Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)([CH3:5])[CH:3]=[CH2:4].C(O)(=[O:21])C.O>[O-2].[Cr+6].[O-2].[O-2].C(Cl)Cl>[CH3:5][C:2]1([CH3:1])[C:6]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[O:18][C:4](=[O:21])[CH2:3]1
Reactant: C=CC(C)(C)C1(O)CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(C1)OC(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of borane-dimethyl sulfide complex (0.409 mL, 0.00460 mol) in methylene chloride (6.00 mL, 0.0936 mol) was slowly added a solution of tert-butyl 3-(1,1-dimethylprop-2-en-1-yl)-3-hydroxypyrrolidine-1-carboxylate (3.20 g, 0.0125 mol) in methylene chloride (6.00 mL, 0.0936 mol) with stirring at rt. After 2 h, the reaction mixture was slowly added to a solution of chromium(VI) oxide (7.52 g, 0.0752 mol) in acetic acid (45.00 mL, 0.7915 mol), and water (5.00 mL, 0.278 mol) at 5° C. After stirring the reaction mixture at it for 12 h, water (60 mL) and methylene chloride (30 mL) were added. The organic layer was separated and the aqueous layer was farther extracted with methylene chloride (2×30 mL). The organic layers were combined, washed with brine (2×30 mL), dried and concentrated. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to give the product. LCMS (M+Na) 292.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9])#[N:2].[H][H]>[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([O:10][CH2:11][C@@H:12]2[CH2:15][CH2:14][N:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[N:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C#N)c1
Reactant: [H][H]
Agent: [Ni]
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(CN)c1

Procedure:
5-Cyano-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine (0.26 g, 0.80 mmol) from step 92a was stirred in the presence of Raney nickel (0.047 g, 0.80 mmol) under 1 atm of hydrogen at room temperature for 2 hours. The mixture was filtered, and the solvent was removed to give the title compound.
Reaction SMILES: C[CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:4].N[C:20]1C=CC(C2CCN(C(OC(C)(C)C)=O)CC2)=CC=1.C(Cl)(=O)CCC>>[NH:15]1[CH2:14][CH2:13][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][CH2:18][CH3:20])=[CH:11][CH:10]=2)[CH2:17][CH2:16]1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: CCCC(=O)Cl
Product: CCCC(=O)Nc1ccc(C2CCNCC2)cc1

Procedure:
Prepared by the procedure for 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide using tert-butyl 4-(4-aminophenyl)-1-piperidinecarboxylate and butanoyl chloride: ESMS m/e: 247.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])S(C2C=CC=CC=2)(=O)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:39])[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C1C=C(NC(N[C@@H]2CCCC[C@H]2N(C)C)=S)C=C(C(F)(F)F)C=1>O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C@@H:15]([NH:25][C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[CH:34]([C:35]([O:37][CH3:38])=[O:36])[C:33]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NC(c1cccc(OCc2ccccc2)c1)S(=O)(=O)c1ccccc1
Agent: CN(C)[C@@H]1CCCC[C@H]1NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(C(=O)OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
Tert-butyl {[3-(benzyloxy)phenyl](phenylsulfonyl)methyl}carbamate (3.0 g, 5.93 mmol) was suspended in a toluene (21.6 mL) water (16 mL) mixture. At 0° C. tert-butyl methyl malonate (1.2 mL, 7.1 mmol), cesium carbonate (1.94 g, 5.9 mmol) and 1-[3,5-bis(trifluoromethy) phenyl]-3-[(1R,2R)-(−)-2-(dimethylamino)cyclohexyl]thiourea (246 mg, 0.59 mmol) was added and the mixture was stirred for 72 hours at 0° C. After storage at −20° C. for 72 hours the mixture was diluted with water and ethyl acetate, after filtration the phases were separated and the aqueous phase extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (ethyl acetate in hexane 0 to 35%) to yield 2.17 g of enantiomerically enriched tert-butyl methyl 2-{(1S)-[3-(benzyloxy)phenyl][(tert-butoxycarbonyl)amino]methyl}propanedioate.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[F:11][C:12]1[CH:13]=[C:14]([C@@:25]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)([NH2:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:17]=1>ClCCCl.C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([C@:25]([NH:33][CH:8]=[O:10])([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=[C:16]([O:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[CH:17]=1
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: ClCCCl
