Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.Cl.[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[SH:29].[Cl:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[C:33]([Cl:40])[C:32]=1[CH2:41][C:42](O)=O>>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]2[S:29][C:42]([CH2:41][C:32]3[C:33]([Cl:40])=[CH:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][C:31]=3[Cl:30])=[N:21][C:22]=2[CH:27]=1
Reactant: O=C(O)Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: Nc1cc(Cl)ccc1S
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=[N+]([O-])c1cc(Cl)c(Cc2nc3cc(Cl)ccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
By a modification of the procedure of D. L. Boger (J. Org. Chem. 43, 2296–2297 (1978) a solution of P2O5/MeSO3H (Aldrich, 7.5 g, 1:10, w:w) was treated with 2-amino-4-chloro-benzenethiol hydrochloride (example 112, 1.96 g, 10.0 mmol) and (2,6-dichloro-4-nitro-phenyl)-acetic acid (example 110, 2.50 g, 10.0 mmol). The resulting mixture was stirred at room temperature for 1 hour, then heated at 90° C. overnight (15 hours). After cooled to room temperature, the reaction mixture was poured to ice and the resulting mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (CH2C12) to yield 3.7 g (99%) of compound 114 as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([O-:14])=[O:13]>[OH-].[Na+]>[N+:12]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:23])=[O:22])=[CH:19][CH:20]=1)([O-:14])=[O:13]
Reactant: NCCCCCCCC(=O)O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 8-aminooctanoic acid in 10% sodium hydroxide solution was treated with 4-nitrobenzenesulphonyl chloride in the manner of Example 2 to give the title compound which, on recrystallisation from aqueous ethanol, had a melting point of 126°-7° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH3:29][C:30]1[CH:39]=[CH:38][C:33]2[N:34]=[C:35]([NH2:37])[S:36][C:32]=2[CH:31]=1>>[CH3:26][C:23]1[C:22]([CH2:27][NH:37][C:35]2[S:36][C:32]3[CH:31]=[C:30]([CH3:29])[CH:39]=[CH:38][C:33]=3[N:34]=2)=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:6]4([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]4)=[CH:10][CH:11]=3)=[CH:20][CH:19]=2)[O:25][N:24]=1
Reactant: Cc1ccc2nc(N)sc2c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: Cc1ccc2nc(NCc3c(C)noc3-c3ccc(-c4ccc(C5(C(=O)O)CC5)cc4)cc3)sc2c1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 6-methyl-benzothiazol-2-ylamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]O>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Reactant: CN(C)CCO
Product: CN(C)CCOc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccccc3)nc12

Procedure:
This was similarly prepared from 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide and 2-(dimethylamino)ethanol. MS (ESI) m/z 375.1 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.25-8.33 (1H, m), 8.16 (1H, s), 8.08-8.13 (2H, m), 7.53 (2H, t, J=7.78 Hz), 7.44 (1H, t, J=7.32 Hz), 7.20 (1H, d, J=2.14 Hz), 6.98 (1H, dd, J=8.85, 2.14 Hz), 4.30 (2H, t, J=5.34 Hz), 3.01 (2H, t, J=5.34 Hz), 2.52 (6H, s).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH:6]([C:11]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=O)[CH2:5]1)(=[O:3])[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[NH:22][N:23]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)N1CCC(=O)C(C(=O)c2cccc(C#N)c2)C1
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCc2[nH]nc(-c3cccc(C#N)c3)c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a mixture of 3-(1-Acetyl-4-oxo-piperidine-3-carbonyl)-benzonitrile (2a) (8 g, 29.6 mmol) in ethanol (26 ml) at 10° C. hydrazine hydrate (4.44 g, 88.8 mmol) was added slowly within 5 min. The mixture was stirred 3 h and allowed to warm to room temperature overnight. The mixture was concentrated to ¼ of its volume until a precipitate formed. The suspension was stirred for 2 h, cooled down and filtrated. The solid was washed with a small amount of ethanol. A second portion of product precipitated overnight from the filtrate and was pooled with the first portion of solid to give 4.02 g of 3-(5-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile (3a) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:13](=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S.CI.[N:30]1C=CC=CC=1>CCN(CC)CC>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24](=[NH:30])[NH2:25])=[CH:22][CH:23]=2)[C:13](=[O:26])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: N#Cc1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Agent: S
Solvent: CCN(CC)CC
Solvent: CI
Product: N=C(N)c1ccc(CN2CCN(C(=O)OCc3ccccc3)CC2=O)cc1
