Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]([CH3:19])=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=[CH:4][CH:3]=1.C(Cl)(Cl)=O.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.C1COCC1.CS(C)=O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]2[NH:8][CH:9]=[C:10]([CH3:19])[C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=Cc1ccc(F)cc1)CNC(=O)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)Cl
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using the general procedure of N. Engel and W. Steglich, Angew. Chem. Int. Ed. Engl., 17, 676 (1978), to a slurry at room temperature of 28.7 g (0.1 mole) of 4-fluoro-N-[3-(4-fluorophenyl)-2-methyl-2-propenyl]benzamide in 100 ml toluene containing 1 ml DMF, stirred under nitrogen, with a dry ice condenser attached, was added dropwise a solution of 39.6 g (28.3 ml, 0.4 mole) of phosgene in 100 ml toluene. The mixture was warmed slightly with a heat gun, then stirred at room temperature overnight. The solution was concentrated by rotary evaporation to give a yellow oil. This was dissolved in 100 ml dry THF (small amount of insoluble solid removed by decanting the solution) and the solution was added dropwise to a cool (15°) solution of 33.5 g (0.3 mole) of potassium t-butoxide in 150 ml DMSO. The dark purple solution was stirred at ~20° C. for 1 hour, then was poured into 1 liter ice water. This was extracted with ether and the ether layers backwashed with water. The ether layer was dried and concentrated and the residue was chromatographed on 900 g of silica gel, eluting with hexane containing 10-40% toluene, to give, after recrystallization from methyl cyclohexane, 10.8 g (40%) of white product, m.p. 126°-7° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-(4-tert-butyldimethylsilyloxy-phenyl)-1-propanol (P. A. Grieco and C. J. Markworth, Tet. Lett., 1999, 40: 665) (2.86 g, 10.73 mmol) in dry dichloromethane (25 ml), was cooled to 0-5° C. and treated with triethylamine (2.4 ml, 17.0 mmol). Then methanesulfonyl chloride (1.08 ml, 14 mmol) was added dropwise over 10 minutes. The reaction mixture was stirred at 0-5° C. for 1 hour, then quenched with sat. sodium bicarbonate, diluted with ethyl acetate (300 mL), washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was filtered aon a silica gel pad (toluene/ethyl acetate 95:5) to give the title material (3.68 g, 100%) as a clear oil.
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:16](=O)([O-])[O-].[K+].[K+].BrC[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:16][C:33]2[CH:32]=[CH:31][C:30]([C:26]3[C:25]([C:36]([O:38][CH3:39])=[O:37])=[CH:24][CH:29]=[CH:28][CH:27]=3)=[CH:35][CH:34]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c(CBr)cccc1-c1ccccc1
Reactant: CCCCc1c[nH]c2ccccc2c1=O
Agent: [K+]
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2c1=O
Yield: 94.1 %

