Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([O:9][C:10]1[CH:11]=[C:12]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:13][C@H:14]([NH:34][C:35](=[O:37])[CH3:36])[C@H:15]([OH:33])[CH2:16][NH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)C1C=CC=CC=1.[H][H].Cl>C(O)C.[Pd]>[ClH:1].[OH:9][C:10]1[CH:11]=[C:12]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:13][C@H:14]([NH:34][C:35](=[O:37])[CH3:36])[C@H:15]([OH:33])[CH2:16][NH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(OCc2ccccc2)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1cc(O)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reaction time: 21 h

Procedure:
To a solution of compound 10 (0.70 g, 1.2 mmol) in 70 mL of ethanol in a Parr bottle is added 0.33 g of 10% palladium on carbon. The mixture is placed under 20 psi of hydrogen and shaken for 21 h. The mixture is filtered and the catalyst is washed with ethanol. Concentration in vacuo affords a colorless oil, which is treated with ethereal HCl to give a quantitiative yield of hydrochloride 11 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.44 (s, 1H), 7.37 (m, 2H), 7.28 (m, 1H), 6.59 (s, 1H), 6.40 (m, 1H), 6.31 (m, 1H), 4.0 (m, 1H), 3.79 (m, 1H), 2.95 (m, 2H), 2.63 (m, 4H), 2.44 (m, 1H), 2.05 (m, 2H), 1.90 (s, 3H), 1.79 (m, 2H), 1.59 (m, 1H), 1.5-1.3 (m, 3H), 1.26 (d, J=7 Hz, 6H); MS (CI) m/z 457.4 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[N:7]=[C:8]([O:13]C)[N:9]([CH3:12])[C:10]=1[CH3:11])=[O:4]>C(OCC)C>[F:22][C:17]1[CH:16]=[C:15]([C@@H:6]2[C:5]([C:3]([OH:4])=[O:2])=[C:10]([CH3:11])[N:9]([CH3:12])[C:8](=[O:13])[NH:7]2)[CH:20]=[CH:19][C:18]=1[F:21]
Reactant: COC(=O)C1=C(C)N(C)C(OC)=NC1c1ccc(F)c(F)c1
Solvent: CCOCC
Product: CC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1C

Procedure:
4-(3,4-Difluorophenyl)-2-methoxy-1,6-dimethyl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester was converted to (+)-4-(3,4-difluorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrinidine-5-carboxylic acid following steps C and D above in Example 14 to give the product as a crystalline solid from diethyl ether ([αD]=+48°, c=0.145 MeOH).
Reaction SMILES: C[O:2][C:3](=[O:29])/[C:4](=[N:25]/[N:26]([CH3:28])[CH3:27])/[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[CH3:27][N:26]([CH3:28])/[N:25]=[C:4](\[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1)/[C:3]([OH:29])=[O:2]
Reactant: COC(=O)/C(=N/N(C)C)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)/N=C(/C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Yield: 87.6 %

Procedure:
A mixture of (E)-alpha-(dimethylhydrazono)-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid methyl ester (0.45 g) in warm methanol (3 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL), heated on the steam bath for one hour, and the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from dichloromethane-hexane provided 0.38 g of pure (E)-alpha-(dimethylhydrazono)-4-[2-(2-naphthalenyloxy)ethoxy]benzeneacetic acid as a colorless solid, mp 135° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[S:23]([C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1)(=[O:26])(=[O:25])[NH2:24]>>[S:23]([C:27]1[CH:28]=[C:29]([NH:33][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]([F:15])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:21])[CH:30]=[CH:31][CH:32]=1)(=[O:25])(=[O:26])[NH2:24]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Light yellow solid. MS (ISP) 476.0 [(M−H)−]; mp 278° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1[CH:17]=[CH:16][C:15]([S-:18])=[CH:14][CH:13]=1.[Na+].[H-].[Na+].C1(S)C=CC=CC=1>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([S:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: [S-]c1ccccc1
