Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:34]([C:36]1[CH:37]=[CH:38][C:39]([O:45][CH3:46])=[C:40](B(O)O)[CH:41]=1)=[O:35].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:38]3[C:39]([O:45][CH3:46])=[CH:40][CH:41]=[C:36]([CH:34]=[O:35])[CH:37]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C=O)cc1B(O)O
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C=O)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (0.50 g, 0.84 mmol), 5-formyl 2-methoxy phenyl boronic acid (0.22 g, 1.25 mmol), tetrakis(triphenylphosphine) palladium (48 mg, 5% mol) and sodium carbonate (0.19 g, 1.84 mmol) in 20 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (CH2Cl2:hexane/1:1) showed that the reaction was over. The solvents were removed. Water (30 ml) was added. The organic was extracted with methylene chloride (3×40 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/3:7 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 1:1 mixture of atropisomers 9.95 (s, 1H), 7.62-7.98 (m, 6H), 7.42 (m, 1H), 7.17 (m, 2H), 5.65 (d, J=8 Hz, 0.5H), 5.20 (d, J=8 Hz, 0.5H), 4.96 (d, J=15.5 Hz, 0.5H), 4.92 (d, J=16.5 Hz, 0.5H), 3.85-4.10 (m, 2H), 3.98 (s, 1.5H), 3.92 (s, 1.5H), 0.59 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=6 Hz, 1.5H).
Reaction SMILES: C[O-:2].[Na+].C([C@@H]1CC[C@@H](C)C[C@H]1OC([N:17]1[CH:22]=[CH:21][CH2:20][C:19](=O)[C@H:18]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH3:31])=O)(C)C>CO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C@H:18]2[CH2:19][C:20](=[O:2])[CH:21]=[CH:22][NH:17]2)=[C:25]([CH3:31])[CH:26]=1
Reactant: Cc1cc(F)ccc1[C@@H]1C(=O)CC=CN1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1CC(=O)C=CN1
Yield: 161 %

Procedure:
Sodium methoxide (100 mg) was added to a solution of intermediate 6b (170 mg) in MeOH (15 mL) under a nitrogen atmosphere. The mixture was refluxed for two hours, and the solvent was removed in vacuo. The residue was partitioned between water (10 mL) and AcOEt (15 mL). The layers were separated, and the aqueous phase was extracted with further AcOEt (4×10 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to give the title compound (145 mg) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=C1Cc2ccc(Br)cc2N1
Product: O=C1Cc2cc(S(=O)(=O)Cl)c(Br)cc2N1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Chlorosulphonic acid (30 mL) is taken, cooled to 0° C. cooled and combined with 8 g of 6-bromoindolinone with vigorous stirring. The ice bath is removed and the mixture is stirred for a further 16 h at RT. The reaction mixture is slowly poured onto ice with vigorous stirring, the precipitate formed is filtered off and dried in the vacuum dryer. 6-Bromindolinone-5-sulphonyl chloride is obtained as crude product, which is further used directly.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:15]([NH:17][C@@H:18]([C:20]([NH:22][C@H:23]3[CH2:27][C:26](=[O:28])[O:25][C@@H:24]3[O:29]CC3C=CC=CC=3)=[O:21])[CH3:19])=[O:16])[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:15]([NH:17][C@H:18]([C:20]([NH:22][C@H:23]([CH:24]=[O:29])[CH2:27][C:26]([OH:28])=[O:25])=[O:21])[CH3:19])=[O:16])[NH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](NC(=O)c1nc(CCCc2ccccc2)c[nH]1)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](NC(=O)c1nc(CCCc2ccccc2)c[nH]1)C(=O)N[C@H](C=O)CC(=O)O
Yield: 52.7 %

