Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.[C:19](Cl)([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>ClCCl>[CH3:12][O:11][C:10]1[C:2]([NH:1][C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C(=O)O)c1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
2-amino-3-methoxybenzoic acid 97 (1 g, 6.0 mmol) and pyridine (0.97 mL, 12.0 mmol) were dissolved in dry dichloromethane (30 mL). The resulting mixture was cooled and Troc-Cl (0.9 mL, 6.6 mmol) was added drop wise. The reaction mixture was allowed to stir overnight at room temperature, then washed with HCl (1N, 50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over MgSO4 and evaporated to yield 1.42 g of crude product, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][N:10]([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Clc1nccc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.0 g) obtained in Step C of Example 305 in DMF (10 mL) was added sodium hydride (60%, 130 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added trityl chloride (1.1 g) at room temperature, and the mixture was stirred for 15 hr. To the reaction mixture was added water, and the resulting solid was collected by filtration, and dried to give the title compound (1.7 g).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:5]=[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=[C:7]2[N:8]=1.[CH3:14]OS(=O)(=O)OC>CO>[CH3:14][S:3][C:4]1[N:8]=[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[N:5]=1
Reactant: COS(=O)(=O)OC
Reactant: Sc1nc2cccccc-2n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2cccccc-2n1
Temperature: 45 °C
Yield: 81.9 %

Procedure:
38 g of potassium hydroxide was dissolved in 800 ml of methanol and then 100 g of 2-mercaptocycloheptimidazole was added thereto and stirred under heating at an internal temperature of about 45° C. Next, 131.2 g of dimethylsulfuric acid was dropwise added and further stirred under heating at an internal temperature of about 45° C. for 1 hour. After the solvent was evaporated off to some degree under reduced pressure, one liter of water was added, and the resulting solution was extracted with chloroform (0.5 liter×2). Then, the chloroform layer was dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure until the chloroform solution became 200 ml. Next, one liter of hexane was added to the thus concentrated solution whereby a precipitate crystallized out. This was separated by filtration and dried. 89 g of colorless crystals was obtained.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]3[O:33][CH2:34][O:35][C:29]=3[CH:28]=2)[CH2:20]1>CS(C)=O>[CH2:34]1[O:33][C:30]2[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][N:21]3[CH2:22][CH2:23][CH2:24][C@H:20]3[CH2:19][N:8]3[C:7]4[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=4[CH2:12][O:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]3=4)=[CH:28][C:29]=2[O:35]1
Reactant: Cl[C@@H]1CCCN(CCc2ccc3c(c2)OCO3)C1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc2c(c1)COc1ccccc1N2C[C@@H]1CCCN1CCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
Sixty-percent sodium hydride (0.11 g, 2.8 mmols) was washed with petroleum ether, and then suspended in 10 ml of dimethyl sulfoxide. To the suspension were added 450 mg (2.3 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 0.56 g (2.1 mmols) of (R)-(−)-3-chloro-1-(3,4-methylenedioxyphenethyl) piperidine[[α]D25=−11.9° (c=1.0, ethanol)] in 5 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 12 hours and at 40° C. for 4 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:5. This mixed solvent was distilled off under reduced pressure. Further, the thus-obtained residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform and methanol at a ratio of 200:1. This mixed solvent was then distilled off under reduced pressure to give 0.46 g of (S)-(−)-5,11-dihydro-5-[1-(3,4-methylenedioxyphenethyl)-2-pyrrolidinyl-methyl]dibenzo [b,e][1,4]oxazepine as a pale yellow oil in a yield of 51%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([C:13]3[N:14]=[C:15]([NH2:18])[S:16][CH:17]=3)=[C:8]([CH3:19])[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH3:19])[C:9]([C:13]3[N:14]=[C:15]([NH:18][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[S:16][CH:17]=3)=[C:10]([CH3:12])[CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(OCC2CC2)cc(C)c1-c1csc(N)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCC2CC2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.6 %

