Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[CH2:10][C@H:9]1[C:22]([O:24]C(C)(C)C)=[O:23])=O)(C)(C)C>Cl.O1CCOCC1>[Cl:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10]1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H](COc2cccc(Cl)c2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@H](COc2cccc(Cl)c2)CN1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(2S,4S)-4-(3-chloro-phenoxymethyl)-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (Preparation 46, 67 mg, 0.16 mmol) was dissolved in a solution of anhydrous hydrogen chloride in dioxane (4M, 5 ml) and stirred for 18 hours at room temperature. The solvent was removed under reduced pressure and the residue triturated with ethyl acetate to give the title compound as a white solid hydrochloride salt (13 mg, 27%)
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCNCc1ccccc1
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN(Cc1ccccc1)C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 6.0 g of N-benzyl-n-butylamine in 3 ml of methylene chloride containing 4.5 ml of triethylamine, under inert gas, was cooled to 0° C. and treated by the dropwise addition of 4.27 ml of iso-valerylchloride. Another 3 ml of methylene chloride was added and stirred at ambient temperature for 18 hours. The insolubles were filtered and the cake washed with methylene chloride. The combined filtrates were washed with water, brine and dried. Evaporation of the volatiles gave a brown oil which was purified by chromatography on silica gel using 1:8 ethyl acetate:-hexanes giving 7.75 g of the desired product as a yellowish oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20]O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20][Cl:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(CO)nn(Cc2ccccc2)c2cccc(Cl)c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c(CCl)nn(Cc2ccccc2)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.2 %

Procedure:
To 0.42 g (1.4 mmol) of 1-benzyl-5-chloro-3-hydroxymethylcinnolin-4(1H)-one in 25 mL of dichloromethane at 0° C. was added 0.97 mL (7.0 mmol) of triethylamine and 0.33 mL (4.2 mmol) of methanesulfonyl chloride. The reaction was allowed to warm to room temperature and stirred for 5 h. The reaction was concentrated by rotary evaporation and was subsequently dissolved in dichloromethane and concentrated onto silica gel. The crude material was purified by flash chromatography eluting with a 33-50% ethyl acetate/hexanes gradient mixture to give 0.26 g (59%) of the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24](O)=[O:25])=[C:12]2[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][OH:25])=[C:12]2[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOc1c(C(=O)O)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: C1CCOC1
Product: CCCCOc1c(CO)n(CC(C)C)c(=O)c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of 6-benzyloxy-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (7.62 g, 18 mmol) in tetrahydrofuran (50 mL) were added oxalyl chloride (1.9 mL, 21.6 mmol) and N,N-dimethylformamide (2 drops), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (30 mL). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (2.38 g, 63 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-4-butoxy-3-hydroxymethyl-2-isobutyl-1(2H)-isoquinolinone (7.11 g, 96.5%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I:12]([O-])(=O)(=O)=O.[Na+].II.S(=O)(=O)(O)O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(O)(=O)C.O>[I:12][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)O)cc1I
Temperature: 25 °C
Yield: 162.9 %

Procedure:
A solution of 2,4-dimethylbenzoic acid (20.0 g, 133 mmol), sodium periodate (14.27 g, 66.72 mmol), iodine (37.25 g, 146.8 mmol), and sulfuric acid (1.96 g, 20.0 mmol) in acetic acid (150 mL) was stirred at 110° C. for 6 h. The mixture was allowed to cool to ambient temperature then carefully diluted into water (1.2 L). To this mixture was carefully added saturated aqueous Na2S2O3 (800 mL). The resulting solids were collected by filtration, then dissolved in ethyl acetate (1.2 L) and washed with saturated aqueous Na2S2O3 (300 mL) followed by brine (400 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was re-crystallized from ethanol:H2O (2:1) to yield the title compound as a white solid (30 g, 82%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:13])=[C:8]([CH2:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Br[CH:20]([CH3:22])[CH3:21]>>[CH2:17]([O:16][C:14]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[C:7]([O:13][CH:20]([CH3:22])[CH3:21])[C:6]=2[C:2]=1[CH3:1])=[O:15])[CH3:18]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1oc2ccc(CC)c(O)c2c1C
Product: CCOC(=O)c1oc2ccc(CC)c(OC(C)C)c2c1C
Yield: 89.7 %

