Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.[C:3]([C:7]1[CH:12]=[C:11]([CH2:13][S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:10]=[C:9]([CH3:23])[C:8]=1[OH:24])([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([C:7]1[CH:12]=[C:11]([CH2:13][S:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:1])[CH:10]=[C:9]([CH3:23])[C:8]=1[OH:24])([CH3:5])([CH3:6])[CH3:4]
Reactant: CCCCCCCCSCc1cc(C)c(O)c(C(C)(C)C)c1
Reactant: OO
Solvent: CC(C)=O
Product: CCCCCCCCS(=O)Cc1cc(C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 26 h
Yield: 72.1 %

Procedure:
5.7 g of 30% hydrogen peroxide are added dropwise at 0° C. to 16.1 g (0.05 mol) of 2-tert-butyl-6-methyl-4-(n-octylthiomethyl)phenol, dissolved in 120 ml of acetone. After stirring at room temperature for 26 hours, the solvent is distilled off under reduced pressure. Chromatography on silica gel using methylene chloride/ethyl acetate in a ratio of 9:1 as eluent gives 12.2 g of 2-tert-butyl-6-methyl-4-(octylsulfinylmethyl)phenol as a yellowish oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[C:20](O)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([F:37])[C:30]=1[C:31]([CH3:36])([CH3:35])[CH2:32][O:33][CH3:34])[NH2:27].CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:23][C:24]1[CH:25]=[C:26]([NH:27][C:20]([CH:9]2[C:10]3[C:15](=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=3)[CH2:16][CH2:17][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:21])[CH:28]=[C:29]([F:37])[C:30]=1[C:31]([CH3:35])([CH3:36])[CH2:32][O:33][CH3:34]
Reactant: COc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: COCC(C)(C)c1c(F)cc(N)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(C)c1c(F)cc(NC(=O)C2c3ccc(OC)cc3CCN2C(=O)OC(C)(C)C)cc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of 2-(tert-butoxycarbonyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (671 mg, 2.18 mmol), 3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (470 mg, 2.18 mmol), DIEA (1.907 mL, 10.92 mmol) and DMAP (267 mg, 2.18 mmol) in ethyl acetate (30 mL) was added T3P (3.85 mL, 6.55 mmol) at room temperature, and the mixture was stirred overnight at 60° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→60% ethyl acetate/hexane), and then silica gel column chromatography (NH, solvent gradient; 5→60% ethyl acetate/hexane), and the precipitate was washed with ethyl acetate/hexane to give tert-butyl 1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (440 mg, 0.872 mmol, 39.9%) as white crystals.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].O[NH:9][C:10]([C:12]1[N:13]=[N:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1)=[NH:11]>>[CH2:2]([C:1]1[O:6][N:11]=[C:10]([C:12]2[N:13]=[N:14][C:15]([N:18]3[CH2:19][CH2:20][N:21]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])=[O:35])[CH2:22][CH2:23]3)=[CH:16][CH:17]=2)[N:9]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: N=C(NO)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCCCc1nc(-c2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)no1
Yield: 48 %

Procedure:
Following the procedure as described in Example 4, making variations only as required to use valeryl chloride in place of propionyl chloride to react with N-hydroxy-6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxamidine, the title compound was obtained as white crystals in 48% yield (0.110 g). m.p. 175° C. 1H NMR (300 MHz, CDCl3) 7.90 (d, J=9.3 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.67-7.48 (m, 2H), 7.30 (d, J=7.5 Hz, 1H), 7.00 (d, J=9.3 Hz, 1H), 4.15-3.65 (m, 6H), 3.32 7.30 (t, J=4.9 Hz, 2H), 2.95 (t, J=7.7 Hz, 2H), 1.92-1.75 (m, 2H), 1.48-1.35 (m, 2H), 0.90 (t, J=7.3 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 167.6, 166.5, 142.0, 134.3, 134.3, 132.3, 129.4, 127.3, 127.2, 127.1, 126.9, 126.8, 126.8, 111.8, 46.4, 44.6, 44.3, 41.2, 28.5, 26.3, 22.1, 13.5. MS (ES+) m/z 461.2 (M+1).