Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:7]([NH:9][NH2:10])=O)[CH3:2].[CH3:17][N:18]=[C:19]=[S:20].C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[N:18]([CH3:17])[C:19]([SH:20])=[N:10][N:9]=2)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH3:2]
Reactant: CN=C=S
Reactant: CCOc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1cc(-c2nnc(S)n2C)ccc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 22 h
Yield: 72.3 %

Procedure:
3-Ethoxy-4-nitrobenzohydrazide (Preparation 219, 1287 mg 5.72 mmole) was stirred in THF (26 mL) and a solution of methyl isothiocyanate (422 mg 5.78 mmole) in THF (5 mL) was added. Triethylamine (102 uL, 0.71 mmole) was added and the reaction was stirred at 20° C. for 22 hours. The solvent was evaporated and replaced with 1M sodium hydroxide solution (85 mL) and the reaction was stirred at 45° C. for 2.5 hours. The reaction was filtered through Celite and the filtrate extracted with ether (2×45 mL). The aqueous was acidified using conc. hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined ethyl acetate extracts were washed with water and with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound (1.16 g, 72%).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.C(OC(Cl)=O)C(C)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:33]2([CH2:39][CH2:40][CH2:41][NH:42][CH3:43])[S:38][CH2:37][CH2:36][CH2:35][S:34]2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].ClCCCC1(C2C=CC(OC)=C(OC)C=2)SCCCS1.CN>O1CCCC1.C(N(CC)CC)C>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:8]=1[O:9][CH3:10])[CH2:2][CH2:1][N:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C:33]1([C:27]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=2)[S:38][CH2:37][CH2:36][CH2:35][S:34]1
Reactant: CNCCCC1(c2ccc(OC)c(OC)c2)SCCCS1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CC(C)COC(=O)Cl
Agent: CN
Agent: COc1ccc(C2(CCCCl)SCCCS2)cc1OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CCN(C)CCCC2(c3ccc(OC)c(OC)c3)SCCCS2)cc1OC
Reaction time: 1 h

Procedure:
1 g of homoveratric acid is dissolved in 15 ml of absolute tetrahydrofuran and treated wih 0.15 g of triethylamine. 0.72 g of chloroformic acid isobutyl ester are then slowly added dropwise at 0°-5° C and the mixture is stirred for 1 hour at 5°-10° C. There is then added dropwise a solution of 1.63 g of 2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine [prepared in a manner analogous to that described in Example 15 from 2-(γ-chloropropyl)-2-(3,4-dimethoxyphenyl)-m-dithiane and methylamine] in 5 ml of tetrahydrofuran. The resulting mixture is left to stand at room temperature overnight. After evaporation of the solvent, the residue is partitioned between 1-M hydrochloric acid and ether. The organic extracts are washed with 5% sodium carbonate solution and water. After drying over magnesium sulphate, the solvent is removed by evaporation. The oily residue (1.5g) is dissolved in 15 ml of tetrahydrofuran and added dropwise to a suspension of 0.15 g of lithium aluminium hydride under reflux and under argon. The mixture is boiled for 2 hours and then treated slowly with a concentrated sodium sulphate solution in water and then with 10 ml of methylene chloride. The mixture is filtered under suction and then concentrated. The residue is chromatographed on silica gel and there is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-N-methyl-m-dithiane-2-propylamine in the form of a thick oil.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[CH:9]=2)[N:4]([S:25]([C:28]2[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH:3]=1
Reactant: COc1cc(-c2cnc3[nH]cc(I)c3c2)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
A solution of 3-iodo-5-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (870 mg, 2.12 mmol) in anh. THF (10 ml) was cooled to 0° C. and NaH (60% dispersion, 130 mg, 3.18 mmol) was added. After 20 min tosyl chloride (450 mg, 2.33 mmol) was added and the mixture was allowed to warm to room temperature. After 3 hrs the mixture was cooled to 0° C. and quenched by the addition of 0.5 N HCl. The product was extracted with DCM and purified by silica gel chromatography using DCM as an eluent affording 648 mg (54%). 1H NMR (CDCl3, 300 MHz): δ 8.61 (d, J=2.4 Hz, 1H), 8.12 (d. J=8.4 Hz, 1H), 7.91 (s, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 6.73 (s, 2H), 3.94 (s, 6H), 3.90 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)=[C:10]([F:22])[CH:9]=2)[CH2:4][CH2:3]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH2:36][CH2:37][C@H:38]1[CH2:43][CH2:42][Si@H:41]([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:40][CH2:39]1>[Cu]I.C1COCC1>[CH2:44]([Si@H:41]1[CH2:42][CH2:43][C@H:38]([CH2:37][CH2:36][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)=[C:10]([F:22])[CH:9]=3)[CH2:4][CH2:3]2)[CH2:39][CH2:40]1)[CH2:45][CH2:46][CH3:47]
Reactant: Fc1ccc(-c2ccc(C3CCC(Br)CC3)cc2F)cc1F
Reactant: CCCC[Si@H]1CC[C@H](CCBr)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOP(=O)(OCC)OCC
Product: CCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)c(F)c3)CC2)CC1