Product: O=CN[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A solution of acetic anhydride (10 mL, 106 mmol) and formic acid (6 mL, 159 mmol) was heated at 60° C. for 3 h, then cooled to rt. An aliquot of the resulting solution (0.623 mL) was added to a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine prepared as described in Procedure 3, 4, 5 and 6 (83 mg, 0.2 mmol) in DCE (1 mL). The reaction mixture was stirred at rt for 1.5 h, then concentrated under reduced pressure to yield a clear oil. The resulting oil was dissolved in DCM and purified by ISCO chromatography (12 g) with 0-30% EtOAc in hexane to yield (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamide as white solid (72 mg, 81% yield). LCMS: RT=2.02 min [M−NHCOH] 409.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). At 0° C. to a solution of (R)—N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)formamide (72 mg, 0.16 mmol) in DCM (2 mL) was added triethylamine (0.06 mL, 0.43 mmol) and POCl3 (0.016 mL, 0.18 mmol). The reaction mixture was stirred at rt overnight, then diluted with EtOAc (15 mL). The organic layer was washed with sat. NaHCO3 and sat. NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by ISCO chromatography (12 g) with 0-30% EtOAc in hexane to yield (R)-1-fluoro-3-(1-(4-fluorophenyl)-1-isocyano-2-phenylethyl)-5-(1,1,2,2-tetrafluoroethoxy)benzene as a white solid (60 mg, 87% yield). LCMS: RT=2.10 min [M−NC] 409.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm). 1H NMR (400 MHz, CDCl3) δ ppm 3.56-3.65 (m, 2H), 5.74-6.01 (m, 1H), 6.84 (d, J=7.03 Hz, 2H), 6.94 (d, J=7.03 Hz, 3H), 7.04-7.10 (m, 2H), 7.16-7.26 (m, 3H), 7.32 (dd, J=9.01, 5.05 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[Cl:15][C:16]1[CH:17]=[C:18]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23](=[O:28])[N:22]([C:29]3[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=3)[C:19]2=[N:20][CH:21]=1.[H-].[Na+]>CN(C=O)C.CO>[Cl:15][C:16]1[CH:17]=[C:18]2[N:24]([CH:25]([CH3:27])[CH3:26])[C:23](=[O:28])[N:22]([C:29]3[CH:34]=[CH:33][C:32]([O:35][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:31][CH:30]=3)[C:19]2=[N:20][CH:21]=1
Reactant: CC(C)n1c(=O)n(-c2ccc(O)cc2)c2ncc(Cl)cc21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncc(Cl)cc21
Temperature: 180 °C
Yield: 58.3 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (100 mg) was added to a solution of 6-chloro-3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (148 mg) and NaH (20.83 mg) in DMF (3 mL) at room temperature. The mixture was heated at 180° C. for 30 min under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 6-chloro-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (120 mg) as white crystals:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH:21]1[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:49][C:50]1[C:58](O)=[CH:57][CH:56]=[C:55]2[C:51]=1[CH:52]=[N:53][NH:54]2.Cl.O1CCOCC1>O1CCCC1.CO>[NH:24]1[CH:25]=[CH:26][CH:27]=[C:21]([O:20][C:58]2[C:50]([Cl:49])=[C:51]3[C:55](=[CH:56][CH:57]=2)[NH:54][N:53]=[CH:52]3)[CH:22]=[CH:23]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)CC1
Reactant: Oc1ccc2[nH]ncc2c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: Clc1c(OC2=CC=CNC=C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Under a nitrogen atmosphere, triphenylphosphine (280 mg, 1.07 mmol), the tert-butyl 4-hydroxyazepane-1-carboxylate (192 mg, 0.890 mmol) obtained in Example 322, (c) and diisopropyl azodicarboxylate (193 μl, 0.979 mmol) were added at 0° C. to a solution of the 4-chloro-1H-indazol-5-ol (150 mg, 0.890 mmol) obtained in Example 468 in tetrahydrofuran (6 ml). After 30 minutes, the mixture thus obtained was warmed up to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform (20 ml) and washed with a 1M-aqueous sodium hydroxide solution (10 ml). After the aqueous layer was re-extracted with chloroform (10 ml), the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The oil thus obtained was dissolved in methanol (3 ml) at room temperature and 4N-hydrochloric acid-dioxane (3 ml) was added thereto. After 1 hour, the mixture thus obtained was concentrated under reduced pressure, and the resulting residue was dissolved in methanol (5 ml) and the resulting solution was adjusted to pH 10 by dropwise addition of a 2M-aqueous sodium hydroxide solution. The solution adjusted was concentrated under reduced pressure and the resulting residue was re-dissolved in methanol (5 ml). Silica gel (1 g) was added thereto and the resulting mixture was concentrated under reduced pressure and then dried. The resulting solid was purified by a silica gel column chromatography (eluent: chloroform/methanol→chloroform/methanol (1%-aqueous ammonia)) to obtain 5-(azepin-4-yloxy)-4-chloro-1H-indazole (128.1 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].[CH2:13]([O:20][CH2:21][CH:22]1[CH2:24][O:23]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][CH2:21][CH:22]([OH:23])[CH2:24][NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(COCC2CO2)cc1
