Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][C:6](O)=[O:7])[CH3:2].C(Cl)(=O)C(C)(C)C.[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[NH:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Br-].[Li+]>O1CCCC1.C(N(CC)CC)C>[CH2:35]([C@@H:42]1[CH2:46][O:45][C:44](=[O:47])[N:43]1[C:6](=[O:7])[CH2:5][CH:4]([O:3][CH2:1][CH3:2])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]2[CH2:22][CH2:21][CH2:20][C:19]3([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:18]=2)=[CH:13][CH:14]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC(CC(=O)O)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(CC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(OCC2=CC3(CCCCC3)CCC2)cc1
Temperature: -32.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-pr opionic acid (2.95 g) obtained in Example 41 and triethylamine (3.3 mL) in tetrahydrofuran (60 mL) was added dropwise a solution of pivaloyl chloride (1.265 mL) in tetrahydrofuran (5 mL) at −35° C., followed by stirring the reaction mixture at −35 to −30° C. for 30 minutes. Then, to the reaction mixture was added dropwise a solution of (R)-4-benzyl-2-oxazolidinone (1.82 g) and lithium bromide (892 mg) in tetrahydrofuran (10 mL), followed by raising the temperature up to 0° C. over 2 hours while stirring the reaction mixture. The reaction mixture was poured into ice-cold water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by mid-pressure preparative chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:5) to give (R)-4-benzyl-3-(3-ethoxy-3-[4-(spiro[5.5]undec-1-en-2-ylmethoxy)-phenyl]-propionyl)oxazolidin-2-one.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH:32]1([NH:36][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]3)=[CH:22][CH:23]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCC1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC5CCC5)cc4)cc23)CC1
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (40 mg, 0.091 mmol) in DMSO (900 μL) and acetic acid (2 drops) was added cyclobutylamine (94 μL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (120 mg, 1.10 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 26.3 mg of the title compound (59%).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:31]3[CH:39]=[CH:38][C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>C1COCC1.C(O)C>[O:35]1[C:34]2[CH:38]=[CH:39][C:31]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])=[CH:32][C:33]=2[O:37][CH2:36]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of the 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (152 mg, 0.23 mmol) in THF (5 mL) and ethanol (5 mL) was added aqueous 1.0 N sodium hydroxide (5 mL) at room temperature. The resulting suspension was stirred for 5 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with diethyl ether (30 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N hydrochloric acid and the precipitated white organic compound was extracted into ethyl acetate (2×30 mL). The combined ethyl acetate extracts were washed with brine solution (50 mL) and the organic layers were dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent afforded 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-ethoxy-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (129 mg, 95%) as a off-white waxy solid: ES(+)-HRMS m/e calcd for C34H40O9 (M+H)+ 593.2745. found 593.2744.
Reaction SMILES: [CH:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:12]([Li])[CH2:13][CH2:14]C.C(I)C=C>C1COCC1>[CH2:14]([C:1]1([S:4]([O:7][CH2:8][CH2:9][CH2:10][CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1)[CH:13]=[CH2:12]
Reactant: CCCCOS(=O)(=O)C1CC1
Reactant: [Li]CCCC
Agent: C=CCI
Solvent: C1CCOC1
Product: C=CCC1(S(=O)(=O)OCCCC)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
To a solution of 1-butyl cyclopropanesulfonate (4.8 g, 24.9 mmol) in THF at −78° C. was added simultaneously butyllithium solution (15.6 ml, 24.9 mmol, 1.6M, THF) and allyl iodide (24.9 mmol) under nitrogen atmosphere. The reaction mixture was stirred 2 hours at −78° C. and 3 hours at room temperature. The volatiles were evaporated under reduced pressure and the residue extracted with CH2Cl2 (100 ml). The extract was washed with water, dried (MgSO4) and evaporated. The residue was purified over silica gel chromatography (eluants: hexane/CH2Cl2) to obtain the titled product (3.75 g, 69.0%) as a colorless oil, 1H NMR (300 MHz, CDCl3): δ 5.6 (m, 1H), 5.13-5.08 (t, 2H), 4.21 (t, 2H), 2.65 (d, 2H), 1.7 (m, 2H), 1.4 (m, 4H), 0.93 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:13])[NH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.ClCCl>[CH3:18][N:9]1[C:8](=[O:13])[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10]1
Reactant: O=c1[nH][nH]c2cc([N+](=O)[O-])ccc12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1[nH]c2cc([N+](=O)[O-])ccc2c1=O
Temperature: 60 °C

