Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:8][CH:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4([CH2:23][NH2:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([N:5]2[CH2:8][CH:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4([CH2:23][NH:24][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCC1(c2ccc(OCC3CN(C4CCC4)C3)cc2)CCOCC1
Reactant: Brc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: c1ccc(NCC2(c3ccc(OCC4CN(C5CCC5)C4)cc3)CCOCC2)nc1
Temperature: 70 °C
Yield: 7.4 %

Procedure:
1-(4-{4-[(1-cyclobutylazetidin-3-yl)methoxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine (0.175 g, 0.53 mmol) was dissolved in toluene (5 mL), 2-bromopyridine (0.051 mL, 0.53 mmol), 2,2′-bis(diphenylphosphino)-1,1′binapthyl (0.013 g, 0.02 mmol) and sodium tert-butoxide (0.076 g, 0.79 mmol) were added. The reaction mixture was purged with nitrogen, tris(dibenzylideneacetone)dipalladium(0) (0.011 g, 0.01 mmol) was added. The mixture was heated under nitrogen at 70° C. for 18 hours. The reaction mixture was diluted with water (20 mL) and extracted with DCM (2×30 mL). The combined organics were dried over sodium sulphate, filtered and concentrated in vacuo to provide a yellow oil. This was purified by HPLC eluting with methanol: 10 nM ammonium formate (aq) (1:1), fractions were combined and concentrated in vacuo to leave a clear oil. This was dissolved in DCM (50 mL) and washed with saturated sodium hydrogen carbonate solution in water (10 mL). The organic was dried over sodium sulphate, filtered and concentrated in vacuo to provide the title compound (0.016 g, 7%) as a clear colourless oil. 1H NMR (400 MHz, CDCl3) δ 1.60-1.70 (m, 2H), 1.70-1.80 (m, 2H), 1.80-1.92 (m, 2H), 1.92-2.0 (m, 2H), 2.18 (m, 2H), 2.90 (m, 1H), 3.10 (t, 2H), 3.15 (m, 1H), 3.40 (t, 2H), 3.50 (d, 2H), 3.60 (m, 2H), 3.80 (m, 2H), 4.0 (m, 1H), 4.10 (d, 2H), 6.22 (d, 1H), 6.50 (d, 1H), 6.90 (d, 2H), 7.28 (d, 2H), 7.32 (t, 1H), 8.0 (d, 1H). HRMS ESI+ m/z 408.2641 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B-:8](O)([OH:10])[OH:9])=[C:4]([F:12])[C:3]=1[O:13][CH3:14].[K+].Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:9])[OH:10])=[C:4]([F:12])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(Cl)ccc([B-](O)(O)O)c1F
Agent: Cl
Agent: [K+]
Product: COc1c(Cl)ccc(B(O)O)c1F

Procedure:
Another embodiment of the present disclosure includes a method of forming 2-(4-chloro-2-fluro-3-methoxylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane that comprises contacting 2-chloro-6-fluoroanisole with n-butyl lithium to form 6-chloro-2-fluoro-3-lithioanisole. The 6-chloro-2-fluoro-3-lithioanisole may be contacted with trimethyl borate to form dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate. The dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronate may be reacted with aqueous potassium hydroxide to form potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate. The potassium (4-chloro-2-fluoro-3-methoxyphenyl)trihydroxyborate then may be reacted with aqueous hydrochloric acid to form 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid may be reacted with 2,3-dimethyl-2,3-butanediol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:19])=[O:6]
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
To a solution of 3,5-dimethyl-4-nitro-benzoic acid (10.0 g, 0.0512 mol) in MeOH (150 mL) is added thionyl chloride (10 ml) at 0° C. and the reaction is heated to 80° C. After 16 h, the reaction mixture is cooled to room temperature and solvent is removed under reduced pressure. The residue is diluted with water (50 ml) and basified with saturated NaHCO3 solution to pH 7-8 and extracted with EtOAc (2×120 mL). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to afford the title compound as a light yellow solid (10.71 g, 98.3%). 1H NMR (400 MHz, DMSO): δ 7.83 (s, 2H), 3.88 (s, 3H), 2.30 (s, 6H).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])C.C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC>CN(C=O)C.C(OCC)(=O)C.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>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:4]([C:6]1[S:10][C:9]([C:38]2[S:37][CH:36]=[CH:40][CH:39]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:19]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)c1sc(-c2cccs2)nc1CN(CC(=O)OCC)Cc1ccc(OC)cc1OC

