Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(Cl)(Cl)(Cl)Cl.[OH2:14]>CC#N>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:14])=[O:8]
Reactant: O
Reactant: OCC1CCCCO1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C1CCCCO1
Reaction time: 0.33 h

Procedure:
To a vigorously stirred solution of tetrahydropyran-2-methanol (2.32 g, 40 mmol) in a mixture of CH3CN (20 ml), CCl4 (20 ml) and water (10 ml) at 0° C. was added NaIO4 (9.42 g, 44 mmol) and then RuCl3H2O(414 mg, 2 mmol). After 20 min, the cooling bath was removed. After 40 min at room temperature, TLC showed reaction was complete. The reaction mixture was partitioned into ethyl acetate and ice-cold Na2S2O5 solution. More Na2S2O5 was added until all the brown material dissolved and a greenish mixture was obtained. The aqueous portion was extracted with more ethyl acetate and combined layer was washed with 10% Na2S2O5, H2O, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using methylene chloride/methanol/acetic acid=95:5:0.5 to afford the product as an oil (1.5 g).
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([N:10]=[N+:11]=[N-:12])[N:7]=[C:6]([NH:13][NH:14][C:15]2[N:20]=[C:19]([N:21]=[N+:22]=[N-:23])[N:18]=[C:17]([N:24]=[N+:25]=[N-:26])[N:16]=2)[N:5]=1)=[N+:2]=[N-:3].C(Cl)(Cl)Cl.ClCl>O>[N:1]([C:4]1[N:9]=[C:8]([N:10]=[N+:11]=[N-:12])[N:7]=[C:6]([N:13]=[N:14][C:15]2[N:20]=[C:19]([N:21]=[N+:22]=[N-:23])[N:18]=[C:17]([N:24]=[N+:25]=[N-:26])[N:16]=2)[N:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1nc(N=[N+]=[N-])nc(NNc2nc(N=[N+]=[N-])nc(N=[N+]=[N-])n2)n1
Agent: ClCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: [N-]=[N+]=Nc1nc(N=Nc2nc(N=[N+]=[N-])nc(N=[N+]=[N-])n2)nc(N=[N+]=[N-])n1

Procedure:
Briefly, 4,4′,6,6′-tetra(chloro)hydrazo-1,3,5-triazine (1) [9] reacts rapidly with an excess of hydrazine monohydrate in acetonitrile to give 4,4′,6,6′-tetra(hydrazino)-hydrazo-1,3,5-triazine (2). Compound (2) undergoes diazotization to yield 4,4′,6,6′-tetra(azido)hydrazo-1,3,5-triazine (3). A suspension of (3) in 1:2 (v/v) H2O:CHCl3 solution reacts with chlorine gas at room temperature to provide 4,4′,6,6′-tetra(azido)azo-1,3,5-triazine (4, TAAT).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
A slurry of 10% palladium on carbon (10 g) in a solution of 4-tert-butoxycarbonyl-1-(2-methoxy-5-nitrophenyl)piperazine (D2) (124.5 g) in ethanol (3.5L) and water (50 ml) was stirred with hydrogen at ambient temperature and atmospheric pressure for 18 h. The reaction mixture was filtered and the filtrate concentrated to afford the title compound (D3) as a gum (112 g, 99%). MH+308.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].[C:6]([OH:9])(=[S:8])[CH3:7]>C(O)C.C(N(CC)CC)C>[C:6]([S:8]/[CH:3]=[CH:2]\[C:1]([OH:5])=[O:4])(=[O:9])[CH3:7]
Reactant: CC(O)=S
Reactant: C#CC(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)S/C=C\C(=O)O
Reaction time: 0.08 h
Yield: 117.9 %

Procedure:
To a stirred, cooled (0° C.) solution of 1.0 ml (0.01625 mol) of propiolic acid in 12 ml of absolute ethanol under nitrogen was added 0.22 ml (0.0016 mol) of triethylamine. After 5 min, 1.45 ml (0.0203 mol) of thioacetic acid was added. After 20 h at 0° C. the reaction mixture was stripped of solvents to give 2.8 g of cis-3-(acetylthio)propenoic acid as a waxy solid. This product was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:26])[NH:19]2)(=[O:3])N.[OH-:27].[K+].Cl>O.C(O)C>[OH2:3].[C:1]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:26])[NH:19]2)([OH:3])=[O:27].[C:1]([CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:14]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18](=[O:26])[NH:19]2)([OH:3])=[O:27]
Reactant: COc1ccc(-c2nc3ccccn3c2CC(N)=O)c2ccc(=O)[nH]c12
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc3ccccn3c2CC(=O)O)c2ccc(=O)[nH]c12
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 5-{3-carbamoylmethylimidazo-[1,2-a]pyridine-2-yl}-8-methoxycarbostyril (1.6 g), potassium hydroxide (2.6 g), water (3 ml) and ethanol (9 ml) was refluxed for 1 hour. After completion of reaction, water was added to the reaction mixture, which was then treated with activated carbon and adjusted to pH of about 1 by the addition of concentrated hydrochloric acid followed by allowing to stand overnight. Crystals which precipitated were collected by filtration and recrystallized from dilute hydrochloric acid to give 0.9 g of 5-{3-carboxymethylimidazo[1,2-a]pyridine-2-yl}-8-methoxycarbostyril hemihydrate.
