Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:14][N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])C=Cc1ccc(Cl)c(F)c1
Yield: 43.3 %

Procedure:
Using the same reaction procedure and workup as described in Example 1, 4-chloro-3-fluoro-benzaldehyde (2 g, 12.61 mmol) in ethanol (20 mL) was reacted with nitro methane (0.7 mL, 12.61 mmol), 10N NaOH solution (529 mg, 12.61 mmol) at 0° C. for 2 hours to afford 1.1 g of the product (44% yield).
Reaction SMILES: C[O:2][C:3](=[O:24])/[C:4](/[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:15]([Cl:23])[CH:14]=1)=[N:5]/[O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Li+]>CO>[Cl:23][C:15]1[CH:14]=[C:13](/[C:4](=[N:5]\[O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)/[C:3]([OH:24])=[O:2])[CH:18]=[CH:17][C:16]=1[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: COC(=O)/C(=N/OC1CCCCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid methyl ester (487 mg, 1.30 mmol) was dissolved in methanol (14 mL) and cooled to 0° C. A 2.0 N aqueous solution of lithium hydroxide (1.95 mL, 3.90 mmol) was added dropwise and the cooling bath was removed. After stirring 1 h, the reaction mixture was diluted with chloroform (175 mL) and washed with 0.2 M aqueous potassium bisulfate solution (50 mL). The aqueous phase was extracted with chloroform (75 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford (E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (458 mg, 98%) as a white foam that was used without further purification.
Reaction SMILES: [CH2:1]([C@H:8]([CH2:37][C:38]([N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)=[O:39])[C:9]([NH:11][C@H:12]([C:19]([NH:21][C@H:22]([C@H:30]1[O:34][C:33](=[O:35])[C@H:32]([CH3:36])[CH2:31]1)[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:20])[CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:46][NH2:47]>CO>[CH2:1]([C@H:8]([CH2:37][C:38]([N:40]1[CH2:41][CH2:42][O:43][CH2:44][CH2:45]1)=[O:39])[C:9]([NH:11][C@H:12]([C:19]([NH:21][C@@H:22]([CH2:23][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)[C@@H:30]([OH:34])[CH2:31][C@@H:32]([CH3:36])[C:33]([NH:47][CH3:46])=[O:35])=[O:20])[CH2:13][C:14]1[N:15]=[CH:16][S:17][CH:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)[C@H](Cc2cscn2)NC(=O)[C@@H](CC(=O)N2CCOCC2)Cc2ccccc2)OC1=O
Reactant: CN
Solvent: CO
Product: CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(=O)N1CCOCC1)Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 200 mg (0.313 mmole) of (3R, 5S)-5-[(1S)-1{N-[2(R)-benzyl-3-(morpholinocarbonyl)propionyl]-3-(4-thiazolyl)-L-alanyl}amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H) -one [prepared as described in Preparation 21(a) above] in 2 ml of methanol was added, whilst ice-cooling, to 2.5 ml of a 40% by volume methanolic solution of methylamine, and the mixture was allowed to stand at room temperature for 1 hour. At the end of this time, any excess of the methylamine and the methanol were removed by distillation under reduced pressure. The resulting residue was dissolved in 4 ml of ethyl acetate, and the solution was allowed to stand overnight at room temperature to deposit crystals. These were collected by filtration to afford 150 mg of the title compound as white crystals, melting at 130°-132° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>C(O)C.O1CCOCC1>[ClH:27].[ClH:27].[C:21]1([C:18]2[CH:19]=[N:20][C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:16][CH:17]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccccc3)cn2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: c1ccc(-c2cnc(NC3CCNCC3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(5-phenyl-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.06 g, 3.00 mmol) in ethanol (10 mL) was added 4 M HCl in dioxane (10 mL) and the reaction mixture stirred at rt for 2 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 (ISP): 255.6 [M+H]+.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CCCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Yield: 97.9 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-butoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.3 g.), conc. hydrochloric acid (1.3 ml.) and methanol (20 ml.) was treated in a similar manner to that of Example 21-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-butoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.), pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:34])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C)C=O>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:34])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:31][CH:32]=2)=[CH:22][CH:21]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Sc2ccc(O)cc2)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(Sc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-[4-[(4-hydroxyphenyl)thio]phenyl]ethyl]-carbamate (195 mg) and potassium carbonate (59 mg) in N,N-dimethylformamide (3 ml) was added tert-butyl bromoacetate (84 mg), and the mixture was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give tert-butyl [4-[[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]thio]-phenoxy]acetate (168 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[N:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[NH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cn1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Br)c[nH]2)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
To a solution of 5-bromopyridin-2-amine (10.4 g, 60 mmol, Aldrich, St. Louis, Mo.) in pyridine (50 mL) was added p-toluenesulfonyl chloride (13 g, 66 mmol). The mixture was heated to 85° C. for 12 h. The solvent was removed under reduced pressure and the residue was taken up in 1 L of water and stirred for 1.5 h. The solid was collected by filtration and recrystallized from EtOAc to afford N-(5-bromopyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide (11.3 g, 57% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.23 (s, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.89 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.8 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([OH:28])[CH2:4]1)[CH3:2].[OH-].[K+].O1CCOCC1.Br[CH2:38][C:39]1[CH:43]=[C:42]([CH3:44])[O:41][N:40]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O.CCOC(C)=O>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@H:5]([O:28][CH2:38][C:39]2[CH:43]=[C:42]([CH3:44])[O:41][N:40]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1CC(O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: Cc1cc(CBr)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC[C@@H]1C[C@@H](OCc2cc(C)on2)C[C@@H]1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 70 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
A mixture of 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.072 g, 0.179 mmol, Example #35, Step H), KOH aqueous (50% w/v 0.118 g, 2.10 mmol) and 1,4-dioxane (0.1 mL) was heated to about 70° C. To the reaction mixture was added 3-(bromomethyl)-5-methylisoxazole (0.063 g, 0.359 mmol, Maybridge) and TBAB (0.004 g, 0.01 mmol) and the reaction mixture was stirred for about 24 h. To the reaction mixture was added 3-(bromomethyl)-5-methylisoxazole (0.063 g, 0.36 mmol, Maybridge) and aqueous KOH (50% w/v 0.118 g, 2.10 mmol) and stirring was continued for about 24 h. The reaction was cooled to ambient temperature and EtOAc (10 mL) and water (5 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give 3-(((1R,3R,4S)-3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)methyl)-5-methylisoxazole (0.064 g, 72%): LC/MS (Table 1, Method b) Rt=2.58 min; MS m/z: 497 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=O.O1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[CH:12]1([N:8]=[C:1]=[N:3][CH:7]2[CH2:6][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:11][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
Malonitrile is alkylated (or dialkylated) by treatment with NaH in an appropriate solvent such as dimethylformamide or tetrahydrofuran at 0° to 25° C. to give compounds (51). Treatment of the substituted nitrile with (n-Bu)3SnN3 in refluxing dioxane for 24 hours gives, after acidic hydrolysis, the tetrazole (52), which is then alkylated with an alkyl halide (R4Br) in CH3CN employing Et3N as base to give a mixture of regioisomers (53) and (54). The regioisomers are then separated by flash chromatography and each nitrile is then reduced to the corresponding aldehydes (55) and (56) by treatment with Raney nickel in formic acid at 60° C. The resulting aldehydes are then treated with a stabilized ylide such as ethyl (triphenylphosphoranylidene)acetate in CH2Cl2 at room temperature to give (57) and (58) which are reduced catalytically using hydrogen gas, Pd/C as catalyst in methanol or ethanol at room temperature to give esters (59) and (60). These are then hydrolyzed to the corresponding acids (61) and (62) by treatment with alcoholic (MeOH/EtOH) alkali metal hydroxide (NaOH or KOH) at reflux. The acids are then coupled with an appropriate amine employing carbonyldiimidazole in tetrahydrofuran at room temperature or dicyclohexylcarbodiimide in CH2Cl2 at 0° C. to give amides (63) and (64).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]([F:30])([F:29])[F:28])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24]CC)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.[OH-].[Na+].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]([F:30])([F:28])[F:29])=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn2ccc(N3CCCC3c3cc(F)ccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.9 %

