Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[N:9]=[N:10][CH:11]=[C:12]3[C:16]([CH3:17])=[C:15]([CH3:18])[NH:14][C:13]=23)=[CH:4][CH:3]=1.[Cl:21][CH:22]=[CH:23][CH2:24]Cl>>[Cl:21][CH:22]=[CH:23][CH2:24][N:14]1[C:13]2=[C:8]([O:7][CH2:6][C:5]3[CH:19]=[CH:20][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[N:10][CH:11]=[C:12]2[C:16]([CH3:17])=[C:15]1[CH3:18]
Reactant: ClC=CCCl
Reactant: Cc1[nH]c2c(OCc3ccc(F)cc3)nncc2c1C
Product: Cc1c(C)n(CC=CCl)c2c(OCc3ccc(F)cc3)nncc12
Yield: 31.4 %

Procedure:
The title compound (cis/trans=1/1) was prepared as a pale yellow powder in 31.4% yield in a similar procedure to that described in Example 41 by using 7-(4-fluorobenzyloxy)-2,3-dimethylpyrrolo[2,3-d]pyridazine and 1,3-dichloropropene (a mixture of cis and trans isomers).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11](OCC)=[O:12])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[S:19][CH:20]=[N:21][N:22]=1.BrC1C=CC=CC=1>CCCCCC>[S:19]1[CH:20]=[N:21][N:22]=[C:18]1[NH:17][C:11]([C:4]1[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=1[OH:16])=[O:12]
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Reactant: Nc1nncs1
Solvent: Brc1ccccc1
Solvent: CCCCCC
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nncs2)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
197 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 76 mg of 2-amino-1,3,4-thiadiazole were added to 2 ml of bromobenzene, then, the mixture was stirred for 5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, to the reaction mixture was added n-hexane. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 183 mg of N-(1,3,4-thiadiazol-2-yl)-5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 14) represented by the formula:
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)[CH2:6][C:7]1[C:8]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][CH:12]=1)C.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[C:21]1([N:20]2[C:8]3[N:9]=[C:10]([NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:11]=[CH:12][C:7]=3[CH2:6][CH:5]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:4]2=[O:3])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cccnc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1C(c2cccnc2)Cc2cnc(Nc3ccccc3)nc2N1c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester (60 mg, 0.36 mmol) (from Example 10b supra) was added 5% concentrated sulfuric acid in glacial acetic acid (3 mL) in one portion. The reaction mixture was heated at 120° C. for 3 hours. The reaction mixture was then diluted with ethyl acetate (100 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product which was crystallized from ethyl acetate-hexanes to give 8-phenyl-2-phenylamino-6-pyridin-3-yl-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as a white solid. (Yield 37.3 mg, 69.3%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[N+:24]([O-])=O)[CH3:2].CO>[C].[Pd].C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]#[N:23])=[CH:12]2)=[CH:7][C:6]=1[NH2:24])[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3)c2)cc1N
Temperature: 40 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
To a solution of 4-(3-cyano-4-phenylpyrrole-1-yl)-2-nitro-benzoic acid ethyl ester (0.090 g) in a mixed solvent of methanol (2.5 mL) and ethyl acetate (2.5 mL) was added 10% palladium-carbon powder (0.016 g) under an argon atmosphere, and this mixture was stirred at 40° C. under a hydrogen atmosphere for 3 hours. After this reaction mixture was replaced under an argon atmosphere, the insoluble material was removed by suction through a Celite pad. This filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/hexane=50/50) to give the title compound (0.070 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4]([C:17]([O:19]CC)=O)=[C:5]([C:12](OCC)=[O:13])[NH:6]2.O.[NH2:23][NH2:24]>C(O)C>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]2[C:4]3[C:17](=[O:19])[N:24]=[N:23][C:12](=[O:13])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: NN
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1C(=O)OCC
Solvent: CCO
Solvent: O
Product: O=C1N=NC(=O)c2c1[nH]c1cc(Cl)cc(Cl)c21
Temperature: 25 °C
Yield: 90 %

