Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9]([C:16](OCC)=[O:17])[CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9]([CH2:16][OH:17])[CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1cccc2c3c([nH]c12)CCC(N(C)C)C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C1CCc2[nH]c3c(CO)cccc3c2C1

Procedure:
Following a procedure similar to that described in Example 55 and using 2.4 g. of 3-(dimethylamino)-8-ethoxycarbonyl-1,2,3,4-tetrahydrocarbazole (Example 44), 1.6 g. of lithium aluminum hydride and 150 ml. of dry tetrahydrofuran there was obtained, after successive recrystallizations from isopropyl alcohol and ethyl alcohol, 0.56 g. of 3-(dimethylamino)-8-hydroxymethyl-1,2,3,4-tetrahydrocarbazole, m.p. 227°-230°C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[K+].O.C(O)C>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)OCCO3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)OCCO3)cc1

Procedure:
Hydrolysis of this ester with potassium hydroxide/water/ethanol at 50° C. during 2 hours yielded p-(1,4-benzodioxane-6-carboxamido)benzoic acid, melting point 278°-280° C.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[N:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[CH2:33]([S:37](Cl)(=[O:39])=[O:38])[CH2:34][CH2:35][CH3:36]>ClCCl>[N:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][NH:30][S:37]([CH2:33][CH2:34][CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:31][CH:32]=3)[CH2:19][CH2:18]2)=[CH:15][CH:16]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: NCc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NCc1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Reaction time: 0.08 h

Procedure:
Triethylamine (0.41 ml) was added to a stirred suspension of 4-[2-[4-(4-pyridyl)piperazin-1-yl]ethyl]benzylamine, trihydrochloride (300 mg) in dry dichloromethane (20 ml). After 5 minutes, 1-butanesulphonyl chloride (0.10 ml) was added and the mixture stirred overnight. Dichloromethane (80 ml) was added and the solution washed with water (2×25 ml), dried (MgSO4) and the solvent removed in vacuo, Trituration of the residue with a small volume of ethyl acetate gave the title compound, 50 mg, as an off-white solid: m.p. 154°-156° C.; NMR (d6DMSO) δ8.16(2H,d), 7.53(1H,t), 7.22(4H,m), 6.37(2H,d), 4.10(2H,d), 3.35(6H,m+H2O), 2.81(4H,m), 2.54(4H,m+DMSO), 1.56(2H,m), 1.29(2H,m). 0.82(3H,t), m/e 417 (M+H)+ ; calculated for C22H32N4O2S.0.75H2O: C, 61.5; H, 7.8;, 13.0. found: C, 61.5; H, 7.6; N, 12.7%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
From 4-fluoro-benzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1I.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:3]1[C:2]([OH:1])=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=[C:5]([C:6]#[N:7])[CH:4]=1
Reactant: OB(O)c1ccccc1F
Reactant: N#Cc1cc(I)c(O)c([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1cc(-c2ccccc2F)c(O)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 86.2 %

