Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[CH:6]1([Na])[CH:10]=[CH:9][CH:8]=[CH:7]1>O1CCCC1>[CH3:1][Si:2]([C:7]1[CH2:6][CH:10]=[CH:9][CH:8]=1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: [Na]C1C=CC=C1
Solvent: C1CCOC1
Product: C[Si](C)(C)C1=CC=CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
11 g of trimethylsilyl chloride was dissolved in 30 mol of well dried tetrahydrofuran in a 300 ml flask whose inside had been substituted by nitrogen, and the obtained solution was cooled to −78° C. 100 ml of a tetrahydrofuran solution (2.0 mol/l) of cyclopentadienyl sodium was added dropwise to the above solution in a stream of nitrogen over 1 hour. The solution was stirred at −78° C. for 1 hour and returned to room temperature over 6 hours. A salt precipitated in the mixture solution was removed by filtration in a nitrogen atmosphere, and the residual solution was distilled to obtain 8 g of trimethylsilyl cyclopentadiene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][N:22]([CH3:33])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][CH2:31][NH2:32])=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:32][CH2:31][CH2:30][NH:29][C:26]3[CH:27]=[CH:28][C:23]([N:22]([CH3:33])[CH3:21])=[CH:24][CH:25]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CN(C)c1ccc(NCCN)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCNCCNc1ccc(N(C)C)cc1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-1-chloropropane and 2-(4-dimethylaminophenylamino)-ethylamine analogously to Example 1.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]([CH3:49])[C:28]2[O:34][C:33]3[C:35]([Cl:45])=[CH:36][C:37]([N:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)=[CH:38][C:32]=3[CH2:31][S:30](=[O:47])(=[O:46])[C:29]=2[CH:48]=1)=[O:24]>CN(C=O)C>[CH2:13]([O:20][C:1]([N:42]1[CH2:41][CH2:40][N:39]([C:37]2[CH:36]=[C:35]([Cl:45])[C:33]3[O:34][C:28]4[C:27]([CH3:49])=[CH:26][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:48][C:29]=4[S:30](=[O:46])(=[O:47])[CH2:31][C:32]=3[CH:38]=2)[CH2:44][CH2:43]1)=[O:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: OCc1ccccc1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(=O)OCc4ccccc4)CC3)cc(Cl)c1O2
Temperature: 22 °C
Reaction time: 1 h

Procedure:
Carbonyl diimidazole (0.34 g, 0.021 mmol) was added to a solution of benzyl alcohol (0.2 g, 0.014 mmol) in DMF (3 mL) and stirred at 22° C. for 1 h. To this, a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.228 g, 0.016 mmol) in DMF (2 mL) was added dropwise and stirred at 22° C. for 1 h. Solvent was removed and ice water (5 mL) was added. The solid separated was filtered, washed with water. Crude was crystallised using ethyl acetate to obtain the title compound. Yield: 0.093 g (53%); mp: 170-173° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.47 (s, 3H, CH3), 3.25 (s, 4H, 2CH2), 3.52 (s, 4H, 2CH2), 3.85 (s, 3H, OCH3), 5.09 (s, 2H, CH2), 5.15 (s, 2H, CH2), 7.09 (s, 1H, Ar), 7.14 (s, 1H, Ar), 7.32 (m, 5H, Ar), 8.09 (s, 1H, Ar), 8.15 (s, 1H, Ar); MS: m/e (ES+) 572 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH:20]1[CH:24]=[CH:23][CH:22]=[N:21]1.CC(C)([O-])C.[K+]>CS(C)=O.O>[C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[N:20]1[CH:24]=[CH:23][CH:22]=[N:21]1)#[N:2]
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Reactant: c1cn[nH]c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccnc(-c2ccc(-n3cccn3)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
212 mg of methyl 2-(3-cyano-4-fluorophenyl)isonicotinate and 68 mg of pyrazole were dissolved in 4 ml of DMSO, and 102 mg of potassium tert-butoxide was added, followed by stirring at room temperature for 30 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=67:33) to obtain 251 mg of methyl 2-[3-cyano-4-(1H-pyrazol-1-yl)phenyl]isonicotinate. (2) 236 mg of this compound was dissolved in a mixture liquid of 10 ml of methanol and 5 ml of THF, and 1.16 ml of aqueous 1 M sodium hydroxide solution was added, followed by heating at 80° C. for 40 minutes. The reaction liquid was cooled to room temperature, washed with water, and the organic solvent was evaporated away under reduced pressure. The reaction liquid was washed with diethyl ether to obtain an aqueous layer. The aqueous layer was neutralized with 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried and concentrated under reduced pressure, and the resulting residue was recrystallized from a mixture of ethanol and water to obtain 103 mg of 2-[3-cyano-4-(1H-pyrazol-1-yl)phenyl]isonicotinic acid. (3) 92 mg of this compound was dissolved in ethanol, and 0.317 ml of aqueous 1 M sodium hydroxide solution was added thereto, followed by stirring at room temperature for 15 minutes. The reaction liquid was concentrated, the residue was suspended in 2-propanol, and the precipitate was collected by filtration to obtain 93 mg of sodium 2-[3-cyano-4-(1H-pyrazol-1-yl)phenyl]isonicotinate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[NH2:34][C@H:35]([CH3:38])[CH2:36][OH:37]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][NH:34][C@H:35]([CH3:38])[CH2:36][OH:37])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: C[C@@H](N)CO
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@H](C)CO)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and (R)-2-amino-1-propanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H33N6O5SF2 [(M+H)+] 543.2196, observed 543.2201.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[C:16]4[S:23][C:22]([C:24]5[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=5)=[CH:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1>>[CH:1]1([NH:4][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:22]3[S:23][C:16]4[C:15]([NH:14][C:10]5[CH:9]=[C:8]6[C:13](=[CH:12][CH:11]=5)[NH:5][CH:6]=[CH:7]6)=[N:20][CH:19]=[N:18][C:17]=4[CH:21]=3)=[CH:31][CH:30]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: c1nc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CNC4CC4)cc3)cc2n1

