Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO.C1COCC1>[Br:12][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)=[O:11]
Reactant: CC(=O)c1ccc(CO)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7.00 g (46.6 mmol) 1-(4-hydroxymethyl-phenyl)-ethanone in 100 mL THF is added 22.5 g (46.6 mmol) tetrabutylammonium-tribromide dissolved in MeOH/THF. The reaction mixture is stirred 1 h at RT and the solvent is evaporated. The residue is dissolved with water and tertbutylmethylether. The organic phase is washed eight times with water. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is elutriated with diisopropylether and the precipitate is collected and dried.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH2:17])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:21](OC1C=CC=CC=1)=[O:22].[OH:30][CH2:31][C:32]1([CH3:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[O:4]1[CH2:5][CH:6]([C:8]2[C:16]3[S:15][C:14]([NH:17][C:21]([N:35]4[CH2:36][CH2:37][C:32]([CH2:31][OH:30])([CH3:38])[CH2:33][CH2:34]4)=[O:22])=[N:13][C:12]=3[C:11]([O:18][CH3:19])=[CH:10][CH:9]=2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: CC1(CO)CCNCC1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1ccc(C2COCCOC2)c2sc(N)nc12
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)N3CCC(C)(CO)CC3)nc12

Procedure:
Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine, phenyl chloroformate and 4-hydroxymethyl-4-methyl-piperidine, the title compound was prepared as light brown powder. MS: m/e=436(M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[O-]CC.[Na+].[C:14](OCC)(=[O:22])/[CH:15]=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(O)C.O.C(O)(=O)C>[Cl:1][C:2]1[C:3]([N:8]2[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][C:14](=[O:22])[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: NNc1ncccc1Cl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 65 °C

Procedure:
To a mixture of 20 g of 3-chloro-2-hydrazinopyridine, 56 ml of sodium ethoxide (a 21% solution in ethanol) and 75 ml of ethanol was added dropwise 27 ml of diethyl maleate. The resulting mixture was heated to reflux for 10 minutes. The reaction mixture was allowed to cool to 65° C., and 15 ml of acetic acid was poured into the mixture. The reaction mixture was allowed to cool to room temperature. After 190 ml of water was poured into the reaction mixture, the mixture was adjusted to pH 2 by an addition of 6N hydrochloric acid and then extracted with methyl tert-butyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and a solid was collected by filtration to obtain 4.28 g of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate of the formula:
Reaction SMILES: [CH3:1][C@@H:2]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[C:4]([O:6]N1C(=O)CCC1=O)=O.[NH2:30][C@H:31]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C>CN(C)C=O>[NH:14]([C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[C@H:3]([C:4]([NH:30][C@H:31]([C:39]([N:41]1[CH2:48][CH2:47][CH2:46][C@H:42]1[C:43]([OH:45])=[O:44])=[O:40])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:6])[C@@H:2]([CH3:1])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29]
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 8 h

Procedure:
20.2 g of Z-Thr(tBu)-OSU, 13.3 g of H-Phe-Pro-OH (monohydrate) and 6.54 ml of triethylamine are dissolved in 80 ml of dimethylformamide, allowed to stand overnight at about 20° C. and then concentrated in a high vacuum until a sticky mass forms. The latter is dissolved in 500 ml of ethyl acetate and washed five times with 200 ml at a time of 5 % strength tartaric acid solution and subsequently with water until neutral. The organic phase is concentrated to dryness and the remaining solid foam is powdered and dried in a high vacuum at 40° C. On twice reprecipitating from ethyl acetatepetroleum ether 13.3 g of amorphous chromatographically pure tripeptide derivative having an unsharp melting range at about 75°- 85° C. are obtained. In a thin layer chromatogram on silica gel Rf115 = 0.68; Rf121A = 0.57.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([NH:14][CH2:15][CH3:16])[CH:6]=1)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][CH2+:37]1SC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[C:40](=[O:41])[C:39](=[C:42]2[N:46]([CH3:47])[C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[S:43]2)[S:38][C:37]1=[N:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH:3][CH2:1][CH3:2])=[O:17])=[CH:6][C:7]=1[NH:14][CH2:15][CH3:16])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(NCC)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNC(=O)c1ccc(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)c(NCC)c1

