Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=4)[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br>C(Cl)Cl.C(O)(=O)C.C(OCC)C>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][NH:38][C:34]2[N:33]=[C:32]([C:19]3[NH:18][C:17]([CH:14]4[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]4)=[N:21][C:20]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[CH:37]=[CH:36][N:35]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(CNc2nccc(-c3[nH]c(C4CCN(C(=O)OCc5ccccc5)CC4)nc3-c3cccc(C(F)(F)F)c3)n2)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(CNc2nccc(-c3[nH]c(C4CCNCC4)nc3-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
To a stirred solution of 4-[5-[2-(4-methoxybenzylamino)-pyrimidin-4-yl]-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (1.0 g, 0.00156 mole) in methylene chloride (16 mL) under argon was slowly added 30% hydrogen bromide in acetic acid (16 mL). The mixture was stirred at 20° C. for 30 minutes and then diluted with diethyl ether (160 mL). The resulting mixture was stirred for I hour, filtered and solid washed with ether (10 mL). The resulting solid was dissolved in 10% aqueous sodium bicarbonate (40 mL) and methylene chloride (50 mL). The methylene chloride was separated and the aqueous layer washed with methylene chloride (25 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to a foam (0.80 g). The solid was chromatographed on silica using methylene chloride/methanol/aqueous ammonium hydroxide (90:10:2) to give upon concentration of product containing fractions 180 mg of the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([O-:7])(O)=O.[Na+].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[N:17]1[C:26]2[C:21](=[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[CH:23]=[C:24]([CH:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)[CH:25]=2)[CH2:20][NH:19]C1=O>CO>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[N:17]1[C:26]2[C:21](=[C:22]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:40])[CH:23]=[C:24]([CH:27]3[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]3)[CH:25]=2)[CH2:20][NH:19][C:4]1=[O:7]
Reactant: NO
Reactant: O=C1CCC(c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1NCc2c(-c3ccccc3Cl)cc(C3CCC(=NO)CC3)cc2N1c1c(Cl)cccc1Cl
Reaction time: 18 h

Procedure:
To a solution of hydroxylamine hydrochloride (29 mg, 0.416 mmol) in methanol (1.0 mL) was added solid NaHCO3 (37 mg, 0.437 mmol). After stirring 15 minutes at RT 1-(2,6-Dichlorophenyl)-5-(2-chlorophenyl)-7-(1-cyclohexanon-4-yl)-3,4-dihydro-2(1H)-quinazolinone (52 mg, 0.104 mmol) (INTERMEDIATE 73) was added. After stirring 18 hours the solution was concentrated. The residue was suspended in DCM and the solid filtered. The filtrate solution was concentrated and the residue purified by preparative thin layer chromatography using 5% MeOH in DCM as the eluent to give 1-(2,6-Dichlorophenyl)-5-(2-chlorophenyl)-7-(1-hydroxyiminocyclohexan-4-yl)-3,4-dihydro-2(1H)-quinazolinone. 1H NMR (CDCl3, 500 MHz): selected data 1.53 (m, 2H), 1.87 (dt, 1H, J=5.4, 14.2 Hz), 1.98 (m, 2H), 2.19 (m, 1H), 2.57 (brd, 1H, J=14.4 Hz), 2.64 (m, 1H), 3.38 (brd, 1H, J=15.2 Hz).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][CH:17]=1.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.O>[O:13]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:3])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1
Reactant: ClCc1ccccc1
Reactant: N#Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)c(CCN1C(=O)c3ccccc3C1=O)cn2Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.16 g) was added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-carbonitrile (2.0 g) in dry dimethylformamide (40 ml) under nitrogen. After 0.5 hour. benzyl chloride was added and after a further 2 hours the mixture was diluted with water (150 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of the washed (H2O) and dried (MgSO4) extract gave a red oil which was triturated with ether and then crystallised from ethanol to give the title compound as yellow microcrystals (1.2 g) m.p. 182°-4° C. T.L.C. Silica, ether Rf 0.45.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:3]=12.C1(O)C=CC=CC=1.[CH3:24][N:25]([CH2:27][CH2:28][NH2:29])[CH3:26]>CCOCC>[CH3:24][N:25]([CH3:26])[CH2:27][CH2:28][NH:29][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:3]=12
Reactant: CN(C)CCN
Reactant: CC1(C)OCc2c1nc1ccccc1c2Cl
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: CN(C)CCNc1c2c(nc3ccccc13)C(C)(C)OC2

