Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].O.Cl[CH2:28][Cl:29]>CN(C)C=O>[Cl:29][CH2:28][CH2:20][O:1][C:2]1[C:11]2[O:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: O=C([O-])[O-]
Reactant: Cc1c(-c2ccccc2)oc2c(O)cccc2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(OCCCl)cccc2c1=O
Temperature: 60 °C
Reaction time: 25 h

Procedure:
A mixture of 7.52 g of 8-hydroxy-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Da Re, P. et al., Ann. Chim., 1962, p. 506 et seq.), 6.22 g of anhydrous potassium carbonate and 25.5 ml of 1-bromo-2-chloromethane in 70 ml of dimethylformamide was stirred at 60° C. for 25 hours. The mixture was cooled to 20°-25° C. and poured into 600 ml of water. The organic solution, obtained by extraction with dichloromethane, was washed with aqueous sodium chloride solution and dried on anhydrous sodium sulfate. The solvents and excess 1-bromo-2-chloromethane were evaporated off in vacuo to yield 8.8 g of the title compound, m.p. 141°-142° C. after crystallization from chloroform:hexane.
Reaction SMILES: [I-].C([N+]1(C)[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10]1)C1C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH2:16]([CH:11]1[C:12](=[O:15])[CH2:13][CH2:14][N:26]([C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)[CH2:10]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCC1C[N+](C)(Cc2ccccc2)CCC1=O
Reactant: COc1cc(N)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCC1CN(c2cc(OC)c(OC)c(OC)c2)CCC1=O
Yield: 204.8 %

Procedure:
A slurry of 1-benzyl-3-butyl-1-methyl-4-oxo-piperidinium iodide (306 mg) in water (2 ml) was added in one portion to a refluxing solution of 3,4,5-trimethoxy aniline (929 mg) and anhydrous potassium carbonate (33 mg) in ethanol (4 ml). The dark solution was heated to reflux for three hours. Water was added and the reaction was extracted twice with DCM. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated to leave a dark oil, which was purified by flash chromatography (ethyl acetate/hexanes 1:1) to give the product as a colorless oil (520 mg). MS (ESI): 322.4 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:20]1[N:24]([CH2:25][C:26]([O:28]C)=[O:27])[CH:23]=[N:22][CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([F:19])[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+:30].[OH-].O.Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]([C:20]1[N:24]([CH2:25][C:26]([O-:28])=[O:27])[CH:23]=[N:22][CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([F:19])[CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4].[Li+:30]
Reactant: COC(=O)Cn1cncc1C(C)(NC(=O)OC(C)(C)C)c1ccc(C#N)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(c1ccc(C#N)c(F)c1)c1cncn1CC(=O)[O-]

Procedure:
A mixture of methyl {5-[1-(tert-butoxycarbonylamino)-1-(4-cyano-3-fluorophenyl)ethyl]imidazol-1-yl}acetate, as described above in Step C, (321 mg, 0.798 mmol) and LiOH (21.0 mg, 0.877 mmol) was stirred in THF (5 mL) and H2O (1.8 mL) at ambient temperature for 1 hour. The solution was adjusted to pH≈7 by the addition of 1.0 N aqueous HCl and then concentrated in vacuo to give the desired product.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]1([CH3:22])[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH3:51])[C:30]2[O:36][C:35]3[C:37]([Cl:47])=[CH:38][C:39]([N:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[CH:40][C:34]=3[CH2:33][S:32](=[O:49])(=[O:48])[C:31]=2[CH:50]=1)=[O:26]>CN(C=O)C>[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29]([CH3:51])[C:30]2[O:36][C:35]3[C:37]([Cl:47])=[CH:38][C:39]([N:41]4[CH2:42][CH2:43][N:44]([C:19](=[O:20])[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=5[CH3:22])[CH2:45][CH2:46]4)=[CH:40][C:34]=3[CH2:33][S:32](=[O:48])(=[O:49])[C:31]=2[CH:50]=1)=[O:26]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: Cc1ccccc1C(=O)O
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(=O)c4ccccc4C)CC3)cc(Cl)c1O2
Temperature: 22 °C
Reaction time: 1 h

