Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:27]=[CH:26][CH:25]=2)O1.O.CCOC(C)=O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].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>[CH3:34][Si:33]([CH3:36])([CH3:35])[CH2:32][CH2:31][O:30][CH2:29][N:28]1[C:24]([C:2]2[CH:15]=[CH:14][C:5]([O:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)=[CH:4][CH:3]=2)=[CH:25][CH:26]=[N:27]1
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Reactant: Oc1ccc(Oc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1nccc1-c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(4-Bromo-phenoxy)-phenol (7.0 g, 26 mmol), and 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole (9.4 g, 39 mmol) in a mixture of DME (120 mL) and 2N aqueous Na2CO3 (33 mL) is sparged with Argon for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (1.5 g, 1.3 mmol) is added to the mixture, and the mixture is heated to 100° C. After 16 hours, the mixture is cooled to room temperature and poured into water/EtOAc. The organic layer is collected, and the aqueous layer is extracted twice with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified on SiO2 (EtOAc/heptanes) to provide Intermediate A.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:7]2[CH:28]=1)(=O)[NH2:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CCN(CC)CC>C(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]2[N:11]=[C:10]([CH3:12])[C:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:8]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:7]2[CH:28]=1)#[N:2]
Reactant: Cc1nc2nc(C(N)=O)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1nc2nc(C#N)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
To a stirred solution of tert-butyl 2-carbamoyl-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (Example 156, Step 1, 50 mg, 0.12 mmol) in CH2Cl2 (3 mL) was added TFAA (50 mg, 0.24 mmol) and Et3N (33 μL, 0.24 mmol). After 2 h, the reaction was extracted with H2O and brine prior to drying over anhydrous MgSO4. Filtration, concentration under reduced pressure afforded tert-butyl 2-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (50 mg, 95% pure) as a yellow oil.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:10]>>[CH:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:4]1([CH:3]2[O:10][CH:2]2[CH3:1])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: C/C=C/c1ccccc1
Product: CC1OC1c1ccccc1
Product: O=Cc1ccccc1
Yield: 14 %
Yield: 86 %

Procedure:
The metal-catalyzed epoxidation of trans-β-methylstyrene was performed as described in Example 2 with the substitution of Co(OAc)2. 4 H2O (where OAc=acetate) (0.0058 g, 2.3×10-5 moles) as the catalyst. After 16 hours of reaction, the complete oxidation of the substrate produced benzaldehyde (14%) and 1-phenylpropylene oxide (86%).
Reaction SMILES: Br[C:2](=[CH2:33])[CH2:3][N:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[C:5]([C@H:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH:9]=[CH2:10])=[O:6].[C:34]1(B(O)O)[CH:39]=[CH:38]C=[CH:36][CH:35]=1.[C:43](=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.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>[CH3:32][O:31][C:24]1[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:23]=1[CH2:22][N:4]([CH2:3][C:2]([C:33]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1)=[CH2:43])[C:5]([C@H:7]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)Br)Cc1ccc(OC)cc1OC
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=C)c1ccccc1)Cc1ccc(OC)cc1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (1.11 g, 0.962 mmol) was added to a solution of benzyl (1R)-1-{[(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate (2.49 g, 4.81 mmol), phenylboronic acid (0.65 g, 5.29 mmol) and sodium carbonate (2M in water; 4.81 mL, 9.63 mmol) in tetrahydrofuran (54 mL) and water (20 mL), and the mixture heated to 60° C. After 1 h, the mixture was allowed to cool to ambient temperature and extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (2.02 g). MS 515 (M+1).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1
Reactant: Cn1nnnc1SCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1nnnc1SCI
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloromethylthio-1-methyltetrazole (987 mg: 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g: 12.0 mMol.), and the mixture is stirred at 50° C. for 3 hours. After cooling, the reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, filtered, and concentrated to give 5-iodomethylthio-1-methyltetrazole as yellow oil (1.33 g: containing about 20 Mol. % of the chloride).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2NC1=O

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3(R,S)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylacetyl chloride. The product was purified by chromatography on silica gel (hexane-ethyl acetate elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.: m.p. 238°-240° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 108 %

