Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:13][N:12]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:11](=[O:21])[C@@H:10]([NH:22][C:23](=[O:42])[C@@H:24]([C@H:27]2[C@H:32]([OH:33])[C@@H:31](/[CH:34]=[CH:35]/[C:36]([CH3:39])([CH3:38])[CH3:37])[O:30][C:29]([CH3:41])([CH3:40])[O:28]2)[O:25][CH3:26])[CH2:9][CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:37][C:36]([CH3:39])([CH3:38])/[CH:35]=[CH:34]/[C@H:31]1[O:30][C:29]([CH3:40])([CH3:41])[O:28][C@@H:27]([C@@H:24]([O:25][CH3:26])[C:23]([NH:22][C@H:10]2[CH2:9][CH2:8][C@@H:7]([OH:6])[CH2:13][N:12]([CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[C:11]2=[O:21])=[O:42])[C@@H:32]1[OH:33]
Reactant: CO[C@@H](C(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN(Cc2cccnc2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CO[C@@H](C(=O)N[C@H]1CC[C@@H](O)CN(Cc2cccnc2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of (R)-N-[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide (1.2 g, 1.9 mmol) at room temperature is added tetrabutylammonium fluoride (5.68 mL, 1 M THF, 5.68 mmol). After 2 h, the solution is evaporated and chromatographed on silica (95% CH2Cl2/5% CH3OH) to give 0.74 g (75.2%) of (R)-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-N-((3S,6R)-6-hydroxy-2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl)-2-methoxy-acetamide as a white solid. 1H NMR 300 MHz δ 8.52(m, 2H), 7.69 (m, 1H), 7.29 (m, 1H), 5.77 (d, 1H), 5.54(dd, 1H), 4.69 (m, 2H), 4.29 (m, 2H), 4.10 (m, 2H), 3.92 (d, 1H), 3.54 (m, 2H), 3.50 (s, 3H), 3.33 (m,2H), 2.15 (m, 1H), 2.00 (m, 1H), 1.90 (m, 1H), 1.67 (m, 3H), 1.46 (m, 4H), 1.04 (s, 9H), 1.00 (t, 2H); MS (ESI) 520.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:20]=[C:19]([C:21]([O:23]CC)=O)[NH:18][N:17]=2)[CH:11]=1.[NH3:28]>>[F:27][C:2]([F:26])([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:20]=[C:19]([C:21]([NH2:28])=[O:23])[NH:18][N:17]=2)[CH:11]=1
Reactant: N
Reactant: CCOC(=O)c1cc(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n[nH]1
Product: NC(=O)c1cc(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n[nH]1
Yield: 74 %

Procedure:
The pyrazole ester (47 mg, 0.1 mmol) from Step 2 was treated with ammonia gas in a sealed tube as described in Step 2 of EXAMPLE 140 to provide the titled compound, after purification by reverse phase HPLC (acetonitrile/water system) (gradient: 40% to 100% acetonitrile over 11 minutes) in 74% yield (0.036 g, retention time 6.57 minutes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:15]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH2:13][N:23]3[CH2:22][CH2:21][N:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[CH2:25][CH2:24]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1nnn(-c2cccc(Cl)c2)n1
Reactant: CCOC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(Cc2nnn(-c3cccc(Cl)c3)n2)CC1
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-(3-Chloro-phenyl)-2H-tetrazole-5-carbaldehyde (22.3 mg, 0.107 mmol) was dissolved in 1,2-dichloroethane under argon and ethyl-1-piperazine carboxylate (16.4 uL, 0.112 mmol) was added followed by sodium triacetoxy borohydride (31.8 mg, 0.150 mmol). The reaction was allowed to stir overnight. Ethyl acetate was added and the solution was washed with sodium bicarbonate (sat.), brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using 45% EtOAc/Hexanes and 100% EtOAc to yield the title compound as a white solid (17.4 mg, 46%). 1H NMR (CDCl3) δ (ppm): 8.190 (s, 1H); 8.070 (m, 1H); 7.469 (m, 2H); 4.139 (q, 2H); 3.983 (s, 2H); 3.541 (m, 4H); 2.604 (m, 4H); 1.263 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](O)[N:7]=1)=[O:5])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1.O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([SH:22])[N:7]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1cccc(O)n1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(S)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 119.4 %

