Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:30][CH2:31][CH2:32]O.C([O:38][C:39](=[O:42])[CH2:40][NH2:41])(C)(C)C>>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:30][CH2:31][CH2:32][NH:41][CH2:40][C:39]([OH:38])=[O:42])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: OCCCBr
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1O
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OCCCNCC(=O)O

Procedure:
The title compound is prepared starting from 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (Example 53, step b) in analogy to Example 1 using 3-bromo-propanol and glycine tert.-butyl ester; LC-MS: tR=0.97 min, [M+H]+=495.24; 1H NMR (CDCl3): δ 7.84 (s, 1H), 7.80 (s, 1H), 7.41 (s, 1H), 7.22 (s, 1H), 3.97 (s, 3H), 3.91 (t, J=5.3 Hz, 2H), 3.66 (s, 2H), 3.34-3.41 (m, 2H), 3.13-3.23 (m, 1H), 2.68 (q, J=7.4 Hz, 2H), 2.35-2.43 (m, 2H), 2.33 (s, 3H), 2.02-2.11 (m, 2H), 1.81-1.93 (m, 4H), 1.67-1.76 (m, 2H), 1.29 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3): δ 175.7, 170.8, 167.7, 165.0, 164.2, 158.8, 137.9, 136.7, 131.9, 129.0, 127.3, 120.0, 111.9, 105.5, 70.0, 53.5, 50.0, 47.5, 45.4, 33.3, 27.2, 25.9, 22.8, 16.5, 14.7.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[N:6][O:7][C:8]=1[CH3:9])[CH3:2].C(N(CC)CC)C.[CH3:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[C:20]([N:3]([C:4]1[CH:5]=[N:6][O:7][C:8]=1[CH3:9])[CH2:1][CH3:2])(=[O:21])[CH2:19][CH2:18][CH3:17]
Reactant: CCNc1cnoc1C
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)N(CC)c1cnoc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, ice cooled solution of 4-ethylamino-5-methylisoxazole (Method 5 of WO 03/76436; 49.6 g, 305 mM) and triethylamine (77.0 g, 763 mM, 107 ml) in DCM (800 ml), was slowly added a solution of n-butyryl chloride (35.5, 333 mM, 35 ml) in DCM (100 ml). There was a moderate exotherm. The solution was allowed to warm to ambient temperature and stir for 1 hour. The reaction mixture was washed with water, 2N HCl, brine, sat. NaHCO3 and brine. It was dried and the solvent was evaporated to give the title compound as an oil, which crystallized to a waxy solid (45.1 g, 75%). NMR (300 Mz, DMS0-d6): 0.78 (t, 3H), 0.96 (t, 3H), 1.44 (sext, 2H), 1.93 (t, 2H), 2.33 (s, 3H), 3.49 (q, 2H), 8.68 (s, 1H); m/z 197.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH2:5]([N:12]1[C:17]([CH3:18])=[N:16][C:15](=[O:19])[C:14]([CH:20](C)C(NN)=O)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>O.Cl>[NH2:1][CH2:20][C:14]1[C:15](=[O:19])[NH:16][CH:17]([CH3:18])[N:12]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:13]=1
Reactant: Cc1nc(=O)c(C(C)C(=O)NN)nn1Cc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1NC(=O)C(CN)=NN1Cc1ccccc1
Reaction time: 2 h
Yield: 108.1 %

Procedure:
Sodium nitrite (1.29 g) in water (25 ml) was added to a stirred solution of 2-benzyl-2,5-dihydro-3,α-dimethyl-5-oxo-1,2,4-triazine-6-acetic acid, hydrazide (5.0 g) in conc. hydrochloric acid (3.3 ml) and water (75 ml) keeping the temperature at -1° to -2°. The azide separated as a white solid which rapidly became a thick gum. Conc. hydrochloric acid (5 ml) was added and the mixture was raised to 65° over 30 minutes and left at this temperature for 2 hours. During this period the gum gradually dissolved to give a clear yellow solution. This was cooled and brought to pH 8 by the addition of sodium bicarbonate. Water was removed by rotary evaporation and the residual solid was extracted with boiling isopropanol (6×100 ml). The extract was filtered and concentrated to give the amine as a gum (4.37 g) which failed to crystallise.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.OC1(C2C=CC=CC=2)CCN(C2N=CNC(=O)N=2)CC1.CC1C=CC(S(O[CH2:53][N:54]2[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[N:55]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[OH:21][C:8]1([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][N:17]([CH2:53][N:54]3[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[N:55]3)[C:16](=[O:20])[N:15]=2)[CH2:10][CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)OCn2ccc(C(F)(F)F)n2)cc1
Reactant: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)nc[nH]1
Agent: O=C([O-])[O-]
Agent: O=c1nc(N2CCC(O)(c3ccccc3)CC2)nc[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(N2CCC(O)(c3ccccc3)CC2)ncn1Cn1ccc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 6.8 %

