Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][C:10]([C:12]([O:14]C)=[O:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2ccncc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccncc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of the obtained methyl 5-(4-pyridyl)-2-furancarboxylate (100 mg) in ethanol (10 ml) was added 1 N sodium hydroxide solution (4 ml) and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was dissolved in water, to which was added 1 N hydrochloric acid (4 ml). The precipitate was filtered, washed with water and dried to give the title compound (59 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][C:9]([NH:11][NH2:12])=[O:10])=[O:5])[CH3:2].[C:13](=[S:15])=[S:14].[OH-].[K+:17]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][O:7][CH2:8][C:9]([NH:11][NH:12][C:13]([S-:15])=[S:14])=[O:10])=[O:5])[CH3:2].[K+:17]
Reactant: S=C=S
Reactant: CCOC(=O)COCC(=O)NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)COCC(=O)NNC(=S)[S-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethoxycarbonylmethoxyacetohydrazide (15.0 g.) was suspended in chilled ethanol (200 ml.) at 0° C. and carbon disulfide (26.7 ml.) was next added dropwise to the suspension. A solution of potassium hydroxide (5.6 g.) in ethanol (60 ml.) was then added to the mixture over a period of 30 minutes, and the resulting reaction mixture was stirred at 0° C. for a further 30 minutes. Finally, the coolant was removed and the reaction mixture was stirred overnight for approximately 16 hours. The product, viz., potassium 3-(ethoxycarbonylmethoxyacetyl)dithiocarbazate, was subsequently removed from the mixture by means of filtration, washed successively with ethanol and diethyl ether and finally dried in vacuo to constant weight (yield, 43.5 g.). This product was immediately used in the next reaction step without any further purification being necessary.
Reaction SMILES: FC(F)(F)C(O)=O.C([O-])(=O)C.[NH4+:12].[F:13][C:14]1[C:19]([N:20]([CH2:23][C:24](=O)[CH3:25])[CH:21]=O)=[CH:18][CH:17]=[C:16]([F:27])[N:15]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:13][C:14]1[C:19]([N:20]2[CH:23]=[C:24]([CH3:25])[N:12]=[CH:21]2)=[CH:18][CH:17]=[C:16]([F:27])[N:15]=1
Reactant: CC(=O)CN(C=O)c1ccc(F)nc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2ccc(F)nc2F)cn1
Yield: 95.4 %

Procedure:
Trifluoroacetic acid (1.08 ml) and ammonium acetate (1.08 g) were added to a solution of N-(2,6-difluoropyridin-3-yl)-N-(2-oxopropyl)formamide (2.52 g) in toluene (40 ml), and the reaction solution was heated under reflux in a nitrogen atmosphere for four hours. After leaving to cool, ethyl acetate and a saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (2.19 g). The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]2=[O:20])=[CH:5][CH:4]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH:31]1[O:33][CH2:32]1.[ClH:34]>C(O)(C)C>[ClH:34].[OH:33][CH:31]([CH2:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[O:22][CH3:21])[CH2:32][N:17]1[CH2:18][CH2:19][CH:14]([N:11]2[CH2:12][CH2:13][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:10]2=[O:20])[CH2:15][CH2:16]1
Reactant: COc1ccc(N2CCN(C3CCNCC3)C2=O)cc1
Reactant: COc1ccccc1OCC1CO1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(N2CCN(C3CCN(CC(O)COc4ccccc4OC)CC3)C2=O)cc1

