Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]3([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:21]Br.[OH-].[Na+].C(N(CC)CC)C>C(O)(=O)C.O>[Br:21][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:12][CH2:13][C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: BrBr
Reactant: OC1(CNc2ccnc3cc(Cl)ccc23)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: OC1(CNc2c(Br)cnc3cc(Cl)ccc23)CCCCC1
Reaction time: 2 h
Yield: 49.2 %

Procedure:
A solution of 11.2 g of 7-chloro-N-(1-hydroxycyclohexylmethyl)-4-quinolinamine in 130 ml of glacial acetic acid was stirred at room temperature and 6.15 g of bromine was added dropwise. The product precipitated from the solution as the hydrobromide salt and was isolated by filtration. The solid was then suspended in water and basified with sodium hydroxide. After two hours of stirring, the solid was collected by filtration. By combustion analysis, the product proved to be a hemi-hydrobromide salt, and therefore it was necessary to dissolve the solid in methanol and 1 equivalent of trietylamine with heating. A solid resulted which was recrystallized from ethanol to give 7 g of crystalline solid with melting point of 151°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[N:31]2[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:35][CH2:36]2)=[CH:42][CH:41]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
113 mg (69%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (78 mg, 0.272 mmol), DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)3 (173 mg, 0.816 mmol).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[CH:5]1)(=O)C.CCN(CC)CC>CO>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:4][CH:5]=2)[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(=O)n1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2c[nH]c3ccccc23)CC1
Reaction time: 1 h

Procedure:
Into a 250 mL round bottom flask was placed a solution of tert-butyl 4-(1-acetyl-1H-indol-3-yl)piperazine-1-carboxylate (2.6 g, 7.58 mmol) in methanol (80 mL). To the mixture was added Et3N (2.3 g, 22.73 mmol). The resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by LCMS and TLC (ethyl acetate/petroleum ether=1:1). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed 3 times with 150 mL of NaCl(aq.). The residue was purified by eluting through a column with a 10:1 petroleum ether/ethyl acetate solvent system. This resulted in 2.1 g (89%) of tert-butyl 4-(1H-indol-3-yl)piperazine-1-carboxylate as a light pink solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:24])[N:12]([O:20][CH2:21][CH:22]=[CH2:23])[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7](Cl)[CH:6]=1)(=[O:3])[CH3:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>C(#N)C>[C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:24])[N:12]([O:20][CH2:21][CH:22]=[CH2:23])[C:13](=[O:19])[C:14]3=[CH:15][CH:16]=[C:17]([Cl:18])[C:8]([C:9]=23)=[C:7]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=CCON1C(=O)c2ccc(Cl)c3c(Cl)cc(NC(C)=O)c(c23)C1=O
Reactant: C1CCNC1
Solvent: CC#N
Product: C=CCON1C(=O)c2ccc(Cl)c3c(N4CCCC4)cc(NC(C)=O)c(c23)C1=O
Yield: 78.5 %

Procedure:
A near solution of 4-acetylamino-2-allyloxy-6,7-dichlorobenzo[de]isoquinoline-1,3-dione (0.3 g, 0.8 mmol, from Example G4), pyrrolidine (0.16 g, 2.2 mmol), and 15 mL of acetonitrile was heated from room temperature to reflux over 0.5 hour. The solvent was removed in vacuo and the residue partitioned between dichloromethane and water. The organic layer was washed with water, dried, and evaporated in vacuo to give 0.26 g of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1C(=O)N([Cl:20])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:20][C:3]1[C:4]2=[N:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: CC(=O)c1ccc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2[nH]cc(Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a solution 1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone (517.0 mg, 3.23 mmol) in anhydrous DMF (5.0 mL) at 0° C. was added a solution of NCS (462.0 mg, 3.39 mmol) dissolved in anhydrous DMF (10 mL). The reaction mixture was stirred at 0° C. for 1 h and then at RT for 18 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed with sat'd. aq. NaHCO3 solution, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with EtOAc/heptane. Recovered product was crystallized from DCM to afford 600 mg (95.5%) of 1-(3-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanone as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 11.96 (br s, 1H), 8.01 (d, J=2.9 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 2.71 (s, 3H); MS (ESI) m/z: 195.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=O.CC(OC(C)=O)=O>>[CH2:16]([O:15][C:11](=[O:14])/[CH:12]=[CH:1]/[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[CH3:17]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)C=O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)/C=C/c1ccc(C(=O)O)cn1
Temperature: 130 °C
Yield: 145.7 %

