Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:8][C:7]=1[Cl:17])(=[O:3])[CH3:2].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CC#N>[C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([S:13](=[O:15])(=[O:16])[N:14]=[CH:20][N:21]([CH3:23])[CH3:22])=[CH:8][C:7]=1[Cl:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)cc(S(N)(=O)=O)cc1Cl
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CC(=O)OCc1c(F)cc(S(=O)(=O)N=CN(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of 2-chloro-6-fluoro-4-sulfamoylbenzyl acetate (1 g, 3.6 mmol) in CH3CN (20 mL) at 0° C. under N2 was added 1,1-dimethoxy-N,N-dimethylmethanamine (0.7 ml, 5.4 mmol). The resulting solution was stirred at room temperature 1 h, concentrated under reduced pressure, and purified by column chromatography (DCM/EtOAc=9:1) to afford 2-chloro-4-(N-((dimethylamino)methylene)sulfamoyl)-6-fluorobenzyl acetate (850 mg, 76%) as ivory solid. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.76 (s, 1H), 7.55 (d, 1H), 5.26 (s, 2H), 3.18 (s, 3H), 3.05 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1.CCOCC>[CH2:1]([N:8]1[CH2:9][C@@H:10]([CH3:15])[NH:11][C@H:12]([CH3:14])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)C(=O)[C@@H](C)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN(Cc2ccccc2)C[C@@H](C)N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
a solution of (R,R) 1-benzyl-3,5-dimethylpiperazine-2-one (1.3 g) in THF (10 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.68 g) in THF (30 ml) at 0° C. under Ar. The mixture was stirred for 30 min then heated under reflux for a further 18 h. The mixture was cooled to 0° C. and diluted with ether (50 ml). To the stirred mixture were added water (2 ml) sodium hydroxide solution (2 ml) and water (2 ml). The mixture was stirred for 1 h then filtered through a pad of kieselguhr, washing with DCM. The filtrate was concentrated in vacuo to give the product as a clear oil (0.99 g); δH (400 MHz, CDCl3) 7.35–7.20 (5H, m), 3.48 (1H, d, J 13 Hz), 3.38 (1H, d, J 13 Hz), 3.19 (1H, m), 2.49 (2H, dd, J 10.5, 3 Hz), 2.09 (2H, dd, J 10, 6.5 Hz) and 1.14 (6H, d, J 6.5 Hz); LC 93%, 1.91 min.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:33])[C:7]2=[O:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:40]>ClCCl.C(OCC)(=O)C>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:40])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([C:18]3[CH:23]=[C:22]([C:24]4[O:25][C:26]([CH2:29][CH:30]([CH3:32])[CH3:31])=[N:27][N:28]=4)[CH:21]=[CH:20][C:19]=3[CH3:33])[C:7]2=[O:34])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2cc(-c3cc(-c4nnc(CC(C)C)o4)ccc3C)c(=O)n(C3CCCC3)c2n1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nnc(CC(C)C)o2)cc1-c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 152.6 %

Procedure:
To a solution of 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl}-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (40.0 mg, 0.08 mmol) in dichloromethane (3 mL) at 0° C. was added 3-chloroperoxybenzoic acid (0.04 g, 0.19 mmol). The mixture was stirred at 0° C. for 1 hour, then was diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure to give 8-cyclopentyl-6-{5-(5-isobutyl-[1,3,4]-oxadiazol-2-yl)-2-methyl-phenyl}-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.06 g). The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH-:8].[Mg+2:9].[OH-].[CH3:11]O>>[CH3:11]/[C:2](=[CH:3]/[C:4]([O-:8])=[O:5])/[C:1]([O-:6])=[O:7].[CH3:11]/[C:2](=[CH:3]/[C:4]([O-:8])=[O:5])/[C:1]([O-:6])=[O:7].[Mg+2:9].[Mg+2:9]
Reactant: O=C1C=CC(=O)O1
Reactant: CO
Reactant: [OH-]
Agent: [Mg+2]
Product: C/C(=C/C(=O)[O-])C(=O)[O-]