Reactant: COc1ccc(CN)c(OC)c1
Product: COc1ccc(CNCC(O)COCc2ccccc2)c(OC)c1

Procedure:
Starting materials: 2,4-dimethoxy-benzylamine and 2-[(benzyloxy)methyl]oxirane
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([N:74]4[CH2:79][CH2:78][O:77][CH2:76][CH2:75]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: C1COCCN1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N1CCOCC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (80 mg, 0.16 mmol), PyBOP® (46 mg, 0.088 mmol), DIEA (28 μL, 0.16 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added morpholine (8.7 mg, 0.10 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalent of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of morpholine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (20-45—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-morpholinoethanone. (13 mg, 0.027 mmol, 17%)
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[NH:8][C:7]3[N:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:18][CH:17]=4)=[CH:15][C:6]=3[C:5]=2[CH:4]=1)#[N:2].C1(C2[O:37]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C(Cl)Cl>[C:1]([C:3]1[N:11]=[CH:10][C:9]2[NH:8][C:7]3=[N+:12]([O-:37])[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)=[CH:20][CH:21]=4)[CH:15]=[C:6]3[C:5]=2[CH:4]=1)#[N:2]
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: N#Cc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Solvent: ClCCl
Product: N#Cc1cc2c(cn1)[nH]c1c2cc(-c2ccc(CN3CCCCC3)cc2)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 6-cyano-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (110 mg, 0.30 mmol) and 3-phenyl-2-(phenylsulfonyl)oxaziridine (102 mg, 0.39 mmol) in DCM (5.8 mL) was stirred at room temperature for 2 h. The solid was collected by filtration and washed with DCM (3×20 mL) to afford a bright yellow solid (100 mg, 90%). NMR (400 MHz, DMSO-D6): 8.98 (s, 1H), 8.91 (s, 1H), 8.90 (s, 1H), 8.83 (s, 1H), 7.66 (m, 4H), 4.43 (s, 2H), 3.13 (m, 2H), 2.14 (m, 2H), 1.59 (m, 4H), 1.34 (m, 2H). LCMS (method D): RT=8.82 min, M+H+=384.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([O:20][C@:21]1([CH3:46])[C@H:26]([O:27]C(=O)C2C=CC=CC=2)[C@@H:25]([CH2:36][O:37]C(=O)C2C=CC=CC=2)[O:24][CH:22]1O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:66](C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH2:66][C:9]1[C:10]2[C:2]([F:1])=[CH:3][N:4]([C@@H:22]3[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:27])[C@@:21]3([CH3:46])[OH:20])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: C[C@]1(OC(=O)c2ccccc2)C(O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: Fc1c[nH]c2ncnc(Cl)c12
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound from Step C (0.075 g, 0.44 mmol), 2,3,5-tri-O-benzoyl-2-C-methyl-D-ribofuranose [Harry-O'kuru, Rogers E.; Smith, Jennifer M.; Wolfe, Michael S, “A Short, Flexible Route toward 2′-C-Branched Ribonucleosides,” J. Org. Chem., 62: 1754-1759 (1997)] (4-5) (0.25 g, 0.53 mmol) and triphenylphosphine (0.23 g, 0.88 mmol) in THF (15 mL) was added diethyl azodicarboxylate (DEAD) (0.14 mL, 0.88 mmol). The reaction mixture was stirred at room temperature overnight. The solution was directly adsorbed onto silica gel and purified over silica gel using ethyl acetate/hexane 1:9 as the eluent Appropriate fractions were dissolved in dioxane (3 mL) and liquid ammonia (4 mL) and the mixture was heated in a steel bomb at 85° C. for 24 h. The solvent was evaporated and the residue was purified over silica gel using methanol/dichloromethane (1:9) as the eluent. Fractions containing the desired compound were pooled and evaporated in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[F:24])[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][C:38]=1[NH:52][S:53]([CH3:56])(=[O:55])=[O:54].