Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]2[C:30]([CH:31]3[CH2:33][CH2:32]3)=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:34])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]2[C:30]([CH:31]3[CH2:33][CH2:32]3)=[CH:29][C:25]([C:26]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:27])=[C:24]([F:34])[CH:23]=2)[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Yield: 4.7 %

Procedure:
A solution of 4-((1-benzhydrylpiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (270 mg, 0.59 mmol), methanesulfonamide (84 mg, 0.88 mmol), EDCI (169 mg, 0.88 mmol) and DMAP (107 mg, 0.88 mmol) in DCM (5 mL) was stirred at room temperature for 16 h. The reaction was quenched with water (5 mL) then adjusted pH to 1 with HCl (1 M). The resulting mixture was extracted with DCM (5 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by reverse phase Combiflash (20%-50% CH3CN/H2O in 0.1% NH4HCO3) to afford the target compound (15 mg, 5%) as a white solid. LCMS (ESI) Method A: RT=6.10 min, m/z: 537.2 [M+H]+. 1H-NMR (500 MHz, MeOD-d4,): δ 7.40-7.42 (m, 4H), 7.15-7.30 (m, 7H), 6.67 (d, J=13 Hz, 1H), 4.30 (s, 1H), 3.87 (d, J=6 Hz, 2H), 2.82 (s, 3H), 1.73-1.98 (m, 7H), 1.37-1.40 (m, 3H), 0.83-0.86 (m, 2H), 0.50-0.53 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=[O:7])[CH3:6].[CH2:15]([O:17][C:18](=[O:24])[C:19](OCC)=[O:20])[CH3:16].CC[O-].[Na+]>CCO>[CH2:15]([O:17][C:18](=[O:24])[C:19](=[O:20])[CH2:6][C:5](=[O:7])[CH:4]([CH3:3])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C(C)Cc1ccccc1
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)C(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (0.3965 g, 16.52 mmol) was added slowly to a NaCl ice bath containing EtOH (5.6 mL, 2.6 M) stirring under N2. 59 (2.2727 g, 14.01 mmol) and diethyloxalate (2.0649 g, 14.13 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After stirring for 5 h, the reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 67:30:3 Hexanes:CH2Cl2:2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 60. 1H (CDCl3, 400 MHz): δ 14.55 (1H, broad s), 7.32-7.12 (5H, m), 6.36 (1H, s), 4.33 (2H, q, J=7.0 Hz), 3.05 (1H, dd, J=13.5, 6.8 Hz), 2.84 (1H, app sex, J=7.0 Hz), 2.67 (1H, dd, J=13.5, 7.8 Hz), 1.36 (3H, t, J=7.1 Hz), 2.33 (3H, d, J=7.0 Hz) ppm. 13C (CDCl3, 100 MHz): δ 205.78, 166.96, 161.88, 138.75, 128.80, 128.30, 126.29, 100.75, 62.32, 46.35, 39.10, 16.51, 13.88 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 16.51, 13.88; CH2 carbons: 62.32, 39.10; CH carbons: 128.80, 128.30, 126.29, 100.75, 46.35 ppm. HPLC: 11.084 min.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:17]2[C:18]([NH:20][C:21](=[O:22])[C:16]=12)=[O:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[O:9]=[C:6]1[CH2:7][CH2:8][N:3]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[C:17]3[C:18]([NH:20][C:21](=[O:22])[C:16]=23)=[O:19])[CH2:4][CH2:5]1
Reactant: O=C1CCNCC1
Reactant: O=C1NC(=O)c2c(CCCCBr)cccc21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCN(CCCCc2cccc3c2C(=O)NC3=O)CC1
Yield: 21.8 %

