Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc(OC)c1
Yield: 98 %

Procedure:
Prepared from VII and 3,5-dimethoxyaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 98%; yellow solid; mp 248° C.; IR (KBr) νmax/cm−1 3242, 2940, 2837, 2223, 1711, 1647, 1578, 1455, 1419, 1383, 1357, 1306, 1265, 1205, 1144, 1058, 1046, 968, 943, 917, 833, 806; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.06 (s, 1H), 7.79 (d, 1H, J=9.0 Hz), 6.31 (m, 3H), 3.74 (s, 6H); HRMS calcd for C18H14N5O2S (M+H+): 364.0868, found 364.0856.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH2:14][OH:15])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@@H:13]([CH2:14][O:15][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1COS(C)(=O)=O
Temperature: 25 °C
Yield: 97.1 %

Procedure:
The product of Example 52B (43.7 g, 125 mmol) and triethylamine (25.2 g, 250 mmol) in CH2Cl2 (600 mL) was treated with methanesulfonyl chloride (12.6 mL, 163 mmol) over 30 minutes at −10° C. The solution was allowed to warm to room temperature over 1 hour and then quenched with water (100 mL). The layers were separated and the aqueous phase was extracted with CH2Cl2 (2×400 mL). The combined organic phases were washed with brine (2×100 mL), dried over Na2SO4, filtered and the filtrate concentrated to provide the title compound as a brown dark brown oil (52.0 g, yield, 97%).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+].[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]2[C:37]([O:38][C:39]3[CH:53]=[CH:52][C:42]([O:43][CH2:44][CH2:45][N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]4)=[CH:41][CH:40]=3)=[C:36]([C:54]3[CH:59]=CC(S(C)(=O)=O)=C(F)C=3)S[C:34]=2[CH:65]=1)C1C=CC=CC=1.B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.Br[C:83]1[CH:84]=[C:85]([CH3:94])[C:86]([S:90]([CH3:93])(=[O:92])=[O:91])=[C:87]([CH3:89])[CH:88]=1>C(#N)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:94][C:85]1[CH:84]=[C:83]([C:36]2[CH:54]=[CH:59][C:34]3[C:33](=[CH:32][CH:31]=[C:30]([O:29][CH3:22])[CH:65]=3)[C:37]=2[O:38][C:39]2[CH:40]=[CH:41][C:42]([O:43][CH2:44][CH2:45][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)=[CH:52][CH:53]=2)[CH:88]=[C:87]([CH3:89])[C:86]=1[S:90]([CH3:93])(=[O:92])=[O:91]
Reactant: CS(=O)(=O)c1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1F
Reactant: Cc1cc(Br)cc(C)c1S(C)(=O)=O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(C)c(S(C)(=O)=O)c(C)c3)ccc2c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 84.6 %

Procedure:
Combine palladium (II) acetate (13 mg, 0.06 mmol), tricyclohexylphosphine (27 mg, 0.10 mmol), cesium fluoride (518 mg, 3.4 mmol) and acetonitrile (10 mL). Stir for 5 minutes. Add the compound of Preparation 1 (200 mg, 0.38 mmol) and bis(neopentylglycolato)diboron (129 mg, 0.57 mmol). Heat to 90° C. for 1 minute and add 5-bromo-2-methanesulfonyl-1,3-dimethyl-benzene (110 mg, 0.42 mmol) in acetonitrile (4 mL). Stir at 90° C. for 10 minutes. Cool to room temperature and dilute the solution with ethyl acetate (20 mL) and wash with saturated aqueous NaHCO3 (10 mL). Separate the layers, wash the organic layer with brine, dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting with methanol (4%) in dichloromethane to give 180 mg (76%) of the title compound. Mass spectrum (ion spray): m/z=560.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.[CH2:19](I)[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CC(=O)CC.CCOCC>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:21][CH:20]=[CH2:19])=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: C=CCI
Reactant: COC(=O)c1ccc(Oc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: C=CCOc1ccc(Oc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 4-(4-hydroxyphenoxy)benzoic acid methyl ester (5.00 g, 20.5 retool), allyl iodide (3.79 g, 22.5 mmol), potassium carbonate (8.49 g, 61.5 mmol), and dimethylsulfoxide (10 mL) in 2-butanone (40 mL) was refluxed for 24 hours. The mixture was cooled to room temperature and diluted with ether. The resulting mixture was washed once with water and once with saturated sodium bicarbonate solution. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo to provide 4.52 g (78%) of the title intermediate as a white solid: mp 75° C.; 1H--NMR (CDCl3) 7.99 (d, J=9 Hz, 2H), 7.03 (d, J=9 Hz, 2H), 6.95 (m, 4H), 6.08 (m, 1H), 5.46 (d, J=14 Hz, 1H), 5.31 (d, J=10 Hz, 1H), 4.55 (d, J=7 Hz, 2H), 3.92 (s, 3H).
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.[CH3:12][Si](C=[N+]=[N-])(C)C>CO>[S:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc2sccc2[nH]1
Solvent: CO
Product: COC(=O)c1cc2sccc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
4H-thieno[3,2-b]pyrrole-5-carboxylic acid (3.0 g, 17.9 mmol) was dissolved in anhydrous MeOH (50.0 mL) and cooled to 0° C. A solution (45.0 mL, 2 M in hexanes) of trimethylsilyldiazomethane (45 mL) was added in portions and the yellow color of the TMSCH2N2 remained. Stirring was continued for 10 min and then the excess TMSCH2N2 was quenched with acetic acid (5.0 mL). The solvent was removed with N2 stream, and the residue was chromatographed over silica gel (5%-40%, 30 min, EtOAc in heptane) to give methyl 4H-thieno[3,2-b]pyrrole-5-carboxylate (2.8 g, 86% yield). 1H NMR (400 MHz, CD3Cl) δ ppm 3.90 (s, 3H) 6.95 (dd, J=5.32, 0.78 Hz, 1H) 7.13 (dd, J=1.88, 0.76 Hz, 1H) 7.33 (d, J=5.37 Hz, 1H) 9.02 (br. s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)C.[CH2:9]1[O:17][CH:10]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OC(C)C)(C)C>O.N1C=CC=CC=1>[OH:17][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1ccc(C2CO2)cc1
Reactant: c1c[nH]cn1
Solvent: CC(C)OC(C)C
Solvent: CCO
Solvent: O
Product: OC(Cn1ccnc1)c1ccccc1

