Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[O:17]1[CH2:19][CH:18]1[CH2:20]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[CH:34]1([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[ClH:46]>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH2:19][CH:18]([OH:17])[CH2:20][N:43]3[CH2:44][CH2:45][N:40]([CH:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:41][CH2:42]3)[C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[ClH:46]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OCC2CO2)c1
Reactant: Clc1ccc2[nH]c3ccccc3c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(CN1CCN(C2CCCCC2)CC1)Cn1c2ccccc2c2cc(Cl)ccc21
Temperature: 60 °C
Reaction time: 15 h

Procedure:
A solution of NaH (0.026 g, 0.60 mmol, 55% in mineral oil) is added into a solution of 3-chloro-9H-carbazole (0.100 g, 0.50 mmol) in anhydrous THF (5 mL). After 30 min of stirring at rt a solution of (±)-3-nitro-benzenesulfonic acid oxiranylmethyl ester in anhydrous THF (0.5 mL) is added. After 90 min of stirring at rt a solution of 1-cyclohexyl piperazine (0.25 g, 1.50 mmol) in anhydrous THF (1 mL) is then added. The resulting mixture is allowed to stir at 60° C. for 15 hours. The reaction mixture is quenched with brine (15 mL) and extracted with Et2O (50 mL+2×25 mL). After drying over MgSO4, evaporation under reduced pressure, the crude compound is purified via flash chromatography on a 3×24 cm2 SiO2 column using EtOAc/MeOH (8/1) and (4/1) as eluant. A solution of the purified above compound (0.088 g, 0.21 mmol, 41%) is treated with HCl (1M in Et2O) to give the title compound hydrochloride (0.085 g, 0.17 mmol) as a white powder in a 34% yield.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33]>>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:14][CH2:13][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:28])[NH:33][CH2:32][CH2:31][O:30][CH3:29])=[CH:5][N:6]=3)=[O:11])[CH2:17][CH2:16]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: COCCN
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Product: COCCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)nc1
Yield: 73 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 2-methoxyethylamine. And then, the product was recrystallized with methylene chloride and hexane to give a desired compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].C([N:15]1[CH2:19][CH2:18][C@H:17]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16]1)C1C=CC=CC=1.CO.O>CCCCCCC>[CH2:5]([O:4][C:2]([N:15]1[CH2:19][CH2:18][CH:17]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16]1)=[O:3])[CH:6]=[CH2:7]
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1
Reactant: C=CCOC(=O)Cl
Solvent: CO
Solvent: O
Solvent: CCCCCCC
Product: C=CCOC(=O)N1CCC(OS(C)(=O)=O)C1
Reaction time: 0.75 h

Procedure:
6.4 ml of allyl chloroformate were added dropwise to 10.2 g of methanesulphonic acid (S)-1-benzyl-pyrrolidin-3-yl ester in 880 ml of n-heptane at room temperature within 10 minutes under argon and with slight cooling. The two-phase mixture was stirred vigorously for 2 hours 45 minutes and subsequently treated with 40 ml of methanol/water (1:1). The aqueous methanolic phase was separated, extracted with 40 ml of heptane and thereafter the methanol was distilled off on a rotary evaporator. The aqueous phase was extracted twice with 30 ml of ethyl acetate. The organic phases were combined, dried over Na2SO4, filtered and the filtrate was concentrated. 8.23 g of beige oil were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:11](O)(=O)[CH2:12][CH3:13].Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([CH2:12][CH3:13])=[N:9][C:4]=2[C:3]=1[Cl:10]
Reactant: Nc1ccc(Br)c(Cl)c1N
Reactant: CCC(=O)O
Agent: Cl
Product: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Temperature: 140 °C
Yield: 89 %

