Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5]=[CH:6][C:7]1[S:8][C:9]([Br:12])=[CH:10][CH:11]=1.Cl.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[NH:24][NH2:25]>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH2:5][CH:6]([C:7]2[S:8][C:9]([Br:12])=[CH:10][CH:11]=2)[N:24]([C:18]2[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=2[F:16])[N:25]=1)=[O:14]
Reactant: COC(=O)C(=O)C=Cc1ccc(Br)s1
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)C1=NN(c2ccc(F)cc2F)C(c2ccc(Br)s2)C1
Temperature: 125 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
4-(5-Bromo-thiophen-2-yl)-2-oxo-3-butenoic acid methyl ester (17.0 g, 61.8 mmol) prepared in Step 2 and 2,4-difluorophenylhydrazine hydrochloride (12.3 g, 68.0 mmol) were added to acetic acid (200.0 mL). The reaction mixture was stirred at 125° C. for 2 hours, concentrated under reduced pressure, and then ethyl acetate was added thereto. The mixture was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/20) to give 15.1 g of the titled compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:34])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([NH:21][C:22](=[O:30])[O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:31](=[O:33])[NH2:32])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([CH:45]=O)=[C:40]([CH:44]=1)[C:41]([OH:43])=[O:42].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O1CCCC1.O.CCOC(C)=O>[C:31]([C:11]1[C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:8]([C:4]2[C:3]([CH3:34])=[C:2]([NH:1][CH2:45][C:39]4[CH:38]=[CH:37][C:36]([Cl:35])=[CH:44][C:40]=4[C:41]([OH:43])=[O:42])[CH:7]=[CH:6][CH:5]=2)=[CH:9][N:10]=1)=[CH:18][CH:17]=[C:16]([NH:21][C:22]([O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])=[O:30])[CH:15]=3)(=[O:33])[NH2:32]
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(NC(=O)OCC[Si](C)(C)C)ccc3c12
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(NCc2ccc(Cl)cc2C(=O)O)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(NC(=O)OCC[Si](C)(C)C)ccc3c12
Reaction time: 8 h

Procedure:
To a homogeneous, light burgundy solution of 2-(trimethylsilyl)ethyl 4-(3-amino-2-methylphenyl)-1-carbamoyl-9H-pyrido[3,4-b]indol-7-ylcarbamate (0.2535 g, 0.533 mmol), 5-chloro-2-formylbenzoic acid (0.246 g, 1.332 mmol), and acetic acid (0.076 mL, 1.332 mmol) in dichloromethane (10.66 mL) and tetrahydrofuran (7.11 mL) under nitrogen was added sodium triacetoxyborohydride (0.339 g, 1.599 mmol). The reaction was stirred overnight. Water (5 mL) was added, and the reaction was stirred for 10 min. EtOAc (50 mL) and water (20 mL) were added, and the layers were separated. The organic layer was washed with water (6×20 mL) and brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a crude product that was used in the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([OH:18])[C:11]3[S:17][CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:26][C:27]([F:33])([F:32])[S:28](O)(=[O:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:33])([F:32])[S:28]([O:18][C:10]1[C:11]2[S:17][CH2:16][CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)(=[O:30])=[O:29]
Reactant: Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1nc(-c2cccc(Cl)c2)nc2c1SCCC2)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
