Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[C:17]([CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:19])=[O:18].CC(C)([O-])C.[K+]>O1CCCC1>[O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:21]/[CH2:20][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1
Reactant: O=Cc1ccc(-n2ccc(=O)cc2)cc1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C/C=C/c1ccc(-n2ccc(=O)cc2)cc1
Temperature: -5 °C
Reaction time: 14 h
Yield: 67.9 %

Procedure:
4.0 g of 4-(1,4-dihydro-4-oxo-1-pyridyl)benzaldehyde and 8.2 g of β-carboxyethyltriphenylphosphonium chloride were suspended in 40 ml of tetrahydrofuran in a nitrogen atmosphere. The obtained suspension was cooled to -5° C., followed by the gradual addition of a solution of 4.96 g of potassium tertbutoxide in 30 ml of tetrahydrofuran. The temperature of the mixture was gradually raised to a room temperature. The resulting mixture was stirred for 14 hours, followed by the addition of ice-water. The obtained aqueous phase was washed with chloroform. The pH of the aqueous phase was adjusted with concentrated hydrochloric acid to about 3 to precipitate a crystal. This crystal was recovered by filtration and washed with water and methanol successively to obtain 3.48 g of the title compound as a pale yellow powder (yield: 68%).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:32])[CH2:4][CH2:5][N:6]1[C:29](=[O:30])[C:10]2[CH:11]=[C:12]([N+:26]([O-])=O)[CH:13]=[C:14]3[O:15][C:16]4[CH:17]=[C:18]5[CH:25]=[CH:24][CH:23]=[CH:22][C:19]5=[CH:20][C:21]=4[N:8]([C:9]=23)[C:7]1=[O:31].[H][H]>C(O)(=O)C.[C].[Pd]>[ClH:1].[ClH:1].[NH2:26][C:12]1[CH:13]=[C:14]2[C:9]3=[C:10]([C:29](=[O:30])[N:6]([CH2:5][CH2:4][N:3]([CH3:2])[CH3:32])[C:7](=[O:31])[N:8]3[C:21]3[CH:20]=[C:19]4[CH:22]=[CH:23][CH:24]=[CH:25][C:18]4=[CH:17][C:16]=3[O:15]2)[CH:11]=1
Reactant: [H][H]
Reactant: CN(C)CCn1c(=O)c2cc([N+](=O)[O-])cc3c2n(c1=O)-c1cc2ccccc2cc1O3
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: CN(C)CCn1c(=O)c2cc(N)cc3c2n(c1=O)-c1cc2ccccc2cc1O3
Temperature: 25 °C

Procedure:
268 mg (0.641 mmol) of the free base of the compound of Example 27 was dissolved in acetic acid (10 ml) and 10% palladium-carbon was added thereto. Then catalytic reduction was effected at room temperature in a hydrogen atmosphere. After filtering off the palladium-carbon through celite, the filtrate was concentrated. Next, water and a saturated aqueous solution of sodium hydrogencarbonate were added thereto and the obtained mixture was stirred at room temperature. The precipitate was recovered by filtration, washed with water and suspended in methanol. After adding conc. hydrochloric acid thereto, the obtained mixture was stirred at room temperature. Thus it turned into a homogeneous solution and then a precipitate was formed. The precipitate was recovered by filtration to thereby give 179 mg of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[CH3:9][O:10][C:11](Cl)=[O:12]>C(OCC)C>[CH3:9][O:10][C:11]([NH:1][C@@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:12]
Reactant: COC(=O)Cl
Reactant: C[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COC(=O)N[C@H](C)C(=O)O
Reaction time: 3 h

Procedure:
To a solution of D-alanine (5 g, 56.1 mmol) in 1 N NaOH (152 mL, 152 mmol) at 0° C. is added a solution of MeOC(O)Cl (6.5 ml., 84.2 mmol) in diethyl ether (30 mL). The mixture is stirred in ice bath for 3 hours and then adjusted to pH 9 with 1 N NaOH. After stirring at room temperature for 1 hour, the mixture is washed with ether (3×50 mL), acidified to pH ˜2 with 5 N HCl, extracted with EtOAc (5×50 mL). The organic extract is washed with water, brine, and then dried (MgSO4). The solvent is removed to yield compound cxxxiv, N-methoxycarbonyl-D-alanine, as colorless oil (6.48 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([NH2:19])[N:13]=2)=[CH:6][C:5](I)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>O1CCOCC1>[CH3:18][C:16]1[CH:17]=[C:12]([CH2:11][CH2:10][C:9]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([C:32]4[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=4)[CH:6]=[C:7]3[N:8]=2)[N:13]=[C:14]([NH2:19])[CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(N)nc(CCC(=O)Nc2cc(I)cnc2N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4ccc(C(F)(F)F)cc4)cnc3[nH]2)c1
Temperature: 110 °C
Yield: 54.1 %

