Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C[O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[C:12]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:27]C(OCC2C=CC=CC=2)=O)=[C:20]2[C:25]=1[S:24][CH2:23][CH2:22][C:21]2=[O:26])(=[O:14])[CH3:13].[N:38](OCCCC)=O>CCOCC>[C:3]([NH:38][CH:22]1[C:21](=[O:26])[C:20]2[C:25](=[C:16]([NH:15][C:12](=[O:14])[CH3:13])[CH:17]=[CH:18][C:19]=2[NH2:27])[S:24][CH2:23]1)(=[O:4])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCc2ccccc2)c2c1SCCC2=O
Reactant: CCCCON=O
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(=O)Nc1ccc(N)c2c1SCC(NC(C)=O)C2=O
Reaction time: 0.08 h

Procedure:
To 5 ml of a THF solution containing 168 mg of potassium-t-butoxide was added 5 ml of a THF solution containing 370 mg of the compound prepared in (1) above. After stirring for 5 minutes, 0.24 ml of n-butyl nitrite was added to the mixture, followed by further stirring for 1 hour at room temperature. After the addition of 20 ml of ether, the reaction mixture was stirred for another 1 hour. The deposited precipitate was collected by filtration, washed thoroughly with ether, and dissolved into a mixture of 20 ml of acetic acid and 20 ml of acetic anhydride. To the solution was slowly added about 200 mg of zinc powder at room temperature while stirring. After the addition, the stirring was continued for a further 0.5 hour. Insoluble substances were removed by filtration, the solvent was evaporated, and 20 ml of chloroform was added to the residue. The residue, after washing with water, saturated aqueous solution of sodium hydroxide, and saturated brine in this order, was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography using a hexane-ethyl acetate (4:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated and the residue was dissolved in 20 ml of a mixed solvent of dioxane-methanol (1:1) and catalytically hydrogenated using 100 mg of palladium-on-carbon. After evaporating the solvent, the residue was subjected to silica gel column chromatography using a hexane-ethyl acetate (4:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 23 mg of the title compound.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15]=1/[CH:20]=[C:21]1\[C:22](=[O:30])[NH:23][C:24]2[C:29]\1=[CH:28][CH:27]=[CH:26][CH:25]=2>C1COCC1>[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][C:15]=1/[CH:20]=[C:21]1\[C:22](=[O:30])[N:23]([C:7]([Cl:10])=[O:6])[C:24]2[C:29]\1=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(C)c(/C=C2\C(=O)Nc3ccccc32)[nH]1
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To the solution of triphosgene (7.2 gram, 24.2 mmol) in 500 mL of anhydrous THF was added 56 mL of thiethylamine in one portion and the resulting mixture was stirred at room temperature for 10 minutes. Solid 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole (5.768 gram, 24.2 mmol) was added in one portion to the above mixture. The reaction mixture was stirred at room temperature for 1 h and then cooled on ice bath to 0-4° C. Ice-cold 4M HCl aq. (1.5 L) was added in one portion upon vigorous stirring. The resulting suspension was further stirred for 10 min., and filtered. The solid was washed with ice-cold 4M HCl aq. and dried on the high vacuum oven overnight. The crude product was recrystallized from anhydrous benzene and filtered. The solid was then washed with cyclohexane and dried in a vacuum oven overnight to yield 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (5.531 gram, 76%). 1HNMR (400 MHz, DMSO-d6) δ 12.41 (s, br, 1H), 7.98 (m, 1H), 7.52 (m, 1H), 7.43 (s, 1H), 7.25 (m, 1H), 6.08 (d, br, J=2 Hz, 1H), 2.43 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[K+].[CH3:6][O:7][C:8]([C@H:10]1[CH2:13][C@@H:12]([O:14]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11]1)=[O:9]>CN(C=O)C>[CH3:6][O:7][C:8]([C@H:10]1[CH2:11][C@H:12]([O:14][C:1](=[O:3])[CH3:2])[CH2:13]1)=[O:9]
Reactant: COC(=O)[C@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)C1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](OC(C)=O)C1
Temperature: 120 °C

Procedure:
A mixture of potassium acetate (16.9 g, 172 mmol) and cis-3-(toluene-4-sulfonyloxy)-cyclobutanecarboxylic acid methyl ester (9.8 g, 34 mmol; trans/cis=1:5) in dry DMF (50 mL) was heated to 120° C. for 21 h. DMF was partially distilled off (≈30 mL), water was added, and the mixture was extracted with EtOAc (6×50 mL). The combined organic layers were washed with water (2×), brine, dried over MgSO4, filtered and concentrated to give the title compound as brown oil, trans/cis=5:1 based on 1H NMR. The material thus obtained was used without further purification.
