Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:13]([C:24](O)=[O:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:27][C:28]1[CH:41]=[CH:40][C:31]([O:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:27][C:28]1[CH:41]=[CH:40][C:31]([O:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:24]([C@@H:13]3[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[CH2:16][CH2:15][N:14]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:25])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100.4 %

Procedure:
Step (a) A flask was charged with (S)-4-(benzyloxycarbonyl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1 g, 2.74 mmol), obtained commercially, 4-(4-fluorophenoxy)aniline (558 mg, 2.75 mmol), DIEA (3 mL, 17.3 mmol), HATU (1.15 g, 3.03 mmol) and DMF (8 mL). The reaction mixture was stirred at ambient temperature for 20 minutes and then quenched with saturated sodium bicarbonate (aq., 10 mL). The mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 mL) and then brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-4-benzyl 1-tert-butyl 2-(4-(4-fluorophenoxy)phenylcarbamoyl)piperazine-1,4-dicarboxylate (1.46 g, 2.75 mmol), which was carried forward without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([N+:11]([O-])=O)=[CH:6][CH:5]=2.NN>[Pd].C(O)C>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Cc1cc2cc(N)ccc2[nH]1
Temperature: 80 °C

Procedure:
To a mixture of 2-methyl-5-nitroindole (200 mg, 1.13 mmol) and palladium on carbon (20 mg, 10%) in 10 mL of ethanol was added hydrazine (100 mg, 3.4 mmol) and heated at 80° C. for 16 hours. The reaction mixture was filtered through celite and concentrated in vacuo to provide a red-brown solid which was used without further purification. RP18-HPLC RT: 1.278 minutes; API MS: 147.1 (M+1).
Reaction SMILES: C1(C)C=CC=CC=1.S(Cl)([Cl:10])=O.[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[O:26][CH:27]([F:29])[F:28])[C:20](O)=[O:21])[CH2:14][CH2:13]1>CN(C=O)C>[CH:12]1([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=2[O:26][CH:27]([F:29])[F:28])[C:20]([Cl:10])=[O:21])[CH2:14][CH2:13]1
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
A reaction vessel is charged with toluene, a catalytic amount of DMF (1-5% by weight of the amount of thionyl chloride employed) and 1 equivalent of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid. While stirring, 1 to 4 equivalents of thionyl chloride are slowly added at 70 to 90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][CH2:12][CH2:13][CH2:14][Cl:15]>CO>[Cl:1][C:2]1[C:3]([S:11][CH2:12][CH2:13][CH2:14][Cl:15])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: O=[N+]([O-])c1cccc(Cl)c1SCCCCl
Solvent: CO
Product: Nc1cccc(Cl)c1SCCCCl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
The crude 1-chloro-2-[(3-chloropropyl)sulfanyl]-3-nitrobenzene was dissolved in MeOH (150 mL) and degassed with N2. Palladium hydroxide (1.8 g) was added in four portions to this solution in a Parr appararus. The resulting heterogeneous solution was shaken under hydrogenation conditions (55 psi) at room temp for 18 h. The catalyst was removed via filtration in the same manner as above and the filtrate was concentrated in vacuo. to afford 3-chloro-2-[(3-chloropropyl)sulfanyl]aniline (9.94 g, 93%) as a dark oil: 1H NMR (CHCl3, 300 MHz) δ7.03 (t, 1H, J=8.1 Hz), 6.82 (t, 1H, J=8.1 Hz), 6.63 (t, 1H, J=8.0 Hz), 4.62 (br s, 1H), 3.68 (t, 2H, J=6.4 Hz), 2.92 (t, 2H, J=6.9 Hz), 1.98 (quintet, 2H, J=6.6 Hz) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH:14](=O)[CH2:15][CH:16]([CH3:18])[CH3:17].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: CC(C)CC=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
(1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.5 g, 2.7 mmol) was dissolved in methanol (25 mL). Isovaleraldehyde (0.233 g, 2.7 mmol) was added followed by acetic acid (1 mL). The solution continued to stir at 25° C. for 10 min. Sodium cyanoborohydride (0.424 g, 6.75 mmol) was added and the mixture was stirred at 25° C. for 5 h. The mixture was poured into aqueous half-saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-(3-methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.43 g, 1.7 mmol, 63%), as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C15H27NO2 253.2, found 254.1 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8](Cl)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.Cl.[Cl:17][C:18]1[C:19]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:20][CH:21]=[CH:22][CH:23]=1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([N:27]3[CH2:28][CH2:29][N:24]([C:19]4[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:25][CH2:26]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: Clc1cccnc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (210 mg, 0.7 mmol), 1-(3-chloropyridin-2-yl)piperazine hydrochloride (187 mg, 0.8 mmol, Example 3b) and N,N-diisopropylethylamine (0.28 mL, 1.6 mmol, Aldrich) were reacted under the conditions of Example 3c to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:18])[CH:12]([OH:17])[C:13]([OH:16])([CH3:15])[CH3:14])(=O)[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH2:5]([NH:10][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:18])[CH:12]([OH:17])[C:13]([OH:16])([CH3:15])[CH3:14])[CH3:2])[CH:4]=[CH2:1]
Reactant: CC(=O)c1ccccc1NC(=O)C(O)C(C)(C)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCNC(C)c1ccccc1NC(=O)C(O)C(C)(C)O

