Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:20]3[C:21]4=[C:22]5[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=[C:13]5[CH:12]=[CH:11][C:10]4=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1>[Br:33][C:9]1[C:10]2[C:21]3=[C:22]4[C:13](=[CH:12][CH:11]=2)[CH:14]=[C:15]([C:23]([CH3:26])([CH3:24])[CH3:25])[CH:16]=[C:17]4[CH:18]=[CH:19][C:20]3=[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:6][CH:5]=2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1cc2ccc3ccc(-c4ccc(-c5ccccc5)cc4)c4ccc(c1)c2c34
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ccc3c(Br)cc(-c4ccc(-c5ccccc5)cc4)c4ccc(c1)c2c34
Temperature: 30 °C
Reaction time: 3 h
Yield: 85.3 %

Procedure:
Then, to a mixed solution of 8.65 g of 1-(4-biphenylyl)-7-t-butylpyrene, and 126 ml of tetrahydrofuran was added 4.1 g of N-bromosuccinimide under a nitrogen stream. This mixed solution was stirred at 30° C. for about 3 hours, and concentrated, 126 ml of methanol was added, and the mixture was stirred for about 1 hour, and filtered. To the resulting solid was added 30 ml of tetrahydrofuran, the mixture was heated and dissolved, 180 ml of methanol was added, and the mixture was stirred for about 1 hour, and filtered. After the resultant was purified by silica gel column chromatography, the solid obtained by evaporation was washed with 126 ml of methanol, and vacuum dried to obtain 8.8 g of 1-bromo-3-(4-biphenylyl)-7-t-butylpyrene.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[C:16]([CH3:17])=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[NH:14]2)=[CH:9][C:8]=1[CH2:19][CH2:20]C(OCC)=O.[OH-:26].[Na+].Cl>CCO.C1COCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][CH2:6][C:7]1[C:16]([CH3:17])=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:18])[NH:14]2)=[CH:9][C:8]=1[CH2:19][CH2:20][NH:14][C:13](=[O:18])[O:26][C:7]([CH3:16])([CH3:8])[CH3:6]
Reactant: [OH-]
Reactant: CCOC(=O)CCc1cc2c(c(C)c1CCOCOC)NC(=O)CC2
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COCOCCc1c(CCNC(=O)OC(C)(C)C)cc2c(c1C)NC(=O)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10.81 g of ethyl 3-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}propanoate in 100 ml of EtOH and 100 ml of THF was added 100 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature for 1 hour. The reaction mixture was neutralized by the addition of hydrochloric acid and then concentrated under reduced pressure to one third of the liquid amount, and the residue was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in 300 ml of t-butanol were added 9.0 ml of triethylamine and 7.0 ml of DPPA, followed by heating and refluxing for 24 hours. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc), and then the resulting solid was washed with HEX to obtain 8.006 g of t-butyl (2-{7-[2-(methoxymethoxy)ethyl]-8-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl}ethyl)carbamate as a milky white solid.