Procedure:
6-Methylnicotinic acid (5 g, 36 mmol) and ethyl glyoxalate (50% solution in toluene −8.7 mL, 44 mmol) were added to Ac2O (25 mL) and stirred under a nitrogen atmosphere. The reaction was heated at 130° C. for 3 h then allowed to cool to RT over 17 h. The reaction was then quenched with water (10 mL) and concentrated to dryness in vacuo to afford the product as a brown solid (11.6 g, >100%). m/z=222 [M+H]+.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[C:17](Cl)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]>>[C:17]([O:10][C:8]1[CH:7]=[CH:6][NH:5][C:4](=[O:3])[CH:9]=1)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC(=O)Cl
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Product: CCCCC(=O)Oc1cc[nH]c(=O)c1
Yield: 41 %

Procedure:
The general procedure of Example 31 was followed using 1.00 g of 2,4-bis(trimethylsilyloxy)-pyridine and 1.02 ml of n-pentanoyl chloride, thereby giving 310 mg of the title compound in a yield of 41%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)=[C:9]2[C:26]([O:28]CC)=[O:27])=[CH:4][CH:3]=1.FC1C=CC(C2(O)C3C(=CC=CC=3)C(C3C=CC4OCOC=4C=3)=C2C(OCC)=O)=CC=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(F)cc1
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Ethyl (RS)-1-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1-(4-fluorophenyl)-1-hydroxy-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (45 mg, 0.11 mmol) in CH2Cl2 (3 ml) at 0° C. was added triethylsilane (38 μl, 0.24 mmol), followed by boron trifluoride etherate (121 μl, 0.98 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (40 mg, 90%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+:26]([O-])([OH:28])=[O:27].N([O-])=O.[Na+].O>C(O)(=O)C>[C:7]1([C:6]2[C:5]3[CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:4]=3[O:3][C:2]=2[N+:26]([O-:28])=[O:27])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c(Br)oc12
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)cc2c(-c3ccccc3)c([N+](=O)[O-])oc12

Procedure:
A solution of 6 g. (0.018 mole) of the product of step E in hot acetic acid is treated with 6 ml. of 70 percent nitric acid while the solution is maintained at about 80° C. Sodium nitrite (2.7 g., 2 equivalents) is added gradually, and the mixture is heated on a steam bath for 45 minutes. The mixture is then poured into 500 ml. of water. The solid is filtered, recrystallized twice from acetone, then from an ethyl acetate-hexane mixture to provide yellow crystals of 3,5-diphenyl-2-nitrobenzofuran-7-carboxylic acid, m.p. 207°-209° C.
Reaction SMILES: C(C1NC(C(N[C@H](C(NC(C=O)CC(O)=O)=O)C)=O)=CC=1)C1C=CC=CC=1.C([C:35]1[NH:39][C:38]([C:40]([NH:42][C@@H:43]([C:45]([NH:47][C@H:48]2[CH2:52][C:51](=[O:53])[O:50][C@@H:49]2[O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:46])[CH3:44])=[O:41])=[CH:37][CH:36]=1)C1C=CC=CC=1.N1C=CC=C1C(N[C@H](C(NC(C=O)CC(O)=O)=O)C)=O.[K+].[Br-]>O.CO>[NH:39]1[CH:35]=[CH:36][CH:37]=[C:38]1[C:40]([NH:42][C@@H:43]([C:45]([NH:47][C@H:48]1[CH2:52][C:51](=[O:53])[O:50][C@@H:49]1[O:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:46])[CH3:44])=[O:41]
Reactant: C[C@@H](NC(=O)c1ccc(Cc2ccccc2)[nH]1)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1
Agent: C[C@H](NC(=O)c1ccc(Cc2ccccc2)[nH]1)C(=O)NC(C=O)CC(=O)O
Agent: C[C@H](NC(=O)c1ccc[nH]1)C(=O)NC(C=O)CC(=O)O
Agent: [Br-]
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)c1ccc[nH]1)C(=O)N[C@H]1CC(=O)O[C@@H]1OCc1ccccc1

