Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([Br:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reaction time: 8 h
Yield: 98.2 %

Procedure:
2,6-Dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-phenol (1.0 g, 1.78 mmol), methyl bromoacetate (0.35 mL, 3.70 mmol), potassium carbonate (0.50 g, 3.62 mmol) and N,N-dimethylformamide (5 mL) were combined and stirred at ambient temperatures overnight. The reaction mixture was added to water and filtered. The solid was washed with water and dried in vacuo to provide the title compound as a white solid (1.11 g, 98%): mp 183-184° C.: NMR (CDCl3); δ8.36 (ddd, J=8, 1, 1 Hz, 1 H), 7.84 (ddd, J=8, 1, 1 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.62 (s, 2 H), 7.57 (ddd, J=8, 1, 1 Hz, 1 H), 7.51 (ddd, J=8, 7, 1 Hz, 1 H), 7.42 (ddd, J=8, 7, 1 Hz, 1 H), 7.18 (ddd, J=8, 7, 1 Hz, 1 H), 6.72 (ddd, J=8, 1, 1 Hz, 1 H), 4.88 (s, 2 H), 3.94 (s, 3 H); MS (EI): [M+], 3 bromine isotope pattern, 632 (30%), 634 (90%) 636 (100%) 638 (35%); Anal. Calc. for C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00. Found: C, 47.17, H, 2.19, N, 0.09.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15]=4[N:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)=O.[Li+].[BH4-].CO.Cl>CCOC(C)=O.C1COCC1>[OH:2][CH2:3][C:5]12[CH2:10][CH2:9][C:8]([C:13]3[NH:21][C:20]4[C:19](=[O:22])[N:18]([CH2:23][CH2:24][CH3:25])[C:17](=[O:26])[N:16]([CH2:27][CH2:28][CH3:29])[C:15]=4[N:14]=3)([CH2:11][CH2:12]1)[CH2:7][CH2:6]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CO)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane 1-carboxylic acid methyl ester (Example 14) (1.40 g, 3.48 mmol) was combined with LiBH4 (0.379 g, 17.4 mmol), MeOH (0.141 ml. 3.48 mmol), and 100 ml of THF and the resultant mixture was brought to reflux for 18 h. After cooling to rt, 50 ml of 1 M HCl were added and the mixture conc'd in vacuo. The residue was dissolved in EtOAc and washed with 1 M HCl, sat'd NaHCO3, brine, and dried over Na2SO4. The EtOAc solution was conc'd in vacuo to give 1.15 g (88% yield) of a white solid. (MH+=375.50)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][CH:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[O:18]=[C:19]1[NH:24][C:23]2[CH:25]=[C:26]([C:29](O)=[O:30])[CH:27]=[CH:28][C:22]=2[O:21][CH2:20]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCOC(C)=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:29]([C:26]3[CH:27]=[CH:28][C:22]4[O:21][CH2:20][C:19](=[O:18])[NH:24][C:23]=4[CH:25]=3)=[O:30])[CH:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1COc2cc(Cl)ccc2N1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1COc2cc(Cl)ccc2N1C(=O)c1ccc2c(c1)NC(=O)CO2
Temperature: 160 °C
Yield: 101 %

Procedure:
Ethyl (7-chloro-3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate (Intermediate 20, 0.67 g, 2.62 mmol), 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (0.607 g, 3.14 mmol), and TEA (1.090 mL, 7.86 mmol) were dissolved in EtOAc (15 mL). Then T3P (50 wt. % in EtOAc, 3.12 mL, 5.24 mmol) was added and the mixture was heated in a microwave reactor for 2 h at 160° C. EtOAc (100 mL) was added and the mixture was washed with sat. aq. NaHCO3 (100 mL), 1 M HCl (100 mL) and brine (100 mL). The mixture was dried by passage through a phase separator. Concentration under reduced pressure gave 1.14 g of an oil that was purified by flash chromatography on silica gel using a gradient from 12% to 100% of EtOAc in heptane as eluent. Concentration to dryness gave the title compound (0.530 g, 46.9%).
Reaction SMILES: C(O[C:4](=O)[C:5](=[CH:11][NH:12][C:13]1[N:14]([CH2:18][CH3:19])[N:15]=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.O=P(Cl)(Cl)[Cl:23]>>[CH2:9]([O:8][C:6]([C:5]1[C:4]([Cl:23])=[C:17]2[CH:16]=[N:15][N:14]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Product: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Temperature: 135 °C
Yield: 69 %

