Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16](F)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][NH2:23]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:23][CH3:22])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:20]#[N:21])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1cccc(Br)c1
Reactant: CN
Solvent: CCO
Product: CNc1cc2c(Nc3cccc(Br)c3)c(C#N)cnc2cn1
Temperature: 90 °C

Procedure:
To 500 mg of 4-(3-bromo-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 15 mL of absolute ethanol was added 4 mL of 40% aqueous methyl amine. The sealed reaction was heated at 90° C. for 24 hours, stripped of solvents, and purified by flash chromatography on silica gel with a gradient of 0-1% methanol/chloroform followed by purification by preparative thin-layer chromatography with 5% methanol/chloroform to yield 86 mg of 4-(3-bromo-phenylamino)-6-methylamino-[1.7]naphthyridine-3-carbonitrile as an amorphous solid: melting point 250° C. (decomposed); mass spectrum (m/e): M+H 354.1, 356.1.
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:35]([CH3:37])[CH3:36])[C:24](=[O:34])[C:25]([F:33])([F:32])[C:26](=[O:31])[NH:27][CH2:28][CH2:29][CH3:30])=[O:21])[C:15]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl.C1(OC)C=CC=CC=1>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:35]([CH3:37])[CH3:36])[C:24](=[O:34])[C:25]([F:33])([F:32])[C:26](=[O:31])[NH:27][CH2:28][CH2:29][CH3:30])=[O:21])[C:15]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[N:14][CH:13]=1
Reactant: CCCNC(=O)C(F)(F)C(=O)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CCCNC(=O)C(F)(F)C(=O)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A suspension of the product from Example 1 (0.29 g) in dichloromethane (4 mL) and anisole (0.17 mL) was cooled in an ice-water bath. Trifluoromethanesulfonic acid (0.23 mL) was added to the mixture dropwise. The dark colored, gummy reaction mixture was allowed to warm to room temperature. After 30 minutes, the reaction mixture was cooled in an ice-water bath and was quenched with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate and the extracts were washed (saturated sodium bicarbonate, brine), dried, and evaporated. The crude product was purified by trituration with ether to yield the title compound as a white solid (0.16 g); TLC: Rf =0.19, methanol:dichloromethane (5:95); NMR: 0.75 (d,3), 0.82 (t,3), 0.86 (d,3), 1.40-1.50 (m,2), 2.20-2.30 (m,1), 3.08 (q,2), 4.50 (q,2), 4.82 (dd,1), 5.17 (broad s, 2); MS: m/z=464 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([N:17]=[C:18]=[S:19])=[O:16]>CCOCC>[NH2:6][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:18](=[S:19])[NH:17][C:15](=[O:16])[C:14]1[CH:20]=[CH:21][CH:22]=[C:12]([CH3:11])[CH:13]=1)=[O:5]
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: CCOCC
Product: Cc1cccc(C(=O)NC(=S)Nc2ccccc2C(N)=O)c1
Yield: 89.3 %