Procedure:
An N,N-dimethylformamide suspension (1.4 mL) of a mixture of 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1,3,5-triazin-2(1H)-one synthesized in Reference Synthesis Example 22a and 4-(4-hydroxy-4-phenylpiperidin-1-yl)-1,3,5-triazin-2(1H)-one (140 mg), [3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl 4-methylbenzenesulfonate (282 mg, 0.91 mmol) synthesized in Reference Synthesis Example 15, and potassium carbonate (252 mg, 1.83 mmol) was stirred at 80° C. for 3 hours. After completion of the reaction, water was added thereto and extraction with ethyl acetate from the resultant mixture was performed. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/4 (v/v)) and preparative high-performance liquid chromatography to obtain the title compound (14 mg, yield 6.8%) in Reference Synthesis Example 91a and the title compound (7.4 mg, yield 3.9%) in Reference Synthesis Example 91b.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1B(O)O>>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c(OC)c1

Procedure:
The title compound was prepared from the product of Example 65A and 2,4-dimethoxyphenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 366.0 (M+H)+, retention time 1.37 minutes.
Reaction SMILES: I[C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:22][C:5]=3[C:4]=2[CH:3]=1.[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1B1OC(C)(C)C(C)(C)O1>C(=O)([O-])[O-].[Na+].[Na+].C(#N)C.O>[Cl:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[C:6]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:22][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1(C)OB(c2cnccc2Cl)OC1(C)C
Reactant: Cn1cc(-c2cnc3c(c2)c2cc(I)ncc2n3COCC[Si](C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2cnc3c(c2)c2cc(-c4cnccc4Cl)ncc2n3COCC[Si](C)(C)C)cn1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
6-Iodo-3-(1-methyl-1H-pyrazol-4-yl)-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.21 g, 0.41 mmol), 4-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.15 g, 0.615 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloro palladium(II) (17 mg, 0.021 mmol) in saturated aqueous sodium carbonate solution (1 mL) and acetonitrile (4 mL) were placed under an atmosphere of argon and heated with microwave irradiation at 100° C. for 45 minutes. The cooled reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to afford a residue which was purified by flash chromatography (silica, 12 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a yellow oil (0.13 g, 66%). 1H NMR (CDCl3, 400 MHz): 9.22 (d, J=1.1 Hz, 1H), 8.91 (d, J=0.5 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.48 (d, J=2.1 Hz, 1H), 8.32 (d, J=1.1 Hz, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.73 (s, 1H), 7.48 (dd, J=5.4, 0.5 Hz, 1H), 6.01 (s, 2H), 4.01 (s, 3H), 3.70-3.63 (m, 2H), 1.02-0.94 (m, 2H), −0.06 (s, 9H). LCMS (Method G): RT=4.8 min, M+H+=491.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[NH2:10][C@@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13].[OH-].[Na+].C(Cl)(Cl)Cl>C1COCC1>[O:8]=[C:1]([NH:10][C@@H:11]([C:15]([OH:17])=[O:16])[C@@H:12]([CH3:14])[OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)Cl
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCC(=O)N[C@@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of n-heptanoyl chloride (440 mL, 2.83 mmol) in THF (250 mL) is added dropwise, over a period of 30 min, to a cold (-5 to 0° C., vigorously stirred mixture of D-allo-Thr (300 mg, 2.51 mmol) and 2N aq. NaOH (3.5 mL, 7.0 meq) in THF (4.0 mL). The resulting mixture is stirred for 2 h at the same temperature and overnight at room temperature. The volatiles are removed and the residue is diluted with o water and acidified, using conc. HCl. The mixture is extracted with EtOAc and the combined organic solution is washed with brine, dried, filtered, and concentrated to provide crude 2c-1 (420 mg, containing 10% excess heptanoyl reagent) which solidifies upon standing. NMR δ1.28 (d, J=6.5, 3H), 4.20 (m, 1H), 4.61 (dd, J=3.4, 6.6, 1H), 6.56 (br d, J=6.9, 1H); [α]D26 -38±2 (CHCl3).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C:15]1([CH2:25][OH:26])[CH2:24][CH2:23][C:18]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:17][CH2:16]1.C(N(CC)CC)C.O>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C:15]2([CH2:25][OH:26])[CH2:24][CH2:23][C:18]3([O:19][CH2:20][CH2:21][O:22]3)[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: NC1(CO)CCC2(CC1)OCCO2
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccsc2c1NC1(CO)CCC2(CC1)OCCO2
Temperature: 90 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (229 mg, 1.07 mmol), (8-amino-1,4-dioxaspiro[4.5]dec-8-yl)methanol (240 mg, 1.28 mmol) and triethylamine (300 μL, 2 mmol) in isopropyl alcohol (3.5 mL) was stirred at 90° C. overnight. After cooling to room temperature, water was added, which caused more solids to form. The solids were filtered, washed with water, and dried to give 219 mg (56%) of the desired product. LCMS calculated for C16H20N3O5S (M+H)+: m/z=366.1. Found: 366.1. 1H NMR (300 MHz, CDCl3) δ 8.93 (s, 1H), 7.78-7.75 (m, 2H), 4.17 (s, 2H), 4.02-3.84 (m, 4H), 2.52 (d, J=13.3 Hz, 2H), 2.12-1.82 (m, 4H), 1.78-1.44 (m, 4H) ppm.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([NH:12][NH:13][C:14](=[O:34])[C@H:15]([CH2:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:16][N:17]([O:20]CC3C=CC=CC=3)[CH:18]=[O:19])[C:6]=2[F:35])[CH2:4][CH2:3][CH2:2]1>CO>[N:1]1([C:5]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([NH:12][NH:13][C:14](=[O:34])[C@H:15]([CH2:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:16][N:17]([OH:20])[CH:18]=[O:19])[C:6]=2[F:35])[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCC2)n1
Solvent: CO
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCC2)n1
Yield: 98.2 %

