Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]=[CH:19][CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>O.C(Cl)(Cl)Cl>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]4[O:29][CH:19]4[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)N1CC2CC=Cc3cccc1c32
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1)N1CC2CC3OC3c3cccc1c32
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution was prepared from 2.71 g. of 1-benzoyl-1,2,2a,3-tetrahydrobenz[cd]indole in 100 ml. of chloroform. A second solution containing 2.1 g. of 85% m-chloroperbenzoic acid in 100 ml. of chloroform was added. The reaction mixture was stirred at ambient temperature for 41/4 hours. TLC of an aliquot of the solution indicated that most of the starting material had been comsumed. The reaction mixture was diluted with water and the organic layer washed with 1N aqueous sodium hydroxide, with water and with saturated aqueous sodium chloride. The organic layer was dried and the solvent removed therefrom by evaporation in vacuo. The resulting residue containing 1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole formed in the above reaction was dissolved in chloroform and the chloroform solution filtered through florisil. The chloroform was evaporated from the filtrate and the resulting residue crystallized from a mixture of ether and hexane, yielding 1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole melting in the range 103°-115° C. (the above procedure is based upon that of Kornfeld et al., J. Am. Chem. Soc., 78, 3101 (1956))
Reaction SMILES: CS([CH2:5][CH:6]([CH3:18])[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)(=O)=O.[CH3:19][CH:20]1[O:25][CH:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>O>[CH3:26][CH:24]1[O:25][CH:20]([CH3:19])[CH2:21][N:22]([CH2:5][CH:6]([CH3:18])[CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[CH2:23]1
Reactant: CC1CNCC(C)O1
Reactant: CC(Cc1ccc2ccccc2c1)CS(C)(=O)=O
Solvent: O
Product: CC(Cc1ccc2ccccc2c1)CN1CC(C)OC(C)C1
Yield: 52.1 %

Procedure:
10.8 g (0.04 mol) of 1-methanesulphonyl-2-methyl-3-β-naphthylpropane and 9 g (0.078 mol) of 2,6-dimethylmorpholine are stirred at a bath temperature of 140° C. for 15 hours. Water is added to the resulting reaction mixture and the mixture is extracted several times with ether. The combined organic phases are dried over sodium sulphate and freed from the solvent in vacuo; the oily residue is purified by column chromatography (silica gel 60, petroleum ether/ethyl acetate=2:1). 6.2 g (52% of theory) of 1-(2,6-dimethylmorpholin-4-yl)-2-methyl-3-β-naphthyl-propane of refractive index nD20 =1.5527 are obtained.
Reaction SMILES: [C:1]1([C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]=1.[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26][CH2:25][C:24]=12>>[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]([C:15]([C:14]3[CH:13]=[CH:12][C:11]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH2:4][CH2:3][CH:2]=4)=[CH:19][CH:18]=3)=[O:16])[CH2:25][C:24]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(O)c1ccc(C2=CCCc3ccccc32)cc1
Product: O=C(c1ccc(C2=CCCc3ccccc32)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 51 %

Procedure:
4-(3,4-Dihydro-naphthalen-1-yl)-benzoic acid of Step B (0.280 g, 1.12 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.227 g, 1.23 mmol) were reacted in the manner of Example 15, Step D. Recrystallization from petroleum ether afforded the title compound (0.238 g) as white crystals, m.p. 166° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[N+:11]([O-:12])=[C:10]([CH3:13])[CH:9]=[C:8]([N:14]([CH3:16])[CH3:15])[N:7]=1>C(N(CC)CC)C>[C:1]([NH:5][C:6]1[N+:11]([O-:12])=[C:10]([CH3:13])[CH:9]=[C:8]([N:14]([CH3:15])[CH3:16])[N:7]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(N(C)C)nc(N)[n+]1[O-]
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(N(C)C)cc(C)[n+]1[O-]

Procedure:
Following the procedure described in Example 11, acetyl chloride is reacted in the presence of triethylamine with 2-amino-4-methyl-6-dimethylaminopyrimidine 3-oxide.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O.O>[Si:19]([O:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: O=c1[nH]c2ccc(O)cc2c(=O)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a mixture of 5-hydroxyisatoic anhydride (1.6 g, 9.0 mmol) and imidazole (670 mg, 9.9 mmol) in N,N-dimethylformamide (10 mL) was added tert-butyldimethylsilyl chloride (1.42 g, 9.45 mmol). After stirring for 2 h, the reaction mixture was diluted with ice and water. After warming to room temperature, the resulting precipitate was filtered and washed with water and hexane. The solid was vacuum dried at 55° C./0.1 mm for 14 h to give 2.55 g (96%) of the title compound as a light gray solid; mp 198-200° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].CCOC(C)=O.O>CCO.[Cl-].[Zn+2].[Cl-]>[Br:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([F:1])[CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)ccc1-c1nnn[nH]1
Yield: 32.9 %

Procedure:
2-Fluoro-4-bromobenzonitrile (300 mg, 1.5 mmol) dissolved in EtOH, added sodium azide (320 mg, 4.9 mmol), Zinc chloride (240 mg, 1.8 mmol). This mixture was stirred refluxed for 38 h. Work up (EtOAc/H2O) afforded the crude. Crude was washed with petether to obtain the titled compound (120 mg) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.89-7.79 (m, 1H), 7.59 (dd, J 1.6, 10.04, 1H), 7.45 (dd, J 1.8, 8.3, 1H).
