Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]C.C[O-].[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15]
Reactant: CCCCCCCCO
Reactant: COC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCCOC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Temperature: 80 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
Into a 200-ml four-necked flask, were charged 23.6 g of methyl (2-methyl-4-t-butyl-5-hydroxyphenyl)acetate, 13.0 g of octylalcohol and 0.5 g of sodium methoxide. The mixture was allowed to react at 120° C. for 2 hours, and then at 140° to 150° C. under a reduced pressure of 20 mmHg for 5 hours. During the course of this reaction, along with the progress of reaction 1.5 g of sodium methoxide was added in three equal portions. After completion of the reaction, the reaction mixture was cooled to 80° C., neutralized with glacial acetic acid, then dissolved in toluene, washed with water, dried over anhydrons sodium sulfate, and freed from the solvent under reduced pressure to obtain 29.4 g (88% yield) of viscous octyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[OH:17][NH3+:18].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:18][OH:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: [NH3+]O
Solvent: O
Solvent: CCO
Product: ON=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Yield: 42.8 %

Procedure:
106.8 g (0.44 mol) of 1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-1-ethanone are dissolved in 780 ml of ethanol, 48 g of hydroxylammonium nydrochloride are added and the mixture is heated under reflux for five hours. Thereafter, 1000 ml of water are added and the reaction mixture is filtered. 51 g (45% of theory) of 1-(2,4-dichlorophenyl)-1-oximino-2-(1,2,4-triazol-1-yl)-ethane of melting point 165°-170° C. are obtained. ##STR15##
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>C(#N)C.C(OCC)(=O)C>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[NH:9]1[C:10]2[C:6](=[C:5]([O:4][CH2:3][CH2:2][N:27]3[CH2:28][CH2:29][CH:24]([C:15]4[CH:16]=[CH:17][C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[CH:14]=4)[CH2:25][CH2:26]3)[CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: ClCCOc1cccc2[nH]ccc12
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc2cc(C3CCN(CCOc4cccc5[nH]ccc45)CC3)ccc2c1

Procedure:
A solution of 1-chloro-2-(4-indolyloxy)ethane, 4-(2-naphthyl)piperidine and 3 equivalents of potassium carbonate in acetonitrile was heated at reflux for 12 h. The mixture was cooled, diluted with ethyl acetate, and the organic layer was separated and washed with brine. The crude residue was purified by silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent). The resulting free base was dissolved in ethyl acetate and precipitated with one equivalent of oxalic acid in ethyl acetate, to give the title compound in 29% overall yield as a white solid. mp. 119°-120° C. FDMS m/e=370 (M+ of free base).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][OH:15].[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][O:15][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1
Reactant: OCc1cccs1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2cccs2)n1
Temperature: 0 °C
Reaction time: 4 h
Yield: 13.5 %

Procedure:
To 4 ml of N,N-dimethylformamide, 0.334 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 228 mg of 2-thiophenemethanol were dissolved, and added 0.084 g of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 0.5 hours and at room temperature for 4 hours. Then, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with tert-butylmethylether. The organic layer was concentrated, and the residue obtaind was subjected to silica gel column chromatography to obtain 66 mg of 5-(2-thienyl)methoxy-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][CH:11]([C:16]([CH3:18])=[CH2:17])[C:10]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28].[C:29](O)(=[O:31])[CH3:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][CH:11]([C:16]([CH3:18])=[CH2:17])[C:10]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28])(=[O:31])[CH3:30]
Reactant: CC(=O)O
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2N)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2NC(C)=O)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 19.6 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.1 mmol), acetic acid (9 mg, 0.15 mmol), EDCI.HCl (29 mg, 0.15 mmol), and HOBt (20 mg, 0.15 mmol) in acetonitrile (5 mL) was added DIPEA (0.052 mL, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep HPLC to give the title compound as a white solid (Yield: 9 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[C:20]([F:21])=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=3[F:22])[NH:6][CH:5]=2)[CH2:3][CH2:2]1.Cl[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:27]=[C:26]([NH2:34])[N:25]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][C:11]=3[O:13][C:14]3[C:15]([F:22])=[CH:16][C:17]([NH:18][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[N:27]=[C:26]([NH2:34])[N:25]=4)=[CH:19][C:20]=3[F:21])[NH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(F)c(Oc2ccnc3[nH]cc(C4CC4)c23)c(F)c1
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(Nc2cc(F)c(Oc3ccnc4[nH]cc(C5CC5)c34)c(F)c2)cc(C(F)(F)F)n1

