Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]([NH-:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[CH:7][CH:6]=1.C(N(CC)CC)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@H:30]1[CH2:32][C@@H:31]1[C:33](Cl)=[O:34]>ClCCl>[OH:2][CH2:3][C@H:4]([NH:17][C:33]([C@H:31]1[CH2:32][C@@H:30]1[C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)=[O:34])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])=[CH:7][CH:6]=1
Reactant: CC[C@H](C)COc1ccc([C@@H]([NH-])CO)cc1
Reactant: O=C(Cl)[C@H]1C[C@@H]1c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)COc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58 %

Procedure:
To a solution of (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic acid (1.08 g, 6.45 mmol) in dichloromethane (50 ml) in an ice-bath was added oxalyl chloride (6.50 ml, 64.4 mmol), then DMF (0.1 ml) under nitrogen. The reaction mixture was stirred for 30 minutes at 0° C. The excessive solvent was removed on ratovapor and dried under high vacuum for 2 hrs to give (1S,2S)-2-thiophen-2-yl-cyclopropanecarboxylic chloride. In a separated 250 ml round-bottom flask was charged with {(R)-2-hydroxy-1-[4-((S)-2-methyl-butoxy)-phenyl]-ethyl}-amide HCl (6.47 mmol), dichloromethane (60 ml) and triethylamine (4.30 ml, 32.35 mmol) in an ice cold bath under nitrogen. The (1S,2S)-2-Thiophen-2-yl-cyclopropanecarboxylic chloride, made freshly in dichloromethane (10 ml) was added into the reaction mixture dropwise. The final reaction mixture was stirred for 1.5 hrs at room temperature. The finished reaction was quenched with water. The organic phase was washed with brine (3×30 ml), dried over MgSO4, filtrated, concentrated in vacuum and purified via column chromatography on silica gel with a gradient of 0%-100% of ethyl acetate in hexane to give a white solid (1.42 g, 58% yield): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (d, J=8.6 Hz, 2H), 7.09 (m, 1H), 6.91 (m, 3H), 6.82 (d, J=3.5 Hz, 1H), 6.23 (d, J=6.1 Hz, 1H), 5.06 (td, J=6.3, 4.3 Hz, 1H), 3.91 (m, 2H), 3.78 (m, 2H), 2.75 (m, 2H), 1.88 (m, 1H), 1.70 (m, 2H), 1.58 (m, 1H), 1.29 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.96 (t, J=7.5 Hz, 3H); LCMS (ESI) m/e 374.2 [(M+H)+, calcd for C21H28NO3S 374.5].
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1)[CH3:3].C1C[O:23][CH2:22]C1.Cl>O>[CH3:1][N:2]([CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH:22]=[O:23])[CH2:7][CH2:6]1)[CH3:3]
Reactant: C1CCOC1
Reactant: CN(C)C(c1cccc(F)c1)C1CCC(C=O)CC1
Agent: Cl
Solvent: O
Product: CN(C)C(c1cccc(F)c1)C1CCC(CC=O)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The aldehyde 34 (13.69 g, 52 mmol) dissolved in abs. THF (90 ml) was then added dropwise at RT, and stirring was carried out overnight at RT. Hydrolysis was carried out dropwise with water (50 ml) and 6N HCl (150 ml), while cooling with ice-water. After 1 hour's stirring at RT, extraction with ether was carried out ten times (50 ml each time). The aqueous phase was adjusted to pH 11 with 5N NaOH, extracted by shaking three times with ethyl acetate (100 ml each time), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/cyclohexane (1:1).
