Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[CH2:11]([O:10][C:9]1[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=1)[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CCOc1ccc(CC(=O)O)cc1OCC
Solvent: CC(=O)O
Product: CCOc1cc(CC(=O)O)c([N+](=O)[O-])cc1OCC
Temperature: 40 °C

Procedure:
0.5 g of 3,4-diethoxy-phenylacetic acid are placed in 10 ml of acetic acid p.a. and 0.5 ml of 659 nitric acid are added dropwise, so that the internal temperature does not rise above 15° C. The mixture is then heated to 40° C. for 0.5 hours. After this time the solution is poured onto ice water and the precipitate formed is suction filtered. The product is washed with water and dried at 100° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22](O)=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:45])([C:41]([F:44])([F:43])[F:42])[CH2:38][CH2:39][NH2:40]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22]([NH:40][CH2:39][CH2:38][C:37]([F:45])([F:36])[C:41]([F:44])([F:43])[F:42])=[O:23])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCC(F)(F)C(F)(F)F
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@@](F)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 3,3,4,4,4-pentafluoro-butylamine, the title compound was prepared in the same manner as described for example 1c. White solid (85%). MS: m/e=622(M+H+).
Reaction SMILES: [NH3:1].[CH2:2]=[CH:3][CH3:4].O.[I-].[NH4+].[CH2:8](O)[CH2:9][CH3:10]>C(O)(C)C>[CH:3]([NH2:1])([CH3:4])[CH3:2].[CH:3]([NH:1][CH:9]([CH3:10])[CH3:8])([CH3:4])[CH3:2]
Reactant: C=CC
Reactant: CCCO
Reactant: N
Agent: [I-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)N
Product: CC(C)NC(C)C
Temperature: 335 °C

Procedure:
A mixture of 16.9 g (1.0 mole) of anhydrous ammonia, 21.1 g (0.5 mole) of propylene, 50.0 g water and 43.5 g (0.3 mole) of ammonium iodide were charged to a 300 cm3 stainless steel autoclave. The autoclave was heated to 335° C. and held there with agitation. A total of 5.8 g of monoisopropylamine, 0.13 g of diisopropylamine, 1.6 g isopropyl alcohol, 0.20 g of n-propyl alcohol and 0.6 g of a hydrocarbon oil were obtained, corresponding to a propylene conversion of 29% and a combined isopropylamines yield of 69%, propyl alcohols yield of 21% and oil yield of 10%.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][C:14](=O)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)(=[O:33])[CH3:32]>ClCCCl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:37]4[CH2:38][CH2:39][N:34]([C:31](=[O:33])[CH3:32])[CH2:35][CH2:36]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: CC(=O)N1CCNCC1
Reactant: O=C1CC(c2nc(I)c3c(Cl)nccn23)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)N1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a RBF 3-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (1.00 g, 0.0029 mol) and sodium triacetoxyborohydride (1.30 g, 0.006 mol) were dissolved in 1,2-dichloroethane (65.0 mL) and a solution of 1-acetylpiperazine (0.39 g, 0.003 mol) in 1,2-dichloroethane was added to the reaction. The reaction mixture was stirred at rt for 2 h. The crude product was concentrated in vacuo and the dissolved in CH2Cl2 (25.0 mL) and washed with saturated NaHCO3 solution (1×40 mL). The product was dried with sodium sulfate and concentrated in vacuo to yield a light yellow solid; MS (ES+): m/z 459.84 (100) [MH+], 461.80 (40) [MH+++]; HPLC: tR=1.81 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.04-2.15 (m, 3H) 2.26-2.50 (m, 6H) 2.55-2.72 (m, 2H) 2.83-2.99 (m, 1H) 3.29-3.52 (m, 3H) 3.56-3.67 (m, 2H) 7.29 (d, 1H) 7.58 (d, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[C:7]([NH2:9])[N:6]=[N:5]1.Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([NH:9][C:7]2[N:6]=[N:5][N:4]([CH2:3][O:2][CH3:1])[CH:8]=2)=[N:12][CH:13]=1
Reactant: COCn1cc(N)nn1
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1cc(Nc2ccc(Br)cn2)nn1
Temperature: 70 °C
Reaction time: 72 h
Yield: 4 %

Procedure:
1-(methoxymethyl)-4-amino-1H-1,2,3-triazole (3.56 g, 27.784 mmol), 2,5-dibromopyridine (19.608 g, 82.773 mmol) and potassium tert-butylate (9.345 g, 83.252 mmol) were added into DMF (100 mL), heated to 70° C., and stirred for 72 hours. The reaction solution was poured into water, and extracted with ethyl acetate. The combined organic phase was washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated, and separated on a silica gel column chromatograph (ethyl acetate:petroleum ether=1:30) to obtain 0.318 g of 5-bromo-N-(1-(methoxymethyl)-1H-1,2,3-triazol-4-yl)pyridine-2-amine as a yellow solid, at a yield of 4%.