Procedure:
330 mg (1.10 mmol) of 4-[(3-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluoroaniline and 320 mg (1.64 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 4 ml of water and 2 ml of ethanol. 0.55 ml (2.2 mmol) of 4N hydrochloric acid is added, and the mixture is heated at reflux for 1 h. Another 107 mg (0.55 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are then added, and the mixture is heated for a further 2 hours. The mixture is made alkaline by addition of 1N aqueous sodium hydroxide solution and extracted with ethyl acetate, and the organic phase is washed with water. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The product is purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:6][C:7]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:8]([C:10]([OH:12])=O)[N:9]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:51][C:52]1[N:57]=[C:56]([NH2:58])[CH:55]=[CH:54][CH:53]=1>CN(C)C=O>[CH3:51][C:52]1[N:57]=[C:56]([NH:58][C:10]([C:8]2[N:9]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6][C:7]=2[NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:55]=[CH:54][CH:53]=1
Reactant: COCCc1nc(C(=O)O)c(Nc2cccnc2)s1
Reactant: Cc1cccc(N)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCc1nc(C(=O)Nc2cccc(C)n2)c(Nc2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A solution of 2-(2-methoxy-ethyl)-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (0.032 g, 0.11 mmol) in dimethylformamide (1.00 ml) was treated with DIPEA (0.042 g, 0.33 mmol), TBTU (0.053 g, 0.16 mmol) and 6-methyl-pyridin-2-yl-amine (0.018 g, 0.16 mmol). The mixture was stirred at room temperature overnight, then purified by direct injection in preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid). The tide compound (0.011 g, 27%) was obtained as a white solid, MS (ISP): m/e=370.1 (M+H+).
Reaction SMILES: C[Al](C)C.[CH3:5][C@H:6]1[NH:11][C@@H:10]([CH3:12])[CH2:9][N:8]([C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=O)=[CH:15][CH:14]=2)[CH2:7]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH:41][C:17](=[O:19])[C:16]3[CH:15]=[CH:14][C:13]([N:8]4[CH2:9][C@H:10]([CH3:12])[NH:11][C@H:6]([CH3:5])[CH2:7]4)=[CH:23][CH:22]=3)[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4C[C@@H](C)N[C@@H](C)C4)cc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 41.1 %

Procedure:
A 2M solution of trimethylaluminium in toluene (1.875 mL, 3.75 mmol) was added dropwise to a stirred suspension of ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (0.394 g, 1.50 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (0.374 g, 1.5 mmol) in toluene (10 mL) at 20° C., over a period of 5 mins under nitrogen. The resulting solution was stirred at 60° C. for 5 h. The reaction mixture was cooled and the reaction quenched by diluting with acetone (100 ml) and excess damp sodium sulphite added in portions. This was stirred for 60 mins. The resulting solid filtered off, washed with 10% methanol in DCM. The filtrate was evaporated to give crude product. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% 2M ammonia/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (0.287 g, 41.1%) as a white solid. 1H NMR (500.13 MHz, DMSO-d6) δ 1.08 (6H, d), 2.31 (2H, t), 3.70-3.73 (2H, m), 3.78 (6H, s), 5.10 (2H, s), 5.64 (1H, s), 6.46 (1H, t), 6.62 (2H, d), 6.95-6.97 (2H, m), 7.83-7.85 (2H, m), 10.21 (1H, s), 11.09 (1H, s). MS: m/z 466 (MH+).
Reaction SMILES: Cl[C:2]([N:4]=[C:5]=[O:6])=[O:3].[Cl:7][C:8]1[CH:28]=[CH:27][C:11]2[N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[S:14][C:10]=2[CH:9]=1>O1CCOCC1>[Cl:7][C:8]1[CH:28]=[CH:27][C:11]2[N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[C:2](=[O:3])[NH:4][C:5](=[O:6])[N:25]([CH3:26])[C:23]4=[O:24])=[CH:18][CH:17]=3)[S:14][C:10]=2[CH:9]=1
Reactant: CNC(=O)Nc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1
Reactant: O=C=NC(=O)Cl
Solvent: C1COCCO1
Product: Cn1c(=O)[nH]c(=O)n(-c2ccc(Oc3nc4ccc(Cl)cc4s3)cc2)c1=O
Yield: 72.5 %

