Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:21][C:11]3=[N:12][C:13]4[C:18]([C:19](=[O:20])[N:10]3[C:8]=2[CH:9]=1)=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH3:2].[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>>[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25]([N:21]1[C:11]2=[N:12][C:13]3[C:18]([C:19](=[O:20])[N:10]2[C:8]2[CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:26]
Reactant: CCOc1ccc2[nH]c3nc4ccccc4c(=O)n3c2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: CCOc1ccc2c(c1)n1c(=O)c3ccccc3nc1n2C(=O)c1ccc(Cl)cc1Cl

Procedure:
6-(2,4-Dichlorobenzoyl)-9-ethoxybenzimidazo[2,1-b]-quinazolin-12(6H)one is prepared with 9-ethoxybenzimidazo[2,1-b]-quinazolin-12(6H)one and 2,4-dichlorobenzoyl chloride.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N.CCN(CC)CC>C(O)C>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1ccccc1Cl
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 33.6 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (674 mg, 2.0 mmol) in ethanol (200 mL) were added 2-chlorophenylhydrazine hydrochloride (538 mg, 3.0 mmol) and Et3N (0.56 mL, 4.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(2-chlorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (280 mg, 34%).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:32])[C:15](=[O:31])[C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[CH:18][C:17]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:8]=1)C.[OH-].[Li+]>CO.O>[O:31]=[C:15]([C:16]1[N:24]2[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]2)=[CH:18][C:17]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14]([NH:13][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][CH2:5][C:4]([OH:33])=[O:3])=[O:32]
Reactant: CCOC(=O)COc1cccc(NC(=O)C(=O)c2c(-c3ccccc3)cc3ccccn23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1cccc(NC(=O)C(=O)c2c(-c3ccccc3)cc3ccccn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a solution of {3-[2-Oxo-2-(2-phenyl-indolizin-3-yl)-acetylamino]-phenoxy}-acetic acid ethyl ester (0.4 g, 0.90 mmol) in methanol (3 ml) was added lithium hydroxide (38 mg, 1.8 mmol) and a few drops of water. The reaction mixture was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The reaction mixture was diluted with water (10 ml) and adjusted to pH 3 with 2N hydrochloric acid. The product was extracted with ether and the organic layer dried over sodium sulphate, filtered, then evaporated to dryness to yield {3-[2-oxo-2-(2-phenyl-indolizin-3-yl)-acetylamino]-phenoxy}-acetic acid (0.2 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=4)[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH2:28]([O:30][C:31](=[O:41])[C@H:32]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[NH2:33])[CH3:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:33][C@H:32]([C:31]([O:30][CH2:28][CH3:29])=[O:41])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:23])=[CH:20][CH:19]=4)[C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Nc1nc2ccc3c(Nc4ccc(C(=O)O)cc4)cccc3c2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Nc2cccc3c2ccc2nc(N)[nH]c(=O)c23)cc1)C(=O)OCC

