Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:13]2[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:22][OH:23].C(=O)(O)[O-].[Na+]>C(O)C>[OH:23][NH:22][C:1](=[NH:2])[C:3]1[C:13]2[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCOc2c(C#N)cccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2C(=N)NO)C1
Temperature: 60 °C
Yield: 69 %

Procedure:
A suspension of 1,1-dimethylethyl 9-cyano-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 64) (5.1 g, 18.59 mmol), hydroxylamine hydrochloride (2.58 g, 37.2 mmol) and sodium bicarbonate (7.81 g, 93 mmol) in ethanol (50 ml) was heated at 60° C. overnight. A further portion of hydroxylamine hydrochloride (1 g) was added and the reaction was heated at 60° C. overnight. The solid was filtered from the reaction mixture and the filtrate evaporated. The residue from the evaporation was dissolved in EtOAc, washed with water, dried over magnesium sulphate and evaporated. Trituration with ether to gave the title compound (3.94 g) as a white solid. MS (ES): C15H21N3O4 requires 307; found 308 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:19]3[CH:20]=[CH:21][NH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[NH:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:7][C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:14]3)=[O:17])[C:19]=2[CH:20]=[CH:21]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3[nH]ccc23)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
The mixture of 2-[(1H-indole-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (55) (200 mg, 0.57 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (56) as white solid (162 mg, 89%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.Cl.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:13])([F:14])[F:15])[CH:8]=[CH:7][C:3]=1[CH2:4][NH2:6]
Reactant: Cc1cc(OC(F)(F)F)ccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OC(F)(F)F)ccc1CN
Reaction time: 8 h

Procedure:
18.8 ml (18.8 mmol) of borane-THF-complex (1M) are provided under argon and ice cooling. A solution of 823 mg (3.76 mmol) of 2-methyl-4-(trifluoromethoxy)benzamide (Example 68A) in 80 ml of THF is added dropwise and the reaction mixture is subsequently stirred for 8 h under reflux. Under ice cooling 80 ml of 1N hydrochloric acid are added dropwise (until the end of the evolution of gas) and the reaction mixture is heated for 1 h under reflux. The reaction mixture is subsequently adjusted to an alkaline pH with a 1N sodium hydroxide solution, extracted three times with dichloromethane and the combined organic phases are dried over sodium sulfate and the solvent is removed under vacuum. An oil is obtained which is reacted further without further purification. Yield: 732 mg (95% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:18]1C=C(O)C=C[C:23]=1[O:24]C)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C.C(OCC=C)C=C.C1(C)C=C(C)C=C(C)C=1.C(C1C=C(OC)C=C(C(C)(C)C)C=1O)C=C.C(C1C=C(OC)C(C(C)(C)C)=CC=1O)C=C.C1(O)C=CC=CC=1.ClC1C=C(C=CC=1)C(OO)=O>>[C:1]([C:5]1[C:6]2[O:13][CH:18]([CH2:23][OH:24])[CH2:14][C:7]=2[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(O)cc1C(C)(C)C
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Agent: C=CCOCC=C
Agent: C=CCc1cc(OC)c(C(C)(C)C)cc1O
Agent: C=CCc1cc(OC)cc(C(C)(C)C)c1O
Solvent: C=CCBr
Solvent: Oc1ccccc1
Solvent: Cc1cc(C)cc(C)c1
Product: COc1cc2c(c(C(C)(C)C)c1)OC(CO)C2
Yield: 14 %

Procedure:
Treatment of 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol (18.25 g, 0.101 mol) with potassium carbonate (55.28 g, 0.400 mol) and allyl bromide (14.69 g, 0.121 mol) followed by treatment of the resultant allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-tert-butyl-4-methoxyphenol and 2-allyl-5-tert-butyl-4-methoxyphenol. Treatment of the phenol with 3-chloroperoxybenzoic acid (49.58 g, 0.287 mol, 77%) and potassium carbonate (33.0 g, 0.238 mol) generally according to the procedure described for Intermediate 9 gave 3.23 g (14%) of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. Treatment of the benzofuran with p-toluenesulfonyl chloride (2.86 g, 0.015 mol) generally according to the procedure described for Intermediate 10 afforded (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (1.46 g, 22.5 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.14 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 1.5 g (40%) of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylamine) as a white solid, hydrochloride salt. mp 174-176° C.; Anal calcd. for C14H21O2NHCl: C, 61.87; H, 8.16; N, 5.15. Found C, 61.67; H, 8.37; N, 4.93.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([O:15]C)[C:7]=1[CH:8]=[O:9].CO.O>ClCCl>[F:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([OH:15])[C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(F)c(F)c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=Cc1c(O)ccc(F)c1F
Temperature: 25 °C