Procedure:
6-Hydroxy-pyridine-2-carboxylic acid ethyl ester (1.8 g, 10.7 mmol) was dissolved in THF (50 mL), and Lawesson's reagent (2.18 g, 5.35 mmol) was added thereto. The mixture was stirred at room temperature for 24 hours. After the termination of the reaction, the reactant was added with water and then extracted with DCM. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure and then separated by column chromatography to obtain the title compound (1.17 g, 59%).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:29]>C(Cl)Cl>[Cl:29][C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Reaction time: 2 h

Procedure:
Slurry 7-hydroxy-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a] pyrimidine in 10 mL POCl3 and reflux at 130° C. under N2. After 2 h, monitoring by TLC (alcohol Rf=0.5, chloride Rf=1.0; EtOAc as eluent), quench the reaction carefully at ambient temperature by diluting with 50 mL CH2Cl2 and pouring slowlyj into non-stirring saturated NaHCO3. Adjust stirring speed to control rate of quenching of residual POCl3 and stir until gas evolution ceases. Separate the layers and extract the aqueous layer with CH2Cl2 (2×50 mL). Pool the organic layers and dry over Na2SO4. Filter and evaporate to yellow oil, which is used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)=[C:11]=[O:12]>C(Cl)Cl>[CH2:20]([O:19][C:17](=[O:18])[C:16]1[CH:22]=[CH:23][C:13]([NH:10][C:11]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][C:4]=2[F:9])=[O:12])=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: Nc1ccc(Br)cc1F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)Nc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (0.5 g, 0.0026 mol) and TEA (0.38 mL, 0.0026 mol) in DCM (15 mL) was added ethyl 4-isocyanatobenzoate (0.503 g, 0.0026 mol). The reaction mixture was stirred at room temperature for 3 h. The white solid was obtained and was filtered and dried to afford the title compound [0.7 g, 70%]; LC-MS (ESI): Calculated mass: 380.0; Observed mass: 381.0 [M+H]+ (RT: 1.78 min).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:12][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccc(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cccc(CBr)c1
Temperature: 25 °C
Yield: 20.6 %

Procedure:
To a mixture of m-tolylacetic acid ethyl ester (3.0 g, 16.8 mmol) and N-bromosuccinimide (3.0 g, 16.8 mmol) was added carbon tetrachloride (45 mL), followed by benzoyl peroxide (5 mg), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, eluent 5:95 to 2:3 EtOAc/hexanes) afforded ethyl (3-bromomethylphenyl)acetate as an off-white solid (0.89 g, 21%): 1H NMR (300 MHz, CDCl3) δ 7.32-7.21 (m, 4H), 4.48 (s, 2H), 4.16 (q, J=6 Hz, 2H), 3.63, (s, 2H), 1.27 (t, J=6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:16])[O:9][C:10]([C:12]([F:15])([F:14])[F:13])=[N:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)[CH:20]=[CH:21][CH3:22])C>>[F:13][C:12]([F:15])([F:14])[C:10]1[C:21]([CH3:22])=[CH:20][C:5]2[C:6](=[C:7]([C:8]([OH:9])=[O:16])[C:2]([Cl:1])=[CH:3][CH:4]=2)[N:11]=1
Reactant: O=c1oc(C(F)(F)F)nc2cccc(Cl)c12
Reactant: CC=CN(CC)CC
Product: Cc1cc2ccc(Cl)c(C(=O)O)c2nc1C(F)(F)F
Yield: 41 %

Procedure:
2-trifluoromethyl-3-methyl-7-chloroquinoline-8-carboxylic acid of melting point 186°-188° C. is prepared, in a yield of 41%, from 5-chloro-2-trifluoromethyl-3,1-benzoxazin-4-one and 1-diethylaminoprop-1-ene, using a method similar to that described in Example 3.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]([CH3:32])([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)[CH3:9])(=O)=O.[C-:33]#[N:34].[K+]>CN(C=O)C.O>[CH3:32][C:8]([N:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:22]=[CH:23][C:16]=23)[CH:12]=[N:11]1)([CH3:9])[CH2:7][CH2:6][C:33]#[N:34]
Reactant: [C-]#N
Reactant: CC(C)(CCOS(C)(=O)=O)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CCC#N)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 169.2 %

