Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Br)Br.C(=O)(O)[O-].[Na+].[CH3:9]N(C)C=O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([NH:20][C:21](=[S:23])[S-:22])=[CH:16][CH:15]=1.[NH4+]>O>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([N:20]=[C:21]2[S:22][CH2:9][S:23]2)=[CH:16][CH:15]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(NC(=S)[S-])cc1
Agent: O=C([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: BrCBr
Product: Cc1ccc(N=C2SCS2)cc1
Temperature: 12 °C
Reaction time: 4 h

Procedure:
In a suitable reaction vessel is mixed 6,090 grams of methylene bromide, 1,955 grams of sodium bicarbonate and 13.2 liters of dimethylformamide. The mixture is cooled to 12°C. and maintained between 12°C. and 20°C. while adding powdered ammonium p-tolyldithiocarbamate in small portions over about a 2-hour period. After stirring for an additional 4 hours at room temperature, the mixture is poured into a separatory funnel and diluted with an equal volume of water. The lower oily phase is separated and the upper aqueous DMF phase is extracted three times with 3.5 liter portions of ethylene chloride. The combined organic phase is washed with water and filtered. In a suitable vessel, the washed ethylene chloride mixture is diluted with an additional 36 liters of ethylene chloride, cooled to 10°C. to 15°C., and well stirred while adding 3,690 ml. of 37% aqueous solution of hydrochloric acid. After the mixture comes to room temperature, the solids are collected by filtration and washed with ethylene chloride and then methyl ethyl ketone. The air-dried hydrochloride salt of 2-p-tolylimino-1,3-dithietane, amounting to 3,432 grams, is finely pulverized and mixed with 14.5 liters of water. The mixture is cooled and about 2800 ml. of ammonium hydroxide is added over about 30 minutes to give a final acidity of pH 8. The solids are collected by filtration, washed with water, and air-dried to give 2,566 grams of 2-p-tolylimino-1,3-dithietane, melting point 54.5°C. to 55.0°C. The infrared spectrum shows C=N absorption at 1640 cm.-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10](=[CH2:16])[CH:11]=[CH:12][C:13](=O)[CH:14]=2)=[CH:5][CH:4]=1.[NH2:17][C:18]1[S:19][CH2:20][CH2:21][N:22]=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:22]3[CH2:21][CH2:20][S:19][C:18]3=[N:17][C:13]3[C:12](=[CH:9][C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[CH2:11][S:10][CH2:16][C:14]2=3)=[CH:5][CH:4]=1
Reactant: NC1=NCCS1
Reactant: C=S1C=CC(=O)C=C1c1ccc(OC)cc1
Solvent: CC(C)=O
Product: COc1ccc(C=C2CSCC3=C2N=C2SCCN2C3c2ccc(OC)cc2)cc1

