Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[Br:15]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[Br:15][CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1
Reactant: OCC1COC(c2ccccc2)OC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: BrCC1COC(c2ccccc2)OC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a vigorously stirred solution of 19.4 g (0.1M) of 5-hydroxymethyl-2-phenyl-1,3-dioxane ml and 33.1 g (0.1M) of tetrabromomethane in 60 ml of anhydrous benzene at 70° C., is added 26.2 g (0.1M) of triphenylphosphine in 45 minutes. After stirring at 70° C. for an another 30 minutes, the solvent is evaporated. To the residue is added 200 ml of ether and ether insoluble triphenylphosphine oxide is removed by filtration. After repeating this procedure twice, the solvent of the filtrated is evaporated. Distillation of the residual product gives 19.391 g (75.4% yield) of the titled compound m2. B.P. 145°~158° C. (1 mmHg).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11].[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].N1C=CN=C1>O>[O:6]([C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[C:10]([O:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:11])[Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCCOc1ccccc1)c1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCOc2ccccc2)c1
Reaction time: 10 h

Procedure:
Into a 250 mL round bottom flask was added 30 mL of dry dimethyl formamide. Five parts of hydroxy ester (53) and 3.5 parts of tert-butyldimethyl silyl chloride were added to the reaction flask with stirring. Three parts of Imidazole was added in portions and stirring was continued for 10 hours. The reaction mixture was diluted with 80 mL of water and the product was extracted with ethyl acetate. The organic layer was washed with water and dried on anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give an oil, yield 6.80 parts. This material was pure enough for next step of the reaction. The reaction proceeded as follows:
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:8]([CH:13]([NH:30][C:31]([CH:33]2[CH2:36][CH2:35][CH2:34]2)=O)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][N:12]=1.N.CC(O)C>>[Cl:6][C:7]1[C:8]2[N:9]([CH:31]([CH:33]3[CH2:36][CH2:35][CH2:34]3)[NH:30][C:13]=2[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:21]3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCC1
Agent: N
Solvent: CC(C)O
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1=NC=CN2C1=C(c1ccc3ccc(-c4ccccc4)nc3c1)NC2C1CCC1
Temperature: 70 °C

Procedure:
A mixture of POCl3 (5 mL, 8 g, 55 mmol) and cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-(2-phenylquinolin-7-yl)methyl]-amide [275 mg, 0.583 mmol] is heated to 70° C. for 21.5 h. POCl3 is evaporated, a cold solution of NH3 in iPrOH (2M, 11 mL, 22 mmol) is added, the suspension is sonicated, the solid is filtered off and washed with iPrOH. The solid is suspended in CHCl3 and filtered, and the filtrate is concentrated to obtain the title compound as yellow solid. 1H NMR (CDCl3, 400 MHz) δ 2.04-2.15 (m, 1H), 2.15-2.28 (m, 1H), 2.50-2.60 (m, 2H), 2.64-2.76 (m, 2H), 3.89 (quint, J=8.4 Hz, 1H), 7.35 (d, J=4.8 Hz, 1H), 7.44-7.50 (m, 1H), 7.51-7.57 (m, 3H), 7.89-7.93 (m, 3H), 8.17-8.22 (m, 2H), 8.27 (dd, J=0.8, 8.8 Hz, 1H), 8.53 (d, J=0.8 Hz, 1H). MS (ES+): m/z 410.9/412.9 (100/39) [MH+].
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13]C(C#N)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:17]([OH:20])(=[O:19])[CH3:18]>Cl>[N:1]1([C:7]2[CH:14]=[CH:13][C:18]([C:17]([OH:20])=[O:19])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(N2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(N2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
A suspension of 4-piperidin-1-ylbenzonitrile of Step A (1.13 g, 6.07 mmol) in acetic acid (30 mL) and concentrated hydrochloric acid (30 mL) was stirred at 100° C. for 18 hours. The cooled reaction mixture was then poured over crushed ice, the pH adjusted to 3 by the addition of 2 M sodium hydroxide, and the resulting suspension allowed to stand overnight. The solid product was filtered and dried at 50° C. in vacuo overnight to afford the title compound (1.09 g, 88%) as a white solid, m.p. 225-230° C. (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=O.[NH:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:18]2[NH:12][C:13](=[S:14])[NH:15][C:16]2=[O:17])[CH:7]=[C:8]([Br:11])[C:9]=1[OH:10]
Reactant: O=C1CNC(=S)N1
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)NC1=Cc1cc(Br)c(O)c(Br)c1
Yield: 24.7 %

