Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].C(=O)(O)[O-].[Na+]>C(O)C>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Yield: 82.8 %

Procedure:
A mixture of 2.1 g (7.6 mmol) of 4-chloro-7-ethoxy-6-nitro-3-quinolinecarbonitrile and 0.91 ml (8.3 mmol) of 3-bromo aniline in 100 ml ethanol was refluxed under nitrogen for 4.5 hours. The reaction mixture was poured into diluted sodium bicarbonate solution. Ethanol was removed under vacuum. The mixture was diluted with ethyl acetate and the organic layer was separated and dried over sodium sulfate. The solution was concentrated and solid was collected and then washed with hexane. Upon drying, 2.6 g of yellow solid obtained: mass spectrum (electrospray, m/e) M+H 412.8 and 414.9.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>CN1CCCC1=O>[N:21]1[CH:22]=[CH:23][C:18]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:19][CH:20]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Yield: 60.7 %

Procedure:
A solution ethyl 3-aminoindole-2-carboxylate (4.94 g, 24.2 mmole) and 4-chloropyridine hydrochloride (3.63 g, 24.2 mmole) in 70 mL of 1-methyl-2-pyrrolidinone was heated at 165° C. for 6 hours. The reaction mixture was then quenched into water and the aqueous phase was washed with ethyl acetate. After basification with a potassium carbonate solution, a solid was filtered, rinsed with water and ether and dried to give 4.13 g of a brown solid. A 2.2 g portion was recrystallized from methanol (charcoal treatment) to give 1.40 g of an off-white solid, mp: 248°-250° C. (dec.)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[B:15]([O:24]C(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>CCCCCC.C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([O:16][B:15]([OH:24])[OH:20])[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)Oc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a mixture of 1-bromo-3,5-difluorobenzene (743 mmol) and 500 ml of THF was added dropwise 500 ml of a solution of n-butyl lithium (corresponding to 780 mmol) in hexane at −78° C. in 1.6 hours, and stirred at the same temperature for 1.5 hours. To this solution was wadded dropwise 200 ml of a solution of triisopropyl borate (1,486 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 750 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from about 1,000 ml of toluene to give a white solid of 3,5-difluorophenyl boric acid (520 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O[C:15]1(O[Si](C)(C)C)[CH2:17][CH2:16]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH:15]2[CH2:17][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1cc(Cl)ccc1NC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of 500 mg of 2-amino-5-chloro-benzoic acid (2.91 mmol) in methanol were added 3 Å molecular sieves, 2.34 ml of [(1-ethoxycyclopropyl)oxy]trimethylsilane (11.66 mmol) and 1.67 ml of acetic acid and the mixture was stirred for 30 min at RT. Then 916 mg of sodium cyanoborohydride (14.57 mmol) were added and the reaction mixture was heated to reflux for 16 h. The reaction mixture was allowed to cool to RT, filtered and the filtrate was concentrated in vacuo. The remaining solid was dissolved in ethyl acetate and the solution was washed with 1N HCl and brine, dried (MgSO4), filtered and concentrated to give 312 mg of the crude title compound that was used in the following step without further purification. 1HNMR (DMSO-d6, 300 MHz): δ 0.46 (m, 2H), 0.79 (m, 2H), 3.44 (m, 1H), 7.10 (d, J=8.9 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.70 (s, 1H), 7.89 (br s, 1H), 13.09 (br s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[C:12](Cl)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17].[NH:32]1[CH2:36][CH2:35][C@H:34]([CH2:37][OH:38])[CH2:33]1>CC(O)C.CCOC(C)=O>[Br:10][C:11]1[C:12]([N:32]2[CH2:36][CH2:35][C@H:34]([CH2:37][OH:38])[CH2:33]2)=[N:13][CH:14]=[C:15]([CH:30]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=[O:17]
Reactant: OC[C@H]1CCNC1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Temperature: 140 °C

