Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C([NH:9]C(C)C)(C)C.[C:13]([Si:17]([CH3:28])(C)[C:18]1[C:23]([F:24])=[CH:22][N:21]=[C:20]([F:25])[C:19]=1[F:26])([CH3:16])([CH3:15])[CH3:14].F[C:30]1[N:41]=[CH:40][CH:39]=[CH:38][C:31]=1[C:32]([N:34](OC)C)=O.NN>C1COCC1>[C:13]([SiH:17]([CH3:28])[C:18]1[C:19]([F:26])=[C:20]([F:25])[N:21]=[C:22]([C:32]2[C:31]3[C:30](=[N:41][CH:40]=[CH:39][CH:38]=3)[NH:9][N:34]=2)[C:23]=1[F:24])([CH3:14])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1F
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: CC(C)NC(C)C
Agent: NN
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[SiH](c1c(F)c(F)nc(-c2n[nH]c3ncccc23)c1F)C(C)(C)C
Temperature: -10 °C
Reaction time: 0.79 h
Yield: 25.4 %

Procedure:
n-BuLi (1.6M in hexane) (13.90 mL of 1.6 M, 22.24 mmol) was added to a solution of diisopropylamine (2.353 g, 3.259 mL, 23.25 mmol) in THF (50.00 mL) cooled to −5/−10° C. under N2. Fifteen minutes later, the solution was cooled to −78° C. A solution of tert-butyl-dimethyl-(2,3,5-trifluoro-4-pyridyl)silane (5 g, 20.22 mmol) in THF (10.00 mL) was added to the reaction mixture which was stirred for 45-50 min. 2-Fluoro-N-methoxy-N-methylnicotinamide (4.282 g, 23.25 mmol) was added to the reaction mixture which was stirred at −78° C. for a further 2 hours. The reaction mixture was quenched with a saturated ammonium chloride aqueous solution. It was diluted with ethyl acetate. The organic was washed with brine. It was dried over magnesium sulfate and concentrated in vacuo after filtration. The crude mixture was taken up in a 1M hydrazine solution in THF (80 mL of 1 M, 80.00 mmol) and stirred at room temperature for 18 hours. The brown solution was concentrated under reduced pressure. The residue was triturated with DCM. A brown solid was filtered off. The filtrate was partially concentrated and purified on silica gel eluting with petrol ether/ethyl acetate to afford the title compound as a beige solid (1.8 g, 30%). 1H NMR (CDCl3) 0.54 (6H, s), 1.03 (9H, s), 7.32-7.35 (1H, d), 8.70-8.71 (1H, d), 8.89-8.91 (1H, d), 12.1 (1H, s).
Reaction SMILES: C([CH:4]([C:18](/[CH:20]=[CH:21]/[C:22]1[CH:30]=[C:27]([O:28][CH3:29])[C:25]([OH:26])=[CH:24][CH:23]=1)=[O:19])[C:5](=[O:17])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]([C:13]([OH:16])=[CH:14][CH:15]=1)[O:11][CH3:12])C#C.[N:31]([CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42])=[N+:32]=[N-:33].O=[C:44]1O[C@H]([C@H](CO)O)[C:47]([O-])=[C:45]1O.[Na+]>CC(O)(C)C.C(Cl)(Cl)Cl.O.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:29][O:28][C:27]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22](/[CH:21]=[CH:20]/[C:18]([CH2:4][C:5](/[CH:6]=[CH:7]/[C:8]2[CH:9]=[C:10]([O:11][CH3:12])[C:13]([OH:16])=[CH:14][CH:15]=2)=[O:17])=[O:19])[CH:30]=1.[CH2:44]=[C:45]1[CH2:47][N:31]([CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][OH:42])[N:32]=[N:33]1
Reactant: [N-]=[N+]=NCCOCCOCCO
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: C#CCC(C(=O)/C=C/c1ccc(O)c(OC)c1)C(=O)/C=C/c1ccc(O)c(OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: C=C1CN(CCOCCOCCO)N=N1
Product: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Reaction time: 8 h
Yield: 26 %

