Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)=[O:29])=[CH:16][C:15]=2[NH:30][C:31]2[C:32]3[CH:40]=[CH:39][C:38]([CH:41]([CH3:43])[CH3:42])=[N:37][C:33]=3[N:34]=[CH:35][N:36]=2)=[CH:9][CH:8]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(F)cn4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(F)cn4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 174B in tetrahydrofuran and water (1:1) was added 1 M NaOH (5 equiv). The solution was heated at 60° C. for 40 minutes, cooled, adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. The resultant residue was purified by silica gel chromatography eluting with 2% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.15-3.29 (m, J=6.89, 6.89, 6.89, 6.89 Hz, 1 H) 5.62 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.83 (d, J=8.46 Hz, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.64 (d, J=8.46 Hz, 1 H) 7.79 (dt, J=8.64, 2.94 Hz, 1 H) 7.87 (dd, J=8.46, 1.84 Hz, 1 H) 8.04 (d, J=1.84 Hz, 1 H) 8.20 (dd, J=9.19, 4.04 Hz, 1 H) 8.38 (d, J=2.94 Hz, 1 H) 8.58 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 10.85 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH2:21]([CH:23]([C:28]1[S:32][C:31]([NH2:33])=[N:30][N:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27])[CH3:22].F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:21]([CH:23]([C:28]1[S:32][C:31]([NH:33][C:15](=[O:17])[C@@H:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])=[N:30][N:29]=1)[CH2:24][CH2:25][CH2:26][CH3:27])[CH3:22]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CCCCC(CC)c1nnc(N)s1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC(CC)c1nnc(NC(=O)[C@H](CCC)NC2CCc3cc(F)cc(F)c3C2)s1

Procedure:
A mixture of 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (28 mg), 5-(1-ethyl-pentyl)-[1,3,4]thiadiazol-2-ylamine (20 mg), O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (30 mg), diisopropylethylamine (0.04 ml) in DMF (1 ml) was shaked in shaker overnight. The mixture was quenched with water, basified with satuated sodium bicarbonate, and extracted twice with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated to give the crude material. The crude material was purified by biotage silica gel column chromatography using methylene chloride to 3% methanol in methylene chloride to give the title compound as a glass foam. LC-MS RT=2.5 min, M+1=465.0, M−1=463.2. The corresponding HCl salt was prepared as an off-white solid.
Reaction SMILES: [C:1]([C:9]1[C:10]([CH3:28])=[N:11][C:12]([CH2:26][CH3:27])=[CH:13][C:14]=1[NH:15]S(C1C=CC(C)=CC=1)(=O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>>[NH2:15][C:14]1[CH:13]=[C:12]([CH2:26][CH3:27])[N:11]=[C:10]([CH3:28])[C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(NS(=O)(=O)c2ccc(C)cc2)c(C(=O)c2ccccc2)c(C)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCc1cc(N)c(C(=O)c2ccccc2)c(C)n1
Temperature: 55 °C
Yield: 70.4 %