Procedure:
4-Bromo-3-chloro-1,2-benzenediamine (0.17 g, 0.766 mmol), propionic acid (0.17 g, 2.298 mmol), and 4 N HCl (1.724 ml, 6.894 mmol) were combined and heated to 140° C. for 3 h. Treatment with 1 N NaOH was followed by extraction with EtOAc (×3), and washing with brine. The dried (Na2SO4) organic portions were filtered, concentrated, and chromatographed (SiO2, MeOH/CH2Cl2) to obtain 0.177 g of the title compound: 1HNMR (400 MHz, CDCl3) δ 9.50 (broad s, 1H), 7.43 (d, J=8.31 Hz, 1H), 7.35 (broad s, 1H), 2.96 (q, J=7.5 Hz, 2H), 1.43 (t, J=7.5 Hz, 3H); MS (ESI) m/z 261 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C.O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[CH:13]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCBr
Reactant: O=CC1=Cc2cc(O)ccc2OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1ccc2c(c1)C=C(C=O)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: A mixture of 6-hydroxy-2H-1-benzopyran-3-carboxaldehyde (4.0 g, 22.7 mmol) and potassium carbonate (6.26 g, 45.3 mmol) in 80 ml of DMF is treated with n-hexyl bromide (4.5 g, 27.2 mmol). The mixture is stirred overnight at room temperature. Additional potassium carbonate (3.1 g, 22.4 mmol) and n-hexyl bromide (1.0 g, 6.1 mmol) are added and, after another overnight reaction, no more starting material is detected in the reaction mixture. The reaction mixture is diluted with water and extracted three times with dichloromethane. The combined organic phases are dried (MgSO4) and evaporated. Purification by silica gel chromatography (10% ethyl acetate/hexane) yields 6-(n-hexyloxy)-2H-1-benzopyran-3-carboxaldehyde, m.p. 36°-38° C., which is converted as described above to 3-(N-hydroxyaminomethyl)-6-(n-hexyloxy)-2H-1-benzopyran.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14])=[CH2:2].CC(N=NC(C#N)(C)C)(C#N)C.[C:29]([OH:32])(=[S:31])[CH3:30]>C1C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:29]([S:31][CH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])[CH3:30]
Reactant: C=Cc1ccc(C(=O)OC)cc1C(=O)OC
Reactant: CC(O)=S
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CCSC(C)=O)c(C(=O)OC)c1
Yield: 26.9 %

Procedure:
To a degassed solution of dimethyl 4-ethenyl-1,3-benzenedicarboxylate (415 mg, 1.88 mmol) in benzene (6 mL) were added AIBN (33 mg, 0.21 mmol) and thioacetic acid (0.27 mL, 3.78 mmol), and the mixture was refluxed for 5 hours. The reaction mixture was diluted with aqueous NaHCO3 solution (15 mL) and extracted with EtOAc (15 mL). The organic layer was dried over MgSO4 and concentrated. The residual material was purified by silica gel chromatography (hexanes/EtOAc=10:1) to give 0.150 g of colorless oil (27% yield).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([O-:13])=[O:12]>CN1C(=O)CCC1.C(OCC)(=O)C>[N+:11]([C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(Nc2nc3ccccc3[nH]2)cc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
A mixture of 2-chlorobenzimidazole (10.0 g) and 4-nitroaniline (9.05 g) in NMP (130 mL) was stirred at 120° C. for 3 days. After this time, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (750 mL) and washed with water (750 mL). The aqueous layer was extracted with ethyl acetate (750 mL) and the combined organic extracts were washed with water (3×750 mL) then brine (750 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was triturated with 1:1 ethyl acetate/heptane (200 mL) and the solid that formed was collected by filtration to afford N-(4-nitrophenyl)-1H-benzimidazol-2-amine (4.00 g) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:24][O:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:24][O:25][C@@H:26]1[CH2:30][N:29]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 97.3 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (375 mg, 1.19 mmol), methyl 4-[(2S,4S)4-methoxy-2-pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC.HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) and Et3 N (0.83 ml, 5.95 mmol) in DMF (5 ml) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/Aectone (10/1)CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-4-methoxy-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxybenzoate (650 mg, 98%) as a pale brown amorphous solid 1H-NMR (CDCl3) δ 2.03 (m, 1H), 2.31 (s, 3H), 2.32 (m, 1H), 3.29 (d, J=1.0 Hz, 3H), 3.57–3.68 (m, 5H), 3.88 (d, J=1.0 Hz, 3H), 3.99–4.06 (m, 2H), 4.46 (m, 1H), 6.19 (m, 1H), 6.80 (s, 1H), 6.81 (d, J=9.0 Hz, 1H), 6.96–7.19 (m, 4H), 7.29 (m, 2H), 7.50 (d, J=6.7 Hz, 1H), 7.95–8.10 (m, 3H); MS (ESI) m/z 562 (M++1).
Reaction SMILES: [C:1]([CH:3]([C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]1)[CH2:4][CH2:5][C:6](=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])#[N:2].CO.[BH4-].[Na+]>C1COCC1.O>[C:1]([CH:3]([C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]1)[CH2:4][CH2:5][CH:6]([OH:13])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])#[N:2]
Reactant: CCCCCCC(=O)CCC(C#N)[C@H]1CC[C@H](OC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCC(O)CCC(C#N)[C@H]1CC[C@H](OC)CC1