Reaction SMILES: ClC1C=CC(S(O[CH2:12][C@@H:13]2[O:19][C@@H:18]3[N:15]([C:16](=[O:20])[CH2:17]3)[CH2:14]2)(=O)=O)=CC=1.[N-:21]=[N+:22]=[N-:23].[Na+].CN(C=O)C>C(OCC)(=O)C>[N:21]([CH2:12][C@H:13]1[O:19][C@@H:18]2[N:15]([C:16](=[O:20])[CH2:17]2)[CH2:14]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C[C@@H]2O[C@@H](COS(=O)(=O)c3ccc(Cl)cc3)CN12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@@H]1CN2C(=O)C[C@@H]2O1
Temperature: 65 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of (3R,5S)-3-(4-chlorobenzenesulfonyl)oxymethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one (400 mg, 1.26 mmol), sodium azide (212 mg, 3.8 mmol) and DMF (5 ml) was stirred at 65° C. for 2 hrs. The resulting mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as eluent and 210 mg of (3S,5S)-3-azidomethyl-4-oxa-1-azabicyclo [3,2,0] heptan-7-one was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[N+:17]([O-])=O)[CH3:2].[H][H]>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[NH2:17])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CO
Product: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Reaction time: 12 h

Procedure:
Subsequently, the crude 2-nitro-5-piperidin-1-yl-benzoic acid ethyl ester (3.8 g) was dissolved in methanol (35 ml). Platinum oxide (300 mg) was added to the solution at room temperature, the air in the reaction system was replaced by hydrogen, and the mixture was then stirred for 12 hr. After the completion of the reaction, the atmosphere in the reaction system was replaced by nitrogen, and the reaction solution was then filtered through Celite to remove platinum oxide and was then concentrated under the reduced pressure to give crude 2-amino-5-piperidin-1-yl-benzoic acid ethyl ester (compound A) as a useful intermediate (3.4 g, crude yield 100%).
Reaction SMILES: [CH2:1]([C:8]1([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O.[Cl-].[Na+].O>[CH2:1]([C:8]1([C:18]#[C:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CC1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[Si](C)(C)C#CC1(Cc2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A sample of 29 (243.1 mg, 0.74 mmol) was dissolved in acetone (2.89 mL) to give a translucent, yellow solution. To the solution was added a solution of 10% aqueous hydrochloric acid solution (1.15 mL) and the reaction mixture was stirred at room temperature for 5 hours. The mixture was then diluted with brine (25 mL) and the aqueous layer was extracted with methylene chloride/ethyl ether (1:2, 3×20 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (2×20 mL) and brine (1×20 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude 30 as pale yellow crystals (195 mg). The crystals were combined with the crude product of a previous reaction (62.5 mg) and were purified by flash column chromatography [hexanes-ethyl acetate (5:1)] to give 30 as white crystals (197.1 mg, 0.69 mmol, 74%). Note, an impure fraction was collected and saved for future purification. 1H NMR (CDCl3) δ 7.31-7.24 (5H, m), 2.81 (2H, s), 2.74 (2H, td, J=6, 14.5 Hz), 2.30 (2H, dt, J=2, 15 Hz), 2.00 (2H, dt, J=3, 14 Hz), 1.68 (2H, dt, J=4, 13.5 Hz), 0.17 (9H, s); 13C NMR (CDCl3) δ 211.7, 137.1, 130.8, 128.0, 126.9, 109.0, 47.6, 38.6, 38.0, 37.2, 0.29. MS (ESI+) m/z 285.1 [M+H]+, HRMS (ESI+) calcd for C18H24OSi+H 285.1675. found 285.1661.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].Br[CH2:11][C:12]1[C:17]2[N:18]=[C:19]([N:21](C(OC(C)(C)C)=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:20][C:16]=2[CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:11][C:12]1[C:17]2[N:18]=[C:19]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[S:20][C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2c(CBr)cccc2s1
Reactant: CCOC(CN)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(CNCc1cccc2sc(NC(=O)OC(C)(C)C)nc12)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of 2,2-diethoxyethanamine (8.72 ml, 60.0 mmol) in acetonitrile (300 ml) were added 4-bromomethyl-2-bis(tert-butoxycarbonyl)aminobenzothiazole (Compound XIX-1) (1.33 g, 3.00 mmol) and potassium carbonate (3.14 g, 18.0 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (300 ml) and the mixture was washed with water (300 ml) and brine (200 ml). The organic layer was dried over magnesium sulfate (5 g) and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=100:0 to 80:20) to obtain the title compound (1.01 g, yield: 85%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:12](Cl)(Cl)=[S:13]>O.Cl>[N:11]([C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1)=[C:12]=[S:13]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: O
