Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:18])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:5]=[C:4]([CH3:19])[N:3]=1.[CH2:20]([NH:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)[CH2:21][CH3:22].[NH4+].[OH-]>CN1CCCC1=O>[CH:25]1([CH2:24][N:23]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C:7]([CH3:18])([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]=3[N:5]=[C:4]([CH3:19])[N:3]=2)[CH2:20][CH2:21][CH3:22])[CH2:27][CH2:26]1
Reactant: Cc1nc(Cl)c2c(n1)C(C)(c1ccccc1)CCC2
Reactant: CCCNCC1CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCN(CC1CC1)c1nc(C)nc2c1CCCC2(C)c1ccccc1
Yield: 36.8 %

Procedure:
A solution of 4-chloro-2,8-dimethyl-8-phenyl-5,6,7,8-tetrahydroquinazoline (180 mg, 0.7 mmol), N-propylcyclopropanemethylamine (1 mL, 7 mmol) and 1 mL of 1-methyl-2-pyrrolidinone was heated in an oil bath at 160-170° C. for 3 h. After cooling, the mixture was added to aqueous NH4OH and extracted with ethyl acetate. The extract was washed with 1N NaOH and brine, dried, (sodium sulfate) and evaporated. Purification by flash chromatography (15% ethyl acetate/hexane) afforded 90 mg of cyclopropylmethyl-(2,8-dimethyl-8-phenyl-5,6,7,8-tetrahydro-quinazolin-4-yl)-propyl-amine as an oil. MS MH+ 349.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(F)c(Br)c1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.1 %

Procedure:
A mixture of 3-bromo-4-fluorobenzene-1-sulfonyl chloride (2.53 g, 8.33 mmol), indoline (0.933 mL, 8.33 mmol), and N,N-diisopropylethyl-amine (1.60 mL, 9.16 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 20 hours. The reaction mixture was partitioned between water and ether. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to a solid residue. Recrystallization from ether and heptane provided the title compound (1.99 g, 67%).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:15])=[CH:12][CH:13]=1)([C:4]([OH:6])=[O:5])[CH3:3].C(O[CH:27]([CH3:29])[CH3:28])(=O)C.C(=O)([O-])[O-].[K+].[K+].BrC(C)C>CS(C)=O>[CH3:28][CH:27]([O:5][C:4]([C:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:13]=1)([CH3:1])[CH3:3])=[O:6])[CH3:29]
Reactant: CC(=O)OC(C)C
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Product: CC(C)OC(=O)C(C)(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1 kg (3.14 mol) of fenofibric acid (II), 500 ml of dimethyl sulfoxide and 1 l of isopropyl acetate were charged into a jacketed 5 l reactor under nitrogen. 433.5 g (3.14 mol) of potassium carbonate were then added, with stirring at ambient temperature, and the reaction mixture was brought to 85-90° C. for 45 min. The temperature of the reaction mixture was subsequently reduced to approximately 80° C. and 354 ml (3.77 mol) of 2-bromopropane and then 100 ml of isopropyl acetate were added over a period of 50 min. The mixture was kept stirring at 85-95° C. for 5 hours and then slightly cooled to approximately 80° C. In-process monitoring showed that the degree of conversion to give fenofibrate was approximately 99.5%. The content of the reactor was hot-filtered and the salts separated on the filter were washed with 1 l of isopropyl acetate, which was combined with the filtrate. The isolated salts, which essentially comprise potassium bromide, were dried and kept for recycling. The filtrate was concentrated under reduced pressure while maintaining a bulk temperature of approximately 80° C., and of 95° C. at the end of concentrating. After removal of the solvents, 2.27 l of isopropanol and 455 ml of pure water were added. The mixture was brought to gentle reflux for 10 min and then hot-filtered. Under stirring, the filtrate was slowly cooled down to a temperature of 0° C. The crystallized fenofibrate was separated by filtration on a filtering device, washed on the filtering device with approximately 500 ml of ice-cold isopropanol and then dried under vacuum at 45-50° C. 1075 g of fenofibrate with a purity of greater than 99.5% and comprising no impurity at a level of greater than 0.05% were thus obtained (yield=94.9%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12](Cl)(=[O:14])=[O:13])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:22]([C:29]([F:32])([F:31])[F:30])=[CH:21][C:19]=1[NH2:20]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([NH:20][C:19]2[CH:21]=[C:22]([C:29]([F:30])([F:31])[F:32])[CH:23]=[C:24]([C:25]([F:26])([F:27])[F:28])[C:18]=2[Cl:17])(=[O:14])=[O:13])=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1Cl
Solvent: c1ccncc1
Product: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.4 %