Procedure:
A mixture of the starting material of formula I, 9-chloro-1,3-dihydro-3,3-dimethylfuro[3,4-b]quinoline (8.0 g, described in Example 31), phenol (15g) and the amine of formula H--Y--X, dimethylaminoethylamine (9.8 g), is heated at 150° C. for 18 hours under an atmosphere of nitrogen. Ether is added and the reaction is washed with 10% sodium hydroxide solution. The organic phase is extracted with 6 N hydrochloric acid and the aqueous phase is washed with ether. The aqueous phase is basified with 10% sodium hydroxide and extracted with ether. The organic extract is washed with water, dried, evaporated and crystallized from ethyl acetate to yield the title compound, mp 126°-127° C. The corresponding hydrochloride salt of the title compound is crystallized from ethanol, mp 182°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=3)(O)[CH3:13])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=3)\[CH3:13])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([F:23])[CH:16]=3)=[CH2:13])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(C(C)(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C=C(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(OC)c(F)c1
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Temperature: 5 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(3-fluoro-4-methoxyphenyl)propan-2-ol (1 equiv.) was refluxed with 25% sulfuric acid for 2 h. The reaction mixture was cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain 8-chloro-5-((E)-2-(3-fluoro-4-methoxyphenyl)prop-1-enyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole and 8-chloro-5-(2-(3-fluoro-4-methoxyphenyl)allyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, which were separated by HPLC.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1>C(Cl)(Cl)Cl>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C@@H:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: c1cn[nH]c1
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCCCl)CC[C@H]2c2ccc(F)cc2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCn3cccn3)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=428.5 (M+H′) and [α]D20=−67.7° (c=0.2955 in chloroform), was prepared in accordance with the general method of example 82b from (2R,5S)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-pyrazole.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.[H-].[Na+].[CH:16](/[C:22]#[N:23])=[CH:17]\[C:18]([F:21])([F:20])[F:19].[CH2:24](OCC)C>CS(C)=O>[F:19][C:18]([F:21])([F:20])[C:17]1[C:16]([C:10]#[N:11])=[CH:22][NH:23][CH:24]=1
Reactant: N#C/C=C/C(F)(F)F
Reactant: CCOCC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1c[nH]cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of p-tolylsulfonylmethylisocyanide (0.72 g, 3.2 mmol) and sodium hydride (0.09 g, 3.8 mmol) in anhydrous ethyl ether is treated dropwise with a solution of 4,4,4-trifluorocrotonitrile (0.38 g, 3.2 mmol) in ether and dimethyl sulfoxide over a 35 minute period, stirred at room temperature for 20 minutes and quenched with water. The phases are separated and the aqueous phase is extracted with ether. The organic phases are combined, washed with brine, dried over MgSO4 and concentrated in vacuo to afford an orange solid residue. The residue is flash chromatographed using silica gel and 100:100:1 petroleum ether: ethyl ether: acetic acid followed by 100% methylene chloride to give the title product as a white solid, mp 96°-97° C.
Reaction SMILES: CI.[NH2:3][C:4]1[CH:5]=[C:6]([C:10]2[C:18]([CH:19]=[CH:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[CH2:29][CH3:30])=[O:22])=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1.[C:31](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:31][NH:3][C:4]1[CH:5]=[C:6]([C:10]2[C:18]([CH:19]=[CH:20][C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]3[CH2:29][CH3:30])=[O:22])=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(N)c2)nn2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(NC)c2)nn2ccccc12
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 26.7 %

