Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])O1.Br[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][C:33]=2[Cl:35])[N:28]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:35][C:33]1[CH:32]=[CH:31][N:30]=[C:29]2[N:28]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:27]=[C:26]([C:9]3[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=3)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:34]=12
Reactant: CC(C)(C)OC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3nccc(Cl)c23)c1
Temperature: 90 °C
Yield: 40.4 %

Procedure:
tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (333 mg, 1.0 mmol), 3-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (372 mg, 1.0 mmol), potassium carbonate (270 mg, 2 mmol) and PdCl2(dppf)CH2Cl2 (41 mg, 0.05 mmol) were added to a reaction flask which was purged thoroughly with N2. 10 ml of dried dioxane was added via syringe and the reaction was heated to 90° C. for overnight. After LC-MS showed the reaction was complete, the solution was then cooled to room temperature and filtered and concentrated. The residue was purified by chromatography (0-50% EtOAc:hexane), giving 201 mg of tert-butyl 3-(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzylcarbamate as a white solid, yield: 40.4%.
Reaction SMILES: [NH2:1][C:2](=[O:23])[CH2:3][N:4]1[C:12]2[C:11](Br)=[CH:10][CH:9]=[CH:8][C:7]=2[C@@H:6]2[CH2:14][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][C@H:5]12.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1>[O:23]=[C:2]1[CH2:3][N:4]2[C@H:5]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][C@H:6]3[C:7]3[C:12]2=[C:11]([CH:10]=[CH:9][CH:8]=3)[NH:1]1
Reactant: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc(Br)c1N2CC(N)=O
Agent: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)N1CC[C@H]2[C@@H](C1)c1cccc3c1N2CC(=O)N3
Reaction time: 66 h

Procedure:
A suspension of [4aS,9bR]-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (254 mg, 1.34 mmol), cuprous iodide (254 mg, 1.34 mol), potassium carbonate (3.96 g, 28.7 mmol) and N,N′-dimethylethylenediamine (0.31 mL, 2.87 mmol) in dioxane (20 mL) is heated at reflux for 4.5 hours. Another portion of cuprous iodide (250 mg, 1.32 mmol) and N,N′-dimethylethylenediamine (0.33 mL, 3.05 mmol) is added. The resulting mixture is heated to a reflux for another 3 hours and then at 73° C. for about 66 hours. The reaction mixture is concentrated and passed through a short alumina column using 100:3:3 dichloromethan:triethylamine:methanol. The resulting solvent from the column is evaporated to a solid and redissolved in dichloromethane. The dichloromethane solution is washed with brine, dried with sodium phosphate and concentrated to a solid (3.7 g, 95%, 83% pure by HPLC).
Reaction SMILES: [CH:1]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][NH:19]C(=O)C(F)(F)F)[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO>O>[CH:1]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(NCCCc1cccc(OCC2CCCCCC2)c1)C(F)(F)F
Solvent: O
Solvent: CO
Product: NCCCc1cccc(OCC2CCCCCC2)c1

Procedure:
N-(3-(3-(cycloheptylmethoxy)phenyl)propyl)-2,2,2-trifluoroacetamide was deprotected following the method used in Example 10 except that the MeOH:water mixture was 4:1. After the extractive work up, the residue was dissolved in hexanes, filtered through Celite and concentrated under reduced pressure. Example 14 was isolated in pure form without further manipulation. 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=7.6 Hz, 1H), 6.70-6.76 (m, 3H), 3.71 (d, J=6.8 Hz, 2H), 2.74 (t, J=7.2 Hz, 2H), 2.62 (t, J=8 Hz, 2H), 1.43-2.02 (m, 15H), 1.23-1.33 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1)#[N:2].[CH3:12][NH:13][NH2:14]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[S:11])[N:13]([CH3:12])[NH2:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N=C=S)cc1
Reactant: CNN
Solvent: CCO
Product: CN(N)C(=S)Nc1ccc(C#N)cc1
Yield: 98.9 %

