Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([N:15]2[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[N:17]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[CH:26][CH:25]=3)[C:16]2=[O:34])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])C.Cl.C1(C)C=CC=CC=1>O1CCOCC1>[CH3:21][C:18]1([CH3:22])[C:19](=[O:20])[N:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([CH:8]=2)[O:6][CH2:5][CH:4]=[O:3])[C:16](=[O:34])[N:17]1[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1
Reactant: CCOC(COc1cc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)ccc1OC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(N2C(=O)N(Cc3ccnc4ccccc34)C(C)(C)C2=O)cc1OCC=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
410 mg 3-[3-(2,2-Diethoxy-ethoxy)-4-methoxy-phenyl]-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione were dissolved in 8 ml 1,4-dioxane and 2.05 ml of an aqueous 1 N solution of hydrochloric acid were added. The mixture was stirred for 2 hours at 80° C. Removal of the solvent under reduced pressure yielded a white solid, which was coevaporated twice with toluene. Yield: 340 mg
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][N:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CC(O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][N:3]=[C:2]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[Si](C)(C)C#Cc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C1CCNCC1
Solvent: CC(C)O
Product: C[Si](C)(C)C#Cc1cnc(N2CCCCC2)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.2 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine (200 mg, 0.6 mmol, 1.0 eq), piperidine (102.7 mg, 1.2 mmol, 2.0 eq) in iPrOH (4 ml) was stirred at room temperature for 2 h. Then the mixture was washed with water, extracted with EtOAc, dried (Na2SO4). EtOAc was removed by evaporation and the residue was recrystalized by PE to give compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(piperidin-1-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (101 mg, 44.3%).
Reaction SMILES: [CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[CH2:19][CH2:20]S(C)(=O)=O)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1.I.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][N:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[C:52]([CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1)=[O:53]>>[CH3:1][N:2]([CH2:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[CH2:19][CH2:20][N:57]1[CH2:58][CH2:59][CH:54]([C:52]([C:44]2[N:43]([CH2:42][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[N:45]=2)=[O:53])[CH2:55][CH2:56]1)[C:3](=[O:16])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1
Reactant: O=C(c1nc2ccccc2n1Cc1ccccn1)C1CCNCC1
Reactant: COc1cc(C(=O)N(C)CC(CCS(C)(=O)=O)c2cccc(C(F)(F)F)c2)cc(OC)c1OC
Agent: I
Product: COc1cc(C(=O)N(C)CC(CCN2CCC(C(=O)c3nc4ccccc4n3Cc3ccccn3)CC2)c2cccc(C(F)(F)F)c2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3-trifluoromethylphenyl)-4-methanesulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1-(pyrid-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodic acid salt to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22][C:23]1([CH3:34])[O:27][C@@H:26]([CH2:28]OS(C)(=O)=O)[CH2:25][O:24]1.Cl>CN(C)C=O.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:28][C@H:26]2[CH2:25][O:24][C:23]([CH3:34])([CH3:22])[O:27]2)=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(O)cc1
Reactant: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OC[C@H]2COC(C)(C)O2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
(R)-tert-Butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (200 mg, 0.75 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) followed by the addition of sodium hydride (60% dispersion in mineral oil) (63 mg, 1.57 mmol) at room temperature. The reaction was stirred for 30 minutes followed by the dropwise addition of methanesulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan4-ylmethyl ester (189 mg, 0.90 mmol) dissolved in N,N-dimethylformamide (2 mL) at room temperature. The mixture was heated to 100° C. overnight. The reaction was cooled to room temperature, acidified to pH=4 with 0.2 M aqueous hydrochloric acid, poured into ethyl acetate and diluted with water. The organic layer was washed with brine and dried over sodium sulfate. Removal of solvents gave (R)-tert-butoxycarbonylamino-[4-((S)-2,2-dimethyl-[1,3]dioxolan4-ylmethoxy)-phenyl]-acetic acid as a foam (280 mg, 98%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7](#[N:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S([CH2:27][N+:28]#[C-])(C1C=CC(C)=CC=1)(=O)=O.[Cl-].[Na+]>O1CCCC1.C(Cl)(Cl)Cl>[C:10]1([C:9]2[C:8]([C:27]#[N:28])=[CH:7][NH:16][CH:1]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)[O-]
Reactant: N#CC=Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: N#Cc1c[nH]cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
To a suspension of 53.7 g (464 mmol) of potassium tert-butoxide in 500 ml of anhydrous tetrahydrofuran is added dropwise a mixture of 48.5 g (330 mmol) of the mixture of 50.0 g (387 mmol) of cinnamonitrile (CAS 1885-38-7) and 75.6 g (387 mmol) of tosylmethyl isocyanide (CAS 36635-61-7) dissolved in 500 ml of tetrahydrofuran, while maintaining the temperature of the reaction medium at about 25° C. The mixture is then stirred for 1 hour 30 minutes at room temperature and is then poured into saturated sodium chloride solution. The reaction product is then extracted with ethyl acetate, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give a brown solid, which is dissolved in 350 ml of hot chloroform and purified by chromatography on silica gel, eluting with dichloromethane, to give 44.3 g of 4-phenyl-1H-pyrrole-3-carbonitrile in the form of a beige-coloured powder after triturating in diisopropyl ether, filtering off and drying.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[C@@H:23](O)[CH2:22]2.O.N1(O)C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:9][C@@H:23]2[CH:24]3[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]3)[CH2:22]2)=[O:8])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: O=C(O)C(Nc1ccccc1)c1csc2ccccc12
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.1 %