Procedure:
3-[N-(5-Benzylpyrrole-2-carbonyl)-L-alaninyl]amino-4-oxobutanoic acid (36b), was prepared (41%) from 35b by the method described for compound 36a, to afford an off white solid: mp. 109-112° C.; [α]D25 +6.3° (c 0.3, methanol); IR (KBr) 3368, 1724, 1630, 1530, 1453, 1414, 1233, 1049; 1H NMR(d4 methanol) δ7.25-7.11 (5H, m), 6.76 (1H, d, J=3.5), 5.84 (1H, d, J=3.5), 4.51 (1H, m), 4.43 (1H, q, J=7.1), 4.23 (1H, m), 2.5 (2H, m),1.35 (3H, d, J=7.0). Anal. Calcd for C19H21N3O5. 1.75 H2O: C, 56.64; H, 6.13; N, 10.43. Found: C, 56.34; H, 5.72; N, 10.00.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:5][N:4]1CC)[CH3:2].Cl[O-].[Na+]>>[CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCN1CC(NC(=O)c2ccc(F)cc2)CN1CC
Agent: [Na+]
Agent: [O-]Cl
Product: CCN1CC(NC(=O)c2ccc(F)cc2)C=N1

Procedure:
In accordance with the procedure of Example 2, N-(1,2-diethyl-4-pyrazolidinyl)-4-fluorobenzamide is reacted with sodium hypochlorite and the product is isolated.
Reaction SMILES: [Cl:1][C:2]([C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[Na+].[CH3:23][S:24]([NH-:27])(=[O:26])=[O:25]>O1CCCC1>[Cl:1][C:2]([C:12]1[N:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[N:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[O:4]
Reactant: COc1cc(OC)nc(C(Cl)(C(=O)Cl)c2ccccc2)n1
Reactant: CS([NH-])(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C(Cl)(C(=O)NS(C)(=O)=O)c2ccccc2)n1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
The product from Stage (b) (3.1 g) in dry tetrahydrofuran (10 ml) was added dropwise to stirred, cooled (5° C.) methanesulfonamide sodium salt (2.8 g) in dry tetrahydrofuran (25 ml). Stirring was continued until most solid had dissolved (2 hours) and the reaction mixture was allowed to stand at room temperature overnight. The solvent was then evaporated off under vacuum and the residue was treated with ether. The precipitated solid was taken up in aqueous potassium bicarbonate, the ether solution extracted again with bicarbonate and then with water. The combined aqueous phases were washed with ether, fresh ether was then added and the whole was acidified to pH=1 with hydrochloric acid as quickly as possible with stirring. The ether solution was separated, and the aqueous phase was extracted twice more. The combined ether solutions were washed with water (5 times), dried over magnesium sulfate and evaporated under vacuum to give 2.3 g of the desired product. Washing with a small volume of diisopropyl ether gave 1.95 g of pure product as a viscous liquid.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C:38](=[O:39])[N:11]2[C:12]([C:35]([OH:37])=[O:36])=[C:13]([CH2:16][O:17][C:18](=[O:34])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25](=[O:33])(=[O:32])[NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.CCOCC>FC(F)(F)C(O)=O>[NH2:8][C@@H:9]1[C:38](=[O:39])[N:11]2[C:12]([C:35]([OH:37])=[O:36])=[C:13]([CH2:16][O:17][C:18](=[O:34])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[S:25](=[O:33])(=[O:32])[NH:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][S:15][C@H:10]12
