Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:8][CH:7]=2.Cl.[NH:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][S:17]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=1)[C:3]([CH2:2][N:32]1[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]1)=[C:12]2[C:13]([O:15][CH3:16])=[O:14])(=[O:19])=[O:18]
Reactant: COC(=O)c1c(CBr)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1c(CN2CCC(=O)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Yield: 50.7 %

Procedure:
Methyl 3-(bromomethyl)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2 g, 3.98 mmol), 4-piperidone HCl salt (0.648 g, 4.78 mmol), N,N-diisopropylethylamine (1.53 mL, 8.76 mmol) in acetonitrile (13.27 mL) was heated to 50° C. overnight. The solvent was removed under reduced pressure. The residue was diluted with Na2CO3 and extracted with methylene chloride (four times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 40 g silica, 5-100% ethyl acetate/hexanes) to afford methyl 6-(methylsulfonyl)-3-[(4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.051 g, 51% yield). MS (m/z) 521.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=O)=[CH:10][CH:9]=2)[C:4]([CH3:18])=[N:3]1.[CH3:19][NH:20][CH3:21].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:19][N:20]([CH3:21])[CH:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[C:4]([CH3:18])=[N:3][N:2]([CH3:1])[C:6]=3[CH3:7])[CH:16]=2)[CH2:12][CH2:13]1
Reactant: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(=O)CC2
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(N(C)C)CC2

Procedure:
(Method 2): 6-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-indan-1-one (1.1 mmol) was dissolved in MeOH. Dimethyl-amine (24.5 mmol), acetic acid (0.11 mmol) and sodium cyanoborohydride (2.2 mmol) were added under argon atmosphere. The suspension was refluxed overnight and then cooled. The crude was evaporated to dryness and then suspended in water. The product was extracted with CH2Cl2 and washed with water. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion™ system to yield the base of the title compound. The obtained product was diluted in ethyl acetate and a solution of hydrogen chloride 2.0 M in diethylether was added. The resulting precipitate was filtered and dried under vacuum to yield the title compound dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine dihydrochloride (79%). MS [MH]+=270.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([CH2:37][C:38](O)=[O:39])=[N:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([CH2:37][C:38]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:39])=[N:29]1
Reactant: O=C(O)Cc1noc2ccccc12
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(Cc1noc2ccccc12)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (122 mg, 100%), MS (ISP) m/z=490.4 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2-benzo[d]isoxazol-3-yl-acetic acid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at −75° C. 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried (MgSO4). After evaporation of the solvent 20 ml of dichlorometane and 20 ml of trifluoracetic acid was added and the mixture was stirred for 2.5 h at room temperature. For workup the mixture was concentrated in vacuo, then ethylacetate was added and the mixture was extracted two times with water. The aqueouos phase was basified with sodium hydroxide and extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=9:1) to yield 2.1 g (65%) of (S)-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4] diazepin-2-one.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][NH2:12]>CCCCCC.ClCCl>[C:1]([N:9]([CH2:10][CH2:11][NH2:12])[CH2:8][CH2:7][NH2:6])(=[O:4])[CH:2]=[CH2:3]
Reactant: NCCNCCN
Reactant: C=CC(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: C=CC(=O)N(CCN)CCN
Temperature: 105 °C
Reaction time: 0.01 h