Procedure:
Using the procedure of Example 1, 4.02 g of the compound of Step E of Example 1 and 5.52 g of potassium carbonate and 6.2 g of methyl bromomethyl-(1,1'biphenyl)-2-carboxylate (preparation according to EP 0,253,310) were reacted to obtain after chromatography on silica (eluant: methylene chloride-methanol (98-2)), 8 g of the desired product.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:22])[C:9]([N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[CH:12]1)=[O:10])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42](=S)=[S:43]>C1(C)C=CC=CC=1>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:22])[C:9]([N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[CH:12]1)=[O:10])=[C:42]=[S:43]
Reactant: CN(CCCCN=[N+]=[N-])C(=O)n1cnc(-c2ccccc2)c1
Reactant: S=C=S
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(CCCCN=C=S)C(=O)n1cnc(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a compound 48 (0.85 mmol) in anhydrous toluene (20 mL) was added triphenylphosphine (1 mmol) and reaction mixture was stirred at 50° C. for 2 h. Carbondisulfide (10 mmol) was added and the stirring continued at 50° C. for 4 h. Reaction was cooled to r.t. and solvent was evaporated on Rotavapor to give a crude compound which on purification by Biotage SP1 gave a pure isothiocyante 49.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]([Cl:12])=[C:8]([CH2:10][OH:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(C1N(CC2C=CC(C3C=CC=CC=3C(OC(C)(C)C)=O)=CC=2)C(Cl)=C(CO)N=1)CCC>>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30]([C:31]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]([Cl:12])=[C:8]([CH:10]=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CO)c(Cl)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCc1nc(CO)c(Cl)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCCc1nc(C=O)c(Cl)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
This Step A compound can be prepared as described in Example 3, Step A, except that 2-butyl-1-[(2'-{N-triphenylmethyltetrazol-5-yl}biphen-4-yl)-methyl]-5-chloro-1H-imidazole-4-methanol (European Patent Applications 253,310 and 291,969) can be used as the starting material for the oxidation instead of 2-butyl-1-[(2'-t-butoxycarbonylbiphen-4-yl)methyl]-5-chloro-1H-imidazole-4-methanol.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:34]=[CH:33][CH:32]=[C:31]5[C:27]=4[CH:28]=[N:29][N:30]5[CH3:35])=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.Cl.C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:34]=[CH:33][CH:32]=[C:31]4[C:27]=3[CH:28]=[N:29][N:30]4[CH3:35])=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc3c2cnn3C)=CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
A solution of (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (0.025 g, 0.05 mmol) in tetrahydrofuran (5 mL) was treated with 1M aqueous hydrochloric acid (1 mL) and the resulting mixture was stirred at room temperature overnight. The mixture was partioned between ethyl acetate and water. The aqueous phase was made basic with 1N aqueous sodium hydroxide and extracted with ethyl acetate twice. The combined organic phase was concentrated in vacuo and the residue purified by flash column chromatography (silica gel, 0% to 40% tetrahydrofuran/ethyl acetate) which afforded (S)-4-methyl-2-[4-(1-methyl-1H-indazol-4-yloxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-pentanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (0.013 g, 56%) as a white solid: HR-ES-MS m/z calculated for C24H30N6O5 [M+H]+ 483.2351, observed 483.235; 1H NMR (300 MHz, CDCl3) δ ppm 0.97 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 1.59 (br. s., 1H), 1.69-1.97 (m, 2H), 2.72 (br. s., 2H), 3.56 (dd, J=11.8, 4.8 Hz, 1H), 3.68 (dd, J=11.8, 3.3 Hz, 1H), 4.06-4.16 (m, 5H), 4.20 (d, J=18.4 Hz, 1H), 4.48 (d, J=18.4 Hz, 1H), 4.88 (t, J=7.8 Hz, 1H), 5.03 (s, 1H), 6.66 (d, J=2.1 Hz, 1H), 6.94 (d, J=7.2 Hz, 1H), 7.29-7.43 (m, 4H), 7.96 (s, 1H), 9.39 (br. s., 1H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([CH2:13]I)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1>>[C:1]([O:5][C:6]([C@@H:8]([CH2:13][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1nccc(Cl)n1
Reactant: COC(=O)[C@@H](CI)C(=O)OC(C)(C)C
Product: COC(=O)[C@H](Cc1ccnc(C(F)(F)F)n1)C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized in a manner analogous to that described Example 408, using (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and 4-chloro-2-(trifluoromethyl)pyrimidine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH2:12].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH:12][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: CCCCCC(CCCN)OC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCCC(CCCNS(C)(=O)=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred, ice cold solution of 4-(2-tetrahydropyranyloxy)nonylamine (7.29 g., 0.03 mole) in pyridine (40 ml.) is added methanesulfonylchloride (3.42 g., 0.03 mole) at such a rate as to maintain the reaction temperature at 5°-10° C. The reaction is then allowed to stand at room temperature for 6 hours, poured into ice water (200 ml.) and extracted with ether (2 × 100 ml.). The ether is washed with ice cold 5% hydrochloric acid (2 × 20 ml.), with brine (2 × 25 ml.), and then dried over sodium sulfate. Evaporation in vacuo affords N-[4-(2-tetrahydropyranyloxy)nonyl]methanesulfonamide as a pale yellow liquid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([CH3:15])=[CH:8][CH2:9][CH2:10][C:11](Cl)([CH3:13])[CH3:12])(=O)C.[H][H].[O:18]1CCOCC1>[Pd]>[OH:18][CH2:12]/[C:11](=[CH:10]\[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][OH:4])[CH3:15])/[CH3:13]
Reactant: [H][H]
Reactant: C1COCCO1
Reactant: CC(=O)OCCC(C)=CCCC(C)(C)Cl
Agent: [Pd]
Product: C/C(=C/CCC(C)CCO)CO

