Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:16])[C:5]1[N:10]=[C:9]([N:11]([CH3:15])[CH2:12][CH2:13]O)[CH:8]=[CH:7][CH:6]=1.[CH3:17][O:18][C:19](=[O:32])[CH:20]([O:29][CH2:30][CH3:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.[OH2:33]>C1COCC1>[CH3:17][O:18][C:19](=[O:32])[CH:20]([O:29][CH2:30][CH3:31])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:2][CH2:3][N:4]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:11]([CH2:12][CH2:13][S:28][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][CH:20]([O:29][CH2:30][CH3:31])[C:19]([O:18][CH3:17])=[O:33])=[CH:27][CH:26]=3)[CH3:15])[N:10]=2)[CH3:16])=[CH:24][CH:23]=1
Reactant: CN(CCO)c1cccc(N(C)CCO)n1
Reactant: O
Reactant: CCOC(Cc1ccc(S)cc1)C(=O)OC
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(SCCN(C)c2cccc(N(C)CCSc3ccc(CC(OCC)C(=O)OC)cc3)n2)cc1)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-({6-[(2-hydroxy-ethyl)-methyl-amino]-pyridin-2-yl}-methyl-amino)-ethanol (intermediate 4) (38 mg, 0.17 mmol) in dry THF (3.5 ml) was added at 0° C. under nitrogen tributylphosphine (100 mg, 0.50 mmol) and 2-ethoxy-3-(4-mercapto-phenyl)-propionic acid methyl ester (intermediate 2) (98 mg, 0.41 mmol). The reaction mixture was stirred for 15 min. and azodicarboxylic dipiperidine (126 mg, 0.50 mmol) was added. The reaction was stirred for 6 h, after which water (5 ml) was added and the mixture was extracted with methylene chloride (3×20 ml). The combined organic phases were dried (MgSO4), filtered and evaporated. The crude product was purified on column chromatograph using heptanes: ethyl acetate (3:1) as eluent to give the title compound in 85 mg (75%) yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[CH:7]([N:8]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
74 mg of tert-butyl(benzhydrylideneamino)acetate, 2.0 mg of an optically active quaternary ammonium salt compound (R,R)-(29), and 36 μl of benzylbromide were added to 2 ml of a toluene solvent at 0° C. 0.5 ml of 50% KOH aqueous solution was added dropwise to the resulting solution while stirring. The reaction solution was stirred for 8 hours at 0° C. and thereafter extracted by adding water and ether. The reaction product was purified by column chromatography (hexane: ether=15:1) to obtain targeted tert-butyl-2-(benzhydrylideneamino)-3-phenylpropionate (yield was 95%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:22])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.1 %

Procedure:
3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid (0.20 g, 0.64 mmol) as dissolved in N,N-dimethylformamide (3 ml), and glycine tert-butyl ester (0.11 g, 0.67 mmol), WSC (0.25 g, 1.3 mmol) and HOBt (0.18 g, 1.3 mmol) were added successively thereto. The reaction mixture was stirred at room temperature for 17 hrs, concentrated under reduced pressure and combined with ethyl acetate and water. 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 (15 g) column chromatography. The fractions eluted with hexane-ethylacetate (1:1, v/v) were collected and concentrated to give the titled compound (0.27 g, 99%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH:32]1[C:37]([CH:38]=[O:39])=[CH:36][C:35]2[O:40][CH2:41][O:42][C:34]=2[CH:33]=1>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:38]([OH:39])[C:37]1[CH:32]=[CH:33][C:34]2[O:42][CH2:41][O:40][C:35]=2[CH:36]=1)(=[O:9])=[O:10]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2ccc3c(c2)OCO3)sc2ncccc12
Reaction time: 1 h
Yield: 43.3 %

