Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[N:7]O)[CH2:3][CH2:2]1.[CH3:9][O:10][C:11]([C:13]#[C:14][C:15]([O:17][CH3:18])=[O:16])=[O:12].C1N2CCN(CC2)C1>C1(C)C=CC=CC=1>[NH:7]1[C:13]([C:11]([O:10][CH3:9])=[O:12])=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:3]2[CH2:2][O:1][CH2:6][CH2:5][C:4]1=2
Reactant: COC(=O)C#CC(=O)OC
Reactant: ON=C1CCOCC1
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: COC(=O)c1[nH]c2c(c1C(=O)OC)COCC2
Temperature: 165 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A suspension of dihydro-2H-pyran-4(3H)-one oxime (7 g, 60.8 mmol), dimethylacetylene dicarboxylate (9.72 ml, 79 mmol), and DABCO (2.046 g, 18.24 mmol) in Toluene (27.5 ml) were heated to 165° C. After 2 h, the reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by ISCO (0-100% EtOAc-hexanes) to afford dimethyl 1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2,3-dicarboxylate (3.2 g, 13.38 mmol, 22.00% yield) as a yellow solid. The residue was dissolved in DMF (30 mL), and treated with Cs2CO3 (5.29 g, 16.23 mmol) and 4-fluorobenzyl bromide (2.023 ml, 16.23 mmol). After 2 h, the reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl. The organic layer was washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by ISCO (0-50% EtOAc-hexanes; 120 g column) to afford dimethyl 1-(4-fluorobenzyl)-1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2,3-dicarboxylate (3.92 g, 11.29 mmol, 18.56% yield) as a yellow oil. LCMS (m/z) ES+=348 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[CH2:10]([N:9]([CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:22](=[O:24])[CH3:23])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(CCNCc2ccccc2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N(CCc1ccccc1)Cc1ccccc1
Reaction time: 0.67 h
Yield: 102.6 %

Procedure:
N-benzyl-2-phenethylamine (2.2 g, 10 mmol) was dissolved in 7 mL of CH2Cl2. To this was added 7 mL of satd (aq.) NaHCO3 followed by acetyl chloride (0.88 g, 11 mmol) and the resulting mixture stirred for 40 min. The organic layer was separated, dried over Na2SO4 filtered and the solvent removed to yield 2.60 g (100%) oil. LC/MS (M+H) calcd for C17H20NO: 254.15; found: 254.07. 1H NMR and 13C NMR show a mixture of rotamers at room temperature. 1H NMR (500 MHz, CDCl3), δ: 2.04 (br s), 2.14 (br s), 2.81 (br m), 2.87 (br m), 3.44 (br m), 3.58 (br m), 4.36 (s), 4.62 (s), 7.11-7.36 (overlapping m, 10). 13C NMR (125 MHz, CDCl3) δ: 21.19, 21.80, 33.99, 34.87, 48.18, 48.28, 49.49, 52.75, 126.34, 126.81, 127.44, 127.65, 128.18, 128.52, 128.64, 128.73, 128.80, 128.85, 128.94, 136.74, 137.56, 138.17, 139.24, 170.81, 171.07.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13](=O)[NH:14]2)=[CH:9][CH:8]=1.C(Cl)(=O)C([Cl:30])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Cl:30][C:13]1[C:12]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]2[C:15](=[CH:16][C:7]([O:6][CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=3)=[CH:8][CH:9]=2)[N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)Cc1cc2ccc(OCc3cccc(Cl)c3)cc2[nH]c1=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1cc2ccc(OCc3cccc(Cl)c3)cc2nc1Cl
Yield: 89 %

