Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:10]([CH3:37])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[C:10]([CH3:37])[C:11]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:26]=3)[CH:23]=2)=[O:18])=[C:12]([CH3:14])[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cn(Cc2ccc(-c3ccccc3)cc2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5-{[(1-Biphenyl-4-ylmethyl-1H-[1,2,3]triazole-4-carbonyl)-amino]-methyl}-4,6-dimethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (27 mg, 0.053 mmol), 1 mL TFA and 2 mL DCM was stirred at room temperature for 2 h. The mixture was evaporated in vacuo to yield the final product (TFA salt). 1H-NMR (DMSO-d6, 400 MHz) 13.24 (bs, 1H), 8.87 (t, 1H), 8.70 (s, 1H), 7.65-7.69 (m, 4H), 7.43-7.52 (m, 6H), 7.36-7.40 (t, 1H), 6.62 (s, 1H), 5.70 (s, 2H), 4.43 (d, 2H), 2.52 (s, 3H), 2.40 (s, 3H); LCMS (method A) RtA=1.317 min; [M+H]+=413.0.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:19]([CH:16]1[CH2:18][CH2:17]1)=[O:20]
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Reactant: O=C(Cl)C1CC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and cyclopropanecarbonyl chloride.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[C:20]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=3[F:38])[C:21]([N+:27]([O-])=O)=[C:22]([O:25][CH3:26])[CH:23]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1COCC1.C(=O)([O-])O.[Na+]>O.O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[C:24]2[C:19](=[C:20]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=3[F:38])[C:21]([NH2:27])=[C:22]([O:25][CH3:26])[CH:23]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: COc1cc2c(cnn2C(=O)OC(C)(C)C)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1cc2c(cnn2C(=O)OC(C)(C)C)c(Nc2ccc(I)cc2F)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
A suspension of sodium dithionite (524 mg, 3.48 mmol) and 4-(2-fluoro-4-iodo-phenylamino)-6-methoxy-5-nitro-indazole-1-carboxylic acid tert-butyl ester (434 mg, 0.87 mmol) in water (10 mL) was treated with a 1:1 mixture of THF:dioxane (10 mL). The homogeneous reaction mixture stirred at room temperature for 18 hours. The reaction mixture was basified by the addition of saturated aqueous sodium hydrogen carbonate and then extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow solid (300 mg, 73%). LCMS (Method B) RT 4.16 min, [M+H]+=499 [M−H]−=497.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[O:13][CH:12]([CH2:15][OH:16])[CH2:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][CH2:15][CH:12]2[CH2:11][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[C:14]=3[O:13]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cccc(C3CCCC3)c2O1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(C4CCCC4)c3O2)cc1

Procedure:
Treatment of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (4.08 g, 18.7 mmol) with p-toluenesulfonyl chloride (3.92 g, 21.9 mmol) in anhydrous pyridine (76 mL) generally according to the procedure described for Intermediate 10 gave (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a tan oil. Treatment of the tosylate with sodium azide (4.39 g, 67.57 mmol) generally according to the procedure described for Intermediate 98 afforded 4.1 g of (±)-2-(azidomethyl)-7-cyclopentyl-2,3-dihydro-1-benzofuran as a yellow oil. Treatment of the azide with palladium on carbon (0.41 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 2.5 g (58%) of (±)-(7-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 174° C.; Anal. calcd. for C14H900N2HCl: C, 66.26; H, 7.94; N, 5.52. Found C, 66.13; H, 7.71; N, 5.5.
Reaction SMILES: C([CH:5]1[O:17][CH:6]1[CH2:7][O:8][CH2:9][CH:10]1O[CH:11]1[CH2:12]CCC)CCC.[C:18]1([C:28]2[N:33]=[N:32][N:31]=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][C:35]=3[OH:41])[C:29]=2[C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=[CH:44][CH:43]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C(C)=CC=CC=1>[C:18]1([C:28]2[N:33]=[N:32][N:31]=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH2:5][CH:6]([OH:17])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:36][C:35]=3[OH:41])[C:29]=2[C:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=[CH:44][CH:43]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCCCC1OC1COCC1OC1CCCC
Reactant: Oc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: CCCCOCC(O)COc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.60 g of butyl-2,3-epoxypropyl ether and 0.78 g of ethyl-triphenyl-phosphonium bromide are added to a solution of 20.0 g of the product from Example A6 in 200 ml of xylene. That reaction mixture is heated to boiling for 18 h. 0.5 g of activated carbon is then added to the reaction mixture and the resulting mixture is stirred at 25° C. for 1 h. After filtration of the reaction mixture on Hyflo® (kieselguhr; Fluka 56678), the solvent is removed in vac. Chromatography of the residue on silica gel yields the product of melting point: 118–119° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>CCOC(C)=O>[F:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=1[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3ccccc3F)nc12