Procedure:
To a stirred mixture of 7.2 g of 2-aminobenzamide and 200 ml of ether was added dropwise, a solution of 10 g of 3-methylbenzoyl isothiocyanate over 10 minutes. After 48 hours the solid was recovered, giving 14.8 g of N-[[[2-(aminocarbonyl)phenyl]amino]thioxomethyl]-3-methylbenzamide.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:9]([C:12]1[CH:13]=[C:14]([C:22]([OH:24])=[O:23])[C:15]2[O:20][CH2:19][CH2:18][O:17][C:16]=2[CH:21]=1)(=[O:11])=[O:10]>O>[CH:1]1([NH:7][S:9]([C:12]2[CH:13]=[C:14]([C:22]([OH:24])=[O:23])[C:15]3[O:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCCC2)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
250 ml of water and 300 ml of cyclohexylamine were put into a 1-liter balloon flask. 139 g of moist 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added by fractions, the temperature being maintained at from 20°-30° C. The mixture was stirred at room temperature for three hours and then the solution was treated with 30 g of black carbon 3 S. After filtration, 300 ml of hydrochloric acid (d=1.18) were added. The precipitate was recrystallized, washed with water and dried. 92 g of 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 150° C.).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][NH2:30])[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:30][CH2:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:14])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCc1cccnc1
Product: CCCc1c(OCCCC(=O)NCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butanoic acid was allowed to react with 3-pyridine propanamine according to procedure A and the product was purified by chromatography on silica gel to give 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-N-[3-(3-pyridinyl)propyl]butanamide, the title compound, mp 97°-98° (from methylene chloride-ether) in 88% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:13]2[C:9]=1[C:10](=[O:24])[N:11]([CH3:23])[CH2:12]2)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)=[C:13]2[C:9]=1[C:10](=[O:24])[N:11]([CH3:23])[CH2:12]2
Reactant: CN1Cc2c(CN3CCCC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1Cc2c(CN3CCCC3)ccc(N)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To tert-butyl[2-methyl-3-oxo-7-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 109B) was added DCM (0.5 mL) and TFA (0.5 mL, 6 mmol). The solution was stirred at room temperature for 20 minutes. The crude product was dried in vacuo and used directly in next step without further purification. MS (ES+): m/z 246.31 (100) [MH+]; HPLC: tR=0.29 min (UPLC, Analytical).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:28]([C:30]1[CH:31]=[C:32]([S:37](Cl)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]>O1CCCC1.C(OCC)(=O)C>[C:28]([C:30]1[CH:31]=[C:32]([S:37]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:39])=[O:38])[CH:33]=[CH:34][C:35]=1[F:36])#[N:29]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 70.8 %

Procedure:
N-(2,4-Dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (Preparation 18, 42.8 g, 170 mmol) was dissolved in anhydrous tetrahydrofuran (600 mL) and stirred under a nitrogen atmosphere at −78° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (238 mL, 238 mmol) was added drop wise over 30 minutes maintaining the temperature between −65° C. and −70° C. The reaction mixture was left at −78° C. for 5 minutes, then allowed to warm to −10° C. over 1.5 hours. Upon reaching −10° C., the brown reaction mixture was cooled to −78° C. again, and a solution of 3-cyano-4-fluorobenzene sulfonyl chloride (48.6 g, 221 mmol) in tetrahydrofuran (200 mL) was added drop wise over 30 minutes maintaining the temperature between −65° C. and −70° C. The brown solution was allowed to warm gradually to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with a saturated ammonium chloride solution, and extracted with further ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown residue. The residue was purified by silica gel column chromatography (10%-30% ethyl acetate in heptane gradient elution) to afford the title compound as a white solid (52.3 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:20]2[CH2:23][CH2:22][CH2:21]2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:25]\[OH:26])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCC2)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(Br)cc2)C2CCC2)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-cyclobutyl-propionyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=389.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[CH:20][C:19]=1[NH2:30]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:30][C:19]2[CH:20]=[CH:21][C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:23][C:18]=2[O:17][CH3:16])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cc(N2CCOCC2)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reaction time: 8 h