Procedure:
A solution of boron tribromide in dichloromethane (1.0 M; 197.4 ml) was added to a solution of 2,3-difluoro-6-methoxybenzaldehyde (10.4 g; prepared in a similar manner to that described above) in dichloromethane (100 ml) under nitrogen stirring below -20° C. The resulting solution was allowed to warm to ambient temperature overnight, then methanol (200 ml) followed by water (100 ml) were added, and the mixture heated at 40° C. for 2 hours. The aqueous layer was separated and extracted with dichloromethane (2×300 ml). The combined organic solutions were extracted with aqueous sodium hydroxide solution (1 M; 3×400 ml) and the combined extracts acidified with concentrated hydrochloric acid, then extracted with ethyl acetate (3×300 ml). These combined extracts were dried over magnesium sulphate and the solvent removed in vacuo to give 2,3-difluoro-6-hydroxybenzaldehyde (8.12 g) as a solid.
Reaction SMILES: [C:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[CH3:9])(=[O:3])[CH3:2].[Li][C:11]1[O:12][CH:13]=[CH:14][CH:15]=1>C(OCC)C>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[CH3:9])([OH:3])[CH3:2]
Reactant: CC(=O)c1ocnc1C
Reactant: [Li]c1ccco1
Solvent: CCOCC
Product: Cc1ncoc1C(C)(O)c1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Acetyl-4-methyloxazole (4 g) in dry diethylether was added dropwise to a stirred solution of 2-lithiofuran (1 equivalent) in diethylether at -20° C. The mixture was allowed to warm to room temperature and was then left overnight. Work-up and flash chromatography then gave the title compound as a white solid, m.p. 73°-75° C.
Reaction SMILES: [C:1](=[NH:21])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[CH2:22](/[C:24](=[CH:30]/O)/[C:25](OCC)=[O:26])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:30]=[C:24]([CH2:22][CH3:23])[C:25](=[O:26])[N:21]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[CH3:20]
Reactant: CCOC(=O)/C(=C\O)CC
Reactant: Cc1cc(Oc2ccc(CCOC(=N)N)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C)c3)cc2)nc1=O
Temperature: 110 °C
Yield: 30.4 %

Procedure:
A mixture of 2-{4-[(4-chloro-3-methylphenyl)oxy]phenyl}ethyl imidocarbamate (130 mg, 0.427 mmol), ethyl (2Z)-2-ethyl-3-hydroxy-2-propenoate (123 mg, 0.853 mmol) and K2CO3 (118 mg, 0.853 mmol) in DMF (3 mL) was heated with a microwave condition at 110° C. for 1.5 h. After cooling, the mixture was filtered, and purified via MDAP to afford the title compound (50 mg, 30.5% yield) as white solid. LCMS: rt=3.80 min, [M+H+]=385
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:18]([CH3:30])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:31]([O-:33])=[O:32].CS(C)=O>O>[CH3:1][O:2][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:18]([CH3:30])[CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[N+:31]([O-:33])=[O:32]
Reactant: C[O-]
Reactant: Cc1cc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)ccc1OCc1ccccn1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1[N+](=O)[O-]
Temperature: 18 °C
Yield: 83.4 %

Procedure:
After appropriate repetition of the previous steps, sodium methoxide (11 g) was added portionwise to a stirred mixture of 7-chloro-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline (20 g) and DMSO (200 ml) which was cooled in a water bath to approximately 18° C. The resultant mixture was stirred at ambient temperature for 4 hours. The mixture was poured slowly onto a mixture of ice and water. The precipitate was isolated to give 7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-6-nitroquinazoline (16.5 g) which was used without further purification.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH2:8][CH2:7][CH2:6][C:5]([CH3:10])([CH3:9])[C:4]=1[CH2:11][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Br:36][C:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=1[CH:43]=O.CCCCCC>O1CCCC1>[Br:36][C:37]1[CH2:42][CH2:41][CH2:40][CH2:39][C:38]=1/[CH:43]=[CH:11]/[C:4]1[C:5]([CH3:9])([CH3:10])[CH2:6][CH2:7][CH2:8][C:3]=1[CH3:2]
Reactant: CC1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Reactant: O=CC1=C(Br)CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1=C(/C=C/C2=C(Br)CCCC2)C(C)(C)CCC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 97.7 %

