Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[C@@H:13]([OH:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19]1.CCN(C(C)C)C(C)C.CC#N.O>CCCCO>[Br:1][C:2]1[C:3]([N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:19]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[C@@H:13]([OH:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[C@H](O)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CC#N
Solvent: O
Solvent: CCCCO
Product: C[C@H](O)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 65.7 %

Procedure:
(S)-N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamide (0.040 g, 0.13 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.074 g, 0.40 mmol) and DIEA (0.069 mL, 0.40 mmol, d 0.742) were placed in n-BuOH (1 mL) and heated to 135° C. for 8 hours. The reaction was then cooled to room temperature and concentrated to dryness. The resulting residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-60% CH3CN/water) to give tert-butyl (R)-1-(5-bromo-3-((S)-2-hydroxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.040 g, 65% yield).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[OH-].[K+].[NH2:17]OS(O)(=O)=O>O>[NH2:17][N:7]1[C:8]2[C:3](=[C:2]([Br:1])[CH:11]=[C:10]([Br:12])[CH:9]=2)[NH:4][C:5](=[O:14])[C:6]1=[O:13]
Reactant: NOS(=O)(=O)O
Reactant: O=c1[nH]c2cc(Br)cc(Br)c2[nH]c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c(Br)cc(Br)cc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
The procedure of Shin, S. C. and Lee. Y. Y., Taehan Hwahakhoe Chi 27(5):382-4 (1983) was adapted. 5,7-Dibromo-1,4-dihydroquinoxaline-2,3-dione (46 mg, 0.144 mmole) was dissolved into 3N KOH (2 mL) at 60° C. for 1 h, and NH2OSO3H (20 mg, 0.172 mmole, Aldrich) in distilled water (0.5 mL) was dropwise added into above solution with stirring at 60° C. Some precipitate came out after 15 mins, then a second 20 mg NH2OSO3H portion was added. The mixture was stirred at room temperature for 1 h. The white precipitate was collected by filtration, washed with cold distilled water (0.5 mL), affording crude 1-amino-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (38 mg, 79%) after drying in the air at 60° C. for 2 h (contains the isomeric 4-amino-5,7-dibromo-2,3-quinoxalinedione, by NMR, but it is not known which is produced in a greater amount). A 38 mg sample of crude 1-amino-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione was dissolved into distilled water (4 mL) at 60° C., the insoluble material was removed by filtration, and the filtrate was acidified with AcOH to pH=5 to give a white precipitate, which was collected by filtration and washed with cold distilled water (2×1 mL). The precipitate was dried at 60° C. for 2 h affording 1-amino-5,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (28 mg, 58.5%) as a white powder with some isomer. Mp: 273°-5° C. (dec. from 270° C.). IR (KBr, cm-1): 3435; 3289; 3190; 1719; 1672; 1625; 1584. NMR (1H, DMSO-d6): δ5.831 ((s, 2H); 7.672 (d, J=15 Hz, 1H); 7.810 (d, J=15 Hz, 1H); 11.275 (s, 1H). HRMS: calcd for C8H5N3O2Br2 (M+) m/z: 332.8746; Found: 332.8744.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20](O)=[O:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C.C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:20]([C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[NH:11][CH:12]=[CH:13]3)=[O:21])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a mixture of 2-(4-chlorophenyl)ethylamine (0.531 g, 3.41 mmol), indole-5-carboxylic acid (0.500 g, 3.10 mmol) and DIEA (0.811 mL, 4.65 mmol) in DCM (10 mL) was added HBTU (1.29 g, 3.41 mmol) and acetonitrile (5 mL), and the reaction was stirred at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (75 mL) and the organic layer was washed with 2N HCl (50 mL) and brine (50 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0.5% methanol/DCM to 10% methanl/DCM to provide N-(4chlorophenethyl)-1H-indole-5carboxamide (0.650 g, 70.1% yield) as waxy yellow solid.
Reaction SMILES: [N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12.[CH3:15][CH2:16][C:17](=O)[CH2:18][CH3:19].[BH4-].[Na+].[OH-].[NH4+]>C(O)(=O)C>[CH2:16]([CH:17]([NH:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3=[N:1][CH2:2][CH2:3][CH2:4][N:5]3[C:9]=2[CH:10]=1)[CH2:18][CH3:19])[CH3:15]
Reactant: CCC(=O)CC
Reactant: Nc1ccc2c(c1)N1CCCN=C1S2
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(CC)Nc1ccc2c(c1)N1CCCN=C1S2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3 parts of 3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine, 1.6 parts of 3-pentanone and 30 parts of acetic acid is stirred for 10 minutes at room temperature. Then there is added portionwise 1 part of sodium borohydride at a temperature between 18°-20° C. (cooling is necessary). Upon completion, stirring is continued for 20 minutes at room temperature. The reaction mixture is alkalized to pH 8-9 with ammonium hydroxide while cooling. The product is extracted with trichloromethane. The aqueous phase is separated and extracted with trichloromethane. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume), saturated with ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 2.2 parts of N-(1-ethylpropyl)-3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-amine; mp. 114.4° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:27]=[C:26]2[C:9]([C:10](=[O:28])[CH2:11][C:12]3([O:25]2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[CH:8][CH:7]=1.Cl.COC(=O)/C=C/C1C=C2C(=CC=1)OC1(CCNCC1)CC2=O>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:27]=[C:26]2[C:9]([C:10](=[O:28])[CH2:11][C:12]3([O:25]2)[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[CH:8][CH:7]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)CC2=O
Agent: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Product: COC(=O)/C=C/c1ccc2c(c1)OC1(CCNCC1)CC2=O
Yield: 107.7 %