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O>CO>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3n[nH]c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a stirring solution of 1.0 g of 2-[3-(1-tert-butoxycarbonyl-1H-Indazol-3-ylmethyl)-3-methyl-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 75, in 10 mL of methanol is added 2.0 g of solid K2CO3. The reaction mixture is stirred 2 h at RT and then 15 mL H2O is added and the reaction mixture stirred 15 min at RT. The resulting white precipitate is filtered, washed with 15 mL of H2O, and dried under vacuum at 90° C. to afford 668 mg of the title compound as a white solid: mp 161°-5° C.; 1H NMR (CDCl3, 400 MHz) δ10.38 (s, br, 1H), 8.55 (s, 1H), 8.48 (m, 1H), 7.74 (d, 1H, J=7.0), 7.42-6.93 (m, 13H), 6.62 (d, 1H, J=8.2), 5.09 (m, 1H), 4.49 (m, 1H), 4.08 (m, 1H), 3.85 (s, 3H), 3.05 (d, 2H, AB quartet, J=15.9), 1.67 (s, 3H), 1.13 (m, 6H); low resolution MS (FAB)m/e 603 (MH+), 424; Anal. (C35H34N6O4) Calcd. C, 69.75; H, 5.69; N, 13.94 Found C, 66.54; H, 5.549; N, 13.19.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1.[I:40]N1C(=O)CCC1=O>CC#N.ClCCl>[CH3:37][Si:34]([CH3:36])([CH3:35])[CH2:33][CH2:32][O:31][CH2:30][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:38])[CH3:39])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:40])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
To tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9f, 18.8 g, 32.5 mmol) in CH3CN (130 mL) and dichloromethane (130 mL) was added N-iodosuccinimide (8 g, 35.8 mmol) portionwise and the resulting mixture was stirred at room temperature for 1.5 h, at which time LC/MS confirmed full conversion of starting material to product. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave the desired product, tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (Int-9g) (21.7 g, 95%). LC/MS: m/z=704.2 (M+H4).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](O)[C:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:16][S:17][C:10]=2[C:9]=1[OH:25])=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:28])=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([Br:28])[C:11]2[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:16][S:17][C:10]=2[C:9]=1[OH:25])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2c(-c3ccc(F)cc3)csc2c1O
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(Br)c2c(-c3ccc(F)cc3)csc2c1O
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
3-(4-Fluoro-phenyl)-4,7-dihydroxy-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester (77.9 mg, 0.216 mmol), example 30-f, was suspended in 1.1 mL of anhydrous toluene. Phosphorous oxybromide (0.155 g, 0.539 mmol) was added, and the reaction mixture was heated at 120° C. for 20 min. using a CEM microwave reactor (CEM, Matthews, N.C.). The reaction mixture was diluted with ethyl acetate, and saturated sodium bicarbonate solution was then added. The biphasic mixture was stirred for 15 min. and separated to isolate the organic fraction. The organic fraction was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography eluting from silica gel with dichloromethane to produce 51.2 mg of the title compound. MS: (−) m/z 422.1, 424.1 (M−1, 79Br/81Br).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][O:6][CH3:7])[CH3:2].C(N)C.BrCCOC.[OH-].[Na+].[C:18](Cl)([Cl:20])=[O:19]>CCOCC>[CH3:7][O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:18]([Cl:20])=[O:19]
Reactant: CCNCCOC
Reactant: O=C(Cl)Cl
Agent: CCN
Agent: COCCBr
Agent: [Na+]
Solvent: CCOCC
Product: CCN(CCOC)C(=O)Cl