Procedure:
To a stirred solution of diethyl 4,6-dichloroindole-2,3-dicarboxylate (3.22 g, 9.8 mM) in ethanol (20 mL) was added hydrazine hydrate (14.2 mL, 294 mM). The solution was refluxed for 3 hours during which time a precipitate formed. The reaction mixture was then cooled to room temperature, the solid was filtered and heated to reflux in 3N HCl. After several minutes, the mixture was cooled to room temperature and the solid was filtered, washed with ethanol, and dried. This afforded the titled product as a white solid (2.6 g, 90%), mp >300° C. NMR (d6 -DMSO): 13.02 (br s, 1H), 11.72 (br s, 2H), 7.54 (s, 1H), 7.40 (s, 1H). MS(CI): 271(M+1).
Reaction SMILES: C(N[C:6](=[O:37])[C@@H:7]([NH:19][C:20](=[O:36])[CH2:21][NH:22][C:23](=[O:35])[C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[NH2:34])[CH2:8][NH:9][CH2:10]C1C=CC(Br)=CC=1C)(C)(C)C.[CH2:38]([C:40]1[CH:47]=[CH:46][C:43](C=O)=[CH:42][CH:41]=1)[CH3:39]>>[CH2:38]([C:40]1[CH:41]=[CH:42][C:43]([CH2:10][NH:9][CH2:8][C@H:7]([NH:19][C:20](=[O:36])[CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=2[NH:34][C:20]([NH:19][CH:7]([CH3:8])[CH3:6])=[O:36])[C@@H:6]([OH:37])[CH2:23][CH2:24][CH3:25])=[CH:46][CH:47]=1)[CH3:39]
Reactant: Cc1cc(Br)ccc1CNC[C@H](NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1N)C(=O)NC(C)(C)C
Reactant: CCc1ccc(C=O)cc1
Product: CCC[C@H](O)[C@H](CNCc1ccc(CC)cc1)NC(=O)CNC(=O)c1cc(C(F)(F)F)ccc1NC(=O)NC(C)C

Procedure:
The compound 1.2 (Z=—C(O)—, R2=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all other R=H; cf. procedure (65a); 0.93 g, 2.67 mmol) and (2S, 3S)-11.5 (l=m=0, PGN=CbzHN, R=propynyl, all other R=H; cf. procedure (68a); 1.0 g, 2.76 mmol) were combined in procedure (1c). A portion (52 mg, 0.11 mmol) of the resultant product was combined with 4-ethylbenzaldehyde (0.015 mL, 0.11 mmol) and taken through procedure (1d). The crude product was purified by RP-HPLC to afford the title compound (1S, 2S)-1.5 (l=m=0, R1=4-ethylphenyl, R3=—CH(OH)n-propyl, Z=—C(O)—, R2=2-(isopropylaminocarbonyl)amino-5-(trifluoromethyl)phenyl, all other R=H; 20 mg). Exact MS calcd for C29H41F3N5O4, the formula for (M+H)+=580.3111. Found: 580.3131.
Reaction SMILES: [ClH:1].[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[C:4]=1[F:20].C(N(C(C)C)CC)(C)C.[O:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:1].[F:2][C:3]1[C:11]2[NH:10][C:9](=[O:12])[N:8]([CH:13]3[CH2:14][CH2:15][N:16]([CH:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)[CH2:17][CH2:18]3)[C:7]=2[CH:6]=[C:5]([CH3:19])[C:4]=1[F:20]
Reactant: O=C1CCOCC1
Reactant: Cc1cc2c([nH]c(=O)n2C2CCNCC2)c(F)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c([nH]c(=O)n2C2CCN(C3CCOCC3)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4,5-Difluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride D23 (120 mg) was dissolved in dichloromethane (5 ml) and diisopropylethylamine (0.2 ml, 1.2 mmol), tetrahydro-4H-pyran-4-one (0.2 ml, 2.0 mmol) and sodium triacetoxyborohydride (250 mg, 1.2 mmol) were added and the mixture stirred at room temperature for 4 h. The mixture was partitioned with water/MDC at pH9. Drying (MgSO4), evaporation, and crystallisation of the residue from diethyl ether, washing with dichloromethane gave the title compound free base, which was converted to the hydrochloride. Trituration with diethyl ether gave 35 mg of hydrochloride salt. MH+=352,
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1.Cl>[ClH:25].[ClH:25].[Cl:25][C:21]1[CH:20]=[C:19]2[C:24]([C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=[N:18]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3cc(Cl)ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc2c(NC3CCNCC3)ncnc2c1

