Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)([OH:17])[CH:10]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH3:11])=[CH:5][CH:4]=1.[H-].[Na+].[C:32](Cl)(=[O:34])[CH3:33]>CN(C)C=O.O>[C:32]([O:17][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=1)([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=1)[CH:10]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[CH3:11])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CC(n1cncn1)C(O)(c1ccc(C(F)(F)F)cc1)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C(C)n1cncn1
Yield: 29.1 %

Procedure:
1,1-Bis-(4-trifluoromethylphenyl)-2-(1,2,4-1H-triazol-1-yl)propan-1-ol (0.5 g) was added carefully to a suspension of sodium hydride (60 mg, freed from dispersion in oil by washing with hexane) in dry dimethylformamide (20 cm3) under a nitrogen atmosphere. After stirring the mixture for 2 hours acetyl chloride (0.1 g) was added and after a further 2 hours the mixture was diluted with water and extracted with chloroform. The chloroform layer was separated, washed with water, dried over anhydrous magnesium sulphate, and concentrated by evaporation of the solvent under reduced pressure to yield a residual oil which was purified by hplc and which solidified on trituration with petroleum ether (boiling range 60°-80° C.) to yield 1,1-bis(4-trifluoromethylphenyl)-2-(1,2,4-1H-triazol-1-yl)propyl acetate (160 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[Li]C(C)(C)C.Cl([O-])(=O)(=O)=O.[CH2:19]1[C:26]2[CH2:25][CH2:24][CH2:23][N+:22]=2[CH2:21][CH2:20]1>CCCCC>[Br:8][C:6]1[CH:7]=[C:2]([C:26]23[CH2:25][CH2:24][CH2:23][N:22]2[CH2:21][CH2:20][CH2:19]3)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: C1CC2=[N+](C1)CCC2
Agent: [Li]C(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCCCC
Product: Brc1cncc(C23CCCN2CCC3)c1
Temperature: -95 °C
Yield: 28.4 %

Procedure:
3,5-dibromopyridine (500 mg, 2.11 mmol, Aldrich) was dissolved in Et2 O and cooled to -95° C. A solution of 2.5M t-BuLi (1.7M in pentane, 2.7 mL, 4.64 mmol) in pentane was added dropwise. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (663 mg, 3.2 mmol) was added, and the reaction mixture was allowed to stir and warm to -10° C. and stir for 2 hours. The cold bath was removed, 2N HCl was added, and the phases were separated. The aqueous phase was basified with 15% NaOH and extracted with CH2Cl2 (2×). The CH2 Cl2 fractions were combined, dried (MgSO4) and concentrated, and the residue was chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (160 mg, 28%): 1H NMR (CDCl3, 300 MHz) 67 1.57-1.71 (m, 2H), 1.79-2.04 (m, 6H), 2.62-2.73 (m, 2H), 3.11-3.20 (m, 2H), 8.04 (dd, J=2.0, 2.0 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H); MS (CI/NH3) m/z: 267/269 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9].[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:18][C:3]1[C:2]([CH3:1])=[C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:5][N:4]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccc(NC(=O)CCC(=O)O)cc2)c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of sulfisoxazole (267 mg, 1.00 mmol) in DMF (10 ml) was added succinic anhydride (1.00 g, 10.0 mmol) and 4-dimethylaminopyridine (122 mg, 1.00 mmol). The reaction mixture was stirred at 80° C. for 2 hours and then concentrated. The residue was taken up in 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The aqueous solution was acidified with dilute hydrochloric acid and organic material was extracted into ethyl acetate. The organic phase was washed with dilute hydrochloric acid, water and brine, treated with active charcoal and dried (MgSO4). The solution was filtered and concentrated to give 280 mg (76%) of white solid. The structure was verified by 1H (300 MHz) and 13C (75 MHz) NMR spectroscopy. Further characterisation was carried out using MALDI mass spectrometry (ACH matrix), giving a M+Na peak at m/z 390 and a M+K peak at m/z 406 as expected.