Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCCCO)c1

Procedure:
Alkylation reaction of phenol 58 with 3-bromo-1-propanol gave 2-(3-(3-(3-hydroxypropoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.300 g, 25%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.83 (m, 2H), 7.69-7.71 (m, 2H), 7.12-7.16 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 6.65 (dd, J=8.0, 2.4 Hz, 1H), 4.10 (d, J=6.0 Hz, 2H), 3.84-3.89 (m, 2H), 3.73 (t, J=7.2 Hz, 2H), 2.65 (t, J=8.0 Hz, 2H), 1.98-2.05 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:16]1[CH:20]=[C:19]([NH:21]C(=O)OC(C)(C)C)[O:18][N:17]=1)=[O:15].FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:19]1[O:18][N:17]=[C:16]([C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:15])[CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
To a solution of tert-butyl 3-(2-(5-chloro-1H-indol-3-yl)ethylcarbamoyl)isoxazol-5-ylcarbamate (0.400 g; 0.988 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 4 h and was then evaporated to dryness to remove the excess of TFA. The residue was dissolved in dichloromethane and the solution was washed with an aqueous solution of sodium carbonate. The organic layer was evaporated and the crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% methanol in dichloromethane) to afford 0.207 g (69%) of 5-amino-N-(2-(5-chloro-1H-indol-3-yl)ethyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:15][CH2:14]2)[CH2:8][CH2:7]1)=O)C.[OH-].[Na+]>Cl>[NH:6]1[CH2:7][CH2:8][CH:9]([NH:12][C@H:13]2[CH2:14][CH2:15][C@H:16]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[NH:21][C:20]3=[O:28])[CH2:17][CH2:18]2)[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCC(N[C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](NC2CCNCC2)CC1

Procedure:
A stirred solution of 1.2 g of 1,3-dihydro-1-{trans-4-[1-ethoxycarbonyl-4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one in 20 mL of 6N HCl was heated to reflux for 12 h, cooled and basified with 6N NaOH. The basic mixture was extracted with 2×50 mL portions of chloroform. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. After drying overnight under vacuum, there was obtained 0.51 g of 1,3-dihydro-1-{trans-4-[4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 7.33 (m, 1H), 7.11 (m, 1H), 7.04 (m, 2H), 4.37 (m, 1H), 3.16 (m, 3H), 2.61-2.52 (m, 5H), 2.0 (d, 2H), 1.86 (d, 2H), 1.64 (m, 4H), 1.3 (m, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[N:10]1([C:16]2[C:17]3[C:24](B4OC(C)(C)C(C)(C)O4)=[CH:23][N:22]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[N:10]1([C:16]2[C:17]3[C:24]([C:2]4[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=4)=[CH:23][N:22]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: N#Cc1cccc(Br)n1
Reactant: CC1(C)OB(c2cn(COCC[Si](C)(C)C)c3ncnc(N4CCOCC4)c23)OC1(C)C
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: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)n2)c2c(N3CCOCC3)ncnc21
Temperature: 120 °C

Procedure:
To a solution of 6-bromopyridine-2-carbonitrile (80 mg, 0.44 mmol) and 4-(morpholin-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (P2) (241 mg, 0.523 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (51 mg, 44 μmol) and sodium carbonate (140 mg, 1.32 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 15 minutes, then diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo; purification via preparative thin layer chromatography (Eluent: 1:1 petroleum ether/ethyl acetate) afforded the product as a brown oil. Yield: 110 mg, 0.252 mmol, 57%. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.84-7.93 (m, 2H), 7.74 (s, 1H), 7.59 (dd, J=7.0, 1.2 Hz, 1H), 5.66 (s, 2H), 3.56-3.65 (m, 6H), 3.34-3.40 (m, 4H), 0.93 (dd, J=8.3, 8.0 Hz, 2H), −0.05 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:20]1[Se:24][C:23]([C:25]([NH2:27])=[O:26])=[C:22]([OH:28])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+].Cl>CN(C=O)C.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:22]1[CH:21]=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[Se:24][C:23]=1[C:25]([NH2:27])=[O:26]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: CC(C)(C)c1cc(O)c(C(N)=O)[se]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.4 %

