Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:3][N:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCCC3)c2c1
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), prepared as described in example 45, in DMF (25 ml) was stirred under dry N2 at room temperature, and dropwise added with pyrrolidine. The mixture was heated at 100° C. for 20 hours, then concentrated and partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a solid which was crystallised from ethyl acetate (25 ml) to give 0.77 g of the title compound (yield: 71%). m.p.: 170-172° C.
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:48])[C@H:11]([C@H:44]([CH2:46][CH3:47])[CH3:45])[NH:12][CH2:13][C@@H:14]([NH:36]C(OC(C)(C)C)=O)[CH2:15][S:16]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]([NH:9][C:10](=[O:48])[C@H:11]([C@H:44]([CH2:46][CH3:47])[CH3:45])[NH:12][CH2:13][C@@H:14]([NH2:36])[CH2:15][SH:16])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC[C@H](C)[C@H](NC[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC[C@@H](N)CS)C(=O)NCCc1ccccc1
Reaction time: 3 h
Yield: 44.2 %

Procedure:
The product of Step D (0.09 g, 0.14 mmol) was dissolved in 4 mL of 25% trifluoroacetic acid (TFA) in CH2Cl2 at ambient temperature, triethylsilane (0.089 mL, 0.56 mmol) was added and the solution was stirred for 3 h. The reaction mixture was concentrated and partitioned between EtOAc and aqueous saturated NaHCO3 solution. The organic layer was washed with brine and dried (Na2SO4). Filtration, concentration and trituration with hexane provided 0.02 g (44%) of the title compound, mp 69°-73° C.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][N:5](C2CCCCO2)[C:4](=[O:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:14])[CH:3]=1
Reactant: O=c1cc(I)cnn1C1CCCCO1
Reactant: Oc1ccccc1Cl
Product: O=c1cc(Oc2ccccc2Cl)cn[nH]1

Procedure:
In an analogous manner to the stepwise sequence outlined in Intermediate 18, starting from 5-iodo-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (Intermediate 18, step 2) and 2-chloro-phenol afforded 5-(2-chloro-phenoxy)-2H-pyridazin-3-one which was then reacted in an analogous manner to that outlined in the synthesis of Intermediate 19 (steps 4 and 5) alkylating with 2-bromo-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (Intermediate 14) to afforded 2-[4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid. This material was used crude without further purification in Example 135. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.38 (m, 3H), 1.45 (d, J=12.4 Hz, 1H), 1.60 (d, J=12.1 Hz, 1H), 1.88-2.00 (m, 1H), 2.04-2.17 (m, 1H), 3.09-3.25 (m, 2H), 3.74-3.85 (m, 2H), 5.42 (dd, J=10.8, 4.4 Hz, 1H), 5.73 (d, J=2.9 Hz, 1H), 7.36-7.47 (m, 1H), 7.47-7.55 (m, 2H), 7.71 (d, J=7.7 Hz, 1H), 8.21 (d, J=2.9 Hz, 1H), 13.10 (br. s., 1H).
Reaction SMILES: [I:1]I.[CH2:3]([N:7]([CH2:14][CH2:15][CH2:16][CH3:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH2:5][CH3:6].C([O-])(O)=O.[Na+].CCOCC>O>[I:1][C:11]1[CH:12]=[CH:13][C:8]([N:7]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH3:6])=[CH:9][CH:10]=1
Reactant: II
Reactant: CCCCN(CCCC)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCCCN(CCCC)c1ccc(I)cc1
Temperature: 12.5 °C
Yield: 70.7 %

Procedure:
Iodine (7.88 g, 31 mmol) was added portionwise to a mixture of N,N-dibutylaniline (7 g, 34 mmol) and NaHCO3 (2.87 g, 34 mmol) in water (25 mL) with stirring at 10-15° C. After 1 h the mixture was poured into Et2O (200 mL), washed with water (100 mL), Na2S2O3 (2×100 mL), water (2×100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexane as eluent. The first fraction was collected and the solvent removed under reduced pressure to give the title compound (7.26 g, 71%) as a pale brown oil.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C>[NH:8]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1
Reactant: N#Cc1ccc2[nH]cc(CC3CCN(Cc4ccccc4)C3)c2c1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc2[nH]cc(CC3CCNC3)c2c1