Reaction SMILES: [CH:1]1[C:13]2[N:12]([CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:25](Cl)[O:26]C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CO.O>[CH3:19][N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:12]1[C:11]2[CH:10]=[CH:9][C:8]([CH:25]=[O:26])=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: COC(Cl)Cl
Reactant: CN(C)CCCn1c2ccccc2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CN(C)CCCn1c2ccccc2c2cc(C=O)ccc21
Temperature: 0 °C
Reaction time: 20 h
Yield: 81 %

Procedure:
A 100-mL round-bottomed flask was charged with a solution of 3-(9H-carbazol-9-yl)-N,N-dimethylpropan-1-amine (500 mg, 1.98 mmol, 1.00 equiv) in DCM (10 mL), aluminum (III) chloride (550 mg, 4.17 mmol, 2.00 equiv), dichloro(methoxy)methane (0.24 mL, 1.10 equiv), water (10 mL) and K2CO3 (20 mL). The resulting mixture was stirred at 0° C. for 20 hours. The reaction progress was monitored by TLC (DCM: MeOH=10:1). Upon completion, the resulting solution was extracted with ethyl acetate (3×30 mL). Combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator affording 9-(3-(dimethylamino)propyl)-9H-carbazole-3-carbaldehyde as yellow oil (0.45 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:30](=O)[CH3:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:29])[C:15]2[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=2[O:25][CH:26]([CH3:28])[CH3:27])[CH2:10][CH2:9]1.Cl.[CH3:34][O:35][NH2:36].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:34][O:35][N:36]=[C:30]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:29])[C:15]3[CH:20]=[C:19]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=3[O:25][CH:26]([CH3:28])[CH3:27])[CH2:12][CH2:13]2)=[C:2]([F:1])[CH:3]=1)[CH3:31]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CON=C(C)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of O-methyl-hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The slurry was stirred overnight at room temperature, diluted with water, extracted with ethyl acetate, dried and concentrated. The resulting gum was triturated with diethyl ether/heptane to yield the title compound as a colorless solid. MS (m/e): 492.3 (MH+, 100%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O-:29])=[O:28])=[CH:23][CH:22]=1.[Na+]>C(Cl)(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:12]([OH:13])([C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:11])[CH2:14][S:27]([C:24]1[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=1)(=[O:29])=[O:28]
Reactant: O=S([O-])c1ccc(F)cc1
Reactant: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
0.500 g of the epoxyamide (5A) was dissolved in a mixture of 40 ml of chloroform and 40 ml of water and 371 mg of sodium p-fluorobenzenesulfinate was added. Subsequently, 298 mg of tetrabutylammonium bromide was added. The reaction mixture was heated till reflux, while stirring vigorously. The reaction was monitored with HPLC. After 96 hours of reflux, the reaction mixture was cooled to room temperature. 20 ml of chloroform was added and the organic layer was washed with 3×50 ml of water, dried (Na2SO4) and evaporated to dryness. Yield: 860 mg. Purification of the crude product by column chromatography (Merck silica gel 60; eluent: heptane/ethyl acetate=1/1) afforded bicalutamide as white solid. Isolated yield: 380 mg (48%). 1H-NMR: confirmed the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH2:23][CH3:24]>C(Cl)Cl>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]([CH2:23][CH3:24])[CH3:21])=[O:12])=[CH:9][CH:8]=2)=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reactant: CCNC
Solvent: ClCCl
Product: CCN(C)C(=O)c1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
The compound from Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of N-methylethanamine (379 mg, 6.41 mmol) in CH2Cl2. Mixture was stirred for 12 hours. Mixture was concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 50% EtOAc/hexane giving a yellow oil (1.03 g, 100%).
