Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[C:10]([CH3:17])=[N:9]2)[CH:7]=1.[N:20]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([N:28]3[CH2:29][CH2:30][CH:25]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[CH2:26][CH2:27]3)=[O:16])[C:10]([CH3:17])=[N:9]2)[CH:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COc1ccc(Cl)cc1-n1nc(C)c(C(=O)O)c1C
Product: COc1ccc(Cl)cc1-n1nc(C)c(C(=O)N2CCC(N3CCCC3)CC2)c1C
Yield: 99 %

Procedure:
In analogy to the procedure described in Example 18], 1-(5-chloro-2-methoxy-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 99% yield as light yellow foam. MS: 417.0 (MH+, 1 Cl).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH3:16][C:17]([C:20]1[CH:27]=[CH:26][C:23](C=O)=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>CCCCCC.O1CCCC1>[CH3:16][C:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C2CC(O)=CC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5.0 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 31.5 mL of 1.6M n-butyl lithium in hexane, 9.0 g of 4-(1,1-dimethylethyl)benzaldehyde and 100 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 164°-165° C.). 'H NMR (CDCl3) δ1.33 (s, 9H), 2.94 (dd, 2H), 3.59 (dd, 2H), 5.69 (dd, 1H), 7.31-7.47 (m, 4H).
Reaction SMILES: Br[C:2]1[C:7]2[C:8]([NH2:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)=[O:25].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCOCC1.O.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>[NH2:11][C:8]1[C:7]2[C:2]([C:30]3[CH:29]=[CH:28][C:27]([NH:26][C:24]([NH:23][C:14]4[CH:15]=[C:16]([C:19]([F:20])([F:22])[F:21])[CH:17]=[CH:18][C:13]=4[F:12])=[O:25])=[CH:32][CH:31]=3)=[N:3][CH:4]=[CH:5][C:6]=2[NH:10][N:9]=1
Reactant: Nc1n[nH]c2ccnc(Br)c12
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1n[nH]c2ccnc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 100 °C
Yield: 31.8 %

Procedure:
To a solution of 53 mg of 4-bromo-1H-pyrazolo[4,3-c]pyrid-3-ylamine in 6 mL of dioxane are added 127 mg of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea, 60 mg of sodium bicarbonate in 1.8 mL of water and 30 mg of tetrakis(triphenylphosphine)palladium. The reaction is heated in a bath at 100° C. for 2 hours. The mixture is allowed to cool and ethyl acetate is then added. The mixture is washed with water. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The oily residue is purified on a prepacked Biotage KP-Sil column of 60 Å SiO2 32-63 μm (gradient: 90/10 to 70/30 dichloromethane/solution A; solution A=38/17/2 dichloromethane/methanol/aqueous ammonia). 34 mg of 1-[4-(3-amino-1H-pyrazolo[4,3-c]pyrid-4-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea are obtained in the form of a cream-coloured solid, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][C:21]2[CH:22]=[C:23]([NH:27]C(=O)OC(C)(C)C)[CH:24]=[CH:25][CH:26]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(OCC)(=O)C.CCCCCC>C(Cl)Cl>[NH2:27][C:23]1[CH:22]=[C:21]([NH:20][C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[CH:11][CH:10]=3)[N:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)OC(C)(C)C)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
In a 25 mL, 3-neck RBF equipped with a magnetic stirrer, and thermo pocket was sequentially charged with tert-butyl (3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)carbamate (1.2 g) in DCM (10 mL). Trifluoroacetic acid (6.0 mL) was added drop wise into the reaction mixture at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes. The reaction was monitored by TLC using ethyl acetate:hexane (7:3) as mobile phase. After completion, the reaction mixture was quenched in water and neutralized with sodium bicarbonate. The mixture was extracted into DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. to give 0.94 g of N4-(3-aminophenyl)-5-fluoro-N2-(4-(2-methoxyethoxy)phenyl)pyrimidine-2,4-diamine which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH2:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:12][C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: Nc1ccsc1-c1cnccn1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2cnccn2)cc1

