Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]=2[CH:14]=1)=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C(O)C>[N:15]1[C:3]([C:5]2[CH:6]=[CH:7][C:8]3[S:12][C:11](=[O:13])[NH:10][C:9]=3[CH:14]=2)=[CH:2][N:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=12
Reactant: O=C(CBr)c1ccc2sc(=O)[nH]c2c1
Reactant: Nc1ccccn1
Solvent: CCO
Product: O=c1[nH]c2cc(-c3cn4ccccc4n3)ccc2s1
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
A solution of 5-bromoacetyl-2-benzothiazolinone (3.3 g) and 2-aminopyridine (4.2 g) in ethanol was refluxed for 5 hours and the reaction mixture was evaporated in vacuo. To the residue was added a mixture of water and ethyl acetate and the resulting mixture was acidified to pH 1.0 with 10 % hydrochloric acid. The precipitate was collected by filtration and added to a solution of saturated aqueous sodium bicarbonate. The mixture was stirred for 30 minutes. The precipitate was collected by filtration, washed with water and recrystallized from aqueous ethanol to give 5-(imidazo[1,2-a]pyridin-2-yl)-2-benzothiazolinone (0.24 g). mp>270° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[NH:23][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2cc(C)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (100 mg, 0.486 mmol) and m-anisidine (55 μl, 0.486 mmol) similar to Example 13 as an tan oil (139 mg, 98%). 1HNMR (CDCl3): 8.78–8.75 (m, 1H), 8.45 (dt, J=1.2, 8.1 Hz, 1H), 7.78 (td, J=1.9, 7.8 Hz, 1H), 7.73 (s, 1H), 7.34–7.30 (m, 1H), 7.23 (t, J=8.1 Hz, 1H), 7.03 (t, J=2.1 Hz, 1H), 6.92 (dd, J=2.0, 7.7 Hz, 1H), 6.67 (dd, J=2.4, 8.1 Hz, 1H), 6.61 (s, 1H), 3.77 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([C:11](=[O:13])[CH3:12])[O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3].[CH2:16]=[CH:17][CH2:18]CC>ClCCl.[Ru](Cl)Cl.C1(C(P(C2CCCCC2)(C2CCCCC2)C2CCCCC2)P(C2CCCCC2)(C2CCCCC2)C2CCCCC2)C=CC=CC=1>[CH2:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([C:11](=[O:13])[CH3:12])[O:10][C:6]=2[CH:5]=1)[CH:2]=[CH:3][CH2:16][CH2:17][CH3:18]
Reactant: C=CCc1ccc2c(c1)OC(C(C)=O)O2
Reactant: C=CCCC
Agent: Cl[Ru]Cl
Agent: c1ccc(C([PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)[PH](C2CCCCC2)(C2CCCCC2)C2CCCCC2)cc1
Solvent: ClCCl
Product: CCCC=CCc1ccc2c(c1)OC(C(C)=O)O2
Reaction time: 2 h
Yield: 13.3 %

Procedure:
A solution of 1-(5-allylbenzo[d][1,3]dioxol-2-yl)ethanone (5 g), phenylmethylenebis(tricyclohexylphosphine) ruthenium dichloride (0.9 g) and pent-1-ene (5 g) in dichloromethane (40 ml) was stirred at room temperature. After 2 hours, a control by gc analysis shows 60% conversion, but three additional portions of 5 g of pent-1-ene were added during the reaction time (48 hours) to go to completion. Then, the reaction mixture was filtered on a short column of silica gel and concentrated in vacuum to remove the solvent. Finely the crude product was purified by flash chromatography on silica gel (eluant heptane/ethyl acetate 95/5) to give 0.8 g (19%) of a colorless oil, identified as a 85/15 E/Z mixture.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:23])[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=2)=[CH:6][N:5]=[C:4]([NH:24][C:25](=[O:35])[CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[N:3]=1.CCOCC>FC(F)(F)C(O)=O>[OH:1][C:2]1[C:7]([C:8](=[O:23])[NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=2)=[CH:6][N:5]=[C:4]([NH:24][C:25](=[O:35])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[N:3]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)Nc1ncc(C(=O)NCc2cccc(-c3ccccc3)c2)c(O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C(O)CCC(=O)Nc1ncc(C(=O)NCc2cccc(-c3ccccc3)c2)c(O)n1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of tert-butyl 4-({4-hydroxy-5-[(3-phenylphenyl)methylcarbamoyl]pyrimidin-2-yl}amino)-4-oxobutanoate (110 mg) in trifluoroacetic acid (1.5 mL) was left standing at room temperature for 1 hour. Ether (30 mL) was added to the reaction solution, and the resulting suspension was filtered. The product collected by filtration was washed with ether and hexane and dried under reduced pressure to obtain the title compound (88 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N+:27]([CH2:30][CH3:31])([O-:29])=[O:28].C1CCN2C(=NCCC2)CC1>>[N+:27]([CH:30]([C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:31])([O-:29])=[O:28]
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: CC[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]