Procedure:
A suspension of ((2,6,6-trimethyl-1-cyclohexen-1-yl)methyl)triphenylphosphonium chloride (18 g) in tetrahydrofuran (300 ml) was cooled to -60° C., treated dropwise with n-butyllithium (1.4M in hexane; 32 ml), and then stirred a further 10 minutes. To this cold solution was added the 2-bromocyclohexene-1-carboxaldehyde (8.5 g,75% pure by HNMR analysis) dissolved in tetrahydrofuran, and the mixture was allowed to warm to room temperature after which it was stirred for a further 2 hours. Hexane was then added to the reaction and the resulting mixture was washed with water, 50% aqueous methanol and dried (magnesium sulphate). Removal of the solvents yielded the crude (E)-1-bromo-2-(2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl)-cyclohexene (12.5 g) as a mixture of isomers which was used, as is, in the next step. Standard transmetalation and reaction with DMF yielded a cruce aldehyde (4.5 g) which was dissolved in tetrahydrofuran (100 ml) and reacted with an excess of the phosphonate as in Example 1to give methyl (2E,4E)-3-methyl-5-(2-((E)-2(2,6,6-trimethyl-cyclohexen-1-yl)ethenyl)-1-cyclohexen-1-yl)-2,4-pentadienoate (3 g) as an oil after purification by HPLC (2.5% ether in hexane). Hydrolysis with aqueous potassium hydroxide solution gave crystalline (2E,4E)-3-Methyl-5-(2-((E)-2(2,6,6-trimethyl-cyclohexen-1-yl)ethenyl)-1-cyclohexen-1-yl)-2,4-pentadienoic acid (1.6 g from hexane-tetrahydrofuran).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3ccc(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.3 %

Procedure:
(2R,4R)-Methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (32.5 mg, 0.09 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 0.8 mL, 4.57 mmol) and the mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx III, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4R)-2-(3,4-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (10.4 mg, 38%). 1H NMR (600 MHz, cd3od) δ 1.71-1.78 (m, 1H), 1.96-2.04 (m, 1H), 2.05-2.12 (m, 2H), 2.80-2.92 (m, 2H), 2.96-3.03 (m, 1H), 3.15-3.25 (m, 2H), 3.26-3.35 (m, 1H), 5.50 (s, 1H), 6.99-7.05 (m, 1H), 7.13-7.23 (m, 2H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1267
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([NH:20][C:21]3[N:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][N:31](C(OCC5C=CC=CC=5)=O)[CH2:30][CH2:29]4)=[CH:23][CH:22]=3)=[O:19])[C:11]=2[N:10]=1>CO.[Pd]>[N:28]1([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:18]([C:17]3[C:11]4[N:10]=[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[C:2]([F:1])([F:44])[F:45])[NH:13][C:12]=4[CH:14]=[CH:15][CH:16]=3)=[O:19])=[N:26][CH:25]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: O=C(Nc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2)cn1)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(CN2CCNCC2)cn1)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Reaction time: 12 h
Yield: 12.7 %

Procedure:
To a solution of benzyl 4-((6-(2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamido)pyridin-3-yl)methyl)piperazine-1-carboxylate (106; 280 mg, 0.46 mmol) in methanol (20 mL) was added Pd/C (0.1 g, 5% on carbon). The reaction mixture was stirred under 1 atm of H2 for 12 h and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (dichloromethane:methanol=5:1) to afford N-(5-(piperazin-1-ylmethyl)pyridin-2-yl)-2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxamide (Compound 621) (28.0 mg, 13%). MS (ESI) calcd for C25H23F3N6O: 480.19; found: 481 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.O=[Mn]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[O:22])=[CH:19][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Reaction time: 2 h
Yield: 84.2 %

