Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(N(C)C)=C(C)C.[Cl:9][C:10]1[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=[C:12]([Cl:24])[C:11]=1[NH:25][C:26]1[N:30]([CH3:31])[C:29]2[CH:32]=[C:33]([O:39][CH2:40][CH:41]([F:43])[F:42])[C:34]([C:36]([OH:38])=O)=[CH:35][C:28]=2[N:27]=1.[NH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[C:48]#[N:49].N1C=CC=CC=1>C(#N)C>[C:48]([C:47]1[CH:46]=[C:45]([NH:44][C:36]([C:34]2[C:33]([O:39][CH2:40][CH:41]([F:42])[F:43])=[CH:32][C:29]3[N:30]([CH3:31])[C:26]([NH:25][C:11]4[C:12]([Cl:24])=[CH:13][CH:14]=[C:15]([CH2:16][NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])[C:10]=4[Cl:9])=[N:27][C:28]=3[CH:35]=2)=[O:38])[CH:52]=[CH:51][CH:50]=1)#[N:49]
Reactant: N#Cc1cccc(N)c1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(OCC(F)F)cc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3cccc(C#N)c3)c(OCC(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethylamine (20 μl) is added to a mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid (53 mg, 0.10 mmol) in 2.0 mL acetonitrile and it is stirred 10 min at rt. Additional (1-chloro-2-methyl-propenyl)-dimethylamine (20 μl) is added and the mixture is stirred for additional 20 min at rt. The crude acid chloride solution is added to a mixture of 3-aminobenzonitrile (12 mg, 0.10 mmol), pyridine (24 μL, 0.30 mmol) and acetonitrile (1.0 mL) and it is stirred for 15 min at rt and additional 5 h at 55° C. The solvent is removed in vacuo and the residue is dissolved in 2 mL of a 19:1 DMF/water-solution and is purified via preparative HPLC to furnish the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1>CCCCCC.C(O)C>[CH3:1][C:2]1[S:3][C:4]2[C:13]3[C@H:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(C)sc3c21
Solvent: CCCCCC
Solvent: CCO
Product: CC(=O)NCC[C@@H]1CCc2ccc3nc(C)sc3c21
Yield: 50.4 %

Procedure:
Racemic N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]thiazol-8-yl)ethyl]acetamide (1.00 g) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mmID×500 mmL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 80 mL/min, column temperature: 30° C., sample concentration: 10 mg/mL (hexane/ethanol=90/10), injection weight: 500 mg×2). A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give the title compound (504 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mmID×250 mmL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0 mL/min, column temperature: 30° C., sample concentration: 0.25 mg/mL (hexane/ethanol=90/10), injection volume: 10 μL).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][C:7]([C:9]1[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])[C:12]([O:21][CH3:22])=[CH:11][CH:10]=1)=[O:8]>CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[N:14]=[C:13]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12]([O:21][CH3:22])=[CH:11][CH:10]=1)[OH:8]
Reactant: COC(=O)/C=C/c1nc(C(=O)CCCC(=O)OC)ccc1OC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCCC(O)c1ccc(OC)c(CCC(=O)OC)n1
Yield: 99.3 %

Procedure:
Under the conditions of example 1 C, a solution of 1.89 g of 5-[3-methoxy-2-(2-methoxycarbonyl-(1E)-1-ethenyl)-6-pyridyl]-5-oxopentanoic acid methyl ester in 75 ml of methanol and 15 ml of tetrahydrofuran is hydrogenated in the presence 400 mg of 10% palladium catalyst and worked up. 1.9 g of 5-[3-methoxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-(5RS)-5-hydroxypentanoic acid methyl ester is obtained as oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(#N)C>[F:10][C:11]([F:19])([F:20])[C:12]1[CH:13]=[CH:14][C:15]([NH:16][C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])=[CH:17][CH:18]=1
Reactant: Cc1oncc1C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.33 h

