Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[CH3:32][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22]([OH:24])([CH3:32])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.8 %

Procedure:
1-(2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)-methyl)pyrimidin-4-yl)ethanone (178 mg, 0.41 mmol) was dissolved in THF (5 mL). The mixture was added to methylmagnesium bromide (3 M in THF, 1.090 mL, 3.27 mmol) in THF (5 mL). The mixture was stirred at rt for 5 min. The mixture was cooled at 0° C. and ammonium chloride (aq) was added. The mixture was extracted by EtOAc, the organic phase was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica eluting with a gradient of methanol in DCM to give the title compound as a solid 107 mg (58%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:23]4[CH:22]=[C:21]([CH2:24]O)[S:20][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12.N(C(OCC)=O)=NC(OCC)=O.[ClH:68]>ClCCl.C(O)C.C(O)(=O)C.O1CCCC1>[ClH:68].[CH2:8]([N:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:23]3[CH:22]=[C:21]([CH2:24][N:49]4[C:45](=[O:55])[C:46]5[C:47](=[CH:51][CH:52]=[CH:53][CH:54]=5)[C:48]4=[O:50])[S:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc2c(N3CCN(CCc4ccccc4)CC3)cccc2s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1Cc1cc2c(N3CCN(CCc4ccccc4)CC3)cccc2s1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Anhydrous tetrahydrofuran (30 mL) was added to a flask containing 4- [4- (2-phenylethyl ) -1-piperazinyl]benzo[b]thiophene-2-methanol (3.20 g, 9.08 mmol), triphenylphosphine (2.50 g, 9.53 mmol) and phthalimide (1.40 g, 9.53 mmol). The reaction was cooled to 0° C. in an ice bath and diethyl azodicarboxylate (1.5 mL, 9.53 mmol) was added over 3 min. The bath was removed after stirring under nitrogen for 20 min and allowed to stir at room temperature for 15.5 h. The reaction was concentrated in vacuo and the crude product was chromatographed using 40:60 ethyl acetate:hexane. The component with Rf of ca. 0.4 was isolated. The compound was rechromatographed to remove a by product using 95:5 dichloromethane:acetone, then using 5:95 acetic acid: ethyl acetate. the component with Rf of ca. 0.3 was isolated (3.26 g), along with acetic acid. The compound was dissolved in dichloromethane (75 mL), washed with saturated aqueous sodium bicarbonate (50 mL), dried over magnesium sulfate/sodium sulfate, filtered and concentrated in vacuo (2.80 g). A solution of product (1.00 g, 2.08 mmol) in a mixture of ethanol (50 mL) and dichloromethane (50 mL) was treated with 1.0M aqueous hydrochloric acid (2.10 mL) and concentrated in vacuo. The resulting solid was recrystallized from a mixture of methanol (50 mL), dichloromethane (80 mL) and water (8 drops) to yield the title compound (0.87 g). 1H NMR (DMSO-d6 +CD3OD+D2O): 7.85 (4H, m), 7.54 (1H, d, J=7.8 Hz), 7.45 (1H, s), 7.31 (6H, m), 6.96 (1H, d, J=7.8 Hz), 5.04 (2H, s), 3.60-3.10 (10H), 3.01 (2H, m) ppm. 13C NMR (DMSO-d6 +CD3OD+D2O): 168.56, 147.08, 141.37, 139,90, 135.89, 133.75, 131.94, 129.64, 127.93, 126.53, 124.35, 122.11, 118.74, 114.07, 57.78, 52.51, 49.74, 37.49, 30.53 ppm. IR (KBr): 2456, 2434, 1769, 1719, 1427, 1393, 1356 cm-1. CIMS (methane): 482 (100%).
Reaction SMILES: [CH3:1][N:2]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:24]([O-])=O)[CH:21]=2)[CH2:16]1)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>C(OCC)(=O)C.[Pd]>[NH2:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([N:2]([CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)[CH3:1])[CH2:23]2
Reactant: CN(CCOc1ccc([N+](=O)[O-])cc1)C1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(N)cc1)C1Cc2ccc(N)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-[N-methyl-N-(2-{4-nitrophenoxy}ethyl)amino]-5-nitroindane (0.3 g) in ethyl acetate (30 ml) containing 5% Pd/C (0.03 g) was stirred under a hydrogen atmosphere [206.8 kPa (30 p.s.i.)] for 2 hours at room temperature. The catalyst was then removed by filtration and the filtrate evaporated in vacuo to afford the title compound as a gum, yield 0.25 g, which was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
2.0 g of 4-chloro-3-nitrophenol was dissolved in 15 ml of N,N-dimethylformamide. Thereto was added 490 mg of sodium hydride (purity: 60%) in 10 minutes at 5°-10° C. Then, 1.53 g of benzyl chloride was added dropwise in 10 minutes. Stirring was conducted for 1 hour at 70° C. The reaction mixture was introduced into a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The resulting organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was washed with n-hexane and then mixed with a mixture of diisopropyl ether and n-hexane. The resulting crystal was collected by filtration to obtain 1.8 g (yield: 59.4%) of 4-benzyloxy-2-nitro-chlorobenzene having a melting point of 50°-50.5° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.O=[C:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH2:13]1>CC(O)=O>[F:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:12]1[CH2:13][CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH2:15][CH2:16][C:17]2=1
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)NC1CCCC(=O)C1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)NC1CCc2c([nH]c3ccc(F)cc23)C1
Reaction time: 4.5 h

