Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[OH:12].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:15]=1.O>O1CCOCC1>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][C:18]1[CH:19]=[CH:14][N:15]=[C:16]([NH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:17]=1
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(Oc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
To a suspension of NaH (0.006 mol) in 1,4-dioxane (30 ml), 2,4,6-trimethyl-phenol (0.006 mol) was added. The mixture was stirred for 15 minutes at room temperature, and a clear solution formed. 4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.004 mol) was added, and the reaction mixture was heated to reflux under Argon for 15 hours. The reaction mixture was allowed to cool to room temperature, 0.5 ml of water was added, followed by 4 g of silica gel, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH 100:0:0 to 97:3). The pure fractions were collected and the solvent was evaporated, yielding 1.18 g (89.4%) of 4-[[4-(2,4,6-trimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile (compound 58).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([NH2:34])=O)=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[NH4+]>C(Cl)Cl>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]#[N:34])=[CH:27][CH:26]=[CH:25]4)=[CH:20][CH:21]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(N)=O)cccc3c2)cc1
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C#N)cccc3c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.3 %

Procedure:
To a solution of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxamide (94 mg, 0.18 mmol) and triethylamine (0.111 mL, 0.80 mmol) in methylene chloride (2 mL) at ambient temperature under nitrogen was added phosphorous oxychloride (0.068 mL, 0.71 mmol). The mixture was stirred at ambient temperature for four hours, at which time an additional equivalent of phosphorous oxychloride (0.027 mL) was added. Ammonium hydrogen carbonate (25 mg, 0.273 mmol) was then added to the mixture and the reaction was stirred at ambient temperature for 48 hours. The solvent was then removed on a rotary evaporator and the crude residue was dissolved in ethyl acetate. The organic solution was then washed with water three times, followed by saturated sodium bicarbonate, and then brine. The crude organic extract was then dried over magnesium sulfate, filtered, and then evaporated to dryness to give the title compound (89 mg, 98%). 1H NMR (CDCl3): 8.24 (d, J=9 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 8.02 (d, J=9 Hz, 1H), 7.82-7.90 (m, 2H), 7.61-7.50 (m, 3H), 7.31-7.52 (m, 3H), 6.88 (d, J=9 Hz, 2H), 4.78 (s, 2H), 3.28-3.42 (m, 1H), 1.34-1.53 (m, 6H). ESI-LCMS m/z 513 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:10])(C(F)F)[C:3]([F:6])([F:5])[F:4].Cl[Si:12]([CH3:15])([CH3:14])[CH3:13].[CH3:16][N:17]([CH3:20])[CH:18]=[O:19]>[Zn]>[CH3:13][Si:12]([CH3:15])([CH3:14])[O:19][CH:18]([N:17]([CH3:20])[CH3:16])[C:2]([Cl:10])([Cl:1])[C:3]([F:6])([F:5])[F:4]
Reactant: CN(C)C=O
Reactant: FC(F)C(Cl)(Cl)C(F)(F)F
Reactant: C[Si](C)(C)Cl
Agent: [Zn]
Product: CN(C)C(O[Si](C)(C)C)C(Cl)(Cl)C(F)(F)F

Procedure:
Until HCFC-225a becomes available in commercial quantities, HCFC-225a may be prepared by a standard and well-known organic synthesis technique. For example, 2,2-dichloro-1,1,1,3,3-pentafluoropropane may be prepared by reacting a dimethylformamide solution of 1,1,1-trichloro-2,2,2-trifluoromethane with chlorotrimethylsilane in the presence of zinc, forming 1-(trimethylsiloxy)-2,2-dichloro-3,3,3-trifluoro-N,N-dimethy lpropylamine. The 1-(trimethylsiloxy)-2,2-dichloro-3,3,3-trifluoro-N,N-dimethyl propylamine is reacted with sulfuric acid to form 2,2-dichloro-3,3,3-trifluoropropionaldehyde. The 2,2-dichloro-3,3,3-trifluoropropionaldehyde is then reacted with sulfur tetrafluoride to produce 2,2-dichloro-1,1,1,3,3-pentafluoropropane.
Reaction SMILES: [OH:1][C:2]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C)C=O>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]([C:8]([F:11])([F:10])[F:9])([C:12]([F:13])([F:14])[F:15])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Reaction time: 144 h

Procedure:
Ethyl 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionate (12.0 g.) is added dropwise at ambient temperature to a stirred mixture of sodium hydride (2.4 g. of a 60% dispersion in oil) and dimethylformamide (100 ml.). The mixture is stirred for 4 hours 4-chlorobenzyl chloride (8.4 g.) is added, and the stirring is continued for 6 days. The mixture is filtered, and the filtrate is evaporated in vacuo. The residue is fractionally distilled at 0.1 mm. pressure, collecting the fraction, (9.9 g.) b.p. 78°-80° C., m.p. 32°-33° C, which is crystallised from pentane to give ethyl 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionate, m.p. 33° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[C:10]1([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccoc1
Reactant: Brc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccoc2)cc1
Temperature: 80 °C
Yield: 77.6 %