Reaction SMILES: C[O:2][C:3]([C@@H:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9][CH2:8]1)=O.[BH4-].[Na+]>CCO>[C:24]([O:23][C:22]([NH:21][C@@H:5]([CH2:6][CH:7]1[CH2:8][CH2:9][CH:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:11][CH2:12]1)[CH2:3][OH:2])=[O:28])([CH3:26])([CH3:25])[CH3:27]
Reactant: COC(=O)[C@H](CC1CCC(O[Si](C)(C)C(C)(C)C)CC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
To a solution of tert-butyl (S)-1-(methoxycarbonyl)-2-(4-(t-butyldimethylsilyloxy)-cyclohexyl)ethylcarbamate (25 g, 60 mmol) in EtOH (500 mL) at 0° C. was added NaBH4 (18 g, 480 mmol) in portions. The mixture was stirred for 6 h at rt and then evaporated. The residue was partitioned between water (200 mL) and EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over MgSO4, and evaporated to give (2S)-2-(t-butoxycarbonylamino)-3-(4-(t-butyldimethylsilyloxy)cyclohexyl)propan-1-ol (23 g, yield 98%). 1H NMR (CDCl3, 400 MHz) δ 0.08 (d, 6H), 0.89 (d, 9H), 1.30 (m, 4H), 1.40 (t, 2H), 1.45 (s, 9H), 1.61 (m, 1H), 1.58 (m, 1H), 1.68 (t, 4H), 1.85 (d, 1H), 3.50 (m, 1H), 3.65 (m, 1H), 3.73 (m, 1H), 3.91 (s, 1H), 4.53 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[O:19]=[CH:20][C:21]1[CH:29]=[CH:28][C:26]([OH:27])=[C:23]([O:24][CH3:25])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:20]([C:21]1[CH:29]=[CH:28][C:26]([O:27][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[C:23]([O:24][CH3:25])[CH:22]=1)=[O:19]
Reactant: CCOC(=O)c1ccc(-c2nc(CCl)c(C)o2)s1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)s1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)thiophene-2-carboxylate (5.0 g), vanillin (2.66 g), anhydrous potassium carbonate (2.42 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration, and washed with diethyl ether. The obtained crystals were recrystallized from acetone-hexane to give ethyl 5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate as colorless prism crystals (5.75 g, yield 82%). melting point: 155-156° C.
