Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[CH:16][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(Cl)Cl.CCO[C:43]([CH3:45])=[O:44]>>[F:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([C:30]([S:33]([CH3:36])(=[O:34])=[O:35])([CH3:32])[CH3:31])[CH:23]=[C:24]3[C:29]=2[N:28]=[CH:27][CH:26]=[CH:25]3)=[CH:16][C:3]=1[CH2:4][N:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[C:43](=[O:44])[C:45]1[CH:18]=[CH:19][CH:2]=[CH:3][CH:4]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(c1cc(-c2ccc(F)c(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Solvent: ClCCl
Product: CC(C)(c1cc(-c2ccc(F)c(CN(C(=O)c3ccccc3)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
Prepared in two steps according to the procedures described in EXAMPLE 44 (Steps 2 and 3) but using {2-fluoro-5-[6-(1-methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-benzyl}-(4-methanesulfonyl-phenyl)-amine from EXAMPLE 61 (Step 4) as the starting material. Flash chromatography (CH2Cl2:EtOAc; 3:7) afforded the title compound as a foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Solvent: O
Product: CCOC(=O)c1c(N2CCOCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
To a stirred solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 100 mg, 0.29 mmol) in a sealed tube was added morpholine (0.038 ml, 0.43 mmol). Then the mixture was stirred at 150° C. for 3 h. After cooling, this reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a crude residue which was purified by flash column chromatography (100-200 mesh silica, eluting with 10% ethyl acetate in hexane) to give 6-chloro-2-morpholin-4-yl-4-phenyl-quinoline-3-carboxylic acid ethyl ester (65 mg, 57%) as pale yellow solid. LC-MS: 397 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][C:12]([O:27]C)=[C:13]([C:23]([O:25][CH3:26])=[O:24])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][C:12]([OH:27])=[C:13]([C:23]([O:25][CH3:26])=[O:24])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(isopropyl(methyl)amino)-7-methoxyquinoxaline-6-carboxylate (500 mg, 1.31 mmol) in dichloromethane (80 mL) was added BBr3 (2.0 mL) dropwise with stirring at −78° C. for 30 minutes. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with dichloromethane (3×80 mL), and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-7-hydroxy-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate as a yellow solid (145 mg, 30%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-])=O)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:17][C:18]1[C:19]([CH:41]2[CH2:45][CH2:44][CH2:43][N:42]2[C:46](=[O:48])[CH3:47])=[CH:20][C:21]2[N:25](COCC[Si](C)(C)C)[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[N:23][C:22]=2[CH:40]=1.[Cl-].[NH4+]>[Cu]=O.N1C=CC=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([O:17][C:18]2[C:19]([CH:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:48])[CH3:47])=[CH:20][C:21]3[NH:25][C:24]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[N:23][C:22]=3[CH:40]=2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1O)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(N)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
53.5 mg of 5-bromo-2-nitro-pyridine, 84.2 mg of cesium carbonate and 25 mg of copper(II) oxide were added to a pyridine (1 ml) solution of 55.0 mg of 1-(2-(6-hydroxy-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 121 (step 10), and the reaction liquid was stirred overnight in a sealed tube at 120° C. After cooled, aqueous saturated ammonium chloride and saturated saline were added in order to the reaction liquid, extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and 0.016 ml of hydrazine monohydrate and 20 mg of developed Raney nickel catalyst were added to an ethanol (2 ml) solution of the resulting residue, and the reaction liquid was stirred at room temperature for 30 minutes. The catalyst was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: CC(C)([O-])C.[K+].CN(C)C=O.[C:12]([OH:15])(=[S:14])[CH3:13].Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>O>[C:12]([S:14][CH2:17][CH2:18][N:19]1[C:20](=[O:29])[C:21]2[C:22](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:24])(=[O:15])[CH3:13]
Reactant: CC(O)=S
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCCN1C(=O)c2ccccc2C1=O
Reaction time: 1 h