Procedure:
Prepared according to the procedure described in Example 1 using 3,5-dibromo-4-hydroxybenzaldehyde (4.5 g, 16 mmoles), 2-thiohydantoin (1.7 g, 15 mmoles), sodium acetate (4.5 g, 55 mmoles), and acetic acid (35 ml). Recrystallization from ethanol gave the pure product (1.4 g), mp 267° C. (dec).
Reaction SMILES: [CH:1]([NH:3][NH2:4])=[O:2].C1(C)C=CC=CC=1.[CH2:12]([O:19][C@@H:20]([CH3:23])[CH:21]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:19][C@@H:20]([CH3:23])[CH:21]=[N:4][NH:3][CH:1]=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H](C=O)OCc1ccccc1
Reactant: NNC=O
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@@H](C=NNC=O)OCc1ccccc1
Temperature: 27.5 °C
Reaction time: 4 h

Procedure:
To a pre-cooled solution of formyl hydrazine (40.3 g) in methanol (290 ml) at 0-5° C., toluene layer containing (S)-2-(benzyloxy)propanal compound of formula-15 obtained in step-b) was added. Slowly raised the temperature of reaction mixture to 25-30° C. and stirred for 4 hours at 25-30° C. After completion of the reaction, distilled off the solvent under reduced pressure to get title compound. Ethyl acetate (210 ml) was added to the obtained compound and stirred for 1 hour at 25-30° C. Filtered the reaction mixture to remove the unwanted solid and washed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure to get semi-solid. Petroleum ether (210 ml) was added to the obtained semi-solid and stirred for 2 hours at 25-30° C. Filtered the precipitated solid, washed with petroleum ether and then dried to get title compound.
Reaction SMILES: [F:1][C:2]([F:19])([CH:8]([OH:18])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>N1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]([F:19])([CH:8]([O:18][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(F)(F)C(O)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)C(OS(=O)(=O)c1ccc(C)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.2 %

Procedure:
To a solution of ethyl 2,2-difluoro-3-hydroxy-3-(4-nitrophenyl)propanoate (800 mg, 2.91 mmol) in pyridine (20 mL) was added dropwise p-toluenesulfonyl chloride (665 mg, 3.49 mmol), and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-40% ethyl acetate/hexane) to give the title compound (1.09 g, yield 99%) as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][C:6]2[C:7](=[O:25])[CH2:8][CH2:9][CH2:10][N:11]([C:16]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])=[O:17])[C:12](=[O:15])[CH2:13][CH2:14][C:5]=2[CH:4]=1.[O:28]1CCCC1>>[C:22]([NH:21][CH2:20][CH2:19][CH2:18][C:16]([NH:11][CH2:10][CH2:9][CH2:8][C:7]([C:6]1[CH:26]=[CH:27][C:3]([Cl:2])=[CH:4][C:5]=1[CH2:14][CH2:13][C:12]([OH:28])=[O:15])=[O:25])=[O:17])(=[O:24])[CH3:23]
Reactant: CC(=O)NCCCC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Reactant: C1CCOC1
Agent: Cl
Product: CC(=O)NCCCC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 192 h

Procedure:
120 ml of 2N hydrochloric acid are added to a solution of 23.8 g (0.06 ml) of N-[3-[(11-chloro-2,3,5,6,7,8-hexahydro-3,8-dioxo-4-benzazecin-4(1H)-yl)-carbonyl]propyl]acetamide in 240 ml of tetrahydrofuran and the mixture is stirred at room temperature for 8 days. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Recrystallization from methanol/ether gives 2-[4-(4-acetamidobutyramido)butyryl]-5-chlorohydrocinnamic acid as beige crystals with melting point 108°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@@H:9]([OH:28])[C@@H:10]2[NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@@H:9]([OH:28])[C@@H:10]2[NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1O)c1ccc(-c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)[C@@H](NC(=O)c1ccc(-c3ccccc3)cc1)[C@H](O)C2
Reaction time: 19 h
Yield: 90.8 %