Procedure:
1 mole of 7-chloro-3,7-dimethyl-3-octenyl acetate was dissolved into 200 milliliters of dioxane and the solution was subjected to hydrogenation reaction in a reactor containing 20 grams of activated palladium black at about 25° C. under normal pressure until hydrogen was no more absorbed. Then, the palladium black was filtered off from the reaction mixture, and dioxane was distilled off from the filtrate. To the resulting residue were added 50 milliliters of water, 200 milliliters of acetone and 10 grams of silver oxide, and the mixture was heated under reflux for 72 hours. After filtrating off precipitate contained in the reaction mixture, acetone and water were distilled off from the filtrate. By distillation of the residual liquid a fraction boiling in the temperature range of 135°-145° C./4.0mmHg was collected, whereby 0.6 mole of hydroxycitronellol was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9]N=C[C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:37](=[O:38])[NH:36][C:35]3[CH:39]=[CH:40][S:41][C:34]=3[CH:33]=2)[CH2:28][CH2:27]1.[CH:42]1C=CC2N(O)N=NC=2[CH:47]=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:15][C@@H:14]([CH2:16][C:17]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[C:37](=[O:38])[NH:36][C:35]5[CH:39]=[CH:40][S:41][C:34]=5[CH:33]=4)[CH2:30][CH2:31]3)=[O:19])[C:13](=[O:20])[N:12]([CH2:21][C:22]([CH3:25])([CH3:23])[CH3:24])[CH2:11][C:5]2=[C:6]2[C:10]=1[NH:9][CH:47]=[CH:42]2
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)O)C1=O
Reactant: On1nnc2ccccc21
Reactant: O=c1[nH]c2ccsc2cc1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ccc23)C[C@@H](CC(=O)N2CCC(c3cc4sccc4[nH]c3=O)CC2)C1=O
Yield: 57.7 %

Procedure:
To a solution of (S)-2-(4-chloro-9-neopentyl-8-oxo-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl)acetic acid (123 mg, 0.338 mmol), 6-(piperidin-4-yl)thieno[3,2-b]pyridin-5(4H)-one (79 mg, 0.338 mmol), HOBT (56.9 mg, 0.372 mmol), EDC (71.3 mg, 0.372 mmol) in DMF (5 mL) was added DIEA (0.295 mL, 1.690 mmol) at rt, and the mixture was stirred over night. Partial of the solvent was removed under N2 at 60° C., and the residue was purified on reverse phase PrepHPLC to afford the expected product, (S)-6-(1-(2-(7-chloro-2-neopentyl-3-oxo-1,2,3,4,5,8-hexahydroazepino [3,4-e]indol-4-yl)acetyl)piperidin-4-yl)thieno[3,2-b]pyridin-5(4H)-one (113 mg, 57.6%) as a white solid. 1H-NMR (400 MHz, CHLOROFORM-D) δ ppm 0.80 (d, J=6.80 Hz, 11 H) 1.52 (ddd, J=12.46, 8.06, 4.41 Hz, 1H) 1.87-1.96 (m, 1H) 2.00 (s, 1H) 2.38-2.49 (m, 1H) 2.75 (td, J=12.84, 2.01 Hz, 1H) 2.94-3.04 (m, 1H) 3.07-3.18 (m, 4 H) 3.66 (dd, J=13.60, 2.77 Hz, 1H) 3.96-4.06 (m, 1H) 4.23 (s, 1H) 4.61-4.72 (m, 2H) 5.51 (d, J=17.37 Hz, 1H) 7.04 (dd, J=5.29, 2.01 Hz, 1H) 7.22 (s, 1H) 7.70 (dd, J=5.41, 2.14 Hz, 1H) 7.89 (d, J=18.38 Hz, 1H) 8.24 (s, 1H); Mass spec. 580.25 (MH+), Calc. for C30H34ClN5O3S 579.21.
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH:14]([OH:23])[C:15]2[S:19][C:18]3=[CH:20][N:21]=[CH:22][N:17]3[CH:16]=2)[CH2:12][C@H:11]([S:24][C:25]2[C@H:26]([CH3:42])[C@@H:27]3[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:28]3[C:29]=2[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:28]2[C:29]([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[C:25]([S:24][C@H:11]3[CH2:12][C@@H:13]([CH:14]([OH:23])[C:15]4[S:19][C:18]5=[CH:20][N:21]([CH3:2])[CH:22]=[N+:17]5[CH:16]=4)[N:9]([C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[O:8])[CH2:10]3)[C@H:26]([CH3:42])[C@H:27]12)[CH3:39]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3cn4cncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: CI
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(O)c3c[n+]4cn(C)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Iodomethane (0.6 ml) is added to 54.0 mg of allyl (1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate (stereoisomer A) described in Example 16-a), and the mixture is stirred in an argon atmosphere in a light-shielded state at room temperature for 5 hr. The excess reagent is removed by evaporation under reduced pressure to give 68.9 mg of allyl(1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[(3S,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(6-methylimidazo[5,1-b]thiazolium-2-yl)methyl]pyrrolidin-3-yl]thio-1-methylcarbapen-2-em-3-carboxylate iodide (stereoisomer A) as a slightly yellow amorphous material.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH:11]([O:15][CH2:16][CH2:17][CH3:18])[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:19](=O)([O-])O.[Na+].CI>CN(C)C=O>[CH3:19][O:13][C:12](=[O:14])[CH:11]([O:15][CH2:16][CH2:17][CH3:18])[CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2
Reactant: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Crude rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid was dissolved in 5 ml N,N-dimethylformamide, 0.54 g of sodium hydrogencarbonate was added followed by 0.32 nm of methyl iodide. The mixture was stirred at r.t. for 7 hours, then poured into ice water and extracted 3 times with ethyl acetate; after drying over MgSO4 and evaporation, the crude product was purified by chromatograph) (silicagel, eluent: gradient of n-heptane/ethyl acetate) to yield 0.47 g of rac-3-(1H-indol-5-yl)-2-propoxy-propionic acid methyl ester as light yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][O:9][CH2:8][CH2:7][NH:6]1)[CH3:3].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH:17]([C:21](Cl)=[O:22])[CH2:16][C:15]2=[O:24]>C(N(CC)CC)C>[ClH:11].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH:17]([C:21]([N:6]1[CH2:7][CH2:8][O:9][CH2:10][CH:5]1[CH2:4][N:2]([CH3:3])[CH3:1])=[O:22])[CH2:16][C:15]2=[O:24]
Reactant: CN(C)CC1COCCN1
Reactant: O=C1CC(C(=O)Cl)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Product: CN(C)CC1COCCN1C(=O)C1CC(=O)c2cc(Cl)ccc21
Product: Cl
Yield: 122.7 %