Procedure:
2,4,5-Trichloropyrimidine (978 mg, 5.33 mmol) was dissolved in Tetrahydrofuran (30 mL), then Potassium carbonate (1.52 g, 11.0 mmol) was added. 2-Methoxy-4-morpholin-4-yl-phenylamine (1.030 g, 4.95 mmol) was added, and the reaction was stirred under an atmosphere of Nitrogen, overnight. The reaction was partitioned between 30 mL water, 30 mL dichloromethane and separated. The aq. layer was extracted once with 30 mL dichloromethane, the combined organics washed once with 50 mL brine, then dried over sodium sulfate. The contents were concentrated onto silica gel, and chromatographed on an ISCO cartridge (120 g SiO2, 0-40% EA:Hex). (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine was isolated as a yellow solid (1.40 g, 80%). m.p.=156-160° C.; LCMS (m/e)=355 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.30 (d, 1H, J=8.8 Hz), 8.13 (s, 1H), 7.87 (s, 1H), 6.57 (d, 1H, J=8.8 Hz), 6.52 (s, 1H), 3.93 (s, 3H), 3.88 (t, 4H, J=4.8 Hz), 3.16 (t, 4H, J=4.8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[OH:38]>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:38][C:32]4[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=4[Cl:30])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(Cl)cc4Cl)ncnc32)CC1
Temperature: 100 °C
Reaction time: 18 h
Yield: 14.4 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 42 mg, 0.12 mmol), anhydrous potassium carbonate (22 mg, 0.16 mmol) and 2,4-dichlorophenol (26 mg, 0.16 mmol) in N-methylpyrrolidinone (0.5 mL) was heated to 100° C. in a sealed scintillation vial. After 18 hr, the mixture was allowed to cool to room temperature and the reaction mixture purified by reverse phase HPLC to give 4-[4-(2,4-dichloro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (8 mg, 14%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.97-2.05 (m, 2H), 2.18-2.33 (m, 2H), 2.90-3.04 (m, 2H), 4.24-4.40 (m, 2H), 4.90-5.02 (m, 1H), 7.23-7.25 (m, 1H), 7.36 (dd, 1H, J=8.6, 2.6 Hz), 7.64 (d, 1H, J=2.1 Hz), 8.12 (s, 1H), 8.49 (s, 1H). Mass spectrum MH+=464.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
To a solution of pentan-1-ol (9.2 mL, 85 mmol) in CH2Cl2 (70 mL) and pyridine (50 mL) was added 4-(dimethylamino)pyridine (0.52 g, 4.3 mmol) followed by p-toluenesulfonyl chloride (16.2 g, 85 mmol). The mixture was allowed to stir at ambient temperature for 18 h then was quenched with 5% aqueous HCl (10 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (13.1 g, 53.9 mmol, 63% yield). MS (DCI/NH3) m/z 260 (M+NH4)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][OH:21]>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:19][CH2:20][OH:21])[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(I)nn2CCO
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.8 %

Procedure:
To 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.766 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added cesium carbonate (300 mg, 0.919 mmol) followed by 2-bromoethanol (0.057 mL, 0.805 mmol), and the reaction mixture was stirred over the weekend (3 days) at 80 C into a sealed vessel. The reaction was allowed to cool down to room temperature. The mixture was concentrated and treated with water (˜10 mL). The resulting aqueous mixture was sonicated, and then filtered. The solid in the filter was washed with water (2×10 mL) to afford 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol (128 mg) as a white solid after drying. LC/MS (ES) m/z=306.0 [M+H]+.
Reaction SMILES: C([NH:8][C@H:9]([C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=2[N:15]=1)[CH2:10][CH2:11][O:12][CH3:13])(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>ClCCl>[Cl:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:14]([C@@H:9]([NH2:8])[CH2:10][CH2:11][O:12][CH3:13])=[N:15][C:16]=2[CH:22]=1
Reactant: COCC[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1g from (1S)-N-Boc-1-(5-chloro-1H-benzimidazol-2-yl)-3-methoxy-propylamine and TFA in dichloromethane.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7](Cl)[N:6]=1.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].[OH-].[Na+]>O>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[Cl:16])[N:6]=1
Reactant: Nc1ccccc1Cl
Reactant: OCCNc1nc(Cl)nc(NCCO)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCNc1nc(NCCO)nc(Nc2ccccc2Cl)n1
Temperature: 90 °C
Yield: 82 %

