Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(OCCO)C>[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2ccsc2c1Cl
Solvent: CCOCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc2ccsc2c1NCc1ccc(Cl)cc1Cl
Yield: 75.9 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol), 2,4-dichlorobenzylamine (217.6 mg, 0.17 mL, 1.24 mmol), N,N-diisopropylethylamine in 5 mL of 2-ethoxyethanol is heated at reflux for 4 hours. After cooling the mixture is concentrated in vacuo and the residue is treated with a saturated aqueous sodium bicarbonate solution for 1 hour. The precipitate is collected by filtration, washed with water, dried in vacuo, and then purified by flash column chromatography eluting with a gradient of 2% methanol in dichloromethane to 4% methanol in dichloromethane to provide 261.2 mg of 7-[(2,4-dichlorobenzyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 215-216° C.; 1H NMR (DMSO-d6) δ 4.95 (d, J=5 Hz, 2H), 7.28 (d, J=6 Hz, 1H), 7.40 (dd, J=6, 2 Hz, 1H), 7.46 (dd, J=4, 2 Hz, 1H), 7.69 (d, J=2 Hz, 1H), 8.12 (d, J=5 Hz, 1H), 8.16 (m, 1H) 8.47 (d, J=6 Hz, 1H); MS 334.0, 335.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:5]=[C:6]([CH3:8])[N:7]=2)[CH:23]=[CH:22][N:21]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-methyl-6-(4-trifluoromethyl-phenyl)pyrimidine (example A.12) (0.27 g, 1.0 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.21 g, 1.3 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.175 g, 50%). MS (ISP) 350.4 [(M+H)+]; mp 147° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[C:16]([NH:23][C@H:24]([C:33]([OH:35])=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.O>[C:19]([O:18][C:16]([NH:23][CH:24]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])=[CH:28][CH:27]=1)[C:33]([OH:35])=[O:34])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccccc2C=O)cc1)C(=O)O
Temperature: 75 °C
Reaction time: 48 h

Procedure:
Potassium carbonate (7.36 g, 53.31 mmol) and -2-fluorobenzaldehyde (9.3 mL, 88.85 mmol) were added to a solution of Boc-tyrosine (5.0 g, 17.77 mmol) in anhydrous DMF (20 mL). The resulting suspension was refluxed at 75±5° C. under an atmosphere of argon. After 48 hr, the reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with EtOAc (2×50.0 mL). The aqueous layer was collected, acidified with 5.0 M HCl to pH ˜2.0 and extracted with EtOAc (2×100 mL). The resulting EtOAc layer was extracted with water (1×100 mL) and brine (1×100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired aldehyde, 58, as a low melting solid (6.4 g, ˜99%). 1H NMR (400 MHz, DMSO-d6): 12.62(s, 1H), 10.38 (s, 1H), 7.84 (dd, J=8.0 and 2.0 Hz, 1H), 7.64 (dt, J=7.2 and 1.6 Hz, 1H) 7.31 (d, J=8.8 Hz, 1H), 7.27 (t, J=7.6 Hz, 2 Hz), 7.13 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H) 6.89 (d, J=8.4 Hz, 1H), 4.09 (ddd, J=12.8, 10.8 and 4.4 Hz, 1H), 3.02 (dd, J=13.6 and 4.4 Hz, 1H), 2.81 (dd, J=13.6 and 10.4 Hz, 1H) 1.32 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[N+:21]([O-])=O)=[N:7]1)[CH3:2].[O:25]1[C:29]2([CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)[O:28][CH2:27][CH2:26]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[NH:21][CH:32]2[CH2:33][CH2:34][C:29]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:30][CH2:31]2)=[N:7]1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CSC(c2cc3cc(C)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: O=C1CCC2(CC1)OCCO2
Product: CCOC(=O)C[C@@H]1CSC(c2cc3cc(C)cc(NC4CCC5(CC4)OCCO5)c3[nH]2)=N1

Procedure:
{(R)-2-[5-methyl-7-nitro-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid ethyl ester prepared in Preparation 54 and 1,4-dioxa-spiro[4,5]decan-8-one were reacted according to the same procedure as Example 1 to give the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[S:3].C[C:15]1[N:16]=[CH:17][N:18]([CH2:20][CH2:21][CH2:22][NH2:23])[CH:19]=1>>[N:18]1([CH2:20][CH2:21][CH2:22][N:23]2[C:6](=[O:8])[C:5]3[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:1][C:2]2=[S:3])[CH:19]=[CH:15][N:16]=[CH:17]1
Reactant: Cc1cn(CCCN)cn1
Reactant: COC(=O)c1ccccc1N=C=S
Product: O=c1c2ccccc2[nH]c(=S)n1CCCn1ccnc1

