Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:12][CH2:11][CH2:10][C:9]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[N:7]=[CH:6][C:5]1=2.C([O-])([O-])=O.[K+].[K+].[C:27]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:20][C:15]1[CH:14]=[C:13]([N:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH:4]([CH2:3][CH2:2][N:36]4[CH2:37][CH2:38][CH:33]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH2:34][CH2:35]4)[C:5]=3[CH:6]=[N:7]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: ClCCC1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ccc(-n2ncc3c2CCCC3CCN2CCC(c3ccccc3)CC2)cc1Cl
Yield: 45.1 %

Procedure:
A mixture of 4-(2-chloroethyl)-4,5,6,7-tetrahydro-1-(3,4-dichlorophenyl)-1H-indazole (235 mg, 0.71 mmol), K2CO3 (99 mg, 0.71 mmol), 4-phenylpiperidine (97 mg, 0.71 mmol) and a catalytic amount of K1 in 5 mL of DMF is heated to reflux during 18 hours. The solvent is eliminated at reduced pressure, the crude is diluted with ethyl acetate, washed with water, and the organic phase is evaporated at reduced pressure. The resultant crude is purified by chromatography on silica-gel to obtain 1-(3,4-dichlorophenyl)-4,5,6,7-tetrahydro-4-(2-(4-phenylpiperidin-1-yl)ethyl)-1H-indazole (146 mg, 0.32 mmol, 45%, oil).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][CH:32]([OH:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([O:27][C:28](=[O:43])[NH:29][CH2:30][CH2:31][C:32](=[O:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCC(O)CO[Si](C)(C)C(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Dess-Martin periodinane (5.0 g, 11.8 mmol) in anhydrous dichloromethane (35 mL) at room temperature was added a solution of [4-(tert-butyldimethylsilanyloxy)-3-hydroxybutyl]carbamic acid tert-butyl ester (3.77 g, 11.8 mmol) in anhydrous dichloromethane. The resulting mixture was stirred at room temperature for one hour, evaporated in vacuo to one third of the initial volume and applied to a column packed with silica. Elution with ethyl acetate-petroleum ether solvent mixture afforded a colourless oil.
Reaction SMILES: [F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@H:7]([C:9](=[O:16])[CH2:10][C:11](OCC)=[O:12])[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18].[OH-].[Na+].[NH2:24]O.Cl>CO.O.C(Cl)Cl>[F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@H:7]([C:9]2[O:16][NH:24][C:11](=[O:12])[CH:10]=2)[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](C(F)F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1C(F)F
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
Trans-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (203 mg, 0.66 mmol) (from example 87, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (26.4 mg, 0.66 mmol) dissolved in water (0.300 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.040 mL, 0.66 mmol) was added. The resulting solution was stirred at −40° C. for 2 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (3.41 mL, 20.48 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 5-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 15 minutes with a flow of 19 mL/min. Trans-methyl 2-(difluoromethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (122 mg, 67%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.35-1.65 (m, 1H), 1.68-1.82 (m, 1H), 1.87-2.12 (m, 1H), 2.30-2.45 (m, 1H), 2.70-3.22 (m, 2H), 3.74 (s, 3H), 4.10-4.74 (m, 2H), 5.69 (s, 1H), 5.75-6.09 (m, 1H). MS m/z 275 (M−H)−
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].I[C:8]1[NH:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1.C(O)CO>CCOC(C)=O.[Cu]I.CC(O)C>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2I)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2Sc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
CuI (20 mg, 0.104 mmol), K2CO3 (573 mg, 4.15 mmol), the product of Step 2 (770 mg, 2.0 mmol), and 4-chlorobenzenethiol (330 mg, 2.2 mmol) were added to a flask, which was flushed with N2. 2-Propanol (8 mL) and ethylene glycol (0.23 mL, 4.15 mmol) were added. The reaction mixture was heated at 80° C. for 24 h. Then the reaction was diluted with EtOAc, filtered, concentrated, and the residue was subject to silica column chromatography (5-25% EtOAc in hexanes) to give the title compound. 1H NMR (500 MHz, (CD3OD): 8.08 (m, 1H), 8.01 (d, 2H), 7.78 (d, 2H), 7.47 (m, 4H), 7.24 (d, 2H), 7.17 (d, 2H). LCMS: m/z 388.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[C:11](OCC)(=[O:17])[C:12](OCC)=[O:13]>>[CH3:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:10][C:12](=[O:13])[C:11](=[O:17])[NH:9]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(N)c(N)cc1C
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C