Procedure:
To a solution of N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)thieno[2,3-b]pyridine-3-sulfonamide (0.25 g, 0.61 mmoles) in THF (10 ml) at −78° C. was added t-BuLi (1.7 M, 0.46 ml, 0.79 mmoles). Thirty minutes later piperonal (0.14 g, 0.91 mmoles) in THF (2 ml) was added via cannula, as a solution. The cooling bath was removed and the reaction was stirred 1 hr. at ambient temperature and then diluted with EtOAc (50 ml) and washed with H2O (2×75 ml). The organic layer was dried (MgSO4), filtered and concentrated. Flash chromatography (40% EtOAc/hexanes) provided 0.15 g (44%) of the title compound as a white foamy solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[N:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[C:31](=[O:35])[N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:29][CH:28]=2)[CH:34]=[N:33]1)[CH3:12]
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=c1[nH]ncn1-c1ccc(-n2cccn2)cc1
Product: C[C@@H](n1ncn(-c2ccc(-n3cccn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(1H-1-pyrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 11 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1H-1-pyrazolyl)phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 19).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([N:10]([CH2:12][C:13]1[S:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1)[CH3:11])[CH3:9].[CH3:41][NH:42][CH2:43][CH3:44]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:39]([S:36]([N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:15]4[CH:14]=[C:13]([CH2:12][N:10]([CH3:11])[CH2:8][C:9]5[CH:41]=[N:42][CH:43]=[CH:44][CH:2]=5)[S:17][CH:16]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:31][CH2:32]1)(=[O:37])=[O:38])[CH3:40]
Reactant: CCNC
Reactant: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5cccnc5)c4)cc23)CC1
Yield: 14.3 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting methyl(3-pyridinylmethyl)amine (122 mg, 1.0 mmol) for N-methylethanamine to afford 9.5 mg of the title compound (14.3%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([CH2:25][NH:26][CH2:27][CH2:28][CH3:29])[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]#[C:32]Br>C(O)C>[CH2:1]([O:8][C:9](=[O:30])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:19]=[C:20]3[C:21](=[CH:22][CH:23]=2)[N:24]=[C:32]([NH2:31])[N:26]([CH2:27][CH2:28][CH3:29])[CH2:25]3)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CBr
Reactant: CCCNCc1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1N
Solvent: CCO
Product: CCCN1Cc2cc(Oc3cccc(NC(=O)OCc4ccccc4)c3)ccc2N=C1N
Temperature: 25 °C

Procedure:
A mixture of [3-(4-Amino-3-propylaminomethyl-phenoxy)-phenyl]-carbamic acid benzyl ester (0.032 mol) and cyanogen bromide (0.035 mol) in ethanol (250 mL) was stirred and refluxed for 2 hours, then the reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was converted into its free base with a NaOH solution and the resulting mixture was extracted with CH2Cl2. The organic layer was separated and the solvent was evaporated, then the residue was stirred in diisopropyl ether, filtered off and dried under vacuum to yield the title compound as a solid.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:37]([NH:44][C:45](=[O:51])[C@H:46]([CH:48]([CH3:50])[CH3:49])[NH2:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:44]([CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:45](=[O:51])[C@H:46]([CH:48]([CH3:50])[CH3:49])[NH2:47])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)[C@H](N)C(=O)NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 71.6 %

Procedure:
Using the procedure described in Example 3, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (109.1 mg, 0.37 mmol, 1.0 eq), triethylamine (156 uL, 1.12 mmol, 3.0 eq), and THF (1.5 mL), was treated with isobutyl chloroformate (53 uL, 0.41 mL, 1.1 eq), then with L-valine benzylamide (117.5 mg, 570 umol, 1.5 eq). Workup as before provided 127 mg (71%) of L-valine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide as a white foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][CH2:29][C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[N:34]1([C:30](=[O:31])[CH2:29][O:28][C:26]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:27]=2[C:18]([NH:17][C:13]2[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:9]=[CH:10]4)=[N:19][CH:20]=[N:21]3)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: COC(=O)COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Reactant: C1COCCN1
Product: O=C(COc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12)N1CCOCC1
Yield: 58 %