Procedure:
A mixture of 0.05 mol of 4-fluorophenylhydrazine hydrochloride and 0.05 mol of N-(3-oxocyclohexyl)acetamide in 75 ml of glacial HOAc was stirred and heated on the steam bath. At 80°-90° an exothermic reaction occurred and the source of heat was removed until the temperature had fallen to 85°. After an additional 4-5 hr at 85°-90°, the warm mixture was poured into H2O and the gummy insolubles triturated until solid. The filtered solid was washed thoroughly with H2O and then with Et2O until the washings were essentially colorless. The crude product was recrystallized from ethanol to give the title compound, mp 209°-210°.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][CH2:17][CH2:18][CH3:19])[C:3]=1[C:20](O)=[O:21].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl>CN(C)C=O.[OH-].[Na+]>[S:25]1[CH:26]=[CH:27][N:28]=[C:24]1[NH:23][C:20]([C:3]1[C:4]([CH2:16][CH2:17][CH2:18][CH3:19])=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:14])([F:13])[F:15])=[O:21]
Reactant: Nc1nccs1
Reactant: CCCCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 48.4 %

Procedure:
Using the procedure of Step F of Example 6, 6.8 g of the product of Step E and 2.17 g of 2-aminothiazole were reacted in the presence of dicyclohexylcarbodiimide in dimethylformamide to form a raw product which was dissolved in aqueous N sodium hydroxide solution. Hydrochloric acid was added to the solution to obtain 4.15 g of N-(2thiazolyl)-4-hydroxy-2-butyl-8-trifluoromethyl-quinoline-3-carboxamide in the form of colorless crystals melting at 181° C after crystallization from isopropanol.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])C.[N+:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([O-:20])=[O:19]>C1(C)C(C)=CC=CC=1>[CH3:17][O:16][C:14]([C:6]1[NH:7][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:13]2[C:5]=1[CH2:4][CH:21]([N+:18]([O-:20])=[O:19])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: COC(=O)c1[nH]c2cnccc2c1CN(C)C
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(Cc1c(C(=O)OC)[nH]c2cnccc12)[N+](=O)[O-]
Temperature: 156 °C
Reaction time: 3 h