Procedure:
1-[2-(2-Fluoro-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-fluorobenzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 20-100% EtOAc in hexanes as eluant gave a brown solid which was washed with 1:1 Et2O/Hexanes to provide 10 mg (12%) of a pale yellow solid. M+H=298.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([O:24]C)=[O:23].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:22]([OH:24])=[O:23]
Reactant: COC(=O)C(Cc1ccccc1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2c(C(Cc3ccccc3)C(=O)O)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 70 °C
Yield: 36.4 %

Procedure:
To a solution of methyl 2-[2-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-3-phenylpropanoate (0.159 g; 0.36 mmol) in methanol (3.6 mL) was added a solution of sodium hydroxide 10 N (0.36 ml) and the mixture was heated at 70° C. for 4 h. After cooling, the reaction mixture was concentrated under reduced pressure and the crude solid was suspended in ethyl acetate and the mixture was acidified with 1N HCl (pH˜2). The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica using a mixture ethyl acetate/heptane (1/1)+0.5% acetic acid as eluent to afford 0.056 g (38%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:15]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: NS(=O)(=O)CSc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: NS(=O)(=O)CS(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 7 h

Procedure:
To a solution of 0.50 g. (0.0018 mol.) of 1-((3,4-dichlorophenyl)thio)methanesulfonamide in 25 ml. of glacial acetic acid is added 0.10 g. of 30% hydrogen peroxide, and the reaction mixture is heated at 65° to 70° C. The progress of the reaction is followed by nuclear magnetic resonance spectroscopy, and over a period of 7 hours an additional 0.37 g. of 30% hydrogen peroxide is added in small incremental amounts. After the 7 hour reaction period, the acetic acid solution is allowed to cool, and the title compound separates as fluffy, white crystals. The crystals are filtered, washed with ether, and dried to give 0.37 g. of 1-((3,4-dichlorophenyl)sulfinyl)methanesulfonamide, m.p. 205°-207° C.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=3)[N:15]=[C:14]([N:23]3[CH2:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26](=[O:34])[CH2:25][CH2:24]3)[N:13]=2)[CH2:10][O:9][CH2:8]1)=O.[OH-].[Na+]>C(O)C.O>[NH2:5][CH2:6][C:7]1([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:22])[CH:20]=3)[N:15]=[C:14]([N:23]3[CH2:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[S:26](=[O:34])[CH2:25][CH2:24]3)[N:13]=2)[CH2:8][O:9][CH2:10]1
Reactant: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NC3(CNC(=O)C(F)(F)F)COC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NC3(CN)COC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
To a stirred of 2,2,2-trifluoro-N-[(3-{[6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4-yl]amino}oxetan-3-yl)methyl]acetamide (70 mg, 0.135 mmol) in ethanol (5 mL) was added an aqueous solution of sodium hydroxide (5 N, 1 mL). After being stirred at room temperature overnight, the resulting mixture was diluted with water (15 mL), and extracted with dichloromethane (15 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford 7 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (s, 1 H), 7.83-7.78 (m, 2 H), 7.71-7.68 (m, 1 H), 7.61-7.54 (m, 3 H), 5.45 (d, 1 H), 5.15 (brs, 1 H), 4.81-4.74 (m, 5 H), 4.51 (brs, 3 H), 3.54 (brs, 2 H), 2.45 (s, 3 H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[C:28](O)(=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=1>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: COc1cccc(C(=O)O)c1
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Agent: Cl
Product: COc1cccc(C(=O)NCc2ccc(C(=N)N)cc2NCC(=O)O)c1

Procedure:
Compound 58d was reacted with m-anisic acid and subsequently hydrogenated according to the procedure described in Example 58, to give example 66. ESI-MS m/e 357.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([O:27]C)=O)[CH3:9].[NH3:29]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][CH:23]=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:25]([NH2:29])=[O:27])[CH3:9]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3ccncc32)cc1OC(C)c1ccccc1Cl
Solvent: CO
Product: CC(Oc1cc(-n2cnc3ccncc32)sc1C(N)=O)c1ccccc1Cl
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 49 mg of the above-synthesized methyl 3-[1-(2-chlorophenyl)ethoxy]-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol was stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture was allowed to cool down to room temperature, then another 5 ml of a saturated solution of ammonia in methanol were added and the procedure was repeated as described above. The solvent was removed under vacuum and the residue was purified by flash chromatography to yield the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([N:22]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][C:24]([CH:33]=O)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:25][C:24]([CH2:33][NH:15][CH2:14][CH2:13][N:10]3[CH2:9][CH2:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: c1ccc(-c2cc(CNCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1
Yield: 78.8 %

