Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1.I.O>O1CCOCC1>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:27][C:24]3[CH:25]=[N:26][C:21]([C:20]([F:29])([F:19])[F:28])=[CH:22][CH:23]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Agent: I
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cn1
Temperature: 130 °C
Yield: 95 %

Procedure:
6-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.5 g, 1.93 mmol) was dissolved in anhydrous dioxane (3 mL) and 6-trifluoromethylpyridin-3-ylamine was added (469 mg, 2.9 mmol), followed by HI/H2O (0.3 mL, 47%). The mixture was heated at 130° C. for 600 s in a Personal Chemistry microwave. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product as an orange solid (700 mg, 95% crude). The crude product was used for the subsequent step.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4]CC.CCN(CC)CC.[ClH:14].[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[N:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28]2)[CH2:24][CH2:23]1>CO>[ClH:14].[OH:15][CH:16]1[CH:17]([N:22]2[CH2:23][CH2:24][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28]3)[CH2:26][CH2:27]2)[CH2:18][C:19]2[C:20](=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:21]1
Reactant: CCCCCC
Reactant: OC1CCCCC1N1CCC2(C=Cc3ccccc32)CC1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: OC1Cc2ccccc2CC1N1CCC2(C=Cc3ccccc32)CC1

Procedure:
A biphasic mixture of the bromohydrin (1.14 g, 5.0 mmol) in 2M aq. NaOH (100mL) and CHCl3 (100 mL) was refluxed for 2.5 h. TLC (silica gel; 50% hexane-CH2Cl2) confirmed that formation of the epoxide was complete. The mixture was cooled to room temperature and the two layers were separated. The aq. phase was re-extracted with CHCl3 (2×30 mL) and discarded. The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield the crude epoxide as a pale yellow syrup which was redissolved in EtOH (30 mL) and Et3N (2 mL). Spiro[1H-indene-1,4'-piperidine]hydrochloride (1.11 g, 5.0 mmol) was added to this solution, and the resulting mixture was refluxed overnight. After 17 h, heating was stopped. The mixture was cooled to room temperature and concentrated to a residue in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and the solution was washed with satd aq. NaHCO3 (30 mL). The aqueous extract was washed with CH2Cl2 (30 mL) and discarded. The organic extracts were combined, dried over anhydrous Na2SO4 and concentrated to a residue. The latter was dissolved in a minimum volume of CH2Cl2 and applied to a short column of silica gel which was subsequently eluted with 25% acetone-hexane. Concentration of the eluent yielded the product (0.91 g, 55%) as a brown syrup. The latter was estimated by tlc (silica gel, acetone(25):hexane (74):Et3N (1)) to be greater than 97% pure. The corresponding hydrochloride was prepared in MeOH as outlined for (11a) above, and recrystallized from isopropyl alcohol; mp 254°-257° C.; 1H NMR (CDCl3) δ1.46 (d, 2, piperidyl β-Heq., J= 12.8 Hz), 2.17 (m, 2, piperidyl β-Hax.), 2.86-3.49 (m, 8, tetrahydronaphthyl C1-H, C3-H, C4-H & piperidyl α-Hax.,eq.), 3.93-4.20 (m, 3, piperidyl α-Heq & C HOH), 6.79 (d, 1, indenyl C2-H, J=5.6 Hz), 6.90 (d, 1, indenyl C3-H, J=5.7 Hz), 7.03-7.42 (m, 8, aryl).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C:52]1[C:53](=[O:62])[NH:54][C:55]([CH3:61])=[CH:56][C:57]=1[CH2:58][O:59][CH3:60].O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:50][CH2:51][C:52]2[C:53](=[O:62])[NH:54][C:55]([CH3:61])=[CH:56][C:57]=2[CH2:58][O:59][CH3:60])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:12])[CH3:13])[C:6]=2[N:7]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)nc21
