Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[C:24]([CH2:25][C:26](O)=[O:27])=[CH:23][CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[N:20]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][C:26](=[O:27])[CH2:25][C:24]2[C:19]([CH3:18])=[N:20][C:21]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)O
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1

Procedure:
In analogy to the procedures described in example 26B] and 26C), 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. (2002), WO 2002/096895A1] was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-[4-({2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless amorphous solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:20]([OH:22])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(I)cc1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Product: COc1ccc(-c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 85 %

Procedure:
(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(4-methoxyphenyl)-1H-indol-3-yl)propanoic acid (1.12 g, 85%) was obtained from (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1H-indol-3-yl)propanoic acid and 1-iodo-4-methoxybenzene using the procedure described for (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(3-methoxyphenyl)-1H-indol-3-yl)propanoic acid. 1H NMR (400 MHz, DMSO-d6) δ 12.89-12.48 (m, 1H), 11.14 (s, 1H), 7.93-7.77 (m, 2H), 7.72-7.58 (m, 5H), 7.46-7.22 (m, 6H), 7.11-6.94 (m, 4H), 4.30 (dd, J=8.5, 6.0 Hz, 1H), 4.18-4.07 (m, 3H), 3.84-3.77 (s, 3H), 3.35 (m, 1H), 3.23-3.14 (m, 1H); [α]20D −9.44° (3.05 mg/mL, MeOH). LCMS retention time=1.810 min., m/z=533 (M+H), 97.3% purity. The LCMS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using The following set of conditions: PHENOMENEX® Luna 3 μm C18, 2×50 mm column, with a gradient of 0-100% B (B=90% HPLC grade acetonitrile/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade acetonitrile), in 2 minutes with a 1 minute hold at a flow rate of 1 mL/minute.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:5]=1>CO.[OH-].[Na+]>[C:33]1([CH2:32][O:31][C:18]2[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:39])=[O:2])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)c1cccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)c1
Yield: 70 %

Procedure:
A solution of 0.5 g of 3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid methyl ester in 15 mL of methanol and 5 mL of 1N sodium hydroxide was stirred at reflux for 2 hours. Workup as in Example 24 and crystallization from methanol gave 0.34 g (70% yield), mp 72°-74°of 3-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]benzoic acid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]2[C:21](=[O:22])[CH2:20][C:19]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:18]=3[CH:17]=[CH:16]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]2[C:21](=[O:22])[CH2:20][C:19]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:18]=3[CH2:17][CH2:16]2)[CH2:9]1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CC1CCCN(Cc3ccccc3)C1)C=C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CC1CCCNC1)CC2

Procedure:
14.3 g (0.0352 mol) of 3-[(N-benzyl-piperidin-3-yl)-methyl]7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one are hydrogenated in 120 ml of glacial acetic acid in the presence of 1.5 g of 10% palladium/charcoal for 4 hours at 50° C. under 5 bar of hydrogen. The catalyst is then removed by suction filtering, the glacial acetic acid is distilled off in vacuo and, after the addition of water, the residue is neutralized with potassium carbonate. The greasy precipitate is extracted with methylene chloride, the organic phase is dried over magnesium sulphate and concentrated by evaporation in vacuo. Yield: 9.3 g (83% of theory), Melting point: 152°-156° C.
Reaction SMILES: C[O-:2].[Na+].[CH3:4][C:5]([C:8]1[C:9](O)=[C:10]([CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:20]=1)[C:11]([NH:13][NH:14][C:15](=[S:17])[NH2:16])=O)([CH3:7])[CH3:6]>CO>[CH3:4][C:5]([C:8]1[CH:9]=[C:10]([C:11]2[NH:16][C:15](=[S:17])[NH:14][N:13]=2)[CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:20]=1[OH:2])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1cc(C(=O)NNC(N)=S)c(O)c(C(C)(C)C)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1cc(-c2n[nH]c(=S)[nH]2)cc(C(C)(C)C)c1O
Yield: 60.7 %