Procedure:
96 mg N-(2-amino-5-iodo-pyridin-3-yl)-3-(6-amino-4-methyl-pyridin-2-yl)-propionamide (compound A10) is dissolved in 3.0 ml anoxic dioxane under a nitrogen atmosphere. Subsequently, 0.7 ml of an aqueous sodium bicarbonate solution (2.0 M), 52 mg 4-(trifluoromethyl)phenyl-boronic acid, and 14 mg trans-dichloro-bis(tricyclohexylphosphane)palladium-(II) are added. The reaction mixture is refluxed at 110° C. for 20 h. Thereafter, the volatile components are removed in vacuo and the remaining residue is re-dissolved in a mixture of water/dichloromethane (1:1). The aqueous phase is extracted several times with dichloromethane. The organic layer is separated, dried using sodium sulfate, and evaporated to dryness to yield 161 mg of a colourless, crude solid. Subsequently, the residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethanol 8:1) to afford 52 mg of the title compound. M.p. 170° C. ESI-MS: 398.3 (MH+). TLC: Rf=0.25 (dichloromethane/methanol 8:1).
Reaction SMILES: F[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[OH-].[NH4+:19].Cl>[OH-].[NH4+].O>[NH2:19][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2
Reactant: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c(F)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Temperature: 80 °C
Yield: 76 %

Procedure:
To a solution of 20 mg (0.082 mmol) of 6,7-difluoro-5-nitro-1,4-dihydroquinoxaline-2,3-dione in 0.5 mL of DMSO-d6 was added 2 drops of 30% ammonium hydroxide and the solution was heated at 80° C. for 24 h. To the mixture was added one more drop of 30% ammonium hydroxide and it was heated at 80° C. for 10 h. The mixture was added to 4 mL of water and then acidified with 2N HCl to pH=1. The precipitate was filtered, washed with water, and dried to leave a yellow solid (15 mg, 76%); mp 250° C. (dec.); 1H NMR (DMSO-d6), 7.202 (1, d, J=11.5), 7.232 (sb, 2), 11.15 (mb, 1), 12.0 (mb, 1). 19F NMR, -133.84 (d, J=11.6). MS, 240 (M+, 100), 212 (10), 177 (10), 166 (20). HRMS, Calcd for C8H5FN4O4 240.0290, found 240.0294.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO.O>[CH:1]1([CH2:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:11])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)C(CC1CCCCC1)n1cncn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(O)C(CC1CCCCC1)n1cncn1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
13.2 g (0.05 mol) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentan-3-one are dissolved in a mixture of 100 ml of methanol and 20 ml of water, a total of 2 g (0.05 mol) of sodium borohydride is added in several portions, and the mixture is stirred overnight. To work up the reaction mixture, it is brought to pH 5 with dilute hydrochloric acid, and the solvent is evaporated off in vacuo. The residue is taken up in water and extracted several times with methylene chloride. The combined organic extracts are washed with sodium bicarbonate solution and water, dried over sodium sulphate and evaporated down in vacuo. The residue is crystallized using petroleum ether. 10 g (75.2% of theory) of 1-cyclohexyl-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pentan-3-ol are obtained in the form of colorless crystals of melting point 104° C. to 107° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.C=O.[C:38](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH3:38])[CH2:31][CH2:32]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:34][CH:35]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCNCC2)c2ccccc2C1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.08 mmol of 4-(4-chlorobenzoyl)-1-(4-piperidinylmethyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on trifluoroacetate obtained in Example 140 and 5 mg (0.17 mmol) of paraformaldehyde were dissolved in 3 ml of dichloromethane. 12 mg (0.20 mmol) of acetic acid was added to the obtained solution. After stirring at room temperature for 30 minutes, 53 mg (0.25 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].N1C=CN=C1.Cl[Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C)C=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:18]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cn(CCO[Si](C)(C)C(C)(C)C)nn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A solution of 1,1-dimethylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see intermediate 47) (659 mg, 1.586 mmol) and imidazole (216 mg, 3.17 mmol) in N,N-dimethylformamide (DMF) (20.0 mL) was treated with chloro(1,1-dimethylethyl)dimethylsilane (0.330 mL, 1.903 mmol) and the resulting reaction mixture was stirred at room temperature for 16 h. Another equivalent of imidazole (216 mg, 3.17 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (0.330 mL, 1.903 mmol) were then added to the reaction which was stirred at room temperature for 1 h then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed twice with brine, dried over MgSO4, and concentrated in vacuovacuo. Purification of the residue on SP4 using a 50 G silica cartridge (gradient:10 to 50% AcOEt in Hexanes) gave 1,1-dimethylethyl {(2S,4R)-1-acetyl-6-[1-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (599 mg, 1.085 mmol, 68.4% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.Cl[C:13]1([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:18])[CH:16]=[CH:15][S:14]1.CC1(C)CCCC(C)(C)N1>C(Cl)(Cl)Cl>[OH:18][C:17]1[CH:16]=[C:15]([N:9]2[C:7]3=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]3[N:11]=[CH:10]2)[S:14][C:13]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: COc1ccc2[nH]cnc2n1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3ccc(OC)nc32)cc1O

