Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8](=[CH:14]N(C)C)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=O)=[C:4]([Cl:20])[CH:3]=1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:43][C:44]([NH2:46])=[NH:45])[CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1>>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:46]=[C:44]([NH:43][C:33]3[CH:34]=[CH:35][C:36]([N:37]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]4)=[C:31]([O:30][CH3:29])[CH:32]=3)[N:45]=2)=[C:4]([Cl:20])[CH:3]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc(Br)cc1Cl
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc1-c1ccc(Br)cc1Cl
Yield: 28 %

Procedure:
The title compound was prepared from crude ethyl 2-(4-bromo-2-chloro-benzoyl)-3-dimethylamino-acrylate (50 mg, 0.14 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (43 mg, 0.12 mmol) using in analogous manner the procedure described in example 28b). Obtained as a yellow solid (50 mg) in 28% yield.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[O:8][C@@H:7]([N:19]2[C:32]3[N:31]=[CH:30][N:29]=[C:23]([N:24]=CN(C)C)[C:22]=3[N:21]=[CH:20]2)[CH2:6]1)[CH:2]=[CH2:3]>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:19]2[C:32]3[N:31]=[CH:30][N:29]=[C:23]([NH2:24])[C:22]=3[N:21]=[CH:20]2)[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@H](n2cnc3c(N=CN(C)C)ncnc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a stirred solution of 57 (875 mg; 1.90 mmol) in anhydrous THF (45 mL), 1 M TBAF in THF solution (2.09 mL; 2.09 mmol) was added and the reaction was stirred at room temperature for 1 h. After evaporation, the residue was dissolved in 7 M ammonia in methanol solution (34 mL). The mixture was then stirred in a sealed flask at 50° C. for 9 h. After evaporation, the residue was purified by flash column chromatography using CH3OH—CH2Cl2 (1:10) as the eluent to afford 58 as white solid (548 mg; 99% yield): 1H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H, 2-H), 8.17 (s, 1H, 8-H), 6.38 (dd, J=5.8, 8.6 Hz, 1H, 1′-H), 5.91-6.01 (m, 1H, CH2CH═CH2), 5.30-5.37 (dm, J=17.3 Hz, 1H, one of CH2CH═CH2), 5.17-5.22 (dm, J=10.6 Hz, 1H, one of CH2CH═CH2), 4.36 (m, 1H, 3′-H), 4.21 (m, 1H, 4′-H), 4.04-4.15 (m, 2H, CH2CH═CH2), 3.85 (dd, J=3.2, 12.3 Hz, 1H, one of 5′-H), 3.74 (dd, J=3.2, 12.3 Hz, 1H, one of 5′-H), 2.75-2.83 (ddd, J=5.7, 8.6, 13.6 Hz, 1H, one of 2′-H), 2.52-2.58 (ddd, J=1.8, 5.8, 13.6 Hz, 1H, one of 2′-H); 13C NMR (100 MHz, CD3OD) δ 157.1, 153.1, 149.5, 141.2, 135.6, 120.6, 117.0, 87.5, 87.2, 80.9, 71.0, 63.9, 38.7; HRMS (FAB+) calcd for C13H18O3N5 (M+H+): 292.1410. found: 292.1426.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: CCNCc1ccnc2ccccc12
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: CCN(Cc1ccnc2ccccc12)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-quinolin-4-ylmethyl-amine
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[H-].[Na+].Br[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1.CCOCC>[CH:21]1([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Oc1ccc2ncn(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.5 %

Procedure:
5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine (0.300 g, 1.33 mmol) was dissolved in THF and NaH (0.050 g, 2.0 mmol) was added portionwise. The resulting mixture was heated in a sealed tube for 1 h and then cooled to room temperature. Bromocyclopentane (0.20 g, 17.8 mmol) was added and the reaction was heated to 70° C. overnight. The solution was then diluted with ether and washed with water. The aqueous layer was back extracted with additional ether and the combined organic portions were washed with brine, dried over MgSO4 and purified by preparative HPLC. The resulting 5-(benzyloxy)-3-cycloheptyl-3H-imidazo[4,5-b]pyridine was then dissolved in DCM and diluted with excess sulfuric acid. The resulting solution was stirred for 30 minutes at room temperature then acidified with the addition of 1 M aqueous hydrochloric acid. The solvent was removed from the organic layer and the residue was purified via preparative HPLC to give the title compound (0.0284 g). LCMS m/z=204.31 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.80 (m, 2H), 1.80-1.95 (m, 2H), 2.0-2.1 (m, 2H), 2.15-2.30 (m, 2H), 4.95-5.05 (m, 1H), 6.88 (d, J=8.8 Hz, 1H), 8.13 (d, J=8.8 Hz, 1H), 9.35 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].N1C=CC=CC=1>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 67.5 %