Procedure:
Sodium methoxide (2.2 g, 0.041 mole) is added to a solution of 2-[3,5-bis(1,1-dimethylethyl)-hydroxybenzoyl]-hydrazinecarbothioamide (4.0 g, 0.0124 mole) in methanol (50 ml). The resulting mixture is stirred at reflux under an atmosphere of nitrogen for 24 hours. The solution is cooled and concentrated in vacuo. The residue is dissolved in water (25 ml) and washed with ether (2×20 ml). The aqueous layer is acidified with cold aqueous 2M HCl (25 ml) and the product extracted out with a 1:1 mixture of ethyl acetate/ether (2×30 ml). The combined organic extracts are washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration gives a residue which is purified by flash chromatography (SiO2, 30% ethyl acetate/hexane eluent). The solid product is recrystallized from ethyl acetate/hexane to give 2.3 g of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione. (3.8 g theor., 61%): mp 271 ° C.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([NH2:13])[CH2:8][O:7]2)([O-:3])=[O:2].CCN(CC)CC.[F:21][C:22]([F:43])([F:42])[O:23][C:24]1[CH:41]=[CH:40][C:27]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH2:31][CH2:30]2)=[CH:26][CH:25]=1.ClCCl>CN(C=O)C>[N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][C@H:9]([NH:13][C:37](=[O:38])[CH2:36][CH2:35][N:32]1[CH2:31][CH2:30][CH:29]([O:28][C:27]3[CH:40]=[CH:41][C:24]([O:23][C:22]([F:21])([F:42])[F:43])=[CH:25][CH:26]=3)[CH2:34][CH2:33]1)[CH2:8][O:7]2)([O-:3])=[O:2]
Reactant: O=C(Cl)CCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Reactant: NC1COc2nc([N+](=O)[O-])cn2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCN1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1)N[C@@H]1COc2nc([N+](=O)[O-])cn2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
Under Ar, (S)-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine-6-amine (110 mg, 0.6 mmol) was dissolved in DMF (6 mL), cooled to 0° C., added Et3N (0.21 mL, 2 mmol), added 3-(4-(4-(trifluoromethoxy)phenoxy)piperidin-1-yl) propionyl chloride (291 mg, 0.75 mmol) in batches, naturally rose to room temperature and stirred for 3 h, added an appropriate amount of dichloromethane, washed by distilled water for 3 times, followed by anhydrous sodium sulphate drying, filtrated out drying agent and spinning dry, residuals were purified by column chromatography (eluent CH2Cl2: MeOH=30:1) to give 70 mg target product, yield was 23%.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][N:6]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:27][N:28]=1)=[CH:20]2)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8])C.[OH-].[K+].Cl>O1CCCC1.CO.O>[O:33]1[CH2:32][CH2:31][N:30]([CH2:29][CH:26]2[S:25][C:24]([C:21]3[NH:22][C:23]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][C:15]=4[N:6]([S:7]([C:10]3[S:11][CH:12]=[CH:13][CH:14]=3)(=[O:8])=[O:9])[CH2:5][C:4]([OH:36])=[O:3])=[N:28][CH2:27]2)[CH2:35][CH2:34]1
Reactant: CCOC(=O)CN(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CN(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of N-{2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-(2-thienylsulfonyl)glycine ethyl ester (120 mg) in tetrahydrofuran (3 mL) and methanol (3 mL) was added, under ice-cooling, a solution prepared by dissolving potassium hydroxide (purity 85%, 30 mg) in water (1 mL), and the mixture was stirred for 30 min, and then at room temperature for 1 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (106 mg, yield 93%) as white crystals. MS:521(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](OC(=O)C(F)(F)F)[C:17]2[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=2[Cl:23])=[C:11]([N+:33]([O-:35])=[O:34])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]2[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=2[Cl:23])=[C:11]([N+:33]([O-:35])=[O:34])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1nccc(Cl)c1C(Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-])OC(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: COc1nccc(Cl)c1/C=C/c1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
A solution of trifluoro-acetic acid 2-(4-tert-butoxycarbonylamino-2-nitro-phenyl)-1-(4-chloro-2-methoxy-pyridin-3-yl)-ethyl ester (crude 1.60 g, 3.08 mmol) in THF (10 mL) was added 8-diazabicyclo[5.4.0]undec-7-ene (1.33 g, 8,74 mmol) at 25° C. The reaction was allowed to stir at 70° C. for 3 hours. The reaction mixture was cooled to 25° C., and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded {4-[(E)-2-(4-chloro-2-methoxy-pyridin-3-yl)-vinyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester (800 mg, 68%) as an oil. MH+ 406.0.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([O:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=[O:11])=O.[NH:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)C(=O)[C:14]1=O>N1C=CC=CC=1>[CH:20]1[CH:21]=[CH:22][C:23]2[N:13]=[C:14]3[N:12]([C:4]4[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=4[C:7]3=[O:9])[C:10](=[O:11])[C:18]=2[CH:19]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=C1Nc2ccccc2C1=O
Solvent: c1ccncc1
Product: O=C1c2ccccc2-n2c1nc1ccccc1c2=O
Yield: 38.3 %