Procedure:
To a solution of 4-chloro-6,7-dimethoxyquinazoline (200 mg, 0.89 mmol) in DMF (5 mL) was added sequentially 5-tert-butyl-3-hydroxyselenophene-2-carboxamide (220 mg, 0.89 mmol), powdered NaOH (147 mg, 3.568 mmol) and catalytic amount of KI at rt and the mixture was stirred at rt for 3 h. The mixture was poured into ice cooled water, neutralized with dil. HCl and stirred for 15 min. The precipitated solid was filtered, washed with water and dried. The crude product was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as an yellow color solid (245 mg, 63%), mp 220-224° C. 1H NMR (400 MHz, CDCl3): δ 15.16 (1H, br s, exchangeable with D2O), 13.63 (1H, br s, exchangeable with D2O), 8.17 (1H, s), 7.51 (1H, s), 7.21 (1H, s), 6.87 (1H, s), 4.05 (6H, s), 1.38 (9H, s); 13C NMR (100 MHz, CDCl3): δ 175.5, 172.0, 164.8, 156.6. 155.1, 150.7, 145.9, 139.9, 118.7, 113.1, 112.7, 108.4, 103.3, 56.5, 56.3, 37.1, 32.2; LC-MS (positive ion mode): m/z 434, 436 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:16][CH2:17]CC.[Li]C(C)(C)C.C(I)C>C1COCC1>[CH2:16]([C:11]1[C:12]2[NH:13][C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1)[CH3:17]
Reactant: [Li]CCCC
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cccc2c1Nc1ccccc1S2
Temperature: 25 °C

Procedure:
This compound was prepared according to a procedure by A. R. Katritzky et al., Synthesis, 1988, 215-217. To a solution of phenothiazine (10.0 g, 50.18 mmol) in anhydrous THF (200 mL) and cooled to −78° C. was added a solution of n-BuLi (24.1 mL, 60.2 mmol, 2.5 M in hexanes) dropwise. The mixture is stirred until a yellow precipitate forms and then allowed to warm to room temperature, until a clear yellow solution results. the solution is again cooled to −78° C. and CO2 gas is bubbled through the mixture for 5 min. The resulting solution is allowed to warm to RT and the solvent was evaporated to give a residue. The residue was again dissolved in anhydrous THF (200 mL) and cooled to −78° C., before t-BuLi (50 mL, 85 mmol, 1.7 M in pentane) was added dropwise. The resulting mixture was allowed to warm to −20° C. and was stirred at this temperature for 2 h. The reaction mixture was again cooled to −78° C. and a solution of ethyl iodide (100.0 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at this temperature for 1 hour then allowed to warm to −20° C. and stirred for 2 h. The reaction mixture was quenched with ice cold 1N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give a residue. The residue was purified by flash silica gel chromatography to give the desired product.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21]1([C:27]#[C:28][C:29](OCC)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CS(C)=O>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:29](=[O:30])[CH:28]=[C:27]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: CS(C)=O
Product: O=c1cc(-c2ccccc2)n2c(n1)O[C@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and ethyl phenylpropiolate employing the procedure described in Example 76. [α]D25 +100.26 (c 0.507, DMSO).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:5]([CH3:6])[CH:4]1[C:7]1[N:12]=[C:11]2[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]2=[CH:9][CH:8]=1.[O:23]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[N:24]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:19][C:17]([CH3:18])([CH3:20])[CH2:16][N:15]1[C:10]2[C:11](=[N:12][C:7]([CH:4]3[CH:5]([CH3:6])[CH:3]3[CH2:2][NH:1][C:28]([C:25]3[CH:26]=[CH:27][O:23][N:24]=3)=[O:29])=[CH:8][CH:9]=2)[N:13]([CH3:22])[C:14]1=[O:21]
Reactant: CC1C(CN)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1C(CNC(=O)c2ccon2)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-[2-(Aminomethyl)-3-methylcyclopropyl]-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (35-2, 35 mg, 0.11 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 14.3 mg, 0.12 mmol, 1.5 equiv), DIPEA (0.040 mL, 0.23 mmol, 2.0 equiv) and HATU (48.4 mg, 0.12 mmol, 1.1 equiv) were added to anhydrous acetonitrile (1 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 35-3 as a white solid. MS m/z (M+H): calculated=398.2188; observed=398.2195. 1H NMR δ (ppm)(CHCl3-d): 8.47 (1H, d, J=1.68 Hz), 7.04 (1H, d, J=7.90 Hz), 6.96 (1H, s), 6.83 (1H, d, J=1.67 Hz), 6.81 (1H, d, J=7.90 Hz), 3.76-3.65 (1H, m), 3.61 (2H, s), 3.60-3.52 (1H, m), 3.43 (3H, s), 1.82 (1H, dd, J=7.68, 3.43 Hz), 1.70-1.65 (1H, m), 1.64 (1H, dd, J=7.82, 0.02 Hz), 1.30 (3H, d, J=6.23 Hz), 1.02 (9H, s).
Reaction SMILES: COC1C=[C:5]([CH2:11][CH2:12][CH2:13]C(=O)C=C)[CH:6]=[CH:7][C:8]=1[O:9]C.C[O:19]C1C=C(CCCC(=O)CCN(CC)CC)C=CC=1OC>[OH-].[K+]>[CH2:12]([CH:11]1[C:5](=[O:19])[CH2:6][CH2:7][C:8]1=[O:9])[CH3:13]
Reactant: CCN(CC)CCC(=O)CCCc1ccc(OC)c(OC)c1
Reactant: C=CC(=O)CCCc1ccc(OC)c(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux 6-(3,4-dimethoxyphenyl)hex-1-en-3-one, containing a small amount of 6-(3,4-dimethoxyphenyl)-1-diethylaminohexan-3-one (6 g, produced by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% anhydrous methanolic potassium hydroxide (10 cc) for 10 hours. Remove most of the methanol under reduced pressure, add benzene (25 cc) and ether (25 cc) and wash the solution with water, dilute aqueous potassium hydroxide, dilute hydrochloric acid and water. Dry and evaporate the solvent to give the triketone adduct 2-[6-(3,4-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione; infrared absorption (gum) 5.80, 6.25 μ (split peak).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][NH:13][C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([CH:31]=[CH:32][CH2:33]Cl)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][N:13]([CH2:33][CH:32]=[CH:31][C:30]3[CH:35]=[CH:36][C:27]([Cl:26])=[CH:28][CH:29]=3)[C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1F
Reactant: ClCC=Cc1ccc(Cl)cc1
Product: COc1ccc(-c2cc(=O)n(CC=Cc3ccc(Cl)cc3)nc2-c2ccc(OC)c(F)c2)cc1F
Yield: 42.9 %

