Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11]C(C2C=CC(C3C=CC(F)=CC=3)=CC=2)=O)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[C:30]([O:34][C:35](=[O:38])[NH:36][NH2:37])([CH3:33])([CH3:32])[CH3:31]>C(O)C.C(OCC)(=O)C>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:37][NH:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])=[C:3]([N+:27]([O-:29])=[O:28])[CH:4]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A solution of Example 1D (212 mg, 0.49 mmol) and tert-butylcarbazate (976 mg, 2.3 mmol) in ethanol (5 mL) was heated to reflux, stirred for 16 hours, diluted with ethyl acetate (50 mL), washed with water and brine, dried (MgSO4), filtered, and concentrated The concentrate was purified by flash column chromatography on silica gel with 1:0.5:98. 5/methanol:acetic acid:dichloromethane, then 2:0.5:97.5/methanol:acetic acid:dichloromethane to provide the desired product. MS (ESI(−)) m/e 331 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][NH:3]1.[CH3:24][S-:25].[Na+].O>CN1CCCC1=O>[O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[C:18]([S:25][CH3:24])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: O=c1[nH]cccc1CN1CCC(CCc2cccnc2Cl)CC1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CSc1ncccc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 11.5 %

Procedure:
168 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-(2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in Example 117 and 354 mg of sodium thiomethoxide were suspended in 5 ml of 1-methyl-2-pyrrolidinone, and the mixture was stirred at 150° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (methanol:ethyl acetate=1:19), to give 20 mg of the title compound as colorless crystals.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
To a cooled (0° C.) solution of cyclohexylamine (2.31 mL, 20 mmol) in DCM (20 mL) was added triethylamine (5.7 mL, 40 mmol) followed by chloro acetylchloride (1.61 mL, 20 mmol). The reaction was warmed to RT and stirred for 3 h. The reaction mixture was concentrated, redissolved in EtOAc (20 mL) and washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to yield crude product which was further purified by flash column chromatography using 7:3 Pet. Ether:EtOAc as the eluant. 1.8 g of pure 2-chloro-N-cyclohexylacetamide was isolated.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@H:7]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:8][CH2:9][CH:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C)C=O>[C:14]([O:13][C:11](=[O:12])[C@@H:10]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:9][CH2:8][C:7]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:36])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:42][CH:41]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(CC[C@@H](C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 157.2 %

Procedure:
1.00 g (1.97 mmol) (2S)-2-Benzyloxycarbonyl-5-tert.-butoxycarbonylamino-hexane dioic acid di-tert.-butyl ester were dissolved in 25 mL dimethylformamide, 87 mg (2.2 mmol) NaH (60% in mineral oil) added and stirred at room temperature for 30 min. 601 mg (2.17 mmol) 4-benzloxy benzyl bromide 1 mL dimethylformamide were added and the reaction stirred for 1 h at 60° C. The solvent was removed i. vac. And the residue partitioned between ethyl acetate and brine. The organic phase was adsorbed on Isolute and directly chromatographed on a Biotage Isolera system (SNAP 100 g, A=n-Hexane, B=ethyl acetate. A 3 CV, A to 25% B in 10 CV, 4.7 CV 25% B, 50 mL/min, Fr. a 18 mL). Fractions 68 to 75 were collected to give 1.09 g (79%) of (2S,5SR)-5-Benzyloxycarbonyl-6-(4-benzyloxy-phenyl)-5-tert.