Procedure:
A solution of 2-Bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethyl ester (1 g, 2 mmol, example 96(b), 2-(tributylstannyl)thiophene (1.26 mL, 2 mmol), dichlorobis(triphenylphosphine)palladium II (140 mg, 0.2 mmol) in 13 mL anhydrous DMF was heated to 130° C. for 20 min. The reaction mixture was cooled, diluted with ethyl acetate, and washed successively with water, saturated sodium bicarbonate, and brine. The organic fraction was dried over anhydrous sodium sulfate, concentrated to a crude residue and purified by column chromatography (eluting from silica gel with a gradient of 15-70% ethyl acetate in hexanes) to give 867 mg of a yellow oil. MS (ESI+): m/z 527.2 (M+23)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][CH3:15])[CH2:12][CH2:11][CH2:10][CH:9]1[CH:16]([OH:40])[C@@H:17]([N:25](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][CH3:15])[CH2:12][CH2:11][CH2:10][CH:9]1[CH:16]([OH:40])[C@@H:17]([NH2:25])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC1CCCC(C(O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)N1C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1CCCC(C(O)[C@@H](N)Cc2ccccc2)N1C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
Stir 2-((2S)-2-dibenzylamino-1-hydroxy-3-phenylpropyl)-6-ethylpiperidine-1-carboxylic acid tert-butyl ester-Isomer 2 (0.7 g, 1.23 mmol) and 20% palladium hydroxide (0.2 g, 50% wet) in methanol (10 mL) under a balloon of hydrogen gas at room temperature for 2 days. Filter the suspension through a pad of filtering agent, wash with methanol and concentrate to give the title compound (0.4 g, 95%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][CH:14]([CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1>ClCCl>[CH:13]([CH:14]([CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)=[O:12]
Reactant: COC(=O)c1ccc(CCC(CO)Cc2ccc(C(=O)OC)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCC(C=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
13.07 g (60.6 mmol) of pyridinium chlorochromate (PCC) are added to a solution of 18.02 g (50.5 mmol) of dimethyl 4,4′-[2-(hydroxymethyl)butane-1,4-diyl]dibenzoate in 350 ml of dichloromethane, and the mixture is stirred at room temperature for 12 hours. After the reaction has gone to completion, about 60 g of silica gel are added and the solvent is removed to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 5:1→4:1). This gives 14.73 g (41.46 mmol, 82% of theory) of a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[C:17]([NH:24][C@H:25]([C:34]([OH:36])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)(OC(C)(C)C)=O>O>[C:34]([C@@H:25]([NH:24][C:17]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)=[CH:31][CH:32]=1)([OH:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Solvent: O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1N[C@@H](Cc1ccc(Oc2nc3c(Cl)cc(Cl)cc3cc2C(=O)O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with N-Boc-L-tyrosine in H2O to provide the title compound in good yield.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@H:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>CO.O.C(#N)C>[N:13]12[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]1)[C@H:11]([NH:10][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[CH:25][CH:26]=1)[CH2:12]2
Reactant: O=C(O)c1ccc(-c2cccs2)cc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
0.5 ml of Acetonitrile, 0.25 ml of water, and Triethylamine (108 uL, 0.78 mmol) was dissolved in a flask charged with (S)-(−)-3-Aminoquinuclidine dihydrochloride (47.8 mg, 0.2 mmol) at room temperature. To the mixture was added 4-(2-Thienyl)benzoic acid (49 mg, 2.4 mmol) and 1-hydroxy benzotriazole (33.8 mg, 0.25 mmol) followed by addition of N,N′-Diisopropyl carbodimide (38.7 uL, 0.25 mmol). The mixture was then stirred overnight at room temperature. About 2 ml of methanol was added to reaction mixture to resolve a clear solution that was subsequently injected into a Preparative HPLC instrument for purification. Desired fractions were combined and concentrated under vacuum. (S)—N-(quinuclidin-3-yl) -4-(thiophen-2-yl)benzamide (8.2 mg, 13% yield) was isolated at an oil. 1H NMR (400 MHz, Methanol-D4) δ (ppm): 7.90 (dt, J=8.7, 1.9 Hz, 2H), 7.76 (dt, J=8.6, 1.9 Hz, 2H), 7.53 (dd, J=3.7, 1.1 Hz, 1H), 7.48 (dd, J=4.0, 1.1 Hz, 1H), 7.14 (dd, J=3.5, 1.6 Hz, 1H), 4.45 (m, 1H), 3.86 (ddd, J=10.0, 3.0, 2.5 Hz, 1H), 3.37 (m, 4H), 2.38 (m, 1H), 2.26 (m, 1H), 2.11 (m, 2H), 1.95 (m, 1H). LCMS (ESI): m/z 313.1 (M+H [C18H20N2OS]=313.13).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([S:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[S:28][CH2:29][C:30]([OH:32])=O)[CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=1)([CH3:10])[CH3:9].[CH3:33][NH:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:20][C:17]([C:15]1[CH:14]=[C:13]([S:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[S:28][CH2:29][C:30]([N:34]([CH3:33])[CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[O:32])[CH:12]=[C:11]([C:8]([CH3:10])([CH3:9])[CH3:7])[CH:16]=1)([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)O)cc(C(C)(C)C)c1
Reactant: CNCCc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C

