Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH:12]([O:13]C2CCCCO2)[CH2:11][CH:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]1[CH2:31][CH2:32][CH:33]([O:39]C1CCCCO1)[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].Cl>C(O)C>[OH:7][CH:8]1[CH:12]([OH:13])[CH2:11][CH:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]1[CH2:31][CH2:32][CH:33]([OH:39])[CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCC(CCC1C(CCCCCCC(=O)OCC)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Agent: Cl
Solvent: CCO
Product: CCCCCC(O)CCC1C(CCCCCCC(=O)OCC)CC(O)C1O
Reaction time: 18 h
Yield: 96.2 %

Procedure:
A mixture of ethyl 7-{3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentyl}heptanoate (5.5 g.) [prepared as described in (o) above], ethanol (100 ml.), N hydrochloric acid (100 ml.) and a cation-exchange resin [Dowex resin AG50W - X8H+ (7.5 g.)] was stirred at 50°-60° C. for 18 hours. The mixture was then cooled and filtered and the solid washed with diethyl ether and water. The combined filtrate and washings were evaporated in vacuo to remove organic solvents and the aqueous residue extracted with diethyl ether. The ethereal extract was dried over anhydrous sodium carbonate and evaporated in vacuo to give ethyl 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)cyclopentyl]heptanoate (3.2 g.), which was used as starting material in the following preparation (q) of 7-[3,4-dihydroxy-2-(3-hydroxyoctyl)-cyclopentyl]heptanoic acid without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([O:34][CH2:35][C:36]([O:38]CC)=[O:37])[CH:22]=2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([O:34][CH2:35][C:36]([OH:38])=[O:37])[CH:22]=2)=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)COc1ccc(CCNC(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)cc1OCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)NCCc2ccc(OCC(=O)O)c(OCC(=O)O)c2)CC1
Yield: 89.6 %

Procedure:
The compound obtained in the above process (a) (150 mg) was hydrolyzed with 1.3 ml of 1N sodium hydroxide to give 121 mg of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.[CH:18]([C:21]1([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:23][O:22]1)([CH3:20])[CH3:19]>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:23][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([OH:22])[CH:18]([CH3:20])[CH3:19])[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: CC(C)C1(c2ccncc2)CO1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of sodium hydride (0.261 g, 50-60%) in dry DMF (5 mL) at 0° C. was added 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (0.3 g). The reaction mixture was stirred at RT for 30 min. To the reaction mixture was added 4-(2-isopropyloxiran-2-yl)pyridine (0.288 g in 2 mL DMF) at RT. After 12 h stirring, the reaction mixture was diluted with ice-water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was triturated with diethyl ether to obtain pure product, 90 mg). 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.30 (d, 2H), 7.30 (m, 3H), 7.10 (d, 1H), 6.82 (d, 1H), 4.50 (m, 2H), 4.22 (m, 2H), 3.42 (m, 1H), 3.30 (m, 2H), 2.80 (s, 3H), 2.62 (m, 1H), 1.78 (m, 1H), 1.15 (d, 3H), 0.6 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[OH:9])[O:5][C:6]=1[CH3:7]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:9])[O:5][C:6]=1[CH3:7]
Reactant: Cc1cccnc1C(O)c1cc(C)c(C)o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1cccnc1C(=O)c1cc(C)c(C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(3-methylpyridin-2-yl)-methanol (1.17 g) was dissolved in chloroform (30 ml) to prepare a solution. Manganese dioxide (4.69 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through Celite, and the solvent was removed from the filtrate by distillation under the reduced pressure to give (4,5-dimethylfuran-2-yl)-(3-methylpyridin-2-yl)-methanone (940 mg, yield 81%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([CH2:22][N:23]([CH3:24])[CH3:25])[CH2:20][CH2:21]2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@@H](CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{cis-4-[(dimethylamino)methyl]-cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (120 mg, 0.30 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (100 mg, 0.30 mmol) followed by formation of the dihydrochloride salt to afford the desired product (150 mg, 81%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.17 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.34 (d, J=8.9 Hz, 1H), 8.11 (s, 2H), 5.92 (p, J=4.4 Hz, 1H), 3.21 (d, J=7.2 Hz, 2H), 2.96 (s, 6H), 2.78 (s, 3H), 2.25-2.05 (m, 3H), 1.99-1.88 (m, 2H), 1.62 (dtd, J=14.1, 11.2, 10.8, 3.7 Hz, 3H), 1.20 (s, 1H); ESI MS m/z 487 [M+H]+; HPLC 96.5% (AUC), tR=9.9 min.