Procedure:
A mixture of 17.9 g of 1-[4-methoxy-phenyl)-3-(4-piperidyl)-2-imidazolidinone and 11.7 g of 1-(2-methoxyphenyloxy)-2,3-epoxypropane in 200 ml of isopropyl alcohol is refluxed for 6 hours. The mixture is thereafter acidified with 5N methanolic hydrochloric acid and concentrated under reduced pressure. The residue is freed from moisture still adhering to it by treatment with toluene. Recrystallisation of the residue from methanol with the addition of activated charcoal yields the 1-{1-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-4-piperidyl}-3-(4-methoxy-phenyl)-imidazolidin-2-one-hydrochloride as a white crystalline substance with a melting point of 214°-215° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:5][C:6]#[N:7].[CH3:18]OS(OC)(=O)=O>C1COCC1.O>[CH3:18][O:3][CH:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH2:5][C:6]#[N:7]
Reactant: COS(=O)(=O)OC
Reactant: N#CCC(O)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CC#N)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a suspension of NaH (1.50 g, 37.5 mmol, 60% dispersion) in dry THF (200 mL) cooled to 0° C. was added 3-hydroxy-3-(2-naphthalenyl)propionitrile (4.92 g, 25 mmol) in THF (50 mL) dropwise over 20 minutes. The resulting solution was stirred at 0° C. for 5 minutes and dimethylsulfate (4.72 g, 37.5 mmol) was added in one portion. The reaction mixture was stirred at 0° C. for 20 minutes and room temperature for 1.5 hours. The reaction was then diluted with H2O (50 mL) and the volatiles were removed in vacuo. The residue was partitioned between CH2Cl2 (250 mL) and H2O (200 mL). The aqueous phase was extracted with CH2Cl2 (1×250 mL), the combined organic layers dried (Na2SO4) and concentrated in vacuo to give a thick yellow oil. This was purified by preparative HPLC (SiO2 : gradient EtOAc/hexane) to give the product as a light yellow oil (4.58 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:24])[C:20]=1[N:21]=[C:22]=S.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:11])[C:22]([NH:21][C:20]3[C:15]([Cl:14])=[CH:16][N:17]=[CH:18][C:19]=3[Cl:24])=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: CNc1ccc(C(=O)OC)cc1N
Reactant: S=C=Nc1c(Cl)cncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)nc(Nc1c(Cl)cncc1Cl)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-methylamino-benzoic acid methyl ester (360 mg, 2.0 mmol) and 3,5-dichloro-4-isothiocyanato-pyridine (585 mg, 70%, 2.0 mmol) in 10 mL ethyl acetate was stirred for 2 h at ambient temperature. 1-Ethyl-3-(3′-dimethylaminopropyl)-carbodiimide*HCl (383 mg, 2.0 mmol) was added and the mixture stirred overnight. The mixture was concentrated i. vac., the residue was taken up in DMF and purified by RP-HPLC.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][N:9]=[N:8][C:7]=1[CH3:11])=[O:5].[CH2:13](OCC)C.C[Mg]I>C1COCC1>[C:4]([C:6]1[S:10][N:9]=[N:8][C:7]=1[CH3:11])(=[O:5])[CH3:13]
Reactant: CCOCC
Reactant: CON(C)C(=O)c1snnc1C
Agent: C[Mg]I
Solvent: C1CCOC1
Product: CC(=O)c1snnc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of N-methoxy-N-methyl-4-methyl-1,2,3-thiadiazole-5-carboxamide (11.31 g, 60.4 mmol) in THF (100 ml) was added 2M diethyl ether solution of methylmagnesium iodide (45.3 ml, 90.6 mmol) over 0.5 h at 0° C. The mixture was allowed to warm to room temperature and stirred for 3 h. The mixture was quenched with saturated aqueous ammonium chloride (100 ml) and then extracted with diethyl ether (200 ml×2). The extracts were dried (MgSO4) and concentrated to give 7.49 g (87%) of the title compound as a pale brown oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1)=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:24]=[CH:23][C:22]4[CH:25]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:11]1
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-7-oxo-7H-thieno[2,3-c]pyridin-6-yl]-2-methoxy-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (280 mg, 0.52 mmol) in trifluoroacetic acid (5 mL) and stir the solution at RT for 1 h. Concentrate the solution in vacuo and purify the crude material by flash chromatography, using 8% MeOH (2 N NH3) in CH2Cl2 as eluent, to give 213 mg (93%) of the title compound. LC-MS/ES m/z (35Cl) 439.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]2=[CH:4][CH:3]=1.[NH2:14][NH2:15]>C(O)C>[NH:14]([C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]2=[CH:4][CH:3]=1)[NH2:15]
Reactant: Clc1ccc2c(n1)CCCCCC2
Reactant: NN
Solvent: CCO
Product: NNc1ccc2c(n1)CCCCCC2
Temperature: 150 °C