Procedure:
36.9 g (0.1 mol) of 4-(4-bromocyclohexyl)-2,3',4'-trifluorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 26.3 g (0.1 mol) of trans-1-(2-bromoethyl)-4-n-butyl-4-silacyclohexane. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-butyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,3',4'-trifluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 34.3 g (yield 72.6%) of the trans isomer.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([CH3:19])[CH:15]=[C:14]([OH:20])[CH:13]=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:27][CH2:28][CH2:29]Br>C(#N)C.O>[Br:27][CH2:28][CH2:29][O:20][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[NH:11]2)=[C:16]([CH3:19])[CH:15]=1
Reactant: Cc1cc(O)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(OCCBr)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 20.5 %

Procedure:
To a stirred solution of N-cyclohexyl-6-hydroxy-4-methyl-1H-indole-2-carboxamide (I-9A-b: 0.7 g, 2.57 mmol) in acetonitrile (20 mL) was added Cs2CO3 (1.67 g, 5.14 mmol) cooled to 0° C. followed by 1,2-dibromoethane (1.1 mL, 12.86 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 h, diluted with water (20 mL) and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layers were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 50% ethyl acetate in petroleum ether as eluent to afford 200 mg (21%) of 6-(2-bromoethoxy)-N-cyclohexyl-4-methyl-1H-indole-2-carboxamide (I-9A-c) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([O:13][Si](C)(C)C)([CH3:12])[C:3]#[C:4][C:5]([C:7]1[N:8]=[CH:9][S:10][CH:11]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:13][C:2]([CH3:12])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[N:8]=[CH:9][S:10][CH:11]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1cscn1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1cscn1
Reaction time: 1 h
Yield: 109.8 %

Procedure:
To a stirred solution of 4-methyl-1-(thiazol-4-yl)-4-(trimethylsilyloxy) pent-2-yn-1-one (0.15 g, 0.56 mmol) in DCM (3 mL) was added PTSA (0.16 g, 0.84 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-1-(thiazol-4-yl) pent-2-yn-1-one (0.12 g, crude) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([NH:23][C:24]([C:26]2([C:29](=[O:38])[NH:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:28][CH2:27]2)=[O:25])[C:20]([F:39])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11]C(=O)OC(C)(C)C)[CH:6]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:11][C:7]1[CH:6]=[C:5]([O:4][C:3]2[C:2]([F:1])=[CH:22][C:21]([NH:23][C:24]([C:26]3([C:29]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)=[O:38])[CH2:28][CH2:27]3)=[O:25])=[C:20]([F:39])[CH:19]=2)[CH:10]=[CH:9][N:8]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of tert-butyl 4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamate (1.8 g, 3.3 mmol) in CH2Cl2 (100 mL) was added TFA (5 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted to pH>7 with saturated NaHCO3 solution and the separated organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (1.2 g, yield 82% yield). 1H-NMR (400 MHz, DMSO-d6): δ 10.99 (s, 1H), 9.76 (s, 1H), 8.04 (dd, J=12.4, 7.6 Hz, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.58-7.55 (m, 2H), 7.47 (dd, J=10.8, 7.2 Hz, 1H), 7.16 (t, J=8.8 Hz, 2H), 6.16 (dd, J=6.0, 2.4 Hz, 1H), 6.00 (br s, 2H), 5.81 (d, J=2.0 Hz, 1H), 1.65-1.62 (m, 2H), 1.56-1.53 (m, 2H); MS (ESI): m/z 443.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[C:6]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)[C:3]=1[C:4]#[N:5].[NH2:30][NH2:31].CCN(C(C)C)C(C)C>C(O)C>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:6]1[CH:7]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:30][NH:31]2
Reactant: NN
Reactant: CNc1nc(-c2cc(F)c(C#N)c(-c3ccco3)c2)cc(N2CCOC[C@H]2C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CNc1nc(-c2cc(-c3ccco3)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 67.7 %