Procedure:
The compound was synthesized starting from methyl 2-isothiocyanatobenzoate (0.773 g, 4.0 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (9) (0.5 g, 4.0 mmol) as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:11]([NH2:13])=[O:12])[NH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O.[C:15]1([C:21]([CH:23]=O)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:11](=[O:12])[N:13]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:23]=[N:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NC(=O)N(N)c1cc(Cl)cc(Cl)c1
Reactant: O=CC(=O)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: O=c1nc(-c2ccccc2)cnn1-c1cc(Cl)cc(Cl)c1
Yield: 42.2 %

Procedure:
In 50 ml of dioxane was dissolved 2.20 g of 2-(3,5-dichlorophenyl)semicarbazide followed by addition of 1.52 g of phenylglyoxal monohydrate, and the mixture was refluxed for 5 hours. The reaction mixture was then concentrated and the residue was recrystallized from acetonitrile to provide 1.34 g of the title compound. m.p. 160-161° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[N:20]=[CH:21][N:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cn1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)Cn1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
A mixture of ethyl (4-{5-[4-(cyclopropylsulfonyl)phenyl]-4-oxo-6-(tetrahydro-2H-pyran-4-yl)hexanoyl}-1H-imidazol-1-yl)acetate (1.05 g), ammonium acetate (0.70 g) and acetic acid (5 mL) was stirred at 80° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.44 g, yield 51%) was obtained as a pale-yellow amorphous solid from a fraction eluted with tetrahydrofuran-hexane (5:1, volume ratio). MS: 512 (MH+).
Reaction SMILES: [Br:1][CH:2]([CH:14]([Br:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[C:10]([OH:12])=[O:11].[CH3:24]O.B(F)(F)F>CO>[Br:1][CH:2]([CH:14]([Br:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](=[CH2:13])[C:10]([O:12][CH3:24])=[O:11]
Reactant: CO
Reactant: C=C(CCCCCCC(Br)C(Br)CCCCCCCC)C(=O)O
Agent: FB(F)F
Product: C=C(CCCCCCC(Br)C(Br)CCCCCCCC)C(=O)OC

Procedure:
The crude dibromo acid, 2-(7,8-dibromohexadecyl)-acrylic acid is dissolved in 50 ml of methanol and 5 ml of boron trifluoride methanol solution is added. The solution is heated under reflux for 6 hours. The solution is concentrated to 1/2 volume and the acid is neutralized with saturated NaHCO3 solution to about pH 7. The oily material is extracted with ether, washed with water and dried over Na2SO4. The ether solvent is removed under reduced pressure to give 4.80 g of crude product, methyl 2-(7,8-dibromohexadecyl)-acrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14].[CH3:16][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc([N+](=O)[O-])ccc1CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
To a solution of 2-(2-methoxy-4-nitrophenyl)acetic acid (step 2, 1.2 g, 5.5 mmol) in methanol/dichloromethane (11 ml, 1/1) was added trimethylsilyldiazomethane (2 M, 5.6 ml, 11.8 mmol) and stirred for 10 min at room temperature. The mixture was quenched with saturated citric acid aqueous solution and the extracted with ethyl acetate (3×20 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 1.2 g of title compound as orange solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>CCCCCC>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCCCCCCBr
Solvent: CCCCCC
Product: BrCCCCCCCCCCCCOC1CCCCO1
Reaction time: 15 h
Yield: 118.9 %

Procedure:
12-Bromo-dodecan-1-ol (5.12 g, 19.3 mmol) was added to a vigorously stirred solution of dihydropyran (2.1 mL, 23.2 mmol) and Amberlyst HI5 (0.25 g, Aldrich D10,620-8) in hexane (100 mL). After 3 hours dihydropyran (2.1 mL) was added and the solution stirred for a further 15 hours. The mixture was then filtered, and the filtrate concentrated in vacuo and chromatographed graphed on silica gel, eluting with 2% ethyl acetate in hexane to give the title compound, (a), 8.02 g (75%), as an oil.
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>O.C(O)C>[C:18]1([CH:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][CH2:10]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(c1ccccc1)N1CC(c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(C2CNc3ccccc32)cc1
Temperature: 0 °C
Yield: 97.2 %

Procedure:
The amount, 5.50 g, of the 1-benzoyl-3-phenylindoline obtained in Example 6 and a solution of 4.0 g of sodium hydroxide in 40 ml of water and 84 ml of ethanol added thereto were refluxed together for six hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous potassium carbonate solution, then dried over anhydrous magnesium sulfate, and distilled to expel the ethyl acetate and obtain 3.49 g of 3-phenylindoline (97.2%) in the form of an oily semi-solid substance.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:15]1[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Oc1ccc(Br)nc1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 80 °C
Yield: 61.4 %