Procedure:
A solution of 1-cyano-1-(trans-4-methoxycyclohexyl)-4-decanone (48) (5.1 g, 17.4 mmol) obtained in the second step dissolved in 100 mL of THF and 50 mL of methanol was cooled with ice, to which sodium borohydride (0.79 g, 20.9 mmol) was then gradually added, followed by stirring under cooling with ice for 1 hour. The reaction mixture was put in 100 mL of iced water, and then extracted with 100 mL of ethyl acetate. The resulting organic layer was washed with water (100 mL×2) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (developing solvent: heptane/ethyl acetate=4/1, column packing: silica gel) to obtain 1-cyano-1-(trans-4-methoxycyclohexyl)-4-decanol (49) (5.1 g, 17.4 mmol). The resulting compound was in the form of colorless crystals, and the yield based on the compound (48) was 100%.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)[C@@H:59]([C@H:69](O)[CH3:70])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][C@H:60]([C:62]2[CH:63]=[CH:64][C:65]([Cl:68])=[CH:66][CH:67]=2)[C@@H:59]([C@@H:69]([O:27][C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][N:25]=2)[CH3:70])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Oc1ccc(F)cn1
Reactant: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(F)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (0.914 g, 2.74 mmol) in THF (15 mL) at 0° C. were added 5-fluoro-pyridin-2-ol (0.215 g, 1.90 mmol) and then DBAD (0.47 g, 2.02 mmol). After 5 minutes was added (R)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol (0.40 g, 1.26 mmol; described herein above). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:3) yielded 0.315 g (44%) of the title compound as a colorless oil. ES-MS m/e: 411.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C(N(CC)CC)C.CN(C)C=O.[CH2:29](Br)[CH:30]=[CH2:31]>O>[CH2:31]([O:8][C:7]1[C:6]([Cl:9])=[CH:5][C:4]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:3][C:2]=1[Cl:1])[CH:30]=[CH2:29]
Reactant: C=CCBr
Reactant: O=c1ccc(-c2cc(Cl)c(O)c(Cl)c2)n[nH]1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Temperature: 50 °C
Reaction time: 5 h

Procedure:
To a mixture of 4.9 g. of 6-(3,5-dichloro-4-hydroxyphenyl)-3-(2H)pyridazinone obtained in Example 5 and 2 g. of triethylamine in 30 ml. of dimethylformamide was added dropwise 2.4 g. of allyl bromide at 50° C. while stirring. The mixture was stirred at 50° C. for further 5 hours. After cooling, the reaction mixture was poured into 200 ml. of water and allowed to stand for a while. White solid substance thus formed was recovered by filtration, washed with water, dried to give 3.6 g. of crude crystalline substance, which was then recrystallized from methanol to give 3.2 g. of the desired product as colorless needles of m.p. 214° - 215° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCl
Product: Cc1nc(-c2ccc(Cl)cc2)sc1CO[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 78.5 %