Procedure:
Chlorocarbonyl isocyanate (0.8 g) was added to a suspension of N-[4-(6-chlorobenzothiazol-2-yloxy)phenyl]-N'-methylurea (2.4 g) in 1,4-dioxane (50 ml), and the mixture was heated at the boiling point for 5 hours. The mixture was evaporated under reduced pressure and the residue was dissolved in a minimal volume of boiling 1,4-dioxane. After addition of ethanol (50 ml), the clear solution was cooled in a refrigerator. The resulting solid substance was collected by filtration, washed with cold ethanol and dried to give 2.1 g of 1-[4-(6-chlorobenzothiazol-2-yloxy)phenyl]-3-methyl-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione of melting point 270°-271° C. Preparation of N-[4-(6-chlorobenzothiazol-2-yloxy)phenyl]-N'-methylurea: ##STR15##
Reaction SMILES: Br[CH2:2][C:3]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:4]([NH:12][CH:13]=[S:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[C:8]([O:7][C:5]([C@@H:4]1[C@@:3]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH2:2][S:14][CH:13]=[N:12]1)=[O:6])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)C(NC=S)C(O)(CBr)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H]1N=CSC[C@]1(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of 3.67 gms of (2R,3S) and 2S,3R)-t-butyl 4-bromo-3-hydroxy-2-thioformamido-3-trifluoromethylbutyrate in 65 ml acetone was added 4.15 g powdered anhydrous potassium carbonate. The reaction mixture was stirred for 30 minutes at room temperature, filtered and evaporated to dryness under reduced pressure. The crude brown oil was then purified by chromatography on silica gel using 80:20 hexane:ethyl acetate as the eluting, solvent to give 0.781 gms of white solid, (4R,5S) and (4S,5R)-t-butyl-5-hydroxy-5-trifluoromethyl-4,5-dihydro-6H-1,3-thiazine-4-carboxylate (yield 27%) m.p. 126.5°-127.5° C.
Reaction SMILES: Cl[C:2]1[C:18]([Cl:19])=[C:17]([OH:20])[CH:16]=[CH:15][C:3]=1[C:4](=[N:13][OH:14])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].O>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:20][C:17]1[CH:16]=[CH:15][C:3]2[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=3[CH3:12])=[N:13][O:14][C:2]=2[C:18]=1[Cl:19])[CH3:29]
Reactant: Cc1cccc(C(=NO)c2ccc(O)c(Cl)c2Cl)c1C
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc2c(-c3cccc(C)c3C)noc2c1Cl
Temperature: 130 °C
Reaction time: 7 h

Procedure:
To a solution of 5 g of 2,3-dichloro-4-hydroxy-2',3'-dimethylbenzophenone oxime in 70 ml of DMF, 0.96 g of NaH is added. The internal temperature is held between 95°-120° C. for seven hours, then the mixture is heated at 130° C. for 1.5 hours. The reaction mixture is cooled and 2.94 g of ethyl bromoacetate is added dropwise. The mixture is stirred one hour and water is added dropwise. The product which forms is filtered off and recrystallized from 95% ethanol to yield ethyl-{[7-chloro-3-(2,3-dimethylphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 89°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[NH:36][C:37]([NH:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[F:47])=[O:38])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([C:26]([O:28]C(C)(C)C)=[O:27])[CH2:22]3)=[O:16])[S:14][C:7]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[NH:36][C:37]([NH:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[F:47])=[O:38])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[CH:12]=[C:13]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=[O:27])[CH2:22]3)=[O:16])[S:14][C:7]=12
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN5CCC(C(=O)OC(C)(C)C)C5)sc34)cc2F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN5CCC(C(=O)O)C5)sc34)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylate (40 mg, 0.060 mmol) in 5 ml of methylene chloride was added 2 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 2 hours, and evaporated to dryness under reduced pressure. 5 ml of water was added to the residue, and the mixture was neutralized to pH=7 with saturated NaHCO3 solution with vigorous stirring. The precipitates were filtered, washed with 5 ml of water, and dried in vacuo to give 1-{3-[({7-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}pyrrolidine-3-carboxylic acid as light brown solid. Yield: 37 mg, 100%.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[O:87]=[C:88]([NH:92][C:93]1[S:94][CH:95]=[CH:96][N:97]=1)[C:89](O)=[O:90]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:89](=[O:90])[C:88](=[O:87])[NH:92][C:93]1[S:94][CH:95]=[CH:96][N:97]=1)[CH2:19][CH2:18]2
Reactant: O=C(O)C(=O)Nc1nccs1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)C(=O)Nc3nccs3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 23 %

