Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:13]1([N:19]([CH2:39][CH:40](OC)OC)[C:20](=[O:38])[CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]3[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=3)[CH:27]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[NH2:46][CH2:47][CH2:48][C:49]1[C:54]2[O:55][CH2:56][C:57](=[O:59])[NH:58][C:53]=2[C:52]([OH:60])=[CH:51][CH:50]=1.C(=O)(O)[O-].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)(=O)C.CN1C(=O)CCC1.O>[CH:13]1([N:19]([CH2:39][CH2:40][NH:46][CH2:47][CH2:48][C:49]2[C:54]3[O:55][CH2:56][C:57](=[O:59])[NH:58][C:53]=3[C:52]([OH:60])=[CH:51][CH:50]=2)[C:20](=[O:38])[CH2:21][CH2:22][O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]3[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=3)[CH:27]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)C1CCCCC1)OC
Reactant: NCCc1ccc(O)c2c1OCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cn1cc(-c2cccc(CCOCCC(=O)N(CCNCCc3ccc(O)c4c3OCC(=O)N4)C3CCCCC3)c2)cn1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
p-Toluenesulfonic acid monohydrate (5.31 g) was added in one portion to N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanamide (7.74 g, prepared as in Example 2a, Step ii)) in tetrahydrofuran (60 mL). The resulting solution was stirred at 20° C. for 30 min. This solution was added to a stirred mixture of 8-(2-aminoethyl)-5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one hydrochloride (4.27 g), sodium bicarbonate (4.40 g), water (6 mL) and NMP (60 mL). The mixture was stirred for 10 min. and sodium triacetoxyborohydride (9.25 g) and acetic acid (1 mL) were added. The mixture was stirred for 3 h. The reaction mixture was neutralised with saturated sodium hydrogen carbonate (100 mL) and extracted into ethyl actate (5×100 mL). Methanol (50 mL) was added and the organic was washed with a 1:1 mixture of water and saturated brine (2×70 mL). The organic was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 100% isohexane in ethyl acetate, then elution gradient 2 to 10% methanol in dichloromethane to afford N-cyclohexyl-N-(2-(2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)ethylamino)ethyl)-3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanamide (5.38 g) as a gum.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([CH2:16][OH:17])=[CH:3][CH:2]=1.[Cl:18][C:19]1([Cl:34])[CH2:21][C:20]1([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)[C:22](Cl)=[O:23]>>[Cl:18][C:19]1([Cl:34])[CH2:21][C:20]1([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)[C:22]([O:17][CH2:16][C:4]1[C:5]2[CH2:11][CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=2[CH:1]=[CH:2][CH:3]=1)=[O:23]
Reactant: CCOc1ccc(C2(C(=O)Cl)CC2(Cl)Cl)cc1
Reactant: OCc1cccc2c1CCCc1ccccc1-2
Product: CCOc1ccc(C2(C(=O)OCc3cccc4c3CCCc3ccccc3-4)CC2(Cl)Cl)cc1

Procedure:
In the manner of Example I, but substituting 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-methanol and 2,2-dichloro-1-(4-ethoxyphenyl)cyclopropanecarbonyl chloride, the title compound was prepared.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)=[CH:17][CH:18]=2)[CH2:13][CH2:12]1)(=[O:10])[CH3:9]>C(Cl)Cl>[N:22]1([CH2:21][CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([C:8](=[O:10])[CH3:9])[CH2:12][CH2:13]3)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: CC(=O)N1CCc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2cc(CCN3CCNCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