Procedure:
Fifty grams of maleic anhydride is dissolved in 200 ml methanol and magnesium hydroxide is added to a pH of 7.3. The solution is filtered, the methanol is distilled off and the product is dried under vacuum. An NMR analysis of the product taken using potassium acid phthalate as the standard indicates that the product contains 78.7% magnesium bis(methyl maleate).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([OH:34])[CH2:33][CH2:32][C:27]4(OCC[O:28]4)[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[N-:35]=[N+]=[N-].[Na+].CS(O)(=O)=O.O>C(Cl)(Cl)Cl>[OH:34][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:33][CH2:32][NH:35][C:27](=[O:28])[CH2:26][CH2:25]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC4(CC3)OCCO4)s2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCNC(=O)CC3)s2)c1
Temperature: 65 °C
Yield: 63.9 %

Procedure:
A mixture of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decan-8-ol (60 mg, 0.122 mmol), sodium azide (23.76 mg, 0.365 mmol) and methanesulfonic acid (95 L, 1.462 mmol) in CHCl3 (1.2 mL) was heated at 65° C. for 1 h and cooled to room temperature. The mixture was treated with water, and extracted with ethyl acetate. The combined organics were dried, filtered, concentrated and purified by flash chromatography to afford 5-hydroxy-5-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]azepan-2-one (36 mg, 0.078 mmol). APCI: [M+H]+ m/z 464.2. 1H NMR (600 MHz, CDCl3): δ 8.63 (d, J=4.9, 1H), 7.89 (s, 1H), 7.83 (s, 1H), 7.62 (s, 1H), 7.26 (s, 1H), 7.05 (s, 1H), 7.03 (d, J=4.9, 1H), 6.21 (s, 1H), 3.81 (s, 1H), 3.46 (s, 1H), 3.21-3.03 (m, 2H), 2.41 (dd, J=7.5, 14.4, 1H), 2.37 (s, 3H), 2.24 (t, J=13.3, 1H), 2.18-2.04 (m, 3H). rhSYK activity=+++
Reaction SMILES: [NH:1]([C:8]1[CH:16]=[C:15]([C:17](O)=[O:18])[C:14]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(OC)=CC=3)=CC=2C(O)=O)=CC=1.CO>O>[CH:24]1[CH:25]=[C:26]2[C:17]([C:15]3[C:14]([NH:20][C:21]2=[CH:22][CH:23]=1)=[CH:13][C:9]1[C:10]([C:7]2[C:2]([NH:1][C:8]=1[CH:16]=3)=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[O:18]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: COc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(OC)cc3)cc2C(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 130 °C

Procedure:
A mixture (one part) of 2,5-dianilino-terephthalic acid (80 wt. %) and 2,5-dianisidino-terephthalic acid (20 wt. %) was dissolved in polyphosphoric acid (6.14 parts at 118.5%). The solution, already at 110° C., was heated to 130° C. for 3 hours, cooled to 100° C. and diluted to a fluid mass with water (0.5 parts). The solution was drowned into methanol (11.6 parts) and heated at 120° C. for 4 hours. A very bluish, transparent quinacridone pigment was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1([CH3:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(C)(C)C.CCN(C(C)C)C(C)C.CN1C(=O)CCC1.[Cl:33][C:34]1[N:42]2[C:38](=[N:39][C:40]3[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=32)[C:37]([C:47]([NH2:49])=[O:48])=[C:36]2[CH2:50][CH2:51][CH2:52][C:35]=12>O>[ClH:33].[ClH:33].[NH2:7][CH2:8][C:9]1([CH3:15])[CH2:10][CH2:11][N:12]([C:34]2[N:42]3[C:38](=[N:39][C:40]4[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=43)[C:37]([C:47]([NH2:49])=[O:48])=[C:36]3[CH2:50][CH2:51][CH2:52][C:35]=23)[CH2:13][CH2:14]1
Reactant: CC1(CNC(=O)OC(C)(C)C)CCNCC1
Reactant: NC(=O)c1c2c(c(Cl)n3c1nc1ccccc13)CCC2
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(CN)CCN(c2c3c(c(C(N)=O)c4nc5ccccc5n24)CCC3)CC1
Product: Cl
Reaction time: 1 h
Yield: 78.5 %