Reaction SMILES: [C:1]1(=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17]C(C)(C)C)=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[C:1]1(=[C:6]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:7]2[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCC2)c2ccc(O)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=C2CCCC2)c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-water cooled solution of 1,1-dimethylethyl (2E)-3-{4-[cyclopentylidene(4-hydroxyphenyl)methyl]phenyl}-2-propenoate (4) (0.28 g, 0.74 mmol) in dichloromethane (5 mL) was slowly added trifluoroacetic acid (5 mL) with stirring under a nitrogen atmosphere. After 1 h, the reaction mixture was concentrated in vacuo to give a solid. The solid was dissolved in dichloromethane and the solution was concentrated in vacuo to give a pale tan solid. The solid was triturated with diethyl ether and filtered to give the acrylic acid as an off-white solid. The solid was dried overnight under vacuum at 70° C., however, 1H NMR indicated that solvent remained in the sample. The solid was dissolved in methanol and the solution was concentrated in vacuo to give an oil. The oil was dissolved in methanol and the solution was concentrated in vacuo under high vacuum at 60° C. to give an oil. Dichloromethane was added to the oil and crystallization was induced with the aid of a spatula. The suspension was filtered and the solid was dried in a vacuum oven overnight at 70° C. to give 0.072 g (30%) of compound 5 as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.60 (m, 4H), 2.30 (m, 4H), 6.44 (d, J=15.9 Hz, 1H), 6.67 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 9.32 (s, 1H). The compound was silated prior to EI analysis. HRMS (EI) Calcd for C27H36Si2O3: 464.2203 (M+). Found: 464.2210.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][C@@H:5]3[CH2:30][C@H:31]([N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:32][C:3]=1[C:4]=23.C([Li])CCC.CN(C)[CH:47]=[O:48]>O1CCCC1.CCCCCC>[CH:47]([C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:6][C@@H:5]3[CH2:30][C@H:31]([N:33]([CH2:37][CH2:38][CH3:39])[CH2:34][CH2:35][CH3:36])[CH2:32][C:3]=1[C:4]=23)=[O:48]
Reactant: CN(C)C=O
Reactant: CCCN(CCC)[C@@H]1Cc2c(Br)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCN(CCC)[C@@H]1Cc2c(C=O)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (-)(2aR,4S)-6-bromo-1-trityl-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (6.8 g, 12 mmol) in 100 ml of tetrahydrofuran cooled to -78° C. under a nitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithium in hexane. The reaction mixture was stirred at -78° C. for 1 hour. Dimethylformamide (3 ml) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water and then extracted with ethyl acetate. The ethyl acetate solution was washed with a saturated brine solution, dried over magnesium sulfate and concentrated to dryness to provide 5.6 g of the above-titled compound as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)C#N.C[Mg]Br.C([O:17][CH2:18][CH3:19])C>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([C:18](=[O:17])[CH3:19])[CH:8]=[CH:9][N:10]=1
Reactant: CN(C)c1cc(C#N)ccn1
Reactant: CCOCC
Agent: C[Mg]Br
Product: CC(=O)c1ccnc(N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 7.4 g. (50 mmoles) of 2-dimethylaminoisonicotinonitrile in 150 ml. of diethyl ether was added dropwise 33 ml. (100 mmoles) of a 3 M solution of methyl magnesium bromide under a nitrogen atmosphere. On completion, the reaction was allowed to stir at room temperature for 16 hours, and was then quenched by the careful addition of 80 ml. of 2 N hydrochloric acid. The aqueous phase was separated and the organic phase extracted further with 2 N hydrochloric acid (2×10 ml.). The combined acid extracts were neutralized with solid sodium carbonate and extracted with chloroform (5×50 ml.). The combined chloroform extracts were dried and concentrated to a brown oil. Distillation of the residue gave 5.0 g. (61%) of the product as an oil (b.p. 110° C./1 torr). On standing the oil crystallized, m.p. 37°-42° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[C:9]2=[O:16])=[CH:4][CH:3]=1.C(OC1C=[CH:29][C:28]([NH:31][C:32]2[N:37]=CN=[C:34]([O:38][C:39]3[CH:44]=[CH:43][C:42]([NH:45]C(=O)CC(NC4C=CC(F)=CC=4)=O)=[CH:41][C:40]=3[F:59])[CH:33]=2)=CC=1)C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:37][C:32]1[CH:33]=[C:34]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:13]([CH:10]3[CH2:11][CH2:12][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:9]3=[O:16])=[O:15])=[CH:41][C:40]=2[F:59])[CH:29]=[CH:28][N:31]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Reactant: O=C(O)C1CCN(c2ccc(F)cc2)C1=O
