Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C.[CH3:42][C:43]1[CH:44]=[C:45]([CH2:50][CH:51]([NH:55][C:56]([N:58]2[CH2:63][CH2:62][CH:61]([N:64]3[CH2:73][C:72]4[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=4)[NH:66][C:65]3=[O:74])[CH2:60][CH2:59]2)=[O:57])[C:52]([OH:54])=O)[CH:46]=[CH:47][C:48]=1[CH3:49].[CH3:75][N:76]1[CH2:81][CH2:80][N:79]([CH:82]2[CH2:87][CH2:86][NH:85][CH2:84][CH2:83]2)[CH2:78][CH2:77]1>CN(C=O)C.C1COCC1>[CH3:42][C:43]1[CH:44]=[C:45]([CH:46]=[CH:47][C:48]=1[CH3:49])[CH2:50][CH:51]([NH:55][C:56]([N:58]1[CH2:59][CH2:60][CH:61]([N:64]2[CH2:73][C:68]3[C:67](=[CH:72][CH:71]=[CH:70][CH:69]=3)[NH:66][C:65]2=[O:74])[CH2:62][CH2:63]1)=[O:57])[C:52]([N:85]1[CH2:84][CH2:83][CH:82]([N:79]2[CH2:78][CH2:77][N:76]([CH3:75])[CH2:81][CH2:80]2)[CH2:87][CH2:86]1)=[O:54]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.90 g (2.80 mmol) TBTU, 0.35 g (2.55 mol) HOBt, 0.49 mL (2.80 mmol) ethyldiisopropylamine was added to a mixture of 1.15 g (2.55 mol) 3-(3,4-dimethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 100 mL THF and the mixture was stirred for 30 min at RT. Then 20 mL DMF was added, the mixture was stirred for 15 min and combined with 0.49 g (2.65 mmol) 1-methyl-4-piperidin-4-yl-piperazine. The reaction mixture was stirred overnight at RT, evaporated down under reduced pressure and the residue was combined with 70 mL saturated NaHCO3 solution. The aqueous phase was extracted three times with DCM, the combined organic phases were dried over Na2SO4, filtered and evaporated down under reduced pressure. The residue was purified by column chromatography over silica gel, the product fractions were evaporated down under reduced pressure, triturated with diethyl ether and suction filtered.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[N:26][C:27]([Cl:33])=[C:28]([CH:32]=1)[C:29](O)=[O:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@@H:11]([NH:14][C:29]([C:28]2[C:27]([Cl:33])=[N:26][CH:25]=[C:24]([F:23])[CH:32]=2)=[O:30])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=C(O)c1cc(F)cnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
(4-Amino-cyclohexyl)-carbamic acid tert-butyl ester (80:20 syn:anti, 4.49 g, 20.9 mmol) was dissolved in dimethylformamide (100 ml) and triethylamine (8.34 ml, 59.8 mmol) was added followed by 5-fluoro-2-chloronicotinic acid (3.5 g, 19.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.2 g, 21.9 mmol) and 1-hydroxybenzotriazole (2.96 g, 21.9 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (50 ml) and ethyl acetate (100 ml) and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic extracts were concentrated under reduced pressure, re-dissolved in dichloromethane (100 ml), washed with water (50 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (2:3 changing to 1:1, by volume) to give {cis-4-[(2-Chloro-5-fluoro-pyridine-3-carbonyl)-amino]-cyclohexyl}-carbamic acid tert-butyl ester (5.44 g) as a white foam.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]=[CH:11][C:12]([CH3:24])=[CH:13][C:14](=[S:21](=[O:23])=[O:22])C1C=CC=CC=1.I([O-])(=O)(=O)=O.[Na+].C1(S([O-])=[O:38])C=CC=CC=1.[Na+].C[C:42]1[CH2:47][CH2:46][CH2:45][C:44](C)(C)[C:43]=1C=CC(C)=CCCl>>[CH3:1][C:2]1[C:7](=[O:38])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[CH:10]=[CH:11][C:12]([CH3:24])=[CH:13][CH2:14][S:21]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=[O:22])=[O:23]
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CC(c1ccccc1)=S(=O)=O
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C=CC1=C(C)CCCC1(C)C)=CCCl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Product: CC(C=CC1=C(C)C(=O)CCC1(C)C)=CCS(=O)(=O)c1ccccc1

Procedure:
5-(2,6,6-trimethyl-3-oxo-cyclohex-1-enyl)-3-methyl-1-phenylsulphonyl-penta-2,4-diene was prepared by oxidation of 5-(2,6,6-trimethyl-cyclohex-1-enyl)-3-methyl-1-phenyl-sulphonyl-penta-2,4-diene by means of sodium meta-periodate in accordance with the process described in French Pat. No. 2,071,508. The product oxidised in this way was itself obtained by reacting sodium phenylsulphinate with 5-(2,6,6-trimethyl-cyclohex-1-enyl)-3-methyl-1-chloro-penta-2,4-diene as described in Example 1.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[NH2:10][C:11]1[S:12][C:13](Br)=[N:14][N:15]=1>O.C(O)C>[NH2:10][C:11]1[S:12][C:13]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:14][N:15]=1
