Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][N:5]([C:19](=[O:34])[C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18].O.O.[OH-].[Li+].Cl>O1CCOCC1.CCOC(C)=O>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=1)[C:19]([N:5]([CH2:4][C:3]([OH:35])=[O:2])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:34]
Reactant: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of {(3,5-bis-trifluoromethyl-benzoyl)-[4-(2-chloro-phenyl)-pyridin-3-yl]-amino}-acetic acid methyl ester (109 mg, 211 μmol, example 88) in dioxane (2 mL) was added water (2 mL) and lithium hydroxide hydrate (11.1 mg, 264 μmol). The reaction mixture was stirred at room temperature for 2 hours and then poured on 30 mL 1M aqueous HCl and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and evaporated to give a yellow solid which was pure enough for the next step (119 mg, 112%). MS (ESI): m/z=503.060 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([OH:8])[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(C(O)c2ccc(C#N)cc2)cc1
Reaction time: 4 h

Procedure:
To a suspension of 4-(4-methoxybenzoyl)benzonitrile 26-1 (J. Med. Chem. 1991, 34, 2768-2778) (0.783 g, 3.3 mmol) in ethanol (35 ml) under nitrogen cooled in an ice-bath was added sodium borohydride (0.250 g, 6.6 mmol). The mixture was stirred 4 h with ice-bath cooling. To the resulting solution was added saturated ammonium chloride solution (35 ml). The mixture was partially evaporated under reduced pressure, and the resulting aqueous mixture was extracted with ethyl acetate (2×100 ml). The combined organic fractions were washed with brine (50 ml), dried (sodium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1:6 increasing to 1:3), to give product 26-2 as an oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19])=[CH:10][CH:9]=1.O.[OH-].[K+]>CCOCC>[F:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:13]=1
Reactant: O=C(O)CCCCc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: OCCCCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (0.46 g, 12.23 mmol) in dry Et2O (5 mL), 5-(4-fluorophenyl)-pentanoic acid (0.6 g, 3.05 mmol) in dry Et2O (35 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0° C. H2O (0.46 mL), 3M KOH solution (0.46 mL) and H2O (1.54 mL) were very slowly added. The mixture was stirred for 1 h at 0° C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness affording the title compound (0.53 g, 95%) as a colorless oil. 1H NMR (CDCl3): δ 1.36-1.47 (m, 2H), 1.58-1.71 (m, 4H), 2.58-2.65 (m, 2H), 3.66 (t, J=5.8 Hz, 2H), 6.94-7.02 (m, 2H), 7.11-7.17 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[CH3:1][N:2]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CN(CCCC(=O)O)c1ccccc1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A mixture of N-methylaniline (10 g), ethyl 4-bromobutyrate (13.2 ml) and potassium carbonate (12.7 g) was stirred for 1.5 hour at 110° C. After cooling to room temperature, ethanol (100 ml) and 3N aqueous sodium hydroxide (100 ml) were added to the mixture, and the mixture was stirred for 30 minutes under reflux. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with water and then washed with ether. The aqueous layer was acidified to pH 4 with concentrated hydrochloric acid and extracted three times with ethyl acetate. The organic layers were collected and extracted twice with 3N hydrochloric acid. The aqueous layers were collected, adjusted to pH 4 by using 20% NaCl aqueous solution, and extracted five times with an ethyl acetate. The combined organic layer was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 14.8 g (84%) of the objective compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:9]([O:11]C)=[O:10])=[N:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1cnc(Cl)c(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(C(=O)O)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A mixture of methyl 5-chloro-6-methyl-2-pyrazine carboxylate (0.16 g, 0.86 mmol), K2CO3 (0.31 g, 2.18 mmol) and H2O was stirred for 2 h at room temperature. The reaction was filtered and acidified (20% HCl), and the resulting solid collected to provide the title compound (0.057 g, 39% yield); m.p. 116°-117° C.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].O=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>CN(C)C=O>[Cl:2][C:3]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:4]=1[CH:5]=[C:36]1[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=C2CN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.7 %