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: Nc1cc(Oc2ccc(NC(=O)C3CCN(c4ccc(F)cc4)C3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-2-oxopyrrolidine-3-carboxylic acid (0.3 mol), 4-(4-amino-2-fluorophenoxy)pyridin-2-amine (Compound B of Example 24, 21.9 mg, 0.1 mmol) in DMF (0.5 ml), was added HATU (76 mg, 0.2 mmol) and followed by diisopropylethylamine (0.1 mL, 0.57 mmol). The reaction mixture was stirred at room temperature overnight and was then quenched with 2 mL of methanol. The reaction mixture was purified by prep HPLC. The desired fractions were combined, neutralized with sat. aq. NaHCO3 solution, and concentrated in vacuo to afford the title compound (18 mg, 43%) as a white solid. 1H NMR (DMSO-d6) δ 10.76 (br s, 1H), 7.95 (d, 1H, J=7.2 Hz), 7.91 (m, 1H), 7.68 (m, 2H), 7.50 (m, 1H), 7.44 (t, 1H, J=10.0 Hz), 7.24 (m, 2H), 6.70 (m, 1H), 6.11 (d, 1H, J=2.8 Hz), 3.91 (m, 2H), 3.78 (t, 1H, J=5.0 Hz), 2.41 (m, 2H); MS (ESI+) m/z 425.15 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]([O:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][O:18][C:17]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:16]=1
Reactant: C1CNCCN1
Reactant: Clc1ccccc1OCCOc1nc2ccccc2nc1Cl
Product: Clc1ccccc1OCCOc1nc2ccccc2nc1N1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
Piperazine (0.580 g, 6.65 mmol) was added to the crude material from Step 1 and the resulting mixture was stirred at room temperature for 5 h. The solvent was evaporated, and the crude mixture was dissolved in DMSO and precipitated with water. The precipitate was purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (40:3:3:2) as eluent to afford 0.100 g (22%) of the title compound as a yellow oil. HRMS m/z calcd for C20H21CIN4O2(M)+384.1353, found 384.1334.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([NH:22][C:23](=[S:24])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccc(NNC(=O)C(F)(F)F)cc1
Solvent: CCO
Product: O=C(NNc1ccc(NC(=S)Nc2ccccc2)cc1)C(F)(F)F

Procedure:
2-(4-Aminophenyl)-1-trifluoroacetylhydrazine (2.0 g, 0.0091 mole) and phenyl isothiocyanate (1.2 g, 0.0091 mole) were mixed together in ethanol (25 ml) and the mixture was heated to reflux for 20 minutes. A white solid precipitated out of the mixture during the heating. The mixture was chilled in ice and the solid was filtered off, washed with ethanol, and dried. Spectral data on this material indicated that it was not the desired product. The filtrate from above was diluted with water and a second solid material formed. This material was filtered off, washed with water and dried to give a white crystalline powder. Yield 0.80 g (25%), m.p. 172°-174° C. Spectral evidence verified that this substance was the desired product.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH2:9]([NH2:13])[CH2:10][CH:11]=[CH2:12]>O>[CH2:9]([NH:13]/[C:2](=[CH:3]\[CH3:5])/[C:1]([O:7][CH3:8])=[O:6])[CH2:10][CH:11]=[CH2:12]
Reactant: C=CCCN
Reactant: COC(=O)CC(C)=O
Solvent: O
Product: C=CCCN/C(=C\C)C(=O)OC
Temperature: 25 °C

Procedure:
2.15 milliliters (2.32 grams, 20.0 millimoles) of methyl acetoacetate was added with stirring to 1.42 grams (20.0 millimoles) of homoallylamine cooled in an ice bath and the stirring continued while the mixture was allowed to warm to room temperature and thereafter for three hours to obtain a methyl 2-(3-butenyl)aminocrotonate intermediate product and water by-product in the reaction mixture.
Reaction SMILES: [CH3:1][C:2]([S:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:7])[C:3](=[O:6])[CH2:4][CH3:5].[Br-:13].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O>C(Cl)Cl>[Br:13][CH:4]([CH3:5])[C:3](=[O:6])[C:2]([S:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:1])[CH3:7]
Reactant: CCC(=O)C(C)(C)SCC(=O)O
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: CC(Br)C(=O)C(C)(C)SCC(=O)O
Reaction time: 0.25 h

Procedure:
To a solution of [(1,1-dimethyl-2-oxobutyl)thio]acetic acid (0.3 g, 1.58 mmol) in CH2Cl2 (10 ml) was added phenyltrimethylammonium tribromide (0.62 g, 1.65 mmol) at 0° C. After stirring for 15 min, the solution was allowed to come to room temperature and stirring was continued for 1 h. Water (30 ml) was added and the aqueous layer was extracted with diethyl ether (15 ml). The combined organic layers were washed with brine (25 ml), dried over Na2SO4, filtered and concentrated in vacuo. The remaining oil was purified by flash chromatography (ethyl acetate-petroleum ether 1:1 containing 0.1% glacial acetic acid). Yield: 0.39 mg (91%). 1H-NMR (400 MHz, CDCl3): δ=1.15, 1.64 (2×s, 6H, C(CH3)2), 1.81 (d, 3H, J=7.0 Hz), 3.14, 3.21 (2×d, 2H, J=6.8 Hz), 5.07 (q, 1H, J=7.0 Hz) ppm. C8H13BrO3S (269.16, 267.98), HRMS: calcd (M+Na)+ 290.9661, found 290.9669.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:12](=[O:13])[O:11][N:10]=[C:9]2[C:14]2[C:18]([NH:19][CH2:20][CH2:21][OH:22])=[N:17][O:16][N:15]=2)[O:5][CH:6]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:23][S:24]([O:22][CH2:21][CH2:20][NH:19][C:18]1[C:14]([C:9]2[N:8]([CH2:7][C:4]3[O:5][CH:6]=[C:2]([Br:1])[CH:3]=3)[C:12](=[O:13])[O:11][N:10]=2)=[N:15][O:16][N:17]=1)(=[O:26])=[O:25]
Reactant: O=c1onc(-c2nonc2NCCO)n1Cc1cc(Br)co1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of 4-[(4-bromo-2-furyl)methyl]-3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazol-5(4H)-one (7.7 g, 21 mmol, containing also some of the corresponding bromo-compound) in ethyl acetate (100 mL) was added methanesulfonyl chloride (0.96 mL, 12 mmol) in one portion. The reaction was stirred for 5 minutes and triethylamine (1.6 mL, 11 mmol) was added, also in one portion. After stirring for 30 minutes, additional methanesulfonyl chloride (0.4 mL, 5 mmol) was added, followed 5 minutes later by triethylamine (0.58 mL, 4.2 mmol). After 15 minutes, the reaction was quenched with the addition of water (100 mL). The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers washed with brine (100 mL). After drying over sodium sulfate, the solvent was removed in vacuo to give the desired product (9.3 g, 100%). LCMS calculated for C12H13BrN5O7S (M+H)+: m/z=449.8, 451.8. 1H NMR (300 MHz, DMSO-d6): δ 7.88 (s, 1H), 6.73 (t, J=6.2 Hz, 1H), 6.68 (s, 1H), 5.08 (s, 2H), 4.37 (m, 2H), 3.59 (q, J=5.8 Hz, 2H), 3.16 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([OH:13])=[O:12])=[C:2]1[CH3:1])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccccc2c1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)O)c2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a stirred solution of 0.50 g (3.1 mmol) 2-methyl-1H-indole-3-carboxylic acid (described in J. Heterocyclic Chem. 1977, 14, 1123) in 5 ml DMF were added 0.27 g (6.75 mmol) of NaH (60% in oil). The mixture was stirred at RT for 30 min. and then 0.39 ml (3.28 mmol) of benzyl bromid were added. The mixture was stirred an additional hour and then poured onto water and extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Crystallization in Et2O afforded 0.61 g (78%) of 1-benzyl-2-methyl-1H-indole-3-carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)=[CH:11][CH:12]=2)=[CH:5][NH:4][N:3]=1
Reactant: Cc1cccc(Cc2ccc(-c3cnn(C(N)=O)c3N)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(Cc2ccc(-c3c[nH]nc3N)cc2)c1

Procedure:
To a solution of 3-amino-2-carbamoyl-4-[4-(3-methylphenylmethyl) phenyl]pyrazole (2.0 g) in methanol (20 ml) was added 5N sodium hydroxide solution (10 ml), and the mixture was refluxed for 4 hours. Methanol was distilled away under reduced pressure. To the residue was added water (100 ml), and the mixture was neutralized (pH 7 to 8) with conc. hydrochloric acid, and extracted with chloroform. The extract was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:1 followed by chloroform:methanol=10:1) to give a mixture containing the title compound. This mixture Was used in the subsequent reaction without isolation.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[C:3]=1[F:11].[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[Cl:1][C:2]1[C:3]([F:11])=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[NH:9][C:13](=[O:14])[C:12](=[O:16])[NH:10]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(F)c(Cl)c(F)c1N
Agent: Cl
Product: O=c1[nH]c2cc(F)c(Cl)c(F)c2[nH]c1=O
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 230 mg (1.29 mmol) of 4-chloro-3,5-difluoro-1,2-phenylenediamine and 125 mg (1.38 mmol) of oxalic acid in 4 mL of 2N HCl was refluxed for 3 h and cooled to room temperature. The mixture was filtered, washed with water, and dried to leave a brown solid (245 mg, 82%); mp>250° C.; 1H NMR (DMSO-d6), 6.921 (d, 1, J=9.61), 12.143 (s, 1), 12.168 (s, 1). MS, 232 (M+, 100), 204 (80), 176 (40), 149 (70), 171 (80). HRMS calcd for C8H335ClF2N2O2, 231.9848, found 231.9851.