Procedure:
In a manner similar to Example 30, intermediate N-ethyl-3-ethylamino-4-nitrobenzamide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 7.46–7.54 (3H, m), 7.27–7.38 (4H, m), 7.19 (1H, m), 6.96–7.08 (4H, m), 6.04 (1H, br t), 5.19 (2H, s), 3.76 (3H, s), 3.49 (2H, m), 3.06 (2H, q), 1.25 (3H, t), 1.05 (3H, t); MS(ESI): 544 (MH+).
Reaction SMILES: CN(C=O)C.[CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([S:16]([OH:19])(=O)=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[ClH:22].[CH:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([S:16]([Cl:22])(=[O:19])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: O=S(=O)(O)c1cccc2cnccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: O=S(=O)(Cl)c1cccc2cnccc12
Temperature: 25 °C
Yield: 82.2 %

Procedure:
Anhydrous DMF (1.5 mL) is added dropwise to a stirred suspension of isoquinoline-5-sulfonic acid (28.3 g, 135 mmol) in thionyl chloride (150 mL, 2.06 mole) at ambient temperature under nitrogen. The resultant mixture is heated to reflux for 2.5 hours. After being cooled to ambient temperature, the mixture is concentrated under vacuum to give a yellowish powder. The powder is suspended in dry CH2Cl2 (200 mL), sonicated, filtered and dried at 40° C. under vacuum to give 29.2 g (111 mmol, 82% yield) of the title compound. 1H NMR (TFA-d1): δ8.48 (t, J=7.9 Hz, 1H), 9.13-9.14 (m, 2H), 9.29 (d, J=7.9 Hz, 1H), 9.57 (d, J=7.0 Hz, 1H), 10.26 (s, 1H).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([NH:19]C(=O)C)[CH:18]=1)[CH2:4][CH2:5][CH3:6].[CH3:38][S:39]([Cl:42])(=[O:41])=[O:40].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CCOCC>[ClH:42].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:17]([NH:19][S:39]([CH3:38])(=[O:41])=[O:40])[CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(C)=O)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine (Example 62, 0.2 mmol, 88 mg) in DCM (1.0 mL) at 0° C. was added methanesulfonyl chloride (0.3 mmol, 24 μL) and DIEA (0.3 mmol, 53 μL). And the mixture was stirred at room temperature for 1 hour. It was then condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to afford N-{5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-methanesulfonamide dihydrochloride (72 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([OH:14])=O)[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34].[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:14])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[F:33])[CH2:25][CH2:26]3)[CH:16]=1)[CH2:6][C:5]2([CH3:35])[CH3:34]
Reactant: CS(N)(=O)=O
Reactant: CC1(C)CC(c2cccc(N3CCN(c4ccccc4F)CC3)c2)Nc2c(C(=O)O)cc(F)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(N3CCN(c4ccccc4F)CC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(F)cc21
Yield: 29.8 %

Procedure:
A mixture of 6-fluoro-2-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-(6-fluoro-2-{3-[4-(2-fluoro-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carbonyl)-methanesulfonamide (34.7 mg, 30%) as a light yellow solid: MS (ESI) M+1=555.3.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])[CH3:6].Cl[C:17]1[CH:18]=[CH:19][C:20]2[C:32]3[C:27](=[CH:28][N:29]=[C:30]([NH:33][C:34](=[O:36])[CH3:35])[CH:31]=3)[CH2:26][O:25][C:21]=2[C:22]=1[O:23][CH3:24]>>[C:34]([NH:33][C:30]1[CH:31]=[C:32]2[C:20]3[CH:19]=[CH:18][C:17]([O:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:4][CH:5]([CH3:7])[CH3:6])=[C:22]([O:23][CH3:24])[C:21]=3[O:25][CH2:26][C:27]2=[CH:28][N:29]=1)(=[O:36])[CH3:35]
Reactant: COc1c(Cl)ccc2c1OCc1cnc(NC(C)=O)cc1-2
Reactant: CC(C)C[C@@H](CO)NC(=O)OC(C)(C)C
Product: COc1c(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc2c1OCc1cnc(NC(C)=O)cc1-2
Yield: 60 %

