Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[CH2:2]([O:9][CH2:10][O:11][CH2:12][C@@H:13]([CH3:26])[CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li+].[Cl-]>C1COCC1>[CH2:2]([O:9][CH2:10][O:11][CH2:12][C@@H:13]([CH3:26])[CH2:14][CH2:5][CH:4]=[C:3]([CH3:8])[CH3:2])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)COCOCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)COCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 156.6 %

Procedure:
4-Chloro-2-methyl-2-butane (15.5 mL, 14.4 g, 137.5 mmol) was added dropwise to stirred magnesium turnings (6.75 g, 225 mmol) in anhydrous THF (465 mL) under argon at 0° C. The stirring was continued 0° C. for 1 hour. The cooling bath was removed, and the mixture was stirred at room temperature for an additional 1.5 hours. The mixture was then cooled to −78° C. and the formed Grignard reagent was added via cannula to a solution of tosylate 4 (10 g, 27.5 mmol) in anhydrous THF (70 mL). Li2CuCl4 (160mL) [previously prepared from LiCl (1.36 g, 32.1 mmol) and CuCl2 (2.17 g, 16.1 mmol)] was then added to the reaction mixture. The cooling bath was removed, and the reaction was stirred at room temperature for 17 hours. The mixture was extracted with CH2Cl2, and the organic layer was washed with NH4Cl and NaHCO3, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel using hexane/EtOAc (7:3) as an eluent to give oily product 5 (5.65 g, 78%).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5]CC)=[O:4].Cl[C:31]1[S:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1.[OH-].[Na+]>>[S:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[N:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=1)[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([OH:5])=[O:4])=[CH:11][CH:12]=1
Reactant: Clc1nc2ccccc2s1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2nc3ccccc3s2)cc1)C(=O)O

Procedure:
Similarly, condensation of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate with 2-chlorobenzothiazole, followed by standard hydrolysis with NaOH afforded the title compound.
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:4]
Reactant: CC(C/C=C/c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
Under a nitrogen atmosphere, a cold (0-5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(3,4-dichlorophenyl)-4-penten-2-amine (1.38 g, 4.01 mmol) in anisole (20 mL) was treated drop-wise over 45 min with trifluoroacetic acid (20.72 g, 181.7 mmol). The resulting solution was stirred for 1.5 h at 0-5° C. The solution was then concentrated by rotary evaporation followed by further drying under high vacuum. The resulting residue was cooled (0-5° C.), basified with 10% NaOH solution (15 mL), treated with saturated NaCl solution (10 mL) and extracted with CHCl3 (6×20 mL). The combined CHCl3 extracts were washed with saturated NaCl solution (25 mL), dried (Na2SO4), filtered, concentrated by rotary evaporation, followed by further drying under high vacuum to produce a light-brown oil (0.96 g). The crude product was purified by column chromatography on silica gel (50 g), eluting with CH3OH—Et3N (98:2, v/v). Selected fractions containing the product (Rf 0.44) were combined and concentrated on a rotary evaporator. The residue was dissolved in CHCl3. The CHCl3 solution was dried (Na2SO4), filtered, concentrated by rotary evaporation and dried under high vacuum to give 467 mg (47.7%) of a light-yellow oil.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([N:16]1[CH2:29][CH2:28][CH2:27][C@H:17]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])=[O:15])[CH3:13])=O)C1C=CC=CC=1.CCOCC.[BrH:35]>C(O)(=O)C>[BrH:35].[NH2:11][C@H:12]([C:14]([N:16]1[CH2:29][CH2:28][CH2:27][C@H:17]1[C:18]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=[O:15])[CH3:13]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
10 g (0.025 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline anilide were dissolved in 50 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. 300 ml of dry ether were then added. An oil precipitated out and was allowed to settle. The solution was decanted off and the oil was washed with two 150 ml portions of ether, dissolved in the minimum volume of methanol and treated with an excess of ethyl acetate. The product soon crystallised, there being obtained 7.2 g (83%) of L-alanyl-L-proline anilide hydrobromide of melting point 211°-214° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)OCC[O:11]2)=[CH:6][CH:5]=1.CCCCCCC.CCOCC>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:11])[CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2(CCCOCCc3ccccc3)OCCO2)cc1
Agent: Cl
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=O)CCCOCCc2ccccc2)cc1
Yield: 77.6 %

