Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([C:15]2[CH:20]=[C:19]([Cl:21])[N:18]=[C:17]([NH2:22])[N:16]=2)[CH:14]=1)C1C=CC=CC=1.ClB(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:22][C:17]1[N:16]=[C:15]([C:13]2[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=2[CH3:23])[CH:20]=[C:19]([Cl:21])[N:18]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1-c1cc(Cl)nc(N)n1
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(O)cc1-c1cc(Cl)nc(N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
4-(5-Benzyloxy-2-methylphenyl)-6-chloropyrimidin-2-ylamine (12.5 g, 38.4 mmol) obtained in Step 3 above was placed in a reaction vessel, and then dichloromethane (500 ml) was added thereto. The resulting solution was cooled to 0° C. Then, a dichloromethane solution of 1.0 M trichloroborane was added dropwise over 30 minutes. The mixture was stirred at 0° C. for 1 hour, and diluted with dichloromethane (1500 ml). A saturated aqueous sodium bicarbonate solution (2000 ml) was added, and the mixture was warmed to room temperature. The organic layer was separated, and then sequentially washed with water (1500 ml) and a saturated aqueous sodium chloride solution (1000 ml). The aqueous layer was extracted with ethyl acetate (3000 ml), and the ethyl acetate solution was sequentially washed with water (1500 ml) and a saturated aqueous sodium chloride solution (1000 ml). The washed organic layers were combined together, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:1) to yield 3-(2-amino-6-chloropyrimidin-4-yl)-4-methylphenol (6.45 g, 71%) as a white solid material.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C.[CH3:22][NH:23][NH2:24]>O>[CH3:22][N:23]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:24]1
Reactant: CNN
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 85 °C

Procedure:
5.0 Grams of dibenzoylmethane in 40 ml. of isopropanol is heated to 50° C. The temperature of the reaction mixture is then raised to about 85° C. and 10.5 grams of methyl hydrazine in 10 ml. of isopropanol added thereto. The mixture is heated at this temperature for 30 minutes, then cooled and cold water added thereto. A white solid precipitate forms and is filtered, washed and dried to yield 5.22 grams of product having a melting point of 59.5° C. to 60° C., 99+% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH:9]1B1OC(C)(C)C(C)(C)O1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)=[N:32][CH:31]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[O:34][C:33]([NH:35][C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)=[N:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC=CCC1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cccc(Nc2ncc(-c3ccc(Br)cc3)o2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3cnc(Nc4cccc(Cl)c4)o3)cc2)CC1
Temperature: 100 °C

Procedure:
Preparation of -(4,4,5, 5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester has been described [Tet. Lett. 41(19), 3705-3708, 2000]. The boronate ester (1.1 g, 3.6 mmol, 1.5 equiv) and [5-(4-bromo-phenyl)-oxazol-2-yl]-(3-chloro-phenyl)-amine (0.84 g, 2.4 mmol, 1.0 equiv) were dissolved in 12 mL DME and then charged with 3 mL of a 2M Na2CO3 solution. Pd(Ph3)4 on polystyrene resin (0.72 g, 0.072 mmol) was added, and the suspension was sparged with nitrogen for 10 min, then heated to 100° C. overnight. The reaction was then filtered to remove catalyst, and following solvent removal the product was triturated with hexanes and ether to afford the title compound: (M+H)+ 452.1.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([CH:14]=[C:15]([CH3:17])[CH3:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>CN(C)C=O>[CH3:18][N:19]([C:20](=[S:21])[O:3][C:4]1[C:13]([CH2:14][C:15]([CH3:17])=[CH2:16])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:23]
Reactant: CN(C)C(=S)Cl
Reactant: COC(=O)c1cccc(C=C(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)Cc1cccc(C(=O)OC)c1OC(=S)N(C)C
Yield: 60.1 %