Procedure:
Combine a slurry of 0.176 kg of 10% Pd-C (50% water wet) and 1.7 kg of biphenyl-4-carboxylic acid (R)-(6-nitro-2(R)-hydroxyindan-1-yl)amide in 17.5 L of DMF with hydrogen (50 psi, 345 kPa). After 19 h, filter the reaction mixture, add a portion of the DMF solution (5 L) to water (10 L), and stir the slurry for 2 h-repeat twice to work up the entire reaction volume. Filter the slurries together, and wash the resulting filter cake with water (3×7 L). Dry the filter cake to afford 1.42 kg of biphenyl-4-carboxylic acid (R)-(6-amino-2(R)-hydroxyindan-1-yl)amide.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][C@H:12]1[O:17][C@@H:16]([CH3:18])[CH2:15][NH:14][CH2:13]1>>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:14]2[CH2:13][C@H:12]([CH3:11])[O:17][C@H:16]([CH3:18])[CH2:15]2)=[N:6][CH:7]=1
Reactant: COc1nc(Cl)ncc1Br
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: COc1nc(N2C[C@@H](C)O[C@@H](C)C2)ncc1Br
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 5-bromo-2-chloro-4-methoxypyrimidine (17.2 g, 77 mmol) stirred in air at 0° C. was added neat cis-2,6-dimethylmorpholine (24.5 g, 213 mmol) dropwise in 10 minutes. The reaction mixture was stirred at 45° C. for 30 minutes. The organic phase was evaporated in vacuo to give the crude product as a white solid. The crude product was added to a silica gel column and was eluted with hexane/ethyl acetate (20/1). Collected fractions were evaporated to give the title compound as white solid (17.4 g, 49.3 mmol, 64.1% yield). LC/MS [M+H]+=302/304.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][NH2:12].CC[O:15][C:16]([CH:18]1[C:23](=O)[CH2:22][CH2:21][CH2:20][CH2:19]1)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:16](=[O:15])[C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:12]1
Reactant: NNc1cc([N+](=O)[O-])ccc1F
Reactant: CCOC(=O)C1CCCCC1=O
Product: O=c1c2c([nH]n1-c1cc([N+](=O)[O-])ccc1F)CCCC2
Temperature: 0 °C

Procedure:
A solution of 2-fluoro-5-nitrophenylhydrazine (53.95 g) in ethyl 2-cyclohexanonecarboxylate (53.65 g) was heated under reflux for 4 hours. After cooling, the reaction mixture was poured into ice-water. The precipitated crystals were collected by filtration, washed with water add hexane and dried to obtain 2-(2-fluoro-5-nitrophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one. m.p., 220.0° C.
Reaction SMILES: [I:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][C:8]3([C:11]4[N:12]([N:13]=[C:14]([C:16](OCC)=[O:17])[CH:15]=4)[C:4]=2[CH:3]=1)[CH2:10][CH2:9]3.[OH-].[NH4+:24]>O1CCOCC1.C(OCC)(=O)C.O>[I:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][C:8]3([C:11]4[N:12]([N:13]=[C:14]([C:16]([NH2:24])=[O:17])[CH:15]=4)[C:4]=2[CH:3]=1)[CH2:10][CH2:9]3
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC21CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC21CC1
Temperature: 110 °C

Procedure:
A solution of ethyl 9-iodo-5H-spiro[benzo[b]pyrazolo[1,5-d][1,4]oxazepine-4,1′-cyclopropane]-2-carboxylate (313 mg, 0.76 mmol) in ammonium hydroxide (3 mL) and dioxane (2 mL) was sealed in a 20 mL microwave vial and heated at 110° C. behind a blast shield. The mixture was cooled to room temperature, diluted with ethyl acetate and water and washed with sodium bicarbonate solution. The organics were dried over sodium sulfate and concentrated by rotoevaporation to give the titled compound which was used without purification in subsequent operations. 1H NMR (400 MHz, DMSO) δ 8.44 (d, J=2.1 Hz, 1H), 7.83 (br s, 1H), 7.61 (dd, J=8.5, 2.2 Hz, 1H), 7.33 (br s, 1H), 6.99 (d, J=8.5 Hz, 1H), 6.55 (s, 1H), 4.22 (s, 2H), 1.10-0.96 (m, 4H).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([NH:1][N:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CN1CCN(N)CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CCN(Nc2ccc(Br)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
Heat a mixture of 1-amino-4-methyl piperazine (0.217 mol, 25.0 g), 5-bromo-2-fluoronitrobenzene (0.239 mol, 52.6 g) and triethylamine (0.46 mol, 46 g) in ethyl acetate (900 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 5% methanol in dichloromethane as eluent to give the title compound (43.2 g, 63%). ES-MS m/z 315 [M+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([C:10]2[N:15]=[C:14]([NH:16][C@@H:17]([CH:20]([CH3:22])[CH3:21])[CH2:18][OH:19])[C:13]([N+:23]([O-])=O)=[CH:12][CH:11]=2)[CH:9]=1)([CH3:3])[CH3:2].ClC1N=C(N[C@@H](C(C)C)[CH2:37][OH:38])C([N+]([O-])=O)=CC=1.C(C1C=CC(OC)=C(B(O)O)C=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.[Pd].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.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>[OH:19][CH2:18][C@@H:17]([N:16]1[C:14]2=[N:15][C:10]([C:8]3[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=3[O:26][CH3:27])=[CH:11][CH:12]=[C:13]2[NH:23][C:37]1=[O:38])[CH:20]([CH3:22])[CH3:21]
Reactant: COc1ccc(C(C)C)cc1-c1ccc([N+](=O)[O-])c(N[C@H](CO)C(C)C)n1
Reactant: CC(C)[C@@H](CO)Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: COc1ccc(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc2[nH]c(=O)n([C@H](CO)C(C)C)c2n1
Temperature: 85 °C
Yield: 96 %