Procedure:
0.855 kg (7.9M) Potassium-tert-butoxide is added in portions at -5° under nitrogen atmosphere to 4 1 dimethylformamide. A solution of 0.6 kg (7.9M) thioacetic acid in 2 1 dimethylformamide is added in a steady stream at such a rate that the temperature can be maintained between -5° and 0° . The reaction mixture is then stirred for 1 hour at -5° . 2.0 kg (7.9M) N-(2-bromoethyl)phthalimide in 4 1 dimethylformamide is added to the reaction mixture at such a rate that the temperature does not exceed 5° and the reaction mixture is stirred for 2 hours. 40 1 of water cooled at 5°-10° are added which raises the reaction temperature to 20° . The reaction mixture is stirred overnight at room temperature and filtered. The crude product is washed with water and dried. M.P. 112°-114°.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:9][S:8][CH2:7][CH2:6][N:5]1[S:10]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH:4]2[CH2:9][S:8][CH2:7][CH2:6][N:5]2[S:10]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:26][CH2:25]1
Reactant: CC1CCNCC1
Reactant: O=S(=O)(c1cccc2ccccc12)N1CCSCC1CCCl
Product: CC1CCN(CCC2CSCCN2S(=O)(=O)c2cccc3ccccc23)CC1
Yield: 63 %

Procedure:
The title compound (250 mg, 63%) was prepared according to the procedure outlined in Examples 5-44 using 3-(2-chloroethyl)-4-(naphthalene-1-sulfonyl)thiomorpholine and 4-methylpiperidine. MH+ 419.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.O1CCCC1.O.[OH-].[Li+]>O>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])=[CH:12][CH:11]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(NC(=O)CC4CCCC4)cc23)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Cc1cccc2ccc(NC(=O)CC3CCCC3)cc12
Reaction time: 72 h
Yield: 81 %

Procedure:
To a mixture of methyl 4-[7-(cyclopentyl acetamido)naphth-1-ylmethyl]-3-methoxybenzoate (660 mg), methanol (23 ml) and tetrahydrofuran (23 ml) was added a solution of lithium hydroxide monohydrate (321 mg) in water (7.7 ml). Nitrogen was bubbled through the mixture for 30 seconds before it was stoppered and stirred for 72 h. The reaction mixture was evaporated and the residue taken up in 75 ml of 1:9 tetrahydrofuran:ethyl acetate and acidified with 3 ml of 6N HCl. The organic layer was washed (water, brine), dried (MgSO4) and evaporated. Recrystallization of the resulting solid from 1:9 methanol:methylene chloride and petroleum ether gave the title compound as a colorless solid (517 mg, 81%); mp 248.0°-250.0° C.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][OH:13])([O-:5])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1.Cl>N1C=CC=CC=1>[OH:5][N:3]=[C:6]1[CH:11]=[CH:10][C:9](=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C:23]#[N:24])[CH:8]=[C:7]1[CH2:12][OH:13]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: COc1ccc(CC#N)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(C(C#N)=C2C=CC(=NO)C(CO)=C2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a stirred and cooled (<15° C.) mixture of 134 parts of potassium hydroxide and 940 parts of pyridine were added portion wise 92 parts of 2-nitrobenzenemethanol. Next there were added 132.5 parts of 4-methoxybenzeneacetonitrile and stirring was continued for 4 hours at room temperature. The reaction mixture was diluted with 3000 parts of ice-water and the whole was acidified with 1270 parts of hydrochloric acid. The precipitate was filtered off, stirred overnight in methylbenzene and dried in vacuo at 60° C., yielding 128.8 parts (50.7%) of α-[4-(hydroxyimino)-3-(hydroxymethyl)-2,5-cyclohexadien-1-ylidene]-4-methoxybenzeneacetonitrile (interm. 40).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:31](=[O:33])[NH2:32])[CH:5]=[CH:6][CH:7]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:31](=[O:33])[NH2:32])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(F)c1
Yield: 100 %