Reactant: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
7β-(t-Butoxycarbonyl)amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (2.2 g) is dissolved in ice cooled solution of trifluoroacetic acid (20 ml) and the mixture is stirred for 20 minutes. Then, trifluoroacetic acid is taken off under reduced pressure and viscous residue is obtained. The residue becomes solid upon addition of ether (50 ml). The solid is triturated, collected by filtration, washed with ether and dried over phosphorus pentoxide. The procedure provides 7β-amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (1.55 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:27]2[CH:39]=[CH:38][C:30]([CH2:31][NH:32][C:33](=O)[CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].B.CSC>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)=[O:12])[N:7]([C:27]2[CH:39]=[CH:38][C:30]([CH2:31][NH:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)NCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COCCNCc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
To a solution of N-[4-(3-tert-butyl-5-{3-[4-(pyridin-4-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-benzyl]-2-methoxy-acetamide (200 mg, 0.38 mmol) in anhydrous THF (10 mL) was added borane-methyl sulfide complex (2.0 M solution in THF, 1 mL, 2 mmol), and the reaction was stirred at reflux for 7 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc (50 mL) and water (50 mL), and then the organic layer was separated and washed with brine, dried over Na2SO4, and concentrated at reduced pressure. The residue was purified by MPLC (90:10 CH2Cl2/MeOH) to give 30 mg (15%) of the desired product. 1H-NMR (DMSO-d6) δ 8.79 (s, 1H), 8.42 (d, J=4.8 Hz, 2H), 7.61 to 7.46 (m, 7H), 7.06 (d, J=6.6 Hz, 2H), 6.84 (d, J=4.5 Hz, 2H), 6.44 (s, 1H), 3.85 (s, 2H), 3.49 (t, J=5.7 HZ, 2H), 3.29 (s, 3H), 2.81 (t, J=5.7 Hz, 2H), 1.31 (s, 9H); MS LC-MS [M+H]+=515, RT=2.02 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc(O)cc1

Procedure:
To a solution of 4-hydroxyphenylacetic acid (10 g) in methylene chloride (66 mL) and methanol (26 mL) was added p-toluenesulfonic acid (1.25 g), and the resulting solution was heated at reflux overnight. The solvent was evaporated, the residue dissolved in ethyl acetate, and the the solution washed (H2O), dried (MgSO4), and evaporated to give crude methyl 4-hydroxyphenylacetate (10.4 TLC: Rf =0.72, ethyl acetate:dichloromethane (10:90); MS: m/z=167(M+1).
Reaction SMILES: I.CS[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.CCOCC>C(O)C>[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][CH2:6][N:5]=2)=[CH:17][CH:16]=1
Reactant: NCc1ccc(O)cc1
Reactant: CSC1=NCCc2ccccc21
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: Oc1ccc(CNC2=NCCc3ccccc32)cc1
Yield: 22.4 %

