Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[S:16].[C:17](=O)([O:20]C)[O:18][CH3:19].[H-].[Na+].[CH3:25]O>O1CCOCC1>[CH3:19][O:18][C:17]([C:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[Cl:1])[C:11]=1[S:16][CH3:25])=[O:20]
Reactant: COC(=O)OC
Reactant: Cc1cc(C)c(N2CCCCC2=S)c(Cl)c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)C1=C(SC)N(c2c(C)cc(C)cc2Cl)CCC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
1-(2-Chloro-4,6-dimethylphenyl)piperidine-2-thione (5.11 g), dimethyl carbonate (17.0 mL), sodium hydride (3.7 g of a 60% dispersion in mineral oil), and methanol (0.5 mL) were combined in 100 mL of dioxane and the mixture was stirred in a 120° C. oil bath for 4 h. After the reaction had cooled to room temperature, it was quenched by the addition of aqueous ammonium chloride, diluted with water and washed twice with ethyl acetate. After drying over magnesium sulfate, the ethyl acetate was concentrated and the residue chromatographed on silica gel using an acetone/hexane gradient to provide 5.00 g 1-(2-chloro-4,6-dimethylphenyl)-2-methylsulfanyl-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl ester, mp 85.3-87.6° C.
Reaction SMILES: Cl.[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1)(=[O:6])=[O:5])[CH3:3].C(N(CC)CC)C.[CH2:31]1[O:34][C@H:32]1[CH3:33].O>CO>[CH2:2]([S:4]([CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:31][C@@H:32]([OH:34])[CH3:33])(=[O:6])=[O:5])[CH3:3]
Reactant: C[C@H]1CO1
Reactant: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3C[C@H](C)O)c2c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
To a stirred solution of 5-(2-ethylsulphonylethyl)-3-(2(R)-pyrrolidinylmethyl)-1H-indole hydrochloride (Preparation 5; 200 mg, 0.56 mmol) in methanol (2 ml) at room temperature under nitrogen was added triethylamine (0.09 ml). After 10 minutes, (S)-(-)-propylene oxide (0.05 ml, 0.71 mmol) and then water (12 ml) were added and the reaction mixture was warmed at 50° C. for 18 hours. The cool reaction mixture was evaporated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed with water, dried (Na2SO4) and evaporated under reduced pressure to give an oil. Purification by column chromatography on silica gel, eluting with a gradient of ethanol in dichloromethane (0 to 10% ethanol), afforded the title compound as a gum (48 mg). Rf 0.50 (SS 4). [α]D25 +58° (c=0.1, CH3OH). Found: C,57.44; H,7.58; N,6.39. C20H30N2O3S; 0.50 H2O; 0.50 CH2Cl2 requires C,57.26; H,7.50; N,6.52%. δ(CDCl3): 1.15(3H,d), 1.38(3H,t), 1.50-1.90(4H,m), 2.20-2.38(2H,m), 2.60-2.75(2H,m), 2.85-2.95(3H,m), 3.10(1H,m), 3.20-3.38(5H,m), 3.60-3.90(2H,m), 5.30(1H,s,CH2Cl2), 7.02(1H,d), 7.05(1H,s), 7.32(1H,d), 7.40(1H,s), 8.10(1H,br s).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C(O)(=O)C.Cl>C(O)(C)C.CC(C)=O>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[CH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nccc2ccccc12
Reactant: O=Cc1cccc(F)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: Fc1cccc(C=Cc2nccc3ccccc23)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of 6.44 g (0.045 mole) of 1-methylisoquinoline, 6.2 g (0.05 mole) of 3-fluorobenzaldehyde and 18 ml of acetic acid is stirred at a temperature between 130° C. and 140° C. for 3 hours. The termination of the reaction is controlled by thin layer chromatography. The reaction mixture is cooled and 100 ml of anhydrous acetone are added to it. Then it is acidified with a mixture of hydrogen chloride and isopropanol until pH=1 under stirring and cooling with ice-water. The suspension is stirred at a temperature between 0° C. and 5° C. for 2 hours. The separated hydrogen chloride salt is filtered, washed with cold acetone and dissolved in 180 ml of water. To the thus-obtained mixture 20% sodium hydroxide solution is dropped until pH=11-12 under stirring and cooling with ice-water, and the solution is extracted three times with 75 ml each of dichloromethane. The extracts are combined, washed with an aqueous sodium chloride solution, dried over Na2SO4 and evaporated. The crude product is recrystallized from 30 ml of isopropanol. Thus 8.7 g (78%) of 1-(3-fluorostyryl)-isoquinoline are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[N:30]=2)[CH:22]=1.