Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[C:3]=1[CH2:11][Br:12]
Reactant: COc1cc(Br)c(C)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Br)c(CBr)c(Br)c1

Procedure:
To a suspension of 5.0 g of 2,6-dibromo-4-methoxytoluene in 90 mL of CCl4 was added N-bromosuccinimide and benzoyl peroxide. The resulting mixture was heated to reflux and stirred at the refluxing temperature while irradiating with a sunlamp for 2 h, then cooled and concentrated. The resulting residue was dissolved in 1:1 hexanes-Et2O and filtered through a pad of silica gel, then purified by flash chromatography on a Biotage 40M column, eluting with 98:2 hexanes-Et2O, to yield 2,6-Dibromo-4-methoxy-benzyl bromide as a pale yellow solid. 1H NMR (500 MHz, CDCl3): δ 7.11 (s, 2H); 4.82 (s, 2H); 3.80 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCOC(C)=O.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][C:13]([OH:15])=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)O)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (3-methoxy-4-nitrophenyl)acetic acid (2.08 g, 9.86 mmol) in 100 mL of EtOAc was added 600 mg of Pd/C under Ar, and the mixture was stirred at ambient temperature under H2 atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated to give (4-amino-3-methoxyphenyl)acetic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:12]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:19][C:18]2[CH:20]=[CH:21][C:15]([CH:12]([CH3:14])[CH3:13])=[CH:16][CH:17]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(C)c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To a 0.33 M solution of 4-(dimethylamino)benzaldehyde in THF at 0° C. was added 1.1 equiv of 4-isopropylaniline followed by 1.5 equiv of sodium triacetoxyborohydride. After allowing the reaction to warm to room temperature overnight, this mixture was poured into a separatory funnel containing aqueous NH4Cl/EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material was further purified by flash chromatography, eluting with a gradient from 100% hexanes to 10% EtOAc/hexanes to provide the title compound as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=1.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1.O>CCCCCC.O1CCCC1.C(Cl)Cl>[CH3:17][N:18]1[CH2:23][CH2:22][C:21]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)([OH:24])[CH2:20][CH2:19]1
Reactant: FC(F)(F)c1cccc(Br)c1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCC(O)(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.25 h

Procedure:
A 1.5M solution of n-butyllithium in hexane (150 mL) was added under nitrogen at -70° to a stirred solution of 50 mg of 3-bromobenzotrifluoride in 300 mL of tetrahydrofuran. The mixture was stirred at -70° for 15 min and then allowed to warm to -20°. A solution of 30 g of freshly distilled 1-methyl-4-piperidone in 50 mL of tetrahydrofuran was added slowly, keeping the temperature at -20°. The mixture was then stirred at 0° for 0.5 h, and at room temperature for 3 h. Water and methylene chloride were added and the aqueous layer was extracted several times with methylene chloride. Removal of the solvent from the combined and dried methylene chloride solutions, and short-path distillation of the residue (110°-130° bath temp., 5×10-4 mm Hg [0.07 Pa]) gave 41.6 g of 1-methyl-4-(3'-trifluoromethylphenyl)-4 -piperidinol (I: R1 =Me; R2, R3 =H; R4 =m-trifluoromethylphenyl) as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH2:32]([OH:37])[CH2:33][CH2:34][CH2:35][OH:36].C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>>[OH:36][CH2:35][CH2:34][CH2:33][CH2:32][O:37][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:29]([NH2:31])=[O:30])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Reactant: OCCCCO
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCOCCCCO)CC3)c[nH]c12
Yield: 20.4 %

Procedure:
Following the general procedure of example 159, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-phenyl-1H-indole-7-carboxamide (40.0 mg, 0.087 mmol), 1,4-butanediol (90 mg, 0.87 mmol), K2CO3 (35.0 mg, 0.35 mmol) and sodium iodide (0.5 mg) were reacted to give the title compound (9.1 mg, 20.4%).
Reaction SMILES: Cl[CH2:2][CH:3]=O.[NH2:5][C:6]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[CH:8][N:7]=1>C(#N)C>[CH3:13][C:9]1[CH:10]=[C:11]([Br:12])[C:6]2[N:7]([CH:2]=[CH:3][N:5]=2)[CH:8]=1
Reactant: Cc1cnc(N)c(Br)c1
Reactant: O=CCCl
Solvent: CC#N
Product: Cc1cc(Br)c2nccn2c1

