Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C@@:25]3([OH:37])[CH2:30][CH2:29][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[C:27]([CH3:36])([CH3:35])[CH2:26]3)=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1.[O-:38][C:39]#[N:40].[K+].C(O)(=O)C.O>C1COCC1>[C:39]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C@@:25]3([OH:37])[CH2:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[C:27]([CH3:35])([CH3:36])[CH2:26]3)=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][N:11]=2)[CH:8]=1)(=[O:38])[NH2:40].[C:39]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C@@:25]3([OH:37])[CH2:30][CH2:29][C@H:28]([C:31]([O:33][CH3:34])=[O:32])[C:27]([CH3:35])([CH3:36])[CH2:26]3)=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1)(=[O:38])[NH2:40]
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C[C@@](O)(c2ncc(-c3cc(CNC(N)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC[C@@H]1C(=O)O
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CNC(N)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 50 °C
Reaction time: 14 h
Yield: 184.4 %

Procedure:
To a solution of methyl(1S,4R)-4-{5-[3-(aminomethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (40 mg, 0.075 mmol) in anhydrous THF (1.5 ml) was added potassium cyanate (12.12 mg, 0.149 mmol, 2.0 equiv), acetic acid (8.55 μl, 0.149 mmol, 2.0 equiv), and water (4.5 ml). The mixture was stirred at 50° C. for 14 h. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (40 ml). The organic layer were dried over Na2SO4, filtered and concentrated to provide the desired product, methyl (1S,4R)-4-[5-(3-[(carbarnoylamino)methyl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (40 mg, 88%), as an orange oil. MS ESI: [M+H]+ m/z 579.2. 1H NMR (500 MHz, DMSO) δ 10.3 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 8.03 (bs, 1H), 7.88 (s, 1H), 7.50 (s, 1H), 7.28 (d, 1H, J=4.9 Hz), 7.17 (s, 1H), 6.46 (m, 1H), 5.55 (s, 2H), 4.16 (m, 2H), 3.59 (s, 3H), 2.31 (m, 1H), 1.87-1.84 (m, 4H), 1.75-1.73 (m, 2H), 1.17 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].CCCCCC.C(OCC)(=O)C>C(#N)C>[C:13]([NH:17][CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Reactant: CC(C)(C)N
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Crude 2-bromo-1-(3-chlorophenyl)propan-1-one (2) (152 g, 0.65 mol) was dissolved in 600 ml of acetonitrile (HPLC grade) in a 3-necked 2 L round bottomed flask fitted with a condenser and a dropping funnel. Tert-butylamine (172.5 ml, 1.63 mol) was added drop wise to the resulting mixture, at room temperature and under nitrogen. The reaction mixture was then heated to reflux for approximately 5 hours. During this time the reaction progress was monitored by TLC analysis (silica, hexane: ethyl acetate, 90:10). On consumption of the starting material, the reaction mixture was cooled to room temperature, filtered through celite and the celite washed with approximately 250 ml of ethyl acetate. The filtrate was washed with a 2M solution of KOH (350 ml). The layers were separated and the organic phase was dried over sodium sulphate anhydrous, filtered and concentrated to dryness to give a pale orange oil (147 g, quantitative yield), which did not need any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.O.[NH2:36][NH2:37]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[C:11]([CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:36][NH2:37])=[O:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(Cc1nc(-c2cccc(Cl)c2)no1)C(=O)O
Reactant: NN
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Cc1nc(-c2cccc(Cl)c2)no1)C(=O)NN
Reaction time: 1 h
Yield: 81.8 %

Procedure:
3,3-Dimethyl-dihydro-furan-2,5-dione (6.4 g) was heated at 50° C. in ethanol (150 mL) overnight. The solvent was removed in vacuo and the residue triturated with hexane to yield 2,2-Dimethyl-succinic acid 4-ethyl ester (4.66 g) which was used without further purification. t-Butanol (7.5 mL) was added to a mixture of 2,2-Dimethyl-succinic acid 4-ethyl ester (2.74 g, 15.7 mmol) in dichloromethane (62 mL) containing magnesium sulfate (7.5 g) and conc. sulfuric acid (0.85 mL) and the mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added and the product was extracted into dichloromethane, washed with brine solution, dried and concentrated to yield the diested as a colorloess oil (1.89 g). The ethyl ester was hydrolyzed by trating the crude sample with potassium hydroxide (2.75 g) in a mixture of ethanol (50 mL) and water (25 mL) at room temperatire for 2 h. The reaction was acidified using 1N HCl (aq) and extracted into ether, dried and concentrated to yield 2,2-Dimethyl-succinic acid 1-tert-butyl ester (1.4 g). This acid was treated under the conditions of Example 320 (step 1) to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid tert-butyl ester (1.9 g). This t-Bu ester was deprotected using formic acid (19 mL) at 50° C. for 20 min. The crude product was concentrated and triturated with a mixture of ether and hexane to yield 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid (1.12 g). To a solution of 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionic acid (561 mg, 2 mmol) and triethylamine (1.1 mL, 8 mmol) in THF (9 ml), isobutyl chloroformate (0.31 mL, 2.4 mmol) was added dropwise at −78 ° C. After being stirred for 1 h, hydrazine hydrate (1 mL, 11 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and concentrated. A small amount of ice was added to quence any excess reagent and precipitate the product, which was collected by filtration to give 482 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])S(CCC)(=O)=O)[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[F:35][C:15]1[C:14]([C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:11]3)=[O:13])=[C:19]([F:20])[C:18]([F:21])=[CH:17][C:16]=1[NH:22][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30]
Reactant: OB(O)c1ccccc1
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(-c4ccccc4)nc3c2)c1F
Temperature: 80 °C