Procedure:
1.66 g (9.27 mmol) of 6-nitro-1,2-dihydro-3H-indazol-3-one were initially charged in 20 ml of DMF, and 1.75 ml (18.5 mmol, 2.0 eq.) of dimethyl sulphate were added. The reaction mixture was heated at 60° C. for 8 h and then diluted with dichloromethane and shaken with saturated aqueous sodium carbonate solution. The aqueous phase was washed three times each with dichloromethane and with ethyl acetate and the organic fractions were discarded. Using 4N aqueous hydrochloric acid, the aqueous phase was then carefully adjusted to pH 4.5 and extracted three times with ethyl acetate. These combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 50, mobile phase: gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate/methanol 15:1), giving the title compound. Yield: 770 mg (43% of theory)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7](O)[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][CH2:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncsc1C(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ncsc1CCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A solution of 1 g (7 mmol) of 4-methyl-5-thiazolylethanol in 15 mL of dichloromethane is cooled to 0° C. under argon. In a first stage, 1.8 g (7 mmol) of triphenylphosphine are added. Next, 1.30 g (7 mmol) of N-bromosuccinimide are added portionwise over 5 minutes. After stirring for 2 hours at 0° C., the solvent is evaporated off under vacuum. The residue obtained is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 900 mg of 5-(2-bromoethyl)-4-methylthiazole, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N+:7]([O-])[CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:16][CH:15]=2)[C:4]1=[O:31])[CH3:2].[Cl-].[Cl-].[Ca+2].[C:35]([O:38]C(=O)C)(=[O:37])[CH3:36]>>[C:35]([O:38][CH2:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[N:5]([C:14]3[CH:15]=[CH:16][C:17]([O:20][Si:21]([CH:22]([CH3:23])[CH3:24])([CH:25]([CH3:26])[CH3:27])[CH:28]([CH3:30])[CH3:29])=[CH:18][CH:19]=3)[C:4](=[O:31])[N:3]([CH2:1][CH3:2])[C:11]=12)(=[O:37])[CH3:36]
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2c1c(C)cc[n+]2[O-]
Reactant: CC(=O)OC(C)=O
Agent: [Ca+2]
Agent: [Cl-]
Product: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(COC(C)=O)c21

Procedure:
The mixture of 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (500 mg) in acetic anhydride (10 mL) was stirred at 80° C. under a dry atmosphere (CaCl2 tube) for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give [1-ethyl-2-oxo-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (300 mg) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([F:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:10]=[C:9]([F:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:17][CH:16]=1
Reactant: COc1cc(C(=O)O)c(Br)cc1F
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)c(Oc2ccc(Br)cc2)cc1F
Temperature: 110 °C
Yield: 94.8 %

