Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[I:27][C:28]1[CH:29]=[CH:30][C:31]2[NH:32][C:33]3[C:38]([C:39]=2[CH:40]=1)=[CH:37][CH:36]=[CH:35][CH:34]=3.[C:41](#[N:44])[CH:42]=[CH2:43]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O.CCCCCC.O1CCOCC1>[C:41]([CH:42]=[CH:43][C:28]1[CH:29]=[CH:30][C:31]2[NH:32][C:33]3[C:38]([C:39]=2[CH:40]=1)=[CH:37][CH:36]=[CH:35][CH:34]=3)#[N:44].[I:27][C:28]1[CH:29]=[CH:30][C:31]2[NH:32][C:33]3[C:38]([C:39]=2[CH:40]=1)=[CH:37][CH:36]=[CH:35][CH:34]=3
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Ic1ccc2[nH]c3ccccc3c2c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCCCCC
Product: N#CC=Cc1ccc2[nH]c3ccccc3c2c1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 18 %

Procedure:
To a dioxane solution (10 mL) of triphenylphosphine (139 mg, 0.53 μmol), palladium acetate (40.0 mg, 0.18 μmol) and triethylamine (0.59 μL, 4.23 mmol) were sequentially added, and the mixture was stirred for 5 minutes at 75° C. A dioxane solution (15 mL) of compound 1 (1.03 g, 3.52 mmol) and acrylonitrile (0.46 μL, 7.04 mmol) were added, and the reaction solution was refluxed for 11.5 hours. The product was confirmed by TLC (HexH:AcOEt=4:1), and then the palladium powder was removed by cotton filtration. The product was purified by column chromatography (HexH:AcOEt=4:1), and compound 2 (0.14 g, 18%, trans:cis=97:3) was obtained as a white powder, while compound 1 (0.37 g, recovery rate 37%) was recovered as a white powder.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][O:7][CH2:8][C:9]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][C:11]#[N:12].[C:29]([O-])([O-])=O.[K+].[K+].ClC(OC)=O.C(=O)([O-])N.[Li].[H-]>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:22]=1)[CH2:6][O:7][CH2:8][C:9]([CH3:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][CH2:11][NH:12][CH3:29]
Reactant: O=C([O-])[O-]
Reactant: CC(CC#N)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: COC(=O)Cl
Agent: NC(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNCCC(C)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
4-(3,5-bis(trifluoromethyl)benzyloxy)-3-methyl-3-phenylbutanenitrile (46.2 mg, 0.115 mmol) was treated with neat borane-dimethylsulfide complex for 2 hour at room temperature until completion of reaction. The excess amount of borane was removed under nitrogen stream. The residue was quenched further with methanol and then heated at 80° C. for 1 hour to decompose the borane-amine complex. The resultant solution was concentrated and re-dissolved in CH2Cl2. It was washed with brine and dried with sodium sulfate. After concentration, the residue was mixed with K2CO3 (200 mg) and methyl chloroformate (21.8 mg, 0.23 mmol) in anhydrous CH2Cl2. After stirring overnight, it was worked up routinely and submitted for preparative HPLC. The obtained carbamate was treated with lithium aluminun hydride (0.168 mmol) in THF at 80° C. for 1 hour. Afterwards the reaction mixture was concentrated to dryness under nitrogen stream, re-dissolved in methanol, and purified by preparative HPLC and then silica flash chromatography (10% methanol in CH2Cl2) to give 8.5 mg of the desired product as a free base. 1H NMR (500 MHz, CDCl3) δ ppm 1.42 (s, 3 H) 1.93 (m, 1 H) 2.09 (m, 1 H) 2.35 (s, 3 H) 2.37 (m, 1 H) 2.52 (m, 1 H) 3.54 (s, 2 H) 7.24 (m, 2 H) 7.34 (m, 4 H) 7.65 (s, 2 H) 7.76 (s, 1 H); 13C NMR (500 MHz, CDCl3) δ 144.64, 141.36, 131.68(q, JCCF=33.3 Hz), 128.45, 127.14, 126.65, 126.34, 123.39, (q, JCF=272.5 Hz), 121.4 (m), 80.33, 71.89, 47.16, 41.67, 38.03, 35.70, 22.76.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].C(O)(C)C>O>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)(=[O:22])[CH3:21]
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)O
Solvent: O
Product: CC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a 0.33 g. sample of 5-amino-2-nitro-3-phenylbenzofuran is added 1 ml. of acetic anhydride, and the mixture is heated for 5 minutes on a steam bath. About 10 ml. of isopropanol is added, and the mixture is again heated on a steam bath to dissolve the solid. It is then saturated with hot water and cooled to provide yellow needles of 5-acetamido-2-nitro-3-phenylbenzofuran, m.p. 204°-207° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:34]4[CH2:37][C:36]([F:39])([F:38])[CH2:35]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:40][CH3:41])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:34]4[CH2:37][C:36]([F:38])([F:39])[CH2:35]4)[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:40][CH3:41])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N4CC(F)(F)C4)n2)CCC3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N4CC(F)(F)C4)n2)CC[C@@H]3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-4-(3,3-difluoroazetidin-1-yl)-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (165.2 mg, 0.279 mmol from Example 99) was purified using chiral SFC to afford 16.7 mg of peak A (Example 99A) and 17.0 mg of peak B (Example 99B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 30% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 20 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=4.9 min, tR (peak B) 15.0 min. The absolute stereochemistry of individual enantiomers (Examples 99A and 99B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 99).
Reaction SMILES: [NH2:1][C:2](=[O:28])[C:3]([NH:5][CH:6]([C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)[C:7]([O:9]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:8])=[O:4]>O>[NH2:1][C:2](=[O:28])[C:3]([NH:5][CH:6]([C:23]1[O:24][CH:25]=[CH:26][CH:27]=1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: NC(=O)C(=O)NC(C(=O)OC(c1ccccc1)c1ccccc1)c1ccco1
Solvent: O
Product: NC(=O)C(=O)NC(C(=O)O)c1ccco1

