Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:42])[F:41])[NH:36][CH:35]=[CH:34]2.CC(N(C)C)=O>ClCCl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][C:39]=1[C:40]([F:43])([F:41])[F:42])[NH:36][CH:35]=[CH:34]2
Reactant: Oc1cc2cc[nH]c2cc1C(F)(F)F
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3cc4cc[nH]c4cc3C(F)(F)F)ncnc2cc1OCCCN1CCCCC1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (168 mg, 0.5 mmol), (prepared as described for the starting material in Example 67), potassium carbonate (276 mg, 2.0 mmol) and 5-hydroxy-6-trifluoromethylindole (110 mg, 0.55 mmol) and DMA (4.0 ml) were stirred at 95° C. for 1.5 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated under vacuum. The residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (89/10/1) to give a partially purified oil. This oil was further purified by high performance column chromatography on octadecylsilane reverse phase silica eluting with acetonitrile/water/trifluoroacetic acid (60/39.8/0.2) to give an oil which was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The dichloromethane layer was evaporated to give 6-methoxy-7-(3-piperidinopropoxy)-4-(6-trifluoromethylindol-5-yloxy)quinazoline (62 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:13]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCCO2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@H]2CCCO2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-furan-2(R)-yl)-propionic acid (168 mg, 0.51 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylfomamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 291 μL, 0.58 mmol) which produced gas evolution and it was then stirred at 0° C. for 15 minutes and 30 min at 25° C. After this time, the reaction was concentrated in vacuo to ⅓ of the original volume. In a separate flask a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in Example 80, 86 mg, 0.56 mmol), 2,6-lutidine (84 μL, 0.76 mmol) and methylene chloride (10 mL) was cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (1×20 mL) and the aqueous layers were than extracted with methylene chloride (2×10 mL). The combined organic layers were then washed with a 1 N aqueous hydrochloric acid solution (1×20 mL) and then dried over sodium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 70% ethyl acetate/hexanes to 90% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-furan-2(R)-yl)-propionamide (155 mg, 65%) as a mixture of roughly 1:1 mixture of diastereomers as a white foam: ES-HRMS m/e calcd for C21H28N3O5SCl (M+H)+ 470.1511, observed 470.1504; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.02, 1.03 (2×s, 6H, 2×CH3), 1.37-1.52 (m, 1H, CH of CH2), 1.64-1.99 (m, 4H, 4×CH of CH2), 2.08-2.40 (m, 1H, CH of CH2), 3.34, 3.35 (2×s, 3H, SO2CH3), 3.43-3.77 (m, 3H, OCH2 and OCH), 3.86 (brs, 2H, NCH2), 3.97-4.12 (m, 1H, ArCH), 4.62, 4.63 (2×s, 1H, OH), 6.43 (m, 1H, Ar), 7.49 (m, 1H, Ar), 7.59 (2×dd, Jo=8.2 Hz, Jm=1.7 Hz, 1H, Ar), 7.69 (2×d, Jm=1.7 Hz, 1H, Ar), 7.99 (2×d, Jo=8.2 Hz, 1H, Ar), 10.75, 10.81 (2×s, 1 H, NH).
Reaction SMILES: [K].[OH:2][CH2:3][CH2:4][O:5][C:6]([C:8]1[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)=[C:10]([C:17](O)=[O:18])[C:11]([CH2:15][OH:16])=[N:12][C:13]=1[CH3:14])=[O:7].Cl>O>[CH3:14][C:13]1[N:12]=[C:11]2[CH2:15][O:16][C:17](=[O:18])[C:10]2=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:8]=1[C:6]([O:5][CH2:4][CH2:3][OH:2])=[O:7]
Reactant: Cc1nc(CO)c(C(=O)O)c(-c2cccc([N+](=O)[O-])c2)c1C(=O)OCCO
Agent: Cl
Agent: [K]
Solvent: O
Product: Cc1nc2c(c(-c3cccc([N+](=O)[O-])c3)c1C(=O)OCCO)C(=O)OC2
Reaction time: 8 h