Procedure:
Compound C (1.4 g) was added to concentrated sulphuric acid (6 ml) and the mixture was stirred and heated at 55° C. for 1.5 hours. The reaction mixture was cooled to ambient temperature and poured onto crushed ice. The mixture was then basified by addition of solid potassium carbonate and then extracted with dichloromethane. The combined extracts were dried (MgSO4) and solvent was removed by evaporation to leave a solid. The solid was washed with petroleum ether and collected by filtration to give 4-amino-3-benzoyl-6-ethyl-2-methylpyridine (D) (0.6 g); NMR (d6 -DMSO): 1.19(t, 3H), 1.97(s, 3H), 2.55(q, 2H), 5.85(s, 2H), 6.41(s, 1H), 7.45-7.75(complex m, 5H); mass spectrum (CI, ammonia): 241(M+H)+ ; and which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1.Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)(O)[O-].[Na+]>C(O)(C)C>[CH2:26]([O:25][C:23]([C:22]1[N:19]=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:17])[CH3:18])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:21]=1)=[O:24])[CH3:27]
Reactant: CC(C)c1ccccc1C(=N)Nc1ccc(Br)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2C(C)C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a 250 mL round bottom flask attached with condenser was added N-(4-Bromo-phenyl)-2-isopropyl-benzamidine (1.94 g, 6.11 mmol), ethyl bromopyruvate (1.54 mL, 12.2 mmol), sodium bicarbonate (1.02 g, 12.2 mmol), and iso-propanol (45 mL). The reaction slurry was allowed to stir at 80° C. for approximately 2 hrs. The reaction solution was decanted into a clean round bottom flask and concentrated in vacuo. The resulting residue was dissolved in acetic acid (25 mL), and the solution was allowed to stir at reflux for approximately 2 hrs. The solution was concentrated in vacuo, and the product residue was taken into EtOAc (200 mL) and washed with aq NaCl (200 mL×2) and aq NaHCO3 (100 mL). The organic phase was partitioned, dried over Na2SO4, filtered, concentrated, and chromatographed through a 40 g SiO2 column using a mobile gradient of 100% Hx to 70% EtOAc to afford 1.90 g (75% yield) of title compound. MS (ES): 414.0 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]1=[O:16])([CH3:3])[CH3:2].[CH:17]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[CH2:10]([C:9]1[N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:16])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:8]=1)[CH3:17]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)c1ccc(C)n(C(C)C)c1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1ccc(CC)n(C(C)C)c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
To a stirred solution of ethyl 1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in Example 1(5) (515 mg, 2.0 mmol) in tetrahydrofuran (3 mL) was added a solution of lithium diisopropylamide (2.0M, 1.0 mL, 1.0 mmol) dropwise at −30° C. over 40 min. After addition, the mixture was stirred at 0° C. for 3 h. Then, methyl iodide (426 mg, 3.0 mmol) was added at 0° C., and the mixture was stirred at room temperature for 16 h. The mixture was quenched with water (5.0 mL), and extracted with dichloromethane (30 mL×3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified with plate TLC eluting with n-hexane/ethyl acetate (v/v=2/1) to give 110 mg (23%) of the title compound as yellow oil.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:23]=[CH:22][C:15]([C:16](N(OC)C)=[O:17])=[C:14]([N:24]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)(=[O:30])=[O:29])[CH2:25][O:26][CH3:27])[CH:13]=1.C([O-])(=O)C(C(C([O-])=O)O)O.[K+].[Na+]>C1COCC1>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([N:24]([C:14]2[CH:13]=[C:12]([Cl:11])[CH:23]=[CH:22][C:15]=2[CH:16]=[O:17])[CH2:25][O:26][CH3:27])(=[O:29])=[O:30])=[CH:32][C:33]=1[C:38]([F:40])([F:41])[F:39]
Reactant: COCN(c1cc(Cl)ccc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)ccc1C=O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
Diisobutylaluminium hydride (DIBAL-H, 1.5 M solution in toluene, 0.73 mL, 1.1 mmol) was added drop wise to a solution of 4-chloro-2-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-N-methoxy-N-methyl-benzamide (220 mg, 0.44 mmol) in THF (3 mL) at −78° C. and stirred at the same temperature for an hour. Saturated aqueous sodium potassium tartarate solution (10 mL) was added slowly, warmed to room temperature, extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. Obtained residue was purified by column chromatography (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-(5-chloro-2-formyl-phenyl)-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (120 mg) in 62% yield. ESMS m/z (relative intensity): 410 (M−31)+ (95), 464 (M+Na)+ (100).
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)[C:3]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CNC(N)=O
Reactant: COC(=O)C(CC1CCCC1)c1ccc(SC)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(SC)cc1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
3-Cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid methyl ester (400 mg, 1.44 mmol) and methyl urea (267 mg, 3.60 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt %, 5.6 mL, 3.89 mmol). The reaction mixture was then concentrated in vacuo to approximately one-half the volume of methanol. The resulting reaction mixture was then heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C., filtered through celite, and the celite was thoroughly washed with ethyl acetate. The ethyl acetate filtrate was washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-propionyl]-3-methyl urea (141 mg, 31%) as a white solid: mp 185-186° C.; EI-HRMS m/e calcd for C17H24N2O2S (M+) 320.1559, found 320.1559.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:7]([C:28]#[N:29])[CH2:6]1)=O.CO.[BH4-].[Na+].C(OCC)(=O)C>O1CCCC1.N1C=CC=CC=1>[C:28]([N:7]1[C@H:8]2[C@@H:18]([C:17]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:20]=3[C:10]([CH2:9]2)=[C:11]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[NH:12]4)[CH2:19][C@@H:5]([CH2:3][OH:2])[CH2:6]1)#[N:29]
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(CN5CCOCC5)c(c34)C[C@H]2N(C#N)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#CN1C[C@H](CO)C[C@@H]2c3cccc4[nH]c(CN5CCOCC5)c(c34)C[C@H]21

