Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1(C(OCC)=O)[C:15]([O:17]CC)=[O:16])(=[O:3])[CH3:2].[OH-].[K+]>C(O)C>[C:1]([N:4]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@H:5]1[C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)C(c2ccccc2)CCN1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1CCC(c2ccccc2)[C@H]1C(=O)O
Temperature: 0 °C
Yield: 95 %

Procedure:
To a solution of diethyl 1-acetyl-3-phenylpyrrolidine-2,2-dicarboxylate (110.6 g, 331 mmol) in ethanol (500 ml) was added potassium hydroxide (55.7 g, 993 mmol). The reaction was allowed to stir at reflux for 8 h and was then concentrated. The residue was dissolved in water and extracted with EtOAc. The aqueous layer was cooled to 0° C., carefully acidified to pH 2-3 using conc HCl, and exhaustively extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield 1-acetyl-3-phenylproline as a solid (95%).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][OH:8]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]([CH3:10])([CH3:9])[C:3]#[C:4][CH:5]=[CH:6][CH:7]=[O:8]
Reactant: CC(C)(C)C#CC=CCO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)C#CC=CC=O
Reaction time: 17 h
Yield: 78.1 %

Procedure:
To 6,6-dimethyl-2-hepten-4-yn-1-ol (3.56 g, 25.8S mmol) dissolved in 100 ml of freshly distilled methylene chloride was added manganese dioxide (37 g, 425 mmol) and the mixture was stirred for 17 hours. An additional 5.2 g of manganese dioxide was then added and the mixture was stirred for 2 hours, then filtered and washed copiously with methylene chloride. Evaporation of the solvent afforded 2.74 g of 6,6-dimethyl-2-hepten-4-ynal.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14][O:15][NH2:16])=[CH:9][CH:10]=1)=[O:4].[CH2:27]([N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1[CH:43]=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]1/[CH:43]=[N:16]/[O:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[C:7]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=2)=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][CH:9]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc(OCCCON)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=Cc1cc2ccccc2n1Cc1ccccc1
Product: O=C(O)c1ccc(OCCCO/N=C/c2cc3ccccc3n2Cc2ccccc2)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 53.9 %

Procedure:
This compound was produced using similar methods as those used in Step 6, example 4, starting with 6-(3-aminooxy-propoxy)-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.25 g, 0.68 mmol) and 1-benzyl-1H-indole-2-carbaldehyde (0.16 g, 0.68 mmol). The crude material was purified by recrystallizing two times from ethyl acetate/hexanes followed by HPLC (82% acetonitrile in 0.1% trifluoroacetic acid solution) and one final recrystallization from ethyl acetate/hexanes to give 6-[3-({[(1E)-(1-benzyl-1H-indol-2-yl)methylidene]amino}oxy)propoxy]-4′-(trifluoromethyl)-1,1 ′-biphenyl-3-carboxylic acid (0.21 g, 54%) as a white solid. mp=196-197° C. 1H NMR (400 MHz, DMSO-d6); δ 12.80 (bs, 1H), (s, 1H), 7.96 (dd, 1H), 7.88 (d, 1H), 7.74 (AA′BB′, 4H), 7.60 (d, 1H), 7.46 (d, 1H), 7.22-7.16 (m, 4H), 7.12 (t, 1H), 7.06 (t, 1H), 6.94 (d, 2H), 6.89 (s, 1H), 5.72 (s, 2H), 4.13 (t, 2H), 4.11 (t, 2H), 2.49 (m, 2H). Mass spec; (ES−) m/z 571.2. Elemental analysis; Calculated for C33H27F3N2O4: C, 69.22; H, 4.75; N, 4.89. Found: C, 69.04; H, 4.55; N, 4.82.
Reaction SMILES: [CH2:1]([C:3]1[C:11]([NH:12][C:13]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].CC(C)([O-])C.[K+].COCCOC.Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>C1(C)C=CC=CC=1.O>[CH:35]1([CH2:34][N:12]([C:11]2[C:3]([CH2:1][CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[C:13]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[CH2:37][CH2:36]1
Reactant: BrCC1CC1
Reactant: CCc1nn2ccccc2c1NC(=O)C1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1nn2ccccc2c1N(CC1CC1)C(=O)C1CCOCC1
Reaction time: 4 h
Yield: 92.5 %