Procedure:
To a stirred solution of Mono-Propargyl Curcumin 5 (63 mg, 0.16 mmol) and 2-(2-(2-azidoethoxy)ethoxy)ethanol (46 mg, 0.26 mmol) in tBuOH (1.1 mL) and CHCl3 (0.3 mL) was added a prepared solution of Cu(OAc)2 (8 mg, 0.03 mmol) and sodium ascorbate (13 mg, 0.07 mmol) in H2O (1.3 mL). After vigorous stirring overnight the solvent was removed under vacuum. The mixture was dissolved in CHCl3, washed with H2O and the organic phase was separated, dried over Na2SO4 and evaporated. Purification was performed by column chromatography, eluting with CH2Cl2—CH2Cl2: MeOH 98:2. Yield 26%. NMR 1H (CDCl3), δ (ppm): 3.55-3.60 (m, 8H); 3.72-3.72 (t, 3H); 3.87-3.94 (m, 8H); 4.54-4.55 (t, 2H); 5.80 (s, 1H); 6.07 (s, 1H); 6.46-6.50 (dd, 2H); 6.92-6.94 (d, 1H); 7.05-7.12 (m, 5H); 7.56-7.60 (q, 2H); 7.92 (s, 1H).). MS (ESI) calcd. for C30H35N3O9: 581.61. found: 582.3 [M+H]+, 604.3 [M++Na], 620.3 [M++K].
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23](O)=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8].[CH3:35][NH:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=2)=[CH:4][C:5]([O:27][CH3:28])=[C:6]([CH:26]=1)[C:7]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]2[C:20]([C:23]([N:36]([CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[CH3:35])=[O:24])=[CH:21][CH:22]=[C:11]2[CH2:10]1)=[O:8]
Reactant: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)O)n2Cc2ccccc21
Reactant: CNCC(O)CO
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2ccc(C(=O)N(C)CC(O)CO)n2Cc2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]benzodiazepine-3-carboxylic acid of Example 1, Step G (0.370 g, 0.776 mmol), 3-methylamino-1,2-propanediol (0.098 g, 0.931 mmol), 1-hydroxy benzotriazole (0.115 g, 0.854 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.164 g, 0.854 mmol) were combined in amine-free N,N-dimethylformamide (3.9 mL), followed by addition of N,N-diisopropylethylamine (0.202 mL, 1.16 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate and washed with 1 N hydrochloric acid, 1 N sodium hydeoxide and brine. The combined aqueous washings were saturated with sodium chloride and extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient from 0 to 5% of methanol in chloroform, to afford 0.400 g of the title compound as a white, crystalline solid, m.p.155-157° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]([F:25])([F:24])[F:23]>N1C=CC=CC=1>[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:17][C:16]=1[C:22]([F:23])([F:24])[F:25]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Yield: 908.4 %

Procedure:
Analogously to Example 10, 2.21 g (10 mmol) of 4-chlorosulfonyl-benzoic acid is reacted with 1.79 g (10 mmol) of 4-fluoro-3-(trifluoromethyl)-aniline in pyridine and the crude product is crystallized from ethanol. 3.3 g=90.84 mmol of crystalline product is obtained. Melting point 238°-241° C.
Reaction SMILES: C([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][O:15][CH:16]([CH2:25][O:26]C(=O)C(C)(C)C)[CH2:17][O:18]C(=O)C(C)(C)C)=[C:7](Cl)[N:6]=1)(=O)C.[NH3:34]>>[NH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][O:15][CH:16]([CH2:25][OH:26])[CH2:17][OH:18])=[C:7]([NH2:34])[N:6]=1
Reactant: N
Reactant: CC(=O)Nc1nc(Cl)c2ncn(COC(COC(=O)C(C)(C)C)COC(=O)C(C)(C)C)c2n1
Product: Nc1nc(N)c2ncn(COC(CO)CO)c2n1