Procedure:
(S)-2-(6-(5-Isopropyl-2-methoxyphenyl)-3-nitropyridin-2-ylamino)-3-methylbutan-1-ol. To a solution of (S)-2-(6-Chloro-3-nitropyridin-2-ylamino)-3-methylbutan-1-ol (0.80 g, 3.08 mmol) and 5-isopropyl-2-methoxyphenylboronic acid (0.78 g, 4.00 mmol) in DMF (50 mL) was added potassium carbonate (1.7 g, 12.3 mmol) in water (8 mL). The reaction solution was purged with a stream of nitrogen followed by the addition of tetrakis(triphenylphosphine) palladium(0) (0.358 g, 0.308 mmol). After heating at 85° C. for 2 h, the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography to afford the title compound (1.11 g, 96% yield). MS (ESI) m/z 374.3 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:23][O:24][CH2:25]Cl.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[N:10]([CH2:23][O:24][CH3:25])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: COC(=O)c1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCn1nc(-c2cccc(F)c2)c2cc(C(=O)OC)ccc21
Reaction time: 0.5 h

Procedure:
A total of 1.0 g of methyl 3-(3-fluorophenyl)-1H-5-indazolecarboxylate obtained in Production Example I-4-e was dissolved in 15 ml of N,N-dimethylformamide, and 200 mg of sodium hydride (60% oily) was added under ice-cooling, followed by stirring for 30 minutes. To the reaction mixture was added 0.4 ml of chloromethyl methyl ether, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added water and the mixture was extracted with ethyl acetate for two times. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 0.95 g of methyl 3-(3-fluorophenyl)-1-(methoxymethyl)-1H-5-indazolecarboxylate as colorless needles. This compound was dissolved in 15 ml of tetrahydrofuran, and 8.0 ml of a solution of diisobutylaluminium hydride in toluene was added dropwise at room temperature. While cooling the reaction mixture, water was added. The mixture was acidified with diluted hydrochloric, and extracted with ethyl acetate for two times. The organic layer was-washed with sodium hydrogencarbonate and water, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 0.78 g of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:30][CH2:29][C:26]([CH2:31][C:32]([O:34]CC6C=CC=CC=6)=[O:33])([CH2:27][CH2:28]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.C1COCC1.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[CH2:28][CH2:27][C:26]([CH2:31][C:32]([OH:34])=[O:33])([CH2:29][CH2:30]4)[O:25][CH2:24]5)=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[N:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)OCc6ccccc6)(CC4)OC5)cc3)nc2)o1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)OC5)cc3)nc2)o1
Yield: 33.5 %

