Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][O:23][CH3:24])[CH:18]=[CH:17][C:16]=1[C:25](=[O:28])[CH2:26]I)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(C)=O>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:1][OH:4])=[C:19]([CH:20]=1)[O:21][CH2:26][C:25]([C:16]1[CH:17]=[CH:18][C:19]([O:21][CH2:22][O:23][CH3:24])=[CH:20][C:15]=1[O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:28])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: COCOc1ccc(C(=O)CI)c(OCc2ccccc2)c1
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(C(=O)COc2cc(OCc3ccccc3)ccc2CO)c(OCc2ccccc2)c1
Yield: 144.2 %

Procedure:
Potassium carbonate (0.165 g, 1.2 mmol) was added to a solution of 1-[2-benzyloxy-4-(methoxymethyloxy)phenyl]-2-iodo-ethanone (0.412 g, 1 mmol) and 4-benzyloxy-salicylalchohol (0.254 g, 1.1 mmol) in 10 mL of acetone and the mixture refluxed for 10 hours. After completion of the reaction (TLC), the solvent was evaporated and the residue extracted with EtOAc:water (2×20 mL:20 mL). The organic layers were combined, dried over sodium sulfate and evaporated. The residue was chromatographed over silica using hexanes:EtOAc (2:1). The organic fractions were evaporated to provide 0.371 g (72%) of white solid: mp 115-118° C.; TLC Rf0.16 in hexanes:EtOAc (2:1); 1H NMR (600 MHz, CDCl3) δ 7.88-7.86 (d, 1H, J=9 Hz, Ar—H5), 7.64-7.25 (m. 10H, 2×C6H5), 7.21-7.20 (d, 1H, J=8.4 Hz, Ar—H6′), 6.92 (d, 1H, J=2.4 Hz, Ar—H8), 6.78-6.76 (dd, 1H, 2J=9 Hz, 3J=2.4 Hz, Ar—H6), 6.56-6.54 (dd, 1H, 2J=8.4 Hz, 3J=2.4 Hz, Ar—H5′), 6.26-6.25 (d, 1H, J=2.4 Hz, Ar—H3′), 5.30 (s, 4H, PhCH2), 5.21 (s, 2H, O—CH2—O), 4.98 (s, 2H, H-2), 4.57-4.56 (d, 2H, J=6 Hz, CH2OH), 4.13-4.11 (t, 1H, CH2OH), 3.44 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ 194.6, 164.4, 162.2, 160.7, 158.6, 138.9, 137.6, 133.6, 130.2, 129.9, 129.8, 129.2, 125.1, 120.4, 110, 106.8, 102.5, 101.7, 95.6, 75.3, 72.4, 71.2, 61.5, 56.9; analysis calcd. for C31H30O7. C, 72.36; H, 5.88. found: C, 72.1; H, 5.85.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25](B(O)O)=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25]([C:2]2[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:5]3[O:11][CH2:10][C:9]([CH3:13])([CH3:12])[O:8][C:6]=3[N:7]=2)=[CH:24][N:23]=1
Reactant: CC1(C)COc2c(nc(Cl)nc2N2CCOCC2)O1
Reactant: COc1ncc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ncc(-c2nc3c(c(N4CCOCC4)n2)OCC(C)(C)O3)cn1
Temperature: 120 °C