Reaction time: 16 h

Procedure:
A solution of 4-(4-cyanobenzyl)-3-oxopiperazine-1-carboxylic acid benzyl ester (2.4 g, 6.87 mmol) in 30 mL of pyridine and 3 ml of Et3N is saturated with H2S. The resulting mixture is sealed and stirred for 16 hours. After this time, the solution is concentrated. The residue is dissolved in 30 mL of acetone and methyl iodide (19.4 g, 137 mmol) is added. The solution is refluxed for 2 hours. After this time, the solution is concentrated. The residue is dissolved in MeOH (40 mL) and NH4OAc (5.0 g, 65 mol) is added. The solution is reluxed for 3 hours. After this time, the solution is concentrated. The crude product is purified by RP-HPLC eluting in a gradient of CH3CN to 60% CH3CN/H2O(0.1%TFA). The appropriate collected fractions are lyophilized to give the product as a white foam. MS (FAB) m/z 367, (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(Cl)Cl>CN(C=O)C>[CH2:30]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([O:8][CH3:7])=[O:17])=[CH:11][CH:12]=1)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccc(C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a thoroughly degassed suspension of K2CO3 (127 g, 921 mmol) in DMF (600 mL) was added methyl-4-hydroxybenzoate (70 g, 461 mmol) and the mixture heated to 70° C. after which was added bromododecane (126 g, 507 mmol) and the reaction allowed to stir at 70° C. under argon for 3 hours, after which TLC (CH2Cl2) showed completion. Reaction was cooled to room temperature and precipitated into cold water. The precipitate was collected by suction filtration and purified by re-crystallization from acetone to give the title compound (140 g, 95%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[CH2:34]([O:36][CH2:37]Cl)[CH3:35].Cl>C1COCC1>[CH2:34]([O:36][CH2:37][N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:18]([F:20])([F:21])[F:19])[C:14]([F:17])([F:16])[F:15])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[CH3:35]
Reactant: COC(c1ccc(NC(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Reactant: CCOCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCN(C(=O)c1nccnc1C)c1ccc(C(OC)(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Sodium hydride (32 mg, 60% by weight, 0.8 mmol) was suspended in THF (10 ml) and a THF (5 ml) solution of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]phenyl}-3-methylpyrazine-2-carboxamide (300 mg, 0.67 mmol) was added dropwise thereto. The reaction solution was stirred at room temperature for 30 minutes, and was added with a THF (2 ml) solution of chloromethyl ethyl ether (76 mg, 0.8 mmol) and stirred for 5 hours. The reaction solution was poured into a diluted HCl solution, followed by extracting with ethyl acetate, and washing with water. The solution was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 0.24 g of the desired compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([F:23])[CH:15]=2)[CH2:10][CH:9]1[CH2:24][OH:25])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:23][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=1)[O:13][CH:11]1[CH2:12][NH:8][CH:9]([CH2:24][OH:25])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(F)cc(OC2CNC(CO)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To 2.0 g of 4-(3-fluoro-5-nitro-phenoxy)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6) in 5 mL of dichloromethane was added 10 mL of TFA. The mixture was stirred for 0.5 hours at room temperature and then solvents were removed in vacuo. The resulting residue was dissolved in 50 mL of EtOAc and washed with aq. NaOH (3×25 mL) and brine (25 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give 1.29 g (90%) of [4-(3-fluoro-5-nitro-phenoxy)-pyrrolidin-2-yl]-methanol as a thick yellow oil, which was used directly in the following reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:16])=[C:13]([OH:15])[CH:14]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>CC(C)=O>[Cl:16][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][N:5]=2)=[CH:14][C:13]=1[O:15][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]
Reactant: CC(C)=CCBr
Reactant: Nc1ccnc(Nc2ccc(Cl)c(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)=CCOc1cc(Nc2nccc(N)n2)ccc1Cl
Yield: 43 %

Procedure:
Following the general procedure for O-alkylation of 2-R-5-(heteroaryl-2-ylamino)phenol, 5-(4-aminopyrimidin-2-ylamino)-2-chlorophenol (56 mg, 0.24 mmol) and Cs2CO3 (77 mg, 0.24 mmol) in acetone (3.0 mL) was treated with 4-bromo-2-methyl-2-butene (27 μL, 0.24 mmol) at room temperature. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 43% yield (31 mg).