Procedure:
A solution of 2-[(2-ethyl-2H-pyrazol-3-ylamino)-methylene]-malonic acid diethyl ester (11.75 g, 0.041 mol) in POCl3 (70 mL) was heated at reflux (135° C.) for 8 hours. The excess of POCl3 were distilled off and the reaction mixture cooled to 0° C., before careful addition of water (100 mL) and then aqueous NaOH (3N) until pH reached 7. The product was extracted with CH2Cl2 several times, and the combined orgnic phase were dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/Heptane 1/5) afforded 7.22 g (69%) of the title product as a white solid. ES-MS m/e: 254.2 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:18]([CH3:19])[N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:19][N:18]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][N:16]=[N:17]1
Reactant: Cn1nnnc1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cn1nnnc1C1CCNCC1
Reaction time: 16 h

Procedure:
Pd(OH)2 (20% on C, 30 mg) was added to a solution of 1-benzyl-4-(1-methyl-1H-tetrazol-5-yl)-piperidine (37) (150 mg, 0.58 mmol) in 15 ml of ethanol and the mixture was hydrogenated at 4-5 bar H2 at 50° C. for 16 h. The catalyst was filtered off and the solvent was evaporated to give 38 as a colorless solid.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][N:9]=[C:8]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[N:7]=1.Cl>O1CCOCC1>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:8]2[N:7]3[CH:3]=[CH:4][N:5]=[C:6]3[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][N:9]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)nc1NCC(OC)OC
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cnc(Cc2ccc([N+](=O)[O-])cc2)n2ccnc12
Temperature: 85 °C
Reaction time: 3 h
Yield: 3.4 %

Procedure:
A solution of methyl [4-[(2,2-dimethoxyethyl)amino]-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (1.00 g, 2.56 mmol) and HCl (1.0 M in water, 3.84 mL, 3.85 mmol) in dioxane (10 mL) was stirred at 85° C. for 1 hour. After the removal of the solvent in vacuo, water was added to the residue. The aqueous solution was neutralized by 1M NaOH and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. To the resulting crude product was added phosphorus oxychloride (1.4 mL) and the mixture was stirred at 85° C. for 3 hours. After the removal of the excess phosphorus oxychloride, the residue was dissolved with ethyl acetate. The organic layer was washed with water, sat.NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica-gel, (chloroform:methanol, 98/2) to give methyl [5-(4-nitrobenzyl)imidazo[1,2-c]pyrimidin-8-yl]acetate (28 mg, 3%) as brown oil.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[NH:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([O:25]C)=O)[C:3]1=2.O.[NH2:28][NH2:29].C(O)(=O)C.O>CC(N(C)C)=O.CCOC(C)=O>[O:25]=[C:23]1[C:22]2[C:3]3=[C:4]([CH:19]=[CH:20][CH:21]=2)[NH:5][C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:9][CH2:10][C:11]=2[C:2]3=[N:29][NH:28]1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)OC(C)(C)C)C3
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2=C(C1)Nc1cccc3c(=O)[nH]nc2c13
Temperature: 130 °C
Reaction time: 6 h
Yield: 21 %

Procedure:
A solution of 2-tert-butyl 6-methyl 5-oxo-3,4,5,10-tetrahydrobenzo[b][1,7]naphthyridine-2,6(1H)-dicarboxylate (0.55 g) and hydrazine hydrate (2.5 mL) in DMA (4 mL) was heated at 130° C. for 2.0 h, acetic acid (4 mL) was added and the mixture was stirred at 130° C. for another 6 hours. The reaction mixture was cooled to room temperature, then water (30 mL) and EtOAc (100 mL) were added. The organic phase was separated and then washed with aqueous NaHCO3 (2×10 ml) and brine (20 ml), dried with Na2SO4 and filtered. The organic phase was concentrated in vacuum to give the crude product, which was then recrystallized from MeOH to afford the product (110 mg, 21%) as a yellow solid. 1H NMR (DMSO-d6) δ 11.7 (s, 1H), 10.52 (s, 1H), 7.60 (t, 1H, J=8.0 Hz), 7.43 (d, 1H, J=8.0 Hz), 7.21 (d, 1H, J=8.0 Hz), 4.22 (s, 2H), 3.54-3.55 (m, 2H), 2.30-2.33 (m, 2H), and 1.40 (s, 9H). MS (ESI) m/e [M+1]+341.0.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>N1C=CC=CC=1.O>[C:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[CH:6]=[C:5]([CH3:7])[O:4][N:3]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(N)no1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cc(C)on2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
Ex-1B: To a solution of 3-amino-5-methylisoxazole (0.27 g, 2.75 mmol) in pyridine (1 mL) at 0° C. was added a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.29 mmol) in 1 mL pyridine dropwise to the reaction. The resulting solution was stirred at 0° C. for 30 min and then warmed to room temperature and stirred for an additional 18 h. The mixture was diluted with water (100 mL), cooled to 0° C., and stirred for 1 h. The resulting precipitate was collected on filter paper and rinsed with several portions of water. The filtrate was acidified with 3 N HCl and the resulting precipitate was collected and rinsed with water. The solids were combined and dried in vacuo to afford 0.50 g (80%) of 4-acetyl-N-(5-methylisoxazole-3-yl)benzenesulfonamide as a pale green solid, mp 189–190° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.14 (d, 2H, J=8.1 Hz), 7.98 (d, 2H, J=8.1 Hz), 6.16 (s, 1H), 2.62 (s, 3H), 2.30 (s, 3H). HRMS (EI) Calcd. for C12H12N2O4S: 280.0518 (M+); Found: 280.0514. Anal. Calcd. for C12H12N2O4S: C, 51.42; H, 4.32; N, 9.99; S, 11.44; Found: C, 51.73; H, 4.39; N, 10.12; S, 11.30.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][CH:23]=[C:22]2[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CCCCCCC(=O)c1cc(C)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COC(=O)CCCCCCC(=O)c1cc(C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 3.5 %

