Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:30])[CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37]C(N(C)C)N(C)C)(C)(C)C.CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:30])[C:19]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:33][OH:37])=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COc1cc(CCNC(=O)Cc2ccc3c(c2)CCCC3)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
8.8 g (13.6 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetamide, 8.9 g (51.1 mmol) of t-butoxybis (dimethylamino)methane and 100 ml of N,N-dimethylformamide were mixed and stirred at 100° C. for 6 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the residue, 50 ml of 5% hydrochloric acid and 100 ml of tetrahydrofuran were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (eluent, hexane:ethyl acetate=2:1) and dried to give 4.20 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:27]1[NH:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>CCN(CC)CC.C(OCC)(=O)C>[NH:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[O:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: O=c1ccn(-c2cccc(O)c2)nc1-c1ccnn1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(Oc3nc4ccccc4[nH]3)c2)nc1-c1ccnn1-c1ccccc1
Temperature: 120 °C
Reaction time: 14 h
Yield: 21.6 %

Procedure:
A mixture of 1-(3-hydroxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (0.113 g, 0.342 mmol) and 2-chlorobenzimidazole (0.075 g, 0.49 mmol) in Et3N (1 mL) was sealed and stirred at 120° C. for 14 h and then at 160° C. for 64 h. After this time, the reaction was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate aqueous solution (40 mL), and then with 2 N sodium hydroxide (3×20 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Flash chromatography (silica, methylene chloride to 1:19 methanol/methylene chloride) afforded 1-[3-(1H-benzimidazol-2-yloxy)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (33 mg, 18%) as a light-yellow solid.
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:29])[CH2:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(O)CC(C)C.C(#N)C>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[O:29])[CH2:22][N:23]1[CH2:24][CH2:25][N:26]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:27][CH2:28]1
Reactant: O=C(CN1CCNCC1)Nc1ccccn1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CCN(CC)CC
Solvent: CC(C)CCO
Solvent: CC#N
Product: O=C(CN1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1)Nc1ccccn1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol), N-(2-pyridyl)-2-(piperazin-1-yl)acetamide * 3HCl * 2H2O (279.5 mg; 0.76 mmol) and triethylamine (282.5 μl; 2.04 mmol) are reacted in isoamyl alcohol (2 ml) in accordance with the procedure for Example 9 (reaction time 8 h) and worked up. The crystals obtained are dissolved in acetonitrile and water and freeze-dried; yield: 19 mg (10%), crystals;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]3=[N:10][C:9]=2[C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[C:24]([NH:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])=[O:25])[CH:5]=[CH:4][N:3]=1.[F:38][CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][N:44]([CH:47]2[CH2:52][CH2:51][N:50]([C:53]3[CH:59]=[CH:58][C:56]([NH2:57])=[C:55]([O:60][CH3:61])[CH:54]=3)[CH2:49][CH2:48]2)[CH2:43][CH2:42]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([F:33])[C:27]=1[NH:26][C:24](=[O:25])[C:23]1[CH:35]=[CH:36][CH:37]=[C:21]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:57][C:56]3[CH:58]=[CH:59][C:53]([N:50]4[CH2:49][CH2:48][CH:47]([N:44]5[CH2:43][CH2:42][N:41]([CH2:40][CH2:39][F:38])[CH2:46][CH2:45]5)[CH2:52][CH2:51]4)=[CH:54][C:55]=3[O:60][CH3:61])[N:7]=2)[CH:22]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3cc(C(F)(F)F)ccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3cc(C(F)(F)F)ccn23)n1
Temperature: 150 °C
Yield: 36.8 %