Procedure:
Using the same procedure as in Example 5, methyl [(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]acetate (180 mg, 0.40 mmol) was reacted with morpholine (0.346 ml, 3.96 mmol) to give the title compound as a solid (115 mg, 59%), except that the reaction was run at 60° C. for 32 hours in the presence of 3 Å molecular sieve. NMR Spectrum 3.68-3.52 (m, 8H), 5.20 (s, 2H), 5.77 (s, 2H), 6.96 (d, 1H), 7.23 (d, 1H), 7.30 (m, 1H), 7.37 (d, 1H), 7.77-7.68 (m, 3H), 7.90 (m, 1H), 8.15 (s, 1H), 8.53 (s, 2H), 8.56 (s, 1H), 11.18 (br s, 1H); Mass spectrum MH+ 496.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][CH2:20][NH:21][C:22]2[C:23]([CH3:29])=[N:24][C:25]([Br:28])=[CH:26][CH:27]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:3])[N:21]([C:22]3[C:23]([CH3:29])=[N:24][C:25]([Br:28])=[CH:26][CH:27]=3)[CH2:20][CH2:19]2)[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1(CCNc2ccc(Br)nc2C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(Br)ccc1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[2-(6-bromo-2-methyl-pyridin-3-ylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.44 g, 0.94 mmols) in THF (20 mL) was added a solution of potassium t-butoxide (1 M in THF) (2 mL), and allowed to stir at room temperature for 4 hours. The reaction mixture was then diluted with ethyl acetate (20 mL), quenched with water (5 mL). The aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were washed with brine, and concentrated under vacuum to afford crude product. Purification on silica gel eluting with ethyl acetate in heptanes (0-75%) afforded 0.238 (60%) of title compound.
Reaction SMILES: FF.[CH2:3]([CH2:6]OC)OC.[CH2:9]([Li])[CH2:10][CH2:11][CH3:12].[C:14]1([Si:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([Cl:22])Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.CCCCCCC>[Cl:22][Si:20]([C:6]1[CH:3]=[CH:16][CH:15]=[CH:14][CH:19]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:14]1[C:16]2[CH:15]=[CH:28][CH:23]=[CH:24][C:17]=2[C:18]2[C:19]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: COCCOC
Reactant: [Li]CCCC
Reactant: Cl[Si](Cl)(c1ccccc1)c1ccccc1
Agent: FF
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cl[Si](c1ccccc1)(c1ccccc1)C1c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
80 g (0.48 mol) of fluorine and 160 ml of toluene/12.8 ml (0.12 mol) of dimethoxyethane (DME) were placed in a reaction vessel and admixed with 182 ml (0.48 mo) of a 20% strength solution of butyllithium in toluene. The suspension was stirred for another 2 hours at 50° C. The suspension was diluted with 400 ml of heptane, cooled to −30° C. and added to a solution, cooled to −30° C., of 182 g (0.72 mol) of diphenyldichlorosilane in 400 ml of heptane. After stirring for 1.5 hours at room temperature, the suspension was heated to 60° C. and the lithium chloride was filtered off. After removal of the solvent, the solid which precipitated was suspended in heptane, filtered off, washed with heptane until virtually colorless and dried under reduced pressure. 123 g (66%) of 2a were obtained.
Reaction SMILES: [Br:1]Br.[CH2:3]([CH2:10][C:11](=[O:13])[CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CO>[Br:1][CH2:12][C:11](=[O:13])[CH2:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: CC(=O)CCc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(CBr)CCc1ccccc1
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A freshly prepared solution of bromine (258.9 g) in methanol (600 mL) was added dropwise during 1 h 20 min to a stirred solution of benzylacetone (222.3 g) in methanol (600 mL) at 7–10° C. An exothermic reaction took place, and to maintain the necessary temperature (7–10° C.), the flask should be immersed in a ice-water bath. When orange-red color of bromine disappeared, water (1500 mL) was added to the mixture and the obtained mixture was stirred overnight. The organic layer (on the bottom) was separated, water phase was extracted with dichloromethane (2×600 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The oily residue was dissolved in hexane (2500 mL) and the obtained solution was kept overnight at −10° C. Precipitated fine crystals (needles) were filtered off, washed on filter with cold hexane, dried under reduced pressure at room temperature to give 1-bromo-4-phenyl-2-butanone (213.0 g, 63% yield), mp 39–40° C. 1H NMR (CDCl3) δ 2.95–3.00 (m, 4H); 3.83 (s, 2H); 7.16–7.30 (m, 5H).
Reaction SMILES: N#N.[CH2:3]([CH:5]1[O:7][CH2:6]1)Cl.[C:8]1([O:18][CH3:19])[C:9](=[CH:11][CH:12]=[C:13]([CH:17]=1)[CH2:14][CH:15]=[CH2:16])[OH:10].[OH-].[Na+]>>[CH2:3]([O:10][C:9]1[CH:11]=[CH:12][C:13]([CH2:14][CH:15]=[CH2:16])=[CH:17][C:8]=1[O:18][CH3:19])[CH:5]1[O:7][CH2:6]1
Reactant: C=CCc1ccc(O)c(OC)c1
Reactant: ClCC1CO1
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1ccc(OCC2CO2)c(OC)c1