Procedure:
To 1 liter of dry dimethylformamide were added 16 g of 60% sodium hydride in oil. After stirring under a nitrogen atmosphere, 81.7 g of 2-hydroxy-3-(2-methylpropenyl)benzoic acid, methyl ester, as a solution in dimethylformamide, were added in dropwise fashion. After stirring at room temperature, a solution 49.6 g of dimethylthiocarbamoyl chloride in dimethylformamide was added over a one hour period. The reaction mixture was stirred at room temperature overnight, then poured onto ice and extracted with diethyl ether and ethyl acetate. The combined organic extracts were washed successively with a 10% sodium hydroxide solution and water, dried over sodium sulfate, and concentrated in vacuo. The residue was vacuum distilled, and the fraction distilling at 162°-168° C. and 0.6 torr provided 69.9 g of the desired subtitle intermediate. NMR, MS.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:24]3[CH2:27][CH:26]([NH:28]C(=O)OC(C)(C)C)[CH2:25]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:24]3[CH2:25][CH:26]([NH2:28])[CH2:27]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCOCC1
Yield: 85.9 %

Procedure:
tert-butyl (1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}azetidin-3-yl)carbamate (0.84 g, 1.66 mmol) (see following step B for preparation) in CH2Cl2 (10 mL) was treated with TFA (5 mL) for 1 h at room temperature. Upon evaporation, the residue was dissolved in H2O (20 mL), neutralized with 2 N NaOH to pH=10, and extracted with CH2Cl2 (5×30 mL). The combined organic phases were washed with NaCl (10 mL) and dried over Na2SO4. After concentration, 0.58 g (86%) of a white solid was obtained as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.45-1.62 (m, 4 H), 1.63 (s, 9 H), 2.28-2.44 (m, 1 H), 3.30-3.39 (m, 2 H), 3.82-3.89 (m, 3 H), 3.89-3.97 (m, 2 H), 3.99-4.10 (m, 2 H), 4.48 (d, J=7.62 Hz, 2 H), 7.85 (dd, J=8.69, 1.66 Hz, 1 H), 7.98 (d, J=8.79 Hz, 1 H), 8.15 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=407.0; Anal. Calcd for C20H30N4O3S+2.10 TFA+0.20 CH3OH+0.20H2O (656.01): C, 44.67; H, 5.12; N, 8.54. Found: C, 44.68; H, 5.15; N, 8.56.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>C1COCC1>[F:32][C:33]([F:37])([F:36])[CH2:34][NH:35][C:16]1[N:17]=[C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[CH3:26])[C:13]2[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[C:14]=2[N:15]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NCC(F)(F)F)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 48 (300 mg, 0.67 mmol) and trifluoroethylamine (300 mg, 3 mmol) were dissolved in THF (10 ml) and sealed in a vial under Ar. The mixture was heated in an oil bath to 60° for 4 days. The solvents were removed ill vacuo, and the residue was flash chromatographed with 60-90% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 195-196°, LC MS m/z=465(MH+) Retention time=2.38 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1COCC1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([NH:29][CH3:30])=[O:28])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][NH:29][C:27]([C:23]1[CH:22]=[C:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:26]=[CH:25][N:24]=1)=[O:28]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 4-aminophenol (1 g, 9.2 mmol) in DMF (20 mL) was added 1M potassium tert-butoxide in THF (9.7 mL, 9.7 mmol) at room temperature. After 2 h, (4-chloro(2-pyridyl))-N-methylcarboxamide (1.6 g, 9.2 mmol) and potassium carbonate (0.64 g, 4.6 mmol) were added and then the reaction mixture was heated to 80° C. for 6 h. After cooling, the reaction mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with brine (20 mL), dried over magnesium sulfate. The solvent was removed in vacuo. The residue was purified by column chromatography to afford 4-(4-amino-phenoxy)-pyridine-2-carboxylic acid methylamide (2.2 g, 80%) as a light-brown solid. 1H NMR (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.89 (s, 1H), 8.78 (q, J=5 Hz, 1H), 8.50 (d, J=6 Hz, 1H), 7.61-7.54 (m, 4H), 7.38 (d, J=3 Hz, 1H), 7.29 (d, J=9 Hz, 2H), 7.19-7.12 (m, 3H), 2.78 (d, J=5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)C1CCN(CCc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCN5CCC(C(=O)O)CC5)cn(C)c34)no2)cc1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 6.3 %