Reaction SMILES: [CH:1]([CH:3]1[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4]1)=O.C(O)(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+]>[CH3:31][C:27]1[N:26]=[C:25]([NH:24][CH2:1][CH:3]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:10][C:5]3([CH2:9][CH2:8][CH2:7][CH2:6]3)[CH2:4]2)[CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cccc(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2)CC1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cccc(NCC2CC3(CCCC3)CCN2C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
(±)tert-butyl 7-formyl-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 72, 2 g, 7.48 mmol) was dissolved in dichloroethane (25 ml), then acetic acid (5 eq) and 2-amino 6 picoline (810 mg, 7.48 mmol) were added. After 3 hours at room temperature NaBH(OAc)3 (2.53 g, 11.96 mmol) was added and the reaction was maintained under stirring at room temperature for 18 hours. The reaction was poured in aqueous NaHCO3 and extracted with ethylacetate. The organic layers were combined, dried (Na2SO4) and concentrated under vacuum; the crude was then purified by silica gel column chromatography (petroleum ether/ethyl acetate=9/1) to obtain 1.3 g of intermediate as colourless oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([Cl:30])=[CH:24][C:23]=2[Cl:31])=[C:5]2[S:11][C:10](/[CH:12]=[CH:13]/[C:14]([O:16]C(C)(C)C)=[O:15])=[CH:9][C:6]2=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[C:4]([NH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([Cl:30])=[CH:24][C:23]=2[Cl:31])=[C:5]2[S:11][C:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(/C=C/C(=O)OC(C)(C)C)sc23)c(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Nc2c(C#N)cnc3cc(/C=C/C(=O)O)sc23)c(Cl)cc1Cl
Yield: 92.3 %

Procedure:
A solution of tert-butyl (2E)-3-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2yl)prop-2-enoate (910.8 mg, 1.91 mmol), trifluoroacetic acid (2.18 g, 19.1 mmol) in 27 mL of dichloromethane is stirred at room temperature for 3 days, then concentrated in vacuo. The residue is triturated with ether to provide 741 mg of (2E)-3-(6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridin-2-yl)prop-2-enoic acid as a beige solid, mp>250° C.; 1H NMR (DMSO-d6) δ 3.84 (s, 3H), 6.28 (d, J=16 Hz, 1H), 7.38 (s, 1H), 7.70-7.88 (m, 2H), 7.90 (s, 1H), 8.62 (s, 1H), 9.81 (s, 1H), 12.50 (s, 1H); MS 420.1, 422.0 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][N:17]=1)[CH3:2].[Br:19]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Br:19][C:16]1[N:17]=[C:12]([C:4]2[N:3]([CH2:1][CH3:2])[C:11]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=3[N:5]=2)[C:13]([NH2:18])=[N:14][CH:15]=1
Reactant: CCn1c(-c2nccnc2N)nc2cnccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
To a solution of 3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.45 g, 1.8 mmol) (see Example 1) in THF is added N-bromosuccinimide (0.37 g, 2.1 mmol). The reaction is stirred for 4 hours at ambient temperature. Sodium sulfite (excess) was added and stirred vigorously for 30 minutes. The mixture was then concentrated to dryness and treated with water. After sonication, the solids were collected on filter. Rinsing (×2) with diethyl ether afforded 5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.47 g, 79%) as tan solids.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:11][C:12]1([NH3+:15])[CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCCC1>[OH:11][C:12]1([NH:15][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: [NH3+]C1(O)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1(O)CC1)c1ccccc1

Procedure:
Benzoyl chloride (4.2 g, 30 mmol) is added to a suspension of 1-hydroxycyclopropylammonium chloride (2.67 g, 24.5 mmol) in dry tetrahydrofuran. Triethylamine (6.5 g, 65 mmol) is added dropwise with stirring and ice-cooling (1 hr). The precipitate is filtered off and washed with tetrahydrofuran. The filtrate obtained is evaporated in vacuo. The crystalline residue is recrystallised from chloroform yielding N-(1-hydroxycyclopropyl)-benzamide, mp 153°-155° (3.0 g, 69%); NMR=δCDCl 3=0.87-1.38 (m, 4H), 4.7 (br. s, 1H), 7.3-7.9 (m, 6H, incl. NH).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1>>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: Nc1ccc(CCO)cc1
Product: O=[N+]([O-])c1ccccc1Nc1ccc(CCO)cc1
Temperature: 150 °C
Yield: 54.2 %

Procedure:
A mixture of 2-chloronitrobenzene (3.9 g, 25 mmol) and 4-aminophenylethyl alcohol (4.1 g, 30 mmol) was placed in a sealed tube and heated at 150° C. for 3 h. The reaction mixture was cooled and purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 3.5 g (55%) of the title compound as orange solids: 1H-NMR (CDCl3)δ2.90 (2H, t, J=6.5 Hz), 3.91 (2H, t, J=6.5 Hz), 6.81-6.70 (1H, m), 7.40-7.16 (6H, m), 8.21 (1H, dd, J=1.5, 8.8 Hz), 9.47 (1H, s).