Procedure:
Prepared analogously to Example 11, starting with the product of Example 13 in 29% isolated yield (mixture of diastereomers), from flash column chromatography in ethyl acetate-hexane (3:2 to 4:1). 1H NMR (250 MHz, CDCl3) δ 8.35-8.18 (m, 1H), 7.30-7.19 (m, 1H), 7.15-6.98 (m, 2H), 5.99-5.77 (m, 1H), 5.23-5.03 (m, 2H), 4.06-3.91 (m, 2H), 3.13 (d, J=5.6 Hz, 2H), 1.42 (d, J=6.7 Hz, 3H), 1.31 (s, 3H), 1.29 (d, J=2.5 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:9][S:10]([C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=2)[C:16]([O:18]CC[Si](C)(C)C)=[O:17])(=[O:12])=[O:11])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:28](I)([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1.O.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([N:9]([CH:28]([CH3:30])[CH3:29])[S:10]([C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=2)[C:16]([OH:18])=[O:17])(=[O:11])=[O:12])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(N(C(C)C)S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of 450 mg of 2-(trimethylsilyl)ethyl 3-{[1-(ethoxycarbonyl)cyclopropyl]sulfamoyl}benzoate, 0.22 mL of isopropyl iodide, 451 mg of potassium carbonate, and 4.5 mL of DMF were stirred at 65° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a pale yellow oily substance. To the obtained oily substance were added a solution of TBAF in THF (1.0 M, 2.0 mL) and 4.5 mL of THF, followed by stirring at room temperature for 2 hours. To the reaction mixture was added 0.2 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 0.2 M hydrochloric acid, water, and saturated brine in this order, and then dried over anhydrous sodium sulfate. The resultant was concentrated under reduced pressure to obtain 319 mg of 3-{[1-(ethoxycarbonyl)cyclopropyl](isopropyl)sulfamoyl}benzoic acid as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=[CH:7]2
Reactant: CCOC(=O)CBr
Reactant: Fc1cccc2cn[nH]c12
Product: CCOC(=O)Cn1ncc2cccc(F)c21

Procedure:
The title compound was prepared according to the method described for Preparation 93 using 7-fluoro-1H-indazole and ethyl bromoacetate to afford the title compound as an off-white solid in 41% yield, 200 mg.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C@H:5](O)[CH2:4][C@H:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1.C1(=O)OC(=O)CC1.N1C=CC=CC=1>CN(C)C=O>[CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C@H:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1
Reactant: CN1C(=O)[C@H](O)C[C@H]1c1cccnc1
Agent: O=C1CCC(=O)O1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@H]1c1cccnc1
Reaction time: 8 h

Procedure:
Cotinine hemisuccinate was prepared by dissolving 19 mg of trans-3'-hydroxycotinine in 1 ml of dimethylformamide (Aldrich). 21 mg of succinic anhydride (Aldrich) were added, followed by 15 μl of pyridine (Aldrich). The mixture was incubated overnight at 45° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([CH2:16][CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:18]O)[CH:12]=[CH:11]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42]N1C(=O)CCC1=O>ClCCl>[Br:42][CH2:18][CH:17]([CH:20]([CH3:22])[CH3:21])[CH2:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[CH:8][CH:7]=[C:6]2[O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCOc1cccc2ccc(CC(CO)C(C)C)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCOc1cccc2ccc(CC(CBr)C(C)C)cc12
Reaction time: 4 h

Procedure:
A solution of 0.30 g of 2-[8-(2-methoxyethoxy)naphthalen-2-ylmethyl]-3-methylbutan-1-ol in 10 ml of dichloromethane at 0° C. is admixed with 0.29 g of triphenylphosphine and 0.20 g of N-bromosuccinimide. After 4 hours, the reaction mixture is concentrated by evaporation to a volume of approx. 3 ml, diluted with hexane, clarified by filtration and then concentrated fully by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: C([O:3][C:4](=[O:15])[C:5]([S:8]([N:11]1[CH2:14][CH2:13][CH2:12]1)(=[O:10])=[O:9])([CH3:7])[CH3:6])C.C[Si](C)(C)[O-].[K+]>C1COCC1.Cl>[N:11]1([S:8]([C:5]([CH3:7])([CH3:6])[C:4]([OH:15])=[O:3])(=[O:10])=[O:9])[CH2:12][CH2:13][CH2:14]1
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)N1CCC1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)N1CCC1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a solution of 5 g (21 mmol) of 2-(azetidine-1-sulfonyl)-2-methyl-propionic acid ethyl ester in THF (200 mL) at room temperature are added 8.2 g (64 mmol) of potassium trimethylsilanolate. The reaction is stirred for 1 h. The mixture is diluted with 1M aqueous HCl solution (50 mL) and extracted with DCM (250 mL). The organic phase is dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure to provide 4.1 g of 2-(azetidine-1-sulfonyl)-2-methyl-propionic acid as a white solid. Yield: 94%, ES-MS: m/z 208 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([O:9][CH2:18][CH3:19])=[O:8]
Reactant: CCO
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1cccc(Br)c1