Reactant: Sc1ccccc1
Reactant: Nc1nnc(Br)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nnc(Sc2ccccc2)s1
Temperature: 82 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
In a mixture of 20 ml of water and 30 ml of ethanol, 7.3 g of thiophenol and 4.5 g of potassium hydroxide were added. To this solution, 11.7 g of 2-amino-5-bromo-1,3,4-thiadiazole was added, and the mixture was heated to 82° C. and stirred for 2 hours. After cooling, water was added and the mixture was filtered. The residue was washed with water and n-hexane respectively, dried under reduced pressure, and thus 10.8 g of 2-amino-5-phenylthio-1,3,4-thiadiazole was obtained. m.p. 202°~203° C. Yield 77%.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([O:12][C:13]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C(OCC)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[F:21][C:18]1[CH:19]=[CH:20][C:13]([O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[C:14]([C:15]2([NH2:16])[CH2:2][CH2:1]2)[CH:17]=1
Reactant: N#Cc1cc(F)ccc1OCc1ccccc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2cc(F)ccc2OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Ethylmagnesium bromide, (35.2 ml of a 3M solution in diethyl ether) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (16.37 mL) and 2-(benzyloxy)-5-fluorobenzonitrile (12 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1.5 h. Boron trifluoride etherate (13.38 mL) was added and the mixture was stirred for 30 min. The reaction was quenched with 1 M HCl (400 ml) and the aqueous layer was separated. The diethyl ether layer was further extracted into 1M HCl (2×200 mL). The combined aqueous layers were cooled in an ice bath and basified with 1M aqueous NaOH solution. The resulting precipitate was filtered through celite washing the pad extensively with water (200 mL), dichloromethane (4×200 mL) then dichloromethane/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted into dichloromethane (2×200 mL). The combined organics were dried (MgSO4) and evaporated and residue purified by SCX resin (eluting with methanol followed by 10% 880 ammonia in methanol). The basic fractions were evaporated to give the subtitle compound (3.4 g).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:20])[C:7]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:19]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>CS(C)=O.O>[CH3:3][C:4]1[CH:5]=[C:6]([O:20][CH2:21][CH:23]2[CH2:24][O:25]2)[C:7]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:19]=1
Reactant: Cc1cc(O)c2c(c1)OC(C)(C)C1=C2CCCC1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(OCC2CO2)c2c(c1)OC(C)(C)C1=C2CCCC1

Procedure:
To a stirred solution of NaOH (2.4 g, 0.06 m) in DMSO (125 ml) and water (125 ml) was added 7,8,9,10-tetrahydro-3,6,6-trimethyl-1-hydroxy-6H-dibenzo[b,d]pyran (13.1 g, 0.054 m) in DMSO (125 ml) and water (125 ml) and then epichlorohydrin (34.8 g, 0.376 m) and the mixture stirred for 5 hours, treated with water (0.5 L) and extracted with ether (3×300 ml). The combined ether extracts were dried over MgSO4 and evaporated to give 7,8,9,10-tetrahydro-3,6,6-trimethyl-1-(oxiranylmethoxy)-6H-dibenzo[b,d]pyran as a pale yellow oil, 14.0 g. This material was of sufficient purity to use as is for further chemical processing.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][C:21]([S:24][CH2:25][C:26]2[O:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][N:30]=2)=[CH:22][N:23]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(Cl)Cl.O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([C:15]([NH:18][C:19]2[S:20][C:21]([S:24][CH2:25][C:26]3[O:27][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:29][N:30]=3)=[CH:22][N:23]=2)=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cnc(CSc2cnc(N)s2)o1
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(C(=O)Nc2ncc(SCc3ncc(C(C)(C)C)o3)s2)CC1
Reaction time: 8 h

Procedure:
To a solution of 5 g of crude 4-(t-butoxycarbonylamino)cyclohexane carboxylic acid and 3.50 g (13 mmol) of 2-amino-5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]thiazole in 13 mL of N,N-dimethylformamide and 36 mL of methylene chloride was added 5.0 g (26 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature. The reaction mixture was stirred overnight and diluted with 100 mL of water. The aqueous layer was separated and extracted with two-150 mL portions of ethyl acetate. The combined organic phases were dried (sodium sulfate) then filtered through a pad of silica gel. The filtrate was concentrated in vacuo to afford an orange solid. The crude material was recrystallized (95% ethanol) to give 4-(t-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide as a yellow solid. The mother liquors were also concentrated in vacuo to give additional 4-(t-butoxycarbonylamino)-N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]cyclohexylcarboxamide as a brown solid.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[C:37]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:35][C:36]1[C:37]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)=[C:38]([C:39]([N:3]2[CH2:4][CH2:5][C@@H:6]3[C@@H:1]([N:8]([C:9]4[CH:18]=[N:17][C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[N:10]=4)[CH2:7]3)[CH2:2]2)=[O:40])[CH:42]=[CH:43][CH:44]=1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: O=C(c1cccc(F)c1-n1nccn1)N1CC[C@H]2CN(c3cnc4ccccc4n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline (Intermediate 3) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 50) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C23H20FN7O, 429.46; m/z found 430.1 [M+H]+. 1H NMR (CD3OD): 8.27-8.14 (m, 1H), 8.08-7.58 (m, 5H), 7.48-6.45 (m, 4H), 4.83-4.54 (m, 1H), 4.25-3.97 (m, 3H), 3.74-3.63 (m, 1H), 3.43-3.37 (m, 1H), 3.19-3.06 (m, 2H), 2.27-1.82 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:20]=2)[N:5]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COCc1n[nH]cc1C(=O)OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COCc1nn(-c2cccc(OC)c2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (2.8 g) synthesized in Example 29 (1) in N,N-dimethylacetamide (50 mL) were added 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.1 g, 23%) as a pale-yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:15])[C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.CS(C)=O.[CH2:20]([O:27][CH2:28][C:29]([C:32]1[O:33][C:34]2[C:35](=[C:37]([C:49]#[N:50])[C:38]([CH3:48])=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:40]=2F)[N:36]=1)([CH3:31])[CH3:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C>[CH2:20]([O:27][CH2:28][C:29]([C:32]1[O:33][C:34]2[C:35](=[C:37]([C:49]#[N:50])[C:38]([CH3:48])=[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:40]=2[N:12]2[CH2:13][CH2:14][C@H:10]([N:9]([CH3:15])[CH3:8])[CH2:11]2)[N:36]=1)([CH3:31])[CH3:30])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)COCc3ccccc3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)COCc3ccccc3)nc2c1C#N
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Triethylamine (222 μl, 1.59 mmol), (3S)-3-(dimethylamino)pyrrolidine (152 μl, 1.19 mmol) were added to a dimethyl sulfoxide (16.5 ml) solution of 2-[2-(benzyloxy)-1,1-dimethylethyl]-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-66) (330 mg, 0.796 mmol), followed by stirring overnight at 90° C. After cooling, the reaction liquid was diluted with ethyl acetate, washed three times with saturated brine, then dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to obtain the entitled compound (369 mg, 91%) as a pale brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12](Cl)(=[O:14])=[O:13])=[CH:7]2.C(Cl)Cl.[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22].C(N(CC)CC)C>CCOC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])(=[O:13])=[O:14])=[CH:7]2
Reactant: OCC(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc2c(Br)cccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=S(=O)(OCC(F)(F)F)c1ccc2c(Br)cccc2c1
Temperature: 25 °C
Yield: 41.3 %

Procedure:
A round bottom flask was charged with 5-bromonaphthalene-2-sulfonyl chloride (5.00 g, 16.36 mmol) and CH2Cl2 (16.36 mL) was added. To this solution was added 2,2,2-trifluoroethanol (1.542 mL, 21.27 mmol) followed by triethylamine (3.42 mL, 24.54 mmol). The resulting solution was maintained at rt for 1 h and then concentrated. The residue was purified by MPLC using a silica gel column (80 g) using a 98:2 Heptane:EtOAc to 100% EtOAc gradient to afford 2,2,2-trifluoroethyl 5-bromonaphthalene-2-sulfonate (2.49 g, 6.75 mmol) as a white amorphous solid.