Procedure:
A solution of Example 40H (2.89 g, 6.07 mmol), mesyl chloride (1.88 mL, 24.3 mmol), and pyridine (3.93 mL, 48.6 mmol) in acetone (80 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (2.12 g, 68%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1H) 0.74 (m, 7H) 1.34 (m, 1H) 1.57 (m, 3H) 2.15 (m, 2H) 3.08 (m, 3H) 7.56 (m, 3H) 7.75 (m, 3H) 8.16 (m, 1H) 10.26 (m, 1H) 13.76 (m, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].CO[Si:8](OC)(OC)[CH2:9][CH2:10][CH2:11][Cl:12].Cl>>[ClH:12].[CH2:1]([NH:5][CH2:11][CH2:10][CH2:9][SiH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CCCCN
Agent: Cl
Product: CCCCNCCC[SiH3]

Procedure:
A reaction of n-butylamine with CPTMO with a ratio of 3:1 consumes 1 mol of n-butylamine. 2 moles of n-butylamine can be removed again by distillation without any addition. This is because the reaction forms 1 mol of HCl, and, as a result of the distillation, 1 mol of n-butylaminopropylsilane hydrochloride is present at the end of the reaction.
Reaction SMILES: [CH3:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:17]=1[N:25]=[C:26]=[O:27])([CH3:15])[CH3:14].C([N-]C(C)C)(C)C.[Li+]>>[CH3:15][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:23])[CH3:24])[C:17]=1[NH:25][C:26](=[O:27])[CH2:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:14]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
The title compound was prepared from 2-undecanone (5.0 g, 0.029 mol), 2,6-diisopropylphenyl isocyanate (5.96 g, 0.029 mol), and lithium diisopropylamide (0.029 mol) using the procedure described in Example 1. The desired product was obtained in 79.4% yield (8.6 g, 0.023 mol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C:24]2[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:31])[N:20]=[CH:19][N:18]=1>>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[O:23][C:21]1[CH:22]=[CH:17][N:18]=[C:19]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:20]=1
Reactant: Clc1cc(Oc2c(Cl)cccc2Cl)ncn1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nccc(Oc3c(Cl)cccc3Cl)n2)ccc1-n1cnc(C)c1
Yield: 29 %

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 4-chloro-6-(2,6-dichloro-phenoxy)-pyrimidine. It was obtained as a yellow solid in 29% yield.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])[N:5]=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[F:8][C:7]1[C:2]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:3][CH:4]=[N:5][C:6]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14]
Reactant: C1CCNCC1
Reactant: CCC#CCOc1ncnc(Cl)c1F
Product: CCC#CCOc1ncnc(N2CCCCC2)c1F
Reaction time: 3 h
Yield: 97.8 %

Procedure:
0.2 g of 4-chloro-5-fluoro-6-(2-pentynyloxy)pyrimidine and 0.24 g of piperidine were mixed and left for 3 hours at room temperature. The reaction mixture was subjected to silica gel column chromatography to obtain 0.24 g of 5-fluoro-4-piperidino-6-(2-pentynyloxy)pyrimidine (hereinafter, referred to as Compound (12)).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:32](=[O:33])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: NCC1Cc2cccc(-c3ccccc3C(F)(F)F)c2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3ccccc3C(F)(F)F)c2O1)OCc1ccccc1
Yield: 94.2 %

Procedure:
Treatment of (±)-1-{7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (0.813 g, 2.46 mmol) with diisopropylethylamine (0.478 g, 3.69 mmol) and benzyl chloroformate (0.462 g, 2.71 mmol) generally according to the procedure described for Intermediate 12 gave 0.99 g (94%) of (±)-benzyl {7-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methylcarbamate as a pale yellow oil Rf=0.60 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C24H20F3NO3: C, 67.44; H, 4.71; N, 3.15. Found: C, 67.43H, 4.76; N, 3.15. Chiral HPLC separation of (±)-benzyl[7-(2-(trifluoromethyl))-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, isopropanol:carbon dioxide 3:17) provided two fractions. Fraction 1 (Rt=5.252 min, Chiralcel OJ, isopropanol:carbon dioxide 3:17); Fraction 2 (Rt=6.280 min, Chiralcel OJ, isopropanol:carbon dioxide 3:17).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[NH:4][C:5]([NH2:8])=[N:6][N:7]=1.[C:11](OCC)(=[O:16])[CH2:12][C:13]([CH3:15])=O>C(O)(=O)C>[CH3:15][C:13]1[CH:12]=[C:11]([OH:16])[N:6]2[N:7]=[C:3]([C:2]([F:10])([F:9])[F:1])[N:4]=[C:5]2[N:8]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nnc(C(F)(F)F)[nH]1
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(C(F)(F)F)nc2n1
Yield: 52.3 %