Procedure:
Trans m-bromocinnamic acid (14.8 g), ethanol (173 ml) and concentrated sulfuric acid (0.4 ml) were combined and heated at reflux for 15 hours. About 150 ml of the ethanol was distilled off, and the remaining solution was poured into ice/water (140 ml). The cold mixture was made strongly alkaline with 40% sodium hydroxide and extracted with methylene chloride (4 × 60 ml). The combined methylene chloride extract was dried over anhydrous potassium carbonate. The potassium carbonate was removed by filtration and the solvent stripped off under reduced pressure. Trans ethyl 3-bromocinnamate, was obtained as a partially solidified oil. (IR spectrum was consistent with this compound).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][CH2:8][N:7]([C:12](=[O:14])[CH3:13])[C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][C:31]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:41])=[CH:19][N:18]=1>>[C:12]([N:7]1[C:6]2[CH:15]=[C:2]([NH:1][C:17]3[N:22]=[C:21]([NH:23][C:24]4[C:33]([F:34])=[CH:32][C:31]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)=[CH:30][C:25]=4[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:41])=[CH:19][N:18]=3)[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][CH2:9][CH2:8]1)(=[O:14])[CH3:13]
Reactant: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)N1CCCOc2ccc(N)cc21
Product: CNC(=O)c1cc(-c2cnn(C)c2)cc(F)c1Nc1nc(Nc2ccc3c(c2)N(C(C)=O)CCCO3)ncc1Cl

Procedure:
2-[2-(9-Acetyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide was prepared from 1-(2-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl)-ethanone and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-5-(1-methyl-1H-pyrazol-4-yl)-benzamide in an analogous manner to Example 1410. Product isolated as a pale yellow solid (140 mg, 72%). m.p.=172-177° C.; LCMS (m/e) 565 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.85 (bs, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.89-7.81 (m, 2H), 7.45 (s, 1H), 7.38 (d, 1H, J=11.5 Hz), 7.03-6.87 (m, 3H), 6.60-6.50 (m, 1H), 4.65-4.50 (m, 1H), 4.43-4.29 (m, 1H), 4.01 (s, 3H), 3.63-3.47 (m, 1H), 3.00 (d, 3H, J=4.8 Hz), 2.55-2.37 (m, 1H), 2.23-2.06 (m, 1H), 1.87 (s, 3H), 1.72-1.57 (m, 1H); 19F-NMR (CDCl3, 400 MHz) 6-111.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:30]1([CH3:42])[CH:35]=[CH:34][C:33]([S:36]([N:39]=[C:40]=[O:41])(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:42][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[O:41])(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)cc1
Yield: 87 %

Procedure:
To a suspension of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine (2 g, 0.005 mol) in 15 ml of methylene chloride under nitrogen is added dropwise a solution of p-tolylsulfonyl-isocyanate in 10 ml of methylene chloride over a period of 10 minutes. After complete addition, the resultant suspension is stirred at room temperature for 1 hour. The white solid is filtered, washed with more methylene chloride, and dried giving 2.6 g (87%) of N-[(4-methylphenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine-1-carboxamide of melting point 253°-255° C. Infrared and mass spectra are consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5]1.[BH4-].[Na+].O.Cl>C(O)C.C(OCC)(=O)C.CCCCCC>[OH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([N:6]3[CH2:5][CH:4]([CH2:3][O:2][CH3:1])[O:8][C:7]3=[O:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1
Reactant: COCC1CN(c2ccc(C3CCC(=O)CC3)cc2)C(=O)O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COCC1CN(c2ccc([C@H]3CC[C@H](O)CC3)cc2)C(=O)O1