Procedure:
To 2,3-dichloro-5-trifluoromethylpyridine (25 g) were added 1-BOC-piperazine (23.84 g), potassium carbonate (32.08 g), N,N-dimethylformamide (50 mL) and toluene (50 mL), and the mixture was stirred at 100° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (45.71 g). To 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11 g) were added palladium (II) acetate (0.726 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.692 g), potassium fluoride (15.06 g), methylboronic acid (7.88 g) and tetrahydrofuran (300 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g). To 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g) were added 4N hydrogen chloride/ethyl acetate (26 mL) and chloroform (64 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and sodium hydrogen carbonate, and the mixture was extracted with chloroform. The solvent was evaporated to give the title compound (6.38 g).
Reaction SMILES: [NH2:1][C:2](=[C:7]1C(=O)O[C:10](C)([CH3:14])[O:9][C:8]1=[O:16])[CH2:3][CH:4]1[CH2:6][CH2:5]1.[Na].[Cl-].[Na+].O>C(O)C.ClCCl>[CH2:10]([O:9][C:8](=[O:16])[CH:7]=[C:2]([NH2:1])[CH2:3][CH:4]1[CH2:5][CH2:6]1)[CH3:14]
Reactant: CC1(C)OC(=O)C(=C(N)CC2CC2)C(=O)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C=C(N)CC1CC1
Yield: 70 %

Procedure:
5-(1-Amino-2-cyclopropyl-ethylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (397 mg, 2 mmol) was added to a solution of sodium (45 mg, 2 mmol) in ethanol (3 ml). The reaction mixture was heated under reflux for 14 h, diluted with dichloromethane and poured onto ice water/brine 1/1. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to give 231 mg (1.4 mmol, 77%) of the title compound as orange oil.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[C:14]1[C:23]2[C:18](=[C:19]([Cl:24])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[C:5]12[CH:8]=[CH:9][CH:10]=[CH:11][CH:4]1[C:3]([NH:2][C:6]2=[O:7])=[O:12]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Clc1cccc2c(Br)ccnc12
Product: O=C1NC(=O)C2(c3ccnc4c(Cl)cccc34)C=CC=CC12

Procedure:
N-hydroxy-phthalimide and 4-bromo-8-chloro-quinoline (a known compound) were reacted to obtain 0-(8-chloro-4-quinolyl)-phthalimide which was reacted to obtain 0-(8-chloro-4-quinolyl)-hydroxylamine melting at 194° C.
Reaction SMILES: [F:1][C:2]([F:18])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].[F:19][C:20]([S:23][CH2:24][CH2:25]OS(C(F)(F)F)(=O)=O)([F:22])[F:21]>>[F:18][C:2]([F:1])([C:11]([F:16])([F:17])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:4][S:5]([CH:8]([CH2:25][CH2:24][S:23][C:20]([F:22])([F:21])[F:19])[C:9]#[N:10])(=[O:6])=[O:7]
Reactant: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(OCCSC(F)(F)F)C(F)(F)F
Product: N#CC(CCSC(F)(F)F)S(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)F