Procedure:
A mixture of 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butyl methanesulfonate (42 mg, 0.000088 mol) and potassium cyanide (46 mg, 0.000702 mol) in DMF (1 mL) was heated in the microwave reactor for 30 min at 125° C. followed by additional 30 min at 135° C. The mixture was then diluted with water, and the product was extracted with three portions of MTBE. The combined extracts were dried over sodium sulfate, filtered and concentrated to give 61 mg of crude 4-methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo-[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile, which was used without further purification. MS(ES): 410 (M+1).
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[CH:8]=1)[C:2]#N.[CH2:26](I)C>>[CH3:26][N:5]1[CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:11]=[C:12]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:13]([OH:20])=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[CH:15]=2)[CH:8]=[C:4]1[S:1][CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)c2c[nH]c(SC#N)c2)cc(C(C)(C)C)c1O
Reactant: CCI
Product: CSc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1C

Procedure:
Similarly, by following the procedure of part A above and substituting N-methyl-2-thiocyano-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole for 2-thiocyano-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole, and substituting methyl iodide for ethyl iodide, there is obtained N-methyl-2-methylthio-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole [mp 173°-175° C.; 1H nmr: 1.50s (18H), 2.3s (3H), 3.73s (3H), 5.6s (OH), 6.81m (1H), 7.38m (1H), 7.76s (2H)].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]2[C:18]3[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:22])[CH2:3][CH2:2]1.[H][H]>[Pd].C(O)C>[NH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]([CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)[C:10](=[O:22])[CH2:11][CH2:12]2
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CCC(=O)N2CCN1CCOCC1
Yield: 96.5 %

Procedure:
A suspension of compound 2 (0.9211 g, 3.017 mmol) and palladium on carbon (10% wt, 0.092 g) in ethanol (10 mL) was stirred and fitted with a hydrogen balloon overnight. The suspension was filtered through a pad of celite and was rinsed with methanol (100 mL). The crude product was subject to flash chromatography on silica gel 2.5% 2M NH3 methanol/CH2Cl2, which resulted in a light brown solid, compound 3 (0.802 g, 96%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:39])[C:29]([O:31]C)=[O:30]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:28]([C:29]([OH:31])=[O:30])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])=[CH:13][CH:12]=2)[C:8]([S:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)C(Br)c1ccccc1Cl
Reactant: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(O)cc1
Product: CCCCc1nnc(SCc2ccc(Cl)cc2)n1Cc1ccc(OC(C(=O)O)c2ccccc2Cl)cc1
Yield: 75 %

Procedure:
Reaction of 3-butyl-5-(4-chlorobenzylthio)-4-(4-hydroxybenzyl)-4H-1,2,4-triazole (from Example 5, Step A) with methyl 2-bromo-2-(2-chlorophenyl)acetate, from Step A, according to the procedure of Example 5, Step B, provided a 75% yield of the title compound as a glass; homogeneous by TLC in 97:3 C2Cl2 -MeOH.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:5]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])#[N:16]>>[C:15]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[N:4]1[CH:3]=[N:2][N:1]=[CH:5]1)=[O:21])#[N:16]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: Oc1ccc(CNn2cnnc2)cc1
Product: N#Cc1cccc(C(=O)N(Cc2ccc(O)cc2)n2cnnc2)c1
Yield: 15.3 %

Procedure:
The procedure of Preparation Example 34 was repeated, except that 101 mg of 4-[N-(1,2,4-triazol-4-yl)aminomethyl]phenol was used in place of 4-methoxybenzylamine, and 105 mg of 3-cyanobenzoyl chloride was used in place of 4-cyanobenzoyl chloride. The resulting crude product was purified by TLC (using a 10:1 mixture of chloroform and methanol as the developing solvent) to obtain 26 mg of 3-cyano-N-(4-hydroxybenzyl)-N-(1,2,4-triazol-4-yl)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9](Br)=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[CH3:29][CH:30]([OH:33])[C:31]#[CH:32]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I.N1CCCCC1>[CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([C:32]#[C:31][CH:30]([OH:33])[CH3:29])=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2
Reactant: C#CC(C)O
Reactant: COc1cnc(Br)c2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: N#Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cnc(C#CC(C)O)c2[nH]ccc12
Temperature: 80 °C
Yield: 105.1 %