Trifluoroacetic acid (4.08 mL, 53.08 mmol) was added to a solution of tert-butyl 4-(2-(1-acetylindolin-5-yl)ethyl)piperazine-1-carboxylate (0.793 g, 2.12 mmol) in dry DCM and the reaction was stirred at room temperature for 60 min. The mixture was evaporated and the crude mixture was made basic with 10% NaOH aq. The aq phase was extracted with DCM (3×), dried (Na2SO4), filtered and evaporated to give 0.590 g of the product. This product was taken to the next step assuming quantitative yield without further purification. MS (ES+) m/z 274.2 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].O=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(C)C=CC=CC=1.Cl>O1CCOCC1.C(OCC)(=O)C.CCCCCC>[CH2:23]([O:22][C:21]([NH:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]3[C:3]([C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[F:10])=[CH:2][N:1]=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C=O
Reactant: NCC(c1ccccc1F)c1c[nH]c2cc(NC(=O)OCc3ccccc3)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(NC(=O)OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
To a solution of benzyl 3-(2-amino-1-(2-fluorophenyl)ethyl)-1H-indol-6-ylcarbamate (0.586 g, 1.452 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.576 mL, 2.90 mmol) in 1,4-dioxane (15 mL) at room temperature was added hydrogen chloride in 1,4-dioxane (0.436 mL, 1.743 mmol). The mixture was stirred room temperature for 16 hr. The volatiles were removed under vacuum. The residue was diluted with water (30 mL), basified with NaHCO3 solution to pH 10, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 ml), dried over anhydrous MgSO4, and concentrated to dryness under vacuum. To the residue were added toluene (15 mL) and 10% Pd/C (0.2 g), and the mixture was heated at 110° C. under an ambient atmosphere for 3.5 hr. The solid phase was removed by suction filtration. The filtrate was diluted with ethyl acetate (100 ml), washed with brine (25 ml), and dried over anhydrous MgSO4. The desired product (0.238 g, 0.492 mmol, 33.9% yield) was isolated as a beige solid by ISCO (40 g silica gel, solid loading, 20-40% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:15](OCC)=[O:16].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1.C(OCC)C>[OH:16][CH2:15][C:3]1[N:4]=[C:5]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1nc(C=Cc2ccccc2)oc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1oc(C=Cc2ccccc2)nc1CO

Procedure:
Ethyl 5-methyl-2-styryl-4-oxazolecarboxylate (2.14 g) was dissolved in a mixture of dry tetrahydrofuran (10 ml) and dry ethyl ether (15 ml) and the solution was added dropwise to a suspension of lithiumaluminum hydride (0.34 g) in dry ethyl ether (20 ml) with ice-cooling and stirring. The mixture was further stirred under ice-cooling for an hour and water (2 ml) was added portionwise for decomposition. The precipitate was filtered off and the filtrate was concentrated to give 4-hydroxymethyl-5-methyl-2-styryloxazole as crystals; yield 1.28 g (71.5%). Recrystallization from acetone gave colorless prisms melting at 106°-107° C.
Reaction SMILES: C(O[C:6]([C:8]1[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:11]2[CH2:12][CH:13]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1>O>[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:6]([C:8]2[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:11]3[CH2:12][CH:13]([CH2:15][O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:31]1
Reactant: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(COc1ccccc1)O2
Reactant: Cn1ccc(N)n1
Solvent: O
Product: CC(C)Oc1cc(C(=O)Nc2ccn(C)n2)cc2c1CC(COc1ccccc1)O2

Procedure:
The title compound was prepared in a similar manner as described for Example 200 from 4-isopropoxy-2-phenoxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (214c) and 1-methyl-3-aminopyrazole. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1 H) 7.28-7.32 (m, 3 H) 7.05 (s, 1 H) 6.93-7.00 (m, 3 H) 6.89 (s, 1 H) 6.84 (s, 1 H) 5.19-5.27 (m, 1 H) 4.64-4.72 (m, 1 H) 4.20-4.26 (m, 1 H) 4.11 (dd, J=9.98, 4.67 Hz, 1 H) 3.82 (s, 3 H) 3.35 (dd, J=16.42, 9.35 Hz, 1 H) 3.11 (dd, J=16.55, 6.95 Hz, 1 H) 1.36 (d, J=5.81 Hz, 6 H); LCMS for C23H25N3O4 m/z 408.20 (M+H)+; Anal. Calcd. for C23H25N3O4.0.50 H2O: C, 66.33; H, 6.29; N, 10.09. Found: C, 66.29; H, 6.05; N, 9.87.
