Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]=O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.[C:21]1(C2CCC(=O)CC2)[N:22]=NN2[C:29]=1C1C=CNC=1N=C2>>[C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16](/[CH:19]=[CH:29]/[C:21]#[N:22])[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: O=C1CCC(c2nnn3cnc4[nH]ccc4c23)CC1
Reactant: O=C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Product: N#C/C=C/[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1

Procedure:
The reactions in Synthetic Examplea 434 were carried out in substantially the same manners except that trans-4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde (30.0 mg, 0.111 mmol) obtained in Synthetic Examplea 78 was used instead of 4-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanone to give the title compound as a colorless solid (3.60 mg, yield 7%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH:16]([C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:33][CH3:34])=[C:26]([C:29](=O)[CH2:30][CH3:31])[CH:27]=2)[O:22][C:21]([CH3:36])([CH3:35])[CH:20]=1)([CH3:18])[CH3:17]>>[F:7]/[C:6](=[C:29](/[C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:33][CH3:34])[O:22][C:21]([CH3:36])([CH3:35])[CH:20]=[C:19]2[CH:16]([CH3:17])[CH3:18])\[CH2:30][CH3:31])/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCC(=O)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (605 mg, 2.50 mmol) and 1-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-propan-1-one (Compound 58, 148 mg, 0.50 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes).
Reaction SMILES: FC1C=C(C[C@H](NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C2N(C3C=CC(OC)=CC=3)C=CN=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH2:64])[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1.[F:65][C:66]1[CH:67]=[C:68]2[C:72](=[CH:73][CH:74]=1)[NH:71][CH:70]=[C:69]2[CH2:75][C:76](O)=[O:77]>>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[O:53][CH:52]=[N:51][C:50]=2[CH:54]([NH:64][C:76](=[O:77])[CH2:75][C:69]2[C:68]3[C:72](=[CH:73][CH:74]=[C:66]([F:65])[CH:67]=3)[NH:71][CH:70]=2)[CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:45][CH:44]=1
Reactant: NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Agent: COc1ccc(-n2ccnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Agent: Cl
Product: O=C(Cc1c[nH]c2ccc(F)cc12)NC(Cc1cc(F)cc(F)c1)c1ncoc1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared according to the method presented for the synthesis of compound 5F of Example 5 utilizing 33G and 2-(5-fluoro-1H-indol-3-yl)acetic acid. 1H NMR (400 MHz, DMSO) δ 10.88 (s, 1H), 8.76 (d, J=8.3 Hz, 1H), 8.47 (s, 1H), 7.63 (d, J=7.9 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.26 (dd, J=8.8, 4.6 Hz, 1H), 7.08 (d, J=12.4 Hz, 2H), 6.91-6.83 (m, 4H), 5.31 (d, J=7.9 Hz, 1H), 3.44 (s, 2H), 3.22-3.11 (m, 1H), 3.06 (dd, J=13.3, 7.0 Hz, 1H). MS (m/z) 510.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[CH3:16][O:17][C:18](=[O:21])[CH:19]=[CH2:20].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][O:17][C:18]([CH:19]=[CH:20][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1)=[O:21]
Reactant: C=CC(=O)OC
Reactant: O=C1Nc2ccc(Br)cc2C2CCCC12
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc2c(c1)C1CCCC1C(=O)N2
Temperature: 120 °C
Reaction time: 18 h
Yield: 50.4 %

Procedure:
A solution of 4.0 g (15.0 mmol) of 8-bromo-1,2,3,3a,5,9b-hexahydrocyclo-penta[c]quinolin-4-one (DE file number: 198 06 348.2) in 150 ml of DMF is heated for 4 hours to 120° C. with 2.7 ml (30.0 mmol) of acrylic acid-methyl ester, 4.2 ml (30 mmol) of triethylamine, 168 mg (0.75 mmol) of palladium(II) acetate and 457 mg (1.5 mmol) of tri-o-tolyl-phosphine. After 868 mg (0.75 mmol) of tetrakis(triphenylphosphine)palladium is added, the batch is stirred for 18 hours at 120° C., diluted at room temperature with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 2.05 g of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].Cl>CN(C)C=O>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][N:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1)[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Nc1cc(C)cc(C)n1
Reactant: ClCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(CCCCCl)c1cc(C)cc(C)n1

