Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:12]OC(C)(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:23])[CH2:21][CH3:22]>>[C:1]1([CH2:7][C:8]([O:23][CH2:20][CH2:21][CH3:22])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCO
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1ccccc1
Agent: [C]=O
Product: CCCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
Toluene (1.38 g), n-propanol (60 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 78 mg n-propyl phenylacetate was obtained by column chromatography, in a yield of 88%. 1HNMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 3H), 1.59-1.67 (m, 2H), 3.61 (s, 2H), 4.12 (t, J=6.8 Hz, 2H), 7.23-7.33 (m, 5H); 13CNMR (100 MHz, CDCl3) δ 10.3, 21.9, 41.5, 66.4, 127.0, 129.3, 134.3, 171.7; HRMS (ESI) calcd. for C11H14NaO2 [M+Na]: 201.0886. found: 201.0886. The n-propyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 56 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 94%.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]2[N:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:29]=[C:28]5[C:23]([CH:24]=[CH:25][CH:26]=[N:27]5)=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH2:3]1.C(N(CC)C(C)C)(C)C.[N:39]1([C:45](Cl)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>ClCCl>[N:39]1([C:45]([N:2]2[CH2:6][CH2:5][C@@H:4]([CH2:7][C:8]3[N:9]([C:14]4[CH:15]=[CH:16][C:17]([C:20]5[CH:29]=[C:28]6[C:23]([CH:24]=[CH:25][CH:26]=[N:27]6)=[CH:22][CH:21]=5)=[CH:18][CH:19]=4)[C:10](=[O:13])[NH:11][N:12]=3)[CH2:3]2)=[O:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CCOCC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 4 mL vial was placed 5-[(3S)-3-pyrrolidinylmethyl]-4-[4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.147 mmol). Added in succession was dichloromethane (2 mL), N,N-diisopropylethylamine (0.458 mmol), and 4-morpholinecarbonyl chloride (0.157 mmol). The vial was capped and the solution was stirred at room temperature for 30 min. The solution was concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (23 mg, 31%). MS(ES)+ m/e 485.2 [M+H]+.
Reaction SMILES: F[B-](F)(F)F.[F:6][B-](F)(F)F.[F:11][N+]1C=CC=CC=1C1C=CC=C[N+]=1F.[CH3:25][C:26]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:33][C:27]=1[C:28]([N:30]([CH3:32])[CH3:31])=[O:29].C(=O)(O)[O-].[Na+]>C(#N)C>[F:11][C:35]1[C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:33][C:27]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[C:26]([CH3:25])[CH:36]=1.[F:6][C:33]1[C:34]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:35][CH:36]=[C:26]([CH3:25])[C:27]=1[C:28]([N:30]([CH3:32])[CH3:31])=[O:29]
Reactant: F[B-](F)(F)F
Reactant: Cc1ccc(N2CCOCC2)cc1C(=O)N(C)C
Reactant: F[n+]1ccccc1-c1cccc[n+]1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(F)c(N2CCOCC2)cc1C(=O)N(C)C
Product: Cc1ccc(N2CCOCC2)c(F)c1C(=O)N(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.2 %
Yield: 5.3 %

Procedure:
393 mg (1.10 mmol) of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added to 7 ml of an acetonitrile solution containing 458 mg (1.84 mmol) of the 2, N,N-trimethyl-5-morpholin-4-ylbenzamide obtained in Step B of Example 80 under cooling on ice. The obtained mixture was stirred at 0° C. for 1 hour, then at a room temperature for 1 hour, then at 50° C. for 1 hour, then at 80° C. for 2.5 days, and then under heating to reflux for 2 hours. Thereafter, 357 mg (1.0 mmol) of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was further added to the reaction solution, and the obtained mixture was further stirred for 20 minutes. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3 to 1:1), so as to obtain 25.8 mg (5.3%) of 4-fluoro-2,N,N-trimethyl-5-morpholin-4-ylbenzamide in the form of an oily substance, and also obtain 35.1 mg (7.2%) of 2-fluoro-6,N,N-trimethyl-3-morpholin-4-ylbenzamide in the form of an oily substance.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:27][CH3:28]>CN(C)C=O>[I-:27].[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N+:13]([CH3:28])([CH2:16][CH2:17][CH2:18][C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Reactant: CI
