Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[O:35][N:34]=[C:33]([CH3:36])[N:32]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[O:35][N:34]=[C:33]([CH3:36])[N:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: COC(=O)Cc1nc(C)no1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)no3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 35 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (3-methyl-[1,2,4]oxadiazol-5-yl)-acetic acid methyl ester with heating for 5 days to afford the title compound as an off-white solid (49 mg, 35%). LC/MS (Method B) 3.80 min, [M+1]+ 477.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][NH:11]2)=[C:7]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH:6]=1.[OH-].[K+].[I:27]I>CN(C=O)C>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([I:27])=[N:10][NH:11]2)=[C:7]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH:6]=1
Reactant: II
Reactant: OCC(O)COc1cc(Oc2ccc(F)cc2F)cc2[nH]ncc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: OCC(O)COc1cc(Oc2ccc(F)cc2F)cc2[nH]nc(I)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
3-[6-(2,4-Difluoro-phenoxy)-1H-indazol-4-yloxy]-propane-1,2-diol (0.45 g, 1.34 mmol) was dissolved in 5 mL of dry DMF, and powdered KOH (0.288 g, 5.1 mmol) was added. The reaction mixture was stirred under nitrogen for 10 minutes at room temperature, and iodine (0.536 g, 2.11 mmol) was added in two portions. The reaction mixture was stirred for 90 minutes. The reaction mixture was partitioned between EtOAc and 5% aqueous sodium bisulfite solution, and the organic layer was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was chromatographed through silica (0%-5% MeOH in dichloromethane) to give 0.408 g of 3-[6-(2,4-difluoro-phenoxy)-3-iodo-1H-indazol-4-yloxy]-propane-1,2-diol, MS(M+H)=436.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][C:9]2[C:10](=[O:16])[NH:11][C:12](=[S:15])[NH:13][CH:14]=2)[CH:4]=[CH:3]1.[OH-].[K+].[CH3:19]I>C(O)C>[CH3:19][S:15][C:12]1[NH:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2](=[O:1])[NH:7][CH:6]=2)[C:10](=[O:16])[N:11]=1
Reactant: O=c1ccc(Cc2c[nH]c(=S)[nH]c2=O)c[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc(=O)c(Cc2ccc(=O)[nH]c2)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
A suspension of 5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (130 mg, 0.55 mmol, 1 eq) and KOH, 85% (1.2 eq, 44 mg) in 5 ml of absolute ethanol was stirred with ultrasound bath at room temperature for 1 hour. In the suspension was then added MeI (1.2 eq, 42 μl) dropwise and the mixture was stirred in a sealed vial at 70° C. (temperature on display of heating device) for 20 hours (overnight). The solvent was then evaporated. In the crude was added 10 ml of water and pH of the solution was adjusted to 7-7.5. The resulting suspension was filtered over filter paper. The filtrate was washed with chloroform (3 times, 30 ml was used in total). pH of the water layer was adjusted to 5-5.5 and using ultrasound bath precipitate was formed. The precipitate was collected, it was dried and obtained was 2-methylsulfanyl-5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (22 mg, yield=15.9%, purity=95%) in form of white powder. MS: [M+H]+=250.18 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.46 (s, 3H), 3.31 (s, 2H), 6.25 (d, J=9.37 Hz, 1H), 7.19 (d, J=2.06 Hz, 1H), 7.35 (dd, J=9.37 Hz, J=2.45 Hz, 1H), 7.77 (s, 1H)
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Rh]>[C:1]([N:8]1[CH2:15][CH:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)C[C@H]1C(=O)O
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(C2CCCCC2)C[C@H]1C(=O)O
Yield: 95.4 %