Procedure:
1-Methylthio-3,4-dihydroisoquinoline hydroiodide (0.6 g, 0.00197 mol) and 4-hydroxybenzylamine (0.24 g, 0.00195 mol) were heated together at reflux temperature in ethanol (25 ml) for five hours. Effluent gases were passed through a CHLOROS trap. The mixture was then cooled and the ethanol evaporated off at reduced pressure. The tacky residue was dissolved in dilute HCl and the solution extracted with ethyl acetate. The clear aqueous solution was basified with 6N. NaOH and re-extracted with ethyl acetate. The latter organic extract was washed with water, dried and evaporated to dryness to give a white sticky solid. This was treated with ether and the ether decanted off. The residual solid was crystallised from absolute ethanol to give the title compound (0.11 g) as white crystals, m.p. 177°-179°.
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][CH:2]1[C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([O:14][CH3:15])=[C:10]([CH:13]=1)[CH:11]=O.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])[CH3:19].C[O-].[Li+]>CN(C)C=O.CO.O>[O:1]1[CH2:5][CH:4]=[CH:3][CH:2]1[C:6]1[C:7]([O:16][CH3:17])=[CH:8][C:9]([O:14][CH3:15])=[C:10](/[CH:11]=[CH:19]/[C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[O:20])[CH:13]=1
Reactant: COc1cc(OC)c(C2C=CCO2)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cc(OC)c(C2C=CCO2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
5-(2,5-Dihydro-furan-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-121A, 0.10 g, 0.43 mmol) and 4-acetylbenzenesulfonamide (Ex-26A, 0.085 g, 0.43 mmol) were dissolved in a dimethylformamide-methanol solution (2.9 mL, 7:3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 4 h. Upon completion, as determined by HPLC, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.13 g (70%) of the title compound as a yellow solid, mp 194–195° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.23 (d, 2H, J=8.2 Hz), 8.03 (d, 1H, J=15.3 Hz), 7.97 (d, 2H, J=8.2 Hz), 7.69 (s, 1H), 7.65 (d, 1H, J=15.3 Hz), 7.55 (brs, 2H), 6.73 (s, 1H), 6.06–6.09 (m, 1H), 5.90–5.98 (m, 2H), 4.86–4.92 (m, 1H), 4.63–4.68 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H). MS (ESI) m/z=416 ([M+H]+, 100%). Anal. Calcd. C21H21NO6S: C, 60.71; H, 5.09; N, 3.37; S, 7.72. Found: C, 60.95; H, 5.24; N, 3.46; S, 7.72.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][C:13]4=[CH:12][C:11]=3[CH:10]=2)O1.[CH2:30]([O:37][C:38]1[N:53]=[C:52](Cl)[C:51]([CH2:55]C)=[C:50]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:39]=1[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CS(C)=O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH2:30]([O:37][C:38]1[N:53]=[C:52]([C:9]2[CH:17]=[CH:16][C:15]3[N:14]4[CH2:18][CH:19]([NH:21][C:22]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:28])[CH2:20][C:13]4=[CH:12][C:11]=3[CH:10]=2)[C:51]([CH3:55])=[C:50]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:39]=1[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3n2C1
Reactant: CCc1c(Cl)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Product: Cc1c(-c2ccc3c(c2)cc2n3CC(NC(=O)OC(C)(C)C)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 120 °C
Yield: 55.1 %

Procedure:
The intermediate from Step 2 (280 mg, 0.7 mmol) was combined with benzyl 2,4-bis(benzyloxy)-6-chloro-5-methylnicotinate (332 mg, 0.7 mmol, prepared according to Example 379, Step 3), potassium carbonate (193 mg, 1.4 mmol), tris(dibenzylideneacetone) dipalladium(0) (32 mg, 0.035 mmol) and tri-tert-butylphosphine tetrafluoroborate (41 mg, 0.14 mmol) in DMSO (3 mL). The mixture was heated under Ar at 120° C. for 20 min. The mixture was cooled to room temperature and partitioned in CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (10 mL). The organic layer was removed, concentrated and chromatographed on silica gel (0-30% EtOAc in hexanes) to provide the product as a white powder (274 mg, 55%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14](=[O:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([OH:16])[CH3:15])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Oc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cccc(Oc2ccccc2)c1

Procedure:
m-Phenoxyacetophenone is reduced with sodium borohydride to form alpha-(m-phenoxyphenyl)ethyl alcohol which is then reacted with phosphorus tribromide to form alpha-(m-phenoxyphenyl)ethyl bromide. This product is reacted with sodium cyanide under heat in dimethyl sulfoxide. Hydrolysis of the product with sodium hydroxide gives the desired alpha-(m-phenoxyphenyl)propionic acid. (For details, see U.S. Pat. No. 3,600,437).