Procedure:
The title compound was prepared from 2-(pyrazin-2-yl)thiophen-3-amine and 2-(4-methoxyphenyl)acetic acid according to protocol B and was purified by HPLC. Method [7] Retention time 5.91 min by HPLC (MH+ 326). 1H NMR (300 MHz, DMSO) δ s (11.02, 1H), 8.81 (d, J=0.9 Hz, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.26 (m, 1H), 7.92 (d, J=5.4 Hz, 1H), 7.74 (d, J=5.4 Hz, 1H), 7.33 (d, 8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([OH:26])=O)=[O:5])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:26])=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N1CCCCC1

Procedure:
Starting materials: 19-ethoxycarbonyl-2,6,10,14,18-pentamethyl-2,6,10,14,18-nonadecapentaenoic acid and piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12](Br)=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1.C([Li])CCC.CN(C)[CH:30]=[O:31].O>O1CCCC1>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([CH:30]=[O:31])=[CH:11][CH:10]=3)[NH:8][C:4]=2[CH:3]=1
Reactant: Clc1cc2nc(-c3ccc(Br)c4ccccc34)[nH]c2cc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)c2ccccc12
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
To a solution of 5,6-dichloro-2-(4-bromo-1-naphthyl)benzimidazole (160 mg, 0.408 mmol) in tetrahydrofuran (6 mL) were added n-butyllithium (1.6 mol/L; 0.64 mL) and dimethylformamide (0.077 mL, 1.0 mmol) sequentially at −78° C. under nitrogen atmosphere, and the mixture was stirred for 15 min. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was combined, washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (2:1 hexane/ethyl acetate) to afford 5,6-dichloro-2-(4-formyl-1-naphthyl)benzimidazole (72 mg, 52%).
Reaction SMILES: Br.[CH2:2]([N:9]([CH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-].[Na+]>O1CCCC1>[CH2:2]([N:9]([CH2:11][C@H:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:13]1[OH:21])[CH3:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(Cc1ccccc1)CC1Cc2ccccc2C1=O
Agent: Br
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C[C@H]1Cc2ccccc2[C@H]1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
To an ice-cooled suspension of 3.46 g (0.01M) of 2,3-dihydro-2-(N-benzyl-N-methyl-aminomethyl)-1H-inden-1-one hydrobromide in 50 ml of dry tetrahydrofuran add 25 ml of 1M solution of L-Selectride®. Stir the mixture for 1.5 hours and decompose with 5 ml of 10% sodium hydroxide solution. Evaporate the solvent at reduced pressure and distribute the residue between ether and water. Separate the ether layer and extract with dilute hydrochloric acid. Basify the acid extract to yield an oil. Extract the oil into ethyl acetate. Evaporate the solvent and Kugelrohr distill at 90°-100°/0.4 mm to yield 1.78 g (67%) of the title compound [bp=135°-40° C. at 0.3 mmHg].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([OH:27])[CH:22]1[CH3:28])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.O>[CH2:11]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]1[CH3:28])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1C(O)CCCN1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC1C(=O)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a stirred solution of 309.5 ul (3.530 mmol) oxalyl chloride in 3 ml dichloromethane at −50° C. to −60° C. was added a solution of 873 ul DMSO in 2 ml dichloromethane. The reaction mixture was stirred for 10 minutes, after which a solution of 800 mg (3.209 mmol) 3-hydroxy-2-methyl-piperidine-1-carboxylic acid benzyl ester in 3 ml dichloromethane was added over a period of 10 minutes. Stirring was continued for an additional 30 minutes. To this, was subsequently added 2.24 ml (16.05 mmol) triethylamine. The reaction mixture was stirred for 15 minutes, then allowed to warm to room temperature, taken in water, separated, and the aqueous layer extracted with dichloromethane. The combined organic layers were washed twice with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified with flash column chromatography on silica gel (Eluent: Heptane/ethyl acetate 0 to 40) to provide 600 mg (76%) of the title compound as a light yellow oil. MS (m/e): 270.2 (M+Na+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:34])[C:22](=[O:33])[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:24][C:14]3=2)[S:9][CH:10]=1)=O)C.[Li+].[BH4-].[OH-].[Na+]>C(Cl)Cl.C1COCC1>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[C:23]1[C:22](=[O:33])[N:21]([CH3:34])[C:15]2[N:16]([CH3:20])[C:17]3[C:13]([C:14]=2[CH:24]=1)=[CH:12][C:11]([C:8]1[S:9][CH:10]=[C:6]([CH2:4][OH:3])[N:7]=1)=[CH:19][CH:18]=3
Reactant: CCOC(=O)c1csc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4nc(CO)cs4)ccc3n(C)c21