Reaction SMILES: FC(F)(F)S(O[C@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@@:9]([O:33][CH3:34])([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:8]1)(=O)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:37]([C@@H:7]1[CH2:12][C@@H:11]([CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[O:10][C@:9]([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)([O:33][CH3:34])[CH2:8]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCCC[C@@H]1C[C@H](OS(=O)(=O)C(F)(F)F)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCC[C@@H]1C[C@@H](N=[N+]=[N-])C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Temperature: 25 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
A solution of the title compound from Example 22 (1.19 mmol, used directly from the previous reaction) in DMF (12 mL) was treated with sodium azide (400 mg, 6.15 mmol), and the mixture was stirred at room temperature for 22 h. The reaction mixture was diluted with ethyl acetate, washed with satd aq NaHCO3, ice cold 5% aq citric acid, and brine, and the organic phase was dried and concentrated. Chromatography of the residue on silica gel eluting with dichloromethane/ethyl acetate gave the title compound (432 mg, 82%) as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].[CH2:14]([C@H:16]1[O:18][CH2:17]1)[Cl:15]>C(O)C.ClCCl>[Cl:15][CH2:14][C@@H:16]([OH:18])[CH2:17][N:11]1[CH2:10][CH2:9][N:8]([C:6]([C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:7])[CH2:13][CH2:12]1
Reactant: ClC[C@@H]1CO1
Reactant: O=C([C@H]1CCCO1)N1CCNCC1
Solvent: CCO
Solvent: ClCCl
Product: O=C([C@H]1CCCO1)N1CCN(C[C@H](O)CCl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[(R)-tetrahydro-2-furoyl]piperazine (1.89 g, 10.26 mmol) in ethanol (25 mL) was added (S)-epichlorohydrin (1.09 g, 11.8 mmol). The mixture was stirred at room temperature overnight, then concentrated in vacuo, yielding a pale yellow oil. The oil was dissolved in dichloromethane (100 mL), and washed with 1M H3PO4, dried and evaporated, to provide the title intermediate.
Reaction SMILES: [CH:1]([C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[CH:10]=[CH:9]1)=O.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[O:28]1[CH2:29][CH2:30][N:25]([CH2:1][C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[O:5][CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[CH:10]=[CH:9]2)[CH2:26][CH2:27]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2ccn(CCOc3ccccc3C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc2ccn(CCOc3ccccc3CN3CCOCC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a solution of methyl 1-(2-(2-formylphenoxy)ethyl)-1H-indole-6-carboxylate (0.27 g, 0.84 mmol) and morpholine (0.22 mL, 2.5 mmol) in 1,2-dichloroethane (20 mL) was added NaBH(OAc)3 (0.35 g, 1.7 mmol). After stirring the solution for 4 hr at room temperature, the solution was concentrated and then diluted with ethyl acetate (100 mL) and washed with H2O (100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 0.33 g (˜100%) of methyl 1-(2-(2-(morpholinomethyl)phenoxy)ethyl)-1H-indole-6-carboxylate as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1.C(O)(=O)C>C1COCC1.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[CH:3]=[N:4][CH:5]=[N:6][CH:7]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cncnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cncnc2)nc(N2CCOCC2)n1
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
To 0.186 g (1.96 mmol) of 5-aminopyrimidine in THF (4 mL) was added 1.1 mL of NaHMDS (2 M solution in THF) at 0° C. and the mixture was stirred for 15 min. A solution of 0.238 g (0.65 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (5 mL) was added and the resulting mixture WAS stirred for 1 hr at room temperature. The resulting mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed with water, and aq. NH3, and dried. Removal of the solvent, followed by chromatography on alumina, eluting with CH2Cl2/EtOAc (1:9), then CH2Cl2/EtOAc (1:3), gave an off-white powder. Recrystallization from ethanol gave 0.123 g (47% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(5-pyrimidinyl)-1,3,5-triazin-2-amine: mp 290-292° C.; 1H NMR (CDCl3) δ9.07 (s, 2H), 9.02 (s, 1H), 8.37 (d, J=7.2 Hz, 1H), 7.89 (dd, J=7.7, 1.5 Hz, 1H), 7.57 (t, JHF=53.7 Hz, 1H), 7.47-7.40 (m, 2H), 7.11 (s, 1H), 3.95-3.92 (m, 4H), 3.83 (br s, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.0; N, 29.6. Found: C, 53.4; H, 4.2; N, 29.4%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.I[CH3:15].[NH2-].[Na+].O>C1(C)C=CC=CC=1.ClCCl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]([CH3:15])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Reactant: CI