Procedure:
(E)-3-{1′-tert-Butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-acrylic acid methyl ester (2.45 g, 6.1 mmol) was deprotected with HCl according to the procedure for preparation of Intermediate 1, Step C, giving (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-7-yl}-acrylic acid methyl ester (1.98 g) as a yellow solid (hydrochloride salt).
Reaction SMILES: Cl.[N:2]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:6][NH:5][CH:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.C(N(CC)CC)C.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>ClCCl>[CH:26]1([C:29]([N:5]2[CH2:6][CH2:7][N:2]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH:4]2[C:8]([O:10][CH3:11])=[O:9])=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1CC1
Reaction time: 0.58 h
Yield: 103.4 %

Procedure:
To a solution cooled to 0° C. of 10.0 g (35.6 mmol) of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate hydrochloride (CAS 129799-08-2) in 350 ml of dichloromethane are added 11.0 ml (79.1 mmol) of triethylamine and then, over 35 minutes, 3.6 ml (40 mmol) of cyclopropylcarbonyl chloride dissolved in 50 ml of dichloromethane. The medium is stirred from 0° C. to room temperature over 4 hours 30 minutes and is then washed with twice 40 ml of water and dried over sodium sulfate. The solvent is evaporated off under reduced pressure and the residue is chromatographed on a column of 90 g of silica gel, eluting with a mixture of 5 to 50% ethyl acetate in dichloromethane, to give 11.5 g 1-tert-butyl 3-methyl 4-cyclopropanecarbonylpiperazine-1,3-dicarboxylate in the form of a viscous oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.[CH3:13]O>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:13])=[O:7]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(C)cc1O
Temperature: 60 °C
Yield: 94 %

Procedure:
To a suspension of 10 g (0.0651 mol) of 4-methylsalicylic acid in 150 mL of methanol was added 50 mL of ethereal hydrochloric acid. The reaction mixture was heated at 60° C. for 60 hours. The solvent was removed under vacuum. After adding hexane-ethyl acetate, the resulting solid was filtered and the filtrate was evaporated to give 10.2 g (94%) of product as an oil.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14][CH:15]=2)=[CH:7][CH:6]=1.[C:24]1([C:30]2[C:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][NH:32][N:31]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C=O>[C:24]1([C:30]2[C:34]([CH2:35][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:32]([CH2:4][C:5]3[CH:23]=[CH:22][C:8]([O:9][CH2:10][C:11]4[N:12]=[C:13]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)[S:14][CH:15]=4)=[CH:7][CH:6]=3)[N:31]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
Sodium hydride (60%, oily, 110 mg) was added to a solution of 4-(4-chloromethylphenoxymethyl)-2-phenylthiazole (760 mg) and ethyl 3-(3-phenyl-1H-pyrazol-4-yl)propionate (580 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1110 mg, yield: 89%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](NC4C=C(S(N)(=O)=O)C=CC=4)[N:24]=3)[NH:19][N:18]=2)[CH2:16][CH2:15]1>>[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=4)[N:24]=3)[NH:19][N:18]=2)[CH2:16][CH2:15]1
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Reactant: NS(=O)(=O)c1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Product: CN(C)S(=O)(=O)c1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1
Yield: 9.8 %

Procedure:
Compound 103 (25.0 mg, 9.8%) was prepared from 4-amino-N,N-dimethylbenzenesulfonamide as described in Compound 82 and purified by prep HPLC. LC-MS (m/z): 400.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.69-0.73 (m, 2H), 0.91-0.96 (m, 2H), 1.86-1.90 (m, 1H), 2.58 (s, 6H), 6.28 (bs, 1H), 6.54 (bs, 1H), 7.60 (d, J=4.0 Hz, 2H), 8.04 (d, J=4.0 Hz, 3H), 9.66 (s, 2H), 12.08 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1.CCN(CC)CC.[CH3:31][O:32][C:33](Cl)=[O:34].[OH-].[Na+]>CN(C=O)C>[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]2[CH2:17][N:16]([C:33]([O:32][CH3:31])=[O:34])[CH2:15][C:13]=2[N:14]=1
Reactant: COC(=O)Cl
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CNC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Temperature: 20 °C
Reaction time: 0.03 h