Procedure:
In a similar manner as described for example C2, 8.54 g of the above-synthesized 5-methoxy-1H-imidazo[4,5-b]pyridine and 4.46 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate and 13.07 g of 2,2,6,6-tetramethylpiperidine in 620 ml chloroform yield the title compounds as an isomeric mixture which was used for the next step (example B7) without further purification.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:16]([NH:18][O:19][CH3:20])=[O:17].C(N(CC)CC)C>C(#N)C>[C:4]([C:3]1[C:2]([NH:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:16]([NH:18][O:19][CH3:20])=[O:17])=[N:9][C:8]([Cl:10])=[C:7]([F:11])[CH:6]=1)#[N:5]
Reactant: CONC(=O)c1ccc(C)c(N)c1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CONC(=O)c1ccc(C)c(Nc2nc(Cl)c(F)cc2C#N)c1
Temperature: 70 °C
Yield: 20.5 %

Procedure:
A mixture of 2,6-dichloro-5-fluoro-nicotinonitrile (830 mg, 4.34 mmol), 3-amino-N-methoxy-4-methyl-benzamide (576 mg, 3.2 mmol) and triethylamine (0.5 mL) in acetonitrile (10 mL) was heated to 70° C. overnight. Then the solvent was removed under reduced pressure and the reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure. The product (220 mg, 21%) was isolated after purification by silica gel chromatography. C15H12ClFN4O2 MS m/e=335 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].O.[CH2:14](O)[CH2:15]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:14]=[CH2:15])[CH:6]=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CCCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Product: C=Cc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 100 °C
Yield: 58 %