Procedure:
To a mixture of 4-methoxy-7-bromo-6-azaindole (0.200 g, 0.88 mmol), PdCl2(PhCN)2 (0.017 g, 0.044 mmol), tri-2-furylphosphine (0.0410 g, 0.176 mmol) and CuI (0.017 g, 0.088 mmol) was added piperidine (10 mL), followed by 3-butyn-2-ol (0.09 mL, 1.15 mmol). The mixture was heated at 80° C. for 6 h and then the solvent was removed in vacuo. The residue was partitioned with EtOAc-H2O and then the aqueous phase was separated and re-extracted with EtOAc (×2). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated to afford the title compound (0.200 g, 95%) as a brown solid which was of sufficient purity for use in the following step:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([C:14]([F:17])([F:16])[F:15])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[C:21]([Cu])#[N:22].Cl>CN1C(=O)CCC1>[N+:18]([C:3]1[CH:4]=[C:5]([C:14]([F:17])([F:16])[F:15])[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:7][C:2]=1[C:21]#[N:22])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(OCC(F)(F)F)cc1Br
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 84.6 %

Procedure:
A mixture of 1-bromo-2-nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzene from step 2 (30.54 g, 83.0 mmol) and CuCN (7.80 g, 87.1 mmol) in NMP (83 mL) was heated to 150° C. for 30 min. Cooled to 23° C., poured into 1 N HCl, extracted with EtOAc, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a dark brown oil (33.9 g). Silica gel column chromatography with heptane/EtOAc 9:1→4:1 gave the title compound as a yellow solid (22.05 g, 85%). MS (EI) 314 [M].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1C=N[N:12]=[N:11]1>>[I:1][C:2]1[CH:3]=[C:4]([C:5]2[N:10]=[N:11][NH:12][N:6]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(I)c1
Reactant: c1nnn[nH]1
Product: Ic1cccc(-c2nn[nH]n2)c1

Procedure:
The 3-iodobenzonitrile (3.6 g, 16.6 mmol) was converted to the corresponding tetrazole (4.1 g, 91%) utilizing reaction conditions previously described in Step (a) of example 1. CI-MS: C7H51N2 [M+1] 273.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([C:16]([O:18]C)=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.[Li+].[OH-]>CO>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][C:4]([CH2:3][O:2][CH3:1])([C:16]([OH:18])=[O:17])[CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCC1(C(=O)O)CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared according to general procedure B described in connection with Scheme 2. 1-tert-Butyl 3-methyl 3-(methoxymethyl)pyrrolidine-1,3-dicarboxylate (4.5 g, 16.5 mmol) was dissolved in 30 mL of MeOH and a solution LiOH (0.79 g, 33 mmol) in 20 mL was added. The reaction mixture was microwaved at 130° C. for 25 min in 5 vials. The methanol was evaporated and the residue was acidified to pH 1-2 with KHSO4 solid. The acid was extracted with EtOAc (3×50 mL). The combined organic fractions were washed with 1N KHSO4 and with brine and then dried over Na2SO4. The solvent was evaporated to give 7.09 g of the desired acid (91% crude yield). 1H NMR (400 MHz, CDCl3): δ 10.70 (bs, 1H), 3.76 (d, 1H), 3.62-3.41 (m, 5H), 3.35 (s, 3H), 2.34-2.25 (m, 1H), 1.98-1.93 (m, 1H), 1.45 (s, 9H); MS (ESI) m/z: Calculated for C12H21NO5: 259.1. found: 260 (M+1)+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=1[O:35][CH3:36])(=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl>O1CCCC1>[CH2:37]([N:20]1[C:21]2[C:17](=[CH:16][C:15]([NH:14][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:23][CH:22]=2)[C:18]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][C:26]=2[O:35][CH3:36])=[CH:19]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCC(=O)Nc1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCC(=O)Nc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2Cc1ccccc1
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
Potassium t-butoxide (0.04 g.) was added to a stirred solution of methyl 4-(5-hexanamidoindol-3-ylmethyl)-3-methoxybenzoate (0.15 g.) in dry tetrahydrofuran (5 ml.), under an atmosphere of nitrogen. The resulting dark-green mixture was stirred for 30 minutes. Benzyl bromide (0.062 g.) was added, causing the color to change to light brown. After 1 hour, the mixture was poured into 1M hydrochloric acid (20 ml.). This mixture was extracted with ethyl acetate (2×25 ml.). The combined extracts were dried (MgSO4) and evaporated. The brown oil obtained was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound (0.04 g, 17%) as an oil; NMR: 0.86(t,3H, CH2.CH3), 1.27(m,4H, CH2.CH2.CH3), 1.57(m,2H, CH2.CH2.CON), 2.24(t,2H, CH2.CH2.CON), 3.82(s,3H, CO.OCH3), 3.91(s,3H, OCH3), 3.99(s,2H, CH2.Ar), 5.32 (s,2H, NCH2Ph), 7.21(m,10H), 7.44(m,2H), 7.75(d, 1H), 9.64(s,1H, NH).
Reaction SMILES: [CH3:1][C:2]1([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21]N(C)[CH2:19][CH2:18]2)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(O)(=O)/C=C\C(O)=O>>[CH3:1][C:2]1([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH2:21][CH2:22]2)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CN1CCN(CCC2(C)OCCc3c2[nH]c2ccccc32)CC1
Agent: O=C(O)/C=C\C(=O)O
Product: CC1(CCN2CCCC2)OCCc2c1[nH]c1ccccc21