-butoxycarbonyl-2-tert.-butoxycarbonylamino-hexanoic acid tert.-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:21])=[C:4]2[C:10](=[CH:11][CH:12]=1)[CH:9]1[CH2:13][CH2:14][CH:5]2[CH2:6][N:7]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:8]1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:40])=[CH:25][N:24]=1.Cl.O1CCOCC1>CC(O)C>[Br:21][C:3]1[C:2]([NH:1][C:23]2[N:28]=[C:27]([NH:29][C:30]3[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=3[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:40])=[CH:25][N:24]=2)=[CH:12][CH:11]=[C:10]2[C:4]=1[CH:5]1[CH2:14][CH2:13][CH:9]2[CH2:8][N:7]([C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:6]1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1Br)C1CCC2CN(C(=O)C(F)(F)F)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2Br)C2CCC3CN(C(=O)C(F)(F)F)C2)ncc1Cl
Temperature: 120 °C
Yield: 19.2 %

Procedure:
1-(4-Amino-3-bromo-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-10-yl)-2,2,2-trifluoro-ethanone (76 mg, 0.209 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (68.4 mg, 0.230 mmol, 1.1 eq) were dissolved in IPA (2 mL). 4.0 M HCl in dioxane (57.5 μL, 0.230 mmol, 1.1 eq) was added and the reaction was heated at 120° C. in a microwave for 4 hours. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain 2-{2-[3-bromo-10-(2,2,2-trifluoro-acetyl)-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino]-5-chloro-pyrimidin-4-ylamino}-N-methyl-benzamide as a pale yellow foam (24.99 mg, 19%). LCMS (m/e) 623 (M+1); 1H-NMR (CDCl3, 400 MHz) major rotomer δ 11.03 (s, 1H), 8.55 (d, 1H, J=8.4 Hz), 8.26 (s, 1H), 8.14 (s, 1H), 7.55-7.26 (m, 4H), 7.15-7.05 (m, 1H), 6.30-6.20 (m, 1H), 4.23 (dd, 1H, J=5.3 and 13.5 Hz), 3.95-3.83 (m, 1H), 3.47-3.38 (m, 1H), 3.30-3.20 (m, 1H), 3.20-3.09 (m, 1H), 3.04 (s, 3H), 3.06-2.97 (m, 1H), 2.10-1.97 (m, 2H), 1.87-1.70 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([CH3:38])=[CH:32]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([CH3:38])=[CH:32]2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCN(CCS(C)(=O)=O)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
A solution of 4-chloro-6-methoxy-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (115 mg, 0.28 mmol), (prepared as described for the starting material in Example 12), 5-hydroxy-2-methylindole (50 mg, 0.33 mmol) and potassium carbonate (60 mg, 0.42 mmol) in DMF (1.5 ml) was stirred at 100° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by methanol/ethyl acetate/methylene chloride (1/4/5 and 1/0/9) to give 6-methoxy-4-(2-methylindol-5-yloxy)-7-((1-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)quinazoline (60 mg, 41%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:21])=[C:6]([Br:20])[CH:7]=[C:8]2[C:12]=1[C@H:11]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:2]=C.[O:22]=[O+][O-].[BH4-].[Na+].Cl>CO>[Br:20][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([CH2:1][CH2:2][OH:22])[C:5]=1[OH:21])[C@H:11]([CH2:13][CH2:14][NH:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:10][CH2:9]2
Reactant: O=[O+][O-]
Reactant: C=CCc1c(O)c(Br)cc2c1[C@H](CCNC(=O)CC)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)NCC[C@@H]1CCc2cc(Br)c(O)c(CCO)c21