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[CH2:14]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C:36]2[S:37][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH3:47])=[N:39][N:40]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C([O-])(O)=O.[Na+]>CO>[CH2:14]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:36]2[S:37][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]([CH3:47])[C:2]3[C:10]4[C:6](=[N:7][O:8][N:9]=4)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=3)=[N:39][N:40]=2)(=[O:33])=[O:34])=[CH:30][CH:31]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCNC)s2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCN(C)c3ccc([N+](=O)[O-])c4nonc34)s2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) (18 mg, 0.085 mmol) was dissolved in methanol (1 mL). After the addition of 4-dodecyl-N-(5-(5-(methylamino)pentyl)-1,3,4-thiadiazol-2-yl)benzenesulfonamide (43 mg, 0.085 mmol) and NaHCO3 (7 mg, 0.085 mmol) in methanol (2 mL), the solution was stirred for 2 h at 40° C. The reaction mixture was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel 60 (70-230 mesh) eluted with CH2Cl2:MeOH 49:1. Product 137 was obtained in 53% yield (30 mg, 0.045 mmol), mp 102-104° C. 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3, J=7.2 Hz), 1.25 (m, 18), 1.51-1.57 (m, 4), 1.79-1.85 (m, 4), 2.63 (t, 2, J=6.6 Hz), 2.84 (t, 2, J=7.5 Hz), 3.45 (s, 3), 4.14 (s, 2), 6.11 (d, 1, J=9.3 Hz), 7.27 (d, 2, J=8.1 Hz), 7.79 (d, 2, J=8.4 Hz), 8.44 (d, 1, J=9.0 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 25.7, 27.7, 29.2, 29.3, 29.4, 29.5, 29.6, 30.4, 31.1, 31.9, 35.9, 55.6, 101.2, 126.5, 128.9, 135.4, 138.3, 145.3, 148.5, 154.7, 158.3, 163.8, 167.9; HRMS (ESI+, m/z) calculated for C32H46N7O5S2 672.3002. observed 672.2996 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S@:27]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41]C)=[O:40])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:43])=[N:3]1.[OH-].[Na+].Cl>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]#[C:17][C:18]3[CH:19]=[C:20]([C:24]([N:26]=[S@:27]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][C:4]([CH3:43])=[N:3]1
Reactant: COC(=O)CCCC[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CCCCC(=O)O)c4ccccc4)c3)c2)n(C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of (S)-Methyl 5-[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]pentanoate (120 mg, 0.2 mmol) in THF (4 mL) at 0° C. was added dropwise a solution of aqueous NaOH (0.5 N, 2.0 mL). After the reaction mixture was stirred at 0° C. for 2 hours, 2 N HCl was carefully added to adjust the pH ˜5 followed by a partition between aqueous NH4Cl and EtOAc. The EtOAc layer was further washed with brine once and dried with anhydrous sodium sulfate. The organic layer was decanted, concentrated and subject to a gradient column chromatography (from EtOAc to MeOH-EtOAc 1:5) yielding the title compound as white foam in amount of (85 mg, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:13])=[N:8][NH:9][C:10]=1[NH:11][CH3:12])=[O:5])[CH3:2].[OH-].[Na+].I[CH3:17]>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:17])[C:10]=1[NH:11][CH3:12])=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1c(C)n[nH]c1NC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)c1c(C)nn(C)c1NC
Temperature: 25 °C
Yield: 31 %

Procedure:
To a solution of 100 mg of 3-methyl-5-methylamino-1H-pyrazole-4-carboxylic acid ethyl ester (0.55 mmol) in methanol (5 ml) were added 52 mg of sodium hydroxide (1.3 mmol) and 77 mg of iodomethane (0.54 mmol) and the mixture was stirred at RT over night. The reaction mixture was then concentrated in vacuo at low temperature and 33 mg (31%) of 1,3-dimethyl-5-methylamino-1H-pyrazole-4-carboxylic acid ethyl ester were isolated from the remaining solid by HPLC (reversed phase, MeCN/water 20:80 to 50:50). MS (ISP) 198.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5](=[O:19])[C:6]([C:16]([OH:18])=O)=[N:7][N:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[CH3:24][O:23][N:22]([CH3:21])[C:16]([C:6]1[C:5](=[O:19])[C:4]([O:3][CH3:2])=[CH:9][N:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:7]=1)=[O:18]
Reactant: COc1cn(-c2cccnc2)nc(C(=O)O)c1=O