Temperature: 25 °C

Procedure:
Novel intermediate compounds used in the preparation described above were prepared as follows. N-ethyl-N-2-methoxyethylamine, b.p. 115°-116° C., was prepared by reaction of 3 molecular proportions of ethylamine with 1 molecular proportion of 1-bromo-2-methoxyethane in aqueous solution containing 1 equivalant of sodium hydroxide at 30°-50° C. To a stirred solution of 89.1 g. phosgene in 500 ml. dry ether at -20° C. was added a solution of 30.9 g. N-ethyl-N-2-methoxyethylamine in 50 ml. dry ether, maintaining the temperature of the reaction mixture at -20° C. The stirred mixture was then allowed to warm to room temperature during 1 hour. The reaction mixture was filtered and the filtrate evaporated in vacuo below 25° C. to remove the solvent and give the product, N-(2-methoxyethyl)-N-ethylcarbamoyl chloride as a pale yellow liquid.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of methyl 3,5-dihydroxybenzoate (50 g, 297 mmol) in DMF (270 ml) is added under nitrogen K2CO3 (61.6 g, 446 mmol, 1.5 eq.). Then benzyl bromide (53 ml, 446 mmol, 1.5 eq.) is added dropwise at 0° C. and the reaction mixture is stirred at RT for 24 h. The reaction mixture is filtered over celite, DMF is evaporated, water (500 ml) added and the reaction mixture extracted with ethyl acetate (2×500 ml). The combined organic layer is washed with brine, dried over MgSO4 and the solvent removed in vacuo. The residue is purified by column chromatography (cyclohexane/ethyl acetate 100/00 to 95/05) to give a mixture of the desired product and the di-alkylated compound. This mixture is purified by column chromatography (cyclohexane/acetone 95/05 to 90/10) to give 17.7 g of the title compound as white powder (yield of 23%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]([C:28]1[CH:49]=[CH:48][C:31]([C:32]([NH:34][C@H:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:33])=[CH:30][CH:29]=1)=[CH:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:20]=[C:14]2[N:13]=[CH:12]1>C(O)(=O)C.CO.[Pt](=O)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]([C:28]1[CH:49]=[CH:48][C:31]([C:32]([NH:34][C@H:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:33])=[CH:30][CH:29]=1)[CH2:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[N:20]=[C:14]2[N:13]=[CH:12]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(=Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)COC2CCCCO2)cc1)C(=O)OCC
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(COC2CCCCO2)Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OCC

Procedure:
A solution of 1.16 g of diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)prop-2-en-2-yl}benzoyl]glutamate and 174 mg (20%) of amorphous platinum (IV) oxide in 150 ml of glacial acetic acid is hydrogenated for 10 hours at 50 psi. The reaction mixture is diluted with 50 ml of methanol and filtered through Celite. The filtrate is concentrated and diluted with ethyl acetate. The solid which forms after cooling for 15 hour is collected by filtration, washed with cold ethyl acetate and dried to give diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)prop--2-yl}benzoyl]glutamate.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Reactant: CN1CCNCC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCN(C)CC1