Procedure:
To a mixture of 4-hydroxy-3-iodo-5-nitrobenzonitrile (870 mg) and 2-fluorophenylboronic acid (630 mg) in acetone (50 ml) and water (12.5 ml) was added the palladium(II) acetate (73 mg) and potassium carbonate (830 mg). The reaction was then heated for 18 h at 60° C. The mixture was then concentrated in vacuo and filtered through a plug of silica gel, eluting with ethyl acetate. The eluent was concentrated in vacuo and the residue was purified via flash chromatography on a Biotage Horizon, 40 M column, eluting with 1 column volume of 100% hexanes, followed by a gradient of 0-40% ethyl acetate in hexanes over 10 column volumes to provide the title compound (668 mg, 86%). Mass spectrum (ESI) 257.1 (M−1).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=3)=[N:28][CH:29]=2)O1>>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:27]2[N:28]=[CH:29][C:24]([C:2]3[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=3[O:4][C:5]3[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=3)=[CH:25][CH:26]=2)=[CH:31][N:32]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: Nc1nccc(Oc2ccccc2Br)n1
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3ccnc(N)n3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)pyrimidin-2-amine and 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H15N7O, 357.13; m/z found, 358.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.91 (s, 2H), 8.68-8.59 (m, 1H), 8.03 (dd, J=6.9, 0.9, 1H), 7.97-7.89 (m, 1H), 7.83 (d, J=8.3, 1H), 7.60-7.53 (m, 2H), 7.52-7.44 (m, 1H), 7.35 (d, J=7.9, 1H), 6.53 (dd, J=6.9, 0.9, 1H).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:14](=[O:16])[CH:15]=2)[CH:5]=1.[OH-].[Na+:25]>CO>[Na+:25].[N:17]1([C:12]2[O:11][C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([O-:23])=[O:2])=[CH:15][C:14](=[O:16])[CH:13]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1cccc(-c2cc(=O)cc(N3CCOCC3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1cccc(-c2cc(=O)cc(N3CCOCC3)o2)c1
Yield: 77.3 %

Procedure:
3-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-benzoic acid methyl ester (5.42 g, 17.20 mmol) was dissolved in methanol (25 ml) and sodium hydroxide (0.75 g, 18.90 mmol) was added. The stirred solution was then refluxed under nitrogen for three hours. The methanol was removed in vacuo and the residue was triturated in ether to give the title compound as a brown solid (4.30 g, 83.33%). m/z (LC-MS, ESP): 301 (M++1).
Reaction SMILES: N#N.[C:3]([SiH2:7][O:8][C:9]([CH3:23])([CH3:22])[C:10]1[O:11][CH:12]=[C:13]([CH2:15][N:16]2[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]2)[N:14]=1)([CH3:6])([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.[CH:33]1[CH:38]=[C:37]([CH2:39][O:40][C:41](Cl)=[O:42])[C:36]([Cl:44])=[CH:35][CH:34]=1>C(Cl)Cl.O>[Cl:44][C:36]1[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[CH2:39][O:40][C:41](=[O:42])[NH:21][C:19]1[CH:18]=[N:17][N:16]([CH2:15][C:13]2[N:14]=[C:10]([C:9]([CH3:23])([CH3:22])[O:8][SiH2:7][C:3]([CH3:6])([CH3:4])[CH3:5])[O:11][CH:12]=2)[CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2cc(N)cn2)co1
Agent: N#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(C)(C)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)co1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-ylmethyl]-1H-pyrazol-4-ylamine (347 mg, 1.12 mmol) in CH2Cl2 (5.0 mL) was treated with DIPEA (0.31 mL, 1.78 mmol) followed by 2-chlorobenzylchloroformate (0.23 mL, 1.45 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and water (5.0 mL) was added. The layers were separated and the aq. layer extracted with CH2Cl2 (2×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (9:1 to 1:1 hept-EA) gave the title compound as an orange oil. TLC: rf (1:1 hept-EA)=0.27. LC-MS-conditions 02: tR=1.13 min; [M+H]+=476.95.
Reaction SMILES: C1(C)C=CC=CC=1.I[C:9]1([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10]1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[C:25](=[O:31])[CH2:24][CH2:23]2>C(=O)([O-])[O-].[Ag+2].C(OCC)(=O)C.CCCCCC>[CH3:30][N:26]1[C:27]2[C:22](=[CH:21][C:20]([O:19][C:9]3([S:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][CH2:10]3)=[CH:29][CH:28]=2)[CH2:23][CH2:24][C:25]1=[O:31]
Reactant: IC1(Sc2ccccc2)CC1
Reactant: CN1C(=O)CCc2cc(O)ccc21
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN1C(=O)CCc2cc(OC3(Sc4ccccc4)CC3)ccc21
Temperature: 55 °C
Yield: 17.4 %