Procedure:
To 3-[3-(2-chloro-4-pyrimidinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide (110 mg, 0.21 mmol) and 4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2-(methyloxy)aniline (Example 57, step E) (63 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (2 mL) was added p-toluenesulfonic acid monohydrate (134 mg, 0.71 mmol). The mixture was stirred and heated on a microwave at 150° C. for 45 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (59 mg, 0.07 mmol, 38%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.26 (s, 1H), 9.47 (br s, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.27 (d, 1H, J=5.32 Hz), 8.24 (s, 1H), 8.08 (d, 1H, J=7.88 Hz), 7.84 (d, 1H, J=7.70 Hz), 7.64 (t, 1H, J=7.79 Hz), 7.31-7.45 (m, 2H), 7.21 (t, 3H, J=8.06 Hz), 6.70-6.72 (m, 1H), 6.47-6.53 (m, 2H), 4.56 (t, 1H, J=4.86 Hz), 4.44 (t, 1H, J=4.86 Hz), 3.80 (s, 3H), 3.71-3.77 (m, 2H), 2.59-2.70 (m, 4H), 2.40-2.55 (m, 8H), 2.25-2.34 (m, 1H), 1.81-1.87 (m, 2H), 1.46-1.56 (m, 2H). MS (ESI): 830 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[N:8](CC=C)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1.C(O)=O.C(N(CC)CC)C>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>[CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9](=[O:10])[NH:8][C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:6]1
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(CC(=O)OC)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 200 mg (0.65 mmol) of the compound from Example 214A, 49 μl of formic acid (1.3 mmol), 226 μl of triethylamine (1.63 mmol) and 38 mg of tetrakis(triphenylphosphine)palladium(0) (32 μmol) are dissolved in 2 ml degassed dioxan and stirred overnight at reflux temperature. To dissolve the precipitated solid, the reaction mixture is diluted with 20 ml of methanol after cooling to RT. The palladium catalyst is filtered off and the filtrate freed of the volatile components on the rotary evaporator. The residue is stirred with 5 ml acetonitrile and then suction-filtered. The solid is washed with acetonitrile and dried under high vacuum. It corresponds to the title compound with a purity of ca. 76% (130 mg, 57% of theory) and is used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([NH2:26])=[N:21][N:22]2[CH3:25])=[CH:18][CH:17]=1.[CH:27](=O)[CH3:28]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([NH:26][CH2:27][CH3:28])=[N:21][N:22]2[CH3:25])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc4c(N)nn(C)c4c3)c2cc1OC
Reactant: CC=O
Solvent: ClCCl
Product: CCNc1nn(C)c2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 6-((6,7-bis(methyloxy)-4-quinolinyl)oxy)-1-methyl-1H-indazol-3-amine (Example 120, 140 mg, 0.40 mmol) in dry DCM (Aldrich, 4.0 mL) at RT were added acetaldehyde (Aldrich, 21.1 mg, 0.48 mmol) followed by NaHB(OAc)3 (Aldrich, 102 mg, 0.48 mmol). After being stirred for 4 h at RT, the reaction was quenched by addition of water. The aqueous layer was extracted with DCM. The organic layer was dried with MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (DCM/acetone: 100/0 to 60/40) afforded the title compound. MS (ESI, pos. ion) m/z: 379.3 (M+1). Mass Calc'd for C21H22N4O3: 378.43.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:17](=[O:23])[CH2:18][NH:19][CH2:20][CH2:21][OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:24]1[C:26]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:25]1.O>CCO>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:17](=[O:23])[CH2:18][N:19]([CH2:25][C:26]2([OH:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:20][CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CNCCO)N1CCc2ccccc2C1C1CCCCC1
Reactant: C1CCC2(CC1)CO2
Solvent: CCO
Solvent: O
Product: O=C(CN(CCO)CC1(O)CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Yield: 74.7 %

Procedure:
2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]amino}ethanol (342 mg) was dissolved in EtOH (5 mL). 1-oxaspiro[2.5]octane (363 mg) and water (5 mL) were added thereto, followed by stirring under heating at reflux for 2 days. The solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 1-({[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](2-hydroxyethyl)amino}methyl)cyclohexanol (346 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH:57]([C:60]1[CH:65]=[CH:64][C:63]([N:66]2[CH2:70][CH2:69][CH:68]([C:71](O)=[O:72])[C:67]2=[O:74])=[CH:62][CH:61]=1)([CH3:59])[CH3:58]>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:71]([CH:68]1[CH2:69][CH2:70][N:66]([C:63]2[CH:64]=[CH:65][C:60]([CH:57]([CH3:58])[CH3:59])=[CH:61][CH:62]=2)[C:67]1=[O:74])=[O:72]
Reactant: CC(C)c1ccc(N2CCC(C(=O)O)C2=O)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1ccc(N2CCC(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)C2=O)cc1
Yield: 32.3 %

