Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:22])[CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:35]=[CH:34][N:33]=[CH:32][C:31]2=[O:36])=[CH:26][C:25]=1[F:37]>>[F:37][C:25]1[CH:26]=[C:27]([N:30]2[CH:35]=[CH:34][N:33]=[CH:32][C:31]2=[O:36])[CH:28]=[CH:29][C:24]=1[NH:23][C:4]([CH2:5][N:6]1[CH2:10][C@H:9]([O:11][CH3:12])[C@@H:8]([NH:13][C:14]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[O:15])[CH2:7]1)=[O:22]
Reactant: CCOC(=O)CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Product: CO[C@H]1CN(CC(=O)Nc2ccc(-n3ccncc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
Using general procedure F {(3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-pyrrolidin-1-yl}-acetic acid ethyl ester (example 25.2) was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one (prepared from 2-fluoro-4-iodoaniline by reaction with 1H-pyrazin-2-one, Cu(I)I, N,N′-dimethylethylenediamine and cesium carbonate in dioxane at 120° C.) to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-1-{[2-fluoro-4-(2-oxo-pyrazin-1-yl)-phenylcarbamoyl]-methyl}-4-methoxy-pyrrolidin-3-yl)-amide. Yellow solid. MS 506.3 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([Br:30])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Yield: 50.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (65 mg, 0.17 mmol) and N-bromosuccinimide (31 mg, 0.18 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (10-80% EtOAc/hexanes+1% AcOH) to give 40 mg of the title compound. MS: (+) m/z 466.17, 468.12 (M+1, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[O:38]1[CH2:42][CH2:41][CH:40]([C:43](=[S:45])[NH2:44])[CH2:39]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:45][C:43]([CH:40]3[CH2:41][CH2:42][O:38][CH2:39]3)=[N:44][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Reactant: NC(=S)C1CCOC1
Agent: O=C1CCC(=O)N1Br
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCOC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1.00 g, 2.26 mmol), NBS (0.423 g, 2.38 mmol) and tetrahydro-3-furancarbothioamide (0.386 g, 2.94 mmol) the title compound of Step D was obtained as an orange solid (890 mg, 1.42 mmol, 62.6% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (s, 1H), 8.56 (d, J=5.5 Hz, 1H), 7.59-7.83 (m, 1H), 7.40-7.55 (m, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.24 (t, J=9.1 Hz, 2H), 6.87 (d, J=5.3 Hz, 1H), 3.98-4.09 (m, 1H), 3.71-3.99 (m, 4H), 2.35-2.48 (m, 1H), 2.09-2.28 (m, 1H). MS (ESI) 553.03 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)=[O:10])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)=[O:10])=[CH:22][CH:23]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)CC(=O)N3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1Cc2cc(NC(=O)c3ccc(C(=O)O)cc3)ccc2N1
Yield: 87.3 %

Procedure:
5-(4-Methoxycarbonylbenzamido)-2-oxindole (0.9 g) and 0.4 g of sodium hydroxide in 25 mL of methanol were refluxed for 3 hours. The mixture was concentrated, water added, and the mixture acidified with 6N hydrochloric acid. The precipitate was collected by vacuum filtration to give 0.75 g (87%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[O:9][C:10]([CH3:24])([CH3:23])[CH:11]([C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)[S:12](=[O:15])(=[O:14])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25]C(C)([O-])C.[K+].CI>CN1C(=O)CCC1.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH:1]1([NH:7][C:8]2[O:9][C:10]([CH3:24])([CH3:23])[CH:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:25])[CH:17]=3)[S:12](=[O:15])(=[O:14])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(NC2CCCCC2)=NS(=O)(=O)C1c1cccc(O)c1