Procedure:
Compound II-24 was prepared from (3,3,4,4,5,5,5-heptafluoro-pentane-1-sulfonyl)-acetonitrile and trifluoro-methanesulfonic acid 2-trifluoromethylsulfanyl-ethyl ester as described for compound II-1.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][C:12]1[O:13][CH:14]=[CH:15][CH:16]=1>>[O:13]1[CH:14]=[CH:15][CH:16]=[C:12]1[CH2:11][NH:10][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: NCc1ccco1
Product: N#Cc1ccccc1NCc1ccco1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and 2-(aminomethyl)furan.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:5])[CH3:2].[C:15]([O-])(=[O:17])[CH3:16].[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.CCCCCON=O>C(Cl)(Cl)Cl>[C:15]([N:11]1[C:12]2[C:8](=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:14][CH:13]=2)[CH:9]=[N:10]1)(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)c1ccc2[nH]ncc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCCON=O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccc2c(cnn2C(C)=O)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
5-Ethoxycarbonylindazole. A mixture of the product prepared according to Example E-19 Part B (250.55 g, 1.4 mol), potassium acetate (143.3 g, 1.46 mol), acetic anhydride (285.9 g, 2.8 mol) and chloroform (ethanol-free; 2700 mL) was stirred at room temperature. The temperature rose to 40° C., then started to decline, at which time no starting material was detected by TLC. A mixture of 18-crown-6 (75 g, 280 mmol) and n-amyl nitrite (364.5 g, 3.1 mol) was added and the mixture was heated at reflux overnight. The cooled mixture was washed with saturated aqueous sodium bicarbonate, then with water, and was dried (MgSO4), filtered and concentrated. The residue was combined with that from another batch (711.3 g) and distilled through a 10 cm vigreaux column under vacuum to provide 1-Acetyl-5-ethoxycarbonyl-indazole (576 g, 82%), bp 115-165 ° C. (1.0 Torr). This intermediate was combined with hydrochloric acid (6N; 2000 mL) and ethanol (2000 mL), and the mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, and the solid was combined with water. The pH of the mixture was adjusted to 8 with aqueous ammonia, and the mixture was extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and concentrated to provide a solid (460 g). This was recrystallized from acetonitrile (1000 mL), and the crystals were washed with ethanol, then hexane, and dried to provide the title product (281 g, 60%) as a tan solid, mp 122-124° C.: 1H NMR (CDCl3) d 10.23 (bs, 1H), 8.57 (s, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 7.53 (d, 1H), 4.42 (q, 2H), 1.42 (t, 3H); High resolution mass spectrum (NH3-CI) calculated (M+H+) 191.0821, found 191.0838.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH2:14][C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1.CO.[CH:29]1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([F:26])[C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH2:14][C:15]([O:17][CH3:29])=[O:16])=[CH:7][CH:6]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cn1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cn1ncc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(2-Chloro-6-fluoro-4-trifluoromethylphenoxy)-indazol-1-ylacetic acid prepared as described in Example 3 (0.319 g) was suspended in dry dichloromethane (6 cm3) and methanol (0.04 cm3) and DMAP (10 mg) added. Dicyclohexylcarbodiimide (0.169 g) was added and the mixture stirred at room temperature for 2 hours and left to stand overnight. The mixture was filtered and the solvent removed from the filtrate under vacuum. The residue was purified by flash chromatography (hexane: TMBE,3:2) to yield methyl 2-[6-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)indazol-1-yl]acetate (0.28 g) as an oil which solidified on standing.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N(S(F)(F)[F:24])C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([F:24])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FS(F)(F)N(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccccc1
Solvent: ClCCl
Product: O=C(F)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of benzoic acid (122 mg, 1 mmol) in CH2Cl2 (5.0 mL) was added to diphenylaminosulfur trifluoride (771 mg, 3.0 mmol ) under N2 and stirred for 16 h at room temperature. After work-up as above benzoyl fluoride (124 mg, quantitative yield) was obtained. The product was identified by g.c.m.s. M+=124
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[Cl:9][C:10]1[C:11](=[O:19])[NH:12][C:13](=[O:18])[NH:14][C:15]=1[CH2:16]Cl.Cl>[OH-].[K+]>[Cl:9][C:10]1[C:11](=[O:19])[NH:12][C:13](=[O:18])[NH:14][C:15]=1[CH2:16][N:6]1[CH:7]=[N:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Reactant: O=[N+]([O-])c1nc[nH]n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c(Cn2cnc([N+](=O)[O-])n2)c(Cl)c(=O)[nH]1
Temperature: 80 °C
Yield: 73 %

Procedure:
To a solution of 0.88 g of 3-nitro-1,2,4-triazole in a 1 N aqueous solution of KOH (10 ml), 0.50 g of 5-chloro-6-chloromethyluracil was added, followed by heating at 80° C. for 2.5 hours under stirring. The reaction mixture was neutralized with 6 N hydrochloric acid. A precipitate was collected by filtration and then washed with water and methanol, whereby 510 mg of the title compound were obtained (yield: 73%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[C:15]([CH3:16])=[N:14][N:13]=[N:12]1)(=[O:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]2[C:15]([CH3:16])=[N:14][N:13]=[N:12]2)(=[O:4])=[O:3])=[O:29])[N:22]=1
Reactant: Cc1nnnn1-c1ccccc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2-n2nnnc2C)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To 0.48 g of 1-(2-aminosulfonylphenyl)-5-methyl 1H-tetrazole in 25 mL of acetonitrile was added at ambient temperature and pressure 0.54 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate and 0.3 mL of DBU. The reaction mixture was stirred for three hours, added to 25 g of ice and acidified to pH 3 with hydrochloric acid. The precipitate thus obtained was filtered, washed with water and dried to yield 0.74 g of the desired product, melting point at 213°-216° C. Infrared absorption spectra showed peaks at 1710, 1605 and 1570 cm-1, consistent for the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][CH3:10].O[CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:4][C:3]=1[CH2:9][CH3:10]
Reactant: COC(=O)C(C)(C)CO
Reactant: CCc1cc(O)ccc1Cl
Product: CCc1cc(OCC(C)(C)C(=O)OC)ccc1Cl
Yield: 85.3 %