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([O:23]COC)=[N:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:27]>CO>[ClH:27].[C:1]([C:5]1[O:6][CH:7]=[C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([OH:23])=[N:14][N:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1nn(-c2ccccc2)cc1/C=C/c1coc(C(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2-tert-butyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-oxazole (2.15 g) in methanol (25 mL) was added concentrated hydrochloric acid (1.00 mL) at room temperature, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was evaporated under reduced pressure, and the residue was washed with diethyl ether to give 4-[(E)-2-(2-tert-butyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol-hydrochloride (1.74 g, yield 83%) as orange crystals. melting point: 220-221° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[CH3:27][N:28]1[C:32](=[O:33])[CH2:31][C:30]([CH3:34])=[N:29]1.CC(C)(O)C#N>C(Cl)(=O)C(Cl)=O.CN(C)C=O>[OH:33][C:32]1[N:28]([CH3:27])[N:29]=[C:30]([CH3:34])[C:31]=1[C:9]([C:8]1[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:12]=1)=[O:11]
Reactant: CC1=NN(C)C(=O)C1
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)c1c(C)nn(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
1.0 g (0.004 mol) of 2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinic acid is dissolved in 10 ml of oxalyl chloride. Three drops of dimethylformamide are added, and the mixture is stirred at room temperature for 1 hour. The mixture is then concentrated using a rotary evaporator, and the residue (2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinoyl chloride) is taken up in 10 ml of methylene chloride. At a temperature of 0° C., 0.84 ml (0.006 mol) of triethylamine and 0.45 g (0.004 mol) of 2,5-dimethyl-2,4-dihydropyrazol-3-one are added. After 2 hours at a temperature of 22° C., the solvent is removed using a vacuum rotary evaporator, and the residue that remains is dissolved in 10 ml of acetonitrile and, to rearrange the intermediate (2,5-dimethyl-2H-pyrazol-3-yl 2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinate), admixed with 0.1 ml of acetone cyanohydrin and 1.13 ml (0.008 mol) of triethylamine. The reaction solution is stirred at room temperature for four hours and then concentrated. The syrup that remains is chromatographed on silica gel. The viscous oil obtained by eluting with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 parts by volume) is dissolved in ethyl acetate and washed successively with 10% hydrochloric acid and water. The organic solution is dried over Na2SO4 and concentrated, giving 0.93 g of (5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)-[2-(2-methoxyethoxymethyl)-6-trifluoromethylpyridin-3-yl]methanone in the form of a viscous oil. 1H NMR (300 MHz, CDCl3, 8 in ppm): 7.81, (d, J=6 Hz), 1H, 7.74, (d, J=6 Hz), 1H, 4.84, (s), 2H; 2H, 3.71, (s), 3H, 3.59, (t, J=6 Hz) 2H, 3.38, (dd, J 4.0, 3.0 Hz), 1H, 3.26, (s), 3H, 1.82 ppm, (s), 1H.