Procedure:
A solution of 4-(7-chloro-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.33 g, 11.9 mmol) in dioxane (35 mL) and conc. HCl (10 mL) was stirred at rt for 18 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ESP): 263.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([NH:24][C@@H:25]([CH2:30]O)[C:26]([O:28][CH3:29])=[O:27])=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1.CC(C)C(NC(C1ON=C(C2C=CC(NC(NC3C=CC(C(F)(F)F)=CC=3)=O)=CC=2)C=1)=O)C(OC)=O.S(Cl)(C)(=O)=O.CCN(CC)CC>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:21]=[C:20]([C:22]([NH:24][C:25](=[CH2:30])[C:26]([O:28][CH3:29])=[O:27])=[O:23])[O:19][N:18]=2)=[CH:13][CH:12]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Agent: COC(=O)C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)cc2)no1)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1)C(=O)OC
Temperature: 25 °C
Yield: 29.2 %

Procedure:
(S)-methyl 2-(3-(4-(3-(2-fluorophenyl)ureido)phenyl)isoxazole-5-carboxamido)-3-hydroxypropanoate (compound of Example 275, 500 mg, 1.13 mmol) was taken in DCM and mesyl chloride (0.13 ml, 1.69 mmol) and Et3N (0.24, 1.69 mmol) were added and the reaction mixture was stirred at RT for half an hour. Water was added to quench the reaction and the organic layer was extracted with DCM. Organic layer was dried over Na2SO4 and concentrated under vacuum. Crude compound was purified by precipitation using DCM and petroleum ether to yield 140 mg (30%) of the required compound as white solid. MS: ES (+) m/z 425(M+1); 1HNMR (DMSO-d6, 300 MHz) δ: 10.241 (s, 1H), 8.367 (s, 1H), 8.656 (d, 1H), 8.180 (t, 1H), 7.907 (d, 2H), 7.769 (s, 1H), 7.645 (d, 2H), 7.290 (m, 1H), 7.189 (t, 1H), 7.067 (m, 1H), 6.046 (s, 1H), 5.918 (s, 1H), 3.782 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:15])=O)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])[CH3:3].C1CCC(NC2CCCCC2)CC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:60]([NH:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][C:66]=1[O:73][CH3:74])[CH:61]=[CH2:62]>CN(C)C=O>[C:2]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:13](=[O:15])[N:63]([CH2:60][CH:61]=[CH2:62])[CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][C:66]=1[O:73][CH3:74])[CH2:10][CH:11]=[CH2:12])([CH3:1])([CH3:3])[CH3:4]
Reactant: C=CCNCc1ccc(OC)cc1OC
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC=C)Cc1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(R)-N-Boc-allylglycine (2.3 g, 9.9 mmol) was dissolved in dimethylformamide (20 ml) and activated with the coupling reagent TATU (3.5 g, 10.9 mmol) and Hünig's base (3.8 ml, 21.9 mmol) for 2 min. Allyl-(2,4-dimethoxy-benzyl)-amine (2.1 g, 9.9 mmol) dissolved in dimethylformamide (20 ml) was added to the chilled (ice-water bath) reaction mixture and the stirring was continued overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate, washed with saturated NaHCO3 solution, 1 M KHSO4 solution, brine, dried (MgSO4.2H2O), filtered and concentrated under reduce pressure and purified over silica gel (ethyl acetate/n-heptane 1:4): colorless gum 2.6 g (62%);
Reaction SMILES: [CH:1]1([C:17]([O-:19])=[O:18])[CH:15]2[C:16]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:3][CH2:2]1.[C:20](C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH3:20][O:18][C:17]([C:1]1[C:15]2=[C:16]3[C:8]([C:9]4[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1)=[O:19]
Reactant: O=C([O-])C1CCc2cccc3c2C1c1ccccc1-3
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cccc3c2c1-c1ccccc1-3
Yield: 97.6 %