Procedure:
To a solution of 4-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)thiazol-2-amine (4-5, 0.410 g, 1.51 mmol) in CH2Cl2 (10 mL) was added triethylamine (1.0 mL, 7.2 mmol) followed by isonicotinoyl chloride hydrochloride (0.470 g, 2.62 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered, and recrystallized in toluene to give N-{4-(4-(cyclopropylmethoxy)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (4, 0.41 g) as light yellow solids in 72% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.0 (s, 1 H), 8.80 (d, J=4.9 Hz, 2 H), 7.99 (d, J=6.0 Hz, 2 H), 7.10 (s, 1 H), 6.68 (s, 2 H), 3.81 (d, J=7.0 Hz, 2 H), 2.06 (s, 6 H), 1.21 (s, 1 H), 0.57 (d, J=6.5 Hz, 2 H), 0.32 (d, J=5.7 Hz, 2 H). ESI-MS: m/z 380.3 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[CH:14]=[C:15]([O:18][CH2:19][C@@H:20]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH:16]=[CH:17][C:12]=2[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]1=[O:33])([CH3:3])[CH3:2].Cl.C(OCC)C>ClCCl>[NH2:25][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]2[C:11]3[C:6](=[CH:7][N:8]=[CH:9][CH:10]=3)[C:5](=[O:33])[N:4]([CH:1]([CH3:2])[CH3:3])[C:13]=2[CH:14]=1
Reactant: CC(C)C[C@@H](COc1ccc2c3ccncc3c(=O)n(C(C)C)c2c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C[C@H](N)COc1ccc2c3ccncc3c(=O)n(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of ((S)-tert-butyl (1-((6-isopropyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (160 mg, 0.353 mmol) in anhydrous dichloromethane (4 mL) was added a 2 M solution of HCl in diethyl ether (0.88 mL, 1.76 mmol) dropwise at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then concentrated under reduced pressure to afford crude product which was purified by preparative HPLC (10 mM ammonium acetate in water; acetonitrile) to afford (S)-8-((2-amino-4-methylpentyl)oxy)-6-isopropylbenzo[c][2,7]naphthyridin-5(6H)-one (45 mg, 0.127 mmol, 36% yield) as an off-white solid. LC/MS (ESI) m/e 354.2 [(M+H)+, calcd for C21H28N3O2 354.2]; LC/MS retention time (method C): tR=1.81 min; HPLC retention time (method A): tR=8.85 min; HPLC retention time (method B): tR=9.50 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.43 (d, J=0.75 Hz, 1H), 8.75 (d, J=5.77 Hz, 1H), 8.42 (d, J=9.04 Hz, 1H), 8.22 (d, J=5.52 Hz, 1H), 7.30 (d, J=2.26 Hz, 1H), 7.10 (dd, J=8.78, 2.26 Hz, 1H), 5.26-5.43 (m, 1H), 4.16 (dd, J=9.16, 3.89 Hz, 1H), 3.98 (dd, J=9.29, 7.03 Hz, 1H), 3.27-3.31 (m, 1H), 1.81-1.92 (m, 1H), 1.73 (d, J=7.03 Hz, 6H), 1.41-1.51 (m, 2H), 1.02 (dd, J=9.54, 6.53 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)ON=1.CC1[O:18][N:17]=C(C(OCC)=O)C=1>>[CH3:1][C:2]1[O:18][N:17]=[C:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]2)[CH:6]=1
Reactant: CCOC(=O)c1cc(C)on1
Reactant: Cc1cc(C2(C(=O)O)CC2)on1
Product: Cc1cc(C2(C(=O)O)CC2)no1