Procedure:
2-Chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine was treated with ethanol (20 mL) and anhydrous hydrazine (5 mL) in a sealed tube at 150° C. bath temperature for 7 h. Initial experiments showed that the addition did not proceed in boiling ethanol at atmospheric pressure. HPLC showed that the addition was incomplete, so the reaction mixture was heated at 150° C. for a further 7 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with 95% dichloromethane and 5% of a 2M solution of ammonia in methanol; 1H NMR (CDCl3, 300 MHz) 7.19 (d, 1H), 6.51 (d, 1H), 5.85 (br s, 1H), 3.77 (br s, 2H), 2.79 (m, 2H), 2.63 (m, 2H), 1.73 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 156.87, 158.54, 138.81, 126.67, 104.58, 34.72, 32.67, 31.45, 30.85, 26.41, 26.37; MS (ES) 192 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].[CH2:17]([O:19][C:20](=[O:24])[CH:21](Cl)[CH3:22])[CH3:18].C([O-])(O)=O.[Na+]>CN(C)C=O.C(OC(=O)C)C>[CH3:7][C:8]1[CH:13]=[C:12]([CH:21]([CH3:22])[C:20]([O:19][CH2:17][CH3:18])=[O:24])[CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]
Reactant: CCOC(=O)C(C)Cl
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.4 %

Procedure:
To a stirred solution of added potassium tertiary butoxide (2.05 g, 18.3 mmol) in dimethylformamide (10 mL) were slowly added the mixture of 1-methyl-2-nitrobenzene (1 g, 7.29 mmol) and ethyl-2-chloropropionate (0.98 mL, 7.70 mmol) at −30° C. The reaction mixture was stirred for 10 min and warmed to room temperature. The residue was dissolved with ethylacetate and neutralized with NaHCO3. The organic layer was washed with water two times, then dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. Ethyl 2-(3-methyl-4-nitrophenyl)propanoate (1.20 g) was obtained as 70% yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:27]O>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:27])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CCCCCCCCCCCCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCCCCCc1ccccc1

Procedure:
13-Phenyltridecanoic acid (22.4 g, 77 mmol) was reacted for 1 h in methanol (60 ml) and sulfuric acid (2.2 g) under reflux. The reaction mixture was concentrated, poured into H2O (100 ml) and extracted with dichloromethane. The organic layer was washed with H2O, dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue (33 g) was chromatographed on silica gel (Wako Gel C-200) with dichloromethane as eluent to give the title compound as a white solid; yield: 17.6 g; mp 30.5°-31.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.OS(O)(=O)=O.[C:20]([O-])(O)=O.[Na+]>CO>[CH3:20][O:12][C:11]([C:8]1[C:7]2[C:2]([CH3:1])=[CH:3][C:4]([CH3:14])=[CH:5][C:6]=2[S:10][N:9]=1)=[O:13]
Reactant: Cc1cc(C)c2c(C(=O)O)nsc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nsc2cc(C)cc(C)c12
Temperature: 60 °C
Yield: 94 %

Procedure:
To a solution of 4,6-dimethyl-benzo[d]isothiazole-3-carboxylic acid (10 mg, 0.048 mmol) in MeOH (5 mL) was added conc. H2SO4 (0.1 mL) at room temperature. The solution was heated up to 60° C. for 24 hours. The solution was cooled and was neutralized with sat. NaHCO3. The solution was extracted with EtOAc. The combined organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography with 20% EtOAc in Hexane as the eluent to afford the title compound (10 mg, 94%) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC([N:16]([CH:20]([CH2:24][OH:25])[CH:21]([CH3:23])[CH3:22])[C:17](=[O:19])[OH:18])(C)C.O>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:25][CH2:24][CH:20]([NH:16][C:17](=[O:19])[O:18][C:2]([CH3:7])([CH3:3])[CH3:1])[CH:21]([CH3:22])[CH3:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(CO)N(C(=O)O)C(C)(C)C
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 123.4 %