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 7.8 g (0.049 mole) of 4-cyanophenyl isothiocyanate with 2.24 g (0.0490 mole) of methylhydrazine in 50 ml of ethanol yielded 10.0 g of 4-(4-cyanophenyl)-2-methyl-3-thiosemicarbazide as a solid, mp 178°-179° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][N:14]([CH3:20])[CH:15]1[CH2:19][CH2:18][NH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH3:13][N:14]([CH3:20])[CH:15]1[CH2:19][CH2:18][N:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CN(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CCC(N(C)C)C2)cc1
Temperature: 130 °C

Procedure:
A mixture of ethyl 4-fluorobenzoate (4.47 g), dimethylpyrrolidin-3-ylamine (3.04 g), potassium carbonate (3.68 g) and dimethyl sulfoxide (20 ml) was heated at 130° C. for 7 hours. After cooling, the mixture was diluted with water and extracted with methyl tert-butyl ether. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The product with the molecular weight of 262.35 (C15H22N2O2) was obtained in this way; MS (ESI): 263 (M+H+).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH:30][CH3:31]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([N:30]([CH3:31])[CH3:29])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CNC
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)N(C)C)C1(C)C

Procedure:
The product from Example 173 and dimethylamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.49 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 3H), 1.26 (s, 3H), 1.28-1.33 (m, 2H), 1.37-1.46 (m, 1H), 1.57 (s, 9H), 1.57-1.70 (m, 3H), 2.01-2.10 (m, 1H), 2.62-2.67 (m, 2H), 2.74-2.83 (m, 1H), 2.83 (s, 3H), 3.05 (s, 3H), 3.33-3.39 (m, 1H), 8.50 (s, 1H). MS (ESI+) m/z 422 (M+H)+. Anal. calcd. for C23H39N3O2S: C, 65.52; H, 9.32; N, 9.97. Found: C, 65.26; H, 9.15; N, 9.88.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Li]CCCC.CN([CH:25]=[O:26])C>C1COCC1>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH:25]=[O:26])=[CH:3][C:4]=2[C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(Br)ccc1C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CCCC2)c(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
In a 15 mL round-bottomed flask were placed 4-bromo-1-cyclopentyl-2-(trifluoromethyl)benzene (0.186 g, 0.635 mmol) and anhydrous THF (1.86 mL) under argon atmosphere. The solution was stirred well and cooled to −78° C. (dry ice IPA bath). BuLi (2.5 M in hexanes, 0.281 mL, 0.703 mmol) was added in drops (slowly) and the reaction mixture was stirred at low temperature for 25 min. Anhydrous DMF (0.1 mL, 0.766 mmol) was added in drops at −78° C. (slowly). The mixture was stirred at −78° C. for 20 min then at room temperature for 30 min. The reaction was quenched with water, acidified with 2 M HCl and extracted with EtOAc. The EtOAc layer was washed with water, dried over Na2SO4, and concentrated in vacuo to give the title compound as an oil (60 mg). LCMS m/z=243.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.7 (m, 4H), 1.79-1.94 (m, 2H), 1.95-2.09 (m, 2H), 3.29-3.37 (m, 1H), 7.86 (d, J=8 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 8.16 (d, J=1.2 Hz, 1H), 10.46 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CO>[Cl:16][CH2:15][CH2:14][CH2:13][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: ClCCCBr
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCCCCl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
4-Nitrothiophenol (80%, 25.0 g, 129 mmol) was added to a solution formed by adding sodium (5.55 g, 242 mmol) to methanol (500 mL) maintained at 0° C. After 0.5 h the reaction was warmed to ambient temperature and 1-bromo-3-chloropropane (50.7 g, 322 mmol) was added in one portion. The reaction mixture was stirred overnight and filtered. The filtrate was reduced to half volume and the solid which formed was collected by filtration. Recrystallization from methanol afforded 15.4 g (52%) of yellow solid, mp 50°-52° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:4])=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:15]1([NH:14][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)NCCCCCC(=O)O
Reactant: Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CS(=O)(=O)NCCCCCC(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of acid 69 (100 mg, 0.48 mmol), aniline (60 μL, 0.66 mmol), and DMAP (5 mg) in THF (5 mL) was added EDC (119 mg, 0.57 mmol). The reaction mixture was stirred overnight, then partitioned between H2O (10 mL) and EtOAc (15 mL). The layers were separated, and the aqueous portion extracted with EtOAc (3×10 mL). The organic fractions were combined, washed with sat. NH4Cl (5 mL), then brine, dried over MgSO4, and filtered. Concentration under reduced pressure gave 70 as a white crystalline solid (130 mg, 0.46 mmol, 95%). 1H-NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.57 (d, 2H), 7.26 (t, 2H), 7.00 (t, 1H), 6.92 (t, 1H), 2.91 (dt, 2H), 2.85 (s, 3H), 1.58 (m, 2H), 1.47 (m, 2H), 1.31 (m, 2H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].[H][H].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1>CN1CCCC1=O>[N:3]1([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9]
Reactant: [H][H]
Reactant: O=C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Nc1ccc(N2CCOCC2=O)cc1
Reaction time: 2 h