Procedure:
A solution of 0.05 mol of 5-methylisoxazole-4-carbonyl chloride (7.3 g) in 20 ml of acetonitrile is added dropwise at room temperature to a solution of 0.1 mol of 4-trifluoromethylaniline (16.1 g) in 150 ml of acetonitrile. After stirring for 20 minutes, the precipitated 4-trifluoromethylaniline hydrochloride is filtered off with suction and washed twice with 20 ml of acetonitrile each time, and the combined filtrates are concentrated under reduced pressure. 12.8 g of white, crystalline N-(4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (compound 1) are thus obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)[S:14][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1.O>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][N:16]([C:13]2[S:14][CH:15]=[C:11]([CH2:10][O:9][C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:30][CH:29]=3)[N:12]=2)[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc(OCc2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(COc3ccc(C(=O)O)cc3)cs2)CC1
Temperature: 55 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A solution of tert-butyl 4-(4-(4-methoxycarbonylphenoxymethyl)thiazol-2-yl]piperazine-1-carboxylate (820 mg, 1.89 mmol) in methanol (30 mL) and THF (10 mL) was treated with a solution of sodium hydroxide (226 mg, 5.67 mmol) in water (10 mL). The mixture was stirred at 55 ° C. for 8 hours and then concentrated by evaporation. The aqueous solution was diluted with water (10 mL) and the dilution was acidified with dilute hydrochloric acid. A resulting solid was collected by filtration to provide 4-[2-(4-tert-butoxycarbonylpiperazin-1-yl)thiazol-4-ylmethoxy]benzoic acid (800 mg, 100% yield). HNMR (dmso-d6): 7.88 (2H, d), 7.09 (2H, d), 6.91 (1H, s), 4.99 (2H, s), 3.44 (8H, m), 1.41 (9H, s).
Reaction SMILES: [CH3:1][N:2]([S:6]Cl)[C:3]([Cl:5])=[O:4].[CH2:8]([Cl:12])[C:9](=[CH2:11])[CH3:10].C(Cl)[Cl:14]>>[CH3:1][N:2]([S:6][C:9]([CH3:10])([CH2:11][Cl:14])[CH2:8][Cl:12])[C:3]([Cl:5])=[O:4]
Reactant: ClCCl
Reactant: C=C(C)CCl
Reactant: CN(SCl)C(=O)Cl
Product: CN(SC(C)(CCl)CCl)C(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of 16.0 g of N-methyl-N-chlorosulfenyl carbamoyl chloride in 100 ml of methylene chloride was added 12.0 g of methallyl chloride with stirring, at room temperature. On slight heating there was a spontaneous exotherm which raised the temperature of the reaction mixture to 39° C. On removal of the solvent under reduced pressure 19.6 g of oil was obtained, N25D 1.5379.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[O:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O:20]C)[O:18][CH3:19].[H-].[Na+].CO>C1CCCCC1.O>[CH3:19][O:18][C:17]([C:12]1[CH:13]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH2:10][C:11]=1[OH:16])[CH2:15][CH2:14]2)=[O:20]
Reactant: COC(=O)OC
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCCCC1
Solvent: CO
Product: COC(=O)C1=C(O)CC2CCC1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 87.7 %

Procedure:
3-Oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester from Step 1 (14.1 g, 62 mmol) was dissolved in cyclohexane (550 mL), to which was added dimethyl carbonate (12.4 g, 137 mmol), followed by sodium hydride (5.0 g, 125 mmol) and methanol (0.2 mL). The reaction mixture was stirred at reflux for 15 hours, then cooled to room temperature, and water (25 mL) was added. The reaction mixture was concentrated under reduced pressure to a volume of 50 mL, which was then partitioned between ethyl acetate and saturated aqueous ammonium chloride. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to provide 3-hydroxy-8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester as a light yellow oil (15.4 g, 87% yield).
Reaction SMILES: C(O[C@@H]1[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1[N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][C:22]([Cl:29])=[N:23][C:24]=2Cl)(=O)C.[C:30]1([CH:36]([CH3:43])[CH2:37][C:38]2[NH:39][CH:40]=[CH:41][N:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(Cl)(C)=O>CC#N.CC(O)=O>[Cl:29][C:22]1[N:21]=[C:20]2[C:25]([NH:26][CH:27]=[N:19]2)=[C:24]([N:39]2[CH:40]=[CH:41][N:42]=[C:38]2[CH2:37][CH:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:43])[N:23]=1
Reactant: CC(Cc1ncc[nH]1)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)Cl
Solvent: CC#N
Product: CC(Cc1nccn1-c1nc(Cl)nc2nc[nH]c12)c1ccccc1
Temperature: 65 °C
Reaction time: 17 h
Yield: 62 %