Procedure:
A solution of methyliodide (0.84 g) in N,N-dimethylformamide (2 ml) was added dropwise to a stirred mixture of 1-[3-{2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (1.50 g) and powdered potassium carbonate (0.28 g) in N,N-dimethylformamide (10 ml) at room temperature. After being stirred at room temperature for 2 hours and 50 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (36 g) with a mixture of methylene chloride and acetonitrile (5:1) as an eluent. The fractions containing major product were combined and evaporated in vacuo to give crystals of 1-[3-{2-(3-methylaminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (0.21 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18]4=[C:19]([CH2:21][CH2:22][N:17]4[C:16](=[O:23])[CH2:15][CH2:14]3)[CH:20]=2)=[O:10])[CH2:3][CH2:2]1.Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1>>[ClH:33].[Cl:33][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][N:1]2[CH2:2][CH2:3][CH:4]([CH2:7][CH2:8][C:9]([C:11]3[CH:12]=[C:13]4[C:18]5=[C:19]([CH2:21][CH2:22][N:17]5[C:16](=[O:23])[CH2:15][CH2:14]4)[CH:20]=3)=[O:10])[CH2:5][CH2:6]2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CCC1CCNCC1)c1cc2c3c(c1)CCN3C(=O)CC2
Reactant: Clc1cccc(CCBr)c1
Product: Cl
Product: O=C(CCC1CCN(CCc2cccc(Cl)c2)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Yield: 84.3 %

Procedure:
Using 8-[3-(4-piperidinyl)propanoyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (500 mg) and 1-(2-bromoethyl)-3-chlorobenzene (394 mg) according to the same method as that of Example 81, the title compound (369 mg) was obtained as colorless crystals having a melting point of 223 to 225° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].Cl[S:22]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:28]([O:30][CH3:31])=[O:29])(=[O:24])=[O:23]>C(Cl)Cl.N1C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:25]([S:22](=[O:23])(=[O:24])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:26]=1
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol) in DCM (2 mL) and pyridine (2 mL), methyl 3-(chlorosulfonyl)-4-methoxybenzoate (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 350 mg of 3-[2-(benzo[b]thiophene-2-sulfonylamino)phenylsulfamoyl]-4-methoxybenzoic acid methyl ester. Tr 1.10 min, MS: 533.7 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 3.84 (s, 3H), 4.18 (s, 3H), 7.0-7.2 (m, 5H), 7.4-7.6 (m, 3H), 7.66 (s, 1H), 7.80 (d, 1H), 7.83 (d, 1H), 8.22 (dd, 1H), 8.34 (d, 1H) ppm.
Reaction SMILES: Br[C:2]1[N+:3]([O-:8])=[N:4][CH:5]=[CH:6][N:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH2:18])=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C>CC#N>[F:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([CH3:20])([CH3:19])[CH2:17][NH:18][C:2]2[N+:3]([O-:8])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:14][CH:15]=1
Reactant: [O-][n+]1nccnc1Br
Reactant: CC(C)(CN)c1ccc(F)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CNc1nccn[n+]1[O-])c1ccc(F)cc1
Yield: 41.6 %

Procedure:
A solution of 3-bromo-1,2,4-triazin-2-oxide (2.0 g, 11 mmol), (2-(4-fluorophenyl)-2-methylpropan-1-amine (3.0 g, 17 mmol), and diisopropylethylamine (3.0 mL, 17 mmol) in CH3CN (20 mL) was stirred at rt for 24 h. The solvents were removed and the residue dissolved in EtOAc. The solution was washed with saturated NaHCO3, dried over Na2SO4, and evaporated to dryness. The residue was mixed with ether and then filtered to give the desired product (1.2 g) as a yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[N:15]=[C:14]([O:20][CH3:21])[CH:13]=[CH:12]2>ClCCl>[C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([CH3:19])[CH:18]=1)[N:15]=[C:14]([O:20][CH3:21])[CH:13]=[CH:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2cc(N)cc(C)c2n1
Solvent: ClCCl
Product: COc1ccc2cc(NC(C)=O)cc(C)c2n1

Procedure:
A solution of acetic anhydride (0.55 cm3) in dichloromethane (20 cm3) was added dropwise to a stirred solution of 6-amino-2-methoxy-8-methylquinoline (1.0 g) in dichloromethane (30 cm3) at room temperature. After 1 hour the solution was diluted with dichloromethane (50 cm3), washed with saturated sodium carbonate solution (10 cm3), and dried (MgSO4). Evaporation of the solution in vacuo afforded to a solid which was recrystallised from dichloromethane/hexane to give 6-acetamido-2-methoxy-8-methylquinoline, m.p. 193°-196° (1.143 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:12]=[C:11]([CH2:13][N:14]3[CH:18]=[C:17]([NH2:19])[CH:16]=[N:15]3)[CH:10]=[CH:9][CH:8]=2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[N:12]=[C:11]([CH2:13][N:14]2[CH:18]=[C:17]([NH:19][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:32])[CH:16]=[N:15]2)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cccc(Cn3cc(N)cn3)n2)OCCO1
Product: CC(=O)c1cccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[6-(2-methyl-[1,3]dioxolan-2-yl)-pyridin-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.99 min; [M+H]+=388.43.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(Cl)c1ccccc1Cl