Procedure:
(R)-ethyl 5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.92 g, 2.2 mmol) was combined with 1N NaOH (25 mL) and MeOH (40 mL). The reaction mixture was stirred at ambient temperature for 20 hours, followed by heating to 40° C. until complete. Citric acid solid) was added until the mixture was pH 4-5. Brine (10 mL) was added and this was extracted with DCM and EtOAc. The combined organic layers were concentrated and the crude product was purified by reverse phase silica gel column chromatography eluting with 0-60% acetonitrile/water to yield 5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.45 g, 52%). MS (apci) m/z=395.0 (M+H).
Reaction SMILES: [H-].[Na+].C(OC(=O)CC[SH:9])C.[CH2:11]([O:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.OC1C=CC=C(CC2C=CC(N3CC(=O)NS3(=O)=O)=C(O)C=2)C=1C#N>CN(C=O)C.CCOC(C)=O>[CH2:11]([O:18][C:19]1[CH:24]=[C:23]([SH:9])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: CCOC(=O)CCS
Agent: N#Cc1c(O)cccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(S)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of NaH (60%, 1.21 g, 30.3 mmol) in dry DMF (20 mL) under N2 at 0° C. is added dropwise 3-mercaptopropionic acid ethyl ester (1.9 mL, 15.2 mmol) and 2-benzyloxy-4-fluoro-1-nitrobenzene (intermediate from Example 27) (2.5 g, 10.1 mmol) in dry DMF (10 mL). The reaction is allowed to warm to ambient temperature and stirred for 4 days. The mixture is then diluted with EtOAc (100 mL) and extracted with 1N HCl (50 mL). The organics are washed with brine and dried with Na2SO4. Evaporation yields a yellow oil which is purified by flash chromatography (30-50% EtOAc). The title compound is isolated as a yellow oil: MS (M−H)−=260.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1COCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
(S)-3-formylpyrrolidine-1 -carboxylic acid t-butyl ester (3.0 g, 15.0 mmol, 1.0 eq.) in THF (10 mL) was slowly added and the mixture was stirred at −78° C. for 2 hours. The mixture was warmed to room temperature over 3 hours and the reaction was quenched with half saturated NH4Cl (50mL). The organic layer was washed with saturated aqueous NaCl (50 mL). The organic layer was collected, dried over MgSO4, filtered, and concentrated. The resulting oil was slurried in hexanes (50 mL) and the precipitate was filtered off The filtrate was concentrated, diluted with hexanes (25 mL), and chilled at −20° C. overnight. The precipitate was filtered off and the filtrate was purified by column chromatography (0-100% EtOAc in hexanes) to yield (R)-3-vinylpyrrolidine-1-carboxylic acid t-butyl ester as an oil (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[N:22]([CH3:26])[CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH:7]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:10][CH:8]([C:6]1[C:5]([O:18][CH3:19])=[C:4]([CH:20]2[CH2:21][N:22]([CH3:26])[C:23](=[O:25])[CH2:24]2)[C:3]([CH3:27])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CC(=O)N(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CC(=O)N(C)C1
Reaction time: 0.5 h