Procedure:
Prepared as described in Example 18, Part H using (S)-tert-butyl (1-hydroxy-4-methylpentan-2-yl)carbamate and N-(8-chloro-7-methoxy-5H-chromeno[3,4-c]pyridin-2-yl)acetamide to afford (S)-tert-butyl (1-((2-acetamido-7-methoxy-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (112 mg, 0.089 mmol, 60% yield) as a brown oil. LCMS (ESI) m/e 486.2 [(M+H)+, calcd for C26H36N3O6 486.2]; LC/MS retention time (Method F): tR=0.91 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C1COCC1.CC([O-])(C)C.[Li+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([NH:43][C:39]1[S:38][CH:42]=[CH:41][N:40]=1)(=[O:25])=[O:24])=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(C3CCCN3Cc3ccccc3)cccc2c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 87.5 %

Procedure:
A flask was charged with perfluorophenyl 5-(1-benzylpyrrolidin-2-yl)naphthalene-2-sulfonate (Intermediate LL, 21.5 mg, 0.040 mmol), thiazol-2-amine (4.84 mg, 0.048 mmol), and THF (403 μl) to give a clear, colorless solution. The flask was cooled in an dry ice-acetone bath for 5 min, then lithium 2-methylpropan-2-olate (1M in hexane) (89 μl, 0.089 mmol) was added dropwise. The resulting mixture was stirred for 1 min, then the flask was lowered into an ice-bath. After 1 h, the mixture was warmed to room temperature then was loaded directly onto a 5-g silica gel loading column with the aid of DCM. The column was dried under vacuum, then eluted onto a prequilibrated 12-g column with 0 to 10% MeOH/DCM to give 5-(1-benzylpyrrolidin-2-yl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (15.85 mg, 0.035 mmol, 87% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.97-12.23 (m, 1H), 8.51 (d, J=9.1 Hz, 1H), 8.46 (d, J=1.9 Hz, 1H), 8.09-7.96 (m, 2H), 7.83 (dd, J=2.1, 9.0 Hz, 1H), 7.69-7.61 (m, 1H), 7.29 (d, J=4.4 Hz, 4H), 7.27-7.24 (m, 1H), 7.24-7.20 (m, 1H), 6.83 (d, J=4.6 Hz, 1H), 4.16 (t, J=8.2 Hz, 1H), 3.78 (d, J=13.2 Hz, 1H), 3.15 (d, J=13.2 Hz, 1H), 3.07 (td, J=4.6, 9.1 Hz, 1H), 2.47-2.38 (m, 1H), 2.30 (q, J=8.6 Hz, 1H), 1.89-1.79 (m, 2H), 1.68-1.57 (m, 1H); m/z (ESI) 450.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.[CH3:26][O:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[CH:35]([NH2:37])[CH2:34][CH2:33]2>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:37][CH:35]2[C:36]4[C:32](=[CH:31][CH:30]=[CH:29][C:28]=4[O:27][CH3:26])[CH2:33][CH2:34]2)=[N:9]3)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: COc1cccc2c1C(N)CC2
Product: COc1cccc2c1C(Nc1ccc3c(NS(=O)(=O)c4ccc(F)cc4)cccc3n1)CC2