Procedure:
6-Phenylhexanoic acid (0.154 g, 0.80 mmol) and CDI (0.261 g, 1.60 mmol) were added together and then reacted with nitroethane (0.090 g, 1.21 mmol) and DBU (0.306 g, 2.00 mmol) according to the general procedure. Purification by column chromatography gave 0.060 g (30%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.31 (m, 2H), 7.21 (m, 3H), 5.24 (q, J=7.2 Hz, 1H), 2.64 (t, J=7.6 Hz, 2H), 2.58 (td, J=3.2, 6.8 Hz, 2H), 1.69 (d, J=7.2 Hz, 3H), 1.68 (m, 4H), 1.37 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 200.1, 142.6, 128.7, 128.6, 126.0, 89.1, 39.3, 35.9, 31.4, 28.7, 23.3, 15.2 ppm; IR νmax (cm−1) 3026, 2933, 2858, 1732, 1559, 1453, 1362, 1030, 749, 701; HRMS (FAB) calcd for C14H19NO3 (MNa+) 272.1257, found 272.1255.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)(=[O:21])[NH2:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)c1ccc(Cl)cc1
Product: NC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccc(Cl)cc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αS)-α-amino-4-chloro-benzeneacetamide (CAN 488836-04-0) as starting materials; LC-MS (UV peak area/ESI) 95%, 400.1434 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12]O)[CH:2]=[CH2:3].N1C=CC=CC=1.P(Br)(Br)[Br:21].[Br-].[Na+]>CCOCC>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][Br:21])[CH:2]=[CH2:3]
Reactant: BrP(Br)Br
Reactant: C=CCOCCOCCOCCO
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCC
Product: C=CCOCCOCCOCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
To a stirred solution of alcohol (15) (3.83 g, 20.1 mmol, 1.0 equiv.) and pyridine (0.16 mL, 2.00 mmol, 0.1 equiv.) in Et2O (20 mL) was added dropwise phosphorus tribromide (0.74 mL, 7.60 mmol, 0.36 equiv.) at 0° C. After 30 min, the reaction was allowed to warm to room temperature. As the reaction was not completed after 12 h, pyridine (1.60 mL, 20.0 mmol, 1.0 equiv.) and sodium bromide (4.14 g, 40.2 mmol, 2.0 equiv.) were successively added. After 12 h of reflux, the resulting solution was submitted to a EtOAc/NH4Cl-saturated aqueous solution extraction. The combined organic phases were dried over anhydrous Na2SO4, filtered then evaporated under reduced pressure. Purification was achieved by column chromatography (Hexanes/EtOAc gradient) to afford bromide (16) (0.90 g, 18%) as a yellow oil; 1H NMR (300 MHz, CDCl3) δ 5.93 (ddt, J=17.3, 10.5, 5.7 Hz, 1H), 5.28 (dq, J=17.3, 1.5 Hz, 1H), 5.19 (dq, J=10.5, 1.5 Hz, 1H), 4.03 (dt, J=5.7, 1.5 Hz, 2H), 3.82 (t, J=6.3 Hz, 2H), 3.71-3.65 (m, 6H), 3.64-3.59 (m, 2H), 3.48 (t, J=6.3 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 134.9, 117.4, 72.5, 71.4, 70.9, 70.8, 70.7, 69.6, 30.5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>N1C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:24])/[CH:21]=[CH:22]/[CH3:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: C/C=C/C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C/C=C/C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
A solution of 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 0.57 ml of trans-crotonoyl chloride in 6 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the resulting solid recrystallized from n-butanol to give 0.69 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-(E)-2-butenamide: mp=153-160° C., mass spectrum (m/e): M+H 383, 385.
Reaction SMILES: C(O)(C(F)(F)[F:4])=O.C(OC(=O)[NH:14][C@H:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:19]=1F)[CH2:16][OH:17])(C)(C)C>C(Cl)Cl>[NH2:14][C@H:15]([C:18]1[CH:23]=[CH:22][C:21]([F:4])=[C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=1)[CH2:16][OH:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1cccc(N2CCOCC2)c1F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1

Procedure:
A solution of TFA (5 mL) and (R )-[1-(fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester(1.2 g) in methylene chloride (15 mL) was stirred for 2 h. After concentration, the residue was neutralized with 10 N NaOH and extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound as a solid (720 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(N(CC)CC)C>ClCCl.O>[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C1
Temperature: -60 °C