Procedure:
4 g of potassium salt of 2-hydroxymethyl-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 5-(2-hydroxyethyl) ester (Example 52) were dissolved in 4 ml of water and acidified with concentrated hydrochloric acid. After standing overnight at room temperature, the mixture was diluted with water, the oil which separated out was extracted with methylene chloride, the organic extracts, after drying over sodium sulphate, were evaporated in vacuo and the residue was recrystallized from isopropanol, melting point 130° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14]>CN(C)C=O>[OH:14][N:13]=[C:12]([Cl:1])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[CH3:9]
Reactant: Cc1ccccc1C=NO
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(Cl)=NO
Reaction time: 2 h
Yield: 73.5 %

Procedure:
N-Chlorosuccinimide (2.22 g, 16.6 mmol, 1.0 equiv) was added to a stirred solution of 2-methyl-benzaldehyde oxime (2.25 g, 16.6 mmol, 1.0 equiv) in N,N-dimethylformamide (30 mL) at ambient temperature. Stirring was continued for 2 hours and the reaction quenched (ice-water). The resultant mixture was extracted with ethyl acetate. The combined organic extracts were washed sequentially with water (6×) and saturated aqueous sodium chloride solution (2×). The organic was then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give 2.07 g (74%) of N-hydroxy-2-methylbenzenecarboximidoyl chloride as a green oil. 1H NMR (300 MHz, CDCl3) δ: 8.14 (s, 1H), 7.48-7.44 (m, 1H), 7.37-7.20 (m, 3H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(C)cc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(C)cc1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-p-tolyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=248.2.
Reaction SMILES: [C:1]([NH:6][N:7]=[C:8]([CH3:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Cl:19]Cl>CCCCC>[C:1]([N:6]=[N:7][C:8]([Cl:19])([CH3:18])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: ClCl
Reactant: CCCCOC(=O)CCC(C)=NNC(C)(C)CC
Solvent: CCCCC
Product: CCCCOC(=O)CCC(C)(Cl)N=NC(C)(C)CC
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 104 %

Procedure:
To a solution of 90 grams (.316 moles) of butyl levulinate t-amylhydrazone in 150 mls. of pentane in a 500 ml. round bottom flask was passed 10.9 grams (.154 moles) of chlorine holding the temperature at -20°C with a dry ice- isopropanol bath. The chlorine was added over 30 minutes and then the reaction was stirred an additional 15 minutes at -20°C and filtered. The filtrate was dried and the pentane evaporated leaving 46.6 grams of crude butyl 4-t-amylazo-4-chlorovalerate.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[CH2:4][NH2:1])=[CH:15][CH:14]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(-c2ccc(Br)cc2)c1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Azidomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole (3.18 g, 10.85 mmol) in THF (30 mL) and H2O (10 mL) was treated with triphenylphosphine (2.85 g, 10.86 mmol) and the reaction stirred overnight at room temperature. After aqueous workup, the crude material was purified by silica gel chromatography to afford the title compound.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][NH2:15]>CCO>[F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:15][CH3:14]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1F
Reactant: CN
Solvent: CCO
Product: CNc1c([N+](=O)[O-])ccc(OC)c1F
Reaction time: 1 h

Procedure:
A solution of 2,3-Difluoro-4-nitroanisole (7-1, 1.0 g, 5.29 mmol) in EtOH (20 ml) was treated with Methylamine (2M in THF, 3.17 ml, 6.35 mmol, 1.2 eq) and the resulting yellow solution was stirred at 23 deg C. for 1 h. The reaction was complete by LC/MS, but allowed to stir at 23 deg C. for an additional 17 h. The residual bright orange-yellow solution was concentrated in vacuo, then partitioned between EtOAc (2×80 ml) and water (90 ml). The combined organic layers were dried over Na2SO4 and concentrated, leaving the title compound, 2-fluoro-3-methoxy-N-methyl-6-nitroaniline (7-2), as an orange solid with >90% purity. 1H NMR (500 MHz, CDCl3) δ 8.01 (d, 1H, J=1.9 Hz), 7.84 (bs, 1H), 6.81-6.83 (m, 1H), 3.95 (s, 3H), 3.24 (m, 3H). LRMS m/z: Calc'd for C8H9FN2O3 (M+H) 201.2, found 200.9.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2].[CH3:37][NH2:38]>CN(C=O)C.C(O)C>[C:1]([N:3]=[C:4]([NH:38][CH3:37])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2]
Reactant: CSC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reactant: CN
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 16 h