Procedure:
According to the procedure of Example 86, Step 3 0.200 g (0.81 mmol) of 3-methyl-4-hydroxy-5-ethylbenzofuran carboxylic acid ethyl ester (Example 86, Step 2) and 0.379 mL (4.03 mmol) of 2-bromopropane gave 0.211 g of 5-ethyl-4-isopropoxy-3-methylbenzofuran-2-carboxylic acid ethyl ester after chromatography on silica gel eluting with ethyl acetate/hexanes (1:20).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[O:10].C1(=[O:18])CCCCC1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:11])[C:2]=1[C:9]([OH:18])=[O:10]
Reactant: O=C1CCCCC1
Reactant: Cc1cc(C)c(C=O)c(C)c1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)O)c(C)c1

Procedure:
To a flask equipped with a stirrer, condenser and an oxygen inlet were added mesitaldehyde (14.8 g, 0.10 mol), 30 mL (0.29 mol) of cyclohexanone and 10 mg of cobalt (II) acetate dissolved in 1 mL of acetic acid. Oxygen was bubbled in while the solution was stirred rapidly. Within an hour the temperature had risen to 70°, then declined rapidly. After 3 hr the solution was mixed with 75 ml of methylene chloride and 100 ml of water. Aqueous potassium hydroxide (40%) was added dropwise until the pH reached 7.5. The aqueous layer was separated and rinsed first with 50 mL of methylene chloride, then with 50 mL of petroleum ether. After acidification with concentrated hydrochloric acid, the white crystalline product was collected by filtration, washed with water and air dried: 12.54 g (77%) of mesitoic acid, mp 154°-156°.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[CH:20](O)[CH2:21][CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[CH2:20][CH2:21][CH2:22][CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(O)c1cc(-c2ccccc2)ccc1C(=O)NC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCCc1cc(-c2ccccc2)ccc1C(=O)NC(C)(C)C
Reaction time: 48 h

Procedure:
To 500 mL Parr flask was added (N-tert-butyl)-3-(1-hydroxybutyl)-4-biphenylcarboxamide (3.50 g, 10.75 mmol), abs EtOH (125 mL) and 10% palladium on carbon (3.50 g). This mixture was hyrogenolyzed at 60 psig and ambient temperature for 48 h. The catalyst was removed by filtration on a celite pad and the solvent was removed in vacuo. This material was chromatographed on silica gel using 10% EtOAc in hexane as eluant to afford the title compound as a white crystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[CH2:12]([N:19]1[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[C:20]1[CH:26]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([N:19]1[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[C:20]1/[CH:26]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CCc1ccc(C=O)n1Cc1ccccc1
Solvent: C1CCOC1
Product: CCc1ccc(/C=C/C(=O)OC)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(E)-methyl 3-(1-benzyl-5-ethyl-1H-pyrrol-2-yl)acrylate, 15: Sodium (0.75 g, 32 mmol) was added in portions to a dry methanol (30 mL). To the fresh formed sodium methoxide solution was added dropwise the solution of trimethyl phosphonoacetate (2.6 mL, 15.2 mmol) in tetrahydrofuran (7 mL) at room temperature. After addition the mixture was stirred for additional 60 min at room temperature. Then to the reaction mixture was added dropwise the solution of 1-benzyl-5-ethyl-1H-pyrrole-2-carbaldehyde, 14 (2 g) in tetrahydrofuran (50 mL) at room temperature. The reaction mixture was stirred for 2 h at room temperature. The mixture was concentrated and redissolved in ethyl acetate (200 L). The mixture was washed with 1 M HCl solution, then saturated NaHCO3, H2O. The organic solution were dried over MgSO4 and then filtered, concentrated to afford the crude product, (E)-methyl 3-(1-benzyl-5-ethyl-1H-pyrrol-2-yl)acrylate, 15.Yield: 2 g
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]([F:39])([F:38])[C:13]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:35][CH2:36][CH3:37])[CH2:33][C:13]([CH2:14][NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[N:19][N:20]2[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)([OH:32])[C:12]([F:11])([F:39])[F:38])=[O:6]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1Cl
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1Cl