Procedure:
A solution of 4-piperidone hydrochloride hydrate (2 gram, 13 mmol), bromobutylphthalimide (3.67 gram, 13 mmol) and triethylamine (3.4 ml, 26 mmol) in Chloroform (25 ml) was refluxed overnight. The reaction mixture was washed with sat. NaHCO3 and was dried over Na2SO4. Purification using flash chromatography gave 4-(4'-ketopiperidinyl)butylphthalimide (0.85 gram).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C1([O:24][C:25](=O)[NH:26][C:27]2[CH:32]=[C:31]([O:33][C@H:34]([CH3:38])[CH2:35][O:36][CH3:37])[C:30]([C:39]#[N:40])=[CH:29][N:28]=2)C=CC=CC=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:39]([C:30]1[C:31]([O:33][C@H:34]([CH3:38])[CH2:35][O:36][CH3:37])=[CH:32][C:27]([NH:26][C:25]([N:7]2[C:6]3[C:11](=[CH:12][C:13]([CH:14]=[O:15])=[C:4]([CH:3]([O:2][CH3:1])[O:16][CH3:17])[N:5]=3)[CH2:10][CH2:9][CH2:8]2)=[O:24])=[N:28][CH:29]=1)#[N:40]
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: COC[C@@H](C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC[C@@H](C)Oc1cc(NC(=O)N2CCCc3cc(C=O)c(C(OC)OC)nc32)ncc1C#N
Temperature: 90 °C

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 156 mg, 0.660 mmol), (R)-phenyl(5-cyano-4-((1-methoxypropan-2-yl)oxy)pyridin-2-yl)carbamate (intermediate 145, 281 mg, 0.858 mmol) and DMAP (121 mg, 0.990 mmol) in DMF (3 ml) was heated for 1 h at 90° C. The cooled reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution, extracted 2× with EtOAc, the organic layers dried over Na2SO4 and evaporated. The residue was applied to a 40 g RediSep® column and purified by normal phase chromatography, eluting with hetane and then a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound. (UPLC-MS 6) tR 1.20; ESI-MS 470.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][N:20](C(OCC(Cl)(Cl)Cl)=O)[CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:31]=1)#[N:2].[OH-].[Na+]>[Zn].C(O)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:31]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CCc1cccnc1C2=C1CCN(C(=O)OCC(Cl)(Cl)Cl)CC1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
Acetic acid (25 ml) was added to 1 g of 8-cyano-11-[1-(2,2,2-trichloroethoxycarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine to dissolve the latter, followed by the addition of 2.75 g of zinc powder. The resulting mixture was heated under stirring for 2.5 hours over an oil bath of 70°-80° C. After the reaction, the reaction mixture was basified with a sodium hydroxide solution and then extracted with chloroform. The extract was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel column. From relevant fractions eluted with chloroform:methanol (10:1), 0.41 g of 8-cyano-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5.6]cyclohepta[1,2-b]pyridine was obtained (yield: 65%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@H:6]([O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH2:5][C:4](=[O:16])[CH2:3]1.ClC1C=CC=C(C(OO)=[O:25])C=1>>[OH:25][CH2:3][C@@H:4]1[O:16][C:2](=[O:1])[CH2:7][C@@H:6]([O:8][Si:9]([C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:10])[CH3:11])[CH2:5]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)C[C@H](O)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)O[C@@H](CO)C1
Reaction time: 20 h

Procedure:
reacting 3-hydroxy-5-(tert-butyldimethyl silyloxy)-(3R,5S)-cyclohexan-1-one having formula 7 with m-chloroperbezoic acid at room temperature for the period ranging from 16-24 hours, extracting with organic layer, washing with sodium metabisulphite, brine, drying and on evaporation to obtain 6-hydroxymethyl-4-(tert-butyldimethylsilyloxy)-(4S,6R)-tetrahydro-2H-2-pyranone having formula 1,
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([C:17]4[CH:18]=[C:19]([NH:23][C:24]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[O:25])[CH:20]=[CH:21][CH:22]=4)=[CH:15][N:16]=[C:10]3[CH:9]=2)[CH:4]=[CH:3]1.Cl.[Cl:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CN(C=O)C>[ClH:33].[O:1]=[C:2]1[N:7]([CH2:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14]([C:17]4[CH:18]=[C:19]([NH:23][C:24]([NH:26][CH2:27][C:28]([F:29])([F:30])[F:31])=[O:25])[CH:20]=[CH:21][CH:22]=4)=[CH:15][N:16]=[C:10]3[CH:9]=2)[CH:4]=[CH:3]1
Reactant: ClCCCN1CCCCC1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(=O)[nH]c4)ccn23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(=O)n(CCCN5CCCCC5)c4)ccn23)c1
Temperature: 80 °C
Yield: 4.3 %