Procedure:
4-Tert-butyl-2,6-dimethyl-benzenesulfonyl chloride (0.100 g, 0.383 mmol) was added to a solution of 2-chloro-3,5-bis(trifluoromethyl)aniline (0.101 g, 0.387 mmol) in dry pyridine (1 mL). The reaction was capped and stirred at room temperature for 1 day then stirred at 30° C. for 1 day. The reaction was then concentrated under vacuum. To this was added diethyl ether (60 mL) and the mixture was washed with 0.1 N HCl (3×20 mL) followed by 0.1 N NaOH (2×20 mL) then saturated NaCl (2×20 mL). After drying the organic layer over MgSO4, the solution was filtered and concentrated under vacuum. The crude compound was triturated with hexanes (2×10 mL) to afford the title compound (0.027 g, 14% yield). LCMS (M+Na) 510.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1cccnc1)N1CCOCC1
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Product: Cc1ccc(Cl)c(C(=O)NCC(c2cccnc2)N2CCOCC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine. LCMS (MH+): m/z=360.0, tR (minutes, Method A)=0.77
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:19])=[O:18])[C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:61][CH2:62][CH2:63][OH:64]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([S:17]([C:20]2[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=2)(=[O:18])=[O:19])[C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH:61][CH2:62][CH2:63][OH:64])=[O:12])=[CH:26][CH:27]=1
Reactant: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)O)c2)n1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)NCCO)c2)n1

Procedure:
A solution of 3-[(4-chloro-benzyl)-(1-methyl-1H-pyrazole-3-sulfonyl)-amino]-benzoic acid (30 mg, 0.07 mmol), diisopropylethylamine (0.26 ml, 0.14 mmol). HATU (56 mg, 0.15 mmol) and 2-aminoethanol (9 μL, 0.14 mmol) were stirred in dry acetonitrile (3 ml) for 18 hrs. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (3 ml) and water (3 ml). The organic layer was separated and dried by passage through a hydrophobic frit, then concentrated in vacuo. The crude residue was purified by preparative HPLC to afford the title compound as an off white solid (11.9 mg). HPLC retention time 5.03 min. Mass spectrum (ES+) m/z 449 (M+H).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+].C(O)CCCCC>>[CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc(N=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCO
Product: CC(C)Nc1ccc(N)cc1
Reaction time: 1.5 h