Procedure:
By substituting DL-α-[(2-amino-1,2-dioxoethyl)amino]-2-furanacetic acid, diphenylmethyl ester in the procedure of Example 13, DL-α-[(2-amino-1,2-dioxoethyl)amino]-2-furanacetic acid is obtained as white crystals, m.p. 174° (water).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[CH:35]([NH:37][NH2:38])=[O:36].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:38][NH:37][CH:35]=[O:36])=[O:26])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Reactant: NNC=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NNC=O)ccn34)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridine-7-carboxylic acid (26 mg, 0.057 mmol; prepared as in Example 28, Step A) in DMF was added formohydrazide (6.9 mg, 0.11 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (22 mg, 0.11 mmol), 1H-benzo[c/][1,2,3]triazol-1-ol hydrate (15 mg, 0.11 mmol) and triethylamine (17 mg, 0.17 mmol). The reaction mixture was stirred for 16 hours at ambient temperature, diluted with DCM (30 mL), washed with H2O, dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated with Et2O (30 mL) to give the product (20 mg).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=3)[NH2:12])[O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[O:25]1CC[CH2:27][CH2:26]1.C(Cl)(=O)C>O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([NH:12][C:26](=[O:25])[CH3:27])[CH:13]=[CH:14][CH:15]=3)[O:8][C:4]=2[CH:3]=1
Reactant: Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Reactant: C1CCOC1
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 3-(6-bromobenzoxazol-2-yl)aniline (Compound of Example 267) (925 mg), triethylamine (390 mg) and tetrahydrofuran (35 ml) was added acetyl chloride (276 mg) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with 1 N hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and water, successively and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain N-[3-(6-bromobenzoxazol-2-yl)phenyl]acetamide (923 mg, 87%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][OH:14].[CH2:15](Br)[CH:16]=[CH2:17]>CN1C(=O)CCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:15]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][OH:14])[CH:16]=[CH2:17]
Reactant: C=CCBr
Reactant: CNc1ccc([N+](=O)[O-])cc1CCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=CCN(C)c1ccc([N+](=O)[O-])cc1CCO
Temperature: 25 °C

