Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:12].[Cl:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl>C(O)CCC>[ClH:13].[ClH:12].[C:2]1([N:1]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCCNCCCl
Reactant: Nc1cccc2c1CCCC2
Agent: Cl
Solvent: CCCCO
Product: c1cc2c(c(N3CCNCC3)c1)CCCC2
Temperature: 20 °C

Procedure:
A mixture of 1-amino-5,6,7,8-tetrahydronaphthalene (2.44 g, 16.60 mmol) and bis-(2-chloroethyl)amine hydrochloride (2.69 g, 15.09 mmol) in n-butanol (15 mL) was heated at reflux under nitrogen for 3 d. The reaction was cooled to 20° C. The white precipitate was collected by filtration and washed with n-butanol, then dried under vacuum. The title compound was obtained as a white solid (1.64 g). NMR (300 MHz, CD3OD) δ 7.1 (1H, t, J=8 Hz), 6.9 (1H, d, J=8 Hz), 6.15 (1H, d, J=8 Hz), 3.35 (4H, m), 3.1 (4H, m), 2.75 (4H, m), 1.8 (4m).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10](O)=[O:11].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[CH2:10][OH:11]
Reactant: Nc1cccc(F)c1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1cccc(F)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
LAH (987 mg, 26 mmol) was added slowly to a solution of 2-amino-6-fluoro-benzoic acid (2.69 g, 17.3 mmol) in dry THF (20 mL) at 0° C. The mixture was stirred at room temperature for approximately 1 hr and cooled to 0° C. again. Na2SO4. 10H2O (10 g) was added slowly with stirring for 20 minutes. The mixture was filtered, the solid was washed with THF. The solution was concentrated to yield a yellow solid as (2-amino-6-fluoro-phenyl)-methanol (2.49 g). MS [M−OH]+: 124.1; tR=0.57 min. (method 1)
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][N:13]2[C:22](=[O:23])[C:21]3[N:20]([CH2:24][C:25]#[C:26][CH3:27])[C:19]([N:28]4[CH2:33][CH2:32][CH2:31][C@@H:30]([N:34]5C(=O)C6=CC(C)=CC=C6C5=O)[CH2:29]4)=[N:18][C:17]=3[N:16]([CH3:46])[C:14]2=[O:15])[N:3]=1.C(CN)O>O>[CH3:27][C:26]#[C:25][CH2:24][N:20]1[C:19]([N:28]2[CH2:29][C@H:30]([NH2:34])[CH2:31][CH2:32][CH2:33]2)=[N:18][C:17]2[N:16]([CH3:46])[C:14]([N:13]([CH2:12][C:4]3[N:3]=[C:2]([CH3:1])[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=3)[C:22](=[O:23])[C:21]1=2)=[O:15]
Reactant: CC#CCn1c(N2CCC[C@@H](N3C(=O)c4ccc(C)cc4C3=O)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Solvent: O
Solvent: NCCO
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 95 °C

Procedure:
In a clean round bottom flask, 10.0 gms of 1[(4-Methylquinazolin-2yl) methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-4-methyl phthalimidopiperidine-yl)-xanthine and 50 ml ethanolamine were charged. The reaction mass was heated to 90-100° C. for 1 hr and cooled to room temperature. 100 ml water was added and the solid was filtered. 150 ml of toluene was added and completely distilled out under vacuum at 45-50° C. to get pale yellow solid. Dry wt: 6.0 gm.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C@H:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:4]=1[C:28](OCC)=[O:29].[C:33]1([NH:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1>[O:19]=[C:7]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:3]2[CH2:2][N:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:40][C:28](=[O:29])[C:4]=2[C@@H:5]([C:20]2[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=2)[NH:6]1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc([C@H]2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)NN(c2ccccc2)C3)cc1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
80 mg (0.16 mmol) of ethyl (4R)-6-(bromomethyl)-4-(4-cyanophenyl)-2-oxo-1-[3-(tri-fluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 6A) were dissolved in 2 ml of dioxane, 51 mg (0.47 mmol) of phenylhydrazine were added and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was then concentrated, and the residue that remained was purified by preparative HPLC (Method 10). The product fractions were combined and concentrated, and the solid that remained was dried under reduced pressure (Yield: 24.0 mg, 31% of theory).
Reaction SMILES: [Si]([O:8][CH2:9][C@@:10]1([C:26]#[C:27][Si](CC)(CC)CC)[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[C:22]([F:25])[N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[C:26]([C@:10]1([CH2:9][OH:8])[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[C:22]([F:25])[N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[CH:16]2)[CH2:12][CH2:11]1)#[CH:27]
Reactant: CC[Si](C#C[C@@]1(CO[Si](C)(C)C(C)(C)C)CC[C@H](n2cnc3c(N)nc(F)nc32)O1)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#C[C@@]1(CO)CC[C@H](n2cnc3c(N)nc(F)nc32)O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound 22 (101 mg, 0.200 mmol) was dissolved in tetrahydrofuran (10 ml), and a solution of 1-M tetrabutylammonium fluoride in tetrahydrofuran (0.42 ml, 0.42 mmol) was added to the resultant solution, followed by stirring at room temperature for five minutes. After acetic acid (24 μl) was added to the resultant reaction mixture, the resultant mixture was concentrated under reduced pressure. The thus-obtained residue was purified by means of silica gel column chromatography (silica gel 15 ml, chloroform methanol=40:1 to 20:1), to thereby yield compound 23 (53.0 mg, 0.191 mmol, 95.7%).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([O:15][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(O)cc1
Reactant: CC(C)(C)N1C(=O)C(NCC(=O)O)=C(c2ccccc2)S1(=O)=O
Product: COc1ccc(OC(=O)CNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Yield: 21 %

