Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH2:5]([O:12][C@@H:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14]C=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br-].[NH4+].Cl>CO>[NH2:2][CH2:1][CH2:14][C@@H:13]([O:12][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: [BH3-]C#N
Reactant: CCCCC[C@@H](CC=O)OCc1ccccc1
Agent: Cl
Agent: [Br-]
Agent: [NH4+]
Solvent: CO
Product: CCCCC[C@@H](CCN)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Sodium cyanoborohydride (5% excess over theoretical amount) is allowed portionwise over 1/2 hour to a stirred mixture of 3-(S)-benzyloxy-1-octanal (1 molar equivalent) and ammonium bromide (15 molar equivalents) in methanol at room temperature. The resulting reaction mixture is stirred at room temperature for 48 hours, then is cooled to 0° to 5° C. and cautiously treated with concentrated hydrochloric acid to destroy excess hydride reagent. The resulting reaction mixture is evaporated in vacuo at or below 40° C. leaving a residual mass which is partitioned between 5% hydrochloric acid and ether. The aqueous phase is separated, slowly basicified with potassium carbonate, and extracted with ether three times. The combined organic extract is washed with saturated aqueous brine, dried over sodium sulfate, and filtered. In vacuo evaporation of the filtrate leaves the title compound as an essentially colorless oil.
Reaction SMILES: [Na:1].[CH3:2][C:3]1([CH3:31])[O:8]C[CH:6]([CH2:9][O:10][C:11]2[C:16](C)=[CH:15][N:14]=[C:13]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:12]=2[CH3:30])[CH2:5][O:4]1.CC1(C)OC(CO)CO1.ClC1C=C[N+]([O-])=C(C)C=1C.[F:51]C1C=CC2NC(S)=NC=2C=1>>[Na:1].[CH3:2][C:3]1([CH3:31])[O:8][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([F:51])=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:12]=2[CH3:30])[CH2:5][O:4]1
Reactant: Fc1ccc2[nH]c(S)nc2c1
Reactant: Cc1cnc(CS(=O)c2nc3ccccc3[nH]2)c(C)c1OCC1COC(C)(C)OC1
Agent: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na]
Solvent: CC1(C)OCC(CO)O1
Product: Cc1c(OCC2COC(C)(C)O2)ccnc1CS(=O)c1nc2cc(F)ccc2[nH]1
Yield: 14.1 %

Procedure:
The same procedure as in the step (10b) of Example 10 and the step (14b) of Example 14, the step (5f) of Example 5, the steps (11h) and (11i) of Example 11 was repeated using solketal, 4-chloro-2,3-dimethylpyridine 1-oxide, and 5-fluoro-1H-benzimidazole-2-thiol to obtain the title compound (210 mg, yield: 14.1%) as a white solid. Note that methanol was used as a solvent instead of ethanol in the same operation as in the step (5f).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O>C1CCCCC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:19]([O:18][C:12](=[O:17])[CH:13]=[C:14]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:16])[CH3:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1=CCCCC1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1ccc(F)c([N+](=O)[O-])c1
Yield: 12 %