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]([NH:12][C@H:13]([C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][C:31]([C:33]3[CH:34]=[C:35]4[C:40](=[CH:41][CH:42]=3)[CH:39]=[C:38]([C:43]3[CH:63]=[CH:62][C:46]5[NH:47][C:48]([C@@H:50]6[CH2:54][CH2:53][CH2:52][N:51]6C(OC(C)(C)C)=O)=[N:49][C:45]=5[CH:44]=3)[CH:37]=[CH:36]4)=[CH:32][C:26]=2[N:25]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11]>C(Cl)Cl>[CH3:15][CH:14]([CH3:16])[C@H:13]([NH:12][C:10](=[O:11])[O:9][CH3:8])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[C:24]1[NH:28][C:27]2[CH:29]=[CH:30][C:31]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[C:38]([C:43]5[CH:63]=[CH:62][C:46]6[NH:47][C:48]([C@@H:50]7[CH2:54][CH2:53][CH2:52][NH:51]7)=[N:49][C:45]=6[CH:44]=5)[CH:39]=4)[CH:34]=3)=[CH:32][C:26]=2[N:25]=1)=[O:18]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ccc4cc(-c5ccc6[nH]c([C@@H]7CCCN7C(=O)OC(C)(C)C)nc6c5)ccc4c3)ccc2[nH]1)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2cc(-c3ccc4cc(-c5ccc6[nH]c([C@@H]7CCCN7)nc6c5)ccc4c3)ccc2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of a TFA salt of tert-butyl (2S)-2-(5-(6-(2-((2S)-1-(N-(methoxycarbonyl)-L-valyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinecarboxylate (445 mg) in DCM (10 mL) at room temp was added TFA (1 mL, 13 mmol). The mixture was stirred at rt for 3 h, concentrated, and the residue was diluted in MeOH, loaded onto a Strata XC MCX cartridge and washed with methanol. The compound was release from the cartridge by eluting with a solution of 2M ammonia in methanol and then evaporated under reduced pressure to give methyl ((1S)-2-methyl-1-(((2S)-2-(5-(6-(2-((2S)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-2-naphthyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate (275 mg) as orange solid LC-MS retention time 1.120 min; m/z 656.27 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min and an analysis time of 4 min where Solvent A was 10% acetonitrile/90% water/0.1% TFA and Solvent B was 90% acetonitrile/10% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.26 (br s, 1H), 8.22 (br s, 1H), 8.08-8.16 (m, 3H), 8.04-8.08 (m, 1H), 8.03 (s, 1H), 7.86-7.96 (m, 3H), 7.73-7.82 (m, 2H), 5.88-5.93 (m, 0.1H), 5.37-5.44 (m, 0.9H), 5.07-5.15 (m, 1H), 4.28-4.33 (m, 1H), 4.12-4.19 (m, 0.8H), 4.06-4.10 (m, 0.2H), 3.94-4.02 (m, 1H), 3.59-3.75 (m, 4H), 3.50-3.59 (m, 1H), 2.63-2.74 (m, 2H), 2.41-2.47 (m, 1H), 2.23-2.40 (m, 5H), 2.06-2.16 (m, 1H), 1.00-1.04 (m, 0.4H), 0.94-1.00 (m, 3H), 0.88-0.93 (m, 2.6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[N:7]=1)[CH3:2].Cl[C:15]1N=C(C)C(C)=CC=1.[Li+].CC([N-]C(C)C)C.C(=O)(OCC)OCC>C1COCC1>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:11]([CH3:15])=[CH:10][CH:9]=[C:8]([Cl:12])[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Cl)n1
Reactant: Cc1ccc(Cl)nc1C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(=O)OCC
Product: CCOC(=O)Cc1nc(Cl)ccc1C

Procedure:
Following the same procedure described for the preparation of ethyl(6-chloro-2-pyridinyl)acetate (Example 469) and starting from 6-chloro-2,3dimethylpyridine (0.35 g, 2.5 mmol), LDA (5.17 mmol), and diethyl carbonate (0.75 mL, 6.2 mmol) in THF (10 mL), the title compound was obtained (0.15 g, 29%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.42 (d, 1H), 7.15 (d, 1H), 4.18 (q, 2H), 3.84 (s, 2H), 2.29 (s, 3H), 1.27 (t, 3H); LC-MS: RT=2.30 min, (M+H)+ 214.2.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][N:23]([CH3:39])[C:24]1[N:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:27]3[CH:28]=[N:29][C:24]([N:23]([CH3:22])[CH3:39])=[N:25][CH:26]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: CN(C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3cnc(N(C)C)nc3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester (129 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)cyclopent-1-enyl)-N,N-dimethylpyrimidin-2-amine. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.8 (d, 2H), 7.3 (s, 1H), 6.98-7.1 (m, 2H), 4.7 (m, 1H), 4.38 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 2.78-3.1 (m, 15H), 2.4 (s, 3H), 2.2 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:5]([CH:45]=1)=[CH:6][C:7]1[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]3[C:14]([C:15]=1[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3.C([Li])CCC.C(N)(C)(C)C.[C:56]([NH:60][Si:61](C1C2C(=CC3C(CCCCCCCCCCCCCC)(CCCCCCCCCCCCCC)C4C(C=3C=2)=CC=CC=4)C=C1C)([CH3:63])[CH3:62])([CH3:59])([CH3:58])[CH3:57]>C(OCC)C>[C:56]([NH:60][Si:61]([CH:45]1[C:5]2=[CH:6][C:7]3[C:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9]4[C:14]([C:15]=3[CH:16]=[C:4]2[CH:3]=[C:2]1[CH3:1])=[CH:13][CH:12]=[CH:11][CH:10]=4)([CH3:63])[CH3:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3[Si](C)(C)NC(C)(C)C
Reactant: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C=C(C)C3
Agent: [Li]CCCC
Solvent: CC(C)(C)N
Solvent: CCOCC
Product: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2cc3c(cc21)C([Si](C)(C)NC(C)(C)C)C(C)=C3