Procedure:
DIPEA (4.89 mL, 28.0 mmol) was added to a solution of 5-bromo-6-chloro-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 11.2, 2.88 g, 7.0 mmol) and (S)-1-pyrrolidin-3-yl-methanol (1.156, 8.40 mmol) in iPrOH (7.0 mL) in a vial, which was sealed and then heated at 140° C. for 1 h. After cooling at RT, the RM was dissolved in EtOAc, washed with aq. 0.5 M HCl and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was triturated with iPr2O, filtered and dried to give the title compound as a beige crystalline powder. HPLC (Condition 4) tR=6.17 min, UPLC-MS (Condition 3) tR=1.20 min, m/z=476.2/478.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[Cl:52][C:48]1[CH:47]=[C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:51]=[CH:50][CH:49]=1
Reactant: [O-]B([O-])Oc1cccc(Cl)c1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cccc(Cl)c4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-chlorophenyl borate (108 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(3-chlorophenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 116) (64 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To a solution of 2-(4-aminobenzyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (139 mg) in tetrahydrofuran (5 ml) was added triethylamine (0.083 ml) and then methanesulfonyl chloride (0.028 ml) was added. The mixture was stirred at room temperature for 3 hrs. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1→2/3) to give the title compound (90 mg, 55%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl[CH2:20][CH2:21][OH:22]>C(O)C.C1C=CC=CC=1>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:20][CH2:21][OH:22])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CCO
Product: CC(C)(C)c1cc(SCCO)cc(C(C)(C)C)c1O

Procedure:
Using the equipment described in Example I, 2,6-ditertiary butyl-4-mercaptophenol (50 grams) was dissolved in 90 millimeters of ethanol (denatured alcohol) and 30 millimeters of benzene. A solution of 12 grams of KOH in 60 millimeters of ethanol was added under a nitrogen blanket. 2-Chloroethanol (19 grams) was slowly added dropwise at room temperature. The combination was reacted for three hours and then diluted with benzene and washed with water. The volatiles were then stripped off.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:44][O:45][C:46]1[CH:52]=[CH:51][CH:50]=[CH:49][C:47]=1[NH2:48]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:48][C:47]4[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=4[O:45][CH3:44])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccccc1N
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4OC)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 68 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 2-methoxyaniline yielded the title compound (68% yield) as a yellow foam. MS (ISP): m/z=696.5 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[OH-:33].[Li+].C[O:36]CCOC>O.C(OCC)(=O)C>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[C:20]([OH:22])=[O:36])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc3c(c2)OCO3)C(=O)O1
Reactant: COCCOC
Reactant: [OH-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc2c(c1)OCO2)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 278 mg of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-[(3,4-methylenedioxyphenyl)methyl]dihydrofuran-2-(3H)-one in 10.25 ml of ethylene glycol dimethyl ether and 5.15 ml of water is treated dropwise, at RT, with 2,53 ml of a 1M lithium hydroxide solution. After that, the reaction mixture is stirred at RT for 3 h. diluted with ethyl acetate and low, and washed in a separating funnel until neutral with a mixture consisting of 31 ml of sat. ammonium chloride solution and 2.6 ml of 10% citric acid solution, followed by saline and water. The title compound, which is subjected to further processing without any further purification, is obtained after drying over sodium sulfate and removing the solvent. FAB-MS (M+H)+ =458.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39]O)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[N:20]([CH2:39][CH2:38][N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1
Reactant: CN1CCN(CCO)CC1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CCN(C)CC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-5-[(1-{[4-(Methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 2-(4-methylpiperazin-1-yl)ethanol following General Procedure J.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([NH2:27])[CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1>C(OCC)(=O)C>[ClH:1].[ClH:15].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([CH:22]([NH:27][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:14])[CH:3]=2)[CH2:23][N:24]([CH3:25])[CH3:26])=[CH:20][CH:21]=1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Reactant: CN(C)CC(N)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: COc1cccc2c(NC(CN(C)C)c3ccc(Cl)cc3)cc(C)nc12
Product: Cl
Yield: 60.4 %

Procedure:
4-Chloro-8-methoxy-2-methylquinoline (2.00 g, 9.63 mmole), 1-(4-chlorophenyl)N*2*,N*2*-dimethylethane-1,2-diamine (2.30 g, 11.6 mmole), sodium tert-butylate (1.3 g, 13.5 mmole), tris(dibenzylidenaceton)-dipalladium(0) (0.18 g, 0.193 mmole) and 2-dicyclohexyl-phosphino-2(N,N-dimethylamino)biphenyl (0.27 g, 0.674 mmole) were stirred at 150° C. under nitrogen atmosphere in a microwave oven for 30 min. The reaction mixture was dissolved in ethyl acetate and filtered. The filtrate was extracted with water. The organic phases were dried, concentrated and the residue was purified using silica gel chromatography, eluting with dichloromethane:methanol 90:10. Precipitation in isopropanol/HCl and in ethyl acetate gave the product (1.55 g, 36%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[CH3:19])/[C:14]([O:16]CC)=[O:15])[CH:9]=[CH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1)[CH3:4]>C(O)C.C(OCC)C.CCCCC>[CH2:3]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[CH3:19])/[C:14]([OH:16])=[O:15])[CH:9]=[CH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1)[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)OCC)cc2OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: CCCCC
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\C)C(=O)O)cc2OCC)c1
Temperature: 50 °C
Yield: 74.6 %