Procedure:
(4-Methylsulfonylphenyl)boronic acid (4.40 g, 21.55 mmol) was added to a solution of 6-bromo-3-pyridinol (2.5 g, 14.37 mmol) in DME (125 mL), followed by addition of 2M Na2CO3 (75 mL) and Pd(PPh3)4 (0.83 g, 0.72 mmol). The reaction mixture was degassed with N2 and heated at 80° C. overnight, then cooled to ambient temperature. Water (50 mL), 1N NaOH (50 mL), brine (50 mL) and CH2Cl2 (150 mL) were added. The CH2Cl2 layer was separated and the aqueous layer was washed with CH2Cl2 (100 mL). The combined CH2Cl2 extract was further washed with a mixture of water (50 mL), 1N NaOH (50 mL) and brine (50 mL). The aqueous layers were combined and washed with CH2Cl2 (100 mL), neutralized with concentrated HCl and extracted with EtOAc (250 mL×2). The combined EtOAc extract was filtered through celite on top of a layer of silica gel, which was further washed with EtOAc (100 mL). The EtOAc filtrate was washed with brine and dried over Na2SO4, filtered, and concentrated to a light yellow solid, which was triturated with small amount of hot MeOH to give 2.20 g (61%) of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].C(OC(C)C)(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:11])[CH3:10]
Reactant: OCCCCCCBr
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CC(=O)OCCCCCCBr
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
20.1 g (0.16 mol) of DMAP were added to 297.4 g (1.64 mol) of 6-bromo-1-hexanol in 1500 ml of THF. A solution of 184.4 g (1.81 mol) of acetic anhydride in 300 ml of THF was added dropwise in such a way that the reaction temperature did not exceed 30° C. After completion of the addition, the mixture was stirred for a further 30 minutes. The reaction mixture was mixed with 500 ml of diisopropyl ether and extracted successively with 700 ml each of water, 2× saturated NaHCO3 solution and water. After drying over sodium sulfate, the solvent was removed in vacuo. 352.8 g (1.58 mol, 96%) of 6-bromohexyl acetate were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([S:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Cn1ccnc1S
Agent: [H-]
Agent: [Na+]
Product: Cn1ccnc1Sc1ccnc(Cl)c1
Yield: 73.7 %

Procedure:
Using the method of Example 3, Step A, 1-methyl-1H-imidazole-2-thiol (720 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(1-methyl-1H-imidazol-2-ylthio)pyridine (1.05 g, 74% yield) as an oil. 1H NMR (CDCl3) δ 8.17 (d, 1H), 7.30 (d, 1H), 7.20 (d, 1H), 6.88 (s, 1H), 6.80 (d, 1H), 3.70 (s, 3H).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:4]([NH:5][C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[NH:8][C:9]2=[O:11])[CH2:3][CH2:2]1.[C:16]1(=[O:30])[N:20]([CH2:21][C:22](Cl)=[O:23])[C:19](=[O:25])[C:18]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:17]12.C(=O)([O-])O.[Na+]>ClCCCl>[C:19]1(=[O:25])[N:20]([CH2:21][C:22]([N:5]2[CH:4]3[CH2:3][CH2:2][CH2:1][CH:10]3[C:9](=[O:11])[NH:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]2=3)=[O:23])[C:16](=[O:30])[C:17]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:18]12
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: O=C1Nc2ccccc2NC2CCCC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1Nc2ccccc2N(C(=O)CN2C(=O)c3ccccc3C2=O)C2CCCC12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.1 %