Procedure:
To a dry toluene solution of [1-Iodo-cyclopropylsulfanyl]-benzene (375 mg, 1.36 mmol) was added 6-Hydroxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (200 mg, 1.13 mmol) and silver carbonate (312 mg, 1.13 mmol) under nitrogen and the reaction mixture was heated to 55° C. It took 3 more additions of the reagents to take the reaction to completion. The reaction was cooled to room temperature, filtered to remove the silver iodide and concentrated under vacuum to yield crude material. This was flash chromatograhed using 30% ethyl acetate/hexane to yield the title compound as a viscous oil (64 mg, 17% yield). 1H NMR (400 MHz, CDCl3) δ 1.31–1.33 (2H, m), 1.41–1.43 (2H, m), 2.59–2.62 (2H, m), 2.83–2.87 (2H, m), 3.31 (3H, s), 6.86–6.98 (4H, m), 7.20–7.31 (2H, m), 7.44–7.47 (2H, m). m/z (APCI+) 326 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 6.59 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.CCCCCC.[CH3:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=[O:35])=[CH:33][C:28]=2[N:27]=[N:26]1>C1COCC1.O.C(O)(C)C>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([CH:34]([C:32]2[CH:31]=[CH:30][C:29]3[N:25]([CH3:24])[N:26]=[N:27][C:28]=3[CH:33]=2)[OH:35])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: Cn1nnc2cc(C=O)ccc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOc1cc(C(O)c2ccc3c(c2)nnn3C)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.4 %

Procedure:
To a solution of 4-bromo-2-ethoxy-1-methoxy-benzene (1.5 g, 6.5 mmol) in THF (15 mL) was added a solution of n-butyllitium in hexane (2.5 mL, 2.5 N, 6.3 mmol) at −78° C. and kept for 20 min. To the mixture was added a slurry of 1-methyl-1H-benzotriazole-5-carbaldehyde (1.0 g, 6.0 mmol) in THF (5 mL) at −78° C. After 18 h, isopropanol (2 mL) and water (10 mL) was added to the mixture, and the cold bath was removed. The mixture was stirred at room temperature for 20 min. The mixture was extracted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers was washed with water (50 mL), brine (50 mL) and dried over MgSO4. Removal of solvent gave (3-ethoxy-4-methoxy-phenyl)-(1-methyl-1H-benzotriazol-5-yl)-methanol as an oil (2 g). The oil was used in the next step without further purification.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([CH3:79])([CH2:68][N:69]1[CH2:78][CH2:77][C:72]2([O:76][CH2:75][CH2:74][O:73]2)[CH2:71][CH2:70]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][CH:54]=[CH:53][C:52]=2[N:58]([CH3:67])[S:59]([C:62]1[S:63][CH:64]=[CH:65][CH:66]=1)(=[O:61])=[O:60])=O)C1C=CC=CC=1.CSC.C(=O)([O-])O.[Na+]>ClCCl>[O:73]1[C:72]2([CH2:77][CH2:78][N:69]([CH2:68][C:44]3([CH3:79])[S:43][C:47]([C:49]4[NH:50][C:51]5[C:56]([CH:57]=4)=[CH:55][CH:54]=[CH:53][C:52]=5[N:58]([CH3:67])[S:59]([C:62]4[S:63][CH:64]=[CH:65][CH:66]=4)(=[O:60])=[O:61])=[N:46][CH2:45]3)[CH2:70][CH2:71]2)[O:76][CH2:75][CH2:74]1
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(CN3CCC4(CC3)OCCO4)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CSC
Product: CN(c1cccc2cc(C3=NCC(C)(CN4CCC5(CC4)OCCO5)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 46.6 %