Procedure:
Following essentially the procedure of Example 1, 66.0 g (0.25 mole) N-isopropyl-4-nitrosoaniline, 20 g (50%) sodium hydroxide and 264 g n-hexanol were kept at 100° C. for 1.5 hours. HPLC analysis of the reaction mixture indicated absence of the nitroso starting compound. By vacuum distillation (95°-101° C. at 13.3-26.6 Pa), 31.3 g of product were recovered (48.6 wt. % yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][S:15]([CH2:18][C:19]#[N:20])(=[O:17])=[O:16].N1C=CC=CC=1.C1C=CC=CC=1>N1CCCCC1.O>[CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:18]([C:19]#[N:20])[S:15]([CH3:14])(=[O:17])=[O:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C=O)cc1
Reactant: CS(=O)(=O)CC#N
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCCCOc1ccc(C=C(C#N)S(C)(=O)=O)cc1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 20.0 g (0.112 mol) of 4-butoxybenzaldehyde, 13.6 g (0.114 mol) of methylsulfonylacetonitrile, 8.9 g (0.11 mol) of pyridine, 4 drops of piperidine, and 100 mL of benzene were heated at reflux for 18 hr, with continuous azeotropic separation of the water evolved. Approximately half of the benzene was then distilled, and 50 mL of heptane was added. Upon cooling to room temperature, a white precipitate was formed, which was collected and recrystallized twice from toluene to afford 15.3 g (49%) of (5). A sample of (5) that was sublimed in vacuo melted at 96.5°-7° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:17](O)[CH3:18].C(C1C=CC(C(O)=O)=CC=1)CC>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH2:17][CH3:18])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CCCc1ccc(C(=O)O)cc1
Solvent: CO
Product: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
The reaction was conducted in the same manner as in the step (i) of the Example 33, except for using 4-(4-hydroxyphenyl)benzoic acid and ethanol in lieu of 4-n-propylbenzoic acid and methanol, respectively, and the resultant was recrystallized from toluene to give ethyl 4-(4-hydroxyphenyl)benzoate.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].CCOCC>C(Cl)(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CCC(CO)CC1
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
To a 100 mL-flask containing 83 (3.4 g, 13.2 mmol) in CHCl3 (30 mL) was added tosyl chloride (3.26 g, 17.1 mmol) and pyidine (3.2 mL, 39.6 mmol). The reaction was allowed to stir at 25° C. for 14 hours after which time the reaction was concentrated in vacuo to yield a wet white solid. To this solid was added ether (50 mL) and the solid was filtered and subsequently washed with additional ether (2×50 mL). The ether layers were pooled, concentrated in vacuo to yield a clear oil which was purified by flash chromatography, on a silica gel column, eluting with 1:4 ether/petroleum ether to yield 84 (4.5 g, 83%) as a white solid. 1H NMR (CDCl3) δ 7.78 (d, J=7.7, 2H), 7.33 (d, J=7.7 Hz, 2H), 3,81 (d, J=6.2 Hz, 2H), 3.37 (d, J=6.2, 2H), 2.44 (s, 3H), 1.95–1.72 (m, 4H), 1.65 (m, 1H), 1.40 (m, 1 H), 1.03–0.89 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) δ 145.1, 133.7, 130.3, 128.4, 75.8, 68.9, 40.7, 38.0, 29.1, 26.5, 22.1, 18.9, −4.9; APCI m/z (rel intensity) 413 (MH+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.CN([CH:17]=[O:18])C.[Cl-].[NH4+]>C(OCC)C.O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[CH:17]=[O:18]
Reactant: Brc1cncc(Br)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: O=Cc1cncc(Br)c1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
In diethyl ether (42.0 mL) was dissolved 3,5-dibromopyridine (1.00 g, 4.22 mmol). n-Butyllithium (2.76 mol/L solution in n-hexane, 1.61 mL, 4.43 mmol) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Further, DMF (0.98 mL, 12.7 mmol) was added and the mixture was stirred for 3 hours allowing the temperature to rise slowly to room temperature. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 5-bromonicotinaldehyde (314 mg, 40%).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([OH:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:48][C:49]#[CH:50].Cl>CN(C)C=O>[F:38][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[C:35]([O:36][CH2:50][C:49]#[CH:48])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1
Reactant: C#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: C#CCOc1cccc(Cl)c1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 80 °C
Reaction time: 9 h
Yield: 54 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (33 mg) and potassium carbonate (12 mg) in N,N-dimethylformamide (5 ml) are added, at room temperature, potassium iodide (5 mg) and 3-bromoprop-1-yne (11 mg). The reaction mixture is stirred at 80° C. for 9 h. Then the mixture is admixed with dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-chloro-6-(prop-2-yn-1-yloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (19 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[N:4]=[C:5]([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.Cl.[Br:19][C:20]1[N:21]=[C:22]([C@H:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)[N:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=12.C(N(CC)C(C)C)(C)C.[CH3:44][O:45][CH2:46][C:47]([Cl:49])=[O:48]>ClCCl>[ClH:49].[Br:2][C:3]1[N:4]=[C:5]([C@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.[Br:19][C:20]1[N:21]=[C:22]([C@H:30]2[CH2:34][CH2:33][N:32]([C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH2:31]2)[N:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[C:24]=12
Reactant: Cc1nccn2c([C@@H]3CCNC3)nc(Br)c12
Reactant: COCC(=O)Cl
Agent: Cc1nccn2c([C@H]3CCNC3)nc(Br)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)N1CC[C@H](c2nc(Br)c3c(C)nccn23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-Bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride was prepared in a similar way as (R)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride. To (S)-1-bromo-8-methyl-3-(pyrrolidin-3-yl)imidazo[1,5-a]pyrazine hydrochloride (0.31 mmol, 100 mg) in dichloromethane (5 ml) and N,N-diisopropylethylamine (1.778 mmol, 0.311 ml) at 0° C. was added a solution of methoxyacetyl chloride (0.534 mmol, 0.049 ml) in dichloromethane (0.5 ml). After stirring for one hour at room temperature the reaction mixture was diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate solution, water, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give (S)-1-(3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-1-yl)-2-methoxyethanone (80 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19])([O-])=[O:2].C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.CO>[OH:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:2])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: c1ccc(N=Nc2ccccc2)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1