Procedure:
Over a period of 2 hours, sodium hydride (88 g, 2.2 mol, 60% in paraffin) is added a little at a time to a solution of morpholin-3-one (202 g, 2 mol) in N-methylpyrrolidone (2 l). After the evolution of hydrogen has ceased, 4-fluoronitrobenzene (282 g, 2 mol) is added dropwise with cooling over a period of one hour, and the reaction mixture is stirred overnight. At 12 mbar and 76° C., 1.7 l of the volume of the liquid is then distilled off, the residue is poured into water (2 l) and this mixture is extracted twice with ethyl acetate (in each case 1 l). The combined organic phases are washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification is carried out by chromatography (on silica gel, hexane/ethyl acetate 1:1) and subsequent crystallization from ethyl acetate. Yield: 78 g (colorless to brownish solid), 17.6% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CCOC(=O)c1cccc(O)c1
Product: O=C(O)c1cccc(Oc2ccc(Br)nc2)c1

Procedure:
Prepared from 2-bromo-5-fluoropyridine and ethyl 3-hydroxybenzoate. 1H NMR (400 MHz, DMSO-d6) δ 13.12 (br. s., 1H), 8.28 (d, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.56 (t, 1H), 7.48-7.54 (m, 2H), 7.39 (dd, 1H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[SH:12].C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[CH2:21][C:22]1[CH:31]=C2C(C=CC=C2)=C[CH:23]=1.ClCC(C)=C>CC(C)=O>[CH:21]([S:12][C:3]1[C:4]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])=[C:22]([CH3:31])[CH3:23]
Reactant: CC(C)(C)c1cccc(Br)c1S
Reactant: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CSc1c(Br)cccc1C(C)(C)C
Temperature: 24 °C