Procedure:
To a slurry of ethyl 2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetate (31.4 g, 0.08 mol) in chloroform (314 mL) at ambient temperature was added oxalyl dichloride (21.7 mL, 0.25 mol) and DMF (0.66 mL, 0.01 mol). The resulting slurry was heated to reflux for 1 h. The reaction was quenched with sat. aqueous NaHCO3 (400 mL). The aqueous layer was extracted with DCM (2×200 mL) and the combined organic layers were washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure to furnish a black solid that was triturated in 1:1 EtOAc:hexanes (400 mL) and filtered. The solid was recrystallized from MeOH to furnish (17.0 g, 52%). Two additional crops of product were acquired from the mother liquor to furnish a total of 27.8 g (84.3%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.59 (s, 1H), 7.51-7.37 (m, 5H), 5.31 (s, 2H), 4.13 (q, J=7.1 Hz, 2H), 3.94 (s, 2H), 1.19 (t, J=7.1 Hz, 3H). [M+H]=390.2
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:19])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:19])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2ccc(Br)cc2)COC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC1(c2ccc(Br)cc2)COC1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
3-(4-Bromophenyl)oxetan-3-ol (1.55 g, 6.77 mmol) was taken up in DCM (100 mL) and cooled to −78° C. DAST (1.073 mL, 8.12 mmol) was added and the mixture was stirred at −78° C. for 90 minutes followed by 0° C. for 20 minutes. Saturated NaHCO3 was added and the products extracted into DCM (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (0-10% EtOAc-hexanes) gave the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([Cl:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([Cl:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(Cl)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1cc(Cl)c2c(C(=O)O)cc(Br)cc21
Temperature: 55 °C
Yield: 56 %

Procedure:
To a solution of methyl 6-bromo-3-chloro-1-(1-methylethyl)-1H-indole-4-carboxylate (1.2 g, 3.63 mmol) in THF (2.368 ml) and MeOH (14.21 ml) was added 3 N NaOH (1.573 ml, 4.72 mmol). The resulting mixture was heated at 55° C. for 4 h. The reaction was removed from the heat and the solvent removed in-vacuo. The remaining residue was dissolved with water (12 ml) and made acidic dropwise with 1 N HCl. The product precipitated and the slurry became too thick to stir and was diluted with water (10 ml). After the precipitation haulted no more acid was added. The solid was collected by vacuum filtration, washed with water, and air dried under vacuum overnight to give 6-bromo-3-chloro-1-(1-methylethyl)-1H-indole-4-carboxylic acid (650 mg, 2.033 mmol, 56.0% yield over 2 steps) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H), 8.09 (d, J=1.77 Hz, 1H), 7.89 (s, 1H), 7.45 (d, J=1.77 Hz, 1H), 4.88 (quin, J=6.63 Hz, 1H), 1.43 (d, J=6.57 Hz, 6H). MS (ES) [M+H]+ 316.0.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C(#N)C>[CH:14]1([NH:17][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]2[C:12]#[N:13])=[O:4])[CH2:16][CH2:15]1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1CC1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CC1
Reaction time: 8 h

Procedure:
To a stirred solution of Example 8D (0.045 g, 0.228 mmol) in acetonitrile (2 mL) at room temperature under nitrogen was added cyclopropylamine (0.032 ml, 0.457 mmol). The reaction mixture was stirred overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 3% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS m/z 218 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.5-2 (4H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13](O)=O>P(Cl)(Cl)(Cl)=O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: Nc1ccncc1N
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2cnccc2[nH]1

Procedure:
Quantities of 5.45 gm (50 mmol) of 3,4-diaminopyridine and 12.25 gm (50 mmol) of 2-methoxy-4-methanesulfonylaminobenzoic acid were triturated together and refluxed for four hours in 300 ml of phosphorus oxychloride. Excess phosphorus oxychloride was then distilled off, and the residue was mixed with 500 ml of water and adjusted to a pH of 8 with concentrated ammonia. The insoluble components were filtered off, the filtrate was saturated with sodium chloride, and the crude product precipitated. After purification by chromatography (800 gm of aluminum oxide; eluant: dichloromethane with 5 to 10% of ethanol), 4.8 gm (25.2% of theory) were obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:16])([F:15])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1>>[Cl:3][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([F:16])([F:15])[F:5])=[CH:8][CH:9]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1ccc(CCl)cc1