Procedure:
A flask was charged with a solution of oxalyl chloride (3.2 ml, 33 mmol) in dichloromethane (60 ml). The solution was cooled to −60° C., and a solution of dimethylsulfoxide (5.1 ml, 66 mmol) in dichloromethane (10 ml) was added dropwise, such that the internal temperature was maintained at −60° C. This was followed by the dropwise addition of a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (5.6 g, 30 mmol) in dichloromethane (25 ml). The resulting solution was allowed to stir for 1 hour −60° C., then triethyamine (21 ml) was added and the mixture was allowed to warm to room temperature. The solution was diluted with 150 ml of water and extracted with dichloromethane (2×150 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to afford tert-butyl 3-oxopyrrolidine-1-carboxylate as a white solid.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:35]1[CH:36]=[C:37]([NH2:41])[CH:38]=[N:39][CH:40]=1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C>[NH2:41][C:37]1[CH:38]=[N:39][CH:40]=[C:35]([CH:1]2[CH2:3][CH2:2]2)[CH:36]=1
Reactant: Nc1cncc(Br)c1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cncc(C2CC2)c1
Temperature: 100 °C
Reaction time: 11 h

Procedure:
A solution of cyclopropyl boronic acid (497 mg), palladium acetate (II) (65 mg), tricyclohexylphosphine (162 mg), and potassium phosphate (2.5 g) in toluene (9 mL) and water (0.45 mL) was added to 5-bromopyridin-3-amine (500 mg), and the mixture was stirred at 100° C. for 11 hours. Ethyl acetate and water were added, the organic layer was separated, and the resultant was washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 3-amino-5-cyclopropylpyridine.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[ClH:16].S(=O)(O)O>O>[ClH:16].[NH:5]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])[NH2:1]
Reactant: O=N[O-]
Reactant: COC(=O)c1cccc(N)c1
Agent: Cl
Agent: O=S(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cccc(NN)c1
Reaction time: 0.08 h

Procedure:
A solution of 5.75 g of sodium nitrite in 30 ml of water was dropwise added to a solution of 11.7 g of methyl 3-aminobenzoate and 20 ml of concentrated hydrochloric acid in 200 ml of water, at about 0° C. with cooling with ice-methanol. The mixture was stirred at the same temperature for 5 minutes. The mixture was then added to 650 ml of a 6% aqueous sulfurous acid solution being ice-cooled. The resulting mixture was stirred at 50°-60° C. for 2 days. The reaction mixture was allowed to cool and then extracted with ethyl acetate. The aqueous layer was made basic with an aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with water and an aqueous sodium chloride solution in this order, then dried with anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added ethanol. The mixture was made acidic with concentrated hydrochloric acid and then concentrated under reduced pressure. To the residue was added a slight amount of ethanol. The resulting insolubles were collected by filtration, washed with ethanol, and dried to obtain 3.1 g of methyl 3-hydrazinobenzoate hydrochloride as a white powder.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[CH:17]=[N:16]3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Li+]>C(O)C.O>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[N:16]3)[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnn(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnn(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
The compound (0.85 g) obtained in Example 114b was dissolved in ethanol (8 mL) and water (2 ml), and lithium hydroxide (0.42 g) was added. The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 5-6 with 1N hydrochloric acid. The resulting precipitate was collected by filtration and the obtained solid was recrystallized from ethyl acetate-petroleum ether to give the title compound (0.22 g) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](O)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([CH3:26])([CH3:27])[C:28](=[O:29])[N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)N2CCCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 17.9 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.07 mmol), pyrrolidine (0.0083 mL, 0.1 mmol), EDC.HCl (20 mg, 0.1 mmol), and HOBt (14 mg, 0.1 mmol) in THF (5 mL) was added DIPEA (0.018 mL, 0.2 mmol) at rt. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:45]([CH3:47])[CH3:46])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.OCCN(C(C)C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C=C(Cl)C=CC=3Cl)CCCC2)N=1)=O>>[OH:8][CH2:9][CH2:10][N:11]([CH:45]([CH3:47])[CH3:46])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:44])[F:42])=[CH:39][CH:40]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)N(CCO)C(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Product: CC(C)N(CCO)C(=O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 70.5 %