Procedure:
A mixture of {6-[(1-benzyl-4-piperidyl)amino]-3-pyridyl}methanol (670 mg) and MnO2 (2.94 g) in AcOEt (30 ml) was refluxed under stirring for 2 hours. After removal of the insoluble material, and the solvent was evaporated in vacuo to give 6-[(1-benzyl-4-piperidyl)amino]nicotinaldehyde (560 mg)
Reaction SMILES: C1(C[NH:5][CH2:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([B:13]3[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]3)[CH:12]=2)CC1.C(S(N1CC[CH:30](C2C3C(=C(C(N)=O)C=C(C4C=NC=C(CNC(C)C)C=4)C=3)NC=2)[CH2:29][CH2:28]1)(=O)=O)C.C(N)(C)C.CC1(C)C(C)(C)OB(C2C=C(C=O)C=NC=2)O1.[BH3-]C#N.[Na+]>CO>[CH3:28][CH:29]([NH:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]2)[CH:12]=1)[CH3:30]
Reactant: CC1(C)OB(c2cncc(CNCC3CC3)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNC(C)C)c4)cc23)CC1
Agent: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(C)N
Product: CC(C)NCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine used to prepare 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-pyridinyl)-1H-indole-7-carboxamide was prepared as follows: isopropylamine (0.011 mL, 0.129 mmol) was added to a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol) in MeOH (1 mL) in a 2-dram vial. NaCNBH3 (16 mg, 0.258 mmol) was then added, the vial was capped and the reaction was stirred at room temperature for 24 h. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with MeOH (6 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was concentrated under a stream of nitrogen to give 22 mg of crude (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3](=[O:9])[CH2:2]2.Cl[C:11]1[O:12][C:13]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=2[N:15]=1>>[OH:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([N:8]3[CH:5]4[CH2:6][CH2:7][CH:1]3[CH2:2][C:3](=[O:9])[CH2:4]4)[O:12][C:13]=2[CH:19]=1
Reactant: Oc1ccc2nc(Cl)oc2c1
Reactant: O=C1CC2CCC(C1)N2
Product: O=C1CC2CCC(C1)N2c1nc2ccc(O)cc2o1

Procedure:
By a method similar to Example 1, step F, and using 8-azabicyclo[3.2.1]octan-3-one and 2-chloro-1,3-benzoxazol-6-ol, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH2:16]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][N:25]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:20][CH:19]=1)[CH3:17]
Reactant: CCc1ccc(CNc2ccc(C(C)C)cc2)cn1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: CCc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 55.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.58 g) and [(6-ethylpyridin-3-yl)methyl](4-isopropylphenyl)amine (0.71 g) as starting materials, N-[(6-ethylpyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.[CH3:28][N:29]1[C@@H:34]([CH3:35])[CH2:33][NH:32][CH2:31][C@H:30]1[CH3:36].C[C@H]1CNC[C@@H](C)N1CC#N.C(N(C(C)C)C(C)C)C>CS(C)=O.CO>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][C:14]2[CH:15]=[C:11]([NH:10][C:8]([C:5]3[CH:4]=[N:3][C:2]([N:32]4[CH2:33][C@H:34]([CH3:35])[N:29]([CH3:28])[C@H:30]([CH3:36])[CH2:31]4)=[CH:7][N:6]=3)=[O:9])[NH:12][N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C[C@@H]1CNC[C@H](C)N1C
Agent: C[C@@H]1CNC[C@H](C)N1CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4C[C@@H](C)N(C)[C@@H](C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
5-Chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (271 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of (2R,6S)-1,2,6-trimethylpiperazine and 2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol) in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The reaction was incomplete and N-ethyl-N-propan-2-ylpropan-2-amine (0.24 ml, 1.40 mmol) was added and the solution was stirred at 60° C. for a further 2 h. The reaction mixture was diluted with methanol (20 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (246 mg, 73%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]Br)=[CH:5][O:6][CH2:7][F:8].[C:18]1([CH3:25])[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[CH3:1][O:2][C:3](=[O:17])[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][O:24][C:23]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:25])=[CH:5][O:6][CH2:7][F:8]
Reactant: COC(=O)C(=COCF)c1ccccc1CBr
Reactant: Cc1ccccc1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(=COCF)c1ccccc1COc1ccccc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1.66 g of 2-(2-bromomethylphenyl)-3-fluoromethoxyacrylic acid methyl ester, 0.65 g of o-cresol, 1.38 g of pulverized potash and 0.07 g of 18-crown-6 in 15 ml of acetonitrile is stirred at room temperature for 24 hours. Water is then added, the reaction mixture is acidified with 1N hydrochloric acid and extraction is carried out with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated by evaporation. Chromatography on silica gel with hexane/ethyl acetate yields pure 3-fluoromethoxy-2-[2-(2-methylphenoxymethyl)phenyl]-acrylic acid methyl ester in the form of a viscous oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.40 g, 2.1 mmol, Aldrich, Cat. 525057), ethyl 2-bromopropanoate (290 μL, 2.3 mmol), and cesium carbonate (1.5 g, 4.6 mmol) in acetonitrile (8 mL) was stirred at 90° C. for 4 h. After cooling, the reaction mixture was worked up with aqueous Na2CO3, extracted with ethyl acetate (3×20 mL), and washed with brine. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.42 g, 61%). LCMS (M+H)+: m/z=295.1.