Procedure:
4-Methylbenzenesulfonyl chloride (0.2222 mol) was added portionwise at 10° C. to a mixture of 1,1-dimethylethyl [1-(hydroxymethyl)-2-methylpropyl]carbamic acid (ester) (0.202 mol) in pyridine (65 ml). The mixture was stirred at 10° C. for 2 hours. H2O (75 ml) was added at 10° C. The precipitate was filtered off, washed with H2O and taken up in CH2Cl2. The organic solution was washed with H2O, dried, filtered and the solvent was evaporated, yielding 49 g (68%) of (±)-1,1-dimethylethyl [1-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-2-methylpropyl]carbamate; mp. 85° C. (interm. 32).
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:43]([O:47][C:48](=[O:54])[CH2:49][NH:50][C:51]([NH2:53])=[O:52])([CH3:46])([CH3:45])[CH3:44].C([O-])([O-])=O.[Cs+].[Cs+].I[C:62]1[C:63]([C:68](OC)=[O:69])=[N:64][CH:65]=[CH:66][CH:67]=1>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[C:43]([O:47][C:48](=[O:54])[CH2:49][N:50]1[C:68](=[O:69])[C:63]2[N:64]=[CH:65][CH:66]=[CH:67][C:62]=2[NH:53][C:51]1=[O:52])([CH3:46])([CH3:44])[CH3:45]
Reactant: COC(=O)c1ncccc1I
Reactant: CC(C)(C)OC(=O)CNC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2cccnc2c1=O

Procedure:
A 2-5 ml Biotage microwave vial is charged with Pd(OAc)2 (2.5 mol %, 4.6 mg, 0.019 mmol), Xantphos (5 mol %, 22.3 mg, 0.038 mmol), ureido-acetic acid tert-butyl ester (223.7 mg, 1.216 mmol), and Cs2CO3 (736.6 mg, 1.9 mmol). Methyl 3-iodopyridine-2-carboxylate (200.4 mg, 0.76 mmol) is added, followed by 1-4-dioxane (4 ml). The vessel is sealed and treated in the microwave at 120° C. for 5400 seconds. EtOAc was added to the mixture and decanted off. LCMS of this (+ELS) indicated no product. Water added to the residue giving rise to a white solid. LCMS of this material (+ELS) showed product. Material taken up in EtOAc, washed with brine (3×20 ml), then water (2×20 ml). The organic portions are passed through Celite® and the solvent removed in vacuo to give the title compound; [M+H]+ 278
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([CH2:11][CH2:12][CH3:13])=[N:9][CH:10]=[C:6]2[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH3:15]>>[NH2:15][C:2]1[N:7]2[C:8]([CH2:11][CH2:12][CH3:13])=[N:9][CH:10]=[C:6]2[CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: N
Reactant: CCCc1ncc2cc(Cl)nc(Cl)n12
Product: CCCc1ncc2cc(Cl)nc(N)n12

Procedure:
Using the method of Example 39, 5,7-dichloro-3-(n-propyl)imidazo[1,5-c]pyrimidine (from Example 36) was reacted with ammonia to provide white solid 5-amino-7-chloro-3-(n-propyl)imidazo[1,5-c]pyrimidine, m.p. 160°-161° C. (dec.). Analysis: Calculated for C9H11ClN4 : %C, 51.3; %H, 5.3; %N, 26.6; Found %C, 51.5; %H, 5.2; %N, 26.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][NH:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O>[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][N:23]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=2)[C:11]([C:9]2[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1cc(Br)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Br)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.9 %

Procedure:
To a solution of 80 mg (0.3 mmol) 5-bromo-1H-indole-7-carboxylic acid and 112 mg (0.33 mmol) (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 3 ml DMF, were added 0.1 ml (0.91 mmol) of N-methylmorpholine and 173 mg of TBTU (0.45 mmol) at rt. After stirring for 17 h at rt, the reaction mixture was diluted with 33 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; DCM/heptane 50:50 to 70:30) to give 152 mg white powder (90%). MS (ISP) 574.3 (M+H)+.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Yield: 65 %