Procedure:
To a solution of N-methyl-2-(2-hydroxyethyl)-4-nitrobenzenamine (4.90 g, 0.025 mol) in NMP (15 ml) is added allyl bromide (4.55 g, 0.037 mol) at room temperature. The mixture is heated to 85°-90° C. for 6 hours and cooled to room temperature. The mixture is diluted with 1M sodium carbonate solution (250 ml) and extracted with ether twice (250 and 150 ml portions). The extracts are washed with water twice, dried over potassium carbonate and concentrated to a solid. The solid is purified by chromatography on silica gel with hexane-tetrahydrofuran solvent to give N-allyl-N-methyl-2-(2-hydroxyethyl)-4-nitrobenzenamine.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH:20]([NH:22][C:23]([C:25]2[C:26]([C:31]3[C:36](F)=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:38])=[N:27][O:28][C:29]=2[CH3:30])=[O:24])[CH2:19][N:18]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:17]1)=[O:15])[CH3:12]>CN(C=O)C>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH:20]([N:22]2[C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:38])[C:31]=3[C:26]3=[N:27][O:28][C:29]([CH3:30])=[C:25]3[C:23]2=[O:24])[CH2:19][N:18]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)C1CC(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)CN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)CN(C(=O)OC(C)(C)C)C1
Reaction time: 0.08 h
Yield: 36.2 %

Procedure:
Add KHMDS (1.6 mL, 0.80 mmol, 0.5 M in toluene) to a solution of 5-{[3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (0.27 g, 0.53 mmol) in DMF (10 mL). After 5 min, quench with water and concentrate to dryness. Dissolve in 20% iPrOH/CHCl3. Wash 2× with sat. aq NaHCO3, wash 2× with brine, dry over Na2SO4, filter, and concentrate to dryness. Purify by radial chromatography using EtOAc/hexanes as eluant and concentrate to dryness to afford the title compound (94 mg, 35%) as a colorless oil as a mixture of cis isomers. MS(IS) 490.1 (M+); HPLC (100% EtOH on a Chiralpak AD (0.46×25 cm) 1.0 mL/min flow; 20 μL Inj. Vol.; 225 nM) Rt=5.688 min (66.3%), 6.462 min (22.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37](O[C:40](=[O:41])[C:30]=2[CH:29]=1)=[O:38]>C1C(O)=CC=CC=1C>[C:34]([C:33]1[CH:32]=[C:31]2[C:37](=[O:38])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4([C:21]5[CH:22]=[CH:23][C:24]([N:27]6[C:37](=[O:38])[C:31]7=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:28][CH:29]=[C:30]7[C:40]6=[O:41])=[CH:25][CH:26]=5)[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=5[C:15]5[C:20]4=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:6][CH:7]=3)[C:40](=[O:41])[C:30]2=[CH:29][CH:28]=1)([OH:36])=[O:35]
Reactant: Nc1ccc(C2(c3ccc(N)cc3)c3ccccc3-c3ccccc32)cc1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: Cc1cccc(O)c1
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1ccc(C3(c4ccc(N5C(=O)c6ccc(C(=O)O)cc6C5=O)cc4)c4ccccc4-c4ccccc43)cc1)C2=O
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a stirred mixture of 9,9-bis(4-aminophenyl)fluorene (13.9 g, 40 mmol) and 80 ml of m-cresol was added 1,2,4-benzenetricarboxylic anhydride (16.1 g, 84 mmol) over two minutes. The resulting mixture was stirred under gentle reflux (163°-170° C.) for three hours and then at ambient temperature for 16 hours. A pale yellow precipitate was filtered, washed with methanol, washed with toluene, and then dried in a vacuum oven at 100°-105° C. for 16 hours to provide the title compound as a pale yellow powder (24.7 g, 88.7% yield) that had a melting point of 328°-331° C. and a 1H NMR spectrum (DMSO d6) corresponding to δ8.39 (d,2H), 8.29 (br s, 2H), 8.05 (d, 2H), 8.00 (d, 2H), 7.61 (d, 2H), and 7.40 (m, 12H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Reactant: N#Cc1cccc(O)c1
Product: N#Cc1cccc(Oc2ccc(C=O)cc2C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluoro-3-(trifluoromethyl)benzaldehyde and 3-hydroxybenzonitrile. LC-MS (ESI): m/z 290 [M−H]−; 1.69 min (ret time).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8](C(=O)C(OC)=O)[C:7](=[O:15])[C@H:6]1[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(=[O:3])[CH3:2].O>CO>[C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:15])[C@H:6]1[NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Reaction time: 48 h
Yield: 74.3 %

