Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH:6]=[C:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13]>[OH-].[Na+].[Ni]>[CH3:20][O:19][C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:16]=1[O:17][CH3:18])[CH2:6][CH:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13]
Reactant: COc1cc(C=C2NC(=O)NC2=O)cc(OC)c1OC
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CC2NC(=O)NC2=O)cc(OC)c1OC
Yield: 78 %

Procedure:
278.3 g (1 mole) of 5-(3,4,5-trimethoxy-benzylidene)-hydantoin are dissolved in 2 l of a N sodium hydroxide solution and 40 g of wet Raney-nickel are added. The reaction mixture is worked up according to Example 6. Thus 218.6 g of the desired compound are obtained, yield 78%. Mp.: 180°-181° C.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:28][OH:29].Cl.[OH-].[Na+]>CO>[F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20](/[C:23](=[N:28]/[OH:29])/[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=N\O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
1-(3-(1-(5,7-difluoroquinolin-6-yl)ethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (53.5, 491 mg, 1.390 mmol) in methanol (30 mL) was added hydroxylamine hydrochloride (140 mg, 2.015 mmol), followed by hydrochloride dropwise to give a pale yellow clear solution. The reaction mixture was stirred at it overnight. LCMS showed the reaction was complete. Aqueous NaOH (1N) solution was added at 0° C. until pH 8-9. Solvent was evaporated, and the residue was purified by column chromatography to afford 410 mg (88% yield) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) 3 ppm 12.21 (s, 1H), 8.97 (dd, 1H), 8.45 (d, 1H), 8.22 (d, 1H), 7.57-7.71 (m, 3H), 5.25 (q, 1H), 2.01 (d, 3H), 1.84 (s, 3H). LCMS (method A): [MH]+=369, tR=5.45 min.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH2:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][S:10]([CH3:9])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC1CCCC1N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1CCCC1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a stirred solution of 2-methylcyclopentanamine hydrochloride (0.100 g, 0.7 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The mixture was diluted with ethyl acetate and washed with 2 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown solid (0.100 g, 84%). The material was used without further purification.
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:26][C:27]([CH3:56])=[C:28]([CH2:30][O:31][C:32]2[CH:53]=[CH:52][C:35]([CH2:36][N:37]([CH3:51])[C:38]3[C:42]([CH:43]=O)=[CH:41][N:40]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:39]=3)=[CH:34][C:33]=2[O:54][CH3:55])[N:29]=1.O>CN(C)C=O>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[O:26][C:27]([CH3:56])=[C:28]([CH2:30][O:31][C:32]2[CH:53]=[CH:52][C:35]([CH2:36][N:37]([CH3:51])[C:38]3[C:42](/[CH:43]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:41][N:40]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[N:39]=3)=[CH:34][C:33]=2[O:54][CH3:55])[N:29]=1
Reactant: COc1cc(CN(C)c2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1N(C)Cc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OCC
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (63 mg) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% in oil, 8.8 mg) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added 3-([4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl](methyl)amino)-1-phenyl-1H-pyrazole-4-carbaldehyde (100 mg) and the mixture was further stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to flash silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 4:1, v/v) to give diethyl ((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)(methyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenyl)phosphonate as a colorless oil (84.9 mg, yield 67%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CC(C)OC(=O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)OC(C)C)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 60.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2.52 g, 5 mmol) was reacted with isopropyl morpholine-3-carboxylate hydrochloride (1.05 g, 5 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (1.79 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20]C(C)(C)C)=O)[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[CH2:34]([O:36][C:37](=[O:43])/[CH:38]=[CH:39]/C(O)=O)[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>CO.