Reaction SMILES: FC1C=CC(CNC)=CC=1.[CH3:11][NH:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[F:20][C:21]1[CH:43]=[CH:42][C:24]([CH2:25][NH:26][C:27]([C:29]2[S:33][C:32]([C:34]3[CH:39]=[N:38][CH:37]=[C:36](I)[N:35]=3)=[N:31][C:30]=2[CH3:41])=[O:28])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:43]=[CH:42][C:24]([CH2:25][NH:26][C:27]([C:29]2[S:33][C:32]([C:34]3[CH:39]=[N:38][CH:37]=[C:36]([N:12]([CH3:11])[CH2:13][C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[N:35]=3)=[N:31][C:30]=2[CH3:41])=[O:28])=[CH:23][CH:22]=1
Reactant: CNCc1cccnc1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Agent: CNCc1ccc(F)cc1
Product: Cc1nc(-c2cncc(N(C)Cc3cccnc3)n2)sc1C(=O)NCc1ccc(F)cc1
Yield: 78 %

Procedure:
Following the procedure described in Example 14, making variations as required to replace 4-fluoro-N-methyl-benzylamine with methyl-pyridin-3-ylmethyl-amine to react with 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro benzylamide, the title compound was obtained in 78% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.58-8.65 (m, 2H), 8.45-8.49 (m, 1H), 8.11 (s, 1H), 7.62-7.68 (m, 1H), 7.29-7.37 (m, 2H), 7.22-7.28 (m, 1H), 6.98-7.08 (m, 2H), 6.35 (bs, 1H), 4.84 (s, 2H), 4.54 (d, J=8.0 Hz, 2H), 3.18 (s, 3H), 2.69 (s, 3H); MS (ES+) m/z 449.2 (M+1), Rt=1.32 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:14](O)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 59.5 g. of 3,4-dichlorophenylacetic acid in 500 ml. of absolute ethanol is saturated with anhydrous hydrogen chloride and then heated at reflux for 2 hours. The mixture is concentrated under reduced pressure to 200 ml., diluted with 200 ml. of water and neutralized with concentrated ammonium hydroxide. This aqueous mixture is extracted 3 times with chloroform. Concentration and decolorization of the chloroform extracts gives ethyl 3,4-dichlorophenylacetate as a yellow oil.
Reaction SMILES: [Cl:1][Si:2]([Cl:5])(Cl)[Cl:3].[CH3:6][C:7]([Li])([CH3:10])[CH2:8][CH3:9]>C(OCC)C>[CH3:6][C:7]([Si:2]([Cl:5])([Cl:3])[Cl:1])([CH3:10])[CH2:8][CH3:9]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: [Li]C(C)(C)CC
Solvent: CCOCC
Product: CCC(C)(C)[Si](Cl)(Cl)Cl
Reaction time: 1 h
Yield: 35 %

Procedure:
A two-liter four-necked flask equipped with a stirrer, a reflux cooling tube and a dropping funnel was charged in a nitrogen atmosphere with 85 grams (0.5 mol) of tetrachlorosilane and 500 ml of diethylether and then added with the droplets of 500 ml of 1,1-dimethylpropyllithium (1.0 M diethylether solution) as being stirred and cooled with ice over 2 hours. After completion of the addition, stirring was continued for another one hour at room temperature. The resulting mixture was filtered out in a nitrogen atmosphere and then purified by distillation thereby obtaining 36 grams (yield : 35%) of 1,1-dimethylpropyltrichlorosilane.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=O)[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=O)[CH3:18])[O:8][CH:7]=[CH:6]1)(=O)[CH3:2].C[O-].[Na+].[H-].[Na+].[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=CC=1>CO>[CH2:1]([O:4][C@H:5]1[C@H:10]([O:11][CH2:12][C:13]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)[C@@H:9]([CH2:15][O:16][CH2:17][C:18]2[CH:31]=[CH:28][CH:29]=[CH:30][CH:25]=2)[O:8][CH:7]=[CH:6]1)[C:2]1[CH:31]=[CH:28][CH:29]=[CH:30][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: C1=C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
3,4,6-Tri-O-acetyl-D-glucal (5.0 g, 18.4 mmol) was dissolved in methanol (100 mL) and a solution of sodium methoxide in methanol (0.25 mL, 25% solution by weight, 1.1 mmol). The solution was stirred at room temperature for 3 hours. The solvent was removed and the resulting residue was co-evaporated with toluene (3×10 mL) before being taken up in a 4:1 solution of NMP:THF and cooled to 0° C. Solid NaH (3.3 g of 60% suspension, 82.5 mmol) was added and the mixture was stirred for 30 minutes before the addition of BnBr. The reaction mixture was stirred at room temperature overnight, quenched with methanol and the solvent removed. The residue was suspended in ethyl acetate, washed with 1 N HCl, brine, and saturated NaHCO3 (100 mL each). The ethyl acetate solution was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified on a silica gel column (80 g) using an ISCO automated chromatography system, eluting with a 0→50% gradient of ethyl acetate in heptane, to give 3,4,6-tri-O-benzyl-D-glucal (7.2 g, 94%).