Reaction SMILES: C([O:5][C:6](=[O:24])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:23])[CH:13]([C:19]([F:22])([F:21])[F:20])[CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH:13]([C:19]([F:20])([F:21])[F:22])[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:24])=[O:5])=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(C(=O)N1CCC[C@H]1C(=O)O)C(F)(F)F

Procedure:
N-(3-Acetylthio-2-trifluoromethylpropanoyl)-L-proline tertbutyl ester (8 g) is dissolved in a mixture of anisole (55 ml) and trifluoroacetic acid (110 ml). After one hour storage at room temperature the solvent is removed in vacuo and the residue is precipitated several times from ether-hexane to give N-(3-acetylthio-2-trifluoromethylpropanoyl)-L-proline.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=1[OH:29])[CH:20]=[CH:21][C:22]([NH:24][NH2:25])=[O:23])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:31][C:30]([C:27]1[CH:26]=[C:19]([CH:20]=[CH:21][C:22]2[O:23][C:1](=[O:2])[NH:25][N:24]=2)[CH:18]=[C:17]([C:14]([CH3:13])([CH3:15])[CH3:16])[C:28]=1[OH:29])([CH3:33])[CH3:32]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)c1cc(C=CC(=O)NN)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C=Cc2n[nH]c(=O)o2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 105.4 %

Procedure:
Carbonyl diimidazole (0.7 g, 0.004 mole) is added in one portion to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-cinnamic acid hydrazide (1.0 g, 0.003 mole) and triethylamine (0.4 g, 0.004 mole) in tetrahydrofuran (12 ml). The mixture is stirred at 0° C. for 15 minutes and then allowed to warm to room temperature and stir 45 minutes. The solution is concentrated and the residue dissolved in ether (50 ml) and washed with aqueous 2M HCl. The product is extracted from the organic layer by treatment with aqueous 1M NaOH (20 ml). The aqueous extract is made acidic by treatment with cold aqueous 2M HCl and the product is extracted with ether. The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provided a solid which was recrystallized from ethyl acetate/hexane to give 1.0 g (1.1 g theor., 94%) of 5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-oxadiazole-2(3H)-one, mp >260° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C@@H:15]([O:28][CH2:29][CH:30]=C)[C@H:14]([CH3:32])[O:13][C:12]1=[O:33])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=[O:36].[Na+].O=[O+][O-].CSC>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:34])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C@@H:15]([O:28][CH2:29][CH:30]=[O:36])[C@H:14]([CH3:32])[O:13][C:12]1=[O:33])[CH2:8][O:9][CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCO[C@@H]1[C@@H](Cc2ccc(F)cc2)CCC[C@H](N(COC)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reactant: O=C([O-])O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(F)cc2)[C@@H](OCC=O)[C@H](C)OC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of tert-butyl((3S,7R,8R,9S)-8-(allyloxy)-7-(4-fluorobenzyl)-9-methyl-2-oxooxonan-3-yl)(methoxymethyl)carbamate (480 mg, 1.001 mmol), NaHCO3 (8.41 mg, 0.10 mmol) and anhydrous MeOH (0.31 mL) in anhydrous CH2Cl2 (9.7 mL) was treated with ozone at −78° C. until the solution became light blue in color. The mixture was purged with nitrogen until colorless and then quenched by addition of dimethyl sulfide (0.148 mL, 2.00 mmol). The reaction mixture was warmed to room temperature and stirred for 20 h, concentrated, and purified by column chromatography on SiO2 (gradient, hexanes/EtOAc) to provide the title compound as a mixture of rotamers in the form of a white solid (461 mg, 96%): mp 51-53° C.; IR (neat) 2935, 1740, 1701, 1509, 1367, 1297, 1173, 1081 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.68 (s, 1H), 7.17-7.06 (m, 2H), 7.00-6.91 (m, 2H), 4.99-4.16 (m, 6H), 3.87-2.97 (m, 4H), 2.46-2.27 (m, 1H), 2.17-2.01 (m, 1H), 1.97-1.75 (m, 1H), 1.74-1.37 (m, 17H), 0.95-0.78 (m, 1H); HRMS-ESI (m/z) ([M]+) calcd for C25H36FNO7, 481.2476; found, 481.2481.