Procedure:
(2-Chloro-4-(methoxycarbonyl)benzyl)triphenylphosphonium bromide (1.04 g, 1.98 mmol) was dissolved in N,N-dimethylformamide (DMF, 20 mL) and the solution was cooled to 0° C. A 60% suspension of NaH in paraffin oil (80 mg, 2.00 mmol) was added and the reaction mixture was stirred at 0° C. for 15 mins. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (0.32 g, 1.87 mmol) in anhydrous DMF (5 mL) was added and the reaction mixture was heated overnight at 65° C. After completion of the reaction as indicated by HPLC/MS, the cooled reaction mixture was diluted with EtOAC (20 mL) and quenched with a saturated NH4Cl solution (10 mL). The organic layer was washed with water (3×20 mL) and brine (15 mL). It was then dried over anhydrous Na2SO4, filtered and evaporated to get the crude product. This crude was purified by silica gel column chromatography using 50-80% EtOAc in Hexanes as eluent to provide tert-butyl 3-(2-chloro-4-(methoxycarbonyl)benzylidene)azetidine-1-carboxylate (0.27 g) as a white solid. ES+(M+Na)+360.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH3:14]>>[CH2:11]([O:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=2)[CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: CCCCOc1cccc(B(O)O)c1
Product: CCCCOc1cccc(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 72.7 %

Procedure:
The title compound (0.190 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.2 g, 0.89 mmol) and 3-butoxyphenylboronic acid (0.224 g, 1.16 mmol) as a yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.44-7.41 (m, 2H), 7.27 (t, J 7.9, 1H), 7.17-7.10 (m, 2H), 6.81-6.84 (m, 1H), 5.50 (s, 2H), 4.01 (t, J 5.3, 2H), 1.72-1.65 (m, 2H), 1.50-1.41 (m, 2H), 0.93 (t, J 7.4, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].[Cl-].[NH4+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C(CNCCNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(CCNC(=O)OC(C)(C)C)CC(C(=O)OC)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 90.8 %

Procedure:
To a solution of 18.80 g (47.54 mmol) of 3-(2-tert-butoxycarbonylamino-ethylamino)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid methyl ester dissolved in 156 mL of anhydrous dichloromethane was added 8.02 mL (57.05 mmol) of triethylamine. The resulting mixture was cooled at 0° C. and 5.00 mL (52.29 mmol) of ethyl chloroformate dissolved in 30 mL of anhydrous dichloromethane was added. The resulting mixture was stirred at room temperature for 12 h. Saturated aqueous solution of ammonium chloride was added and the mixture extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of sodium chloride, sodium carbonate, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 99/1 led to afford 20.00 g (90%) of the desired compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])CCC.[CH:17]1([N:22]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:23](=[O:32])[C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:33]1([N:22]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:23](=[O:32])[C:24]2[CH:25]=[CH:26][C:27]([CH:28]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)[OH:29])=[CH:30][CH:31]=2)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: O=Cc1ccc(C(=O)N(C2CCCCC2)C2CCCC2)cc1
Reactant: COc1ccc(Br)cc1OC
Agent: [Li]CCCC
Product: COc1ccc(C(O)c2ccc(C(=O)N(C3CCCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The reaction and workup were carried out in the same manner as described in Example 8, using 4-bromoveratrole (0.9 mL, 7.0 mmol), n-butyl lithium (4.38 mL of 1.6 M solution in hexane), terephthalaldehydic acid N-cyclopentyl-N-cyclohexyl amide (1.9 g, 6.36 mmol). The crude product was chromatographed on silica gel using mixtures of ethyl acetate and hexane to give the title compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([NH:24][C@@H:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)[C:17]4[S:22](=[O:23])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[C:35](O)=[O:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:15]=[C:16]([NH:24][C@@H:25]4[CH2:29][CH2:28][N:27]([C:35]([C@H:31]5[CH2:32][CH2:33][CH2:34][O:30]5)=[O:36])[CH2:26]4)[C:17]4[S:22](=[O:23])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(N[C@@H]3CCNC3)c21
Reactant: O=C(O)[C@H]1CCCO1
Product: O=C([C@H]1CCCO1)N1CC[C@@H](Nc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc3c2S(=O)CC3)C1