Procedure:
Ethyl 3-[2-(methoxycarbonyl)pyrrolo[2,3-c]pyridine-3-yl]-2-nitropropanoate (32) was synthesized according to a procedure previously published (Synthetic Commun. 1997, 27, 3201-3211). A 1 L single-necked round-bottomed flask was equipped with a magnetic bead and a reflux condenser and placed into an oil bath. The flask was charged with methyl 3-[(dimethyl amino)methyl]pyrrolo[2,3-c]pyridine-2-carboxylate (31, 8 g) and xylene (200 mL), and stirring was initiated. The solid did not dissolve in xylene and remained as a slurry. The resulting solution was degassed with nitrogen for 10 minutes. Ethyl nitroacetate (12, ˜11.4 mL) was added as a single portion to the slurry. The solution was continued to be degassed with nitrogen for a minimum of 1 h while stirring. At this stage a slight change in the nature of the slurry was observed, probably due to the formation of the gramine salt of ethyl nitroacetate. The reaction mixture was heated to reflux (˜156° C.) for 4 h. During reflux, the solid went into solution and simultaneously a white/light yellowish solid precipitated. The reaction mixture was continued to be stirred at reflux until the reaction was deemed complete, i.e., when no starting material peaks were observed on NMR. Indeed, the NMR matched with the NMR of pure product. If reaction was not complete, stirring was continued at 156° C. for another 3 h until the reaction was deemed to be complete, with additional ethyl nitroacetate added as required. This reaction was typically complete in 3-4 h. The reaction was monitored by NMR by taking an aliquot of reaction mixture (˜1 mL), cooling to room temperature, filtering through a polypad, washing with diethyl ether (˜2 mL), and submitting the solid for NMR analysis. Materials used to synthesize ethyl 3-[2-(methoxycarbonyl)pyrrolo[2,3-c]pyridine-3-yl]-2-nitropropanoate (32) are shown in Table 19.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)[CH:2]=1.B.O1CCCC1.CO>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCc2cccnc2)CC1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCc2cccnc2)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1.5 g of tert-butyl 4-[3-(pyridin-3-yl)propanoyl]piperazine-1-carboxylate in 25 mL of tetrahydrofuran was added 7 mL of a 1 M borane/tetrahydrofuran solution under ice-cooling. The mixture was heated to reflux for 6 hours, and then cooled to room temperature, and 10 mL of methanol was added thereto, followed by further heating to reflux for 16 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and a mixture of a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate was added thereto. The aqueous layer was separated, and then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 1.43 g of tert-butyl 4-[3-(pyridin-3-yl)propyl]piperazine-1-carboxylate.
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@@H](C)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[C:29]([C@@H:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1)#N>>[CH3:29][C@H:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 94 %

Procedure:
The title compound II-ax was prepared in 94% yield from 3,3:17,17-bis(ethylendioxy)-6β-methylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.77-0.75 (m, 21H), 1.18 (s, 3H), 0.98 (d, 3H), 0.90 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]([NH:26][C:27](OCC)=[O:28])=[N:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2].ClCCCl>[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:26][C:27](=[O:28])[C:14]3[C:13](=[CH:18][CH:17]=[C:16]([C:19]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[O:20])[CH:15]=3)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(=Nc1ccc(C(=O)N2CCCC2)cc1)n1cc(C(=O)OCC)cn1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2nc3ccc(C(=O)N4CCCC4)cc3c(=O)[nH]2)c1
Temperature: 100 °C
Yield: 2.1 %