Procedure:
A mixture of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloropurine (0.98 g, 2.19 mmol) and 2-(2-phenylpropyl)imidazole (4.07 g, 21.9 mmol) in CH3CN (20 mL) was stirred at 65° C. for 17 h (reaction complete, TLC). Volatiles were evaporated in vacuo, and the residue was chromatographed (MeOH/CH2Cl2, 1:90) to give a mixture of diastereomers (quantitative, contaminated with 2-(2-phenylpropyl)imidazole). The mixture was dissolved in HOAc (91 mL), and to the solution was added AcCl (0.92 mL, 1.00 g, 12.8 mmol). The mixture was stirred at 65° C. for 25.5 h in a sealed flask (reaction complete, TLC). Volatiles were evaporated in vacuo, and the residue was dissolved in 0.1 N NaOH/H2O (300 mL) and CHCl3 (150 mL). The mixture was stirred for 2 h, and then neutralized with CO2. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phase was dried (Na2SO4) and concentrated to dryness. The residue was washed (H2O), suspended in EtOH, and filtered to give 2-chloro-6-[2-(2-phenylpropyl)imidazol-1-yl]purine (0.46 g, 62%) of material. The mother liquor was evaporated to dryness, and the residue was chromatographed (MeOH/CH2Cl2, 1:30→1:12) to give a solid, which was washed (H2O) to give the second crop (0.18 g, 86% total). The combined solids were dissolved in 0.1 N NaOH/H2O (300 mL). Precipitation with CO2 gave 2-chloro-6-[2-(2-phenylpropyl)imidazol-1-yl]purine as an enantiomeric mixture (0.59 g, 80%): mp 258.5-259° C.; UV (MeOH) max 254, 289 nm (∈ 12 000, 4100), min 240, 256 nm (F 3600, 4100); 1H NMR (500 MHz, DMSO-d6) δ 14.00 (s, 1H), 8.68 (s, 1H), 8.35 (s, 1H), 7.13-7.14 (m, 4H), 7.07 (d, J=1.9 Hz, 1H), 7.00-7.04 (m, 1H), 3.58 (dd, J=14.4, 6.7 Hz, 1H), 3.43 (dd, J=14.2, 7.7 Hz, 1H), 3.30 (sext, J=7.0 Hz, 1H), 1.23 (1.22) (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 156.4, 150.9, 147.9, 146.4, 145.8, 145.7, 128.2, 127.9, 126.6, 125.7, 121.7, 120.5, 38.3, 37.7, 21.0; HRMS m/z 361.0935 (MNa+[C17H15ClN6Na]=361.0944). Anal. Calcd for C17H15ClN6: C, 60.27; H, 4.46; N, 24.81. Found: C, 60.12; H, 4.60; N, 24.66.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[N:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=[O:24])=[CH:17][CH:16]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][O:20][C:21]2[C:22]([CH2:23][OH:24])=[CH:25][CH:26]=[CH:27][N:28]=2)=[CH:17][CH:16]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(COc2ncccc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a mixture of 2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]nicotinaldehyde (2.16 g), tetrahydrofuran (30 ml) and ethanol (30 mL) was added sodium borohydride (0.20 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, and dried with air to give crystals (2.12 g, 97%) of [2-[4-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]benzyloxy]-3-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 111-112° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[S:14]1[C:18]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)=[CH:17][N:16]=[CH:15]1.O>ClCCCl.C1COCC1>[S:14]1[C:18]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[N:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)=[CH:17][N:16]=[CH:15]1
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: Nc1ccc(Oc2ccnc(-c3cncs3)c2)cn1
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(-c3cncs3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of 2,2,2-trimethylacetamide (0.090 g, 0.888 mmol) in DCE (3 mL) was treated with oxalyl chloride (0.078 mL, 0.888 mmol), stirred at RT for 1 h, then heated at 75° C. for 2 h. The mixture was cooled to RT, treated with a solution of 5-((2-(thiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.12 g, 0.444 mmol) and TEA (0.186 mL, 1.332 mmol) in THF (5 mL) and stirred at RT for 1 h. The mixture was treated with water, extracted with DCM (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford N-((5-((2-(thiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (67 mg, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.44 (s, 1H), 9.13 (s, 1H), 8.61 (s, 1H), 8.44 (d, J=5.8 Hz, 1H), 8.29 (d, J=2.9 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.77 (dd, J=9.0, 2.9 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 6.86 (dd, J=5.8, 2.4 Hz, 1H), 1.21 (s, 9H); MS (ESI) m/z: 398.1 (M+H+).
Reaction SMILES: CC1C(CS([C:12]2[NH:13][C:14]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=O)=NC=C(C)C=1.[NH2:25][CH2:26][CH2:27][SH:28].[ClH:29]>O1CCCC1>[Cl-:29].[NH2:25][CH2:26][CH2:27][S:28][S:28][CH2:27][C:26]1[C:17]([CH3:15])=[CH:18][C:19]([CH3:21])=[CH:20][N+:25]=1[C:12]1[NH:13][C:14]2[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: NCCS
Reactant: Cl
Reactant: Cc1cnc(CS(=O)c2nc3ccc(C(F)(F)F)cc3[nH]2)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(CSSCCN)[n+](-c2nc3ccc(C(F)(F)F)cc3[nH]2)c1
Product: [Cl-]
Reaction time: 8 h