Procedure:
[(2R)-3-{2-[6-(1-Azetidinyl)-5-fluoro-2-methyl-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (3.9 g, 8.0 mmol) was dissolved in 50 mL of MeOH and degassed with argon. 10% Pd/C (400 mg) was added, and the contents were placed under a hydrogen balloon for 4.5 h. The contents were then degassed with argon and filtered through Celite, and the Celite pad was washed with DCM and MeOH. The resulting filtrate was concentrated in vacuo to provide the pure [(2R)-3-{2-[6-(1-azetidinyl)-5-fluoro-2-methyl-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (3.1 g, 98%). LCMS: (M+H)+: 395.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23]>O>[CH3:1][C:2]1[C:7]([N+:22]([O-:24])=[O:23])=[CH:6][C:5]2[C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:14](=[O:16])[O:15][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Temperature: 25 °C

Procedure:
A stirred suspension of 1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (10.0 g, 0.046 moles) in water (10 ml) is cooled in an ice bath. Concentrated sulfuric acid (25 ml) is added, followed after 15 minutes by the dropwise addition of concentrated nitric acid (12 ml). The ice bath is removed and the mixture allowed to warm to room temperature. After 48 hours the mixture is poured over crushed ice, stirred, and made strongly basic by the addition of concentrated ammonium hydroxide. The precipitated product is filtered off, rinsed with water and dried. Recrystallization from acetonitrile gave the product (8.7 g), mp 197°-199° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[N:20])[CH:18]=[C:13]3[C:12]([C:21]3[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=3)[CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:11]2)(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:19]([C:17]1[CH:18]=[C:13]2[C:12]([C:21]3[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=3)[CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:11][NH:10][C:14]2=[N:15][CH:16]=1)#[N:20]
Reactant: N#Cc1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(1-benzenesulfonyl-5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide (128 mg, 0.000201 mol) was dissolved in methanol (4.5 mL; Fisher) and water (1.5 mL, Fisher). To this was added potassium carbonate (129 mg, 0.000933 mol; Fisher) and the reaction was heated at reflux for 1 hour. The reaction was evaporated, taken up in N,N-dimethylformamide, neutralized with TFA (200 uL) and purified by preparative HPLC chromatography to yield the product in 26.9 mg yield (22%). 1H NMR (400 MHz, DMSO-d6) d ppm 12.582 (s (br), 1H) 10.078 (t, J=5.7 Hz, 1H) 8.804 (s, 1H) 8.648 (s, 1H) 8.405 (d, J=7.2 Hz, 1H) 8.224 (d, J=6.4 Hz, 1H) 8.098 (d, J=1.8 Hz, 1H) 7.750 (s, 1H) 7.639 (d, J=8.0 Hz, 1H) 7.470-7.334 (m, 3H) 7.236 (d, J=7.4 Hz, 1H) 7.183-7.128 (m, 1H) 6.589 (t, J=7.2 Hz, 1H) 5.212 (s, 2H) 4.596 (d, J=6.0 Hz, 2H); MS m/z=496.02 M+H.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])(C)(C)C.[NH2:14][C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])N(C)OC)=[CH:19][N:18]2[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1COCC1>[NH2:14][C:15]1[N:16]=[C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:28])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[F:8])=[CH:19][N:18]2[C:29]=1[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CON(C)C(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Reactant: Fc1ccccc1Br