Reaction SMILES: [Cl-].[CH3:2][NH:3][C:4](=O)[CH3:5].N1C(C)=CC=CC=1C.C(OC([N:22]1[CH2:29][CH2:28][C@:27]2([CH3:32])[C@H:30]([CH3:31])[C@H:23]1[CH2:24][C:25]1[CH:36]=[CH:35][C:34]([C:37]([NH:39][NH2:40])=O)=[CH:33][C:26]=12)=O)(C)(C)C>ClCCl>[CH3:2][N:3]1[C:4]([CH3:5])=[N:40][N:39]=[C:37]1[C:34]1[CH:35]=[CH:36][C:25]2[CH2:24][C@@H:23]3[C@@H:30]([CH3:31])[C@:27]([CH3:32])([C:26]=2[CH:33]=1)[CH2:28][CH2:29][NH:22]3
Reactant: C[C@@H]1[C@H]2Cc3ccc(C(=O)NN)cc3[C@]1(C)CCN2C(=O)OC(C)(C)C
Reactant: CNC(C)=O
Agent: [Cl-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1nnc(-c2ccc3c(c2)[C@]2(C)CCN[C@H](C3)[C@H]2C)n1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Oxalylic chloride (0.12 mL) is added to a solution N-methylacetamide (102 mg) and 2,6-lutidine (0.33 mL) in dichloromethane (5 mL) chilled in an ice bath. After stirring the solution for 15 min, (2R,6R,11S)-8-hydrazinocarbonyl-6,11-dimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester (0.50 g) is added and the cooling bath is removed. The resulting solution is stirred at ambient temperature for 1 h and then neutralized with aqueous NaHCO3 solution. The resulting mixture is extracted with dichloromethane, the combined organic extracts are dried (MgSO4), and the solvent is evaporated. The residue is taken up in acetic acid (3 mL) and stirred at 120° C. for 2.5 h. After cooling to room temperature, the mixture is concentrated under reduced pressure and the residue is taken up in trifluoroacetic acid (1 mL) and dichloromethane (5 mL) to cleave off the tert-butoxycarbonyl group. The solution is stirred at room temperature overnight and then concentrated. The residue is dissolved in little methanol/acetonitrile, neutralized with aqueous ammonia, and purified by HPLC on reversed phase (MeCN/H2O/NH4OH) to give the title compound.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[C:19]([O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])(=[O:23])[CH:20]([CH3:22])[CH3:21].[N:31]1[CH:36]=[CH:35][C:34]([CH:37]=[O:38])=[CH:33][CH:32]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:21][C:20]([CH3:22])([CH:37]([OH:38])[C:34]1[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=1)[C:19]([O:24][CH2:25][CH2:26][Si:27]([CH3:29])([CH3:28])[CH3:30])=[O:23]
Reactant: O=Cc1ccncc1
Reactant: CC(C)C(=O)OCC[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C(=O)OCC[Si](C)(C)C)C(O)c1ccncc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
1.6 M n-butyl lithium in hexane (14.0 ml, 22.4 mmol) was added to a solution of diisopropylamine (2.3 g, 22.4 mmol) in tetrahydrofuran (15 ml) under ice cooling condition, and the mixture was stirred for 30 minutes. The reaction mixture was cooled to −78° C., and a solution of 2-(trimethylsilyl)ethyl isobutyrate (4.0 g, 21.2 mmol) in tetrahydrofuran (5 ml) was added dropwise to the mixture. The reaction mixture was stirred for 45 minutes. Successively, a solution of 4-pyridinecarbaldehyde (2.5 g, 23.3 mmol) in tetrahydrofuran (10 ml) was added to the mixture, and the mixture was stirred with warming from −78° C. to room temperature for 2.5 hrs. The reaction mixture was combined with saturated aqueous ammonium chloride solution and extracted with ethylacetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (100 g) column chromatography. The fraction eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated to give the titled compound (3.2 g, 51%) as a colorless oil.