Procedure:
A 2,000 mL, 3-necked, round-bottom flask was equipped with a mechanical stirrer, a 250 mL pressure equalizing addition funnel and a reflux condenser. The addition funnel served as the N2 inlet and the reflux condenser served as the N2 outlet. The flask was purged with a vigorous stream of N2 for 10 min. prior to its use. The flask was charged with epichlorohydrin (740 g, 8.0 mol) and eugenol (328 g, 2.0 mol). These were heated to ca. 80° using a heating mantle while stirring at a moderate rate (ca. 500 rpm). The 50% NaOH (168 g, 2.0 mol) was placed in the addition funnel and was added dropwise to the reaction flask over a 3 hour period. The mixture was allowed to cool and was filtered through a Buchner funnel. The epichlorohydrin was removed by rotary evaporation. The residue was taken up in CH2Cl2 (800 mL) and was washed with 10% NaOH (100 mL) brine and dried (Na2SO4). The crude product was vacuum distilled through a 10 cm Vigreux column to yield 4-allyl-2-methoxyphenyl glycidyl ether, i.e., ##STR22##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13](N)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[Li+].C[Si]([N-:26][Si](C)(C)C)(C)C.F[C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=[O:35]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:40]3[C:32]([NH2:26])=[C:33]([CH:37]=[CH:38][CH:39]=3)[C:34]([OH:36])=[O:35])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=C(O)c1ccccc1F
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Nc1ccc(CCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c(C(=O)O)cccc1-c1ccc(CCc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a cold solution of 4-[2-(4-chloro-3-trifluoromethylphenyl)ethyl]-benzenamine (4.33 g, 14.45 mmol) in THF (50 mL) at −78° C., was added LHMDS (43.35 mL, 43.35 mmol) (1M/THF) dropwise. Allowed the reaction mixture to stir for 10 minutes at −78° C. A solution of 2-fluorobenzoic acid (2.02 g, 14.45 mmol) in THF (50 mL) was added dropwise. The mixture was stirred for 2 hours at −78° C., then warmed to room temperature and let stir for additional 3 hours. The reaction mixture was concentrated in vacuo (40° C.) to remove the organic solvent. This residue was acidified to pH 3 with 3N HCl (aq.). This precipitate was collected by filtration, rinsed with 10% HCl (40 mL), and dried in vacuum for overnight to give as a pale solid, 4.3 g (10.24 mmol, 70%) of the desired product. mp 150-152° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:5])C.CO.O.[OH-].[Na+]>C1COCC1>[F:17][C:11]1[CH:10]=[C:9]([CH:7]2[CH2:8][CH:6]2[C:4]([OH:5])=[O:3])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CCOC(=O)C1CC1c1ccc(OC)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2CC2C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid ethyl ester (1.15 g, 4.83 mmol) was dissolved in THF (6 mL), methyl alcohol (1 mL) and water (1 mL), an excess amount of sodium hydroxide was added, and then the mixture was stirred at room temperature for 4 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and 1N HCl was added to adjust the pH of the solution to 2. The organic layer obtained by the extraction with ethyl acetate was separated, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.985 g, 97%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:22]([O-:24])=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([CH2:19][O:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].C(=O)([O-])O.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:22]([O:24][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:23])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([CH2:19][O:20][CH3:21])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: COCc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: CC(C)(C)C(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1ncn2cc(C3=C(C(=O)OCOC(=O)C(C)(C)C)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Temperature: -30 °C
Reaction time: 1 h