Procedure:
A solution of imidazole (47.0 g, 0.69 mol) in `super-dry` ethanol (175 ml) containing dry pyridine (3.0 ml) was stirred and heated to 75° when styrene oxide (80.0 g, 0.67 mol) was added dropwise at such a rate that the temperature of the reaction mixture was maintained at 80°-85°. Following the addition, the reaction mixture was stirred until the internal temperature had fallen to 50°. Isopropyl ether (300 ml) was then added to the reaction mixture, and the resulting mixture was poured into iced-water (1,000 ml). Separation of the resulting solid by filtration afforded the product which was washed with acetone (1×500 ml) and with ether (2×300 ml), to give 1-(2-hydroxy-2-phenylethyl)imidazole, m.p. 149°-151°.
Reaction SMILES: CN1CCCCC1.[C:8]([O:12][C:13]([NH:15][CH:16]([C:20]([CH3:22])=[CH2:21])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[C:31]([C:33]1[CH:43]=[CH:42][C:36]([O:37][CH2:38][CH:39]([NH2:41])[CH3:40])=[CH:35][CH:34]=1)#[N:32]>C(Cl)Cl.O>[C:8]([O:12][C:13]([NH:15][CH:16]([C:20]([CH3:22])=[CH2:21])[C:17]([NH:41][CH:39]([CH3:40])[CH2:38][O:37][C:36]1[CH:42]=[CH:43][C:33]([C:31]#[N:32])=[CH:34][CH:35]=1)=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C=C(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(N)COc1ccc(C#N)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCCC1
Product: C=C(C)C(NC(=O)OC(C)(C)C)C(=O)NC(C)COc1ccc(C#N)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
0.5 g of N-methylpiperidine was added to a solution containing 1.1 g of 2-tert-butoxycarbonylamino-3-methyl-3-butenic acid dissolved in 40 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.7 g of isobutyl chloroformate was added to the mixture at -40° C., and stirred for 1 hour at -20° C. 1.9 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 0.3 g of the desired product in the form of a colorless glutinous substance (yield: 32%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]4)[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:29]([C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH:14]([N:16]5[CH2:21][CH2:20][NH:19][C:18](=[O:22])[CH2:17]5)[CH2:15]4)[S:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: O=C1CN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)C2)CCN1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCNC(=O)C4)C3)sc2n1
Temperature: 115 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of 4-[1-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)azetidin-3-yl]piperazin-2-one (315 mg, 0.74 mmol), 2-ethylbenzimidazole (120 mg, 0.82 mmol), tris(dibenzylideneacetone)dipalladium (17 mg, 0.02 mmol), XPhos (35 mg, 0.07 mmol) and Cs2CO3 (365 mg, 1.12 mmol) in dioxane (10 mL) was purged with argon then heated at 115° C. for 4 h then stirred at r.t. for 16 h. The reaction mixture was filtered through Celite®, washing with dioxane, and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 1-10%) affording 796 (146 mg, 37%). LCMS (method G): RT 4.90 min, [M+H]+ 534.3. 1H NMR (DMSO, 400 MHz): δ 7.99-7.99 (1 H, m), 7.75 (1 H, s), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 4.32 (4 H, brd s), 4.04 (2 H, s), 3.79 (4 H, t, J=4.61 Hz), 3.57-3.52 (2 H, m), 3.31 (2 H, s), 3.25 (2 H, q, J=7.43 Hz), 3.18-3.14 (5 H, m), 2.87 (2 H, s), 1.32 (3 H, t, J=7.42 Hz)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])=[CH:15][CH:14]=1.Cl>O.CO>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])=[CH:26][CH:27]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccccc1)c1ccc(CCl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccccc1)c1ccc(CSc2ccc(O)cc2)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
In a 200 ml four-necked flask equipped with a stirrer and a thermometer, 1.34 g (10.6 mmol) of 4-mercaptophenol, 0.7 g (10.6 mmol) of potassium hydroxide and 50 ml of methanol were added at room temperature. After confirming that potassium hydroxide has been dissolved, the inner temperature was cooled to 10° C. and 2.6 g (10.6 mmol) of 4-chloromethyl-N-phenylbenzamide was added, followed by stirring at room temperature for 3 hours. After the completion of the reaction, the reaction solution was acidified with hydrochloric acid and 50 ml of water was added, and then the deposited crystal was collected by filtration to obtain 3.0 g of 4-(4-hydroxyphenylthiomethyl)-N-phenylbenzamide. The yield was 84%. The melting point was 220–222° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:22][OH:23].C(N(CC)CC)C>C(O)C.O>[OH:23]/[N:22]=[C:1](/[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:20]2)=[O:11])=[CH:5][CH:4]=1)\[NH2:2]
Reactant: NO
Reactant: N#Cc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: N/C(=N\O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Temperature: 80 °C