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:25]1[C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][C:23]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: Cc1noc(-c2cc(Cl)ccc2C=O)n1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1noc(-c2cc(Cl)ccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.6 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (11 mg, 0.043 mmol) and 4-chloro-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (10 mg, 0.045 mmol) in DMF (5.0 mL) is added Oxone (27 mg, 0.044 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1.5 hours and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (10 mg, 50%) as a white solid. LCMS (ESMS): m/z 460.20 (M++1)
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[Sn:26](Cl)([CH2:35][CH2:36][CH2:37][CH3:38])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30]>C1COCC1.CCCCCC>[CH2:35]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)[CH2:36][CH2:37][CH3:38]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)nc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
Into the solution of tert-butyl 4-(6-bromopyridin-3-yl)piperazine-1-carboxylate 7.13 (1.65 g, 4.8 mmol) in THF (30 mL) was added 1M solution of n-BuLi in hexane (5 mL) and n-Bu3SnCl (1.66 g, 5.1 mmol) at −70° C. After 30 min., the reaction was warmed up to rt. After stirring for 1 h., the reaction mixture was extracted with ethyl acetate and washed with brine. After drying with MgSO4, the organic solvent was removed under vaco., the residue was purified by silica gel chromatography to obtain 0.58 g of tert-butyl 4-(6-(tributylstannyl)pyridin-3-yl)piperazine-1-carboxylate 7.14. LCMS [M+H]+: 554.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:10]=3[O:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[O:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:18])=[CH:16][C:10]=3[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc2c(c1)OC(c1cccc(Cl)c1)(c1cccc(Cl)c1)O2
Product: O=C(c1ccc2c(c1)OC(c1cccc(Cl)c1)(c1cccc(Cl)c1)O2)N1CCCCC1

Procedure:
This compound was prepared from 2,2-bis-(3-chloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and piperidine according to Example 269f; light yellow solid, mp.: 54° C.,
Reaction SMILES: C1(C)C=CC=CC=1.[OH-].[Na+].[C:10]([C:14]1[CH:15]=[C:16]([CH:37]=[C:38]([C:41]([CH3:44])([CH3:43])[CH3:42])[C:39]=1[OH:40])[C:17]([O:19][C:20]1[C:28]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][C:23]([C:24]([O-:26])=[O:25])=[CH:22][C:21]=1[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:18])([CH3:13])([CH3:12])[CH3:11].[Na+].Cl>CCOCC>[C:41]([C:38]1[CH:37]=[C:16]([CH:15]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:39]=1[OH:40])[C:17]([O:19][C:20]1[C:21]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][C:28]=1[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:18])([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)[O-])cc2C(C)(C)C)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)O)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Temperature: 30 °C

Procedure:
To the toluene filtrate were added at room temperature 450 ml of 2N sodium hydroxide and the reaction mixture was gradually heated to reflux to minimize initial foaming. The reaction was heated at reflux for 41/2 hours. The reaction mixture was cooled to 0° to 5° C. by an ice-water bath whereupon a thick precipitate formed, consisting of the intermediate sodium 4-(3,5-di-tert-butyl-4-hydroxybenzoyloxy)-3,5-di-tert-butyl-benzoate. This compound was a white solid which did not melt at 300° C. 70 ml of concentrated aqueous hydrochloric acid was gradually added dropwise with cooling at 30° C. 150 ml of ether were added with stirring to the reaction mixture at 20° to 25° C. The aqueous phase was separated and the organic phase washed with two 100 ml portions of water. The separated organic phase was then dried over anhydrous sodium sulfate. The residue was isolated from the organic phase by evaporation of the solvent initially at about 20 mm. Hg. pressure and finally at 0.5 mm. Hg. The glassy residue was ground and then triturated with stirring at reflux with a 150 ml. portion of petroleum ether in a 3-neck flask. The slurry was then cooled to room temperature, the solid isolated by filtration and triturated once again. The white crystalline precipitate from the second trituration was dried in the vacuum oven overnight at 40° C. at 1 mm. Hg. pressure. The product was isolated as a white powder weighing 102 grams (84.5% yield). The product melted at about 301° to 306° C., the melting range depending on the heating rate.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:12]N1C(=O)C2=CC=CC=C2C1=O.[C:24]([OH:27])(=O)[CH3:25]>>[C:3]12([OH:12])[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][C:1]([OH:11])([CH2:10]3)[CH2:2]1)[CH2:9]2.[C:24]12([OH:27])[CH2:25][C:1]3([OH:11])[CH2:8][CH:7]([CH2:9][C:3]([OH:12])([CH2:2]3)[CH2:4]1)[CH2:6]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1O
Product: OC12CC3CC(C1)CC(O)(C3)C2
Product: OC12CC3CC(O)(C1)CC(O)(C3)C2
Yield: 53 %
Yield: 26 %

Procedure:
To 25 milliliters of acetic acid were added 1.52 grams (10 millimoles) of 1-adamantanol, 0.13 gram (0.8 millimole) of N-hydroxyphthalimide and 0.015 gram (0.06 millimole) of Co(AA)2, and the resultant mixture was stirred under an oxygen atmosphere at a temperature of 75° C. for three hours. As a result, 1-adamantanol was transformed, with a transformation rate of 80%, into 1,3-adamantanediol (selectivity for 1-adamantanol 66%, yield 53%) and 1,3,5-adamantanetriol (selectivity for 1-adamantanol 33%, yield 26%), with a selectivity for the alcohols of 99%.
Reaction SMILES: [C:1]([C:3]1([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH2:8][CH2:7][N:6]([CH2:9][C:10]([NH2:12])=[O:11])[CH2:5][CH2:4]1)#[N:2]>[Pt].CO.C(Cl)Cl>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:3]2([C:1]#[N:2])[CH2:4][CH2:5][N:6]([CH2:9][C:10]([NH2:12])=[O:11])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCN(CC(N)=O)CC1
Agent: [Pt]
Solvent: ClCCl
Solvent: CO
Product: N#CC1(c2ccc(N)cc2)CCN(CC(N)=O)CC1
Yield: 98.9 %

Procedure:
2-[4-Cyano-4-(4-nitro-phenyl)-piperidin-1-yl]-acetamide (0.644 g, 2.23 mmol) was shaken over 5% Platinum on Carbon, Sulfided (0.5%) (94 mg, 0.024 mmol) in Methanol (10.0 mL) under an atmosphere of Hydrogen (40 psi) for 5 h. The precipitate was solubilized in DCM and then filtered to remove catalyst, washing with DCM. Conc. in vacuo to give 2-[4-(4-Amino-phenyl)-4-cyano-piperidin-1-yl]-acetamide (0.570 g; Yield=98.8) as an off white solid. 1H-NMR (DMSO-d6): 7.29 (s, 1H), 7.14 (m, 3H), 6.58 (d, 2H, J=8.4 Hz), 5.17 (s, 2H), 3.17 (d, 1H, J=5.2 Hz), 2.92 (s, 2H), 2.90 (m, 2H), 2.39 (m, 2H), 2.00 (m, 4H).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl>[Cl:24][CH2:2][C:3]1[N:4]=[C:5]([S:8][CH2:9][CH2:10][C:11]([F:15])=[C:12]([F:14])[F:13])[O:6][CH:7]=1
Reactant: OCc1coc(SCCC(F)=C(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: FC(F)=C(F)CCSc1nc(CCl)co1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