Procedure:
Oxalyl chloride (0.19 g, 0.0015 moles) was added by syringe to a cold (10° C.) solution of trans-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]acetic acid (0.55 g, 0.0014 moles) in benzene (50 ml). The cold bath was removed and the reaction mixture was stirred at room temperature for hours. The reaction mixture was concentrated to an oil (rotary evaporator). The oil was dissolved in toluene (50 ml) and concentrated to an oil. The process was repeated using tetrahydrofuran (25 ml) instead of toluene. The residue was dissolved in tetrahydrofuran (50 ml). To this solution was added 2-(2-methylaminoethyl)pyridine (0.19 g, 0.0014 moles) and triethylamine (0.22 g) and the reaction mixture was stirred at room temperature for 48 hours. The white solid precipitate was removed by filtration and washed with ethyl acetate (25 ml). The filtrate was concentrated to give the crude product as an oil. The product was purified by silica gel chromatography and dried in vacuo at 100° C. for 1 hour to give the title compound. The structure assignment was supported by NMR, infrared spectroscopy and elemental analysis.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[C:26]1[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:31]([C:29]3[S:30][C:26]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[CH3:19])=[CH:27][CH:28]=3)=[O:32])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1ccncc1-c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccncc1-c1ccc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)s1
Yield: 55.8 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.116 g, 0.446 mmol), 5-(4-methylpyridin-3-yl)thiophene-2-carboxylic acid (0.098 g, 0.446 mmol), DIPEA (0.233 ml, 1.337 mmol), HOBt hydrate (0.102 g, 0.668 mmol) and EDCI (0.128 g, 0.668 mmol) as described in the previous Example affording 0.115 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 2.41 (s, 3H), 4.32 (m, 2H), 4.43 (m, 1H), 6.95 (d, 1H), 7.33 (d, 1H) 7.37 (d, 1H), 7.79 (d, 1H), 7.85 (d, 1H), 7.94 (m, 2H), 8.07 (d, 1H), 8.45 (m, 2H), 8.55 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[NH2:27][C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:29]=1[S:37][CH2:38][CH2:39]O>C1COCC1.C(OCC)(=O)C>[I:25][CH2:39][CH2:38][S:37][C:29]1[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:28]=1[NH2:27]
Reactant: Nc1cc([N+](=O)[O-])ccc1SCCO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])ccc1SCCI
Reaction time: 0.08 h

Procedure:
To a stirred solution of triphenylphosphine (1.81 g, 6.93 mmol) and imidazole (1.887 mL, 13.86 mmol) in THF (15 mL) at 0° C. was added iodine (1.759 g, 6.93 mmol). After stirring for 5 minutes, 2-(2-amino-4-nitrophenylthio)ethanol (990 mg, 4.62 mmol) was added as a solution in THF (5 mL). The resulting mixture was stirred at 0° C. for 1 hour, then diluted with ethyl acetate and washed with water (3×) and brine. The organic phase was dried, filtered, and concentrated then chromatographed in 4:1 hexanes:ethyl acetate giving the desired compound (1.18 g, 79%) as an orange solid. 1H NMR (DMSO-d6) δ 7.55 (d, J=2.4 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.4, 2.4 Hz, 1H), 5.89 (brs, 2H), 3.38-3.26 (m, 4H); EI-MS (m/z, %): 324 (M+, 46), 196 (81), 154 (100), 126 (95).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32]>>[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:32]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Reactant: Cc1cccc(C(=O)O)c1
Product: Cc1cccc(C(=O)NC[C@@H]2[C@H]3CC(C)C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-methyl-benzoic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:15])=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:2].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH:12][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:10][C:9]=2[F:15])=[C:5]([O:18][CH3:19])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OC)c1
Reactant: O=Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(Oc2ccc(NCc3cccnc3)cc2F)c(OC)c1
Temperature: 30 °C
Reaction time: 17 h
Yield: 45.5 %