Procedure:
A mixture of (2R,S,3S)N2-[4-(3-Phenylpropyl)imidazole-2-carbonyl]-N-(tetrahydro-2-benzyloxy-5-oxo-3-furanyl)-L-alaninamide (0.93 g, 1.90 mmol) and 1:0% palladium on activated carbon (0.93 g) in methanol (100 ml) was stirred under a hydrogen atmosphere for 5 h. The resulting mixture was filtered and concentrated to yield a colorless glass. Recrystallization from methanol-diethyl ether afforded 401 mg (53%) of 20d as a colorless solid: mp. 94-96° C.; [α]D27 +16.4° (c 0.5, MeOH); IR (KBr) 3300, 3287, 1786, 1732, 1659, 1651, 1532, 1451; 1H NMR (CD3OD) δ 7.19 (5H, m), 6.91 (1H, s), 4.60-4.46 (2H, m), 4.27 (1H, m), 2.63 (4H, m), 2.75-2.40 (2H, m), 1.96 (2H, m), 1.44 (3H, d, J=7.0).
Reaction SMILES: Br.[C:2]1([C:8]2[N:9]=[C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:22])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>C1COCC1.C(O)(=O)C.CCN(CC)CC.CO>[CH:20]([N:16]1[CH2:17][CH2:18][CH:13]([C:10]2[S:11][CH:12]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:9]=2)[CH2:14][CH2:15]1)([CH3:22])[CH3:19]
Reactant: CC(C)=O
Reactant: c1ccc(-c2csc(C3CCNCC3)n2)cc1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 24.5 mg (0.1 mmol) 4-(4-phenyl-thiazol-2-yl)-piperidine hydrobromide, excess acetone and excess sodium triacetoxyborohydride in 1 ml THF and 20 μl acetic acid was stirred at room temperature for 16 h. After addition of 0.2 ml water, 0.2 ml methanol and 0.15 ml NEt3 the mixture was purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water (0.1% NEt3) to yield after evaporation of the product fractions 12.8 mg (45 %) of the title compound. (m/e): 287.3 (MH+; 100%).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:20]=[CH:19][C:9]([CH2:10]P(=O)(OCC)OCC)=[CH:8][CH:7]=1)([O-:5])=[O:4].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.C(OCC)(=O)C>CN(C)C=O>[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:24](/[CH:25]=[CH:10]/[C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:20][CH:19]=2)[CH:23]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(/C=C/c2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
A suspension of 677 mg of sodium hydride (55% dispersion in oil) in 10 ml of N,N-dimethylformamide is cooled to 0° C. Thereupon, 5.61 g (20.5 mmol) of diethyl (4-nitrobenzyl)phosphonate are added portionwise. The reaction mixture is left to warm to RT and stirred for 1.5 hours. Thereafter, the mixture is cooled to −10° C. and a solution of 1.5 g (12.1 mmol) of 3-fluorobenzaldehyde in 5 ml N,N-dimethylformamide is added dropwise. Stirring is continued for 30 min at 0° C., then at RT. For the working-up, ice and ethyl acetate are added to the reaction mixture. The organic layer is separated, dried over magnesium sulfate and evaporated under reduced pressure to yield the crude crystalline product, which after recrystallisation from a mixture of ether and heptane gives 2.41 g (82% of theory) of (E)-1-fluoro-3-[2-(4-nitrophenyl)ethenyl]-benzene as a yellow solid; MS: m/e=243(M)+.
Reaction SMILES: C(NCCCC)CCC.C(NNC1C=CC(N=C=S)=CC=1)=O.[CH:23]([NH:25][NH:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:36]([CH2:44][C:45]2C=CC=[CH:47][CH:46]=2)[CH2:37][C:38]2C=CC=[CH:40][CH:39]=2)=[S:35])=[CH:29][CH:28]=1)=[O:24]>>[CH:23]([NH:25][NH:26][C:27]1[CH:28]=[CH:29][C:30]([NH:33][C:34]([N:36]([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:37][CH2:38][CH2:39][CH3:40])=[S:35])=[CH:31][CH:32]=1)=[O:24]
Reactant: O=CNNc1ccc(NC(=S)N(Cc2ccccc2)Cc2ccccc2)cc1
Agent: O=CNNc1ccc(N=C=S)cc1
Solvent: CCCCNCCCC
Product: CCCCN(CCCC)C(=S)Nc1ccc(NNC=O)cc1

Procedure:
Di-n-butylamine (0.13 g, 0.001 mole) and 4-(2-formylhydrazino)phenyl isothiocyanate (0.19 g, 0.001 mole) were reacted according to the procedure described for NA-11 in Example 3. Yield 0.10 g (31 percent), m.p. 139°-141° C.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([C:37]([N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[O:38])[CH:34]=[CH:35][CH:36]=1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:30][C:31]3[CH:32]=[C:33]([C:37]([N:39]4[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]4)=[O:38])[CH:34]=[CH:35][CH:36]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(C(=O)c2cccc(N)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(C(=O)N4CCN(C)CC4)c3)nn12
Yield: 21.1 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and (3-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone (0.191 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 40.55 mg of {3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-(4-methyl-piperazin-1-yl)-methanone as a lyophilized powder. (M+H)=443.9. 1H NMR (400 MHz, DMSO, d6) δ 9.63 (s, 1H), 8.99 (s, 1H), 7.76 (m, 3H), 7.45 (t, 1H, J=7.12 Hz), 7.30 (t, 1H, 7.84 Hz), 7.18 (d, 1H, J=8.25 Hz), 7.08 (t, 1H, J=7.45 Hz), 6.96 (m, 3H), 4.05 (m, 2H), 3.81 (s, 3H), 3.44 (m, 2H), 3.19 (m, 2H), 2.99 (m, 2H), 2.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:25])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:21]=[C:20]([C:22](O)=[O:23])[O:19][N:18]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][O:28][C:29](=[O:36])[C@@H:30]([NH2:35])[CH2:31][CH:32]([CH3:34])[CH3:33].[K+].[Br-]>>[CH3:27][O:28][C:29](=[O:36])[C@@H:30]([NH:35][C:22]([C:20]1[O:19][N:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:25])=[CH:16][CH:15]=2)[CH:21]=1)=[O:23])[CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2cc(C(=O)O)on2)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)no1
Yield: 69.5 %

