Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](O)=O.[NH2:11][NH:12][C:13]([NH2:15])=[S:14].O1CCOCC1.O=P(Cl)(Cl)Cl>C(Cl)Cl.O>[NH2:15][C:13]1[S:14][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[N:11][N:12]=1
Reactant: O=C(O)CCCCCCBr
Reactant: NNC(N)=S
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(CCCCCCBr)s1
Temperature: 90 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
5 g of 7-bromoheptanoic acid and 2.17 g of thiosemicarbazide were introduced into 50 ml of dioxane at 90° C. and, at this temperature, 4.0 g of POCl3 were added dropwise. The mixture was then stirred at 90° C. for 1 hour. Then water was added to the mixture, and extraction 3 times with methylene chloride, drying over MgSO4 and concentration were carried out. 6.1 g (=96% yield) of product were obtained as residue.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:35][C:36](=[O:50])[C:37]3[N:42]([CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[N:41]=[C:40]([CH3:49])[C:38]=3[N:39]=2)=[C:30]([O:51][CH3:52])[CH:29]=1>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:43]1([N:42]2[C:37]3[C:36](=[O:50])[NH:35][C:34]([C:31]4[CH:32]=[CH:33][C:28]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:29][C:30]=4[O:51][CH3:52])=[N:39][C:38]=3[C:40]([CH3:49])=[N:41]2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CN1CCNCC1
Reactant: COc1cc(Br)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(N2CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 110 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
In a stream of argon, 166 μl (1.50 mmol) of N-methylpiperazine, 72 mg (0.75 mmol) of sodium tert-butoxide, 166 mg (0.01 mmol) of tri-tert-butylphosphine, and 1.6 mg (0.008 mmol) of palladium(II) acetate were added to a 2 ml toluene solution of 209 mg (0.50 mmol) of the compound obtained in Example 15, and the mixture was stirred at 110° C. for 2 hours. Further, 166 mg (0.01 mmol) of tri-tert-butylphosphine and 1.6 mg (0.008 mmol) of palladium(II) acetate were added, and the mixture was stirred at 110° C. for 8 hours. Then, the reaction mixture was brought to room temperature, diluted with water, and then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to obtain 82 mg (38%) of the captioned compound.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>ClCCl.C(OCC)(=O)C>[CH2:1]([C:3]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:17][CH2:18][C:19](=[O:22])[CH2:20][CH2:21]3)=[CH:13][CH:14]=2)[C:7](=[O:23])[C:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:41][C:40](=[O:42])[O:39][N:38]=3)=[CH:27][CH:26]=2)=[C:5]([CH2:43][CH2:44][CH3:45])[N:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
2-Ethyl-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.4 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.42 g) were dissolved in dichloromethane (4 mL) and the mixture was stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.32 g, 80%) as a colorless amorphous solid.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]1[O:12][C:11]([SiH:13]([CH3:15])[CH3:14])=[CH:10][C@@H:9]([OH:16])[C@@H:8]1[OH:17])([CH3:4])([CH3:3])[CH3:2].[C:18](OC=C)(=[O:20])[CH3:19]>>[C:18]([O:16][C@H:9]1[C@H:8]([OH:17])[C@@H:7]([CH2:6][O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[O:12][C:11]([SiH:13]([CH3:14])[CH3:15])=[CH:10]1)(=[O:20])[CH3:19]
Reactant: C=COC(C)=O
Reactant: C[SiH](C)C1=C[C@@H](O)[C@H](O)[C@@H](COC(C)(C)C)O1
Product: CC(=O)O[C@@H]1C=C([SiH](C)C)O[C@H](COC(C)(C)C)[C@H]1O
Reaction time: 3.5 h
Yield: 85 %

Procedure:
1.0 g (4 mmol) of 6-O-tert.butyldimethylsilyl-glucal in 5-10 ml of vinyl acetate is stirred with 1.0 g of lipase from Pseudomonas spec. at room temperature for 3-4 hours. Filtration, concentration and chromatography (SiO2, ether/hexane 1:3) yields the desired 3-O-acetyl-6-O-tert.-butyldimethylsilyl-glucal in approximately 85% yield (0.98-1.0 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]2[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]([OH:12])[CH2:13][N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1cn(C[C@@H]2CO2)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 50.5 %