Reaction SMILES: CC1C=C(C)N([C:8]([CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])N=1.[CH3:24][O:25][CH2:26][C:27]1[O:31][C:30]([NH2:32])=[N:29][N:28]=1>>[CH3:24][O:25][CH2:26][C:27]1[O:31][C:30]([NH:32][C:8]([CH:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:9])=[N:29][N:28]=1
Reactant: Cc1cc(C)n(C(=O)C2c3ccccc3Oc3ccccc32)n1
Reactant: COCc1nnc(N)o1
Product: COCc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 233-234° C. and MS: m/e=337.1 (M+H+) was prepared in accordance with the general method of example 48a from (3,5-dimethylpyrazol-1-yl)-(9H-xanthen-9-yl)-methanone and 5-methoxymethyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14](O)=[O:15])=[CH:13][C:9]=2[C:8]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[N:7]1)=[O:5])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:65]([NH2:74])([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)([CH3:67])[CH3:66]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14](=[O:15])[NH:74][C:65]([CH3:67])([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH3:66])=[CH:13][C:9]=2[C:8]([NH:17][C:18](=[O:33])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[CH:31][CH:32]=2)=[O:27])=[N:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(N)c1ccccc1
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2NC(=O)c2ccc[nH]2)c2cc(C(=O)O)sc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2NC(=O)c2ccc[nH]2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 25 °C

Procedure:
A mixture of 3-{2-[(1H-Pyrrole-2-carbonyl)-amino]-benzoylamino}-thieno[2,3-c]pyrazole-1,5-dicarboxylic acid 1-ethyl ester (198.5 mg, 0.4246 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 204 mg, 0.6369 mmol), DIEA (0.29 mL, 1.6984 mmol) and cumylamine (115 mg, 0.8492 mmol) in DMF (10 mL) was stirred at room temperature. After 2 hours the mixture was diluted with AcOEt (40 mL) and washed with saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4 and evaporated to give 495 mg of crude that was used in the next step without further purification, LC-MS: Rt 7.36; [M+H]+ 585.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](O)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][OH:33])[CH:27]=2)=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:33][CH2:32][C:28]3[CH:27]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=4)[N:30]([CH3:31])[N:29]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nc(CO)cc1-c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cn1nc(COc2ccc3c(ccn3CC(=O)OC(C)(C)C)c2)cc1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 1 d]) was reacted with [5-(4-chloro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {5-[5-(4-chloro-phenyl)-1-methyl-1H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5].[C:14]([O:18][C:19](=[O:22])[CH2:20][NH2:21])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCC1=O>[C:14]([O:18][C:19](=[O:22])[CH2:20][NH:21][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:5])([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)CN
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNc1ccc(C(F)(F)F)cc1C#N
Temperature: 110 °C
Yield: 95.8 %

Procedure:
To a solution of 2-fluoro-5-trifluoromethylbenzonitrile 1A (10 g, 52.9 mmol) in N-methylpyrrolidinone (NMP) (100 mL) was added glycine tert-butyl ester 5A (13.8 g, 105 mmol) and diisopropylethylamine (20 g, 155 mmol). The reaction mixture was heated at 110° C. for 4 hours. Ethyl acetate (500 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide (2-cyano-4-trifluoromethylphenylamino)acetic acid tert-butyl ester 5B (15.2 g, 50.7 mmol).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:20]>C(Cl)(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCNCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN(CCNC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
