Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:2].[N:12]1[CH:17]=[CH:16]C=[CH:14][CH:13]=1.O[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[N:12]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH2:17][CH2:16][O:2][CH2:14][CH2:13]1
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(-c2ccc(OCCCO)cc2)cc1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(-c2ccc(OCCCN3CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
TsCl (12 g) and pyridine (10 mL) were added to a chloroform (0.1 L) solution of 4′-(3-hydroxypropoxy)biphenyl-4-carbonitrile (5.1 g) as obtained in Example 4-(1), and the mixture was stirred overnight at room temperature. Chloroform was added to the reaction mixture, and the mixture was washed with a 1.0 mol/L hydrochloric acid aqueous solution and a 1.0 mol/L sodium hydrogen carbonate aqueous solution. After the organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. IPE was added to the resulting residue, and the precipitated solid was collected by filtration. Then, ethanol (40 mL) and morpholine (8.8 mL) were added, and the mixture was stirred for 1 hour at 80° C. The reaction mixture was distilled under reduced pressure, and the resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=50/50→90/10) to obtain 4′-[3-(morpholin-4-yl)propoxy]biphenyl-4-carbonitrile (light brown solid) (5.1 g, 79%).
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:11][C:12](=[O:50])[CH:13]([NH:39]C(OCC1C=CC=CC=1)=O)[CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4].[H][H].[CH:53](O)([CH3:55])[CH3:54]>[Pd]>[NH2:39][CH:13]([CH2:14][C:15]1[N:16]=[CH:17][N:18]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:19]=1)[C:12]([NH:11][CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH:2]([OH:1])[C:3]([O:5][CH:53]([CH3:55])[CH3:54])=[O:4])=[O:50]
Reactant: CC(C)CC(NC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)NC(=O)OCc1ccccc1)C(O)C(=O)O
Reactant: CC(C)O
Reactant: [H][H]
Agent: [Pd]
Product: CC(C)CC(NC(=O)C(N)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(O)C(=O)OC(C)C

Procedure:
Palladium on charcoal, 10%, 1 g, is added to 11.8 g (16.5 mmol) of 2-hydroxy-5-methyl-3-[[1-oxo-2[[(phenylmethoxy)carbonyl]amino]-3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propyl]amino]hexanoic acid (mixture of [2R-[2R*,3S*(S*)]] and [2S-[2R*,3R*(R*)]]isomers) dissolved in isopropanol and the mixture is exposed to hydrogen gas. After complete uptake of hydrogen the mixture is filtered, the solvent evaporated in vacuo and the residue co-evaporated with diethyl ether to give 9.5 g of the title compound as a beige foam after drying under high vacuum for one hour.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]1[CH:11]=CC(C)=[CH:14][CH:15]=1.P(=O)(O)(O)O.C=CC(=C)C>O.CCCCCC>[CH3:9][C:10]1([CH3:11])[CH2:15][CH2:14][C:8]2[CH:7]=[CH:6][CH:5]=[C:3]([OH:4])[C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: Cc1ccc(C)cc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCCCCC
Solvent: C=CC(=C)C
Product: CC1(C)CCc2cccc(O)c2O1
Temperature: 100 °C
Reaction time: 7 h
Yield: 11 %

Procedure:
While a mixture of 10 g of catechol, 50 ml of p-xylene, 25 ml of hexane, 1 ml of phosphoric acid and 0.3 ml of water was heated at 100° C., 7.3 g of isoprene was added dropwise over 10 minutes, and the reaction was further carried out for 7 hours. After cooling, the resulting precipitate was separated by filtration. The filtrate was concentrated, and purified by column chromatography to give 1.7 g (yield 11%) of the product as a pale pink liquid.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+]>O>[NH2:10][C:8](=[N:9][C:12](=[O:13])[O:14][CH3:15])[O:7][CH3:6]
Reactant: COC(=N)N
Reactant: COC(=O)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N=C(N)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 52 parts of 2-methylpseudourea hydrogen sulfate in 250 parts of water at 0°-5° C. is added 31 parts of methyl chloroformate followed by dropwise addition of 74 parts of 50% sodium hydroxide. The reaction mass is stirred at room temperature for 3 hours and then extracted with methylene chloride. The methylene chloride extract is dried and the solvent evaporated. The residue is triturated with hexane to give 23 parts of methyl N-(1-amino-1-methoxymethylene)carbamate melting at 36°-39.5° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1F)[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:25]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=4[F:17])=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Reactant: N#Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(F)c1
Temperature: 85 °C