Procedure:
By using 4-chloro-3-ethylphenol (2000 mg) and methyl hydroxypivalate (2025 mg), the procedure was carried out in the same manner as in Example 1-1) to obtain methyl 3-(4-chloro-3-ethylphenoxy)-2,2-dimethylpropanoate (2951 mg).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[N+:16]([O-])=O)([CH3:6])[C:3]([OH:5])=[O:4].[H][H]>O1CCCC1.[Ni]>[CH3:6][C:2]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[NH2:16])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COc1ccc(NC(C)(C)C(=O)O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc(NC(C)(C)C(=O)O)c(N)c1

Procedure:
32.6 g (mol/7.8) of 2-methyl-(2'-nitro-4'-methoxyanilino)-propionic acid, in solution in 330 ml of tetrahydrofuran, are hydrogenated in the presence of 20 g of Raney nickel in an autoclave with a capacity of 500 ml. Hydrogen pressure in the cold: 150 kg/cm2. Temperature = 70°-90° C.; Duration: 3 hours
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:6]2[C:7](=[O:10])[O:8][CH2:9][C:5]=2[C:4]=1[CH3:14])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:14][C:4]1[C:5]2[CH2:9][O:8][C:7](=[O:10])[C:6]=2[CH:11]=[C:12]([CH3:13])[C:3]=1[CH:1]1[CH2:2][O:23]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1c(C)cc2c(c1C)COC2=O
Solvent: ClCCl
Product: Cc1cc2c(c(C)c1C1CO1)COC2=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Ethenyl-4,6-dimethyl-2-benzofuran-1(3H)-one (150 mg, 0.797 mmol), mCPBA (275 mg, 1.59 mmol), were combined together in DCM (20 mL) and stirred at room temperature for 12 h. The reaction mixture was then diluted with DCM and washed with Na2S2O3 solution, NaHCO3 solution, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was then re-dissolved DCM, absorbed onto silica gel, concentrated, and loaded into silica column for separation giving 4,6-dimethyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([NH:23][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH:13]=[CH:14][CH3:15])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: NCc1ccccc1
Product: CC=Cn1c(C)c(C)c2cnnc(NCc3ccccc3)c21
Yield: 31.5 %

Procedure:
The title compound (trans) was prepared as a beige powder in 31.5% yield in a similar procedure to that described in Example 44 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and benzylamine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3]CO[C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][N:12](C)[CH2:13]2)=[CH:8][CH:7]=1.COC1C(OC)=N[S:21](=[O:26])[N:20]=1>CO>[S:21]1(=[O:26])[CH:3]=[CH:2][N:1]=[N:20]1.[CH2:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][CH:15]=2)[CH2:10][CH2:11][NH:12]1
Reactant: CN1CCc2ccc(OCCCN)cc2C1
Reactant: COC1=NS(=O)N=C1OC
Solvent: CO
Product: O=S1C=CN=N1
Product: c1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7-(3-aminopropoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline (5.43 g) in methanol (70 ml) is slowly added over a period of 45 minutes to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole-1-oxide (3.68 g) in 375 ml of methanol at a temperature of 3° C. The reaction mixture is stirred for an additional one hour and 25.0 g anhydrous ammonia is bubbled in over a period of 10 minutes. The resulting mixture is warmed to RT with stirring and the solution is evaporated in vacuo. The near-white solid residue is dissolved in hot 95% ethanol, filtered hot and rinsed with hot ethanol. The solution is cooled with stirring, then stirred in an ice bath for 30 minutes and filtered. The resulting solid is washed with cold ethanol and diethyl ether and dried in air, giving the desired tetrahydroisoquinoline thiadiazole-1-oxide as a white powder, M.P. 193°-194° C.