Procedure:
3.53 g of 2-[[(3,5-dimethyl-2-pyridyl)methyl]sulphinyl]-5 -(trifluoromethyl)benzimidazole are dissolved in 50 ml of tetrahydrofuran and treated with 0.77 g of cysteamine. 40 ml of 3N hydrochloric acid are added thereto at an internal temperature of 40°. The mixture is stirred at 40° overnight and subseguently evaporated in vacuo. The residue is crystallized from tert.butyl methyl ether/ether. There is obtained 2-[[(2-aminoethyl)dithio]methyl]-3,5-dimethyl-1 -[5-(trifluoromethyl)-2-benzimidazolyl]pyridinium chloride of melting point 115°-120°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3([CH2:15][O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OCC1(Nc2ccc3[nH]ncc3c2)CCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(Nc2ccc3[nH]ncc3c2)CCC1
Yield: 139.5 %

Procedure:
To a stirred suspension of [1-(1H-indazol-5-ylamino)-cyclobutyl]-methanol (0.690 g, 3.18 mmol) in DCM (100 mL) at ambient temperature and under nitrogen was added Et3N (2.66 mL, 19.1 mmol) followed by methanesulfonyl chloride (0.74 mL, 9.54 mmol). After 5 minutes the mixture was washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated in vacuo to give methanesulfonic acid 1-(1H-indazol-5-ylamino)-cyclobutylmethyl ester (1.31 g) as a gum that was used directly in the next step without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]#[N:8])[CH:2]=1.N[C@@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12].C(=O)([O-])[O-:19].[K+].[K+].[ClH:24]>CO.O>[ClH:24].[C:7]([NH:8][C@@H:10]([C:15]([OH:17])=[O:16])[C:11]([SH:14])([CH3:13])[CH3:12])(=[O:19])[C:3]1[CH:2]=[CH:1][CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(S)[C@@H](NC(=O)c1cccnc1)C(=O)O