Procedure:
This compound was synthesized as described under 5.c) with 0.8 ml of HCl (1N) and 0.65 g (1.9 mmol) of 2-(4-methoxyphenyl)-2-[3-(2-phenylethoxy)propyl]-1,3-dioxolane obtained under a) in 50 ml of THF. Column chromatography (SiO2, heptane/ether 4:1) gave 0.44 g (78%) of white crystals.
Reaction SMILES: [CH:1]([C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1)=O.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.S([O-])([O-])(=O)=O.[Mg+2].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:46]([NH:53][CH2:1][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C=O)CO1)C(c1ccccc1)c1ccccc1
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNCc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (2R,5S)-5-formyl-2-[2-(2-{[N-(methoxycarbonyl)-b-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (1 eq.) in MeOH (0.05 M) was added benzylamine (7 eq.), magnesium sulfate (1.2 eq.) and acetic acid (7 eq.). The solution was stirred for 30 minutes and sodium cyanoborohydride (2.3 eq.) was added and the reaction mixture was further stirred for 2 hours. The reaction mixture was then quenched by the addition of aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 30% to 100% of EtOAc/Hex to afford title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[K+]>COCCOC.O.C(OCC)C>[CH2:10]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Solvent: O
Product: Fc1c(Cl)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A mixture of 3-chloro-2-fluorophenol (1.5 g, 10.2 mmol), benzyl bromide (1.71 g, 10.0 mmol) and sodium carbonate (1.10 g, 10.38 mmol) in 20 mL ethylene glycol dimethyl ether and 10 mL H2O was stirred at rt for 36 h. The reaction mixture was charged with 20 mL 1N KOH and 50 mL diethyl ether. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford the title compound as a white solid which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 5.16 (s, 2Hs) 6.86-7.03 (m, 3Hs) 7.31-7.48 (m, 5Hs).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([Cl:9])[CH:4]=1.C(=O)([O-])[O-:11].[K+].[K+]>O>[Cl:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:11])[CH:8]=[CH:7][N:6]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: OCc1ccnc(Cl)c1
Temperature: 25 °C
Yield: 9.3 %

Procedure:
The crude product of 4-(chloromethyl)-2-chloropyridine (9.25 g), and potassium carbonate (9.5 g, 68.7 mmol) were suspended in water (100 mL) and heated at reflux for 2.5 h. The mixture was allowed to cool to room temperature and the phases were separated. The oily phase was further extracted with water. The combined aqueous phases were washed with hexanes and extracted with EtOAc. The combined EtOAc phases were dried over MgSO4 and concentrated in vacuo to yield 2-Chloro-4-pyridinemethanol as an off white solid (762 mg, 9.3% yield over 2 steps).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[H-].[Na+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Cl-].[NH4+]>CN(C)C=O.O>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC(=O)Nc1[nH]c(-c2cccc(O)c2)cc1C(N)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)Nc1[nH]c(-c2cccc(Oc3ccc([N+](=O)[O-])cc3)c2)cc1C(N)=O
Reaction time: 0.58 h
Yield: 8.3 %

Procedure:
Under ice-cooling, a solution of 2-aminocarbonylamino-5-(3-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-2, 100 mg, 0.38 mmol) in N,N-dimethylformamide (1.5 mL) was added to a suspension of 60% sodium hydride (23 mg, 0.58 mmol) in N,N-dimethylformamide (1.5 mL) and the mixture was stirred for 35 minutes. Moreover, 4-fluoronitrobenzene (61 μL, 0.57 mmol) was added thereto and the whole was stirred overnight at 50° C. Saturated aqueous ammonium chloride solution (3 mL) and water (3 mL) were added to the reaction solution, extracted with ethyl acetate (10 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the target compound (12 mg) as a yellow solid (Yield 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:11](F)=[N:12][CH:13]=1.[NH2:22][NH2:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:11]([NH:22][NH2:23])=[N:12][CH:13]=1
Reactant: NN
Reactant: Fc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Solvent: c1ccncc1
Product: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a suspension of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-fluoropyridine (0.32 g, 1 mmol) in pyridine (4 mL) at room temperature was added anhydrous hydrazine (1 mL). The resulting mixture was stirred at 90° C. for 1 h. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the resulting suspension was extracted with EtOAc (50 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure to afford 0.28 g (85%) of the title compound as a white foam. HPLC/MS: retention time=3.03 min, [M+H]+=330.1.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][CH:4]=[N:3]1.[C:7]1([C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1.CCOCC>[C:7]1([C:13]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:1][N:2]2[CH:6]=[N:5][CH:4]=[N:3]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: Nn1cncn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(CC(=Nn2cncn2)c2ccccc2)cc1