Reaction SMILES: [S:1]1[C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=[CH:2]1.[Br:16]Br.O>C(O)(=O)C>[Br:16][C:2]1[S:1][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: BrBr
Reactant: O=C1Nc2ccccc2Oc2sccc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1Nc2ccccc2Oc2sc(Br)cc21
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 80.7 %

Procedure:
Thieno[2,3-b][1,5]benzoxazepin-4(5H)-one (2 g) was suspended in acetic acid (30 ml) and a solution of bromine (1.5 g) in acetic acid (10 ml) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 35 minutes and poured into water. The precipitated crystals were collected by filtration and washed with water and diisopropyl ether to give 2-bromothieno[2,3-b][1,5]benzoxazepin-4(5H)-one (2.2 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][C@@H:25]1[CH2:29][S:28](=[O:31])(=[O:30])[NH:27][CH2:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[CH2:26][C@H:25]([CH3:24])[CH2:29][S:28]4(=[O:31])=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 24.2 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (130 mg) described in Preparation Example 113 and (S)-4-methylisothiazolidine 1,1-dioxide (84 mg) described in Preparation Example 4 and by the reaction and treatment in the same manner as in Example 1, the title compound (32 mg) was obtained.
Reaction SMILES: [CH2:1]([C:19]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(C(OC(C)(C)C)=O)[C:20]([O:22]C(C)(C)C)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([CH:19]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:20]([OH:22])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCC(CCCCCCCC/C=C\CCCCCCCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCC(CCCCCCCC/C=C\CCCCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
A 3 g of this di-t-butyl dioleylmalonate was dissolved in a solution comprising 20 ml of anisole, 20 ml of dichloromethane and 10 ml of trifluoroacetic acid, followed by stirring at room temperature overnight. After reaction, volatile components were distilled off. The residue was then heated at 150° C. for 4 hours to remove carbonic acid, thereby obtaining 2.32 g of α,α-dioleylacetic acid [RF =0.12 (chloroform:methanol=10:1)].
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].C([O-])([O-])=O.[K+].[K+].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)([O-:27])=[O:26].C(O)CO>C(OCC)(=O)C.CC(O)C>[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34][C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])=[O:5])=[CH:30][CH:29]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: COc1ccccc1NC(=O)c1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COc1ccccc1NC(=O)c1ccccc1Sc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
2-Iodo-N-(2-methoxyphenyl)benzamide 3 (0.355 g, 1.0 mmol), Cu(I) iodide (20 mg, 0.1 mmol), K2CO3 (0.276 g, 2.0 mmol), and 4-nitrothiophenol (0.155 g, 1 mmol) were added to a 10 mL reaction vessel with Teflon-lined septum. The tube was evacuated and backfilled with dry N2 (3 cycles). Ethylene glycol (0.1 mL, 2.0 mmol) and 2-propanol (1 mL) were added by syringe at room temperature. The reaction vessel was heated in a microwave reactor (CEM, Explorer) at 80° C. and 150 W power for 30 min (2×). The reaction mixture was then allowed to reach room temperature. Ethyl acetate (approx. 10 mL) was added; the reaction mixture was filtered and concentrated. The crude product was purified by flash column chromatography on silica, eluting with 20% EtOAc in hexanes. This procedure provided 2-(4-nitrophenylthio)-N-(2-methoxyphenyl)benzamide 1 as pale yellow crystalline solid (0.24 g, 63%); 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J=8.0 Hz, 1H), 8.39 (s, 1H, overlapping signal), 8.05 (ddd, J=9.2, 2.4, 1.6 Hz, 2H), 7.77 (dd, J=6.4, 2.4 Hz, 1H), 7.56-7.49 (m, 3H), 7.29-7.25 (m, 2H), 7.06 (ddd, J=9.2, 7.6, 1.6 Hz, 1H), 6.95 (dt, J=8.8, 0.8, 1.2 Hz, 1H), 6.85 (dd, J=8.0, 0.8 Hz, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.44, 148.22, 146.87, 146.15, 140.63, 135.76, 131.66, 130.09, 129.87, 129.49, 128.79 (2C), 127.54, 124.54, 124.35 (2C), 121.37, 120.05, 110.19, 55.88; MS (ESI): m/z 402.99 (M+Na)+.