Reactant: COCc1cc(C)[nH]c(=O)c1CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: O
Product: COCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To a solution of 6-bromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.155 g, 0.549 mmol) in DMSO (2 mL), PyBOP (0.429 g, 0.823 mmol) was added and reaction stirred at room temperature for 15 min. Then 3-(aminomethyl)-4-(methoxymethyl)-6-methylpyridin-2(1H)-one (0.1 g, 0.549 mmol) was added and reaction stirred overnight. On completion, water was added and solid that precipitates out was filtered and washed with water to obtain the desired intermediate (0.06 g, 24.5%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2([CH2:23][CH2:22][C:21](=[CH:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:20][CH2:19]2)[S:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:30](I)[CH3:31].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][CH:8]1[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]([O:18][CH2:30][CH3:31])=[O:17])[C:10]2([CH2:19][CH2:20][C:21](=[CH:24][CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:23]2)[S:9]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CC=C1CCC2(CC1)SC(CC(=O)OC(C)(C)C)C(=O)N2CCC(=O)O
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN1C(=O)C(CC(=O)OC(C)(C)C)SC12CCC(=CCC(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 7 ml of N,N-dimethylformamide was added 0.70 g of 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionic acid. After adding 0.14 ml of ethyl iodide and 0.25 g of anhydrous potassium carbonate at 0-5° C., the resulting mixture was stirred at ambient temperature for 3 hours. The resulting mixture was poured into a mixture of ice water and ethyl acetate, pH was adjusted to 2.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, 0.70 g of ethyl 3-[2-[2-(tert-butoxy)-2-oxoethyl]-8-(3-methylbutylidene)-3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl]-propionate was obtained as a light yellow oily product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][CH2:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14].C(N(CC)CC)C>C(O)C>[N+:8]([C:7]1[C:2]([NH:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[OH:14])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCC(O)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1NCC(O)c1ccccc1
Yield: 5.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (20.0 g, 0.13 mole), 2-amino-1-phenylethanol (20.74 g, 0.15 mole), and triethylamine (17.5ml, 0.13 mole) in 200 ml of absolute ethanol was heated to reflux for 11/2 hours. The reaction mixture was filtered and evaporated to dryness. The residue was partitioned between water and methylene chloride (2×). The methylene chloride layers were combined and extracted with water. The methylene chloride layers were dried, filtered, and evaporated to a solid (30.8 g, 94.5%). A 2.4-g sample was recrystallized from methanol and water to give a yellow solid, which was collected by filtration, washed with water, and dried under high vacuum overnight to give 1.8 g of the compound, mp 101°-103° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.COC(=O)C=CC1C=CC(O)=CC=1.[CH2:27](Cl)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].C(Cl)CCCCCC(C)C>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CC(C)CCCCCCCCCCCl
Agent: CC(C)CCCCCCCl
Agent: COC(=O)C=Cc1ccc(O)cc1
Product: COC(=O)CCc1ccc(OCCCCCCCCCCC(C)C)cc1