Procedure:
A solution of 5.7 g (50.8 mmol) of 75% pure 1-amino-1H-1,2,4-triazole, 5.0 g (25.5 mmol) of deoxybenzoin and 0.6 g p-toluenesulfonic acid in 150 mL of benzene was heated at reflux with azeotropic removal of water for 7 days. Solvent was stripped and the residue was diluted with ether, which was washed with saturated aqueous Na2CO3, water and brine. Drying (MgSO4) and removal of solvent gave an off-white solid which was recrystallized from hexane affording 3.23 g of the desired product, m.p. 78°-80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.I[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])I>[Cu].CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(I)cc1
Reactant: FC(F)(I)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: Fc1ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)c2ccc(F)cc2)cc1
Temperature: 110 °C
Yield: 74.2 %

Procedure:
26.64 g of p-fluoroiodobenzene, 100 ml of DMSO and 15.24 g of copper powder were put in a flask under an atmosphere of nitrogen to be sufficiently stirred at a temperature of 110° C. Next, 30.46 g of 1,6-diiodoperfluorohexane was slowly dropped and stirred at a temperature of 120° C. for 20 hours. Then, the reaction solution was filtered so as to remove the unreacted copper, and was dropped into an aqueous solution containing a small quantity of NaCl. Then, the resulting deposits were filtered. The deposits were dissolved in acetone to be filtered and thereafter distill out the acetone. The residue was dissolved in methanol to add water and deposits were filtered. The deposits were distilled at a reduced pressure (155° C., 5 mmHg), thereby obtaining 20 g of a colorless solid.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O.[Br:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(O)(C)(C)C>[Br:12][CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][C:14]([CH3:22])([CH3:15])[CH3:13])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reaction time: 0.25 h

Procedure:
Magnesium sulfate (7.8494 g, 65.21 mmol) was suspended in dichloromethane (65 mL). Concentrated sulfuric acid (0.9 mL) was added and allowed to stir for 15 minutes. 4-(bromomethyl)benzoic acid (3.4851 g, 16.21 mmol) and tert-butanol (7.8 mL) were added. The reaction was allowed to stir overnight at room temperature. Saturated sodium bicarbonate (15 ml) was added and the reaction was allowed to stir. Magnesium sulfate was filtered off. The reaction was washed with saturated sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting material was dissolved in ethyl acetate and the product was partially recrystallized. To optimize the yield, the product remaining in the ethyl acetate was purified by column chromatography. 1H NMR 600 MHz (CD3OD) δ 7.91 (d, 2H, J=8.2 Hz), 7.48 (d, 2H, J=8.2 Hz), 4.58 (s, 2H), 1.60 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](I)[CH3:20]>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:19][CH3:20])=[CH:4][N:3]=1
Reactant: CCI
Reactant: Oc1cnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1cnc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 1-chloroisoquinolin-4-ol (1.0 g, 5.5 mmol) in acetonitrile (10 mL) was added K2CO3 (2.3 g, 16.7 mmol) followed by ethyl iodide (0.87 ml, 11.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get 1-chloro-4-ethoxyisoquinoline (0.7 g, 62%) as off-white solid. 1H NMR (400 MHz, CD3OD): δ ppm 8.26-8.24 (m, 2H), 7.79 (s, 1H), 7.76-7.26 (m, 2H), 4.29-4.24 (q, J=6.8 Hz, 2H), 1.58-1.54 (t, J=6.8 Hz, 3H); MS: MS m/z 207.7 (M++1).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:29])[NH:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:2]2[N:11]=[C:10]([N:12]([CH3:14])[CH3:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:26][CH:27]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CN(C)c1nc(Cl)nc2ccccc12
Solvent: ClCCl
Product: CN(C)c1nc(Nc2ccc(NC(=O)OC(C)(C)C)cc2)nc2ccccc12
Temperature: 130 °C
Yield: 87.2 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-dimethyl-amine obtained in step B of example 1 (0.5 g, 2.6 mmol) and (4-amino-phenyl)-carbamic acid tert-butyl ester (0.5 g, 2.6 mmol) in CH2Cl2 (2 mL) was heated by Smith Synthesizer at 130° C. for 20 min. The mixture was concentrated to give [4-(4-dimethylamino-quinazolin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester as a pale yellow solid (0.86 g, 87%). The reaction was repeated six times, and the total product combined was 8.5 g. To a solution of above product (8.5 g, 22.4 mmol) in MeOH (250 mL) was added 4 M HCl in dioxane (8.4 ml, 33.6 mmol) dropwise, and the mixture was stirred at ambient temperature for overnight. The mixture was concentrated to give N2-(4-amino-phenyl)-N4,N4-dimethyl-quinazoline-2,4-diamine hydrochloride as a pale pink solid (6.2 g, 87.5%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2ccc(C(F)(F)F)cc2)C1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)cc1
Yield: 43.8 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(4-trifluoromethylphenyl)piperidin-1-yl]methanone (18 mg, 0.046 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 7.6 mg of the title compound.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([C:10](Cl)=[O:11])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:13]([C:16]1[C:21]([NH:22]C(C2SC=C(C3CC3)N=2)=O)=[C:20]([Cl:33])[C:19]([O:34][CH3:35])=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[C:13]([C:16]1[C:21]([NH:22][C:10]([C:7]2[S:8][CH:9]=[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[N:6]=2)=[O:11])=[C:20]([Cl:33])[C:19]([O:34][CH3:35])=[CH:18][CH:17]=1)(=[O:15])[CH3:14]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C3CC3)cs2)c1Cl
Reactant: O=C(Cl)c1nc(C2CCC2)cs1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C3CCC3)cs2)c1Cl
Yield: 70 %