Procedure:
A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (E3) (100 mg, 0.46 mmol), 3,4-difluorobenzonitrile (70 mg, 0.51 mmol) and potassium carbonate (159 mg, 1.15 mmol) in dimethylsulfoxide (2 ml) was heated at 85° C. for 2 hours. The reaction mixture was cooled and applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia/methanol (1:9). The combined basic fractions were concentrated in vacuo to afford the title compound (E271). MS (ES+) m/e 337 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]3[N:14]=[C:15]([NH2:17])[N:16]=[C:9]23)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[S:21][N:20]=1.[BH4-].[Na+].C(O)C>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]3[N:14]=[C:15]([NH:17][CH:27]4[CH2:26][CH2:25][N:24]([C:22]5[S:21][N:20]=[C:19]([CH3:18])[N:23]=5)[CH2:29][CH2:28]4)[N:16]=[C:9]23)=[CH:4][CH:3]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1nc2n(n1)CCCC2c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(Cl)Cl
Product: Cc1nsc(N2CCC(Nc3nc4n(n3)CCCC4c3ccc(F)cc3)CC2)n1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (60 mg, 0.258 mmol) and 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (76 mg, 0.387 mmol) in dry dichloroethane (3 mL) was added tetraisopropyl-orthotitanate (236 μL, 0.775 mmol) under an argon atmosphere and heated to 85° C. for 12 hours. The reaction mixture was cooled to room temperature, sodium borohydride (20 mg, 0.517 mmol) and ethanol (1.5 mL) were added and stirred at room temperature for 3 hour and at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and evaporated. An aqueous solution of Na2CO3 (2M) was added to the residue. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol (with 10% ammonia) as eluent. The title compound was obtained as a white solid (28.8 mg, 27%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:20]([F:23])([F:22])[F:21])[N:4]=1.I([O-])(=O)(=O)=[O:25].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH:2]=[O:25])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:20]([F:23])([F:22])[F:21])[CH:8]=[CH:7][CH:6]=2
Reactant: FC(F)(F)c1cccc2nc(CBr)c(-c3ccccc3Cl)nc12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1nc2cccc(C(F)(F)F)c2nc1-c1ccccc1Cl
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(bromomethyl)-3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxaline (0.5137 g, 1.279 mmol) and sodium metaperiodate (0.1416 mL, 2.558 mmol) in DMF (8.527 mL, 1.279 mmol) was heated at 150° C. with stirring. After 3 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 40% gradient of EtOAc in hexane over 20 min, then 40% isocratic of EtOAc for 5 min as eluent to give 3-(2-chlorophenyl)-5-(trifluoromethyl)quinoxaline-2-carbaldehyde as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.15 (1H, s), 8.66 (1H, dd, J=8.6, 1.2 Hz), 8.52 (1H, d, J=7.0 Hz), 8.18 (1H, t, J=8.0 Hz), 7.53-7.67 (4H, m); LC-MS (ESI) m/z 337.0 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:33][C:29]1[CH:28]=[C:27]([NH:26][S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)Nc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Lithium hydroxide monohydrate (0.030 g, 0.72 mmol) was added to a stirred solution of {4-[4-(3-chloro-phenylsulfamoyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.090 g, 0.18 mmol) in a 3:1 mixture of THF—H2O mixture (10 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {4-[4-(3-chloro-phenylsulfamoyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.082 g, 93%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.47 (br. s, 1 H), 10.60 (br. s, 1 H), 8.00 (dd, J=8.80, 6.80 Hz, 1 H), 7.88-7.92 (m, 3 H), 7.45 (d, J=8.31 Hz, 2 H), 7.29-7.40 (m, 2 H), 7.09-7.17 (m, 3 H), 6.52 (d, J=11.74 Hz, 1 H), 3.83 (s, 2 H), 2.00 (s, 3 H). MS calcd. for C25H18FClNO4S [(M−H)−] 482, obsd. 482.3.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].[OH:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CN1C(=O)CCC1.C(Cl)Cl.CO>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([N:28]3[CH2:29][CH2:30][C@H:26]([OH:25])[CH2:27]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: O[C@H]1CCNC1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: O[C@H]1CCN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)C1
Temperature: 170 °C
Reaction time: 1 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Stage 173.1, 100 mg, 0.316 mmol), KF (92 mg, 1.581 mmol) and (S)-3-hydroxypyrrolidine (83 mg, 0.949 mmol) were suspended in NMP (1.5 mL). The RM was stirred at 170° C. for 1 h. The mixture was diluted with DCM/MeOH (95:5) and washed with water (2×). The aqueous phases were further extracted with DCM/MeOH (95:5) (2×). The combined organic layer was dried over Na2SO4, filtered and concentrated. The residue was crystallized in DCM to afford the title compound as a beige solid (tR 2.63 min (conditions 13), MH+=364).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:25])[C:11]([F:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2]2.[C:26]1([O:32][C:33](=[O:36])[CH2:34][Br:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CS(C)=O>[Br-:35].[F:24][C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N+:1]([CH2:34][C:33]([O:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:36])([CH2:8][CH2:7]2)[CH2:2]1)=[O:25]
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(F)(c1ccccc1)c1ccccc1
Reactant: O=C(CBr)Oc1ccccc1
Solvent: CS(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(F)(c1ccccc1)c1ccccc1)C2)Oc1ccccc1
Product: [Br-]
Reaction time: 8 h