Procedure:
To 5-bromo-2-nitrophenyl methyl ether (8.0 g, 34.47 mmol) in 80 mL of n-propanol was added, PdCl2(dppf)*DCM (0.5 g, 0.69 mmol), potassium ethenyl(trifluoro)borate (6.47 g, 48.3 mmol), and TEA (3.48 g, 34.47 mmol). The mixture was heated to 100° C. for 3 h. The mixture was poured into 250 mL of H2O and extracted with DCM, dried (Na2SO4), filtered, and rotovaped down, and purified by flash chromatography to give the title compound of step B (3.58 g, 19.98 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ ppm 7.82-7.87 (m, 1H), 7.02-7.07 (m, 2H), 6.70 (dd, J=17.58, 10.80 Hz, 1H), 5.87 (d, J=17.58 Hz, 1H), 5.46 (d, J=10.99 Hz, 1H), 3.97 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:37][C:34]1[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(CCNC(=O)OC(C)(C)C)Cc2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A stirred solution of 1.5 grams (0.0052 mole) of (tert-butoxy)-N-(2-{[(6-chloro(3-pyridyl))methyl]amino}ethyl)carboxamide and 2.3 mL (0.013 mole) of diisopropylethyl amine in about 15 mL of methylene chloride was cooled to 0° C., and 0.7 mL (0.0052 mole) of (4-methoxyphenyl)methyl chloride in about 3 mL of methylene chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature, where it stirred during an 18 hour period. After this time, analysis of the reaction mixture by thin layer chromatography (TLC) indicated that no reaction had taken place. The reaction mixture was then heated at reflux for two hours, after which TLC analysis indicated that no reaction had taken place. The methylene chloride solvent was removed under reduced pressure from the reaction mixture, which was replaced with chloroform. The reaction mixture was heated at reflux during one hour, and then it was allowed to cool to ambient temperature, where it stirred during an 18 hour period. After this time TLC analysis indicated the presence of some reaction product. The reaction mixture was then heated at reflux for about a nine hour period and then it was allowed to cool to ambient temperature as it stirred during an additional 18 hour period. After this time the chloroform solvent was removed under reduced pressure from the reaction mixture, which was replaced with acetonitrile. The reaction mixture was then stirred at ambient temperature during a four hour period, warmed to 60° C. where it stirred for a ten hour period, and finally stirred at ambient temperature during a 60 hour period. The reaction mixture was concentrated under reduced pressure to a residue, and the residue was purified with column chromatography on silica gel. Elution was accomplished using 30% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])=O.[C:14]([NH2:17])(=[O:16])[CH3:15]>>[CH3:15][C:14]1[O:16][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])[N:17]=1
Reactant: O=C(O)c1cccc(C(=O)CBr)c1
Reactant: CC(N)=O
Product: Cc1nc(-c2cccc(C(=O)O)c2)co1
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
A mixture of 3-(2-bromo-acetyl)-benzoic acid (2.43 g) and acetamide (1.77 g) was heated with stirring to 130° C. for 40 min. The mixture was cooled and diluted with H2(30 mL) and the precipitate formed was collected by filtration to give 3-(2-methyl-oxazol-4-yl)-benzoic acid (1.51 g) as brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=[O:21])[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(C=O)ccc2n1Cc1cccc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(CO)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(4-tert-butylphenyl)-5-formyl-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 140, 700 mg, 1.493 mmol) was dissolved in ethanol (15 mL) and cooled to 0° C. Sodium borohydride (57 mg, 1.50 mmol) was added, and the solution was stirred for 1 hour. Water (27 μL, 1.5 mmol) was added, and the mixture was allowed to warm to room temperature. The mixture was concentrated via rotary evaporation, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude oil was purified by flash chromatography on silica gel eluted with hexane then 20% ethyl acetate/hexane. The title compound was collected as a foam (530 mg, 75%). The product had: 1H NMR (300 MHz, acetone-d6) δ 7.56-7.55 (m, 1 H), 7.53-7.51 (m, 1 H), 7.50-7.47 (m, 2 H), 7.41-7.39 (m, 1 H), 7.37-7.34 (m, 2 H), 7.18-7.16 (m, 1 H), 6.77-6.75 (m, 1 H), 6.68-6.70 (m, 2 H), 5.85 (s, 2 H), 4.65 (d, 2 H), 4.09 (q, 2 H), 4.06-4.04 (m, 1 H), 3.70 (s, 3 H), 1.38 (s, 9 H), 0.96 (t, 3 H); mass spectroscopy gave MH+=472.2 (calc'd exact mass for C30H33NO4=471.24).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C@H:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](N)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 4-fluoro-benzenesulfonyl chloride (1.65 g, 0.00848 mol), (R)-2-amino-4-methyl-pentanoic acid (1.233 g, 0.009398 mol), and sodium carbonate (1.91 g, 0.0180 mol) in water (15 mL) was stirred at room temperature for 5 days. The solution was filtered, and the filtrate was acidified with concentrated hydrochloric acid to pH=4. The mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried (MgSO4), and rotary evaporated to a yellow oil. The oil was chromatographed on silica gel (320 g, 230-400 mesh) eluting with dichloromethane-methanol (10:1, 10×300 mL). Fractions containing product were combined and rotary evaporated to give a pale yellow oil. The oil was dried in vacuo; yield 1.44 g (59%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:37])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([CH3:37])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cc(O)ccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1C
Yield: 87 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (320 mg) in acetonitrile (10 mL) were added ethyl 3-(5-hydroxy-2-methylphenyl)propanoate (230 mg) and cesium carbonate (546 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (427 mg) as a colorless oil.
Reaction SMILES: [O:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][CH:4]=1)C.O>II>[OH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: II
Solvent: O
Product: O=C(O)CCC(=O)c1ccc(O)cc1
Temperature: 140 °C
Yield: 87.8 %

Procedure:
The methoxy derivative, Compound 3.2 (14.54 g, 70 mmol), was dissolved in iodine free hydriodic acid (150 mL) and refluxed at 140° C. for four hours. After the resulting brown solution was cooled to room temperature, water was added and the mixture was neutralized. The aqueous phase was then washed with ether; the organic layers were combined, decolorized, dried and evaporated. The remaining residue was purified by flash silica chromatography to yield a white solid (11.93 g, 88%). NMR (CDCl3) δ 8.20 (d, 2H), 7.02 (d, 2H), 3.32 (t, 2H), 2.88 (d, 2H).