cl)nc3ccc(Br)cc3c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN(c1c(Cl)cc(F)cc1Cl)c1nc2ccc(Br)cc2c2c(=O)n(COCC[Si](C)(C)C)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slurry of NaH (252 mg, 6.29 mmol) in THF (20 ml) was added 9-bromo-5-[(2,6-dichloro-4-fluorophenyl)amino]benzo[c]-2,6-naphthyridin-1(2H)-one (950 mg, 2.097 mmol) and the mixture was stirred for 5 min. [2-(Chloromethoxy)ethyl](trimethyl)silane (1.116 ml, 6.29 mmol) was added and the mixture was stirred at room temperature overnight. The solution was quenched with MeOH and concentrated under reduced pressure. The residue was purified by flash chromatography (0-30% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19](=[O:21])[N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3cccnc3n2CC(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.1 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.2 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 120 ml of tetrahydrofuran was stirred at room temperature for 3 hrs. Then, under nitrogen atmosphere, piperidine (1.92 g, 0.022 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was filtered and the filtrate was evaporated to dryness, then placed under high vacuum for 3-4 hrs. The residue was treated with water and the solid was collected by filtration, washed with water, and dried under high vacuum at 50°-60° C. overnight. The solid was recrystallized from isopropyl alcohol with refrigeration overnight. The solid was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 50°-60° C. overnight to give 3.21 g (62%) of title compound, mp 153°-55° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: Fc1cnc(Nc2ccc(Cl)cc2)nc1Nc1ccc(Cl)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-chloroaniline were reacted to yield N2,N4-bis(4-chlorophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3+CD3OD): δ 7.80 (d, 1H, J=4.2 Hz), 7.45 (d, 2H, J=8.7 Hz), 7.33 (d, 2H, J=9 Hz), 7.20 (d, 2H, J=8.7 Hz), 7.14 (d, 2H, J=9.6 Hz); LCMS: ret. time: 28.84 min.; purity: 87%; MS (m/e): 349 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH:9]2[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[OH-].[Na+].[CH3:23][O:24]/[N:25]=[C:26](\[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH2:37]Br)/[C:27]([O:29][CH3:30])=[O:28]>O>[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH:9]1[CH2:10][CH:8]1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:26](=[N:25][O:24][CH3:23])[C:27]([O:29][CH3:30])=[O:28]
Reactant: Oc1cccc(C2CC2c2cccs2)c1
Reactant: CO/N=C(/C(=O)OC)c1ccccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C(=O)OC)c1ccccc1COc1cccc(C2CC2c2cccs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a 20 ml glass vial equipped with a magnetic stirring bar was charged 2.2 g (0.0102 moles) of 1-(3-hydroxyphenyl)-2-(2-thienyl)cyclopropane, 15 mls of dry N,N-dimethylformamide, and 0.41 g (0.0102 moles) of powdered sodium hydroxide. To this solution was added 2.9 g (0.0102 moles) of methyl (E)-2-(bromomethyl)phenylglyoxylate O-methyloxime in one portion. The vial was capped and stirred overnight at ambient temperature. The reaction mixture was then poured into 100 mls of water, and extracted with s×100 mls of ethyl ether. The ether extract was then washed with 2×100 mls of water and 100 mls of saturated aqueous sodium chloride solution. The ether extract was then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure with a rotary evaporator at 45° C. to afford 5.1 g of the crude product as an dark green oil. This material was chromatographed on a mixed bed of neutral alumina and silica gel with 50% ethyl acetate, 50% hexane. The pure fractions were combined, and concentrated under reduced pressure with a rotary evaporator to afford 3.7 g of the title compound, Methyl2-[2-((3-(2-(thien-2-yl)cyclopropyl))phenoxymethyl)phenyl]-2-methoxyiminoacetate as a viscous yellow oil. 86% isolated yield.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38].I([O-])(=O)(=O)=[O:45].[Na+]>CO.O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32]([CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40])=[O:45]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CS(=O)CCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Yield: 66 %

Procedure:
A solution of 300 mg of 11β-fluoro-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol in 4.3 ml of methanol and 2.1 ml of water is stirred with 131 mg of sodium periodate for 4 hours at room temperature. Then, it is added to water, extracted three times with ethyl acetate, washed with common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/ethyl acetate. 203 mg of 11β-fluoro-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfinylmethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained. [α]D22=+11.8° (c=0.53% in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[OH-].[K+].Cl>C(O)C.O>[CH3:16][C:14]1[CH2:13][C:12](=[O:17])[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=1
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 280 g of 2,4,6-trichlorophenylhydrazine was added 180 ml of ethyl acetoacetate, and the resulting mixture was stirred at room temperature for 30 minutes. After adding thereto a solution prepared by dissolving 215 g of potassium hydroxide in 7 l of ethanol, the reaction solution was refluxed with heating for 1 hour. The reaction solution was poured into 6 l of water and neutralized with conc. hydrochloric acid. After being cooled to room temperature, a precipitate thus formed was filtered off, washed with water, and then dried under reduced pressure to obtain the titled compound. Yield: 300 g. Melting point: 178° to 180° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[S:14][C:10]=2[CH:9]=1)([O-])=O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[CH:22]=[CH:21][C:11]2[N:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[S:14][C:10]=2[CH:9]=1
Reactant: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cc2s1)C1CC1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c1
Yield: 108.5 %

Procedure:
To a solution of N-[6-(3-nitrophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (840 mg, 2.36 mmol) in ethanol (100 mL) was added iron powder (11.9 g, 212 mmol) with heating under reflux. The obtained suspension was vigorously stirred, and 6N hydrochloric acid (50 mL) was slowly added dropwise. The reaction mixture was refluxed for 2 hr with vigorous stirring, and excess iron powder was filtered off through celite. The filtrate was concentrated to about 50 mL, and the residue was diluted with ethyl acetate (250 mL), washed with 1N aqueous sodium hydroxide solution (100 mLx2) and saturated brine (100 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (833 mg) as a pale-yellow solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:15][C:16]([F:24])([F:25])[C:17]1[CH:18]=[C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C(F)(F)F)c2)CC1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A Solution of 1,1-Dimethylethyl 4-Oxo-1-Piperidinecarboxylate (0.5 g, 2.5 mmol), 3-(trifluoromethyl)aniline (0.402 g, 2.5 mmol) and sodium tri(acetoxy)borohydride (0.80 g, 3.75 mmol) in 1,2-DCE (5 ml) was stirred at room temperature, under argon overnight. Saturated aq. NaHCO3 solution (15 ml) was added and stirring continued for 1 h. The reaction mixture was extracted with DCM and the organic phase concentrated in vacuo. Recrystallisation of the solid residue gave the title compound as a white solid (0.86 g). δH (CDCl3, 250 MHz)) 7.25 (1H, t), 6.92 (1H, d), 6.75 (2H, m), 4.06 (2H, m), 3.45 (1H, m), 2.94 (2H, m), 2.04 (2H, m), 1.46 (9H, s), 1.36 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH3:11]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: N
Solvent: CCOCC
Product: NC(=S)Nc1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A stirred solution of 4-chlorophenyl isothiocyanate (10.0 g, 0.077 mol) in 100 ml ether was saturated with ammonia gas for five minutes. The reaction mixture was then stirred for 18 hr. The white solid which precipitated was collected by filtration and yielded 6.3 g of N-(4-chlorophenyl)thiourea, M.P. 147°-148° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](Cl)=[O:18].Cl.[C:21]1([C:27]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:46]1([C:27]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:35]3[CH:31]([CH2:32][N:33]([C:17](=[O:18])[CH2:16][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][CH3:8])[CH2:34]3)[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: COc1ccccc1CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2C(C1)C(O)(c1ccccc1OC)C(O)CC2(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4.2 cm3 of triethylamine and then 2.4 g of (2-methoxyphenyl)-acetyl chloride in 50 cm3 of methylene chloride are added to a solution of 4.5 g of (3aRS, 4RS, 5RS, 7aRS )-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindole-4,5-diol hydrochloride in 100 cm3 of methylene chloride, cooled to 0° C. The reaction mixture is stirred at room temperature for 90 minutes; it is washed with twice 10 cm3 of water, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid which has crystallised out is taken up in 100 cm3 of diisopropyl ether and then filtered off and washed with 50 cm3 of a saturated solution of sodium bicarbonate and then 50 cm3 of diisopropyl ether. 4.35 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)-acetyl]-perhydroisoindole-4,5-diol are obtained in the form of a light beige solid which melts at 278° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(Cc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Cc3ccccc3)c2)CC1
Yield: 96.2 %