Procedure:
Solutions of the individual diastereoisomers of tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate (28 mg, 0.070 mmol [peak 1 from step 1]; 56 mg, 0.14 mmol [peak 2 from step 1]) in separate reaction flasks in methylene chloride (1 mL) were each treated individually with trifluoroacetic acid (1 mL) dropwise and stirred for 30 minutes. The reaction mixtures were individually concentrated to give diastereoisomer from peak 1 (38 mg, quantitative) and diastereoisomer from peak 2 (65 mg, quantitative) as residues that were used without further purification. Peak 1: LCMS for C15H19ClNO2 (M−NH2)+: m/z=280.1. Found: 280.1. Peak 2: LCMS for C15H22ClN2O2 (M+H)+: m/z=297.1. Found: 297.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:18][NH2:19]>>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:22]([Cl:23])=[C:15]([Cl:14])[CH:16]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(Cl)c2n1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(Cl)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4,8-dichloro-2-methylquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][C:4]=2[OH:8])[N:1]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(O)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2cccc(O)c2c1O
Temperature: 80 °C

Procedure:
A mixture of 3-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to 80° C. and 50 ml of diphenyl ether is added. The mixture is heated to 250° C. for 30 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to 80° C. and the resulting solid is collected and washed with hexanes. A portion of this solid is adsorbed onto silica and chromatographed, eluting with 5% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield ethyl 4,5-dihydroxyquinoline-3-carboxylate as a gold solid. A mixture of this ester (0.125 g) and 4-chlorobenzylamine (0.379 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature. The crude reaction is chromatographed on silica, eluting with 2% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to yield 0.050 g of the desired product as a pale-yellow solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:25]2[N:26]=[C:27]([CH3:30])[O:28][CH:29]=2)[C:22](O)=[O:23])[C:11]1=[O:31].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([C@H:21]([C:25]2[N:26]=[C:27]([CH3:30])[O:28][CH:29]=2)[C:22]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:23])[C:11]1=[O:31]
Reactant: C1COCCN1
Reactant: CC[C@@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1coc(C)n1
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N1CCOCC1)c1coc(C)n1

Procedure:
Similarly was prepared from intermediate 4 and morpholine
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.C(OCC)(=O)C.[C:25](#[N:27])[CH3:26]>>[NH2:27][C:25]1[CH:26]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[C:4](=[CH:17][CH:16]=[C:15]([Cl:18])[CH:14]=2)[N:3]=1
Reactant: CC#N
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Reaction time: 0.5 h

Procedure:
A suspension of 1.4 g of powdered KOH in 25 ml of anhydrous acetonitrile stirred under an argon atmosphere was heated to boiling under reflux conditions for 30 minutes and then a solution of 1.15 g of 2-amino-5-chlorobenzophenone in 5 ml of anhydrous acetonitrile was added. The mixture was boiled with a reflux condenser for 12 hours. Cooling was followed by pouring into ice, extraction with ethyl acetate, washing with water and removal of the solvent by distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[C:24]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:25]=[CH:26][C:27]=2[CH3:28])[CH2:18][CH2:17]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[C:24]([NH:29][C:30](=[O:34])[CH:31]([CH3:32])[CH3:33])[CH:25]=[CH:26][C:27]=3[CH3:28])[CH2:18][CH2:17]2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)Cc1ccc(F)cc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)Cc2ccc(F)cc2)CC1

Procedure:
Example 175 was prepared from (4-fluorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 1 H), 7.32 (s, 1 H), 7.28–7.16 (m, 3 H), 7.04–6.90 (m, 3 H), 6.86 (s, 1 H), 3.47 (s, 2 H), 3.27 (q, 2 H, J=6.0 Hz), 2.95 (d, 2 H, J=11.6 Hz), 2.69–2.53 (m, 1 H), 2.50–2.32 (m, 3 H), 2.19 (s, 3 H), 2.09–1.94 (m, 2 H), 1.74–1.53 (m, 6 H), 1.15 (d, 6 H, J=7.2 Hz); ESMS m/e: 454.3 (M+H)+.