Procedure:
Furan-3-boronic acid (1.0 g, 8.93 mmol), bromo benzene (1.26 g, 8.04 mmol) and sodium carbonate (1.89 g, 17.86 mmol) were dissolved in a mixture of toluene (15 mL) and methanol (5 mL) and purged with argon for 15 min. Tetrakis palladium (0) (20 mg) was added and the mixture again degassed for 15 min. The reaction was heated at 80° C. for 4 h and the resultant solids which formed were filtered and the filtrate was concentrated in vacuo to give a crude residue. Purification by flash chromatography over silica gel (100-200 mesh) using 2% ethyl acetate/petroleum ether as eluent afforded 3-phenylfuran (0.9 g, 70%).
Reaction SMILES: O[CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:43]=[C:41]1[C:40]2[C:39](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:38](=[O:48])[N:42]1[CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(O)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2-hydroxy-3-phenylpropyl)carbamate (10.0 g, 39.8 mmol), PPh3 (12.5 g, 47.8 mmol) and phthalimide (6.44 g, 43.8 mmol) in THF (125 mL) at RT was added DEAD (9.4 mL, 59.7 mmol) over 5 min. After 1 h at RT, the reaction solution was concentrated and purified on silica (hexanes/EtOAc, 2:1) to give the title compound as a white solid (12.6 g, 83%): LCMS (ES) m/z 381 (M+H)+.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21](O)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]2[N:37]([CH3:38])[CH2:36][CH2:35][N:34]([CH3:39])[C:33]2=[O:40])[CH:29]=[CH:30][CH:31]=1>>[CH3:39][N:34]1[CH2:35][CH2:36][N:37]([CH3:38])[CH:32]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([NH:25][C:21]3[N:20]=[CH:19][C:18]4=[CH:17][CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)(=[O:8])=[O:7])[CH:10]=5)[N:23]4[N:22]=3)[CH:27]=2)[C:33]1=[O:40]
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCCC1
Product: CN1CCN(C)C(c2cccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)N6CCCC6)c5)n4n3)c2)C1=O

Procedure:
1,4-Dimethyl-3-(3-{7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-phenyl)-piperazin-2-one was prepared from 7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as an orange foam (82 mg, 49%). LCMS (m/e) 546 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.75 (s, 1H), 8.65 (d, 1H, J=8.2 Hz), 8.31 (s, 1H), 7.87-7.77 (m, 2H), 7.70-7.62 (m, 1H), 7.41-7.32 (m, 2H), 7.12-7.03 (m, 2H), 6.94 (s, 1H), 6.85 (d, 1H, J=4.7 Hz), 3.78-3.65 (m, 2H), 3.34-3.25 (m, 4H), 3.25-3.15 (m, 1H), 3.70-2.96 (m, 1H), 2.99 (s, 3H), 2.74-2.62 (m, 1H), 2.18 (s, 3H), 1.82-1.72 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[N:40][CH:41]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:11]2[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]3[C:5]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[N:40][CH:41]=4)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:10]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.723 g, 1.51 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (Example 190, Step 2, 0.317 g, 1.52 mmol) in THF (5 mL) was treated dropwise with LiHMDS (4.52 mL, 4.52 mmol) at 0° C. The dark red mixture was stirred at 0° C. for 30 min. Water (0.2 mL) was added to quench the reaction. The reaction mixture was partitioned between saturated aqueous ammonium chloride (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g, eluent: EtOAc in hexanes 0%-35%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-ylcarbamate (0.697 g, 69% yield) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 11.77 (s, 1H); 8.74 (d, J=2.34 Hz, 1H); 8.39 (br. s., 1H); 8.22 (s, 1H); 7.79-7.94 (m, 2H); 7.28 (br. s., 1H); 7.19 (t, J=9.28 Hz, 4H); 6.86 (dd, J=8.18, 3.95 Hz, 4H); 4.83 (d, J=11.55 Hz, 4H); 3.80 (d, J=4.97 Hz, 6H); 2.58 (s, 3H); 1.53 (s, 9H). m/z (ESI, +ve ion) 669.2 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[C:15]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16]1>ClCCl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:15]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[O:22]
Reactant: O=C1CCCC(=O)O1
Reactant: CC(C)(S)CN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(S)CNC(=O)CCCC(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.6 %