Procedure:
20 g (156 mmol) of 4-fluor-3-nitro-aniline, 18.9 ml (134 mmol) of ethyl acetoacetate in cyclohexene (35 ml) were treated with p-toluene sulfonic acid monohydrate (0.24 g) and heated for 9 h at reflux under a water separator funnel. The solvent was removed in vacuo, the residue applied to silica gel column with AcOEt/n-hexane (1:1)) as eluent. Combination of the purified fractions and concentration in vacuo gave 4.3 g (12.5%) of the 3-(4-fluoro-3-nitro-phenylamino)-but-2-enoic acid ethyl ester as yellow crystals. ISN mass spectrum, m/e: 267.2 (M−1 calculated for C12H13FN2O4: 267).
Reaction SMILES: [C:1]12([CH:11]([OH:20])[C:12]([F:19])([F:18])[C:13]([O:15]CC)=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+].Cl.[Cl-].[F:25][C:26]1[CH:31]=[CH:30][C:29]([S+:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>C(Cl)Cl.O.O1CCOCC1>[C:1]12([CH:11]([OH:20])[C:12]([F:19])([F:18])[C:13]([O-:15])=[O:14])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S+:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)C(F)(F)C(O)C12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: Fc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: O=C([O-])C(F)(F)C(O)C12CC3CC(CC(C3)C1)C2
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of 6.6 g of ethyl 3-(1-adamantyl)-2,2-difluoro-3-hydroxypropionate, prepared in Synthesis Example 1-11, 50 g of 1,4-dioxane, 8.0 g of 25 wt % sodium hydroxide, and 20 g of water was stirred for 2 hours. To the reaction solution, 2.0 g of 35 wt % hydrochloric acid was added, and then 53 g of an aqueous solution of 4-fluorophenyldiphenylsulfonium chloride and 100 g of methylene chloride were added. After stirring for 30 minutes, the organic layer was taken out, washed with water, and concentrated under reduced pressure. Methyl isobutyl ketone was added to the concentrate, which was concentrated again. Diisopropyl ether was added to the concentrate for crystallization. The resulting solid was dried in vacuum, obtaining 6.2 g of the target compound, 4-fluorophenyldiphenylsulfonium 3-(1-adamantyl)-2,2-difluoro-3-hydroxypropionate as white crystals (yield 57%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](Cl)[N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:17]=[C:18]([C:29]5[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cn1
Temperature: 80 °C
Yield: 42.1 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-chloro-5-methylpyridin-2-yl)cyclopropanecarboxamide (66 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 6-Methoxypyridin-3-ylboronic acid (37 mg, 0.24 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexane to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3-methyl-2,3′-bipyridin-6-yl)cyclo-propanecarboxamide (34 mg, 51%). ESI-MS m/z calc. 403.2. found 404.7 (M+1)+. Retention time 1.84 minutes.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH:32]3O)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>C(Cl)(Cl)Cl.C(OCC)C>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:39])([CH3:38])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[CH:32]=[CH:33][O:34][CH2:35][CH2:36]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1-c1cc(N2C=COCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 65 mg (0.11 mmol) (RS)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-(3-hydroxy-morpholin-4-yl)-4-o-tolyl-pyridin-3-yl]-N-methyl-isobutyramide in 2 ml chloroform were added a few drops of a 2.3 N hydrochloric acid solution in diethyl ether. After stirring at room temperature for 2 h, the organic layer was washed with saturated sodium carbonate solution, dried (magnesium sulfate) and evaporated. The residue was purified by flash-chromatography to give 47 mg (75%) of the title compound as white foam.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10]C)=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[F:20].COC(=O)C1C=CC(Cl)=NC=1NC1C=CC(Br)=CC=1F.C[O-].[Na+].CO>C(O)(=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:5]2[NH:6][C:7](=[O:10])[CH:8]=[CH:9][C:4]=2[C:3]([OH:21])=[O:2])=[C:14]([F:20])[CH:15]=1
Reactant: COC(=O)c1ccc(OC)nc1Nc1ccc(Br)cc1F
Agent: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Temperature: 62.5 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamino)-6-methoxynicotinic acid methyl ester: To a mixture of 2-(4-bromo-2-fluorophenylamino)-6-chloronicotinic acid methyl ester (2.00 g, 5.56 mmol) and sodium methoxide (0.791 g, 13.9 mmol) was added MeOH (50 mL) to give a slurry that was stirred at 60-65° C. for 16 hours under N2. Additional sodium methoxide (0.791 g, 13.9 mmol) was added and the reaction mixture was allowed to stir another 3 days at 60-65° C. The reaction mixture was cooled to room temperature and glacial acetic acid was added dropwise until the pH was 7. The resulting suspension was filtered and washed with H2O to yield a pink solid that was collected and dried under vacuum to yield 1.74 g (88%) pure desired product.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH:15][C:16]([NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=1[CH:21]=[N:22][NH:23]3)=[O:17])[CH2:10][CH2:9]2)([CH3:5])[CH3:4])#[N:2]>CO>[C:1]([C:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C@H:11]([NH:15][C:16]([NH:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=1[CH:21]=[N:22][NH:23]3)=[O:17])[CH2:10][CH2:9]2)([CH3:5])[CH3:4])#[N:2]
Reactant: CC(C)(C#N)c1ccc2c(c1)CCC2NC(=O)Nc1cccc2[nH]ncc12
Solvent: CO
Product: CC(C)(C#N)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2[nH]ncc12

Procedure:
The title compound was prepared by chiral separation of the corresponding racemic compound 1-[5-(cyano-isopropyl)-indan-1-yl]-3-(1H-indazol-4-yl)-urea (Ex. 57E) using a chiral column ChiralCel OD. [α]D: +35.4° (c: 1.04, MeOH). MS (ESI) m/z: 360.07 [M+H]. 1H NMR (DMSO-d6) □: 1.69 (s, 6H), 1.87 (m, 1H), 2.47 (m, 1H), 2.89 (m, 1H), 2.98 (m, 1H), 5.19 (q, 1H), 6.73 (d, 1H), 7.08 (d, 1H), 7.22 (t, 1H), 7.39 (s, 2H), 7.44 (s, 1H), 7.66 (d, 1H), 8.04 (s, 1H), 8.59 (s, 1H), 13.00 (s, 1H). Anal Calcd for C21H21N5O.0.3H2O: C, 69.14; H, 5.97; N, 19.20. Found: C, 69.08; H, 5.95; N, 19.31.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[CH:27]=[N:28][CH:29]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH2:23][C:24]2[CH:25]=[C:26]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH:27]=[N:28][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cc2)CC1
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cncc(CN(c3ccc(Br)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
4-(4-Bromophenyl)amino-1-(tert-butoxycarbonyl)piperidine (711 mg) and 5-chloromethyl-3-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:31]([C:33]([F:35])([F:36])[F:34])=[CH:32][C:24]=2[O:23][CH3:22])[CH:4]=1)[C:13]([OH:15])=[O:14])([CH3:20])[CH3:21]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: COc1cc(C(F)(F)F)ccc1C(=O)O
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1OC
Yield: 62.9 %