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.7 %

Procedure:
In a 250 mL round flask, 2-methyl-9,9-ditetradecyl-3,9-dihydrocyclopenta[b]fluorene (4.9 g, 8.0 mmol) was dissolved in 100 mL of anhydrous diethyl ether, and then the temperature was lowered to −78° C. Then, n-butyllithium (1.6M hexane solution, 5.5 mL) was slowly injected thereto, followed by stirring at room temperature for 12 hours. After volatile materials were removed by vacuum, 100 mL of n-hexane was added to the mixture to lower the reactor temperature to −78° C., followed by addition of dichlorodimethylsilane (2.9 g). The temperature was again raised to room temperature, followed by stirring for 24 hours, and then salts were removed through filtering. Then, volatile materials were removed by vacuum. The product was again inputted to a 250 mL round flask, and dissolved in 100 mL of diethyl ether. The temperature was lowered to −78° C., and tert-butylamine (1.8 g, 24.1 mmol) was added thereto. The temperature was raised to room temperature, followed by stirring for 12 hours, and then volatile materials were completely removed by vacuum. Then, 200 mL of n-hexane was added to dissolve the resultant material, and salts were removed through filtering. The solvent was removed, to thereby obtain 5.5 g of a mixture of N-tert-butyl-1-(9,9-ditetradecyl-2-methyl-3,9-dihydrocyclopenta[b]fluoren-3-yl)-1,1-dimethylsilanamine and N-tert-butyl-1-(9,9-ditetradecyl-2-methyl-1,9-dihydrocyclopenta[b]fluoren-1-yl)-1,1-dimethylsilanamine (ratio=˜1:1), (yield: 92.7%), as high viscous material.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH3:4].[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH3:14])=[N:12][CH:13]=1)#[N:7]>S1(CCCC1)(=O)=O.CCOC(C)=O>[CH3:4][C:3]1[CH:14]=[C:11]2[N:12]([CH:2]=1)[CH:13]=[C:8]([C:6]#[N:7])[CH:9]=[CH:10]2
Reactant: Cc1ccc(C#N)cn1
Reactant: CC(=O)CBr
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Product: Cc1cc2ccc(C#N)cn2c1
Temperature: 45 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
1-Bromo-propan-2-one (2.26 ml) is added under an atmosphere of argon to a solution of 5-cyano-2-methylpyridine (5.0 g, 41.9 mmol) in sulfolane (30 ml). The reaction mixture is stirred for 48 hours at 45° C., then diluted with EtOAc. The precipitated salt is filtered off and dissolved in water (50 ml). The aqueous solution is washed with EtOAc, then a 10% aqueous solution of NaHCO3 (30 ml) is added, and the mixture is heated to reflux for 1 hour. After cooling, the reaction mixture is filtered, and the filtrate is extracted three times with EtOAc. The combined organic layers are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified via flash chromatography (hexane/EtOAc 8:1, +0.2% NEt3) to afford the title compound (5.50 g, 84%). 1H NMR (400 MHz, d6-DMSO): δ=9.10-9.09 (m, 1H), 7.59 (s, 1H), 7.55 (d, J=9.0 Hz, 1H), 6.90 (dd, J=9.3/1.7 Hz, 1H), 6.55 (s, 1H), 2.39 (s, 3H). MS (ES+): 157 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH3:10].[H-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C=O)C>[CH3:1][N:2]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][C:4]=1[CH3:10]
Reactant: CNc1ccc(Br)cc1C
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(C)c2ccc(Br)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.7 g (13.57 mmol) of N-methyl-4-bromo-2-methylaniline in 20 ml of DMF at room temperature was added 608 mg (15.2 mmol) of NaH and the mixture was stirred at room temperature for 0.5 h. After this time, 2.05 ml (15.1 mmol) of 4-methoxybenzyl chloride was added and the reaction mixture was heated to 60° C. for 12 hours. After this time, the reaction mixture was allowed to cool to room temperature and was quenched by the addition of a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:EtOAc, 20:1) to give the title compound. 1H-NMR (CDCl3) δ 2.41 (s, 3H), 2.58 (s, 3H), 3.84 (s, 3H), 3.98 (s, 2H), 6.89–6.94 (m, 3H), 7.29–7.36 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2.Cl.O.[C:28](OCC)(=O)C>CO>[CH3:28][O:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7]2