Procedure:
A solution of 2-acetylamino-6-chloro-9-[1,3-di(2,2-dimethylpropanoyloxy)-2-propoxymethyl]purine (200 mg) in methanolic ammonia (15 ml) was heated in a Parr bomb at 90° C. for 18 hours. The solution was evaporated and the residue recrystallized from methanol to give 136 mg of 2,6-diamino-9-(1,3-dihydroxy-2-propoxymethyl)purine, m.p. 176°-177° C.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:23]>>[NH2:23]/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1
Reactant: [NH4+]
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: CC(=O)[O-]
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1

Procedure:
When 2-benzoyl-benzo[b]thiophen-3-ol was reacted with the following reagents instead of with ammonium acetate under the conditions of Example 31, the title compound, m.p. 121°-122° C. (petroleum ether/ethyl acetate 2:1), was obtained with the yields given to the right below:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C)C=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13]
Reactant: BrCCCCBr
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1CCCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A suspension of sodium hydride (6.8 g, 60% dispersion in mineral oil) and dimethyl formamide (200 mL) was kept at 20–30° C. followed by the addition of a solution of 3,4-dihydroquinolin-2(1H)-one (25 g) in dimethyl formamide (100 mL). The resulting mixture was stirred at room temperature for 30 min followed by the addition of a solution of 1,4-dibromobutane (184 g) in dimethyl formamide (200 mL) at a temperature of 20–40° C. The reaction mixture was stirred at room temperature for 30 min and evaporated in vacuo. The remaining oil was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with water and brine, treated with charcoal, dried (MgSO4) and evaporated in vacuo. The remaining oil was purified by flash chromatography (eluent: ethyl acetate/heptane 1:1) giving the title compound as a red oil (36 g).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(=O)=O.[NH2:35][C:36]1[NH:37][C:38]([SH:41])=[N:39][N:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:32][Si:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:11][CH2:12][C@H:7]([CH2:6][S:41][C:38]5[NH:37][C:36]([NH2:35])=[N:40][N:39]=5)[CH2:8][CH2:9]4)[CH:17]=3)[C:19]=2[CH:26]=[CH:25]1
Reactant: Nc1nnc(S)[nH]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSc5nnc(N)[nH]5)CC4)c3)ncnc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl methanesulfonate (124.56 mg, 0.00024 mol), and 5-amino-4H-1,2,4-triazole-3-thiol (43.00 mg, 0.0003702 mol) were dissolved in DMF (1.20 mL) and potassium carbonate (0.122 g, 0.000887 mol) was added. The reaction was stirred at 50° C. for 18 h, at which time LCMS showed nearly complete reaction, and product present. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 526, 1H NMR(CDCl3):δ 8.90 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (brs, 2H), 4.41 (m, 1H), 3.60 (m, 2H), 3.22 (d, 2H, J=7.2 Hz), 2.29 (m, 2H), 1.70-2.10 (m, 7H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.CCCCCC.[CH3:19][C:20](=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH3:21].Cl>O1CCCC1>[CH:22]1([C:20]([CH3:21])([CH3:19])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1
Reactant: CC(C)=C1C=Cc2ccccc21
Reactant: Cc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(Cc1ccccn1)C1C=Cc2ccccc21
Yield: 85.8 %