Procedure:
A mixture of 4,5-dimethyl-benzene-1,2-diamine (60 g) and diethyl oxalate (600 mL) was heated under reflux for 1 h and then cooled. The precipitate of 6,7-dimethyl-1,4-dihydro-quinoxaline-2,3-dione was filtered off and washed with 96% ethanol to give 38 g of the title compound. ESI-MS: m/z 191.1 [MH+], 403.3 [2MNa+]; required MW=190.2
Reaction SMILES: Cl.C([O:4][C:5](=[O:17])[CH2:6][NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)C>Cl>[CH:8]1([NH:7][CH2:6][C:5]([OH:17])=[O:4])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)CNC1CCc2ccccc21
Agent: Cl
Product: O=C(O)CNC1CCc2ccccc21
Yield: 89.2 %

Procedure:
N-(1-Indanyl)glycine ethyl ester hydrochloride (9.0 g) is dissolved in 100 ml of 5N hydrochloric acid, and the mixture is refluxed for 4 hours. The reaction mixture is concentrated to dryness under reduced pressure, 10 ml of water is added to the residue, and the mixture is neutralized with aqueous ammonia. The resulting crystalline precipitates are collected by filtration, washed with water, and dried, to give 6.0 g N-(1-indanyl)glycine as colorless needles. Melting point: 184°-186° C.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([S:19][CH2:20][CH2:21][C:22](OCC)=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>O1CCCC1.Cl>[CH2:3]([S:19][CH2:20][CH2:21][CH2:22][OH:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCSCCC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCSCCCO
Yield: 99.1 %

Procedure:
To a slurry of 147 mg of lithium borohydride in 20 ml of tetrahydrofuran is added slowly with stirring 2.4 g of ethyl 3-(hexadecylthio)propanoate. The mixture is refluxed for 18 hours and poured into water. A few drops of hydrochloric acid is added followed by ether extraction. The organic layer is dried and evaporated to give 2.1 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][CH:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 125 °C
Yield: 80.1 %

Procedure:
A mixture of 4-bromo-N-(4-fluoro-benzyl)-N-isobutyl-benzenesulfonamide (200 mg, 500 μmol), 4-amino-1-boc-piperidine (120 mg, 600 μmol), Pd2(dba)3 (46 mg, 50 μmol), XantPhos (29 mg, 50 μmol), and sodium tert-butoxide (106 mg, 1.1 mmol) in toluene (5 mL) was degassed with nitrogen then heated at 125° C. for 30 minutes in a microwave reactor. Water was added then extracted with EtOAc, washed with brine, dried with Na2SO4, concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give 4-{4-[(4-fluoro-benzyl)-isobutyl-sulfamoyl]-phenylamino}-piperidine-1-carboxylic acid tert-butyl ester (208 mg, 80%). LCMS (m/z, Method A) ES− 518[M−1]−.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=4)[CH:24]=O)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.CO.[CH3:31][NH:32][CH3:33].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:31][N:32]([CH2:24][C:23]1[CH:22]=[C:21]([CH:13]2[NH:12][C:7]3[C:6]4[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=4[CH:10]=[CH:9][CH:8]=3)[CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:33]
Reactant: O=Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C)Cc1cccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 61.3 %

Procedure:
A mixture of 3-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (50 mg, 0.14 mmol) and IM dimethylamine methanol solution (0.5 ml, 0.41 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium cyanoborohydride (13 mg, 0.20 mmol) and acetic acid (40.8 mg, 0.68 mmol) was added. After the addition, the mixture was stirred at 0° C. for 2 hr. Methanol was removed under reduced pressure. The residue was resolved with 1N hydrochloric acid and washed with ethyl acetate. The mother liquor was adjusted to pH=8 and extracted with ethyl acetate. The solvent was removed to give 8-(3-((dimethylamino)methyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (34 mg, yield 64%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.17 (s, 6H), 3.17-3.41 (q, 2H), 4.31 (d, J=8.0 Hz, 1H), 4.74 (d, J=8.0 Hz, 1H), 7.08-7.10 (m, 2H), 7.13-7.25 (m, 8H), 7.55-7.57 (d, J=8.0 Hz, 1H), 7.61-7.65 (m, 1H). LC-MS (ESI) m/z: 397 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].F[C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([F:19])[C:10]=1[C:11]#[N:12].O>O1CCCC1>[F:19][C:13]1[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:9]([O:7][CH2:6][CH2:5][O:4][CH3:3])[C:10]=1[C:11]#[N:12]
Reactant: COCCO
Reactant: COc1cc(F)c(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(OC)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.4 %