Procedure:
Hydrogenolysis of 0.32 mol (96 g) of 3-(1-benzyl-3-pyrrolidinylmethyl)-1H-indole-5-carbonitrile (described in Patent Application EP 610 134) is carried out in 1.7 liters of ethanol in the presence of 9.6 g of carbon containing 20% palladium hydroxide moist (Pearlman's catalyst) and 0.32 mol of hydrochloric acid in ethanol at 70° C. and at atmospheric pressure. After absorption of the theoretical amount of hydrogen, the catalyst is filtered off and the filtrate is then concentrated. The base is precipitated out by 1N sodium hydroxide solution and extracted using dichloromethane to yield the expected product.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([NH2:18])(=[O:17])=[O:16].S([O-])(O)(=O)=O.[Na+]>CN(C)C=O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([N:18]=[CH:3][N:4]([CH3:6])[CH3:5])(=[O:17])=[O:16]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)CCCCCCl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C=NS(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.29 ml of N,N-dimethylformamide-dimethyl acetal were added dropwise at ambient temperature under an inert gas atmosphere to a solution of 1.5 g of the product of Step A in 8 ml of dimethyl-formamide. The solution was stirred at ambient temperature for 3 hours, then poured into a 1% aqueous solution of sodium hydrogen sulfate, extracted with ethyl acetate, washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 1.809 g of the expected product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][C:6](=O)[C:5]=2[C:4]([CH3:18])=[CH:3]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:6]1[CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:10]2[N:2]([CH3:1])[CH:3]=[C:4]([CH3:18])[C:5]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: N=C(N)NN
Reactant: Cc1cn(C)c2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cn(C)c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 23.3 %

Procedure:
A mixture of 1,3-dimethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.31 g), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.065 ml), water (0.065 ml) and ethanol (50 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the mixture was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid. The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-1,3-dimethyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 8) (0.1 g) as colorless crystals.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:35])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([C@H:21]3[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:23][CH2:22]3)=[O:20])=[CH:14][C:13]=2[Cl:34])=[CH:6][CH:5]=1)=[O:3].[Cl:36][C:37]1[CH:38]=[C:39]([OH:46])[CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44]>C1C=CC=CC=1.N1C=CC=CC=1>[Cl:36][C:37]1[CH:38]=[C:39]([CH:40]=[CH:41][C:42]=1[N+:43]([O-:45])=[O:44])[O:46][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:35])[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([C@H:21]3[CH2:22][CH2:23][C@H:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][CH2:26]3)=[O:20])=[CH:14][C:13]=2[Cl:34])=[CH:8][CH:9]=1)=[O:3]
Reactant: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C(=O)Cl)cc3)c(Cl)c2)CC1
Reactant: O=[N+]([O-])c1ccc(O)cc1Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(C(=O)Oc3ccc(C(=O)Oc4ccc([N+](=O)[O-])c(Cl)c4)cc3)c(Cl)c2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
The crude 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-(chlorocarbonyl)phenyl ester obtained was dissolved in 70 ml of benzene and then added dropwise to a solution of 1.04 g of 3-chloro-4-nitrophenol in 50 ml of pyridine. The reaction mixture was stirred overnight at a bath temperature of 65° C., then poured into ice-cold dilute hydrochloric acid and extracted with diethyl ether. The extract was washed four times with 50 ml of 3N hydrochloric acid each time and once with 50 ml of 2N sodium carbonate solution, washed neutral with water, dried and concentrated. The crude 2-chloro-4-[[(trans-4-heptylcyclohexyl)carbonyl]oxy]benzoic acid p-[(3-chloro-4-nitrophenoxy)carbonyl]phenyl ester (3.2 g) obtained was chromatographed on silica gel with hexane/dioxan (volume ratio 3:1). The fractions which were pure according to thin-layer chromatography (1.8 g) were recrystallized twice from ethyl acetate; m.p. (C-N) 138° C., cl.p. (N-I) 237.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][C:16]([NH2:19])([CH3:18])[CH3:17].CCN(C(C)C)C(C)C>C(O)C>[C:16]([NH:19][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:18])([CH3:17])[CH3:15]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CC(C)(C)N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1NC(C)(C)C
Temperature: 60 °C
Yield: 92 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3 g, 12.89 mmol), 2-methylpropan-2-amine (1.565 mL, 14.83 mmol) and DIEA (2.93 mL, 16.76 mmol) in ethanol (20 mL) was heated at 60° C. overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure and water was added. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over anhydrous magnesium sulfate, filtered and evaporated to give ethyl 4-(tert-butylamino)-2-(methylthio)pyrimidine-5-carboxylate (3.20 g, 11.86 mmol, 92% yield) as a colorless oil. MS (ESI) m/z. 269.5 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>ClCCl.CO>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: CC(C)N=C=O
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Solvent: CO
Solvent: ClCCl
Product: CC(C)NC(=O)NCc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.060 g, 0.192 mmol) in dichloromethane (3 mL) is added isopropyl isocyanate (0.027 g, 0.240 mmol) and the reaction is stirred at room temperature for 45 min. The mixture is then washed with water and extracted with dichloromethane twice. The organic phase is concentrated in vacuo to give a residue which is redissolved in methanol. A precipitate crashes out upon standing. The solid is filtered to afford 1-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-3-isopropyl-urea as a solid. 1H NMR (400 MHz, MeOD) δ ppm 1.17 (d, J=6.6 Hz, 6H), 3.76-3.91 (m, 4H), 4.52 (s, 2H), 7.38 (dd, J=8.5, 1.9 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.08 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 382.1431 [(M+H)+ Calcd for C20H21N5OCl: 382.1435].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[C:38]([O:39][CH3:40])=[CH:37][C:28]2[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][OH:36])[CH2:32][CH2:33][C:27]=2[CH:26]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N:7][C:2]([NH:24][C:25]2[C:38]([O:39][CH3:40])=[CH:37][C:28]3[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][OH:36])[CH2:32][CH2:33][C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CCCC3)n1)CCN(CCO)CC2
Yield: 43 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(pyrrolidine-1-sulfonyl)-phenyl]-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol. The product was isolated as a light yellow foam (40 mg, 43%). mp: 110° C., MS (ESI+): 573 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.44 (s, 1H), 8.55 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 7.52 (s, 1H), 7.26 (m, 1H), 6.67 (s, 1H), 3.89 (s, 3H), 3.66 (t, 2H), 3.28 (t, J=5 Hz, 4H), 2.89 (t, 2H), 2.74-2.69 (m, 8H), 1.80 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:46][N:47]([CH3:49])[NH2:48].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14]([NH:48][N:47]([CH3:49])[CH3:46])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Reactant: CN(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a solution of 4-benzylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester (0.75 g, 2.35 mmol) (prepared as in Gilligan et al J. Med. Chem. 1994, 364-370) in methylene chloride (10 ml) was added 1-hydroxy-7-azabenzotriazole (0.32 mg, 2.35 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.45 g, 2.35 mmol) and the mixture was stirred for 30 min. Then N′,N′-dimethylhydrazine (0.27 ml, 3.53 mmol) and diisopropylethylamine (0.52 ml, 3.06 mmol) was added and the mixture was stirred for 2 days. Methylene chloride (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The obtained oil was chromatographed on silica (40 g) with heptane/ethyl acetate (1:2) to give 0.76 g of 4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [H-].[Na+].[N:3]1([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2=[O:18])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[F:19][C:20]1[CH:25]=[C:24]([CH2:26]Cl)[CH:23]=[CH:22][N:21]=1>O1CCCC1>[F:19][C:20]1[CH:25]=[C:24]([CH2:26][C:11]2([CH2:26][C:24]3[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][CH2:8]3)[C:10]2=[O:18])[CH:23]=[CH:22][N:21]=1
Reactant: O=C1Cc2ccccc2N1N1CCOCC1
Reactant: Fc1cc(CCl)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N(N2CCOCC2)c2ccccc2C1(Cc1ccnc(F)c1)Cc1ccnc(F)c1
Temperature: 0 °C