To a suspension of 2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (5.2 g, 18.6 mmol) in methylene chloride (200 mL) at 0° C. was added N,N-dimethylaminopyridine (0.020 g, cat.), triethylamine (5.2 mL, 37.3 mmol) and trifluoromethanesulfonic acid (3.7 mL, 22.4 mmol). The suspension was warmed to rt and stirred for 3 h. The mixture was cooled to 0° C. and the reaction was quenched with a saturated solution of NaHCO3. The organic layer was washed a saturated solution of NaHCO3 and brine. The organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, methylene chloride) to afford title compound (6.6 g, 86%) as a white solid. MW=410.82. 1H NMR (CDCl3, 300 MHz) δ 8.35-8.31 (m, 1H), 8.25-8.18 (m, 1H), 7.48-7.36 (m, 2H), 3.18-3.05 (m, 4H), 2.38-2.27 (m, 2H); APCI MS m/z 411 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=4)[CH:18]=3)(=[O:16])=[O:15])[CH2:10][C:9]2=[O:28])=[CH:5][CH:4]=1.Cl.[C:32](=[NH:37])(OCC)[CH3:33].C(N(CC)CC)C>CO>[ClH:27].[C:32]([NH:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=4)[CH:18]=3)(=[O:15])=[O:16])[CH2:10][C:9]2=[O:28])=[CH:5][CH:4]=1)(=[NH:37])[CH3:33]
Reactant: CCOC(C)=N
Reactant: Nc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=N)Nc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
To a solution of 1-(4-aminobenzyl)-4-(6-chloro-naphthalene-2-sulfonyl)-2-piperazinone hydrochloride (233 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (618 mg) and triethylamine (0.836 ml), and the mixture was stirred at room temperature overnight. The solvent was concentrated and purified with CHP20 column chromatography (water:acetonitrile:1 N hydrochloric acid=70:30:1) to give pale yellow amorphous of the title compound (134 mg).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O.[ClH:16]>CO.[Pd]>[ClH:16].[ClH:16].[F:12][C:8]1([F:11])[O:7][C:6]2=[CH:5][CH:4]=[C:3]([NH2:13])[C:2]([NH2:1])=[C:10]2[O:9]1
Reactant: Nc1c([N+](=O)[O-])ccc2c1OC(F)(F)O2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1N)OC(F)(F)O2
Yield: 97 %

Procedure:
30 g of 4-amino-2,2-difluoro-5-nitro-1,3-benzodioxole are hydrogenated in 300 ml of methanol on 0.5 g of 10% strength palladium-on-charcoal in a circulatory hydrogenation apparatus under atmospheric pressure and at room temperature, 2.5 equivalents of methanolic hydrogen chloride solution are added, the mixture is filtered, the solution is concentrated in vacuo and isopropanol and ether are added to the residue to give 35 g (97%) of 2,2-difluoro-1,3-benzodioxole-4,5-diamine dihydrochloride of m.p. 232°-233° C. (decomposition).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[CH3:9][N:10]1[C:19]2[NH:18][C:17]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:16]=3[N:15]([C:25]([C:27]3[CH:43]=[CH:42][C:30]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:29]([F:44])[CH:28]=3)=[O:26])[CH2:14][C:13]=2[CH:12]=[N:11]1>CN(C=O)C.C(N(CC)CC)C>[CH3:9][N:10]1[C:19]2[NH:18][C:17]3[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:16]=3[N:15]([C:25]([C:27]3[CH:43]=[CH:42][C:30]([CH2:31][NH:32][C:33](=[O:41])[CH2:34][CH:35]4[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:37][CH2:36]4)=[C:29]([F:44])[CH:28]=3)=[O:26])[CH2:14][C:13]=2[CH:12]=[N:11]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)CC2CCNCC2)c(F)c1
Reactant: CCCCCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCN1CCC(CC(=O)NCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(C)ccc43)cc2F)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of N-[4-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-2-piperidin-4-yl-acetamide hydrochloride (Compound number 1110) (2.82 mg, 0.005 mmol) in DMF (0.05 ml) and triethyl-amine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=575.7
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C>C(Cl)Cl.O>[C:11]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:25])([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)NCCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCC=O
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 95.6 %

Procedure:
To a stirred solution of 5.3 mL (7.71 g, 60.7 mmoles) oxalyl chloride in 100 mL methylene choride at -70° C. under argon was added 8.6 mL (10.23 g, 121.5 mmoles) dimethyl sulfoxide in 30 mL methylene chloride. After 2 min. a solution of 12 g (55.2 mmoles) of (6) in 50 mL methylene chloride was added over 5 min. After 20 min. 38.5 mL (27.9 g, 276 mmoles) triethylamine was added. After 10 min. more, the mixture was allowed to warm to 20° C. and 250 mL water was added. After separation, the aqueous layer was extracted again with methylene chloride and the combined organic layers were washed with brine and dried over sodium sulfate. After evaporation in vacuo, the residue was chromatographed (Flash, hexane-ethyl acetate, 7:3) to provide 11.36 g of a pale yellow oil (7).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:38])[CH3:37])=[CH:34][C:33]([OH:39])=[CH:32][C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:22][CH2:21]1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C1COCC1.O>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]2[C:35]([CH:36]([CH3:37])[CH3:38])=[CH:34][C:33]([O:39][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:32][C:31]=2[CH:40]([CH3:42])[CH3:41])=[O:28])[CH2:22][CH2:21]1
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cc(OS(C)(=O)=O)cc(C(C)C)c1NC(=O)CN1CCN(CCSc2nc3ccccc3o2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Triethylamine (30 mg, 0.3 mmol) was added to a solution of 2-[4-[2-(benzoxazol-2-ylthio)ethyl]piperazin-1-yl]-N-(2,6-diisopropyl-4-hydroxyphenyl)acetamide (50 mg, 0.1 mmol) in THF (1 ml), then methanesulfonyl chloride (34 mg, 0.3 mmol) was dropped thereinto with ice cooling and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over sodium sulfate and the solvent was evaporated therefrom. The residue was purified by a preparative thin layer chromatography (developing solvent, chloroform:methanol=19:1) to provide 47 mg (yield 82%) of the desired compound as colorless needles.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:16])=[O:15])[CH:9]=1.[Cl:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:24]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:23]2.CC(C1C=C(C(C)C)C(C2C(P(C(C)(C)C)C(C)(C)C)=CC=CC=2)=C(C(C)C)C=1)C.N#N>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.C(Cl)(Cl)Cl.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:24]([S:35]([NH:38][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:16])=[O:15])[CH:9]=1)(=[O:36])=[O:37])=[CH:23]2
Reactant: NC(=O)c1cc(Br)ccn1
Reactant: NS(=O)(=O)c1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc(NS(=O)(=O)c2cc3cccc(Cl)c3nc2-c2ccccc2Cl)ccn1
Temperature: 100 °C

Procedure:
The flask was charged with tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (53.2 mg, 51.4 μmol), cesium carbonate (402 mg, 1.23 mmol), 4-bromo-picolinamide (103.4 mg, 0.514 mmol), 8-chloro-2-(2-chlorophenyl)quinoline-3-sulfonamide (200 mg, 0.566 mmol), tBuXPhos (37.0 mg, 77.2 μmol) and filled with N2. Then toluene (15.0 ml) was added and N2 was bubbled through the mixture for 10 minutes. The mixture was heated at 100° C. for 16 hours. The mixture was cooled to room temperature, evaporation of the solvent, diluted with CH2Cl2-MeOH (1:1, 25 mL), filtered through a pad of Celite™. The mixture was concentrated, and the residue was diluted with MeOH. The solution was purified by HPLC, 20%-70% of B in 35 min. The collected fractions were concentrated and neutralized by adding aq. NaHCO3 Filtration and rinse with water gave 4-(8-chloro-2-(2-chlorophenyl)quinoline-3-sulfonamido)picolinamide, 1H-NMR (MeOD) δ 9.33 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.61 (s, 1H), 7.36-7.50 (m, 6H), 7.08 (d, J=8.0 Hz, 1H). Mass Spectrum (ESI) m/e=472.9 (M+1).