Procedure:
To a 2-mL microwave vial was added 2-fluoro-6-(2-furanyl)-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}benzonitrile (50 mg, 0.127 mmol), hydrazine (0.044 mL, 0.763 mmol), Hunig's base (0.067 mL, 0.381 mmol) and ethanol (1 mL). The reaction was heated at 150° C. for 90 minutes in a microwave reactor. The reaction mixture was allowed to cool, then was concentrated in vacuo, and the residue was purified by flash chromatography (0-10% CH3OH in CH2Cl2) to afford the title compound (35 mg, 0.086 mmol) as a yellow solid. LC-MS (ES) m/z=406 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, J=6.6 Hz, 3H), 2.75-2.94 (m, 3H), 3.05-3.21 (m, 1H), 3.41-3.52 (m, 1H), 3.57-3.67 (m, 1H), 3.68-3.80 (m, 1H), 3.87-4.00 (m, 1H), 4.06-4.21 (m, 1H), 4.45-4.62 (m, 1H), 5.11 (s, 2H), 6.46-6.68 (m, 2H), 6.68-6.74 (m, 1H), 6.97-7.16 (m, 1H), 7.74-7.82 (m, 1H), 7.89-7.95 (m, 1H), 7.97-8.07 (m, 1H), 11.95 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.ClCC[I:35]>C1COCC1.O.[Au]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][O:17][CH3:18])[C:10]=1[I:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCI
Reactant: COCOc1cccc(NC(=O)OC(C)(C)C)c1
Agent: [Au]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cccc(NC(=O)OC(C)(C)C)c1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 13 (124 mg, 0.49 mmol) in 2.0 mL anhydrous THF was cooled to −20° C. and treated with TMEDA (0.26 mL, 1.71 mmol) followed by n-BuLi (0.69 mL of a 2.5 M solution in hexanes, 1.71 mmol) in a slow dropwise manner. The resulting gold solution stirred for 4 h at −20° C. The reaction mixture was treated with 1-chloro-2-iodoethane (0.126 mL, 1.71 mmol) and stirred for 15 min at 25° C. The reaction was diluted with H2O (30 mL), extracted with Et2O (3×20 mL), and the combined organic extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×10 cm, 0-10% EtOAc/hexane gradient) yielded recovered 13 (51.8 mg, 41%) and 14 (85.5 mg, 46%) as a white solid: mp 82-84° C.; 1H NMR (CDCl3, 400 MHz) δ7.72 (d, J=8.2 Hz, 1H), 7.21 (t, J=6.0 Hz, 1H), 7.01 (br s, 1H), 6.72 (dd, J=1.2, 8.2 Hz, 1H), 5.21 (s, 2H), 3.47 (s, 3H), 1.49 (s, 9H);13C NMR (CDCl3, 100 MHz) δ156.0, 152.5, 140.1, 129.5, 113.4, 108.9, 94.8, 82.4, 80.9, 54.4, 28.3; IR (film) νmax 3388, 2977, 1736, 1592, 1515, 1465, 1406, 1252, 1226, 1153, 1005 cm−1; FABHRMS (NBA/CsI) m/z 511.9351 (C13H18INO4+Cs+ requires 511.9335).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:3])[CH3:2].O.[N+:12]([CH:15]([CH:18]=O)[CH:16]=O)([O-:14])=[O:13].[Na].C(O)(=O)C>O>[CH:1]([NH:4][C:5]1[C:9]2[C:8](=[N:10][CH:16]=[C:15]([N+:12]([O-:14])=[O:13])[CH:18]=2)[NH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: CC(C)Nc1cc(N)[nH]n1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Nc1n[nH]c2ncc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A solution of N3-isopropyl-1H-pyrazole-3,5-diamine (0.231 g, 1.85 mmol) and sodium nitromalonaldehyde monohydrate (0.307 g, 1.95 mmol) in water (20 mL) was heated to 100° C. overnight. The reaction mixture was cooled to room temperature, and the pH was adjusted to about 6 with acetic acid. The resulting solids were collected by filtration, washed with water and dried in vacuo to give N-isopropyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-3-amine (0.243 g, 59%). m/z (APCI-neg) M−1=220.3.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:15])[C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OC)(O[CH3:20])(=O)=O.[OH-].[K+]>C(O)C>[CH3:20][O:14][C:13]1[C:12]([CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Oc2ccccc2)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cccc1Oc1ccccc1
Yield: 74.8 %