Procedure:
Sodium hydride (60% in mineral oil, 0.88 g, 22 mmol) was added to 2-methoxyethanol (1.84 g, 24 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 20 minutes. 2,6-Difluoro-4-methoxy-benzonitrile (Mol. Cryst. Liq. Cryst. 1989, 172) (3.38 g, 20 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and the solution was extracted with dichloromethane (3×50 ml). The combined organic solutions were dried over magnesium sulphate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel using methanol in dichloromethane as eluant (gradient from 0:100 to 3:97) to give the title compound (3.8 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=[O:8].Cl.Cl[C:15]([NH2:17])=[NH:16].CS(C)(=O)=O.N>O>[NH2:17][C:15]1[NH:1][C:2]2[S:3][CH:4]=[C:5]([CH3:12])[C:6]=2[C:7](=[O:8])[N:16]=1
Reactant: N=C(N)Cl
Reactant: CCOC(=O)c1c(C)csc1N
Agent: CS(C)(=O)=O
Agent: Cl
Agent: N
Solvent: O
Product: Cc1csc2[nH]c(N)nc(=O)c12
Temperature: 135 °C
Yield: 87.9 %

Procedure:
A mixture of ethyl 2-amino-4-methylthiophene-3-carboxylate (2.0 g, 11.7 mmol), chloroformamidine hydrochloride (3.357 g, 29.0 mmol) and dimethylsulfone (5.489 g, 58.4 mmol) was heated at 135° C. for 45 minutes. Water was added and the mixture was cooled down to room temperature. An aqueous ammonia solution was added to adjust the solution to pH 9. The precipitate was filtered off, yielding the title compound (1.863 g) as a white powder. 13C NMR δ (75 MHz, DMSO-d6) 168.98, 159.12, 153.21, 133.26, 114.37, 110.81, 16.35. MS (m/z) 182 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH:21][C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Reactant: O=C(Cl)c1ccco1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)c2ccco2)nn1
Yield: 86 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using 2-furoyl chloride instead of methoxyacetyl chloride, to the title compound (330 mg, 86%) which was obtained as a white solid. MS: m/e=377.2 [M+H]−.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:20][C:21]1[C:27]([OH:28])=[CH:26][C:24]([NH2:25])=[C:23]([F:29])[CH:22]=1>>[ClH:2].[Cl:20][C:21]1[C:27]([OH:28])=[CH:26][C:24]([NH:25][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:23]([F:29])[CH:22]=1
Reactant: COCCOc1cc2nccc(Cl)c2cc1OC
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Product: COCCOc1cc2nccc(Nc3cc(O)c(Cl)cc3F)c2cc1OC
Yield: 67.5 %

Procedure:
Using an analogous procedure to that described in Example 25, 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (500 mg, 1.64 mmol), (prepared as described for the starting material in Example 5), was reacted with 4-chloro-2-fluoro-5-hydroxyaniline (270 mg, 1.64 mmol), (as described in EP 61741 A2), for 5 hours to give 4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy-7-(2-methoxyethoxy)quinoline hydrochloride (475 mg, 67%).
Reaction SMILES: C(O)(=O)C.[N:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][CH2:10][CH2:9][CH2:8]1)=O.O.Cl.[NH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>[Zn].C(O)C>[NH:20]1[CH2:25][CH2:24][C:23](=[N:5][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][CH2:10][CH2:9][CH2:8]2)[CH2:22][CH2:21]1
Reactant: O=C1CCNCC1
Reactant: O=NN1CCCSc2ccccc21
Agent: Cl
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: c1ccc2c(c1)SCCCN2N=C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Glacial acetic acid (700 ml) is added dropwise to a vigorously stirred mixture of 62 g of 2,3,4,5-tetrahydro-5-nitroso-1,5-benzothiazepine, 49 g of 4-piperidone hydrochloride monohydrate, 400 ml of anhydrous ethanol, and 140 g of zinc dust, cooled in an ice-bath. After the addition is complete, the mixture is stirred at room temperature for 1 hr. and filtered. The residue is washed with a small quantity of ethanol and the combined filtrates heated at 65°-70° C. for 1 hour and then stripped of ethanol and acetic acid under reduced pressure. The residual viscous liquid is dissolved in minimum quantity of water and added with stirring, to excess of well-cooled 25% aqueous sodium hydroxide. The mixture is thoroughly extracted with chloroform and the combined chloroform extract washed well with water, dried over anhydrous magnesium sulfate and stripped of the solvent under reduced pressure. The residue on trituration with ether and cooling yields 2,3,4,5-tetrahydro-5-[(4-piperidylidene)amino]-1,5-benzothiazepine as cream colored crystals, m.p. 113°-115°. A sample of this hydrazone melts at 115°-117° C. after recrystallization from a mixture of benzene and hexane.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O)=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:11]=[O:12])[CH:10]=[CH:9][C:5]1=2
Reactant: O=Cc1ccccc1B(O)O
Reactant: Brc1ccc2sccc2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=Cc1ccccc1-c1ccc2sccc2c1
Temperature: 80 °C
Yield: 80.8 %