Procedure:
A mixture of tetrahydro-3,5-bis[(4-methoxyphenyl)-methylene-4H-thiopyran-4-one (4.9 g, 14 mmole) and 2-amino-2-thiazoline (1.8 g, 17.6 mmole) in acetone (300 ml) is heated at reflux temperature overnight. The precipitate (4.7 g) collected is a mixture of starting ketone and intermediate aminol (4-[(4,5-dihydro-2-thiazolyl)amino]tetrahydro-3,5-bis[(4-methoxyphenyl)methylene]thiopyran-4-ol) in a ratio of 4:6.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[O:67]=[S:68]1(=[O:82])[CH2:73][CH2:72][N:71]([C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:70][CH2:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([N:71]4[CH2:70][CH2:69][S:68](=[O:82])(=[O:67])[CH2:73][CH2:72]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(N2CCS(=O)(=O)CC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=S1(=O)CCN(c2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 31.6 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(1,1-dioxothiomorpholino)benzaldehyde (1.1 eq, 0.084 mmol, 20 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (14 mg, 32%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.61 (s, br, 4H, piperazine N(CH2)2), 3.14 (t, J=4.7 Hz, 4H, 1,1-dioxothiomorpholine N(CH2)2), 3.61 (s, 2H, NCH2), 3.65 (t, J=4.6 Hz, 4H, piperazine N(CH2)2), 3.91 (t, J=5.0 Hz, 4H, 1,1-dioxothiomorpholine S(CH2)2), 7.16 (d, J=9.0 Hz, 2H, phenyl H-2 & H-6), 7.39 (dd, J=7.5, 4.8 Hz, 1H, pyridine H-5), 7.78 (dt, J=7.8, 1.9 Hz, 1H, pyridine H-4), 8.06 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.8 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2), 13.26 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH2:1]([C:8]([NH:28]C(=O)OC(C)(C)C)([CH3:27])[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[C:16]([N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:19][CH2:20][CH3:21])[N:15]=[C:14](Cl)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][CH:37]1[CH2:39][CH:38]1[CH2:40][NH2:41].C(O)(C(F)(F)F)=O.C(NS(C)(=O)=O)CC>CCO>[NH2:28][C:8]([CH3:27])([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:41][CH2:40][CH:38]2[CH2:39][CH:37]2[CH3:36])[N:15]=[C:16]([N:18]([CH2:19][CH2:20][CH3:21])[S:22]([CH3:25])(=[O:23])=[O:24])[CH:17]=1
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Reactant: CC1CC1CN
Agent: CCCNS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(NCC2CC2C)n1)S(C)(=O)=O

Procedure:
N-(4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-6-{[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-propylmethanesulfonamide was prepared from intermediate VI and [(2-methylcyclopropyl)methyl]amine (prepared from N-benzyl-1-(2-trans-methylcyclopropyl)methenamine by hydrogenation on Pd(OH)2, in EtOH, in the presence of TFA), following a similar procedure as described for the preparation of N-4-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-6-{benzyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-propylmethanesulfonamide. HRMS (ES, M+H) calcd. for C25H38N4O3S: 475.2737, found: 475.2719.
Reaction SMILES: [Cl-].[Br:2][C:3]1[C:15]2[C:14]3[CH2:13][CH2:12][NH2+:11][CH2:10][C:9]=3[CH:8]=[N:7][C:6]=2[NH:5][N:4]=1.CCN(C(C)C)C(C)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Br:2][C:3]1[C:15]2[C:14]3[CH2:13][CH2:12][N:11]([C:32]([NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:33])[CH2:10][C:9]=3[CH:8]=[N:7][C:6]=2[NH:5][N:4]=1
Reactant: Brc1n[nH]c2ncc3c(c12)CC[NH2+]C3
Reactant: O=C=Nc1ccccc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Reaction time: 0.17 h
Yield: 293.1 %

Procedure:
To a solution of 1-bromo-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7-ium chloride (0.16 g, 0.55 mmol) in dichloromethane (5 mL), Hunig's Base (0.59 mL, 3.3 mmol) was added and stirred under inert atmosphere. After 10 minutes, phenyl isocyanate (0.06 mL, 0.57 mmol) was added and the reaction was allowed to stir at room temperature for 2 hours. The mixture was diluted with dichloromethane (10 mL) and washed with water (2×5 mL), dried over anhydrous sodium sulfate, filtered and dried in vacuo. The resulting pale brown solid was purified by flash column chromatography (SiO2, 50% ethyl acetate in hexanes) to give the desired product as light pink solid (0.6 g, 30%). M.p.=249-250° C., 400 MHz 1H NMR (DMSO-d6) δ: 10.64 (s, 1H), 9.66 (s, 1H), 8.82 (s, 1H), 8.25 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.2 (d, J=8.8 Hz, 2H), 7.07 (t, J=7.2 Hz, 1H), 6.95 (d, J=6.4 Hz, 1H), 4.25 (t, J=5.2 Hz, 2H), 3.24 (s, 2H), 2.96 (t, J=6 Hz, 2H), 2.2-2.14 (m, 2H); LCMS [M+H]: 350.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=1[F:15])=[O:4].[C:18]([N:21]1[C:32]2[C:24](=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28]C(C(O)=O)=[CH:26]3)[CH2:23][CH2:22]1)(=[O:20])[NH2:19].C(N(CC)CC)C>CN(C=O)C>[C:18]([N:21]1[C:32]2[C:24](=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:2]([C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]([F:14])[C:7]=2[F:15])=[O:4])=[CH:26]3)[CH2:23][CH2:22]1)(=[O:20])[NH2:19]
Reactant: NC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Reactant: O=C(Oc1c(F)c(F)cc(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)N1CCc2c1ccc1[nH]c(C(=O)Oc3c(F)c(F)cc(F)c3F)cc21
Reaction time: 1 h
Yield: 75 %

Procedure:
2,3,5,6-Tetrafluorophenyl trifluoroacetate (2.6 g, 10 mmol, H. B. Gamper, M. W. Reed, T. Cox, J. S. Virosco, A. D. Adams, A. A. Gall, J. K. Scholler and R. B. Meyer,Jr. Nucleic Acids Res., 1993, Vol. 21, No.1, 145-150) was added dropwise to a solution of 3-carbamoyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylic acid (1.4 g, 6.1 mmol, D. L. Boger, R. S. Coleman, and B. J. Invergo. J.Orq.Chem., 1987, Vol.52, 1521-1530) and triethylamine (1.4 ml, 10 mmol) in 15 ml of anhydrous DMF. After 1 hr, the reaction mixture was concentrated under vacuum (0.2 mm). The residue was triturated with 2 ml of dry dichloromethane. Ethyl ether (50 ml) was added and the mixture was left at 0° C. overnight. The precipitate was collected by filtration on sintered glass funnel, washed first with 50% ether/CH2Cl2 (10 ml), then with ether (50 ml) and dried in vacuo. The product was obtained as a yellow solid (1.8 g, 75%): 1H NMR (Me2SO-d6, 200 MHz, ppm) 12.32 (s, 1H, NH), 8.13 (d, 1H, J=9 Hz, C4-H), 8.01 (m, 1H, C6F4H), 7.41 (s, 1H, C8-H), 7.26 (d, 1H, J=9 Hz, C5-H), 6.17 (s, 2H, CONH2), 3.99 (t, 2H, J=9 Hz, NCH2CH2), 3.30 (t, 2H, J=9 Hz, NCH2CH2). Anal. Calcd. for C18H11N3O3F4×2H2O: C, 50.3; H, 3.52; N, 9.7. Found; C, 50.81; H, 3.60; N, 9.95.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[C:4]2[N:3]=1.[CH3:23][CH:24]([CH3:27])[CH2:25][NH2:26]>CN1C(=O)CCC1.CO>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[C:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])=[C:4]3[N:3]=[C:2]([NH:26][CH2:25][CH:24]([CH3:27])[CH3:23])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)S1
Reactant: CC(C)CN
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(C)CNc1cc(NC2CC2)n2ncc(C=C3SC(=O)NC3=O)c2n1
Temperature: 130 °C

Procedure:
To 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione (30 mg, 0.09 mmol) in NMP was added 2-methylpropan-1-amine (20 mg, 0.268 mmol). The reaction was heated at 130° C. overnight. The reaction mixture was diluted with MeOH and purified by prep HPLC to yield 5-((7-(cyclopropylamino)-5-(isobutylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=373)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([OH:39])[CH2:31][N:30]([C:32](OC(C)(C)C)=O)[CH2:29]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:40]([OH:46])([C:42](F)(F)F)=[O:41].C(OC(C)(C)C)(=O)C=C.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5([OH:39])[CH2:29][N:30]([CH2:32][CH2:42][C:40]([OH:46])=[O:41])[CH2:31]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(-c3noc(CCC4(c5cc(Cl)cc(Cl)c5)CCCCC4)n3)cc2)C1
Reactant: O=C(O)C(F)(F)F
Agent: C=CC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)CCN1CC(O)(c2ccc(-c3noc(CCC4(c5cc(Cl)cc(Cl)c5)CCCCC4)n3)cc2)C1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 56 %

Procedure:
tert-Butyl 3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate (56 mg, 0.098 mmol, HPLC purity: 80%) was treated with TFA in dichloromethane for 1 h and concentrated. The residue was dissolved in 2-propanol (3 mL). tert-Butyl acrylate (0.143 mL, 0.978 mmol) and diisopropylethyl amine (0.034 mL, 0.196 mmol) were added and the mixture was heated to 80° C. overnight. The reaction mixture was concentrated and then treated with TFA in dichloromethane for 3 h. The mixture was concentrated and a DMF solution of the crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain 3-(3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxy-1-azetidinyl)propanoic acid (30 mg, 56% yield). HPLC retention time=3.75 minutes (Waters XBridge C18 4.6×50 mm) eluting with 5-95% aqueous AcCN with 0.05% TFA over a 5.3 minute gradient. LC/MS: m/e 544.07, 545.97 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([O:28][CH3:29])=[C:23](B(O)O)[CH:24]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([C:14]2[CH:15]=[CH:16][C:11]([S:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:12][CH:13]=2)[CH:20]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)cc1
Product: COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (i) and 5-chloro-2-methoxybenzene boronic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].[CH:19]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10])[CH3:19]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1nc(-c2ccc(Br)cc2)oc1C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1nc(-c2ccc(Br)cc2)oc1C
Temperature: 50 °C
Yield: 46 %

Procedure:
[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (11.6 g, 37.4 mmol) is dissolved in anhydrous tetrahydrofuran (150 mL) and allowed to stir under nitrogen. Lithium diisopropyl amide solution in tetrahydrofuran (28 mL of 2M soln., 56.1 mmol) is slowly added to the solution at room temperature. This is then heated to 50° C. for 6 hours. The solution is allowed to cool to room temperature and methyl iodide (7.0 mL, 112 mmol) is added in one portion. The mixture is allowed to stir under nitrogen at room temperature overnight. The solution is quenched with a saturated solution of ammonium chloride, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propionic acid methyl ester (5.57 g, 17.19 mmol) is isolated in 46% yield after column chromatography. The racemic 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl)-propionic acid methyl ester is resolved on a Chiralcel OJ column (4.6×250 mm). Eluted with 40% isopropanol in heptane with 0.2% dimethy-ethylamine at 1 mL per minute with detection at 260 nM and concentrated the fractions to provide the pure enantiomer esters (isomer 1, 99.8% ee; isomer 2, 99.4% ee).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[C:25]([NH:29][C:30]([C:32]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)C>[C:25]([NH:29][C:30]([C:32]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:37][CH2:36][N:35]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]3[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)NC(=O)C1(c2ccccc2)CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=O)C1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (19 mg, 0.051 mmol, 1 eq.) in 2 mL of ethanol was added N-tert-butyl-4-phenylpiperidine-4-carboxamide (13.2 mg, 0.051 mmol, 1 eq.) and triethylamine (0.02 mL, 0.15 mmol, 3 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 22 mg (72%) of N-tert-butyl-1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidine-4-carboxamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14-1.32 (m, 9 H) 2.17 (s, 2 H) 2.39-2.58 (m, 2 H) 4.07 (s, 2 H) 5.01 (s, 2 H) 7.10-7.44 (m, 12 H) 7.51 (d, J=6.59 Hz, 1 H) 8.37 (s, 1 H), [M+H]+ 599.7.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[Cl:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=O)=[CH:20][CH:19]=1>O1CCCC1>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[C:2]2[CH:1]=[CH:5][CH:4]=[CH:3]2)=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: C1=CCC=C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1ccc(C(=C2C=CC=C2)c2ccc(Cl)cc2)cc1
Temperature: 0 °C
Yield: 57 %

Procedure:
A reaction vessel equipped with a dropping funnel was charged with 40 ml of dehydrated tetrahydrofuran and 2.15 ml (25.9 mmol) of cyclopentadiene under nitrogen atmosphere, and 18.0 ml (28.5 mmol) of a hexane solution of n-butyllithium of 1.58 mol/L was added dropwise and stirred while cooling the above solution at 0° C. Then, a solution prepared by dissolving 5.00 g (19.9 mmol) of 4,4′-dichlorobenzophenone in 30 ml of dehydrated tetrahydrofuran was placed in the dropping funnel and added dropwise while cooling at 0° C., and the solution was allowed to return to room temperature and stirred for one day. This reaction solution was extracted with diethyl ether, and the separated organic layer was washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated salt solution and dried over anhydrous magnesium sulfate. Then, magnesium sulfate was removed by filtration, and the solvent contained in the filtrate was removed by distillation under reduced pressure by means of a rotary evaporator. The residue was purified through a silica gel column to obtain a targeted product (amount obtained: 3.37 g, yield: 57%). The targeted product was identified by means of 1H-NMR.
Reaction SMILES: [N+:1]([C:4]1[C:5]2[CH2:18][CH:17]([C:19](O)=[O:20])[CH2:16][C:6]=2[C:7]2[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[CH3:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH3:41][N:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:19]([CH:17]1[CH2:16][C:6]2[C:7]3[NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=2[CH2:18]1)=[O:20]
Reactant: CNc1ccccc1
Reactant: O=C(O)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)C1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1)c1ccccc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A solution of 6-nitro-2,3,-dioxo-2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoxaline-8-carboxylic acid (1 mmol, example 78) in anhydrous DMF was treated with carbonyldiimidazole (2 mmol) and triethylamine (1 mL) and then heated at 70° C. for 45 min. After cooling to room temperature methylphenylamine (1.2 mL) was added and the mixture stirred at 50° C. for 6 h. The solvent was removed in vacuo, and the residue triturated with acetone. The solid was collected by filtration, washed with diethyl ether and dried in vacuo. Calc'd for C19H16N4O5.1.2 H2O: C, 56.77; H, 4.61; N, 13.93; found: C, 56.22; H, 4.13; N, 14.62. MS M+1 (381).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:15]([O-])=O)=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[H][H]>CO.[Pd]>[NH2:12][C:5]1[CH:4]=[C:3]([NH2:15])[C:2]([F:1])=[CH:7][C:6]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: O=C(O)Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(N)c(CC(=O)O)cc1F
Temperature: 25 °C
Yield: 99.9 %

Procedure:
(5-Fluoro-2,4-dinitro-phenyl)-acetic acid 9b (10 g, 38.7 mmol) was dissolved in 150 mL of methanol under stirring at room temperature, and palladium on activated carbon (5%, 1.5 g) was then added to the solution. The reaction mixture was hydrogenated under 0.3 Mpa of hydrogen. The reaction was completed until TLC showed the disappearance of starting materials. The above mixture was filtered twice and the filtrate was concentrated under reduced pressure to give the title compound (2,4-diamino-5-fluoro-phenyl)-acetic acid 9c (7.12 g) as a brown solid which was directly used in the further reaction.
Reaction SMILES: [H][H].[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]=[N+]=[N-])=[C:8]([F:16])[CH:7]=1>CO>[CH3:3][O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[C:8]([F:16])[CH:7]=1
Reactant: COC(=O)c1ccc(CN=[N+]=[N-])c(F)c1
Reactant: [H][H]
Solvent: CO
Product: COC(=O)c1ccc(CN)c(F)c1
Yield: 83 %

Procedure:
Hydrogen was passed through a degassed solution of 4-azidomethyl-3-fluorobenzoic acid methyl ester from Example E3.3 (2.11 g, 10 mmol) in methanol containing 10% palladium on carbon for 2 h. The reaction mixture was filtered through Celite® filter agent and the filtrate was concentrated in vacuo to give a colourless oil identified as the title compound (1.51 g, 83%).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CCO>[OH:14][C@@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Temperature: 110 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
To a vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (76 mg, 0.26 mmol) and tert-butyl [(3R,4S,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (60 mg, 0.24 mmol), EtOH was added (2.0 mL), followed by DIPEA (114 mg, 0.883 mmol). The mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow foamy solid (68 mg, 69%). LCMS calc. for C19H29N4O6 (M+H)+: m/z=409.2. found 409.0.