Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[Br:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: C1CNCCN1
Reactant: Brc1cnc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Brc1cnc(N2CCNCC2)s1
Temperature: 160 °C
Yield: 94 %

Procedure:
A mixture of 2.06 mmol 2,5-dibromothiazole, 6.17 mmol piperazine and 6.17 mmol triethylamine in 6 ml tetrahydrofuran in a sealed tube was heated at 160° C. for 10 min under microwave irradiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to afford the title compound as a white crystalline solid (yield 94%). MS (m/e): 250.0 ({81Br}M+H+, 100%), 248.0 ({79Br}M+H+, 76%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][NH2:9])[CH:5]=[CH:4][CH:3]=1.[C:10](OC(OCC)OCC)(=O)C>CCCCC>[Br:1][C:2]1[N:7]2[CH:10]=[N:9][N:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: NNc1cccc(Br)n1
Solvent: CCCCC
Product: Brc1cccc2nncn12
Yield: 78 %

Procedure:
A solution of (6-bromopyridin-2-yl)hydrazine (500 mg, 2.66 mmol) in diethoxymethyl acetate (2.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with pentane and filtered. The precipitate was washed with pentane and dried at 50° C. under vacuum for 1 hour to give 5-bromo-[1,2,4]triazolo[4,3-a]pyridine as a beige solid (410 mg, 78%). 1H NMR (400 MHz, CHCl3-d): δ 8.98 (s, 1 H); 7.83 (dt, J=9.2, 0.9 Hz, 1 H); 7.22 (dd, J=9.2, 7.0 Hz, 1 H); 7.09 (dd, J=7.0, 0.9 Hz, 1 H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.CO.Br[CH:16]([C:19]1[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=1)[C:17]#[N:18]>[OH-].[Na+]>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([S:1][CH:16]([C:19]3[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=3)[C:17]#[N:18])[NH:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: COc1c(C)cnc(C(Br)C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2nc(SC(C#N)c3ncc(C)c(OC)c3C)[nH]c2c1
Yield: 58 %

Procedure:
To a solution of 2-mercapto-5-methoxybenzimidazole (15.1 g, 0.14 mole) dissolved in 40 ml of 8.4% sodium hydroxide, was added 170 ml of methanol, followed by bromo(4-methoxy-3,5-dimethyl-2-pyridyl)acetonitrile(21.4 g, 0.11 mole) at room temperature. The mixture was heated to reflux for 1 h under a nitrogen atmosphere. The resulting precipitate was removed by filtration and the methanol was evaporated. The residue obtained was extracted with chloroform, and the chloroform was washed 3 times with water and dried over magnesium sulfate. After evaporation of the solvent, the crude product was recrystallized from diethyl ether to give 22.6 g (90%) of the title compound as yellowish crystals: mp 193°-197° C.; 1H NMR (CDCl3) δ8.25 (s,1H), 7.65 (dd, 1H), 7.30 (m, 1H), 6.90 (m, 1H), 6.30 (br s, 2H), 3.95 (s, 3H), 3.75 (s, 3H), 2.50 (s, 3H), 2.20 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=2)[CH2:29][CH2:28]1>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([O:12][C:3]1[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:28][CH2:29][CH:30]([C:33]2[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])[CH:36]=[CH:37][CH:38]=2)[CH2:31][CH2:32]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(O)c3ccccc3F)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(Oc3cc(C(F)(F)F)ccc3F)c3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[7-(2-fluorophenyl)-7-hydroxyheptyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 617.3 (M+H)+.
Reaction SMILES: O/[CH:2]=[CH:3]/[C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[CH3:14][NH:15][CH3:16].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[CH3:14][N:15]([CH3:16])/[CH:2]=[CH:3]/[C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(/C=C/O)Cc1ccccc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
A solution of (3E)-4-hydroxy-1-phenylbut-3-en-2-one (1.2 g, 7.4 mmol) in THF (20 mL) was added dimethylamine hydrochloride (1.8 g, 22.2 mmol), K2CO3 (6.1 g, 44.4 mmol) and the mixture was stirred at rt overnight. The mixture was concentrated and purified by flash column chromatography (PE/EtOAc=10:1) to give the title compound (0.6 g, 43%) as a yellow oil. [M+H] Calc'd for C12H15NO, 190; Found, 190.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)[CH:9]=2)[C:4](=[O:19])[CH2:3]1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccc3c(c2)C(C)(C)CC3=O)cc1