Procedure:
6.8 g (0.053 mol) of 2,4-bis-(2-hydroxyethylamino)-6-chloro-1,3,5-triazine, 11.7 g (0.05 mol) of 2-chloroaniline and 85 ml of water are placed in a 250 ml flask equipped with a stirrer, a dropping funnel, a reflux condenser and a thermometer. The mixture is heated with stirring to 90° C., in the course of which a clear solution is formed. A solution of 2 g of sodium hydroxide in 15 ml of water is added dropwise to this mixture, and the whole mixture is heated under reflux for 3 hours. After cooling, the aqueous system is in 2 phases. The supernatant inorganic phase is discarded. The lower phase is extracted by boiling with toluene, the product being obtained in the residue. The melting point is 108°-110° C. and, after reprecipitation with ethyl acetate/petroleum ether, is 112°-114° C. The yield is 82% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: Nc1cc(Cl)cc(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)cc(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-amino-5-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-amino-5-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:48]=[CH:47][C:46]([O:49]CC4C=CC=CC=4)=[CH:45][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:24]([CH2:36][O:37][Si](C(C)(C)C)(C)C)[CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[OH2:57]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:24]([CH2:36][OH:37])[CH:23]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:11][CH2:12][O:57][CH2:13][CH2:14]1
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(CO[Si](C)(C)C(C)(C)C)c3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(CO)c3)sc3cc(O)ccc23)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
The (30.8 mg, 0.0381 mmol) 6-benzyloxy-2-[3-t-butyldimethylsilyloxymethyl-4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-(1-pyrrolidinylmethyl)phenyl ketone (Part C) was dissolved in 0.5 mL of 1N tetrabutylammonium fluoride in THF. The solution was stirred at room temperature for 1 h. To the reaction mixture was added 1.0 mL of water and diluted with 15 mL of EtOAc. The layers were separated and the aqueous layer was extracted (1×10 mL) with EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 80:17:3 THF-Hexanes-Et3N) afforded 5.7 mg (0.0082 mmol, 22%) of a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12]C)[CH:6]=2.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[C:3]([CH3:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2
Reactant: COc1ccc2cc(F)c(C)nc2c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2cc(O)ccc2cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Fluoro-7-methoxy-2-methylquinoline (0.16 g, 0.85 mmol) was taken up in dichloromethane (4 ml) under nitrogen and treated with boron tribromide solution (4 ml of a 1.0M solution in dichloromethane, 4.0 mmol). The reaction was stirred for 24 hours at ambient temperature followed by the slow addition of excess methanol. The solution was stirred for a further 2 hours and then evaporated to dryness to give 3-fluoro-7-hydroxy-2-methylquinoline which was used without further purification.
Reaction SMILES: CC(C)(S([NH:6][C:7]1([CH3:21])[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1)=O)C.[ClH:23]>CO.O1CCOCC1>[ClH:23].[NH2:6][C:7]1([CH3:21])[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9][CH2:8]1
Reactant: CC1(NS(=O)C(C)(C)C)CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC1(N)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of tert-butyl 4-(1,1-dimethylethylsulfinamido)-4-methylcyclohexylcarbamate (0.2 g, 0.6 mmol) in 100 mL of MeOH was added a saturated solution of HCl (g) in dioxane (0.72 mL). The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was triturated with EtOAc (15 mL), then decanted and dried to give tert-butyl 4-amino-4-methylcyclohexylcarbamate hydrochloride (0.1 g, 63%) as a white solid. MS: (M+H)+=229.2. 1H NMR (300 MHz, CD3OD): δ 3.36 (m, 1H), 1.91-1.66 (m, 9H), 1.40 (s, 9H), 1.18 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([OH:13])=[O:12].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:6]=[C:5]2[C:11]([OH:13])=[O:12]
Reactant: COC(=O)CBr
Reactant: O=C(O)c1c[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(=O)O)c2cc(Cl)ccc21
Temperature: -20 °C
Reaction time: 1 h

Procedure:
110 ml of a solution containing 10 g of 5-chloro-1H-indole-3-carboxylic acid (commercial) in DMF is added dropwise to a mixture of 4.50 g of NaH (60% in oil) in 400 ml of DMF at −10° C. After it returns to RT, it is stirred for 1 hour. The reaction mixture is cooled to −20° C. 4.86 ml of methyl bromoacetate is added dropwise, it is returned to RT for a period of 5 hours and is stirred for 15 hours. The reaction mixture is added to 1 L of EtOAc/1N HCl mixture, the organic phase is collected and the aqueous phase is extracted with EtOAc. The organic phases are combined, washed with water and with brine, then dried over Na2SO4 and evaporated to dryness. 8.9 g of the expected compound is obtained in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[C:6](=[O:11])[C:7]=1[N+:8]([O-])=O>[Pd].C(O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=2[C:6](=[O:11])[C:7]=1[NH2:8]
Reactant: Cc1oc2ccccc2c(=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1oc2ccccc2c(=O)c1N
Reaction time: 0.67 h
Yield: 5.6 %

Procedure:
A mixture of 2-methyl-3-nitro-4H-1-benzopyran-4-one (5.0g, 0.244 mole) and 10% palladium on charcoal (0.75g) in ethanol (250 ml) was shaken under a hydrogen atmosphere in a Parr shaker for 40 minutes. The catalyst was filtered off, and the solvent was removed under reduced pressure to give yellow solids. Recrystallization from benzene gave yellow crystals (2.4g, 56%), m.p. 118°-20° C.