Procedure:
The procedure described in Example 24 was repeated, but using 0.90 g of 3-dimethylaminomethylmorpholine, 2.3 ml of triethylamine and 1.03 g of 5-chloro-3-oxoindan-1-carbonyl chloride, to afford 1.03 g of the title compound, melting at 230°-240° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:14]([O:18]C(C)(C)C)(=[O:17])[CH:15]=[CH2:16].C(O)(=O)C=C>>[O:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2](/[CH:16]=[CH:15]/[C:14]([OH:18])=[O:17])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1ccc(N2CCOCC2)nc1
Agent: C=CC(=O)O
Product: O=C(O)/C=C/c1ccc(N2CCOCC2)nc1
Yield: 41 %

Procedure:
Following the same procedure as described in Example 2, step 2 (scheme 2), but substituting compound 37 for compound 163, and compound 38 for acrylic acid, title compound 164 was obtained (41% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:13]2[O:17]C[CH2:15][O:14]2)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8]>CO.O1CCCC1.C(N(CC)CC)C.[C].[Pd]>[CH:7]([C:6]1[C:5]([OH:12])=[C:4]([CH:3]=[CH:2][CH:11]=1)[C:13]([O:14][CH3:15])=[O:17])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(C2OCCO2)c1O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(C=O)c1O
Yield: 85.3 %