Procedure:
A mixture of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 0.1 mmol, 1.0 eq.), phenylboronic acid (13.5 mg, 0.011 mol, 1.1 eq.), Pd(dppf)2C12 (4.1 mg, 0.005 mmol, 0.05 eq.) and Na2CO3 (0.21 g, 0.2 mmol, 2.0 eq.) in dioxane and water (9 mL/1 mL) were heated at 80° C. for 4 h under N2 protection, then cooled and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(2,4,5-trifluoro-3-(3-phenylquinoxaline-6-carbonyl)phenyl)propane-1-sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 10.15 (brs, 1 H), 9.78 (s, 1 H), 8.62 (s, 1 H), 8.38 (m, 2 H), 8.32 (brs, 2 H), 7.79 (m, 1 H), 7.62 (brs, 3 H), 3.22 (t, 2 H), 1.74 (m, 2 H), 0.97 (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[C:7]([CH:18]=[O:19])=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.[CH3:38][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[C:7]([CH:18]([OH:19])[CH3:38])=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:21]1
Reactant: C[Mg]Br
Reactant: Cn1c(=O)c2c(c(C=O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12

Procedure:
A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (132 mg) in tetrahydrofuran (4 ml) was cooled to 0° C., followed by adding thereto methylmagnesium bromide (417 μl), and the resulting mixture was stirred at 0° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (167 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2.[C-]#N.[K+].[Cu][C:24]#[N:25]>CO>[C:24]([C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=[C:10]2[C:15]=1[CH:14]=[C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=[CH:11]2)#[N:25]
Reactant: Clc1c2ccccc2nc2cc3ccccc3cc12
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: N#Cc1c2ccccc2nc2cc3ccccc3cc12
Temperature: 160 °C
Reaction time: 4.5 h
Yield: 136.7 %

