Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNCCO.[CH3:6][C:7]1[C:12]2[O:13][C@:14]3([CH3:54])[O:17][CH:18]=[CH:19][C@H:20]([O:52][CH3:53])[C@@H:21]([CH3:51])[C@@H:22]([O:47][C:48]([CH3:50])=[O:49])[C@H:23]([CH3:46])[C@H:24]([OH:45])[C@H:25]([CH3:44])[C@@H:26]([OH:43])[C@@H:27]([CH3:42])[CH:28]=[CH:29][CH:30]=[C:31]([CH3:41])[C:32]([NH:34][C:35]4[C:39](=[O:40])[C:9](=[C:10]([C:37](=[O:38])[CH:36]=4)[C:11]=2[C:15]3=[O:16])[C:8]=1[OH:55])=[O:33]>O1CCOCC1>[CH3:6][C:7]1[C:12]2[O:13][C@@:14]3([CH3:54])[C:15]([C:11]=2[C:10]2[C:37]([OH:38])=[CH:36][C:35]([NH:34][C:32]([C:31]([CH3:41])=[CH:30][CH:29]=[CH:28][C@H:27]([CH3:42])[C@H:26]([OH:43])[C@@H:25]([CH3:44])[C@@H:24]([OH:45])[C@@H:23]([CH3:46])[C@H:22]([O:47][C:48]([CH3:50])=[O:49])[C@H:21]([CH3:51])[C@@H:20]([O:52][CH3:53])[CH:19]=[CH:18][O:17]3)=[O:33])=[C:39]([OH:40])[C:9]=2[C:8]=1[OH:55])=[O:16]
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: CNCCO
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(cc(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Solvent: C1COCCO1
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(cc(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C

Procedure:
10 g (0.13 mol) of N-methylethanolamine are added to a solution of 21 g (0.03 mol) of rifamycin-S in 20 ml of dioxan and the whole heated for 15 minutes on a boiling water bath. The batch is then evaporated to dryness in vacuo and the residue chromatographed on 2kg of silica gel, using chloroform as eluant. In addition to a dark-colored head zone, two strong, yellow-colored bands are observed. The eluate of the more slowly eluted band is evaporated and the residue crystallized from aqueous methanol. After three crystallizations from aqueous methanol there is obtained 3-N-methylethanol-amino)-rifamycin-SV in the form of coarse prisms melting at 218° C (with decomposition.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([NH:31][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)[CH:28]=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3cccc(OCc4ccccc4)c3)c2c2ccccc12
Yield: 71.5 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using 83 (100 mg, 0.43 mmol) and 3-benzyloxy-phenylamine (130 mg, 0.65 mmol) to provide 227 (121 mg, 71% yield) as a tan solid. LC-MS (M+H=394, obsd.=394).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:36])[C@@H:12]([NH:28]C(OC(C)(C)C)=O)[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:9][C:2]([NH:10][C:11](=[O:36])[C@@H:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([CH3:1])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)NC(C)(C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To 2.18 g of (2S)-N-(α,α-dimethylbenzyl)-2-(t-butoxycarbonylamino)-6-benzyloxycarbonylaminohexanamide (prepared as described in Preparation 8) were added 0.47 g of anisole and 10 ml of trifluoroacetic acid, and the solution was stirred for 30 minutes at room temperature. At the end of this time, the excess trifluoroacetic acid was distilled off under reduced pressure. A 5% w/v aqueous solution of sodium bicarbonate was added to the residue, and the mixture was neutralized and then extracted with ethyl acetate. The organic layer was extracted with a 10% w/v aqueous solution of citric acid. The aqueous extract was separated and neutralized with a 5% w/v aqueous solution of sodium bicarbonate and then extracted again with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 1.01 g of the title compound was obtained as an amorphous material.
Reaction SMILES: [ClH:1].[CH:2]([N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:16]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[C:27]([OH:29])=O)[CH2:22][CH2:21]2)=[O:17])[C:6]1=[O:31])([CH3:4])[CH3:3].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>ClCCl>[ClH:1].[CH:2]([N:5]1[C:14]2[C:9](=[C:10]([CH3:15])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:16]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:26]([CH3:30])[C:27]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:29])[CH2:24][CH2:25]2)=[O:17])[C:6]1=[O:31])([CH3:4])[CH3:3]
Reactant: C1COCCN1
Reactant: Cc1cccc2c1cc(C(=O)NCC1CCN(C(C)C(=O)O)CC1)c(=O)n2C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(C(C)C(=O)N3CCOCC3)CC1)c(=O)n2C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a mixture of 2-[4-({[(1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinolin-3-yl)carbonyl]amino}methyl)piperidin-1-yl]propanoic acid hydrochloride (243 mg, 0.54 mmol, step 2), morpholine (52 mg, 0.60 mmol), and diisopropylethylamine (0.19 mL, 1.08 mmol) in dichloromethane (15 mL) was added HBTU (226 mg, 0.60 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h and at room temperature for 3 h. Then, the resulting mixture was poured onto saturated aqueous sodium hydrogen carbonate (100 mL), and the aqueous layer was extracted with dichloromethane (100 mL×3). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ammonia/methanol/dichloromethane (0.1:1:30) to give 265 mg of the title compound as salt free form. This was treated with 10% hydrogen chloride in methanol (5 mL), and the solvent removed in vacuo to give 194 mg (69%) of the title compound as a yellow amorphous.