Procedure:
11 g (0.068 mol) of the isato acid anhydride of the aforesaid formula (1a-1), and 10 g (0.068 mol) of isatine represented by the following formula: ##STR75## and 20 ml of pyridine were heated under reflux for 6 hours in a 200 ml eggplant type flask to be reacted. After the reaction solution was cooled, a crystal precipitated in the reaction solution was filtered off to give 6.46 g (yield: 38%) of tryptanthrine represented by the following formula. ##STR76##
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:8]=2[CH:9]=1)=[O:4].[H][H]>C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:8]=2[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(N)ccc2o1
Yield: 98.9 %

Procedure:
The product from step (a) (6.9 g) was dissolved in THF (200 mL), followed by the addition of 10% Pd/C (1 g), and the resulting reaction mixture was hydrogenated under 50 psi of hydrogen for 2 hours. The catalyst was removed by filtration through celite, and the solvent was removed in vacuo to provide 5.9 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[C:12]([F:35])=[C:13]([C:28]2[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=2)[N:14]([S:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=O)(=[O:18])=[O:17])[CH:15]=1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:48][CH2:49][CH2:50][OH:51]>CN(C)C=O.O>[F:35][C:12]1[C:11]([CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:15][N:14]([S:16]([C:19]2[CH:27]=[CH:26][CH:25]=[C:21]([C:22]([NH:48][CH2:49][CH2:50][OH:51])=[O:24])[CH:20]=2)(=[O:18])=[O:17])[C:13]=1[C:28]1[C:29]([F:34])=[N:30][CH:31]=[CH:32][CH:33]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)O)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)NCCO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Yield: 35.6 %

Procedure:
To a solution of 3-{[4-{[(tert-butoxycarbonyl)(methyl)amino]methyl}-3-fluoro-2-(2-fluoropyridin-3-yl)-1H-pyrrol-1-yl]sulfonyl}benzoic acid (300 mg) in dimethylformamide (1.5 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (136 mg), then a solution of 2-aminoethanol (40 mg) in dimethylformamide (0.5 mL) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a pale-yellow oil (yield 116 mg, 36%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])=[C:4]([O:18]C)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])=[C:4]([OH:18])[CH:3]=1
Reactant: COc1cc(Br)c(C)cc1C(=O)c1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C(=O)c2ccc(F)cc2)c(O)cc1Br
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of (4-bromo-2-methoxy-5-methylphenyl)(4-fluorophenyl)methanone (1.80 g, 5.57 mmol) in CH2Cl2 (6 mL) was added over 10 min to a 0° C. solution of BBr3 (1.05 mL, 11.1 mmol) in the same solvent (14 mL) and the resulting mixture was stirred at 0° C. After 1.5 h, the reaction mixture was poured into 200 mL of ice-water, vigorously stirred for 10 min and extracted with CHCl3 (3×). The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated, affording the title compound. 1H NMR (500 MHz, acetone-d6): δ 11.46 (s, 1H), 7.88 (m, 2H), 7.58 (s, 1H), 7.37 (m, 2H), 7.32 (s, 1H), 2.34 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1
Reactant: OCC1CCNCC1
Reactant: Clc1ccccn1
Product: OCC1CCN(c2ccccn2)CC1
Yield: 80 %

Procedure:
The title compound (2.7 g, 80%) was prepared as a syrupy liquid from 2-chloropyridine (6.5 ml) and 4-piperidinyl methanol (2 g) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([CH2:19][OH:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]>ClCCl.[O-2].[O-2].[Mn+4]>[CH:19]([C:16]1[N:17]=[CH:18][N:13]2[CH:12]=[C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]4[C:7]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])[S:15][C:14]=12)=[O:20]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(CO)c4s3)[C@H](C)[C@H]12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C=O)c4s3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 38 h
Yield: 69.7 %

Procedure:
To a solution of 183.0 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 15 ml of dichloromethane 15 ml was added 596.7 mg of manganese dioxide, and the mixture was stirred at room temperature for 38 hours. The catalyst was removed by filtration on Celite, and the filtrate was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (ethyl acetate:methanol=9:1) to give 127 mg of 127 mg of 4-nitrobenzyl (1S,5R,6S)-2-(7-formylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6]C(=O)O[C:9](=[O:10])[C:4]=2[CH:3]=1.[CH:14]([C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[CH3:15]>CN(C=O)C>[NH2:6][C:5]1[CH:12]=[CH:13][C:2]([F:1])=[CH:3][C:4]=1[C:9]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:19][CH:20]=1)=[O:10]
Reactant: CCC(C)c1ccc(N)cc1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2cc(F)ccc2N)cc1
Temperature: 70 °C