Procedure:
A solution of 50 mg of the product of Example 50 in 10 ml of DMF was treated with 4 ml of a 33% solution of methylamine in ethanol. The mixture was stirred for 16 hours and the solvents were then removed under reduced pressure. The residue was chromatographed on silica gel with ethyl acetate to give 46 mg of 3-[1-[3-(2-cyano-3-methylguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 190°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:33])[CH:23]=[CH:24][C:25]=1[CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.ClCl>ClCCl.CO>[Cl:19][C:20]1[CH:21]=[C:22]([NH:33][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)[CH:23]=[CH:24][C:25]=1[CH2:26][N:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Nc1ccc(CN2CCCCC2)c(Cl)c1
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Product: O=C(C#Cc1ccc(-c2ccc(Cl)cc2)cc1)Nc1ccc(CN2CCCCC2)c(Cl)c1

Procedure:
Prepared analogously to Example 3.7.c. from (4′-chlorobiphenyl-4-yl)propynoic acid and 3-chloro-4-piperidin-1-ylmethylphenylamine. Yield: 0.1 g (22% of theory); melting point: 277° C.-281° C.; C27H24Cl2N2 0 (M=463.4); calc.: molecular ion peak (M+H)+: 463/5/7 (Cl2); found: molecular ion peak (M+H)+: 463/5/7 (Cl2); Rf value: 0.50 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: C([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:28][CH:27]=1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=O)C1C=CC=CC=1.[C:40](OC(=O)C)(=O)C>CO.[Pd]>[C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:21][C:22]([NH:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:30][CH:31]=1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:8])[CH3:40]
Reactant: CCOC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@@H](CCCNC(C)=O)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
(R)-ethyl 5-(benzyloxycarbonylamino)-2-(3-(4-(tert-butoxy-carbonylamino)benzyl)ureido)pentanoate (1 equivalent, 115 mg, 0.21 mmol) was dissolved in 50 ml of MeOH. The Pd/C (12 mg) and the acetic anhydride (3 equivalent, 60 μl, 0.63 mmol). The reaction mixture was stirred under hydrogen at room temperature for 4 h. Then the mixture was filtrated on celite and the filter was concentrated. the crude was washed by 30 ml NaHCO3 and extracted by 3×30 ml EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude was purified by flash chromatography (CH2Cl2/MeOH) to afford the amide (84 mg, 78%) a colourless oil Rf=0.27 (CH2Cl2/MeOH 95/5). 1H NMR (200 MHz, CDCl3): δ 7.30 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 6.63 (broad s, 1H), 6.28-6.10 (m, 1H), 5.45 (d, J=7.6 Hz, 1H), 5.34-5.20 (m, 1H), 4.52-4.35 (m, 1H), 4.29 (d, J=5.8 Hz 2H), 4.15 (q, J=7.1 Hz, 2H), 3.32-3.12 (m, 2H), 1.94 (s, 3H), 1.90-1.36 (m, 4H) 1.50 (s, 9H), 1.25 (1, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C.