Procedure:
Compound 9 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 1,5-diphenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2C(C(=O)NC3C=CC=CC=3)=CN=C(S(C)(=O)=O)N=2)[CH:9]=1)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2nc(S(C)(=O)=O)ncc2C(=O)Nc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(N)c1
Reaction time: 0.5 h
Yield: 180.4 %

Procedure:
To a stirred solution of 7 (0.4 g, 0.9 mmol) in THF (10 mL) was added LAH (1.8 mL, 1.8 mmol) at −78° C. The reaction mixture was allowed to stir at the same temperature for 30 mins after which it was quenched with Na2SO4 solution (2 mL) and extracted with ethyl acetate (10 mL). The ethyl acetate layer was separated and washed with water (2 mL), brine solution (2 mL) and dried over anhydrous Na2SO4. Filtration followed by concentration under reduced pressure offered a residue which was purified by column chromatography (SiO2, 60-120, pet ether/ethyl acetate 7/3) to get 8 (200 mg, 58%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[Cl-].[Cl:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[CH:22]=[N+:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[CH:22]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:1][CH3:2])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCn1c(-c2ccccc2)cc2ccccc21
Reactant: Clc1ccccc1C=[N+]1CCCCC1
Agent: [Cl-]
Product: CCn1c(-c2ccccc2)c(C(c2ccccc2Cl)N2CCCCC2)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-ethyl-2-phenyl-1H-indole and 1-(2-chloro-benzylidene)-piperidinium chloride
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][CH:7]=[CH:8][C:9]=1[NH:10]C(=O)OC(C)(C)C)=[O:4].FC(F)(F)C(O)=O>ClCCl>[NH2:10][C:9]1[CH:8]=[CH:7][O:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)c1occc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1occc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
Tert-butyl 2-(methoxycarbonyl)furan-3-ylcarbamate 33 (1.14 g, 1.0 eq) was dissolved in dichloromethane (8 ml) and treated with trifluoroacetic acid (5 ml). Reaction mixture was stirred at room temperature for 3 h, and was then concentrated. Residue was dissolved in dichloromethane and washed with saturated aq. NaHCO3. The organic layer was dried (Na2SO4) and concentrated Mixture was extracted with ethyl acetate. The combined organic extracts were dried with Na2SO4 and concentrated. The crude reaction mixture was purified by flash chromatography to yield methyl 3-aminofuran-2-carboxylate 34 (574 mg, 86%): MS (Q1) 142 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C:12]23[C:18]([CH3:20])([CH3:19])[C:15]([CH3:21])([CH2:16][CH2:17]2)[C:14](=[O:22])[CH2:13]3)[C:5]([Cl:23])=[CH:4][N:3]=1>[Ni].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:11][C:12]23[C:18]([CH3:19])([CH3:20])[C:15]([CH3:21])([CH2:16][CH2:17]2)[C:14](=[O:22])[CH2:13]3)[C:5]([Cl:23])=[CH:4][N:3]=1
Reactant: CC12CCC(Nc3c(Cl)cnc(N)c3[N+](=O)[O-])(CC1=O)C2(C)C
Agent: [Ni]
Solvent: CO
Product: CC12CCC(Nc3c(Cl)cnc(N)c3N)(CC1=O)C2(C)C
Yield: 100.1 %