Procedure:
20.8 g (0.2 mole) nicotinic acid nitrile, 29.8 g (0.2 mole) D-penicillamine and 13.8 g (0.1 mole) potassium carbonate were heated in 350 ml methanol and 150 ml water for 6 hours at the boiling point. The mixture was acidified with concentrated hydrochloric acid to pH 4 and heated 45 minutes at the boiling point. After the mixture cooled off, 36.5 g (63% of theory) of the product precipitated as hydrochloride with a melting point of 164° C. [α]25D =+4.0° (c=2 in 1N NaOH)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[C:2]=1[OH:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[C:10]([CH:1]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4cc3O)c2cc1OC
Temperature: 130 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
Naphthalene-2,3-diol (1.00 g), 4-chloro-6,7-dimethoxyquinoline (691 mg), and 4-dimethylaminopyridine (1.14 g) were suspended in o-dichlorobenzene (20 ml), and the mixture was stirred at 130° C. for one hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (627 mg, yield 58%).
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:16][CH:15]2[CH2:25][CH:12]1[CH2:13][CH2:14]2)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH:17]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:16][CH:15]2[CH2:25][CH:12]1[CH2:13][CH2:14]2)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1C2CCC(C2)CC1c1cccc(O)c1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add H2O (70 mg, 3.89 mmol) and TMSCl (126 mg, 1.17 mmol) to a solution of 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol (252 mg, 0.97 mmol) in 2-butanone (30 ml). Then stir the reaction mixture at ambient temperature for 12 hours. Evaporate the mixture under vacuum to give 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol hydrochloride as white solid (286 mg, Yield: 99.8%). 1H NMR (400 MHz, D2O) δ 7.04-7.07 (t, J=10.4, 1H), 6.58-6.72 (m, 3H), 2.80-2.91 (m, 1H), 2.52-2.54 (m, 3H), 2.44-2.48 (m, 3H), 2.33-2.41 (m, 1H), 2.20-2.29 (m, 1H), 2.11 (s, 1H), 1.99 (s, 2H), 1.36-1.47 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7](=[O:16])[C:6]=2[CH:17]=1.C(O)=O>[Pd].CN(C)C=O>[N+:18]([C:4]1[C:5]2[O:10][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7](=[O:16])[C:6]=2[CH:17]=[CH:2][CH:3]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)c1cc(=O)c2cc(Br)cc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: O=CO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 145 °C
Reaction time: 5.75 h
Yield: 55 %

Procedure:
A mixture of ethyl 6-bromo-8-nitro-4-oxo-4H-1-benzopyran-2-carboxylate (5.0 g, 14.6 mmol), 10% palladium-on-charcoal (0.541 g), formic acid (7.90 ml) and N,N-dimethylformamide (42 ml) was stirred at 145° C. for 5.75 h under inert atmosphere. After this time the mixture was left to cool and the catalyst was removed by filtration, washing it with N,N-dimethylformamide. The resulting filtrate was evaporated to dryness and the obtained residue was purified by chromatography through a silica gel column. Eluting with hexane:chloroform, 85:15, 2.109 g of the title product were recovered (55% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[N:28]1[C:37]2[CH:36]=[CH:35][NH:34][C:33](=[O:38])[C:32]=2[CH:31]=[CH:30][CH:29]=1.C1CCN2C(=NCCC2)CC1.Cl>CS(C)=O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([N:34]2[CH:35]=[CH:36][C:37]3[N:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33]2=[O:38])=[CH:4][N:3]=1
Reactant: O=c1[nH]ccc2ncccc12
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1c2cccnc2ccn1-c1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
A mixture of N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (618 mg, 1.499 mmol), 1,6-naphthyridin-5(6H)-one (PrincetonBio, Monmouth Junction, N.J., 146 mg, 0.999 mmol), copper (II) acetate (363 mg, 1.998 mmol), DBU (0.301 mL, 1.998 mmol) in DMSO (4 mL) in a microwave tube equipped with a magnetic stirring bar was irradiated at 100° C. for 15 min in a CEM microwave (J. Comb. Chem. 2008, 10, 358-360). The mixture was diluted with water (10 mL) and acidified with HCl (5 N) to pH ˜5. After agitating at rt overnight, the slurry was filtered and the solid was washed with water. The solid was washed with DCM (3×), acetone (3×), and MeOH (2×) to remove the less polar fraction. The resulting solid was dissolved in hot DMSO (6 mL) and filtered. The mother liquid was diluted with water (6 mL) and the resulting slurry was filtered and washed with water. The solid was dissolved in DMSO and purified by reverse-phase preparative HPLC (Phenomenex Luna column, 5 micron, C8(2), 100 Å, 150×21.2 mm, 0.1% TFA in CH3CN/H2O, gradient 5% to 90% over 10 min) The product fraction was concentrated, and neutralized with NaHCO3. The slurry was filtered and washed with water to provide N-(2-chloro-5-(5-oxo-1,6-naphthyridin-6(5H)-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (37 mg, 0.086 mmol, 8.60% yield) as an off-white powder.