Procedure:
The title compound was prepared from [(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]acetic acid and 4-methoxyphenol as described for Example 171 affording the title compound (28 mg, 21%). 1H NMR (CDCl3, 400 MHz) δ 1.71 (s, 9H), 3.77 (s, 3H), 3.81 (d, 2H), 5.78 (t, 1H), 6.85 (dd, 4H), 7.44-7.51 (m, 5H). 13C NMR (CDCl3, 100 MHz) δ 27.8, 45.6, 55.8, 61.9, 110.1, 114.7, 122.0, 124.5, 129.1, 130.2, 131.6, 134.8, 143.6, 157.8, 159.2, 167.8.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1[CH:28]=O.O>O1CCCC1>[F:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cn1cc2c(C=O)c(F)ccc2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1c(F)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a suspension of sodium hydride (0.88 g, 21.9 mmol) in tetrahydrofuran (20 mL) was added a solution of ethyl diethylphosphonoacetate (4.38 mL, 21.9 mmol) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 5-fluoro-2-methyl-2H-indazole-4-carbaldehyde (3.0 g, 16.8 mmol) in tetrahydrofuran (8.7 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (4.10 g, yield 98%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][OH:8].[H-].[Na+].[S:16](Cl)(=[O:19])(=[O:18])[NH2:17]>CN(C=O)C>[S:16](=[O:19])(=[O:18])([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[NH2:17]
Reactant: NS(=O)(=O)Cl
Reactant: COc1ccc(CCO)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCOS(N)(=O)=O)cc1OC
Yield: 13.5 %

Procedure:
A mixture of 5.0 g (0.027 mole) of 3,4-dimethoxy phenethyl alcohol in 12 ml DMF was added dropwise to a suspension of sodium hydride (1.20 g, 60% in oil; 0.09 mole) in 40 ml DMF at 0°-5° C. The suspension was stirred for 20 min under argon after which sulfamoyl chloride (3.54 g, 0.03 mole) was added portionwise at 0°-5° C. After stirring for 20 min the resultant suspension was poured into ice and extracted twice with Et2O. The combined organic phases were washed with saturated brine, dried over potassium carbonate and concentrated in vacuo to a white solid which was recrystallized in EtOAc/hexane to give 0.95 g (13%) of the title compound as a solid, mp 106°-108° C. Both 13C and 1H NMR in CDCl3 confirmed the structure.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([OH:14])=O)[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[CH:25]1([C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:29])[CH2:27][CH2:26]1>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([N:33]3[CH2:34][CH2:35][N:30]([C:28]([CH:25]4[CH2:26][CH2:27]4)=[O:29])[CH2:31][CH2:32]3)=[O:14])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:17][CH2:18][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:20][CH2:21]1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(C(=O)C5CC5)CC4)[nH]c3cc2Br)CC1
Yield: 48 %