Procedure:
A mixture of (R)-2-chloro-1-(oxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 9 (1 g, 4.91 mmol), tert-butyl piperazine-1-carboxylate (1.01 g, 5.40 mmol) and DMF (3 ml) was stirred at 70° C. for 6 hours. The reaction mixture was allowed to return to room temperature and added water (7 ml). The precipitates were filtered off, and purified by silica gel column chromatography (methylene chloride/methanol=40/1) to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxypropyl]piperazine-1-carboxylate (967 mg, 51%) as a light yellow powder.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[CH:6][N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1)[OH:3]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:22]1([C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:7]2[CH:8]=[C:4]([C:2](=[O:3])[CH3:1])[N:5]=[CH:6]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 50 °C
Yield: 57.8 %

Procedure:
A mixture of 221.3 g (2.544 moles) of manganese dioxide and 56.9 g (0.161 mole) of alpha-methyl-1-triphenylmethyl-1H-imidazole-4-methanol dissolved in 2.5 liters of chloroform is heated under reflux for 90 minutes. The solution is then cooled to about 50° C., filtered and the chloroform is eliminated by distillation. The residue is dissolved in 400 ml of isopropyl alcohol and filtered hot on Norit. The product crystallizes upon cooling. There are obtained 32.8 g of 1-(1-triphenylmethyl-1H-imidazol-4-yl)-1-ethanone. Yield: 58% of theory; M.P.: 158°-160° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]([CH3:15])[CH:9](O)[C:8]=2[CH:17]=1)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:15])=[CH:9][C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: CC1C(O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=Cc2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 104.5 %

Procedure:
A solution of 6-nitro-2,2,3-trimethyl-4-hydroxy-3,4-dihydro-2H-1-benzopyran (31.1 g, 0.131 mol) and p-toluenesulfonic acid (2.5 g, 0.013 mol) in toluene (875 ml) was refluxed for 18 hours, removing water with a Dean and Stark water separator. The cooled solution was washed with aqueous sodium bicarbonate solution and the organic phase separated. Solvent was removed under reduced pressure to give 30 g of 6-nitro-2,2,3-trimethyl-2H-1-benzopyran as an oil, 1H NMR (CDCl3): δ1.45 (s, 6H), 1.9 (s, 3H), 6.15 (s, 1H), 6.8 (d, 1H), 7.8 (s, 1H), 8.0 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN1C(=O)CCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: Fc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc2oc(-c3ccc(N4CCCCC4)cc3)nc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
A mixture containing 2.48 g (10 mmoles) of 5-chloro-2-(4-fluorophenyl)benzoxazole, 2.55 g (30 mmoles) of piperidine and 15 ml of NMP is heated with stirring under nitrogen atmosphere at 100° C. for 16 hours. The reaction is complete as judged by GC analysis. The mixture is cooled, poured into 100 ml of water and stirred for 30 minutes. The title compound (3.05 g, 97 percent yield) is filtered and washed. It has a melting point of 162° C.-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([F:30])[CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=2)[CH2:9]/[C:10](=[N:32]\[OH:33])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([F:30])[CH:3]=1
Reactant: NO
Reactant: CC(=O)Nc1cccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1cccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccc(Cl)cc2F)c1

Procedure:
In analogy to example 151, step 3, N-(3-(1-(4-chloro-2-fluorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)phenyl)acetamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI+): m/z=442.2 [M+H]+.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:5])[CH3:4].[C:6]1([C:16](Cl)=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[OH-].[Na+]>>[C:6]1([C:16]([O:5][CH:3]([CH3:4])[C:2]#[CH:1])=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: C#CC(C)O
Agent: [Na+]
Agent: [OH-]
Product: C#CC(C)OC(=O)c1cccc2ccccc12
Temperature: -10 °C