Procedure:
A suspension of N-(7-(4-cyanoanilino)-1,2-dihydro-1-oxobenzo[f]-quinazolin-3-yl)pivalamide (82 mg, 0.20 mmol) in ethanol (1 ml) and 1N NaOH (4 ml) was stirred under nitrogen at reflux overnight. The solution was allowed to cool, acidified to pH 3 with concentrated HCl, the resulting suspension stirred for 30 minutes,then filtered. The solid was washed with water and dried at 120° C. under reduced pressure to give 4-((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoic acid. 1H NMR (DMSO-d6, 200 MHz) δ: 6.85 (d, J=9 Hz, 2H, Ar), 7.30 (br s, 2H, NH2), 7.39 (d, J=9 Hz, 1H Ar), 7.43 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 7.73 (d, J=9 Hz, 2H, Ar), 8.28 (d, J=9 Hz, 1H, Ar), 8.85 (s, 1H, C7—NH), 9.44 (d, J=9 Hz, 1H, Ar), 11.5-12.9 (2H, CO2H and N2H). A solution of the foregoing benzoic acid, L-glutamic acid diethyl ester hydrochloride (80 mg, 0.33 mmol) (Aldrich), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (90 mg, 0.20 mmol) (Richelieu Biotechnologies), and triethylamine (90 l, 0.64 mmol) in DMF (6 ml) was stirred at room temperature for 1 hour, then concentrated under high vacuum. The residue was purified by chromatography on silica gel (10-15 g) three times eluting with methanol/methylene chloride. Water (˜5 ml) was added to a solution of the solid in ethanol, the ethanol removed under vacuum, and the solid filtered, washed with water, and dried under high vacuum to give diethyl N-(4-((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-7-yl)amino)benzoyl)-L-glutamate (35 mg). 1H NMR (DMSO-d6, 200 MHz) δ: 1.14 (t, J=7 Hz, 3H, CH3), 1.16 (t, J=7 Hz, 3H, CH3), 1.85-2.15 (m, 2H, gluCH2), 2.40 (t, J=7 Hz, 2H, gluCH2), 4.03 (q, J=7 Hz, 2H, esterCH2), 4.08 (q, J=7 Hz, 2H, esterCH2), 4.30-4.45 (m, 1H, gluCH), 6.63 (br s, 2H, NH2), 6.85 (d, J=9 Hz, 2H, Ar), 7.29 (d, J=9 Hz, 1H, Ar), 7.35 (d, J=8 Hz, 1H, Ar), 7.56 (t, J=8 Hz, 1H, Ar), 7.71 (d, J=9 Hz, 2H, Ar), 8.18 (d, J=9 Hz, 1H, Ar), 8.36 (d, J=7 Hz, 1H, gluNH), 8.64 (s, 1H, C7—NH), 9.45 (d, J=9 Hz, 1H, Ar), 11.22 (br s, 1H, N2H). Mass spectrum (CI-CH4): 532 (M+1, 62.5%), Anal. Calculated for C28H29N5O6.H2O: C, 61.19; H, 5.69; N, 12.74. Found: C, 61.20; H, 5.44; N, 12.68.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.CS(O[CH2:23][CH2:24][N:25]1[C:29](=[O:30])[N:28]([C:31]2[S:32][C:33]([C:37](=[O:46])[NH:38][CH2:39][C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[C:34]([CH3:36])[N:35]=2)[CH:27]=[N:26]1)(=O)=O>>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][CH2:23][CH2:24][N:25]2[C:29](=[O:30])[N:28]([C:31]3[S:32][C:33]([C:37]([NH:38][CH2:39][C:40]4[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=4)=[O:46])=[C:34]([CH3:36])[N:35]=3)[CH:27]=[N:26]2)=[CH:13][CH:12]=1
Reactant: Cc1nc(-n2cnn(CCOS(C)(=O)=O)c2=O)sc1C(=O)NCc1cccnc1
Reactant: Nc1ccc(F)cc1
Agent: NCc1ccc(F)cc1
Product: Cc1nc(-n2cnn(CCNc3ccc(F)cc3)c2=O)sc1C(=O)NCc1cccnc1
Yield: 66 %

Procedure:
Following the procedure as described in Example 47, making variations as required to replace (4-fluorophenyl)methanamine with 4-fluoroaniline to react with 2-(4-(4-methyl-5-(pyridin-3-ylmethylcarbamoyl)thiazol-2-yl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)ethyl methanesulfonate, the title compound was obtained as a colorless solid in 66% yield: mp 163-164° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.56 (br s, 1H), 8.51-8.41 (m, 1H), 8.22 (s, 1H), 7.71-7.62 (m, 1H), 7.23-7.19 (m, 1H), 691-6.75 (m, 3H), 6.54-6.47 (m, 2H), 4.57 (d, J=5.8 Hz, 2H), 4.09-3.92 (m, 3H), 3.53-3.39 (m, 2H), 2.61 (s, 3H); MS (ES+) m/z 454.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[CH:15]1([CH2:18]O)[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:15]1([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH2:17][CH2:16]1
Reactant: OCC1CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCC2CC2)cc1C(F)(F)F
Temperature: 20 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
1-Nitro-4-hydroxy-2-trifluromethylbenzene (5.0 g, 14 mmol) and cyclopropylcarbinol (1.75 g, 24 mmol) were dissolved in THF (20 mL) under nitrogen. Triphenylphosphine (9.5 g, 36 mmol) was added and diethyl azodicarboxylate (5.7 mL, 36 mmol) dissolved in THF (10 mL) was added over 30 minutes. The reaction mixture was stirred at 20° C. for 16 hours and then concentrated in vacuo. The residue was dissolved in ethyl acetate (25 mL) and heptane (40 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (350 g silica) using heptane and ethyl acetate (9:1) as eluent to give 1.4 g of 4-cyclopropylmethoxy-1-nitro-2-trifluoromethylbenzene.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[S:15](=[O:19])(=[O:18])(N)[NH2:16]>O1CCOCC1.C(OC(C)C)(C)C>[C:10]([O:9][C:8](=[O:14])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([S:15]([NH2:16])(=[O:19])=[O:18])[CH3:1])([CH3:11])([CH3:13])[CH3:12]
Reactant: NS(N)(=O)=O
Reactant: CNCCCCNC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: CN(CCCCNC(=O)OC(C)(C)C)S(N)(=O)=O
Temperature: 100 °C
Yield: 63.8 %