Solvent: CN(C)C=O
Product: C[N+]1(CCCC(=O)c2ccccc2)CCC(NC(=O)c2ccccc2)CC1
Product: [I-]

Procedure:
A solution of 4-benzamido-1-(4-phenyl-4-oxobutyl)-piperidine (1.75 g., 0.005 mole) and iodomethane (7.10 g., 0.05 mole) in N,N-dimethylformamide (5 ml.) was stirred for 150 hours at room temperature. The reaction mixture was filtered and the residue was washed with fresh N,N-dimethylformamide and then diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][CH2:34][CH2:35][Cl:36].[H-].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[N:14]([CH2:33][CH2:34][CH2:35][Cl:36])[C:15]2[C:20]([C:21]=1[CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[CH:19][CH:18]=[C:17]([C:28]([O:30][CH3:31])=[O:29])[CH:16]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccn3C(=O)OC(C)(C)C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccn3C(=O)OC(C)(C)C)n(CCCCl)c2c1
Reaction time: 2 h
Yield: 101.1 %

Procedure:
To a solution of methyl 2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-cyclohexyl-1H-indole-6-carboxylate (140 mg, 0.331 mmol) and 1-bromo-3-chloropropane (156 mg, 0.994 mmol) in N,N-dimethylformamide (4 ml) was added sodium hydride (17 mg, 0.430 mmol) under ice-cooling, and the mixture was stirred for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give methyl 2-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-1-(3-chloropropyl)-3-cyclohexyl-1H-indole-6-carboxylate (167 mg, yield 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Cl
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCC(=O)Nc1ccc2[nH]cc(C3CCN(CC)CC3)c2n1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.080 mMol) propionyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:18])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7]/[C:8]/2=[CH:11]\[C:12]([Cl:18])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C1\CCc2ccc(F)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C1\CCc2ccc(F)cc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
An ice-cold, stirred suspension of (E)-2-(6-fluoro-1-indanylidene) acetic acid (384 mg, 2 mmol) in benzene (10 mL) was treated with oxalyl chloride (761 mg, 6 mmol) and allowed to warm to room temperature during 1.5 h. The resulting yellow solution was concentrated in vacuo to give (E)-2-(6-fluoro-1-indanylidene)acetyl chloride as a pale yellow solid (421 mg, 100%), m.p., 97°-99° C.; IR (Nujol (high boiling petroleum oil)): 1750, 1600 cm-1 ; NMR (DMSO-d6): d 7.18-7.67 (m, 3H, Ar), 6.39 (t, 1H, =CH), 2.96-2.99, 3.16-3.21 (2m's, 4H, 2XCH2).
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.BrBr.[CH3:12][O:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[CH:15]=1>C(O)(=O)C.C(OC)(C)(C)C>[BrH:1].[Br:1][CH:5]1[C:6]([C:15]2[C:16]([O:22][CH3:23])=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][CH3:12])=[CH:7][CH2:8][N:3]([CH3:2])[CH2:4]1
Reactant: COc1cc(OC)cc(OC)c1
Reactant: CN1CCC(=O)CC1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
75.7 ml (0.44 mol) of 33% strength HBr in glacial acetic acid were added to 200 ml of glacial acetic acid, and 50 g (0.44 mol) of 1-methylpiperidin-4-one (III) were then rapidly added dropwise at 20-25° C. with ice-cooling. 70.4 g (0.44 mol) of bromine were added dropwise at 20-25° C. in the course of 30 min to the suspension of the hydrobromide obtained in this way, a clear, yellowish solution being obtained. This was stirred at 25° C. for a further 15 min and 67.2 g (0.40 mol) of 1,3,5-trimethoxybenzene (V) were then added to the reaction solution. It was then stirred at 25° C. for 1 h. After this, 300 ml of methyl tert-butyl ether were allowed to run in, the product being deposited in oily form. The supernatant was decanted off, the residue was stirred again with 300 ml of methyl tert-butyl ether and the supernatant was decanted off. The residue was then stirred with 150 ml of dichloromethane, the product crystallizing out. The 3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide (VI) obtained was filtered off with suction, washed with 50 ml of dichloromethane and dried in vacuo.