Procedure:
A mixture of 2-bromo-6-tert-butylthiophenol (6.04 g, 22.7 mmol), K2CO3 (3.76 g, 27.2 mmol), Nal (0.34 g, 2.27 mmol), and 3-chloro-2-methylpropene (2.3 mL, 22.7 mmol) in acetone (125 mL) is heated at reflux for 3 h. The reaction is allowed to cool to 24° C. The solids are filtered and discarded, and the filtrate is evaporated to a biphasic oil. The upper light colored layer is separated, taken up in hexane (50 mL), and treated with SiO2 (5 g). Filtration and evaporation provides 2-bromo-6-tert-butylphenyl isobutenyl thioether as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+]>[N+]([O-])([O-])=O.[K+].OS(O)(=O)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To mechanically stirred conc. H2SO4 (700 mL) at 3° C. was added p-hydroxyacetophenone (66.0 g, 480 mmol) followed by KNO3 (48.3 g, 477 mmol) in two approximately equal portions about four minutes apart. An additional 3.76 g of KNO3 was added after 1.67 hours to insure reaction completion. The reaction was slowly poured into 8 L crushed ice/water and extracted with 4 L ethyl acetate (EtOAc). The extract was concentrated in vacuo to a volume of ~1.25 L, 500 mL heptane were added and concentration was continued. Once a thick yellow suspension formed at 50° C., it was cooled to ~10° C. and filtered. The collected solids were washed with ~150 mL heptane and dried in vacuo at ~40° C. to give 81.8 g of the title compound.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][S:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19](O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.[C:29]([O:33][CH3:34])(=[O:32])[CH2:30][SH:31]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:13][S:14][C:15]1[CH:28]=[CH:27][C:18]([CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:31][CH2:30][C:29]([O:33][CH3:34])=[O:32])=[CH:17][CH:16]=1
Reactant: COC(=O)CS
Reactant: CSc1ccc(C(O)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CSC(c1ccccc1)c1ccc(SC)cc1
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of ρ-toluenesulfonic acid monohydrate (50 mg, 0.3 mmol) in 10 mL of toluene, which contains 300-500 mg of activated 3 Å molecular sieves, is added 4-methylthiobenzhydrol (0.30 g, 1.3 mmol) and methyl thioglycolate (140 μL, 1.6 mmol), and the reaction is stirred for 2 hours. The reaction is diluted with ethyl acetate and washed with a saturated solution of sodium bicarbonate, water, followed by brine. The organic phase is dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil is chromatographed on silica gel eluting with ethyl acetate:toluene:hexane (2:18:80) to give 0.23 g (56%) of methyl [[(4-methylthiophenyl)phenylmethyl]thio]acetate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:15])[CH2:13]Br)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[C:33](=[O:36])([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.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]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:15])[CH2:13][C:20]3[CH2:19][C:18]([O:36][C:33]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:17]([F:16])=[CH:22][CH:21]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: FC(=CC1(c2ccc(Cl)cc2)CC1)CBr
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)CC1=CC=C(F)C(Oc2ccccc2)(Oc2ccccc2)C1
Temperature: 25 °C
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-(p-chlorophenyl)-1-(3-bromo-2-fluoropropenyl)cyclopropane, (Z)- (0.434 g, 1.5 mmol), 4-fluoro-3-phenoxybenzeneboronic acid (0.452 g, 1.95 mmol), potassium carbonate (1.86 g, 13.5 mmol) and bis(dibenzylideneacetone)palladium(0) (Pd(dba)2, 4.3 mg, 0.075 mmol) in toluene is heated at 80° C. for one hour, cooled to room temperature, diluted with water, and filtered through diatomaceous earth. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and ethyl acetate extract are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 3:20 methylene chloride/hexanes solution gives the title product as an oil (0.274 g, 63% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:18][C:14]1[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1O