Procedure:
2-(Benzo[b]thiophen-3-yl)-2-(phenylamino)acetic acid (I18) (295 mg, 1.04 mmol), (R)-quinuclidin-3-ol (159 mg, 1.25 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (191 mg, 1.25 mmol), and DCC (258 mg, 1.25 mmol) were dissolved in dry THF and stirred at room temperature for 15 hours. The solvent was evaporated, and the crude product was dissolved in EtOAc and washed with NaHCO3, water and brine. The organic phase was dried with Na2SO4, filtered and evaporated under vacuum. The crude product was purified by flash chromatography (DCM/MeOH=9/1) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(phenylamino)acetate (180 mg, 44% yield).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[CH:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22]>C(O)C>[C:1]([O:9][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[CH:25][O:26][CH3:27])[C:21]([O:23][CH3:24])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: O=C(O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC=C(C(=O)OC)c1ccccc1COC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
12.2 g (0.1 mole) of benzoic acid and 5.6 g (0.1 mole) of potassium hydroxide are dissolved in 150 ml of ethanol and the solution is stirred for 2 hours at room temperature (20° C.). The white precipitate which separates out is filtered off under suction, washed with diethyl ether and suspended in 300 ml of dimethylformamide. Thereafter, 28.5 g (0.1 mole) of methyl alpha-(2-bromomethylphenyl)-β-methoxyacrylate are added. The reaction mixture is then stirred for 24 hours at room temperature, after which it is evaporated down and the residue is taken up in methylene chloride. The organic phase is washed with water, dried over MgSO4 and evaporated down. The oil obtained is chromatographed over silica gel using 10:1 cyclohexane/ethyl acetate. 25.4 g (78%) of the title compound are obtained as a colorless, viscous oil (compound No. 83).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16]Cl)=[CH:9][C:8]1([CH3:20])[CH3:19])(=[O:3])[CH3:2].[C:21]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[OH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])O.[K+].[I-].[K+]>O.C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][N:32]2[CH2:33][CH2:34][CH:29]([C:27]([OH:28])([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][CH2:31]2)=[CH:9][C:8]1([CH3:20])[CH3:19])(=[O:3])[CH3:2]
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: CC(=O)OCCC1C=CC(C(=O)CCCCl)=CC1(C)C
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OCCC1C=CC(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)=CC1(C)C

Procedure:
Mix 4-(4-chloro-1-oxobutyl)-2,2-dimethylphenethyl acetate (99.5 g, 0.335 mol), α,α-diphenyl-4-piperidinemethanol (101.8 g, 0.335 mol), potassium hydrogen carbonate (83.8 g, 0.838 mol), potassium iodide (1.00 g, 0.006 mol), toluene (600 mL) and water (220 mL). Stir at reflux for 72 hours, add toluene (200 mL) and deionized water (100 mL). Filter through filter aid while at 80° C. and separate the organic phase. Dry (MgSO4), filter and purify by chromatography (ethyl acetate) to give 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-2,2-dimethylphenethyl acetate as an oily solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH:14]=[C:13]([C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:24][CH3:25])[N:16]=2)[CH:12]=[N:11]1.CI.[C:28]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:24]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:13]2[CH:12]=[N:11][N:10]([C:2]3[N:1]([CH3:28])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH:14]=2)=[N:16]1)[CH3:25]
Reactant: O=C([O-])[O-]
Reactant: CCn1nc(-c2cnn(-c3nc4ccccc4[nH]3)c2)c2ncccc21
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1nc(-c2cnn(-c3nc4ccccc4n3C)c2)c2ncccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.5 %