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc2ccc(C(=O)c3ccccc3F)cn2c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 50.7 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (191 mL, 1.75mmol) in dry THF (2 mL) under an argon atmosphere was added t-butyl lithium dropwise. After stirring for 50 minutes at −78° C., a solution of 2-amino-3-phenyl-6-(N-methyl-N-methoxycarbamoyl)imidazo[1,2-a]pyridine (148 mg, 0.5 mmol) in dry THF (3 mL) was added. The resulting red-orange solution was stirred at the same temperature for another 50 minutes and then allowed to warm to RT. The solution was poured into H2O (20 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with H2O, dried (Na2SO4), and removed in vacuo to give a brown solid. The crude solid was purified by column chromatography (CH2Cl2/CH3CN 2.5/1) to give 84.0 mg (50.6%) of product as a yellow solid. MS(FAB) m/z 332.2 (M++1, 51.99), NMR (200 MHz, CDCl3) d 4.27 (bs, 2H, NH), 7.12-7.58 (m, 11H, ArH+H7+H8), 8.71 (s, H5).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>O1CCCC1>[CH3:1][N:2]([CH2:3][CH2:4][OH:5])[S:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: CNCCO
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CN(CCO)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
To 20 parts of tetrahydrofuran is added 3.9 parts of N-methyl-ethanolamine. To this solution, 10 parts of tetrahydrofuran containing 5 parts of p-chlorobenzenesulfonyl chloride is added with stirring. After completion of the addition, the resultant mixture is stirred as it is for a while, and then heated for about 1 hour on a water bath at 50° C. to terminate the reaction. Then, the salt is removed by filtration, and the filtrate is freed from the solvent, whereby an oily substance is obtained. This oily substance is subjected to distillation under reduced pressure to obtain 4.2 parts of a distillate, b.p. 180° C./0.5 mmHg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=1.[NH2:18][NH2:19]>C1COCC1>[NH:18]([C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=1)[NH2:19]
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cl)nc1C(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1C(=O)OCC
Yield: 96 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of diethyl 2-chloropyrimidine-4,5-dicarboxylate (0.21 g, 0.83 mmol) and hydrazine (0.13 g, 4.2 mmol) in THF (10 mL) resulting in 96% yield (0.20 g); 1H NMR (CDCl3) δ 8.93 (bs, 1H), 8.34 (bs, 1H), 4.40 (m, 4H), 4.18 (bs, 2H), 1.35 (m, 6H).
Reaction SMILES: [H-].[Na+:2].[SH:3][CH2:4][CH:5]([CH:9]1[CH2:11][CH2:10]1)[C:6]([OH:8])=[O:7]>CN(C)C=O>[Na+:2].[Na+:2].[SH:3][CH2:4][CH:5]([CH:9]1[CH2:11][CH2:10]1)[C:6]([O-:8])=[O:7].[SH:3][CH2:4][CH:5]([CH:9]1[CH2:11][CH2:10]1)[C:6]([O-:8])=[O:7]
Reactant: O=C(O)C(CS)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C([O-])C(CS)C1CC1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
In a light-protected flask and under N2 atmosphere, 4.4 g of 60% sodium hydride and 88 ml of dimethylformamide were mixed. To this mixture, a solution containing 8.1 g of mercaptomethylcyclopropylacetic acid and 20 ml of dimethylformamide was added while maintaining the temperature at 0-5° C. The reaction mixture was kept at this temperature for 1 hour.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7](=[O:14])[NH:6]2.[N+:17]([O-])([O-:19])=[O:18].[K+]>OS(O)(=O)=O>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:17]([O-:19])=[O:18])[NH:9][C:8](=[O:13])[C:7](=[O:14])[NH:6]2
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]c1=O
Temperature: 0 °C
Yield: 50.6 %