Procedure:
A solution containing 218 mg (0.43 mmol) of compound B, 2-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]thiazole-4-carboxylic acid ethyl ester in 8 ml of CH2Cl2 is refluxed. 430 μl (0.85 mmol) of 2M LiBH4 in THF are added. The mixture is refluxed for 16 h. The reaction medium is left to cool, 10 ml of 1M NaOH are added and the reaction medium is concentrated to dryness. The residue is taken up in H2O, filtered and then washed with H2O and then with MeOH.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])=[C:10]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NC1=C(C)CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)NC1CN(Cc2ccccc2)CCC1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
Platinum oxide (1.0 g, 4.41 mmol, 0.11 equiv.) was added to a solution of methyl 1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-ylcarbamate (10 g, 38.46 mmol, 1.00 equiv.) in methanol (200 mL). After introducing hydrogen gas, the mixture was stirred at about 60° C. for about 16 hours and then was filtered. The resulting filtrate was concentrated to give a crude residue that was then purified by silica gel column chromatography (ethyl acetate/petroleum (1:2)) to afford the title product a yellow solid (7 g; yield=66%). LC-MS: m/z=263 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1
Reactant: O=C1CCC(c2cccnc2F)CC1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1CCC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.10 g, 0.52 mmol), 4-(pyridin-2-ylamino)phenol (0.29 g, 1.55 mmol), and cesium carbonate (0.51 g, 1.55 mmol) were mixed in NMP (1.5 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 120° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with 1 M aqueous sodium hydroxide (1×), sat. sodium chloride (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 4-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 360.1 (M+1). IC50 (uM) 0.002.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH:16]([N:19]=[C:20]=S)([CH3:18])[CH3:17]>>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]2[NH:1][C:20]([NH:19][CH:16]([CH3:18])[CH3:17])=[N:15][S:12](=[O:13])(=[O:14])[C:3]=2[CH:4]=1
Reactant: CC(C)N=C=S
Reactant: Nc1c([N+](=O)[O-])cc(Cl)cc1S(N)(=O)=O
Product: CC(C)NC1=NS(=O)(=O)c2cc(Cl)cc([N+](=O)[O-])c2N1

Procedure:
The title compound was prepared from 2-amino-5-chloro-3-nitrobenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 266-267° C.; 1H-NMR (DMSO-d6): δ 1.20 (d, 6H, CH(CH3)2), 3.92 (m, 1H, CH(CH3)2), 8.19 (d, 1H, ArH), 8.48 (d, 1H, ArH), 8.72 (br.s, 1H, NH), 10.57 (br.s, 1H, NH); MS: m/e 318/320 (M+); (C10H11N4Cl1O4S1) calc. C, 37.68; H, 3.48; N, 17.58, found C, 37.82; H, 3.54; N, 17.58.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:16][CH3:15])[C:11]=1[CH3:12]
Reactant: CSc1ccccc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)ccc2c1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CSc1ccccc1-c1nc2cc(F)ccc2c(Cl)c1C
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloro-7-fluoro-3-methylquinoline (100 mg, 0.44 mmol), 2-(methylthio)phenylboronic acid (95 mg, 0.57 mmol) (in a mixture with the 5-F regioisomer; described herein), tetrakis(triphenylphosphine)palladium(o) (25.1 mg, 0.022 mmol), sodium carbonate (230 mg, 2.17 mmol), acetonitrile (3 mL), and water (1.5 mL) was heated in a microwave at 100° C. for 60 min, then partitioned between EtOAc and water. The organic layer was washed with brine, dried (MgSO4), and concentrated. Column chromatography afforded (in order of elution) 4-chloro-7-fluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline and 4-chloro-5-fluoro-3-methyl-2-(2-(methylthio)phenyl) as white solids. Mass Spectrum (ESI) m/e=318 (M+1).
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[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[OH:31]>>[OH:31][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCCCC1O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCCC2O)cn1
Yield: 50 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using rac-(cis and trans)-2-aminocyclohexanol instead of 2-aminoethyl isopropylether, to the title compound (130 mg, 50%) which was obtained as a white solid. MS: m/e=408.4 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:4]1([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH3:3].[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>C1C=CC=CC=1>[OH:1][CH:2]([C:4]1([N:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:5]1)[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CC(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(O)C1(N(C(=O)C2CC2)c2ccccc2)CCN(CCc2ccccc2)CC1
Yield: 66.1 %