Reaction SMILES: [N-]=[N+]=[N-].[Na+].C(O)(=O)C.[N:9]1([C:18](=[NH:33])[N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]2)C2C=CC=CC=2[N:11]=[N:10]1>C(Cl)(Cl)Cl>[NH:33]1[C:18]([N:19]2[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]2)=[N:9][N:10]=[N:11]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=N)n2nnc3ccccc32)CC1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1CCN(c2nnn[nH]2)CC1
Temperature: 25 °C
Reaction time: 25 h
Yield: 99.5 %

Procedure:
Sodium azide (2.00 g, 30.7 mmol) and acetic acid (1.70 ml, 30.7 mmol) were added to a chloroform (300 ml) solution of the compound (10.6 g, 30.7 mmol) obtained in Step 1 above and the resulting mixture was stirred at room temperature for 25 hours. Insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography [chloroform:methanol=30:1→10:1 (v/v)] to give 8.20 g (94%) of the title compound as a solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:33]=[CH:32][C:15]([O:16][CH2:17][CH:18]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:14][CH:13]=1>C(Cl)Cl>[F:11][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH:18]([O:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[O:24])=[CH:32][CH:33]=1
Reactant: COCCOCOC(CCCCCO)COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COCCOCOC(CCCCC=O)COc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Oxalyl chloride (2.9 ml, 33.6 mmol) is added to 25 ml of methylene chloride and cooled to −78° C. Dry dimethyl sulfoxide (4.7 ml, 67.2 mmol) is then added and the reaction is stirred at −78° C. After 45 minutes, (±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)-heptan-1-ol 44 (3.7 g, 11.2 mmol) dissolved in CH2Cl2 is added and the reaction is stirred at −78° C. After 1 hour, the reaction is quenched with 15.7 ml of triethylamine and diluted with CH2Cl2. The reaction mixture is then washed with water, brine dried (Na2SO4) and concentrated. The crude product is purified on silica gel (ethyl acetate:hexane 1:9) to give (±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)-heptan-1-al 45, 3.3 g, 89%.
