Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Br[CH:3]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:24]=1)[C:4]([O:6][CH2:7]C)=[O:5].[C:25](O)(=[O:27])C>CO.O>[CH3:25][O:27][CH:3]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:24]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(Br)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)C(OC)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
Sodium (0.23 g.) was dissolved in dry methanol (60 ml.) and this solution added to ethyl 2-bromo-2-(p-chlorophenyl-5-benzoxazolyl)acetate (2.8 g.). The resulting solution was stirred for 68 hours at room temperature and then evaporated at 20° C. in vacuo to leave a residual oil. The oil was stirred in water (50 ml.) and the pH adjusted to 4 by the addition of glacial acetic acid. The resulting suspension was extracted with ether (3 × 75 ml.). The extracts were combined and washed with saturated sodium bisulphite solution (3 × 25 ml.). After drying (Na2SO4), the ether solution was evaporated to leave a gummy solid (2.15 g.). 1 Gram was purified by chromatography to yield a waxy solid (0.4 g.), which was subsequently recrystallised from carbon tetrachloride and 40°-60° petroleum ether. The resulting solid was the required product, m.p. 100°-105° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12](Cl)[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O>[CH2:1]([N:3]1[C:7]([OH:8])=[C:6]([C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11]=2[Cl:21])[CH:5]=[N:4]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(Cl)c2Cl)c1O
Solvent: O
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(N3CCOCC3)c2Cl)c1O
Reaction time: 48 h

Procedure:
A solution of 1.5 g (4.1 mmol) of 1-ethyl-4-(2,3-dichloro-4-methylsulfonylbenzoyl)-5-hydroxypyrazole in 30 mL of morpholine was heated at 100° C. with stirring for 2 days. The reaction mixture was then diluted with water, washed with diethyl ether, and acidified with hydrochloric acid. The resulting solution was extracted with dichloromethane and the extract was concentrated by evaporation under reduced pressure. The resulting residue was recrystallized from ethanol/dichloromethane to obtain to 0.33 g (20 percent of theory) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])CCC.CCCCCC.[CH:18](=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C1COCC1>[N:22]1[CH:23]=[CH:24][C:19]([CH:18]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)[OH:25])=[CH:20][CH:21]=1
Reactant: Brc1cccs1
Reactant: O=Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1ccncc1)c1cccs1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a stirred solution of 2-bromothiophene (10 g, 61.34 mmol) in dry THF (42 ml) was dropwise added a solution of n-butyl lithium in n-hexane (1.6M, 42.0 ml, 67.48 mmol) at −78° C. The resulting suspension was stirred at the same temperature for 30 min. After 30 min, a solution of isonicotinaldehyde (6.56 g, 61.34 mmol) in dry THF (30 ml) was dropwise added and continued the stirring at −78° C. for another 2 h. The progress of the reaction was monitored by TLC. The reaction was quenched with NH4Cl solution (10 ml) and diluted with diethyl ether (500 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and evaporated. The crude compound was triturated with hexane and diethyl ether to get the desired compound as an off-white solid (4.0 g, 34%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (dd, J=4.9, 1.5 Hz, 2H), 7.45-7.38 (m, 3H), 6.97-6.93 (m, 2H), 6.45 (d, J=4.4 Hz, 1H), 5.97 (d, J=4.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[C:12]([N:16]2[C:20](=[O:21])[N:19]([CH:22]([F:24])[F:23])[C:18]([CH3:25])=[N:17]2)=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].C[O-].[Na+].[CH2:29](O)[CH:30]=C>C(OCC)C>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[C:12]([N:16]2[C:20](=[O:21])[N:19]([CH:22]([F:24])[F:23])[C:18]([CH3:25])=[N:17]2)=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH2:9][CH:29]=[CH2:30])=[O:7]
Reactant: C=CCO
Reactant: COC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: C=CCOC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1Cl