Reaction SMILES: [I:1][C:2]1[CH:51]=[CH:50][C:5]([O:6][CH:7]([CH2:29][O:30]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8][O:9]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>ClCCl.CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:29][OH:30])[CH2:8][OH:9])=[CH:50][CH:51]=1
Reactant: Ic1ccc(OC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: OCC(CO)Oc1ccc(I)cc1
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Compound 2 (2.5 g, 3.21 mmol) was dissolved in dichloromethane (25 mL). A solution of trifluoroacetic acid and trifluoroacetic anhydride in dry dichloromethane (1.83 M; 50 mL) was added and the reaction was allowed to proceed for 15 min at RT. The mixture was cooled on ice-water bath, and it was made basic with triethylamine, poured into methanol and concentrated. Precipitation from the mixture of dichloromethane and petroleum ether gave the title compound. Yield was 86%. Mp. 90° C. 1H NMR (DMSO-d6): 7.57 (2H, d, J 8.9); 6.83 (2H, d, J 8.9); 4.81 (2H, t, J 5.8); 4.22 (1H, m); 3.54 (4H, m).
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][CH3:34])=[CH:28][CH:27]=1.[C:35]1([CH2:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[C:35]1([CH2:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH2:33][CH3:34])[C:45]([NH:44][C:42](=[O:43])[CH2:41][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[S:46])=[CH:28][CH:27]=1
Reactant: CCNc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(C(=S)NC(=O)Cc1ccccc1)c1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N-ethylamine (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenylethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 48%).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[C:26]([O:30][C:31](ON=C(C1C=CC=CC=1)C#N)=[O:32])([CH3:29])([CH3:28])[CH3:27]>O1CCOCC1.O>[C:26]([O:30][C:31]([NH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CCOC(=O)C(N)CCc1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)C(CCc1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 2-amino-4-(o-nitrophenyl)butyrate (17.4 g) in 50% aqueous dioxane (130 ml) is added triethylamine (10.5 g) and 2-(tert-butyloxycarbonyloxyimino-2-phenylacetonitrile (18.7 g). The reaction mixture is stirred at room temperature for 4 hours and then diluted with water (300 ml). The mixture is extracted with ether (2×150 ml) and the aqueous phase acidified with ice-cold 2N hydrochloric acid and extracted with ethyl acetate (2×250 ml). The ethyl acetate layers are combined, washed with water (150 ml) and dried over sodium sulfate. The solvent is removed under reduced pressure to give ethyl 2-t-butyloxycarbonylamino-4-(o-nitrophenyl)butyrate, used without further purification.
Reaction SMILES: O=[C:2]1[CH2:22][CH2:21][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7][CH2:6]2)[CH:4]=[CH:3]1.[ClH:23].[C:24]([NH:28][NH2:29])([CH3:27])([CH3:26])[CH3:25]>C(O)C>[ClH:23].[C:24]([NH:28]/[N:29]=[C:2]1/[CH:3]=[CH:4][C:5]2([CH2:21][CH2:22]/1)[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:7][CH2:6]2)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Product: CC(C)(C)N/N=C1/C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Temperature: 60 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
Benzyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (4.89 g, 16.3 mmol) was dissolved in ethanol (60 mL) and tert-butylhydrazine hydrochloride (2.44 g, 19.6 mmol) was added. The mixture was heated at reflux for 4 hours and then stirred at 60° C. for 48 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give a tan oil which solidified upon standing to yield 6.60 g (99%) of the title compound as a tan solid. +ESI (M+H) 370.3; 1H NMR (400 MHz, CDCl3, δ): 7.26-7.42 (m, 5 H), 6.46 (d, J=10.0 Hz, 1 H), 6.26 (br. s., 1 H), 5.08-5.16 (m, 2 H), 3.43-3.58 (m, 4 H), 3.19 (s, 2 H), 1.78 (s, 2 H), 1.44-1.63 (m, 4 H), 1.17-1.30 (m, 9 H).