Procedure:
To a solution of triphenylphosphine oxide (0.83 g) in dichloromethane (6 mL) was slowly added trifluoromethanesulfonic anhydride (0.25 mL) at 0° C., and the mixture was added for 10 min. N-[2-(benzylthio)-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2-methylpropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.72 g) and dimethylsulfide (0.22 mL) were added, and the reaction mixture was stirred at 0° C. for 20 min. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio) to give the title compound (0.28 g, yield 50%) as colorless crystals. melting point 172-173° C.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.[Li]C(CC)C.[C:14]([C:18]1[CH:26]=C[C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CI>C1COCC1>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[C:3]([CH3:4])[CH:26]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(C(C)(C)C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
A 250 mL round bottom flask was charged with tetramethylethylene diamine (5.6 mL, 37 mmol) in THF (34 mL). After the mixture was cooled to −92° C. (N2(liq)/CH2Cl2 bath), sec-BuLi (26.5 mL, 37 mmol, 1.4M solution in cyclohexane) was added, followed by the dropwise addition of a solution of 4-tert-butylbenzoic acid (3 g, 16.8 mmol) dissolved in THF (22 mL). After stirring for 1 h, methyliodide (4.5 mL, 72.4 mmol) was added to mixture at −80° C. After stirring for 10 min at −80° C., the reaction mixture was quenched H2O (20 mL). Upon warming to room temperature, the aqueous phase adjusted to pH=2 with aqueous HCl (1M). The aqueous phase was extracted with EtOAc (2×15 mL), and the combined organic extracts were dried with Na2SO4 and concentrated. The residue was chromatographed with (gradient, 10%-60% EtOAc/hexanes) to afford 630 mg (20%) 101a.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](Cl)(Cl)=[O:25].C(N(CC)CC)C.N1C=CC=CC=1>C1(C)C=CC=CC=1.O>[C:7]1([CH2:6][N:5]2[CH:4]=[C:3]([O:2][CH3:1])[O:17][C:24]2=[O:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)CNCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cn(Cc2cccc3ccccc23)c(=O)o1
Temperature: 0 °C
Yield: 42.8 %

Procedure:
In 150 ml of toluene was dissolved 28.0 g (122 mmol) of N-(1-naphthyl) methyl -glycine methyl ester to obtain a toluene solution. To the resulting toluene solution was added an aqueous solution in which 12.9 g of anhydrous sodium carbonate had been dissolved in 200 ml of water. The mixture was cooled to 0° C. under stirring and 18.1 g (183 mmol) of a phosgene gas was blown to react these materials. After completion of the blowing, the mixture was reacted for 2 hours, and further stirred at room temperature for one hour. After completion of the reaction, the aqueous layer was separated from the resulting reaction mixture (1). The toluene layer was dried over anhydrous magnesium sulfate and filtered, and 24.7 g (244 mmol) of triethylamine was added to the filtrate and the mixture was heated to 120° C. for 12 hours. Then, 9.65 g (122 mmol) of pyridine was added to the mixture to effect reaction at 120° C. for 10 hours. After completion of the reaction, the resulting reaction mixture (2) was cooled to room temperature and precipitated amine hydrochloride was separated by filtration. The filtrate was washed with 100 ml of a saturated aqueous ammonium chloride solution and 100 ml of a saturated aqueous sodium chloride solution. The toluene layer was dried over anhydrous magnesium sulfate, followed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by applying to silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1 (volume ratio)) and recrystallization was carried out from a n-hexane and ethyl acetate mixed solution to obtain 13.3 g (52.2 mmol) of 3-(1-naphthyl)methyl-5-methoxy-2(3H)-oxazolone as white crystals. (Yield based on N-(1-naphthyl)-methyl-glycine methyl ester=43%)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1.[CH2:25]([NH:28][CH2:29][CH:30]=[CH2:31])[CH:26]=[CH2:27]>O1CCCC1>[CH2:25]([N:28]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[S:6][CH:7]=1)[CH2:29][CH:30]=[CH2:31])[CH:26]=[CH2:27]
Reactant: C=CCNCC=C
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)cc2C1=O
Solvent: C1CCOC1
Product: C=CCN(CC=C)Cc1csc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)n1
Yield: 65.3 %