Procedure:
To a suspension of 1-Amino-2-methylpropane-2-thiol hydrochloride (1.41 g, 10 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (1.5 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and glutaric anhydride (1.14 g, 10 mmol) in anhydrous dichloromethane (20 mL) was added at 0° C. under argon atmosphere. The reaction mixture was stirred at 0° C. for 10 minutes and then at room temperature for 2 hours. The solvent was evaporated at reduced pressure and the residue was extracted with ethyl acetate and water. The combined ethyl acetate extracts were washed with 1 N HCl, dried over sodium sulfate and solvent was evaporated at reduced pressure to give colorless oil, which upon trituration with ethyl ether/hexane gave 1.57 g of the title compound as a colorless powder in 72% yield, mp 101-104° C.; 1H NMR (CDCl3): δ1.31 (s, 6H), 1.94 (m, 2H), 2.22-2.38 (m, 4H), 3.33 (d, J=6.1 Hz, 2H), 6.28 (s, 1H), 9.2 (br s, 1H; LRMS (APIMS) (m/z) 220 (M+1).
Reaction SMILES: FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C2C(=CC(OC)=C(C(OC(C)(C)C)=O)C=2)N=CC=1.[F:41][C:42]1[CH:64]=[C:63]([NH:65][C:66]([NH:68][C:69](=[O:79])[CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[C:73]([O:77][CH3:78])[CH:72]=2)=[S:67])[CH:62]=[CH:61][C:43]=1[O:44][C:45]1[C:54]2[C:49](=[CH:50][C:51]([O:59][CH3:60])=[C:52]([C:55]([NH:57][CH3:58])=[O:56])[CH:53]=2)[N:48]=[CH:47][CH:46]=1>>[NH2:65][C:63]1[CH:62]=[CH:61][C:43]([O:44][C:45]2[C:54]3[C:49](=[CH:50][C:51]([O:59][CH3:60])=[C:52]([C:55]([NH:57][CH3:58])=[O:56])[CH:53]=3)[N:48]=[CH:47][CH:46]=2)=[C:42]([F:41])[CH:64]=1.[CH3:78][O:77][C:73]1[CH:72]=[C:71]([CH2:70][C:69]([N:68]=[C:66]=[S:67])=[O:79])[CH:76]=[CH:75][CH:74]=1
Reactant: CNC(=O)c1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4cccc(OC)c4)cc3F)ccnc2cc1OC
Agent: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2cc1C(=O)OC(C)(C)C
Product: CNC(=O)c1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OC
Product: COc1cccc(CC(=O)N=C=S)c1

Procedure:
Similar to the synthesis of compound 1d, from compound 46a (50.0 mg) and 3-methoxyphenylacetyl isothiocyanate (45.5 mg), the titled compound 46 was yielded (40.1 mg, yield: 50%).
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24](Br)=[O:25].[CH:27]1([NH2:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1>>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:23][C:24]([NH:37][CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccccc1)NCC2
Reactant: NC1CCCc2ccccc21
Product: COc1cc2c(cc1OC)C(Cc1ccccc1)N(CC(=O)NC1CCCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-benzyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:10]1[S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26].[H-].[Na+].CI>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N:19]2[CH2:20][CH2:21][N:22]([CH3:2])[CH2:23][CH2:24]2)[N:10]1[S:25]([C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)(=[O:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)N2c3cccc(N4CCNCC4)c3CCC2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2c3cccc(N4CCN(C)CC4)c3CCC2C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.26 g (0.52 mmol) of 1,2,3,4-tetrahydro-2-methyl-5-(piperazin -1-yl)-1-(4-methylbenzenesulfonyl)quinoline prepared in example 14 and 67 mg (1.56 mmol, 45%) NaH was dissolved in 2 mL DMF at 0° C. After stirring 1 h at 0° C., the mixture was cooled to −78° C. and MeI was added (32 μL, 0.52 mmol). The reaction mixture was stirred over 1 night at room temperature After evaporating the solvent, the residue was dissolved in 15 mL water and extracted with EtOAc. The crude product was purified by column chromatography (eluent: CH2Cl2-MeOH 0.5%). Yield: 82 mg (38%) Rf=0.65 (CH2Cl2-MeOH 9:1).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:6](=O)[CH2:5]1)(O)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N([OH:38])N=NC=2C=1.[NH3:39]>ClCCl>[C:1]([CH:4]1[CH2:5][CH2:6][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:8]1=[O:38])(=[O:2])[NH2:39]
Reactant: N
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CC(=O)N(Cc2ccc(Cl)cc2)C1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: NC(=O)C1CCN(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of 4-carboxy-1-(4-chlorobenzyl)pyrrolidin-2-one (5.05 g, 20 mmol), EDCI (2.85 g, 22 mmol), HOBt (2.97 g, 22 mmol) and dichloromethane (100 mL) was added 0.5 M ammonia indioxane (60 mL, 30 mmol). The reaction mixture was stirred at room temperature for 15 h and washed with 2N HCl (3 times) and 2 N NaOH aqueous solution (100 mL×4). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to afford 3-carbamoyl-1-(4-chlorobenzyl)pyrrolidin-2-one (1.49 g) as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16]Cl)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[OH-].[Na+]>O1CCOCC1.C(O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH3:19])[CH2:32][CH2:31]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc2cccc(OCC(O)CCl)c2o1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(N)=O)oc23)CC1

