Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(OCc4cccc(F)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (53 mg, 0.30 mmol) was reacted with 4-[2-amino-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-phenol (102 mg, 0.30 mmol) for 20 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (60 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3H) 5.16 (s, 2 H) 6.27 (d, J=6.99 Hz, 1 H) 6.64 (d, J=8.46 Hz, 2 H) 7.03-7.36 (m, 7 H) 7.45 (m, J=6.26 Hz, 1 H) 7.80 (d, J=8.82 Hz, 1 H) 8.39 (d, J=6.98 Hz, 1 H) 8.99 (d, J=8.82 Hz, 1 H) 9.78 (s, 1 H) 11.02 (br s,1 H) 14.39 (br s,1 H); MS (ESI+) m/z,484 (M+H−TFA)+; (ESI−) m/z, 482 (M−H−TFA)−.
Reaction SMILES: Cl.[CH2:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20](N(CC)CC)[CH3:21].NC1C=CC2NC(=O)OC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH2:20]([O:17][C:16](=[O:18])[CH:15]([N:12]1[CH2:11][CH2:10][CH:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)[CH3:19])[CH3:21]
Reactant: CC(C(=O)O)N1CCC(Cc2ccccc2)CC1
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
A mixture of 0.5 g (2.0 mmol) of 2-(4-benzyl-piperidin-1-yl)-propionic acid hydrochloride, 0.3 ml (2.1 mmol) of triethylamine, 0.36 g (2.0 mmol) of 6-amino-3H-benzoxazol-2-one, 0.8 g (2.1 mmol) of HBTU and 10 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. The product is crystallized with diethylether to yield 0.095 g (11.6%) of the title compound. Melting Point: 116-118° C. (diethylether).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C-:25]#[N:26].[K+]>CN(C)C=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2[N:6]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=3)[CH:7]=[C:3]([CH2:2][C:25]#[N:26])[N:4]=2)=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)c1ccc(-n2cc(CCl)nc2-c2ccc(Cl)cc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2cc(CC#N)nc2-c2ccc(Cl)cc2)cc1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
A mixture of 250 mg (0.656 mmole) of 4-chloromethyl-2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole (Example 159, Step 1) and 86 mg (1.3 mmol) of potassium cyanide in 4 ml of dimethylformamide was stirred at 85° C. for 24 hours. An additional 86 mg of potassium cyanide was added, and stirring continued for 8 hours. After cooling, the mixture was partitioned between dichloromethane and water and the aqueous layer further extracted with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 60% ethyl acetate in toluene, followed by trituration with ethyl acetate gave the title compound, 59 mg, as a very pale yellow crystalline solid: mp (DSC) 197° C. Anal. Calc'd. for C18H14ClN3O2S (MW 371.85): C, 58.14; H, 3.80; N, 11.30. Found: C, 57.92; H, 3.57; N, 11.01.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#N)=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:33]>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][CH2:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:33])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(C#N)cc2)CC1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of 7.08 g of p-[2-(trans-4-pentylcyclohexyl)ethyl]benzonitrile in 50 ml of absolute toluene was placed at 0° C. in a sulphonation flask under argon gasification and treated within 15 minutes with 29 ml of a 1.21N solution of diisobutylaluminium hydride in toluene in such a manner that the internal temperature did not exceed 5° C. After completion of the addition, the mixture was stirred at room temperature for a further 2 hours, then treated cautiously with 50 ml of 0.5N sulphuric acid and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of semi-saturated sodium chloride solution each time, dried over magnesium sulphate and concentrated. There were obtained 6.20 g (87%) of p-[2-(trans-4-pentylcyclohexyl)ethyl]benzaldehyde as a colourless viscous oil (purity 97%) which was used without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@H:20]3[C@@H:24]4[O:25]C(C)(C)[O:27][C@@H:23]4[C@@H:22]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH2:21]3)=[C:13]([NH:35][CH2:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:12]=2)=[CH:4][CH:3]=1.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:21][C@H:22]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[C@@H:23]([OH:27])[C@H:24]3[OH:25])=[C:13]([NH:35][CH2:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(OCCc4ccc(Cl)cc4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound is prepared by dissolving N-{(3aR,4S,6R,6aS)-6-[2-[2-(4-Chloro-phenyl)-ethoxy]-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (Example 235, Step 2) in THF, adding an equal volume of 1.0M hydrochloric acid, and stirring at room temperature for 48 hours, before diluting with water, and extracting into ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and the volatile components removed under reduced pressure, to yield the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:33])[CH:10]([NH:21][C:22](=[O:32])[C@H:23](Br)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](O)(=[S:36])[CH3:35].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.CCCCCC>CN(C)C=O.O>[CH2:1]([NH:8][C:9](=[O:33])[CH:10]([NH:21][C:22](=[O:32])[C@@H:23]([C:34](=[S:36])[CH3:35])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)=S
Reactant: O=C(NCc1ccccc1)C(NC(=O)[C@H](Br)Cc1ccccc1)C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=S)[C@@H](Cc1ccccc1)C(=O)NC(C(=O)NCc1ccccc1)C(=O)NCc1ccccc1
Reaction time: 18 h
Yield: 46 %