Procedure:
A mixture of N4-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)tetrahydro-2H-4-pyrancarboxamide (272 g, 915 mmol), potassium tert-butoxide (144 g, 1.28 mol) and 1,2-dimethoxyethane (1750 mL) was heated and stirred at an external temperature of 40° C. (Bromomethyl)cyclopropane (161 g, 1.19 mol) was then added dropwise to the reaction mixture keeping the internal temperature below 50° C. After heating and stirring for 4 hours, water (1250 mL) and toluene (3750 mL) were added to the reaction mixture. The aqueous layer was removed, and then the organic extract was washed with 10% brine (1250 mL) and water (1250 mL×2 times) in that order, and concentrated under reduced pressure to afford 277 g of the title compound as a brown oil (92.6% yield).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([CH2:16][C@H:17]2[CH2:21][NH:20][C@H:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[O:23])[CH2:18]2)=[C:14]([CH3:41])[CH:13]=1>>[N:2]1([CH2:7][C:8]([N:20]2[CH2:21][C@H:17]([CH2:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][C:14]=3[CH3:41])[CH2:18][C@H:19]2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[O:23])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: Cc1cc(F)ccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Agent: Cl
Product: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Yield: 41 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 8, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (127.6 mg, 41%). Major isomer 1H-NMR (400 MHz, CDCl3): δ 9.02 (s, 1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.42-7.37 (m, 2H), 7.31-6.82 (m, 9H), 5.06 (d, 1H), 4.98 (d, 1H), 4.79 (d, 1H), 3.69 (t, 1H), 3.27 (t, 1H), 3.04-2.91 (m, 1H), 2.84 (dd, 1H), 2.70 (dd, 1H), 2.59 (dd, 1H), 2.33 (s, 3H), 1.76-1.67 (m, 1H). MS (EI) for C29H28F2N5O3 found 532 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([CH3:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>>[CH3:14][C:5]1[O:4][C:3]([CH2:2][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1oc(CCl)nc1-c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Product: Cc1oc(COc2ccc(C=O)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 45, 2-chloromethyl-5-methyl-4-phenyloxazole was allowed to react with p-hydroxybenzaldehyde to give 4-(5-methyl-4-phenyl-2-oxazolylmethoxy)benzaldehyde. Recrystallization from ethyl acetate--isopropyl ether gave colorless prisms, m.p.90°-91° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[C:9]3[N:31]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:30](=[O:39])[NH:29][C:10]=3[C:11]([N:14](CC3C=CC=CC=3)CC3C=CC=CC=3)=[N:12][CH:13]=2)=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O.O>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[C:9]3[N:31]([CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:30](=[O:39])[NH:29][C:10]=3[C:11]([NH2:14])=[N:12][CH:13]=2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)c1cnc(N(Cc2ccccc2)Cc2ccccc2)c2[nH]c(=O)n(Cc3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Nc1ncc(C(=O)NCC2CC2)c2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
1-benzyl-4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5,c]pyridine-7-carboxylic acid cyclopropylmethyl-amide (10 mg, 0.02 mmol) was dissolved in 1 mL of concentrated sulphuric acid and the mixture was stirred at room temperature for 30 minutes. Once completed, the mixture was diluted in 5 mL of water and potassium carbonate was added portion wise until pH˜12. The mixture was then extracted with ethyl acetate (2×50 mL). The organic layers were combined, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel using 20% of methanol in ethyl acetate to give 1 mg of the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH2:6])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])#[N:12]>CC(N(C)C)=O>[CH3:1][C:2](=[CH2:6])[C:3]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([C:11]#[N:12])=[C:14]([C:20]([F:21])([F:22])[F:23])[CH:15]=1)=[O:4]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: C=C(C)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
Methyl acrylic acid (510 mg, 6 mmol) in DMA (10 ml) was treated with thionyl chloride (714 mg, 6 mmol) at 0° C. The mixture was stirred for 30 min then 4-cyano-3-trifluoromethyl-aniline (1.0 g, 6.0 mmol) was added. The resulting suspension was stirred overnight and then quenched with NaHCO3. The reaction mixture was extracted with ethyl acetate, washed with brine and dried with Na2SO4. The resulting concentrated crude product was purified on column (Ethyl acetate:Hexane, 1:2) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])[N:17]=[C:13]3[NH:12][C:11]([CH3:29])=[C:10]2[C:30]#[N:31])=[CH:5][CH:4]=1)#[N:2].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(N(CC)CC)C.N1C(C)=CC=CC=1C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Cu].N1C=CC=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])[N:17]=[C:13]3[N:12]([C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([C:33]([F:44])([F:43])[F:32])[CH:39]=3)[C:11]([CH3:29])=[C:10]2[C:30]#[N:31])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1