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].[CH2:10]([OH:15])[C:11]([F:14])([F:13])[F:12].O.[OH-].[Li+]>CS(C)=O.O>[Cl:9][C:5]1[N:4]=[N:3][C:2]([O:15][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:7]([NH2:8])[CH:6]=1
Reactant: OCC(F)(F)F
Reactant: Nc1cc(Cl)nnc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(Cl)nnc1OCC(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 3.28 g 3,6-dichloro-pyridazin-4-ylamine in 30 mL dimethylsulfoxide and 4.0 g trifluoroethanol was added 1.84 g lithium hydroxide hydrate and 3 mL water and the mixture was heated to 80° C. for 18 h. The reaction mixture was diluted with 100 mL water and stirred at ambient temperature for 2 h. The resulting solid was collected by filtration washed with water and dried to constant weight under high vacuum to yield 3.84 g of the title compound as off white crystals, MS 228.1 and 230.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[C:7](/[C:12](/[CH2:16][CH2:17][CH3:18])=[CH:13]/[CH2:14][CH3:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1B(O)O.COCCOC.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[C:2]1[C:10]2[C:6](=[C:7](/[C:12](/[CH2:16][CH2:17][CH3:18])=[CH:13]/[CH2:14][CH3:15])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CC/C=C(\CCC)c1c2cccc(Br)c2nn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC/C=C(\CCC)c1c2cccc(-c3ccc(Cl)cc3Cl)c2nn1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of 7-bromo-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole (1.47 g, 4.79 mmol), 2,4-dichlorophenyl boronic acid (1.32 g, 6.94 mmol), 18 mL of ethylene glycol dimethyl ether, tetrakis(triphenylphosphine)palladium(0) (0.166 g, 0.143 mmol), and 20 mL of a 2 M aqueous Na2CO3 solution was stirred at 85° C. overnight, then allowed to cool. Ethyl acetate (50 mL) was added, and the mixture was washed with two 40 mL portions of a saturated aqueous NaCl solution. The combined aqueous layers were extracted with 20 mL of ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a brown oil. Column chromatography (0→5% EtOAc/hexanes) afforded 7-(2,4-dichloro-phenyl)-2-methyl-3-((E)-1-propyl-but-1-enyl)-2H-indazole (15a; 1.57 g; 88%) as a white solid.
Reaction SMILES: [C:1]1([CH2:9][NH2:10])[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.CCCCCC.[C:17]([N:21]=[C:22]=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:21][C:22](=[O:23])[NH:8][CH2:7][C:4]1[CH:5]=[CH:6][C:1]([CH2:9][NH2:10])=[CH:2][CH:3]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N=C=O
Reactant: NCc1ccc(CN)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)NCc1ccc(CN)cc1
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of 2.7 g p-xylylenediamine in 100 ml methylene dichloride, was added slowly with stirring 10 ml of a n-hexan solution containing 990 mg t-butyl isocyanate under ice cooling. Stirring was continued at room temperature for two hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography, giving 1 g of 4-(3-t-butylureidomethyl)-1-aminomethylbenzene.