Reaction SMILES: O[C:2]1([C:29]([F:32])([F:31])[F:30])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[C:8]2[CH2:19][NH:20][CH:21]([C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:22][N:6]3[C:7]2=[C:3]1[CH:4]=[CH:5]3.O=S(Cl)Cl>N1C=CC=CC=1>[CH:26]([NH:25][C:23]([CH:21]1[NH:20][CH2:19][C:8]2=[C:7]3[C:3](=[C:2]([C:29]([F:31])([F:32])[F:30])[C:10]([CH2:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:9]2)[CH:4]=[CH:5][N:6]3[CH2:22]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)NC(=O)C1Cn2ccc3c2C(=CC(CCc2ccccc2)C3(O)C(F)(F)F)CN1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Yield: 88.7 %

Procedure:
The 7-hydroxy-N-isopropyl-6-phenethyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (9 mg, 0.021 mmol) was further processed with SOCl2 and pyridine as described in Example 1, above to yield N-isopropyl-6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (8 mg).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=O.C(O)(=O)CC(O)=O.C([K])C.C(OCC)(=O)C.CCCCCC>C(O)C.N1C=CC=CC=1.C(O)(=O)C>[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:4]=[CH:2]1
Reactant: O=C1Nc2ccccc2C1=O
Agent: CC[K]
Agent: O=C(O)CC(=O)O
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: c1ccc2[nH]ccc2c1
Temperature: 10 °C

Procedure:
The corresponding isatin 1a-1d (10 mmol) was dissolved in a mixture of ethanol/pyridine/acetic acid (50 ml, 15:5:2), ethyl potassium malonate (1.87 g, 11 mmol) was added and the mixture was heated under reflux in accordance with the times stated in the table. The course of the reaction was monitored by means of TLC (eluent: ethyl acetate/hexane 1:1). For working up, the solvent mixture was distilled off in vacuo. The residue was taken up in ethyl acetate (50 ml) and the mixture was extracted by shaking with water (50 ml). After separation of the phases, the aqueous phase was extracted twice with ethyl acetate (30 ml each time). The combined organic phases were washed with 2N HCl (50 ml), dried over Na2SO4 and concentrated to 20 ml in vacuo. Hexane was added to the solution until crystallization of the corresponding 3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetic acid ethyl ester (2a-2d) started. To bring the crystallization to completion, the mixture was cooled to 10° C. for 12 h. The solid was filtered off with suction and dried in vacuo.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]2)(=[O:9])[CH3:8].[N:22](OCCCC)=[O:23].Cl>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:7]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[C:19](=[O:21])[C:18](=[N:22][OH:23])[CH2:17][CH2:16]2)(=[O:9])[CH3:8]
Reactant: CCCCON=O
Reactant: CC(=O)Nc1cccc2c1C(=O)CCC2
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Nc1cccc2c1C(=O)C(=NO)CC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a reaction solution obtained by suspending 316 mg of potassium tert-butoxide in 18 ml of tetrahydrofuran (hereinafter abbreviated as THF) and cooling the suspension to 0° C. under a nitrogen stream was added a solution of 500 mg of the compound prepared in (1) above in 2 ml of THF, a bit at a time. After stirring for 10 minutes at the same temperature and an addition of 0.35 ml of butyl nitrite, the mixture was heated at 50° C. for 1 hour while stirring. Precipitates obtained by the addition of diethyl ether to the reaction mixture were collected by filtration. The powder thus obtained was suspended into a 10% aqueous solution of hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The residue obtained by the concentration of the solvent was subjected to silica gel column chromatography using an ethyl acetate-hexane (1:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 320 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[Cl:1])=[O:8])=[CH:16][C:15]=1[C:21]([F:22])([F:23])[F:24]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C=NC(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1ccccc1Cl)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 18.2 g (0.1 mole) of 2-chlorobenzoylisocyanate in 50 ml of toluene was added dropwise at 40° C to 19.5 g (0.1 mole) of 4-chloro-3-trifluoromethylaniline in 200 ml of toluene. The batch was stirred for 1 hour at 40° C. After cooling, the product which had precipitated was filtered off and washed first with toluene and then with petroleum ether. After drying, 21.0 g (55% of theory) of analytically pure N-(4-chloro-3-trifluoromethylphenyl)-N'-(2-chlorobenzoyl)-urea of melting point 164° C were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)(=[O:10])=[O:9].Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccccc2F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1F)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-((2-fluorophenyl)sulfonyl)piperidine-1-carboxylate (1.31 g, 3.82 mmol) in dioxane (12.7 mL) at room temperature was treated with 4M HCl in dioxane (9.55 ml, 38.2 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting white solid was triturated with hexanes, filtered, collected, and lyophilized overnight to give the title compound, as its HCl salt, as a white solid (815.1 mg, 76%). ESI-MS m/z [M+H]+243.95.