Procedure:
Starting from {2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine Diastereomer 1 (Example 171) (see scheme 3, 3.22) and (R)-(+)-tetrahydrofuran-2-carboxylic acid, Example 196 is prepared as described in Example 231 (see scheme 7). The product is purified by preparative HPLC (method B). Analytical HPLC-MS (method D): RT=1.18 min.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>CO>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]2)[C:3]([OH:20])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(OC)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (458.8 mg, 1.63 mmol) in methanol (1.09 mL, 1.5M) was treated with a 4N aqueous sodium hydroxide solution (0.45 mL, 1.8 mmol) and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was partitioned between water (100 mL), which was then acidified with a 2N aqueous hydrochloric acid solution to pH=2, and a 90/10 methylene chloride/methanol solution. The reaction was then extracted with a 90/10 methylene chloride/methanol solution (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford 3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (430 mg, 98%) as a white solid; ES+-HRMS m/e calcd for C13H18N2O4 [M+Na+] 289.1159, found 289.1159. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93-1.22 (m, 2H), 1.33-1.78 (m, 7H), 1.84-2.03 (m, 1H), 2.06-2.21 (m, 1H), 3.82 (s, 3H), 5.32 (dd, J=10.9, 3.9 Hz, 1H), 6.30 (d, J=2.7 Hz, 1H), 7.82 (d, J=2.7 Hz, 1H), 12.96 (br. s., 1H).
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:17]([CH:19]([N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28])[C:20]([OH:22])=[O:21])[CH3:18]>C1(C)C=CC=CC=1>[CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]([C@H:19]([N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28])[C:20]([OH:22])=[O:21])[CH3:18]
Reactant: CCC(C(=O)O)N1CCCC1=O
Agent: C[C@@H](N)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[C@@H](C(=O)O)N1CCCC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A solution of (R)-alpha-methylbenzylamine (106 g) and triethylamine (89 g) in toluene (100 ml) was added to a suspension of (RS)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (300 g, 1.75 mol) in toluene (1 L). The mixture was heated until complete dissolution, cooled to room temperature and stirred for 3 hours. The solids were filtered and rinsed with toluene (300 ml) to give 250 g of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt. The solids were crystallized from toluene and 205 g (yield 41%) of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid (R)-alpha-methylbenzylamine salt was obtained. The isolated solid was treated with hydrochloric acid solution and the enantiomerically pure (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetic acid could be isolated in 90% yield.
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19]1[C:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=C(C)C=C[C:20]=1S([O-])(=O)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O)CC.[N-:42]=[N+:43]=[N-:44].[Na+].CN(C)C=O>O>[N:42]([CH2:20][CH:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCOCc1c(S(=O)(=O)[O-])ccc(C)c1OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCO
Product: CCCCCCCCCCCCCCCCOCC(CN=[N+]=[N-])COCc1ccccc1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 72.5 %

Procedure:
A mixture of 16.3 g of 2-[(hexadecyloxy)methyl]-3-(phenylmethoxy)-4-methylbenzenesulfonate-1-propanol, 9.22 g of sodium azide and 130 ml of N,N-dimethylformamide is stirred at 80° C. for 3.5 hours and then at room temperature overnight. The mixture is poured into water and extracted with ether. The ether layer is dried and the solvent removed. The residue is purified by chromatography, to give 8.9 g of the desired compound as an oil.
Reaction SMILES: [CH2:1]([NH:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:21])[CH:15](O)[C:16](O)([CH3:18])C)[CH3:6])[CH:2]=[CH2:3].I(O)(=O)(=O)=O.[C:27]1(/C=C/B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO.O.C(OCC)(=O)C>[CH2:1]([N:4]1[CH:5]([CH3:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:21])[CH:15]1[CH:16]=[CH:18][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:2]=[CH2:3]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: C=CCNC(C)c1ccccc1NC(=O)C(O)C(C)(C)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C=CCN1C(C=Cc2ccccc2)C(=O)Nc2ccccc2C1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
The product of Example 14 (117 mg, 0.4 mmol) was placed in a 25 mL round bottom flask and dissolved in methanol (2 mL) and water (1 mL). To this solution was added periodic acid (192 mg, 0.84 mmol), and the mixture was allowed to stir at room temperature for 2 hours. After this time, the solvent was then evaporated and the resulting residue was taken up in ethyl acetate (20 mL) and transferred to a separatory funnel. The organic layer was then washed with a saturated sodium bicarbonate solution (5×15 mL) until the aqueous layer no longer turned pink in color. The organic layer was then washed with brine (1×15 mL), dried over magnesium sulfate, filtered and evaporated. This resulting aminol was then dissolved in acetonitrile (4 mL) and to this solution was added (E)-2-Phenylvinylboronic acid (75 mg, 0.5 mmol), and the solution was brought to reflux for 4 hours. After this time, the reaction was diluted with ethyl acetate (40 mL), and transferred to a separatory funnel. The organic layer was washed with 1N NaOH (3×15 mL), brine (1×15 mL), dried over magnesium sulfate, filtered, and evaporated to yield the desired product, and an isomeric by-product in a combined yield of 81%. 1H NMR was used to estimate the ratio of product to by-product to be approximately 77:23. This mixture was taken crude to the next transformation to avoid further isomerization upon isolation. 1H NMR (250 MHz, CDCl3, major isomer) δ 7.75 (bs, 1H), 7.43-7.37 (m, 2H), 7.33-7.15 (m, 6H), 7.11-7.04 (m, 1H), 6.85-6.82 (m, 1H), 6.57 (dd, J=16.0 Hz, J=4.8 Hz, 1H), 5.92-5.69 (m, 1H), 5.18-5.03 (m, 2H), 4.44-4.39 (m, 1H), 4.29 (q, J=6.6 Hz, 1H), 3.27-3.16 (m, 1H), 2.92-2.80 (m, 1H), 1.55 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21](C)[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C(NC(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])=[CH:29][CH:30]=1
Reactant: CN1CCC(c2ccc(OC(Oc3ccc(Cl)cc3)C(=O)O)cc2)c2ccccc21
Solvent: CC(C)NC(C)C
Product: O=C(O)C(Oc1ccc(Cl)cc1)Oc1ccc(C2CCNc3ccccc32)cc1