Procedure:
To 1-{3-[7-(6-Oxo-1,6-dihydro-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-phenyl}-3-(2,2,2-trifluoro-ethyl)-urea (0.12 g, 0.63 mmol) in DMF (1.5 ml) was added N-(3-chloropropyl)piperidine hydrochloride (0.125 g, 0.63 mmol), Cs2CO3 (0.32 g, 0.98 mmol) and NaI (0.095 g, 0.63 mmol). The reaction was heated at 80° C. for 48 hours then partitioned between EtOAc and water, the organic layer was washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (16 mg) MS: [M+H]+553
Reaction SMILES: CO[C:3]([CH3:5])=[CH2:4].[Br:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH2:17][OH:18])[CH:11]=1)=[O:9]>C(Cl)Cl>[Br:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:3]([CH3:5])([CH3:4])[O:18][CH2:17][C:12]=2[CH:11]=1)=[O:9]
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Reactant: C=C(C)OC
Solvent: ClCCl
Product: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
2-Methoxypropene (10 g) was added over 15 min to a stirred solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (5 g) and toluene-4-sulfphonic acid (0.5 g) in CH2Cl2 (100 ml) at 23° C. The mixture was stirred for 3 h, filtered through a wad of triemethylamine-deactivated silica and evaporated to give an oil. Purification by [FCTS] (300 g) [E] afforded the title compound as an oil (4.8 g) which solidified on cooling. A small sample was crystallized from light petroleum (b.p. 60°-80°) to give white crystals m.p. 47°-48°.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][C:6]=1[CH:11]=O)=O.O.[NH2:14][NH2:15].C(O)(=O)C>C(O)C>[NH2:10][C:8]1[S:9][C:5]2[C:3](=[O:2])[NH:15][N:14]=[CH:11][C:6]=2[N:7]=1
Reactant: COC(=O)c1sc(N)nc1C=O
Reactant: NN
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1nc2cn[nH]c(=O)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound (1.20 g) obtained in Step 4 in ethanol (120 ml) was added hydrazine monohydrate (374 μl), and the mixture was heated under reflux for 24 hr. Since the reaction was not completed, acetic acid (1.0 ml) was added, and the mixture was further heated under reflux for 20 hr. The reaction mixture was concentrated under reduced pressure to an amount of 5 ml, a small amount of ethanol was added, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration, washed with a small amount of ethanol, and dried to give the title compound (822 mg).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH3:22])(=[O:20])[C:18]#[CH:19].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:19]=[C:18]([C:17]([O:21][CH3:22])=[O:20])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1=CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.4 %