Procedure:
Titanium (IV) chloride (0.377 mL, 3.43 mmol) was carefully added to a solution of 1-{ethoxycarbonylamino-[4-(pyrrolidine-1-carbonyl)-phenylimino]-methyl}-1H-pyrazole-4-carboxylic acid ethyl ester (0.977 g, 2.29 mmol) and DCE (5.5 mL). The reaction mixture was heated to 100° C. for 2.5 h and was then cooled to room temperature and quenched with ethanol (10 mL). The resulting solution was concentrated and the residue was partitioned between DCM (30 mL) and water (30 mL). The two layers were filtered to remove a solid byproduct and then separated. The aqueous layer was washed with DCM (30 mL) and the combined organic layers were washed with brine (30 mL), dried (MgSO4), and concentrated. The residue was triturated with diethyl ether and then with ethanol to yield the titled compound (18 mg, 2.0% yield). MS (ESI/Cl): mass calcd. for C19H19N5O4, 381.1; m/z found, 382.1 [M+H]+.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]1[C:10](Cl)=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[C:12](Cl)(Cl)=[O:13].C(Cl)([Cl:18])=O.C1C=CC=CC=1.Br>C1C=CC=CC=1>[Br:2][CH2:3][C:4]1[CH:10]=[C:9]([Cl:18])[CH:8]=[CH:7][C:5]=1[N:6]=[C:12]=[O:13]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(Cl)c1CBr
Agent: Br
Solvent: c1ccccc1
Product: O=C=Nc1ccc(Cl)cc1CBr

Procedure:
2.3 g of 2-bromomethyl-3-chloroaniline hydrobromide are added to 30 ml. of 12% phosgene in benzene. The mixture is heated to reflux in a 250 ml. flask fitted with a Dean-Stark trap and condenser. Small amounts of phosgene/benzene are carefully added until the hydrobromide is no longer detected (as indicated by following the reaction on thin layer chromatographic plates). The benzene solvent is removed from the reaction mixture by evaporation, then the 2-bromomethyl-4-chloroisocyanate product is recovered by vacuum distillation (at about 50° to 56° at about 0.05 to 0.03 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=1.[Sn](Cl)Cl.Cl>CCO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:12]=2)[CH:4]=1
Reactant: COC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2Cl)nc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc(N)ccc2Cl)nc1

Procedure:
75 mL of (5-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 935 mg of 2-(2-chloro-5-nitrophenyl)-5-methylpyridine in 5 mL of Sulfuric Acid was slowly added 2.25 g of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 6-(2-chloro-5-nitrophenyl)nicotinic acid. 704 mg of 6-(2-chloro-5-nitrophenyl)nicotinic acid was esterified with 3.1 mL of 4N HCl in Dioxane in 20 mL of MeOH. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 6-(2-chloro-5-nitrophenyl)nicotinate. 681 mg of methyl 6-(2-chloro-5-nitrophenyl)nicotinate was treated with 2.1 g of Tin (II) Chloride and 1 mL of HCl in 25 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 6-(5-amino-2-chlorophenyl)nicotinate. 296 mg of methyl 6-(5-amino-2-chlorophenyl)nicotinate was coupled to 266 mg of 4-(methylsulfonylmethyl)benzoic acid via Procedure G. To 518 mg of methyl 6-(2-chloro-5-(4-(methylsulfonylmethyl)benzamido)phenyl)nicotinate at 0° C. in 20 mL of EtOH was slowly added 640 mg of Sodium Borohydride. The reaction was subsequently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 431.1 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22](=O)[CH3:23])[N:20]=2)[N:15]=[N:14]1.Cl.[NH:26]1[CH2:30][CH2:29][C@@H:28]([O:31][NH2:32])[CH2:27]1>>[NH:26]1[CH2:30][CH2:29][C@@H:28]([O:31]/[N:32]=[C:22](/[C:19]2[N:20]=[C:21]3[N:13]([CH2:12][C:3]4[CH:4]=[C:5]5[C:10](=[CH:11][C:2]=4[F:1])[N:9]=[CH:8][CH:7]=[CH:6]5)[N:14]=[N:15][C:16]3=[N:17][CH:18]=2)\[CH3:23])[CH2:27]1
Reactant: NO[C@@H]1CCNC1
Reactant: CC(=O)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Agent: Cl
Product: C/C(=N\O[C@@H]1CCNC1)c1cnc2nnn(Cc3cc4cccnc4cc3F)c2n1
Yield: 57.4 %