Procedure:
To a solution of 40 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.6 ml of DMF was added 4.2 mg of sodium hydrogen carbonate, and the mixture was cooled to −30° C. under the atmosphere of argon. Pivaloyloxymethyl iodide (34 mg) was added, and the mixture was stirred for 1 hour, diluted with 30 ml of ethyl acetate, and washed with 20 ml of saturated aqueous saline and 20 ml of semi-saturated squeous saline. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a volume of about 1 ml. The concentrate was purified by column chromatography on silica gel (chloroform:methanol=95:5) to give the title compound was obtained in a yield of 18.4 mg.
Reaction SMILES: [CH:1]1C2C(=O)NC3C=CC=CC=3NC=2C=CC=1.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30](=[O:37])[NH:29][C:28]3[CH:38]=[CH:39][CH:40]=[CH:41][C:27]2=3)=[O:25])=[CH:19][CH:18]=1>>[CH3:1][N:17]1[CH2:18][CH2:19][C:20]([CH2:23][C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30](=[O:37])[NH:29][C:28]3[CH:38]=[CH:39][CH:40]=[CH:41][C:27]2=3)=[O:25])=[CH:21][CH2:22]1
Reactant: O=C1Nc2ccccc2N(C(=O)Cc2ccncc2)c2ccccc21
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Product: CN1CC=C(CC(=O)N2c3ccccc3NC(=O)c3ccccc32)CC1

Procedure:
from 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 4-pyridioacetic acid chloride hydrochloride via 5,10-dihydro-5-[(4-pyridinyl)acetyl]-11H-dibenzo[b,e]-[1,4]diazepin-11-one and 5,10-dihydro-5-[(4-pyridinyl)acetyl]-11H-dibenzo[b,e][1,4]diazepin-11-one methoiodide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[NH:7][C:6]=2[N:14]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:23])C=1Cl>C1COCC1.O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[C:12](=[O:23])[CH2:11][CH2:10][CH2:9][C:8]=3[NH:7][C:6]=2[N:14]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: Brc1ccc2c3c([nH]c2n1)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCCc2[nH]c3nc(Br)ccc3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.2 %

Procedure:
A solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (3.84 g, 15.2 mmol) in THF (135 mL) and H2O (15.2 mL) was cooled to 0° C. and treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.92 g, 30.5 mmol) in THF (60.3 mL) at such a rate that the reaction mixture did not exceed 0° C. The resulting solution was warmed to ambient temperature and stirred for 5 h. The solution was diluted with saturated NaHCO3 solution (100 mL), and the aqueous solution was extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (80 g ISCO dry load 80:18:2 CH2Cl2/MeOH/NH4OH, 1000 mL) followed by trituration with MeOH provided the title compound (1.58 g, 39%) as an off-white solid: 1H NMR (500 MHz, THF-d8) δ 8.23 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0, 1H), 4.73 (s, 1H), 3.02 (t, J=8.0 Hz, 2H), 2.51-2.47 (m, 2H), 2.27-2.22 (m, 2H); ESI MS m/z 265 [M+H]+.