Procedure:
1-methyl-1-[2-(4-methyl-1-piperazinyl)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, nmr (CDCl3) δ1.47 (3H), 2.58 (3H), 3.87 (t, 2H), [m.p. of corresponding maleic acid addition salt (i.e. dimaleate), 208°-210° C.], respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[C:16]2[NH:21][C:20](=[O:22])[C:19](=[CH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:26][N:25]=3)[NH:18][C:17]2=[O:38])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]2[NH:21][C:20](=[O:22])[CH:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:26][N:25]=3)[NH:18][C:17]2=[O:38])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=Cc2ccc(OCc3ccccc3)cn2)c(=O)[nH]c1=Cc1ccc(OCc2ccccc2)cn1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(Cc2ccc(OCc3ccccc3)cn2)C(=O)NC1Cc1ccc(OCc2ccccc2)cn1
Yield: 39.7 %

Procedure:
A suspension of 3,6-di[(5-benzyloxypyridin-2-yl)methylidene]piperazine-2,5-dione (Compound 10; 0.2 g) and excess of zinc powder in a mixture of 10 mL of acetic acid and 10 mL of water was stirred and refluxed for 5-10 minutes and filtered while hot. Water was added to dissolve zinc acetate. The filtrate was concentrated and filtered. The solid thus obtained was collected and washed with water to give 80 mg (40%) of the desired 3,6-di[(5-benzyloxypyridin-2-yl)methyl]piperazine-2,5-dione (Compound 13).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([S:24][CH2:25][C:26]3[C:35]([F:36])=[CH:34][C:29]([O:30][CH2:31][CH2:32][NH2:33])=[CH:28][C:27]=3[F:37])=[N:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][C:4]=1[O:38][CH3:39].[N-:40]([C:43]#[N:44])[C:41]#[N:42]>C(O)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:15]([S:24][CH2:25][C:26]3[C:27]([F:37])=[CH:28][C:29]([O:30][CH2:31][CH2:32][NH:33]/[C:43](/[NH2:44])=[N:40]/[C:41]#[N:42])=[CH:34][C:35]=3[F:36])=[N:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][C:4]=1[O:38][CH3:39]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCN)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: N#C[N-]C#N
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCN/C(N)=N/C#N)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Yield: 57.1 %

Procedure:
To a solution of 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethanamine hydrochloride (100 mg, 0.167 mmol) in isopropylalcohol (5 mL) was added dicyanamide (19.3 mg, 0.217 mmol) and the reaction mixture was heated at reflux for 24 h. Solvent was evaporated in vacuo and the residue was purified by column chromatography (CH2Cl2/MeOH=20:1) to give the title compound (60 mg, 57%) as an ivory solid. 1H NMR (400 MHz, CD3OD) δ 7.22 (s, 1H), 7.17 (d, J=8.2 Hz, 1H), 6.77 (t, J=8.43 Hz, 2H), 6.60-6.42 (m, 5H), 6.25 (dd, J=7.8, 4.7 Hz, 2H), 4.02 (t, J=4.54 Hz, 2H), 3.83 (s, 2H), 3.71 (s, 3H), 3.56 (t, J=4.65 Hz, 2H), 3.51-3.41 (m, 1H), 1.49 (s, 6H), 1.20 (d, J=44.2 Hz, 3H), 0.93-0.80 (m, 1H); MS (EI) m/z 629 (MH+).