Procedure:
Under a dry nitrogen atmosphere, a stirred solution of 0.5 g (0.0013 mole) of methyl 2-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate (Compound 2) and approximately 0.01 g of sodium methoxide in 30 mL of 2-propen-1-ol was heated at reflux. After approximately 5 mL of methanol was collected in a Dean-Stark trap, the reaction mixture was cooled slightly, and the remaining solvent removed by distillation under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 0.55 g of 2-propenyl 2-[2,4-dichloro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound B2.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[OH:17][C:15]1[C:14]([I:18])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(I)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CNCCc2cc(O)c(I)cc21
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A solution of N-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (25 mg, 0.063 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 13 mg of a white solid. 1H NMR (400 MHz, CD3OD) d 7.46 (s, 1 H), 6.64 (s, 1 H), 3.16 (m, 3 H), 2.94 (m, 3 H), 2.81 (m, 1 H), 1.35 (d, J=7 Hz, 3 H). MS calculated for C11H14INO+H: 304, observed: 304.
Reaction SMILES: [SiH:1]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Si:32]([CH:63]=[CH2:64])([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[Si:1]([CH2:64][CH2:63][Si:32]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC[SiH](CCCCCCCCCC)CCCCCCCCCC
Reactant: C=C[Si](CCCCCCCCCC)(CCCCCCCCCC)CCCCCCCCCC
Product: CCCCCCCCCC[Si](CCCCCCCCCC)(CCCCCCCCCC)CC[Si](CCCCCCCCCC)(CCCCCCCCCC)CCCCCCCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
The reaction was carried out in a similar manner as described in Example I. A mixture of (n-C10H21)3SiH (25.0 g, 55.3 mmole), (n-C10H21)3SiCH═CH2 (26.4 g, 55.3 mmole) and Pt(acetylacetonate)2 (22 mg, 5.53×10−2 mmole) was placed in the flask. The reaction mixture was stirred at room temperature for two days and then at ˜40° C. for another two days. The product was purified by column chromatography as described in Example I. After removal of the solvent, a crude product was obtained. The crude product was distilled to remove the low boiling components at <230° C./5×10−5 mmHg and yielded the desired product (n-C10H21)3SiCH2CH2Si(n-C10H21)3 (48.4 g, colorless liquid, 94 percent yield). The infrared spectrum and mass spectra data were consistent with the expected structure. In the analysis for C62H130Si2, the amount calculated was: C, 79.91; H, 14.06; Si, 6.03 percent, while the amount found was: C, 80.12; H, 14.15; Si, 5.92 percent.
Reaction SMILES: [CH:1]([N:3]([CH2:6][CH2:7][C:8]([O:10]C)=O)[CH:4]=[O:5])=[CH2:2].[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C[O-].[Na+]>CO>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][NH:12][C:8](=[O:10])[CH2:7][CH2:6][N:3]([CH:1]=[CH2:2])[CH:4]=[O:5]
Reactant: C=CN(C=O)CCC(=O)OC
Reactant: NCCCCCO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CN(C=O)CCC(=O)NCCCCCO

Procedure:
The apparatus of Example 2 was charged with 15.7 grams (0.1 mol) of methyl 3-(N-vinylformamido)propionate, 10.3 grams (0.1 mol) of 5-amino-1-pentanol and 0.12 gram of 25% sodium methoxide in methanol solution. The mixture was stirred at 90° C. for 3 hours after which the methanol coproduct was removed by distillation at reduced pressure. NMR analysis of the remaining amber liquid indicated about 69% conversion to the desired product.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][S:20][C:21](SC)=[CH:22][N+:23]([O-:25])=[O:24].[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30]>O1CCCC1>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[N+:23]([CH2:22][CH:21]([S:20][CH3:19])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)([O-:25])=[O:24]
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: CSC(C[N+](=O)[O-])NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
A mixture of 3-[3-[(1-piperidinyl)methyl]phenoxy]propaneamine (4.97 g.) and 1,1-bis-(methylthio)-2-nitroethene (6.61 g.) in tetrahydrofuran (100 ml.) was heated under reflux for 19 hours. A solution of oxalic acid (6.25%) in tetrahydrofuran (4 ml.) was added, the suspension filtered and to the filtrate was added a solution of oxalic acid (6.25%) in tetrahydrofuran (36 ml.). The solid which separated on trituration was filtered, washed with tetrahydrofuran and dried to give the title compound (7.36 g.), m.p. 71°-75°.
Reaction SMILES: [CH3:1][C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:13])[CH:9]=2)[NH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].P(Cl)(Cl)([Cl:21])=O.CN(C)C1C=CC=CC=1>>[Cl:21][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:13])[CH:9]=2)[N:4]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]=1[CH3:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1[nH]c2ccc(C)cc2c(=O)c1C
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1nc2ccc(C)cc2c(Cl)c1C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a mixture of ethyl 1,4-dihydro-3,6-dimethyl-4-oxoquinoline-2-carboxylate (4.0 g) and phosphoryl chloride (10 g) was added N,N-dimethylaniline (3.95 g) at ambient temperate and the mixture was stirred for 1 hour. The solvent was removed in vacuo, and the residue was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (n-hexane-dichloromethane) to give ethyl 4-chloro-3,6-dimethylquinoline-2-carboxylate (3.17 g) as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](Cl)=[O:10])[CH:4]=1.[CH3:12][NH2:13]>C1COCC1.CO>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH:13][CH3:12])=[O:10])[CH:4]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)ccn1
Reaction time: 4 h