Procedure:
To a RB flask equipped with magnetic stirrer, condenser and N2 inlet line with bubbler was added methyl, 1,2,3,10b-tetrahydro-1-fluoranthenecarboxylate (Cambridge Chemical, Inc., 202 E. Smith Street, Milwaukee, Wis. 53207, 98.0 g, 0.372 mol), DDQ (Aldrich, 177.0 g, 0.781 mol) and dry PhCH3 (2 L). The reaction mixture was heated at 90° for 10 h, cooled, filtered and concentrated to a 500 mL volume. The crude material was purified on a plug of SiO2 (0.5 kg) using PhCH3 as the eluting solvent. The appropriate fractions were combined and concentrated by rotary evaporation to give a crude pale yellow solid which was recrystallized (CH2Cl2 /hexane), filtered and dried to give 94.5 g (96%) of methyl-1-fluoranthenecarboxylate mp 70°-71°, (C,H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19]Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[S:33])[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1COCC1>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:34]=[C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)[S:33][CH:19]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: COc1cccc(NC(N)=S)c1
Reactant: CCOC(=O)CC1CCC(c2ccc(C(=O)CBr)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC1CCC(c2ccc(-c3csc(Nc4cccc(OC)c4)n3)cc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of {4-[4-(2-bromoacetyl)-phenyl]-cyclohexyl}-acetic acid ethyl ester (100 mg, 0.272 mmol) in EtOH/THF (4:1 v/v, 5 mL) is added 3-methoxyphenylthiourea (99.6 mg, 0.272 mmol) and Na2CO3 (58 mg, 0.545 mmol). The reaction mixture is allowed to stir at 50° C. for 3 h. The reaction mixture is used directly in the next step: (M+H)+451.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:52])[C@@H:5]([O:49][CH2:50][CH3:51])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[C:16](\[CH3:48])/[C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26]/[C:27](/[CH3:47])=[CH:28]/[CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C@H:38]([O:44][CH2:45][CH3:46])[C:39]([O:41]CC)=[O:40])=[CH:33][CH:32]=3)[CH:20]=2)=[CH:9][CH:8]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:45]([O:44][C@@H:38]([CH2:37][C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29]/[CH:28]=[C:27](\[CH3:47])/[C:26]#[C:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]#[C:17]/[C:16](/[CH3:48])=[CH:15]/[CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]([O:49][CH2:50][CH3:51])[C:4]([O:3][CH2:1][CH3:2])=[O:52])=[CH:8][CH:9]=3)[CH:20]=2)=[CH:36][CH:35]=1)[C:39]([OH:41])=[O:40])[CH3:46]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)C#Cc2cccc(C#C/C(C)=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)C#Cc2cccc(C#C/C(C)=C/COc3ccc(C[C@H](OCC)C(=O)O)cc3)c2)cc1)OCC
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of (E)(E)(S)(S) 2-ethoxy-3-{4-[5-(3-{5-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-3-methyl-pent-3-en-1-ynyl}-phenyl)-3-methyl-pent-2-en-4-ynyloxy]-phenyl}-propionic acid ethyl ester (example 27) (255 mg 0.36 mmol) in ethanol (10 mL) was added 1N sodium hydroxide (3.6 mL). After stirring at 60° C. for 30 min, the reaction mixture was concentrated in vacuo and added 1N hydrochloride acid. The product was extracted with dichloromethane (×3). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give 232 mg (99%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:2][O:1][CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9]1
Reactant: COC(OC)c1ccccc1
Reactant: OCCCCC(O)CO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: OCCCCC1COC(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 60 h
Yield: 27.8 %