Procedure:
The title compound was prepared in 23% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-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 following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-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)benzoic acid, except 2-oxo-2-(thiazol-2-ylamino)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 684.5 (M+H)+, 2.04 min (method 9). 1H NMR (500 MHz, 1:1 MeOD:CDCl3) δ=7.92 (d, J=8.5 Hz, 2H), 7.54 (d, J=3.7 Hz, 1H), 7.49 (s, 1H), 7.22-7.19 (m, 3H), 5.30 (dd, J=1.8, 6.1 Hz, 1H), 4.79 (d, J=1.2 Hz, 1H), 2.65-2.55 (m, 2H), 2.53-2.46 (m, 1H), 2.14 (dd, J=6.4, 17.1 Hz, 1H), 1.98-1.89 (m, 1H), 1.88-1.76 (m, 3H), 1.73 (s, 3H), 1.70 (s, 1H), 1.61-1.36 (m, 11H), 1.29-1.22 (m, 1H), 1.21-1.14 (m, 2H), 1.09 (s, 3H), 1.06 (s, 3H), 1.02 (s, 3H), 0.95-0.94 (m, 3H), 0.93 (s, 3H).
Reaction SMILES: ClC(OC)=O.C(N(CC)CC)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[C:29]([OH:31])=[O:30])=O)=[C:16]([F:32])[CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]2[C:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=3[C:29](=[O:31])[O:30]2)=[C:16]([F:32])[CH:15]=1
Reactant: O=C(O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OC(=Nc2ccc(Cl)cc2F)C2=C1CCCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.59 Parts of methyl chloroformate was added dropwise during 15 minutes to a stirred solution of 1.87 parts of triethylamine and 5 parts of 2-(4-chloro-2-fluorophenylaminocarbonyl)-1-cyclohexene-1-carboxylic acid in 200 parts of methylene chloride cooled to 0° C. The reaction mixture was allowed to come to ambient temperature during 1 hour after which it was washed successively with 100 parts of water (twice) and 100 parts of a saturated aqueous sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was evaporated under reduced pressure of 300 mm. Hg at 25° C to 5.6 parts of a yellow semisolid. Analysis of the semisolid by high pressure liquid chromatography indicates the presence of 3-(4-chloro-2-fluorophenylimino)-4,5,6,7-tetrahydro-1-(3H)-isobenzofuranone in 51% concentration.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.BrC1C=CC2C(=CC=CC=2)C=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:15]=1
Reactant: c1csc(-c2cccc3ccccc23)c1
Agent: Brc1ccc2ccccc2c1
Product: c1csc(-c2ccc3ccccc3c2)c1

Procedure:
The 2-(2-thienyl)-naphthalene was prepared in the same manner as for the 1-thienyl-naphthalene derivative, with the Grignard being added to 2-bromonaphthalene (2.07 g, 0.01 m). After workup, a brown solid (2.39 g) was isolated. Column chromatography yielded 2-bromonaphthalene (630 mg) and a white crystalline solid (1.13 g, 73% yield based on recovered starting material); m.p. 103°-104° C.; m/z 210 (M+); (Found: C, 79.75; H, 4,80; S, 15.09. C14H10S requires C, 80.0; H, 4.76; S, 15.24.); H NMR (CDCl3); δ7.17 (dd, J=5.6, 3.5 Hz, 1H), δ7.30 (dd, J=<1, 5.6 Hz, 1H), δ7.42 (dd, J=<1, 5 Hz 1H), δ7.45 (dd, J=<1, 7 Hz, 1H), δ7.46 (dd, J=1, 4.0 Hz, 1H), δ 7.73 (dd, J=1, 8.0 Hz, 1H), δ7.79 (dd, J=1, 8 Hz, 1H), δ7.81 (s, 1H), δ7.83 (s, 1H), δ5.803 (d, <1, Hz, 1H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][OH:9].[C:10](OC)(=[O:14])[C:11]([CH3:13])=[CH2:12].C1(C=CC(O)=CC=1)O.C[O-].[Na+]>CN(C)C=O.O>[C:10]([O:9][CH2:8][CH:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)OC
Reactant: OCC1CC2C=CC1C2
Agent: C[O-]
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)OCC1CC2C=CC1C2

Procedure:
5-norbornen-2-ylmethyl methacrylate monomer was prepared in a flask fitted with a vertical condenser with water at 75° C circulating through the jacket, attached at the top to a downwards cold water-cooled condenser. There were refluxed for 2 hours 372 grams (3.0 moles) of 5-norbornen -2-methanol, 450 grams (4.5 moles) of methyl methacrylate, 526 grams of N,N-dimethylformamide, 28.8 grams of hydroquinone, and 8.1 grams (0.15 mole) of sodium methoxide. A total of 252 ml of distillate was collected (theoretical methanol equals 121 ml.). The flask contents were cooled, diluted with ether, and washed with water, excess dilute hydrochloric acid, water, 5% aqueous sodium hydroxide until the washes were colorless, and again with water. The ether solution was dried with anhydrous sodium sulfate, 11.5 grams of p-(p-tolylsulfonyl-amido) diphenylamine were added, and the ether was removed in a rotary evaporator at 60° C and about 15 mm pressure. To the residual oil 0.58 gram of hydroquinone was added and the product was distilled through a Vigreux column to give 431 grams of product having a boiling point of 770 C/1.4 mm, nD20 = 1.4848. The monomer was then passed through a column of activated sodium aluminum silicate.