To a cooled (˜5° C.) solution of compound A (6.2 g, 25.0 mmol) and TEA (3.0 g, 29.7 mmol, 4.13 mL) in chloroform (50 mL) was added iodomethane (4.2 g, 29.7 mmol, 1.85 mL). The pressure tube was sealed, and the mixture stirred at ambient temperature for 20 h. The mixture was then precipitated with ether (300 mL); the white solid was filtered off and washed with ether (50 mL). The filtrate was concentrated and the residual yellow oil (5.2 g) was purified by silica gel column chromatography (2-10% MeOH gradient in DCM) to give compound B (3.3 g, 12.5 mmol, 50%) as a colorless oil. TLC Rf (DCM/MeOH 9:1): 0.55. LC-MS [M+H] 264.3 (C15H24N2O2+H, calc: 264.4).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=4)[N:9]=[CH:8][C:7]=3[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Br:27]N1C(=O)CCC1=O>CN(C)C=O.[Cl-].[Na+].O>[Br:27][C:6]1[C:7]2[CH:8]=[N:9][C:10]([NH:13][C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C@:21]([OH:25])([CH3:24])[CH2:22][OH:23])=[CH:17][CH:16]=3)=[CH:11][C:12]=2[N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=1
Reactant: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(ccn3C3CC3)cn2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@](O)(CO)c1ccc(C(=O)Nc2cc3c(cn2)c(Br)cn3C2CC2)cc1
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
In a 250 ml round bottom flask was added (R)—N-(1-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)-4-(1,2-dihydroxypropan-2-yl)benzamide (17, 3.2 g, 9.2 mmol) in N,N-dimethylformamide (31 ml). The mixture was cooled in ice bath, followed by addition of N-bromosuccinimide (1.477 g, 8.30 mmol) in portions. The mixture was stirred in ice bath for 30 min, at which point about ˜10% starting material remained. Another 0.1 equivalence (160 mg) of N-bromosuccinimide was added to the reaction mixture, which was stirred in an ice bath for another 30 min. Brine (200 ml) was added, followed by extraction with EtOAc (2×200 mL). Organic layers were combined. After drying and filtering, a suspension was obtained upon concentration. The solid was collected on a filtered, and then washed with 10 ml EtOAc. The resulting 2 g of filtrated solid was purified by silica gel column chromatography, eluting with 5-10% MeOH in EtOAc. Product-containing fractions were combined and concentrated to yield a solid which was washed twice with EtOAc (2×10 ml). The title compound (22, 0.62 g, 16%) was obtained as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.04 (m, 2H) 1.05-1.13 (m, 2H) 1.42 (s, 3H) 3.42-3.54 (m, 3 H) 4.71 (t, J=5.81 Hz, 1H) 4.99 (s, 1H) 7.58 (d, J=8.59 Hz, 2H) 7.62 (s, 1H) 8.01 (d, J=8.59 Hz, 2H) 8.48 (d, J=0.76 Hz, 2H) 8.51 (d, J=0.76 Hz, 2H) 10.63 (s, 1H); ESI-MS: m/z 432 (M+H)+. Additional amounts of the title compound were obtained by combining filtrates and re-purifying them by silica gel column chromatography.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH3:13][C:14]1[CH:20]=[C:19]([C:21]([F:30])([C:26]([F:29])([F:28])[F:27])[C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=1[NH2:16]>C(#N)C>[I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([C:21]([F:30])([C:22]([F:23])([F:24])[F:25])[C:26]([F:27])([F:28])[F:29])=[CH:20][C:14]=2[CH3:13])=[O:6])[C:3]=1[C:8]([OH:7])=[O:9]
Reactant: O=C1OC(=O)c2c(I)cccc21
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Solvent: CC#N
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1NC(=O)c1cccc(I)c1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
In acetonitrile (100 ml) was dissolved 5.5 g (20 mmol) of 3-iodophthalic anhydride, and a solution (20 ml) of 5.5 g (20 mmol) of 2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline in acetonitrile was slowly dropped thereinto. After the resulting mixture was stirred at room temperature for 3 hours, two-thirds of the acetonitrile was distilled off under reduced pressure and the crystals precipitated were filtered and then washed with acetonitrile to obtain 5.6 g (yield 51%) of 6-iodo-N-{2-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl}phthalamic acid.