Procedure:
3.95 g of 6-cyano-2-morpholinomethyl-8beta-ergoline-carboxylic acid methyl ester (10 mmol) is dissolved in 250 ml of tetrahydrofuran and 250 ml of methanol and altogether 4 g of sodium borohydride is added in four portions at room temperature. After two hours of reaction time, the organic phases are mixed with ice and common salt, shaken with ethyl acetate, combined and dried and concentrated by evaporation. After crystallization from the ethyl acetate, 3.26 g (89% of theory) is obtained, [α]D =+46° (0.5% in pyridine).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:15][CH:14]4[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH:13]4[CH2:12]3)[N:7]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:6]=2[C:5](=[O:31])[N:4]([CH2:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:3]1=[O:41].[ClH:42]>C(OCC)(=O)C>[ClH:42].[CH2:12]1[C@@H:13]2[CH2:18][NH:17][CH2:16][C@@H:14]2[CH2:15][N:11]1[C:8]1[N:7]([CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])[C:6]2[C:5](=[O:31])[N:4]([CH2:32][C:33](=[O:40])[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:3](=[O:41])[N:2]([CH3:1])[C:10]=2[N:9]=1
Reactant: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)=CCn1c(N2C[C@H]3CNC[C@H]3C2)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C

Procedure:
This compound was obtained by dissolving 50 mg of tert-butyl 5-[3-methyl-7-(3-methyl-but-2-enyl)-2,6-dioxo-1-(2-oxo-2-phenyl-ethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 5 ml of ethyl acetate, treating the solution with excess hydrogen chloride solution in ethyl acetate, concentrating in a rotary evaporator and stirring with diisopropyl ether.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([NH2:15])[CH:9]=2)[CH:4]=[CH:3]1.[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl>[O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:12][CH:13]=2)[NH:14][C:17](=[O:18])[C:16](=[O:20])[NH:15]3)[CH:4]=[CH:3]1
Reactant: Nc1ccc(-n2ccc(=O)cc2)cc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1ccn(-c2ccc3[nH]c(=O)c(=O)[nH]c3c2)cc1
Yield: 77.8 %

Procedure:
First, 4.849 g of 4-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine and 2.402 g of oxalic acid were added to 60 ml of 4N hydrochloric acid. The mixture was refluxed by heating for 2.5 hours in a nitrogen atmosphere. After the mixture was cooled, precipitated crystals were filtered and recrystallized with dimethylformamide to give 4.786 g of 6-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: O=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[CH:5]=CC.C(OCC)(=[O:22])C.CCCCCC>ClCCl.CO>[O:22]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19]
Reactant: CC=CCC1Cc2cccc(OC)c2C1=O
Reactant: CCOC(C)=O
Agent: O=[O+][O-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: COc1cccc2c1C(=O)C(CC=O)C2
Reaction time: 0.75 h
Yield: 71 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 45 minutes through a solution, cooled to -70°, of 9.9 g of (RS)-2-(2-buten-1-yl)-7-methoxy-1-indanone in 200 ml of anhydrous dichloromethane and 100 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 200 ml of dichloromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was cystallized from ethyl acetate/hexane. 6.6 g (71%) of (RS)-2-(2-oxoethyl)-7-methoxy-1-indanone were obtained as a white solid with m.p. 102°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][C:14]=2[C:15]#[N:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 94.4 %

Procedure:
Using a method similar to Example 39, using 4-chloro-2-nitro-phenylamine (6.4 g, 37.3 mmol), 2-fluoro-5-trifluoromethyl-benzonitrile (7.05 g, 37.3 mmol) to obtain 12.03 g of the title compound (95% yield) as an amorphous yellow solid. Product can be used as is with no further purification: Mass Spectrum (m/e): 342(M+1).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][N:14]=[CH:13]3)=[CH:8][CH:7]=2)=O)[CH2:3][CH2:2]1.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[N:12]1([C:9]2[CH:8]=[CH:7][C:6]([C:4]3[C:20]4[N:19]([C:18]([CH3:17])=[N:22][CH:21]=4)[CH2:2][CH2:3][CH:1]=3)=[CH:11][CH:10]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: O=C(c1ccc(-n2ccnc2)cc1)C1CC1
Reactant: Cc1ncc[nH]1
Product: Cc1ncc2n1CCC=C2c1ccc(-n2ccnc2)cc1