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:20])/[CH:39]=[CH:38]/[C:37]([O:36][CH2:34][CH3:35])=[O:43])[CH2:14][C@H:13]2[O:25][CH3:26])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Reactant: CCOC(=O)/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)/C=C/C(=O)N1CC[C@H](NC(=O)c2nc(Cl)c(CC)[nH]2)[C@H](OC)C1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1g) (133 mg, 0.34 mmol) was dissolved in methanol (2 mL). A 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at 70° C. for 30 minutes. Following concentration under reduced pressure, the residue was dissolved in DMA (5 mL). Fumaric acid monoethyl ester (54.42 mg, 0.38 mmol), WSC hydrochloride (197.41 mg, 1.03 mmol) and DMAP (41.94 mg, 0.34 mmol) were added, and the mixture was stirred at room temperature overnight. Dilute hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH:14]=[CH:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[N:8](CC1C=CC(OC)=CC=1)[C:7]2=[O:32]>C(O)(C(F)(F)F)=O.C(S(O)(=O)=O)(F)(F)F>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH:10]=[CH:11][NH:12][CH2:13][CH2:14]1)[NH:8][C:7]2=[O:32]
Reactant: COc1ccc(CN2C(=O)c3cccc(Br)c3C23C=CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2(C=CNCC2)c2c(Br)cccc21
Yield: 71.7 %

Procedure:
A solution of tert-butyl 7-bromo-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate (5 g, 0.01 mol) in TFA (50 mL) and CF3SO3H (5 mL) was stirred and heated for 8 h. The mixture was concentrated to give a residue which was washed with aq NaOH and extracted with EtOAc. The organic layer was dried and concentrated to give 7-bromo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridin]-3-one (2.0 g, 72%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Mn]([O-])(=O)(=O)=[O:22].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([C:13]([OH:22])=[O:14])=[CH:11][C:10]=1[F:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C=O)cc(F)c1OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(=O)O)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 7.5 g of 4-benzyloxy-3-fluoro-5-methoxybenzaldehyde in 200 ml of acetone was added dropwise at 15 to 20° C. to a mixture of 200 ml of water and 6.8 g of potassium permanganate. The mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated to about a half amount under reduced pressure. Aqueous sodium hydrogen sulfite solution and dilute hydrochloric acid were added to the concentrate and extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 4-benzyloxy-3-fluoro-5-methoxybenzoic acid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]([CH3:19])[CH2:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:25][C:26]1[CH:27]=[C:28]([S:33]C2C=C(Cl)C=C(Cl)C=2)[CH:29]=[C:30]([Cl:32])[CH:31]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:1]([O:8][CH2:9][C:10]([N:12]([CH:13]([S:33][C:28]1[CH:29]=[C:30]([Cl:32])[CH:31]=[C:26]([Cl:25])[CH:27]=1)[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH3:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)cc(Sc2cc(Cl)cc(Cl)c2)c1
Reactant: CC(C)C(=O)CN(C)C(=O)COCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(=O)C(Sc1cc(Cl)cc(Cl)c1)N(C)C(=O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
In 2 ml of dry tetrahydrofuran was dissolved 100 mg (0.4 mmol )of 2-benzyloxy-N-methyl-N-(3-methyl-2-oxobutyl)acetamide (18a'), and there was added 223 μl (0.4 mmol)of n-butyllithium (1.7 M hexane solution)with stirring at -78° C. over 10 minutes. After stirring at -78° C. for 1 hour, and a tetrahydrofuran solution (1 ml)of 135 mg (0.4 mmol)of 3,5-dichlorophenylsulfide was added thereto over 10 minutes. After 30 minutes, the temperature was raised up to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (hexane/ethyl acetate 5:1)to give 79 mg of 2-benzyloxy-N-[1-(3,5-dichlorophenylthio)-3-methyl-2-oxobutyl]-N-methylacetamide (20)(yield 47%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:5][C:6]=1[CH3:7].[Cu](C#N)[C:15]#[N:16].[C-]#N.[Na+]>CN(C)C=O>[C:15]([C:2]1[CH:3]=[C:4]([C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[S:5][C:6]=1[CH3:7])#[N:16]
Reactant: Cc1sc(C(=O)OC(C)C)cc1Br
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc(C(=O)OC(C)C)cc1C#N
Yield: 62.8 %

Procedure:
A stirred solution of 1.9 g (7.3 mmol) of isopropyl 4-bromo-5-methylthiophene-2-carboxylate was dissolved in dry dimethylformamide (30 mL) and refluxed with copper cyanide (785 mg, 8.8 mmol) for 16 hours. The cooled solution was poured into 0.1 M aqueous sodium cyanide solution (300 mL) and extracted with diethyl ether (4×40 mL). The organic layers were washed with brine (2×40 mL), dried over anhydrous sodium sulfate, and the solvents removed in vacuo. Column chromatography on silica gel eluting with hexanes:ethyl acetate 9/1 (v:v), gave isopropyl 4-cyano-5-methylthiophene-2-carboxylate (960 mg, 63%) as a yellow crystalline solid 1H-NMR (DMSO-d6; 300 MHz) δ8.01 (s, 1H), 5.09 (septet, 1H, J=6.2 Hz), 2.67 (s, 3H), 1.29 (d, 6H, J=6.2 Hz).