Agent: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cc(Sc2ccccc2)ccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
5 G. of 2-amino-4-chloro-1-nitrobenzene is added to a solution of sodium phenyl mercaptide, prepared under nitrogen from 2.53 g. 57% sodium hydride and 6.2 ml. thiophenol in 20 ml. dimethylformamide, with a 10 ml. dimethylformamide rinse. The mixture is stirred under nitrogen for 3 hours at 20°-30° C and then diluted with water. The crude product is washed with water and hexane, then recrystallized from methanol, yielding 2-amino-4-phenylthio-1-nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:13]([C@@H:22]([CH2:30][CH3:31])[CH2:23][NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[C:12](=[O:32])[C@:11]([CH2:34][C:35]([OH:37])=[O:36])([CH3:33])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].I[CH3:41]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:14]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:13]([C@@H:22]([CH2:30][CH3:31])[CH2:23][N:24]([CH3:41])[S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[C:12](=[O:32])[C@:11]([CH2:34][C:35]([OH:37])=[O:36])([CH3:33])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC[C@@H](CNS(=O)(=O)CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](CN(C)S(=O)(=O)CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 393, Step D, 26.6 mg, 0.046 mmol) in DMF (464 μl) at rt was added a dispersion of 60% sodium hydride in mineral oil (5.57 mg, 0.139 mmol). The grey slurry was stirred at rt for 30 min then iodomethane (5.80 μl, 0.093 mmol) was added. The mixture was stirred at rt for 1 h. The mixture was quenched with 1 M HCl and diluted with EtOAc. The aqueous layer was extracted with EtOAc 2×. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by reverse phase preparatory HPLC (column: Gemini™ Prep C18 10 um column; Phenomenex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]([CH3:24])[S:22][C:21](=[O:25])[N:20]([CH2:26][CH2:27][NH:28]C(=O)OC(C)(C)C)[N:19]=4)=[CH:17][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[NH2:28][CH2:27][CH2:26][N:20]1[N:19]=[C:18]([C:16]2[CH:15]=[CH:14][C:11]3[N:12]([CH3:13])[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][C:10]=3[CH:17]=2)[CH:23]([CH3:24])[S:22][C:21]1=[O:25]
Reactant: CC1SC(=O)N(CCNC(=O)OC(C)(C)C)N=C1c1ccc2c(c1)nc(-c1cccc(F)c1)n2C
Agent: Cl
Solvent: C1COCCO1
Product: CC1SC(=O)N(CCN)N=C1c1ccc2c(c1)nc(-c1cccc(F)c1)n2C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
6.3 g (13 mM) of tert-butyl 2-[5-[2-(3-fluorophenyl)-1-methyl-1H-benzimidazol-5-yl]-6-methyl-2-oxo-2H-1,3,4-thiadiazin-3(6H)-yl]ethylcarbamate are added to 30 ml of 4N hydrochloric dioxane. The mixture is stirred at room temperature for 20 hours. The crystalline solid, which is the hydrochloride of the desired compound, is filtered off. The free base is obtained via the action of aqueous sodium hydrogen carbonate solution and extraction with ethyl acetate. The aqueous phase is washed with water and then dried over sodium sulfate and concentrated under vacuum to give 3.85 g of 3-(2-aminoethyl)-5-[2-(3-fluorophenyl)-1-methyl-1H-benzimidazol-5-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in solid form.