Procedure:
A mixture of 2-bromo-4-fluoro-5-methoxybenzoic acid 1 (1.0 kg, 4.02 mol), 4-bromophenol (4.41 mol, 1.05 equiv, 729.5 g) and Cs2CO3 (12.06 mol, 3 equiv. 3.92 kg) in anhydrous DMF (12 L) was degassed with N2 for 30 min. To this mixture was added copper (I) triflate toluene complex (2:1) (0.04 equiv. 83.12 g) and the mixture was further degassed again with N2 for 15 min. The resulting mixture was heated at 110° C. for 4 days. The reaction mixture was cooled to ambient temperature and poured onto 5 L of ice water. The pH was adjusted to 1 with concentrated HCl and the aqueous layer was extracted with EtOAc (3×4 L). The combined extracts were washed with brine (2×2 L). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a thick brown oil. The brown oil was triturated with a 5% IPA/water mixture (5 L) at ambient temp to obtain a brown solid. The solid was filtered, washed with water and hexane and dried overnight under vacuum to afford 2-(4-bromophenoxy)-4-fluoro-5-methoxybenzoic acid (1.3 kg, 95% yield) as a brown solid.
Reaction SMILES: [CH3:1][P:2]1(=[O:35])[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=[CH:18][C:17]=3[NH:27]C(=O)OC(C)(C)C)=[O:14])=[CH:9][CH:8]=2)[O:3]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:27][C:17]1[CH:18]=[CH:19][C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[C:10]1[CH:11]=[CH:12][C:7]([CH:4]2[O:3][P:2]([CH3:1])(=[O:35])[CH2:6][CH2:5]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C2CCP(C)(=O)O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CP1(=O)CCC(c2ccc(C(=O)Nc3cc(-c4cccs4)ccc3N)cc2)O1
Reaction time: 3 h

Procedure:
1,1-dimethylethyl [2-({[4-(2-methyl-2-oxido-1,2-oxaphospholan-5-yl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate (95 mg, 0.185 mmol) was taken up in DCM (5 mL)/TFA (2 mL). After 3 hours, saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give N-[2-amino-5-(2-thienyl)phenyl]-4-(2-methyl-2-oxido-1,2-oxaphospholan-5-yl)benzamide as a yellow solid. The title compound was obtained as a 1:1 mixture of diastereosiomers. MS: cal'd 413 (MH+), exp 413 (MH+).
Reaction SMILES: C([O:8][C:9]([NH:11][CH2:12][CH2:13][S:14]([NH2:17])(=[O:16])=[O:15])=O)C1C=CC=CC=1.CO>[Pd].C(O)=O>[CH:9]([NH:11][CH2:12][CH2:13][S:14]([NH2:17])(=[O:16])=[O:15])=[O:8]
Reactant: NS(=O)(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: NS(=O)(=O)CCNC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
In a reaction flask, 10.3 g of 2-benzyloxyformamidoethylsulfonamide, 10% Pd/C (3.0 g) and 600 ml of methanol were added. The mixture was stirred at room temperature overnight under hydrogen atmosphere, added with 35 ml of formic acid, stirred for 30 min, filtered, and concentrated under a reduced pressure to obtain 5.6 g of oily product, yield 93%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[NH4+:12]>CCOC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([NH2:12])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: [NH4+]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cnc2[nH]ccc2c1
Yield: 63 %

Procedure:
5-bromo-1H-pyrrolo[2,3-b]pyridine (6.0 g, 30.45 mmol) in ammonium hydroxide (120 mL) was treated with copper sulphate pentahydrate (1.50 g, 6.09 mmol, 0.2 eq) and heated in a sealed tube overnight. The reaction was diluted with EtOAc and the insoluble black solid was filtered off. The filtrate was extracted (EtOAc/Water) and the organic layer washed with saturated aqueous ammonium chloride, followed by water and brine. The organics were dried over magnesium sulphate, filtered and evaporated to dryness to give the product as a pale brown solid (2.57 g, 63%)
Reaction SMILES: N1C=CC=N1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH2:14][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: c1cn[nH]c1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1