Procedure:
Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 42.9%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:15]1([S:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of indole (2.4 g, 20 mol) in dry THF (20 ml) under argon at −78° C. was added dropwise via syringe over 10 min n-butyllithium (1.6M in hexanes; 14 ml). The cooling bath was removed and the solution was stirred for 1 h while warming to 0° C. The resulting indole anion precipitated as a very fine white solid in a cloudy colorless solution. After the suspension was recooled to −78° C., benzenesulfonyl chloride (2.8 ml, 22 mmol) was added via syringe over 20 min, keeping the temperature below −60° C. The resulting colorless mixture was allowed to warm slowly to room temperature overnight, poured into 2% aqueous sodium bicarbonate (30 ml), and extracted with ethyl acetate (2×25 ml). The combined extracts were washed with 2% aqueous sodium bicarbonate(30 ml), water (2×25 ml), dried over anhydrous sodium sulphate, and evaporated to give a light amber oil which crystallized when triturated with 2:1 hexane/ether (15 ml). After standing in the cold (−20° C.) for several hours, the product was collected by filtration, washed with hexane, and dried in vancum to provide pure 1-phenylsulfonyl-indole (60) as white crystals (4.8 g, 90.6%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[C:18]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: CC(C)(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Yield: 66.3 %

Procedure:
The title compound (88 mg) was prepared as in Example 177, Steps C and D, using 204 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215 Step A) and 194 mg of 4-fluorophenylboronic acid. MS (ESI): exact mass calculated for C17H22FN3, 287.18; found, m/z 288.4 [M+H]+, 232.4 [M-tBu]+. 1H NMR (500 MHz, CD3OD): 7.37-7.33 (m, 2H), 7.26-7.22 (m, 2H), 3.41-3.38 (m, 2H), 3.26-3.24 (m, 2H), 3.18-3.15 (m, 2H), 2.53-2.51 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)#[N:4].[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:35]([N:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]#[N:4])[CH:6]=2)=[O:13])[CH2:15][CH:16]1[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:23][CH2:22]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=Cc1ccccc1
Reactant: N#Cc1cccc(NC(=O)N2CCNC(CN3CCC(Cc4ccc(F)cc4)CC3)C2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: N#Cc1cccc(NC(=O)N2CCN(Cc3ccccc3)C(CN3CCC(Cc4ccc(F)cc4)CC3)C2)c1
Reaction time: 16 h
Yield: 19 %

Procedure:
A solution of N-(3-cyanophenyl)-3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxamide dihydrochloride (20.0 mg, 0.05 mmol) and benzaldhyde (8.5 mg, 0.08 mmol, Aldrich) in dry dichloroethane (5 mL) was stirred for 20 min when sodium triacetoxyborohydride (32 mg, 0.15 mmol, Aldrich) was added. The reaction was stirred for 16 h and then quenched with water (5 mL). The organic layer was separated, dried over MgSO4, and conc. in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, EtOAc and then EtOAc:TEA, 9:1) to yield 5.0 mg of 4-benzyl-N-(3-cyanophenyl)-3-{[4-(4-fluorobenzyl)-1-piperidinyl]methyl}-1-piperazinecarboxamide as a white solid. MS (ESI) 526 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:16]1([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cccc(OCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cccc(OCCN2CCOCC2)c1
Reaction time: 8 h