Procedure:
Sodium hydride (60% oil dispension 92 mg, 2.3 mmole) was charged to a flame-dried flask and washed with pentane (3×3 ml). The flask was flushed with nitrogen, tetrahydrofuran (10 ml) was added and the slurry was stirred at 0° C. 1,3-dihydro-1-(4-morpholinyl)-2H-indol-2-one (225 mg, 1.0 mmole) was added, the resulting solution was stirred for 15 minutes at room temperature and recooled to 0° C. A solution of 2-Fluoro-4-picolyl chloride (410 mg, 2.3 mmole) in tetrahydrofuran (10 ml) was added and the solution allowed to stir at room temperature overnight. The reaction was quenched into water (40 ml) and extracted with dichloromethane(3×25 ml). The combined organics were washed with brine, dried over magnesium sulfate, filter and concentrated under reduced pressure. The residue was chromatographed on silica gel or directly recrystallized from chloroform/hexane to give the desired product; m.p. 198°-203° C. Anal. (C24H22F2N4O2.0.25H2O): C,H,N,F.
Reaction SMILES: [OH:1][CH:2]([CH:21]1[CH2:25][O:24]C(C)(C)[O:22]1)[CH2:3][NH:4][C:5](=[O:20])[CH2:6][S:7](=[O:19])(=[O:18])[NH:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[F:17]>CO.O>[OH:1][CH:2]([CH:21]([OH:22])[CH2:25][OH:24])[CH2:3][NH:4][C:5](=[O:20])[CH2:6][S:7](=[O:18])(=[O:19])[NH:8][C:9]1[C:10]([F:17])=[CH:11][C:12]([F:16])=[CH:13][C:14]=1[F:15]
Reactant: CC1(C)OCC(C(O)CNC(=O)CS(=O)(=O)Nc2c(F)cc(F)cc2F)O1
Solvent: CO
Solvent: O
Product: O=C(CS(=O)(=O)Nc1c(F)cc(F)cc1F)NCC(O)C(O)CO