Procedure:
A microwave vial was charged with 2-chloro-7,7-dimethyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine from Example 104 (50 mg, 0.18 mmol), 2-methoxypyrimidin-5-ylboronic acid (42 mg, 0.27 mmol), Pd(PPh3)2Cl2 (12 mg, 0.02 mmol) and sodium carbonate (0.5 mL, 0.5 mmol, 1M aqueous solution) in acetonitrile (1.5 mL) then evacuated and back filled with nitrogen before being heated at 120° C. using microwave irradiation. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by trituration with diethyl ether affording 110 as a white solid (30 mg, 17%). LCMS: RT=4.18 min, [M+H]+=360. 1H NMR (400 MHz, CDCl3): δ 9.33 (2H, s), 4.07 (3H, s), 3.92 (2H, s), 3.83 (8H, s), 1.47 (6H, s)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:15])(=O)=O.O.[Cl-].[Na+]>C(Cl)(Cl)Cl>[OH:1][N:2]=[C:3]([C:9](=[O:11])[CH2:10][Cl:15])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: O=S(=O)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NO)C(=O)CCl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 31.83 g) in chloroform (70 ml) was added dropwise sulfuryl chloride (29.7 g) over 6 minutes under ice-cooling, and the mixture was stirred for 4.5 hours at ambient temperature. The mixture was cooled to 7° C., and sulfuryl chloride (13.498 g) was further added thereto. The mixture was stirred at ambient temperature for overnight. After the reaction mixture was cooled with ice-water, chloroform (50 ml) and water (40 ml) were added thereto with stirring. The mixture was saturated with sodium chloride, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride (40 ml×2), dried over magnesium sulfate and then filtered. The filtrate was evaporated to give ethyl 2-hydroxyimino-3-oxo-4-chlorobutyrate (syn isomer), quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:39](O)[CH3:40].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH2:39][CH3:40])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:37][CH:38]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CCCC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
5 mg (0.009 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(1-pyrrolidinecarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-8-carboxylic acid was dissolved in 5 ml of dichloromethane. 0.001 ml (0.018 mmol) of ethanol, 2 mg (0.011 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.003 ml (0.018 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([N+:19]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[C:12]([CH:22]=[CH2:23])=[N:11]2)=[CH:7][CH:6]=[C:5]([CH3:24])[N:4]=1.CO>[OH-].[OH-].[Pd+2].ClCCl>[CH2:22]([C:12]1[C:13]2[C:14]([NH2:19])=[CH:15][CH:16]=[CH:17][C:18]=2[N:10]([CH2:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][C:5]([CH3:24])=[CH:6][CH:7]=2)[N:11]=1)[CH3:23]
Reactant: C=Cc1nn(Cc2ccc(C)nc2OC)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1nn(Cc2ccc(C)nc2OC)c2cccc(N)c12
Reaction time: 7 h
Yield: 29.9 %