Procedure:
The title compound was prepared from cyclopropylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 176-180° C.; LC-MS: 412 (MH+); HPLC RT: 4.10 minutes.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]=1[F:36])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:20]1[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)=[CH:18][C:17]([F:36])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Yield: 100.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (367 mg, 0.643 mmol) prepared in Example 10a, trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (304 mg, 99%) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>O.O1CCOCC1>[Cl:11][C:12]1[N:13]=[CH:14][N:15]=[C:16]([NH:1][CH2:2][C@@H:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[CH:17]=1
Reactant: NC[C@H](O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O[C@@H](CNc1cc(Cl)ncn1)c1ccccc1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
To a solution consisting of (R)-(−)-2-amino-1-phenylethanol (4.80 g, 35.0 mmol) in and 1,4-dioxane (150 mL) at rt was added dropwise a solution consisting of 4,6-dichloropyrimidine (5.21 g, 35.0 mmol) and 1,4-dioxane (75 mL). Upon complete addition, NaHCO3 (17.6 g, 0.210 mol) was added and the mixture was heated to reflux (100° C.) for 17 h. The reaction mixture was cooled, diluted with water (60 mL) and the pH was adjusted to 12 by the addition of a 1 N NaOH (25 mL). The solution was extracted with CH2Cl2 (75 mL), washed with satd. aq. NaCl (50 mL), and the organic extract was dried (Na2SO4) and concentrated. The crude material (8.2 g) was suspended in CH2Cl2 (40 mL) and warmed to 50° C. to give a homogeneous solution. The solution was cooled to rt and treated with a few drops of hexanes to give the title compound as a pale yellow solid (7.0 g, 81%). MS (ESI): mass calcd. for C21H20F3N3O2, 403.2; m/z found, 404.2 [M+H]+. 1H NMR (CD3OD): 8.44 (s, 1H), 8.15 (s, 1H), 8.09 (dd, J=8.8, 2.2 Hz, 1H), 7.43 (d, J=7.7 Hz, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.27-7.25 (m, 2H), 6.86 (s, 1H), 4.91-4.88 (m, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.76-3.68 (m, 1H), 3.58 (dd, J=13.7, 7.7 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:10]([CH3:11])=[O:12])=[CH:4][C:3]=1[OH:9]
Reactant: Nc1ccc(Cl)c(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Cl)c(O)c1
Temperature: 70 °C

Procedure:
0.05 Mole (7.17 grams) of 2-chloro-5-aminophenol is dissolved in 21 cc of dioxane at 75°C. There is then added, with agitation, 0.05 mole (5.1 grams) of acetic anhydride. At the end of this addition, the reaction medium is maintained for 10 minutes at 70°C and then cooled. The raw product which has crystallized in then filtered and recrystallized in a hydroalcoholic medium. It exhibits a melting point of 212°C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH2:8][Cl:9])([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[Cl-:9].[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH2:8][N+:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1O
Reactant: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)(C)c1cc(C[n+]2ccccc2)cc(C(C)(C)C)c1O
Product: [Cl-]