Procedure:
A solution of α-Picoline (1.97 ml, 20 mmol) in 10 ml of tetrahydrofuran was cooled to −20° C. and 15% n-butyl-lithium in hexane (13 ml, 20 mmol) was added during 10 min with stirring. The cooling bath was removed and the solution allowed to stir for 1 h while the temperature rose to room temperature. The resulting mixture was treated with a solution of 1-(1-methylethylidene)-1H-indene (3.12 g, 20 mmol) in 5 ml of tetrahydrofuran (5 ml) with vigorous stirring. The resulting solution was stirred for 14 h and hydrolyzed with 60 ml of 15-% hydrochloric acid. The organic layer was isolated and the aqueous phase washed once with ethyl acetate, then neutralized with aqueous ammonia solution and extracted three times with dichloromethane. The combined organic layers were dried over MgSO4, filtered and the solvent removed to give 4.28 g (86%) of 2-[2-(1H-inden-1-yl)-2-methylpropyl]pyridine as an oil. The product was NMR-pure, so no further distillation was necessary.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[O:20][CH:19]([CH2:21][OH:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.O.S(=O)(=O)(O)[OH:25]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[C:3]2[O:20][CH:19]([C:21]([OH:25])=[O:22])[CH2:18][C:4]=2[C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: O=S(=O)(O)O
Reactant: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4F)noc23)O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C1Cc2c(c(Cl)cc3c(-c4ccccc4F)noc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A portion (6.4 g) of the 5-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 11 was dissolved in 150 ml of acetone. To the stirred solution, a mixture of chromium (VI) oxide (7.2 g), water (15 ml) and concentrated sulfuric acid (10.2 g) was added dropwise overtime, and the mixture was agitated for 8 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 6.0 g of 5-chloro-7,8-dihydro-3-(2-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 199°-200° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 333.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([F:45])=[C:23]([NH:22][C:8]([C:4]5[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:10])[CH:24]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Reactant: Cc1cn(C)nc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cn(C)nc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Yield: 83.4 %

Procedure:
In the same manner as in Example 18-4 and using 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (171 mg, 1.22 mmol), tetrahydrofuran (7 mL), oxalyl chloride (160 μL, 1.83 mmol), N-[6-(3-amino-4-fluorophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.611 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (229 mg, 83%) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH:10]=[CH:9][N:8]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl-].[NH4+].C(O)C.CN(C)C=O>[Fe].O>[NH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:11]2[CH:10]=[CH:9][N:8]=[C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:12]=2)=[CH:19][CH:18]=1
Reactant: CCCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCCC(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.6 g of 2-butyrylamino-4-(4-nitrophenoxy)pyridine, 1.2 g of iron powder, 2.8 g of ammonium chloride, 10 ml of ethanol, 10 ml of dimethylformamide and 5 ml of water was vigorously stirred at 100° C. for 10 minutes. The reaction was filtered with celite, the solvent was distilled off under reduced pressure, and then water was added to the filtrate and extraction was performed with ethyl acetate. The extract was dried over magnesium sulfate and the solvent distilled off under reduced pressure to obtain 0.6 g of the target substance as a light yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([SH:6])=[N:2]1.[CH2:7](O[K])C.[Cl-].[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH2:13]>C(O)C>[CH:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:7][S:6][C:3]2[N:4]=[CH:5][NH:1][N:2]=2)=[CH:16][CH:15]=1)=[CH2:13]
Reactant: C=Cc1ccccc1
Reactant: Sc1nc[nH]n1
Reactant: CCO[K]
Agent: [Cl-]
Solvent: CCO
Product: C=Cc1ccc(CSc2nc[nH]n2)cc1
Yield: 82.4 %

Procedure:
10 mmole of 1H-1,2,4-triazole-3-thiol was dissolved in 20 ml of ethanol in stirring. 10 mole of EtOK was added to the solution, stirred for 5 minutes. Then, 10 mmole of 4-vinylbenzene chloride was added, and stirred overnight. The white precipitate was removed by filtration, the solvent in the filtrate was removed in vacuum. The filtrate was separated with a Si gel column (solvents: 4 ethylacetate/hexane). 1.79 g product as white solid was obtained. Yield: 83%. 1H NMR (CD3Cl): 8.73 (1H, s), 7.36 (4H, m), 6.75 (1H, m), 5.85 (1H, d, JH-H=17.66), 3.25 (1H, d, JH-H=10.93), 4.31 (2H, S).
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:26][C@@H:27]1[C@@H:32]([OH:33])[CH2:31][CH2:30][O:29][CH2:28]1>C1COCC1>[CH3:23][C:12]1[CH:13]=[C:14]2[C:15](=[CH:20][C:11]=1[CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:25][CH:24]=1)[C:16](=[O:17])[N:26]([C@@H:27]1[C@@H:32]([OH:33])[CH2:31][CH2:30][O:29][CH2:28]1)[CH2:21]2
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Reactant: N[C@H]1COCC[C@@H]1O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N([C@H]1COCC[C@@H]1O)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.6 %