Procedure:
A mixture of -12-chloro-benz[b]acridine (2.3 g, 8.68 mmol), potassium cyanide (620 mg, 9.55 mmol) and copper(I) cyanide (391 mg, 4.43 mmol) in anhydrous methanol (16 ml) was bubbled with nitrogen for 1 minute and then kept in a sealed tube. The mixture was heated at 160° C. with stirring for 4.5 hours and cooled. The red-brown mixture was evaporated and the residue was flash-chromatographed (W.C. still et al: J. Org. Chem., 43, 2923, (1978)) on a silica column (Baker silica gel, Cat# 7024-1) packed with hexane and eluted with 10% ethyl acetate-hexane, yielding red 12-cyano-benz[b]acridine (1.54 g, 70%). Rf 0.7 (silica gel, hexane/ethyl acetate 2:1). MS (FAB, Thioglycerol Matrix): m/z 255 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C(Cl)=O.[CH:26]1[C:31]([NH2:32])=[CH:30][CH:29]=[C:28]([S:33]([NH:36][C:37]2[S:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])[CH:27]=1.N1C=CC=CC=1>C(Cl)Cl>[S:41]1[CH:40]=[CH:39][N:38]=[C:37]1[NH:36][S:33]([C:28]1[CH:27]=[CH:26][C:31]([NH:32][C:15](=[O:17])[CH2:14][O:13][C:8]2[C:7]3[C:12](=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=[CH:5][CH:6]=3)[N:11]=[CH:10][CH:9]=2)=[CH:30][CH:29]=1)(=[O:35])=[O:34]
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C(O)COc1ccnc2c(C(F)(F)F)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(COc1ccnc2c(C(F)(F)F)cccc12)Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
(8-Trifluoromethylquinolin-4-yloxy)-acetic acid (0.50 g, 1.84 mmol) was suspended in 20 mL DCM with rapid stirring. At rt, oxalyl chloride (0.19 mL, 1.2 equiv) was added dropwise and stirring continued for 4 h. Solvent and excess oxalyl chloride were removed in vacuo, the white residue was re-suspended in DCM, and the mixture cooled to 0° C. N′-(2-thiazolyl)sulfanilamide (0.47 g, 1.0 equiv) was added followed by pyridine (0.30 mL, 2.0 equiv). The mixture was allowed to warm to rt overnight. The solid was collected and rinsed with fresh DCM. Further purification was effected by suspending the solid in 20 mL methanol, stirring vigorously for 4 h, and filtration. After drying under vacuum, white solid 0.65 g (69%) was obtained. 1H-NMR (DMSO-d6) 5.11 (s, 2H), 6.79 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 7.22 (d, J=4.8 Hz, 1H), 7.71 (t, J=8.0 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.85 (d, J=5.2 Hz, 1H),; 13C-NMR (DMSO-d6) 68.0, 103.6, 108.8, 120.0, 122.0, 124.8 (q, J=270 Hz), 125.1, 125.4, 126.4 (q, J=33 Hz), 127.7, 127.8, 129.2, 137.7, 142.1, 145.6, 153.2, 161.2, 166.5, 169.4 LC/MS (10-99%) M/Z: M+1 obs=509.5; tR=3.13 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:34][C:35]1[N:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][CH:36]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:34][C:35]3[N:40]=[C:39]([C:41]#[N:42])[CH:38]=[CH:37][CH:36]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: N#Cc1cccc(CBr)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3ncccc3c2=O)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C#N)n3)c3ncccc3c2=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,8]naphthyridin-4-one in THF 2 ml, was added KHMDS in THF 0.4 ml (0.2 mmol ) slowly. The reaction mixture was stirred at room temperature for 60 min, followed by the addition of 40 mg (0.2 mmol) of 6-Bromomethyl-pyridine-2-carbonitrile. The mixture was heated to 60° C. for 60 min, then quenched with water and purified with HPLC to give the desired product (15 mg). LCMS (M+H)+: 411.1.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([OH:12])=O)[N:8]=1)=[O:2].P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.Cl.[NH2:39][CH:40]1[C:61](=[O:62])[N:42]2[C:43]([C:48]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=3)=[O:49])=[C:44]([Cl:47])[CH2:45][S:46][C@H:41]12>C(OCC)(=O)C.CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:10]([NH:39][CH:40]2[C:61](=[O:62])[N:42]3[C:43]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])=[C:44]([Cl:47])[CH2:45][S:46][C@H:41]23)=[O:12])[N:8]=1)=[O:2]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 89.6 %

Procedure:
2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 2 g.), N,N-dimethylformamide (0.45 g.), phosphoryl chloride (1.03 g.), trimethylsilylacetamide (5.9 g.), 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (2.3 g.) and ethyl acetate (60 ml.) were treated in a similar manner to that of Example 11-(1) to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 3.55 g.)
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.[NH2:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29]>C1COCC1>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:26][CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCC(N)CC
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Solvent: C1CCOC1
Product: CCC(CC)Nc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)OC)c2O)c(=O)c1=O
Temperature: 50 °C