Procedure:
There were dissolved 1.3 g (0.005 mole) of 2-carbamoyl-7-(3-chloro-2-hydroxypropoxy)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine in a mixture solvent of 10 ml of dioxane and 10 ml of ethanol, and the resulting mixture was refluxed with heating for 7 hours. After completion of the reaction, 2N-NaOH solution was added to give the free base, which was extracted from chloroform. The extract was dried with magnesium sulfate. Then, the resultant residue obtained by distilling away the solvent under reduced pressure was crystallized from chloroform and petroleum ether.
Reaction SMILES: C(O[CH:5]1[CH2:10][O:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:7][N:6]1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:22])(=O)C.[CH2:34]([SH:38])[CH2:35][CH2:36][CH3:37].B(F)(F)F.CCOCC>ClCCl>[CH2:34]([S:38][CH:5]1[CH2:10][O:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:7][N:6]1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=1)=[O:22])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCS
Reactant: CC(=O)OC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCSC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) mixture of 3.0 g 5,6-dihydro-5-acetyloxy-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoro-methyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide (prepared in D above) and 2.0 ml butanethiol in 50 ml dichloromethane was added 1.0 ml borontrifluoride etherate. The cooling bath was removed and the mixture was stirred for 1 h. The mixture was then quenched with saturated sodium bicarbonate and the phases were separated. The organic phase was washed with 1 M sodium hydroxide and saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to give 5-(butylthio)-5,6-dihydro-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide. The structure was confirmed by 1H NMR.
Reaction SMILES: CN[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C(Cl)=[O:22])CC1>O1CCCC1>[CH3:13][CH:14]1[CH2:15][C:16]1([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:17]([NH2:12])=[O:22]
Reactant: c1ccncc1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: CC1CC1(C(N)=O)c1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of 2.0 g (13.14 mmol) of N-methyl-4-nitroaniline (Aldrich) and 1.59 mL (19.72 mmol) of pyridine in 15 mL of tetrahydrofuran are added slowly 1.43 mL (15.77 mmol) of cyclopropanoyl chloride. The mixture is refluxed for 2 hours and evaporated to dryness. The residue is taken up in an ethyl acetate/water mixture and the organic phase is then dried over Na2SO4, filtered and concentrated under vacuum. The expected product is obtained in the form of a yellow oil, which is used as obtained in the following step.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:19]=[CH:18][C:8]2[O:9][CH:10]=[C:11]([CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[C:7]=2[CH:6]=1)=O.[OH-].[NH4+:21]>>[C:15]([NH:14][CH2:13][CH2:12][C:11]1[C:7]2[CH:6]=[C:5]([C:3]([NH2:21])=[O:2])[CH:19]=[CH:18][C:8]=2[O:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: COC(=O)c1ccc2occ(CCNC(C)=O)c2c1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(=O)NCCc1coc2ccc(C(N)=O)cc12
Temperature: 60 °C

Procedure:
The ester (0.1 mol) obtained in Example 62, dissolved in an aqueous 20% ammonium hydroxide solution (50 ml), is heated for 5 hours at 60° C. The reaction mixture is cooled and is then evaporated to dryness. The residue obtained is purified by chromatography on a silica gel column.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([S:19]([C:21]([F:24])([F:23])[F:22])=[O:20])[C:15]([C:25]([NH2:27])=O)=[N:14]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([S:19]([C:21]([F:24])([F:22])[F:23])=[O:20])[C:15]([C:25]#[N:27])=[N:14]1
Reactant: Cc1c(S(=O)C(F)(F)F)c(C(N)=O)nn1-c1c(F)cc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(F)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carboxylic acid amide (0.98 g) in dichloromethane (5 mL) was added triethylamine (0.63 g, 6.2 mmol) followed by trifluoroacetic anhydride (0.89 g, 4.2 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 h and quenched by addition of water (2.0 mL) at 0° C. The resulting mixture was extracted with dichloromethane after it was warmed to room temperature. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography, elution with heptanes/EtOAc, to provide 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carbonitrile as a white solid (0.85 g, 2.0 mmol, 99% in three steps). 1H NMR (400 MHz, CDCl3) δ ppm 2.45 (s, 3H), 7.55-7.63 (m, 1H), 7.76 (s, 1H). 19F NMR (376 MHz, CDCl3) δ ppm −113.3 (d, J=7.9 Hz, 0.5F), −113.0 (d, J=7.9 Hz, 0.5F), −73.9 (s, 1.5F), −73.8 (s, 1.5F), −63.9 (s, 3F).