Reaction SMILES: F[C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([OH:31])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)(O)[O-]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][N:33]1[CH:37]=[C:36]([C:9]2[NH:8][C:5]3=[N:6][CH:7]=[CH:2][C:3]([C:22]4[S:26][C:25]([C:27]5([OH:31])[CH2:28][CH2:29][CH2:30]5)=[N:24][CH:23]=4)=[C:4]3[CH:10]=2)[CH:35]=[N:34]1
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)c(F)cnc32)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)ccnc3[nH]2)cn1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(5-fluoro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 107C) (150 mg, 0.272 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (85 mg, 0.408 mmol) in N,N-dimethylformamide (2.04 mL) was added saturated aqueous bicarbonate solution (680 μL) followed by bis(triphenylphosphine) palladium dichloride (13.37 mg, 0.019 mmol). The mixture was heated to 70° C. for 1.5 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane. A solution of the crude material in methanol (2.0 mL) and 2N aqueous sodium hydroxide solution (700 μL) was heated by microwave irradiation (Biotage, Initiator) to 120° C. for 30 minutes. The reaction was cooled to room temperature, and the pH adjusted to ˜3 with 10% aqueous HCl solution. The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.48 (bs, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.18 (d, J=5.1 Hz, 1H), 8.10 (s, 1H), 7.32 (d, J=5.1 Hz, 1H), 3.93 (s, 3H), 2.64-2.55 (m, 2H), 2.45-2.35 (m, 2H), 2.05-1.92 (m, 2H); MS ESI(+) m/z 352.7 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=3[Cl:38])=[C:20]([C:39]([F:42])([F:41])[F:40])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[ClH:38].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:29]=2[Cl:38])=[C:20]([C:39]([F:42])([F:40])[F:41])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cc(C(F)(F)F)ccc3Cl)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cc(C(F)(F)F)ccc2Cl)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 172.8 %

Procedure:
Compound 57-4 (870 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (630 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:6][CH2:7][C:8](O)=[O:9])[C:3](O)=[O:4].[NH2:12]C(N)=O>O>[CH3:1][C:2]1([CH3:11])[CH2:6][CH2:7][C:8](=[O:9])[NH:12][C:3]1=[O:4]
Reactant: CC(C)(CCC(=O)O)C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: CC1(C)CCC(=O)NC1=O
Temperature: 160 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
The mixture of 10 g of 2,2-dimethylglutaric acid and 37.5 g of urea was stirred for 8 hours at 160° C. Into the reaction mixture was added water at 100° C., and the mixture was cooled to near room temperature. The mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.6 g of 3,3-dimethylpiperidin-2,6-dione.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[F:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>CCCCO>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[F:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)c1
Solvent: CCCCO
Product: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Yield: 38.7 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide (208 mg, 0.568 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (341 mg, 1.70 mmol) in n-BuOH (2 mL) was processed as described in Example 62, Step B, to provide (R)-tert-butyl 1-(5-bromo-3-(2-fluoro-5-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 39% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([OH:27])=[CH:24][C:25]=1[OH:26])=[O:19].CC(C1C(O)=CC(O)=CC=1O)=O>>[OH:26][C:25]1[CH:24]=[C:23]([OH:27])[CH:22]=[C:21]2[C:20]=1[C:18](=[O:19])[CH:17]=[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1)[O:8]2
Reactant: CCCCCc1cc(C(=O)Cl)ccc1OC
Reactant: CC(=O)c1ccc(O)cc1O
Agent: CC(=O)c1c(O)cc(O)cc1O
Product: CCCCCc1cc(-c2cc(=O)c3c(O)cc(O)cc3o2)ccc1OC

Procedure:
Using the procedure described in Preparation B, replacing 3-cyclopentyloxy-4-methoxybenzoyl chloride by 4-methoxy-3-pentylbenzoyl chloride, and 2,4-dihydroxyacetophenone by 2,4,6-trihydroxyacetophenone, the expected compound is obtained.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].O=[CH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>CCO>[O:15]=[C:9]1[NH:8]/[C:7](=[N:16]\[N:17]=[CH:19]\[CH2:20][CH2:21][C:22]([OH:24])=[O:23])/[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]2[N:13]=[CH:12][NH:11][C:10]1=2
Reactant: O=CCCC(=O)O
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Solvent: CCO
Product: CCCCCn1/c(=N/N=C/CCC(=O)O)[nH]c(=O)c2[nH]cnc21
Yield: 96.6 %

Procedure:
The mixture of (2E)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (1.0 g, 4.2 mmol) and 4-oxobutanoic acid (3.4 g, 15% in water, 5.1 mmol) in EtOH (70 ml) was refluxed for 1.5 hours. Evaporation of solvent gave the desired product (1.3 g, 96%) as a yellowish solid. LCMS calculated for C14H21N6O3(M+H): 321.1; found: 321.1.