Procedure:
A mixture of methanol 60 ml, water 30 ml, 97% sodium hydroxide 12.4 g and 2-nitro-2'-hydroxy-5'-methylazobenzene 12.9 g was heated and stirred at 45°~50° C. 9-fluorenone 1.0 g and then glucose 5.5 g were added to the resultant mixture over 30 minutes while stirring. The mixture was further stirred at 75° C. (boiling point) for 7 hours. As this result, the azobenzene disappeared to produce 2-(2'-hydroxy-5'-methylphenyl)benzotriazole-N-oxide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]([NH:20][C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:17]([N+:27]([O-])=O)=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:10]=1.O.O.[Sn](Cl)Cl.[N:42]#[C:43]Br>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]3[N:20]([C@H:21]([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:43]([NH2:42])=[N:27][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:10]=1
Reactant: C[C@@H](Nc1nc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccc(F)cc2)ccc1[N+](=O)[O-])C(C)(C)C
Reactant: N#CBr
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: C[C@@H](n1c(N)nc2ccc(-c3[nH]c(-c4c(F)cccc4F)nc3-c3ccc(F)cc3)nc21)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
Dissolve {6-[2-(2,6-difluoro-phenyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-nitro-pyridin-2-yl}-(1(R),2,2-trimethyl-propyl)-amine (673 mg, 1.4 mmol) in 100% ethanol (15 mL) and add tin(II) dichloride dihydrate (1.5 g, 6.8 mmol, 5 equiv). Heat the reaction mixture until starting material is consumed. Cool the reaction solution to room temperature, quench slowly with saturated aqueous NaHCO3. Add Celite® to the quenched reaction and filter the suspension on a Celite® pad, washing with water and ethyl acetate. Separate the layers and wash the organic layer with saturated aqueous NaCl. Dry the organic layer with Na2SO4, filter, and concentrated under reduced pressure. Add 10% aqueous ethanol (14 mL) and cyanogen bromide (216 mg, 2.04 mmol, 1.5 equiv) to the residue and stir overnight. Quench with saturated aqueous NaHCO3 (20 mL). Add ethyl acetate and water to dissolve all solids. Wash the organic layer is with saturated aqueous NaCl, dry with Na2SO4, filter, and concentrate under reduced pressure. Subject the residue to medium pressure silica gel chromatography eluting with a gradient of 1.5-3% (2M ammonia in MeOH)/CH2Cl2 to provide 5-[2-(2,6-difluoro-phenyl)-5-(4-fluoro-phenyl)-3H-imidazol-4-yl]-3-(1(R),2,2-trimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine as a tan glass (289 mg, 43% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([SH:14])[C:8]=1[C:15]#[N:16])[CH3:4].Br[CH2:19][C:20]([NH2:22])=[O:21]>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH2:3]([O:5][C:6]([C:7]1[C:8]2[C:15]([NH2:16])=[C:19]([C:20](=[O:21])[NH2:22])[S:14][C:9]=2[N:10]=[C:11]([CH3:13])[CH:12]=1)=[O:17])[CH3:4]
Reactant: CCOC(=O)c1cc(C)nc(S)c1C#N
Reactant: NC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)nc2sc(C(N)=O)c(N)c12
Reaction time: 0.08 h
Yield: 60.3 %

Procedure:
NaH (39 mg, 0.95 mmol) was added to a solution of the above ester (210 mg, 0.95 mmol) in THF (15 mL) at room temperature. After stirring for 5 min, α-bromoacetamide (134 mg, 0.97 mmol) and n-Bu4NI (10 mg) were added. The mixture was stirred at room temperature for 1 h, then NaH (39 mg, 0.95 mmol) was added, and the mixture was stirred for an additional 0.5 h. The reaction was quenched by addition of saturated aqueous NH4Cl, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated giving an orange solid. The crude residue was recrystallized from MeOH giving 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid ethyl ester (160 mg, 60%), m.p. 205-208° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([NH:8][CH3:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]=[P:13](Cl)([Cl:15])[Cl:14]>C1(C)C=CC=CC=1>[CH3:9][N:8]([C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[P:13]([Cl:15])([Cl:14])=[O:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccccc1
Product: CN(c1ccc([N+](=O)[O-])cc1)P(=O)(Cl)Cl

Procedure:
p-Nitro-N-methylaniline (9.3 g, 0.061 mol) and 9 mL (0.1 mol) POCl3 were heated in 50 mL toluene to 90°-95° C. overnight. The solution was cooled and filtered. The volatiles were removed from the filtrate, giving 15.3 g of a purple, viscous oil. NMR (CDCl3): AA'XX' quartet from δ7.45-7.35 (4H), 3.37 (d,3H, J=14-15 Hz). No N--H was observed in the NMR. Due to an expected very high boiling point, this material was not distilled but used directly in the preparation of N-Methyl-N-(4-nitrophenyl) phosphoric triamide in the following Example VI.