Procedure:
To a solution of ethyl 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-4-piperidinecarboxylate (D91) (30 mg) in THF (5 mL) was added aqueous NaOH (2 M, 1 mL). The reaction was stirred at 50° C. for 5 h. The mixture was cooled to room temperature and acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was washed with water (50 mL) and brine (50 mL), dried over sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-4-piperidinecarboxylic acid (E66) (1.8 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 1.75 (2H, m), 1.91 (1H, m), 2.11 (2H, m), 3.11 (4H, m), 3.48 (4H, m), 3.65 (3H, s), 4.89 (1H, m), 7.23 (1H, t), 7.33 (1H, s), 7.47 (2H, m), 7.87 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d), 9.24 (1H, br s), 12.56 (1H, br s). MS (ES): C28H31ClN4O4 requires 522; found 523.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10]O2)=[CH:4][CH:3]=1.NC(N)=[S:13].O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][S:13]2)=[CH:4][CH:3]=1
Reactant: NC(N)=S
Reactant: Fc1ccc(C2CO2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(C2CS2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-(4-fluoro-phenyl)-oxirane (1.38 g, 10.0 mmol), thiourea (760 mg, 10.0 mmol) and silica gel (200 mg) in CH2Cl2 (10 mL) was stirred at room temperature for 12 hours. Water (20 mL) was added to the suspension and the mixture was extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide the title product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[C:17]([O:20][CH2:21][CH3:22])(=O)[CH3:18]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:20]1[CH:21]=[CH:22][CH:18]=[C:17]1[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(Cl)n1
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2ccco2)n1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
6-Chloro-2-pyridinecarbonitrile (0.90 g, 6.5 mmol) and 2-furanboric acid (1.1 g, 9.8 mmol) were dissolved in toluene (80 ml)-ethanol (205 ml), and potassium carbonate (2.2 g, 15.9 mmol) and water (20 ml) were added thereto. The mixture was deairated under reduced pressure for 10 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.36 g, 0.31 mmol) was added to the reaction mixture under argon atmosphere, and the mixture was refluxed for 13 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (0.97 g, 87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[CH2:16]([C:18]1[S:22][C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:20][C:19]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:17].C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH2:16]([C:18]1[S:22][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:27][CH2:28]2)=[N:20][C:19]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:17]
Reactant: CCc1sc(N2CCNCC2)nc1-c1ccccc1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1sc(N2CCN(C(=O)Nc3cccnc3)CC2)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 48.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (217 mg, 0.805 mmol), 1-(5-ethyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.732 mmol) and diisopropylethylamine (0.255 ml, 1.46 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (140 mg, 48.5%) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[CH2:16][CH2:17][NH:18][S:19]([C:22]1[CH:27]=[C:26]([C:28](=[NH:30])[NH2:29])[CH:25]=[CH:24][C:23]=1[OH:31])(=[O:21])=[O:20])C>Cl.C(#N)C>[C:28]([C:26]1[CH:25]=[CH:24][C:23]([OH:31])=[C:22]([S:19]([NH:18][CH2:17][CH2:16][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:14])[CH3:15])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:32])=[O:3])(=[O:20])=[O:21])[CH:27]=1)(=[NH:29])[NH2:30]
Reactant: CCOC(=O)COc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C(=N)N)ccc1O
Agent: Cl
Solvent: CC#N
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C(=N)N)ccc2O)c(OCC(=O)O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
Ethyl[2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenoxy]acetate (50 mg) was dissolved in a mixture of 3 mL of 1 mol/L hydrochloric acid and 1 mL of acetonitrile at 60° C. The solution was stirred at 60° C. for 4 hours, and the colorless solid obtained by concentration under reduced pressure of the reaction mixture was dissolved in a mixture of 3 mL of 1 mol/L hydrochloric acid and 1 mL of acetnitrile at 60° C. After the solution was stirred at 60° C. for 4 hours, then at room temperature for 10 hours, the reaction mixture was concentrated under reduced pressure to give a colorless solid. The solid was triturated with water and diethyl ether, and collected by filtration to give 31 mg of [2-[2-(5-carbamimidoyl-2-hydroxybenzenesulfonylamino)-ethyl]-5-isopropylphenoxy]acetic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][C@@H:55]([C:57]2[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=2)[OH:56])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][C@@H:55]([C:57]2[CH:58]=[CH:59][C:60]([Cl:63])=[CH:61][CH:62]=2)[OH:56])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNC[C@H](O)c2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(C[C@H](O)c2ccc(Cl)cc2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.1 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 95 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[(R)-2-(4-chloro-phenyl)-2-hydroxy-ethyl]-amine were added. After stirring for 24 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 72 mg light yellow solid (50%). MS (ISP) 461.4 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14]OS(C)(=O)=O)[N:11]=[C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[CH:22][CH:21]=2)[N:9]=1.[CH3:36][O-:37].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:36][O:37][CH2:14][C:12]1[CH:13]=[C:8]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])[N:9]=[C:10]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[CH:24][CH:25]=2)[N:11]=1
Reactant: C[O-]
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[4-[4-[(3S)-3-Methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]-3-phenyl-urea (90 mg) dissolved in a solution of DCM (5 mL) and triethylamine (0.045 mL). Sodium methoxide (33% in methanol) (0.073 mL) was added to the reaction and the mixture stirred at RT for 18 h before being quenched with water and partitioned. The organic phase was dried over magnesium sulphate and evaporated to give a gum which was purified by prep-HPLC (basic) to give the desired compound (32 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]1C=CN[N:12]=1.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2NC=1>>[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:12][C:11]=1[CH2:10][C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:16]
Reactant: O=C(Cc1cc[nH]n1)c1ccc(Cl)cc1Cl
Reactant: c1ccc2[nH]cnc2c1
Product: O=C(Cc1nc2ccccc2[nH]1)c1ccc(Cl)cc1Cl