Procedure:
4-(2-amino-5-chloro-3-nitropyridin-4-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (9) (1.5 g, 4.43 mmol) was added to a suspension of Raney Nickel (1 g) taken in MeOH (50 ml) and hydrogenated for 2 h when TLC confirmed completion of reaction. The reaction mixture was filtered through a bed of celite and the bed was washed well with MeOH. The filtrate was concentrated to afford the product (1.37 g, 77%) as a light grey solid. NMR: δ (1H, 400 MHz, CD3OD): 0.91 (3H, s), 0.96 (3H, s), 1.13 (3H, s), 1.20-1.35 (1H, m), 1.64-1.80 (2H, m), 2.06-2.18 (1H, m), 2.23 (1H, d, J=18 Hz), 2.61 (1H, dd, J=3.6, 18.0 Hz), 7.20 (1H, s) LCMS: (254 nm): [M+H]+ 309.10 (89.4%)
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:13]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with the ethyl 4-iodobenzoate (10 g, 36 mmol) and THF (45 mL). Solution cooled down to 0° C. Turbo Grignard 1.3 M in THF (30.6 mL, 39.8 mmol) was then added in one portion and the reaction stirred for 30 minutes at 0° C. Pivaloyl chloride (5.35 mL, 43.5 mmol) was then charged in a second flask in THF (10 mL) and the preformed anion transferred via canula to the acyl chloride. The reaction was then slowly warmed to room temperature and stirred overnight. The reaction was quenched with ammonium chloride solution (sat. aq.) and extracted with ethyl acetate (2×), washed with brine (1×), dried over sodium sulfate, filtered and concentrated to provide ethyl 4-pivaloylbenzoate as a crude yellow gum (8.50 g). Used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.30-1.36 (m, 9H) 1.42 (t, J=7.04 Hz, 3H) 4.40 (q, J=7.24 Hz, 2H) 7.61-7.69 (m, 2H) 8.04-8.12 (m, 2H); MS (M): 234.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[N:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:22][C:21]([F:24])([F:23])[C:20]1[C:12]([C:8]2[N:7]=[C:6]3[N:5]=[CH:4][CH:3]=[C:2]([NH:25][C:26]4[CH:31]=[N:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=4)[C:11]3=[N:10][CH:9]=2)=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([NH2:18])=[O:17]
Reactant: Nc1cnc(C(F)(F)F)cn1
Reactant: NC(=O)c1cnc(-c2cnc3c(Cl)ccnc3n2)c(C(F)(F)F)c1
Product: NC(=O)c1cnc(-c2cnc3c(Nc4cnc(C(F)(F)F)cn4)ccnc3n2)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 6-(8-chloropyrido[2,3-b]pyrazin-3-yl)-5-(trifluoromethyl)nicotinamide (70.6 mg, 0.2 mmol) and 2-amino-5-trifluoromethyl-pyrazine (98.4 mg, 0.6 mmol) in a screw cap vial at 140° C. for 20 hours under N2 atmosphere. Purify the reaction mixture by column chromatography using EtOAc to 1% MeOH/EtOAc as eluent to afford the title compound as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.182 (s, 1H), 9.456 (s, 1H), 9.44(s, 1H), 9.074 (d, 1H, J=1.3 Hz), 9.052 (s, 1H), 8.87(d, 1H, J=1.3 Hz), 8.828 (d, 1H, J=2.6 Hz), 8.542 (s, 1H), 7.974 (1, 1H). MS=481.42 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH2:24][CH3:25].Cl>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH3:25])[CH2:11][CH2:10]1
Reactant: CCCI
Reactant: OC1(c2cccc(Cl)c2Cl)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to Example 2: 4-(2,3-dichlorophenyl)piperidin-4-ol (0.43 g, 1.75 mmol), acetonitrile (20 ml), potassium carbonate (0.59 g, 4.3 mmol), iodopropane (0.15 ml, 1.9 mmol). Yield: 0.29 g, 57%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 181-183° C. MS m/z (relative intensity, 70 eV) 289 (M+, 2), 287 (M+, 4), 260 (64), 258 (bp) 240 (33).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[C:16](O)(=O)C.C(O)=O.C(OC(=O)C)(=O)C>O1CCCC1>[CH3:16][NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[C:10]([O:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CC(=O)O
Reactant: COc1cc(CCN)cc(OC)c1OC
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: CNCCc1cc(OC)c(OC)c(OC)c1
Reaction time: 3 h

Procedure:
A solution of the crude oil of 3,4,5-trimethoxy-phenethylamine in tetrahydrofuran (30 ml) was added to a mixed acid anhydride of acetic acid and formic acid, which had been synthesized by adding 98% formic acid (6.2 ml) to acetic anhydride (12.5 ml) under ice-cooling and reacting at 60° C. for 3 hours, under room temperature and stirred for 17 hours. The reaction mixture was concentrated under reduced pressure and tetrahydrofuran (40 ml) and borane-methyl sulfide complex (12 ml) were added to the residue under ice-cooling and stirring. The reaction mixture was heated and refluxed for 17 hours. After the reaction mixture was cooled, methanol was added to stop the reaction and concentrated under reduced pressure. A hydrogen chloride-methanol solution was added to the residue and heated and refluxed for 3 hours. The solvent was distilled out under reduced pressure and the residue was dissolved in 2N hydrochloric acid and washed with dichloromethane. The aqueous layer was made basic with sodium hydroxide and the released oil material was extracted with dichloromethane. After washed with water and dried over potassium carbonate, the solvent was distilled out under reduced pressure to yield N-methyl-3,4,5-trimethoxyphenethylamine (1.61 g) as a colorless oil.