Reaction SMILES: [OH:1][C@H:2]1[C@H:16](/[CH:17]=[CH:18]/[CH2:19][C:20]([OH:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])[C:4](=[O:27])[CH2:3]1.[CH2:28](O)C(N)(CO)CO>>[CH3:28][CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C@@H:5]1[C@@H:16](/[CH:17]=[CH:18]/[CH2:19][C:20]([OH:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[C@H:2]([OH:1])[CH2:3][C:4]1=[O:27])[C:12]([OH:14])=[O:13]
Reactant: CCCCC(C)(O)C/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)OC
Reactant: NC(CO)(CO)CO
Product: CCCCC(C)(O)C/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCC(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 3.1 g of (±) methyl 11α, 16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oate in 20 ml Tris buffer (pH 8.0) is added 50 ml porcine liver esterase (Sigma, St. Louis, MO). After 3 hours of stirring at room temperature, the reaction is extracted with 4 portions of ethyl acetate, the extracts combined, dried (Na2SO4), evaporated and chromatographed on silica gel to give 2.8 g of (±) methyl 11α, 16-dihydroxy-16-methyl-9-oxoprost-13E-en-1-oic acid.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[NH2:15][CH:16]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].[OH-].[Na+]>CN(C=O)C>[OH:18][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]([N:15]1[CH2:9][CH2:10][CH2:11][C:12]1=[O:13])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=C(Cl)CCCCl
Reactant: NC(c1ccccn1)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCCN1C(c1ccccn1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
35 ml (252 mmol) of triethylamine and 11.3 ml (101 mmol) of 4-chlorobutyryl chloride were successively added dropwise to a solution of 21.6 g (101 mmol) of 2-amino-1-phenyl-2-pyridin-2-ylethanol in 50 ml of DMF at 50° C. After 1 h at room temperature, 48.4 g of sodium hydroxide were added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice-water and extracted with methylene chloride, and the organic phases were washed with water and sodium bicarbonate solution. Chromatography on silica gel with ethyl acetate/ethanol 20:1 resulted in isolation of 3.0 g each of the syn- and anti-diastereomer of 1-(2-hydroxy-2-phenyl-1-pyridin-2-ylethyl)pyrrolidin-2-one in pure form. The relative stereochemistry was assigned by X-ray spectroscopy.
Reaction SMILES: [I-].[CH:2]([O:15][C:16]([C:18]1[N:23]2[C:24](=[O:48])[CH:25]([NH:26][C:27](=[O:47])[C:28](=[N:37][O:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:29]3[N:30]=[C:31]([NH:34][CH:35]=[O:36])[S:32][CH:33]=3)[C@H:22]2[S:21][CH2:20][C:19]=1[CH2:49][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:69](=O)([O-])[O-].[Na+].[Na+].Cl>C(Cl)Cl.O.C=O>[C:43]([O:42][C:40]([CH2:39][O:38][N:37]=[C:28]([C:29]1[N:30]=[C:31]([NH:34][CH:35]=[O:36])[S:32][CH:33]=1)[C:27]([NH:26][CH:25]1[C:24](=[O:48])[N:23]2[C:18]([C:16]([O:15][CH:2]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:17])=[C:19]([CH:49]=[CH2:69])[CH2:20][S:21][C@H:22]12)=[O:47])=[O:41])([CH3:45])([CH3:44])[CH3:46]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12)c1csc(NC=O)n1
Agent: C=O
Agent: Cl
Agent: [I-]
Solvent: O
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Reaction time: 3 h

Procedure:
[4-Benzhydryloxycarbonyl-7-{2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido}-3-cephem-3-yl]methyltriphenyl-phosphonium iodide (syn isomer) (0.59 g) was dissolved in a mixture of methylene chloride (20 ml), water (10 ml) and 36% aqueous formaldehyde (1 ml), followed by adjusting to pH 8.0 with 20% aqueous sodium carbonate. After stirring for 3 hours at 30°-35° C., the reaction mixture was further adjusted to pH 2.0 with 10% hydrochloric acid and then extracted with methylene chloride. The extract was washed with an aqueous sodium chloride dried over magnesium sulfate and then evaporated. The residue (0.46 g) was chromatographed on silica gel using a mixed solvent of benzene and ethyl acetate (2:1 by volume) as an eluent to obtain benzhydryl 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (0.14 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:3]=1[C:16]#[N:17].[CH2:18]([O:20][CH:21](OCC)OCC)[CH3:19]>C(O)C>[C:16]([C:3]1[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:21][O:20][CH2:18][CH3:19])#[N:17]
Reactant: COc1cccc(Nc2n[nH]c(N)c2C#N)c1
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: CCOC=Nc1[nH]nc(Nc2cccc(OC)c2)c1C#N
Temperature: 120 °C

Procedure:
With stirring, a mixture of 4 g (17.45 mmol) of 5-amino-4-cyano-3-(3-methoxy-phenylamino)-pyrazole (Step 50.1) and 50 ml of orthoformic acid triethyl ester is heated at 120° C. for 1.5 hours, care being taken to ensure that the ethanol formed in the course of the reaction is distilled off from the reaction mixture. The reaction mixture is cooled to 30° C., approx. 100 ml of diethyl ether are added and the reaction mixture is cooled further to 0° C. and filtered. Washing with diethyl ether yields the title compound; m.p. 181-183° C.