Procedure:
Prepared similarly to Example 1 from 2-chlorobenzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:34][N:35]([CH3:45])[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36](=[O:44])[N:35]([CH3:34])[CH3:45])[CH2:43][CH2:42]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CN(C)C(=O)CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (4 mL) was added N,N-dimethyl-2-(piperazin-1-yl)acetamide hydrochloride (72 mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (27.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 27.0% in 2 min); Detector, UV 254/220 nm. This resulted in 73.4 mg (64%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=616.3, RT=2.41 min. 1H NMR (400 MHz, CD3OD-d4) δ: (ppm) 9.09 (dd, 1H, J=1.6, 7.2 Hz), 8.66-8.64 (m, 2H), 8.37 (s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=2.8 Hz), 7.57 (dd, 1H, J=2.8, 8.8 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.4, 7.2 Hz), 6.63 (t, 1H, J=73.6 Hz), 5.29 (s, 2H), 3.84-3.77 (m, 4H), 3.75 (s, 2H), 3.08 (s, 3H), 3.06-2.96 (m, 7H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]([OH:28])=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[NH4+].C(OC1C=CC2C(=CC=CC=2)[N:38]1C(OCC)=O)C>ClCCl>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:15]=[C:16]([C:20]4([C:26]([NH2:38])=[O:28])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: O=C(O)C1(c2cccc(Sc3ccc(Cn4cccc4)cc3)c2)CCOCC1
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: ClCCl
Product: NC(=O)C1(c2cccc(Sc3ccc(Cn4cccc4)cc3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
A suspension of 4-[3-[4-(pyrrol-1-ylmethyl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylic acid (0.36 g, 0.93 mmol), ammonium bicarbonate (0.44 g, 5.58 mmol) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (0.28 g, 1.12 mmol) in dichloromethane (20 ml) were stirred at room temperature overnight. Ammonium bicarbonate and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline were added until the acid was consumed. The reaction mixture was diluted with dichloromethane (50 ml) and washed with water (50 ml). The organic extract was washed with cold 1N hydrochloric acid (50 ml), water (50 ml) and saturated aqueous sodium bicarbonate (5 ml), water (50 ml) and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. Recrystallization of the residue from ethyl acetate afforded the titled compound (198 mg, 54%).
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:25])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(Cl)cc3)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 77 %

Procedure:
As described for example 117, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (108 mg, 0.3 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (99 mg, 77%) which was obtained as a white solid. MS: m/e=428.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][N:9]([CH3:14])[C:10]([NH:12][CH3:13])=[S:11])=O)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[N:12]([CH3:13])[C:10](=[S:11])[N:9]([CH3:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CNC(=S)N(C)NC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(Cl)cc2)n(C)c1=S

Procedure:
The 1:1 mixture of 1-(4-chlorobenzoyl)-2,4-dimethylthiosemicarbazide and pyridine hydrochloride (3.61 g of mixture) from Example 2 and 1 molar aqueous NaHCO3 (100 ml, 1.00×10-1 mole) were stirred and warmed to reflux. After refluxing for 5 hours the reaction was allowed to cool. It was then placed in a refrigerator for several hours before the precipitate was collected by filtration. The collected material was dried partially by suction before being transferred to a desiccator where it was dried at high vacuum. This affords the desired product as a beige powder: 2.01 g (84%). This was purified by flash chromatography and subsequent crystallization from isopropanol yielding small, slightly yellowish plates: 1.74 g (73%), mp 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[NH:11][C:10]([C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][C:32]=3[O:33][CH3:34])[CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:46])[CH:43]([CH3:45])[CH3:44]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:42](=[O:46])[CH:43]([CH3:45])[CH3:44])[C:10]([C:20]3[CH:21]=[C:22]([CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:30]=[CH:31][C:32]=3[O:33][CH3:34])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(CN2CCOCC2)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCOCC2)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)C(C)C
Reaction time: 12 h