6.8 g of 4-hydroxymethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole and 2.5 g of pyridine were dissolved in 30 ml of chloroform, to which a solution of 5.0 g of thionyl chloride in 10 ml of chloroform was added dropwise at 0° C. After the addition the mixture was refluxed for 10 hours. After cooling to room temperature, the solvent was distilled under reduced pressure. The residue was purified by column chromatography (eluent: hexane:dichloromethane=2:1) to obtain 5.7 g of 4-chloromethyl-2-(3,4,4-trifluoro-3-butenylthio)oxazole as colorless oil (yield 77.8%). n20D=1.4933.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][C@H:7]2[N:9]([CH3:10])[C@H:4]([CH2:5][CH2:6]2)[CH2:3]1.[C:11](OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:11][C:2]1([NH2:1])[CH2:3][CH:4]2[N:9]([CH3:10])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1.[CH3:10][N:9]1[CH:7]2[CH2:8][CH:2]([NH2:1])[CH2:3][CH:4]1[CH2:11][CH2:5][CH2:6]2
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CN1[C@@H]2CC[C@H]1CC(N)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN1C2CCC1CC(C)(N)C2
Product: CN1C2CCCC1CC(N)C2

Procedure:
Bicycloamines that can be used in the preparation of the bicyclobase amides are commercially available, can be prepared by known procedures described in the literature, or as described below. For example, 2-Methyl-2-azabicyclo[2.2.2]octan-5-amine was obtained by the reduction of the 2-Boc-2-azabicyclo[2.2.2]octan-5-amine (J. Med. Chem. 1973, 16, 853; Synthesis 1979, 50; WO97/40016). 2-Methyl-2-azabicyclo[2.2.1]heptan-5-amine (Tetrahedron 1998, 54, 8047-8054; J. Med. Chem. 1992, 35, 2184-2191), octahydroindolizin-6-amine (U.S. Pat. No. 4,213,983), 2-azabicyclo[2.2.1]heptan-5-amine (J. Med. Chem. 1990, 33, 1924), 8-azabicyclo[3.2.1]octan-3-amine (WO38680A1; J. Med. Chem., 1993, 36, 3707; J. Med. Chem. 2001, 44, 1815), and 9-azabicyclo[3.3.1]nonan-3-amine (WO38680A1; J. Med. Chem. 1993, 36, 3707; J. Med. Chem. 2001, 44, 1815) were prepared according to literature procedures. 8-Methyl-8-azabicyclo[3.2.1]octan-3-amine was obtained from commercial sources as a variable mixture of endo- and exo-isomers whereas pure exo- and pure endo-isomers were prepared according to the literature (J. Med. Chem. 1998, 41, 988). 3,8-Dimethyl-8-azabicyclo[3.2.1]octan-3-amine was prepared from 3-aminotropane by exposure to di-tert-butyl dicarbonate followed by lithium aluminum hydride reduction. endo-9-Methyl-9-azabicyclo[3.3.1]nonan-3-amine was obtained by the acid hydrolysis of granisetron exo-9-Methyl-9-azabicyclo[3.3.1]nonan-3-amine and a mixture of endo- and exo-9-Methyl-9-azabicyclo[3.3.1]nonan-3-amine may be obtained according to the procedures set forth in European Patent Application No. 0 013 138 A1. 8-Methyl-3,8-diazabicyclo[3.2.1]octane and 3-methyl-3,8-diazabicyclo[3.2.1]octane were prepared from the commercially available 8-Boc protected base by lithium aluminum hydride reduction and reductive alkylation followed by deprotection, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][OH:38])[CH2:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][OH:38])[CH2:32][CH2:31]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCC(CCO)CC3)ccc21
Yield: 110.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-piperidineethanol (94 mg, 0.73 mmol), acetic acid (0.168 mL, 2.93 mmol) and sodium triacetoxyborohydride (54 mg, 0.26 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and ethyl acetate, followed by extracting with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperidinomethyl]indol-2-yl}isoindolinone (42.2 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[N:13]1C=CC=CC=1>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:13])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: c1ccncc1
Product: NC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The free amine obtained from the BOC deprotection step was dissolved in pyridine and nitrobenzoyl chloride (1.2 equiv.) was added to this solution. After stirring for 2 h at 90° C., the reaction mixture was concentrated and the resulting crude product was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[O:10][N:9]=1.C(C1[O:20][CH2:19]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:1]1[C:7]2[C:2]1=[C:3]([C:8]1[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[O:10][N:9]=1)[CH:4]=[CH:5][C:6]=2[O:20][CH3:19]