Procedure:
In a 25 mL pressure tube were mixed N-(4-cyanophenyl)isoindoline-2-carboxamide (500 mg, 1.899 mmol), hydroxylamine hydrochloride (264 mg, 3.80 mmol), and triethylamine (1.323 ml, 9.50 mmol) in ethanol (6 ml)/water (0.5 ml). The reaction vessel was sealed and heated at 80° C. for four hours. The reaction mixture was diluted with water and the solid was filtered off with water washes. HPLC purification provided the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[CH3:12]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: O=c1[nH]cc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1cc(Br)cc([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A 1-L round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 5-Bromo-3-nitropyridin-2(1H)-one (25.0 g, 114 mmol), anhydrous DMF (500 mL) and potassium carbonate (34.7 g, 251 mmol), and the suspension stirred for 15 min at ambient temperature. After this time, methyl iodide (17.8 g, 126 mmol) was added, and the mixture stirred at room temperature for 16 h. The reaction mixture was then diluted with water (500 mL) and extracted with methylene chloride (3×500 mL). The organic extracts were combined, washed with 10% aqueous lithium chloride (300 mL) and water (300 mL) and dried over sodium sulfate. After removing the drying agent by filtration, the filtrate was evaporated to dryness under reduced pressure. The resulting residue was flash chromatographed eluting with a gradient from 50% to 100% of ethyl acetate in hexanes, and the fractions containing 122a were collected to afford, after concentrating under reduced pressure, an 89% yield (23.6 g) of 122a as a yellow solid: mp 122-123° C.; 1H NMR (300 MHz, CDCl3) δ 8.37 (d, 1H, J=2.7 Hz), 7.26 (s, 1H), 3.68 (s, 3H); MS (ESI+) m/z 234 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([F:14])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1F)[CH3:2].O.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)C.C(N(CC)CC)C>[CH2:1]([C:3]1[C:4]([F:14])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([F:10])[C:8]=1[N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1c(F)c(F)cc([N+](=O)[O-])c1F
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1c(F)c([N+](=O)[O-])cc(F)c1N1CCN(C)CC1

Procedure:
To 3-ethyl-2,4,5-trifluoro-nitrobenzene (1.02 g) are added ethanol (4.5 ml) and water (0.5 ml) and the mixture is stirred. To the mixture is added with stirring a mixture of 1-methylpiperazine (0.83 ml), triethylamine (1.0 ml) and ethanol (0.6 ml), and the mixture is refluxed for 5 hours. To the reaction mixture is further added 1-methylpiperazine (1.0 ml), and the mixture is refluxed for 3 hours. The mixture is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (solvent, methylene chloride) to give 3-ethyl-2,5-difluoro-4-(4-methyl-1-piperazinyl)nitrobenzene (1.12 g), as yellow oil.
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=1.[CH:17]1([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C.O>[CH:17]1([C:23]2[N:27]([C:2]3[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:15][CH3:16])[CH:3]=3)[CH:26]=[CH:25][N:24]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1OC
Reactant: c1c[nH]c(C2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])c(-n2ccnc2C2CCCCC2)cc1OC
Temperature: 100 °C
Yield: 100.7 %