Procedure:
1-((2-M ethoxy-6-methylpyridin-3-yl)methyl)-4-nitro-3-vinyl-1H-indazole (395 mg, 1.22 mmol) and palladium hydroxide on carbon (171 mg, 0.244 mmol; 20%) were added to a hydrogenation flask. Methanol (6 mL) was added along with a small amount of dichloromethane. The reaction flask was evacuated and purged with nitrogen prior to being shaken on a Parr apparatus under an atmosphere of hydrogen at 40 psi for 7 hours. The mixture was filtered through Celite, rinsing with methanol and the filtrated was concentrated under reduced pressure. The material was purified using preparative thin layer chromatography on silica, eluting with 10% methanol in dichloromethane containing 0.5% ammonium hydroxide solution. Further purification was carried out using column chromatography on silica, eluting with 1% methanol in dichloromethane containing 0.5% ammonium hydroxide solution to provide 3-ethyl-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine (108 mg). Some material was isolated where the nitro group had not been completely reduced (186 mg). This material was dissolved in ethanol (3 mL). Iron powder (318 mg; 5.70 mmol) and ammonium chloride (15.2 mg; 0.285 mmol) were added and the mixture was heated at reflux for 1 hour. The mixture was allowed to cool and filtered through glass fiber filter paper rinsing with ethanol. The solution was concentrated under reduced pressure and purified using preparative thin layer chromatography, eluting with 2% methanol in dichloromethane containing 0.25% ammonium hydroxide solution to provide an additional 108 mg of 3-ethyl-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-1H-indazol-4-amine.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:23]=[C:22]([O:24][CH3:25])[C:19]([C:20]#[N:21])=[C:18](F)[CH:17]=2)[CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.[NH2:36][NH2:37]>CCO>[CH2:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([C:16]2[CH:17]=[C:18]3[C:19]([C:20]([NH2:21])=[N:36][NH:37]3)=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:9]=1)[CH3:2]
Reactant: NN
Reactant: CC[C@@H]1CCCN1c1cc(-c2cc(F)c(C#N)c(OC)c2)nc(NC)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC[C@@H]1CCCN1c1cc(-c2cc(OC)c3c(N)n[nH]c3c2)nc(NC)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
In a microwave tube, 4-[6-[(2R)-2-ethyl-1-pyrrolidinyl]-2-(methylamino)-4-pyrimidinyl]-2-fluoro-6-(methyloxy)benzonitrile (129 mg, 0.363 mmol), 5 mL of EtOH, Hunig's base (0.063 mL, 0.363 mmol), and hydrazine anhydrous (0.068 mL, 2.178 mmol) were added. The yellow suspension mixture was heated to 100° C. in an oil bath overnight. When the temperature of the reaction reached 100° C., the solid in the mixture was all dissolved. After overnight, there was a white colored solid formed. LCMS showed no more starting material. The reaction was cooled to room temperature, then the white solid was filtered from the yellow solution, washed by CH3CN (2 mL), and dried under reduced pressure to afford the title compound (70 mg) as a white solid. LC-MS (ES) m/z=368 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, J=7.3 Hz, 3H), 1.37 (m, 1H), 1.80 (m, 2H), 1.93 (m, 3H), 2.82 (d, J=4.6 Hz, 3H), 3.39 (m, H), 3.47-3.63 (m, 1H), 3.93 (s, 3H), 4.05 (m, 1H), 5.02 (s, 2H), 6.19 (s, 1H), 6.41 (s, 1H), 6.92 (s, 1H), 7.46 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([Cl:29])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([N:19]3[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]3)[C:15]2=[O:26])=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:37]([Si:40](OS(C(F)(F)F)(=O)=O)([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([N:19]3[CH2:20][CH2:21][CH:22]([O:25][Si:40]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:37]([CH3:39])[CH3:38])[CH2:23][CH2:24]3)[C:15]2=[O:26])=[C:27]([Cl:29])[CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1N1CCC(O)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Yield: 72 %

Procedure:
Stir a mixture of (R)-3-(4-benzyloxy-2,6-dichloro-benzyl)-1-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (1.23 g, 2.75 mmol) and 15 mL of dichloromethane in an ice bath. Add pyridine (0.52 g, 6.6 mmol) followed by triisopropylsilyltrifluoromethane sulfonate (0.924 g, 3.02 mmol). Remove the cold bath and stir the reaction 12 hours at room temperature. Dilute the reaction with dichloromethane and wash with water. Dry the organic phase over sodium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography by eluting with 4:1 hexanes:ethyl acetate to give 1.2 g (72%) of the title compound. MS (m/z): 605 (M+).
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([NH2:14])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:20](Cl)(Cl)=[S:21]>ClCCl>[CH:1]1([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([N:14]=[C:20]=[S:21])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(C2CC2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: S=C=Nc1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 149.7 %

Procedure:
Compound 2 (440 mg, 2.6 mmol) was dissolved in 14 mL of dichloromethane. Sodium bicarbonate (7 mL, sat. solution) and thiophosgene (0.2 mL, 2.6 mmol) were added and the mixture stirred at room temperature for 1 h. Then, the organic layer was separated, dried over sodium sulfate and concentrated to afford 877 mg, 99% yield of 1-cyclopropyl-4-isothiocyanatonaphthalene (3) which was used in the next step without further purification
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]Cl)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:21]([NH2:27])[CH:22]1[O:26][CH2:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:27][CH2:21][CH:22]4[CH2:23][CH2:24][CH2:25][O:26]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NCC1CCCO1
Reactant: ClCCOc1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1
Product: Brc1cnc2[nH]c(-c3ccc(OCCNCC4CCCO4)cc3)nc2c1