Procedure:
4-N-acryloyl-diethylenetriamine was prepared by slowly adding, at 23° C., 200 ml of a solution of acryloyl chloride in a mixture of hexane and dichloromethane (C6H14 :C2Cl2 =3:1) at a concentration of 3.6 wt% (0.4 mEq/ml) to 600 ml of 1.4 wt% (0.4 mEq/ml) diethylenetriamine which had been purified by vacuum distillation. The reaction product was oligomerized by the addition of 200 ml of a 4.1 wt% solution of isophthaloyl chloride in dichloromethane at 20° C. with mechanical stirring. An asymmetric microporous polysulfone support flat sheet membrane 4 mils thick was immersed in a 2 wt% aqueous solution of 4-N-acryloyl-diethylenetriamine oligomer, drained of excess solution, then immersed in a 0.5 wt% solution of trimesoyl chloride at 20° C. for 30 seconds. The composite membrane was then air-dried at room temperature for 30 minutes and subjected to heat treatment at 105° C. for 10 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21](I)[CH3:22]>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([CH2:21][CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(Nc2nc(Cl)nc3ccccc23)cc1
Reactant: CCI
Product: CCN(c1ccc(OC)cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-amine and ethyl iodide by a procedure similar to Example 36 (58% yield). 1H NMR (CDCl3): 7.69-7.72 (m, 1H), 7.53 (ddd, J=8.1, 6.9 and 1.5 Hz, 1H), 7.09-7.14 (m, 2H), 6.94-6.70 (m, 3H), 6.83-6.87 (m, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.87 (s, 1H), 1.30 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:8](O)=[O:9])=[O:4].O=S(Cl)Cl.C[N:22](C=O)C>>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:7]([C:8](=[O:9])[NH2:22])[CH:6]=1
Reactant: COC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(N)=O)cc([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 85 %

Procedure:
A mixture of 3-methoxycarbonyl-5-nitrobenzoic acid (44 mmol), SOCl2 (40 mL) and DMF (1 mL) was heated to reflux for 2 hours. Then the excessive SOCl2 was removed under reduced pressure. The residue was dissolved in DCM (80 mL), and added with NH3.H2O (15 mL) dropwise after cooling by ice-water. After addition, it was continued to stir 5 min. The resulting mixture was filtrated to give methyl-3-carbamoyl-5-nitrobenzoate in 85% yield.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[S:42][CH:43]=[C:44]([C:46](O)=[O:47])[N:45]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>ClCCl.O>[CH:1]1([O:7][C:46]([C:44]2[N:45]=[C:41]([CH:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:40][CH2:39]3)[S:42][CH:43]=2)=[O:47])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)OC3CCCCC3)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, cyclohexanol (1.21 g), dimethylaminopyridine (113 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (1.87 g) are added to a solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VIII-1, 2.90 g) in dichloromethane (30 ml). The mixture is stirred at room temperature overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate, and the combined organic phases are then dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives tert-butyl 4-{4-[(cyclohexyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.63 g, 72%)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18]>>[Cl:8][C:7]1[C:2]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([F:9])([F:22])[F:21])(=[O:18])=[O:19])=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: NS(=O)(=O)c1ccccc1C(F)(F)F
Product: O=S(=O)(Nc1nccnc1Cl)c1ccccc1C(F)(F)F
Yield: 63 %

Procedure:
Following the general method as outlined for Intermediate 2, starting from 2,3-dichloropyrazine and 2-(trifluoromethyl)benzenesulfonamide, the title compound was isolated, after evaporation and recrystallization, as a yellowish solid in 63% yield (97% purity by HPLC).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:11][CH:10]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][OH:43])=[CH:37][CH:36]=1>COCCOC.CCO>[OH:43][CH2:42][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[NH:20][S:21]([CH:24]([CH3:25])[CH3:26])(=[O:22])=[O:23])=[CH:13][CH:14]=2)=[CH:36][CH:37]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2ccc(CCO)cc2)cc1
Temperature: 92.5 °C
Reaction time: 1.5 h

Procedure:
Mix propane-2-sulfonic acid{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-thiophen-3-yl}-amide (0.10 g), 0.1 equiv of tetrakis triphenylphosphine palladium (0), 2 equiv of 2M sodium carbonate aqueous solution in DME (2 mL) and EtOH(1 mL) and warm to 90-95° C. After warming two min, add 2-(4-bromo-phenyl)-ethanol (1.3 equiv) and stir at that temperature for 1.5 h. Evaporate solvents over Celite® and purify by silica gel Strata® cartridges eluting with hexanes-EtOAc gradient to give 0.041 g of the title compound. MS (ES+) (m/z): 402 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:27]=[N:28][CH:29]=1
Reactant: CCC(=O)NCc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)NCc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Temperature: 110 °C
Yield: 17.6 %