Procedure:
A mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.036 g; 0.146 mmol), PyBOP (0.113 g; 0.219 mmol), N,N-diisopropylethylamine (0.075 mL; 0.437 mmol) and 1-(4-isopropylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.100 g; 0.425 mmol) was stirred in DMF (3 mL) overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.020 g (32%) of the title compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.CSC.C([O:18][C:19]1[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=1)C1C=CC=CC=1>O>[OH:18][C:19]1[CH:34]=[CH:33][CH:32]=[CH:31][C:20]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=1
Reactant: N#CCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Solvent: O
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: N#CCc1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Trifluoroacetic acid (17 mL), water (1 mL) and dimethyl sulfide (2 mL) were added to [4-(2-benzyloxybenzyl)phenyl]-acetonitrile (0.41 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) to give [4-(2-hydroxybenzyl)phenyl]acetonitrile (0.26 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Brc1ccc2ncccc2c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3ncccc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (136 mg, 0.6 mmol; Example 2B) and 6-bromoquinoline (187 mg, 0.9 mmol; TCI-US) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.20 (m, 4H) 2.42 (s, 3H) 2.92-2.99 (m, 1H) 3.08-3.28 (m, 4H) 4.32 (s, 2H) 6.90-6.96 (m, 1H) 6.98-7.04 (m, 1H) 7.22 (s, 1H) 7.63 (dd, J=8, 4 Hz, 1H) 7.72 (dd, J=9, 2 Hz, 1H) 7.93 (d, J=2 Hz, 1H) 8.21 (d, J=9 Hz, 1H) 8.46 (d, J=7 Hz, 1H) 8.94 (dd, J=4, 2 Hz, 1H); MS (DCI/NH3) m/z 354 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.FC1C=C(C(O)C)C=C(F)C=1B1O[C:29](C)(C)[C:28](C)(C)[O:27]1>>[F:10][C:4]1[CH:5]=[C:6]([CH:28]([OH:27])[CH3:29])[CH:7]=[C:2]([F:1])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Product: CC(O)c1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 1-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (Intermediate 106) gave the title compound.
Reaction SMILES: [ClH:1].O1CCOCC1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)=[C:11]([F:27])[CH:10]=1>C(OCC)(=O)C.CO>[ClH:1].[ClH:1].[F:27][C:11]1[CH:10]=[C:9]([NH2:8])[CH:14]=[CH:13][C:12]=1[CH:15]1[CH2:19][CH2:18][CH2:17][NH:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(C2CCCN2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 ml of 4 N hydrochloric acid-dioxane solution was added to a solution of 19 g of t-butyl 2-(4-amino-2-fluoro-phenyl)-pyrrolidine-1-carboxylate obtained in Example 338 (step 2) in a mixture of 50 ml of ethyl acetate and 50 ml of methanol, with cooling with ice, and the reaction liquid was stirred overnight at room temperature. The solvent was evaporated away under educed pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21]>C(O)(C)C>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: OCc1ccccc1S
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: OCc1ccccc1SCCCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5 liter 4-neck round-bottom flask fitted with mechanical stirrer, thermowell, and addition funnel, under a nitrogen atmosphere, was added 150.0 g of o-mercaptobenzyl alcohol, 2400 ml of isopropanol and 295.72 g of anhydrous potassium carbonate. The reaction mixture was cooled in an ice bath, as 246.6 ml of 1-bromo-4-chlorobutane was added dropwise. After addition was complete, the mixture was allowed to warm to room temperature, and stirred at room temperature overnight. The mixture was filtered through a pad of filter aid, and the solid was rinsed with fresh isopropanol. The solvent was removed by rotary evaporation to give 246.0 g of the product as a brown oil. 1H-NMR (CDCl3) δ 1.7-2.1(m,4H); 2.3(br s,1H); 2.85-3.0(t,2H); 3.5-3.6(t,2H); 4.75(s,2H); 7.2-7.4(m,4H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>C1(C)C(C)=CC=CC=1.CS(C)=O>[CH:23]1([NH:29][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[C:15]([CH3:16])=[N:14][N:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[C:4]3=[N:5][CH:6]=2)=[O:10])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1O
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)NC3CCCCC3)c(O)c12
Temperature: 25 °C
Yield: 9.7 %

Procedure:
A mixed solution of ethyl 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (1.5 g, 5.0 mmol) and cyclohexylamine (2.2 g, 22 mmol) in xylene (5.0 mL) and dimethylsulfoxide (5.0 mL) was stirred at 130° C. for 28 hours. The solution was cooled to room temperature and water was added thereto. Subsequently, organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by silica gel column chromatography (chloroform:methanol=50:1 to 20:1) gave crude crystals. The crude crystals were recrystallized from ethyl acetate/ethanol to give the title compound (0.17 g, 10% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[C:11](=[O:12])[CH2:10][CH2:9][C@@H:8]1[C:13]([OH:15])=O.[NH2:19][CH:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:21]([OH:25])[C:22]([NH2:24])=[O:23].O[NH-].O=[N-]>>[NH2:24][C:22](=[O:23])[C:21](=[O:25])[CH:20]([NH:19][C:13]([C@H:8]1[CH2:9][CH2:10][C:11](=[O:12])[N:7]1[CH2:6][C:5]1[CH:16]=[CH:17][CH:18]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1cccc(CN2C(=O)CC[C@@H]2C(=O)O)c1
Reactant: NC(=O)C(O)C(N)Cc1ccccc1
Agent: [N-]=O
Agent: [NH-]O
Product: COc1cccc(CN2C(=O)CC[C@@H]2C(=O)NC(Cc2ccccc2)C(=O)C(N)=O)c1