Procedure:
A solution of the commercially available Boc-4-phenylproline (750 mg) and 5% Rh on carbon (750 mg) in methanol (15 mL) was hydrogenated at 50 psi for 24 hours. The mixture was filtered and concentrated to give 730 mg of product.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[N:3][N:2]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>CN(C=O)C>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([NH:14][NH:15][C:16]([NH2:18])=[S:17])=[O:13])[C:5]=2[CH:4]=[N:3][N:2]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1cccc2cnncc12
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1cccc2cnncc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
To a 100 mL round bottom flask was added phthalazine-5-carboxylic acid (0.50 g, 2.9 mmol) 1,1′-carbonyldiimidazole (0.93 g, 5.7 mmol) and DMF (2.2 mL). The mixture was stirred at 70° C. for 1 hour and treated with thiosemicarbazide (0.81 g, 8.9 mmol). The resulting mixture was stirred at 70° C. for 30 minutes. The mixture was concentrated under vacuum to remove almost all of the DMF. The remaining residue was treated with 2 N HCl with stirring until the solution reached pH 4. Upon standing, a yellow solid formed. The precipitate was recovered by filtration, washing with water and air dried to provide 1-(phthalazine-5-carbonyl)thiosemicarbazide (0.45 g, 63%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]2[CH2:13][CH2:14][C:15]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[C:16]=3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=[O:34])C>N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]2[CH2:13][CH2:14][C:15]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[C:16]=3[CH2:17][N:18]([CH:21]=[O:34])[CH2:19][CH2:20][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(c1OC)CN(C)CCc1cc(OCc3ccccc3)ccc1CC2
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Product: COc1ccc2c(c1OC)CN(C=O)CCc1cc(OCc3ccccc3)ccc1CC2
Reaction time: 2 h

Procedure:
To a chromium trioxide - pyridine complex freshly prepared from 28 g of chromium trioxide and 280 ml of anhydrous pyridine is added dropwise a solution of 21 g of 10-benzyloxy-3,4-dimethoxy-6-methyl-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine in 140 ml of pyridine at 10° - 15°C over a period of 35 minutes, and the mixture is allowed to stand at the same temperature for 2 hours and then at room temperature for 15 hours. The mixture is then diluted with 600 ml of ethyl acetate, stirred well, and filtered to remove the inorganic precipitate. The filtrate is passed through a column of alumina and celite (kiesel-guhr) and evaporated to dryness. The resulting residue (14.3 g) is dissolved in 286 ml of methanol, treated with 7 g of sodium borohydride, and chromatographed on 140 g of silica gel. The benzene - ethyl acetate (10 : 1) elution (2.45 g) is recrystallized from methylene chloride - ether to yield 2.11 g of 10-benzyloxy-3,4-dimethoxy-6-formyl-5,6,7,8,13,14-hexahydrodibenz[c,g]azecine as colorless needles having mp. 140° - 141°C. IR: νmaxCHCl 3 1654 cm-1. Anal. Calcd. for C27H29O4N: C, 75.15%; H, 6.77%; N, 3.25%. Found: C, 75.20%; H, 7.02%; N, 3.23%.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C(O)C>[Cl:4][C:5]1[CH:21]=[CH:20][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:2][NH2:3])=[O:16])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(OCc2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
2.75 mol of hydrazine hydrate was added to a solution of 0.275 mol of ethyl ester of 4-(4-chloro benzyloxy) benzoic acid (X) in 300 ml ethanol. The reaction medium was reflux-heated for 48 hours. After cooling, the expected product was separated by filtration and recrystallised from ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([O:11][C:12](=[O:14])[CH3:13])[C:8]([CH3:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[CH3:19]>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[C:7]([O:11][C:12](=[O:14])[CH3:13])([C:8](=[O:9])[CH3:10])[CH2:18][CH3:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)OC(C(C)=O)C(=O)OC(C)(C)C
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(OC(C)=O)(C(C)=O)C(=O)OC(C)(C)C
Yield: 79 %

Procedure:
According to the general alkylation method, tert-butyl-2-acetoxy-aceto-acetate (219a) (1.08 g, 5.00 mmol), NaH (156 mg, 6.5 mmol) and ethylbromide (also propyl and pentyl) (373 μL, 549 mg, 5.00 mmol) were reacted in DMF (10 mL) to give 2-acetoxy-2-acetylbutanoic-acid-tert-butylester (250g) (970 mg, 3.97 mmol, 79%) as a slightly yellow oil. Then, 250 g (1.40 g, 5.73 mmol) and 109 mg (0.57 mmol) p-TsOH.H2O were stirred in 18.0 mL benzene according to decarboxylation method A. Kugelrohr distillation gave 486 mg (3.4 mmol, 59%) of 251 g as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8]([CH3:14])([CH3:13])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8]([CH3:14])([CH3:13])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OC(=O)c2c(O)cccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2c(OCc3ccccc3)cccc2O1
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
A solution of 5-hydroxy-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (6.00 g, 30.9 mmol) (Hadfield, A. et al., Synthetic Communications, 24(7):1025-1028 (1994)) in N,N-dimethylformamide (35 mL) was treated with powdered anhydrous potassium carbonate (5.15 g, 37.26 mmol) added all at once. The resulting mixture was stirred in vacuo for 10 min. and then flushed with nitrogen. The reaction flask was placed in a water bath (22° C.) and treated with benzyl bromide (5.55 g, 32.16 mmol) added dropwise over 15 min. The resulting mixture was then stirred at 22° C. for 18 h. The solid formed was filtered and washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (300 mL), washed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Chromatography on silica gel (4×13 cm, elution toluene-ethyl acetate 0-5%) gave 8.78 g (100% yield) of the title material as a white solid. LC (Method A): 1.982 min. 1H NMR (CDCl3, 600 MHz) δ ppm: 1.69 (s, 6H), 5.23 (s, 2H), 6.53 (d, J=8.2 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 7.24-7.3 (m, 1H), 7.34-7.4 (m, 3H), 7.52 (broad d, J=7.4 Hz 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH:10]12[C:19](=O)[O:18][C:16](=[O:17])[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:16](=[O:17])[CH:11]3[CH:10]([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:19]2=[O:18])=[C:4]([F:9])[CH:3]=1
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: Nc1ccc(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1C2CCCCC2C(=O)N1c1ccc(Cl)cc1F