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 4-methylphenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 251.1; HRMS: calcd for C18H18O+H+, 251.14304; found (ESI, [M+H]+), 251.1431.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C[Si](N([Li])[Si](C)(C)C)(C)C.[P:25](Cl)(=[O:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[O:33]([P:25]([O:1][C:2]1[N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:5][O:6][CH:7]=1)([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOCC1=O
Agent: [Cl-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Tert-butyl 3-oxomorpholine-4-carboxylate (5.2 g, 25.8 mmol) was dissolved in dry THF (52 ml). The mixture was cooled to −30° C. and (bis(trimethylsilyl)amino) lithium (1M THF solution, 28.4 ml, 28.4 mmol) was added dropwise. The resulting mixture was stirred for 1 hr, then diphenyl phosphorochloridate (7.3 g, 27.1 mmol) was added dropwise. The resulting mixture was allowed to warm slowly to ambient temperature over 6 hrs, after which time no starting material was present by HPLC. The reaction mixture was poured into saturated ammonium chloride solution (100 ml) and diluted with ethyl acetate (100 ml). The organic phase was separated and washed with sat NaHCO3 (50 ml), then brine (50 ml), dried (MgSO4), filtered and concentrated. The residue was purified on silica gel, eluting with 25-30% ethyl acetate/petrol. This gave the title compound as an oil which solidified on standing (7.59 g, 68%); 1H-NMR (CDCl3) 1.35 (9H, s), 3.54 (2H, dt), 3.87 (2H, m), 6.26 (1H, s), 7.11-7.17 (6H, m), 7.24-7.28 (4H, m); 31P-NMR (CDCl3)-16.07; 13C-NMR (CDCl3) 28.1, 42.0, 65.8, 120.0, 120.03, 120.09, 120.13, 125.19, 125.61, 125.62, 129.6, 129.86, 129.9; MS ES(+) 378.0 (M+-tBu).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=O)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[C:10]([C:13]3[NH:17][C:16]([C:18]#[N:19])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:31])[CH2:4][O:3]1
Reactant: CC1(C)OCC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)OCC(=S)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Temperature: 100 °C
Yield: 118.4 %

Procedure:
To a solution of 5-(5,5-dimethyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-2-carbonitrile (0.4 g, 1.4 mmol) in a mixture of toluene (20 mL) and THF (10mL, help to dissolve the starting material) was added at rt under nitrogen the Lawesson's reagent (0.29 g, 0.71 mmol). The mixture was heated at 100° C. for 10 minutes, cooled to rt, and concentrated. The residue was purified by a flash chromatography on silica gel column (hexane:THF/4:1) to give the title compound as a yellowish solid (0.25 g, 60%). 1H-NMR (DMSO-d6) δ 12.66 (s, 1H), 11.96 (s, 1H), 7.69 (d, J=1.49 Hz, 1H), 7.64 (dd, J=1.48, 8.44 Hz, 1H), 7.35 (d, J=8.51 Hz, 1H), 7.01 (m, 1H), 6.79 (m, 1H), 4.49 (s, 2H), 1.60 (s, 6H); MS (FI) m/z 296 ([M−H]−, 100%)
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([O-:15])(=[S:14])[CH3:13].[K+]>>[O:1]([CH2:8][CH2:9][CH2:10][S:14][C:12](=[O:15])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccccc1
Reactant: CC([O-])=S
Agent: [K+]
Product: CC(=O)SCCCOc1ccccc1

Procedure:
Prepared in the same manner as Intermediate 3 from 3-phenoxypropyl bromide (8 ml) and potassium thioacetate (7.01 g) to give the title compound (10.35 g) as an orange oil.
Reaction SMILES: C[C:2]1([C:10]2([C:23]3(C)[CH:28]=[CH:27][C:26](C)=[CH:25][CH:24]3N)[C:19]3[C:14](=[CH:15][C:16](N(C)C)=[CH:17][CH:18]=3)C(=O)O2)[CH:7]=[CH:6][C:5](C)=[CH:4][CH:3]1N.CC1(C2(C3(C)C=CC(C)=CC3N)C3C(=CC=CC=3)C(=O)O2)C=CC(C)=CC1N>>[C:2]1([CH:10]([C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=CC(N)C(C)(C2(C3(C)C=CC(C)=CC3N)OC(=O)c3cc(N(C)C)ccc32)C=C1
Agent: CC1=CC(N)C(C)(C2(C3(C)C=CC(C)=CC3N)OC(=O)c3ccccc32)C=C1
Product: c1ccc(C(c2ccccc2)c2ccccc2)cc1