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(O)c2[nH]1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(OC)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Methyl 7-hydroxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.1 g) was dissolved in a mixture of ethyl acetate (20 mL) and methanol (5 mL). The mixture was cooled to 0° C., and 2M trimethylsilyldiazomethane diethyl ether solution (2 mL) was added dropwise to the mixture. The mixture was stirred at 0° C. for 30 min, and then 2M trimethylsilyldiazomethane diethyl ether solution (0.5 mL) was added dropwise to the mixture again. After stirring at 0° C. for 30 min, 1M hydrochloric acid (1 mL) was added to the mixture to quench the reaction. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual oil was solidified with diethyl ether to give the title compound (0.99 g, 88%) as a pale orange solid. MS 377 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][C:20]3([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: BrCC1(c2ccccc2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC2(c3ccccc3)OCCO2)CCN(C)C1
Temperature: 100 °C

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) was dissolved in 20 mL of DMF. The resulting solution was cooled in an ice-water bath and sodium hydride (840 mg, 4.2 mmol) was added under nitrogen atmosphere. 2-Bromomethyl-2-phenyl[1,3]dioxolane (2.43 g, 10 mmol) was added and the reaction mixture was heated at 100° C. overnight. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH:DCM.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:10])[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4]1.CN(C)C=O.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:21][CH:22]=1>O1CCCC1>[F:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:9][CH:5]3[CH2:6][CH2:7][CH2:8][CH:3]([OH:10])[CH2:4]3)[N:19]=2)=[CH:28][CH:27]=1
Reactant: OC1CCCC(O)C1
Reactant: Fc1ccc(-c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OC1CCCC(OCc2coc(-c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
With ice-cooling, initially 2.25 g of an 80 percent suspension of sodium hydride and then 5.8 g of 1,3-cyclohexanediol were added to a mixture of 50 ml of dimethylformamide and 50 ml of tetrahydrofuran. The mixture was stirred at about 25° C. for 3 hours. 10.5 g of 4-chloromethyl-2-(4-fluorophenyl)oxazole (1) was then added, the mixture was heated at 70° C. and the reaction was monitored by thin-layer chromatography. After the reaction ended, the mixture was poured into ice-water and extracted with ethyl acetate. The organic phase was separated off, dried and concentrated and the residue was purified on silica gel by flash chromatography (ethyl acetate/n-heptane=1:1). This gave the alcohol 3 as an oil. C16H18FNO3 (291.33) MS(ESI): 292 (M+H+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])(=O)=O>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@H:10]([O:14][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCCCCCCCC/C=C\CCCCCOS(C)(=O)=O
Product: CCCCCCCCCCC/C=C\CCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCC/C=C\CCCCCCCCCCC

Procedure:
Compound VI-7 (196 mg, 40.7%) was obtained in the same manner as that in Reference Example 1, by using (3R,4R)-1-benzylpyrrolidine-3,4-diol (Diverchim S. A.; 134 mg, 0.693 mmol) and (Z)-octadec-6-enyl methanesulfonate (Nu-Chek Prep, Inc; 600 mg, 1.73 mmol).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:28])[CH:12]([NH:13][C:14](=[O:27])[C:15](=[N:24][O:25][CH3:26])[C:16]3[N:17]=[C:18]([NH:21]C=O)[S:19][CH:20]=3)[C@H:4]2[S:3]1.[ClH:29].C(OCC)C>CO>[ClH:29].[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:28])[CH:12]([NH:13][C:14](=[O:27])[C:15](=[N:24][O:25][CH3:26])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Agent: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(=NC=O)[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methyl-7-[2-methoxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (9.0 g.) in methanol (90 ml.) was added concentrated hydrochloric acid (2.12 ml.) with stirring at room temperature, and the mixture was stirred for 7 hours at the same temperature. To the reaction mixture was gradually added diethyl ether till crystals started to precipitate. The mixture was allowed to stand for 30 minutes, and the precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give white crystals of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer), (7.9 g.) The remaining filtrate was concentrated till the total volume became half. To the concentrated filtrate was gradually added diethyl ether till crystals started to precipitate, and the mixture was allowed to stand for 1 hour. The precipitated crystals were collected by filtration, washed with diethyl ether and then dried to give further the same object compound (0.5 g.).