Procedure:
To N-(4,6-dimethyl-2-pyridyl)acetamide (49.2 g, 0.3 mole) dissolved in dimethylformamide (550 ml) is added sodium hydride in mineral oil (50%) (13.45 g., 0.32 mole) in portions at room temperature. When reaction is complete, the mixture is warmed with stirring to 45° and 1-bromo-4-chlorobutane (52.5 g., 0.306 mole) is added in one portion and stirred one hour on the steam bath. The reaction mixture is then cooled, acidified with hydrochloric acid and concentrated under vacuum. The residue is dissolved in water and extracted with diethyl ether. The aqueous layer is made basic with sodium hydroxide and extracted with ether. The combined etheral extracts are washed with brine, treated with charcoal, dried (sodium sulfate) and concentrated to obtain the product oil, weight 56.6 g.
Reaction SMILES: [C:1]1([C:7]2([CH:13]([CH3:20])[CH2:14]OS(C)(=O)=O)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C1(C)C=CC=CC=1>[CH3:20][CH:13]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[CH:11][CH2:10][CH:9]=[CH:8]1)[CH2:14][N:23]([CH2:24][CH3:25])[CH2:21][CH3:22]
Reactant: CC(COS(C)(=O)=O)C1(c2ccccc2)C=CCC=C1
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)CC(C)C1(c2ccccc2)C=CCC=C1
Reaction time: 25 h

Procedure:
8 g. of methanesulfonic acid 2-(1-phenyl-2,5-cyclohexadien-1-yl)-propyl ester are dissolved in 10 ml. of toluene. 8.4 ml. (about 3 equivalents) of condensed diethylamine are added at -10° C. The mixture is subsequently held at 150° C. in a pressure vessel for 25 hours. After cooling, the toluene phases is washed with water, concentrated, treated with ether and 3 N aqueous hydrochloric acid and extracted. The aqueous phase is made basic with concentrated aqueous ammonia and extracted with ether. The combined ether phases are dried over sodium sulfate, filtered and concentrated completely. There is obtained an oily product which is chromatographed on silica gel with methylene chloride/methanol (10:1). There is obtained β-methyl-N,N-diethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine as an oily product. This product is converted as usual into the hydrochloride which, after recrystallization from ethanol/ether, has a melting point of 132°-137° C.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.[C:11](OCC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]2[C:11](=[O:19])[C:12]3[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:14][C:8]2=[O:9])=[CH:3][CH:2]=1
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CCOC(=O)c1ccccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
A solution of p-tolyl isocyanate (133.2 g, 1.00 mol) in xylene (300 ml) is metered at room temperature into a solution of ethyl anthranilate (165.2 g, 1.00 mol) in xylene (600 ml). After addition is complete, the mixture is stirred at 90° C. for 2.5 hours. 18.0 ml of a 30% strength solution of methanolic sodium methoxide (0.10 mol) are metered in and the mixture is stirred at 90° C. for a further 2 hours, ethanol and methanol being distilled off. After cooling, the product is filtered off with suction and washed with 3×75 ml of xylene. The xylene-moist precipitate is treated with dilute hydrochloric acid and the residual xylene is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 233.0 g of 3-(4-tolyl)-2,4(1H,3H)-quinazolinedione (yield 92.4% of theory) of melting point 267° C. (lit 265° to 266° C.) are obtained.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:50](Cl)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CCCCCC>[CH2:50]([O:22][CH:21]([CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: ClCc1ccccc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCCOCC(COCCOCCO)OCc1ccccc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 93.6 %