Procedure:
3,3-bis(p-Dimethyl aminophenyl)-6-dimethylaminophthalide [alternate name: crystal violet lactone] and 3,3-bis(p-Dimethyl aminophenyl) phthalide [alternate name: malachite green lactone]
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]2[CH2:30][CH2:29][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22]([CH3:28])([CH3:27])[CH2:23][NH:24]5)=[CH:20][CH:19]=4)[C:11]=3[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:31]N(C=O)C.C([O-])([O-])=O.[K+].[K+].CI>CCOC(C)=O>[Cl:2][C:3]1[C:4]([N:9]2[CH2:30][CH2:29][C:12]3[N:13]=[CH:14][N:15]=[C:16]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22]([CH3:27])([CH3:28])[CH2:23][N:24]5[CH3:31])=[CH:20][CH:19]=4)[C:11]=3[CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: CC1(C)CNc2cc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1CC(C)(C)c2ccc(Nc3ncnc4c3CN(c3ncccc3Cl)CC4)cc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred mixture of [6-(3-chloro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-amine HCl salt (10 mg), DMF (5 mL), and K2CO3 (50 mg) was added MeI (50 μL). The reaction-mixture was stirred at rt for 5 h, and then diluted with EtOAc (50 mL). The organic phase was washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column to give an off-white solid (7 mg).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9]O)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]1[S:27][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[N:6]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(C)c1ccc(C(CCO)NC(=O)c2c(F)cccc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C2CCSC(c3c(F)cccc3F)=N2)cc1
Yield: 54.3 %

Procedure:
A mixture of 5.0 g (14.4 mmol) of N-(2,6-difluorobenzoyl)-3-amino-3-(4-tert-butylphenyl)-1-propanol, 3.2 g (14.4 mmol) of phosphorus pentasulfide and 30 ml of toluene is heated under reflux for 6 hours. The mixture is allowed to cool, 10 ml of 20% strength aqueous sodium hydroxide solution are added and the mixture is heated under reflux for 30 minutes. After customary working up, the crude product is purified by column chromatography on silica gel (mobile phase n-hexane/ethyl acetate 8/2). 2.7 g (54.3%) of 2-(2,6-difluorophenyl)-4-(4-tert-butylphenyl)-5,6-dihydro-(4H)1,3-thiazine of melting point 91.0-91.5° C. are obtained.
Reaction SMILES: [CH3:1][CH:2]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:1][CH:2]([N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[S:23]([CH3:22])(=[O:25])=[O:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(C)NCc1cccnc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCC(C)N(Cc1cccnc1)S(C)(=O)=O

Procedure:
A 3.1 g. portion of 3-(1-methylhexylaminomethyl)pyridine was dissolved in dichloromethane with stirring, and to it were added 2.1 g. of potassium carbonate and 1.16 ml. of methanesulfonyl chloride with cooling in an ice bath. The mixture was stirred at ambient temperature for 4 days. The reaction mixture was then extracted twice with 15 ml. portions of water, and the organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was dissolved in ethyl acetate and purified by chromatography over silica gel in ethyl acetate. The product-containing fractions were combined to obtain 1.7 g. of the desired product. Elemental analysis:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH:14]=[C:15]([C:21](O)=[O:22])[NH:16]3)=[CH:2]1.Cl.Cl.Cl.[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][C@@H:35]([N:37]2[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]2)[CH3:36])[CH2:30][CH2:29]1>>[OH:43][CH:40]1[CH2:39][CH2:38][N:37]([C@@H:35]([CH3:36])[CH2:34][N:31]2[CH2:30][CH2:29][CH:28]([NH:27][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:3]3[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[O:1][CH:2]=3)[CH:20]=[CH:19][CH:18]=4)=[O:22])[CH2:33][CH2:32]2)[CH2:42][CH2:41]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4ccccc34)cccc2[nH]1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4coc5ccccc45)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized analogously to example 1 from 4-(benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid, 105 (see example 50) and amine 50.
Reaction SMILES: [C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[O:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39].C(O)C.C(=O)([O-])[O-].[NH4+:47].[NH4+]>ClCCl.C(O)C>[ClH:39].[C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:47])[NH2:26])=[CH:21][C:20]=4[O:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1OC)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Yield: 89 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 89% of theory, C29H32N6O4 (528.6); Rf value: 0.13 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=529; (M+H+Na)++=276; (M+2H)++=265.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1)[CH3:2].Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:7]([F:12])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c(F)c1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCN2CCOCC2)c(F)c1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
3-Fluoro-4-hydroxybenzoic acid ethyl ester (0.20 g, 1.1 mmol) and N-(2-chloroethyl)morpholine (0.22 g, 1.2 mmol) were dissolved in dry DMF (10 ml). Potassium carbonate (1.88 g, 5 mmol) was added and the turbid reaction mixture was stirred overnight at 40° C. under an argon atmosphere. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue followed by washing with NaHCO3 (½ sat., 3×), water, brine, dried (MgSO4), filtered. The crude oil was purified over silica gel (CH2Cl2/MeOH 39:1): colorless oil 0.16 g (49%);
Reaction SMILES: [CH:1](/B(O)O)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCOCC1.Br[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.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.O>[CH:1](/[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][CH:20]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 18.3 %