Procedure:
Benzyl 2-(4-(4-(5-((5-(tert-butyl)oxazol-2-yl)amino)pyridin-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (100 mg, 0.181 mmol) was dissolved in EtOAc/THF and hydrogenated with 10% Pd(OH)2/C under H2 balloon for 3 hr. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC to give the title compound (28 mg, 31.5% yield). HR/MS [M+H]+: found 462.2390. calc. 462.2393. RT: 2.83 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 9H), 1.86-2.03 (m, 8H), 2.32 (s, 2H), 3.90 (s, 2H), 6.60 (s, 1H), 7.39 (d, J=8.59 Hz, 2H), 7.87 (d, J=8.59 Hz, 1H), 7.95 (d, J=8.59 Hz, 2H), 8.15 (dd, J=8.84, 2.78 Hz, 1H), 8.77 (d, J=2.78 Hz, 1H), 10.36 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([O:15]C)=[O:14])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.O.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=[O:14])=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COC(=O)c1cc2ccccc2cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2ccccc2cc1C(=O)O
Reaction time: 3 h
Yield: 91.8 %

Procedure:
A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temp. was treated with a 1N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at the reflux temp. for 3 h, cooled to room temp., and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2×100 mL). The combined organic layers were washed with a saturated NaCl solution, dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 92%): 1H-NMR (DMSO-d6) δ3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, J=8.09 Hz, 1H), 7.91 (d, J=8.09 Hz, 1H), 8.19 (s, 1H), 12.83 (br s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.CC(C)([O-])C.[K+].ClCCl>CN(C=O)C.C1(C)C=CC=CC=1>[F:19][C:18]([F:21])([F:20])[C:14]1[CH:13]=[C:12]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: COC(=O)C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C1CCN(c2cccc(C(F)(F)F)c2)CC1
Temperature: 130 °C
Yield: 46.1 %

Procedure:
Methyl piperidine-4-carboxylate (2.0 g, 14 mmol), 1-bromo-3-(trifluoromethyl)benzene (1.5 g, 6.8 mmol), and potassium tert-butoxide (0.76 g, 6.8 mmol) in a mixed solvent of toluene (20 mL) and DMF (4 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (0.3. g, 0.4 mmol) under nitrogen. The mixture was heated at 130° C. in an oil bath overnight. After cooling to room temperature, the mixture was filtered through celite and diluted with EtOAc. The resulting solution was washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried (MgSO4), concentrated and flash chromatographed with EtOAc/hexanes (20% to 40%) to give 0.90 g of product. MS (M+H) 288.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2[CH:14]=O)[CH3:2].[C:16]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)(=[O:18])[CH3:17].N1CCCCC1>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH3:13])=[C:7]2/[CH:14]=[CH:17]/[C:16]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[O:18])[CH3:2]
Reactant: CCOc1ccc2[nH]c(C)c(C=O)c2c1
Reactant: CC(=O)c1ccncc1
Solvent: C1CCNCC1
Solvent: CO
Product: CCOc1ccc2[nH]c(C)c(/C=C/C(=O)c3ccncc3)c2c1
Yield: 85.6 %

Procedure:
5-Ethoxy-2-methylindole-3-carboxaldehyde 409a (188 mg, 0.93 mmol) was dissolved in anhydrous methanol (12 mL). 4-Acetylpyridine (168 mg, 1.38 mmol) and piperidine (118 mg, 1.38 mmol) were added and the solution was heated at reflux for 24 h. A precipitate slowly formed which was collected, washed with ice-cold MeOH (30 mL) and dried at 40° C. in a vacuum desiccator for 24 h to yield a bright yellow powder (244 mg, 86%): mp 255-257° C. TLC Rf 0.30 (80% EtOAc/hexanes). 1H NMR (600 MHz, d6-DMSO) δ 11.88 (s, 1H), 8.80 (m, 2H), 8.09-8.06 (d, 1H, J=15.3 Hz), 7.93-7.92 (m, 2H), 7.41 (d, 1H, J=2.22 Hz), 7.34-7.32 (d, 1H, J=15.3 Hz), 7.30-7.29 (d, 1H, J=8.64 Hz), 6.84-6.82 (dd, 1H, J1=8.7 Hz, J2=2.28 Hz), 4.14-4.11 (q, 2H, J=6.96 Hz), 2.57 (s, 3H), 1.37-1.36 (t, 3H, J=6.96 Hz). 13C NMR (150 MHz, d6-DMSO) δ 188.1, 154.4, 150.6, 145.8, 145.1, 139.6, 131.0, 126.6, 121.4, 112.82, 112.24, 111.3, 109.3, 104.4, 63.6, 14.9, 12.2. Elemental analysis calculated for C19H18N2O2: C, 74.49; H, 5.92; N, 9.14. Found: C, 74.30; H, 6.02; N, 9.04.