Procedure:
To a suspension of 5-Bromo-benzo[b]thiophene (compound PRE13) (3.68 g, 17.2 mmol) in toluene (183 mL) was added, under nitrogen, tetrakis(triphenylphosphine)-palladium (1.99 g, 1.72 mmol), then a solution of 2-formylphenylboronic acid (3.87 g, 25.8 mmol) in ethanol (20 mL) and at least dropwise aqueous sodium carbonate solution (3.64 g, 34.4 mmol) in water (20 mL). The reaction mixture was then heated to 80° C. for 3 h, cooled, concentrated, partitioned between ethyl acetate (120 mL) and water (70 mL) and acidified with hydrochloric acid (pH˜2). The organic layer was separated, dried over Na2SO4 and concentrated to give a crude residue that was purified by flash chromatography (silica, eluting solvent: (petroleum ether/AcOEt) 9.2/0.8) to give 3.31 g of compound PRE14 (orange yellow powder; yield=81%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([N:17]2[CH2:18][CH2:19][N:20]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)[CH2:21][CH2:22]2)[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 60 °C

Procedure:
A mixture of methyl(2S)-3-(4-nitrophenyl)-2-piperazin-1-ylpropanoate hydrochloride (100 mg, 0.30 mmol), 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.33 mmol), and triethylamine (92 mg, 0.91 mmol) in DMF was heated to 60° C. for 16 hours. LC showed some product. More 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.33 mmol) and triethylamine (92 mg, 0.91 mmol) were added to the reaction, and the mixture was allowed to heat for another 24 hours. LC showed complete reaction at that point. The reaction was diluted with EtOAc, washed with water, and purified by HPLC to deliver the desired product. LC-MS (IE, m/z): 443 [M+1]+. (0.51 μM)
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CS(C)=O>[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: Cc1ccccc1N
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Solvent: CS(C)=O
Product: Cc1ccccc1Nc1c(Nc2ccccc2O)c(=O)c1=O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2-methylaniline (0.023 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 295 (M+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([O:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]=[CH:9][C:8]=1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[F:29])(=O)=O.[CH3:32][Si:33]([CH3:41])([CH3:40])[O:34][C:35]([CH3:39])([C:37]#[CH:38])[CH3:36]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I.C(N(CC)CC)C>[C:14](=[O:15])([O:13][C:11]1[CH:12]=[CH:7][C:8]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=2[F:29])=[C:9]([C:38]#[C:37][C:35]([CH3:39])([O:34][Si:33]([CH3:41])([CH3:40])[CH3:32])[CH3:36])[CH:10]=1)[O:16][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: C#CC(C)(C)O[Si](C)(C)C
Reactant: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2OS(=O)(=O)C(F)(F)F)c1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(F)c(-c2ccc(OC(=O)OC(C)(C)C)cc2C#CC(C)(C)O[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Under a nitrogen atmosphere, to a mixture of 4-((tert-butoxycarbonyl)oxy)-2′-fluoro-5′-methoxybiphenyl-2-yl trifluoromethanesulfonate (408 mg), tetrakis(triphenylphosphine)palladium (308 mg), copper iodide (32 mg) and triethylamine (10 mL) was added trimethyl((2-methylbut-3-yn-2-yl)oxy)silane (1.7 mL). The mixture was stirred at 80° C. for 15 hr, and tetrakis(triphenylphosphine)palladium (308 mg) was added. The mixture was stirred at 80° C. for 20 hr, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (232 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[C:5](=[O:23])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:19]([O:21]C)=[O:20].[OH-].[Li+].CO.C(OCC)(=O)C>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[C:5](=[O:23])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:19]([OH:21])=[O:20]
Reactant: COC(=O)c1[nH]c2cc(Cl)ccc2c1NCCC(=O)c1ccc(F)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)ccc12)c1ccc(F)c(F)c1
Yield: 79.2 %

Procedure:
Dissolve 3-[(3,4-difluorophenacyl)methylamino]-2-carbmethoxy-6-chloroindole 650 mg, 1.7 mmol) in tetrahydrofuran (10 mL) and water (10 mL). Add lithium hydroxide (227 mg, 5.4 mmol). Add methanol dropwise until an homogeneous solution forms. Stir the reaction at room temperature overnight. Dilute the reaction with water(10 mL) and ethyl acetate (25 mL). Acidify with 1N HCl and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate 50% with heat. Reconstitute with hot hexane. Repeat the concentration and reconstitution steps and cool to yield the title compound (510 mg, 82%); mp 260°-264° C.