Reaction SMILES: S(=O)(=O)(O)O.C([O:8][C:9](=O)[NH:10][CH:11]=[C:12]([C:23]#[N:24])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>CCOCC>[CH3:22][O:21][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][C:16]=1[O:19][CH3:20])[C:9](=[O:8])[NH:10][CH:11]=[C:12]2[C:23]#[N:24]
Reactant: CCOC(=O)NC=C(C#N)c1ccc(OC)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2c(C#N)c[nH]c(=O)c2cc1OC
Temperature: 230 °C
Yield: 74.3 %

Procedure:
Concentrated sulfuric acid (0.4 mL) was added the the mixture of [2-cyano-2-(3,4-dimethoxy-phenyl)-vinyl]-carbamic acid ethyl ester (33.5 g, 121 mmol) and diphenyl ether (230 mL). The mixture was heated to 230° C. for 6 hr. After cooling, ether was added to precipitate the solid. The resulting solid was collected by filtration, washed with ether and dried to afford 6,7-dimethoxy-1-oxo-1,2-dihydro-isoquinoline-4-carbonitrile (20.7 g, 74.1%) as a brown solid which was used without further purification. LC-MS m/e calcd for C12H10N2O3 (MH+) 231. found 231.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[S:14][CH:15]=[C:16]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:17]=3[C:18]([O:20]C(C)(C)C)=[O:19])=[O:11])=[N:7][C:6]=2[CH:32]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([NH:12][C:13]3[S:14][CH:15]=[C:16]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[C:17]=3[C:18]([OH:20])=[O:19])=[O:11])=[N:7][C:6]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)c1c(-c2ccc(Cl)cc2)csc1NC(=O)c1nc2cc(Br)ccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1scc(-c2ccc(Cl)cc2)c1C(=O)O)c1nc2cc(Br)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3A in DCM (2 ml) at room was added TFA (2 ml). The mixture was stirred at room temperature for 30 minutes. The solvent was removed under vacuum. The residue was suspended in DCM (1 ml). The solid was collected by filtration, washed with DCM (3×1 ml) and dried to give 4A. 1H NMR (DMSO-d6) δ 7.12 (s, 1H), 7.38 (d, 2H), 7.43 (d, 2H), 7.79 (dd, 1H), 7.96 (d, 1H), 8.29 (d, 1H), 12.80 (bs, 1H), 13.44 (b, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][C:60]([F:64])([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][C:60]([F:64])([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: OCC(F)(F)F
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 38.7 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (120.0 mg, 0.310 mmol) in tetrahydrofuran (3.0 mL) was added 1,1′-(azodicarbonyl)dipiperidine (156.4 mg, 0.620 mmol) and tributylphosphine (154.5 μL, 0.620 mmol). After 10 min, to the mixture was added 2,2,2-trifluoroethanol (225.9 μL, 3.100 mmol). The reaction mixture was stirred at 60° C. for 5 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from diisopropyl ether/n-hexane to give the title compound as a colorless powder (56.5 mg, 0.120 mmol, 39%).