Procedure:
86 g of methyl 5-chloro-3-(1,3-dioxolan-2-yl)-2-hydroxybenzoate are dissolved in a mixture of 700 ml of methanol and 50 ml of tetrahydrofuran, and 70 ml of triethylamine and 7 g of 10% palladium-carbon are added to the solution. The mixture is subjected to catalytic hydrogenation under atmospheric pressure. The reaction mixture is filtered and the filtrate is evaporated to remove solvent. 10% hydrochloric acid is added to the residue and the mixture is concentrated. Water is added to the residue and the aqueous mixture is extracted with ethyl acetate. The extract is dried and evaporated to remove solvent. The resultant crystals are collected, washed with cold ethanol and dried to give 51.1 g of methyl 3-formyl-2-hydroxybenzoate as colorless needles.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7](OC(OCC)OCC)C.[C:17]([OH:26])(=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH2:20].[OH-].[NH4+]>CO.CN(C)C=O>[NH:3]1[C:2]([N:1]2[C:17](=[O:26])[C:18]3[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:20]=[CH:7]2)=[N:6][N:5]=[N:4]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1nnn[nH]1
Reactant: Nc1ccccc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1c2ccccc2ncn1-c1nnn[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture was prepared from 10 g of 5-aminotetrazole and 50 ml N,N-dimethylformamide. This was heated to 100° C. and 17 g of triethoxymethane was added. The resulting mixture was stirred at 100° C. under nitrogen for 2 hours and then a solution of the ammonium salt of anthranilic acid (prepared from 16 g of anthranilic acid and 7.8 ml of 14.8M ammonium hydroxide in methanol, followed by removal of the methanol) in 40 ml of N,N-dimethylformamide was added. The mixture was stirred for 1 hour at 100° C., then cooled to room temperature and finally cooled in an ice bath to induce crystallization. The white crystals which formed were separated by filtration, washed with N,N-dimethylformamide and then with carbon tetrachloride, and vacuum oven dried to give the ammonium salt of 3-(1H-tetrazol-5-yl)4(3H)-quinazolinone.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[CH3:28])[CH2:23][OH:24]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:21]=[C:22]([CH2:23][OH:24])[CH:25]=[CH:26][C:27]=1[CH3:28])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccc(CO)cc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1cc(CO)ccc1C
Yield: 59.5 %

Procedure:
A solution of 3-butyryl-4-chloro-8-methoxyquinoline (0.80 g, 3 mmol) and 3-amino-4-methylbenzyl alcohol (0.48 g, 3.5 mmol) in dioxan (I0 ml) was heated at reflux for 1.5 hours, then the solvent evaporated. Aqueous sodium bicarbonate was added, the product extracted into dichloromethane, dried and evaporated. Recrystallisation from methanol gave 3-butyryl-4-(5-hydroxymethyl-2-methylphenylamino)-8-methoxyquinoline (0.65 g, 59%) 180°-181°.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:13]=[C:12]1[C:28]1[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=1)([OH:3])=[O:2].B(Br)(Br)Br.O>ClCCl>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]=[C:12]1[C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)([OH:3])=[O:2]
Reactant: COc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)n2CCCCCCCC(=O)O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCCCCCCn1c(-c2ccc(O)cc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.2 %

Procedure:
1-(7-Carboxyheptyl)-2-(4-methoxyphenyl)-4,5-diphenyl-imidazole (2.5 g) was added, in portions over 40 minutes, to a solution of boron tribromide (2.17 ml) in anhydrous dichloromethane (40 ml). The reaction was stirred at room temperature for 5 h, cooled and water (50 ml) was carefully added. The organic layer was removed and the aqueous layer was washed with dichloromethane (3×75 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Column chromatography on silica gel eluted with a dichloro-methane:methanol gradient and recrystallisation from ethanol/water and acetonitrile gave 1-(7-carboxy-heptyl)-2-(4-hydroxyphenyl)-4,5-diphenyl-imidazole (0.49 g, 20%) as a white solid, m.p. 171°-172°. Further material was obtained from the mother liquors (0.79 g, 33%) m.p. 167°. Found C: 76.85; H, 6.65; N, 6.20%; C29H30N2O3 requires: C, 76.63; H, 6.65; N, 6.16%;
Reaction SMILES: N1C2C=CC=CC=2NC=1.[F:10][CH:11]([F:21])[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.[NH2:22][C:23]1[C:31]([NH2:32])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[F:10][CH:11]([F:21])[C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[C:14]1[NH:32][C:31]2[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([OH:27])=[O:26])[C:23]=2[N:22]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: O=Cc1ccc(F)cc1C(F)F
Agent: c1ccc2[nH]cnc2c1
Product: O=C(O)c1cccc2[nH]c(-c3ccc(F)cc3C(F)F)nc12

Procedure:
The same general procedure outlined above for the preparation of benzimidazole was used employing 2-(difluoromethyl)-4-fluorobenzaldehyde 45 and 2,3-diaminobenzoic acid 1 as the starting materials to afford 2-(2-(difluoromethyl)-4-fluorophenyl)-1H-benzo[d]imidazole-4-carboxylic acid 46. MS (ESI) calcd for C15H9F3N2O2: 306.6; found: 307 [M+H].