Procedure:
(4-chlorophenoxy)-[4-(1-methyl-1,2,3,4-tetrahydro-4-quinolyl)-phenoxy]-acetic acid,, diisopropylamine salt, m.p. 152°-155°;
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:36]=[CH:35][N:14]3[C:15](=[O:34])[C:16]([C:20]4[N:24]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[N:23]=[N:22][N:21]=4)=[C:17]([OH:19])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:53]1([CH3:63])[CH:58]=[CH:57][C:56]([S:59](Cl)(=[O:61])=[O:60])=[CH:55][CH:54]=1>C(Cl)Cl>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:36]=[CH:35][N:14]3[C:15](=[O:34])[C:16]([C:20]4[N:24]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[N:23]=[N:22][N:21]=4)=[C:17]([O:19][S:59]([C:56]4[CH:57]=[CH:58][C:53]([CH3:63])=[CH:54][CH:55]=4)(=[O:61])=[O:60])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(Cn2nnnc2-c2c(O)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nnnc2-c2c(OS(=O)(=O)c3ccc(C)cc3)nc3cc(CCc4nc(C(C)C)cs4)ccn3c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
The 8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-hydroxy-3-[(4-methoxybenzyl)-tetrazol-5-yl]-4H-pyrido[1,2-a]pyrimidin-4-one(73 mg) obtained in (A) was dissolved in methylene chloride (2 ml), added with dimethylaminopyridine (5 mg), triethylamine(40 ml) and p-toluenesulfonyl chloride (83 mg) at 0° C., and then the mixture was stirred at room temperature for 6 hours. The reaction solution was directly purified by silica gel column chromatography to obtain the title compound (61 mg, 64%) as pale yellow powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].C([O-])(=O)C.[Na+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[O:12]
Reactant: COCCCCCCCCCO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCCCCCCCCC=O
Yield: 54.4 %

Procedure:
a 50-mL, one-necked, round-bottom flask equipped with a magnetic stirrer and stir bar was charged with 9-methoxy-nonanol (1.0 g, 5.9 mmol), dichloromethane (10 mL), molecular sieves (1.0 g, 3 A), sodium acetate (0.1 g) at room temperature. The reaction mixture was stirred at room temperature under nitrogen for 5 minutes. The reaction mixture was charged with pyridinium dichromate (4.7 g, 12.5 mmol) and stirred overnight. The progress of reaction was monitored by TLC (Note 1). After completion of the reaction, the reaction mixture was filtered through a bed of silica gel (˜15 g). The filtrate was evaporated in vacuo to obtain a crude compound. This was purified by column chromatography using silica gel column (250-400 mesh, 40 g). A solvent gradient of ethyl acetate in hexane (10-50%) was used to elute the product from the column. All fractions containing the desired pure product were combined and concentrated in vacuo to give pure 9-methoxy-nonanal (lot D-1027-156, 553 mg, 54.4%). Completion of the reaction was monitored by thin layer chromatography (TLC) using a thin layer silica gel plate; eluent: 60% ethyl acetate in hexanes.