Yield: 8 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(2-chloroethoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.39 mmol) from Example 16C was reacted with N-methyl piperazine (0.130 mL, 1.17 mmol) according to the procedure described for Example 16D to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea as a colorless solid (18 mg, 8%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.00 (brs, 1H), 8.55 (s, 1H), 7.63 (s, 1H), 7.58 (s, 1H), 7.37-7.42 (m, 2H), 7.25 (m, 1H), 6.96 (m, 1H), 6.47 (s, 1H), 4.26-4.30 (m, 2H), 3.99 (s, 3H), 2.75-2.79 (m, 2H), 2.20-2.50 (m, 8H), 2.13 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 576 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:20])[CH2:18][NH2:19])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH2:21]([O:24][C:25]1[CH:41]=[CH:40][C:28]([C:29]([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1)[C:22]#[CH:23].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]([F:20])[CH2:18][NH:19][C:35](=[O:36])[C:34]3[CH:33]=[CH:32][C:31]([C:29](=[O:30])[C:28]4[CH:40]=[CH:41][C:25]([O:24][CH2:21][C:22]#[CH:23])=[CH:26][CH:27]=4)=[CH:39][CH:38]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: C#CCOc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: NCC(F)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCOc1ccc(C(=O)c2ccc(C(=O)NCC(F)Cn3c4ccc(Br)cc4c4cc(Br)ccc43)cc2)cc1
Yield: 90 %

Procedure:
3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropan-1-amine (Naidoo et al., 2014) (40.2 mg, 0.10 mmol) was added to a solution of 4-(4-(prop-2-yn-1-yloxy)benzoyl)benzoic acid (Bandyopadhyay et al., 2011) (28.5 mg, 0.10 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (21.2 mg, 0.11 mmol) and 1-hydroxybenzotriazole hydrate (15.0 mg, 0.11 mmol) in dimethylformamide (0.4 ml). The reaction went to completion within an hour. The mixture was diluted with EtOAc and washed several times with water and then brine. The organic layer was dried over Na2SO4, filtered and condensed to give a light brown solid in 90% yield. 1H NMR (Acetone-d6, 400 MHz) δ 8.41 (dd, J=2.0, 0.6 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 7.82 (dd, J=10.3, 8.6 Hz, 4H), 7.71-7.56 (m, 4H), 7.16 (d, J=8.9 Hz, 2H), 5.39-5.10 (dm, 1H), 4.94 (d, J=2.4 Hz, 2H), 4.91-4.85 (m, 1H), 4.82 (d, J=5.4 Hz, 1H), 4.05-3.89 (m, 1H), 3.87-3.70 (m, 1H), 3.17 (t, J=2.4 Hz, 1H). 13C NMR (CD2Cl2, 100 MHz): 194.6, 167.3, 161.7, 141.4, 140.1, 136.9, 132.8, 130.7, 130.2, 129.7, 127.3, 124.1, 123.6, 114.9, 113.0, 111.2 (JC-F=1.9 Hz), 92.1 (JC-F=176.2 Hz), 78.2, 76.3, 56.4, 45.8 (JC-F=22.5 Hz), 42.3 (JC-F=21.2 Hz). MS (ESI), m/z: calculated 660.01. found 660.7 (M+1).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32]>>[CH3:32][C:31]([OH:33])([CH3:34])[CH2:30][NH:29][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[NH:10][N:9]=2)[N:7]=1
Reactant: CC(C)(O)CN
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Product: Cn1cc(-c2cc3c(-c4cccc(NCC(C)(C)O)n4)n[nH]c3cn2)cn1
Yield: 87 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 1-amino-2-methyl-propan-2-ol were reacted. The product was deprotected and purified to give 297 as a white solid (87% over two steps). 1H NMR (400 MHz, DMSO) δ 13.62 (broad s, 1H), 9.01 (s, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.3 Hz, 1H), 6.63-6.56 (m, 2H), 4.73 (s, 1H), 3.89 (s, 3H), 3.56 (d, J=5.8 Hz, 2H), 1.25 (s, 6H). LC/MS: m/z 364.2 [M+1]
Reaction SMILES: [C:1](/[C:3](=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[N:17]=2)=[CH:12][CH:11]=1)/[C:4]([O:6]CC)=[O:5])#[N:2].[OH-].[Li+]>O1CCCC1.CO.O>[C:1](/[C:3](=[CH:9]/[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]=[CH:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=3)[N:17]=2)=[CH:14][CH:15]=1)/[C:4]([OH:6])=[O:5])#[N:2]
Reactant: CCOC(=O)/C(C#N)=C\c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#C/C(=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