Procedure:
A solution of 4-(1-hydroxyethyl)-4-(N-phenylamino)-1-(2-phenylethyl)-piperidine (0.200 g), cyclopropylcarboxylic acid chloride (1 g) and triethylamine (2.2 g) in dry benzene (30 ml) was stirred for 2.5 hours at 60°-65° C. After cooling the mixture was washed with dilute sodium carbonate solution, dried over MgSO4 and then concentrated. The residue was chromatographed on silica gel using chloroform-methanol 76:1 as eluant to give the title compound (0.160 g), which with oxalic acid gave an oxalate salt, m.p. 158°-159° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]>>[CH3:1][N:2]([CH3:15])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[C:20]3[S:16][C:17](=[O:22])[NH:18][C:19]3=[O:21])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CN(C)c1ncnc2ccc(C=O)cc12
Reactant: O=C1CSC(=O)N1
Product: CN(C)c1ncnc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 4-Dimethylamino-quinazoline-6-carbaldehyde (intermediate 14) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.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>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14]
Reactant: OB(O)c1ccccc1F
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1F
Reaction time: 3 h

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate (10 g, 38.6 mmol) in toluene (80 mL) and water (20 mL) under nitrogen was added 2-fluorophenylboronic acid (7.0 g, 50.2 mmol), followed by potassium carbonate (16 g, 115.8 mmol) and Pd(PPh3)4 (2.23 g, 1.9 mmol). After 3 hours at 100° C., the reaction mixture was diluted with EtOAc (200 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL), water (2×100 mL) and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (silica, pet ether/EtOAc) to afford of the title compound as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.26 (1H, s), 8.04 (1H, d), 7.42 (1H, m), 7.35 (1H, d), 7.14-7.27 (3H, m), 4.34 (2H, s), 3.95 (3H, s), 3.30 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C(O[CH:18]=[C:19]([C:23](=[O:25])[CH3:24])[C:20](=[O:22])[CH3:21])C>C(O)C>[C:20]([C:19]([C:23](=[O:25])[CH3:24])=[CH:18][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)(=[O:22])[CH3:21]
Reactant: CCOC=C(C(C)=O)C(C)=O
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CCO
Product: CC(=O)C(=CNc1ccc(C2=NNC(=O)CC2)cc1)C(C)=O

Procedure:
A solution containing 0.38 g of 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one and 0.4 g of 3-ethoxymethylene-2,4-pentanedione in 5 ml of ethanol was refluxed for 1 h. Yield 0.3 g, mp 218°-222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cl)Cc1ccc(Cl)cc1
Yield: 71 %

Procedure:
The requisite p-chlorophenylacetyl chloride was prepared in the following manner. p-Chlorophenylacetic acid (15 g.; 0.088 mole) and thionyl chloride (31.5 g.; 0.0264 mole) were heated at reflux for 2 hours. Excess thionyl chloride was removed in vacuo to afford the acid chloride which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([I:11])=[CH:6][C:3]=1[CH2:4][OH:5]>ClCCl.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:7]([I:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc(I)cc(CO)c1N
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(I)cc(C=O)c1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Freshly dried manganese dioxide (3.3 g) was added to a solution of 2-amino-5-iodo-3-methylbenzyl alcohol (2.0 g) in dichloromethane (50 cm3) under nitrogen and the mixture was stirred for 3 days at room temperature. The mixture was filtered, the filtrate evaporated to dryness, and the solid residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane. Combination and evaporation of appropriate fractions afforded the title compound, m.p. 134° (1.6 g).