Procedure:
To a mixture of 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22, 168 g, 0.55 mmol) and N-(5-bromo-pyridin-3-ylmethyl)-propionamide (122 mg, 0.5 mmol) in DMF (3 mL), purged with argon for 1 min, was added bis(triphenylphosphine)palladium (II)chloride (38 mg, 0.054 mmol) and 1 N aq. Na2CO3 (2.5 mL). Then, the resulting reaction mixture was heated in a microwave at 110° C. for 45 min. After cooling to room temperature, it was diluted with EtOAc (5 mL) and poured into a satd. aq. solution of NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (3×5 mL) and combined organics were washed with water and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by prep-HPLC to afford the title compound (30 mg, 18%) as a white solid. MS: 342.1 (M+H+)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][NH:13][CH:14]=O>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][N:13]([CH3:14])[C:4]2=[O:5]
Reactant: CNC=O
Reactant: Nc1ccc(Cl)cc1C(=O)O
Solvent: O
Product: Cn1cnc2ccc(Cl)cc2c1=O
Temperature: 180 °C
Yield: 65 %

Procedure:
2-amino-5-chlorobenzoic acid 27 (12.5 g, 73 mmol) was placed in a 250 mL beaker containing n-methylformamide (125 mL). A condenser was utilized and the reaction was heated overnight at 180° C. The reaction was complete the next morning and allowed to cool to room temperature for 1 hr and then poured into 500 mL of water and extracted three times with 250 mL of ethyl acetate. The organic phase was then washed with an additional 1 liter of water and concentrated under vacuum to yield 6-chloro-3-methylquinazolin-4(3H)-one (9.2 g, 47.3 mmol, 65% yield) 1H NMR (300 MHz, D6 DMSO): δ 8.39 (s, 1H), 8.04 (d, 1H, J=3.6 Hz), 7.82 (dd, 1H, J=2.4 Hz, J=8.7 Hz), 7.67 (1H, d, J=8.7 Hz), 3.49 (s, 3H). 13C NMR (75 MHz, D6 DMSO): δ 160.49, 149.75, 147.65, 135.06, 131.99, 130.26, 125.61, 123.45, 34.53. ESMS: m/z 195.2 [MH]+
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([S:13][CH3:14])[C:9]([F:12])([F:11])[F:10])(=O)=O.[F:15][C:16]([F:28])([F:27])[CH2:17][CH2:18][S:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:21])=[O:20].[H-].[Na+].Cl>CS(C)=O>[F:12][C:9]([F:10])([F:11])[CH:8]([S:13][CH3:14])[CH2:7][CH2:6][CH:22]([S:19]([CH2:18][CH2:17][C:16]([F:27])([F:28])[F:15])(=[O:21])=[O:20])[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Reactant: CSC(CCOS(C)(=O)=O)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(SC)C(F)(F)F)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 120 h
Yield: 26.1 %

Procedure:
To a solution of 5.0 g of 4,4,4-trifluoro-3-methylthio-butyl methanesulfonate and 4.6 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide was added 0.8 g of sodium hydride (60% in oil) at room temperature. The reaction mixture was heated to 60° C., stirred at the same temperature for 5 days, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 2.00 g of methyl 6,6,6-trifluoro-5-methylthio-2-(3,3,3-trifluoropropylsulfonyl)hexanoate (hereinafter referred to as the present compound (27)).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])(C)(C)C.C(O[C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:26]=1)(C)(C)C>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:36]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ncccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Product: O=C1CC(c2cccc(-c3ncccn3)c2)=Nc2ccc(Cl)cc2N1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (121 mg, 0.5 mmol) and 3-oxo-3-(3-pyrimidin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K44) (164 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (102 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[CH:8][CH:7]=1.C(OC(CC1C2SC=CC=2C(O[CH2:38][CH2:39][C:40]2[N:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=3[O:53][CH2:54][CH3:55])[O:43][C:44]=2[CH3:45])=CC=1)C(O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH2:38][CH2:39][C:40]2[N:41]=[C:42]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][C:47]=3[O:53][CH2:54][CH3:55])[O:43][C:44]=2[CH3:45])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(O)c2ccccc12)OC
Reactant: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OCC)C(=O)O)c3sccc23)c(C)o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1cc(F)ccc1-c1nc(CCOc2ccc(CC(OC)C(=O)OC)c3ccccc23)c(C)o1