Procedure:
Thionyl chloride (15.0 g) was added to 4-(trifluoromethyl)benzenemethanol (15.0 g) over 30 min. The mixture was heated at reflux for 2 hr and then evaporated. The residue was distilled to afford the product as a colourless liquid b.p. 88°-92°/14 mm (11.0 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][C:22]=1[Br:23])[C:19]1[N:15]([CH:16]=[C:17]([C:24]3[N:28]([CH:29]([CH3:31])[CH3:30])[N:27]=[C:26]([CH3:32])[N:25]=3)[N:18]=1)[CH2:14][CH2:13][O:12]2)C1C=CC=CC=1>FC(F)(F)C(O)=O>[Br:23][C:22]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:24]2[N:28]([CH:29]([CH3:30])[CH3:31])[N:27]=[C:26]([CH3:32])[N:25]=2)=[CH:16]3)=[CH:10][C:9]=1[OH:8]
Reactant: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(OCc4ccccc4)cc2OCC3)n(C(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cn3c(n2)-c2cc(Br)c(O)cc2OCC3)n(C(C)C)n1
Yield: 122.6 %

Procedure:
A solution of 12-(benzyloxy)-13-bromo-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (5.50 g, 11.1 mmol) in trifluoroacetic acid (20 mL) was heated to reflux for 1 h. After cooling down, the mixture was concentrated to give the crude product (5.5 g), which was used directly in the next step without further purification. LCMS m/z [M+H]+ 404.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1.[CH2:12]([Zn]CC)[CH3:13]>O1CCOCC1>[CH2:12]([C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:6][CH:7]=1)[CH3:13]
Reactant: COC(=O)c1cncc(Br)c1
Reactant: CC[Zn]CC
Solvent: C1COCCO1
Product: CCc1cncc(C(=O)OC)c1
Temperature: 70 °C
Yield: 54.9 %

Procedure:
To a solution of methyl 5-bromopyridine-3-carboxylate (10.0 g, 46.29 mmol) in anhydrous dioxane (100 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (677 mg, 0.925 mmol). Then, diethylzinc (5.71 g, 38 mL, 46.29 mmol, 15% solution in toluene) was added dropwise. The reaction mixture was heated at 70° C. for 45 minutes, then cooled to room temperature and quenched with MeOH. The mixture was extracted with ethyl acetate (2×250 mL) and washed with water, 0.1 N HCl, and brine. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated, and the residue was purified by CombiFlash using 0-30% ethyl acetate and hexane to provide methyl 5-ethylpyridine-3-carboxylate as a yellow oil (4.20 g, 55% yield); 1H NMR (400 MHz, CDCl3): δ 1. (t, 3H), 1.45 (t, 3H), 2.78 (q, 2H), 3.99 (s, 3H), 8.15 (s, 1H), 8.65 (s, 1H), 8.89 (s, 1H); M+165.1.
Reaction SMILES: CN(C)[C@@H]1CCCC[C@H]1O.[H-].[Na+].CS(Cl)(=O)=O.C[N-]CC1C=CC=CC=1.[CH3:27][N:28]([CH3:44])[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[N:35](C)[CH2:36]C1C=CC=CC=1>[Pd].CCO.C1COCC1>[CH3:27][N:28]([CH3:44])[C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[NH:35][CH3:36]
Reactant: CN(C)C1CCCCC1N(C)Cc1ccccc1
Agent: [Pd]
Agent: CN(C)[C@@H]1CCCC[C@H]1O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CN[C@@H]1CCCC[C@H]1N(C)C
Reaction time: 18 h