Reaction SMILES: Br[CH:2](C)[C:3]([C:8]1[CH:9]=[CH:10][C:11]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH2:14][C:15]([O-:17])=[O:16])[CH:13]=1)(OC)OC.[C:26](=O)([O-:28])[OH:27].[Na+].C(O)C>O>[C:26]([CH:3]([C:8]1[CH:9]=[CH:10][C:11]([S:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[CH:13]=1)[CH3:2])([OH:28])=[O:27]
Reactant: COC(OC)(c1ccc(Sc2ccccc2)c(CC(=O)[O-])c1)C(C)Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(Sc2ccccc2)c(CC(=O)O)c1
Reaction time: 5 h
Yield: 13.6 %

Procedure:
A mixture of 4.39 g (10 mol.) of 5-(2-bromo-1,1-dimethoxypropyl)-2-phenylthiophenylacetate obtained in Example 1-(2), 4.20 g (50 mmol.) of sodium hydrogen carbonate, 50 ml of ethanol and 35 ml of water was heated under reflux and stirring for 5 hours. The reaction mixture was distilled to remove distillates having a boiling point of below 100° C. The residue was then heated under reflux for 4 hours. The mixture was treated in the same manner as in Example 6-(1) to obtain 2.15 g of the desired product as white crystals (yield 68%), m.p. 145°-146° C.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1>>[C:1]([NH:5][C:6](=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: O=C1C=CC(=O)O1
Product: CC(C)(C)NC(=O)/C=C\C(=O)O
Yield: 97 %

Procedure:
Similarly, t-butylamine is reacted with an equimolar amount of maleic anhydride to produce 97% yield of N-t-butyl maleamic acid, a white crystalline material melting at 138°-142° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14](=[O:36])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29](=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25][CH2:24]3)[CH:17]=2)=[CH:12][CH:13]=1)(C)(C)C.Cl>O1CCOCC1>[C:31]([NH:30][C:29]([CH:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:18]2[CH:17]=[C:16]([NH:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][N:10]=3)=[O:36])[CH:21]=[CH:20][CH:19]=2)[CH2:28][CH2:27]1)=[O:35])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)NC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(NC(=O)OC(C)(C)C)cn3)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(N)cn3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {6-[3-(4-tert-butylcarbamoyl-piperidin-1-ylmethyl)-phenylcarbamoyl]-pyridin-3-yl}-carbamic acid tert-butyl ester (1.21 g, 2.37 mmol) in dioxane (15 mL) is cooled to 0° C. and HCl 4M in dioxane (2.4 mL, 9.497 mmol) is added. The RM is stirred at RT for 1 h and then heated at 60° C. overnight. The red mixture is cooled down to RT and filtered. The filtercake is washed with dioxane (15 mL). The red solid residue is partitioned between DCM (15 mL) and aq.sat.NaHCO3 (15 mL). The aqueous phase is extracted twice with DCM (2×20 mL). The combined org phase are dried over MgSO4, filtered and concentrated until dryness. The title compound is obtained as a yellowish foam LC-MS C: tR=0.61 min; [M+H]+=410.4.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.CN(C)CCN(C)C.C([Li])CCC.[CH:20]12[O:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25]2>C1COCC1.O>[CH3:1][N:2]1[C:6]([C@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]2[OH:26])=[CH:5][CH:4]=[N:3]1
Reactant: C1CCC2OC2C1
Reactant: Cn1cccn1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1[C@H]1CCCC[C@@H]1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a solution of 1-methylpyrazole (9.34 g, 114 mmol) and N,N,N′,N′-tetramethylethylenediamine (17.1 mL, 114 mmol) in THF (300 mL), butyl lithium (1.63 M solution in hexane; 81.7 mL, 133 mmol) was added at −78° C. The reaction solution was stirred at −78° C. for 30 minutes. Then, cyclohexene oxide (13.9 mL, 137 mmol) was added thereto, and the mixture was stirred at room temperature for 15 hours. To the reaction solution, water (1 L) was added, followed by extraction with ethyl acetate (500 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (ethyl acetate) to yield the title compound (11.2 g, 55%) as a colorless solid.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:23][C:12]2=[C:13]3[N:18]([N:19]=[C:11]2[CH2:10]1)[C:17]([CH3:20])=[C:16]([CH3:21])[C:15]([CH3:22])=[N:14]3)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:22][C:15]1[C:16]([CH3:21])=[C:17]([CH3:20])[N:18]2[C:13]([N:14]=1)=[C:12]1[CH2:23][NH:9][CH2:10][C:11]1=[N:19]2