Procedure:
A mixture containing 2.34 g (6.43 mmol) methyl ((3S,4S)-4-acetoxy-3-benzyloxycarbonylaminoazetidin-2-on-1-yl)-2-oxoacetate and 5 ml of water in 250 ml of methanol is left at room temperature for 2 days. The mixture is evaporated in vacuo and the residue dried in high vacuo and recrystallized from methylene chloride-n-hexane. In this way, 1.33 g (74%) of title compound of melting point 110° to 113° C. is obtained. Chromatography of the mother liquors on 70 g of silica gel using a 3:1 mixture of toluene and ethyl acetate (20 fractions, 70 ml each) affords 300 mg (17%) pure crystalline product, additionally. IR spectrum in methylene chloride: 3500, 1800, 1745, 1730, 1510 and 1210 cm-1.
Reaction SMILES: C([Li])CCC.[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH:7]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1.[CH3:24][C:25]([CH3:41])([CH3:40])[CH2:26][C:27]1[N:28]=[C:29]([CH:38]=[O:39])[N:30]([S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[CH:31]=1>O1CCCC1>[CH3:24][C:25]([CH3:41])([CH3:40])[CH2:26][C:27]1[N:28]=[C:29]([CH:38]([OH:39])[C:7]2([C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[CH:16][CH:17]=3)[S:8][CH2:9][CH2:10][CH2:11][S:6]2)[N:30]([S:32]([N:35]([CH3:36])[CH3:37])(=[O:33])=[O:34])[CH:31]=1
Reactant: c1ccc(-c2ccc(C3SCCCS3)cc2)nc1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)C1(c2ccc(-c3ccccn3)cc2)SCCCS1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.5 M in hexane) (0.14 mL, 0.17 mol) was added to a −78° C. solution of 2-[4-(1,3-dithian-2-yl)phenyl]pyridine (50 mg, 0.18 mmol) in tetrahydrofuran (3 mL). After stirring at 0° C. for 10 min, the reaction mixture was re-cooled to −78° C. and a solution of 4-(2,2-dimethylpropyl)-2-formyl-N,N-dimethyl-1H-imidazole-1-sulfonamide (100 mg, 0.37 mmol) in tetrahydrofuran (1 mL) was added. After stirring at −78° C. for 5 min then at ambient temperature for a further 10 min, the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparatory plate chromatography eluting with 50% ethyl acetate/hexane afforded 4-(2,2-dimethylpropyl)-2-{hydroxy[2-(4-pyridin-2-ylphenyl)-1,3-dithian-2-yl]methyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide. LCMS: 547 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1.[ClH:41].[CH2:42]([O:44][C:45](=[O:49])[CH2:46][NH:47][CH3:48])[CH3:43]>>[ClH:41].[O:1]=[C:2]1[N:11]([CH2:12][C:13]([N:47]([CH2:46][C:45]([O:44][CH2:42][CH3:43])=[O:49])[CH3:48])=[O:15])[C:10](=[O:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)CNC
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Agent: Cl
Product: CCOC(=O)CN(C)C(=O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Yield: 79.2 %