Agent: [Cu+2]
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-7-[4-cyanophenyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (12 g, 29.5 mmol) was stirred in abs. dichloromethane (600 ml) with molecular sieve (20 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (16.78 g, 88.4 mmol, 3 eq.) was added together with anhydrous copper(II) acetate (16.05 g, 88.4 mmol, 3 eq.). Abs. pyridine (400 ml) and triethylamine (12.32 ml, 88.4 mmol, 3 eq.) were then added. This mixture was stirred briefly (5 min), more abs. pyridine (440 ml) was then added and the mixture was stirred for 36 h. Since it was subsequently still possible to detect starting material (HPLC), 2,6-lutidine (3.43 ml, 29.6 mmol, 1 eq.) and a catalytic amount (spatula tip) of activated copper were added and the mixture was stirred under an atmosphere of dry air for a further 36 h. More 3-(trifluoromethyl)phenylboronic acid (5.59 g, 29.5 mmol, 1 eq.), anhydrous copper(II) acetate (5.35 g, 29.5 mmol, 1 eq.) and triethylamine (4.11 ml, 29.5 mmol, 1 eq.) were then metered in, and the mixture was then stirred for a further 5 d. The reaction mixture was then concentrated to dryness, and the residue was applied to silica gel using dichloromethane (˜500 ml) and purified by flash chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:2). The product was obtained as a solid (3.07 g, 18.1% of theory).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14].O>CN1C(=O)CCC1>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[N:12]([CH3:11])[S:13]([CH3:16])(=[O:15])=[O:14])#[N:5]
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: CNS(C)(=O)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(C#N)c(N(C)S(C)(=O)=O)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2-fluoro-4-methylbenzonitrile (4.6 g, 34.4 mmol) and N-methyl-methanesulphonamide (7.5 g, 68.7 mmol) are dissolved in 15 mL NMP and stirred for 16 h at 120° C. After the reaction has ended the reaction mixture is mixed with 70 mL water and the solid B-1a (HPLC-MS: tRet.=1.22 min; MS (M+NH4)+=242) is suction filtered and used without any further purification.
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C(Cl)Cl>[C:2]([C@@H:3]([NH:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)#[N:1]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@H](C#N)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
(S)-tert-Butyl 2-((S)-1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)piperidine-1-carboxylate (2.88 g) was dissolved in DCM (40 mL) and to the solution was added (methoxycarbonylsulfamoyl)triethyl ammonium hydroxide (3.42 g). The reaction mixture was stirred under nitrogen, at room temperature overnight, then concentrated in vacuo. Crude material was purified by flash silica chromatography eluting with 20% ethyl acetate in isohexane to give the title compound (2.7 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[CH3:33][O:34][CH2:35][CH2:36][NH:37][CH3:38]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:37]([CH2:36][CH2:35][O:34][CH3:33])[CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CNCCOC
Product: COCCN(C)CCCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and N-(2-methoxyethyl)methylamine (TCI America) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C24H36N6O5SF [(M+H)+] 539.2447, observed 539.2449.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28][CH2:29]Cl>CN(C=O)C.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:29][CH2:28][CH2:27][O:26][C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)=[CH:11][CH:10]=1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and p-anisidine (0.42 gm, 0.003 mole) was taken in dry DMF (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(4-methoxyphenyl)-[3-(naphthalen-2-yloxy) propyl]amine as yellow solid, m.p. 110° C., (yield 0.64 gm, 92.5%).
Reaction SMILES: O.Cl.[CH2:3]([N:10]1[CH2:15][C:14]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21](O)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[O:13][CH2:12][C:11]1=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N1CC(CCN2CCC(C3C=CC=CC=3)(O)CC2)(C2C=CC([Cl:59])=C(Cl)C=2)OCC1=O)C1C=CC=CC=1.Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:89][N:90]([CH3:108])[C:91]1[S:92][CH:93]=[C:94](C2(C3C=CC=CC=3)CCNCC2)[N:95]=1>CN(C=O)C>[ClH:37].[ClH:59].[CH2:3]([N:10]1[CH2:15][C:14]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][C:21]([C:94]3[N:95]=[C:91]([N:90]([CH3:108])[CH3:89])[S:92][CH:93]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:22][CH2:23]2)[O:13][CH2:12][C:11]1=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)c1nc(C2(c3ccccc3)CCNCC2)cs1
Reactant: O=C1COC(CCN2CCC(O)(c3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)c1nc(C2(c3ccccc3)CCN(CCC3(c4ccc(Cl)c(Cl)c4)CN(Cc4ccccc4)C(=O)CO3)CC2)cs1
Yield: 223.7 %