Procedure:
To a solution of fluoro-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester [Example 109(i)] (0.034 g, 0.1 mmol) in DMSO (0.25 ml) is added bromo-acetic acid phenyl ester (0.071 ml, 0.5 mmol). The reaction mixture is left standing at room temperature overnight. Purification is carried out by chromatography on C18 silica, eluting with water:acetonitrile to yield the titled compound as a colourless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: COc1ccc(COC(=O)c2c(N)ncnc2Cl)cc1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: COc1ccc(COC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 323.5 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (515 mg, 0.27 mmol), 4-methoxybenzyl 4-amino-6-chloropyrimidine-5-carboxylate (691 mg, 1.86 mmol), DIEA (1.77 ml, 10.16 mmol) and cesium fluoride (770 mg, 5.07 mmol) were suspended in tert-butanol (50 ml) and the mixture was heated at 80° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by flash chromatography (0 to 50%, hexane-ethyl acetate) using SP1® Purification System to give 459 mg (51% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.[OH-].[K+].O.[F:14][C:15]([F:19])([F:18])[CH:16]=O.Cl>O>[ClH:1].[F:14][C:15]([F:19])([F:18])[CH:16]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1
Reactant: O=CC(F)(F)F
Reactant: NCCc1c[nH]cn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)C1NCCc2[nH]cnc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of histamine dihydrochloride (1.0 g, 5.3 mmol) in H2O (20 mL) was cooled in an ice bath. To this suspension was added solid KOH (85%) (0.9 g, 16 mmol) followed by trifluoroacetaldehyde hydrate (0.5 g, 5.3 mmol). The reaction was allowed to warm to rt and heated to 80° C. After 6 h, the reaction was cooled to rt, acidified using 6N HCl, and concentrated. The resulting residue was dissolved in hot EtOH and filtered through Celite©. The solvent was evaporated to give the product as the HCl salt. This was purified by dissolving in minimal water and loading on silica (SiO2; MeOH(NH3):DCM) to give the title compound (0.6 g, 45%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:38][C@@H:39]([C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=1)[CH2:40][N:41]([CH3:54])[S:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[N+:51]([O-:53])=[O:52])(=[O:44])=[O:43]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:3]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:38][C@@H:39]([C:55]3[CH:60]=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)[CH2:40][N:41]([CH3:54])[S:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[N+:51]([O-:53])=[O:52])(=[O:43])=[O:44])=[O:20])=[C:16]([F:23])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:6][N:7]=1
Reactant: Nc1ncc(C2CCOCC2)nc1-c1ccc(C(=O)O)c(F)c1
Reactant: CN(C[C@@H](N)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.2 %