Procedure:
To 6.5 g (9.6 millimole) of 1-O-octadecyl-3-O-[2-(2-trityloxyethoxy)ethyl]glycerol synthesized in Working Example 1 were added 2.3 g (18 millimole) of benzyl chloride, 4 g (50 millimole) of 50% sodium hydroxide, and 160 mg (0.5 millimole) of cetyltrimethylammonium chloride, and the mixture was stirred at 70° C. for 18 hours. After cooling, hexane was added and the organic layer was collected by decantation. Hexane was distilled off under reduced pressure, and to the residue 50 ml of dioxane, 8 ml of 2N hydrochloric acid and 20 ml of methanol were added, and then the resulting mixture was stirred at 75° C. for 4 hours. After addition of 50 ml of water, the organic solvent was distilled off under reduced pressure, and the residue was partitioned between dichloromethane and water. The organic layer was collected and dichloromethane was distilled off, and the residue was purified by silica gel column chromatography (Merck Co., Art.7734, 150 g, Eluant; hexane-ethyl acetate=6:1, hexane-ethyl acetate-acetone=6:1:1), to give 4.7 g (92%) of the above-mentioned compound.
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=3)[NH:15][C:14](=[O:23])[C@@H:13]2[CH2:24][CH3:25])(=[O:11])=[O:10])=[CH:5][CH:4]=1.IC.[CH2:32]([C@@H]1N(S(C2C=CC(O)=CC=2)(=O)=O)C2C(=CC=C(F)C=2)N(CCC)C1=O)C>>[Br:22][C:18]1[CH:17]=[C:16]2[C:21]([N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C@@H:13]([CH2:24][CH3:25])[C:14](=[O:23])[N:15]2[CH3:32])=[CH:20][CH:19]=1
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3ccc(Br)cc3NC(=O)[C@@H]2CC)cc1
Reactant: CCCN1C(=O)[C@H](CC)N(S(=O)(=O)c2ccc(O)cc2)c2cc(F)ccc21
Solvent: CI
Product: CC[C@H]1C(=O)N(C)c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
4-{[(2S)-6-Bromo-2-ethyl-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl ethyl carbonate was treated with iodomethane according to the procedure for the preparation of (3S)-3-ethyl-6-fluoro-4-[(4-hydroxyphenyl)sulfonyl]-1-propyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 20) to yield (3S)-7-bromo-3-ethyl-4-[(4-hydroxyphenyl)sulfonyl]-1-methyl-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−121° (c=0.0052 G/ML, DMSO); MS (ESI) m/z 425/427 ([M+H]+); MS (ESI) m/z 423/425 ([M−H]−); Anal. Calcd for C17H17BrN2O4S: C, 48.01; H, 4.03; N, 6.59. Found: C, 47.74; H, 4.17; N, 6.22.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[C:38]4[C:33](=[C:34]([Cl:39])[CH:35]=[CH:36][CH:37]=4)[C:32]([O:40][CH3:41])=[CH:31][N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:42])[NH:19][C@:18]2([C:44]([O:46]CC)=[O:45])[CH2:43][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]([CH3:49])[CH2:11][C@H:10]1[CH3:50])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CO>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[C:38]4[C:33](=[C:34]([Cl:39])[CH:35]=[CH:36][CH:37]=4)[C:32]([O:40][CH3:41])=[CH:31][N:30]=3)[CH2:27][C@H:21]2[C:20](=[O:42])[NH:19][C@:18]2([C:44]([OH:46])=[O:45])[CH2:43][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH:12]([CH3:49])[CH2:11][C@H:10]1[CH3:50])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3ncc(OC)c4c(Cl)cccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3ncc(OC)c4c(Cl)cccc34)C[C@H]1C(=O)N2
Agent: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)O)C[C@H]4/C=C\CCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2cccc(Cl)c12
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COc1cnc(O[C@@H]2C[C@H]3C(=O)N[C@]4(C(=O)O)C[C@H]4C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N3C2)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2R,6S,7R,13aS,14aR,16aS,Z)-ethyl 6-((tert-butoxycarbonyl)amino)-2-((5-chloro-4-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (400 mg, 0.56 mmol) in THF/water (1:1) was added LiOH (235 mg, 5.61 mmol) followed by 5 mL of methanol at room temperature. The reaction mixture was stirred at room temperature for overnight. The solvent was removed under reduced pressure and the residue was diluted with water and acidified by aqueous 1.5 N HCl solutions. The aqueous solution was extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated to get desired product (2R,6S,7R,13aS,14aR,16aS,Z)-6-((tert-butoxycarbonyl)amino)-2-((5-chloro-4-methoxyisoquinolin-1-yl)oxy)-7,9-dimethyl-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid as diastereomeric mixture (310 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1CC[CH2:16][CH2:15]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:13][CH2:16][CH2:15][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN(C)c1ccc(N)c(C(N)=O)c1
Reactant: C1CCNC1
Product: NC(=O)c1cc(N2CCCC2)ccc1N

Procedure:
According to the preparation of 25, pyrrolidine was used to afford 26 (0.7 g) as brown powder; MS m/z 205 (M+).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.Cl.[CH2:27]([NH:34]N)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCN(CC)CC.Cl>CO>[CH2:27]([N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1Cc1ccccc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.675 g, 2.0 mmol), benzylhydrazine dihydrochloride (1.56 g, 8.0 mmol), and Et3N (2.23 mL, 16 mmol) in MeOH (20 mL) was refluxed for 3 h. After cooling to room temperature, the reaction mixture was poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give the title compound (375 mg, 47% yield) as a white solid: mp 156-157° C.; 1H NMR (300 MHz, CDCl3): δ ppm 5.75 (2H, s), 6.70 (1H, d, J=7.9 Hz), 6.84-6.91 (2H, m), 7.18-7.24 (3H, m), 7.32-7.37 (1H, m), 7.47-7.53 (2H, m), 7.64-7.67 (2H, m), 7.70 (1H, d, J=1.9 Hz), 8.15 (1H, d, J=7.9 Hz). Anal. Calcd for C21H15F3N4O: C, 63.63; H, 3.81; N, 14.14. Found: C, 63.63; H, 3.85; N, 14.16.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[CH2:12]O.O=S(Cl)[Cl:16]>>[Cl:1][C:2]1[C:3]([CH2:12][Cl:16])=[CH:4][N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(C(F)(F)F)cc1Cl
Product: FC(F)(F)c1cc(Cl)c(CCl)cn1
Yield: 87 %