To (Z)-ethyl 2-cyano-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate (C46) (2.5 g, 5.8 mmol) in tetrahydrofuran/methanol/water (3:2:1, 42 mL) was added lithium hydroxide (2.5 mL, 7.5 mmol) and stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum, cooled in an ice bath, and acidified with hydrogen chloride (2 N). The precipitate was filtered and washed with cold water to afford the title compound as a brown solid (2.2 g, 82%): 1H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.39 (s, 1H), 8.28 (d, J=8.5 Hz, 2H), 8.18 (d, J=8.5 Hz, 2H), 8.13-8.08 (m, 2H), 7.64 (d, J=8.4 Hz, 2H); ESIMS m/z 401 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:27][CH3:28])[C:4]1[C:13]([CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[ClH:29]>CO>[ClH:29].[CH3:28][O:27][CH:3]([O:2][CH3:1])[C:4]1[N:5]=[C:6]2[C:11]([CH2:10][CH2:9][CH2:8][NH:7]2)=[CH:12][C:13]=1[CH:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: COC(OC)c1nc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)CCCN2
Agent: Cl
Solvent: CO
Product: COC(OC)c1nc2c(cc1C1CCNCC1)CCCN2
Temperature: 60 °C

Procedure:
A mixture of tert-butyl 4-(2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)piperidine-1-carboxylate (Intermediate 339, 1.0 g, 2.20 mmol) and 3M HCl in MeOH (7 ml) was stirred at 60° C. After stirring for 13 h, the reaction mixture was cooled to room temperature and evaporated. The residue was diluted with MeOH and evaporated again (4×). The title compound was obtained as a brown solid. (UPLC-MS 3) tR 0.31 min; ESI-MS 292.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[O:9][CH2:10][C:11]([F:24])([F:23])[C@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17](Br)[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[C:30]([CH3:37])[C:31]([C:34]([NH2:36])=[O:35])=[N:32][CH:33]=1)#[N:27].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C(=O)(O)[O-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[O:9][CH2:10][C:11]([F:24])([F:23])[C@:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([NH:36][C:34]([C:31]3[C:30]([CH3:37])=[CH:29][C:28]([C:26]#[N:27])=[CH:33][N:32]=3)=[O:35])[N:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C#N)cnc1C(N)=O
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2nc(Br)ccc2F)C(F)(F)CO1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(NC(=O)OC(C)(C)C)OCC2(F)F)n1
Yield: 38 %

Procedure:
A degassed mixture of [(R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazine-2-yl]-carbamic acid tert-butyl ester (70 mg, 0.145 mmol), 5-cyano-3-methyl-pyridine-2-carboxylic acid amide (25.7 mg, 0.160 mmol), Xantphos (30.2 mg, 0.052 mmol), caesium carbonate (67.6 mg, 0.203 mmol) and Pd2(dba)3 (16.45 mg, 0.017 mmol) was heated under argon in dioxane (2.9 ml) at 60° C. for 5 hours. The reaction mixture (grey-brown suspension) was diluted with ethyl acetate and aq. bicarbonate solution and was then filtered. The filtrate was washed with water and brine, dried over sodium sulfate, filtered and evaporated. 166 mg brown solid. The crude product was chromatographed over silica gel (toluene/ethyl acetate 7:3) to give the title compound as a white solid. 28 mg (38% yield).
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)=[N:11]2)=[CH:6][CH:5]=1>[Pt].C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:23])=[N:11]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1COc1ccn(-c2ccc(Cl)cc2)n1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccccc1COc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 20 h
Yield: 86.4 %

Procedure:
At 20-25° C. and a hydrogen pressure of 20 bar, a mixture of 30 g (90 mmol) of 2-[1-(4-chlorophenyl)pyrazol-3-yl]oxymethylnitrobenzene and 2 g of platinum on activated carbon (5%) in 200 ml of ethyl acetate was hydrogenated with stirring for approximately 20 hours. The mixture was filtered through Al2O3 and the solvent was removed from the filtrate by distillation, giving 23.3 g of the aniline as yellow crystals of m.p. 81-83° C.