Procedure:
A solution of trans-2-dimethylaminocyclohexanol (61.1 g.; 0.427 mole) in 85 ml. of THF was added during 5 minutes to a suspension of NaH (17.97 g.; 0.427 mole of 57% dispersion in mineral oil) in 250 ml. of THF, and the mixture was heated at 95° for 2 hours. It was cooled to 10°, and treated dropwise with methanesulfonyl chloride (48.91 g.; 0.427 mole) during 40 minutes keeping the temperature at 15°. N-Methylbenzylamide (103.48 g.; 0.854 mole distilled) was then added, THF was evaporated and heating continued at 95° for 18 hours. The mixture was treated with 500 ml. of 20% NaOH, heated at 95°, cooled and extracted with ether (6×100 ml.). The ether solution was extracted with 10% HCl (6×100 ml.), backwashed with ether (discard ether), cooled, basified with 20% NaOH and extracted with ether. The ether extract was washed with H2O, saturated salt solution, dried (MgSO4) and evaporated to give 48.6 g. of crude N,N,N'-trimethyl-N'-benzyl-1,2-cyclohexanediamine as an oil. A solution of this oil (46.6 g.) was hydrogenated in two portions each in 130 ml. of EtOH, with 2.6 g. of 10% Pd-C and 28.6 g. of 70% HClO4 at initial pressure of 51 p.s.i. for 22 hours. The mixture was filtered through Celite, the filtrate was evaporated, cooled in ice and basified with 40% KOH. The resulting thick suspension was extracted with ether (4×200 ml.), the ether extract was dried (MgSO4) and evaporated. The product boiled at 87°-88° (15 mm Hg). Vpc-mass spectrum showed that the first peak 3.4 minutes, was N,N-dimethyl-1,2-cyclohexanediamine and the second peak (4.1 minute) was the desired N,N,N'-trimethyl-1,2-cyclohexanediamine.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:23])[CH3:22])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:8]=2[O:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pt]>[C:1]([O:4][C:5]1([CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:23])[CH3:22])[CH2:11][O:10][C:9]2[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:8]=2[O:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1(CN(C(C)=O)C(C)C)COc2ccc([N+](=O)[O-])cc2OC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(=O)OC1(CN(C(C)=O)C(C)C)COc2ccc(N)cc2OC1

Procedure:
The 3-acetoxy-3-(N-acetylisopropylaminomethyl)-7-nitro-3,4-dihydro-2H-1,5-benzodioxepin when dissolved in ethyl acetate is reduced at low pressure over platinum with hydrogen to give 3-acetoxy-3-(N-acetylisopropylaminomethyl)-7-amino-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=1[F:33])=O>CC(=O)OCC>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][N:9]2[C:22]=1[C:23]1[C:24]([F:33])=[C:25]([F:32])[C:26]([F:31])=[C:27]([F:30])[C:28]=1[F:29]
Reactant: O=C(c1ccccc1)c1ccc2nc(NC(=O)C(F)(F)F)c(-c3c(F)c(F)c(F)c(F)c3F)n2c1
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(C(=O)c3ccccc3)cn2c1-c1c(F)c(F)c(F)c(F)c1F

Procedure:
The 2-trifluoroacetamido-3-(2,3,4,5,6-pentafluorophenyl)-6-benzoyl-imidazo[1,2-a]pyridine (5.03 g, 10.1 mmol) was converted to product in a manner substantially analogous to Example 67 to yield 3.79 g. (93.3%). EA, MS(FD).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=O)=[CH:4][N:3]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[NH2:11])=[CH:4][N:3]=1
Reactant: Cc1ccc(N(CCc2ccc(C)nc2)N=O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: Cc1ccc(N(N)CCc2ccc(C)nc2)cc1