Procedure:
To a solution of ethyl 3-[(2-bromoethyl)oxy]benzoate D46 (100 mg), morpholine (44.7 mg, 0.513 mmol) in Acetonitrile (2 mL) stirred under nitrogen at 25° C. was added K2CO3 (106 mg, 0.769 mmol). The reaction mixture was stirred at 60° overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give 98 mg of the crude product D47 without more purification. LCMS Retention time=1.57 mins, [M+H]+280 (5 min run)
Reaction SMILES: Br[C:2]1[N:3]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Br-].[CH:24]1([Zn+])[CH2:26][CH2:25]1>O1CCCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:24]1([C:2]2[N:3]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:4]3[C:9]([C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:26][CH2:25]1
Reactant: COC(=O)c1c(Br)n(C(C)c2ccccc2)c2ccccc12
Reactant: [Zn+]C1CC1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(C2CC2)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of methyl 2-bromo-1-(1-phenylethyl)-1H-indole-3-carboxylate (0.30 g, 0.84 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.09 g, 0.08 mmol) in tetrahydrofuran (20 mL) was added cyclopropylzinc(II) bromide (6.0 mL, 0.5 mol/L in tetrahydrofuran). The reaction mixture was stirred at reflux for 12 hours. After the reaction, it was cooled to room temperature and diluted with water (100 mL). The product was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel: ethyl acetate:petroleum ether=1:10) to give the crude product methyl 2-cyclopropyl-1-(1-phenylethyl)-1H-indole-3-carboxylate (0.22 g, 82%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:20]NC.C=O>>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH2:20])=[CH:17][CH:16]=1
Reactant: CNC
Reactant: O=C(CCc1ccc(F)cc1)c1ccc(F)cc1
Agent: C=O
Agent: Cl
Product: C=C(Cc1ccc(F)cc1)C(=O)c1ccc(F)cc1

Procedure:
59.4 g of 4,4'-difluoro-β-phenylpropiophenone, prepared in accordance with step (a), together with 39.2 g of dimethylamine hydrochloride and 14.4 g of paraformaldehyde are heated overnight under reflux. The reaction mixture is then concentrated by evaporation and the residue is taken up in 300 ml of water and is extracted with three 200 ml portions of ether. The combined ether extracts are washed twice with water and then twice with a saturated solution of NaCl, dried over Na2SO4 and filtered. The filtrate is concentrated, affording 1-(4-fluorophenyl)-2-(4-fluorobenzyl)-prop-2-en-1-one of the formula ##STR9## as a crude product which is immediately reacted further. The crude product is dissolved in 140 ml of ethanol and a solution of 18.8 g of hydrazine hydrate in 70 ml of methanol is added dropwise to this ethanolic solution. When the addition is complete, the reaction mixture is heated under reflux for three hours, cooled and then concentrated by rotary evaporation. The resultant residue is taken up in ether and the ethereal solution is washed twice with water and then twice with a saturated solution of NaCl, dried over Na2SO4 and filtered. The filtrate is concentrated by evaporation, thus affording the title compound of the formula ##STR10##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:53][CH2:54][C:55](=[O:57])[CH3:56].CCN(CC)CC>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])[C:17]([NH:53][CH2:54][C:55](=[O:57])[CH3:56])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccc(OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Reactant: CC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)CNC(=O)C(Cc1ccc(OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid (500 mg, 1.25 mmol), HOBt (180 mg, 2.5 mmol), and EDCI (480 mg, 2.5 mmol) in DMF (3 mL) was stirred at 0° C. for 0.5 h. To this mixture was added 1-amino-2-propanone hydrochloride (4) (272 mg, 2.5 mmol) followed by Et3N (550 □L, 0.6 mmol). The mixture was stirred at 0° C. for 0.5 h and at room temperature for 1 h. Water (10 mL) was added, and the product was extracted with EtOAc (3×15 mL). The combined extracts were dried over Na2SO4 and concentrated, and the residue was triturated with water to obtain 3-(4-benzyloxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-oxo-propyl)-propionamide (5) as a solid (500 mg, 88%). 1H NMR (CDCl3): □7.78 (m, 2H), 7.70 (m, 2H), 7.35 (m, 4H), 7.1 (d, 2H), 6.8 (m, 3H), 4.92 (s, 2H), 4.2 (m, 2H), 3.6 (d, 2H), 2.2 (s, 3H); ). LCMS m/z 457.1 (M+1)