Procedure:
Carbonyl diimidazole (0.074 g 0.55 mmol) was added to a solution of 2-toluic acid (0.111 g, 0.67 mmol) in DMF (3 mL) and stirred at 22° C. for 1 h. To this, a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.2 g, 0.45 mmol) in DMF (2 mL) was added and stirred at 22° C. for 1 h. Solvent was removed and ice water (5 mL) was added. The solid separated was filtered, washed with water. The crude product obtained was purified by column chromatography (silica gel, ethyl acetate/pet ether) to obtain the title compound. Yield: 0.093 g (53%); mp: 201-204° C.; 1H NMR (DMSO-d6, 500 MHz): δ 2.23 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.15 (s, 2H, CH2), 3.28 (s, 2H, CH2), 3.34 (s, 2H, CH2), 3.39 (s, 2H, CH2), 3.87 (s, 3H, OCH3), 5.16 (s, 2H, CH2), 7.12 (s, 1H, Ar), 7.16 (s, 1H, Ar), 7.20 (m, 4H, Ar), 8.11 (s, 1H, Ar), 8.16 (s, 1H, Ar); MS: m/e (ES+) 555 (M+1).
Reaction SMILES: [OH-:1].[Na+].[C:3]([N:7]=[N:8][C:9](Cl)([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4].[C:13]([OH:17])([CH3:16])([CH3:15])C>>[C:3]([N:7]=[N:8][C:9]([OH:17])([CH3:11])[CH3:10])([CH3:6])([CH3:5])[CH3:4].[CH2:9]([N:8]=[N:7][C:3]([OH:1])([CH3:5])[CH3:4])[CH2:15][CH2:13][CH3:16]
Reactant: [OH-]
Reactant: CC(C)(C)N=NC(C)(C)Cl
Reactant: CC(C)(C)O
Agent: [Na+]
Product: CC(C)(C)N=NC(C)(C)O
Product: CCCCN=NC(C)(C)O