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cn(-c2cccnc2)nc(C(=O)N(C)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylic acid hydrochloride (1.0 g, 3.5 mmol), N,O-dimethylhydroxylamine hydrochloride (0.52 g, 5.3 mmol), TEA (1.5 ml, 11 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.2 g, 3.9 mmol) in DMF (15 ml) was stirred at room temperature overnight. The mixture was diluted with AcOEt. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was chromatographed on basic silica gel (0/100-20/80 MeOH/AeOEt) to give the title compound (0.81 g, 79% yield) as white crystals: 1H NMR (300 MHz, CDCl3): δ ppm 3.41 (3H, s), 3.71 (3H, s), 3.98 (3H, s), 7.48 (1H, dd, J=8.3, 4.5 Hz), 7.97 (1H, s), 8.00-8.05 (1H, m), 8.67 (1H, dd, J=4.5, 1.3 Hz), 8.91 (1H, d, J=2.6 Hz).
Reaction SMILES: [CH3:1][C@H:2]([NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C:3]([OH:5])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:29][C:30]1[NH:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:31]=1[C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1>O1CCCC1>[C:7]([NH:6][C@H:2]([C:3]([NH:29][C:30]1[C:31]([C:42]2[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=2)=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[NH:33][N:34]=1)=[O:5])[CH3:1])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1n[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
Under a stream of argon gas, 421 mg of Z-L-alanine and 306 mg of carbonyldiinidazole (CDI) were dissolved in 10 ml of tetrahydrofuran, followed by stirring at room temperature for 10 minutes. Then, 150 mg of 5-amino-3-(4-fluorophenyl)-4-(4-pyridyl)pyrazole and 287 mg of 1,8-diazabicyclo[5.4.2]undec-7-ene (DBU) were added thereto, followed by stirring at room temperature for 4 hours. After the reaction mixture was concentrated under reduced pressure, the resulting residue was purified by column chromatography using 20 g of silica gel [with an elution solvent comprising chloroform-methanol (50:1)]. Thus, 88 mg (32% yield) of the title compound was obtained as a white powder.
Reaction SMILES: [NH:1](/[C:8](=[C:17]1\[C:18](=[O:30])[NH:19][C:20]2[C:25]\1=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[NH:1](/[C:8](=[C:17]1\[C:18](=[O:30])[NH:19][C:20]2[C:25]\1=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)/[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:31](=[O:33])[CH3:32])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(cc1OC)/C(=C(/Nc1ccccc1)c1cccc(CN)c1)C(=O)N2
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccccc1)c1cccc(CNC(C)=O)c1)C(=O)N2

Procedure:
Prepared from 3-(Z)-[1-anilino-1-(3-aminomethyl-phenyl)-methylidene]-5,6-dimethoxy-2-indolinone and acetic anhydride
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:4]=1[C:5](=[O:15])C(=O)[NH:7]2.[OH:16]O.[ClH:18]>[OH-].[Na+]>[ClH:18].[NH2:7][C:8]1[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([OH:15])=[O:16]
Reactant: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(N)c(C(=O)O)c(OC)c1
Temperature: 75 °C
Yield: 59 %

Procedure:
4,6-Dimethoxyisatin (5.00 g, 24.0 mmol) was dissolved in 33% (w/v) aqueous sodium hydroxide solution (42 ml) at 75° C. To this solution was added hydrogen peroxide (30%, 8 ml) dropwise over 30 minutes. The reaction was stirred for an hour at 75° C. and then cooled to room temperature. Ice was added, and the reaction mixture acidified to pH 1 with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water and dried in vacuo to yield 2-amino-4,6-dimethoxybenzoic acid hydrochloride salt (3.3 g, 59% yield) acid as a pale yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:18]#[N:19])=[CH:11][C:12]2[N:13]([CH:15]=[N:16][N:17]=2)[CH:14]=1.B.C1COCC1>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH2:18][NH2:19])=[CH:11][C:12]2[N:13]([CH:15]=[N:16][N:17]=2)[CH:14]=1
Reactant: N#Cc1cc2nncn2cc1-c1ccc(Cl)cc1Cl
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cc2nncn2cc1-c1ccc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 2.4 %

Procedure:
In a sealed flask, a solution of 6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine-7-carbonitrile (50 mg, 0.164 mmol) in THF (0.5 mL) was cooled to 0° C. (ice bath) then treated with BH3.THF complex (1.0 M solution in THF, 0.82 mL, 0.82 mmol). The reaction mixture was heated at 40° C. for 1 h, cooled to RT, and diluted in MeOH (large excess). The mixture was concentrated under vacuum, and the remaining residue was suspended in 2.0 M HCl, and shaken for 15 min. After evaporation to dryness, the remaining residue was purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 1.9 mg, 0.004 mmol, 2%) as a white solid. MS: 293 [M+1]+; HPLC: AtRet=0.95.