Procedure:
The title compound was prepared by a method analogous to the one used for Intermediate 8, but using ethyl 5-methylisoxazole-3-carboxylate as the starting material. MS (ES+) (M+H) 168.0; LCMS retention time: 2.06 minutes. (Method L). 1H NMR (500 MHz, CD3OD) δ 1.38-1.42 (m, 2H), 1.58-1.62 (m, 2H), 2.39 (s, 3H), 6.32 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])(=[O:6])=[O:5])[CH3:3].[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:9]2([OH:13])[CH2:10][CH2:11][CH2:12][CH:8]2[NH:7][S:4]([CH:2]([CH3:1])[CH3:3])(=[O:6])=[O:5])=[CH:17][CH:16]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)S(=O)(=O)NC1CCCC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)S(=O)(=O)NC1CCCC1(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Scheme IA, step D: Into a flame dried 100 mL 3 neck flask that was fitted with a thermometer and condenser, 2-{[(methylethyl)sulfonyl]amino}cyclopentan-1-one (1.10 g, 5.36 mmol) in THF (25 mL) was added dropwise to 4-fluorophenylmagnesium bromide (3 mL, 2M solution in diethyl ether) while stirring at room temperature under a nitrogen atmosphere and keeping the temperature above 25° C. After the addition was complete, the reaction was refluxed for 2 hours and then stirred overnight at room temperature. In the morning, enough saturated ammonium chloride in water was added to precipitate the salts and the organic layer was decanted off. The remaining salts were washed two times with ether and the combined organic layers were concentrated under reduced vacuum. The resulting material was taken into ethyl acetate, washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 930 mg of a dark oil. This isomeric mixture was purified via silica gel chromatography employing the Chromatotron® and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 7:3 to provide the title compound (787 mg, 49%) as an oil. Ion Spray M.S. 300.1 (M*−1). Calculated for C14H20NO3SF—½H2O: Theory: C, 54.16; H, 6.82; N, 4.51. Found: C, 54.39; H, 6.61; N, 4.69.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].[OH:6][C:7]1[CH2:12][CH:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([S:21](=[O:24])(=[O:23])[NH2:22])[C:14]=2[CH3:25])[CH2:10][C:9](=[O:26])[C:8]=1[C:27](=O)[CH2:28][CH3:29]>>[CH2:2]([O:4][N:5]=[C:27]([C:8]1[C:9](=[O:26])[CH2:10][CH:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([S:21](=[O:23])(=[O:24])[NH2:22])[C:14]=2[CH3:25])[CH2:12][C:7]=1[OH:6])[CH2:28][CH3:29])[CH3:3]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(S(N)(=O)=O)c2C)CC1=O
Reactant: CCON
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(S(N)(=O)=O)c2C)CC1=O

Procedure:
Reaction of ethoxyamine hydrochloride with 3-hydroxy-5-(2,4,6-trimethyl-3-sulfamoylphenyl)-2-propionylcyclohex-2-en-one following essentially the same procedure as that described in Example 1 part (iv) gave 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethyl-3-sulfamoylphenyl)cyclohex-2-en-1-one (12). The compound was characterized by its proton magnetic resonance spectrum which is given in Table 5, Example 37.
Reaction SMILES: O=[C:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([O:11]C)=O.[CH2:19]([NH2:22])[CH2:20][NH2:21]>O1CCOCC1>[N:16]1[CH:17]=[CH:18][C:13]([C:2]23[NH:22][CH2:19][CH2:20][N:21]2[C:9](=[O:11])[C:5]2[N:4]([CH:8]=[CH:7][CH:6]=2)[CH2:3]3)=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccncc1
Reactant: NCCN
Solvent: C1COCCO1
Product: O=C1c2cccn2CC2(c3ccncc3)NCCN12
Yield: 59.8 %

Procedure:
To a solution of methyl 1-[2-oxo-2-(pyridin-4-yl)ethyl]-1H-pyrrole-2-carboxylate (55 mg, 0.23 mmol) in 1,4-dioxane (10 mL) was added ethane-1,2-diamine (0.6 mL, 9.0 mmol). The mixture was heated at reflux for 64 hours and then concentrated in vacuo to give a residue that was purified by flash chromatography (Biotage SP4, gradient CH2Cl2 3 CV, 0 to 10% methanol in CH2Cl2 10 CV, hold 10% MeOH 10 CV) to give 10a-(pyridin-4-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as an off-white solid (35 mg, yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 2.84 (dt, 1H, J 15.2, 4.4 Hz), 3.30-3.37 (m, 1H), 3.49 (ddd, 1H, J 11.3, 7.1, 3.5 Hz), 3.79 (dt, 1H, J 11.2, 8.0 Hz), 4.26 (d, 1H, J 12.2 Hz), 4.39 (d, 1H, J 12.3 Hz), 4.48 (dd, 1H, J 2.5, 1.6 Hz), 6.12 (dd, 1H, J 3.8, 2.6 Hz), 6.92 (dd, 1H, J 3.9, 1.5 Hz), 7.25-7.28 (m, 2H), 8.47-8.50 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[NH2:7][C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>>[F:31][C:28]([F:29])([F:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([N:17]1[CH2:16][CH2:15][N:14]([C:11]2[N:12]=[N:13][C:8]([NH:7][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])=[CH:9][CH:10]=2)[CH2:19][CH2:18]1)=[O:21]
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)C1CC1