Reactant: CC(C)(C)[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccc(C2C(C)(C)OC(NC3CCCCC3)=NS2(=O)=O)c1
Yield: 43.5 %

Procedure:
To a solution of 120 mg of 3-(2-cyclohexylamino-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda6-[1,4,3]oxathiazin-5-yl)phenol in 2 ml of NMP were added, at room temperature, 38 mg of potassium tert-butoxide and 97 mg of methyl iodide, and the reaction mixture was stirred at constant temperature for 2.5 hours. The reaction solution was diluted with 60 ml of water, 5 ml of 5% aqueous sodium thiosulfate solution were added, and the mixture was extracted twice with 30 ml of ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation, and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fraction was lyophilized. This gave the product (54 mg) with a molecular weight of 366.5 g/mol (C18H26N2O4S); MS (ESI): m/e=367 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:21])=[CH:18][CH:17]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a mixture of N-methylpiperizine (1.00 g, 10 mmol) and Et3N (2.1 mL, 15 mmol) in CH2Cl2 (50 mL) at rt was added 4-bromobenzoyl chloride (2.195 g, 10 mmol) in one portion. The reaction was heated to reflux briefly and cooled. The resulting mixture was stirred O/N at rt. The reaction was quenched with H2O (30 mL) and sat. NaHCO3 (10 mL), separated and dried (Na2SO4). Evaporation of solvents afforded the title compound as a pale yellowish white solid (2.69 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 3.70-3.20 (m, 4H), 2.40-2.15 (m, 7H; s, 3H at 2.18 ppm and m, 4H overlapping); MS ESI 283.0[M+H]+, calcd. for [C12H15BrN2O+H]+ 283.0.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([CH3:28])[O:27][CH2:26][CH2:25][NH:24][CH2:23]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:24]3[CH2:25][CH2:26][O:27][C:22]([CH3:28])([CH3:21])[CH2:23]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: Cn1c(CCN2CCOC(C)(C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (116 mg, 0.39 mmol) in DCE (10 mL) was added 2,2-dimethylmorpholine (68 mg, 0.59 mmol), trimethyl orthoformate (0.22 mL, 1.96 mmol) and acetic acid (0.02 mL, 0.39 mmol). The reaction mixture was stirred at room temperature for 3 h, sodium triacetoxyborohydride (125 mg, 0.59 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, he cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in EtOAc) to give the title compound as a pale yellow solid (100 mg, 65%). LCMS (Method H): RT=2.51 min, [M+H]+ 395.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([C:14](=[O:20])[CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:11]=[C:10]([O:21][CH3:22])[C:4]=1[N:5]([CH3:9])[C:6](=[O:8])[CH3:7].[BH4-].[Na+]>C(O)C>[OH:20][CH:14]([C:12]1[CH:13]=[C:3]([O:2][CH3:1])[C:4]([N:5]([CH3:9])[C:6](=[O:8])[CH3:7])=[C:10]([O:21][CH3:22])[CH:11]=1)[CH2:15][S:16]([CH3:19])(=[O:17])=[O:18]
Reactant: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1N(C)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1N(C)C(C)=O

Procedure:
A suspension of 20.9 g. of 2',6'-dimethoxy-N-methyl-4'-[(methylsulfonyl)acetyl]-acetanilide and 9.5 g. of sodium borohydride in 300 ml. of ethanol was stirred at room temperature for 20 hours. The solution was diluted with 300 ml. of water and the alcohol removed under vacuum. The resulting suspension was extracted with two 1 liter portions of ethyl acetate. The ethyl acetate extracts were washed with two 200 ml. portions of water, combined, dried over magnesium sulfate and evaporated under vacuum. Recrystallization of the residue from ethyl acetate gave 4'-[1-hydroxy-2-(methylsulfonyl)-ethyl]-2',6'-dimethoxy-N-methylacetanilide having a melting point of 175°-177° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:25]2[CH:30]=[CH:29][C:28]([N:31]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=O)=O.[Br-:48].[Li+].O1CCCC1>O>[Br:48][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:25]2[CH:30]=[CH:29][C:28]([N:31]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[CH:12][CH:11]=1