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of (S)-N-[2-(7-allyl-5-bromo-6-hydroxyindan-1-yl)ethyl]propionamide (588 mg, 1.67 mmol.) in methanol (30 mL) was cooled to about -70° C., to which was introduced ozone for 5 minutes. After confirming the disappearance of the starting material, an excess amount of powdery sodium borohydride (510 mg, 13.4 mmol.) was added to reaction mixture at about -70° C. to decompose ozonide. The reaction mixture was warmed to room temperature, which was neutralized with dilute hydrochloric acid, followed by extracting the organic matter with a mixture of ethyl acetate:butanol=1:1. The extract solution was dried over anhydrous magnesium sulfate, from which the solvent was distilled off under reduced pressure. The residue was then washed with diethyl ether to afford the title compound (yield 0.59 g, 99%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:37]=[CH:36][C:27]([CH2:28][O:29][C:30](=[O:35])[NH:31][CH:32]([CH3:34])[CH3:33])=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:24]3[CH:37]=[CH:36][C:27]([CH2:28][O:29][C:30](=[O:35])[NH:31][CH:32]([CH3:33])[CH3:34])=[CH:26][CH:25]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)NC(=O)OCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCNc1ccc2ncc(-c3ccc(COC(=O)NC(C)C)cc3)n2n1
Temperature: 140 °C
Yield: 138 %

Procedure:
A mixture of (3-bromo-imidazo[1,2-b]pyridazin-6-yl)-butyl-amine (50 mg, 0.19 mmol), isopropyl-carbamic acid 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (from part A, ˜0.5 mmol), K2CO3 (77 mg, 0.56 mmol) and dichlorobis(triphenylphosphine)palladium(II) (6.5 mg, 0.01 mmol) in MeCN/water (2 ml/0.5 ml) was heated in a microwave at 140° C. for 10 min. The reaction was repeated with another half of the bronic ester from Part A. The two reactions were combined for purification. The water layer was removed and the reaction mixture was diluted with MeCN (3 ml) and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (100 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (t, J=7.39 Hz, 3H) 1.19 (d, J=6.62 Hz, 6H) 1.43-1.52 (m, 2H) 1.66-1.73 (m, 2H) 3.41 (td, J=7.06, 5.73 Hz, 2H) 3.87 (d, J=6.84 Hz, 1H) 4.49 (t, J=5.29 Hz, 1H) 5.14 (m, 1H) 6.45 (d, J=9.70 Hz, 1H) 7.46 (d, J=8.16 Hz, 2H) 7.66 (d, J=9.48 Hz, 1H) 7.81 (s, 1H) 8.14 (d, J=8.38 Hz, 2H). LRMS (ESI) m/z 382.2 [(M+H)]+, calc'd for C21H27N5O2: 381.48.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[OH:23])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[O:23][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][F:30])[CH:11]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: FCCCCCBr
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(OCCCCCF)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-hydroxyphenyl}-1H-1,2,3-triazole-4-carboxamide (0.16 g) obtained in Example 139 in DMF (5 ml) were added 1-bromo-5-fluoropentane (0.11 g) and potassium carbonate (0.07 g), and the mixture was stirred at 50° C. overnight. The reaction mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The deposited precipitate was collected by filtration, washed with water, and recrystallized from ethanol-water to give the title compound as a pale-brown powder (0.12 g, 60%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C1C(=O)N([Cl:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:19][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Nc1ccc2ccccc2c1Cl
Temperature: 49 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
To a CCl4 (600 mL) solution of 2-naphthylamine (10 g) at 49° C. was added NCS (9.51 g, 1.02 eq) in portions. The mixture was stirred at 49° C. for 1.5 h then concentrated to dryness to give 1-chloro-2-naphthylamine (11.94 g, 96%) as a dark solid. MS Found: (M+H)+=178.