Procedure:
tert-Butyl [(1R,3S)-3-isopropyl-3-({4-[5-(trifluoromethyl)pyridin-3-yl]piperazin-1-yl}carbonyl)cyclopentyl]carbamate (190 mg, 0.14 mmol) was treated with a 4.0 M solution of HCl in 1,4-dioxane (5 mL) for 1 h at room temperature. The mixture was concentrated and purified by HPLC to provide 35 mg of desired product. MS calculated for C19H27F3N4O; (M+H) 385; found 385.1.
Reaction SMILES: [I-].[Na+].[C:3]([C:7]1[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=1[O:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([O:19]C)[N:11]=1)([CH3:6])([CH3:5])[CH3:4].[Al].Cl[Si](C)(C)C.O>C(#N)C.N1C=CC=CC=1>[C:3]([C:7]1[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=1[O:9][C:10]1[N:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1ccc([N+](=O)[O-])c(Oc2ccccc2C(C)(C)C)n1
Agent: C[Si](C)(C)Cl
Agent: [Al]
Agent: [I-]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccccc1Oc1nc(O)ccc1[N+](=O)[O-]
Yield: 58 %

Procedure:
Sodium iodide (10.6 g, 71 mmol) was added to a green solution of 2a (4.26 g, 14 mmol) in acetonitrile (80 mL) in a vessel covered with aluminum foil to protect from light, followed by chlorotrimethylsilane (8.9 mL, 71 mmol) and water (0.4 mL, 21 mmol). The yellow-orange mixture was refluxed overnight in the dark. HPLC analysis showed that although some starting pyridine was still present, decomposition also appeared to be occurring. The reaction was quenched with saturated sodium thiosulfate solution (30 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate, and concentrated to give a yellow oil. The oil was purified by SiO2 chromatography (120 g), loaded with CH2Cl2 and eluted using a gradient of ethyl acetate in hexanes to afford 136a (2.34 g, 58% yield) as a yellow waxy solid, HPLC purity 100%, 3.66 min (Method A); [M+H]+=289.17; 1H NMR (500 MHz, CDCl3) δ ppm 8.42 (d, 1H, J=5.0 Hz), 7.48 (m, 1H), 7.18 (m, 2H), 6.92 (m, 1H), 6.33 (d, 1H, J=10.0 Hz), 1.37 (s, 9H); 13C (125 MHz, CDCl3) δ (ppm), 163.87, 155.70, 150.61, 142.05, 139.87, 127.86, 126.83, 125.98, 122.98, 104.62, 34.68, 30.17.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:7](=[O:18])[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[CH3:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39]Br>C1COCC1>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:7](=[O:18])[CH:8]([CH2:36][C:37]3[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=3[CH3:39])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)CN=C(c3ccc(F)cc3)c3cc(Cl)ccc32)cc1
Reactant: Cc1ccccc1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3C)N=C(c3ccc(F)cc3)c3cc(Cl)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
7-Chloro-5-(4-fluorophenyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (90 mg, 0.220 mmol) was dissolved in dry THF (2 mL) and cooled to −78° C. under nitrogen. Potassium tert-butoxide (49 mg, 0.437 mmol) was added as a solid in one portion and the resulting red solution was stirred vigorously for 5 min. To this solution was added 2-methylbenzyl bromide (25 μL, 0.262 mmol) by syringe. The mixture was stirred for 1 h at −78° C., then the cold bath was removed. After another 1 h (warming to room temperature), the reaction was quenched with MeOH and diluted with ethyl acetate. The organic layer was washed twice with water and once with brine, and then dried over MgSO4. Chromatography on silica gel eluting with 100% hexanes to 30% ethyl acetate in hexanes provided 7-chloro-5-(4-fluorophenyl)-1-(4-methoxybenzyl)-3-(2-methylbenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (44 mg, 39%). APCI MS m/z 535.2 [M+Na+], 513.3 [M+]; 1H NMR (300 MHz, CDCl3) δ 7.43-6.98 (m, 11H), 6.88 (d, J=9 Hz, 2H), 6.61 (dd, J=7 Hz, 2 Hz, 2H), 5.69 (d, J=15 Hz, 1H), 4.55 (d, J=15 Hz, 1H), 3.85 (t, J=7 Hz, 1H), 3.70 (s, 3H), 3.63 (d, J=7 Hz, 2H), 2.37 (s, 3H).