Procedure:
In analogy to the procedure described in example 17 a], [rac]-3-(4-hydroxy-naphthalen-1-yl)-2-methoxy-propionic acid methyl ester was reacted with 2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol (example 95) in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-methoxy-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-(4-{2-[2-(2-ethoxy-4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-naphthalen-1-yl)-2-methoxy-propionic acid as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(Cl)c(Cl)c1

Procedure:
In a three-necked flask fitted with a Nichrome stirrer and a reflux condenser is placed 7.0 g of ethyl 3,4-dichlorophenylacetate, 5.9 g of N-bromosuccinimide, 0.1 g of benzoyl peroxide and 150 ml of carbon tetrachloride. The reaction mixture is heated at reflux for 18 hours, cooled and filtered. The carbon tetrachloride filtrate is concentrated under reduced pressure to give a deep orange liquid. Vacuum distillation at 115°-120° C. (0.5 mm) gives ethyl α-bromo-3,4-dichlorophenylacetate as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:21]=[O:22]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:21][OH:22])[C:16](=[O:20])[N:15]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc[nH]1
Reactant: C=O
Solvent: O
Solvent: CCO
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1CO

Procedure:
To an ethanol/water solution (2/1 (v/v)) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (94 mg, 0.34 mmol) synthesized in Reference Synthesis Example 3, a formaldehyde aqueous solution (42 mg, 0.51 mmol) was added and the resultant solution was stirred at 50° C. for 5 hours. To the reaction solution, a formaldehyde aqueous solution (83 mg, 1.02 mmol) was added and the resultant mixture was stirred at 50° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1-(hydroxymethyl)-1,3,5-triazin-2(1H)-one. Subsequently, to a dichloromethane solution (2 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1-(hydroxymethyl)-1,3,5-triazin-2(1H)-one, triethylamine (57 mg, 0.41 mmol) and p-toluenesulfonic acid anhydride (123 mg, 0.38 mmol) were added and the resultant mixture was stirred at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound and the crude product was used in the next reaction as it was.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]([CH3:20])[C:16]([CH3:19])=[CH:17][N:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:20][N:15]1[C:16]([CH3:19])=[CH:17][N:18]=[C:14]1[N:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cnc(N2CCC(c3ccc(N)cc3)CC2)n1C
Solvent: c1ccncc1
Product: Cc1cnc(N2CCC(c3ccc(NS(C)(=O)=O)cc3)CC2)n1C

Procedure:
Treatment of the product from part (ii) above (0.46 g) with methanesulphonyl chloride (0.22 g) in pyridine (12 ml) according to the method fo Example 1(iii) gave the title compound, (0.40 g), m.p. 225°-226°.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:18][C:19]3[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(CCl)cn1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2Cc2ccc(C)nc2)C1
Yield: 15.7 %

Procedure:
Preparation of the title compound was carried out according to General Method 4. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, mmol), 5-(chloromethyl)-2-methylpyridine (324 mg, 2.3 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 ml) at 120° C. for 16 h to obtain 50 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-((6-methylpyridin-3-yl)methyl)-1H-pyrido[4,3-b]indole after purification by silica gel chromatography (100-200 mesh or 230-400 mesh) using methanol-dichloromethane gradient