Procedure:
297 mg (7.4 mmol) of sodium hydroxide are added to a solution of 357 mg (0.74 mmol) of ethyl (E)-3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methylacrylate in 15 mL of ethanol. The reaction mixture is heated at 50° C. for 3 hours. After cooling, the medium is evaporated to dryness, taken up in water, acidified with 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulfate and filtered. The solvent is evaporated off and the solid obtained is taken up in a mixture of ethyl ether and pentane, filtered and dried. 250 mg (75%) of (E)-3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methylacrylic acid are obtained in the form of a white powder with a melting point of 123° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([SH:31])([C:27]([F:30])([F:29])[F:28])[CH2:10][C:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]3[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:26])[CH:14]=2)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:32]OS(O)(=O)=O.[OH-].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[S:31][N:32]=[C:11]([C:13]3[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]4[CH2:23][S:22][CH2:21]4)=[O:18])=[C:15]([CH3:26])[CH:14]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1CSC1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-methyl-N-thietan-3-yl-benzamide (493 mg) dissolved in a minimum amount of tetrahydrofuran then was added Hydroxylamine-O-sulfonic acid (2 equiv.). Then a solution of potassium hydroxide (5.6 equiv.) in water (19 mL) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was quenched with a solution of hydrochloric acid (1N), extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The crude mixture was then redissolved in a minimum amount of tetrahydrofuran then was added Hydroxylamine-O-sulfonic acid (2 equiv.) Then a solution of potassium hydroxide (5.6 equiv.) in water (19 mL) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was quenched with a solution of hydrochloric acid (1N), extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isothiazol-3-yl]-2-methyl-N-thietan-3-yl-benzamide (128 mg)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[C:12]([Si:15]([O:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1c(F)cc(Br)cc1F
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cc(Br)cc1F

Procedure:
The title compound was prepared by reacting 4-bromo-2,6-difluoro-phenol (10.54 g, 50.4 mmol) with TBDMS-Cl (9.88 g, 150.7 mmol) according to method E to yield 14.61 g (90%) of a clear, colorless, oil: 1H NMR (CDCl3) δ 0.17 (6H, s), 0.99 (9H, s), 7.02 (H, d, J=7.13 Hz).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:12]=2[O:13][CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH:36](I)([CH3:38])[CH3:37].Cl>CN(C=O)C.O>[CH:36]([N:10]([S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:8])=[O:9])[C:11]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:12]=1[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)([CH3:38])[CH3:37]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(COc2ccc(Cl)cc2NS(=O)(=O)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(COc2ccc(Cl)cc2N(C(C)C)S(=O)(=O)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 9 h

Procedure:
To a solution of methyl 4-(2-phenylsulfonylamino-4-chlorophenoxymethyl)benzoate (402 mg; prepared in Example 7(a).) in DMF (4 ml), potassium carbonate (256 mg) and isopropyl iodide (185 μl) were added. The mixture was stirred overnight at room temperature and for 9 hours at 50° C. To the reaction solution, iced water and 2N HCl were added. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over, concentrated after filtration, solidified with ethanol and washed to give the title compound (411 mg) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:12]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[C:9]32)=[CH:4][CH:3]=1.Cl.C(O)C>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][NH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:13][C:12]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[C:9]32)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccc(Cl)cc3c12
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CN(C)C(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1cc(Cl)ccc1CN2

Procedure:
from 10-chloro-N,N-dimethyl-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazine-1-carboxamide in methanol/glacial acetic acid (10:1), but without the addition of saturated methanolic hydrochloric acid, there is obtained 10-chloro-6,7-dihydro-N,N-dimethyl-4-oxo-3-phenyl-4H-pyrido[2,1-a]-phthalazine-1-carboxamide of m.p. 250°-252° (ethanol);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[CH2:12](N(CC)CC)C.CI>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:12])=[N:7][C:6]=2[CH:11]=1
Reactant: CCN(CC)CC
Reactant: Sc1nc2cc(Br)ccc2s1
Solvent: CCO
Solvent: CI
Product: CSc1nc2cc(Br)ccc2s1
Yield: 78.4 %

Procedure:
To a solution of 5-bromobenzo[d]thiazole-2-thiol (24 mg, 0.098 mmol) in EtOH (1.5 mL) was added triethylamine (10 mg, 0.098 mmol) and methyliodide (14 mg, 0.098 mmol). The mixture was heated at reflux for 1.5 h. Then the mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give 5-bromo-2-(methylthio)benzothiazole 20 mg (80%).