Procedure:
Following the procedure of Example 2, making variations only as required to use cyclopropanecarboxylic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (32% yield). 1H NMR (300 MHz, CDCl3) δ 10.07, 8.40, 7.72, 7.61, 7.53, 7.34, 7.03, 4.02-3.82, 3.67-3.55, 3.49-3.46, 3.30-3.27, 2.09-2.01, 1.09-1.04, 0.88-0.82. MS (ES+) m/z 420.2 (M+1).
Reaction SMILES: Br[C:2]([CH3:15])([CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]=1[OH:13])=[O:4].C([O-])([O-])=O.[K+].[K+].O.C(OCC)(=O)C>CN(C=O)C>[Br:12][C:8]1[C:7]2[O:13][C:2]([CH3:15])([CH3:14])[C:3](=[O:4])[NH:5][C:6]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(Br)C(=O)Nc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)Oc2c(Br)cccc2NC1=O
Temperature: 150 °C
Yield: 84.6 %

Procedure:
The 2-bromo-N-(3-bromo-2-hydroxy-phenyl)-2-methyl-propionamide of step 1 was dissolved in DMF (200 ml), and the DMF solution was added to K2CO3 (6.3 g, 45.58 mmol). The mixture was heated overnight at 150° C., then cooled and poured into a mixture of water/ethyl acetate. The organic fraction was washed with brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 8-Bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one as a white solid (84.6%). MS: (M−H)−256.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=O.[CH3:17][C:18]1[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([NH:24][C:21]1[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][N:22]=1)=[O:7]
Reactant: Cc1cnc(N)cn1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2cnc(C)cn2)c1

Procedure:
It will be appreciated by those skilled in the art that the sequence of steps in the processes described above may be performed in a different order for example 3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid may be reacted with 5-methylpyrazine-2-amine to give (S)-3-hydroxy-5-(1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)benzamide, for example as described below. The conversion of (S)-3-hydroxy-5-(1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)benzamide into 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide may be carried out as described in WO2007/007041.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:9]1)=O)(C)(C)C.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[S:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=[C:12]1[CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc3ccccc3s2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2sc(C3CNC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 48 mg (166 μmol) 3-benzothiazol-2-yl-azetidine-1-carboxylic acid tert-butyl ester was added 5 mL DCM and 5 mL TFA. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give the product as the TFA salt which was used in the next step without further purification.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:37]1[C:46]2[C:41](=[CH:42][C:43]([NH:47][CH:48]([C:52]3[CH:57]=[C:56]([CH3:58])[C:55]([CH2:59][CH2:60][OH:61])=[C:54]([CH3:62])[CH:53]=3)[C:49]([OH:51])=O)=[CH:44][CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[N+:70]([C:73]1[CH:74]=[C:75]([CH:86]=[CH:87][CH:88]=1)[CH2:76][NH:77][CH2:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])([O-:72])=[O:71]>CCOC(C)=O>[C:29]([O:33][C:34]([N:36]([C:63]([O:65][C:66]([CH3:68])([CH3:67])[CH3:69])=[O:64])[C:37]1[C:46]2[C:41](=[CH:42][C:43]([NH:47][CH:48]([C:52]3[CH:57]=[C:56]([CH3:58])[C:55]([CH2:59][CH2:60][OH:61])=[C:54]([CH3:62])[CH:53]=3)[C:49]([N:77]([CH2:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:76][C:75]3[CH:86]=[CH:87][CH:88]=[C:73]([N+:70]([O-:72])=[O:71])[CH:74]=3)=[O:51])=[CH:44][CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc(C)c1CCO
Reactant: CC(C)(C)OC(=O)CNCc1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(CC(=O)OC(C)(C)C)Cc2cccc([N+](=O)[O-])c2)cc(C)c1CCO
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
EDCI (142 mg, 0.74), HOAt (101 mg, 0.74 mmol), and triethylamine (0.18 mL, 1.35 mmol) were added to a solution of 50C (380 mg, 0.67 mmol) and 52C (197 mg, 0.74 mmol) in that order. The reaction mixture was stirred at 60° C. for 3 h. The solution was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude solid was purified by flash chromatography (0% to 100% EtOAc in hexanes) to afford 52D (230 mg, 42%) as a yellow solid. MS (ESI) m/z 814.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][CH2:12][CH2:13][Cl:14])=[O:6]
Reactant: ClCCCBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cccc(OCCCCl)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 97.5 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (183.2 g, 1.5 moles), 1-bromo-3-chloropropane (167 mL, 1.58 moles), potassium carbonate (450 g) and acetonitrile (2.2 L) was heated at reflux temperature with good stirring. After 17 hours, the reaction mixture was cooled to ambient temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was dried in vacuo to give 290.4 g (97%) of 1-(3-formylphenoxy)-3-chloropropane.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:54])[C@H:25]([NH:34][C:35]([C@@H:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][N:38]2C(OC(C)(C)C)=O)=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:20][CH2:19]1)=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([C:24](=[O:54])[C@H:25]([NH:34][C:35]([C@@H:37]2[CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39][NH:38]2)=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCNc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2)CC1
Yield: 89.1 %