Procedure:
N-(6-Acetyl-2-chloro-3-methoxyphenyl)-4-cyclobutylthiazole-2-carboxamide 268b was synthesized from compound 267b (5.48 g, 1.2 eq.) as a white solid in 70% yield, following the procedure as described for compound 268a. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.96-2.12 (m, 2H), 2.34-2.44 (m, 4H), 2.59 (s, 3H), 3.70-3.78 (m, 1H), 3.99 (s, 3H), 6.88 (d, J=8.82 Hz, 1H), 7.20 (s, 1H), 7.68 (d, J=8.76 Hz, 1H), 10.33 (br s, 1H); MS (ESI, EI−): m/z=365 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([NH2:5])=[O:4].[SH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1>>[NH2:5][C:3](=[O:4])[CH2:2][S:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: NC(=O)CBr
Product: COC(=O)c1ccc(SCC(N)=O)cc1

Procedure:
2.5 g of 2-bromoacetamide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(2-amino-2-oxoethylthio)benzoate. 2.6 g of methyl 4-(2-amino-2-oxoethylthio)benzoate was reacted via Procedure R to give methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate. 1 g of methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(2-amino-2-oxoethylsulfonyl)benzoic acid. 150 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-amino-2-oxoethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-amino-2-oxoethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 430.2 (M)+.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=1.O>CN(C)C=O>[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: CCOC(=O)c1csc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1csc(Cn2nc(-c3ccccc3)c3ccccc32)n1
Reaction time: 0.08 h
Yield: 10.5 %

Procedure:
Sodium hydride (added with 40% mineral oil, 9 mg, manufactured by Kanto Chemical Co., Inc.) was added to a solution of 3-phenyl-1H-indazole (40 mg), which had been synthesized according to the literature (T. Edward, C., et al., Tetrahedron, 1991, 47, 9599-9620), in N,N-dimethylformamide (1 mL, manufactured by Kanto Chemical Co., Inc.) under ice cooling, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, ethyl 2-bromomethylthiazole-4-carboxylate (51 mg) synthesized according to the method of the literature (K. Benno, et al., Leibigs. Ann. Chem., 1981, 4, 623-632) was added thereto, and the mixture was stirred overnight at room temperature. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×2 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by PTLC (hexane:ethyl acetate=2:1), to give 7.2 mg of the title compound. LC-MS: HPLC retention time 4.08 minutes, m/z 336 (M+H), condition A-1.