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH:20]=1.[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([O-])=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Na+]>CN(C)C=O>[N:34]1([C:40]2[N:41]=[C:42]([CH2:47][C:48]([NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[O:49])[NH:43][C:44](=[O:46])[CH:45]=2)[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1OCc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.2 %

Procedure:
2 ml of pyridine, 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 366 mg of 2-(pyridin-3-ylmethoxy)phenylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 20 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 150 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-[2-(pyridin-3-ylmethoxy)phenyl]acetamide are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:23][CH2:22][CH2:21][O:20][CH2:19][CH:18]=[CH:17][C@@H:16]2[CH2:24][C@@:15]2([C:25](O)=[O:26])[NH:14][C:13](=[O:28])[C@@H:12]2[CH2:29][C@@H:30]([O:32][C:33]([N:35]3[CH2:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][C:41]=4[F:44])[CH2:36]3)=[O:34])[CH2:31][N:11]2[C:10]1=[O:45])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.S([O-])(O)(=O)=O.[K+]>C1(C)C=CC=CC=1.O>[F:44][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[CH2:43][N:35]([C:33]([O:32][C@H:30]1[CH2:31][N:11]3[C@H:12]([C:13](=[O:28])[NH:14][C@:15]4([C:25](=[O:26])[NH:64][S:61]([CH:58]5[CH2:60][CH2:59]5)(=[O:63])=[O:62])[CH2:24][C@H:16]4[CH:17]=[CH:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:10]3=[O:45])[CH2:29]1)=[O:34])[CH2:36]2
Reactant: NS(=O)(=O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCOCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCOC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CC(C)(C)OC(=O)N[C@H]1CCCOC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCOCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,8,9,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecine-14a-carboxylic acid (0.10 g, 0.16 mmol) in toluene (3 mL) was added di(1H-imidazol-1-yl)methanone (0.036 g, 0.22 mmol) in rt. The reaction was stirred at 60° C. for 3 hrs. Cyclopropanesulfonamide (0.035 g, 0.29 mmol) was added, followed by addition of DBU (0.043 ml, 0.29 mmol). The reaction was then stirred at rt for 17 hrs. Water (5 mL) was added and acidified with saturated potassium hydrogen sulfate until pH=2˜3. The mixture was extracted with ethyl acetate (20 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Ethyl acetate) to give (2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,9,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(e)pyrrolo[2,1-i][1,7,10]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.064 g, 55%). MS: Calcd.: 733; Found: [M+H]+ 734. 1H NMR (400 MHz, d6-DMSO) δ11.14 (s, 1H), 8.68 & 8.59 (s, 1H), 7.34 (m, 1H), 7.08-7.25 (m, 3H), 5.64 (m, 1H), 5.30 (m, 2H), 4.67 (s, 4H), 4.43 (m, 2H), 4.27 (m, 1H), 3.95 (m, 1H), 3.74 (m, 1H), 3.52 (m, 1H), 3.37 (m, 2H), 2.91 (m, 1H), 2.36 (m, 2H), 2.28 (m, 2H), 1.79 (m, 1H), 1.52-1.70 (m, 3H), 1.24 (m, 2H), 1.19 (m, 1H), 1.01-1.19 (m, 1H).
Reaction SMILES: COC[O:4][C@H:5]1[C@:18]23[CH2:19][CH2:20][C@@H:7]([CH2:8][C@H:9]2[C@@:10]2([CH3:25])[C@H:15]([CH2:16][CH2:17]3)[C@:14]([CH3:24])([C:21]([OH:23])=[O:22])[CH2:13][CH2:12][CH2:11]2)[C@@H:6]1[S:26]([CH3:28])=[O:27].FC(F)(F)C(O)=O>O1CCCC1>[OH:4][C@H:5]1[C@:18]23[CH2:19][CH2:20][C@@H:7]([CH2:8][C@H:9]2[C@@:10]2([CH3:25])[C@H:15]([CH2:16][CH2:17]3)[C@:14]([CH3:24])([C:21]([OH:23])=[O:22])[CH2:13][CH2:12][CH2:11]2)[C@@H:6]1[S:26]([CH3:28])=[O:27]
Reactant: COCO[C@@H]1[C@@H](S(C)=O)[C@H]2CC[C@@]13CC[C@H]1[C@@](C)(CCC[C@@]1(C)C(=O)O)[C@@H]3C2
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)[C@H]1[C@H]2CC[C@@]3(CC[C@H]4[C@@](C)(CCC[C@@]4(C)C(=O)O)[C@@H]3C2)[C@@H]1O

Procedure:
To a solution of (1R,4S,5R,9S,10S,12S,13S,14S)-14-(methoxymethoxy)-5,9-dimethyl-13-(methylsulfinyl)tetracyclo[10.2.2.01,10.04,9]hexadecane-5-carboxylic acid (4.1 mg, 0.0099 mmol) obtained in Example 115 in tetrahydrofuran (2 mL) was added trifluoroacetic acid (2 mL) under stirring on ice. After stirring at 50° C. for 29 hours, the reaction mixture was evaporated, to give (1R,4S,5R,9S,10S,12S,13S,14S)-14-hydroxy-5,9-dimethyl-13-(methylsulfinyl)tetracyclo[10.2.2.01,10.04,9]hexadecane-5-carboxylic acid. This product was further purified by silica gel column chromatography so as to separate two isomers based on the configuration of sulfoxide, to give isomer 1 (0.71 mg) and isomer 2 (1.01 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH:28]([CH3:31])[CH2:29][OH:30].Cl>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH:28]([CH3:31])[CH2:29][OH:30])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CC(N)CO
Agent: Cl
Solvent: c1ccncc1
Product: CC(CO)Nc1c(F)cc2c(=O)c(C(=O)O)cn(-c3nc(N)c(F)cc3F)c2c1Cl
Temperature: 45 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) and 2-amino-1-propanol (400 mg) were added to pyridine (1,200 mg), and the mixture was stirred at 45° C. for 16 hours. Concentrated hydrochloric acid (600 mg) was added to the reaction mixture, and the resultant mixture was concentrated under reduced pressure. Ethanol (2 ml) was added to the residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (168 mg) as a colorless powder.
Reaction SMILES: [Br-].[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].[H-].[Na+].[F:33][C:34]([F:44])([F:43])[C@H:35]1[CH2:40][CH2:39][C@H:38]([CH:41]=O)[CH2:37][CH2:36]1>CS(C)=O>[CH2:2]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH:11]=[CH:41][C@H:38]2[CH2:39][CH2:40][C@H:35]([C:34]([F:44])([F:43])[F:33])[CH2:36][CH2:37]2)[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: CCC[C@H]1CC[C@H](C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: O=C[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC[C@H]1CC[C@H](C=C[C@H]2CC[C@H](C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.2 mol of (trans-4-propylcyclohexylmethyl)triphenylphosphonium bromide (prepared from trans-4-propylcyclohexylmethyl bromide and triphenylphosphine) and 150 ml of DMSO gives (sic) at 0° C. to a mixture of 0.2 mol of sodium hydride and 100 ml of DMSO. After the mixture has been stirred at room temperature for 10 minutes, a mixture of 0.2 mol of trans-4-trifluoromethyl-1-formyulcyclohexane (prepared as in Example 3) and 50 ml of DMSO is added dropwise. The mixture is warmed for 1 hour at 65° C. and subjected to customary work-up. The product is obtained as a colourless dye (sic).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH2:16][CH3:17])=[CH:14][C@H:13](O)[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:26]([O:29][NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH:27]=[CH2:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:26]([O:29][N:30]([C@H:13]1[CH2:12][N:11]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:15]([CH2:16][CH3:17])=[CH:14]1)[S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH:27]=[CH2:28]
Reactant: C=CCONS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCC1=C[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCON([C@@H]1C=C(CC)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a stirred suspension of (2S,5S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-ethyl-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 208, 6.36 g, 17.12 mmol), N-(allyloxy)-2-nitrobenzenesulfonamide (Intermediate 9) (8.84 g, 34.23 mmol) and triphenylphosphine (13.47 g, 51.35 mmol) in toluene (25 mL) at 0° C. was added dropwise (E)-diisopropyl diazene-1,2-dicarboxylate (9.95 ml, 51.35 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes. Silica gel chromatography (0-40% ethyl acetate/hexanes) afforded the title compound (7.00 g, 66.8%) as a yellow oil.