Procedure:
5-Benzyloxy-6-hydroxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (246) (110 mg, 70.79%) as a white sticky solid was synthesized from 5-benzyloxy-6-hydroxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (245) (187 mg, 0.28 mmol) and 1N HCl (0.05 mL, 1.39 mmol) following the procedure as described for 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-isopropylamide (207).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[Cl:15][CH2:16]OC.S(=O)(=O)(O)O>>[Br:1][C:2]1[C:3]([C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[CH2:16][Cl:15]
Reactant: COCCl
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1Br
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1c(Br)cc([N+](=O)[O-])cc1CCl
Temperature: 0 °C

Procedure:
A mixture of 30 parts of 2-bromo-1-tert-butyl-4-nitrobenzene and 30 parts of chloromethylmethyl ether is stirred vigorously while adding dropwise 20 parts of 60% fuming sulfuric acid. The resultant mixture is allowed to stand until the apparent reaction ceases and is then poured into ice water. The solid is removed by filtration and washed with water to give 3-bromo-2-tert-butyl-5-nitrobenzyl chloride.
Reaction SMILES: [N+]([CH:4]([CH3:6])[CH3:5])([O-])=O.C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[C:21](\[C:29]#[N:30])/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=1>CCO.CCOC(C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[C:21]([C:29]#[N:30])([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:4]2([CH3:6])[CH3:5])=[CH:18][CH:19]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)/C(C#N)=C/c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(C#N)C(c2ccc(Br)cc2)C1(C)C
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Following a procedure described in Tetrahedron Lett. 1985, 1923, a mixture of 2-nitropropane (1 eq), K2CO3 (1 eq) and ester from step 1 (1 eq) in EtOH (1.2M) was stirred at 100° C. in a close bottle for 3 h. The mixture was cooled to rt, diluted with EtOAc, washed with a NH4Cl sol., brine, dried over MgSO4, filtered and concentrated. Flash chromatography (hexane:EtOAc, 95:5) afforded the title compound as oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[CH2:15]([O:17][C:18](=[O:36])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH3:16].[CH:37]1([CH2:42]I)[CH2:41][CH2:40][CH2:39][CH2:38]1.[NH4+].[Cl-]>C1COCC1.C1COCC1.CN1C(=O)N(C)CCC1>[CH2:15]([O:17][C:18](=[O:36])[CH:19]([C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)(=[O:27])=[O:28])=[CH:24][CH:25]=1)[CH2:42][CH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[CH3:16]
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Reactant: ICC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DIEA (0.742 g, 7.32 mmol) is dissolved in THF (10 mL) and cooled to −78° C., under an atmosphere of N2. n-BuLi (2.5M in hexanes, 2.25 mL, 5.63 mmol) is added to this slowly. The resulting solution is stirred at −78° C. for 15 min. A solution of the title B compound, [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.84 g, 5.63 mmol) in THF/DMPU (10 mL/5 mL) is then added dropwise. The reaction is then stirred at −78° C. for one hour. A solution of cyclopentylmethyl iodide (1.18 g, 5.63 mmol) in THF/DMPU (10 mL/5 mL) is then added dropwise and the reaction is allowed to warm to RT overnight. The reaction is then poured into saturated NH4Cl solution and extracted with EtOAc. The organic layer is dried over MgSO4, filtered and concentrated to afford a brown oil. This is purified by flash chromatography (0→2% EtOAc in MeOH) to afford 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester as a brown oil: 1H NMR (CDCl3) δ 1.12 (m, 2H) 1.24 (m, 3H) 1.50 (m, 2H) 1.60 (m, 3H) 1.76 (m, 2H) 2.08 (m, 2H) 2.27 (s, 3H) 2.47 (s, 4H) 3.04 (s, 4H) 3.65 (m, 1H) 4.13 (m, 2H) 7.48 (m, 2H) 7.69 (m, 2H); LC/MS 409.3 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[CH:18]=2)[OH:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([C:17]2[CH:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)cc(C(O)c2cccc(OCc3ccccc3)c2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(OC)cc(C(=O)c2cccc(OCc3ccccc3)c2)c1
Yield: 93.1 %

Procedure:
To a stirred solution of (3-benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)-methanol (11.51 g, 32.9 mmol) in CH2Cl2 (30 mL) at room temperature was added activated MnO2 powder (13.28 g, 153 mmol) and kept adding 2˜3 equivalents of MnO2 every 3˜5 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (3-benzyloxy-phenyl)-(3,5-dimethoxy-phenyl)-methanone as a clear oil (10.67 g, 93% yield): 1H NMR (CDCl3) δ 3.82 (s, 6H, OCH3), 5.11 (s, 2H, CH2), 6.67 (t, J=2 Hz, 1H, Ar), 6.92 (d, J=2 Hz, 2H, Ar), 7.17-7.22 (m, 1H, Ar), 7.33-7.45 (m, 8H, Ar). The product was used in the next step without further purification.