Procedure:
The title compound, MS: m/e=464.1 (M+H+), was prepared in accordance with the general method of example 13 from 5-nitro-2-chloroquinoline, 4-fluorobenzenesulfonyl chloride and rac-7-methoxy-indane-1-ylamine.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34](=O)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCC=O
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.00 g, 9.1 mmol) in anhydrous DCE (60 mL) were added hexanal (Aldrich, 1.80 mL, 14.6 mmol) and sodium triacetoxyborohydride (6.17 g, 29.1 mmol). The resulting mixture was stirred at 70° C. overnight. Then the reaction mixture was poured into water (60 mL) and extracted with DCM (2×60 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure to give a yellow oil. Purification by flash chromatography on silicagel (c-Hex/EtOAc (9/1)) gave 4.41 g (92%) of the title compound as a yellow oil. HPLC, Rt: 6.2 min (purity: 100%). LC/MS, M+(ESI): 524.1. 1H NMR (CDCl3) δ: 7.48 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.25 (d, J=3.0 Hz, 1H), 7.20 (d, J=8.3 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H), 6.86 (dd, J=9.0, 3.0 Hz, 1H), 6.79 (d, J=9.0 Hz, 1H), 4.51 (s, 2H), 3.37 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.71 (s, 6H), 1.61 (m, 4H), 1.40-1.25 (m, 8H), 0.94 (t, J=7.3 Hz, 3H), 0.90 (t, J=6.7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.CN(C=O)C.[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20]>CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH2:19][C:18]([F:22])([F:21])[F:17])[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: NCC(F)(F)F
Reactant: Clc1nc(Cl)c2occc2n1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: FC(F)(F)CNc1nc(Cl)nc2ccoc12
Temperature: 120 °C
Yield: 71.4 %

Procedure:
To a flask was added 2,4-dichlorofuro[3,2-d]pyrimidine (0.80 g, 4.23 mmol, ArkPharm) and DMF (3.0 mL). 2,2,2-Trifluoroethanamine (1.05 g, 10.58 mmol, Acros) was added. The mixture was heated in a microwave at about 120° C. for about 15 min. The mixture was diluted with Et2O (100 mL). The mixture was washed with water (3×25 mL). The combined aqueous layer was extracted with Et2O (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was transferred neat and was purified by preparative TLC eluting with 3:1 hexanes/EtOAc to give 2-chloro-N-(2,2,2-trifluoroethyl)furo[3,2-d]pyrimidin-4-amine (0.76 g, 71%): LC/MS (Table 2, Method h) Rt=1.85 min; MS m/z: 252, 254 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6]=1[C:7]1[NH:8][C:9](=[S:12])[NH:10][N:11]=1.Br.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6]=1[C:7]1[NH:11][N:10]=[C:9]([S:12][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: BrCc1ccccn1
Reactant: Cc1cc(-c2n[nH]c(=S)[nH]2)c(C)o1
Agent: Br
Product: Cc1cc(-c2nc(SCc3ccccn3)n[nH]2)c(C)o1
Yield: 70 %

Procedure:
Prepared in a similar manner to example 1 using 5-(2,5-dimethylfuran-3-yl)-2H-1,2,4-triazole-3(4H)-thione (example 7a) and 2-(bromomethyl)pyridine hydrobromide. Yield 70%. 1H NMR (500 MHz, CDCl3): δ 2.27 (s, 3H), 2.59 (s, 3H), 4.32 (s,2H), 6.35 (s, 1H), 7.28-7.29 (d, 1H), 7.35-7.36 (d, 1H), 7.75 (t, 1H) 8.62 (s, 1H). MS(M+H, 287).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C@H:6]([S:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][N:4]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])#[N:2].[N-:41]=[N+:42]=[N-:43].[Na+].[Cl-].[NH4+]>CN(C)C=O>[N+:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:30][C:28]([N:4]2[CH2:5][C@@H:6]([S:8][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:7][C@H:3]2[C:1]2[NH:43][N:42]=[N:41][N:2]=2)=[O:29])=[CH:33][CH:34]=1)([O-:40])=[O:39]
Reactant: N#C[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1c1nnn[nH]1
Yield: 86.2 %