Procedure:
Tert-butyl[(4-methylpiperidin-4-yl)methyl]carbamate (343 mg), and DIPEA (348 μl) were added to an NMP (3 ml) solution of 11-chloro-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide (286 mg), and heating and stirring were performed at 200° C. for 60 minutes under microwave irradiation. After adding water to the reaction liquid, the resulting precipitate was collected by filtration and dried under reduced pressure. The resulting solid was suspended in chloroform, TFA was then added thereto and stirring was performed at room temperature for 1 hour. The reaction liquid was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (MeOH/chloroform). The resulting crude purified matter was dissolved in chloroform, a 4 M hydrochloric acid-EtOAc solution was then added thereto and stirring was performed at room temperature for 1 hour. The solvent was concentrated under reduced pressure and the residue was solidified using EtOH/Et2O to obtain 11-[4-(aminomethyl)-4-methylpiperidin-1-yl]-2,3-dihydro-1H-cyclopenta[4,5]pyrido[1,2-a]benzimidazole-4-carboxamide dihydrochloride (177 mg).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].Br[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[O:8]([CH2:7][CH2:6][NH:4][CH2:1][CH2:2][CH3:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCN
Reactant: BrCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCNCCOc1ccccc1

Procedure:
47.2 g. Propylamine was dissolved in 100 ml. absolute alcohol with cooling and 40.2 g. β-bromophenetole was added portionwise to the solution formed. After completion of the addition the reaction mixture was allowed to stand at room temperature for 1 week with occasional agitation. The excess of amine and solvent were then removed under vacuum from the steam bath and the residual colourless solid obtained on cooling was treated with an excess of 5N aqueous sodium hydroxide. An oil was liberated which was then extracted with ether, washed with water and dried over anhydrous sodium sulphate. After removal of the solvent the residual oil was distilled under vacuum to give N-2-phenoxyethyl-N-propylamine, boiling point 90°-92° C./0.2 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CC(N(C)C)=O>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([NH:1][C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:3]([C:4]#[N:5])[CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#Cc1cc(Cl)ccc1N
Agent: CN(C)c1ccccn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1cc(Cl)ccc1NC(=O)Oc1ccccc1
Reaction time: 8 h

Procedure:
(Step 1) To a solution of 2-amino-5-chlorobenzonitrile (5.0 g) and dimethylaminopyridine (0.12 g) in dimethylacetamide (25 ml) was added dropwise phenyl chlorocarbonate (6.2 ml) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5-*3:7) to give phenyl (4-chloro-2-cyanophenyl)carbamate (7.04 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20]O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1>C(Cl)Cl>[ClH:3].[Cl:3][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:12][CH2:11][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccccc1OCCN1CCOCC1
Solvent: ClCCl
Product: Cl
Product: ClCc1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (5 mL, 2M in DCM) was added to a solution of [2-(2-morpholin-4-yl-ethoxy)-phenyl]-methanol (1.97 g, 8.3 mmol) in DCM (15 mL) at 0° C. The mixture was allowed to warm up to rt and stirred for 3 hours. The reaction was concentrated to give 4-[2-(2-chloromethyl-phenoxy)-ethyl]-morpholine hydrochloride.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.N1CCCCC1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:5]#[C:4][CH2:3][CH2:2][C:1]([OH:7])=[O:6])=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(Br)cc1
Reactant: C#CCCC(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: N#Cc1ccc(C#CCCC(=O)O)cc1
Temperature: 80 °C