Procedure:
Using the method similar to that in Example 109 and starting from 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid (1.20 g, 2.22 mmol) obtained in Example 50, and also using sarcosine ethyl ester hydrochloride (408 mg, 2.66 mmol) instead of glycine methyl ester hydrochloride, the ethyl ester of the title compound (1.19 g 83%) was obtained as an oil.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)/[C:11](=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:10]1=[O:35])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][N:9]1[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)/[C:11](=[CH:28]\[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)/[C:10]1=[O:35])([OH:7])=[O:5]
Reactant: COc1cc(/C=C2/C(=O)N(CC(=O)OC(C)(C)C)C(=O)/C2=C/c2ccccc2)cc(OC)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C2/C(=O)N(CC(=O)O)C(=O)/C2=C/c2ccccc2)cc(OC)c1OC
Reaction time: 4 h
Yield: 80.9 %

Procedure:
To a solution of (3E,4E)-1-t-butoxycarbonylmethyl-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidinedione (3.5 g) obtained in Example 42 in dichloromethane (40 ml) is added trifluoroacetic acid (10 ml) at room temperature, and the mixture is allowed to stand for 4 hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added trichloromethane. The mixture is washed, dried, and evaporated to remove the solvent. The resulting residue is crystallized from diethyl ether to give (3E,4E)-1-carboxymethyl-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidinedione (2.5 g) as yellow prisms.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:24][CH2:25][O:26][CH3:27])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[CH2:28][CH2:29][CH3:30])[CH:5]=[CH:4][N:3]=1.O.Cl.O1CCOC[CH2:34]1>CCCCCCC.C[Al](C)C>[F:17][C:16]([F:19])([F:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:34])[CH:7]=2)=[C:10]([CH2:28][CH2:29][CH3:30])[CH:11]=1)([O:24][CH2:25][O:26][CH3:27])[C:20]([F:23])([F:22])[F:21]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(Cl)c1
Reactant: C1COCCO1
Agent: C[Al](C)C
Agent: Cl
Solvent: O
Solvent: CCCCCCC
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccnc(C)c1
Yield: 94 %

Procedure:
To a solution of 2-chloro-4-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy) pyridine (867 mg, 559 μmol) in 1,4-dioxane, trimethylaluminum heptane solution (2 mol/L, 1.13 mL) and tetrakis triphenylphosphine palladium complex (218 mg) were added at room temperature under an argon atmosphere, and then the resultant mixture was heated at 80° C. After completion of the reaction, the reaction solution was neutralized by adding water and 2 mol/L of hydrochloric acid, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (780 mg, yield 94%) was obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:17])[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH2:10][CH:9]2[OH:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].N1C=CN=C1.[C:27]([Si:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)Cl)([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[Si:31]([O:15][CH2:14][CH:12]1[CH2:11][CH2:10][CH:9]([OH:16])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:18]([F:19])([F:20])[F:21])[CH:4]=2)([CH3:17])[CH2:13]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(CO)CCC1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CCC1O
Temperature: 25 °C
Reaction time: 29 h
Yield: 73.4 %

Procedure:
A solution of (1RS,2RS,4RS)-2-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methylcyclohexanol (1.253 g, 3.88 mmol) in DMF (15 mL) was treated with imidazole (0.581 g, 8.54 mmol) followed by tert-butyldiphenylchlorosilane (1.097 mL, 4.27 mmol). The resulting mixture was stirred at rt for 29 h. After this time, the solution was diluted with ethyl acetate (150 mL), washed three times with water, once with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel, eluting with 5-25% ethyl acetate-hexanes, to provide (1RS,2RS,4RS)-4-((tert-butyldiphenylsilyloxy)methyl)-2-(4-chloro-3-(trifluoromethyl)phenyl)-2-methylcyclohexanol as a colorless gummy glass (1.599 g, 73%). 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1 H), 7.82 (dd, J=8.5, 1.6 Hz, 1 H), 7.63 (t, J=6.6 Hz, 4 H), 7.40 (m, 7 H), 3.72 (dt, J=12.0, 3.5, 3.4 Hz, 1 H), 3.42 (m, 2 H), 2.43 (m, 1 H), 1.69 (m, 5 H), 1.33 (s, 3 H), 1.12 (m, 2 H), 1.06 (s, 9 H).