[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Br>C(#N)C>[CH3:1][C@H:2]1[CH2:7][N:6]([CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:39]([F:38])[CH:40]=2)[C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:27][CH:28]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: Fc1cccc(CBr)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A solution of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide (1.898 g, 5.0 mmol) in 25 mL acetonitrile was added to sodium iodide (75 mg, 0.5 mmol) and stirred during the addition of triethylamine (2.5 mL, 1.815 g, 17.94 mmol), followed by 3-fluorobenzyl bromide (1.227 mL, 1.89 g, 10.0 mmol). An immediate turbidity was observed on addition of the 3-fluorobenzyl bromide, thickening to a copious white precipitate over one hour. The flask was sealed under nitrogen and the suspension stirred overnight at room temperature. The reaction mixture was evaporated to dryness and and the residue was partitioned between ethyl acetate (40 mL) and saturated sodium bicarbonate solution (10 mL). The supernatant organic layer was separated and the aqueous layer extracted further with ethyl acetate (2×40 mL). The combined organic extracts were dried over anhydrous sodium sulfate and evaporated to a pale yellow solid which was dissolved in ethyl acetate (˜7.5 mL) and applied to an intermediate (4×15 cm) Biotage silica column. Elution with ethyl acetate gave fractions containing the product, as evidenced by t.l.c. (silica, EM60F254, 100% EtOAc, Rf=0.78) were evaporated to dryness and dried at room temperature and 2 mm Hg to yield the title compound as white crystals (2.372 g, 97.3%). Calc. for C31H38FN3O: C, 76.35; H, 7.85; N, 8.62; F, 3.90. Found C, 76.32; H, 7.89; N, 8.51; F, 3.90%. 1H NMR (CDCl3, 300 MHz); δ 1.06 (d, J=6.1 Hz, 3H); 1.15 (d, J=6.1 Hz, 3H, partially overlapped by br m, 3H); 1.22 (br m, 3H); 1.94 (dd, J=10.8, 8.1 Hz, 1H); 2.02 (dd, J=10.7, 8.2 Hz, 1H); 2.57 (br m, 2H); 2.67 (m, 2H); 3.18 (d, J=13.8 Hz, 1H); 3.28 (br m, 2H); 3.53 (br m, 2H); 3.87 (d, J=13.5 Hz, 1H); 5.15 (s, 1H); 6.90 (br t, J=8.2 Hz, 1H); 7.04 (m, 2H); 7.21 (m, 3H); 7.30 (m, 5H); 7.46 (d, J=8.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][C:11](=O)[CH3:12].N1C=CC=CC=1.Cl.[CH3:21][O:22][NH2:23]>CO>[CH3:21][O:22][N:23]=[C:11]([CH3:12])[CH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9]
Reactant: CON
Reactant: CC(=O)Cc1c(Cl)cc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of crude 1-(2,4,6-trichloro-phenyl)-propan-2-one prepared as described in example P1, (12 g, 0.050 mol) in methanol (100 ml) was added pyridine (6.8 ml, 0.084 mol), followed by O-methyl-hydroxylamine hydrochloride (6.70 g, 0.080 mol). The resulting mixture was stirred at ambient temperature for 18 hours. Methanol was removed under reduced pressure and the residue poured in 1N hydrochloric acid (300 ml) which was extracted with ethyl acetate (3×100 ml). Organics were combined, washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure to give crude 1-(2,4,6-trichloro-phenyl)-propan-2-one O-methyl-oxime E/Z-mixture (12.3 g, 92%), which was taken up for the next reduction step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=O)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[CH3:24][C:25]([S@:28]([NH2:30])=[O:29])([CH3:27])[CH3:26]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:30][S@@:28]([C:25]([CH3:27])([CH3:26])[CH3:24])=[O:29])[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=C(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1