Procedure:
Coupling of (R)-1-(3-methoxy-benzyl)-5-oxo-pyrrolidine-2-carboxylic acid with 3-amino-2-hydroxy-4-phenylbutanamide and oxidation of the resulting hydroxyamide intermediate to the corresponding ketoamide.
Reaction SMILES: ClCC1C(C)=CC(C)=C(CCl)C=1C.[C-]#N.[Na+].[N-]=[N+]=[N-].[Na+].[C:21]([CH2:23][C:24]1[C:25]([CH3:36])=[C:26]([C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34])[CH2:27][N:28]=[N+]=[N-])#[N:22].C(CC1C(C)=CC(C)=C(CC#N)C=1C)#N.N(CC1C(C)=CC(C)=C(CN=[N+]=[N-])C=1C)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C1COCC1.O>[C:21]([CH2:23][C:24]1[C:25]([CH3:36])=[C:26]([C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34])[CH2:27][NH2:28])#[N:22]
Reactant: Cc1cc(C)c(CN=[N+]=[N-])c(C)c1CC#N
Agent: Cc1cc(C)c(CC#N)c(C)c1CC#N
Agent: Cc1cc(C)c(CCl)c(C)c1CCl
Agent: Cc1cc(C)c(CN=[N+]=[N-])c(C)c1CN=[N+]=[N-]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(CC#N)c(C)c1CN
Temperature: 80 °C
Yield: 25 %

Procedure:
To a solution of 1,3-bis(chloromethyl)-2,4,6-trimethylbenzene (10 g, 46 mmol) in DMSO (30 mL) was added sodium cyanide (2.25 g, 46 mmol). The mixture was stirred at rt overnight before sodium azide (4.5 g, 69 mmol) was added. The mixture was heated at 80° C. for 3 h before it was poured into water (300 mL). The resulting precipitate was filtered to give a 2:1:1.5 mixture of 3-cyanomethyl-2,4,6-trimethylbenzyl azide, 1,3-bis(cyanomethyl)-2,4,6-trimethylbenzene and 1,3-bis(azidomethyl)-2,4,6-trimethylbenzene. This mixture was not separated but was treated with triphenylphosphine (18 g, 69 mmol) in wet THF. The reaction was conducted and worked up as in Example 12 (procedure A) only that the HCl solution was basified with K2CO3 until no more gas evolution observed. The mixture was extracted with dichloromethane and concentrated to give only the desired 3-cyanomethyl-2,4,6-trimethylbenzylamine (2 g, 25% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N+:3]=1[O-].[C:16]([O:19]C(=O)C)(=[O:18])[CH3:17]>>[O:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][O:19][C:16](=[O:18])[CH3:17])=[N:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Oc2ccccc2)c[n+]1[O-]
Product: CC(=O)OCc1ccc(Oc2ccccc2)cn1

Procedure:
A mixture of 2-methyl-5-phenoxy-pyridine (3.6 g, 19 mmol) described in Manufacturing Example 121-1-1,3-chloroperoxybenzoic acid (5.6 g, 33 mmol), and methylene chloride (80 mL) was stirred at room temperature for 45 minutes. Aqueous sodium sulfite was added to the reaction solution, and the organic layer was separated and was washed with 5 N aqueous sodium hydroxide (7 mL). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g). 2-methyl-5-phenoxy-pyridine 1-oxide (3.3 g, 16 mmol) and acetic anhydride (20 mL) were stirred for 40 minutes at 115° C. Acetic anhydride was evaporated under a reduced pressure, aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The ethyl acetate solution was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane: ethyl acetate=2:1) to obtain an acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g). Acetic acid 5-phenoxy-pyridin-2-ylmethyl ester (3.0 g, 12 mmol), 5 N aqueous sodium hydroxide (8.0 mL), and methanol (20 mL) were stirred for 20 minutes at 60° C. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound (2.6 g, 65%).