Procedure:
N-[(1R)-2-(4-{2-[(2-Aminoethyl)amino]phenyl}piperazinyl)-1-[(4-chlorophenyl)methyl]-2-oxoethyl]((3S)(3-1,2,3,4-tetrahydroisoquinolyl))carboxamide was prepared according to Preparation XVI using tert-butyl 3-[N-((1R)-2-{4-[2-({2-[(tert-butoxy)carbonylamino]-ethyl}amino)phenyl]-piperazinyl}-1-[(4-chlorophenyl)-methyl]-2-oxoethyl)-carbamoyl](3S)-1,2,3,4-tetrahydro-isoquinoline-2-carboxylate (150 mg, 0.18 mmol) and 25 mL of EtOAc satd with HCl. The crude product was concentrated to provide the desired product (90 mg). MS (ESI, pos. ion) m/z: 561 (M+H), (ESI, neg. ion) m/z: 559 (M−H). Calc'd for C31H37ClN6O2: 560.27.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[F:10][CH:11]([F:41])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[N:24]2[CH:25]=[C:26]([C:30]3[CH:31]=[N:32][C:33]([C:36](O)([CH3:38])[CH3:37])=[N:34][CH:35]=3)[C:27]([F:29])=[CH:28][C:23]2=[N:22][C:21]=1[CH3:40]>O1CCCC1>[F:41][CH:11]([F:10])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[N:24]2[CH:25]=[C:26]([C:30]3[CH:31]=[N:32][C:33]([C:36]([F:7])([CH3:37])[CH3:38])=[N:34][CH:35]=3)[C:27]([F:29])=[CH:28][C:23]2=[N:22][C:21]=1[CH3:40]
Reactant: Cc1nc2cc(F)c(-c3cnc(C(C)(C)O)nc3)cn2c1Cc1ccccc1OC(F)F
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Product: Cc1nc2cc(F)c(-c3cnc(C(C)(C)F)nc3)cn2c1Cc1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
DAST (0.04 mL, 0.34 mmol) was added to a solution of Example 173 (0.1 g, 0.23 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature under N2 gas. The mixture was stirred at room temperature for 2 h, quenched with water (5 mL) and poured onto saturated aqueous NaHCO3 solution (10 mL). The crude residue was extracted with EtOAc (3×10 mL), dried (MgSO4) and concentrated in vacuo. The resulting light yellow glass was purified by chromatography on silica (Biotage, 10 g cartridge), eluting with 0 to 100% EtOAc in heptanes. The resulting crude off white gum was further purified by preparative HPLC (preparative method C, neutral) to give the title compound (0.031 g, 31%) as a pale orange glass. δH (500 MHz, CDCl3) 8.80 (d, J 1.4 Hz, 2H), 7.79 (d, J 7.0 Hz, 1H), 7.37 (d, J 10.6 Hz, 1H), 7.30-7.27 (m, 1H), 7.17 (d, J 7.9 Hz, 1H), 7.11 (t, J 7.5 Hz, 1H), 6.90 (dd, J 7.7, 1.2 Hz, 1H), 6.62 (t, J 73.6 Hz, 1H), 4.29 (s, 2H), 2.52 (s, 3H), 1.83 (d, J 21.7 Hz, 6H). Method D HPLC-MS: MH+ m/z 445, RT 2.24 minutes.