Procedure:
To a well-stirred solution of 5-(trifluoromethyl)-4H-1,2,4-triazol-3-amine (1 g, 6.58 mmol) in 15-20 mL glacial acetic acid, was added ethyl acetoacetate (2.57 g or 2.5 mL, 19.77 mmol) and the reaction mixture was refluxed for 6-6.5 h. Reaction progress was monitored by TLC. After completion, the reaction mixture was brought to room temperature and the excess glacial acetic acid was evaporated in vacuo. The light pinkish white solid, thus obtained, was filtered off, washed with dichloromethane and dried to yield 0.750 g (52.3%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:3](S(C)(=O)=O)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[N:6][CH:7]=1.[OH:21][C:22]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][C:2]1[C:3]([O:21][C:22]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][CH:23]=2)=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: Oc1csc(C(F)(F)F)c1
Reactant: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(-n2cc(C(F)(F)F)cn2)nc1Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 48.8 %

Procedure:
A mixture of 0.8 g (2.6 mmol) of 5-methyl-4-methylsulfonyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)pyrimidine, 0.44 g (2.6 mmol) of 3-hydroxy-5-trifluoromethylthiophene and 0.72 g (5.2 mmol) of K2CO3 in 10 ml of DMF is stirred at 60° C. for 6 h and then at RT for 48 h. It is subsequently poured into 20 ml of water and extracted with four times 15 ml of CH2Cl2. The combined organic phase is dried over Na2SO4, filtered and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.5 g of 5-methyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)-4-(5-trifluoromethyl-3-thienyloxy)pyrimidine as colorless crystals.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:10]2[N:22]([CH3:23])[C:13]3=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:3]([C:4]1[C:5]([C:10]2[N:22]([CH3:23])[C:13]3=[N:14][CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=[C:12]3[N:11]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)=[O:32])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1cccnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1cccnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.4 %

Procedure:
To a mixture of 2-(3-ethylsulfanyl pyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.62 g) and chloroform (10 ml) was added m-chloroperbenzoic acid (purity: not less than 65%) (0.79 g) while ice-cooling, and then the mixture was stirred at room temperature for 5 hours. To the reaction mixture was poured saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 2-(3-ethylsulfinyl pyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (87 mg), which is hereinafter referred to as “the present compound 2”, and 2-(3-ethylsulfonylpyridin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.49 g), which is hereinafter referred to as “the present compound 3”.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH:11]1[CH2:16][C:15](=O)[O:14][C:12]1=[O:13].C(Cl)(=O)C>C1(C)C=CC=CC=1>[Cl:9][CH2:10][CH:11]1[CH2:16][C:15](=[O:14])[N:6]([C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]1=[O:13]
Reactant: Nc1ccc(F)cc1
Reactant: O=C1CC(CCl)C(=O)O1
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: O=C1CC(CCl)C(=O)N1c1ccc(F)cc1
Temperature: 100 °C
Yield: 93 %