Reaction SMILES: [O:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][C:8]=3[CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH:14]=O.[C:16]1([CH2:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H][H]>O(C(C)C)C(C)C.[Pd]>[C:16]1([CH2:22][NH:23][CH2:14][CH:2]2[CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][C:8]4[CH2:11][CH2:12][CH2:13][C:7]=4[C:6]=3[O:1]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: [H][H]
Reactant: O=CC1CCc2ccc3c(c2O1)CCC3
Agent: [Pd]
Solvent: CC(C)OC(C)C
Product: c1ccc(CNCC2CCc3ccc4c(c3O2)CCC4)cc1
Yield: 73.8 %

Procedure:
A mixture of intermediate (5-a) (0.03 mol) and benzenemethanamine (0.073 mol) in 2,2'-oxybispropane (250 ml) and N N-dimethylacetamide (10 ml) was hydrogenated with palladium on activated carbon (10%) (1 g) as a catalyst. After uptake of hydrogen (1 eq.), the catalyst was filtered off. The filtrate was evaporated. The residue was stirred in a mixture of water and 1, 1'-oxybisethane. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 6.5 g of (±)-2,3,4,7,8,9-hexahydro-N-(phenylmethyl)cyclopenta[h]-1-benzopyran-2-methanamine (interm. 14-a).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1.CN.C[CH2:20][N:21](C(C)C)C(C)C>O1CCOCC1>[CH3:20][NH:21][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][N:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Agent: CN
Solvent: C1COCCO1
Product: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (200 mg, 0.84 mmol), methanamine (277 mg, 8.4 mmol), and DIPEA (0.35 mL, 2.01 mmol) in dioxane (5 mL) was stirred at room temperature for 16 hours. It was then concentrated under reduced pressure, and the residue was treated in EtOAc. The insoluble solid was removed by filtration, and the organic solution was concentrated under reduced pressure to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH2:8]P(OCC)(OCC)=O)=[O:7].[CH:17](=O)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>O1CCCC1>[C:6]([O:5][CH2:4][CH3:3])(=[O:7])/[CH:8]=[CH:17]/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCCCC/C=C/C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC/C=C/C=C/C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% wt., 3.11 g) was suspended in dry tetrahydrofuran (200 ml) and cooled to 0° C. O,O-Diethyl ethoxycarbonylmethyl phosphonate (15.43 ml) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min and cooled to −78° C. after which (E)-dec-2-enal (11.90 ml) was added dropwise. Stirring was continued at this temperature for 2 h, after which the mixture was warmed to room temperature. The reaction mixture was poured into water, and the aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated. The crude product was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][N:12]([CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21].C([Li])CCC.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:12]([CH3:22])[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: CCOC(=O)Cl
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2Cl)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4,5-di-(2,4-dichlorophenyl)-1-methylimidazole (200 mg, 0.54 mmol) from Step C in THF (5 mL) cooled to −70° C. in a dry ice/acetone bath was added 1.6N n-butyl lithium in hexanes (0.40 mL, 0.65 mmol). The reaction was stirred for 1 hr and then ethyl chloroformate (0.10 mL, 1.1 mmol) was added via syringe. The reaction was allowed to warm to rt for 1 hr and was then quenched with aq. sodium bicarbonate and extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by Prep TLC (2×1 mm, silica) (25% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17]Br.O.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:16]=1[CH2:17][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
Potassium phthalimide (836 mg) was added to a solution of 2-methoxy-5-nitrobenzyl bromide (1.01 g) in dimethylformamide (41 ml) and stirred at room temperature for 10 minutes. Water and 2 N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then, the organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was washed successively with ethyl acetate and hexane to give 1.2 g of the titled compound (yield, 94%).
Reaction SMILES: C(C1C=CC=CC=1CCC)CC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH3:22])=[C:16]([CH2:23][CH2:24][CH3:25])[CH:15]=1.CNN.[CH2:29]([NH:32]N)[CH2:30][CH3:31].C1(NN)CC1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[C:16](=[C:23]([CH2:24][CH3:25])[N:32]([CH2:29][CH2:30][CH3:31])[C:20]=2[CH2:21][CH3:22])[CH:15]=1
Reactant: CCCNN
Reactant: CCCc1ccc(Br)cc1CCC
Agent: CCCc1ccccc1CCC
Agent: CNN
Agent: NNC1CC1
Product: CCCn1c(CC)c2ccc(Br)cc2c1CC

Procedure:
Following the procedure of Example 3, Step A, except that the o-dipropylbenzene of Example 3 is replaced by an equivalent amount of: 4-chloro-; 4-iodo-; and 4-bromo-1,2-dipropylbenzene and the methylhydrazine is replaced by an equivalent amount of propylhydrazine; cyclopropylhydrazine; and γ-THP-oxy-propylhydrazine, there is obtained 5-chloro, 5-iodo, and 5-bromo-2-propyl-1,3-diethylisoindole; 5-chloro-; 5-iodo-; and 5-bromo-2-cyclopropyl-1,3-diethylisoindole; and 5-chloro-; 5-iodo-; and 5-bromo-2-γ-THP-oxy-propyl-1,3-diethylisoindole, respectively; wherein THP represents tetrahydropyranyloxy.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34]C(=O)OC(C)(C)C)[CH2:29]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:15]=[N:16][N:17](CC4C=CC(OC)=CC=4)[CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:50]>>[ClH:50].[NH2:34][C@@H:30]1[CH2:31][CH2:32][CH2:33][N:28]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]4[CH:18]=[N:17][NH:16][CH:15]=4)=[O:13])[C:4]=23)[CH2:29]1
Reactant: ClCCl
Reactant: COc1ccc(Cn2cc(C(=O)Nc3c[nH]c4ncc(Br)c(N5CCC[C@@H](NC(=O)OC(C)(C)C)C5)c34)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cn[nH]c4)c23)C1
Temperature: 65 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of (R)-tert-butyl 1-(5-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 0.192 mmol) in DCM (3 mL) was treated with TFA (1 mL) at room temperature for 30 minutes. The reaction was then concentrated in vacuo and azeotroped with toluene. The resulting residue was dissolved in neat TFA (5 mL) and stirred at 65° C. for 1 hour. The reaction mixture was then concentrated in vacuo, and the residue obtained was purified by reverse phase HPLC (Gilson) to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazole-4-carboxamide hydrochloride (50 mg, 50% yield). 1H NMR (400 MHz, D2O) δ 8.26 (s, 1H), 8.12 (s, 2H), 7.33 (s, 1H), 3.67-3.63 (m, 1H), 3.41-3.37 (m, 1H), 3.30-3.27 (m, 1H), 3.19-3.10 (m, 2H), 1.90-1.83 (m, 1H), 1.68-1.65 (m, 1H), 1.55-1.51 (m, 1H), 1.36-1.34 (m, 1H); LCMS (APCI+) m/z 404, 406 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=2)[CH:9]=1)=[N+]=[N-]>CCO.CC(O)=O.[Fe]>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:8]2[CH:9]=[C:5]([CH2:4][NH2:1])[N:6]=[CH:7]2)=[N:11][CH:12]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccc(Br)cn2)cn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: NCc1cn(-c2ccc(Br)cn2)cn1
Yield: 55.8 %

Procedure:
A mixture of 2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-bromopyridine (500 mg, 1.79 mmol) and iron powder (767 mg, 13.7 mmol) in EtOH (8 mL) and HOAc (6 mL) was heated at reflux for 2 h. It was filtered through celite. The filtrate was concentrated in vacuo. The residue was partitioned between 5% NaHCO3 and EtOAc. The biphasic solution was filtered. The EtOAc phase was separated, dried over Na2SO4, and concentrated in vacuo to give (1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanamine (253 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:2].[NH4+:37].[Cl-]>O1CCOCC1>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)(=[NH:37])[NH2:2]
Reactant: N#CCc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Reactant: [NH4+]
Agent: [Cl-]
Solvent: C1COCCO1
Product: N=C(N)Cc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
A solution of N-({1-[4-(4-cyanomethyl-phenyl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 21, 250 mg, 0.50 mmol) in dioxane (2 mL) and saturated NH4Cl (2 mL) was heated in a sealed tube to 120° C. overnight. The solvent was removed in vacuo and the residue was purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]([NH:13][C:14]([C:16]2[C:17]([CH3:29])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[N:20][CH:21]=2)=[O:15])[CH:4]=1)#[N:2].[Si]([N:34]=[N+:35]=[N-:36])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.CCOC(C)=O>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([NH:13][C:14]([C:16]1[C:17]([CH3:29])=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[N:20][CH:21]=1)=[O:15])[CH:4]=[C:3]2[C:1]1[NH:36][N:35]=[N:34][N:2]=1
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C#N)c2cc(F)ccc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(-c2nnn[nH]2)c2cc(F)ccc21
Yield: 74.6 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-cyano-5-fluoro-indol-1-yl)-amide (120 mg, 0.31 mmol), TMSN3 (62 μL, 0.465 mmol), and TBAF (0.155 μL, 0.155 mmol, 1 M in THF) in toluene (3 mL) is heated at 80° C. for 18 h. The mixture is cooled, diluted with EtOAc, and washed with 1 M HCl. The organic layer is extracted with Na2CO3. The aqueous layer is acidified to pH ˜3 with 3 N aqueous HCl, extracted with EtOAc The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid [5-fluoro-3-(1H-tetrazol-5-yl)-indol-1-yl]-amide (100 mg, 75%). MS: 433 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.81 (s, 3H), 7.28 (m, 1H), 7.47 (m, 1H), 7.67 (m, 1H), 7.73 (m, 1H), 8.01 (m, 1H), 8.21 (m, 1H), 8.33 (m, 1H), 8.36 (s, 1H), 9.33 (s, 1H). IC50=5 nM.