Procedure:
A mixture of 3-[(1-(1H-benzo[d]imidazol-2-yl)-1H-pyrazol-4-yl]-1-ethyl-1H-pyrazolo[4,3-b]pyridine (8 mg), MeI (2.278 μL) and Cs2CO3 (15.83 mg) in DMF (2 mL) was stirred at room temperature for 3 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). Crystallization from AcOEt/hexane gave the title compound (4.80 mg).
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[C:8](=[O:17])[CH2:7]1)=O.O[C:21]1[CH:22]=C(C=C[CH:28]=1)C=O.F[C:30](F)(F)[C:31](N[C@@H]1C2C(=CC=C(OC(C)C)C=2)[C@H](O)C1)=O>>[CH2:22]([O:17][C@H:8]1[C:9]2[C:14](=[CH:13][C:12]([O:15][CH2:16][CH2:30][CH3:31])=[CH:11][CH:10]=2)[C@@H:6]([NH2:5])[CH2:7]1)[CH:21]=[CH2:28]
Reactant: COc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)CC2=O
Reactant: CC(C)Oc1ccc2c(c1)[C@@H](NC(=O)C(F)(F)F)C[C@H]2O
Reactant: O=Cc1cccc(O)c1
Product: C=CCO[C@@H]1C[C@H](N)c2cc(OCCC)ccc21

Procedure:
Step AY (1). (1S,3R)-3-(Allyloxy)-6-propoxy-2,3-dihydro-1H-inden-1-amine was prepared from 3-hydroxybenzaldehyde using a series of procedures analogous to Steps AU (1-5), X (1) and U (2). 1H NMR (300 MHz, CDCl3) δ 0.9-1.0 (t, 3H) 1.6-1.8 (m, 2H) 2.6-2.8 (m, 1H) 3.8-3.9 (t, 2H) 4.0-4.2 (m, 3H) 4.7-4.8 (t, 1H) 5.1-5.4 (m, 2H) 5.8-6.0 (m, 1H) 6.7-6.9 (m, 2H) 7.2-7.3 (d, 1H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[C:24](Cl)=[N:25][CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)C(C)C)C.C(N(CCC)CCC)C>C(O)CCC>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([N:25]4[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH2:24]4)[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Fc1cccnc1Cl
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Agent: CCCN(CC)CCC
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: FC1=CC=CN(N2CCC(C3c4ccccc4C=Cc4ccccc43)CC2)C1
Reaction time: 24 h

Procedure:
0.50 gram (1.82 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine, 0.24 gram (1.82 millimoles) of 3-fluoro-2-chloropyridine, 0.47 gram (3.64 mole) of ethyl diisopropylamine and 10 milliliters of n-butanol were heated at reflux temperature protected from atmospheric moisture with a drying tube. After 19.25 hours heating, an additional 240 milligrams of the 3-fluoro-2-chloropyridine was added. After another 24 hours, 300 milligrams of ethyl dipropylamine was added and heating continued. After about 140 hours of refluxing, the mixture was concentrated, diluted with ether, washed successively with 10 percent aqueous sodium hydroxide and brine, dried, and the solvent vaporized to obtain a brown semi-solid residue. The residue was purified by chromatographing on silica gel with 7 percent ether in hexanes to obtain the 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(3-fluoro-1-pyridyl)piperidine product as a crystalline white solid, which after drying overnight in vacuo and 4 hours at 100° C. at 1 millimeter of mercury pressure had a melting point of 208°-210° C. Elemental analyses were as follows:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.[BH3-]C#N.[Na+].[CH3:19][C:20](OC(C)=O)=[O:21]>CC(O)=O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:20]([N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])(=[O:21])[CH3:19]
Reactant: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)N1c2cccc(C(F)(F)F)c2CC1C
Temperature: 0 °C
Reaction time: 14 h
Yield: 42.6 %

Procedure:
A mixture of 2-methyl-4-(trifluoromethyl)-1H-indole (Example 114D) (0.48 g, 2.41 mmol) was dissolved in HOAc (3.0 mL), cooled to 0° C. and NaBH3CN (0.454 g, 7.23 mmol) was added in one portion. After 5 min the mixture was removed from the cooling bath and stirred at rt for 14 h. The mixture cooled to 0° C. and the pH was adjusted to ca. 13 by addition of 1 N NaOH (20 mL) and further addition of solid NaOH pellets. The mixture was extracted with Et2O (×3), combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in dry CH2Cl2 (10 mL) and treated with DMAP (0.884 g, 7.23 mmol). The mixture was cooled to 0° C. and Ac2O (0.455 mL, 4.81 mmol) was added dropwise via syringe. The mixture was stirred overnight, slowly warming to rt, diluted with CH2Cl2, washed (10% HCl, H2O, brine), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 0.25 g of the title compound as a pale yellow oil: MS (ES) m/z 244 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:17][O:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])=[CH:21][CH:20]=1.Cl>ClCCCl>[OH:33][C:26]1([C:9]2[C:8]([OH:11])=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=2)[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:36][CH:35]=2)[C:25]1=[O:34]
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Reactant: Cc1noc2ccc(O)cc12
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: ClCCCl
Product: COc1ccc(CN2C(=O)C(O)(c3cc4onc(C)c4cc3O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.6 %