Procedure:
To a suspension of 2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (2.02 g, 10 mmol) in 1,2-dichloroethane (15 mL) was added phthalimidoacetyl chloride (2.24 g, 10 mmol),and the mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (10 mL) to give precipitate, which was filtered off. The aqueous layer of the filtrate was seperated. The organic layer was washed with water, dried over magnesium sulfate and subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was combined with the precipitate filtered previously, which was washed with methanol, followed by recrystallization from chloroform-methanol to give 2.42 g (yield 62%) of a cis-trans mixture (3:2). m.p. 293°-294° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C@H:17]1[CH2:21][C@@H:20]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=4[O:41][CH3:42])[C:25]=3[CH:24]=[CH:23]2)[C@H:19]([OH:43])[C@@H:18]1[OH:44].O=[C:46]1[CH2:49][CH:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:47]1.C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:42][O:41][C:34]1[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][C:30]1[C:25]2[CH:24]=[CH:23][N:22]([C@@H:20]3[CH2:21][C@H:17]([CH2:16][NH:15][CH:46]4[CH2:47][CH:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49]4)[C@@H:18]([OH:44])[C@H:19]3[OH:43])[C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@@H](O)[C@H]2O)c(OC)c1
Reactant: CCOC(=O)CCC1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@H](O)[C@@H]2O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Sodium triacetoxyborohydride (2.43 g, 11.5 mmol) was added to a solution of (1S,2R,3R,5R)-3-(aminomethyl)-5-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (2.6 g, 5.7 mmol) and ethyl 3-(3-oxocyclobutyl)propanoate (0.976 g, 5.73 mmol) and Acetic acid (0.326 ml, 5.73 mmol) in 1,2-Dichloroethane (20 ml) and reaction was stirred at RT overnight. NaHCO3 was added and the aqueous layer was extracted 3× with DCM. The combined organics were dried with MgSO4, filtered, concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to give the desired compound (1.8 g) as a thick yellow resin.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH2:13]2)=[C:9]([S:16](Cl)(=[O:18])=[O:17])[C:8]=1[OH:20])=[O:4].[NH3:21]>CC(C)=O.O>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][CH2:13]2)=[C:9]([S:16](=[O:18])(=[O:17])[NH2:21])[C:8]=1[OH:20])=[O:4]
Reactant: N
Reactant: O=C(CCl)NCc1cc2c(c(S(=O)(=O)Cl)c1O)CCC2
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)c1c(O)c(CNC(=O)CCl)cc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
33.8 g (0.1 mole) of 6-(N-chloroacetylaminomethyl)-5-hydroxy-4-chlorosulfonylindane are dissolved in a little acetone, and the solution is added dropwise to 50 ml of concentrated ammonia solution. The mixture is stirred for 30 minutes at room temperature and is diluted with water. The precipitate which is deposited is filtered off with suction and dissolved in acetone, and the solution is filtered and stirred into water again.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)([C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([Br:20])[CH:19]=2)[N:16]=[C:15]([O:21]C(C)(C)C)[CH:14]=[C:13]3[Br:26])O)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[C:18]([Br:20])[CH:19]=2)[N:16]=[C:15]([OH:21])[CH:14]=[C:13]3[Br:26])=[CH:4][CH:3]=1
Reactant: CC(C)(C)Oc1cc(Br)c2cc(C(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed bis(4-chlorophenyl)[4,8-dibromo-2-(tert-butoxy)quinolin-6-yl]methanol (500 mg, 0.82 mmol, 1.00 equip), dichloromethane (50 mL), triethylsilane (1 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred overnight at 25° C. The resulting solution was diluted with DCM (100 mL). The resulting mixture was washed with saturated sodium bicarbonate (3×100 mL) and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 6-[bis(4-chlorophenyl)methyl]-4,8-dibromoquinolin-2-ol as a yellow solid. LCMS (ES, m/z) 538 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.Cl.[CH3:17][N:18]([CH3:23])[CH2:19][C:20](O)=[O:21].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN1CCCC1=O.C(N(CC)CC)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:20](=[O:21])[CH2:19][N:18]([CH3:23])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN(C)CC(=O)N1CCN(c2ccc(N)cc2)CC1

Procedure:
1-(4-nitrophenyl)piperazine and N,N-dimethylglycine hydrochloride were allowed to undergo the reaction using WSC hydrochloride and HOBt in 1-methyl-2-pyrrolidone in the presence of triethylamine. The resulting compound was subjected to-catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 1-[4-(4-aminophenyl)piperazin-1-yl]-2-dimethylaminoethanone. NMR2: 2.30 (6H, s), 3.74-3.76 (4H, m), 6.64-6.68 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].CCN(CC)CC>C(Cl)Cl>[C:2]1([CH3:1])[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][CH2:10][O:11][S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=1
Reactant: Cc1cccc(CCCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-(m-Methylphenyl)-1-propanol (0.45 g, 3.00 mmol), MsCl(278 uL, 3.60 mmol) and Et3N (0.84 mL, 6.00 mmol) were combined in CH2Cl2 (30 mL) and stirred at 0° C. for 4 hrs. The reaction was then diluted with CH2Cl2 (30 mL) and washed with cold brine, dried over Na2SO4 and concentrated to give a light brown oil. This was used without further purification. 1H NMR (300 MHz, CDCl3) δ 2.04-2.09 (m, 2H), 2.33(s, 3H), 2.69-2.74 (t, 2H), 2.99 (s, 3H), 4.20-4.24 (t, 2H), 6.97-7.04 (m, 3H), 7.16-7.19 (m, 1H).