Procedure:
Add chloroacetaldehyde (2.51 g, 32.08 mmol) to a solution of 2-amino-3-bromo-5-methylpyridine (2.0 g, 10.69 mmol) in acetonitrile (200 ml). Reflux the reaction for 4 hours and then cool. Filter the reaction mixture and partition the white solid between saturated aqueous sodium bicarbonate (300 ml) and ethyl acetate. Separate the organic layer, wash with saturated aqueous sodium bicarbonate, dry over magnesium sulfate, and concentrated under reduced pressure to give the title compound as a tan solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl[C:14]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:28])[CH:20]=2)[N:15]=1>>[OH:28][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)[C:23]([C:24]([F:27])([F:25])[F:26])=[CH:22]2
Reactant: Oc1ccc2nc(Cl)c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2nc3ccc(O)cc3cc2C(F)(F)F)cc1

Procedure:
Followed Scheme 3: starting with 4-carboxyphenylboronic acid and 2-chloro-3-(trifluoromethyl)quinolin-6-ol (Intermediate 6). 1H NMR (DMSO, 400 MHz): δ 13.10 (brs, 1H), 10.45 (brs, 1H), 8.84 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.50 (dd, J=9.2, 2.8 Hz, 1H), 7.40 (d, J=2.8 Hz, 1H). MS (ESI): m/z 333.9 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([O:31]CCCC)=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:12](=[O:36])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(F)cc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of butyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.56 g, 1 mmol) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 1N sodium hydroxide (2 ml). The obtained mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.36 g, 72.0%) as crystals.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@H:6]([C:8]([OH:10])=[O:9])[CH3:7].[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:9][C:8](=[O:10])[C@H:6]([CH3:7])[NH2:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: C[C@H](N)C(=O)O
Solvent: O=S(Cl)Cl
Product: C[C@H](N)C(=O)OCc1ccccc1
Temperature: -10 °C
Yield: 67 %