Procedure:
To a stirred solution of benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (7.3 g, 0.03 mol) and methyl prop-2-ynoate (3.1 mL, 0.04 mol) in dichloromethane (150 mL) at 0° C. under nitrogen was added dropwise a solution of trifluoroacetic acid (0.12 mL, 0.002 mol) in dichloromethane (1 mL). The reaction mixture was allowed to stir at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature for 2 h, then the solvent was evaporated. The residue was purified by FCC, eluting with 0-20% ethyl acetate in heptane, to afford the title compound (2.37 g, 29%) as a yellow oil. δH (250 MHz, CDCl3) 7.35-7.15 (5H, m), 6.70 (1H, s), 3.79 (3H, s), 3.75-3.60 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1)#[N:30]>C(Cl)Cl>[C:29]([C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:39])=[CH:35][CH:36]=1)#[N:30]
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (84.6 mg, 0.20 mmol) and 1-cyano-4-isocyanato-benzene (Aldrich, 34.7 mg, 0.24 mmol) in CH2Cl2 (2 mL) was stirred at rt for 1 h. The reaction mixture was then concentrated and triturated with EtOAt and the solid was collected to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid (4-cyano-phenyl)-amide (1st crop, 54.4 mg, 2nd crop, 60.3 mg: 100%;) as a white solid. HRMS (ES+) m/z Calcd for C30H26Cl2F2N4O+H [(M+H)+]: 567.1525, found: 567.1526.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[N:13]=[C:14]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[CH:15]=[C:16]([C:17]([O:19]C)=[O:18])[C:11]=3[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>CC(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[N:13]=[C:14]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:11]=3[C:10]([CH3:26])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2ccco2)nc2c1c(C)nn2-c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1nn(-c2cccc(Cl)c2)c2nc(-c3ccco3)cc(C(=O)O)c12
Yield: 85.8 %

Procedure:
(see, e.g., Volochnyuk, D. M., et al., J Comb Chem 2010, 12, 510-7). A solution of ester 35 (108 mg, 0.29 mmol) and KOH (29 mg, 0.52 mmol) in iPrOH (6 mL) was refluxed for 1 h 30 min. Reaction mixture was diluted with H2O (10 mL) and washed with EtOAc (10 mL×2). Aqueous layer was acidified with 1N HCl and extracted with EtOAc (10 mL×2). Combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure to give 1 (88 mg, 86%) as a bright yellow solid. 99% pure by HPLC. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.29 (d, J=8.5 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.55 (t, J=8.1 Hz, 1H), 7.37-7.31 (m, 2H), 6.76-6.71 (m, 1H), 2.62 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 166.48, 152.40, 151.70, 148.29, 146.21, 143.65, 140.42, 136.54, 133.86, 131.32, 125.57, 119.83, 118.66, 113.69, 113.32, 112.21, 112.10, 16.20. ESI MS: m/z 354.0 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:36])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]=[CH:29][C:30]3[CH:35]=[CH:34][N:33]=[N:32][CH:31]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:36])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[CH:35]=[CH:34][N:33]=[N:32][CH:31]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3N=Cc3ccnnc3)ccc2C(C)(C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(C)CNCc2cc(NC(=O)c3ccccc3NCc3ccnnc3)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4,4-dimethyl-7-{2-[(pyridazin-4-ylmethylene)-amino]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Example 121, Step B, 200 mg, 0.41 mmol) in EtOAC (1 mL). Concentrated HCl in EtOAc (2 mL) was added. The reaction was stirred for 5 h under N2 atmosphere at RT. The solid was filtered off and dissolved in water. The aqueous solution was basified to pH 11-14 using 5 N NaOH. The resulting precipitate was filtered, washed with water and dried under vacuum, to obtain the titled compound as a tan solid. MS (ES+): 388.0 (M+H)+. Calc'd for C23H25N5O: 387.21.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:18]=[C:17]([N:19]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:15][C:11]=3[C:12]=2[CH:13]=O)=[CH:4][CH:3]=1.[CH2:37]([NH2:40])[CH2:38][NH2:39].BrN1C(=O)CCC1=O>ClCCl>[NH:39]1[CH2:38][CH2:37][N:40]=[C:13]1[C:12]1[C:11]2[CH:15]=[C:16]([O:33][CH:34]([CH3:36])[CH3:35])[C:17]([N:19]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][C:10]=2[O:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C=O)c3cc2OC(C)C)S(C)(=O)=O)cc1
Reactant: NCCN
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C4=NCCN4)c3cc2OC(C)C)S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
N-(2-(4-fluorophenyl)-3-formyl-5-isopropoxybenzofuran-6-yl)-N-(4-methoxybenzyl)methanesulfonamide (0.65 g, 1.27 mmol) was dissolved in dichloromethane, and powdered 4 A molecular sieves (0.7 g) were added. The slurry was cooled to 0° C. in an ice bath and treated with dropwise addition of ethylenediamine (0.1 mL, 1.4 mmol). The resulting slurry was stirred under nitrogen for 30 minutes, then solid N-bromosuccinimide was added in one portion and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with 100 mL dichloromethane and filtered through diatomaceous earth. The organic filtrate was washed with 10% aqueous sodium bicarbonate, 10% aqueous sodium chloride, dried over anhydrous sodium sulfate(s), filtered and the solvent was removed in vacuo leaving a foamy solid (0.54 g, 77%) which was placed under vacuum for 24 hours. The title compound was used without purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([O:31]C)=[CH:10][C:11]([O:29]C)=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:14][C:13]3=[O:28])[CH2:6][CH2:5][N:4]1[CH3:33].Cl.N1C=CC=CC=1>>[OH:29][C:11]1[CH:10]=[C:9]([OH:31])[C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([CH3:33])[C@H:3]2[CH2:2][OH:1])=[C:17]2[C:12]=1[C:13](=[O:28])[CH:14]=[C:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)[O:16]2
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc(C(F)(F)F)cc3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccc(C(F)(F)F)cc4)oc23)[C@@H]1CO