Procedure:
A solution of 5-bromo-2-hydroxybenzoic acid (5.2 g, 23.96 mmol), 3-pyridinamine (2.26 g, 23.96 mmol), EDC (4.59 g, 23.96 mmol), HOBT (3.67 g, 23.96 mmol) and triethylamine (3.34 ml, 23.96 mmol) in DMF (80 ml) was stirred for 3 h. The reaction mixture was filtered. 150 ml water was added to the filtrate to yield a white solid. This was filtered and dried to yield the title compound. 2.8 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9]CC)=O.[Li+:13].CC([N-]C(C)C)C.[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23].CC(O)=O>C1COCC1>[Br:1][C:2]1[C:12]2[CH2:23][C:22]([C:21]([O:25][CH3:26])=[O:24])=[C:7]([O-:9])[C:6]=2[CH:5]=[N:4][CH:3]=1.[Li+:13]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: C=CC(=O)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C1=C([O-])c2cncc(Br)c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Ethyl 5-bromonicotinate (5 g, 21.7 mmol) in THF (22 mL) was added over a period of 20 min to a solution of LDA (23.9 mmol) [generated from N,N-diisopropylamine (3.41 mL, 23.9 mmol) and n-butyllithium (14.9 mL, 23.9 mmol, 1.6M in hexane) in THF (95 mL)] at −78° C. The resulting dark red solution was stirred for 30 min, then methyl acrylate (4.9 mL, 54.3 mmol) in THF (22 mL) was added over 15 min. The reaction was stirred an additional 1.5 h, then aq. 10% AcOH (43.5 mL, 76.1 mmol) was added (giving a pH of 4-5) and the reaction was allowed to warm to room temperature. Evaporation under reduced pressure afforded the title compound (in 50% purity, determined by 1H-NMR) as dark green amorphous solid. MS: 270.0 (M+H+, 1Br).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[NH:11][C:12](=[O:21])[C:13]2[C:18]([CH:19]=1)=[C:17]([CH3:20])[CH:16]=[CH:15][CH:14]=2.[P:22](=[O:26])([OH:25])([OH:24])[OH:23]>C(O)C>[OH2:1].[OH:26][P:22]([O:25][P:22]([OH:25])([OH:24])=[O:23])(=[O:24])[OH:23].[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][C:10]1[NH:11][C:12](=[O:21])[C:13]2[C:18]([CH:19]=1)=[C:17]([CH3:20])[CH:16]=[CH:15][CH:14]=2
Reactant: O=P(O)(O)O
Agent: Cc1cccc2c(=O)[nH]c(CCN3CCC[C@@H]3CO)cc12
Solvent: CCO
Product: O
Product: O=P(O)(O)OP(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A free form (501 mg) of (R)-3-[2-(2-hydroxymethylpyrrolidin-1-yl)ethyl]-5-methyl-2H-isoquinolin-1-one was measured in a reaction test tube, aqueous ethanol (4.3 mL, ethanol:water=8:1) was added and the mixture was completely dissolved by heating under reflux. Thereto was added aqueous phosphoric acid solution (2 mL, solution prepared by diluting commercially available 85% phosphoric acid (2.02 g) with the above-mentioned aqueous ethanol to scale up to 10 mL), and the mixture was stirred at room temperature for one day and left standing. The precipitate was collected by filtration. The obtained precipitate (302 mg) was measured in a reaction test tube, aqueous ethanol (2.4 mL, ethanol:water=6:1) was added, and the mixture was completely dissolved by heating under reflux. The mixture was stirred at room temperature for one day and left standing. The precipitate was collected by filtration and dried under reduced pressure at 50° C. for 5 hr to give the title compound (260 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2([C:15]3[CH:14]=[CH:13][S:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)[N:4]=[C:3]1SC.[I-].[NH4+:19].N>CO>[NH2:19][C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]2([C:15]3[CH:14]=[CH:13][S:12][C:11]=3[CH2:10][CH2:9][CH2:8]2)[N:4]=1
Reactant: [NH4+]
Reactant: CSC1=NC2(CCCc3sccc32)C(=O)N1C
Agent: N
Agent: [I-]
Solvent: CO
Product: CN1C(=O)C2(CCCc3sccc32)N=C1N

Procedure:
1′-Methyl-2′-(methylthio)-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazol]-5′(1′H)-one (1.5 g, 5.63 mmol), ammonium iodide (4.89 g, 33.78 mmol) and 7 N ammonia in methanol (20 mL) were heated at 90° C. for 12 h. The solvent was then evaporated under reduced pressure and the residue was partitioned between water and dichloromethane. The dichloromethane extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure to give an oil. This consisted of the title compound as the major component and its minor regioisomer in a 2:1 ratio. The oil was loaded onto a Biotage SNAP cartridge and eluted with dichloromethane-dichloromethane/7N ammonia in methanol (9:1). The appropriate fractions were combined and evaporated under reduced pressure to give 2′-amino-1′-methyl-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazol]-5′(1′H)-one as a foam (800 mg, 60%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](O)=[O:32])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[C:24]([CH2:31][OH:32])=[CH:23][N:22]=3)[CH2:19][CH2:20]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(C(=O)O)c(C(F)(F)F)n3)CC2)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(CO)c(C(F)(F)F)n3)CC2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Half of the crude 57b was combined with triethylamine (50 μL, 0.36 mmol) in 2 mL of THF and treated at 0° C. with ethyl chloroformate (30 μL, 0.31 mmol). The mix was stirred at room temperature for 4 h then it was added to a stirred suspension of sodium borohydride (32 mg, 0.84 mmol) in water and the stirring was continued for 3 h. The mixture was quenched with aqueous NaHCO3 (5 mL) and water (5 mL) and extracted with EtOAc (3×5 mL). The combined extracts were dried and concentrated and the residue was purified by preparative HPLC to afford 58-1: LC-MS 460.1 (MH+), tR=7.49 (Method 2).