Reaction SMILES: C(OC([N:8]1[CH2:21][CH:20]2[CH2:22][CH:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][C:19]=32)[N:16]=[C:15]([CH3:23])[N:14]4[CH2:24][CH2:25][CH3:26])[CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:33]>>[ClH:33].[CH3:23][C:15]1[N:14]([CH2:24][CH2:25][CH3:26])[C:13]2[C:17](=[CH:18][C:19]3[CH:20]4[CH2:22][CH:10]([C:11]=3[CH:12]=2)[CH2:9][NH:8][CH2:21]4)[N:16]=1
Reactant: CCCn1c(C)nc2cc3c(cc21)C1CC3CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCn1c(C)nc2cc3c(cc21)C1CNCC3C1
Temperature: 100 °C
Yield: 34 %

Procedure:
6-Methyl-7-propyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene-13-carboxylic acid tert-butyl ester (90 mg, 0.253 mmol) was dissolved in 3N HCl ethyl acetate (5 mL) and warmed to 100° C. for ½ hour. The mixture was cooled, concentrated, slurried in ethyl acetate, and filtered to provide a white solid (25 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 9.56 (s, NH), 7.91 (s, 1H), 7.83 (br m, NH), 7.74 (s, 1H), 4.38 (m, 2H), 3.48 (m, 2H), 3.32 (m, 2H), 3.10 (m, 2H), 2.87 (s, 3H), 2.28 (m, 1H), 2.15 (d, J=11.0 Hz, 1H) 1.85 (m, 2H), 0.97 (m, 3H). M.p. 147–150° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([S:19](F)(=[O:21])=[O:20])[N:13]=1>>[Cl:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:3]=1[NH:4][S:19]([C:14]1[N:13]=[C:12]([CH3:11])[CH:17]=[C:16]([CH3:18])[N:15]=1)(=[O:20])=[O:21]
Reactant: Cc1ccc(Cl)c(N)c1Cl
Reactant: Cc1cc(C)nc(S(=O)(=O)F)n1
Product: Cc1cc(C)nc(S(=O)(=O)Nc2c(Cl)ccc(C)c2Cl)n1

Procedure:
This material was prepared from 2,6-dichloro-3-methylaniline and 4,6-dimethyl-2-pyrimidinesulfonyl fluoride following the general procedure described in Example 2. The desired product was isolated as a solid, m.p. 234°-235°. NMR (90 MHZ) D6 -Acetone: δ 7.4 (d, 2H), 7.3 (s, 1H), 2.5 (s, 6H) and 2.3 (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[S:7][CH2:8][C:9]=1[C:10]([OH:12])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CC(C)=O.O>[C:1]([NH:4][C:5]1[CH:6]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[S:7][CH2:8][C:9]=1[C:10]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:12])(=[O:3])[CH3:2]
Reactant: CC(=O)NC1=C(C(=O)O)CSC1CCCCC(=O)N1CCCCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)C1=C(NC(C)=O)C(CCCCC(=O)N2CCCCC2)SC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.12 g (0.0060 moles) of 3-acetamido-4-carboxy-2,5-dihydro-2-thiophenevaleric acid piperidide was dissolved in 25 ml acetone to which 1.3 ml water had been added, and the solution was cooled in an ice bath for 15 min. At this point 1.8 ml (.0063 mole) of triethylamine was added in 25 ml acetone, followed immediately by the dropwise addition of 1.23 ml. (0.0063 mole) of ethyl chloroformate in 2.7 ml of acetone over a 10 minute period. The reaction was stirred at 0°C. for one hour to form 3-acetamido-4-carbethoxycarbonyl-2,5-dihydro-2-thiophenevaleric acid piperidide, which was converted to 3-(N-carbethoxyacetamido)-4-carboxy-2,5-dihydro-2-thiophenevaleric acid piperidide, and which was converted to 3-(N-carbethoxyacetamido)-4-carbethoxycarbonyl-2,5-dihydro-2-thiophenevaleric acid piperidide. A solution of 0.8 g. (0.0063 mole) sodium azide in 5 ml. water was added dropwise over a period of 5 minutes. The reaction was further stirred at 0° C. for 2 hrs. The reaction mixture was then partitioned between 100 ml. of dichloromethane and 75 ml. of ice water. The aqueous phase was extracted three times with anhydrous sodium sulfate to yield 2.8 g. (0.0060 mole, 100%) of 4-azidocarbonyl-3-(N-carbethoxyacetamido)-2,5-dihydro-2-thiophenevaleric acid piperidide as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH:30]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])[CH3:31]>>[CH:30]([C:33]1[N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:3]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])[CH3:31]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