Procedure:
To a solution of 4-{3-[4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazol-2-yl]-4-methoxy-benzyl}-morpholine (100 mg, 0.20 mmol, as in the U.S. Provisional applications incorporated by reference herein, Example 31) in methylene chloride (10 mL) were sequentially added triethylamine (0.10 mL, 0.712 mmol) and isobutyryl chloride (42 μL, 0.392 mmol). The reaction mixture was stirred for 12 h. The solvents were removed under reduced pressure. Saturated sodium bicarbonate (2 mL) and methylene chloride (20 mL) were added and the layers were separated. The aqueous layer was extracted with methylene chloride (1×100 mL). The combined organic extracts were evaporated. Purification of the crude residue by Biotage flash chromatography eluting with 0-5% methanol in ethyl acetate gave 1-[4,5-bis-(4-chloro-phenyl)-2-(2-methoxy-5-morpholin-4-ylmethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-2-methyl-propan-1-one. HR-MS (ES, m/z) calculated for C31H34N3O3Cl2[(M+H)+]566.1972, observed 566.1977.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:13]=[C:14]([C:24](=[O:26])[CH3:25])[CH:15]=[C:16]([NH:20][CH:21]([CH3:23])[CH3:22])[C:17]=1[O:18][CH3:19])([CH3:11])([CH3:10])[CH3:9].[Br:27]N1C(=O)CCC1=O.C(OCC)(=O)C>O1CCCC1>[Br:27][CH2:25][C:24]([C:14]1[CH:15]=[C:16]([NH:20][CH:21]([CH3:22])[CH3:23])[C:17]([O:18][CH3:19])=[C:12]([C:8]([CH3:9])([CH3:11])[CH3:10])[CH:13]=1)=[O:26]
Reactant: COc1c(NC(C)C)cc(C(C)=O)cc1C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(NC(C)C)cc(C(=O)CBr)cc1C(C)(C)C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Triethylamine (0.63 ml, 4.5 mmol) and tert-butyl dimethylsilyltrifluoromethanesulfonate (0.6 g, 2.3 mmol) were added to a solution of the 1-[3-(tert-butyl)-5-(isopropylamino)-4-methoxyphenyl]-1-ethanone (0.4 g, 1.5 mmol) in tetrahydrofuran (50 ml) while cooling on ice and the mixture was stirred at the same temperature for 30 minutes, after which N-bromosuccinimide (0.53 g, 3.0 mmol) was added and stirring was continued for 30 minutes. Ethyl acetate was added to the reaction mixture, the mixture was washed with brine and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (410 mg) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)[C:6]=2[CH:33]=1.[N:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41](=O)[O:42]C2C=CC=CC=2)=[CH:36][CH:35]=1>O1CCOCC1>[F:29][C:28]([F:31])([F:30])[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:13]2[CH2:12][CH2:11][CH:10]([N:7]3[C:6]4[CH:33]=[C:2]([NH:1][C:41]([NH:40][C:37]5[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=5)=[O:42])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH2:15][CH2:14]2)=[CH:18][CH:19]=1)([OH:32])[C:24]([F:25])([F:26])[F:27]
Reactant: Nc1ccc2ncn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccncc1)Nc1ccc2ncn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Yield: 12.7 %

Procedure:
2-(4-((4-(6-Amino-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.212 mmol, 0.1 g) and phenyl pyridin-4-ylcarbamate (0.318 mmol, 0.068 g) were combined and heated in a Reactivial in dioxane (2 mL) for 2 days. The solvent was removed and the resulting residue purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 8% methanol/dichloromethane) to afford the title compound (16 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: COC(=O)CCc1nc(-c2cc(C)cc(C(F)(F)F)c2)co1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-c2coc(CCC(=O)O)n2)cc(C(F)(F)F)c1
Yield: 78.4 %

Procedure:
A solution of methyl 3-(4-(3-methyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 45, 0.091 g, 0.290 mmol) and sodium hydroxide (0.50 mL, 1.0 M in water, 0.50 mmol) in methanol (5.0 mL) was stirred for 6 h at room temperature. After this time, the reaction mixture was quenched with 1.0 M hydrochloric acid (0.60 mL), diluted with ethyl acetate and separated. The organic layer was washed with water, and saturated sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, methylene chloride/methanol 49:1) to provide 3-(4-(3-methyl-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (0.068 g, 75%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]([CH3:30])[CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH:28]([CH3:30])[CH3:29])[CH2:20][CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: CC(C)I
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 2-iodopropane.