Procedure:
In a further embodiment, a pyrazole cyclization reaction is provided in Scheme 14A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The pyrazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydrazine hydrate to provide ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol and glacial acetic acid for about 2 to 16 hours. Ethyl 3-(4-fluorophenyl)-1H-pyrazole-5-carboxylate is then reduced with lithium aluminum hydride to provide 3-(4-fluorophenyl)-1H-pyrazol-5-yl-methanol. In one embodiment, the reduction is performed in THF at a temperature of about 0° C. to about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde is then formed by oxidizing 3-(4-fluorophenyl)-1H-pyrazole-5-methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 3-(4-Fluorophenyl)-1H-pyrazole-5-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:19]([O:21][C:22](=[O:25])[CH2:23]Br)[CH3:20].C(O)C>CC(C)=O>[Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[O:12][CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:25]
Reactant: COc1cc(C=O)cc(Cl)c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(Cl)cc(C=O)cc1OC
Yield: 44.8 %

Procedure:
The compound was prepared according to general procedure E with 5-chlorovanillin (2.7 mmol) in dry acetone (25 ml), anhydrous K2CO3 (3.5 mmol), and ethylbromoacetate (4.05 mmol) at reflux for 1 h30. Ethanol was added and evaporated by azeotropic distillation with ethylbromoacetate. 957 mg of crude product were obtained and purified by silica gel chromatography (eluent dichloromethane). 330 mg of purified compound were obtained (45% yield). 1H NMR (250 MHz, CD3COCD3): δ 1.27 (t, J=7.2 Hz, 3H), 3.98 (s, 3H), 4.22 (q, J=7.2 Hz, 2H), 4.87 (s, 2H), 7.50 (s, 1H), 7.58 (s, 1H), 9.90 (s, 1H) 13C NMR (126 MHz, CD3COCD3): δ 15.1, 57.5, 62.1, 70.5, 112.3, 125.8, 128.9, 134.0, 149.7, 154.5, 169.5, 191.2. MS (ESI): m/z 272.9 and 274.9 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[C:9]([CH2:19][O:20][C@@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[CH:8]2)=[CH:4][CH:3]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.Cl.[CH3:50][NH:51][OH:52]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:51]([OH:52])[CH3:50])=[O:18])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][C@@H:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:22])=[CH:8]2)=[CH:29][CH:30]=1
Reactant: C[C@@H](OCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12)c1ccccc1
Reactant: CNO
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Product: C[C@@H](OCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)N(C)O)cc12)c1ccccc1

Procedure:
The title compound was prepared as in example 116, step 3, using 1-(4-fluorobenzyl)-3-{[(1R)-1-phenylethoxy]methyl}-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid, 2-chloro-4,6-dimethoxy-1,3,5-triazine, N-methyl morpholine, and N-methyl hydroxylamine hydrochloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.35 (d, J=6.32 Hz, 3H) 3.33 (s, 3H) 4.50 (s, 2H) 4.55 (q, J=6.57 Hz, 1H) 5.53 (s, 2H) 7.16 (t, J=8.84 Hz, 2H) 7.29 (td, J=5.49, 3.16 Hz, 1H) 7.34-7.39 (m, 6H) 7.82 (s, 1H) 7.98 (s, 1H) 8.89 (s, 1H)
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:14]([CH:15]=1)=[N:13][CH:12]=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:1][C:2]1[NH:3][C:4](=[O:16])[C:5]2[C:14]([CH:15]=1)=[N:13][CH:12]=[C:11]1[C:6]=2[CH:7]=[CH:8][CH:9]=[CH:10]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1[nH]c(O)cc2ncc3ccccc3c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(OCc2ccccc2)cc2ncc3ccccc3c12
Temperature: 60 °C