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.20 g) in THF (4.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.07 g), and the mixture was stirred at room temperature for 4 hr under argon atmosphere. The reaction mixture was concentrated, and the residue was diluted with acetic acid (4.00 mL). Sodium triacetoxyborohydride (0.19 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]#N)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[OH-:26].[Na+]>C1COCC1.C(Cl)Cl.O>[F:1][C:2]1[C:3]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:26])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: [OH-]
Reactant: Cc1ccncc1-c1ccnc(C#N)c1F
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccncc1-c1ccnc(C(=O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
To a solution of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile (0.027 g, 0.127 mmol) in THF (Volume: 0.633 ml) cooled to 0° C. was added phenylmagnesium bromide (0.317 ml, 0.317 mmol). The reaction mixture was allowed to stir at room temperature overnight. Water and ice were carefully added, followed by acidification with 6 M HCl. After stirring for 1 hr, CH2Cl2 was added and the pH was adjusted to 8.5 with aqueous 4 M NaOH. The layers were separated and the aqueous phase was extracted with CH2Cl2 (5×). Organics combined, dried over Na2SO4, filtered, and concentrated to afford a purple residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (4 g column, 18 mL/min, 70-100% EtOAc in hexanes over 19 min, tr=6.5 min) gave the title compound (0.025 g, 0.081 mmol, 64.2% yield) as an orange residue. ESI MS (M+H)+=293.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22])([CH3:27])[CH3:26]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)n(C)n1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC(C)C)n(C)n1
Yield: 21 %

Procedure:
As described for example 144, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid was converted, using isopropylamine instead of 2-hydroxy-2-methylpropylamine, to the title compound (15 mg, 21%) which was obtained as a white solid. MS: m/e=372.2 [M+H]+.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[Br:7]Br.[CH2:9]([SH:11])[CH3:10].C1OC1C.C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[CH2:9]([S:11][C:4](=[O:5])[CH2:3][C:2](=[O:1])[CH2:6][Br:7])[CH3:10]
Reactant: C=C1CC(=O)O1
Reactant: BrBr
Reactant: CCS
Agent: CC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)CC(=O)CBr
Temperature: -40 °C
Yield: 58.2 %

Procedure:
In 40 ml of anhydrous methylene chloride was dissolved 8.4 g of diketene, and the resulting solution was cooled to -40° C. Then, 14.4 g of bromine was added dropwise to the solution while maintaining the temperature at -40° to -35° C. over a period of 1 hour, and the resulting mixture was subjected to reaction at -30° to -20° C. for 30 minutes. On the other hand, 7.48 g of ethanethiol and 5.84 g of propylene oxide were dissolved in 60 ml of anhydrous methylene chloride, and the resulting solution was cooled to -40° C. Into this solution was introduced the above-mentioned reaction mixture. Then, the temperature of the reaction mixture was raised up to room temperature over a period of 1 hour, and the mixture was further subjected to reaction at the same temperature for 1 hour. The reaction mixture was introduced into 100 ml of water at 5° C., and the pH was adjusted to 6.0 with sodium hydrogencarbonate. The organic layer was separated, washed with 30 ml of saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure and the residue obtained was distilled under reduced pressure to obtain 11.8 g (yield, 58.0%) of 4-bromo-3-oxothiobutyric acid-S-ethyl ester having a boiling point of 110°-120° C./4 mmHg.