Procedure:
To a solution of (E)-styrylboronic acid (289 mg, 1.95 mmol) in mixed solution of dioxane and water (4:1, 15 mL) were added tert-butyl 4-bromobenzoate (500 mg, 1.95 mmol), tetrakis(triphenylphosphine)palladium (225 mg, 0.2 mmol) and sodium carbonate (622 mg, 5.9 mmol). The mixture was stirred at 90° C. under nitrogen atmosphere for 18 hours. Once start material has been consumed, the mixture was concentrated to give a residue and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=25:1) to give (E)-tert-butyl 4-styrylbenzoate (0.1 g, 18%). The product was used for the next step directly without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)=[O:5])#[N:2].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:1]([CH:3]=[C:4]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[O:5][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C(=O)CC#N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=CC#N)OS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 97.2 %

Procedure:
To a mixture of methyl 4-(cyanoacetyl)benzoate (10.29 g), p-toluenesulfonyl chloride (11.58 g) and dichloromethane (110 mL) was added dropwise triethylamine (7.68 g) under ice-cooling. After stirring under ice-cooling for 2.5 hrs, the mixture was diluted with dichloromethane (100 mL), washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=9:1→1:1) to give the title compound (17.60 g) as a mixture of (E)-form and (Z)-form (6:5).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH3:12])[CH2:5]P(=O)(OC)OC.[CH:13]1([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]3[C:25]([CH:26]=2)=[N:24][N:23]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH:33]=O)[CH2:29][CH2:28]2)[CH:22]=3)[CH2:15][CH2:14]1.Cl>COCCOC>[CH:13]1([CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]3[C:25]([CH:26]=2)=[N:24][N:23]([C@H:27]2[CH2:32][CH2:31][C@H:30](/[CH:33]=[CH:5]/[C:4](=[O:3])[CH3:12])[CH2:29][CH2:28]2)[CH:22]=3)[CH2:15][CH2:14]1
Reactant: O=C[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Reactant: COP(=O)(CC(C)=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)/C=C/[C@H]1CC[C@H](n2cc3ccc(OCC4CC4)cc3n2)CC1
Reaction time: 1 h

Procedure:
Sodium hydride (0.292 g) was added to a solution of dimethyl 2-oxopropylphosphonate (2.021 g) in 1,2-dimethoxyethane (50 mL) under ice-cooling in small portions. The reaction mixture was stirred for 1 hr under ice-cooling, and a solution of trans-4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]cyclohexanecarbaldehyde (3.30 g) in 1,2-dimethoxyethane (50 mL) was added under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, poured into 1N hydrochloric acid under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.85 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(O)C.[ClH:47]>O1CCCC1>[ClH:47].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH2:24][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:26]=1)([CH3:17])([CH3:16])[CH3:18]
Reactant: C1CCNCC1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN2CCCCC2)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and piperidine (0.13 mL, 1.3 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. Additional piperidine (013 mL, 1.3 mmol) and sodium triacetoxyborohydride (0.30 g, 1.4 mmol) were added and the reaction was stirred under nitrogen for 4 hours. The reaction was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a yellow syrup which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and the solid was filtered off to afford 4-(tert-butyl)-2-(piperidin-1-ylmethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (0.29 g, 62% yield) as a white solid.