Procedure:
2-t-butylazo-2-hydroxypropane was prepared by reacting aqueous sodium hydroxide and 2-t-butylazo-2-chloropropane in t-butyl alcohol. The 2-butylazo-2-hydroxypropane was isolated by diluting the alcohol solution with water and extracting with pentane.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[C:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[C:22]([C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:33])=[O:32])=[CH:29][CH:30]=1)(=[O:24])[CH3:23].[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCC(=O)O
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1
Product: CCC(=O)[O-]
Yield: 49 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 45 mg (0.21 mmol) f 4-acetyl-benzenesulfonyl chloride. After recrystallization from methanol and trituration in hot methanol, 44 mg (49%) of 8-(4-acetyl-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][S:30]([CH3:29])(=[O:32])=[O:31])[CH:21]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(Cc2cccc([N+](=O)[O-])c2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(Cc2cccc(NS(C)(=O)=O)c2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
A mixture of ethyl N-tert-butoxycarbonyl-4-(3-nitrobenzyl)-piperidine-4-carboxylate (0.85 g, 2.17 mmol; Example 69, Step A) and 5% palladium on charcoal (0.06 g) in ethanol (100 mL) was hydrogenated at room temp. at 50 psi overnight. The resultant mixture was filtered through a plug of Celite, and the filtrate was concentrated under vacuum. The residue was dissolved in pyridine (5 mL), treated with methanesulfonyl chloride (0.24 mL, 3.2 mmol), and heated at 60° C. for 3 h. The product mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluting with 2% methanol in chloroform. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:57]/[O:58][C:59]2([C:62]([OH:64])=[O:63])[CH2:61][CH2:60]2)/[C:8]([NH:10][C@@H:11]2[C:14](=[O:15])[N:13]([S:16]([OH:19])(=[O:18])=[O:17])[C@@H:12]2[CH2:20][N:21]2[N:25]=[C:24]([CH2:26][NH:27]/[C:28](=[N:48]/C(OC(C)(C)C)=O)/[N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[C:23]([CH3:56])=[N:22]2)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:28](=[NH:48])[NH:27][CH2:26][C:24]1[C:23]([CH3:56])=[N:22][N:21]([CH2:20][C@@H:12]2[C@H:11]([NH:10][C:8](=[O:9])/[C:7](=[N:57]\[O:58][C:59]3([C:62]([OH:64])=[O:63])[CH2:61][CH2:60]3)/[C:5]3[N:6]=[C:2]([NH2:1])[S:3][CH:4]=3)[C:14](=[O:15])[N:13]2[S:16]([OH:19])(=[O:18])=[O:17])[N:25]=1
Reactant: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CN/C(=N/C(=O)OC(C)(C)C)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nc1CNC(=N)NCCCN
Temperature: 0 °C
Yield: 47.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using 1-(((Z)-(1-(2-aminothiazol-4-yl)-2-(((2R,3S)-2-((4-((Z)-4-(tert-butoxycarbonyl)-3-((tert-butoxycarbonyl)imino)-11,11-dimethyl-9-oxo-10-oxa-2,4,8-triazadodecyl)-5-methyl-2H-1,2,3-triazol-2-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid (58.5 mg, 0.062 mmol), DCM (621 μL), anisole (20.4 μL, 0.186 mmol) and TFA (427 μL, 4.55 mmol). The reaction mixture was diluted with ice-cold water (1 mL) and the layers were separated. The organic layer was extracted with water (1 mL) and the combined aqueous layers were washed with DCM (1 mL) and then purified by reverse phase preparative HPLC (XSELECT C18, 5μ, 30×100 mm, 1-20% ACN/H2O w/0.1% formic acid buffer over 18 min, 60 mL/min), affording the title compound (19 mg, 44%) as an off-white solid. LCMS: Rt=0.54 min, m/z=643.2 (M+1) Method 2m_acidic_polar. 1H NMR (400 MHz, D2O) δ 7.11 (s, 1H), 5.62 (d, J=5.6 Hz, 1H), 5.01-4.94 (m, 1H), 4.91-4.74 (m, 2H assumed; obscured by solvent residual peak), 4.50 (br s, 2H), 3.36 (t, J=6.9 Hz, 2H), 3.11 (t, J=7.8 Hz, 2H), 2.29 (s, 3H), 2.01 (p, J=7.2 Hz, 2H), 1.35-1.25 (m, 2H), 1.21-1.05 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1C=CC=[C:6]([CH:10](C)C)[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33](C1C=CC=C(C(C)C)C=1CC(Cl)=O)(C)[CH3:34].C1(C(CC)C(Cl)=O)C=CC=CC=1>>[O:15]=[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)[CH:13]([C:5]1[CH:4]=[CH:2][CH:1]=[CH:10][CH:6]=1)[CH2:33][CH3:34]
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)Cl
Agent: CCC(C(=O)Cl)c1ccccc1
Product: CCC(C(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C)c1ccccc1

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetyl chloride was replaced with 2-phenylbutyryl chloride, mp 142°-145° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([O:19][CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]1)=O)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C>O1CCCC1>[CH2:29]([CH:26]1[CH2:25][CH2:24][N:23]([CH2:21][CH2:20][O:19][C:14]2[CH:13]=[CH:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[CH:15]=2)[CH2:28][CH2:27]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(COc1ccc2cc(OCc3ccccc3)ccc2c1)N1CCC(Cc2ccccc2)CC1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: c1ccc(COc2ccc3cc(OCCN4CCC(Cc5ccccc5)CC4)ccc3c2)cc1
Yield: 99.9 %