Procedure:
To a suspension 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (1.06 g, 5.90 mmol) in DMF (5 mL) was added 4-sec-butylphenylamine (1.95 mL, 11.8 mmol) at room temperature. The suspension was heated at 70° C. for 2 days, and cooled to room temperature. The reaction mixture was poured into crushed ice (150 mL), and extracted with dichloromethane. The organic layer was dried over Na2SO4, and evaporated under vacuum. The residue was purified by flash column chromatography on a Biotage (40 M silica column), using a gradient of hexane:ethyl acetate (9:1 to 8:2) mixture as eluent to afford 2-amino-N-(4-sec-butylphenyl)-5-fluorobenzamide. Yield: 1.16 g (69%).
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].O>C(Cl)Cl>[CH3:19][S:20]([O:11][CH:3]([CH2:2][F:1])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)(=[O:22])=[O:21]
Reactant: OC(CF)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(CF)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-fluoromethyl-2-phenylethanol (1.0 g, prepared as described by Bergmann, et al., J. Chem. Soc., 1961, 3448-3452) in DCM (30 mL) at 0° C. under nitrogen was added triethylamine (1.36 mL) followed by dropwise addition of methanesulfonyl chloride (0.6 mL). The mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was poured into water and extracted with EtOAc. The EtOAc extracts were washed with water and brine, dried over Na2SO4, and concentrated to dryness to give 1.3 g of the title compound. MS CI, (M++H)=233, (M++H −CH3SO3H)=138.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH:11]3[CH2:13][CH:8]2[CH2:9][NH:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Na+].Br[CH2:17][CH2:18][CH2:19][Cl:20]>C1(C)C=CC=CC=1>[Cl:20][CH2:19][CH2:18][CH2:17][N:10]1[CH2:9][CH:8]2[CH2:13][CH:11]1[CH2:12][N:7]2[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(N2CC3CC2CN3)cc1
Reactant: ClCCCBr
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: ClCCCN1CC2CC1CN2c1ccccc1

Procedure:
129 (1.0 g, 5.7 mmoles), 0.23 g (5.7 mmoles) of sodium amide and 20 mL of toluene are refluxed for 1 hour. After that, 0.93 g (5.7 mmoles) of 1-bromo-3-chloropropane in 10 mL of toluene are added dropwise over a period of 20 minutes and refluxed for 2 hours. After cooling, the reaction mixture is extracted with 2N HCl (2×50 mL) and the aqueous phase made alkaline with 30% sodium hydroxide and extracted with toluene (3×40 mL). Evaporation and bulb tube evaporation (boiling point at 0.05 mbar: 120°–130° C.) resulted in 0.97 g (70.4% of the theoretical yield) of 136 as a colorless oil.
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH2:21][CH3:22])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1>C(Cl)Cl>[CH2:16]([NH:17][C:2](=[O:3])[O-:4])[CH3:15].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]([CH2:21][CH3:22])[CH:14]3[CH2:18][NH:17][CH2:16][CH:15]3[C:19]=2[CH:20]=1
Reactant: CCOC(=O)Cl
Agent: CCC1c2ccc(OC)cc2C2CNCC12
Solvent: ClCCl
Product: CCNC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl chloroformate (0.16 mL, 1.65 mmol) was added to a solution of 5-methoxy-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 48, Step B) (0.24 g, 1.1 mmol) in CH2Cl2 (6 mL) at 0° C. The resulting solution was stirred overnight at room temperature. The reaction mixture was quenched with aqueous HCl solution (20 mL, 1.0 M) and the product was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-35% EtOAc-hexanes gradient to afford 40 mg (13%) of the subtitle compound. MS calculated for C17H23NO3+H: 290, observed: 290.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[O:10].[CH2:11]([Mg]Br)[CH2:12]C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([OH:10])[CH2:11][CH3:12]
Reactant: CCC[Mg]Br
Reactant: O=CCc1ccccc1Br
Solvent: C1CCOC1
Product: CCC(O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-bromophenyl) acetaldehyde (15 g, 75.37 mmol) in THF (100 ml) was added propyl magnesium bromide (1.0 M in THF) (15.13 g, 113.6 mmol) at 0° C. then stirred at RT for 3 h. The reaction mixture was quenched with ammonium chloride then the title compound was purified by separation methods A, E and M. (Yield 7.0 g). The enantiomer showed up at tr=13.6 min with Chiralcel OJH (4.6×250 mm) 5μ, hexane:ethanol (98:02), 1 ml/min.