Procedure:
To a stirred solution of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (1 g, 2.56 mmol) in THF (20 ml) was added 3-aminopentane (0.596 ml, 5.12 mmol). The reaction mixture was heated at 50° C. overnight. The reaction mixture was concentrated in vacuo and dissolved in EtOAc. The EtOAc solution was washed with 1M HCl (aq) and brine. The EtOAc solution was dried (MgSO4) and concentrated in vacuo. The residue was crystallized from toluene to give a solid; [M+H]+ 432.1. 1H NMR (DMSO) 0.9 (6H, t, 2×CH3), 1.5 (2H, m), 1.6 (2H, m), 3.0 (3H, s, CH3), 3.6 (3H, s, CH3), 3.9 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H, d), 9.4 (1H, s), 10.1 (1H, s).
Reaction SMILES: CN.[CH2:3]([N:5]([CH2:26][CH3:27])[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH3:4].[C:28](O)(=O)/C=C/C(O)=O>C(O)C>[CH2:26]([N:5]([CH2:3][CH3:4])[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23](=[S:25])[NH:24][CH3:28])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])[CH3:27]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: CN
Solvent: CCO
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=S)NC)cc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
A mixture of a 33% strength solution (10 cc) of methylamine in absolute ethanol and 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (2 g) in absolute ethanol (15 cc) is brought for 24 hours to a temperature in the region of 100° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (100° C.), washed with distilled water (2×50 cc), dried over magnesium sulphate in the presence of charcoal 3S, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil (1.7 g) is purified by chromatography on a column (height: 25 cm; diameter: 2.5 cm) of silica gel (0.04-0.063 mm) with a slight excess pressure of nitrogen (40 kPa), eluting successively with ethyl acetate (750 cc) and with a mixture (90:10 by volume) (500 cc) cf ethyl acetate and ethanol and collecting 50-cc fractions. Fractions 2 to 7 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual brown oil (1.3 g) is dissolved at 50° C. in ethanol (3 cc) and the solution obtained is poured into a solution of fumaric acid (0.39 g) in ethanol (3 cc), with stirring and at a temperature in the region of 60° C. After 1 hour with stirring at a temperature in the region of 5° C., the solid formed is drained, washed with ethanol (3×1 cc) and dried in the air. This solid is redissolved in ethanol (20 cc) under reflux and then stored for 1 hour at a temperature in the region of 5° C. The solid formed is drained, washed with ethanol (3×1 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-[(2RS)-1-diethylamino-2-propyl]-N-methyl-2-phenothiazinecarbothioamide acid fumarate (1.15 g) is thereby obtained in the form of a yellow solid, m.p. 224° C.;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][CH2:29][CH2:30][CH2:31][OH:32]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH3:19])[C:16](=[O:20])[C:8]4[CH:9]=[C:10]([O:15][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: OCCCCCl
Reactant: Cc1cn2c3ccc(Br)cc3c3cc(O)cc(c1=O)c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn2c3ccc(Br)cc3c3cc(OCCCCO)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
10-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 49 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 4-chloro-1-butanol (0.09 ml) was added to the mixture. The mixture was stirred at 80° C. in a hot water bath for 14 hours, and the reaction mixture was poured into ice water (500 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methylene chloride containing 4% methanol) to obtain the title compound (80 mg, 26%).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([O:16][C:17](=[O:19])[CH3:18])[CH2:13][CH:12]1[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[NH:23][C:22]=1[C:31]1[NH:32][C:33]2[C:38]([C:39]=1[CH2:40][CH:41]1[CH2:45][CH:44]([O:46][C:47](=[O:49])[CH3:48])[CH2:43][N:42]1C(OCC1C=CC=CC=1)=O)=[CH:37][CH:36]=[C:35]([F:60])[CH:34]=2)=O)C1C=CC=CC=1>[Pd].CCOC(C)=O.CO>[C:17]([O:16][CH:14]1[CH2:15][NH:11][CH:12]([CH2:20][C:21]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[NH:23][C:22]=2[C:31]2[NH:32][C:33]3[C:38]([C:39]=2[CH2:40][CH:41]2[NH:42][CH2:43][CH:44]([O:46][C:47](=[O:49])[CH3:48])[CH2:45]2)=[CH:37][CH:36]=[C:35]([F:60])[CH:34]=3)[CH2:13]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC1CC(Cc2c(-c3[nH]c4cc(F)ccc4c3CC3CC(OC(C)=O)CN3C(=O)OCc3ccccc3)[nH]c3cc(F)ccc23)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OC1CNC(Cc2c(-c3[nH]c4cc(F)ccc4c3CC3CC(OC(C)=O)CN3)[nH]c3cc(F)ccc23)C1
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A suspension containing 9 (35 g, 42.7 mmol) in 1:1 EtOAc/MeOH (400 mL) was distributed into two 500 mL Parr bottles (ca. 200 mL/each), and charged with 10% Pd-on-C (wet, 5000 mg/each, Aldrich®). The reaction mixture was pressurized to 50 PSI H2 and shaken for 3 h. The reaction mixture was filtered through a pad of Celite® and the solids were washed with EtOAc. The clarified filtrate was concentrated in vacuo to afford 24 g of 10 as an off-white solid which was used directly in the next reaction. 1H NMR (300 MHz, CDCl3): δ13.10 (br s, 2H) 7.45 (dd, J=5.2, 8.9 Hz, 2H), 7.03 (dd, J=2.3, 9.8 Hz, 2H), 6.85 (m, 2H), 5.35 (m, 2H), 3.71 (m, 2H), 3.18-3.35 (m, 4H), 2.90-3.14 (m, 4H), 2.56 (m, 2H), 2.00-2.10 (m, 2H), 2.04 (s, 6H), 1.80-1.92 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3): δ171.3, 161.7, 158.6, 136.1, 135.9, 130.5, 130.4, 125.4, 119.1, 118.9, 109.6, 108.0, 107.6, 97.6, 97.5, 75.1, 57.7, 51.6, 38.7, 32.8, 21.6 ppm. Mass spectrum (ESI), m/z 550.9 [(M)+; calcd for C30H32F2N4O4: 550.6].