Procedure:
Thionylchloride (9.8 ml, 135 mmol, 1.2 eqv) was added dropwise during 15 min. to benzyl alcohol (210 ml) stirred under nitrogen and cooled to -10° C. Alanine (10.0 g, 112 mmol, 1.0 eqv) was added in portions during 10 min. The reaction mixture was heated overnight at 60-70° C. The reaction mixture was evaporated in vacuo and the residue was dissolved in water (150 ml). The pH was adjusted to 1-2 by addition of 4N HCl (aq.) and the aqueous phase was extracted with dichloromethane (2×200 ml). The organic phase was washed with hydrochloric acid (pH 1, 1×50 ml). The aqueous phases were collected, alkalinized (to pH 9-10) by addition of 2N NaOH (aq.) and subsequently extracted with dichloromethane (2×200 ml and 1×100 ml--alkaline extract). The alkaline extract was dried (Na2SO4), filtered and evaporated under reduced pressure affording 13.39 g (67%) of the title compound as a colorless oil. The product was characterized as its hydrochloride: The product (0.50 g, 2.8 mmol) was dissolved in ether (5 ml) and HCl in ether (2 ml) was added. The precipitate was collected by filtration and washed with ether (2×5 ml) yielding 0.57 g (95%) of white crystalline alanine benzyl ester hydrochloride. 1H-NMR (D2O/TMS): δ 1.48 (unresolved d, 3H, Me); 4.15 (unresolved q, 1H, CH); 5.20 (s, 2H, CH2); 7.38 (br s, 5H, Ph). 13C-NMR (D2O/TMS): δ 14.7 (Me); 48.4 (CH); 68.1 (CH2); 128.1, 128.5, 134.3 (Ph); 170.1 (C=O). MS(FAB+) m/z (%): 180 (100, M-HCl+H). Anal. Calcd. for C10H14ClNO2 : C, 55.69; H, 6.54; N, 6.49. Found: C, 55.60; H, 6.56; N, 6.40.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-fluorophenol: ESMS m/e: 509.1 (M+H)+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[S:12][C:11]1[C:10]([C:16]3[O:17][C:18]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][C:20](=[O:22])[CH:21]=3)=[CH:9][CH:8]=[CH:7][C:6]=1[S:5]2.F[B-](F)(F)F.[H+].N(OCCCC)=[O:36].C(OCC)C>C(O)C.O>[OH:36][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[S:12][C:11]1[C:10]([C:16]3[O:17][C:18]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:19][C:20](=[O:22])[CH:21]=3)=[CH:9][CH:8]=[CH:7][C:6]=1[S:5]2
Reactant: Nc1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Reactant: CCCCON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: O=c1cc(-c2cccc3c2Sc2ccc(O)cc2S3)oc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
To a solution of 2-(7-Amino-thianthren-1-yl)-6-morpholin-4-yl-pyran-4-one (21) (575 mg, 1.4 mmol) was suspended in ethanol (5 mL) was added tetrafluoroboric acid (54 wt % in ether, 3 ml, 1.68 mmol). The mixture was stirred at room temperature for 10 minutes before being cooled to 0° C. Butyl nitrite (220 μl, 2.8 mmol) was then added dropwise and the mixture stirred for 30 minutes before the addition of diethyl ether (40 ml) which caused a precipitate to form. The solid was collected by filtration and washed with cold diethylether (30 ml) then added to a solution of cupric nitrate trihidrate (210 g, 870 mmol) and cuprous oxide (190 mg, 1.31 mmol) in water (300 ml). The reaction was stirred for 12 hours and then filtered. The filtrant was washed with water, dried in a desiccator and used without further purification give the title compound (0.58 g, 100%). NMR (300 MHz, CDCl3): δH=10.08 (1H, bs); 7.76 (1H, dd); 7.60 (1H, dd); 7.46 (1H, dd); 7.35 (1H, dd); 7.02 (1H, d); 6.74 (1H, dd); 6.24 (1H, d); 5.55 (1H, d); 3.69 (H, m), 3.36 (4H, m); m/z (LC-MS, ESP), RT=3.83 min, (M++1)=412
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:30]([O:34][C:35](=[O:39])[CH:36](Br)[CH3:37])([CH3:33])([CH3:32])[CH3:31]>C(#N)C>[CH3:22][O:21][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:23][CH:36]([CH3:37])[C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:39])[C:10]=2[C:17]=1[CH3:18])=[O:20]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)OC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (100 mg) and Caesium carbonate (240 mg) was dissolved in acetonitrile (2 ml) and 2-bromopropionic acid tert-butylester (70 mg) was added. The reaction mixture was stirred at 60° C. for 2 h. Then the reaction was quenched with water and the precipitate was collected by filtration. The residue cake was washed with water and a few drops of methanol.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]4[O:24][CH2:25][O:26][C:18]=34)=[N:11][CH:12]=[N:13]2)=[C:8]([O:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:22]1[C:17]([NH:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:7][C:8]=3[O:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:13]=[CH:12][N:11]=2)=[C:18]2[O:26][CH2:25][O:24][C:19]2=[CH:20][CH:21]=1
Reactant: Clc1ccc2c(c1Nc1ncnc3cc(OCCCBr)cc(OC4CCOCC4)c13)OCO2
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCCCN4CCCCC4)cc(OC4CCOCC4)c13)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(3-bromopropoxy)-4-(6-chloro-2,3-methylenedioxyanilino)-5-tetrahydropyran-4-yloxyquinazoline (0.536 g), piperidine (0.12 ml), potassium carbonate (0.4 g) and DMF (2 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated and the residue was triturated under methylene chloride. The mixture was filtered and the filtrate was purified by column chromatography on silica using initially a 1:1 mixture of ethyl acetate and methylene chloride and then a 10:9:1 mixture of ethyl acetate, methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.53 g); NMR Spectrum: (CDCl3) 1.4–1.5 (m, 2H), 1.55–1.7 (m, 4H), 1.9–2.1 (m, 4H), 2.2–2.3 (m, 2H), 2.4 (m, 4H), 2.5 (m, 2H), 3.6–3.7 (m, 2H), 4.0–4.1 (m, 2H), 4.15 (m, 2H), 4.8 (m, 1H), 6.08 (s, 2H), 6.52 (d, 1H), 6.75 (d, 1H), 6.85 (d, 1H), 7.0 (d, 1H), 8.55 (s, 1H), 9.35 (s, 1H); Mass Spectrum: M+H+ 541 and 543.
Reaction SMILES: [CH2:1]1[C@@H:5]([OH:6])[C@H:4](/[CH:7]=[CH:8]/[C:9]([F:19])([F:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:3]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C@H:2]1[OH:29].C([O-])([O-])=O.[K+].[K+].I[CH:37]([CH3:39])[CH3:38].O>CN(C=O)C.C(OCC)(=O)C>[CH3:38][CH:37]([O:27][C:26]([CH2:25][CH2:24][CH2:23]/[CH:22]=[CH:21]\[CH2:20][C@@H:3]1[C@@H:4](/[CH:7]=[CH:8]/[C:9]([F:18])([F:19])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:5]([OH:6])[CH2:1][C@@H:2]1[OH:29])=[O:28])[CH3:39]
Reactant: CC(C)I
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(F)(F)COc2ccccc2)[C@H](O)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(F)(F)COc2ccccc2)[C@H](O)C[C@@H]1O
Reaction time: 2 h