Procedure:
(3-Fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methanone (3.3 g, 9.88 mmol) was stirred in anhydrous THF (20 mL) at r.t. under N2. (R)-(+)-2-Methylpropane-2-sulfinamide (1.21 g, 10 mmol, 1.01 eq) was added as one single portion, followed by addition of Ti(OEt)4 (3.09 mL, 14.91 mmol, 1.51 eq). The resulting solution was heated at reflux for 48 hours. The cooled mixture was evaporated. H2O (100 mL) was added, followed by the addition of EtOAc (100 mL). The mixture was filtered through celite, and washed with EtOAc (200 mL). The filtrate was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by silica gel flash chromatography and was eluted with hexanes and EtOAc (0-30% EtOAc in hexanes) to give (R)—N-((3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide as yellowish viscous oil which solidified after drying under vacuum as light yellow solids (3.50 g, yield: 81.0%). LC-MS ESI 437.88 (M+H), retention time=3.83 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min gradient); 1H NMR (400 MHz, CDCl3) δ ppm 7.82-6.99 (br, m, 7H), 5.90 (tt, J=52, 4 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4](F)[N:3]=1.[CH3:13][O-:14].[Na+].Cl>O1CCCC1.CO>[F:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([O:14][CH3:13])[N:3]=1
Reactant: COC(=O)c1ccc(F)nc1F
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OC)nc1F
Temperature: 0 °C

Procedure:
To a stirred solution of 15.0 g (0.0867 mol) of the product from Example 12 in 240 mL dry tetrahydrofuran cooled to -78° was added dropwise 22.7 mL (0.0993 mol) of 25% sodium methoxide in methanol solution over 45 minutes. After warming to -20°, the mixture was poured into ice water, acidified with 1 normal hydrochloric acid and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 3.2 g (17%) light yellow solid: m.p. 81°-82°; NMR (CDCl3, 200 MHz) 3.9 (3H, s), 3.98 (3H, s), 6.67 (1H, d, J=9 Hz), 8.25 (1H, m); IR (nujol) 1715, 1615, 1290 cm-1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:12]1([C:15]([NH2:17])=[O:16])[CH2:14][CH2:13]1>>[CH:12]1([C:15]([NH:17][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=2)=[O:16])[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccnc(Cl)n1
Reactant: NC(=O)C1CC1
Product: COC(=O)c1ccnc(NC(=O)C2CC2)n1

Procedure:
The title compound is prepared in quantitative yield (1.93 g, a pale yellow solid) from methyl 2-chloropyrimidine-4-carboxylate (1.50 g, 8.69 mmol) and cyclopropanecarboxamide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: [CH:1]1([CH:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:5]([CH2:9][CH2:10][CH3:11])[C:6]([NH2:8])=[S:7])[CH2:3][CH2:2]1.Br[CH:19]([CH3:30])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])=O>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:8]=[C:6]([N:5]([CH:4]([CH:1]2[CH2:3][CH2:2]2)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH3:11])[S:7][C:19]=1[CH3:30]
Reactant: CCCN(C(N)=S)C(c1ccncc1)C1CC1
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccncc1)C1CC1

Procedure:
This compound was prepared according to the process described in Example 1, starting with 1.2 g of N-[cyclopropyl(4-pyridyl)methyl]-N-propylthiourea (Compound 74) and 1.52 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone Compound 15). The product was purified on a silica column, using a mixture of methylene chloride and methanol (98:2 V/V) as eluent.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([C:16]([F:19])([F:18])[F:17])([C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:15]=1)[OH:4].[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[CH:22]1([C:25]([N:14]2[C:8]3[CH:7]=[CH:6][C:5]([C:3]([C:2]([F:1])([F:20])[F:21])([C:16]([F:19])([F:17])[F:18])[OH:4])=[CH:15][C:9]=3[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:26])[CH2:24][CH2:23]1
Reactant: OC(c1ccc2c(c1)CCCCN2)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)C1CC1
Solvent: Cc1ccccc1
Product: O=C(C1CC1)N1CCCCc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21

Procedure:
To 200 ml dry toluene is added 6.3 g (0.020 mole) α,α-bis(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-7-methanol and 3.0 g (0.025 mole) cyclopropane carboxylic acid chloride. The solution is stirred and heated at reflux under nitrogen for sixteen hours, then cooled and evaporated at reduced pressure. The residual solid is recrystallized from chlorobutane to give 5.0 g, m.p. 165°-167°.