Agent: [NH2-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C#N)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1.0 g (5.4 mmol) of 3-(trifluoromethyl)phenylacetonitrile and 767 mg of iodomethane (5.4 mmol) are placed in 5 ml toluene at 80° C. and slowly treated with a 50% suspension of sodamide in toluene. Next the mixture is stirred 1 hr more at 80° C., then cooled to RT and treated with water, then dichloromethane. The organic phase is separated, washed with water, dried over magnesium sulphate and freed of solvent on the rotary evaporator. The residue (1.7 g, 84% of theory) contains the title compound with a purity of ca. 53% by GC/MS and is used without purification for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([Cl:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[C:9]=1[N+:15]([O-:17])=[O:16].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>>[NH2:14][C:10]1[C:9]([N+:15]([O-:17])=[O:16])=[C:8]([O:7][C:6]2[C:5]([Cl:19])=[CH:4][C:3]([Cl:20])=[C:2]([NH:1][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=3)=[O:30])[CH:18]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1cc(Oc2ccnc(N)c2[N+](=O)[O-])c(Cl)cc1Cl
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Nc1nccc(Oc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)c(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 73 %

Procedure:
Method G was used with 4-(5-amino-2,4-dichlorophenoxy)-2-amino-3-nitropyridine and 4-chloro-3-trifluoromethylphenyl isocyanate to afford the title compound as a yellow powder (740 mg, 73%). 1H-NMR (δ, ppm, DMSO-d6): 6.01 (d, 1H, HPy,5, J=5.6 Hz), 7.26 (s, 2H, NH2,Py), 7.62 (m, 2H, Harom), 7.90 (s, 1H, Harom), 8.03 (m, 2H, Harom+HPy6), 8.21 (s, 1H, Harom), 8.63 (s, 1H, NHurea), 9.95 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 99.7 (C-4); 114.1 (C-11); 116.8 (C-); 116.9 (C-); 118.7 (C-); 119.7 (C-); 121.1 (C-); 123.1 (C-); 123.2 (C-); 123.8 (C-); 130.5 (C-); 132.2 (C-); 136.2 (C-10 or 13); 138.5 (C-10 or 13); 147.4 (C-6); 151.7 (C-12); 153.4 (C-5); 153.9 (C-1); 157.6 (C-3). LC-MS (m/z): 535 (M+H, 100).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C@:9]([OH:55])([C@@H:17]([C:38](=[O:54])[NH:39][C@H:40]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])OCC[O:27]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:78][C:79]#[C:80][CH3:81]>C(#N)C.CN(C=O)C.O>[CH2:78]([O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@H:40]([NH:39][C:38]([C@@H:17](/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@@:9]([OH:55])([CH2:8][CH2:7][OH:6])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:47][CH:46]=1)[C:79]#[C:80][CH3:81]
Reactant: CC#CCBr
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)OCC)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)OCCO1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
tert-Butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-1-ethoxycarbonyl-2-(4-hydroxy-phenyl)-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate (909 mg) was dissolved in acetonitrile (9.0 mL), and an aqueous solution (3.6 mL) of 0.5 M citric acid was added. The mixture was stirred at 60° C. for 3 hours. Water was then added to the reaction mixture, which was followed by extraction with a mixed solvent of ethyl acetate/n-hexane. The organic extract was dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (660 mg). The obtained crude product (182 mg) was dissolved in DMF, and potassium carbonate (49.4 mg) and 1-bromo-but-2-yne (28.9 μL) were added. The mixture was stirred at room temperature for 20 hours. Water was then added to the reaction mixture, which was followed by extraction with a mixed solvent of ethyl acetate/n-hexane. The organic layer was washed with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (74 mg).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]([CH3:21])[C:10]=1[CH3:22])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[C:13]([CH2:16][C:17]([F:20])([F:18])[F:19])=[CH:12][N:11]([CH3:21])[C:10]=1[CH3:22]