Procedure:
A sample of this product was hydrolyzed using methanol and 3N NaOH. After 2 h at 25° C., the mixture was acidified and extracted with ethyl acetate. After drying-concentration of the extracts, crude 11-protected Tafluprost acid was obtained. The crude 11-protected Tafluprost acid was esterified using K2CO3 and 2-iodopropane in DMF. After 2 h at 60° C., water and ethyl acetate were added and phase separated, the aqueous layer was extracted with ethyl acetate. After drying-concentration of the extracts, crude 11-protected Tafluprost was obtained. The crude 11-protected Tafluprost was deprotected using 3N HCl in THF and water. After 1 h at 25° C., saturated aqueous solution of sodium bicarbonate was added and phase separated, the aqueous layer was extracted with ethyl acetate. After drying-concentration of the extracts, crude Tafluprost was obtained. HPLC (Phenomenex Luna 5 μm silica) analysis of the crude product showed that 0.4% 5,6-trans isomer was found and HPLC (Chiralcel OD-H) analysis of the crude product showed that 0.1% enantiomer was found.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:30])[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)[CH2:12][CH2:11]2.[ClH:31]>CO>[ClH:31].[ClH:31].[NH:20]1[CH2:21][CH2:22][CH:17]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([NH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[NH:30])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(NC(=N)c4cccs4)ccc32)CC1
Agent: Cl
Solvent: CO
Product: N=C(Nc1ccc2c(c1)CCN2C1CCNCC1)c1cccs1
Yield: 84 %