Product: CS(=O)(=O)c1ccc(N=C=S)cc1
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A solution of 4-methanesulfonylphenylamine (2.4 g, 14 mmol) was dissolved in a mixture of water (30 mL) and hydrochloric acid (9 mL, 37%). This was treated drop wise at room temperature with thiophosgene (1.5 g, 13.2 mmol) with good stirring. After 1 h, the suspension was filtered, washed with water and dried over P2O5 to give 2.4 g (85% yield) of 1-isothiocyanato4-methanesulfonylbenzene. 1H NMR (CDCl3), 300 MHz δ3.09 (s, 3H, CH3), 7.41(d, 2H, Aromatic), 7.98 (d, 2H, Aromatic).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]([C:14]([O:16][CH3:17])=[O:15])[NH:5]1.Br[CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[CH:19]([N:5]1[CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:3])[CH3:24]
Reactant: COC(=O)[C@H]1Cc2ccccc2C(=O)N1
Reactant: COC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)N1C(=O)c2ccccc2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
Sodium hydride (60% oil dispersion, 0.51 g, 12.4 mmol) was added to a stirring solution of (R)-methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1.3 g, 6.2 mmol) in DMF (13 ml). After stirring for 30 min at ambient temperature, methyl 2-bromopropionate (1.1 ml, 9.3 mmol) was added. After stirring at 40° C. for 2 h, the reaction was removed from the heat and quenched with water. The reaction mixture was transferred to a separatory funnel with EtOAc/water. Extraction with EtOAc (2×) and washing the combined organic layers with saturated NaHCO3, water, and brine and drying over MgSO4 afforded 2.0 g of crude product after evaporation of the solvent. Flash chromatography (SiO2, hexanes to 80% EtOAc in hexanes) afforded Isomer A (0.53 g, 29% yield), Isomer B (0.28 g, 15% yield) and a mixture of the two isomers (0.28 g, 15% yield). All have MS (ESI) 292 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:32]=[CH:31][C:17]([C:18]([N:20]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])=[CH:16][C:15]=1[O:33][CH3:34]>CN(C)C=O>[CH:26]1([N:20]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:18](=[O:19])[C:17]2[CH:31]=[CH:32][C:14]([CH2:13][N:1]3[C:9]4[C:4](=[N:5][CH:6]=[CH:7][CH:8]=4)[NH:3][CH2:2]3)=[C:15]([O:33][CH3:34])[CH:16]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1CBr
Reactant: c1cnc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C2CCCC2)C2CCCC2)ccc1CN1CNc2ncccc21
Reaction time: 2 h

Procedure:
To a stirred solution of imidazo[4,5-b]pyridine (350 mg, 2.94 mmol) in N,N-dimethylformamide (25 mL), sodium hydride (118 mg, 60% dispersion in mineral oil, 2.94 mmol) was added. After stirring for 2 hr, 4-bromomethyl-3-methoxy-N,N-dicyclopentyl benzamide (1.4 g, 3.57 mmol) was added in small installments over 10 min. The reaction mixture was stirred under argon at 25° C. After 18 h, the reaction was quenched by adding acetic acid (0.5 mL) and the solvent was removed under reduced pressure at <45° C. The crude mixture (2 g) was chromatographed (silica gel, CH2Cl2 -MeOH-NH4OH 90-10-1) to give the title compound. (320 mg, 26%) DSC 185° C.; Anal calcd. for C25H30N4O2 ·0.6H2O: C, 69.94; H, 7.32; N, 13.05. Found C, 69.96; H, 7.58; N, 12.68.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][CH:21]=[CH:20]5)[N:14]=[N:15][C:10]3=[C:9](O)[CH:8]=2)[CH:4]=[N:3]1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[N:12]=[C:11]2[N:13]([CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[N:14]=[N:15][C:10]=12
Reactant: Cn1cc(-c2cc(O)c3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(-c2cc(Cl)c3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