Reactant: Cc1nc2c3c(nn2c(C)c1C)CN(C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1C)CNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (1.24 mL; 4.96 mmol; 15 eq.) was added to a solution of 5,6,7-trimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carboxylic acid tert-butyl ester (100 mg; 0.33 mmol; 1 eq.) in 1,4-dioxane (5 mL) and the resulting mixture was stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was triturated in 1,4-dioxane. Concentration to dryness afforded the title compound (65 mg, 82%) as a white solid. 1H NMR (DMSO-d6) δ 10.40-10.30 (m, 1H), 4.57-4.50 (m, 4H), 2.73 (s, 3H), 2.54 (s, 3H), 2.28 (s, 3H). HPLC (max plot) 100.0%; Rt 1.26 min. UPLC/MS: (MS+) 203.1 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][O:16][CH:17]=3)[NH:10][N:9]=2)[CH:3]=1.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28].C(Cl)Cl>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[N:14]=[CH:15][O:16][CH:17]=3)[N:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:9]=2)[CH:3]=1
Reactant: Fc1ccccc1CBr
Reactant: Brc1ccnc(-c2n[nH]c(-c3cocn3)n2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1cocn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1 %

Procedure:
To a stirring solution of 4-(3-(4-bromopyridin-2-yl)-1H-1,2,4-triazol-5-yl)oxazole (1 eq) in DMF was added sodium hydride (2.1 eq). After 10 minutes, 1-(bromomethyl)-2-fluorobenzene (1.1 eq) was added and the reaction was stirred overnight at room temperature. Brine was used to quench the reaction. Methylene chloride was used to extract the aqueous layer. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. SiO2 chromatography yielded 4-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)oxazole as a solid in 1% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[C:19]3[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH:26]1(Br)[CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C=O)C>[CH:26]1([N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:23])([F:21])[F:22])[C:11]([C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:10])=[N:12]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COc1cccc(C(=O)c2n[nH]c3c(C(F)(F)F)cccc23)c1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)c2nn(C3CCCC3)c3c(C(F)(F)F)cccc23)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
To a solution of [3-(methoxy)phenyl](7-trifluoromethyl-1H-indazol-3-yl)methanone (0.27 g, 0.85 mmol) in 5 mL DMF was added in one portion sodium hydride (0.034 g, 0.85 mmol, 60% in oil). After the gas evolution ceased, cyclopentyl bromide (0.107 mL, 1.0 mmol) was added and the reaction was stirred at ambient to 50° C. for 24 hours. The cool reaction mixture was partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo afforded the crude product which was purified by flash chromatography (silica gel, hexane/EtOAC, 9:1) to give the title compound (0.250 g) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](Br)[CH:8]=[CH2:9].Cl.[NH:12]1[C:20]2[C:15](=[C:16]([C:21]3([OH:27])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([N:23]1[CH2:24][CH2:25][CH2:26][C:21]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:15]=2[CH:14]=[CH:13][NH:12]3)([OH:27])[CH2:22]1)[CH:8]=[CH2:9]
Reactant: OC1(c2cccc3[nH]ccc23)CCCNC1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCCC(O)(c2cccc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
22.9 g of sodium carbonate and 7.6 ml of allyl bromide were added to a mixture of 18 g of 3-(1H-indol-4-yl)-3-piperidinol hydrochloride in 350 ml of dimethylformamide and the mixture was stirred under an inert atmosphere at room temperature for 2 hours. Then, one liter of water and 500 ml of ethyl acetate were added thereto and the decanted organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The 17 g of residue were chromatographed over silica gel and eluted with a 6-3-1 cyclohexanechloroform-triethylamine mixture to obtain 14 g of 1-(2-propenyl)-3-(1H-indol-4-yl)-3-piperidinol with an Rf=0.15.