Procedure:
The title compound was prepared from 6-bromo-2-[4-(2-chloroethoxy)phenyl)-3H-imidazo[4,5-b]pyridine and tetrahydrofurfurylamine.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][C:18]1([CH3:26])[O:25][C:23](=[O:24])[CH2:22][C:20](=[O:21])[O:19]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C=O)C>[CH3:17][C:18]1([CH3:26])[O:25][C:23](=[O:24])[C:22](=[C:12]([OH:14])[CH:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:16][CH2:15]2)[C:20](=[O:21])[O:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(O)=C2C(=O)OC(C)(C)OC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (0° C.) solution of Boc-isonipecotic acid (5.97 g, 26.0 mmol) and Meldrum's acid (3.75 g, 26.0 mmol) in DMF (54 mL) was treated dropwise with diethyl cyanophosphonate (4.34 mL, 28.6 mmol) and triethylamine (11.2 mL, 80.7 mmol). After stirring at 0° C. for an additional 30 min the reaction mixture was permitted to warm to rt and stir over 3 days. The reaction mixture was concentrated under reduced pressure and ether and 1N HCl solution were added. The aqueous layer was extracted again with ether and the ethereal layers were combined and washed with 1N HCl solution, twice with water, and lastly with brine. He ethereal layer was then dried over anhydrous MgSO4, filtered, and concentrated to give tert-butyl 4-[(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)(hydroxy)methyl]piperidine-1-carboxylate which contained approximately 10% of Boc-isonipecotic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:8]1[N:9]=[C:10]([C@@H:12]3[CH2:16][C@H:15]([CH3:17])[CH2:14][NH:13]3)[NH:11][C:7]=1[CH:6]=[CH:5]2.[CH3:21][O:22][C:23]([NH:25][C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:27](O)=[O:28])=[O:24].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:21][O:22][C:23](=[O:24])[NH:25][C@H:26]([C:27]([N:13]1[CH2:14][C@@H:15]([CH3:17])[CH2:16][C@H:12]1[C:10]1[NH:11][C:7]2[CH:6]=[CH:5][C:4]3[C:18](=[CH:19][CH:20]=[C:2]([Br:1])[CH:3]=3)[C:8]=2[N:9]=1)=[O:28])[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[C@@H]1CN[C@H](c2nc3c(ccc4cc(Br)ccc43)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc2c(ccc3cc(Br)ccc32)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.9 %

Procedure:
To a solution of 7-bromo-2-((2S,4S)-4-methyl-pyrrolidin-2-yl)-3H-naphtho[1,2-d]imidazole (1.05 g, 3.2 mmol; Preparation 27) in DCM (20 mL) was added (S)-2-methoxycarbonylamino-3-methyl-butyric acid (672 mg, 3.84 mmol), DIPEA (825 mg, 6.4 mmol), and HATU (1.82 g, 4.8 mmol). The reaction mixture was stirred at RT for 4 h and extracted with DCM (3×250 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (1:1 EtOAc:petroleum ether) to provide the title intermediate (1.2 g) (m/z): [M+H]+ calcd for C23H27BrN4O3 487.13, 489.12 found 489.2.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:5].[C:35](OC(=O)C)(=[O:37])[CH3:36].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:5])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)ccc2N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
2-Amino-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (140 mg, 0.286 mmol) was dissolved in methylene chloride (2 ml). Acetic acid anhydride (32 mg, 0.315 mmol) and ethyl-diisopropylamine (41 mg, 0.315 mmol) were added and the reaction was stirred over night at RT. Further acetic acid anhydride (30 μl) was added and the reaction was stirred for another night at RT. The reaction was extracted with ethyl acetate, the combined organic layers were concentrated in vacuo and the residue was purified by flash column chromatography (heptane/ethyl acetate:7/3) to yield the desired product (110 mg, 72%) as an off-white solid. MS (ISP) 529.2 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](C2C=NC=CC=2)[CH:26]=1)(C)(C)C.[C:40](O)([C:42](F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:8]4[CH:9]=[N:21][CH:22]=[CH:40][CH:42]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M26) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (127 mg).
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[C:8]([NH2:27])=[N:9][CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:15](=[O:26])[O:16][C:17]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=2[C:19]=1[CH3:20].Br[C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:20][C:19]1[C:18]2[CH:21]=[CH:22][C:23]([O:25][C:29]3[N:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:24][C:17]=2[O:16][C:15](=[O:26])[C:14]=1[CH2:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:27])[C:7]=1[F:6]
Reactant: Brc1ncccn1
Reactant: Cc1c(Cc2ccnc(N)c2F)c(=O)oc2cc(O)ccc12
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccnc(N)c2F)c(=O)oc2cc(Oc3ncccn3)ccc12
Temperature: 115 °C
Reaction time: 3.5 h
Yield: 89.5 %