Procedure:
4-Chloropyridine-2-carbonyl chloride HCl salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0° C. The resulting mixture was stored at 3° C. for 4 h, then concentrated under reduced pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCl solution (2×100 mL), dried (Na2SO4) and concentrated under reduced pressure to provide 4-chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 88%): mp 37-40° C.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH2:21][CH3:22]>>[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH2:21][CH3:22]
Reactant: CCCc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCCc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-propylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-propylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.CN(C)[C:18]1[O:19][C:20](=[O:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=1>C1(C)C(C)=CC=CC=1>[CH:1]([N:4]1[C:20](=[O:28])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[NH:23][C:18]1=[O:19])([CH3:3])[CH3:2]
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: CC(C)N
Solvent: Cc1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)n1c(=O)cc(C(F)(F)F)[nH]c1=O
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Isopropylamine (1.2 g, 20.3 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 6 mL) are added to a solution of 2-dimethylamino-4-trifluoromethyl-6H-1,3-oxazin-6-one (4.0 g, 19.2 mmol) in xylene (34 mL). The resultant reaction mixture is held at 100° C. for 3 hours, cooled, washed with 5 wt. % HCl (40 mL), and extracted with ethyl acetate. The combined organic extracts are concentrated and triturated with heptane. The solids are filtered and dried to give the title product as a yellow powder (2.3 g, 54% yield, mp 127°-129° C.) which is identified by 1H NMR (DMSO-d6) δ6.11 (1H, s), 4.96 (1H, sp), 1.35 (6H, d); and 19F NMR δ−68.9 (s).
Reaction SMILES: N[C@H](C=O)CCSC.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18].Cl>O1CCCC1>[OH:33][C:30]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:31][CH2:32][CH:27]([CH2:26][CH2:25][C@H:22]2[CH2:21][CH2:20][C@H:19]([CH2:16][CH2:17][CH3:18])[CH2:24][CH2:23]2)[CH2:28][CH2:29]1
Reactant: Brc1ccccc1
Reactant: CCC[C@H]1CC[C@H](CCC2CCC(=O)CC2)CC1
Agent: CSCC[C@H](N)C=O
Agent: Cl
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H](CCC2CCC(O)(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Metal magnesium in an amount of 11.6 g was suspended in 100 ml of tetrahydrofuran (hereinafter referred to as THF) under nitrogen gas stream, and a solution prepared by dissolving 69 g of bromobenzene in 200 ml of THF was added dropwise in the suspension and then stirred at room temperature for 1 hour. A solution prepared by dissolving 100 g of 4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexanone in 300 ml of THF was added dropwise thereto and stirred at room temperature for 1 hour. After finishing of the reaction, 500 ml of dilute hydrochloric acid was added thereto and extracted with 1 l of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 119 g of (1-hydroxy-4-(2-(trans-4-n-propylcyclohexyl)ethyl)cyclohexyl)benzene.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][N:17]=[C:16]([O:19][CH2:20][CH2:21][NH2:22])[C:15]=3[CH:23]=2)=[CH:7][CH:6]=1.CS([C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)(=O)=O.C(N(CC)CC)C>C(O)C>[F:25][C:3]([F:2])([F:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][N:17]=[C:16]([O:19][CH2:20][CH2:21][NH:22][C:30]4[N:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:15]=3[CH:23]=2)=[CH:7][CH:6]=1
Reactant: NCCOc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: CS(=O)(=O)c1ncccn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)Oc1ccc(-c2ccc3onc(OCCNc4ncccn4)c3c2)cc1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)ethanamine hydrochloride (57 mg, 0.152 mmol) and 2-(methylsulfonyl)pyrimidine (96 mg, 0.608 mmol) were dissolved in 2 mL ethanol in a microwave vial. Triethylamine (0.1 mL) was added and the mixture was heated at 120° C. for one hour in the microwave. All volatiles were removed under vacuum and the residue was purified on 12 g silica gel with 0-100% ethyl acetate in hexane to give the title compound (40 mg, 0.096 mmol). MS: 417 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][C:5]([N:16]2[C:20](=[O:21])[N:19]([CH:22]([F:24])[F:23])[C:18]([CH3:25])=[N:17]2)=[C:4]([F:26])[CH:3]=1.[CH3:27][S:28]([NH:31][C:32](=[O:36])[CH:33](Br)[CH3:34])(=[O:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:27][S:28]([NH:31][C:32](=[O:36])[CH:33]([O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[C:5]([N:16]3[C:20](=[O:21])[N:19]([CH:22]([F:23])[F:24])[C:18]([CH3:25])=[N:17]3)[C:4]([F:26])=[CH:3][C:2]=2[Cl:1])=[CH:10][CH:11]=1)[CH3:34])(=[O:30])=[O:29]
Reactant: CC(Br)C(=O)NS(C)(=O)=O
Reactant: Cc1nn(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nn(-c2cc(Oc3ccc(OC(C)C(=O)NS(C)(=O)=O)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Yield: 40.1 %