Procedure:
A mixture of 6-phenoxy-o-cresol (7.5 g) and dimethyl sulfate (14 g) and aqueous solution (30 ml) of potassium hydroxide (10.5 g) were treated in a similar manner to that of Example 14-(2). The resultant residue was pulverized with ethanol to give phenyl 2-methoxy-3-methylphenyl ether (6 g). mp 52°-53° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:9])[CH:7]=[CH2:8])=[N:2]1.[ClH:10]>CCOCC>[Cl:10][CH2:8][CH2:7][C:6]([C:3]1[CH:4]=[CH:5][O:1][N:2]=1)=[O:9]
Reactant: Cl
Reactant: C=CC(=O)c1ccon1
Solvent: CCOCC
Product: O=C(CCCl)c1ccon1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product of step (b) was treated with 1M HCl in ether (5 ml) and stirred for 4 h at ambient temperature. The solvent was then removed under reduced pressure to leave the product as a dark gum (0.42 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C(Cl)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1.[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([NH:49][C:50]([NH:33][C:32]1[CH:34]=[CH:35][C:29]([O:28][C:19]2[C:18]3[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=3)[N:22]=[CH:21][CH:20]=2)=[CH:30][C:31]=1[F:36])=[S:51])=[O:48]
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (54 mg, yield 67%). Mass spectrometry value (ESI-MS, m/z): 538 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10](=[O:18])[CH2:9]1.[OH:19][C:20]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:21]=1>>[C:20]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:9][C:10]2=[O:18])(=[O:19])[CH3:21]
Reactant: O=C1CC(c2ccccc2F)c2ccc(O)cc21
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1ccccc1F
Yield: 85 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(2-fluorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one to obtain the title compound (85%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[N:41][CH:40]=[CH:39][N:38]=2)[CH:34]=[CH:35][CH:36]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]5[CH:42]=[N:41][CH:40]=[CH:39][N:38]=5)[CH:32]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1cccc(-c2cnccn2)c1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4cnccn4)c3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 2-(3-Chloromethylphenyl)pyrazine (307 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionate (647 mg, yield: 83%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH3:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:21](N=C(N(C)C)N(C)C)([CH3:24])([CH3:23])[CH3:22].BrCC(C)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH3:20])[CH2:22][CH:21]([CH3:24])[CH3:23])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(C)c(NS(=O)(=O)c2ccc(F)cc2)c1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC(C)CBr
Solvent: CC#N
Product: COc1ccc(C)c(N(CC(C)C)S(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-N-[2-methyl-5-(methyloxy)phenyl]benzenesulfonamide (185.8 mg, 0.629 mmol) in Acetonitrile (5 mL) was added neat Barton's base (2-(tert-butyl)-1,1,3,3-tetramethylguanidine) (0.131 mL, 0.629 mmol). The reaction mixture was stirred at room temperature for 1 hour. 1-bromo-2-methylpropane (0.137 mL, 1.258 mmol) was then added. The reaction vessel was sealed and heated in Biotage Initiator microwave using initial high absorbance power setting to 150° C. for 25 min. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The sample was loaded in dichloromethane and purified on automated normal chromatograph on silica (Si) 50 g using a 0-50% ethyl acetate-cyclohexane over 40 mins. The appropriate fractions were combined and dried under a stream of nitrogen in the Radleys blowdown apparatus to give the required product 171 mg as a white solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=[O:29])[CH:27]=[CH2:28]>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:26](=[O:29])[CH:27]=[CH2:28])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(C)(C)C)s1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Acryloyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol- 2-yl)-3-methyl-6-acryloyloxy-2(1H)-pyrimidinone as the residue.