5-(1-Methyl-1H-pyrazol-4-yl)-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-ol (120 mg, 0.336 mmol) was dissolved in POCl3 (2 ml). The reaction mixture was stirred at 110° C. for 1 h. After cooled to 0° C., the mixture was basified with aqueous NaHCO3 to pH=7, and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, concentrated, and purified by chromatography to afford the title compound (25 mg). MS: 376 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[CH:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:35][CH2:36][NH:37][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:14][C:9]4[CH2:8][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:29])([F:1])[F:28])[CH2:11][C:10]=4[CH2:12]3)=[N:16][CH:17]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NCCC1CCCC1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Product: O=C(NCCC1CCCC1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 34 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (50 mg, 0.124 mmol) was reacted with cyclopentylethylamine analogously to example 3d. Yield: 34%, M+H+: 499.28.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[C:11]([O:15][C:16]([NH:18][CH:19]([C:21](O)=[O:22])[CH3:20])=[O:17])([CH3:14])([CH3:13])[CH3:12]>>[OH:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[NH:1][C:21](=[O:22])[CH:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH3:20]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1ccc(O)c(N)c1
Product: COc1ccc(O)c(NC(=O)C(C)NC(=O)OC(C)(C)C)c1
Yield: 80.9 %

Procedure:
Using 2-amino-4-methoxyphenol (3.00 g, 21.6 mmol) and N-(tert-butoxycarbonyl)-D,L-alanine (4.08 g, 21.6 mmol), a method in the same manner as in Reference Example 13 was performed, and the obtained residue was triturated with ethyl acetate to give the title compound (5.42 g, yield 81%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[F:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:56].Cl>>[ClH:1].[ClH:56].[F:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(F)c2)OC1(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(F)c3)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{4-[(dimethylamino)methyl]cyclohexyl-amino}-1,5-naphthyridin-3-yl)ethanone (65 mg, 0.18 mmol) was reacted with 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (69 mg, 0.27 mmol) followed by formation of the dihydrochloride salt to afford the desired product (87 mg, 90%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.13 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 7.78 (dd, J=7.8, 1.7 Hz, 2H), 5.66-5.62 (m, 1H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.76 (s, 3H), 2.47-2.44 (m, 2H), 2.08-2.04 (m, 3H), 1.72-1.68 (m, 2H), 1.37-1.28 (m, 2H); ESI MS m/z 455 [M+H]+; HPLC>99% (AUC), tR=9.49 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:7][C:6]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:5]=2[C:4](=[O:14])[O:3]1.[CH2:16]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[BH4-].[Na+]>O>[CH2:16]([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:36]=[CH:35][C:33]([NH:34][CH2:12][C:9]3[CH:10]=[CH:11][C:5]4[C:4](=[O:14])[O:3][C:2]([CH3:15])([CH3:1])[O:7][C:6]=4[CH:8]=3)=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC1(C)OC(=O)c2ccc(C=O)cc2O1
Reactant: CCCCCCc1ccc(C#Cc2ccc(N)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCCCCc1ccc(C#Cc2ccc(NCc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
A solution of 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-7-carbaldehyde (700 mg; 3.38 mmol) and 4-[(4-hexylphenyl)ethynyl]aniline (940 mg; 3.38 mmol) in toluerene (40 mL) was refluxed for 48 hours with azeotropic removal of water. The solvent was removed under reduced pressure and the residue was taken up in a mixture of MeOH (20 mL) and THF (20 mL). NaBH4 (130 mg, 3.38 mmol) was added and the resulting mixture was stirred at rt for 8 hours. The solvents were removed under reduced pressure. The residue was taken up in EtOAc and washed with a saturated aqueous solution of NaACO3 and brine. The organic layer was dried (Na2SO4) and the solvent was removed under reduced pressure to give a brown oil. Purification by flash chromatography on silica (EtOAc:c-Hex 1:9 then 1:4) gave 466 mg (30%) of the title compound as a pale yellow oil. HPLC, Rt: 6.1 min (purity: 95.6%). LC/MS, M+(ESI: 468.0, M−(ESI): 466.1.