Procedure:
[4-Chloro-6-(trifluoromethyl)pyridin-3-yl]methanol (Int-12) (90 g, 0.426 mol) was added to SOCl2 (700 mL) slowly with ice bath, the mixture was refluxed for 1 hour. The mixture was concentrated and the residue was poured into water (1 L). The mixture was adjusted to pH=7-8 with solid NaHCO3. The mixture was extracted with ethyl acetate (500 mL*3). The combined organic layer was concentrated to yield 4-chloro-5-(chloromethyl)-2-(trifluoromethyl)pyridine (Int-13) (80 g, 87%) as brown syrup which was used for the next step without further purification.
Reaction SMILES: O=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[NH:20]1[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[N:20]1([CH:2]2[CH2:19][CH2:18][C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:4][CH2:3]2)[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (stage (iv) AMN-08) (1 g, 3.74 mmol) and azetidine (0.25 ml, 3.74 mmol) were initially introduced into 1,2-dichloroethane (15 ml), and sodium triacetoxyborohydride (1.1 g, 5.23 mmol) was added. The reaction mixture was stirred at room temperature for 3 d and saturated sodium bicarbonate solution was then added. After separation of the phases, the aqueous phase was extracted with methylene chloride (2×). The combined organic phases were washed with saturated sodium chloride solution (1×), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, ethyl acetate/methanol/ammonia (25% aq.) 100:10:1). Yield: 1 g (89%)
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[C:4]([NH:10][CH3:11])[CH:3]=1.[F:12][C:13]([F:19])([F:18])[CH2:14][C:15](=O)[CH3:16].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[S:6][C:5]2[C:7](=[O:8])[NH:9][C:15]([CH3:16])([CH2:14][C:13]([F:19])([F:18])[F:12])[N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CNc1cc(Br)sc1C(N)=O
Reactant: CC(=O)CC(F)(F)F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: CN1c2cc(Br)sc2C(=O)NC1(C)CC(F)(F)F
Yield: 31.4 %

Procedure:
A mixture of 5-bromo-3-(methylamino)thiophene-2-carboxamide (940 mg, 4.0 mmol), 4,4,4-trifluorobutan-2-one (5.04 g, 40 mmol), CSA (93 mg, 0.40 mmol), MgSO4 (576 mg, 6.0 mmol) and DMA (4 mL) was microwave-irradiated at 150° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, NH, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give a yellow solid. The solid was purified by crystallization from EtOAc/heptane to give the title compound (431 mg, 31%) as a yellow solid:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:19]([OH:21])=O)[C:13](=[CH:17][CH:18]=1)[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([N:25]([CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])[CH2:23][CH3:24].O>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:17][CH:18]=1)[C:14](=[O:16])[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:25]([CH2:31][CH2:32][CH3:33])[CH2:22][CH2:23][CH3:24])[C:19]2=[O:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(CCC)CCCCN
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(C(=O)O)c1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCN(CCC)CCCCN1C(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2C1=O
Yield: 49.2 %

Procedure:
The compound (123 mg) obtained in Example 7-4 was dissolved in xylene (5.0 ml). A xylene solution (5.0 ml) containing the compound (83.4 mg) obtained in Example 1-2 was dropped to the solution and the whole was refluxed under heating for 63 hours. The solution was added with water to stop the reaction and then subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution, followed by drying with anhydrous sodium sulfate. The residue obtained by distilling the solvent off was then purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (88.4 mg) as a yellow solid.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl[CH2:15][CH:16]=[C:17]([Cl:19])[CH3:18]>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[C:3]([CH2:15]/[CH:16]=[C:17](\[Cl:19])/[CH3:18])([CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:13]
Reactant: CC(Cl)=CCCl
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)(C/C=C(/C)Cl)C(=O)OCC
Temperature: 75 °C

Procedure:
11.5 g of sodium cut into small pieces was introduced into a three-necked flask equipped with agitator, reflux condenser, and dropping funnel. To this charge was added dropwise 250 ml of absolute ethanol so quickly that the solution was boiling vigorously. Then 87 g of distilled diethyl methylmalonate was added dropwise to the hot alcoholate solution. After allowing the mixture to cool to about 75° C., the reaction solution was combined with 66 g of 1,3-dichloro-2-butene dropwise; the solution turned yellow during this step. After 2 hours of agitation under heating, the suspension, at this point having pH 5-6 and being almost completely decolorized, was freed of precipitated sodium chloride by filtration. The filtrate was concentrated and combined with the methylene chloride obtained by washing the precipitate. The organic solution was thereafter shaken with saturated sodium chloride solution, dried over magnesium sulfate, concentrated on a forced circulation evaporator, and fractionated under vacuum. Yield: 105 g of the desired diester, bp2.5 110° C.