Reactant: Cc1c(OCc2ccccc2)c(=O)c(CC(F)(F)F)cn1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1c(O)c(=O)c(CC(F)(F)F)cn1C
Yield: 69 %

Procedure:
A clear solution of 3-benzyloxy-1,2-dimethyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (1.1 g, 3.53 mmol) in methanol (32 mL) was debenzylated using Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 0.17 g) as catalyst in a hydrogen atmosphere at a pressure of 50 psi for 30 min. The reaction mixture was diluted with methanol (30 mL), and sonicated for 10 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The volume of the filtrate was reduced to about 20 mL by evaporation under reduced pressure. HPLC analysis (HPLC Method 1, Example 24) of the filtrate indicated the presence of about 42% (peak percent area) of the starting material. Another 150 mg of Pd/C was added, and the mixture was subjected to the debenzylation reaction condition for a further 20 min, and worked up as described above. The catalyst was filtered off, and the filtrate was evaporated to dryness to afford 3-hydroxy-1,2-dimethyl-5-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as a solid product (0.54 g, 69% yield, HPLC Method 1 (Example 24), RT=9.9 min, HPLC purity (peak percent area): 99.3% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 7.70 (s, 1H), 3.65 (s, 3H), 3.39 (q, J=11.5 Hz, 2H), 2.26 (s, 3H). MS-ESI (m/z) 222.2 ([M+1]+, 100%), 202.2, 182.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1.[C:12](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC>>[CH3:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(=O)OC
Product: Cn1cc(C#N)c2ccccc21
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 189.4 %

Procedure:
A mixture of indole-3-carbonitrile (1.0 g, 7.03 mmole), potassium carbonate (0.5 g), N,N-dimethytformamide (10 mL) and dimethyl carbonate (1.8 mL, 21.4 mmol) was stirred and heated to reflux (˜130° C.). The reaction (monitored by HPLC) was complete within 3.5 h. The reaction mixture was then cooled to 3° C. and ice cold water (25 mL) was added slowly. The resulting oily suspension was extracted with tert-butyl methyl ether (40 mL) and the organic phase was washed with water (3×25 mL), dried and evaporated in vacuo to obtain 1.07 g of the product, 1-methylindole-3-carbonitrile, as a dark oil (97.4% yield).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:40][C:37]4[CH:38]=[CH:39][C:34]([N:31]5[CH2:30][CH2:29][NH:28][CH2:33][CH2:32]5)=[CH:35][N:36]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]2[O:15][CH:14]=[N:13][CH:12]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: Clc1ncc2cc(-c3cnco3)n(C3CCCC3)c2n1
Product: c1ncc(-c2cc3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n2C2CCCC2)o1
Yield: 24.2 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-6-oxazol-5-y-l-7H-pyrrolo[2,3-d]pyrimidine (70 mg, 0.24 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (74 mg, 0.27 mmol), followed by deprotection using General Procedure A to give (7-cyclopentyl-6-oxazol-5-yl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-(5-piperazin-1-yl-pyridin-2-yl)-amine (25 mg, 24%). MS (ESI) m/z 431.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][C:12]([CH3:14])=[N:11][CH:10]=1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:28]3[CH2:29][CH2:30][CH2:31][CH:26]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:20][CH:21]=4)[C:27]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: COc1cc(NC(N)=S)ccc1-c1cnc(C)s1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-c1cnc(C)s1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of [3-methoxy-4-(2-methyl-thiazol-5-yl)-phenyl]-thiourea (110 mg, 0.39 mmol) and 2-bromo-6-phenyl-cyclohexanone (105 mg, 0.41 mmol) in ethanol (4 ml) was heated to reflux over night. The precipitated solid was filtered off after cooling to room temperature and dried to yield the title compound (160 mg, 94%) as a yellow solid. MS ISP (m/e): 434.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.32 (br s, 1H, NH), 8.10 (s, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.29 (t, 2H), 7.15-7.21 (m, 3H), 6.85 (d, 1H), 4.00 (m, 1H), 3.48 (s, 3H), 2.75 (m, 2H), 2.68 (s, 3H), 2.14 (m, 1H), 1.70-1.94 (m, 3H).