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). 6-Trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (200 mg, 0.869 mmol) was dissolved in 8 mL of concentrated H2SO4 and the yellow-green solution was cooled to 0° C. with stirring. To this was added in small portions KNO3 (87.8 mg, 1.10 mmol). The reaction was allowed to stir 1 h at 0° C. and then was allowed to come to room temperature and stir overnight. The brown-orange reaction mixture was then poured into 10 mL ice H2O. The product was isolated by vacuum filtration as pale yellow crystals which were rinsed with a small amount of cold H2O and air dried. The crystals were further dried under vacuum (0.1 torr, 25° C.) to yield 121.1 mg (50.6% yield). 1H NMR (d6 -DMSO) δ 7.53 (s, 1H, ArH), 7.80 (s, 1H, ArH), 12.4 (s, 2H, NH). EIMS m/z 275 (81, M+), 217 (36), 201 (100, bp), EIHRMS calc. for C9H4N3O4F3 275.0153, found 275.0170.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]=[C:17]([OH:21])[N:16]=3)[CH2:11][CH:10]=2)[O:3]1.Cl[CH2:24][C:25]1[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=1>>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:22])([CH3:1])[O:3][B:4]([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:24][C:25]4[S:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)[C:17](=[O:21])[N:16]=3)[CH2:11][CH:10]=2)[O:5]1
Reactant: CC1(C)OB(C2=CCN(c3ncnc(O)n3)CC2)OC1(C)C
Reactant: FC(F)(F)c1ccc(CCl)s1
Product: CC1(C)OB(C2=CCN(c3ncn(Cc4ccc(C(F)(F)F)s4)c(=O)n3)CC2)OC1(C)C
Yield: 46 %

Procedure:
4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl]-1,3,5-triazin-2-ol (3.32 g, 10.9 mmol) synthesized in Reference Synthesis Example 345 and 2-(chloromethyl)-5-(trifluoromethyl)thiophene were used to obtain the title compound (2.36 g, yield 46%) by synthesis in a similar manner to Reference Synthesis Example 16.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([NH2:12])[CH:3]=1.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[N:5]=[C:4]([NH:12][C:14](=[O:13])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1
Reactant: Nc1cc(Cl)nc(C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(C(F)(F)F)n1

Procedure:
Method 24 was followed using 6-chloro-2-(trifluoromethyl)pyrimidin-4-amine (1.0 equiv.), BOC2O (1.0 equiv.), and DMAP (cat.) to afford tert-butyl 6-chloro-2-(trifluoromethyl)pyrimidin-4-ylcarbamate in 64%. LCMS (m/z): 298.1 (MH+); LC Rt=4.73 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.Cl.[S:20]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][NH:30][S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[O:11])[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)NCCCCCCN)cc1
Reactant: O=C(O)C=Cc1cccnc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)NCCCCCCNC(=O)C=Cc2cccnc2)cc1

Procedure:
Batch size: 4.1 g (27.5 mmol) 3-(3-pyridyl)-acrylic acid, 4.7 g (37.0 mmol) oxalyl chloride, 5.0 g (49.4 mmol) TEA and 8.6 g (25.0 mmol) 6-(tosylamino)-hexylamine.dihydrochloride.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH3:23])[C:21]=1[OH:22].C([O-])([O-])=O.[K+].[K+]>>[NH2:8][C:5]1[N:6]=[N:7][C:2]([N:18]2[CH:19]=[C:20]([CH3:23])[C:21](=[O:22])[C:16]([CH3:15])=[CH:17]2)=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: Cc1cncc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cn(-c2nnc(N)nc2-c2ccccc2)cc(C)c1=O
Yield: 5.1 %

Procedure:
1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one (40 mg, 5%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.70 g, 2.7 mmol), 3,5-dimethylpyridin-4-ol (0.45 g, 3.7 mmol) and K2CO3 (0.93 g, 6.7 mmol) according to the general procedure of Example 3.