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][O:29]C=O)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.CO>O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][OH:29])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCCOC=O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCCO)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.3 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-formyloxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.), conc. hydrochloric acid (1.8 ml.), methanol (15 ml.) and tetrahydrofuran (15 ml.) was stirred at room temperature for 5 hours. After removing the solvent in vacuo, water was added to the residue and adjusted to pH 4.0 with an aqueous solution of sodium bicarbonate. The solution was subjected to column chromatography on nonionic adsorption resin "Diaion HP-20" (trademark, manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 20% isopropyl alcohol. The eluate was concentrated in vacuo and the residue was lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(2-hydroxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.56 g.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].I[CH2:20][CH:21]([CH3:23])[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O.O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18])[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CI
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Temperature: 70 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
A mixture of (R/S) 5-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (200 mg, 0.81 mmol, 1.00 equiv), 1-iodo-2-methylpropane (300 mg, 1.63 mmol, 2.01 equiv) and Cs2CO3 (270 mg, 0.83 mmol, 1.02 equiv) in N,N-dimethylformamide (10 mL) was stirred under nitrogen at 70° C. for 5 h. The resulting solution was cooled to room temperature and diluted with 10 mL of H2O. The mixture was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-15% of ethyl acetate in petroleum ether to give 0.165 g (67%) of (R/S) 5-iso-butoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a white solid. 1H-NMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.83 (d, J=9.3 Hz, 1H), 7.51 (d, J=2.1 Hz, 1H), 7.22 (dd, J=9.3 Hz, 2.4 Hz, 1H), 6.04-6.01 (m, 1H), 4.07-4.00 (m, 1H), 3.92-3.75 (m, 4H), 2.12-2.00 (m, 2H), 1.63-1.62 (m, 2H), 1.24-1.16 (m, 2H), 1.04 (d, J=6.6 Hz, 6H) ppm. LCMS (method A, ESI): RT=1.71 min, m/z=218.9 [M+H−THP]+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:22][CH2:23][OH:24])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=2[N:21]=1.[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.C(Br)C=CC1C=CC=CC=1>[CH3:3][C:4]1[N:5]([CH2:22][CH2:23][O:24][CH2:25]/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:7]=2[N:21]=1
Reactant: BrCC=Cc1ccccc1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCO)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOC/C=C/c3ccccc3)c2c1C
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
Sodium hydride (0.41 g, 10.24 mmol, 60% in mineral oil) and anhydrous N,N-dimethylformamide (10 mL) were combined and stirred for 5 minutes under nitrogen. A solution of 1-[2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]ethan-2-ol (2.9 g, 9.752 mmol) from Part G of Example 7 in N,N-dimethylformamide (15 mL) was then added to the sodium hydride over 5 minutes. After stirring the resulting reaction solution for 10 minutes at room temperature, a solution of cinnamyl bromide (2.11 g, 10.73 mmol) in N,N-dimethylformamide (15 mL) was added to the reaction solution, and the resulting reaction mixture was stirred for 4 hours and 10 minutes. Sodium hydride (0.10 g, 60% in mineral oil) and then cinnamyl bromide (0.1 g) were added to the reaction mixture, and after stirring for 30 minutes, HPLC monitoring of the reaction mixture indicated about 9% starting material remaining. The reaction mixture was concentrated under reduced pressure, and the resulting oil was dissolved in dichloromethane. The dichloromethane solution was washed with saturated ammonium chloride (3×), water (3×), and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a white solid, which contained about 6% starting material by HPLC analysis. The white solid was passed through a column of silica (120 g, 40×200 mm) using 95/5 ethyl acetate/dichloromethane. The isolated product was triturated with diethyl ether, filtered off, and dried to provide 2.9 g of product with no starting material. This was carried on to the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([CH:15](C#N)[C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])[C:12]([CH2:27][CH3:28])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C=[O:43])C>>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([C:15]([C:16]2[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=2)[C:19]#[N:20])=[O:43])[C:12]([CH2:27][CH3:28])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CCc1c(OCc2ccccc2)nc(OCc2ccccc2)nc1C(C#N)c1cc(C)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Product: CCc1c(OCc2ccccc2)nc(OCc2ccccc2)nc1C(=O)c1cc(C)cc(C#N)c1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of 3-[(2,6-Bis-benzyloxy-5-ethyl-pyrimidin-4-yl)-cyano-methyl]-5-methyl-benzonitrile (40) (10 g, 21.1 mmol) in anhydrous DMF (80 ml) in a water bath under an atmosphere of nitrogen, was portionwise added 60% sodium hydride (869 mg, 21.7 mmol). After 30 min, oxygen gas was bubbled into the reaction mixture for 5 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution. The crude product was extracted with ether and recrystallized from dichloromethane-hexane to afford 8 g (80%) of a white solid; m.p. 123-124° C.; 1H NMR (200 MHz, CDCl3) δ: 1.09 (3H, t, J=7.4 Hz), 2.43 (3H, s), 2.50 (2H, q, J=7.4 Hz), 5.35 (2H, s), 5.50 (2H, s), 7.27-7.46 (10H, m), 7.67 (1H, s), 7.87 (1H, s), 7.92 (1H, s); m/z (EI): 463 (M+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)=[O:14].[CH2:27](N(CC)CC)C.ClC(OC)=O>ClCCl.O>[CH3:27][O:24][C:23](=[O:25])[C:22](=[O:26])[C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:17][CH:18]=1