Procedure:
To a stirring solution of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine trifluoroacetate (intermediate 20) (2.16 g, 2.0 mmol) in DMF (10 ml), was added Et3N (560 uL, 4.0 mmol). Reaction mixture was stirred at room temperature (20° C.) for 2 minutes followed by the addition of methylchloroformate (186 uL, 2.4 mmol) followed by stirring at room temperature overnight. The reaction mixture was basified (with 2M NaOH) before partitioning between water (25 ml) and DCM (50 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo, affording the title compound as a brown solid used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][C:9](Cl)=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])[CH3:2].O.[S-2:23].[Na+].[Na+]>O>[CH2:13]([NH:12][C:11]1[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([SH:23])[N:8]=[C:7]([CH3:21])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:14][CH2:15][CH3:16]
Reactant: [S-2]
Reactant: CCCCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCNc1c(C(=O)OCC)c(C)nc(S)c1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
31.5 g. of 4-butylamino-6-chloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 Mol.) are dissolved in 100 ml. of alcohol. 14.8 g. of sodium sulfide monohydrate and about 2 ml. of water are added and the mixture is stirred for one hour without cooling. The precipitated 4-butylamino-6-mercapto-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester is filtered off, yield 27.5 g. (88%), m.p. 140°-142° (ethanol).
Reaction SMILES: [N:1]1[CH:5]=[CH:4][C:3](=[O:6])[N:2]=1.[Li].[OH-].[Na+].[CH2:10](N=C=NCCCN(C)C)[CH3:11].O[N:22]1[C:26]2[CH:27]=CC=C[C:25]=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.C(O)C.CO.O1CCOCC1.O1CCCC1>[CH:4]([N:22]([CH:26]([CH3:25])[CH3:27])[CH2:10][CH3:11])([CH3:5])[CH3:3].[N:1]1[CH:5]=[CH:4][C:3](=[O:6])[N:2]=1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C1C=CN=N1
Agent: [Li]
Solvent: CCO
Solvent: CO
Solvent: CN(C)C=O
Product: CCN(C(C)C)C(C)C

Procedure:
Condensation of the β-ketoester 1 and benzyl hydrazine 2 described in Scheme 3 is carried out by heating the two components in a solvent such as acetic acid or acetonitrile for 1-8 h to give the pyrazolone 6. Elaboration at this point to β-alanine ester 7 can be achieved by saponification of the ester 6 using a base such as aqueous lithium or sodium hydroxide in a polar solvent such as tetrahydrofuran, dioxane, methanol, ethanol or a mixture of similar solvents. Coupling of the beta alanine ester 8 is then achieved using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and 1-hydroxybenzotriazole (HOBt) or benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP) and a base, generally diisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF) or methylene chloride for 3 to 48 hours at ambient temperature to yield the compound 7. Pyrazolone 7 is then treated with triflic anhydride in a polar aprotic solvent such as THF in the presence of a base such as triethylamine at −78° C. to room temperature to afford the intermediate II. The product is purified from unwanted side products by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel as described by W. C. Still et al, J. Org. Chem., 43, 2923, (1978), or HPLC. Purification of intermediates is achieved in the same manner. If the intermediate II is racemic (ie R2 is not hydrogen), then this compound can be resolved via chiral hplc using either normal phase or supercritical fluid conditions.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[ClH:12].Cl.[CH2:14]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:12].[ClH:12].[C:3]([CH:2]([N:26]1[CH2:27][CH2:28][N:23]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH2:24][CH2:25]1)[CH3:11])(=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Reactant: CC(Br)C(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)c1ccccc1)N1CCN(CC(=O)c2ccccc2)CC1

Procedure:
A mixture of 2-bromo-1-phenylpropan-1-one (3 mmol), N-phenacyl piperazine dihydrochloride (2.5 mmol) and K2CO3 (8.75 mmol) in 30 ml of DMF was treated according to the general preparation 2 to give compound (IV-8), 0.64 g (62%), mp 236-238° C., M+ 336.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5](=[N:21][OH:22])[NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])=O.N1C=CC=CC=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[N:6]=[C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N+:18]([O-:20])=[O:19])[O:22][N:21]=1
Reactant: COC(=O)CC(=NO)NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)Cc1noc(-c2cc3cccc([N+](=O)[O-])c3[nH]2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 274.6 %