Procedure:
In a manner similar to Step D of Example 1, the reaction of 0.60 g (0.0015 mole) of 1-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one, 0.32 g (0.0014 mole) of N-methylsulfonyl-2-bromopropionamide, and 0.24 g (0.0017 mole) of potassium carbonate in 20 mL of acetone produced 0.3 g of N-methylsulfonyl-2-[4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5 -dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]phenoxy]-propionamide as an oil, Compound 32 of Table 1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)#[CH:2].C([Mg]Br)C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21](=[O:26])[C:22]([Cl:25])([F:24])[F:23]>CCOCC.C1COCC1>[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21]([OH:26])([C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:22]([Cl:25])([F:23])[F:24]
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)Cl
Reactant: C#Cc1ccccc1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(O)(C#Cc1ccccc1)C(F)(F)Cl
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 71.5 %

Procedure:
To a 100 mL, 3 necked, oven dried round bottomed flask, with a stirring bar, argon inlet, reflux condenser, and a septum was added ethynyl benzene (2.13 g, 20.83 mmol), dry THF (50 mL) and ethyl magnesium bromide (6.94 mL of a 3.0M solution in ether). This mixture was aged 2h at ambient temperature then a solution of 1-(2-amino-5-chlorophenyl)-2-chloro-2,2-difluoroethanone (1.00 g, 4.17 mmol) in THF (6 mL) was added with a syringe. The resulting orange-red solution was stirred at ambient temperature for 21.5 h. The reaction was quenched by addition of 1N HCl (50 mL) then diluted with EtOAc. The solution was then made basic with concentrated NH4OH and the layers were separated. The organic phase was washed with water and brine. Drying (MgSO4), filtration, removal of the solvent in vacuo, and chromatography on silica gel using 20% EtOAc in hexane as eluant gave 1.02 g of (±) 2-(2-amino-5-chlorophenyl)-4-phenyl-1-chloro-1,1-difluoro-3-butyn-2-ol as an off white solid. 1H NMR (CDCl3): δ4.42 (br s, 2H), 5.10 (br s, 1H), 6.65 (d, 1H, J=8.5 Hz), 7.15 (dd, 1H, J=2.4, 8.5 Hz), 7.38 (m, 3H), 7.55 (m, 2H), 7.70 (d, J=2.4 Hz).
Reaction SMILES: [OH:1][C@@H:2]([CH3:24])[CH2:3][N:4]1[C:12]([C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.[Cl:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[O:30][C:29]([C@@H:31]2[C:5]3=[C:6]4[N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10](=[O:20])[C:11]4=[C:12]([C:13]4[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=4)[N:4]3[CH2:3][C@H:2]([CH3:24])[O:1]2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3cn2C[C@H](C)O)c1
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2C[C@H](C)O[C@@H]3c2ccc(Cl)o2)c1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxypropyl)-1,3-dimethyl-5-m-tolyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and 5-chlorofuran-2-carbaldehyde by an analogous method to Example 12. Purification was carried out by chromatography on silica eluting with 0-55% EtOAc in iso-hexane;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.C(B(CC)[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)C.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:12][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: CCB(CC)c1cccnc1
Reactant: Nc1cc(Br)ccc1S(N)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cc(-c2cccnc2)ccc1S(N)(=O)=O
Yield: 96.3 %

Procedure:
A mixture of 4-bromo-2-aminobenzenesulfonamide (250 mg, 1.0 mmol), diethyl-3-pyridylborane (225 mg, 1.5 mmol), Pd(PPh3)2Cl2 (35 mg, 5 mol %) in 1,2-dimethoxyethane (30 ml) and Na2CO3 (2M, 3 ml, 6 mmol) were refluxed under N2 for 4 h. The solvents were removed under reduced pressure and the residue was treated with saturated NaHCO3 (20 ml) and extracted with EtOAc (2×40 ml). The organic layer was washed with brine (20 ml), dried (Na2SO4) and the solvent was removed under reduced pressure. The product was purified by flash chromatography on SiO2 using EtOAc:n-hexane (1:1, v/v) as eluent, yielding 240 mg (96%) of 2-amino-4-(3-pyridyl)-benzenesulfonamide as colorless powder. The product was further transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 240–243° C.