Procedure:
This compound is prepared by the procedure described in EXAMPLE 41 from 1.1 g of the compound obtained in step B of EXAMPLE 14, 1.3 g of 4-[2-(dimethylamino)thiazol-4-yl]-4-phenylpiperidine p-toluenesulfonate, 0.97 g of K2CO2 and 4 ml of DMF to give 0.76 g of the expected product. M.p.=155-160° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([CH2:31]O)[CH:30]=1)[C:26]#[N:27]>C(#N)C>[Br:20][CH2:31][C:29]1[CH:28]=[C:25]([CH:24]=[C:23]([F:22])[CH:30]=1)[C:26]#[N:27]
Reactant: N#Cc1cc(F)cc(CO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: N#Cc1cc(F)cc(CBr)c1
Reaction time: 0.5 h

Procedure:
(Step 3) Triphenylphosphine (1.91 g) was suspended in acetonitrile (50 ml), bromine (0.38 ml) was added, and the suspension was stirred for 30 min. 3-Fluoro-5-(hydroxymethyl)benzonitrile (1.1 g) synthesized by the method of Steps 1 and 2 was added to the reaction mixture, and the mixture was stirred at 85° C. for 2 hr. The reaction solution was quenched with water and extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was treated by basic silica gel chromatography (ethyl acetate:hexane=1:5) to give 3-(bromomethyl)-5-fluorobenzonitrile (0.69 g).
Reaction SMILES: ClC1SC(CO)=C(C2C=CC(Cl)=CC=2)C=1.OC1C=CC(CCC(OCC)=O)=C(C)C=1C.[Cl:32][C:33]1[S:37][C:36]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]([O:50]CC)=[O:49])=[C:42]([CH3:53])[C:41]=2[CH3:54])=[C:35]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)[CH:34]=1>>[Cl:32][C:33]1[S:37][C:36]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][C:48]([OH:50])=[O:49])=[C:42]([CH3:53])[C:41]=2[CH3:54])=[C:35]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)[CH:34]=1
Reactant: CCOC(=O)CCc1ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c(C)c1C
Agent: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: OCc1sc(Cl)cc1-c1ccc(Cl)cc1
Product: Cc1c(CCC(=O)O)ccc(OCc2sc(Cl)cc2-c2ccc(Cl)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 197 by coupling of [5-chloro-3-(4-chlorophenyl)thiophen-2-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((5-chloro-3-(4-chlorophenyl)thiophen-2-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.40 (s, 4H), 7.03 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 5.04 (s, 2H), 2.85 (t, J=5.1 Hz, 2H), 2.46 (t, J=5.1 Hz, 2H), 2.11 (s, 3H), 2.00 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C22H20Cl2O3S, 433.1 (M−H). found 433.1.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:25]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:24][N:25]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(ON)CN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) were added di-tert-butyl 4-(aminooxy)pyrazolidine-1,2-dicarboxylate 143 (0.411 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 144 (0.43 g, 85%) as a white foam.
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]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[N:12]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[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.[CH3:41][O:42][CH:43]([Si:45]([CH3:48])([CH3:47])[CH3:46])[CH3:44].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:58]2)=CC=1>C1(C)C=CC=CC=1>[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]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:58])[N:12]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[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.[CH3:41][O:42][CH:43]([Si:45]([CH3:48])([CH3:47])[CH3:46])[CH3:44]
Reactant: Cc1ccc(F)cc1C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: COC(C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1N(CC(=O)OC(C)(C)C)C(=S)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 120 °C

Procedure:
The mixture of racemic (2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxo spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1 g, 1.4 mmol) prepared in example 1e and 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (1.5 g, 3.75 mmol) (Aldrich) in toluene (20 mL) was heated at 120° C. for 0.5 h. The mixture was cooled to room temperature and then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:1) to give racemic (2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2-oxo-6′-thioxo spiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a off white foam (Yield 1.0 g, 92%).