Procedure:
As described for Reference Example 21, 3.13 g of 2-chlorobenzoic acid is reacted with 40 ml of thionyl chloride to give 3.32 of product as an off-white semi solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:33]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][N:10]([CH3:33])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: CN1CCN(c2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Product: CN1CCN(c2ccc(Nc3nccc(-c4cn(C)nc4-c4ccc(Cl)cc4)n3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 55 starting from {4-[3-(4-chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (Example 1) and using methanol instead.
Reaction SMILES: C(NC(C)C)(C)C.[O:8]=[C:9]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][NH:10]1.Br[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([S:38]([C:41]2[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH:30]=1>C1COCC1>[O:8]=[C:9]1[C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH2:13][CH2:12][CH2:11][N:10]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([S:38]([C:41]2[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=2)(=[O:40])=[O:39])[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CBr)c3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2=O)CC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (1.238 mL, 8.60 mmol) in THF (40 mL) n-butyllithium (6.01 mL, 9.61 mmol) was added at 0° C. and the mixture was stirred for 30 min at 0° C. Then a solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate [1198284-94-4] (2.57 g, 9.28 mmol) in THF (10 mL) was added within 3 min and the mixture was stirred for 30 min at 0° C. 3-(bromomethyl)-1-tosyl-1H-indole [58550-81-5] (3.2 g, 8.43 mmol) in THF (10 mL) was dropped to the reaction mixture within 15 min. The mixture was stirred at 0° C. for 1 h and allowed to warm to room temperature overnight. The reaction mixture was quenched with ice-cold water and extracted with TBME (2×150 mL). The combined organic layers were washed with 5% aqueous citric acid and brine, dried over anhydrous Na2SO4, filtered and concentrated (5.3 g, 100%). [1H NMR (400 MHz, DMSO-d8) ♀ ppm 7.88 (d, J=8.28 Hz, 1H), 7.81 (d, J=8.28 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J=7.78 Hz, 1H), 7.36 (d, J=8.03 Hz, 2H), 7.32 (t, J=7.91 Hz, 1H), 7.25-7.21 (m, 1H), 4.58 (s, 2H), 3.75-3.63 (m, 2H), 3.09 (t, J=5.77 Hz, 2H), 2.99 (br. s., 2H), 2.30 (s, 3H), 1.90-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.39 (s, 9H), 1.36-1.28 (m, 2H); LCMS RtA=1.37 min, [M+H]+=552.3].
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[N:28]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60].O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:48])[NH:7][CH2:8][CH2:9][N:10]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[N:28]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:27]=[N:26][N:25]=2)=[CH:14][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 114.7 %

Procedure:
Intermediate (7a) (3.3 g, 5.2 mmol) was dissolved in DCM and cooled to 0° C. DIPEA (2.7 mL, 15.6 mmol) was added, followed by benzyl chloroformate (804 μL, 5.7 mmol). After 90 minutes, water (20 mL) was added and the mixture was extracted DCM (3×80 mL) then washed with saturated aqueous NaCl. The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo to afford intermediate (7b) as a white solid (4.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.CC(OC(=O)[N:29]([CH2:33][CH3:34])[CH2:30][CH:31]=[CH2:32])(C)C>>[ClH:1].[ClH:1].[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH2:32][CH2:31][CH2:30][NH:29][CH2:33][CH3:34])[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: C=CCN(CC)C(=O)OC(C)(C)C
Product: CCNCCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Product: Cl
Yield: 57.1 %

Procedure:
Prepared according to the method of example 15, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (500 mg) and ethyl(2-propenyl)carbamic acid 1,1-dimethylethyl ester (330 mg). Recrystallisation (methanol/ethyl acetate) afforded the title compound as a solid (195 mg).