Procedure:
1.5 3-(4-isotridecyloxyphenyl)-propionic acid methyl ester (refractive index at 20° C. : 1.4902) was prepared from 3-(4-hydroxyphenyl)-propionic acid methyl ester, substituted on an equimolar basis for 4-hydroxycinnamic acid methyl ester, and isotridecyl chloride, substituted on an equimolar basis for isononyl chloride, by the method described in 1.1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:15]2[CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1c(Br)cnc(N)c1C#N
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: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(C(F)(F)F)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.5 grams (0.01 2 mole) of 3-fluoro-5-trifluoromethylphenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-fluoro-5-trifluoromethylphenyl]pyridine.
Reaction SMILES: [CH:1]([N:4]([C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[N:21]([CH:23]=[C:24]([C:26](=[O:29])[NH:27][CH3:28])[N:25]=3)[CH:22]=2)=[CH:15][N:16]=1)C(=O)OC(C)(C)C)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([NH:4][C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]3[N:21]([CH:23]=[C:24]([C:26]([NH:27][CH3:28])=[O:29])[N:25]=3)[CH:22]=2)=[CH:15][N:16]=1)([CH3:3])[CH3:2]
Reactant: CNC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1cn2cc(-c3cnc(NC(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
A solution of tert-butyl isopropyl(5-(2-(methylcarbamoyl)-8-phenylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl)carbamate (30 mg) in methylenechloride (2 ml) was treated with TFA (4 ml) and stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue chromatographed on silica gel using ethyl acetate as eluent to give 15 mg of 6-(2-(isopropylamino)thiazol-5-yl)-N-methyl-8-phenylimidazo[1,2-a]pyridine-2-carboxamide as a tan solid. LCMS (Conditions C): 2.62 min (RT); (M+H)+=392.14 (100%). 1H NMR, 500 MHz, CDCl3/CD3OD: δ 8.20 (s, 1 H), 8.19 (d, J=1.65 Hz, 1 H), 7.89 (d, J=1.37 Hz, 1 H), 7.88 (s, 1 H), 7.42-7.53 (m, 3 H), 7.36 (d, J=1.92 Hz, 1H), 7.34 (s, 1 H), 3.55-3.64 (m, 1 H), 1.34 (d, J=6.32 Hz, 6 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[C:11]([Cu])#[N:12]>CN(C=O)C.O>[F:10][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:11]#[N:12]
Reactant: COc1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C#N)cc1F
Temperature: 120 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-methoxybenzene (30.0 g, 146 mmol) and CuCN (15.6 g, 174 mmol) in dry DMF (45 mL) was stirred at 120° C. overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure gave 20.0 g (91%) of the subtitle compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.44 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.36 (dd, J=10.8 Hz, 2.0 Hz, 1H), 7.02 (dd, J=8.8 Hz, 8.4 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH2:19][NH:20][CH:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]3)[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:39]=2[S:40][C:41]=1[C:42](Cl)=[O:43]>>[Cl:36][C:37]1[C:38]2[C:48]([F:49])=[CH:47][CH:46]=[C:45]([F:50])[C:39]=2[S:40][C:41]=1[C:42]([N:20]([CH2:19][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])[CH:21]1[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:23][CH2:22]1)=[O:43]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 103 (1.84 g, 3.66 mmol) is treated with acid chloride 8 (1.17 g, 4.38 mmol) using Method D to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C@H:12]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:13]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:44][NH2:45]>C(Cl)Cl>[OH:44][NH:45][C:14](=[O:15])[CH:13]([CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(S(=O)(=O)[C@H](CCCCc2ccccc2)[C@H](CCOc2ccccc2)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(CCOc2ccccc2)C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
(±)-(2R*,3R*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid (0.17 g, 0.34 mmol) is dissolved in CH2Cl2 (1 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (0.5 mL, 1 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 3 hours. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (3 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.16 g, 1.7 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo. The product is purified by reverse phase HPLC (65% CH3CN in 0.1% TFA/H2O) to yield (±)-(2R*, R*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid hydroxyamide (0.12 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.8 Hz, 2H), 7.28-7.14 (m, 5H), 7.08 (d, J=7.0 Hz, 2H), 6.97-6.89 (m, 3H), 6.73 (d, J=8.1 Hz, 2H), 3.89-3.71 (m, 5H), 3.27-3.20 (m, 2H), 2.51 (t, J=7.2 Hz, 2H), 2.45-2.32 (m, 1H), 1.98-1.75 (m, 3H), 1.55-1.38 (m, 3H), 1.35-1.22 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 168.74, 164.06, 158.25, 141.93, 130.70, 129.46, 128.88, 128.34, 128.30, 125.78, 121.06, 114.63, 114.36, 66.37, 65.16, 55.67, 38.36, 35.30, 31.00, 30.35, 27.75, 25.34; MS (FAB) m/e 512 (M+H)+ ; Anal. (C28H33NO6S.0.2 H2O) C, H, N.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:36]=[C:35]([OH:37])[CH:34]=[C:33]([Cl:38])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:21]1=[O:32]>CS(C)=O.C(OCC)(=O)C>[Cl:16][C:17]1[CH:36]=[C:35]([CH:34]=[C:33]([Cl:38])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:21]1=[O:32])[O:37][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Yield: 49.7 %