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:40]4[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[C:38]([NH:52][S:53]([CH3:56])(=[O:54])=[O:55])[CH:39]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:26])=[O:27])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)ccc4F)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cnc3c(c2)c(-c2cnn(Cc4cc(F)ccc4F)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 49.5 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step-i of example-4) (200 mg, 0.368 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (Intermediate 17) (120 mg, 0.368 mmol) using sodium carbonate (117 mg, 1.1049 mmol) and Pd(PPh3)2Cl2 (14 mg, 0.018 mmol) in DME/water (15/2 ml) to afford 121 mg (49.5% yield) after purification by column chromatography (Silica gel 230/400) using 50% ethyl acetate in hexane as eluent. MS: m/z=664.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br.O>C(O)(=O)C>[Br:19][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:18])=[C:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=1
Reactant: BrBr
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Solvent: O
Solvent: CC(=O)O
Product: Oc1c(Cc2ccccc2)cc(Br)c2ccccc12
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
A solution of 2-(phenylmethyl)-1-naphthol (1.00 g, 4.3 mmole) in acetic acid (20 mL) was stirred at room temperature. A solution of bromine (0.7 g, 4.3 mmole) in acetic acid (6 mL) was added dropwise over 10 minutes. The mixture was stirred for another 5 minutes, then poured into water. The resulting solid was collected by filtration and recrystallized (cyclohexane) to provide the title compound (1.21 g, 88%) as off-white needles, mp 123°-125°.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH3:26][C@H:27]1[CH2:32][C:31](=O)[CH2:30][CH2:29][C@H:28]1[C:34]([O:36][CH2:37][CH3:38])=[O:35].O>C1COCC1>[CH3:2][O:3][CH:4]=[C:31]1[CH2:30][CH2:29][C@@H:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C@@H:27]([CH3:26])[CH2:32]1
Reactant: CCOC(=O)[C@@H]1CCC(=O)C[C@@H]1C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCC(=COC)C[C@@H]1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (1.7 g, 5.0 mmol) in THF (10 mL) was added sodium hydride (108 mg, 4.5 mmol, 60 wt %) in several portions at 0° C. The resulting mixture was stirred at 0° C. for 1 hour. Then ethyl rel-(1R,2S)-2-methyl-4-oxocyclohexanecarboxylate (500 mg, 2.7 mmol) in THF (5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. Water was then added dropwise at 0° C. and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give ethyl rel-(1R,2S)-4-(methoxymethylidene)-2-methylcyclohexanecarboxylate, which was dissolved in THF and aqueous hydrochloric acid (6 M) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hours and then diluted with water. The mixture was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl rel-(1R,2S)-4-formyl-2-methylcyclohexanecarboxylate. MS ESI calc'd for C11H19O3 [M+H]+ 199. found 199. 1H NMR: (400 MHz, CDCl3) δ 9.67-9.57 (m, 1H), 4.22-4.05 (m, 2H), 2.65-1.52 (m, 9H), 1.25 (t, J=7.2 Hz, 3H), 1.03-0.88 (m, 3H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[O:13]=[CH:14][C:15](=[CH2:17])[CH3:16].[Cl-].[NH4+]>C1(C)C=CC=CC=1.O.C1COCC1>[CH3:17][C:15](=[CH2:16])[CH:14]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[OH:13]
Reactant: C=C(C)C=O
Reactant: Brc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C(O)c1cccnc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To toluene (12 mL) were added dropwise at −78° C. n-butyllithium (2.76 mol/L solution in n-hexane, 4.14 mL, 11.4 mmol) and a solution of 3-bromopyridine (1.00 mL, 10.4 mmol) in toluene (4.0 mL), and the mixture was stirred at the same temperature for 30 minutes. THF (4.0 mL) was added to the resulting suspension. After stirring at −78° C. for 15 minutes, methacrolein (1.03 mL, 12.5 mmol) was added, and the mixture was stirred for 1 hour allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give 2-methyl-1-(pyridin-3-yl)prop-2-en-1-ol (1.08 g, 70% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[I:12][CH3:13]>CC(C)=O>[I-:12].[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N+:8]([CH3:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C=NCC2
Reactant: CI
Solvent: CC(C)=O
Product: C[N+]1=Cc2cc(N)ccc2CC1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
7-amino-3,4-dihydroisoquinoline (0.40 g, 2.74 mmol) in acetone (125 ml) was treated with iodomethane (0.50 ml, 8.03 mmol) and left stirring at room temperature for 18 h. The resultant yellow precipitate was collected by filtration and dried in vacuo at ambient temperature (0.73 g, 92%). m/z (API)=161 (M)+