Procedure:
A solution of 4-pentynoic acid (2.15 g, 22 mmol), 4-bromobenzonitrile (3.64 g, 20 mmol), and piperidine (40 mL) was degassed by bubbling nitrogen through the solution for 5 min. prior to the addition of tetrakis(triphenylphosphine)palladium(0) (240 mg, 0.2 mmol). The reaction vial was sealed and warmed to 80° C. for 1.5 hours. After cooling to 23° C., the reaction mixture was diluted with ethyl acetate (200 mL), filtered, and concentrated in vacuo. The residue was diluted with ethyl acetate (300 mL), washed with 5% HCl (2×100 mL), washed with water (1×100 mL), and extracted with 3% sodium carbonate (2×200 mL). The basic aqueous layer was treated with decolorizing carbon, filtered, and acidified to pH=2. The resultant solid was filtered, washed with water, dried, and purified by flash chromatography (gradient ethyl acetate:methylene chloride:acetic acid 1:9:0.005) and fractional recrystallization (methylene chloride-ether) to afford 5-(p-cyanophenyl)-4-pentynoic acid as a white solid: m.p. 149°-152° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O.O>[C:5]([N:1]=[N+:2]=[N-:3])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of sodium azide (19.0 g : 0.283 Mol.) in dimethyl- formamide (130 ml) is added trityl chloride (76.0 g : 0.273 Mol.), and the mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with water and extracted with ether. The extract is washed with brine, dried over sodium sulfate, and concentrated to give trityl azide. To a solution of this azide in acetone (300 ml) is added methyl propiolate (24 ml : 0.27 Mol.), and the mixture is heated under reflux for 6 days. The reaction mixture is cooled to the room temperature and diluted with ether. The separating crystals are collected by filtration to give 1-trityl-1,2,3-triazol-4-ylcarboxylic acid methyl ester (62.0 g) as colorless crystals. Yield: 62%. mp. 189° to 190° C. NMR δ (CDCl3) ppm: 3.93(s, 3H), 7.05-7.15(m, 6H), 7.3-7.4(m, 9H), 8.02(s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([NH:6][C:7]1[NH:11][N:10]=[N:9][N:8]=1)=[O:5].[CH2:17](OC(OCC)OCC)C>>[CH3:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[N:1]=[CH:17][N:6]([C:7]1[NH:11][N:10]=[N:9][N:8]=1)[C:4]2=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(N)c(C(=O)Nc2nnn[nH]2)c1
Product: Cc1ccc2ncn(-c3nnn[nH]3)c(=O)c2c1

Procedure:
2-Amino-5-methyl-N-(1H-tetrazol-5-yl)benzamide in an excess of triethoxymethane was refluxed for 60 hours to give 6-methyl-3-(1H-tetrazol-5-yl)-4(3H)-quinazolinone melting at about 285°-286° C. after recrystallization from a mixture of dimethylsulfoxide and water.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]([C:35]4[CH:39]=[CH:38][O:37][N:36]=4)C(OCC(Cl)(Cl)Cl)=O)[O:22][C:21]3=[O:40])=[CH:16][C:15]=2[F:41])[CH2:10]1)=[O:7]>C(O)(=O)C.O.[Zn]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:35]4[CH:39]=[CH:38][O:37][N:36]=4)[O:22][C:21]3=[O:40])=[CH:16][C:15]=2[F:41])[CH2:10]1)=[O:7]
Reactant: COCCOC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COCCOC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
3-(4-(3(S)-(2-Methoxyethoxycarbonylamino)pyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one (400 mg, 0.5 mM) was stirred in a mixture of acetic acid (10 ml) and water (2 ml). Zinc dust (203 mg, 3.1 mM) was added, and the mixture stirred 30 minutes at ambient temperature. The mixture was filtered through celite, and the residue after evaporation partitioned between ethyl acetate (10 ml) and aqueous sodium bicarbonate (15 ml). The organic phase was washed with sodium bicarbonate (2×15 ml), water (15 ml), dried (magnesium sulfate), and evaporated. The crude product was purified by chromatography on a 10 g Biotage silica column, eluting with a gradient from dichloromethane to ethyl acetate. Relevant fractions were combined to give the desired product (141 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Br:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[N:15]=[C:16]=[O:17].O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[NH:15][C:16]([N:8]=[C:7]1[NH:6][C:4](=[O:5])[CH2:3][N:2]1[CH3:1])=[O:17]
Reactant: O=C=Nc1sccc1Br
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CC(=O)NC1=NC(=O)Nc1sccc1Br
Temperature: 65 °C
Yield: 20.7 %