Reaction SMILES: [CH2:1]([C@H:7]([CH:11]([OH:32])[CH2:12][CH:13](OC1CCCCO1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:8](O)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:1]([C@@H:7]1[CH:11]([OH:32])[CH2:12][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:33][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCC(CC(O)[C@@H](CCCCCC)C(=O)O)OC1CCCCO1
Reactant: O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCCCCCCCCCCC1CC(O)[C@@H](CCCCCC)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.4 g of a diastereomer mixture of 2-hexyl-3-hydroxy-(R)-5 [(tetrahydro-2H -pyran-2-yl)oxy]hexadecanoic acid are dissolved in 160 ml of ethanol and 800 mg of toluene-4-sulphonic acid monohydrate are added. The reaction mixture is heated to 55°-60° C. until the reaction has finished. The solvent is removed in vacuo and the residue is dissolved in 160 ml of dichloromethane. The solution is stirred at room temperature for 1 hour. The reaction mixture is evaporated. The material obtained is chromatographed on silica gel. There is obtained tetrahydro-3-hexyl-4-hydroxy-(R)-6-undecyl-2H-pyran-2-one, m.p. 95°-96° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](OC)(OC)(OC)[CH3:11]>>[CH3:10][C:11]1[O:9][C:3]2[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: COC(C)(OC)OC
Product: Cc1nc2cc(Br)ccc2o1

Procedure:
A solution of 2-amino-4-bromophenol (1 g, 5.32 mmol) in trimethyl orthoacetate (20 mL) was refluxed for 1.5 hours. The reaction was then cooled and the solvent removed under reduced pressure to give 1.1 g of title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]2[CH:41]=[CH:42][CH:43]=[CH:44][C:26]=2[C:25]2[CH:45]=[CH:46][CH:47]=[CH:48][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: CC(C)[C@H](N)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CCCCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-phenbutyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-U), the title compound was prepared. The product was purified by chromatography (silica, 1-2% MeOH/CHCl3).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[OH-].[Ca+2].[OH-].[C:14]([CH:17]1[CH2:22][CH2:21][O:20][C:18]1=[O:19])(=O)[CH3:15]>O.C(O)C>[CH3:6][O:7][C:8]1[NH:9][C:18](=[O:19])[C:17]([CH2:22][CH2:21][OH:20])=[C:14]([CH3:15])[N:10]=1
Reactant: CC(=O)C1CCOC1=O
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1nc(C)c(CCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of O-methylisourea hydrogen sulfate (17.2 g, 0.1 mol) in water (90 ml) was added calcium hydroxide (8.14 g, 0.11 mol) followed by a solution of 2-acetylbutyrolactone (10.7 ml, 0.1 mol) in ethanol (70 ml). The mixture was stirred at room temperature for two days, filtered and washed with ethanol. The filtrate was concentrated in vaccuum and purified by flash chromatografy (dichloromethane/methanol=95/5). Yield 2.6 g (14%) of a white solid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([NH2:17])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CC(C)=O>[CH2:8]([NH:17][C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCN
Solvent: CC(C)=O
Product: CCCCCCCCCNC(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a stirred solution of succinic anhydride (25.0 g, 0.25 mol) in 150 mL acetone was added dropwise 35.8 g (0.25 mol) of nonylamine. The addition of the amine required 15 minutes, with the acetone solution reaching reflux before the addition was complete. Five minutes after the end of addition, a precipitate formed and the reaction mixture quickly became thick with suspended solids. Following addition of the amine the reaction mixture was stirred at room temperature for 1 hr. The precipitated solid was collected by filtration and washed with cold acetone. Air drying afforded 48.5 g of 4-nonylamino-4-oxobutyric acid as white, fluffy crystals, mp 114°-115.5° C. Upon standing the filtrate deposited crystals which were collected by filtration, washed with cold acetone, and air dried to yield an additional 10.9 g of the acid, mp 114°-115.5° C. Total yield was 59.4 g (98% of theoretical).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:9])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(C2CO2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2cccc(Cl)c2)cc1
Temperature: 78 °C
Yield: 9.8 %

Procedure:
To a stirring solution of 2-(3-chlorophenyl)oxirane (6.20 g, 40.0 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (7.30 g, 60.0 mmol), 1M NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. for three hours. The reaction was allowed to cool to RT and then extracted with EtOAc (2×150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was adsorbed onto silica gel and chromatographed eluting with 25-40% EtOAc/hexanes. There are 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.08 g (10%) of the desired product as a colorless oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.95 g (8%) of the regioisomer as a colorless oil, 44B. Some starting epoxide (2.85 g) was also recovered.