Reaction SMILES: [NH2:1][CH:2]([C:8]1([S:21][CH2:22][CH2:23][OH:24])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1([S:21][CH2:22][CH2:23][OH:24])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[NH:1][S:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:25][C:26]#[C:27][CH3:28])=[CH:35][CH:34]=1)(=[O:38])=[O:37])[CH3:7]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(N)C1(SCCO)CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OCC)C2(SCCO)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl amino{1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}acetate (2.1 g, 5 mmol) and 4-but-2-ynyloxy benzenesulfonyl chloride (1.24 g, 5.1 mmol) in dichloromethane (200 ml) at 0° C., N,N-diisopropylethylamine (3.0 g, 23.6 mmol) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 4 h and quenched with water. The reaction mixture was washed with water, dried over anhydrous MgSO4, filtered and concentrated. It was purified by silica gel column chromatography eluting with 80% ethyl acetate:hexane to give ethyl{1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)acetate as a brown oil; Yield: 1.0 g (85%); Electrospray Mass Spec: 561 (M+H)+.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CC[O:19][C:20]([CH:22](P(OCC)(OCC)=O)[CH3:23])=[O:21]>>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:22]([CH3:23])[C:20]([OH:21])=[O:19])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=c1c2ccccc2ccc2ccccc12
Product: CC(C(=O)O)=C1c2ccccc2C=Cc2ccccc21

Procedure:
5H-Dibenzo[a,d]cyclohepten-5-one is reacted with triethyl 2-phosphonopropionate in a manner similar to Example 1, to yield the title compound, m.p. 235°-236° C. (uncorr.)
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[C:22]1([C:5]2[C:6]3[C:11]([C:12]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[C:13]4[C:4]=2[CH:3]=[C:2]([N:39]2[C:38]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:32]5[C:40]2=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:15]=[CH:14]4)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3)c3cc(-n4c5ccccc5c5ccccc54)ccc23)cc1
Temperature: 110 °C
Yield: 93 %

Procedure:
First, 1.5 g (3.7 mmol) of 2-bromo-9,10-diphenylanthracene, which was used in Step 1 of Synthesis Example 5, 610 mg (3.7 mmol) of 9H-carbazole, and 1.5 g (16 mmol) of sodium tert-butoxide were put into a 100 mL three-neck flask, and the air in the flask was replaced with nitrogen. 20 mL of toluene and 0.10 mL of tri(tert-butyl)phosphine (10 wt % hexane solution) were added to this mixture. This mixture was degassed while being stirred under reduced pressure, and after the degassing, 58 mg (0.10 mmol) of bis(dibenzylideneacetone)palladium(0) was added. This mixture was refluxed at 110° C. for 5 hours. After the reflux, this mixture was cooled to room temperature and about 20 mL of toluene was added to this mixture. The mixture was then filtered through alumina, Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The obtained filtrate was concentrated to give a light-brown oily substance. This oily substance was purified by silica gel column chromatography (a developing solvent was a mixed solvent of hexane:toluene=6:4). The obtained light-yellow solid substance was recrystallized from ethanol, so that 1.7 g of a light-yellow powdered solid was obtained in a yield of 93%. At a pressure of 8.7 Pa and with an argon gas flowing at a flow rate of 3.0 mL/min, 1.6 g of the obtained light-yellow powdered solid substance was heated at 230° C. so as to be sublimated and purified (a train sublimation method). After the sublimation purification, 1.5 g of a light-yellow solid substance was recovered in a yield of 93%. A synthesis scheme of Step 1 is shown in (F-3) given below.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[CH2:12][CH:11]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:10]([OH:18])=[C:9]([C:19]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=4[S:21](=[O:35])(=[O:34])[N:20]=3)[C:8]2=[O:36])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[CH2:12][CH:11]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([OH:18])=[C:9]([C:19]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:31])=[O:32])=[CH:28][C:22]=4[S:21](=[O:34])(=[O:35])[N:20]=3)[C:8]2=[O:36])=[CH:4][CH:3]=1
Reactant: CC(C)=CCC1CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)CCC1CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C1O
Reaction time: 12 h
Yield: 89.4 %

Procedure:
A solution of N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-(3-methyl-but-2-enyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (60 mg, 0.107 mmol) in ethyl acetate (2 mL) was treated with 5 wt % Pd/C (10 mg). The reaction was stirred under a hydrogen environment (1 atm) for 12 h and filtered through Celite. The filtrate was concentrated in vacuo to give N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (54 mg, 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 0.78-0.83 (m, 6H), 0.95-1.12 (m, 2H), 1.31-1.45 (m, 2H), 1.64-1.73 (m, 1H), 2.50-2.55 (m, 1H), 3.06 (s, 3H), 3.18 (dd, 1H, J1=12.7 Hz, J2=4.3 Hz), 3.52 (dd, 1H, J1=12.9 Hz, J2=5.0 Hz), 4.31 (d, 1H, J=14.9 Hz), 4.93 (d, 1H, J=14.7 Hz), 6.84 (br s, 1H), 7.06 (t, 2H, J=8.6 Hz), 7.23-7.29 (m, 3H), 7.64 (dd, 1H, J1=8.7 Hz, J2=2.3 Hz), 7.68 (d, 1H, J=2.3 Hz). LC-MS (ESI) calculated for C25H29FN4O6S2: 564.7, found 565.5 [M+H+].