Procedure:
0.15 g of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 0.24 g of 2-methoxy-4-(trifluoromethyl)benzoic acid were treated in the same manners as in Example 19d) and then in Example 1d), to give 0.15 g of 2-isopropoxy-3-[4-methoxy-3-({[2-methoxy-4-(trifluoromethyl)benzoyl]amino}methyl)phenyl]propanoic acid as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2Br)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18].[F-].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH:17]=[CH2:18])[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cccc2cccc(Br)c12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1cccc2cccc(C(=O)OCC)c12
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
A stream of argon was passed through a solution of 8-bromo-naphthalene-1-carboxylic acid ethyl ester (1.44 g) in toluene (15 ml) for 15 min. Then tetrakis(triphenylphosphine)palladium (179 mg) and vinyltributylstannane (1.65 ml) were added. The reaction mixture was heated under an Argon atmosphere to 100° C. overnight, then cooled to r.t. and treated with 4M potassium fluoride solution. The suspension was stirred for 10 min and then filtered. The solids were washed with toluene. The filtrate was washed with 4M KF solution, then dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:cyclohexane→cyclohexane/EtOAc 3:2) to give 8-vinyl-naphthalene-1-carboxylic acid ethyl ester (1.11 g) as light yellow liquid. MS (ISP): 227.1 ((M+H)+).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:13]([CH3:14])=[C:12]([C:15](=O)[NH2:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[F:1][C:2]1[C:3]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]#[N:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1c(-c2ncc(Cl)cc2F)nn(C)c1C(N)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1c(-c2ncc(Cl)cc2F)nn(C)c1C#N
Temperature: 22 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
1.82 g of 3-(3-fluoro-5-chloro-2-pyridyl)-4-methyl-5-carbamoyl-1-methyl-[1H]-pyrazole (Example H44) are suspended in 20 ml of dioxane. First 1.65 ml of pyridine and then 1.44 ml of trifluoroacetic anhydride are added, while cooling in an ice-bath. 5 minutes later, the cooling bath is removed and the mixture is stirred at 22° C. for 1 hour. The brown-red solution is diluted with diethyl ether and washed with one molar hydrochloric acid and then with brine. After drying over sodium sulfate and filtering, the filtrate is concentrated directly together with twice the amount of silica gel. After application of this silica gel to a flash column, the column is eluted with n-hexane/ethyl acetate 4/1. 1.60 g of the desired title compound are obtained as a beige solid of melting point 144-146° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH2:39][CH3:40])([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]4([O:33][Si](C)(C)C)[CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:22]([CH3:38])[CH:21]=3)[CH2:18][CH3:19])=[CH:13][C:12]=2[CH3:41])[CH:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].O>O1CCCC1>[CH3:1][O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH2:18][CH3:19])([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]4([OH:33])[CH2:29][CH2:30][CH2:31][CH2:32]4)=[C:22]([CH3:38])[CH:21]=3)[CH2:39][CH3:40])=[CH:13][C:12]=2[CH3:41])[CH:10]=1
Reactant: CCC(CC)(c1ccc(CCC2(O[Si](C)(C)C)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Reaction time: 2 h
Yield: 69.4 %