Procedure:
A mixture of tert-butyl 4-(methylamino)butylcarbamate (4 g, 19.77 mmoles) and sulfuric diamide (7.6 g, 4 eq) in dioxane (10 mL) was heated at 100° C. in a microwave oven during 30 minutes. The RM was then concentrated in vacuo, and DCM was added. The resulting white precipitate of sulfuric diamide in excess was filtered off, and the filtrate was successively washed with diluted HCl, then brine, dried over magnesium sulfate, filtered and concentrated. Trituration in diisopropyl ether afforded 3.55 g (64% yield) of tert-butyl 4-(methyl(sulfamoyl)amino)butylcarbamate 10b as a white solid; m/z 282 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:26]([O:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[CH:25]=1)=[O:23])[CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO.[Cl-].[Na+]>CC(O)C>[C:38]([O:37][C:26]1[CH:25]=[C:24]([CH:22]([OH:23])[CH2:21][N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:29]=[CH:28][C:27]=1[O:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])(=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C)C(=O)Oc1ccc(C(O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Temperature: -10 °C
Yield: 82.2 %

Procedure:
A suspension of 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(pivaloyloxy)acetophenone (2.0 g.) in 2-propanol (20 ml.) was cooled to -10° C. and sodium borohydride (0.34 g.) added in two portions interspersed by a portion of methanol (4 ml.). After 30 minutes at -10° C. a saturated aqueous solution (150 ml.) of sodium chloride (brine) was added and the mixture was extracted with ether (3×80 ml.). Evaporation of the dried (MgSO4) ethereal extracts gave 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)-N-benzyl-ethylamino]ethanol (1.65 g.) which was dissolved without purification in ethanol (40 ml.). To this solution was added benzyl bromide (0.37 ml., 0.0031 mole) and the mixture was then hydrogenated in the presence of 10% palladium-carbon (0.4 g.) at atmospheric pressure and room temperature during 2 hours. The catalyst was separated, washed with ethanol (10 ml.) and the ethanol washings and reaction solution was evaporated together. The residue was triturated with ether (20 ml.) containing several drops of ethanol to give 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)ethylamino]ethanol hydrobromide, (1.2 g.), m.p. 110°-115° C., identical with that obtained in Example 1.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][N:9]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8]1)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([O-:33])=[O:32].[Na+].[I-].[Na+]>CN(C)C=O>[C:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]2[CH2:8][CH:7]([CH2:6][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[F:24])(=[O:33])=[O:32])[CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=S([O-])c1ccccc1F
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(CC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1F
Yield: 36.5 %

Procedure:
[1-(Diphenylmethyl)azetidin-3-yl]methyl methanesulfonate [Example 1, step 1] (3.15 g, 9.50 mmol), sodium 2-fluorobenzenesulfinate (2.65 g, 14.3 mmol) and sodium iodide (2.18 g, 14.5 mmol) were reacted in dimethylformamide (50 mL) by the procedure of Example I Step 3a to afford the title compound (1.37 g, 36%); 1H NMR (500 MHz, CDCl3) δ 2.80–2.88 (3H, m), 3.33 (2H, t, J=7.0 Hz), 3.57 (2H, d, J=6.9 Hz), 4.28 (1H, s), 7.16 (2H, t, J=7.3 Hz), 7.20–7.26 (5H, m), 7.29–7.35 (5H, m), 7.61–7.65 (1H, m), 7.86–7.90 (1H, m); 19F NMR (471 MHz, CDCl3) δ −108.9; m/z (ES+) 396 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH:9]([C:11]2[N:16]=[N:15][C:14]([NH:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[N:13][CH:12]=2)[CH3:10])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:15]3)=[C:9]([CH3:10])[N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(F)cc3)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc(F)cc4)n3n2)cc(OC)c1OC
Yield: 15.8 %

Procedure:
In a similar manner as described for Example 1, 4-fluoro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 13) (0.16 g, 0.37 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (0.28 mL, 3.0 mmol) gave 7-(4-fluorophenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.024 g) as a yellow solid. 1H NMR (CDCl3): δ8.78 (s, 1H), 8.50-8.42 (m, 2H), 7.17-7.10 (m, 2H), 7.01 (s, 1H), 6.86 (s, 2H), 3.85 (s, 3H), 3.82 (s, 6H), 2.58 (s, 3H). MS m/z 410 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[F:15][C:13]([F:14])([F:16])[C:10]1[N:9]=[CH:8][C:7](/[CH:6]=[CH:5]/[C:4]([OH:17])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.7 %