Procedure:
Compound of example 64 (0.7 g, 1.51 mmol) was demethylated using pyridine hydrochloride (7 g, 60.60 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]([C:11]2([C:14]3[CH:19]=[N:18][CH:17]=[CH:16][N:15]=3)[CH2:13][CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[CH2:21]2)[N:3]=1.CO.C[O-].[Na+]>C(O)C(C)C>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[C:11]1([C:9]2[NH:1][C:2]3=[N:3][C:4]([N:20]4[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:27])[CH2:21]4)=[CH:5][CH:6]=[C:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cnccn2)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)CO
Product: O=C([C@@H]1CCCN(c2ccc3nc(C4(c5cnccn5)CC4)[nH]c3n2)C1)N1CCCC1
Temperature: 100 °C
Yield: 20.7 %

Procedure:
To a solution of (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyrazin-2-yl)cyclopropanecarboxamide (0.1 g, 0.22 mmol) in anhydrous methanol (0.072 mL, 1.78 mmol) was added sodium methoxide (54 mg, 1.1 mmol) and isobutanol (3.5 mL). The reaction mixture was heated at 100° C. for 18 h. The solvent was removed under reduced pressure and the crude material was purified via preparative TLC to afford the title compound (19 mg). MS (ES+APCI) (M+H) 418.1; LCMS retention time 4.792 min (Method R1).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][OH:16])[O:12][C@@H:11]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](O[C@@H]1[C@@](C=O)(CO)O[C@@H](N2C=C(C)C(=O)NC2=O)C1)(C(C)(C)C)(C)C>>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][CH:15]=[O:16])[O:12][C@@H:11]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CCO)O2)c(=O)[nH]c1=O
Agent: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](C=O)(CO)O2)c(=O)[nH]c1=O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CC=O)O2)c(=O)[nH]c1=O

Procedure:
3'-O-t-Butyldimethylsilyl-5'-deoxy-5'-hydroxymethyl thymidine was oxidized to the title aldehyde using the same procedure as described for 3'-O-t-butyl-dimethylsilyl thymidine 4'-aldehyde in Example 11.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[O:3]1.[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>C1COCC1.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[N:10]=2)[O:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccn(COCC[Si](C)(C)C)n2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (388 mg, 2 mmoL) was added to NaH (160 mg, 60%, 4 mmoL) in THF (12 mL). After stirring at room temperature for 30 min, the mixture was cooled to 0° C. and SEMCl (705.7 μL, 4 mmoL) was added. The mixture was stirred at room temperature overnight, diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation afforded crude 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole.