Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=3[O:25][CH3:26])[CH2:16][NH:17][O:18][CH:19]=[C:20]=[O:21])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:31](=[O:41])[NH:32][N:33]=[C:34]([O:37][CH:38]([CH3:40])[CH3:39])[C:35]=1Cl.CN(C)C>CO>[Cl:29][C:30]1[C:31](=[O:41])[NH:32][N:33]=[C:34]([O:37][CH:38]([CH3:39])[CH3:40])[C:35]=1[N:17]([O:18][CH:19]=[C:20]=[O:21])[CH2:16][C:15]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:13]([N:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)[CH:14]=1
Reactant: CC(C)Oc1n[nH]c(=O)c(Cl)c1Cl
Reactant: COc1ccc(CNOC=C=O)cc1N1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C
Solvent: CO
Product: COc1ccc(CN(OC=C=O)c2c(OC(C)C)n[nH]c(=O)c2Cl)cc1N1CCN(Cc2ccc(N)cc2)CC1
Reaction time: 48 h
Yield: 81.5 %

Procedure:
A mixture comprising 1.6 g of 3-[4-(4-aminobenzyl)piperazin-1-yl]-carbonylmethoxy-4-methoxybenzylamine, 770 mg of 4,5-dichloro-6-isopropoxy-3(2H)-pyridazinone, 460 mg of trimethylamine and 20 ml of methanol, was refluxed under heating with stirring for 2 days. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1→chloroform:methanol=15:1) and then crystallized from diethyl ether to obtain 1.6 g of the above-identified compound as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]=[C:11]1[CH2:14][CH:13]([C:15]([OH:17])=O)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:35][O:36][NH:37][CH3:38]>C(Cl)Cl>[CH3:35][O:36][N:37]([CH3:38])[C:15]([CH:13]1[CH2:12][C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:18])[CH2:14]1)=[O:17]
Reactant: O=C(C=C1CC(C(=O)O)C1)OCc1ccccc1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C1CC(=CC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.6 %

Procedure:
To an ice cold solution of 3-[2-(benzyloxy)-2-oxoethylidene]cyclobutane-1-carboxylic acid (2.0 g, 8.12 mmol), N-Methyl-morpholine (2.70 ml, 24.36 mmol) in DCM (50 ml) was added isobutyl chloroformate (1.70 ml, 12.99 mmol) drop-wise over 5 min. After an additional 5 min, methoxy(methyl)amine hydrochloride (1.58 g, 16.24 mmol) was added and the mixture was stirred overnight whilst allowing to warm to RT. The reaction mixture was then diluted with DCM (30 ml), washed with 0.1N HCl (50 ml) then sat. NaHCO3 (50 ml), dried over Na2SO4, filtered and evaporated. Purification by silica gel column chromatography, eluting with EtOAc:heptanes from 1:9 to 3:7 gave the desired product (1.54 g, 65%); MS (ESI+) for C16H19NO4 m/z 290.10 [M+H]+; HPLC purity 100% (ret. time, 1.86 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 2.96 (1 H, ddd, J=16.98, 8.79, 1.81 Hz), 3.17-3.30 (4 H, m), 3.30-3.48 (2 H, m), 3.51-3.63 (1 H, m), 3.64-3.75 (3 H, m), 5.15 (2 H, s), 5.73 (1 H, quirt, J=2.25 Hz), 7.29-7.42 (5 H, m).
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]N1C(=O)CCC1=O>>[Br:19][C:13]1[C:12](=[O:14])[NH:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CC(c2ccccc2)Sc2ccccc2N1
Product: O=C1Nc2ccccc2SC(c2ccccc2)=C1Br

Procedure:
Alternatively, the starting material II may be prepared by reacting 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one (prepared as disclosed by Krapcho et al, J. Med. Chem., 6, 544 (1963)) with N-bromosuccinimide to form 3-bromo-2-phenyl-1,5-benzothiazepin-4(5H)-one which is then reacted with cuprous cyanide in the presence of a solvent such as dimethylformamide to form the 1,2-dihydro-2-oxo-4-phenyl-3-quinolinecarbonitrile starting material.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH2:6].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=3[S:23][C:14]=12>CN(C)C=O>[Cl:3][C:4]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=1[NH:6][C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]2[C:21]3[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:22]=3[S:23][C:14]=12
Reactant: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cnc2c(sc3ccc([N+](=O)[O-])cc32)c1Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
A mixture of 160 mg (4.00 mmol) of sodium hydride (60% dispersion in oil) and 648 mg (4.00 mmol) of 2,4-dichloroaniline in 10 mL of dimethylformamide is stirred at room temperature for 1 hour. 4-Chloro-8-nitrobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile, 578 mg (2.00 mmol), is added and the suspension is heated at 130° C. overnight. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is washed with water then dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration. The solid is suspended in diethyl ether and filtered. The filtrate is concentrated to a small volume and filtered to give 80 mg (29%) of 4-(2,4-dichloroanilino)-8-nitro[1]benzothieno[3,2-b]pyridine-3-carbonitrile as an off-white solid, mp 210-213° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:41]1[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 51476.3 %

Procedure:
Following general procedure II, (R)-tert-butyl 1-(5-(3-acetyl-6-chloro-1,5-naphthyridin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (200 mg, 0.40 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (165 mg, 0.60 mmol) to afford the desired product (125 g, 51%) as a yellow-orange solid. ESI MS m/z 607 [M+H]+
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][N:7]=1)#[N:2].CN(C=O)C.C1C(=O)N([Cl:31])C(=O)C1>C(Cl)(Cl)Cl>[Cl:31][C:6]1[N:7]=[C:3]([C:1]#[N:2])[NH:4][C:5]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C)c(-c2cnc(C#N)[nH]2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2[nH]c(C#N)nc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2-cyano-1H-imidazol-5-yl)-4-methylbenzoate (compound 234.3, 290 mg, 1.20 mmol) in a solvent mixture of DMF and CHCl3 (4/20 mL). NCS (161 mg, 1.21 mmol, 1.00 equiv) was added to the above reaction mixture. The reaction mixture was stirred overnight at room temperature, then was concentrated under reduced pressure. The residue was diluted with 30 mL of EtOAc, then was washed with 3×15 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/10-1/7) as eluent to furnish 160 mg (48%) of the title compound as light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24]C1C=CC(C(Cl)=NO)=CC=1>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]2[C@H:10]([C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:24][CH3:23])=[CH:18][CH:17]=3)=[N:12][O:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3ccc(Cl)cc3)[C@@H]2C1
Reactant: COc1ccc(C(Cl)=NO)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NO[C@H]3CN(C(=O)OC(C)(C)C)C[C@@H]23)cc1

Procedure:
The title compound was prepared in an analogous manner as the 4-chlorophenyl cycloadduct 3a using chloro oxime 2b. However, two additional portions of chloro oxime and triethyl amine were used. 3b was isolated as a white solid.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3]\[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([OH:15])[CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>N1C=CC=CC=1>[C:22]([O:15][C:8]1[CH:7]=[C:6]([O:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)c(O)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(OC/C=C(\C)CCC=C(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To 10 ml of a pyridine solution containing 0.82 g (2.82 mmol) of 4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzoic acid was added 0.72 g (7.1 mmol) of acetic anhydride, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into a 2% hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was recrystallized from an ethyl ether/hexane mixed solvent to obtain 0.45 g (yield: 48%) of 2-acetoxy-4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}benzoic acid represented by the following structural formula (hereinafter referred to as compound 45) as white crystals. The analytical results are shown below. ##STR66##
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[O-2].[Ca+2]>COCCOCCOC>[CH3:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:22]([CH:19]3[CH2:21][CH2:20]3)[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[NH:10][C:11]=12
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Agent: [Ca+2]
Agent: [O-2]
Solvent: COCCOCCOC
Product: Cc1ccnc2c1NC(=O)c1cccnc1N2C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The process according to claim 4, wherein 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide is heated with cyclopropylamine in the presence of 1 to 2 mol of calcium oxide in diglyme to 135° to 145° C. for 6 to 7 hours, the reaction mixture is then cooled down to 20° to 30° C. and filtered, the filter cake is washed with diglyme and the combined filtrates are concentrated, the residue is then diluted with diglyme and this solution is added to a solution or suspension of sodium hydride in diglyme, heated to 130° to 140° C., and the reaction mixture is kept at a temperature of 130° to 140° C. for 30 minutes to one hour and then the reaction medium is distilled off, the residue is hydrolysed at a temperature of 50° to 80° C. and then cooled to a temperature of about 25° C. and mixed with an inert solvent and an organic acid and the reaction mixture is stirred for about 1 hour at 10° to 25° C., the resultant suspension of the product is separated, washed with an inert solvent, followed by water and alcohol to give nevirapine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 3-(4-hydroxyphenyl)propionic acid (20.0 g, 0.12 mol) and benzyl bromide (21.5 mL, 0.18 mol) in 155 mL of THF is added, at ambient temperature to a 1N aqueous solution of soda (301 mL). The phase transfer catalyst, Bu4NHSO4 (155 mg, 0.45 mmol), is finally added. The reaction medium is stirred overnight before being heated for 1 h at 80° C. After cooling down, 150 mL of a 1N aqueous solution of HCl is added slowly. After extraction with CH2Cl2, the organic phases are dried over MgSO4, filtered and concentrated under vacuum. Purification is carried out on silica gel (CH2Cl2 up to CH2Cl2/MeOH 95:5) in order to produce compound 2 (30.4 g, 0.12 mol, 99%) in the form of a white solid.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]2[CH:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:16][C:13]2=[N:14][CH:15]=1>>[CH2:1]([N:16]1[C:13]2=[N:14][CH:15]=[C:10]([F:9])[CH:11]=[C:12]2[CH:18]=[C:17]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(F)cnc2[nH]1
Reactant: OCc1ccccc1
Product: CCOC(=O)c1cc2cc(F)cnc2n1Cc1ccccc1

Procedure:
The ethyl 1-benzyl-5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate was prepared according to a method similar to that described in Example 4.1, from benzyl alcohol and the ethyl 5-fluoro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate prepared in the preceding step.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[S:10](=O)[C:11]3[CH:16]=[N:15][CH:14]=[N:13][C:12]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:21])=O>CN(C=O)C.ClCCCl>[Cl:21][C:16]1[C:11]2[S:10][C:9]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=3[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=[N+]([O-])c1cccc2c1S(=O)c1cncnc1-2
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1sc1c(Cl)ncnc12
Temperature: 85 °C

Procedure:
Dry DMF (5 drops) was added to a mixture of 6-nitrobenzothieno[3,2-d]pyrimidone (161 mg, 0.65 mmol) and oxalyl chloride (0.28 mL, 3.2 mmol) in 1,2-dichloroethane (5 mL). The reaction was heated at 85° C. for 7.5 hours then cooled to 25° C. The solid was Buchner filtered and washed with CH2Cl2 and air dried. 4-Chloro-6-nitrobenzothieno[3,2-d]pyrimidine was obtained as a gray solid (166 mg, 96% crude).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:5][C:4]([CH3:22])=[N:3]1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][N:2]1[C:6]([NH:7][C:8]2[N:9]=[CH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:5][C:4]([CH3:22])=[N:3]1
Reactant: COC(=O)c1ccc2cnc(Nc3cc(C)nn3C)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc3cc(C(=O)O)ccc3cn2)n(C)n1

Procedure:
A slurry of 84 (350 mg, 1.181 mmol) and LiOH (62.2 mg, 2.60 mmol) in THF (5.75 mL) and water (0.85 mL) was stirred at RT for 24 h. The THF was removed on a rotary evaporator. The reaction mixture was suspended in water (6 mL) and treated with 10M HCl in water (0.71 mL, 7.1 mmol). A yellow-brown colored precipitate formed and was collected by filtration to afford 3-(1,3-dimethyl-1H-pyrazol-5-ylamino)isoquinoline-6-carboxylic acid (86) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:38])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:37]=[CH:36][C:26]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:5]1([C:45](=[O:58])[NH:46][CH2:47][CH2:48][C:49](=[O:57])[O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH2:4][CH2:3]2.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH:42]([C@H:39]1[C@@H:6]2[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4][C@@:5]2([C:45](=[O:58])[NH:46][CH2:47][CH2:48][C:49](=[O:57])[O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:55])[CH3:56])[CH2:41][CH2:40]1)[C@@:19]1([CH3:20])[C@@H:10]([C@:11]2([CH3:38])[C@@H:16]([CH2:17][CH2:18]1)[C:15]([CH3:21])([CH3:22])[C@@H:14]([C:23]1[CH:37]=[CH:36][C:26]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[O:28])=[CH:25][CH:24]=1)[CH2:13][CH2:12]2)[CH2:9][CH2:8]3)([CH3:44])[CH3:43]
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(trimethylsilyl)ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.018 mmol) was dissolved in a mixture of ethyl acetate and methanol (2 ml, 1:1) and treated with palladium (10% in carbon, 1 mg, 9.40 mmol) and a balloon with hydrogen. The mixture was stirred at rt for 3 h. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and filtered through a fine pad of celite. The solvent was removed in vacuo and the crude was purified in silica gel to afford 2-(trimethylsilyl)ethyl 4-((1S,3aS,5aR,5bR,7aS,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) (12 mg, 80%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J=8.28 Hz, 2H), 7.23 (d, J=8.53 Hz, 2H), 6.22 (t, J=6.15 Hz, 1H), 4.50-4.36 (m, 2H), 4.24-4.16 (m, 2H), 3.51 (td, J=11.48, 6.40 Hz, 2H), 2.59-2.49 (m, 2H), 2.40 (dd, J=12.92, 2.89 Hz, 2H), 2.35-2.24 (m, 1H), 2.18-2.04 (m, 1H), 2.03-1.95 (m, 1H), 1.89-0.91 (m, 26H), 0.99 (s, 3H), 0.96 (s, 6H), 0.88 (d, J=7.03 Hz, 3H), 0.77 (d, J=7.03 Hz, 3H), 0.76 (s, 3H), 0.70 (s, 3H), 0.09 (s, 9H), 0.06 (s, 9H).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[CH:28]1[O:30][CH2:29]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=2)[CH2:29][CH:28]([OH:30])[C:27]([F:32])([F:31])[F:26])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)C1CO1
Reactant: CC(C)Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Product: CC(C)Oc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Yield: 27.8 %

Procedure:
The N-(3-phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine (0.528 g, 1.59 mmol) product from EX-645B and 1,1,1-trifluoro-2,3-epoxypropane (0.506 g, 4.51 mmol) were heated to 90° C. in a sealed container for 2 d under an argon atmosphere. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (0-10% ethyl acetate) and fractions were pooled after TLC analysis to give 197 mg (28%) of the desired 3-[(3-phenoxyphenyl)[[3-(isopro-poxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as clear, colorless oil. HRMS calcd. for C25H26F3NO3: 446.1943 [M+H]+, found: 446.1936. 1H NMR (C6D6) δ6.9-7.1 (m, 6H), 6.84 (tt, 1H), 6.74 (s, 1H), 6.66 (dd, 1H), 6.61 (d. 1H), 6.56 (t, 1H), 6.41 (td, 2H), 4.33 (s, 2H), 4.17 (septet, 1H), 3.91 (br s, 1H), 3.56 (dd, 1H), 3.31 (m, 1H,), 2.8 (br s, 1H). 1.06 (s, 6H). 19F NMR (C6D6) δ−78.85 (d, 3F).
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: NNCc1ccccc1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(Cc2ccccc2)c1C

Procedure:
Similar to Example 1, equimolar amounts of benzylhydrazine dihydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. The resulting oil was determined to be the named product by 1H-NMR (CDCl3, ppm): 1.35 t (3H); 2.44 s (3H); 2.45 s (3H); 4.38 a (2H); 5.25 s (2H); 7.08 d (2H); 7.29 m (3H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]([CH:19]([C:25]([O:27]CC)=[O:26])[C:20]([O:22]CC)=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O.C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[CH:13]([CH:19]([C:20]([OH:22])=[O:21])[C:25]([OH:27])=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCC(c1ccc(OC)cc1OC)C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(c1ccc(OC)cc1OC)C(C(=O)O)C(=O)O
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A solution of 4.40 g (110 mmol) of sodium hydroxide in 14 ml of water was added to a solution of 8.37 g (22.0 mmol) of diethyl 2-[1-(2,4-dimethoxyphenyl)hexyl]malonate (prepared as described in Preparation 2) in 50 ml of ethanol, and the resulting mixture was heated under reflux for 2.5 hours. At the end of this time, the reaction mixture was allowed to cool to room temperature, after which it was freed from ethanol by evaporation under reduced pressure. The resulting residue was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give 6.57 g of the title compound as a foam-like substance.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[S-:17][C:18]#[N:19].[Na+].O>C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([S:17][C:18]#[N:19])[C:7]([Cl:10])=[CH:6][C:5]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCNc1cc(Cl)ccc1Cl
Reactant: N#C[S-]
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CSc1cc(Cl)c(NCCC(=O)O)cc1Cl
Reaction time: 1 h
Yield: 103 %

Procedure:
A solution of 6 ml (0.11 mole) of bromine in 20 ml of acetic acid was added dropwise over 20 min to a stirred mixture of 25 g (0.10 mole) of N-(2,5-dichloropheyl)-β-alanine, 20.5 g (0.25 mole) of sodium thiocyanate and 100 ml of acetic acid at 15°-20°. An additional 80 ml of acetic acid was added to facilitate stirring which was continued for 1 hr. The reaction mixture was poured into 600 ml of cold water. The yellow solid was collected by filtration, washed with water and dried in an oven at 100° for 2 hrs to give 30 g (100%) of N-(2,5-dichloro-4-thiocyanatophenyl)-β-alanine. Two recrystallizations from CH3NO2 gave an analytical sample, m.p. 133°-135°.