Reaction SMILES: CC([N:5]([C:9]1[CH:10]=[CH:11][C:12]2[NH:17]C(=O)[O:15][C:14](=[O:19])[C:13]=2[C:20]=1[CH3:21])[C:6](=[O:8])[O-:7])(C)C.[OH-].[Na+].Cl>CC(C)=O>[NH2:17][C:12]1[CH:11]=[CH:10][C:9]([NH:5][C:6]([O:7][C:13]([CH3:20])([CH3:14])[CH3:12])=[O:8])=[C:20]([CH3:21])[C:13]=1[C:14]([OH:15])=[O:19]
Reactant: Cc1c(N(C(=O)[O-])C(C)(C)C)ccc2[nH]c(=O)oc(=O)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1c(NC(=O)OC(C)(C)C)ccc(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of the product of step C ((10.5 g, 36.0 mmol) in 15 mL of acetone was added 107 mL of 1N NaOH. After stirring at room temperature for 1 hour, the solution was acidified to pH 3 by the careful addition of 2N HCl. The mixture was extracted (2×) with EtOAc, dried (MgSO4), and concentrated under reduced pressure affording 8.35 g (87%) of 2-amino-5-[[(1,1-dimethylethoxy]carbonyl]amino]-6-methylbenzoic acid: Anal. Calc'd. for C13H18N2O4: C, 58.64; H, 6.81; N, 10.52. Found: C, 58.26; H, 6.72; N, 10.42.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH3:27][O:28][C:29]([O:31][CH:32](I)[CH3:33])=[O:30]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:32]([O:31][C:29]([O:28][CH3:27])=[O:30])[CH3:33])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: COC(=O)OC(C)I
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: COC(=O)OC(C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 74.3 %

Procedure:
In the same manner as in Example 81, 145 mg of the title compound was prepared from 163 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 140 mg of 1-(methoxycarbonyloxy)ethyl iodide.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:34])[C:22]=1[N:23]1[CH2:32][C:28]2(OC[CH2:29]2)[CH2:27][CH:26]([NH2:33])[CH2:25][CH2:24]1)=[O:16].C=C1CN(C2N(C)N=CC=2[N+]([O-])=O)CC[C@H](NC(=O)OC(C)(C)C)C1>>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:8]([F:14])=[CH:9][CH:10]=[CH:11][C:12]=2[F:13])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:34])[C:22]=1[N:23]1[CH2:24][CH2:25][C@H:26]([NH2:33])[CH2:27][C:28](=[CH2:29])[CH2:32]1)=[O:16]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC(N)CC2(CCO2)C1
Agent: C=C1C[C@@H](NC(=O)OC(C)(C)C)CCN(c2c([N+](=O)[O-])cnn2C)C1
Product: C=C1C[C@@H](N)CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnn2C)C1

Procedure:
In the preparation of 448, tert-butyl N-[(4R)-6-methylene-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-yl]carbamate was converted to 449. 1H NMR (400 MHz, DMSO) δ 8.73 (s, 1H), 7.56 (s, 1H), 7.55-7.41 (m, 3H), 7.26 (t, J=8.7 Hz, 2H), 4.89 (d, J=9.7 Hz, 2H), 3.86-3.71 (m, 2H), 3.67 (s, 3H), 3.16-3.05 (m, 1H), 3.05-2.92 (m, 1H), 2.85 (s, 1H), 2.44-2.28 (m, 1H), 1.82-1.69 (m, 2H), 1.53-1.35 (m, 1H). LCMS (ES+) m/z 460 (M+1)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11](=[O:12])[CH:10]=[CH:9][O:8][C:7]=1[CH3:13].[OH-].[K+].[CH3:16]I>>[CH3:16][O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11](=[O:12])[CH:10]=[CH:9][O:8][C:7]=1[CH3:13]
Reactant: Cc1occc(=O)c1OCCCO
Reactant: CI
Agent: [K+]
Agent: [OH-]
Product: COCCCOc1c(C)occc1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
A mixture of 3-(3-hydroxy-1-propoxy)-2-methyl-4-pyrone {1.4 g, 7.6 mmol), 85% KOH (0.55 g, 8.4 mmol) and methyliodide (11 g, 76 mmol) was stirred at room temperature for one day. The red solution was partitioned between methylene chloride and half saturated aqueous ammoniumchloride solution. The organic phase was washed with water, dried over Na2SO4 and evaporated. The residue was purified by chromatography on silica gel with methanol/methylene chloride (3:97) as eluent. Removing the eluent by film evaporation afforded 0.31 g (20%) of the desired product as an oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([CH:14]([O:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1.[CH2:24]([C:26]([C:45]1[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]2[O:55][C:54](=[O:56])[CH2:53][CH2:52]2)=[C:47]([CH3:59])[CH:46]=1)([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[C:31]([CH3:44])[CH:30]=1)[CH2:27][CH3:28])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[CH3:16][C:15]([CH3:18])([CH3:17])[CH:14]([C:10]1[CH:9]=[C:8]([C:32]2[CH:33]=[CH:34][C:29]([C:26]([C:45]3[CH:58]=[CH:57][C:48]([O:49][CH2:50][C@@H:51]4[O:55][C:54](=[O:56])[CH2:53][CH2:52]4)=[C:47]([CH3:59])[CH:46]=3)([CH2:24][CH3:25])[CH2:27][CH3:28])=[CH:30][C:31]=2[CH3:44])[CH:13]=[CH:12][CH:11]=1)[O:19][Si:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)C(O[Si](C)(C)C)c1cccc(Br)c1