Reactant: [Br-]
Reactant: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCOS(C)(=O)=O)cc3)cc2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCBr)cc3)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a dry schlenk flask was added 3-(4-((4-(bis(4-methoxyphenyl)amino)phenyl)(4-methoxyphenyl)amino)phenoxy)propyl methanesulfonate (4.06 g, 6.20 mmol). The flask was evacuated under vacuum and filled with nitrogen. Lithium bromide (5.39 g; 62.0 mmol) and tetrahydrofuran (6.2 mL) were added under nitrogen. The mixture was allowed to stir at 60° C. overnight. Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 100 mL of cold water. The product was extracted using 3×50 mL ether. The organic layers were combined and washed with 3×50 mL of water. The resulting ether layers were dried over Na2SO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure. The residual solvent was removed in vacuo (3.12 g, 78.2%). 1H NMR (400 MHz, C3D6O) δ 6.97 (m, 8H), 6.86 (m, 8H), 6.80 (s, 4H), 4.09 (t, J=5.9 Hz, 2H), 3.75 (s, 9H), 3.66 (t, J=6.6 Hz, 2H), 2.28 (q, J=6.2 Hz, 2H). 13C{1H} NMR (400 MHz, C3D6O) δ 156.39, 155.34, 143.71, 143.51, 142.22, 127.05, 126.27, 126.03, 123.90, 123.70, 116.10, 115.40, 114.61, 66.34, 55.62, 33.25, 31.05. HRMS-EI (m/z): [M]+ calcd for C36H35BrN2O4, 640.18; found, 640.1). Anal. Calcd for C36H35BrN2O4: C, 67.60; H, 5.52; N, 4.38. Found: C, 67.43; H, 5.61; N, 4.24.
Reaction SMILES: [CH:1]([O:3][CH2:4]C)=C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(N(CC)CC)C.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>>[CH3:33][CH:32]([O:31][C:28]([CH3:29])=[O:30])[CH2:1][O:3][CH3:4]
Reactant: C=COCC
Reactant: CCOC(C)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Product: COCC(C)OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
To the reaction solution above, 1.68 g of ethyl vinyl ether and 0.48 g of 2% camphorsulfonic acid (PGMEA solution) were added, and the mixture was stirred at room temperature for 4 hours. Thereafter, 0.35 g of 6% triethylamine (PGMEA solution) was added and after stirring for a while, and the reaction solution was transferred to a separating funnel containing 55 mL of ethyl acetate. The organic layer was washed with 50 mL of distilled water three times and then concentrated by an evaporator, and ethyl acetate was removed. This reaction solution was added dropwise in 800 mL of hexane. A part of the obtained precipitate was sampled for NMR measurement, and the remaining was dissolved in 25 g of PGMEA. From the obtained solution, the low boiling point solvent was removed by an evaporator to obtain 36.1 g of a PGMEA solution (28.9%) of Resin (R-3).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[C:27]1([CH:33]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36](O)([C:43]3[C:44]([OH:54])=[CH:45][C:46]4[O:50][CH2:49][C:48]([CH3:52])([CH3:51])[C:47]=4[CH:53]=3)[C:35]2=[O:56])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:57]1([CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]([C:43]3[C:44]([OH:54])=[CH:45][C:46]4[O:50][CH2:49][C:48]([CH3:51])([CH3:52])[C:47]=4[CH:53]=3)[C:35]2=[O:56])[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CC1(C)COc2cc(O)c(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CC1(C)COc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (73% for two steps): 1H NMR (300 MHz, CDCl3) δ 7.38-7.20 (m, 12H), 7.11-7.04 (m, 2H), 6.97 (s, 1H), 6.58 (s, 1H), 6.57-6.51 (m, 1H), 6.50 (s, 1H), 5.08 (s, 1H), 4.19 (s, 2H), 1.25 (s, 3H), 1.18 (s, 3H); MS (ES+) m/z 426.6 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([C:21]([F:24])([F:23])[F:22])=[N:6][N:7]([CH2:9][C:10]2[NH:11][C:12](=[O:20])[C:13]3[CH:18]=[C:17]([CH3:19])[S:16][C:14]=3[N:15]=2)[CH:8]=1.N1C=CC=CC=1.