Procedure:
To 2-(6-benzyloxy-naphthalen-2-yloxy)-1-(4-benzyl-piperidin-1-yl)-ethanone (0.71 g, 1.53 mmol) in anhydrous tetrahydofuran (25 ml) was added BH3 ·SMe2 (0.62 ml, 6.20 mmol) and diisopropyl amine (0.214 ml, 1.53 mmol), and the solution was refluxed for 18 h under N2. The reaction was cooled in an ice bath and quenched with dropwise addition of methanol (15 ml). The solvent was evaporated, the solid washed with hexanes and evaporated. The solid was washed with hexanes, filtered, and air dried to give 0.69 g (100%) of 4-benzyl-1-[2-(6-benzyloxy-naphthalen-2-yloxy)-ethyl]-piperidine. 1H NMR (CDCl3) 7.64-7.56 (2H, m), 7.45 (2H, d, J=7.3), 7.39-7.003 (12H, m), 5.12 (2H, d, J=3.6), 4.55 (1H, t, J=5.4), 4.51 (1H, t, J=5.4), 3.62 (1H, t, J=5.4), 3.18-3.14 (3H, m), 2.92 (1H, m), 2.60-2.54 (3H, m), 2.15-2.0 (1H, m), 1.66-1.51 (4H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:8]#[C:4][CH2:5][CH2:6][C:22]2[C:16]3[C:17](=[N:18][NH:14][N:15]=3)[CH:19]=[CH:20][C:21]=2[CH3:23])[CH:7]=[CH:6][CH:5]=1.[F:9][CH2:8][C:4]1[N:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[N:18]=[C:17]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:16]3=[N:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2ccc(C)cc2n1
Product: Cc1ccc2n[nH]nc2c1CCC#Cc1cccc(CF)n1
Product: Cc1ccc2nn(CCC#Cc3cccc(CF)n3)nc2c1
Yield: 107.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (73 mg, 0.39 mmol) and 2-but-3-ynyl-5-methyl-2H-benzo[d][1,2,3]triazole (65 mg, 0.35 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 40 mg (0.14 mmol, 39%) of 2-(4(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-5-methyl-2H-benzo[d][1,2,3]triazole as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH2:7][O:6][C:5](=[O:8])[CH:4]=1.[CH3:9][O:10][P:11]([O:14]C)[O:12][CH3:13]>>[O:8]=[C:5]1[CH:4]=[C:3]([CH2:2][P:11](=[O:14])([O:12][CH3:13])[O:10][CH3:9])[CH2:7][O:6]1
Reactant: COP(OC)OC
Reactant: O=C1C=C(CBr)CO1
Product: COP(=O)(CC1=CC(=O)OC1)OC

Procedure:
A solution 15.0 g of 4-bromomethyl-2-oxo-[5H]-furan (Martin R. et al., Helv.Chim. Acta, 1976, 59, 2724) in 100 ml of trimethylphosphite was refluxed for 2 hrs, while a stream of nitrogen was bubbled vigorously into the solution. The mixture was then evaporated to dryness and the residue was purified by chromatography (SiO2 ; ethyl acetate/diethylether 50/50) to give 16.0 g of dimethyl (2-oxo-[5H]-4-furyl)methyl-phosphonate.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH:3]=[O:4].[CH3:15][Li].S([O-])([O-])(=O)=O.[Na+].[Na+].O>C(OCC)C>[CH3:1][CH:2]([CH2:5][CH2:6][CH:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:13])[CH3:14])[CH:3]([OH:4])[CH3:15]
Reactant: [Li]C
Reactant: CC1=CCC(CCC(C)C=O)C1(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1=CCC(CCC(C)C(C)O)C1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 20.8 g (0.12 mole) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)butanal dissolved in ethyl ether-anhydrous (50 ml) was added to a stirred solution of methyllithium (1.7 M) in ethyl ether (250 ml; 0.14 mole) which was previously cooled to 0° C. The mixture was stirred at 0°-5° C for 1.0 hour and then heated at reflux (36° C) for 3.0 hours. The mixture was cooled to 0° C and excess methyllithium was decomposed by slow dropwise addition of saturated sodium sulfate solution (50 ml). The mixture was poured into 150 ml of water, the lower aqueous layer was drawn off and extracted twice with 100 ml of ether. The ether extracts were combined, washed with 150 ml of brine, dried over sodium sulfate, filtered and the solvent removed by distillation. The residual oil was fractionally distilled to yield 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl)pentan-2-ol: 20.4 g (81% yield); bp 96°-98° (0.9 mm); mol wt. 210 (ms).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([CH3:10])[CH:3]=1.[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([CH2:31][S:32][CH3:33])[CH:30]=1)[NH:27][CH:26]=[CH:25]2>C(#N)C.N1CCCC1C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([C:25]2[C:24]3[C:28](=[C:29]([CH2:31][S:32][CH3:33])[CH:30]=[C:22]([F:21])[CH:23]=3)[NH:27][CH:26]=2)[CH:16]2[C:17](=[O:18])[O:19][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:15])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C=O
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cc(F)cc2c(C(c3ccc(Cl)cc3C)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.3 %