Procedure:
A mixture of 1,2,6-trihydroxyhexane (2.58 g) and benzaldehyde dimethyl acetal (3.18 g) is treated with toluene sulfonic acid hydrate (2.08 g). The mixture is allowed to stir at room temperature for 60 hours, and is then partitioned between saturated aqueous sodium bicarbonate (50 ml) and methylene chloride (20 ml). The benzaldehyde dimethyl acetal (3.18 g) is treated with toluene sulfonic acid hydrate (2.08 g). The mixture is allowed to stir at room temperature for 60 hours, and is then partitioned between saturated aqueous sodium bicarbonate (50 ml) and methylene chloride (20 ml). The layers are separated, the aqueous layer is re-extracted with methylene chloride, the organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated to an oil (2.66 g), which is purified by column chromatography (silica gel, 1:1 ethyl acetate/hexanes). Pooling and concentrating the appropriate fractions give the title compound as an oil (1.19 g): TLC Rf =0.18 (silica, 1:1 ethyl acetate/hexanes); 1H NMR (CDCl3), δ, 1.62 (m, 6H), 3.67 (m, 3H), 3.25 (m, 2H), 6.37 (s, 0.6H), 6.50 (s, 0.4H), 8.04 (br. s, 5H).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([C:39]3[CH2:40][CH2:41][O:42][CH2:43][CH:44]=3)([CH3:38])[CH3:37])[NH:13]2)=[O:11])[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([C:39]2[CH2:40][CH2:41][O:42][CH2:43][CH:44]=2)([CH3:38])[CH3:37])[NH:13]1)=[O:11]
Reactant: CC1(C)OC[C@H](CCNC(=O)C2NC(CC(C)(C)C3=CCOCC3)C(C#N)(c3ccc(Cl)cc3F)C2c2cccc(Cl)c2F)O1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C1=CCOCC1
Yield: 92.8 %

Procedure:
In a manner similar to the method described in Examples 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide prepared in Example 129d (0.6 g, 0.9 mmol) was reacted with aqueous HCl solution (1 N, 3 mL, 3 mol) in tetrahydrofuran (7 mL) at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[2-(3,6-dihydro-2H-pyran-4-yl)-2-methyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.52 g, 93%).
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12]CC3C=CC([N+]([O-])=O)=CC=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.[Al].Cl>CO.O>[NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([OH:12])=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: Cl
Agent: [Al]
Solvent: CO
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Reaction time: 1 h

Procedure:
p-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate (10 gm) was suspended in a mixture of methanol (120 ml) and water (25 ml). Aluminum powder (10 gm) was charged at 30° C., followed by the addition of concentrated HCl (12.5 ml) in a methanol (10 ml) and water (2.5 ml) mixture over a period of 15 minutes. The reaction mixture was stirred for 1 hour. After completion of the reaction, aq. KHCO3 was added to bring the pH to 8.0 followed by the addition of activated carbon. After stirring for 10 minutes, the reaction mixture was filtered. To the filtrate was added aq. HCl to bring the pH to 4.0. The product thus separated was filtered and dried. Yield: 3.9 gm (68%).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])=[CH:28][CH:27]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(C=CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(C)cc1
Yield: 100.7 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), 4-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.3 g, 99%) as an oily product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:30][O:31][CH3:32])[O:5][C:6]1[CH:7]=[C:8]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11]2.[OH-].[Na+]>O1CCCC1.C(O)C>[CH3:1][O:2][CH2:3][CH:4]([CH2:30][O:31][CH3:32])[O:5][C:6]1[CH:7]=[C:8]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)OC)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 50 %

Procedure:
To a solution of methyl 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (3.42 g) in a mixture of tetrahydrofuran (20 mL) and ethanol (15 mL) was added 1M aqueous sodium hydroxide solution (18 mL), and the mixture was stirred at 50° C. for 50 min. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was washed with diethyl ether. To the aqueous layer was added 1M hydrochloric acid (18.5 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual amorphous solid was solidified with diethyl ether to give the title compound (1.66 g) as a pale yellow solid. MS 553 (MH+).