Procedure:
1271/2 Grams of 3,5-di-tert.butyl-4-hydroxybenzyl chloride was added dropwise, in 40 minutes, to a solution of 44.0 grams of pyridine in 500 milliliters of acetone. The mixture was stirred briefly and was then filtered, yielding 159 grams of 3,5-di-tert.butyl-4-hydroxybenzyl-pyridinium chloride, with a melting point of 239°-240° C. (with decomposition). This represents 95 percent of theory.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](=[O:41])[CH2:11][C:12](=[O:40])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:39])[C@H:23]([NH:31]C(OC(C)(C)C)=O)[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(OC(NC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=CC=2)=CC=1)=O)(C)(C)C>C(Cl)(Cl)Cl.CO>[NH2:31][C@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15](/[CH:14]=[CH:13]/[C:12](=[O:40])[CH2:11][C:10](=[O:41])/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:16][CH:17]=1)=[O:39]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Agent: CC(C)(C)OC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N[C@H](Cc1ccccc1)C(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1

Procedure:
The title compound was synthesized using the same procedure employed for Example 281, but with (1E,6E)-1-(4-hydroxyphenyl)-7-[4-((R)-2-tert-butoxycarbonylamino-3-phenylpropionylamino)phenyl]hepta-1,6-diene-3,5-dione (30 mg, 54 μmol, synthesized in Example 279) as the starting material instead of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel chromatography (chloroform/methanol=97/3 to 85/15). The product was obtained as a solid (9.2 mg, 37%) having the following characteristics.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](O)=[O:22])[NH:6]2.[CH2:24]([S:31][CH:32]([CH:35]([O:38][CH3:39])[O:36][CH3:37])[CH2:33][NH2:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([S:31][CH:32]([CH:35]([O:36][CH3:37])[O:38][CH3:39])[CH2:33][NH:34][C:21]([C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=2[N:11]([CH3:20])[S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:14])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(OC)C(CNC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Yield: 96.7 %

Procedure:
A solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (3.0 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (2.4 g), N-ethyldiisopropylamine (3.7 mL) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.2 g) in N,N-dimethylformamide (40 mL) was stirred at room temperature for 8 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:3-3:2) to give the title compound (4.75 g, yield: 97%) as a pale-yellow oil. MS: 542 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1Cl.C(N(CC)CC)C.[NH2:20][CH2:21][CH2:22][OH:23]>C(O)(C)C>[NH2:9][C:5]1[N:6]=[C:7]([NH:20][CH2:21][CH2:22][OH:23])[C:2]([Cl:1])=[N:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Reactant: NCCO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(NCCO)c(Cl)nc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To 1.0 g of 5,6-dichloro-3-nitropyrazinamine in 20 ml isopropanol is added 0.5 ml triethylamine and then 0.3 ml 2-aminoethanol. The reaction mixture is stirred for 3 hours and then concentrated in vacuo to solids. The solids are triturated with hot chloroform and recrystallized from acetonitrile to afford 0.6 g of 2[(6-Amino-3-chloro-5-nitropyrazin-2-yl)amino]ethanol, m.p. 196°-197° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([NH:15][NH:16][C:17]2[N:18]=[N:19][C:20]([Cl:30])=[CH:21][C:22]=2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.P(CC)(CC)CC.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]2[N:18]3[N:19]=[C:20]([Cl:30])[CH:21]=[C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:17]3=[N:16][N:15]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)NNc2nnc(Cl)cc2C(=O)OC(C)(C)C)cc1
Agent: CCP(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nnc3c(C(=O)OC(C)(C)C)cc(Cl)nn23)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
To a solution of tert-butyl 3-(2-(4-(tert-butoxycarbonylamino)benzoyl)hydrazinyl)-6-chloropyridazine-4-carboxylate (66C) (1.49 g, 3.20 mmol) in a mixed solvent of THF (10 mL) and CCl4 (5 mL) at 0° C. under argon was added Et3P (3.35 mL, 19.2 mmol), followed by DIPEA (3.35 mL, 19.2 mmol). The reaction mixture was stirred at 0° C. for 10 min. Analysis by LC/MS indicated the starting material was consumed. The reaction mixture was partitioned between EtOAc and water, the separated EtOAc layer washed with water, saturated aqueous NaHCO3, saturated aqueous NaCl (2×), dried (anhydrous Na2SO4), and concentrated. The crude residue was purified using a silica gel cartridge (40 g) which was pretreated with 1% Et3N in hexanes for 10 min at 10 mL/min, eluting with a gradient of EtOAc (0-50%) in hexanes to afford 1.02 g (71%) of the title compound as a yellow solid. HPLC/MS (Method B): retention time=3.78 min, [M+H]+=446.3.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH3:21])[CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][CH2:21][C:15]1[CH:14]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(C(C)(C)C)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(C)(C)C)cc1CBr
Yield: 104.5 %