Procedure:
0.68 g (4.41 mmol) of 4-chloro-2-methylbenzaldehyde, 0.64 g (4.41 mmol) of Meldrum's acid and 24.0 mg (0.21 mmol) of D,L-proline were added to a solution of 1.00 g of the compound from Example 11A with a purity of 82% (4.20 mmol) in 35 ml of acetonitrile. The reaction mixture was stirred at RT overnight. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. 2.40 g of the title compound were obtained and were reacted without further purification.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH3:17][CH:18]1[CH2:23][CH:22]([CH3:24])[CH2:21][N:20]([CH2:25][CH2:26][NH2:27])[CH2:19]1>>[CH3:17][CH:18]1[CH2:23][CH:22]([CH3:24])[CH2:21][N:20]([CH2:25][CH2:26][NH:27][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:19]1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: CC1CC(C)CN(CCN)C1
Product: CC1CC(C)CN(CCNc2ccc3c(=O)[nH]c4ncccc4c3c2)C1
Yield: 8.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (171 mg, 0.74 mmol) and 2-(3,5-dimethylpiperidin-1-yl)ethanamine (464 mg, 2.97 mmol) to provide 478 (23 mg, 9% yield) as a white powder. LC-MS (M+H=351, obsd.=351). 1H NMR (400 MHz, DMSO-D6) δ 11.58 (s, 1H), 9.48 (s, 1H), 8.73 (d, J=6.7, 1H), 8.46 (dd, J=1.6, 4.7, 1H), 8.06 (d, J=8.7, 1H), 7.42 (d, J=2.1, 1H), 7.29 (dd, J=4.7, 7.9, 1H), 6.96 (dd, J=2.1, 8.8, 1H), 3.70 (s, 2H), 3.52 (d, J=11.1, 2H), 3.30 (d, J=5.3, 2H), 2.56 (dt, J=8.1, 16.4, 2H), 1.89 (s, 2H), 1.77 (d, J=13.0, 1H), 0.91 (t, J=8.4, 6H), 0.80 (dd, J=12.3, 24.8, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH3:20]>C1COCC1>[C:1]1([C:7]2[CH:8]=[C:9]([C:16](=[O:18])[CH3:20])[S:10][C:11]=2[C:12]([F:13])([F:14])[F:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(=O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reaction time: 0.17 h