Procedure:
The title compound was prepared from 3-{4-[3-(4-fluoro-phenyl)-ureido]-phenyl}-isoxazole-5-carboxylic acid and (S)-2-amino-4-methyl-pentanoic acid methyl ester hydrochloride using the procedure as set forth in Example 5 and was obtained in 69.5% yield. Mass (ES+): 469 (M++1); IR (KBr): 3312 (br), 2960, 1743, 1665 (br), 1612, 1597, 1542 (br), 1508; 1H NMR (DMSO-d6) δ: 0.85, 0.90 (2×d, 6H), 1.59 (m, 2H), 1.79 (m, 1H), 3.64 (s, 3H), 4.47 (m, 1H), 7.11 (t, 1H), 7.45 (m, 2H), 7.58 (d, 2H), 7.60 (s, 1H), 7.82 (d, 2H), 8.78 (sr, 1H), 8.95 (s, 1H), 9.32 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9](=O)[CH2:10][CH2:11][C:12](=O)[CH3:13].CC(O)=O>Cl>[CH3:13][C:12]1[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([CH3:8])=[CH:10][CH:11]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(C)n1-c1ccccc1
Yield: 12.7 %

Procedure:
A 25 mL round-bottom flask was charged with aniline (1 mL, 8.77 mmol), hexane-2,5-dione (4 mL, 43.86 mmol) and AcOH (5 mL). The reaction mixture was refluxed for 4 hrs. The mixture was diluted with HCl (10%) and extracted with EtOAc. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to give 190 mg of compound 4 (75%). MS [M++1]=172, LC-MS: tR=2.54 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:22]=[N:23][N:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[C:25]=2[CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:39](O)=[O:40])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC.[BH4-].[Na+]>C1COCC1.C(=O)([O-])O.[Na+].CO>[OH:40][CH2:39][C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:22]=[N:23][N:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[C:25]=2[CH2:26][O:27][CH2:28][CH2:29][O:30][CH3:31])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]1
Reactant: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: COCCOCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](CO)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[({5-[(2-methoxyethoxy)methyl]-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl}carbonyl)(2-methylpropyl)amino]piperidine-3-carboxylic acid (900 mg) and 1-methylmorpholine (274 μl) were dissolved in THF (5 ml), ethyl chlorocarbonate (230 μl) was added under ice-cooling and the mixture was stirred at 0° C. for 1 hr. Sodium tetrahydroborate (200 mg) and methanol (2 ml) were added to the reaction mixture, and the mixture was further stirred at room temperature for 14 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-90:10) was concentrated under reduced pressure to give the object product (704 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH3:15])[N:13]=[C:12]([NH:16][C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:6][CH:5]=1.[CH3:32]I>CN(C)C=O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH3:15])[N:13]=[C:12]([N:16]([CH3:32])[C:17](=[O:25])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[CH:6][CH:5]=1
Reactant: CI
Reactant: Cn1nc(NC(=O)Cc2ccccc2)c(-c2ccncc2)c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)Cc1ccccc1)c1nn(C)c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
While 2 1m of a dimethylformamide suspension containing 20 mg of 60% sodium hydride was being cooled with ice, 3 ml of a dimethylformamide solution containing 180 mg of 5-(4-fluorophenyl)-1-methyl-3-phenylacetylamino-4-(4-pyridyl)pyrazole was added dropwise thereto, followed by stirring at room temperature for 30 minutes. Then, 2 ml of a dimethylformamide solution containing 80 mg of methyl iodide was added dropwise thereto, followed by stirring at room temperature for 2 hours. After the dimethylformamide was distilled off under reduced pressure, the resulting residue was purified by column chromatography using 30 g of silica gel [with an elution solvent comprising chloroform-methanol (70:1)]. Thus, 149.2 mg (80% yield) of the title compound was obtained as pale-yellow crystals.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N-:26]=[C:27]=[O:28]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:27]([NH:26][CH:4]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:5]2)=[O:28])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: [N-]=C=O
Reactant: Fc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)c(C(F)(F)F)c1
Agent: Cl
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccc(Cl)cc2)c2ccc(F)cc2C(F)(F)F)C1