[S:31](Cl)([CH3:34])(=[O:33])=[O:32]>O>[CH3:34][S:31]([O:1][CH2:2][CH2:3][C:4]1[C:5]([C:21]([F:23])([F:22])[F:24])=[N:6][N:7]([CH2:9][C:10]2[NH:11][C:12](=[O:20])[C:13]3[CH:18]=[C:17]([CH3:19])[S:16][C:14]=3[N:15]=2)[CH:8]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc2c(=O)[nH]c(Cn3cc(CCO)c(C(F)(F)F)n3)nc2s1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc2c(=O)[nH]c(Cn3cc(CCOS(C)(=O)=O)c(C(F)(F)F)n3)nc2s1
Temperature: -10 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
2-((4-(2-Hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-6-methylthieno[2,3-d]pyrimidin-4(3H)-one (1.99 g, 5.55 mmol) was completely dissolved in pyridine (0.44 g, 20 mL, 5.55 mmol) and cooled in an acetone/sodium chloride/ice bath. Internal temperature was maintained at −10° C. Mesyl chloride (2.07 g, 1.40 mL, 18.1 mmol) was added portionwise and the temperature exothermed to 0° C. The mixture was stirred for 1 h at 0° C. and deionised water was added until solid precipitated out. The reaction was filtered, washed with water, and concentrated in vacuo to give the title compound as a pale yellow solid (2.11 g, 4.83 mmol, 87%).
Reaction SMILES: [O:1]1C[CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[N:11][CH:12]=1.O1CCOC1C1C=CC(C2SC3C(=NC=CC=3OC3C=CC([N+]([O-])=O)=CC=3F)C=2)=NC=1>>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=3[F:30])[CH:14]=2)=[N:11][CH:12]=1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Agent: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1
Yield: 95 %

Procedure:
Following the procedure described above for the synthesis of compound 31 (Scheme 8) but substituting compound 30 for compound 37, title compound 38 was obtained in 95% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68 (d, J=1.8 Hz, 1H), 8.50 (d, J=5.5 Hz, 1H), 8.36 (s, 1H), 8.29 (d, J=8.2 Hz, 1H), 7.96 (dd, J=8.2, 2.0 Hz, 1H), 7.11 (t, J=9.0 Hz, 1H), 6.60 (d, J=5.3 Hz, 1H), 6.53 (dd, J=13.1, 2.5 Hz, 1H), 6.44 (dd, J=8.7, 1.9 Hz, 1H), 5.87 (s, 1H), 5.55 (s, 2H), 4.11-4.07 (m, 2H), 4.00-3.97 (m, 2H). MS (m/z): 410.2 (M+H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:32])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]([C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27][CH3:28])=[O:26])=O)[CH:11]=[CH:10][C:9]1=2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][C:8]1([CH3:32])[CH2:17][CH2:16][C:15]([CH3:19])([CH3:18])[C:14]2[CH:13]=[C:12]([C:20]([C:22]3[CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:29]=[CH:30][CH:31]=3)=[CH2:1])[CH:11]=[CH:10][C:9]1=2
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: C=C(c1cccc(C(=O)OC)c1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (3 g, 26.5 mmol) is added to a solution of methyl 3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylcarbonyl)benzoate (6.6 g, 18.9 mmol) and methyltriphenylphosphonium bromide (9.4 g, 26.3 mmol) in THP (60 ml). The mixture is stirred for 1 h at room temperature. The solution is extracted with ethyl acetate. After separation of the phases by settling, the organic phase is washed twice with 40 ml of water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[F:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>CCCCCC.C(OCC)(=O)C>[F:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccc(F)nc1)OCC2c1ccc(C(C)C)cc1