Procedure:
A solution of the {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester (40.0 mg, 0.089 mM) in 2 mL of trifluoroacetic acid was stirred at room temperature for 5 hours. The solvent was removed in vacuo. The residue was triturated with ethyl ether, then dried in vacuo to afford 35.0 mg (100%) of the {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid as a white powder. 1H NMR (DMSO-d6) δ 13.0 (br s, 1H), 7.75 (s, 1H), 7.6 (d, 1H, J=8 Hz), 7.5-7.25 (m, 5H), 7.2-6.8 (m, 4H), 6.6 (d, 1H, J=8 Hz), 5.7 (s, 2H), and 4.8 (s, 2H). IR (KBr, cm−1) 3423, 3400, 1736, 1637, 1615, 1589, 1499, 1487, 1450, 1436, 1331, 1250, and 1156. MS (ES) m/e 391, 393.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=2)[C:15]2[C:23]3[C:28]([CH2:29][C:14]1=2)=[CH:27][CH:26]=[CH:25][CH:24]=3.[C:30]([NH:34][Si:35]([CH3:38])([CH3:37])Cl)([CH3:33])([CH3:32])[CH3:31]>CCOCC>[CH3:37][SiH:35]([N:34]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]1[C:14]2[N:13]([CH3:12])[C:21]3[C:16]([C:15]=2[C:23]2[C:28]1=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:17][C:18]([CH3:22])=[CH:19][CH:20]=3)[CH3:38]
Reactant: CC(C)(C)N[Si](C)(C)Cl
Reactant: Cc1ccc2c(c1)c1c(n2C)Cc2ccccc2-1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc2c(c1)c1c(n2C)C(N([SiH](C)C)C(C)(C)C)c2ccccc2-1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
6.66 mL of n-BuLi 2.5 M in hexane (16.65 mmol) were added dropwise at 0° C. to a solution of 3.53 g of N-methyl-2-methyl-5,6-dihydroindeno[2,1-b]indole (Mw=233.32, purity 99.0%, 15.13 mmol) in Et2O. At the end of the addition, the reaction mixture was allowed to warm up to room temperature and stirred for two hours. Subsequently, 3.34 g of (tert-butylamino)dimethylchlorosilane (Mw=165.74, purity 75.0% mol., d=0.887, 20.17 mmol) were added at 0° C. to the Li salt suspension and the resulting mixture was allowed to warm up to room temperature. After three hours stirring, the solvents were evaporated under reduced pressure and the residue was dissolved in 50 mL of toluene, obtaining a dark brown suspension, which was filtered. The filtrate was evaporated to dryness under reduced pressure, obtaining 5.86 g of a dark brown oil, which resulted to be 86.5% wt. pure (calculated by 1H-NMR). Yield=92.4%.
Reaction SMILES: [OH-].[Na+].C([NH:11][C:12]([NH:14][C:15]1[C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[CH:19][C:18]([Br:30])=[CH:17][N:16]=1)=[S:13])(=O)C1C=CC=CC=1>CO>[Br:30][C:18]1[CH:19]=[C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)[C:15]([NH:14][C:12]([NH2:11])=[S:13])=[N:16][CH:17]=1
Reactant: N#Cc1ccc(Oc2cc(Br)cnc2NC(=S)NC(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(Oc2cc(Br)cnc2NC(N)=S)cc1
Temperature: 50 °C
Yield: 73.6 %

Procedure:
Added 3 M aqueous sodium hydroxide (4.41 mL, 13.2 mmol) to a mixture of 1-benzoyl-3-(5-bromo-3-(4-cyanophenoxy)pyridin-2-yl)thiourea (3.00 g, 6.62 mmol) and MeOH (50 mL) and heated to 50° C. for 2 hours. Cooled, partitioned between ethyl acetate and water, washed twice with water, brine, dried, and concentrated. Added ethyl acetate (6 mL), heated to try to afford a solution. Added hexanes (8 mL) slowly, and cooled and triturated for 15 minutes. Filtered, to afford the title compound a (1.70 g, 73.6% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6]O.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[C@@H:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:6][Br:18]
Reactant: COC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](CCBr)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a cooled (0° C.) solution of (S)-2-tert-butoxycarbonylamino-4-hydroxy-butyric acid methyl ester (28.7 g, 123 mmol) in dichloromethane (500 mL) was added CBr4 (51.0 g, 154 mmol). The mixture was stirred for 5 minutes before the portion-wise addition of triphenylphosphine (48.41 g, 185 mmol). The mixture continued to stir at 0° C. for 1 hour and was then allowed to warm to room temperature. The solvent was removed under reduced pressure and was then diluted with ether (500 mL) and stirred for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed eluting with ether/hexanes (1:2) to afford 27.5 g of white solid (76% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[CH3:32]>>[CH3:32][C:31]1[CH:30]=[CH:29][C:28]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:27][C:26]=1[NH2:25]
Reactant: Cc1ccc(B(O)O)cc1N
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C)CC4)cc3n2)cc1N

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 3-amino-4-methylbenzeneboronic acid in general procedure A. Purification by flash chromatography on silica yielded 2-Methyl-5-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-phenylamine. To a solution of 2-Methyl-5-[6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-phenylamine (154 mg) in chloroform (10 ml) and acetic acid (2 ml) was added isoamyl nitrite (55 μL). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with chloroform and washed with a 50/50 mixture of saturated sodium bicarbonate solution and brine, dried (MgSO4) and the solvents were removed in vacuo to give a crude residue. This was purified by flash chromatography to yield the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9][CH2:8]1)=[O:6].[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][C:5]([N:7]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH2:10][CH2:9][CH2:8]3)=[O:6])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CCCCl)N1CCCOc2ccccc21
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: O=C(CCCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (16) synthesized in Reference Example 16 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])C.O.[NH2:29][NH2:30]>C(O)C>[CH2:20]([N:6]([CH2:5][C:4]([NH:29][NH2:30])=[O:3])[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17])(=[O:9])=[O:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NN
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Solvent: CCO
Solvent: O
Product: NNC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 50 °C
Reaction time: 22 h
Yield: 93.3 %