Procedure:
A mixture of (2S,4S)-2-cyano-1-(4-nitrobenzyloxycarbonyl)-4-tritylthiopyrrolidine (2.00 g) and sodium azide (0.30 g) in dimethylformamide (20 ml) was stirred at 110°-120° C. for 9 hours in the presence of ammonium chloride (0.05 g). The mixture was concentrated under reduced pressure to give a residue. The residue was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of acetone and chloroform (10:90, V/V) to give (2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-(1H-tetrazol-5-yl)-4-tritylthiopyrrolidine (1.86 g).
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH2:15][CH2:16][OH:17])[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]=2[CH2:7][CH2:6]1)C.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:31]=[CH:32][C:33]([O:40][C:41]([F:44])([F:43])[F:42])=[C:34]([NH:36][C:37]([NH2:39])=[NH:38])[CH:35]=2)[CH2:26][CH2:25]1.O>CN(C=O)C>[OH:17][CH2:16][CH2:15][N:11]1[C:12]2[C:13]3[N:39]=[C:37]([NH:36][C:34]4[CH:35]=[C:30]([N:27]5[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]5)[CH:31]=[CH:32][C:33]=4[O:40][C:41]([F:44])([F:42])[F:43])[N:38]=[CH:4][C:5]=3[CH2:6][CH2:7][C:8]=2[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]1
Reactant: CN1CCN(c2ccc(OC(F)(F)F)c(NC(=N)N)c2)CC1
Reactant: CCOC(=O)c1nn(CCO)c2c1CCC(=CN(C)C)C2=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CCO)c2c1CCc1cnc(Nc3cc(N4CCN(C)CC4)ccc3OC(F)(F)F)nc1-2
Temperature: 110 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a solution of 2.66 g (8.34 mmol) of ethyl 6-[(dimethylamino)methylene]-7-oxo-1-(2-hydroxy-ethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate in 15 mL of DMF, 2.64 g (8.34 mmol) of N-[5-(4-methyl-piperazin-1-yl)-2-trifluoromethoxy-phenyl]-guanidine was added. The mixture was stirred for 4 h at 110° C. After cooling the mixture was poured into water (100 mL) and stirred for 30 minutes. The precipitate was filtered, washed with water and dried to yield 2.86 g of title compound (61%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl-].C[CH:13]=[N+:14]=[CH:15]C.O.[OH-].[Na+].[CH2:20](Cl)Cl>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:13][N:14]([CH3:15])[CH3:20])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: ClCCl
Reactant: CC=[N+]=CC
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)Cc1c[nH]c2cc(Br)ccc12
Yield: 100 %

Procedure:
To a solution of 6-bromoindole (7.18 g, 36.6 mmol) in CH2Cl2 (140 mL) was added N,N-dimethylmethylene ammonium chloride (5.48 g, 58.6 mmol, 1.60 eq.) in one portion and the resultant mixture was stirred at rt for 2 h under N2. Water (150 mL) and 1M NaOH (62 mL, 62 mmol) were added, and the reaction mixture was extracted with EtOAc (300 mL). The organic layer was washed with aqueous saturated NaCl and dried (MgSO4). The solvent was removed in vacuo to give 9.29 g (100%) of the title compound.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13]([CH3:31])[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.[CH2:33](N1CCC(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)[CH:34](C)[CH3:35].ICC(C)C>>[CH2:31]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)=[O:21])[CH:15]=2)[C:11]([CH:8]2[CH2:7][CH2:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]2)=[CH:12]1)[CH:34]([CH3:35])[CH3:33]
Reactant: CC(C)CN1CC=C(c2cn(C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Reactant: CC(C)CN1CCC(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: CC(C)CI
Agent: Cl
Product: CC(C)CN1CCC(c2cn(CC(C)C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (example 42) the title compound was prepared from [3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 2, free base) and 1-iodo-2-methylpropane (commercially available). MS (m/e): 467.5 (MH+).