Procedure:
A suspension of 5.3 g of 1-butyn-3-ol and 5 g of 1-naphthoyl chloride is cooled to -10° C. and 3.1 ml. of 35% sodium hydroxide are slowly added dropwise. The mixture is warmed to room temperature and stirred until it is neutral. The mixture is poured into ice-water and then extracted with ether. The ether solution is washed with 10% sodium hydroxide and with water and dried. After the ether is distilled off, the residue is recrystallized from methanol to yield 1-methyl-2-propynyl 1-naphthoate, m.p. 66°-68° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[O:31]=[C:32]1[NH:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:34][O:33]1>>[C:39]([O:38][CH2:37][C@@H:35]1[CH2:34][O:33][C:32](=[O:31])[N:36]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1)(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 66.2 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (986 mg) described in Preparation Example 118 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (487 mg), the title compound (838 mg) was obtained.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(P(CCCC)CCCC)CCC.[Cl:30][C:31]1[C:39]([F:40])=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][CH2:34][N:35]2[C@@H:41]([CH2:51][CH2:52]O)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:43]>C1COCC1>[Cl:30][C:31]1[C:39]([F:40])=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][CH2:34][N:35]2[C@H:41]1[CH2:51][CH2:52][N:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42]1=[O:43]
Reactant: O=C(Nc1ccccc1)[C@H](CCO)N1CCc2c1ccc(F)c2Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1[C@@H](N2CCc3c2ccc(F)c3Cl)CCN1c1ccccc1
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
Prepared using general procedure 61: To a yellow solution of di-tert-butyl azo-dicarboxylate (2.72 g, 11.9 mmol) in THF (14 mL) at 0° C. under N2 was slowly added tributylphosphine (3.0 mL, 11.9 mmol), The resulting colorless solution of the Mitsunobu reagent was stirred at RT for 10 min, and then added to a solution of (S)-2-(4-chloro-5-fluoroindolin-1-yl)-4-hydroxy-N-phenylbutanamide (1.03 g, 7.4 mmol) in THF (14 mL) at 0° C. under N2. The reaction mixture was stirred for 10 min. at this temperature, and quenched by addition of a saturated aqueous NaHCO3 solution. EtOAc was added, the phases were separated, and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over MgSO4 and concentrated. Purification via silica gel chromatography using 0-50 EtOAc in hexane gave (S)-3-(4-chloro-5-fluoroindolin-1-yl)-1-phenylpyrrolidin-2-one as a white solid (2.1 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 7.71-7.68 (m, 2H), 7.42-7.38 (m, 2H), 7.17 (t, J=7.4 Hz, 1H), 7.04-6.99 (m, 1H), 6.49 (dd, J=3.6, 8.7 Hz, 1H), 4.77 (dd, J=8.8, 10.6 Hz, 1H), 3.85-3.81 (m, 2H), 3.62 (dd, J=2.7, 8.9 Hz, 1H), 3.40 (dd, J=8.6, 17.9 Hz, 1H), 3.05-2.95 (m, 2H), 2.40-2.31 (m, 1H), 2.21-2.10 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=331.5; tR=1.90 min.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].CC1(C)COB([C:22]2[CH:27]=[CH:26][C:25]([C:28]3([OH:32])[CH2:31][O:30][CH2:29]3)=[CH:24][CH:23]=2)OC1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.[Cl-].[NH4+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:3]1[C:2]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3([OH:32])[CH2:31][O:30][CH2:29]3)=[CH:26][CH:27]=2)=[C:10]([F:11])[CH:9]=[C:8]2[C:4]=1[C:5]([CH:12]=[O:13])=[CH:6][NH:7]2
Reactant: O=Cc1c[nH]c2cc(F)c(Br)c(F)c12
Reactant: CC1(C)COB(c2ccc(C3(O)COC3)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=Cc1c[nH]c2cc(F)c(-c3ccc(C4(O)COC4)cc3)c(F)c12
Temperature: 110 °C
Yield: 18 %