Procedure:
Combine 100 g (0.47 mol) of cyclopropyl-[4-(1H-imidazol-1-yl)phenyl]methanone with 300 g (3.7 mol) of 2-methylimidazole and heat to 175° C. under argon for 14 hr. Crystallization from acetonitrile provides the title compound.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:25]2[C:20](=[C:21]([O:29]C)[N:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=2)[N:19]([CH3:31])[CH:18]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:25]2[CH:24]=[C:23]([C:26]([OH:28])=[O:27])[NH:22][C:21](=[O:29])[C:20]=2[N:19]([CH3:31])[CH:18]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nc(C(=O)O)cc23)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(=O)[nH]c(C(=O)O)cc23)c1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A solution of Example 187E (335 mg, 0.647 mmol), 4M hydrogen chloride in dioxane (2.0 mL, 8.00 mmol) and dioxane (10 mL) was stirred at 75° C. for 4 hours. The reaction mixture was cooled to ambient temperature and was concentrated to dryness. The residue was dried (in-vacuo) to provide 315 mg (97%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2([CH3:18])[C:14](OC)=[O:15])[C:5]([N+:19]([O-])=O)=[CH:4][N:3]=1.[H][H]>C1COCC1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:19][C:14](=[O:15])[C:9]3([CH3:18])[CH2:10][O:11][CH2:12][CH2:13][N:8]3[C:6]=2[N:7]=1
Reactant: COC(=O)C1(C)COCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: C1CCOC1
Product: CC12COCCN1c1nc(Cl)ncc1NC2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
Methyl 4-(2-chloro-5-nitropyrimidin-4-yl)-3-methylmorpholine-3-carboxylate (crude material, 8.4 g, about 20 mmol) and vanadyl actylacetonate (0.7 g, 2.64 mmol) were mixed in THF (80 ml). The reaction mixture was hydrogenated under one atmosphere of hydrogen at 35° C. for 18 hours. The starting material was consumed. The reaction mixture was cooled to room temperature. MeOH (10 ml) was added to reaction mixture and stirred for 10 minutes. The mixture was filtered through a Celite® pad. The Celite® pad was washed with mixture of THF (60 ml) and MeOH (10 ml) twice and then a mixture of dichloromethane (80 ml) and methanol (20 ml) three times. The filtrate was combined with washes and concentrated to about 30 ml at which point a solid had precipitated out. EtOAc (40 ml) was added and the mixture was stirred for 10 minutes. The solid was collected by filtration, washed with EtOAc (50 ml) to afford 2.54 g of 2-chloro-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([F:25])[CH2:23][CH:22]2[NH2:24])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C@@:21]2([F:25])[CH2:23][C@H:22]2[NH:24][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[CH:19][CH:20]=1
Reactant: NC1CC1(F)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1C[C@]1(F)c1ccc(Cl)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-trifluoromethylbenzoyl chloride (0.10 g; 0.54 mmol) in dichloromethane (2 ml) added dropwise to a stirred solution of the amine from example P5 (compound Z1.004; 2-(4-chlorophenyl)-2-fluoro-cyclopropylamine; 0.100 g; 0.54 mmol) and triethylamine (0.15 ml; 1.08 m) in dichloromethane (3 ml). Stirred for 1 hr at room temperature then allowed to stand for 18 hr. The white precipitate was filtered off, washed with 2M HCl, saturated NaHCO3 and water and air dried giving the pure cis isomer. 0.065 g (34%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([OH:18])=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:25]=1)=[O:18]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
Diisopropylethylamine (2.3 mL) was added to a DMF solution (15 mL) of picolinic acid (814 mg), methyl 4-aminobenzenecarboxylate (1.0 g) and HATU (2.8 g), and stirred overnight at room temperature. Water was added to the reaction solution, and the resulting precipitate was taken out through filtration. The obtained residue was purified through silica gel column chromatography (chloroform/methanol=500/10 to 500/15) to obtain the entitled compound (1.4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.C([Li])CCC.CN(OC)[C:48](=[O:50])[CH3:49].O>C1COCC1.CCCCCC>[OH:16][C:12]([C:7]1[CH:8]=[C:3]2[C:4](=[CH:5][CH:6]=1)[CH:9]=[C:10]([C:48](=[O:50])[CH3:49])[CH:11]=[CH:2]2)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 96.1 %

Procedure:
1-(6-Bromonaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (7.0 g) was dissolved in THF (150 ml). The solution was cooled to −70° C. To the mixture was slowly added a solution of n-butyl lithium in hexane (1.6 M; 16.4 ml), and the mixture was stirred at −70° C. for 20 min. To the mixture was added dropwise a solution of N-methyl-N-methoxyacetamide (2.45 g) in THF (10 ml), and the mixture was stirred at −70° C. for 20 min. To the mixture was added water, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution and dried. The solvent was distilled off and the residue was purified column chromatography (eluent, hexane:THF=6:1→3:1) to give the titled compound (3.53 g) as a colorless powder.