Procedure:
A mixture of methyl 4-fluoro-2-methoxy-5-nitrobenzoate 8.57 g, 2-cyclohexylimidazole 5.61 g, potassium carbonate 10.34 g and N,N-dimethylacetamide 75 mL was heated at 100° C. for 5 hours in nitrogen atmosphere. The reaction liquid was diluted with ethyl acetate, poured in water and the organic layer was separated. The organic layer was washed with brine, dried over magnesium sulfate and removed of the solvent by distillation to provide 13.52 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[NH:29]([CH3:31])[CH3:30].Cl.N1C=CC=CC=1.ClC1C=CC=CC=1N(C)C(C1SC2C3C=CC(C(Cl)=O)=CC=3OCCC=2C=1)=O>O=S(Cl)Cl.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:28])[C:9]([C:11]1[S:27][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([N:29]([CH3:31])[CH3:30])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CNC
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)O)cc1OCC2)c1ccccc1Cl
Agent: CN(C(=O)c1cc2c(s1)-c1ccc(C(=O)Cl)cc1OCC2)c1ccccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 330.7 %

Procedure:
Alternatively, a solution of 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (100 mg, 0.24 mmol) in 2 mL of SOCl2 was heated at 80° C. for 2 h. After removal of the solvent, the residue was co-evaporated with toluene to give the crude acid chloride 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride. To a solution of (CH3)2NH HCl salt (118 mg, 1.412 mmol) and pyridine (0.2 mL) in 5 mL of THF was slowly added 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride (417 mg, 0.966 mmol) in 20 mL of THF. The mixture was stirred at room temperature overnight, concentrated in vacuo, dissolved in ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated to give 101 (350 mg, yield: 82%). 1H NMR (CDCl3, 400 MHz): δ 6.67-7.59 (m, 8H), 4.16 (t, J=4.8 Hz, 2H), 3.33 (s, 1H), 2.95-2.97 (m, 8H). MS (ESI): 441.1
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(OC2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCCCC4)cc3)C2=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 10.5 g) in THF (dry) (200 mL) was added 2-chloroethanesulfonyl chloride (11.0 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-[4-(cyclohexyloxy)phenyl]pyridin-2-amine (14.1 g) in THF (dry) (150 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 14 hr. The mixture was quenched with water at 0° C. carefully. Water and hexane were added to form precipitates which were washed with EtOAc and collected to give 9-[4-(cyclohexyloxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (17.4 g) as an off-white solid. To 9-[4-(cyclohexyloxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (16.0 g) was added DMSO (280 mL) under heating with oil bath (ca. 90° C.) After being stirred for 10 min., EtOH (520 mL) was dropwised at 85° C. to form precipitates. The mixture was stirred for further 15 min at same temperature and then cooled to room temperature (the oil bath was removed and stirred for 50 min and stirred for 60 min in water bath). The precipitates were collected, washed with EtOH (40 mL) and dried in air for 2 days to give the title compound (13.1 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:49][C:50]1[CH:69]=[CH:68][C:53]([O:54][C:55]2[S:59][C:58]([NH2:60])=[N:57][C:56]=2[C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)=[CH:52][CH:51]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]([C:13](=[O:15])[NH:60][C:58]1[S:59][C:55]([O:54][C:53]2[CH:68]=[CH:69][C:50]([F:49])=[CH:51][CH:52]=2)=[C:56]([C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)[N:57]=1)([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccc(F)cc2)c(Oc2ccc(F)cc2)s1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1nc(-c2ccc(F)cc2)c(Oc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzyloxycarbonylamino-2-methyl-propionic acid (10.5 g, 44.2 mmol), HBTU (16.8 g, 44.3 mmol) and Et3N (6.2 mL, 45 mmol) in DMF (50 mL) was stirred at room temperature for 2 h. To this was added a solution of 5-(4-Fluoro-phenoxy)-4-(4-fluoro-phenyl)-thiazol-2-ylamine (9.62 g, ca. 32 mmol with some impurities present) in DMF (50 mL). The mixture was heated at 85° C. for 18 h and partitioned between EtOAc and, sequentially, 3M HCl and aqueous KOH. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 524.2 (MH+).