Reaction SMILES: CC(S([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:24][C:23]3[C:22]4=[N:32][N:33]=[CH:34][N:21]4[CH:20]=[CH:19][C:18]=3[N:17]=2)=[CH:12][CH:11]=1)[CH3:9])=O)(C)C.Cl.O>CO>[C:26]1([C:25]2[C:16]([C:13]3[CH:12]=[CH:11][C:10]([CH:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=3)=[N:17][C:18]3[CH:19]=[CH:20][N:21]4[CH:34]=[N:33][N:32]=[C:22]4[C:23]=3[CH:24]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(NS(=O)C(C)(C)C)c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(N)c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-methyl-N-{1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethyl}propane-2-sulfinamide (7-3, 180 mg, 0.38 mmol) in methanol (6 mL) was added conc. HCl (1.5 mL). After 1 h, water was added and the mixture was washed with methylene chloride. The aqueous portion was basified with saturated sodium carbonate solution and extracted with methylene chloride. 2N HCl (5 mL) was added to the organic layer and the mixture was concentrated to a minimum volume. The crude product was purified using reverse phase preparative HPLC to give the title compound as a pale yellow solid. LRMS m/z (M+1) Calcd: 366.2. Found 366.3.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:9]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][S:7][CH:6]=1.S(=O)(=O)(O)O.[C:25]([OH:29])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:3](=[O:2])[CH2:4][C:5]1[C:9]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:8][S:7][CH:6]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)O
Reactant: COC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Product: CC(C)(C)OC(=O)Cc1cscc1Nc1c(Cl)cccc1Cl

Procedure:
316 mg (1 mmole) of 4-(2,6-dichloroanilino)-3-thiophenacetic acid methyl ester are warmed to 60° in 20 ml of tert.-butanol and 2 ml of concentrated sulfuric acid for 2 hours. The excess alcohol is distilled off. Chromatography on a column (silica gel/methylene chloride) gives, in the first fraction, 4-(2,6-dichloroanilino)-3-thiophenacetic acid tert.-butyl ester.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3](C(OCC)=O)[CH2:2]1.[N:12]1[S:13][N:14]=[C:15]2[C:20]([CH:21]=O)=[CH:19][CH:18]=[CH:17][C:16]=12.[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1>>[N:12]1[S:13][N:14]=[C:15]2[C:20]([CH:21]3[C:3]([C:2]#[N:1])=[C:9]([CH:9]4[CH2:3][CH2:2][NH:1][CH2:11][CH2:10]4)[NH:23][C:24]4=[N:25][NH:26][CH:27]=[C:28]34)=[CH:19][CH:18]=[CH:17][C:16]=12
Reactant: CCOC(=O)C1CCCNC1
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc2nsnc12
Product: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccc2nsnc12

Procedure:
The title compound was prepared from ethyl nipecotate, 2,1,3-benzothiadiazol-4-aldehyde and 3-aminopyrazole in the same manner as in Examples 1001 and 1002.