Procedure:
The title compound (7.0 mg, 50%) was synthesized from 1-[3-(7-fluoro-quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl]-ethanone (15.4) (10.0 mg, 0.03 mmol) and (R)—O-pyrrolidin-3-yl-hydroxylamine hydrochloride (10.8 mg, 0.06 mmol) using the same procedure as described in the synthesis of example 15. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.31 (s, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.16 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 6.24 (s, 2H), 4.95 (m, 1H), 3.01-2.87 (m, 3H), 2.74-2.67 (m, 1H), 2.27 (s, 3H), 2.15-1.90 (m, 2H). LCMS (method A): [MH]+=407, tR=3.98 min.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:13][NH:14][C:15]1[N:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][N:16]=1.Cl[C:31]1[N:39]=[C:38]2[C:34]([N:35]=[CH:36][N:37]2[CH2:40][CH:41]2[CH2:45][CH2:44][O:43][CH2:42]2)=[C:33]([N:46]2[CH2:51][CH2:50][O:49][CH2:48][CH2:47]2)[N:32]=1>O>[CH3:13][NH:14][C:15]1[N:16]=[CH:17][C:18]([C:31]2[N:39]=[C:38]3[C:34]([N:35]=[CH:36][N:37]3[CH2:40][CH:41]3[CH2:45][CH2:44][O:43][CH2:42]3)=[C:33]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)[N:32]=2)=[CH:19][N:20]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(CC3CCOC3)c2n1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CCOC4)c3n2)cn1
Yield: 40.8 %

Procedure:
1,4-Dioxane (40 ml), water (20 ml), and sodium carbonate (2 g, 19 mmol) were added to N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.45 g, 6.18 mmol) and 2-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purine (2.0 g, 6.18 mmol) and the atmosphere in the reaction vessel was substituted with nitrogen. Tetrakis triphenylphosphine palladium (0.36 g, 0.31 mmol) was added, then the atmosphere in the reaction vessel was substituted with nitrogen again, and the resulting mixture was heated to reflux for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Methylene chloride-ether was added to the residue and the insoluble matter was collected by filtration and dried to give the title compound (1.0 g, 41%) as a white solid.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[S:5][C:6]([CH3:9])=[N:7][N:8]=1.Cl[CH2:11][C:12]([OH:14])=[O:13].Cl>O.CO.C(O)C>[C:12]([CH2:11][S:3][C:4]1[S:5][C:6]([CH3:9])=[N:7][N:8]=1)([OH:14])=[O:13]
Reactant: Cc1nnc(S)s1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: Cc1nnc(SCC(=O)O)s1
Temperature: 25 °C
Yield: 75 %

Procedure:
Aqueous solution of sodium hydroxide 8.8 g (0.22 mol) in 15 ml of water was added to a mixture of 2-mercapto-5-methyl-1,3,4-thiadiazole 26.4 g (0.20 mol), chloroacetic acid 27.0 g (0.22 mol) and ethanol 300 ml with stirring at room temperature. After 20 minutes of stirring it was heated to 50° C., and further aqueous solution of sodium hydroxide 8.8 g (0.22 mol) in 15 ml of water was added slowly drop by drop. After stirring for 3 hours at 50° C., it was cooled to room temperature, and water was added till reaction liquid became uniform. Hydrochloric acid was added for neutralization. Prepared crystal was collected by filtration and 28.7 g (0.150 mol) of 2-carboxymethylthio-5-methyl-1,3,4-thiadiazole was obtained by recrystallization in methanol. Yield 75%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:19][OH:20])=[O:5])[CH3:2].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:19][O:20][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)=[O:5])[CH3:2]
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)c1oc(-c2ccc(OC)cc2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g 4-Hydroxymethyl-2-(4-methoxy-phenyl)-oxazole-5-carboxylic acid ethyl ester were dissolved in 85 ml dichloromethane. 4.0 ml 3,4-dihydro-2H-pyran and 1.85 mg pyridinium p-toluenesulfonate were added and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by flash chromatography on silica gel (eluting with n-heptane:ethyl acetate=4:1=>1:1) to obtain 12.3 g 2-(4-Methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole-5-carboxylic acid ethyl ester as an oil.