Procedure:
The hydrobromide salt 4d (100 mg, 0.34 mmol) was dissolved in 3 mL DMF. Potassium carbonate (100 mg) and benzyl bromide (60 μL, 0.50 mmol) were added to the solution and the mixture was heated to 60° C. for 14 h. The solvent was removed in vacuo and the residue was washed with water (5 mL) and boiling MeOH (10 mL) and filtered. The solid 4e (47 mg, 46%) was pure while the filtrate contained a mixture of isomers. Mp=271-276° C. 1H NMR (d6-DMSO) δ 11.68 (bs, 1H), 8.71 (d, 1H), 8.30 (d, 1H), 7.93 (t, 1H), 7.74 (m, 2H), 7.55 (d, 2H), 7.40 (t, 2H), 7.32 (t, 1H), 7.09 (d, 1H), 5.54 (s, 2H). Anal Calcd. for C19H14N2O2(H2O): C, 71.24; H, 5.03; N, 8.74. Found: C, 71.28; H, 4.83; N, 8.38.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(N(CC)CC)C.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=2[OH:40])[N:23]=1>C(Cl)Cl>[F:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:40])[C:33]=1[C:24]1[N:23]=[C:22]([N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[C:31]2[C:26](=[CH:27][C:28]([CH3:32])=[CH:29][CH:30]=2)[N:25]=1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3c(O)cccc3F)nc2c1
Reaction time: 1 h

Procedure:
A solution of tert-butyl(R)-pyrrolidin-3-ylcarbamate (368 mg, 1.97 mmol) and triethylamine (0.46 mL, 3.28 mmol) in CH2Cl2 was rapidly added to a stirring solution of 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (475 mg, 1.65 mmol) in 15 mL CH2Cl2 at 0° C. under an N2 atmosphere. The reaction was stirred for 1 h before it was quenched with water, and the aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-10% EtOAc/CH2Cl2 yielded tert-butyl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate. LC/MS: m/z 439.5 (M+H)+ at 2.42 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:15])[CH:16]=[C:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
4-tert-Butylcyclohexanone (8.62 g, 56 mmol) was dissolved in toluene (200 ml). Methoxycarbonylmethylenetriphenylphosphorane (56.1 g, 168 mmol) was added with stirring and the reaction mixture was heated under reflux for 3 days. The solvent was removed in vacuo. The residue was dissolved in hot hexanes (100 ml) and cooled to room temperature. The precipitate was filtered off and the filtrate was evaporated in vacuo to afford a yellow oil which was then purified by chromatography (silica gel, hexane/ethyl acetate, 2:1 as eluant) to give the title compound as an oil (10.78g, 92%). 1H-NMR; δ (CDCl3) 5.60 (1H, s), 3.87 (1H, m), 3.69 (3H, s), 2.38-2.10 (2H, m), 2.03-1.77 (3H, m), 1.36-1.02 (3H, m) and 0.87 (9H, s).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([CH:35]=[CH:36][CH:37]=1)[CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:19]([CH3:22])=[N:20][N:21]=3)[C:13]=2[CH:12]=[C:11]1[C:23]1[CH:27]=[CH:26][N:25]([C:28]2([CH2:32][C:33]#[N:34])[CH2:31][NH:30][CH2:29]2)[N:24]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:30]1[CH2:31][C:28]([CH2:32][C:33]#[N:34])([N:25]2[CH:26]=[CH:27][C:23]([C:11]3[N:10]([CH2:9][C:8]4[CH:35]=[CH:36][CH:37]=[C:6]([Cl:5])[CH:7]=4)[C:14]4[CH:15]=[CH:16][C:17]5[N:18]([C:19]([CH3:22])=[N:20][N:21]=5)[C:13]=4[CH:12]=3)=[N:24]2)[CH2:29]1)(=[O:3])[CH3:2]
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3cccc(Cl)c3)n12
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(CC#N)(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3cccc(Cl)c3)n2)C1
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
Acetyl chloride (1.1 μL, 0.016 mmol, Aldrich) in DCM (0.35 mL) was added to (3-{3-[6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl]-1H-pyrazol-1-yl}azetidin-3-yl)acetonitrile (6.0 mg, 0.013 mmol, from Step 1). Triethylamine (3.7 μL, 0.026 mmol) was then added and the reaction was stirred for 10 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product (4.0 mg, 61%).