Procedure:
Combine N,N′-dibenzyl-2-((R)-2-bromo-3-phenylpropionylamino)malonamide (0.49 g, 0.97 mmol) and thioacetic acid (0.172 mL, 2.42 mmol) in dimethylformamide (15 mL). Degas by repeated cycles of vacuum and filing with nitrogen. Add cesium carbonate (0.473 g, 1.45 mmol). After 18 hours, dilute the reaction mixture with water and extract twice with ethyl acetate. Combine the organic layers, extract with brine, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3/2 ethyl acetate/hexane to give the title compound (46%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH2:32][C:33]1[N:38]=[C:37]([CH2:39][CH2:40]O)[CH:36]=[CH:35][CH:34]=1.[C:42]([OH:45])(=[S:44])[CH3:43]>O1CCCC1>[C:42]([S:44][CH2:40][CH2:39][C:37]1[N:38]=[C:33]([NH2:32])[CH:34]=[CH:35][CH:36]=1)(=[O:45])[CH3:43]
Reactant: CC(O)=S
Reactant: Nc1cccc(CCO)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SCCc1cccc(N)n1
Reaction time: 0.08 h

Procedure:
Triphenyl phosphine (2.36 g) was dissolved in tetrahydrofuran (40 ml). To the solution was added, at −20° C., diethyl azodicarboxylate (1.56 g). The mixture was stirred for 5 minutes, to which was added a solution of 2-(6-amino-2-pyridyl)ethanol (0.62 g) in tetrahydrofuran (2 ml). The mixture was stirred for one minutes, to which was added thioacetic acid (0.64 ml), followed by stirring for 4 hours at 25° C. The reaction mixture was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography (carrier: silica gel, 120 g, developing solvent: ethyl acetate-hexane, 2:1) to give the title compound (0.56 g), m.p.55-59° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>>[CH2:40]([N:42]([CH2:43][CH3:44])[CH2:1][CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:24]3[CH:25]=[C:26]([OH:31])[CH:27]=[CH:28][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)[CH3:41]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: CCNCC
Product: CCN(CC)CCc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 11.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and diethylamine (12 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (2.0 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N+:22]([O-])=O)[CH:16]=2)=[O:12])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([NH2:22])[CH:16]=2)=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cc2ccc(N)cc2[nH]1

Procedure:
Compound 35 (0.184 g, 0.528 mmol) was dissolved in 15 ml of MeOH and hydrogenated over 5% Pd/C under 40 psi of H2 for 30 min. TLC showed that reaction was completed. After filtration through celite, the filtrate was evaporated and the residue was dried under high vacuum to give compound 36.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:24]3[CH2:27][C:26](=[O:28])[CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.[BH4-].[Na+]>O1CCCC1.C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:24]3[CH2:25][C@H:26]([OH:28])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2[C@H]1C[C@@H](O)C1

Procedure:
A solution of 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanone (0.208 g, 0.00056 mol) in tetrahydrofuran (10 mL) and absolute ethanol (5 mL) was reacted with sodium borohydride (0.021 g, 0.00056 mol) at room temperature for four hours. Added water (5 mL) and extracted with ethyl acetate (3×15 mL). The combined organics were dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica using dichloromethane/methanol (98:2). The solvent was removed in vacuo to give cis 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol (0.090 g, 0.00024 mol) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1.N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C([O-])(O)=O.[Na+]>[Na+].[Cl-]>[C:21]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[N:3]=1)(=[O:23])[CH3:22]
Reactant: Nc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c([N+](=O)[O-])cccc2n1
Reaction time: 0.5 h

Procedure:
360 mg (1.9 mmol) of 2-amino-5-nitroquinoline is stirred with 4 ml (50 mmol) of pyridine and 2 ml (21 mmol) of acetic anhydride for 15 hours at room temperature. The batch is poured into saturated NaHCO3 solution, stirred for 30 minutes, diluted with saturated NaCl solution and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated by evaporation: 410 mg of a yellow solid.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:25][C:26]1[C:31]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: OB(O)c1cccnc1F
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccnc5F)n4n3)cc2)CC1