Reaction SMILES: [C:1]1([C:7]2[S:8](=O)[CH2:9][CH2:10][S:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1>[C:1]1([C:7]2[S:8][CH2:9][CH2:10][S:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S1CCSC=C1c1ccccc1
Solvent: C1COCCO1
Product: C1=C(c2ccccc2)SCCS1

Procedure:
By following substantially the procedure of Example 1, Step D, except using dioxane as solvent, 2-phenyl-5,6-dihydro-1,4-dithiin (14.0 g.) yields 2-phenyl-5,6-dihydro-1,4-dithiin oxide as a mixture of the 1- and 4-isomers (15.1 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2ccccc2c1
Solvent: CC(=O)O
Product: COc1ccc2ccccc2c1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 2 h

Procedure:
100 g (0.63 mol) of 2-methoxynaphthalene were dissolved in 1.2 l of acetic acid and, at 10° C., 100 ml of 65% strength nitric acid were slowly added dropwise. The mixture was stirred at 10° C. for a further 2 h. The precipitate was then filtered off with suction to yield 72.5 g (57%). Melting point 129°-130° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:12][O:17][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)CO
Solvent: c1ccncc1
Product: CC(C)(C)COS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
Add 4-bromobenzenesulfonyl chloride (2.20 g, 8.61 mmol) and pyridine (30 mL) to a round bottom flask. At ambient temperature, with stirring, add neopentyl alcohol (1.39 mL, 12.91 mmol). After stirring the reaction overnight at ambient temperature quench the reaction with saturated aqueous sodium bicarbonate and extract it with ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, 0.05 N aqueous hydrochloric acid and brine, then dry (sodium sulfate), and concentrate in vacuo. Purify the resulting-material on a flash column (silica gel; 30%-50% gradient of CH2Cl2 in hexanes) to provide 2.24 g of 4-bromo-benzenesulfonic acid 2,2-dimethyl-propyl ester (85%).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:11]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=4)=[N:10][C:9]=3[N:4]2[N:3]=1.[NH:29]1[CH2:39][CH2:38][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1.C(O)(=O)C>[CH3:1][C:2]1[CH:28]=[C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:11]([C:20]4[CH:21]=[CH:22][C:23]([CH2:24][N:29]5[CH2:30][CH2:31][CH:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:38][CH2:39]5)=[CH:26][CH:27]=4)=[N:10][C:9]=3[N:4]2[N:3]=1
Reactant: Cc1cc2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2n1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(Cc2ccc(-c3nc4c(cnc5cc(C)nn54)cc3-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound (11-1) (1.28 g, 3.51 mmol, 1.0 eq) was dissolved in dioxane (38 mL, anhydrous). Ethyl isonipecotate (1.66 g, 10.5 mmol, 3.0 eq), glacial acetic acid (1.90 mL), and NaBH(OAc)3 (2.98 g, 14.1 mmol, 4.0 eq) were added and the reaction stirred at room temperature for 24 hours. The crude reaction was neutralized with NaHCO3 (aq.) and extracted with CHCl3 (×3). The combined organics were dried with brine and Na2SO4, and then concentrated in vacuo. The residue was purified by silica gel chromatography by eluting with a gradient of heptane and EtOAc (20% to 100% EtOAc) to afford Compound (13-1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[CH3:18])=O.[NH2:19][C:20]([NH2:22])=[S:21]>CCO>[CH:13]1([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:19]=[C:20]([NH2:22])[S:21][CH:2]=3)=[C:6]([CH3:18])[CH:7]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cc1cc(OC2CCCC2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(OC2CCCC2)cc(C)c1-c1csc(N)n1
Yield: 73.5 %

Procedure:
A mixture of 2-bromo-1-(4-(cyclopentyloxy)-2,6-dimethylphenyl)ethanone (6.16 g, 19.8 mmol) and thiourea (1.51 g, 19.8 mmol) in 95% EtOH (28.3 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene (30 mL). The solids were filtered and dried under vacuum to give 4-(4-(cyclopentyloxy)-2,6-dimethylphenyl)thiazol-2-amine (4.2 g) as white solids in 73.7% yield: 1H NMR (500 MHz, CDCl3) δ 6.58 (s, 2H), 6.24 (s, 1H), 4.75 (m, 1H), 2.13 (s, 6H), 1.88-1.78 (m, 6H), 1.62-1.59 (m, 2H).