Procedure:
To a stirred solution of [benzyl-(2-trifluoromethyl-benzenesulfonyl)-amino]-acetic acid ethyl ester (2.52 g) in ethanol (15 mL) was added hydrazine monohydrate (1.60 g). The mixture was stirred for 5 h at r.t. and for 22 h at 50° C. The mixture was concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to give N-benzyl-N-hydrazinocarbonylmethyl-2-trifluoromethyl-benzenesulfonamide (2.27 g) as a colorless oil. MS: 388.4 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([NH2:15])=[O:14].C(N(CC)CC)C>C(#N)C>[C:13]([CH2:12][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)CBr
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)COC(=O)c1ccc(O)cc1
Yield: 59.4 %

Procedure:
10 g of p-hydroxybenzoic acid and 10 g of α-bromoacetamide were dissolved in 150 ml of acetonitrile, and 7 g of triethylamine was added to the solution. The resulting mixture was refluxed for 7 hours followed by concentrating under reduced pressure. Water was then added to the residue to obtain 8.4 g of crystals of the above-titled compound having a melting point of 250°-255° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][N:14]2[C:23]3[C:18](=[CH:19][C:20]([I:24])=[CH:21][CH:22]=3)[C:17](=[O:25])[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15]2)[CH2:9]1)=O)(C)(C)C.[ClH:31]>O1CCOCC1>[ClH:31].[I:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH2:13][C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH:15]=[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17]2=[O:25]
Reactant: CCOC(=O)c1cn(C[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ccc(I)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C[C@H]2CCNC2)c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude (S)-ethyl 1-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methyl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 96, ˜4.4 mmol) was dissolved in 1,4-dioxane (20 mL) and 4.0M hydrogen chloride in 1,4-dioxane (20 mL) was added. The reaction mixture was stirred at room temperature for 1 h, and the solvent was removed in vacuo. The solid was then dried in a vacuum oven at 40° C. for 18 h to give 2.3 g (quant. yield) of (S)-ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-ylmethyl)-1,4-dihydroquinoline-3-carboxylate hydrochloride as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][O:11][CH3:12])[N:7]([C:13]3[N:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)[C:6]=2[CH:20]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C@:26]([OH:30])([C:28]#[CH:29])[CH3:27]>N1CCCCC1.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>[NH2:19][C:15]1[N:16]=[CH:17][N:18]=[C:13]([N:7]2[C:6]3[CH:20]=[C:2]([C:29]#[C:28][C@:26]([C:22]4[S:21][CH:25]=[CH:24][N:23]=4)([OH:30])[CH3:27])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][O:11][CH3:12])[N:14]=1
Reactant: C#C[C@@](C)(O)c1nccs1
Reactant: COCc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: COCc1nc2ccc(C#C[C@@](C)(O)c3nccs3)cc2n1-c1ncnc(N)n1
Temperature: 70 °C

Procedure:
To a solution of 4-[6-bromo-2-(methoxymethyl)-1H-1,3-benzodiazol-1-yl]-1,3,5-triazin-2-amine (150 mg at 86% purity, 0.38 mmol) in piperidine (3 mL) was introduced tetrakis(triphenylphosphine)palladium(0) (22.2 mg, 0.02 mmol), copper(I) iodide (7.3 mg, 0.04 mmol) and (2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol (118 mg, 0.77 mmol). The reaction was warmed to 70° C. for 1 hr. After cooling to RT, additional tetrakis(triphenylphosphine)palladium(0) (22.2 mg, 0.02 mmol) was introduced and the reaction mixture warmed to 70° C. for a further 1 hr. The reaction mixture was concentrated in vacuo and the residue purified by silica gel flash chromatography (DCM containing a 0-3% gradient of methanol) to furnish the title compound as a brown oil: 1H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 5.10 (2H, s), 7.06 (1H, br. s.), 7.31-7.40 (1H, m), 7.64-7.73 (2H, m), 7.75-7.80 (1H, m), 8.02 (1H, br. s.), 8.08 (1H, br. s.), 8.30 (1H, s), 8.40-8.45 (1H, m), 8.65 (1H, s); LC-MS: m/z=+408.00 (M+H)+.