Procedure:
[7-(2-Fluoro-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine and 2-fluoro-3-pyridineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (78 mg, 68%). m.p.=201-203° C.; LCMS (m/e) 404 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.95-8.87 (m, 1H), 8.74 (s, 1H), 8.23-8.17 (m, 1H), 7.47 (d, 2H, J=7.7 Hz), 7.34-7.27 (m, 1H), 7.19-7.12 (m, 1H), 6.92 (d, 2H, J=8.0 Hz), 6.85 (d, 1H, J=4.7 Hz), 6.68 (s, 1H), 3.23-3.15 (m, 4H), 2.64-2.56 (m, 4H), 2.37 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CSC.B.Cl>C1COCC1.CO>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: COc1ccc(Br)c(CO)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-Bromo-5-methoxy benzoic acid (1 eq.) was dissolved in anhydrous THF (0.55M solution) and borane dimethylsulfide complex (2M in THF, 1 eq.) was added dropwise to the solution. The mixture was left stirring overnight, then HCl in MeOH was added and the mixture was warmed to 60° C. All volatiles were evaporated and the residual material was dissolved in DCM. The solution was washed with 1N HCl and with brine, then dried over Na2SO4 and evaporated in vacuo. A colorless oil was obtained (94%), which was used without further characterization in the next reaction.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[C:15]([Cl:16])[C:10]=2[N:9]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([O:45]CC)=[O:44])=[CH:39][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:16][C:15]1[C:10]2[N:9]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[N:8]=[C:7]([C:37]3[CH:49]=[CH:48][C:40]([O:41][CH2:42][C:43]([OH:45])=[O:44])=[CH:39][CH:38]=3)[C:11]=2[C:12]([O:17][CH3:18])=[N:13][CH:14]=1
Reactant: CCOC(=O)COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ncc(Cl)c2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Cl)c2c1c(-c1ccc(OCC(=O)O)cc1)nn2-c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To a solution of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate obtained in Step A of Example 152 (250 mg) in DMF (3 mL)/water (0.3 mL) were added ethyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)acetate (241 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (23 mg) and cesium carbonate (367 mg). The reaction mixture was stirred overnight at 90° C. The reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate, and neutralized 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (166 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][CH3:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)=[O:12])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc2[nH]ncc2c1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of the 1H-indazole-5-carboxylic acid (281 mg, 1.73 mmol) obtained in Reference Example 1 in N,N-dimethylformamide (10 ml) were added 1-benzyl-N-methylpiperidin-4-amine (390 mg, 1.91 mmol), triethylamine (0.29 ml, 2.08 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide monohydrochloride (499 mg, 2.60 mmol) and hydroxybenzotriazole (281 mg, 2.08 mmol), and the resulting mixture was stirred overnight at room temperature. An aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate→chloroform/methanol) to obtain N-(1-benzylpiperidin-4-yl)-N-methyl-1H-indazole-5-carboxamide (502 mg, 83%).
Reaction SMILES: C[CH:2](C)[C@@H:3]([N:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[O:24])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[C:8]1=[O:36])[C:4]([OH:6])=[O:5].O=C1C2C(=CC=C(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)C=2)CN1[C@@H](C)C(OC)=O>>[O:36]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=4)=[O:24])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:15][N:7]1[C@@H:3]([CH3:2])[C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Product: C[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 337 was prepared analogous to compound of example 331 by hydrolysis of the compound of example 336.
Reaction SMILES: [N:1]([CH2:4][C:5]1([OH:13])[CH2:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6]1)=[N+:2]=[N-:3].[H-].[Na+].[CH3:16]I>O1CCCC1>[N:1]([CH2:4][C:5]1([O:13][CH3:16])[CH2:10][CH2:9][CH2:8][C:7]([CH3:11])([CH3:12])[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CC1(C)CCCC(O)(CN=[N+]=[N-])C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(CN=[N+]=[N-])CCCC(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of EXAMPLE 166B (1.33 g) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 435 mg) in tetrahydrofuran (15 mL) at 0° C. The mixture was stirred for 10 minutes at 0° C. and for 30 minutes at room temperature. CH3I (1.55 g) was added dropwise. The resulting reaction mixture was stirred overnight at rom temperature, and then quenched with water (100 mL) and extracted with ethyl acetate (3×50 mL). The extracts were washed with brine, dried (Na2SO4), and filtered. After concentration, the crude material was purified by flash chromatography on silica gel using 0 to 7% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36](Cl)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:20]=[C:21]([F:28])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:28][C:21]1[CH:20]=[C:19]([CH:29]([NH:31][C:32]([C:34]2[N:35]=[C:36]([C:5]3[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:37][CH:38]=2)=[O:33])[CH3:30])[CH:18]=[C:17]([F:16])[C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: COc1cc(B(O)O)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(-c2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc(C(F)(F)F)c1
Yield: 22.2 %

Procedure:
3-Methoxy-5-trifluoromethylbenzeneboronic acid (34 mg, 0.16 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylaminophenyl)-ethyl]-amide (30 mg, 0.078 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (30 mg, 0.25 mmol) as described above to give the title compound (9 mg, 22%) after purification by flash chromatography on silica gel (% EtOAc in hexane=12%˜100%).