Reaction SMILES: [N:1]([O-])=O.[Na+].O.[NH2:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[S:12]([CH2:15][C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:17])(=[O:14])=[O:13]>C(O)(=O)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][NH:18][C:16]([C:15]2[S:12](=[O:14])(=[O:13])[C:11]3[CH:10]=[CH:9][S:8][C:7]=3[NH:6][N:1]=2)=[O:17])=[CH:25][CH:24]=1
Reactant: Nc1sccc1S(=O)(=O)CC(=O)NCc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)C1=NNc2sccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A solution containing sodium nitrite (0.06 g) and water (1 mL) is cooled to 0° C. before adding a solution of 2-((2-amino-3-thienyl)sulfonyl)-N-(4-chlorobenzyl)-acetamide (Preparation 54, 0.255 g) in hot acetic acid (10 mL) dropwise. The solution is warmed to room temperature and stirred for 30 minutes. The reactionmixture is poured into a beaker containing ice. The crude product is collected by filtration and dried under high vacuum to provide 0.18 g (66%) of the title compound as a brown solid. Physical characteristics: MS (ESI+) m/z 356 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].CCCCC>CO.[Pd]>[C:1]1([CH:7]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc(C(=C2CCCNC2)c2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCC
Solvent: CO
Product: FC(F)(F)c1ccc(C(c2ccccc2)C2CCCNC2)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To a solution of 3-(phenyl(4-(trifluoromethyl)phenyl)methylene)piperidine (1.0 g, 3.15 mmol) in methanol (25 mL) was charged with Pd/C under nitrogen atmosphere and fitted with hydrogen balloon using stopcock and covered with Teflon. The reaction mixture was stirred under hydrogen atmosphere for 8 h. It was filtered through celite, the celite was washed with methanol, and the solvent was removed under reduced pressure to afford the crude product which was then crashed out of pentane to give pure 3-(phenyl(4-(trifluoromethyl)phenyl)-methyl)piperidine (1.0 g, 98% yield) as a grey oil. MS (ESI, pos. ion) m/z: 320 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:31]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>N1C=CC=CC=1>[C:28]([C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:36](=[O:35])[CH2:37][OH:38])[N:31]=3)[CH:9]=2)[CH:12]=1)=[O:30])([CH3:27])[CH3:26])#[N:29]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)CO)nn4c3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (219 mg, 0.531 mmol) in pyridine (10 mL) was added 2-chloro-2-oxoethyl acetate (171 μL, 1.59 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in methanol (10 mL). Potassium carbonate (147 mg, 1.06 mmol) was added thereto, and the mixture was stirred at room temperature for 19 hr. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL, 2×10 mL). The combined organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→90/10), and fractions containing the desired product were concentrated under reduced pressure. Ethyl acetate and diisopropyl ether were added to the obtained residue. The obtained precipitate was collected by filtration, and dried to give the title compound (140 mg, 56%) as a pale-yellow powder.