Procedure:
2.22 g (6 mmol) of 2-[N-(2,4,6-trifluorophenyl)sulfamoyl]-acetic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethyl-amide] is dissolved in a mixture of 10 ml of methanol and 5 ml of water, about 100 mg of cation exchanger Amberlyst 15 is added and it is warmed to boiling temperature in 1 hour. The ion exchanger is then filtered off and the filtrate is evaporated to dryness in a vacuum. 1.94 g (5.24 mmol) =87.3% of the theoretical yield of the product is obtained as an amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C-:15]#[N:16].[Na+].C([O-])(O)=O.[Na+]>C(OCC)C.O>[C:15]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)#[N:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [C-]#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(C#N)CC1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To a suspension of tert-butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol) in diethyl ether (40 mL), a solution of NaCN (0.54 g, 11 mmol) and NaHCO3 (1.7 g, 20 mmol) in water (25 mL) was added slowly with vigorous stirring at room temperature. The mixture was stirred overnight, and extracted with Et2O (30 mL×2). The organic phase was washed with water (50 mL), brine (50 mL) and dried over MgSO4, filtered and evaporated gave 2.1 g of the title compound as clear colorless oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH2:12][C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=32)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][CH3:26]>>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]([CH2:23][CH2:24][CH2:25][CH3:26])[C:13]3[C:17]=2[N:16]=[C:15]2[CH2:18][CH2:19][CH2:20][CH2:21][C:14]=32)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCBr
Reactant: C1=CC(OCc2ccccc2)=C2N=C3CCCCC3=C2C1
Product: CCCCC1C=CC(OCc2ccccc2)=C2N=C3CCCCC3=C21
Yield: 88.2 %

Procedure:
Using the procedure of Example 9, the alkylation of 5.0 g. of 1,2,3,4-tetrahydro-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole from Example 56 was reacted with 1-bromobutane (2.68 g) to give 5.3 g (88.2%) of 1,2,3,4-tetrahydro-6-phenylmethoxy-9-butyl-9H-dibenzo[b,d]pyrrole as a yellow oil after chromatographic purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11](=[O:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C:11](=[O:13])[N:10]([CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)CCl
Reactant: O=C1CC(c2ccc(Cl)cc2)=NN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)CN1N=C(c2ccc(Cl)cc2)CC1=O
Yield: 104.6 %

Procedure:
A mixture of 3.5 g (16 mmol) of 3-(4-chlorophenyl)-4, 5-dihydropyrazol-5-one, 2.9 g (24 mmol) of chloropinacolone, 5.4 g (39 mmol) of anhydrous potassium carbonate and acetonitrile was heated under reflux for 14 hours. Excess potassium carbonate and the formed salts were removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1 (v/v)) to give 4.9 g of the object compound as white crystals (yield 97%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:12]([C:19]#[N:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[C:13]1([CH:12]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[C:19]#[N:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: N#CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC(c1ccccc1)c1ccc2ccccc2n1

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 12A, using 2-chloroquinoline (5.0 g, 30.6 mmol), benzyl cyanide (3.5 ml, 30.6 mmol) and potassium t-butoxide (6.87 g, 61.2 mmol) in 40 ml of DMF.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[H-].[Na+].Cl.Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>CN(C=O)C>[O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(Cc2cccnc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (230 mg, 1.01 mmol) in DMF (1 mL) was added sodium hydride (129 mg, 3.22 mmol) at rt under argon. The reaction mixture was stirred at rt for 10 min followed by the addition of 3-(chloromethyl)pyridine hydrochloride (197 mg, 1.54 mmol) at rt. The reaction was allowed to stir at rt for an additional 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-80% EtOAc/Hex to give (S)-tert-butyl 2-oxo-1-(pyridin-3-ylmethyl)azepan-3-ylcarbamate (155 mg, 0.485 mmol, 48.2% yield) as colorless oil. Anal. Calcd. for C17H25N3O3 m/z 319.4. found: 320.2 (M+H)+.