Procedure:
To a solution of 4-phenyl-5-trifluoromethyl-thiophene-2-carboxylic acid (272 mg, 1.0 mmol) in THF (10 mL), a solution of MeLi (1.30 mL, 1.6 M solution in diethyl ether) is added. The dark red reaction mixture is stirred at it for 10 min. The reaction is quenched by adding sat. aq. NH4Cl (10 mL). The organic phase is separated, dried over Na2SO4 and evaporated. The crude product is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 1-(4-phenyl-5-trifluoromethyl-thiophen-2-yl)-ethanone (31 mg) as pale yellow oil, LC-MS: tR=1.06 min, 1H NMR (CDCl3): δ 7.62-7.60 (m, 1H), 7.45-7.40 (m, 5H), 2.60 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:20]=[CH:19][N:18]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:17][CH:16]2[OH:29])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:44]([CH:51]([CH3:53])[CH3:52])([CH:48]([CH3:50])[CH3:49])[CH:45]([CH3:47])[CH3:46])(=O)=O.O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:20]=[CH:19][N:18]([CH:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:17][CH:16]2[O:29][Si:44]([CH:51]([CH3:53])[CH3:52])([CH:48]([CH3:50])[CH3:49])[CH:45]([CH3:47])[CH3:46])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(c1ccccc1)N1C=CC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(c1ccccc1)N1C=CC(c2ccc(OCc3ccccc3)cc2)C(O[Si](C(C)C)(C(C)C)C(C)C)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of 14.70 g of 4-(4-benzyloxyphenyl)-1-(1-phenylethyl)-1,2,3,4-tetrahydro-pyridin-3-ol [257928-45-3] in 250 ml of dichloromethane is mixed with 6.80 ml of 2,6-lutidine and cooled to 0° C. 12.60 ml of triisopropysilyl trifluoromethanesulphonate are added dropwise, and the reaction mixture is stirred at 0° C. for 1 hour. The reaction solution is poured into 400 ml of water, and the phases are separated. The aqueous phase is back-extracted with 200 ml of dichloromethane, and the combined organic phases are dried with sodium sulphate and evaporated. The title compound is obtained as a yellow-brown oil from the residue by flash chromatography (SiO2 F60). Rf (EtOAc/heptane 1:2)=0.66; Rt=5.83.
Reaction SMILES: N[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:15]1[C:19]([NH2:20])=[N:18][N:17]=[N:16]1)[CH2:13][CH3:14]>>[Cl:11][C:10]1[CH:2]=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([NH:20][C:19]1[N:15]([CH2:12][CH2:13][CH3:14])[N:16]=[N:17][N:18]=1)=[O:6]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CCCn1nnnc1N
Product: CCCn1nnnc1NC(=O)c1cccc(Cl)c1
Yield: 65 %

Procedure:
Employing 0.25 g (1.5 mmol) of 2-amino-3-chlorobenzoic acid and 0.19 g (1.5 mmol) of 1-propyl-1H-tetrazol-5-amine in the procedure described above and elution with CH2Cl2/MeOH/Et3N (9.4:0.3:0.3) gave the product in 65% yield.
Reaction SMILES: O.[CH2:2]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][C:19](C)=[CH:18][CH:17]=1)CC(OC)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23](=[O:26])([O-])[OH:24].[Na+].[C:28]1(C)C=CC=C[CH:29]=1>>[CH2:10]([NH:9][C@@H:2]([CH2:3][C:8]1[CH:7]=[CH:6][C:5]([CH3:4])=[CH:29][CH:28]=1)[C:23]([OH:24])=[O:26])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C([O-])O
Reactant: Cc1ccccc1
Reactant: COC(=O)CC(NCc1ccccc1)c1ccc(C)cc1
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C[C@H](NCc2ccccc2)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 8.5 h

Procedure:
To 372 mL of water were added 37.20 g (0.13 mol) of methyl (±)-3-benzylamino-3-(p-tolyl)propionate and 11.03 g (0.13 mol) of sodium hydrogen carbonate, and the mixture was maintained at 30° C. To the resulting mixture was added 186 mg of lipase (CAL; available from Roche, CHIRAZYME L-2 (trade name)) originated from Candida antarctica at the same temperature, and the mixture was reacted at 30° C. while stirring. After 8.5 hours, at the time when the conversion rate of the starting materials reached 39.4%, the reaction mixture was filtered to obtain a solid state product. To the resulting product was added 200 ml of toluene and the mixture was stirred at room temperature for 2 hours, then, filtered and dried to obtain 11.11 g (Isolated yield based on methyl (±)-3-benzylamino-3-(4-fluorophenyl)propionate=31.4%) of 3-(R) or (S)-benzylamino-3-(p-tolyl)propionic acid as white crystal.