Reactant: BrCC1CO1
Reactant: Oc1ccccc1-c1noc2ccsc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2noc3ccsc23)c2c1O2
Temperature: 25 °C
Reaction time: 28 h
Yield: 73.4 %

Procedure:
A mixture of 6.3 g of 3-(2-hydroxyphenyl)thieno[2,3-d]isoxazole, 5 g of epibromohydrin and 2.6 g of potassium carbonate in 37 ml of acetonitrile was stirred under nitrogen at 70°-80° C. until completion of the reaction. The reaction was complete after 28 hours and the mixture was left to cool to room temperature. Quenching with water, extraction with ether/ethyl acetate (1:1), washing and drying (over anhydrous magnesium sulfate) gave 6.34 g of a crude oil. The epoxide was separated by high performance liquid chromatography (HPLC hereafter) using ethyl acetate/hexane (2:1) as an eluent, yielding 5.22 g of crystal. This was recrystallized from ether/hexane, m.p. 65°-67° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[O:23][CH3:24])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([OH:35])=[O:34].C[O-].[Na+:38]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:32])[NH:20][CH2:21][CH:22]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[O:23][CH3:24])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:33]([O-:35])=[O:34].[Na+:38]
Reactant: COC(CNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(CNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a solution of 6-chloro-7-(4-(2-(4-chlorophenyl)-2-methoxyethylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.056 g, 0.108 mmol) in methanol (2 ml) was added 0.5M sodium methanolate in methanol (0.228 ml, 0.114 mmol), and the reaction was stirred for 16 hours. The reaction was concentrated, and the residue was taken up in dichloromethane and hexanes, and concentrated to yield 56 mg of the title compound (95.9% yield). MS (apci) m/z=515.8 (M−Na+2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([C:11]([NH:16][CH3:17])=[CH:12][N+:13]([O-:15])=[O:14])[CH3:10])=[CH:4][CH:3]=1.[CH2:18]=O.[CH3:20][NH:21][CH3:22]>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([C:11]([NH:16][CH3:17])=[C:12]([N+:13]([O-:15])=[O:14])[CH2:20][N:21]([CH3:18])[CH3:22])[CH3:10])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: C=O
Reactant: CNC(=C[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Solvent: CC#N
Product: CNC(=C(CN(C)C)[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 102.8 %

Procedure:
A mixture of 1-[N-(6-chloro-3-pyridylmethyl)-N-methylamino]-1-methylamino-2-nitroethylene(0.39 g), 37% aqueous solution of formaldehyde (0.16 g), 50% aqueous solution of dimethylamine (0.18 g) and acetonitrile (3 ml) was stirred at room temperature for 8.5 hours. The reaction mixture was concentrated to give 1-[N-(6-chloro-3-pyridylmethyl)-N-methylamino]-3-dimethylamino-1-methylamino-2-nitro-propene (Compound No. 1) (0.49 g) as a syrupy liquid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:5][C:4]([C:17]([F:20])([F:19])[F:18])=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:8]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:5]=2)=[O:16])[CH:43]=[CH:44][CH:45]=1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(C(F)(F)F)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 15 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 164B (0.114 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.033 g, 15%). 1H NMR (300 MHz, CDCl3) δ 9.5 (br, 1H), 8.63 (s, 1H), 7.60 (m, 1H), 7.55 (s, 1H), 7.32-7.43 (m, 4H), 7.00 (dd, 1H), 6.31 (s, 1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.91 (s and t, 5H), 3.50 (s, 3H); LC-MS (ESI) m/z 533 (M+H)+.