Procedure:
Add potassium carbonate (0.385 g, 2.8 mmol) and 4-fluorobenzonitrile (0.253 g, 2.1 mmol) to a solution of (R)-3-(2,6-dichloro-4-hydroxy-benzyl)-1-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (0.5 g, 1.4 mmol) in DMSO. Stir the reaction at 80° C. for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash three times with water and one time with brine. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 50% ethyl acetate/hexane to 100% ethyl acetate gradient to afford 0.32 g (50%) of the title compound. MS (m/z): 460 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[Sn](C)C.C[Sn](C)C.I[C:19]1[CH:27]=[C:26]2[C:22]([C:23](/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:24][N:25]2[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1>O1CCOCC1.C(OCC)(=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>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([C:19]2[CH:27]=[C:26]3[C:22]([C:23](/[CH:36]=[CH:37]/[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[N:24][N:25]3[CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccccc2)c2ccc(I)cc21
Reactant: COc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3c(/C=C/c4ccccc4)nn(COCC[Si](C)(C)C)c3c2)cn1
Yield: 40.1 %

Procedure:
A solution of 5-bromo-2-methoxypyridine (2.00 g, 6.10 mmol), hexamethylditin (1.15 g, 6.10 mmol), and Pd(PPh3)4 (0.28 g, 0.24 mmol) in degassed dioxane (10 ml ) was refluxed under for 16 h. 6-Iodo-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (2.90 g, 6.10 mmol) was added to above mixture, followed by Pd(PPh3)4 (0.35 g 0.31 mmol ). The reaction mixture was refluxed for 16 h. The mixture was then diluted with ethyl acetate (150ml), and washed with brine (30 ml). The organics were dried over MgSO4, then concentrated under reduced pressure. Purification by silica gel chromatography gave 6-(2-methoxypyridin-5-yl)-3-((E)-styryl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole as a yellow solid (1.12 g, 40%). 1H NMR (300 MHz, CDCl3) δ 8.51 (d, 1H, J=2.5 Hz), 8.50 (d, 1H, J=9.1 Hz), 7.93 (dd, 1H, J=2.5, 8.6 Hz), 7.69 (s, 1H), 7.69-7.28 (m, 8H), 6.89 (d, 1H, J=8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H, J=8.3 Hz), 0.93 (t, 2H, J=8.3 Hz), −0.03 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10](OC)[C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)([O-:3])=[O:2]
Reactant: COC(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ncc(-c3cccnc3)cc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1

Procedure:
To 3-[(3-nitro-phenyl)-methoxy-methyl]-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (535, 431 mg, 1.20 mmol, per Example 26, Scheme 49 Step 1) in acetonitrile (130 mL), were added trifluoroacetic acid (18 mL, 230 mmol) and triethylsilane (36 mL, 230 mmol). The reaction was refluxed for three hours. The reaction mixture was poured into sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 80% ethyl acetate in hexane to give the compound (P-1402, 323 mg, 82%). MS (ESI) [M+H+]+=331.2.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>>[Cl:9][C:8]1[C:3]([CH2:2][N:14]2[C:22]3[C:17](=[CH:18][C:19]([CH:23]=[O:24])=[CH:20][CH:21]=3)[CH:16]=[N:15]2)=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: FC(F)(F)c1cnc(CBr)c(Cl)c1
Product: O=Cc1ccc2c(cnn2Cc2ncc(C(F)(F)F)cc2Cl)c1

Procedure:
1-(3-Chloro-5-trifluoromethyl-pyridin-2-ylmethyl)-1H-indazole-5-carbaldehyde was prepared from 2-Bromomethyl-3-chloro-5-trifluoromethyl-pyridine and 1H-indazole-5-carbaldehyde following General Procedure A.
Reaction SMILES: [CH2:1]1[S:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].C1(NC2CCCCC2)CCCCC1.O1CCOCC1.[C:28]([CH2:36][CH:37]([CH3:41])[C:38](O)=[O:39])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[C:28]([CH2:36][CH:37]([CH3:41])[C:38]([N:3]1[CH:2]([C:6]([OH:8])=[O:7])[CH2:1][S:5][CH2:4]1)=[O:39])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)C1CSCN1
Reactant: CC(CC(=O)c1ccccc1)C(=O)O
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: C1COCCO1
Solvent: CC#N
Product: CC(CC(=O)c1ccccc1)C(=O)N1CSCC1C(=O)O

Procedure:
A mixture of 2.0 g. (0.015 mole) of L-thiazolidine-4-carboxylic acid and 2.72 g. (0.015 mole) of dicyclohexylamine is heated on a steam bath then 50 ml. of dry dioxane and 50 ml. of acetonitrile are added. To this mixture is added 4.2 g. (0.015 mole) of 3-benzoyl-2-methylpropionic acid, N-hydroxysuccinnimide ester, then the mixture is refluxed for 48 hours. The mixture is evaporated in vacuo. The residue is stirred with ethyl acetate and filtered. The filtrate is concentrated in vacuo and the residue is dissolved in dichloromethane. The dichloromethane is washed with sodium bisulfate and then extracted with saturated sodium bicarbonate solution. The sodium bicarbonate wash is added to dilute aqueous hydrochloric acid and the mixture is extracted with dichloromethane. The organic layer is dried over sodium sulfate and concentrated to an oil. The oil is crystallized from acetone-hexane to give [4R-(4R*,2'R*)]-3-(3-benzoyl-2-methylpropionyl)-4-thiazolidinecarboxylic acid as white crystals, m.p. 182°-183° C.; [α]D 23 -63°±4 (C, 0.24, CH3OH).