Reactant: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(-c2cccc(C(O[Si](C)(C)C)C(C)(C)C)c2)c(C)c1
Temperature: 85 °C
Reaction time: 13.5 h
Yield: 28.6 %

Procedure:
A [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.68 mg, 0.002 mmol), a 2 M sodium carbonate aqueous solution (0.1 mL, 0.2 mmol) and [1-(3-bromo-phenyl)-2,2-dimethyl-propoxy]-trimethyl-silane (Example 18-(1); 43.16 mg, 0.137 mmol) were added to a solution of (R)-5-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxymethyl)-dihydro-furan-2-one (Example 15-(3); 33.7 mg, 0.068 mmol) in N,N-dimethylformamide (0.1 mL) at room temperature, and the mixture was stirred at 85° C. for 13.5 hours. Ethyl acetate was added to the reaction solution. The organic layer was washed with distilled water and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound (11.7 mg, 28.5%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19].[CH2:22]([CH:24]1[O:26][CH2:25]1)Cl>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCCCC.CCCCCC>[CH2:22]([O:21][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH:24]1[O:26][CH2:25]1
Reactant: ClCC1CO1
Reactant: CC(C)CCCCCCCCCCCCCCCO
Agent: CCCCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(C)CCCCCCCCCCCCCCCOCC1CO1
Temperature: 50 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
Into a round bottom flask having a capacity of 1 liter and equipped with a reflux condenser, a thermometer, a dropping funnel, and a stirring means, 120 g of a 50% sodium hydroxide solution (60 g (1.5 mole) as pure sodium hydroxide), 68 g (0.25 mole) of isostearyl alcohol [5,7,7-trimethyl-2-(1,3,3-trimethylbutyl) octanol], 200 ml of n-hexane, and 2.51 g (0.0075 mole) of stearyl trimethyl ammonium chloride, were introduced in this order. The reaction mixture was kept at a reaction temperature of 25° C. in a water bath, and while vigorously stirring the mixture at a stirring speed of 400 r.p.m., 93 g (1 mole) of epichlorohydrin was added dropwise from the dropping funnel. It took about 1.5 hours for the addition of the epichlorohydrin, and the reaction mixture was heated to 50° C. and stirred for about 8 hours at this temperature. After the completion of the reaction, the mixture was treated in a usual manner, whereupon 67.9 g (yield: 83%) of isostearyl glycidyl ether (5,7,7-trimethyl-2-(1,3,3-trimethylbutyl)-octyl glycidyl ether) was obtained.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[Cl:18].Br[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>C1COCC1>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][CH2:33][C:19]([C:20]#[N:21])([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([Cl:11])[CH:13]=1)[CH2:22][CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH3:39]
Reactant: CCOC(=O)CCBr
Reactant: N#CC(CCCOC1CCOCC1)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(C#N)(CCCOC1CCOCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
Potassium hexamethyldisilazide (0.5 M in toluene, 285 mL, 0.143 mol) was added dropwise to a solution of (4) (39 g, 0.119 mol) in THF (240 mL) under nitrogen and stirred at room temperature for 1 hour. A solution of ethyl 3-bromopropionate (22.8 mL, 0.178 mol, 1.5 eq) in THF (45 mL) was added to the reaction mixture all at once. After stirring at room temperature for 4 hours, the reaction was quenched with saturated NH4Cl solution (20 mL). The organic solution was dried over MgSO4, and solvent is evaporated. The crude oil was purified by flashed chromatography (hexane-AcOEt/8:1) to give light yellow oil (48.03 g, 94.4% yield).