Procedure:
A mixture of 74 mg (0.21 mmol) of 1-tert-butoxycarbonyl-4-((3-benzyl)phenyl)-1,2,3,6-tetrahydropyridine (from Step D) and 6 mg of 10% palladium on carbon in 1 mL of EtOAc and 3 mL of MeOH was hydrogenated at 40 psi of hydrogen on a Parr shaker for 3 hours. The reaction was filtered and concentrated under reduced pressure to yield 71 mg (95%) of the title compound, which was used without further purification. 1H NMR (500 MHz, CDCl3) δ1.43-1.83 (m, 13H), 2.62 (m, 1H), 2.80 (m, 2H), 3.99 (s, 2H), 4.25 (m, 2H), 7.06-7.33 (m, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][OH:16].Cl>>[OH:16][CH2:15][CH2:14][CH2:13][NH:12][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][CH:10]=1
Reactant: NCCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Product: O=C(NCCCO)c1ccc(O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
A mixture of 76 g of methyl 4-hydroxybenzoate and 112.5 g of 3-amino-1-propanol was heated and stirred at 120° C. for 8 hours. The reaction mixture was acidified with 2N hydrochloric acid and then extracted with ethyl acetate and butanol. The combined extracts were concentrated in vacuo and the residue was recrystallized from acetonitrile to give 37.8 g of N-(3-hydroxypropyl)-4-hydroxybenzamide, m.p. 118°-120° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4]1.[ClH:24]>C(O)(C)C>[ClH:24].[NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2(O)CN
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2CN
Yield: 98 %

Procedure:
1-Aminomethyl-5,6-dimethoxy-1-hydroxy-3-phenyl-1,2,3,4-tetrahydronaphthalene (11.5 g, 37 mmol), from Step 1, was heated at reflux temperature in 300 mL of isopropyl alcohol saturated with hydrochloric acid for 2 h. The resultant solution was concentrated and the solid residue was triturated with hot toluene to give 10.6 g (98% yield) of 1-aminomethyl-5,6-dimethoxy-3-phenyl-3,4-dihydronaphthalene hydrochloride, m.p. 189.5°-190° C.; 1H NMR (d6 -DMSO) δ: 2.78 (dd, 1H), 3.11 (dd, 1H), 3.2-3.4 (m, 2H+H2O), 3.6 (s, 3H), 3.81 (s, 3H), 3.93 (d, 1H), 6.1 (d, 1H), 6.93 (d, 1H), 7.12 (d, 1H), 7.2-7.4 (m, 5H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[C:3]1[NH2:8].[N:9]([C:12](OC1C=CC=CC=1)=[O:13])=[C:10]=[O:11]>C(#N)C>[CH3:7][C:6]1[N:2]([CH3:1])[C:3]2=[N:8][C:10](=[O:11])[NH:9][C:12](=[O:13])[N:4]2[N:5]=1
Reactant: Cc1nnc(N)n1C
Reactant: O=C=NC(=O)Oc1ccccc1
Solvent: CC#N
Product: Cc1nn2c(=O)[nH]c(=O)nc2n1C
Yield: 138.2 %

Procedure:
After suspending 4,5-dimethyl-4H-[1,2,4]triazol-3-ylamine (CAS 53132-83-5) (7.6 g) in acetonitrile (80 ml), a solution of phenyl isocyanatoformate (5.2 g) in acetonitrile (40 ml) was slowly added dropwise while heating to reflux. After heating to reflux for 6 hours, the reaction mixture was cooled on ice. The insoluble matter was collected by filtration to obtain the title compound (7.98 g).