Procedure:
To a stirred suspension of 0.8 g (7.1 mM) of creatinine in 10 ml of anhydrous DMF was added a solution of 1.12 g (5.5 mM) of 3-bromo-2-thienyl isocyanate in 5 ml of toluene. The resulting mixture was heated at 65° C. for 5 hrs. (hours), cooled, and poured into a mixture of 200 ml water and 25 ml toluene. The precipitate was collected and recrystallized from ethyl acetate to give 0.36 g of the above urea as a tan colored solid, m.p. 192°-193° C. (dec.)
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)COc1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A mixture of 15.16 g of methyl (2-hydroxyphenoxy)acetate, 29.23 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyri midin-1-yl]nitrobenzene, 11.5 g of anhydrous potassium carbonate, and 160 ml of N,N-dimethylformamide was stirred at room temperature for 30 minutes and then at 70° C. for 3 hours. Another 5 g of methyl (2-hydroxyphenoxy)acetate was added, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 17.8 g of methyl [2-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyri midin-1-yl]-2-nitrophenoxy}phenoxy]acetate.
Reaction SMILES: [OH2:1].[OH2:2].C[N+]([O-])(C)C.[NH:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]2([CH2:20][CH:19]=[CH:18][CH2:17]2)[C:9]1=[O:21]>ClCCl.[Os](=O)(=O)(=O)=O>[OH:1][CH:18]1[CH:19]([OH:2])[CH2:20][C:10]2([C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8][C:9]2=[O:21])[CH2:17]1
Reactant: O=C1Nc2ncccc2C12CC=CC2
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: ClCCl
Product: O=C1Nc2ncccc2C12CC(O)C(O)C2
Yield: 85.7 %

Procedure:
To a mixture of trimethylamine-N-oxide dihydrate (408 mg, 3.67 mmol) and spiro[cyclopent-3-ene-1,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (622 mg, 3.34 mmol) in dichloromethane (115 mL) was added osmium tetroxide (25 uL of 2.5% solution in 2-methyl-2-propanol). After 24 h the reaction mixture was concentrated. The crude product was loaded onto a silica gel chromatography column with a minimal amount of methanol and eluted with a gradient of 5 to 20% methanol:dichloromethane to give the title compound (0.63 g). MS: m/z=221.0 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:40]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:29][CH2:30]4)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccccc3)CN2C1=O
Yield: 47.4 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and benzoyl chloride (61 μL, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 56 mg (48%) of 18-benzoyloxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 99.0% pure (HPLC), MS m/z 673 (M−H)−, HRMS: calcd. 675.2700 and found 675.2709 (M+H)+, mp 135-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC.O.C(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[CH:5][N:4]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cc[nH]n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Brc1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a solution of 3-bromo-pyrazole (2.0 g, 13.6 mmol) in anh. CH2Cl2 (40 mL), at r.t., under N2, were added triphenylmethyl chloride (4.17 g, 1.1 eq) and Et3N (2.1 mL, 1.1 eq). The reaction mixture was stirred at r.t. for 4 hr. It was poured into water/CH2Cl2. The phases were separated and the aqueous layer was further extracted with CH2Cl2 (2×30 mL). The combined organic extracts were dried over anh. Na2SO4, the solids were filtered and the solvent evaporated. The residue was purified by flash chromatography (silica gel, 100% CH2Cl2) to give the title compound as a white solid (3.39 g, 64%).