Procedure:
{5-[4-(1-Ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclopentyl)-ethyl]-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 114-(1); 26.8 mg, 0.046 mmol) was dissolved in tetrahydrofuran (0.4 mL). Tetra-n-butylammonium fluoride (1 M solution in tetrahydrofuran; 0.05 mL, 0.05 mmol) was added at room temperature, and the mixture was stirred for two hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Then, the resulting residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=3/1) to give the title compound (16.4 mg, 70%).
Reaction SMILES: [SH:1][CH:2]([CH3:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].Br[CH2:12][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(#N)C>[CH2:17]([O:16][C:14](=[O:15])[C:13]([OH:19])=[CH:12][S:1][CH:2]([C:3](=[O:4])[NH:5][CH2:6][C:7]([OH:9])=[O:8])[CH3:10])[CH3:18]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(S)C(=O)NCC(=O)O
Solvent: CC#N
Product: CCOC(=O)C(O)=CSC(C)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
A solution of N-(2-mercaptopropionyl)glycine (1.17 g, 7.17 mmol) and ethyl bromopyruvate (1 mL, 7.17 mmol, 90% purity) in acetonitrile (30 mL) was stirred at room temperature for 3 h. After removal of the solvent, the residue was dissolved in a mixed solvent of ethanol (15 mL) and water (15 mL). After the pH was adjusted to 7-8 with satd. NaHCO3 solution, the mixture was stirred at room temperature overnight. The mixture was acidified to pH 1-2 with concentrated hydrochloric acid and then rotary evaporated to dryness. The residue was purified by column chromatography eluted with EtOAc giving 3-[1-(carboxymethylcarbamoyl)ethylsulfanyl]-2-hydroxyacrylic acid ethyl ester as yellow solid (1.06 g, yield 53.3%). 1H NMR (CDCl3, 300.16 MHz) δ (ppm): 9.10 (broad s, 1H), 7.22 (d, J=0.9 Hz, 1H), 4.62 (d, J=17.7 Hz, 1H), 4.53 (d, J=17.7 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.47 (qd, J=6.2 & 0.9 Hz, 1H), 1.48 (d, J=6.2 Hz, 3H) and 1.30 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3, 75.48 MHz) δ (ppm): 174.02, 165.84,160.57, 130.27, 120.20, 62.04, 46.76, 37.11, 14.45 and 14.09. MS (ESI) m/z: 260 (M+—OH, 100).
Reaction SMILES: [CH:1]([C:4]([CH3:10])([CH:7]([CH3:9])[CH3:8])[CH:5]=[O:6])([CH3:3])[CH3:2].[C:11]1([CH2:17][CH2:18][CH2:19][Mg]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:1]([C:4]([CH3:10])([CH:7]([CH3:9])[CH3:8])[C:5](=[O:6])[CH2:19][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:3])[CH3:2]
Reactant: Br[Mg]CCCc1ccccc1
Reactant: CC(C)C(C)(C=O)C(C)C
Product: CC(C)C(C)(C(=O)CCCc1ccccc1)C(C)C

Procedure:
The title compound was prepared following the general procedure of Example 1 starting from 2-isopropyl-2,3-dimethylbutanal and (3-phenylpropyl)magnesium bromide.
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:44]([C:60](=[O:82])[NH:61][CH:62]2[CH2:65][N:64]([C:66](=[NH:81])[NH:67]C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:63]2)[CH2:43]1>>[C:66]([N:64]1[CH2:63][CH:62]([NH:61][C:60]([C@@H:44]2[CH2:43][C@H:42]([S:41][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:46][NH:45]2)=[O:82])[CH2:65]1)(=[NH:67])[NH2:81]
Reactant: N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC(NC(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)NC4CN(C(=N)N)C4)C3)[C@H](C)[C@H]12

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 32) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[1-(4-nitrobenzyloxycarbonylamidino)azetidin-3-ylcarbamoyl]pyrrolidine (prepared as described in Preparation 112) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)C1CC(NCc2ccccc2)CN1Cc1ccccc1
Reaction time: 3 h

Procedure:
1-Benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester and a corresponding benzylamine are dissolved in DCM, acetic acid and NaBH(OAc)3 is then added. After stirred for about 3 hours the reaction mixture is diluted with DCM, washed, dried and concentrated. The residue is purified to afford 1-benzyl-4-(benzylamino)-pyrrolidine-2-carboxylic acid methyl ester (26).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[N:14]=[C:15]([CH3:19])[NH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:23])=[N:14][C:15]([CH3:19])=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(=O)c2ccc(OCc3ccccc3)cc2[nH]1
Product: Cc1nc(Cl)c2ccc(OCc3ccccc3)cc2n1
Yield: 46.8 %

Procedure:
A suspension of 0.9 g (3.38 mmol) of 7-benzyloxy-2-methyl-1H-quinazolin-4-one in POCl3 (4.6 ml, 50 mmol) were heated at reflux for 1.5 h. The reaction mixture was then concentrated in vacuo, the residue was partitioned between CH2Cl2 and cold diluted NaHCO3 (pH 7–8). The layers were separated and the aqueous layer twice extracted with CH2Cl2. The combined organic layers washed with saturated NaHCO3, brine and then dried over Mg2SO4. The solvent was removed in vacuo give 0.45 g (47.2%) of crude 7-benzyloxy-4-chloro-2-methyl-quinazoline as a dark red waxy solid which was used directly in the next step without further purification. Rf: 0.9 (CH2Cl2/MeOH: 9/1; starting material with Rf: 0.7).