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].ClCCCl.[Cl:16][S:17](O)(=[O:19])=[O:18].S(Cl)(Cl)=O>>[CH:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: O=CN1CCc2ccccc21
Reactant: O=S(=O)(O)Cl
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=CN1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A 17% (w/w) solution of N-formylindoline in 1,2-dichloroethane (100 g, 680 mmol) was cooled to 5° C., treated with chlorosulfonic acid (90.4 mmol, 1.35 mol) at a rate which kept the internal temperature <25° C., heated to 70° C., treated with thionyl chloride (99.2 mL, 1.35 mol), and stirred for 2 hours. The mixture was cooled to 5° C., quenched with water (1.0 L) at a rate which kept the internal temperature <25° C., warmed to 10° C., diluted with heptane (1.0 L), and stirred for 30 minutes. The resulting precipitate was filtered, washed with water (6×1 L) until the filtrate pH was 4.5, washed with heptane, and partially dried under vacuum at 40° C. to provide the desired product (solid assay for 157 g (94%) of 1-formyl-5-indolinesulfonyl chloride. The product was used directly in the next step without further purification.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:14])[CH:11](Br)[CH3:12])[CH:8]=[CH:9][C:2]1=2.C(O)C.[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:14])[CH:11]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:12])[CH:8]=[CH:9][C:2]1=2
Reactant: CC(Br)C(O)c1ccc2c(c1)CCS2
Reactant: NCCCCc1ccccc1
Solvent: CCO
Solvent: CCOCC
Product: CC(NCCCCc1ccccc1)C(O)c1ccc2c(c1)CCS2

Procedure:
4 gr of 1-(2,3-dihydro-5-benzo[b]thienyl-2-bromo-1-propanol, 100 ml of ethanol and 20 gr of 4-phenylbutylamine are refluxed for 5 hours. The solvent and excess amine are evaporated in vacuo and the residue obtained is treated with ether. The solid is recrystallized from a mixture of methanol and ether, and the corresponding free base is obtained by treatment with a diluted NaOH solution and recrystallized from acetone. 1.05 gr of final product are so obtained.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([NH2:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1>>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:20][NH:26][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: NCc1ccco1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1coc(CNc2nccc(-n3cnc4ccccc43)n2)c1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with furfurylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 292.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.64 (s, 1H); 8.45 (s, 1H); 8.18 (m, 1H); 7.87 (m, 1H); 7.40 (m, 4H); 6.86 (d, J=5.5 Hz, 1H); 6.35 (m, 1H); 5.71 (br s, 1H); 4.75 (d, J=5.0 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]([CH2:13][OH:14])[CH2:9][CH2:10][CH2:11]O)([CH3:4])([CH3:3])[CH3:2].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][CH2:11][O:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCCO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCOC1
Temperature: 100 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
((S)-4-Hydroxy-1-hydroxymethyl-butyl)-carbamic acid tert-butyl ester (100 mg, 0.46 mmol) was dissolved in warm benzene (1.5 ml). Cyanomethylenetributylphosphorane (165 mg, 0.68 mmol) was added and the reaction vessel was sealed and stirred at 100° C. for 24 h. The reaction was cooled, evaporated and purified by silica gel chromatography (ethyl acetate/hexanes) to give 64 mg (69%) of (S)-(tetrahydro-pyran-3-yl)-carbamic acid tert-butyl ester. (M+Na)+=224.
Reaction SMILES: [F:1][C:2]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[N:16](COCC[Si](C)(C)C)[C:17]([CH3:29])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[NH:20][C:19]2=[O:28].C(O)(C(F)(F)F)=O.C([O-])(=O)C.[Na+]>ClCCl>[F:1][C:2]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:12])[F:13])=[CH:7][C:6]=1[C:15]1[NH:16][C:17]([CH3:29])=[C:18]2[C:23]=1[CH:22]=[C:21]([C:24]([NH:26][CH3:27])=[O:25])[NH:20][C:19]2=[O:28]