Procedure:
9.44 parts of 4-chloro-2-fluoroaniline were then added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 75 parts of glacial acetic acid. After refluxing for 6 hours, the reaction mixture was poured into 200 parts of ice. The resulting crystals were filtered and recrystallized from 70 parts of methanol at -40° to yield 12.4 parts of white crystals of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)dione melting at 94°-95.5°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH2:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1N
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: Nc1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 97.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (300 mg, 0.88 mmol) and o-phenylenediamine (110 mg, 1 mmol) to give 370 mg of the title compound (98%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.07 (s, 1H), 9.23 (s, 1H), 7.25 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.13 (dd, 1H, J=8.1 Hz), 6.91 (dt, 1H, J=2, 8.1 Hz), 6.72 (dd, 1H, J=2, 8.1 Hz), 6.54 (dt, 1H, J=8.1, 2 Hz), 5.19~5.27 (m, 1H), 4.85 (br, 2H), 3.10 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.85 (dm, 1H, J=17.1 Hz), 2.61 (d, 2H, J=7.3 Hz), 2.12 (dm, 1H, J=13.5 Hz), 1.81~1.95 (m, 1H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[C:29]([O:32][CH2:33][C:34](Cl)=[O:35])(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([O:32][CH2:33][C:34]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:6]=2)[CH2:1]1)=[O:35])(=[O:31])[CH3:30]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)COC(C)=O)C3)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A solution of N-[[(5S)-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 1, Step 6, 350 mg, 1.21 mmol) and triethylamine (0.252 mL, 1.81 mmol) in dry CH2Cl2 (6 mL) under N2 is cooled to 0° C. and treated with acetoxyacetyl chloride (0.156 mL, 1.45 mmol). The resulting mixture is stirred at 0° C. for 1 hr and is then warmed to ambient temperature, diluted with CH2Cl2 (20 mL), washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-3/97), and those fractions with an Rf=0.44 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 323 mg (69%) of the title compound as a glassy solid. An analytical sample is prepared by trituration and filtration from Et2O. MS (ESI+) for C19H23N3O6 m/z 390 (M+H)+; Anal. Calcd for C19H23N3O6: C, 58.60; H, 5.95; N, 10.79. Found: C, 58.46; H, 6.06; N, 10.66; [α]25D =−18° (c 0.93, DMSO).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[CH3:64][C:65]1[S:69][C:68]([NH2:70])=[N:67][CH:66]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:4]1[N:3]=[C:2]([NH:70][C:68]2[S:69][C:65]([CH3:64])=[CH:66][N:67]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)nc1
Reactant: Cc1cnc(N)s1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cnc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3ccccc23)s1
Temperature: 110 °C
Yield: 4.8 %