Procedure:
A solution of compound 6 (0.23 g, 0.539 mmol) in methanol (10 mL) was treated with 1 N HCl solution (10 mL) and the resulting mixture was refluxed for 30 min. The reaction was brought to room temperature and solvent was evaporated. The crude was dissolved into water (10 mL), filtered and washed with water (2×5 mL). The combined water layer was evaporated to obtain compound 54 (0.18 g, 84%) as dihydrochloride salt. 1H NMR (DMSO-d6) δ 11.21 (s, 1H), 9.64 (s, 1H), 9.20-9.04 (m, 2H), 8.60 (s, 1H), 8.15-8.12 (m, 2H), 7.36 (t, 1H, J=4.5 Hz), 7.11-7.03 (m, 2H), 6.66 (d, 1H, J=8.4 Hz), 3.86-3.74 (m, 1H), 3.44-3.32 (m, 4H), 3.06-2.92 (m, 4H), 1.98-1.78 (m, 4H); ESI-MS (m/z, %) 327 (MH+, 100), 244 (81); ESI-HRMS calculated for C18H23N4S (MH+), calculated: 327.1637; observed: 327.1636; HPLC purity: 98.86% by area.
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[C:9]([CH3:15])[N:8]=1)=O.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[OH:5][CH2:6][C:7]1[CH:12]=[C:11]([CH:10]=[C:9]([CH3:15])[N:8]=1)[C:13]#[N:14]
Reactant: Cc1cc(C#N)cc(COC(=O)C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(CO)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a stirring solution of 1.20 g of (4-cyano-6-methylpyridin-2-yl)methyl 2,2,2-trifluoroacetate in 7 mL of THF was added 7% NaHCO3 (aqueous) solution to pH=8. The mixture was stirred at r.t. for 18 h, and EtOAc was added. The aqueous layer was extracted with EtOAc, and the combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (1 to 6) % MeOH/CHCl3 provided 535 mg of 2-(hydroxymethyl)-6-methylisonicotinonitrile in 73% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@:4]([CH3:16])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH-].[K+]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:17])[C@@:4]([CH3:16])([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)[C@@](C)(N)Cc1c[nH]c2ccccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)[C@](C)(N)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 13099.4 %

Procedure:
To a suspension of (±)-α-methyltryptophan methyl ester (79.5 mg, 0.342 mmol) in 30 mL of 50 mM sodium phosphate buffer pH 7.5 was added carboxypeptidase W (3.0 mg of solid). The resulting suspension was stirred at ambient temperature. After 6.5 h, 56% conversion was observed by HPLC (C18 column, 280 nm detection, amino acid tR =8.2 min and amino ester tR =11.1 min). The reaction was adjusted to pH 12 by the addition of 2 N KOH and then extracted with 1×15 and 1×20 mL ethyl acetate. The combined extracts were treated with brine, dried with magnesium sulfate, then concentrated in vacuo to yield (R)-α-methyltryptophan methyl ester (10.4 mg, 44.8 mmol, 13.1%). The enantiomeric excess of the unreacted amino ester was determined by chiral HPLC (Uttron ES-OVM column from Shinwa Chemical Industries, Ltd., 280 nm, (R)-enantiomer tR =13.7 min and (S)-enantiomer tR =18.8 min) to be 89.9% (r)-enantiomer.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([S:19][CH2:20][C:21](O)=[O:22])[CH2:16][CH2:17][CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:21](=[O:22])[CH2:20][S:19][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=1
Reactant: c1cncc(CNC2CCCCC2)c1
Reactant: CCCCSCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCSCC(=O)N(Cc1cccnc1)C1CCCCC1

Procedure:
N-[(3-pyridyl)methyl]-N-cyclohexyl-α-(n-butylthio)acetamide was prepared by the method of Example 2 by reacting 9.5 g. of N-cyclohexyl-[(3-pyridyl)methyl]amine with 7.4 g. of α-(n-butylthio)acetic acid and 9.0 g. of N,N'-dicyclohexylcarbodiimide in 150 ml of toluene. Weight 3.5 g. as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[F:13].C([NH2:16])=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][C:12]=1[F:13])[C:6](=[O:7])[NH:16][C:9]2=[O:8]
Reactant: NC=O
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Product: O=C1NC(=O)c2cc(F)c(F)cc21

Procedure:
At 130° C., 1.0 g (5.4 mmol) of 4,5-difluorophthalic anhydride was stirred in 6 ml of formamide for 2 h. After cooling, the reaction mixture was then added to ice-cold water. The precipitated yellow solid was filtered off with suction, washed thoroughly with cold water and dried under high vacuum. This gave 744 mg of a white solid (74.8% of theory).