Procedure:
To a solution of 4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzoic acid (1.55 g, 4.88 mmol) in DMF (16.28 mL) was added HOAt (0.997 g, 7.33 mmol), EDC (1.498 g, 7.82 mmol) DIEA (2.61 m l, 14.65 mmol) and (S)—N-(2-amino-2-(3-chlorophenyl)ethyl)-N-methyl-2-nitrobenzenesulfonamide (2.084 g, 5.13 mmol). The reaction mixture was stirred at room temperature for 3 h, and LCMS indicated the reaction was completed. The reaction mixture was diluted with EtOAc, and the organic was washed by sat.Na2CO3, water and brine, dried over Na2SO4, filtered off, and concentrated. The crude material was purified by flash chromatography eluting with 50% DCM/EtOAc (10% methanol) to provide (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(1-(3-chlorophenyl)-2-(N-methyl-2-nitrophenylsulfonamido)ethyl)-2-fluorobenzamide (2.68 g, 4.01 mmol, 82%). LCMS: 669.1 (MH+), 0.95 min.
Reaction SMILES: C[N:2](C)/[CH:3]=[C:4](\[C:8]([F:11])([F:10])[F:9])/[C:5](=O)[CH3:6].O.[NH2:14]N>C(O)C>[CH3:6][C:5]1[C:4]([C:8]([F:11])([F:10])[F:9])=[CH:3][NH:2][N:14]=1
Reactant: NN
Reactant: CC(=O)/C(=C/N(C)C)C(F)(F)F
Solvent: O
Solvent: CCO
Product: Cc1n[nH]cc1C(F)(F)F
Temperature: 75 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (Z)-4-(dimethylamino)-3-(trifluoromethyl)but-3-en-2-one (compound 262.1, 2.0 g, 11.0 mmol) in ethanol (30 mL). Hydrazine hydrate (3.7 mL, 77 mmol) was added and the resulting solution was stirred overnight at 75° C., then cooled and concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1:2) as eluent to obtain the title compound as a white solid (1.0 g, 61%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][CH:16]([CH3:19])[CH2:17][NH2:18]>>[OH:15][CH:16]([CH3:19])[CH2:17][NH:18][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(O)CN
Product: CC(O)CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 2-hydroxypropylamine to provide 4-(2-hydroxypropylamino)-3-nitroquinoline.
Reaction SMILES: ClC1C=CC=CC=1C1C=CN=CC=1N(CCS(C)(=O)=O)[C:15](=[O:30])[C:16]1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[NH2:37][C:38]1[CH:39]=[C:40]([CH:58]=[C:59]([C:61]([F:64])([F:63])[F:62])[CH:60]=1)[C:41]([N:43]([CH3:57])[C:44]1[CH:45]=[N:46][CH:47]=[CH:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[CH3:56])=[O:42].BrCCO>>[OH:30][CH2:15][CH2:16][NH:37][C:38]1[CH:39]=[C:40]([CH:58]=[C:59]([C:61]([F:64])([F:62])[F:63])[CH:60]=1)[C:41]([N:43]([CH3:57])[C:44]1[CH:45]=[N:46][CH:47]=[CH:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[CH3:56])=[O:42]
Reactant: CS(=O)(=O)CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Reactant: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(N)cc(C(F)(F)F)c1
Agent: OCCBr
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(NCCO)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 85, intermediate c, from 3-amino-N-methyl-N-(4-o-tolylpyridin-3-yl)-5-(trifluoromethyl)benzamide (example 164) and 2-bromoethanol after a reaction time of 48 hours at 80° C. Light yellow oil (11%). MS (ESI): m/z=430.175 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[NH:31][C:32](=[O:35])[CH2:33]Cl)[C:25]([OH:27])=[O:26].O>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][CH2:33][C:32]([NH:31][C:30]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[Cl:21])=[O:35])=[N:5][N:6]=1
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Reactant: O=C(CCl)Nc1ccc(C(=O)O)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nnc(SCC(=O)Nc2ccc(C(=O)O)cc2Cl)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 75.5 %

Procedure:
Compound 4 (789 mg, 2.79 mmol) and 3-chloro-4-(2-chloroacetamido)benzoic acid (5) (693 mg, 2.79 mmol) were dissolved in DMF (6 mL) and the mixture was stirred at 50° C. for 18 hours. Water was then added and the mixture extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to give 1.04 g, 75% yield of 4-(2-(5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid (6).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)O)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(N(S(F)(F)[F:48])CC)C>C(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=3)([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[F:48])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCOc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Solvent: ClCCl
Product: CCCOc1ccc(CN2CCC(C(F)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.1 %

Procedure:
A stirred solution of 0.6 gram (0.001 mole) of N-(4-propoxyphenylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (prepared in Example 10) in 15 mL of methylene chloride was cooled to -78° C., and 0.15 mL (0.001 mole) of diethylaminosulphur trifluoride (DAST) was added via a syringe. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time, the reaction mixture was poured into ice-water. The mixture was then extracted with two 50 mL portions of methylene chloride. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with mixtures of 5-15% acetone in methylene chloride as the eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.1 gram of N-(4-propoxyphenylmethyl)-4-[bis(4-trifluoromethoxyphenyl)fluoromethyl]piperidine. The NMR spectrum was consistent with the proposed structure.