Reactant: O=C(COc1ccc2ccccc2c1)Nc1ccc(C(=O)C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(=O)c1ccc(NC(=O)COc2ccc3ccccc3c2)cc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
A mixture of 4-[[2-(2-naphthalenyloxy)acetyl]amino]-alpha-oxobenzeneacetic acid (3.0 g) in dichloromethane (50 mL) and triethylamine (2.1 g ) was stirred at 0° C. and treated with methyl chloroformate (1.16 mL). The mixture was stirred for one hour and diluted with water, extracted with dichloromethane, dried (Na2SO4), filtered and evaporated. The residue was crystallized from dichloromethane-hexane to give 2.2 g of 4-[[2-(2-naphthalenyloxy) acetyl]amino]-alpha-oxobenzeneacetic acid methyl ester, mp 175°-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10](OS(OCC)(=O)=O)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(F)c(Cl)c1

Procedure:
A mixture of 3-chloro-4-fluorophenol (2.0 g, 13.7 mmol), diethylsulfate (1.58 mL, 17.8 mmol) and K2CO3 (9.4 g, 68.5 mmol) in acetone (20 mL) was heated under refluxed for 3 h. The reaction mixture was filtered and concentrated. The residue was diluted with ethyl acetate (50 mL), washed with water (30 mL) and brine. The organic layer was dried (Na2SO4) and concentrated to give the title compound as a liquid. 1H NMR (CDCl3, 400 MHz): δ=1.39 (t, 3H, J=7.2 Hz), 3.97 (q, 2H, J=7.2 Hz), 6.71-6.74 (m, 1H), 6.89-6.91 (m, 1H), 7.02 (t, 1H, J=8.8 Hz).
Reaction SMILES: C([Si](CC)(CC)[O:4][C@@H:5]1[CH2:9][C@H:8]([O:10][Si](CC)(CC)CC)[C@H:7]([CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C@H:6]1/[CH:30]=[CH:31]/[C@@H:32]([O:45][Si](CC)(CC)CC)[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=1)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:4][C@@H:5]1[CH2:9][C@H:8]([OH:10])[C@H:7]([CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[C@H:6]1/[CH:30]=[CH:31]/[C@@H:32]([OH:45])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=1
Reactant: CC[Si](CC)(CC)O[C@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O[Si](CC)(CC)CC)C[C@H]1O[Si](CC)(CC)CC)COc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)COc2cccc(C(F)(F)F)c2)[C@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
The product of Example 11 (0.8 g) was dissolved in 10 ml acetone and 2 ml water, followed by addition of 0.1 g p-toluenesulfonic acid monohydrate. The reaction solution was stirred at room temperature for 1 hour and concentrated until two separate layers were observed. 30 ml ethyl acetate was added for extraction and phase separation. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and subjected to vacuum evaporation for removal of the solvent until dryness. The crude Travoprost was purified by column chromatography and then concentrated under reduced pressure to provide 0.44 g of Travoprost. UPLC (ACQUITY UPLC HSS C18) analysis of the product showed that no isomer and impurities were detectable and the purity was higher then 99.9%.
Reaction SMILES: [H-].[Na+].[C:3]([O:12]C)(=O)[CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[C:17]1([C:14](=[O:16])[CH2:15][C:3]([CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:12])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CCCC(C)(C)C
Reactant: CC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(C)(C)CCCC(=O)CC(=O)c1ccccc1
Temperature: 135 °C
Yield: 51.9 %

Procedure:
A 500 mL 4 neck round bottom flask equipped with mechanical stirring, a nitrogen inlet, a thermometer, a condenser, and an addition funnel was charged with 60% sodium hydride in mineral oil (20.5 g, 0.51 mol), methyl neo-octanoate (92.3 g, 0.58 mol), and xylene (42.8 g). The mixture was heated to reflux (135° C.), and then a solution of acetophenone (32.4 g, 0.27 mol) in xylene (19.1 g) was added over 1.25 h. The mixture was kept at reflux for an additional 1 h. After cooling to room temperature, the reaction was quenched by the careful addition of methanol (20 mL), and then acidified with 150 g/L sulfuric acid (180 mL). After separation of layers, the organic phase was washed with water (2×100 mL) and brine (100 mL). After drying by passing through anhydrous sodium sulfate, the solution was concentrated in vacuo at 70° C. down to 12 mbar to yield an orange liquid containing product in a crude yield of 63%. Vacuum distillation (200 mtorr) through a 15 cm Vigreux column yielded the product in the heart cut: 1-phenyl-3-neoheptyl-1,3-propanedione (37.2 g, 96% pure, 0.14 mol; 53% yield; bp: 94-135° C.). Dypnone was undetectable in the product.