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.N1C=CC=CC=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.[Cl-].[NH4+]>ClCCl>[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]2)=[O:28])=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)O[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of t-butyl trans-4-hydroxycyclohexyl-carbamate (1.00 g) and pyridine (773 mg) in dichloromethane (40 ml) under ice-cooling was added a solution of 4-methylbenzoylchloride (754 mg) in dichloromethane (10 ml) over 10 minutes. The mixture was stirred overnight at room temperature, and then saturated aqueous ammonium chloride was added thereto. The mixture was extracted with chloroform, and the organic layer was washed with brine, dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) to give 1.30 g of t-butyl trans-[4-(4-methylphenylcarbonyloxy)cyclohexyl]-carbamate.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([C:16]4[N:20](CCC#N)[N:19]=[N:18][N:17]=4)[CH:15]=[C:10]3[N:9]=[C:8]2[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:33][C:34]1[CH:39]=[C:38]([C:40]([NH:42][CH3:43])=[O:41])[CH:37]=[CH:36][C:35]=1[C:44]1[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[CH3:43][NH:42][C:40]([C:38]1[CH:37]=[CH:36][C:35]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[C:34]([CH2:33][O:31][C:28]2[CH:29]=[CH:30][C:25]([C:8]3[N:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:11]4=[N:12][CH:13]=[C:14]([C:16]5[NH:17][N:18]=[N:19][N:20]=5)[CH:15]=[C:10]4[N:9]=3)=[CH:26][CH:27]=2)[CH:39]=1)=[O:41]
Reactant: N#CCCn1nnnc1-c1cnc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Reactant: CNC(=O)c1ccc(-c2ccc(C#N)cc2)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(-c2ccc(C#N)cc2)c(COc2ccc(-c3nc4cc(-c5nnn[nH]5)cnc4n3C3CCCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.2 %

Procedure:
Intermediate 63 (50 mg, 0.12 mmol) in dimethylformamide was reacted with 2-(bromomethyl)-4′-cyano-N-methyl-1,1′-biphenyl-4-carboxamide (63a) (40 mg, 0.12 mmol), cesium carbonate (20 mg, 0.06 mmol) and the resulting suspension stirred under a nitrogen atmosphere at rt for 3h at which point ethyl acetate (30 mL) was added. The organic phase was washed with water (2×25 mL) and brine (1×), dried (Na2SO4), and concentrated on a rotary evaporator. The resulting residue was dissolved in 10% methanolic sodium hydroxide (5 mL) and water (2 mL) was added. The resulting solution was stirred at rt under a nitrogen atmosphere for 30 minutes at which point 10% hydrochloric acid was added until pH=2. This solution was extracted with ethyl acetate, dried (Na2SO4), and concentrated on a rotary evaporator and the residue purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford the product as a white solid (6 mg, 7%). 1H NMR (CD3OD) δ 9.16 (s, 1H), 8.7 (br s, 1H), 8.15 (d, 1H, J=1.46), 7.94 (dd, 1H, J=8.06, 1.83), 7.80 (d, 2H, J=8.42), 7.71 (br m, 2H), 7.65 (d, 2H, J=8.06), 7.49 (d, 1H, J=8.06), 7.17 (d, 2H, 6.59), 5.14 (s, 1H), 4.46 (br m, 1H), 2.96 (s, 3H), 2.83 (br m, 2H), 1.96 (br m, 4H), 1.75 (br m, 1H), 1.39 (br m, 3H); ESI-MS m/e 610.24 (M+H); HPLC purity (ELSD)>95%.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:17]1[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=3)[N:18]=1)[CH2:12]2)=O)(C)(C)C.FC(F)(F)C(O)=O.N>>[N+:27]([C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:11]1[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][CH2:15][CH2:16]3)[CH2:12]1)[CH:26]=[CH:25]2)([O-:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CN(c1ccc3cc([N+](=O)[O-])ccc3n1)C2
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2nc(N3CC4CCCC(C3)N4)ccc2c1
Reaction time: 0.17 h

Procedure:
A mixture of 3-(6-nitro-quinolin-2-yl)-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (0.6 g, 1.51 mmol), prepared by method A and trifluoroacetic acid (1.7 g, 15.1 mmol) was stirred for 10 min at room-temperature. Aqueous ammonia was added and the mixture was extracted with dichloromethane. The mixture was dried and evaporated followed by stirring in diethylether and filtration. Yield 320 mg (71%).