Procedure:
A mixture of 5-bromo-4,6-difluoro-1H-indole-3-carbaldehyde (157 mg, 0.64 mmol), 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]oxetan-3-ol (190 mg, 0.725 mmol), and 2M aqueous potassium carbonate (1.2 mL, 2.4 mmol) in toluene (4 mL) and ethanol (2 mL) was degassed with nitrogen for 10 minutes, then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg, 0.06 mmol). The reaction mixture was sealed and heated to for 110° C. for 16 hours. The cooled reaction mixture was diluted with ethyl acetate and ammonium chloride. The layers were separated and the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by flash column chromatography to give the title compound (38 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:31]1([CH3:43])[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:32]=1[S:39](Cl)(=[O:41])=[O:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)[S:39]([C:32]2[C:33]([CH3:38])=[CH:34][C:35]([CH3:37])=[CH:36][C:31]=2[CH3:43])(=[O:41])=[O:40])=[CH:7][CH:8]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COc1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(Cc2ccc(OC3CCCCO3)cc2)S(=O)(=O)c2c(C)cc(C)cc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-methoxy-phenyl)-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.100 g, 0.319 mmol) and triethylamine (0.133 mL, 0.957 mmol) in 2 mL methylene chloride was added 2-mesitylenesulfonyl chloride (0.139 g, 0.638 mmol). The reaction mixture was stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with 2 mL methylene chloride and the combined organic layers were evaporated to afford the title compound of Step A which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[C:13]([O:15][CH2:16][O:17][CH3:18])=[CH:12][CH:11]=[CH:10]2.[H-].[Na+].[CH3:21]I.O>CN(C)C=O>[CH3:18][O:17][CH2:16][O:15][C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2][O:1][CH3:21])[CH:10]=[CH:11][CH:12]=1
Reactant: COCOc1cccc2cccc(CCCO)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCc1cccc2cccc(OCOC)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.1 g of 8-(3-hydroxypropyl)-1-methoxymethoxy naphthalene was dissolved in 40 ml of N,N-dimethyl formamide, to which 1.4 g of 55% sodium hydride was added under ice cooling. Then, 1.93 ml of methyl iodide was added and stirred at a room temperature for 2 hours. After adding water to the reaction solution and extracting with ethyl acetate, the organic layer was washed with water and then with a saturated aqueous solution of sodium chloride successively and then dried over magnesium sulfate. After distilling off the solvent, when it was purified on silica gel column chromatography (10% ethyl acetate-hexane), 5.3 g of the above-captioned compound was obtained as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:35]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:33])([CH3:34])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH3:35])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.0 g, 4.1 mmol) and methyl iodide (7.6 mL, 123 mmol) in dry DMF (20 mL) at 0° C. was added NaH (60% suspension in oil, 328 mg, 8.2 mmol) in portion wise. The reaction mixture was stirred for 90 min at 0° C. under nitrogen. The reaction mixture was quenched by addition of aqueous HCl (2N). After extraction with EtOAc, the organic fraction was washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexane-EtOAc (80:20) as eluent affording the 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)amino]-thiophene-2-carboxylic acid methyl ester 950 mg (46%) as a solid.
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:26]2[N:27]=[C:28]([NH:31]C=O)[S:29][CH:30]=2)[C:9]([NH:11][CH:12]2[C:24](=[O:25])[N:14]3[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH:19]=[CH2:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl.O.C(=O)(O)[O-].[Na+]>CO.O1CCCC1.C(OCC)(=O)C>[CH:1]1([O:6][N:7]=[C:8]([C:26]2[N:27]=[C:28]([NH2:31])[S:29][CH:30]=2)[C:9]([NH:11][CH:12]2[C:24](=[O:25])[N:14]3[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH:19]=[CH2:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3C=CCC3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC3C=CCC3)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.4 %

Procedure:
A mixture of 7-[2-(2-cyclopenten-1-yloxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (3.1 g) in methanol (22 ml), tetrahydrofuran (10 ml) and conc. hydrochloric acid (1.3 g) was stirred for 2.5 hours at ambient temperature. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to pH 7.5 with a saturated aqueous sodium bicarbonate. The separated aqueous layer was adjusted to pH 3.0 with 10% hydrochloric acid. The precipitates were filtered off, washed with water and dried over phosphorus pentoxide in vacuo to give 7-[2-(2-cyclopenten-1-yloxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.7 g).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1CCN2C(=NCCC2)CC1.[CH2:39]([O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[N:52]([CH3:56])[C:51]([CH:57]=O)=[CH:50]2)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[CH2:39]([O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[N:52]([CH3:56])[C:51]([CH:57]=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[CH:50]2)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1c(C=O)cc2cc(OCc3ccccc3)ccc21
Agent: [Br-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1c(C=Cc2ccccc2)cc2cc(OCc3ccccc3)ccc21
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
Under N2, to a suspension of benzyltriphenylphosphonium bromide (980 mg, 2.26 mmol) in acetonitrile (10 ml) was added DBU at room temperature. After stirring for 10 min., 5-(benzyloxy)-1-methyl-1H-indole-2-carbaldehyde (500 mg, 1.88 mmol) was added and the mixture was stirred overnight at room temperature. The resulting mixture was filtered and washed with acetonitrile. The filtrate was concentrated in vacuo and then the residue was purified by silica gel (70 g) chromatography eluted with chloroform to give 5-(benzyloxy)-1-methyl-2-(2-phenylethenyl)-1H-indole (221 mg, 34.5%).