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-2-pyrazolylethan-1-one except that benzimidazole (5.3 g, 44.8 mmol) was used in place of pyrazole. The crude residue was purified on silica gel (50% EtOAc/hexanes) to yield a light yellow solid
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>O1CCCC1>[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH3:16])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:30][CH:29]=1)([CH3:27])[CH3:26]
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1
Reactant: CC(C)c1ccc(O)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(C)C)cc1)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-fluorophenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with p-isopropylphenol (0.017 mole) in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:23])[CH3:22])[C:17](=[O:20])[N:18]([CH3:19])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:27]1C(C2C=CC3N(C(C)C)C(=O)NC=3C=2)=NC=C(C(F)(F)F)[CH:32]=1.C(Br)C#C>>[Cl:1][C:2]1[C:3]([C:12]2[CH:25]=[CH:24][C:15]3[N:16]([CH:21]([CH3:22])[CH3:23])[C:17](=[O:20])[N:18]([CH2:19][C:27]#[CH:32])[C:14]=3[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C)n1c(=O)n(C)c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Reactant: CC(C)n1c(=O)[nH]c2cc(-c3ncc(C(F)(F)F)cc3Cl)ccc21
Agent: C#CCBr
Product: C#CCn1c(=O)n(C(C)C)c2ccc(-c3ncc(C(F)(F)F)cc3Cl)cc21
Yield: 47 %

Procedure:
In a similar manner to the preparation of 5-(3-chloro-5-trifluoromethylpyridin-2yl)-3-methyl-1-(1-methylethyl)benzimidazol-2-one described above, 2.5 g of 5-(3-chloro-5-trifluoromethylpyridin-2yl)-1-(1-methylethyl)benzimidazol-2-one and 0.9 g of propargyl bromide gave, after chromatography on silica gel, 1.3 g (47%) of colorless crystals. Yield: 47%; m.p.: 109-111° C.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][O:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([CH2:20][O:21][C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1COC(=O)c1ccccc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(COC(=O)c3ccccc3)cccc2c1=O
Yield: 46 %

Procedure:
Diphenyl ether (500 ml) was heated to boiling, ethyl 2-butyryl-3-(2-(benzoyloxymethyl)phenylamino)acrylate (60.5 g, 0.15 mol) added, and heating continued at reflux for 25 minutes. Most of the diphenyl ether was removed by vacuum distillation. Chromatography (silica gel, 0-3% methanol in dichloromethane) and recrystallisation from methanol gave 3-butyryl-8-(benzoyloxymethyl)-4(1H)-quinolone (24.1 g, 45%), m.p. 115°-11°.