Procedure:
3-(Hydroxyimino)-3-[(7-nitro-1H-indole-2-carbonyl)-amino]-propionic acid methyl ester (960 mg, 1 mmol) prepared in Step B was dissolved in DMF (10 mL). Pyridine (1 mL) was added thereto, and the mixture was stirred for 4 h at 80° C. The reaction was quenched by aqueous NH4Cl solution. The reaction mixture was extracted with EtOAc, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (830 mg, Yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Intermediate 1e (1.81 g, 9.18 mmol), triphenylphosphine (4.83 g, 18.4 mmol), and triethylamine (5.12 mL, 36.7 mmol) in THF (25 mL) at 0° C., hexachloroethane (4.36 g, 18.4 mmol) was added in 2 portions at a 1 min intervals. The resulting pale brown solution was allowed to warm to RT then stirred for 2 h. The resulting yellow suspension was filtered, washing with THF (2×25 mL). The combined organics were purified using SCX-2 cartridge (washed with DCM-MeOH (1:1, 100 mL) and MeOH (50 mL), and then the product was eluted with 2M NH3 in MeOH) to give a pale yellow solid (1.60 g, 97%, contaminated with ˜2.5% Ph3P═O). NMR (400 MHz, CDCl3): 1.53 (6H, d), 3.32 (1H, sept), 7.15 (1H, ddd), 7.75 (1H, ddd), 7.84 (1H, m).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=O.CC([O-])(C)C.[K+]>CN(C=O)C>[C:2]1([C:8]2[CH:13]=[C:12]([CH:14]=[CH:19][C:18]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:17]=3[O:16][CH3:15])[CH:11]=[CH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccnc(-c2ccccc2)c1
Reactant: COc1ccc(OC)c(C=O)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(C=Cc2ccnc(-c3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To a mixture of 2-phenyl-4-methylpyridine hydrochloride (1 g, 4.9 mmol) and 2,5-dimethoxybenzaldehyde (1.2 g, 7.3 mmol) in anhydrous DMF (40 ml), solid t-BuOK (2 g, 18 mmol) was added. The resulting mixture was stirred overnight at 80° C. under nitrogen. After evaporating DMF, Et2O was added thereto and the precipitate was filtered and washed with water. The solid was purified by column chromatography (SiO2, CH2Cl2/MeOH, 99/1) to afford 0.6 g (39%) of the desired compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([C:22]2[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH:27]=2)[C:5]([O:20][CH3:21])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.Cl.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O>O1CCOCC1.C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[C:3]([F:35])=[C:4]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[C:5]([O:20][CH3:21])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1C1=CCNCC1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Into a microwave vial was added tert-butyl 4-{3-chloro-2-fluoro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (10.5 mg, 0.021 mmol) and 4.0 M HCl in 1,4-dioxane (1.0 mL). The mixture was stirred for 30 min and evaporated. Methylene chloride (1.0 mL) and DIPEA (15.6 μL, 0.090 mmol) were added followed by methanesulfonyl chloride (4.8 pt, 0.063 mmol). The mixture was stirred for 15 minutes. The solvents were evaporated. 1 N sodium hydroxide solution (1.0 mL) and methanol (1.0 mL) were added and the mixture was stirred for 1 hour. The solvents were evaporated and purification by preparative LC/MS (pH 10) gave the desired compound (4.0 mg, 40%). LCMS calculated for C20H23ClFN6O3S (M+H)+: m/z=481.1. found: 481.0. 1H NMR (DMSO-d6, 500 MHz) δ 12.88 (1H, br s), 8.18 (2H, m), 7.63 (1H, m), 5.91 (1H, m), 5.78 (1H, br s), 3.94 (5H, m), 3.40 (2H, m), 2.98 (3H, s), 2.55 (2H, m), 2.39 (2H, m), 1.42 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:12](=[CH:13][N:14]=1)[NH:11][C:10](=[O:15])[CH:9]1[CH2:16][N:5]2[CH2:6][CH2:7][CH2:8]1.[C:17](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]2[C:12](=[CH:13][N:14]=1)[N:11]([CH3:17])[C:10](=[O:15])[CH:9]1[CH2:16][N:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCCC1C2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C2CCCN(C2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 0.075 g (0.00032 mole) of (rac)-4-chloro-1,3,5,8-tetraaza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-trien-9-one (VI-67), 0.8 mL of dimethylformamide, 0.17 g (0.0005 mole) of cesium carbonate and 0.055 g (0.0004 mole) of iodomethane was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give (rac)-4-chloro-8-methyl-1,3,5,8-tetraaza-tricyclo[8.3.1.0*2,7*]tetradeca-2,4,6-trien-9-one (VII-67), which was used directly in the next step.