Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>>[CH3:14][Si:15]([C:18]#[C:19][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)CCc1ccc(I)cc1
Product: COC(=O)CCc1ccc(C#C[Si](C)(C)C)cc1

Procedure:
The title compound was prepared from methyl 3-(4-iodophenyl)propanoate (250 mg, 0.86 mmol) and trimethylsilylacetylene (0.22 mL, 1.70 mmol) according to the general procedure IA. After filtration through Celite, the product was obtained as a brown oil and used without purification in the next step. Rf: 0.38 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.39-7.37 (m, 2H), 7.13-7.11 (m, 2H), 3.65 (s, 3H), 2.96-2.91 (t, 2H, J=7.6 Hz), 2.63-2.58 (t, 2H, J=7.8 Hz), 0.24 (s, 9H); 13CNMR (CDCl3) δ 173.1, 141.1, 132.1, 128.2, 121.1, 105.0, 93.8, 51.6, 35.6, 30.8, 0.0.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13][C:12]=3[CH:24]=2)[S:6][CH:7]=1>COCCOC>[CH3:2][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13][C:12]=3[CH:24]=2)[S:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3cc(C)cs3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: Cc1csc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
In 1,2-dimethoxyethane (15.3 ml) was dissolved methyl 7-(4-methyl-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate. (510 mg), and to the solution was added 6N hydrochloric acid (10.2 ml). The mixture was stirred at 100° C. for 15 hours and cooled to room temperature. Under reduced pressure, the solvent was evaporated. To the residue,were added ethyl acetate and potassium carbonate solution, and the mixture was extracted with water. To the solution was added 6N hydrochloric acid, and the solution was made pH 4-5, extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 7-(4-methyl-2-thienyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (459 mg).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:45])([F:44])[C:38](N(OC)C)=[O:39]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:38](=[O:39])[C:37]([F:45])([F:44])[F:36])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Reactant: CON(C)C(=O)C(F)(F)F
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)C(F)(F)F)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and 2,2,2-trifluoro-N-methoxy-N-methylacetamide. Compound exists in the hydrated form.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[C:13]([NH:15][C@@H:16]3[CH2:21][CH2:20][C@H:19]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[C:12]([NH2:28])=[CH:11][N:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[F:29][C:30]1[CH:64]=[CH:63][C:33]([C:34](/[N:36]=[C:37]2/N([C@H]3CC[C@@H](C(=O)NC(C)C)CC3)C3C=C(OCCOC)N=CC=3N/2)=[O:35])=[CH:32][CH:31]=1>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[N:10]=[CH:11][C:12]3[NH:28]/[C:37](=[N:36]\[C:34](=[O:35])[C:33]4[CH:63]=[CH:64][C:30]([F:29])=[CH:31][CH:32]=4)/[N:15]([C@H:16]4[CH2:17][CH2:18][C@@H:19]([C:22](=[O:23])[NH:24][CH:25]([CH3:26])[CH3:27])[CH2:20][CH2:21]4)[C:13]=3[CH:14]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COCCOc1cc2c(cn1)[nH]/c(=N\C(=O)c1ccc(F)cc1)n2[C@H]1CC[C@@H](C(=O)NC(C)C)CC1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCn3cncn3)ncc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3cnc(OCCn4cncn4)cc32)CC1
Yield: 43 %

Procedure:
The title compound was prepared from cis-4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-aminopyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide using a procedure analogous to that used to prepare (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-(2-methoxyethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)benzamide. Isolated as an off-white solid (62 mg, 43% yield, last step). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (d, J=6.55 Hz, 6H) 1.57-1.62 (m, 2H) 1.69-1.73 (m, 2H) 2.02-2.16 (m, 2H) 2.50-2.51 (m, 1H) 2.57-2.79 (m, 2H) 3.92-4.02 (m, 1H) 4.60-4.65 (m, 4H) 4.70-4.80 (m, 1H) 6.99 (s, 1H) 7.25 (dd, J=8.85, 8.85 Hz, 2H) 7.65 (d, J=7.82 Hz, 1H) 7.98 (s, 1H) 8.22 (s, 1H) 8.28-8.36 (m, 2H) 8.53 (s, 1H) 12.70 (s, 1H). M/Z calc'd for C27H31FN8O3: 534.59. found 535 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:10]=[C:9]1[CH:24]=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl([O-])=[O:27].[Na+].P([O-])(O)(O)=O.[Na+].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C(O)(C)(C)C.CC(=CC)C.O.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=2[CH:10]=[C:9]1[C:24]([OH:27])=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(C=O)n2C(=O)OC(C)(C)C)C1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(cc(C(=O)O)n2C(=O)OC(C)(C)C)C1
Reaction time: 21 h

Procedure:
To a solution of 1,5-bis(t-butoxycarbonyl)-2-formyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (44.0 mg) in t-butanol (2.0 ml), 2-methyl-2-butene (150 μl) and an aqueous solution (6.0 ml) of sodium chlorite (102 mg) and sodium dihydrogenphosphate (135 mg) were added at room temperature. After stirring for 21 hours, the reaction mixture was added with diethyl ether (10 ml) and water (10 ml), followed by the addition of ammonium sulfate until saturation. The resulting mixture was separated, followed by extraction with diethyl ether (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby the residue, that is, 1,5-bis(t-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid was obtained as a white foamy substance. To a solution of the resulting residue in N,N-dimethylformamide (2.0 ml), methylene chloride (2.0 ml) and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride (55.0 mg) were dissolved, followed by the addition of 1-(dimethylaminopropyl)-3-ethyl carbodiimide (30.5 mg) and 1-hydroxybenzotriazole (21.5 mg) at room temperature. At 0° C., diisopropylethylamine (67.0 μl) was added thereto. After stirring overnight at room temperature, a 10% aqueous citric acid solution (10 ml) and methylene chloride (10 ml) were added to the reaction mixture to cause separation. The organic layer was extracted with methylene chloride (10 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by thin-layer preparative chromatography on silica gel (methylene chloride:acetone=10:1) and the white solid thus obtained was reprecipitated in a methylene chloride—methanol—water system. After filtration and washing with water, the title compound (50.0 mg) was obtained as a colorless transparent caramel-like substance. IR(KBr)cm−1: 2981, 2929, 2860, 1743, 1693, 1647, 1456, 1421, 1367, 1348, 1325, 1279, 1236, 1165, 1103, 955, 945, 729.
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[C:9]([CH:11]([NH:19][CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][N:7]=1)=[O:5])C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:21]([NH:28][C:4]([C:6]1[N:10]=[C:9]([CH:11]([NH:19][CH3:20])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:8][N:7]=1)=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1noc(C(Cc2ccccc2)NC)n1
Solvent: CCO
Product: CNC(Cc1ccccc1)c1nc(C(=O)NCc2ccccc2)no1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
5-(1-Methylamino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid ethylester (3.3 g, 9.0 mmol) was dissolved in ethanol (30 ml). Benzylamine (3 ml) was added and the reaction mixture was stirred for 18 h at 20° C. The reaction mixture was concentrated in vacuo and the residue was crystallised from ethanol to give 2.07 g of (R) 5-(1-methylamino-2-phenylethyl)-[1,2,4]oxadiazole-3-carboxylic acid benzylamide.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH:23]1([NH2:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1>>[CH3:13][C:12]1[C:7]([NH:33][CH:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: NC1CCCc2ccccc21
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCc3ccccc32)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 1,2,3,4-tetrahydronaphthalen-1-ylamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60-1.69 (m, 3H), 1.83 (bs, 4H), 2.09 (s, 3H), 2.66-2.75 (m, 2H), 4.46 (d, J=5.37 Hz, 2H), 5.31 (bs, 1H), 6.33 (d, J=8.33 Hz, 1H), 6.70-6.78 (m, 1H), 7.07 (dd, J1=15.31 Hz, J2=6.45 Hz, 4H), 7.15 (d, J=5.64 Hz, 1H), 7.26 (d, J=7.52 Hz, 1H), 7.64 (d, J=7.25 Hz, 1H), 8.42 (d, J=4.03 Hz, 1H); MS (ESI) m/z 361.0 (M+1)+.
Reaction SMILES: NN.O=C1C2C(=CC=CC=2)C(=O)[N:5]1[O:14][CH2:15][C:16]1[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[C:18]2[C:23]([CH3:24])=[C:22]([CH3:25])[N:21]3[N:26]=[N:27][N:28]=[C:20]3[C:19]=2[N:29]=1.ClCCl.[CH3:43][C:44]([CH3:46])=O>C(O)C>[CH3:25][C:22]1[N:21]2[N:26]=[N:27][N:28]=[C:20]2[C:19]2[N:29]=[C:16]([CH2:15][O:14][N:5]=[C:44]([CH3:46])[CH3:43])[N:17]([CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:39])[CH:36]([CH3:37])[CH3:38])[C:18]=2[C:23]=1[CH3:24]
Reactant: CC(C)=O
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)C(C)C)c12
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)C(C)C
Reaction time: 4 h

Procedure:
Anhydrous hydrazine (0.91 mL, 29 mmol) was added to a stirred suspension of N-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]-2-methylpropanamide (4.90 g, 9.71 mmol) in ethanol (100 mL). Dichloromethane (50 mL) was added. After four hours, acetone (50 mL) was added and the reaction mixture was stirred overnight. A solid was removed by filtration and washed with methanol. The filtrate was concentrated to provide a solid that was triturated with 1:1 saturated aqueous sodium bicarbonate/water. The solid was isolated by filtration, washed with water, and dissolved in chloroform (300 mL). The solution was washed with water (2×50 mL), dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under vacuum to afford N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}-2-methylpropanamide that was used in the next experiment.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC(O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COC(=O)c1cnc(N2CCN(C)CC2)nc1
Temperature: 100 °C
Yield: 34.3 %

Procedure:
Methyl 2-chloropyrimidine-5-carboxylate (0.863 g, 5.0 mmol), N,N-diethylethanamine (0.697 ml, 5.00 mmol) and 1-methylpiperazine (0.565 ml, 5.09 mmol) were suspended in 2-propanol (10.00 ml) and sealed into a microwave tube. The reaction was heated to 100° C. for 10 mins in the microwave reactor and cooled to room temperature. The precipitate was collected by filtration, washed with EtOH (5 mL) and dried under vacuum to afford methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (0.405 g, 34.3%) as a white solid, which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1.[OH-].[Na+]>C(O)C>[CH:13]1([CH2:12][CH:11]([S:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][CH:6]=2)[C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(SC(CC2CCCCC2)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1

Procedure:
To a solution of 2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol (300 mg, 0.88 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 325.0 mg, 1.29 mmol) at 0° C., followed by the addition of tributylphosphine (0.32 mL, 1.29 mmol) and methyl 4-mercaptobenzoate (173.3 mg, 1.03 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid methyl ester. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-{2-cyclohexyl-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-benzoic acid (190 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=S)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:18]>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[CH2:9][O:10][CH2:11][C:12]([NH2:18])=[N:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: FC(F)C1(c2cccc(Br)c2)COCC(=S)N1
Solvent: CO
Product: NC1=NC(c2cccc(Br)c2)(C(F)F)COC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(3-Bromo-phenyl)-5-difluoromethyl-morpholine-3-thione (7.49 g, 23.25 mmol) was dissolved in 36 ml 7N NH3 in methanol and stirred at room temperature for 18 h. After completion, volatiles were removed under reduced pressure to yield the title compound. 1H-NMR (360 MHz, DMSO-d6): 7.80 (s, 1H), 7.52 (m, 2H), 7.33 (m, 1H), 6.25 (br, 2H, NH2), 6.04 (t, 1H, CHF2), 4.15-3.90 (m, 2H), 3.72 (d, 1H), 3.45 (d, 1H); MS: 305 [(M+)+].
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[CH:16][N+:17]([O-])=[O:18])[CH2:13][N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH:27]=1>C(O)(=O)C.O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:15]=[C:14]([C:16]([N+:1]([O-:3])=[O:2])=[N:17][OH:18])[CH2:13][N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:10]=2[CH:27]=1
Reactant: O=[N+]([O-])C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium nitrite, 5 g (0.072 mole), was added in portions over a period of 5 min to a solution of 20 g (0.06 mole) of 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2-nitromethylene-2H-1,4-benzodiazepine* in 100 ml of glacial acetic acid. Following the addition, the reaction mixture was stirred at room temperature for 15 min. The product, which crystallized partially during this period, was further precipitated by slow addition of 50 ml of water and collected by filtration. The crystals were washed with water, sucked dry and washed with methanol/ether to leave light yellow product. The filtrate was diluted with water and extracted with methylene chloride. The extracts were washed with water, dried and evaporated. Crystallization of the residue from methylene chloride/hexane yielded additional product. The analytical sample was recrystallized from ether to give pale yellow crystals with mp 220°-230° C. dec.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2Cl)=[C:4]([F:24])[CH:3]=1.[CH3:25][CH2:26][O-:27].[Na+]>C(O)C>[CH2:26]([O:27][C:13]1[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]([Br:1])=[CH:3][C:4]=2[F:24])[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=1)[CH3:25]
Reactant: CC[O-]
Reactant: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Br
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Br)cc1F

Procedure:
using 1-(4-bromo-2-fluoro-5-isopropoxyphenyl)-2-chloro-4-trifluoromethyl-6(1H)-pyrimidinone and sodium ethylate in ethanol there is obtained 2-ethoxy-1-(4-bromo-2-fluoro-5 -isopropoxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 106°-108° C.;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH2:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.N1C=CC=CC=1.[CH3:43][N:44]([CH3:59])[C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[C:50]2[S:55](Cl)(=[O:57])=[O:56]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[NH:34][S:55]([C:50]1[C:51]2[C:46](=[C:45]([N:44]([CH3:59])[CH3:43])[CH:54]=[CH:53][CH:52]=2)[CH:47]=[CH:48][CH:49]=1)(=[O:57])=[O:56])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a stirring solution of (S)-2(2-amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)propionic acid methyl ester (100 mg, 0.2 mmol) prepared above dissolved in DCM containing pyridine (31.6 mg, 0.4 mmol), was added 5-Dimethylamino-naphthalene-1-sulfonyl chloride (59.1 mg, 0.0.22 mmol) at 0° C. The reaction mixture was stirred at rt for 3 h, extracted with DCM, washed with 1M HCl and brine evaporation followed by column chromatography purification (silica, CH2Cl2) giving (2S)-[5-chloro-2-(5-dimethylamino-naphthalene-1-sulfonylamino)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (100 mg) as a light yellow solid which was hydrolyzed according to Procedure C yielding the title compound (93 mg) as a light yellow solid. LC/MS (m/z): 720 (M+1)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:15]([Cl:22])[C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1)=[O:12]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:15]([Cl:22])[C:16]2[N:17]([C:19]([Br:1])=[CH:20][N:21]=2)[CH:18]=1)=[O:12]
Reactant: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cn2c(Br)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reaction time: 5 h

Procedure:
N-bromosuccinimide (14 mg, 0.080 mmol) was added to a solution of 7-(4-bromo-2-chlorophenylamino)-8chloroimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (30 mg, 0.072 mmol) in chloroform (1.0 mL). After stirring for five hours the reaction was diluted with ethyl acetate, washed with NaHSO3, brine, dried over Na2SO4, and concentrated to a yellow solid (33 mg, 92%). MS APCI (+) m/z 494, 496, 498 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 8.65 (s, 1H), 7.67 (s, 1H), 7.55 (dd, 1H), 7.22 (dd, 1H), 6.53 (d, 1H), 3.98 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C>[CH3:15][C:16]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:12]=[C:11]([CH3:13])[O:10][N:9]=3)=[CH:4][C:3]=2[CH3:14])=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1nc(-c2ccc(Br)c(C)c2)no1
Reactant: Cc1ccc(NC(=O)c2ccsc2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(-c3cc(NC(=O)c4ccsc4)ccc3C)c(C)c2)no1

Procedure:
Example 31 was prepared using 3-(4-bromo-3-methylphenyl)-5-methyl-[1,2,4]oxadiazole and N-[4methyl-3-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]thiophene-3-amide (Intermediate 27) using DMF as the solvent.
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:29])([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43]([CH2:45][C:46]3C=C[CH:49]=[CH:48][CH:47]=3)[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:6])([CH3:5])[CH3:4].IC(C)CCCC1C=CNN=1.IC1C=CC(CC2C=CNN=2)=CC=1>>[CH3:52][Si:2]([CH3:1])([O:7][C@@H:8]1[C@H:12]([O:13][Si:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:16])[CH3:17])[C@@H:11]([CH2:21][O:22][Si:23]([CH3:28])([CH3:29])[C:24]([CH3:27])([CH3:26])[CH3:25])[O:10][C@H:9]1[N:30]1[CH:38]=[N:37][C:36]2[C:31]1=[N:32][C:33]([C:40]1[CH:41]=[N:42][N:43]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:44]=1)=[N:34][C:35]=2[NH2:39])[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(-c4cnn(Cc5ccccc5)c4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(I)CCCc1cc[nH]n1
Agent: Ic1ccc(Cc2cc[nH]n2)cc1
Product: CCCCCn1cc(-c2nc(N)c3ncn([C@@H]4O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]4O[Si](C)(C)C(C)(C)C)c3n2)cn1

Procedure:
9-{(2R,3R,4R,5R)-3,4-bis(1,1,2,2-tetramethyl-1silapropoxy)-5-[(1,1,2,2-tetramethyl-1-silapropoxy)methyl]oxolan-2-yl}-2-[1-pentylpyrazol-4-yl]purine-6ylamine (14) Compound 14 was prepared in the manner of compound 11 substituting 4-iodo-pentylpyrazole for 4-iodo-benzylpyrazole to afford compound 14:1 H NMR(CDCl3) 0.00(s, 3H, CH3), 0.01(s, 3H, CH3), 0.04(s, 3H, CH3), 0.07 (s, 3H, CH3), 0.11 (s, 3H, CH3), 0.14 (s, 3H, CH3), 0.78 (s, 9H, t-bu), 0.80 (t, 3H), 0.83 (s, 9H, t-bu), 0.91 (s, 9H, t-bu), 1.25–1.40 (m, 4H), 1.85–1.95 (m, 2H), 3.82 (d, 1H), 4.08 (d, 1H), 4.20–4.28 (m, 3H), 4.32–4.34 (m, 1H), 4.55–4.57 (m, 1H), 5.35 (m, 2H), 5.70 (bs, 2H, D20 exchangeable), 6.08 (d, 1H), 7.28–7.40 (m, 5H), 8.05 (s, 1H), 8.15 (s, 1H), 8.20 (s, 1H).