Procedure:
5.0 g (16.44 mmol) of (RS)-5-methoxymethyl-3-[4-(4-oxo-cyclohexyl)-phenyl]-oxazolidin-2-one were dissolved in 150 ml of ethanol while heating and, after cooling, treated while stirring with 620 mg (16.4 mmol) of sodium borohydride, cooled overnight and the solvent was subsequently distilled off. The oily residue obtained was treated with water and 1N hydrochloric acid and the reaction product was taken up in ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and the solvent was distilled off. The colorless oil obtained (5.3 g) was dissolved in ethyl acetate, treated with hexane until turbid and the separated precipitate was filtered off under suction after 1 hour. 3.3 g of an alcohol which was uniform in the nmr spectrum were obtained. M.p. 109°-110°.
Reaction SMILES: CS([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH:13]([CH3:15])[CH2:12][CH:11]([CH3:16])[CH2:10]2)[S:6][N:5]=1)=O.[CH3:17][CH:18]([OH:22])[C:19]#[C:20][CH3:21].[H-].[Na+]>CN(C)C=O.COC(C)(C)C>[CH3:17][CH:18]([O:22][C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH:13]([CH3:15])[CH2:12][CH:11]([CH3:16])[CH2:10]2)[S:6][N:5]=1)[C:19]#[C:20][CH3:21]
Reactant: CC1CC(C)CN(c2nc(S(C)=O)ns2)C1
Reactant: CC#CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC#CC(C)Oc1nsc(N2CC(C)CC(C)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.1 %

Procedure:
In 3 ml of N,N-dimethylformamide were dissolved 287 mg of 3-methylsulfinyl-5-(3,5-dimethylpiperidino)-1,2,4-thiadiazole and 103 mg of 3-pentyn-2-ol, and 58 mg of sodium hydride (oil suspension; content: 60 weight %) was added under ice-cooling. The mixture was stirred for 15 minutes and at room temperature for 1.5 hour. Furthermore, 30 mg of sodium hydride (oil suspension; content: 60 weight %) and 100 mg of 3-pentyn-2-ol were added in the mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with tert-butyl methyl ether, and extracted with tert-butyl methyl ether after the addition of water. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 297 mg of 3-(1-methyl-2-butynyloxy)-5-(3,5-dimethylpiperidino)-1,2,4-thiadiazole (hereinafter, referred to as the present compound (21)).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]([CH3:43])[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH2:26][CH2:25][N:24]([CH3:43])[CH3:23])=[CH:29][CH:30]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4ccc(OCCN(C)C)cc4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine (Combi-Blocks, Cat. No. PN-3972). LCMS (M+H)+=487.0/489.0.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[CH:9][C:10]=1[F:11])[CH:2]=[CH2:3].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[F:11])[O:12][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: C=CCOc1cc(O)ccc1F
Product: C=CCOc1cc(Oc2ccc(C=O)cc2)ccc1F

Procedure:
The product from Example 305C and 4-fluorobenzaldehyde were processed as in Example 61C to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])/[CH:5]=[CH:6]/[C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)[CH3:2]>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[C:12]([NH2:13])=[CH:11][CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1nc(-c2ccc(C(F)(F)F)cc2)ccc1N
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1N
Temperature: 40 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
2.4 g (E)-3-[3-Amino-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-acrylic acid ethyl ester were dissolved in 50 ml tetrahydrofuran. 100 mg palladium on charcoil were added and the reaction mixture was stirred under an atmosphere of hydrogen at 40° C. for 4 hours. The cooled reaction mixture was filtered and the filtrate evaporated in vacuo to obtain 2.4 g 3-[3-Amino-6-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][S:2]([C:5]1[N:6](COCC[Si](C)(C)C)[C:7]([C:11]([OH:13])=O)=[C:8]([Cl:10])[N:9]=1)(=[O:4])=[O:3].[NH2:22][CH2:23][C:24]1[C:25]([F:41])=[C:26]([O:31][C:32]2[CH:33]=[C:34]([CH:37]=[C:38]([Cl:40])[CH:39]=2)[C:35]#[N:36])[C:27]([Cl:30])=[CH:28][CH:29]=1>>[NH2:1][S:2]([C:5]1[NH:6][C:7]([C:11]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31][C:32]3[CH:33]=[C:34]([C:35]#[N:36])[CH:37]=[C:38]([Cl:40])[CH:39]=3)[C:25]=2[F:41])=[O:13])=[C:8]([Cl:10])[N:9]=1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)CCOCn1c(S(N)(=O)=O)nc(Cl)c1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(S(N)(=O)=O)nc3Cl)c2F)c1
Yield: 40.8 %

Procedure:
2-(aminosulfonyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.26 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.089 g, 0.29 mmol) were employed using a procedure similar to that described herein to provide the title compound (0.055 g, 41%) as a white solid after deprotection and purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% formic acid). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.55 (t, 1H), 7.35-7.43 (m, 2H), 7.27 (t, J=2.0 Hz, 1H), 7.24 (s, 1H), 4.63 (s, 2H). ES-LCMS: m/z 516.0, 518.0, 519.9 (M−1).