Yield: 58 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (6-fluoropyridin-3-yl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 58%. Melting point: 135-137° C. (hexane-ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81208.1 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)ethanone (10 g, 0.07 mol) in DMF (15 mL), were added anhydrous K2CO3 (20.3 g, 0.14 mol) and benzyl chloride (11.16 g, 0.08 mmol). The reaction mixture was then stirred at RT for 16 h, quenched with ice, and a solid was precipitated. The obtained solid residue was filtered and dried in vacuo to afford 1-(4-(benzyloxy)phenyl)ethanone (14.7 g, 89%) as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]3[C:19]([C:20]#[N:21])=[C:18]([CH3:22])[NH:17][C:16]([CH3:23])=[C:15]3[C:24]#[N:25])[CH:12]=2)[NH:7][N:6]=1)=[O:4].[Li+].[OH-].Cl>CO.O>[C:20]([C:19]1[CH:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:3]([OH:4])=[O:2])[C:15]([C:24]#[N:25])=[C:16]([CH3:23])[NH:17][C:18]=1[CH3:22])#[N:21]
Reactant: COC(=O)c1n[nH]c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C(=O)O)c3c2)C(C#N)=C(C)N1
Temperature: 70 °C
Yield: 93 %

Procedure:
To 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-3-carboxylic acid methyl ester (110 mg, 0.33 mmol) in MeOH—H2O (1:1, 8 mL) was added LiOH (1.08 g, 26.4 mmol) at rt. The reaction mixture was heated up to 70° C. for 2 days. After cooling to rt, the solution was acidified to pH 7 with 1 N HCl. After the removal of MeOH, the residue was purified by HPLC to afford 5-(3,5-dicyano-1,4-dihydro-2,6-dimethyl-4-pyridinyl)-1H-indazole-3-carboxylic acid (98 mg, 93%) (Cpd. No. 86, Table 2). 1H-NMR (400 MHz, DMSO-D6): δ=8.04 (s, 1H), 7.78 (s, 1H), 7.41 (d, 1H), 4.62 (s, 1H), 2.1 (s, 6H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C@@H:16]([NH:27]C(=O)OC(C)(C)C)[CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:3]=1[C:35]([NH:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1)=[O:36].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][C@H:16]([C:4]1[C:3]([C:35]([NH:37][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[O:36])=[C:2]([OH:1])[C:11]2[C:6](=[C:7]([C:12]([F:13])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.6 %

Procedure:
A mixture of 16.9 g of product of Example 11, 170 ml of methylene chloride and 85 ml of trifluoroacetic acid was stirred for 3 hours at ambient temperature and the solvents were eliminated under reduced pressure. The crude oil residue was crystallized from ether and after filtering, rinsing and drying under reduced pressure at 50° C., 16.4 g of 2-[(S) 1-amino-2-(1H-indol-3-yl)-ethyl]-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide were obtained in the form of trifluoroacetate melting at about 190° C.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11](I)=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:21]([NH2:23])=[O:22])[C:16]([C:17]([F:20])([F:19])[F:18])=[C:3]12.[C:25]([C@:27]1([OH:34])[CH2:31][CH2:30][N:29]([CH3:32])[C:28]1=[O:33])#[CH:26]>>[F:1][C:2]1([F:24])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([C:26]#[C:25][C@:27]3([OH:34])[CH2:31][CH2:30][N:29]([CH3:32])[C:28]3=[O:33])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:21]([NH2:23])=[O:22])[C:16]([C:17]([F:20])([F:19])[F:18])=[C:3]12
Reactant: NC(=O)c1nn2c(c1C(F)(F)F)C(F)(F)COc1ccc(I)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-n2nc(C(N)=O)c(C(F)(F)F)c2C(F)(F)CO3)C1=O

Procedure:
Similar to as described in General Procedure G, 4,4-difluoro-9-iodo-3-(trifluoromethyl)-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-3-ethynyl-3-hydroxy-1-methylpyrrolidin-2-one to give a titled compound after purification by HPLC.