Procedure:
Methyl 8-(2-hydroxy-5-methyl-phenyl)-8-oxo-octanoate (271 mg), 4-chloro-6,7-dimethoxyquinoline (220 mg), and 4-dimethylaminopyridine (237 mg) were suspended in o-dichlorobenzene (20 ml) to prepare a suspension which was then stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (16 mg, yield 3.5%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH2:17][CH2:18][CH3:19])[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1.Br[CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([O:25][CH3:26])=[O:24]>>[Cl:1][C:2]1[C:3]([O:20][CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]([O:25][CH3:26])=[O:24])=[C:4]([CH2:17][CH2:18][CH3:19])[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:16]=1
Reactant: CCCc1c(O)c(Cl)cc2c(-c3ccccc3)noc12
Reactant: COC(=O)C(Br)c1ccccc1
Product: CCCc1c(OC(C(=O)OC)c2ccccc2)c(Cl)cc2c(-c3ccccc3)noc12

Procedure:
The phenol of step 1 (0.25 g, 0.86 mmol) was coupled with commercially available methyl 2-bromo-2-phenylacetate (0.20 g, 0.86 mmol) as was described for example 9, step 5. The product was purified by chromatography on silica gel eluting with ethyl acetate:hexane (10:90).
Reaction SMILES: [H-].[Na+].[C:3]([N:7]1[C:11]2=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:15]=[C:10]2[C:9]([NH2:25])=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[N:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)=[C:27]=[O:28].O>CC(N(C)C)=O>[C:3]([N:7]1[C:11]2=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:15]=[C:10]2[C:9]([NH:25][C:27]([NH:26][C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)=[CH:33][CH:34]=2)=[O:28])=[N:8]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)n1nc(N)c2cc(Sc3cc(F)cc(F)c3)cnc21
Reactant: CN1CCN(c2ccc(N=C=O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(c2ccc(NC(=O)Nc3nn(C(C)(C)C)c4ncc(Sc5cc(F)cc(F)c5)cc34)cc2)CC1
Reaction time: 0.17 h
Yield: 45.5 %