Procedure:
To a stirred solution of 3-methyl-1,2-benzisoxazol-5-ol (Lindemann, et al Justus Liebigs Annalen der Chemie 1927, 456:308) (3.10 g, 20.8 mmol) in 1,2-dichloroethane (200 mL) was added isopropylmagnesium chloride (10.4 mL, 2.0 M solution in tetrahydrofuran, 20.8 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and then at ambient temperature for 2 h. 1-(4-methoxybenzyl)-1H-indole-2,3-dione (5.3 g, 19.8 mmol) was added and the reaction mixture was stirred at reflux for 120 h. The mixture was cooled to 0° C. and 5% w/v hydrochloric acid was added. The organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluted with ethyl acetate/hexanes (1/1) to afford 3-hydroxy-3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (0.87 g, 10%): 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.01 (s, 1H), 7.37-6.76 (m, 10H), 4.83 (ABq, 2H), 3.70 (s, 3H), 2.46 (s, 3H); MS (ES+) m/z 415.0 (M−1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].O.Cl>CN(C)C=O.C(OCC)(=O)C>[S:12]1[CH:13]=[CH:14][C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:19]([CH2:20][CH3:21])[CH2:17][CH3:18])[CH:16]=[CH:15][C:11]1=2
Reactant: CCNCC
Reactant: ClCCCOCCc1ccc2sccc2c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOCCc1ccc2sccc2c1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
In 6 mL of N,N-dimethylformamide is dissolved 0.80 g of 5-[2-(3-chloropropyloxy)ethyl]benzo[b]-thiophene, to which is added 3.2 mL of diethylamine. The mixture is stirred in an ampoule at 100° C. for 10 hours. After cooling, the reaction mixture is introduced into a mixture of water and ethyl acetate, pH is adjusted to 1.0 with 6 mol/L hydrochloric acid, and the aqueous layer is separated. Ethyl acetate is added to the aqueous layer, pH is adjusted to 10.0 with 5 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=10:1 to 4:1). Thus, 0.48 g of N-[3-(2-benzo[b]thiophen-5-ylethoxy)propyl]-N,N-diethylamine is obtained as an oily product.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:16][CH2:17][CH2:18][OH:19])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:20]([Li])[CH2:21]CC.CS(Cl)(=O)=O.[NH:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CC(C)=O>[CH2:39]([O:38][C:36]([C@@H:32]1[CH2:33][CH2:34][CH2:35][N:30]([CH2:20][CH2:21][O:19][CH2:18][CH2:17][CH2:16][N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:31]1)=[O:37])[CH3:40]
Reactant: OCCCN1c2ccccc2CCc2ccccc21
Reactant: [Li]CCCC
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCCN(CCOCCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A solution of the above alcohol (0.60 g, 2.0 mmol) in dry THF (15 ml) was placed under an atmosphere of nitrogen and then cooled on an ice-bath. A solution of n-butyllithium in hexanes (0.88 ml, 2.5 M) was added dropwise at 10° C. When addition was complete the mixture was stirred at 10° C. for 30 minutes. Methanesulfonyl chloride (0.25 g, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 90 minutes. The volatiles were evaporated in vacuo leaving a residue which was dissolved in acetone (20 ml). Ethyl (R)-3-piperidinecarboxylate (0.50 g, 3.0 mmol) and potassium carbonate (0.7 g, 5 mmol) were added and the suspension was stirred at room temperature for 16 h and the heated at reflux temperature for 7 h. The cooled reaction mixture was filtered and the solvent was evaporated in vacuo. The oily residue was submitted to column chromatography on silica gel (150 g) using a mixture of ethyl acetate and n-heptane (2:3) as eluent. Collecting the proper fractions afforded 0.4 g of (R)-N-(2((3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]#[N:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li].[CH3:19]C(NC(C)C)C.IC>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:19])[C:16]#[N:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(CC#N)cc1OC1CCCC1
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(C(C)C#N)cc1OC1CCCC1
Temperature: -78 °C
Yield: 100 %

Procedure:
A mixture of 3-(cylcopentyloxy)-4-methoxybenzeneacetonitrile (20 g) in THF (200 ml) was stirred at -78° C. under a N2 flow. N-(1-methylethyl)-2-propanamine lithium salt (45 ml) was added dropwise and the resulting mixture was stirred for 30 minutes at -78° C. Iodomethane (13.5 g) was added dropwise and the resulting reaction mixture was allowed to warm to RT. The reaction mixture was stirred for 2 hours. The mixture was quenched with a saturated aqueous NH4Cl solution (200 ml) and was extracted with CH2Cl2 (3×φml). The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated, yielding 17.7 g (100%) of (±)-3-(cyclopentyloxy)-4-methoxy-α-methylbenzeneacetonitrile (interm. 8).