Procedure:
A suspension of 1.0 g (0.00275 mol) of 3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 50 ml of tetrahydrofuran was treated wth 4.1 ml (0.033 mol) of diallylamine. After stirring at reflux for 18 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with dichloromethane/methanol 19:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 0.76 g (66%) of 3-(4-diallylaminomethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 125-127°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=[O:13])=[C:10]([CH3:11])[C:5]=2[N:4]=[CH:3]1>CO.[OH-].[Na+]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[C:10]([CH3:11])[C:5]=2[N:4]=[CH:3]1
Reactant: COC(=O)c1ccc2c(ncn2C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)ccc2c1ncn2C
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
A mixture of the methyl 1,4-dimethyl-1H-benzimidazole-5-carboxylate (78 mg, 0.38 mmol) in methanol (2 mL) and 5% aqueous sodium hydroxide solution (2 mL) was stirred at 60° C. for one hour. The reaction mixture was concentrated, diluted with water (10 mL) and the pH adjusted to 4 then saturated with solid sodium chloride. The aqueous mixture was extracted ethyl acetate (3×10 mL) and the combined extract was washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and concentrated to give 1,4-dimethyl-1H-benzimidazole-5-carboxylic acid (46 mg, 63% yield), MS (EI) for C10H10N2O2: 191 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[OH:13]S(O)(=O)=O.N([O-])=O.[Na+]>O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([OH:13])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Br)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-3-trifluoromethylaniline (48 g, 0.2 mol) was treated with water (300 ml) and concentrated H2SO4 (36 ml) at 60° C. for 1 hour. The resulting suspension was cooled in an ice bath and treated with sodium nitrite (16 g, 0.23 mol) in water (30 ml) maintaining the temperature of the reaction mixture below 10° C. The resulting solution was stirred at 0° C. for 1 hour, and then added portionwise, over 1 hour, to a 25% H2SO4 aqueous solution (160 ml) whilst steam distilling. After collecting approximately 1 liter of distillate, the aqueous distillate was extracted with ether and the organic solution dried using MgSO4, filtered and concentrated. The product, 4-bromo-3-trifluoromethylphenol, was obtained by distillation under reduced pressure. Yield 18.0 g (37%); boiling point 68-71/1 mmHg.
Reaction SMILES: [OH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:14])=[O:13])=[CH:6][CH:5]=1)=[O:3].Cl.[CH3:16]O>>[CH3:16][O:3][C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([CH3:14])=[O:13])=[CH:6][CH:5]=1)=[O:1]
Reactant: CO
Reactant: CC(=O)CCc1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)c1ccc(CCC(C)=O)cc1

Procedure:
Methyl 2-(4-hydroxycarbonylphenyl)ethyl ketone was esterified by reaction with methyl alcohol and hydrochloric acid to provide methyl 2-(4-methoxycarbonylphenyl)ethyl ketone. The ketone was condensed with optically active S-α-methylbenzylamine, and the imine which was formed was reduced to provide N-(α-methylbenzyl)-1-methyl-3-(4-methoxycarbonylphenyl)propylamine. The amine was converted to the hydrochloride salt, and fractional crystallization of the salt thus formed afforded optically active S-N-(α-methylbenzyl)-1-methyl-3-(4-methoxycarbonylphenyl)propylaminium chloride. M.P. 198°-205° C. [α]D -81.2° (MeOH).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([N+:77]([O-:79])=[O:78])=[CH:73][CH:72]=3)=[O:68])[CH2:63]2)[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]5[CH:72]=[CH:73][C:74]([N+:77]([O-:79])=[O:78])=[CH:75][CH:76]=5)=[O:68])[CH2:63]4)[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 88.3 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.27 g, 2.14 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidine diastereomer B (1.14 g, 2.15 mmol, compound of Reference Example 16) to obtain p-nitrobenzyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidin-4ylthio]-1-carbapen-2-em-3-carboxylate diastereomer B (1.65 g, yield: 88.3%).