Reactant: CNC(=O)c1cc2c(-c3cc(C(F)(F)F)ccc3Oc3ccc(F)cc3F)n(COCC[Si](C)(C)C)c(C)c2c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cc2c(-c3cc(C(F)(F)F)ccc3Oc3ccc(F)cc3F)[nH]c(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a solution of Example 34d (0.023 g, 0.038 mmol) in dichloromethane was added TFA (0.5 mL, 6.49 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated by rotary evaporation. The residue was concentrated down from toluene (2×), then taken up in methanol/tetrahydrofuran. Sodium acetate (0.124 g, 1.514 mmol) was added, and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was concentrated by rotary evaporation. The residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 20-80% ethyl acetate in hexanes) to give the title compound (0.004 g, 22% yield). 1H NMR (300 MHz, DMSO-d6) δ 12.20-12.46 (m, 1 H), 9.06 (s, 1 H), 8.41-8.52 (m, 1 H), 7.82 (d, J=2.03 Hz, 1 H), 7.66 (dd, J=8.82, 1.70 Hz, 1 H), 7.44-7.54 (m, 2 H), 7.15-7.23 (m, 2 H), 6.99 (d, J=8.48 Hz, 1 H), 2.74 (d, J=4.41 Hz, 3 H), 2.65 (s, 3H). MS (ESI+) m/z 478.0)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[SH:9][CH2:10][C:11](O)=O.[OH-].[Na+]>Cl>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:11]1[CH2:10][SH:9]
Reactant: O=C(O)CS
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: SCc1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
To 1,2-phenylenediamine (1.88 g, 17 mmol) in 50% v/v hydrochloric acid (20 ml) was added 2-mercaptoacetic acid (1.3 ml, 1.7 g, 19 mmol). The reaction mixture was heated, under nitrogen, at 60° C. then at 90° C. for 48 hours. Additional 2-mercaptoacetic acid (400 μl, 530 mg, 6 mmol) was added in this time. A sample was analyzed by HPLC. The reaction mixture was cooled and neutralized to pH 5 with 40% v/v NaOH. The resulting solid was washed with water (50 ml) and dried under vacuum to yield (1H-Benzo[d]imidazol-2-yl)-methanethiol 1.95 g, 93% yield, Rt=7.6 min, purity >95% together with disulfide (Rt=8.0 mins) 4%. 1H NMR (d6-DMSO, 400 MHz) 14.3 ppm (bs, 0.5H), 7.46 ppm (m, 2H), 7.13 (m, 2H), 4.17 ppm (s 0.1H). MS (Electrospray+) 164 m/z (M+), 131 m/z (M−SH).
Reaction SMILES: Cl.C([O:6][C:7]1[C:8](=[O:23])[C:9]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])(O)[C:10]=1[O:11]CCCC)CCC.O>C1COCC1>[CH2:17]([C:9]1[C:10](=[O:11])[C:7](=[O:6])[C:8]=1[OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC1(O)C(=O)C(OCCCC)=C1OCCCC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCc1c(O)c(=O)c1=O
Yield: 33 %

Procedure:
6N Hydrochloric acid (150 mL) was added in one portion to a stirred solution of crude 2,3-dibutoxy-4-hexyl-4-hydroxycyclobut-2-en-1-one (15.1 g, prepared in Part A above) in THF (150 mL), and the resultant solution was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under reduced pressure to give a yellow solid. To this solid was added water (100 mL), which was then removed under reduced pressure. Toluene (100 mL) was similarly added and removed under reduced pressure, and then dichloromethane (200 mL) was added to the residue and the resultant solution was filtered and concentrated to produce a yellow oil. Hexanes (200 mL) were added and the resultant solution was cooled to induce crystallization. After recrystallization from hexanes, the desired compound was isolated as tan crystals (4.28 g, 33% yield over Parts A and B). The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[BH3-]C#N.[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: COc1ccc2cc[nH]c2c1
Reactant: CC(=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(methyloxy)-1H-indole (5.0 g, 34 mmols) in acetic acid (150 mL) was added NaBH3CN (5.12 g, 81.6 mmol) in several small portions. After stirring overnight at rt, the solvent was removed, the residue redissolved in ethyl acetate (300 mL), washed with saturated NaHCO3 (600 mL), filtered through a cotton plug and concentrated under reduced pressure to provide the crude indoline. ESIMS (M+H)+=150. The residue was then dissolved in glacial acetic acid (150 mL) and acetic anhydride (3.45 g, 33.86 mmol) was added. After stirring at rt for two hrs, the solvent was removed, residue resuspended in ethyl acetate (200 mL), washed with saturated NaHCO3 (600 mL). The aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined, filtered through a cotton plug, and concentrated under reduced pressure to provide 1-acetyl-6-(methyloxy)-2,3-dihydro-1H-indole which was used without any further purification. ESIMS (M+H)+=192.