Procedure:
To 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (261.2 mg, 1 mmol) were added methanol (4 mL) and nicotinaldehyde (120 μL, 1.2 mmol). The reaction was stirred at 30° C. for 17 h under argon. To the reaction mixture was added NaBH4 (38 mg, 1 mmol). The reaction was stirred at 30° C. for 4 h under argon. The resulting mixture was concentrated in vacuo, dissolved in dichloromethane, washed with a saturated solution of NH4Cl and extracted with dichloromethane. Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give the title product as a yellow oil (160.5 mg; 46%), after purification by preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: C(O)C.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14]2[N:19]=[C:18]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])[C:17]([CH:29]=[CH:30][C:31]([O:33][CH3:34])=[O:32])=[CH:16][C:15]=2[F:35])(=[O:13])=[O:12])=[CH:7][CH:6]=1>ClCCl>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([C:14]2[N:19]=[C:18]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[F:28])[C:17]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:16][C:15]=2[F:35])(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: COC(=O)C=Cc1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCc1cc(F)c(S(=O)(=O)c2ccc(Cl)cc2)nc1Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A Raney nickel suspension (“R-100”, product of Nikko Rica Corporation) (1 ml) was washed sequentially with water and ethanol to give an ethanol (10 ml) suspension. The resulting suspension was added to an ethanol (40 ml) solution of methyl 3-[6-(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl-5-fluoropyridin-3-yl]acrylate (1.38 g, 2.86 mmol). Under a hydrogen atmosphere, the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue thus obtained was dissolved in dichloromethane. The resulting solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound 1.37 g, 2.83 mmol, 99%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[Se:4][C:3]=1[C:13]#[N:14].C([OH:17])C>[OH-].[Na+]>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[Se:4][C:3]=1[C:13]([NH2:14])=[O:17]
Reactant: N#Cc1[se]c(-c2ccccc2)cc1N
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1[se]c(-c2ccccc2)cc1N
Yield: 67 %

Procedure:
To a suspension of 3-amino-5-phenylselenophene-2-carbonitrile (4.0 g) in aqueous sodium hydroxide solution (120 mL, 10%) was added ethanol (50 mL) and the mixture refluxed for 45 min. The mixture was allowed to rt and the crystals separated were filtered off, washed with cold water and dried to give the product as golden yellow color solid (2.8 g, 67%), mp 184-186° C. 1H NMR (400 MHz, CDCl3): δ 7.50-7.53 (2H, m, Ar—H), 7.36-7.38 (3H, m, Ar—H), 7.04 (1H, s, H-4), 5.84 (2H, br s, —CONH2), 5.12 (2H, br s, —NH2).
Reaction SMILES: [C:1]([N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:40][C:41]1[O:42][C:43](=[O:57])[C:44]2[C:49]([C:50]=1[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[CH:48][CH:47]=[CH:46][CH:45]=2.O>CN(C=O)C>[O:57]=[C:43]1[C:44]2[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[C:41]([CH2:40][N:29]([C:25]2[N:24]=[CH:23][N:22]=[C:21]3[C:26]=2[N:27]=[CH:28][N:20]3[C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[O:42]1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1oc(CBr)c(-c2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1oc(=O)c2ccccc2c1-c1ccccc1)c1ncnc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
tert-Butyl 9-trityl-9H-purin-6-ylcarbamate (63.6 mg, 0.133 mmol) in DMF (0.1 ml) was added to a suspension of 50% dispersion in mineral oil NaH (5.33 mg, 0.133 mmol) in DMF (0.1 ml) at 0° C. 3-(bromomethyl)-4-phenyl-1H-isochromen-1-one (intermediate C1, 35 mg, 0.111 mmol) in DMF (0.2 ml) was added and the resulting mixture was allowed to warm to RT. The reaction mixture was then poured into water and extracted with EtOAc. The collected organic phases were dried and concentrated under reduced pressure and the resulting crude (80 mg) was used in the next step without any further purification and characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[C:6]=2[CH:16]=1.CN(C)[CH:19]1[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH2:22][C:21](=[O:29])[O:20]1>C(O)(=O)C>[CH3:15][N:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[C:6]2[CH:16]=[C:2]([N:1]3[C:21](=[O:29])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[NH:24][C:19]3=[O:20])[CH:3]=[CH:4][C:5]=2[S:9][N:8]=1
Reactant: CN(C)C1N=C(C(F)(F)F)CC(=O)O1
Reactant: Cn1cccc1-c1nsc2ccc(N)cc12
Solvent: CC(=O)O
Product: Cn1cccc1-c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a mixture of 5-amino-3-(1-methylpyrrol-2-yl)-1,2-benzisothiazole(1.05 g, 4.59 mmol) and acetic acid is added 2-(dimethylamino)-4-(trifluoromethyl)-5H-1,3-oxazin-6-one (0.960 g, 4.60 mmol). The resultant mixture is stirred at reflux for two hours, cooled to room temperature, diluted with ice water and stirred vigorously for approximately 15 minutes. Filtration and drying affords the title compound as a gray solid (1.50 g, 83.3%, mp 125-130° C.) which is identified by NMR spectral analysis.