Procedure:
To a mixture of 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline from Example 4 Step A (100 mg, 0.32 mmol), Pd2(dibenzylideneacetone)3 (12 mg, 0.013 mmol), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 0.04 mmol), 5-methylthiazol-2-amine (51 mg, 0.45 mmol), and Na2CO3 (48 mg, 0.45 mmol) was added toluene (3 mL). The mixture was evacuated and flushed with argon three times and then heated at 110° C. for 2 h. The mixture was diluted with MeOH, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/ACN and solvent A=0.05% HOAc/H2O) to afford N-(2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-yl)-5-methylthiazol-2-amine (6 mg, 5%). 1H NMR (300 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.64 (d, J=2.4 Hz, 2H), 7.88-8.15 (m, 4H), 7.66-7.76 (m, 1H), 7.19 (s, 1H), 2.28 (s, 3H). LCMS (ESI) m/z 388 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:29])[F:30])=[CH:28][CH:27]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: OCCOc1ccc(OC(F)(F)F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(Br)ccc2n1CCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (1.7 g, 6.3 mmol), 2-[4-(trifluoromethoxy)phenoxy]ethanol (1.7 g, 7.6 mmol) and triphenylphosphine (3.3 g, 12.7 mmol) in toluene (20 ml) was added DIAD (1.85 ml, 9.5 mmol) dropwise at 0° C. The mixture was left to warm up to RT and stirred overnight. The mixture was then concentrated in vacuo. The residue was purified on silica gel (0-20% EtOAc in hexanes) to yield the title product (1.6 g).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65](=[O:73])[NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56]([OH:58])=O)=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[CH3:74][C@H:75]1[O:80][C@@H:79]([CH3:81])[CH2:78][NH:77][CH2:76]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]1([C:31]2[C:32]3[CH:33]=[CH:34][C:35]([C:65]([NH:66][S:67]([CH:70]([CH3:72])[CH3:71])(=[O:69])=[O:68])=[O:73])=[CH:36][C:37]=3[N:38]3[CH2:44][C:43]([C:45]4[N:49]([CH:50]5[CH2:52][CH2:51]5)[N:48]=[C:47]([CH:53]([CH3:55])[CH3:54])[C:46]=4[C:56]([N:77]4[CH2:76][C@H:75]([CH3:74])[O:80][C@H:79]([CH3:81])[CH2:78]4)=[O:58])=[CH:42][C:41]4[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:40]=4[C:39]=23)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1ccc2c(c1)C=C(c1c(C(=O)O)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)C=C(c1c(C(=O)N3C[C@@H](C)O[C@@H](C)C3)c(C(C)C)nn1C1CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C(C)C)cc21
Reaction time: 2 h
Yield: 30.7 %

Procedure:
HATU (65.0 mg, 0.171 mmol) was added to a stirring solution of 5-(13-cyclohexyl-10-((isopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxylic acid (78 mg, 0.114 mmol), cis-2,6-dimethylmorpholine (28 μL, 0.23 mmol), DIEA (80 μL, 0.456 mmol) in DMF (1 mL) at room temperature. The reaction was allowed to stir for 2 hours. The reaction was purified by preparative reverse phase HPLC on a C18 column using a TFA buffered H2O/CH3CN gradient, and concentrated to give the titled compound (28 mg, 0.035 mmol, 31% yield) consistent by LCMS and NMR, with sufficient purity by HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=1)[CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>CO>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=1)[CH2:9][NH2:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CN)Cc1ccc(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution in methanol (15 ml) of the mixture containing [1-[(3-tert-butyl-4-hydroxyphenyl)methyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)ethyl]carbamic acid tert-butyl ester, hydrazine monohydrate (2 ml) was added and the resulting mixture was stirred at room temperature for 4 hours. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of chloroform, methanol and aqueous ammonia at a ratio of 10:1:0.1) to give [2-amino-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]carbamic acid tert-butyl ester in the amount of 1.55 g (69%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH3:29][CH:30]([CH3:35])[CH2:31][CH2:32]C=O>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:32][CH2:31][CH:30]([CH3:35])[CH3:29])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: CC(C)CCC=O
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)ccc1c2CCC(C)C

Procedure:
The product of Example 84 is treated with 4-methylpentanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:11][C@@H:12]([CH3:28])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[CH:20]=2)=[N:15]1>>[Cl:27][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[O:3][C:4]=3[CH3:10])=[O:9])[CH3:28])[N:15]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c(C)o1
Yield: 64.7 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2,5-dimethyloxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2,5-dimethyl-1,3-oxazole-4-carboxylic acid (0.262 g, 1.804 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.504 mmol). The product was triturated using diethyl ether. Yield 64.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.08 (d, 3H), 2.43 (d, 6H), 4.23 (dd, 1H), 4.34-4.45 (m, 2H), 6.96 (d, 1H), 7.83 (d, 1H), 7.96-8.01 (m, 2H), 8.10 (dd, 1H), 8.23 (d, 1H).