Procedure:
reacting 2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine with sodium thiosulfate to obtain 2-methyl-5-(N-amino-2-p-tolylaminoethyl)pyridine;
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][CH3:19].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[ClH:40]>O1CCOCC1.O.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[ClH:40].[ClH:40].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[C:3]([CH3:20])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[NH:18][CH3:19]
Reactant: CNc1nc(-c2cccnc2)nc2ccc(Br)c(C)c12
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(F)cc3F)c(C)c12
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
6-Bromo-N,5-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine (350 mg, 1.06 mmol), 2,4-difluorophenylboronic acid (252 mg, 1.595 mmol), K3PO4 (677 mg, 3.19 mmol) and Pd(dppf)Cl2—CH2Cl2 (87 mg, 0.106 mmol) were dissolved in the mixed solvent of 1,4-dioxane (10 mL) and water (1 mL). The resulting mixture was stirred at 90° C. for 2.5 hours under N2. After the reaction was completed, water was added to the mixture and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4. After filtration and evaporation, the crude product was purified by column chromatography on NH-silica gel (eluted with isocratic 33% ethyl acetate/67% hexane) to give a white powder. The solid was suspended in ethanol and 5N HCl (1.0 mL) was added to the mixture. The mixture was sonicated for 10 min and the resultant precipitate was collected by filtration and dried to give 139 mg of 6-(2,4-difluorophenyl)-N,5-dimethyl-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride as a pale yellow powder in a 30% yield.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:29]=[CH:28][C:20]2[S:21][CH:22]=[C:23]([C:24]([F:27])([F:26])[F:25])[C:19]=2[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:29]=[CH:28][C:20]4[S:21][CH:22]=[C:23]([C:24]([F:26])([F:27])[F:25])[C:19]=4[CH:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1csc2ccc(Br)cc12
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2ccc3scc(C(F)(F)F)c3c2)CCN1c1cnccc1C1CC1
Yield: 7.8 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 100 mg, 0.492 mmol) was reacted with 5-bromo-3-(trifluoromethyl)benzo[b]thiophene (151 mg, 0.54 mmol), 1,4-dioxane (5 mL), copper iodide (9.3 mg, 0.049 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (6.9 mg, 0.049 mmol) and potassium phosphate (313 mg, 1.47 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in CHCl3), followed by preparative HPLC afforded 15.4 mg of the product (8% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:4]([NH:22][NH2:23])[N:3]=1.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:1][C:2]1[N:3]2[C:25](=[O:27])[NH:23][N:22]=[C:4]2[C:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NNc1nc(Cl)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of a mixture of 2-chloro-4,5-bis(4-chlorophenyl)-6-hydrazinylpyrimidine and its regioisomer prepared above (900 mg, 2.46 mmol) in THF (10 mL) at room temperature under argon was added triphosgene (1.46 g, 4.91 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled in an ice bath and carefully quenched with water (10 mL) and then extracted with EtOAc (15 mL×2). The combined organic extracts were washed with water and then saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with 20% ethyl acetate-hexanes to obtain 400 mg of the title compound as a yellow solid. HPLC/MS: retention time=3.923 min, [M+H]+=391; 1H NMR (DMSO-d6, 500 MHz): δ 12.68 (s, 1H), 7.39 (d, J=8.25 Hz, 2H), 7.31 (d, J=8.25 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H). Regioisomeric product derived from starting material regioisomeric impurity: HPLC/MS: retention time=3.545 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc2ccccc2nc1Cl
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 2-chloroquinoline-3-carbaldehyde (1.0 g, 5.21 mmol) in anhydrous ethanol (20 mL) at 0° C., was added sodium borohydride (0.197 g, 5.21 mmol). The reaction mixture was stirred at the same temperature for 1 hour. After completion of the reaction, as monitored by TLC and HPLC, the reaction mixture was quenched with water. The solvent was evaporated, and the crude residue was extracted with dichloromethane. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate to provide the (2-chloroquinolin-3-yl)methanol as a white solid (0.96 g, 95% yield); M+193.64.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][NH:23][CH3:24]>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([N:23]([CH3:24])[CH3:22])=[O:15])=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: CC(C(=O)Cl)c1ccc2c(c1)CCc1ccccc1C2=O
Reactant: CNC
Product: CC(C(=O)N(C)C)c1ccc2c(c1)CCc1ccccc1C2=O
Yield: 97.2 %

Procedure:
Following the procedure of Example 6 but starting with 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionyl chloride (10 g.) and dimethylamine (4.5 g.), 2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)-N,N-dimethylpropionamide (10 g.) is obtained in the form of an oil.