Procedure:
In a variant of (b), into a toluene solution of 33.3 g (0.3 moles) 4-fluoroaniline, a toluene solution of 44.6 g (0.3 moles) 2-chloromethylsuccinic acid anhydride were added dropwise at room temperature while stirring. The temperature of the mixture rose to 40° C. during the operation. To the suspension of the semi-anilide obtained, 0.35 moles of acetylchloride was added dropwise at 60° C. while stirring, the addition being carried out so slowly that the ensuing gas development could be easily controlled. After 3 hours the reaction mixture was heated to 100° C. and held at that temperature until the gas development was terminated. The semi-anilide thereby dissolved. When the reaction mixture was cooled down, the desired product crystallized. The actual yield was 93% of the theoretical yield.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][NH:31][CH2:30][CH2:29][C:27]=2[N:28]=1.[N:33]1([CH2:38][CH2:39][CH2:40][CH2:41][C:42](O)=[O:43])[CH:37]=[CH:36][N:35]=[CH:34]1.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[NH:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][N:31]([C:42](=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][N:33]3[CH:37]=[CH:36][N:35]=[CH:34]3)[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: c1ccc2c(c1)CC(Nc1ncc3c(n1)CCNC3)C2
Reactant: O=C(O)CCCCn1ccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCn1ccnc1)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 18 h
Yield: 44.8 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288 g; 2.0 equiv; 1.50 mmoles) to a solution of N-indan-2-yl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (0.20 m; 1.0 equiv; 0.75 mmoles), 5-imidazol-1-ylpentanoic acid (0.152 g; 1.2 equiv; 0.90 mmoles), and 1-hydroxybenzotriazole (0.203 g; 2.0 equiv; 1.50 mmoles) in dichloromethane (20 mL) and triethylamine (0.52 mL). Stir the mixture for 18 hours, then concentrate, add water (10 mL), and extract with ethyl acetate (3×20 mL). Dry the combined organic extracts over anhydrous sodium sulfate, filter, and concentrate. Purify the crude product by column chromatography (0 to 10% methanol in dichloromethane) to afford 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-5-(1H-imidazol-1-yl)pentan-1-one (0.14 g; 45%) as a colorless oil: MS (m/z): 417 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5][C:4]([NH2:25])=[N:3]1.[CH3:26][N:27]=[C:28]=[O:29]>C(#N)C>[CH3:26][NH:27][C:28]([NH:25][C:4]1[N:5]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)[N:2]([CH3:1])[N:3]=1)=[O:29]
Reactant: CN=C=O
Reactant: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CC#N
Product: CNC(=O)Nc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Yield: 81.5 %

Procedure:
A mixture of 1-methyl-N5 -[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (2.00 g) and methylisocyanate (1.2 g) in dry acetonitrile (60 ml) was heated at reflux for 2 h. and allowed to cool. The precipitated solid was collected and recrystallised from methanol to give the title compound (1.9 g).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12](Cl)[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:9][C:10]1[N:11]=[C:12]([N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)[CH:13]=[N:14][CH:15]=1
Reactant: Clc1cncc(Cl)n1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(c2cncc(Cl)n2)C[C@H](C)O1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
cis-2,6-Dimethylmorpholine (0.850 g, 7.38 mmol) was added to a suspension of 2,6-dichloropyrazine (1 g, 6.71 mmol) and potassium carbonate (2.78 g, 20.14 mmol) in anhydrous acetonitrile (50 mL). After addition, the reaction mixture was stirred at 90° C. for 3 hours. Crude LCMS showed desired product can be seen and no starting material left, so the reaction mixture was diluted with ethyl acetate (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (˜10 ml) and purified on silica by a Biotage SP4 chromatographic system (40+M cartridge, eluted with 0-100% ethyl acetate in isohexanes). Fractions containing the pure product were combined and concentrated under reduced pressure to give the title compound as a white solid (742 mg, 3.10 mmol, 46.1% yield). LC/MS [M+H]+=228/230.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)[CH2:13][N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7][N:6]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:4].[OH-].[Li+].Cl>C1COCC1.CO>[C:39]([O:38][C:36]([N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)[CH2:13][N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1C[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)Oc2cc3c(cc21)CC(C(=O)O)N(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester was dissolved in THF:methanol (4:1). 2 N lithium hydroxide (0.5 mL) was added and the resulting reaction mixture was stirred at room temperature for 4 hours. Excess 1N HCl was added and the mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to afford the product in pure form (122 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])(O)[CH3:10])=[CH:5][CH:4]=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[S:16][C:15]([CH3:17])=[N:14][C:13]=2[CH3:18])=[CH2:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)(O)c2sc(C)nc2C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C=C(c1ccc(OC)cc1)c1sc(C)nc1C
Reaction time: 2 h

Procedure:
1- (4-Methoxyphenyl) -1- (2, 4-dimethyl-5-thiazolyl) ethanol (3.69g) in chloroform (50ml) was treated with hydrogen chloride in dry diethyl ether (1M, 14.5ml). After 2 hours at room temperature, aqueous sodium hydrogen carbonate was added and the mixture was extracted with chloroform. The material thus obtained was purified by flash chromatography to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:21][O:22]C1C=CC(N)=CC=1>>[CH3:21][O:22][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:15][CH:16]=1
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
(RK1-1-27E) I This compound was prepared according to the procedure described for compound 11a except using p-anisidine to obtain the required product as a light brown solid. (278 mg, 100%) Mp=173-175° C. (lit 187-189° C., Tetrahedron 62(25), 6100-6106; 2006); 1H NMR (400 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 6.80 (d, J=9.0 Hz, 2H), 6.36 (br s, 1H), 3.78 (s, 3H).