Procedure:
N-Bromosuccinimide (5.66 g) and 2,2′-azobis(isobutyronitrile) (71 mg) were added to a solution of 4-tert-butyl-1-methoxy-2-methylbenzene (5.16 g) in carbon tetrachloride (25 mL), and the mixture was heated under reflux for 1.5 hours. The reaction solution was ice-cooled and then the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain 7.78 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.FC(F)(F)O[C:29]1C=CC(Br)=C[CH:30]=1>>[CH:4]([C:3]1[CH:6]=[C:7]([O:10][CH2:11][CH2:29][CH3:30])[CH:8]=[CH:9][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([O:14][C:13]([F:25])([F:24])[F:12])=[CH:16][CH:17]=1)=[O:5]
Reactant: COc1ccc(Br)c(C=O)c1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCCOc1ccc(-c2ccc(OC(F)(F)F)cc2)c(C=O)c1

Procedure:
Similarly to the method described by Kumar, S., J.Org.Chem. 62, 8535 (1997), 2-bromo-5-methoxy-benzaldehyde (for preparation see Ex. 1) and 4-trifluoromethoxyphenylboronic acid {prepared in a conventional manner from 4-trifluoromethoxy-bromobenzene [407-14-7]} are reacted to give 2-formyl-4-propyloxy-4′-trifluoromethoxy-biphenyl. Similarly to the method described in the same reference, this compound is reacted with trimethylsulfonium iodide under phase transfer conditions to give the corresponding oxiranyl derivative which can be isolated, but can alternatively advantageously be directly converted into the target compound by reaction with methanesulfonic acid (as described by Kumar, loc. cit.). Aqueous workup can be followed by purification as described in Ex. 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[Cl:22][C:23]1[CH:28]=[C:27]([Br:29])[CH:26]=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:30][C:24]1[CH:25]=[CH:26][C:27]([Br:29])=[CH:28][C:23]=1[Cl:22])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: Oc1ccc(Br)cc1Cl
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(Br)cc3Cl)cc2OC1C(F)(F)F
Temperature: 110 °C
Yield: 76.2 %

Procedure:
To the mixture of 1.5 g (4.61 mmol) of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate, 1.04 g (6.44mmol) of 2-chloro-4-bromophenol, and 0.89 g (8.76 mmol) potassium carbonate was added 10 mL of anhydrous DMF. The resulting mixture was heated to 110° C. for five hrs. After cooling to room temperature the reaction was treated with 150 mL of ethyl acetate. The organic phase was washed with saturated sodium bicarbonate three times and brine three times and dried over anhydrous magnesium sulfate. After removing the volatiles, the residue was purified on a silica gel column with EtOAc/hexane (1:9) to afford 1.8 g (76.3%) of a light yellow solid: 1H NMR (CDCl3/400MHz) 7.69(s, 1H), 7.68(s, 1H), 7.47 (dd,1H, J=2.4 Hz, 8.7 Hz), 7.37 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.38(s, 1H), 5.70(q, 1H, J=6.6 Hz), 4.35 (m, 2H), 1.38(t, 3H, J=7.2 Hz). MS (ESI+) 511 (M+1, 60), 513 (M+3, 100); HRMS (El) m/z calcd for (C19H12BrCl2F3O4) 509.9248, found 509.9274.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].Cl[CH2:10][C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13].Cl.C(N(CC)CC)C>ClCCl.C(N(CC)CC)C>[CH3:10][C:11]1([CH3:16])[CH2:15][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[NH:8][C:12]1=[O:13]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: NNc1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2ccccn2)NC1=O
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
2-Pyridylhydrazine (10.9 g) in dichloromethane (120 ml) and dry triethylamine (28 ml) were chilled in an ice bath. -chloropivaloyl chloride (15.5 g) in dichloromethane (20 ml) was added dropwise with stirring for 15 minutes and the mixture was refluxed for 3 hours. When cool the triethylamine hydrochloride was filtered off and the filtrate evaporated to dryness and rinsed four times with the minimum quantity of ether to give the title compound (13.6 g) after recrystallisation from cyclohexane mp 141°-144°.