Procedure:
This material was prepared 3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]azetidine hydrochloride (125) and the corresponding isocyanate using the procedure described for compound (10).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][S:11]([O-:13])=[O:12].[Na+].CNCCNC>CS(C)=O.[Cl-].[NH4+].[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O>[CH3:10][S:11]([C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CS(=O)[O-]
Reactant: N#Cc1ccc(Br)cn1
Agent: [Cu+2]
Agent: CNCCNC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C#N)nc1
Temperature: 115 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-pyridine-2-carbonitrile (500 mg, 2.73 mmol) in DMSO (10 mL) in a microwave tube was added 85% sodium methanesulfinate (525 mg, 4.37 mmol) followed by copper (II) triflate (990 mg, 2.74 mmol) and dimethylethylene diamine (890 μL, 8.36 mmol). The mixture was warmed in a microwave reactor at 115° C. After 30 minutes, the mixture was diluted with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (2×15 mL), brine (3×15 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was triturated with ether to afford 5-methanesulfonyl-pyridine-2-carbonitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[NH2:25].[CH3:26][N:27](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:25][C:3]1[CH:4]=[C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[C:26]#[N:27]
Reactant: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a solution of 2-bromo-5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenylamine (Example I3) (0.840 g, 1.84 mmol) in N,N-dimethylformamide (3 ml) under a nitrogen atmosphere was added zinc(II) cyanide (0.346 g, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.255 g, 0.22 mmol). The reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with toluene and the phases were separated. The aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine and aqueous ammonium hydroxide (saturated), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:5) to give 2-amino-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzonitrile (0.480 g, 36% yield). 1H-NMR (CDCl3, 400 MHz): 7.45 (m, 4H), 7.08 (s, 1H), 6.95 (q, 1H), 4.52 (s, 2H), 4.02 (d, 1H), 3.62 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[N:16]4[CH:17]=[C:18]([CH:21]([N:26]5[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]5)[C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1.C(N(CC)CC)C>CC(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:22]([F:24])([F:25])[CH:21]([N:26]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]1)[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([C:43]5[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=5)=[CH:3][CH:4]=4)[N:9]=3)=[N:13][N:14]=2)[CH:17]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5ccc(Br)cc5n4)n3c2)C(F)(F)F)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1cc(-c2ccc3ccc(-c4nnc5ccc(C(N6CC[C@H](NC(=O)OC(C)(C)C)C6)C(F)(F)F)cn45)nc3c2)cn1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of tert-butyl (3S)-1-(1-(3-(7-bromo quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (Example 2, Step A; 0.18 g, 0.30 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.127 g, 0.61 mmol), PdCl2(dppf)*dcm (0.0249 g, 0.030 mmol), and triethylamine (0.064 mL, 0.46 mmol) in IPA (3 mL) was heated at 100° C. for 3 hours. After cooling to ambient temperature, the residue was directly purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH3CN/water gradient; 30 CV) to give tert-butyl (3S)-1-(2,2,2-trifluoro-1-(3-(7-(1-methyl-1H-pyrazol-4-yl)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.15 g, 83.2%) as a solid.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:27])[C:6]1[CH:15]=[C:14]([O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[CH:7]=1.Cl>O.CCO>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][C:14]1[CH:13]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[C:6]([CH:15]=1)[C:5]([OH:27])=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc3ccccc3c2)cc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Oc2ccc3ccccc3c2)cc(C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of LiOH (1.5 mmol) in water (1 ml) was added to 5-(naphthalene-2-yloxy)-isophthalic acid dimethylester (0.5 mmol) suspended in 5 ml EtOH. The mixture was stirred at room temperature. The reaction was monitored by TLC until completion. 2.5 ml 1 M HCl solution was added and the precipitation was collected. The product was used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][NH2:11]>>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:11][CH3:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=Cc1cccc(Br)n1
Product: CNCc1cccc(Br)n1

Procedure:
The title compound was prepared according to the procedure in Example 45 Step 1 using 6-bromopyridine-2-carbaldehyde (0.50 g, 2.69 mmol) and methylamine (0.253 mg, 2.69 mmol) as the starting materials
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:26][CH:25]=2)=[CH:32][CH:33]=1
Reactant: NCc1ccc(COc2ccc(Cl)cc2)cc1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Product: O=c1c(NCc2ccc(COc3ccc(Cl)cc3)cc2)c(Nc2cccnc2)c1=O
Yield: 81 %

Procedure:
The title compound was prepared according to the procedure described in example 1B starting from 3-ethoxy-4-(pyridine-3-yl-amino)-3-cyclobutene-1,2-dione prepared according to example 1A and 4-(4-chlorophenoxy-methyl)-benzylamine.