Procedure:
In an argon atmosphere, (R)-1-(tert-butoxycarbonyl)-3-hydroxypiperidine (604 mg, 3.00 mmol) and 5-chloromethyl-2-(4-chlorophenyl)-4-methylthiazole (775 mg, 3.00 mmol) were reacted in the same manner as in Step 6a of Example 6 to give 996 mg (78%) of the desired compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)[CH3:32]>CN(C1C=CN=CC=1)C>[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:19])[CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:37][CH:36]=1)[CH3:32]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 6, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was converted into the corresponding acid chloride with thionyl chloride which subsequently reacted with 4-amino-benzoic acid ethyl ester (CAS Reg. No. 94-09-7) in the presence of DMAP to give the title compound as yellow oil. MS: m/e=520.4 [M+H+].
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[CH2:3][CH2:2]1.[NH2:13][C:14]([NH2:16])=[S:15].[I:17]I>O>[IH:17].[N:13]1[C:4]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][CH2:1][CH2:2][C:3]=2[S:15][C:14]=1[NH2:16]
Reactant: NC(N)=S
Reactant: O=C1CCCCc2ccccc21
Reactant: II
Solvent: O
Product: I
Product: Nc1nc2c(s1)CCCc1ccccc1-2
Temperature: 95 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
A mixture of 1-benzosuberone (1.00 mL; 6.7 mmol), thiourea (1.02 g; 13.4 mmol) and iodine (1.70 g; 6.7 mmol) were heated to 95° C. with stirring. After 20 hr., the mixture was allowed to cool to room temperature, diluted with 200 mL of water, the solid material filtered off washed twice with 25 mL of water followed by diethyl ether (3×20 mL) to provide 1.50 g of 5,6-Dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-ylamine hydroiodide 17 as an off white powder.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>O1CCOCC1>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][N:17]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
4N HCl in 1,4-dioxane (1 mL) was added to a mixture of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (462 mg, 1.03 mmol) in 1,4-dioxane (10 mL) at ambient temperature. The mixture was stirred at ambient temperature overnight. The mixture was charged with additional 4N HCl in 1,4-dioxane (1 mL), and stirred at ambient temperature overnight. The mixture was then charged with TFA (2 mL), and stirred at ambient temperature for 4 h. The mixture was concentrated, diluted with water, basified with saturated NaHCO3, and extracted with EtOAc. The organics were dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by reverse-phase preparative HPLC using CH3CN:H2O gradient (5:95 to 75:25) with 0.05% TFA as a modifier to give 107 mg (23%) of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine trifluoroacetate as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.59-8.50 (m, 1H), 8.44 (d, 1H, J=2.9 Hz), 8.28 (d, 2H, J=8.6 Hz), 8.08 (d, 1H, J=8.8 Hz), 8.00 (d, 2H, J=8.6 Hz), 7.55 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.04 (d, 2H, J=6.2 Hz), 3.40-3.25 (m, 2H), 3.25 (s, 3H), 3.00-2.86 (m, 2H), 2.16-2.06 (m, 1H), 2.05-1.90 (m, 2H), 1.56-1.40 (m, 2H); LRMS (ESI), m/z 347 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: COc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1=CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
1-t-Butoxycarbonyl-4-hydroxy-4-(2-methoxyphenyl)piperidine (240 mg, 0.78 mmol) was dissolved in methylene chloride (4 ml). Thereto was added trifluoroacetic acid (4 ml) and the resulting solution was stirred at room temperature for 1 hour. The solvent was evaporated under a reduced pressure, and ethyl acetate was added to the thus obtained residue. This was washed with 1 N sodium hydroxide aqueous solution and saturated brine in that order, and then the solvent was evaporated under a reduced pressure to obtain 150 mg of the aforementioned compound of interest (0.78 mmol, 100% in yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][N:12]=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[N:12]=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc(Sc2cnn[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nncc1Sc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of compound 63a (360 mg, 1.40 mmol) and 60% NaH (135 mg, 3.40 mmol) in DMF (2 mL) was stirred for 20 min at rt. At that time, 2-(trimethylsilyl) ethoxymethyl chloride (0.558 mL, 3.10 mmol) was added and the resulting mixture was stirred at rt for 12 h. The reaction mixture was diluted with DCM (300 mL) and washed with saturated NH4Cl solution (200 mL), water (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-50% EtOAc/heptanes) to give compound 63b. Mass Spectrum LCMS, ESI (pos.) Calcd. for C14H20BrN3OSSi: 386.1 [M+H]. found 386.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40](OCC)=[NH:41])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].[CH2:47](N)[CH2:48][NH2:49].C(OCC)(=O)C>C(O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[C:24]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)=[CH:23][C:22]([C:40]3[NH:49][CH2:48][CH2:47][N:41]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCOC(=N)c1cnc(N[C@H]2C[C@@H](CC)N(C(=O)OCC)c3ccc(OC)nc32)c(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: NCCN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(C3=NCCN3)cc2Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1CC
Temperature: 25 °C

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-ethoxycarbonimidoylpyridin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (100 mg) and ethylenediamine (150 μl) are dissolved in ethanol (3 ml), and the mixture is stirred under reflux for 4 hours. After cooling to room temperature, a saturated brine and ethyl acetate are added to the reaction solution. The organic layer is dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (NH-silica gel; hexane: ethyl acetate=1:1→1:2) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (96 mg). MS (m/z): 651 [M+H]+