Procedure:
To a solution of (E)-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)acrylate (2.65 g, 10.8 mmol) in THF/EtOH (1/1, 20 mL) was added 2.28 M NaOH (aq.) (14.2 mL) at rt. The reaction mixture was stirred at rt for 4 h and was then neutralized by adding 1M HCl(aq.). The water-phase was extracted with CH2Cl2/MeOH 9/1 (5×20 mL), the combined organics dried (MgSO4), filtered and evaporated to give the title compound (2.15 g, 9.90 mmol, 91%) as an off white solid. This material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]=[CH:5][C:6]1[S:7][C:8]([C:11](=[O:37])[NH:12][CH2:13][C@H:14]([NH:22][C:23]([O:25][CH2:26][C:27]23[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]4)[CH2:28]2)[CH2:34]3)=[O:24])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:10]=1.[N+](=[CH2:41])=[N-]>CCOCC.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:1][O:2][C:3]([CH:4]1[CH2:41][CH:5]1[C:6]1[S:7][C:8]([C:11](=[O:37])[NH:12][CH2:13][C@H:14]([NH:22][C:23]([O:25][CH2:26][C:27]23[CH2:36][CH:31]4[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]4)[CH2:28]2)[CH2:34]3)=[O:24])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:9][CH:10]=1)=[O:38]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)C=Cc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: COC(=O)C1CC1c1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)OC(C)(C)C)s1

Procedure:
The compound was synthesized analogously to example 3, step b) from 108 mg (0.2 mmol) of 3-(5-(((2S)-2-(1-adamantylmethoxycarbonylamino)-2-tert-butoxycarbonylethyl)carbamoyl)-2-thienyl)-acrylic acid methyl ester and a diazomethane solution in ether (generated from 0.5 g of N-nitroso-N-methyl-urea) in the presence of 10 mg palladium diacetate. 105 mg of a colourless oil were obtained which was sufficiently pure for use in the subsequent step.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12](O)=[O:13])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[ClH:19]>S(Cl)(Cl)=O>[CH2:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])[C:12]([Cl:19])=[O:13])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNS(=O)(=O)c1cc(C(=O)O)ccc1Cl
Reactant: Cl
Solvent: O=S(Cl)Cl
Product: CCCCNS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl

Procedure:
29.4 g of 3-n-butylsulfamoyl-4-chlorobenzoic acid were boiled under reflux in 140 ml of thionyl chloride until complete dissolution and until HCl had finished to develop (about 2 hours), the thionyl chloride was distilled off under reduced pressure and the residue was crystallized under diisopropyl ether. Colorless crystals, melting point: 110° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23](Br)[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[C:37](F)C=C[C:34]=1[N+:40]([O-])=O.[Si](C#C)(C)(C)C.C(N)CCC>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.CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([NH:40][CH2:34][CH2:33][CH2:38][CH3:37])[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])c(Br)c3)c(=O)c2cc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C[Si](C)(C)C
Solvent: CCCCN
Solvent: CN(C)C=O
Product: CCCCNc1cc(-n2ccc3cc(N(C)C(=O)OC(C)(C)C)c(F)cc3c2=O)ccc1[N+](=O)[O-]

Procedure:
[2-(3-Bromo-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester was generated by Method A (Example 46) using 2-bromo-4-fluoro-1-nitro-benzene. A mixture of [2-(3-Bromo-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (21 mg, 0.0427 mmol), tetrakis(triphenylphosphine)palladium(0) (2.5 mg, 0.002 mmol), copper (I) iodide (2 mg, 0.008 mmol), TMS acetylene (10 ul, 0.07 mmol), n-butylamine (1.5 ml) and 1 mL DMF was purged with argon for 2 minutes. The mixture was then subjected to microwave irradiation (120° C.) for 5 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give [2-(3-butylamino-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:26][CH:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NCc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 1-methyl-piperidin-4-ylamine using standard reductive amination conditions. The resulting crude solid was purified on silica using a gradient of 0-20% methanol in ethyl acetate as the eluent to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(1-methyl-piperidin-4-yl)-amine as an off white solid (34% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 333 as an off white solid (35% yield). NMR (CDCl3, 400 MHz), 1.42-1.50 (3H, m), 1.94-2.02 (4H, m), 2.28 (3H, s), 2.54-2.60 (1H, m), 2.84 (2H, d, J=11.9), 3.88-3.91 (4H, m), 4.04-4.06 (4H, m), 4.18 (2H, s), 5.23 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=441
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([NH:41][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCc4ccccc4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and benzylamine. ES-MS m/e (%): 476 (M+H+, 100).