Procedure:
Under a nitrogen atmosphere, 3-(3-fluoro-2-aminopyridin-4-ylmethyl)-7-hydroxy-4-methyl-2-oxo-2H-1-benzopyran methanesulfonate (7.6 g, 19.2 mmol) and 2-bromopyrimidine (4.0 g, 24.9 mmol) were dissolved in DMF (122 mL), potassium carbonate (5.8 g, 42.2 mmol) was added, and the mixture was stirred at 115° C. for 3.5 hours. The reaction mixture was cooled to 28° C., water (122 mL) was added dropwise over a period of 0.5 hours at that temperature, and the mixture was stirred for 2 minutes. The mixture was further cooled to 0° C. and stirred for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water (61 mL) and acetonitrile (61 mL) in that order, and dried under reduced pressure to obtain the title compound as crystals (6.5 g).
Reaction SMILES: C[O-].[Na+].[CH3:4][S:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[N:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16]>CO.O>[CH3:21][O:20][C:18](=[O:19])[C:17]([N:14]=[N+:15]=[N-:16])=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([S:5][CH3:4])=[CH:7][CH:8]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(=Cc1ccc(SC)cc1)N=[N+]=[N-]
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of sodium methoxide prepared from Na metal (8.65 g, 0.38 m) in methanol(200 mL) at 0°-5° C., was added a solution of 4-(methylthio)benzaldehyde (12.6 ml, 94.7 mmol) and methyl azidoacetate (44 g, 0.382 mol) in methanol (30 mL). After stirring at the same temperature for 3 hours, the suspension was diluted with H2O (300 mL). The solids were filtered, washed with water and dried under vacuum to provide 19.4 g (82.0%) of methyl-2-azido-3-(4-methylthiophenyl)propenoate as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CN(C=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH3:26])[N:20]=[CH:19][C:18]=3[N:35]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H](COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)nc2cn1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](COc1cc2oc(-c3ccc(O)cc3)nc2cn1)NC(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 71.6 %

Procedure:
A mixture of tert-butyl ((2S)-1-((2-(4-(benzyloxy)phenyl) [1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (2.5 g), 10% palladium/carbon (containing water (50%), 0.5 g), THF (200 mL) and DMF (50 mL) was stirred for 15 hr under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure. The obtained solid was collected by filtration, washed with hexane/ethyl acetate (4/1), dried to give the title compound (1.45 g).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6]2.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>>[Si:21]([O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH:7]([C:13]([O:15][CH3:16])=[O:14])[CH2:6]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C1Cc2cc(O)ccc2CN1
Agent: Cl
Product: COC(=O)C1Cc2cc(O[Si](C)(C)C(C)(C)C)ccc2CN1
Yield: 83 %

Procedure:
Prepared as in Example 12-1c from methyl 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (Example 13-3c) and tert-butylchlorodimethylsilane. Yield 83%, yellowish. MS 322 (MH+).