2-(4-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropan-1-ol (70 mg) was reacted with 2-isopropylbenzimidazole via General Procedure I for Buchwald coupling to give 28 mg 476 following reverse phase purification. MS (Q1) 548.3 (M)+
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21](NC4CCOCC4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.[CH3:38][C:39]([NH2:48])([CH3:47])[CH2:40][N:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>>[OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:48][C:39]([CH3:38])([CH3:47])[CH2:40][N:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Reactant: CC(C)(N)CN1CCOCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC(C)(C)CN4CCOCC4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing 4-aminotetrahydropyran with 2-methyl-1-morpholinopropan-2-amine. Off-white solid 20 mg, 12%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[ClH:7].C([S:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH2:14]/[C:13]/1=[CH:31]\[C:32]1[N:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:36]=1)(=O)C.C(#N)C>CO.C(OCC)(=O)C>[ClH:7].[CH:21]1([C:19](=[O:20])[CH:18]([N:15]2[CH2:16][CH2:17][CH:12]([SH:11])/[C:13](=[CH:31]/[C:32]3[N:33]=[N:34][N:35]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[N:36]=3)/[CH2:14]2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:23][CH2:22]1
Reactant: COC(=O)Cn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2SC(C)=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC#N
Product: COC(=O)Cn1nnc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
Potassium carbonate (275 mg) was added to a solution of (E)-4-(acetylsulfanyl)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[2-(methoxycarbonylmethyl)-2H-tetrazol-5-yl]methylidene}piperidine hydrochloride (347 mg) in methanol (10 ml). After being stirred at room temperature for 15 minutes, the mixture was diluted with ethyl acetate, and the reaction was quenched by addition of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure followed by purification of the residue by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 35/65, v/v) to afford the title compound (185 mg, yield: 58%) as a colourless amorphous solid.
Reaction SMILES: P(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2[N+:14]([O-])=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)[N+:9]([O-])=[CH:10][CH:11]=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([C:8]2[CH:7]=[C:6]([Cl:5])[CH:11]=[CH:10][N:9]=2)[CH:18]=1
Reactant: [O-][n+]1ccc(Cl)cc1-c1cc(Cl)cc[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: Clc1ccnc(-c2cc(Cl)ccn2)c1
Temperature: 60 °C

Procedure:
2 mL of chloroform, 0.326 mL of phosphorus trichloride and 0.082 g of 4,4′-dichloro-2,2′-bipyridyl-N,N′-dioxide were added to a 100 mL round bottom flask equipped with a condenser, and the mixture was refluxed in a hot water bath for 75 hours. The reaction solution was cooled with ice, poured into crushed ice and neutralized with 25% NaOH to pH 7 or higher. Chloroform was removed from the solution by distilling off under reduced pressure. The precipitated white powder was collected by filtration and washed with water. The powder was dissolved in a small amount of petroleum ether and recrystallized in a refrigerator overnight to give white needle crystal. The crystal was dried by heating to 60° C. under reduced pressure to give 4,4′-dichloro-2,2′-bipyridine.