Procedure:
0.048 g (1.19 mmol) of sodium hydride is added at 0° C. to 0.200 g (0.598 mmol) of 1-tert-butyl-5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine dissolved in 10 ml of anhydrous dimethylacetamide. The reaction is left under stirring for 10 minutes. 0.130 g (0.598 mmol) of 1-(4-isocyanatophenyl)-4-methylpiperazine is then added at 0° C. The mixture is left under stirring for 3 hours at room temperature. The reaction is treated by adding 20 ml of water drop by drop at 0° C. and then is extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The product is purified by silica chromatography to yield 0.150 g (yield=45%) of 1-(1-tert-butyl-5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea in the form of a light brown solid.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.[CH3:30][C:31]([CH3:33])=[O:32]>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([CH2:30][CH:31]([OH:32])[CH3:33])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CC(C)=O
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(CC(C)O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, acetone was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 7.17(s,2H), 6.08(s,1H), 3.73(d,1H), 3.33(m,1H), 2.19(s,3H), 2.15(s,3H), 2.12(s,6H), 1.4–1.7(m,4H), 1.26(s,6H), 0.96(t,6H) ppm.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:26]2[N:35]=[CH:34][C:33]3[C:28](=[C:29]([F:40])[CH:30]=[C:31]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:32]=3)[C:27]2=[O:41])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[C:15](=[O:24])[N:14]([CH3:25])[CH:13]=1)(=O)C.O.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:36]([C:31]1[CH:32]=[C:33]2[C:28](=[C:29]([F:40])[CH:30]=1)[C:27](=[O:41])[N:26]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:23]=[CH:22][NH:21][N:20]=4)[C:15](=[O:24])[N:14]([CH3:25])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:35]=[CH:34]2)([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc[nH]n3)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc[nH]n2)c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
A mixture of 152c (100 mg, 0.18 mmol) and lithium hydroxide hydrate (84 mg, 2.0 mmol) in THF (8 mL), i-propanol (8 mL) and water (2 mL) was stirred at 40° C. for 0.5 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was then extracted with ethyl acetate (2×10 mL). The combined extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 152 (6.5 mg, 7%) as a pale yellow solid. MS-ESI: [M+H]+ 515.8. 1H NMR (500 MHz, CDCl3) δ 8.62-8.61 (m, 1H), 8.32 (s, 1H), 8.04 (m, 1H), 7.55-7.53 (m, 4H), 7.50-7.49 (m, 1H), 7.44 (s, 1H), 6.01 (s, 1H), 4.49-4.48 (m, 2H), 3.71 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:29]1[CH:30]=[CH:31][N:32]=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]([C:21]2[CH2:20][C:19](=[O:35])[NH:18][C:9]3[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M81) (0.33 g, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (197 mg, 78%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[O:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCCCCCOc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: O=CCCCCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a stirred solution of 61.1 (0.56 g, 2.24 mmol) in dry THF (20 mL), at −78° C., under a nitrogen atmosphere was added diisobutylaluminum hydride (5 mL, 5 mmol, using a 1M solution in hexanes) dropwise. The reaction mixture was stirred at the same temperature for 30 min and then quenched by dropwise addition of potassium sodium tartrate (10% solution in water). The resulting mixture was warmed to room temperature and stirred vigorously for 1 h. The organic layer was separated and the aqueous phase extracted with diethyl ether. The combined organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 25% diethyl ether-hexane to give 62.1 (0.26 g, 65% yield) as a colorless viscous liquid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:34]=[CH:33][C:27]([CH2:28][CH2:29][PH:30](=[O:32])[O-:31])=[CH:26][C:25]=3[O:35][CH3:36])[N:14]=2)=[CH:4][CH:3]=1.Br[Si](C)(C)C>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:34]=[CH:33][C:27]([CH2:28][CH2:29][PH:30](=[O:31])[OH:32])=[CH:26][C:25]=3[O:35][CH3:36])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)[O-])cc2OC)ncc1C(F)(F)F
Agent: C[Si](C)(C)Br
Solvent: c1ccncc1
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
(4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)methylphosphinate (Compound 61C, 130 mg, 0.215 mmol) in pyridine (10 mL) was charged with bromotrimethylsilane (0.171 mL, 1.29 mmol). The reaction mixture stirred at rt for 16 hrs. The reaction was concentrated in vacuo to solid to afford 100 mg of the title compound (79%). 1H NMR (400 MHz, CD3OD) δ 9.04 (br. s., 1H), 8.36 (s, 1H), 7.72 (br. s., 1H), 7.56 (d, J=8.8 Hz, 1H), 7.05 (s, 1H), 6.84-6.95 (m, 1H), 3.86 (s, 3H), 3.20 (d, J=17.7 Hz, 2H), 2.94 (s, 3H), 1.42 (s, 3H). MS (ESI): m/z=589.38/591.37 [M+H]+. UPLC: tR=1.19 min (UPLC-TOF: polar—2 min).
Reaction SMILES: I[C:2]1[N:14](S(C2C=CC(C)=CC=2)(=O)=O)[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>O1CCOCC1.O.CO>[CH3:13][N:10]1[C:9]2=[C:4]3[CH:3]=[C:2]([C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)[NH:14][C:5]3=[N:6][CH:7]=[C:8]2[CH:12]=[N:11]1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3c(ncc4cnn(C)c43)[nH]2)cn1
Temperature: 80 °C
Yield: 50.9 %

Procedure:
A flask was charged with 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.134 g, 0.296 mmol, Example #41, Step C), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.074 g, 0.36 mmol), (PPh3)4 (0.024 g, 0.021 mmol, Strem) and Na2CO3 (0.079 g, 0.74 mmol) in 1,4-dioxane:water (3:1, 10 mL) The reaction was heated at about 80° C. for about 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a solid that was added to a 5 mL microwave reaction vial. MeOH (3 mL) and aqueous NaOH (5 N, 0.77 ml, 3.8 mmol) were added and the reaction vessel was sealed and heated to about 120° C. in a microwave for about 20 min (250 psi maximum pressure, 2 min ramp time, 300 max watts). The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated, redissolved in MeOH/DCM, and purified by silica gel chromatography (12 g column) eluting with a gradient of 0-5% MeOH in DCM. The product-containing fractions were combined and concentrated to give 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.038 g, 39% over 2 steps): LC/MS (Table 2, Method d) Rt=1.13 min; MS m/z: 253 (M+H)+.