Procedure:
The title compound was synthesized in analogy to example 1, from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate a) and 1-(cyclopropanecarbonyl)piperazine to afford the title compound as a light-yellow foam (48%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]([OH:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]([O:11][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OS(C)(=O)=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a solution of tert-butyl (2S,3R)-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (0.44 g, 1.62 mmol) in dry CH2Cl2 (10 mL) was added Et3N (0.71 g, 7 mmol, 4 eq) at 0 to −5° C. A solution of methanesulfonyl chloride (0.8 g, 7 mmol, 2 eq) in dry CH2Cl2 (5 mL) was added dropwise at the same temperature. The mixture was allowed to warm to rt gradually. TLC showed that the starting material had disappeared. Water (30 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers was washed with 10% aq citric acid, satd aq NaHCO3 and brine, then dried over Na2SO4, filtered and concentrated to give tert-butyl (2S,3R)-1-cyclohexyl-3-(methanesulfonyloxy)butan-2-yl-carbamate (0.46 g, 81%), which was used in the next step without purification.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C@H:15](O)([C:21]([O-])=O)[C@@H:16]([OH:20])[C:17]([O-])=[O:18].[Na+].[K+].[OH-].[Na+]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:7]([NH:14][CH:15]([CH3:21])[CH:16]([OH:20])[CH2:17][OH:18])([C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(NC(c1ccccc1)c1ccccc1)C(O)CO
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(methyloxiran-2-yl)methanol (0.826 g, 9.38 mmol) in DCM was added α-aminodiphenylmethane (1.50 mL, 8.44 mmol) and titanium(IV) isopropoxide (5.5 mL, 18.7 mmol), and the reaction mixture was heated at 60° C. for 16 h. A saturated aqueous solution of Rochelle's salt was added to the mixture followed by a solution of 3 N NaOH. The reaction miture was stirred overnight. The aqueous phase was then extracted with DCM (3×). The combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via FCC (30-60% EtOAc/heptanes) to give the title compound. MS (ESI+) m/z 272.4 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CO>[CH2:11]([NH:18][C:8]([C@H:5]1[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:7][CH2:6]1)=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: NCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccccc1)[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of cis-4-hydroxycyclohexanecarboxylic acid (1.0 g, 6.94 mmol), benzylamine (0.82 mL, 7.51 mmol) and HOAt (1.0 g, 7.35 mmol) in dichloromethane (50 mL) was added EDC free base (1.2 g, 7.73 mmol). The reaction was stirred overnight at room temperature, at which time it was washed with 1 N HCl, 1 N Na2CO3, brine, dried (MgSO4), filtered and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-80 g, 0 to 4% MeOH in CH2Cl2) gave (cis)-N -benzyl-4-hydroxycyclohexanecarboxamide (1.0 g, 4.29 mmol, 61.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (t, J=5.81Hz, 1H), 7.26-7.38 (m, 2H), 7.11-7.27 (m, 3H), 4.31 (d, J=3.28 Hz, 1H), 4.25 (d, J=6.06 Hz, 2H), 3.76 (d, J=2.53 Hz, 1H), 2.08-2.22 (m, 1H), 1.73-1.89 (m, 2H), 1.56-1.69 (m, 2H), 1.33-1.49 (m, 4H). MS(ES) [M+H]+ 234.0.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[CH2:28](O)[CH3:29]>S(=O)(=O)(O)O.C1C=CC=CC=1>[C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH:9]=[CH:8][CH:7]=2)([O:3][CH2:28][CH3:29])=[O:2]
Reactant: CCO
Reactant: Cc1ccccc1OCC(O)COc1cccc2oc(C(=O)O)cc(=O)c12
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3ccccc3C)cccc2o1

Procedure:
A mixture of 1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-o-cresyloxypropane (10.0 g), ethyl alcohol (5 ml), benzene (100 ml) and concentrated sulphuric acid (5 drops) were heated together under a Dean and Stark trap for 18 hours. After cooling, the solution was washed successively with sodium bicarbonate solution and water. Removal of the benzene afforded a viscous oil nucleated with crystals. Recrystallization of the crude product from aqueous dioxane gave 1-(2-carbethoxychromon-5-yloxy)-2-hydroxy-3-o-cresyloxypropane (8.75 g), m.p. 75°-76° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[C:7]([F:25])[CH:6]=1.[OH-].[Na+]>CO.O1CCCC1.O>[F:25][C:7]1[CH:6]=[C:5]([C:4](=[O:26])[C:3]([OH:27])=[O:2])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)c(F)c1
Yield: 87.3 %

Procedure:
A solution of 3-fluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (10 mL) and tetrahydrofuran (10 mL) was treated with 1N sodium hydroxide (2 mL) and after 10 minutes the mixture was diluted with water and concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.42 g of purified 3-fluoro-4-[2-(2-naphthalenyloxy)ethoxy]-alpha-oxobenzeneacetic acid as a yellow solid, mp 168°-169° C.
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[O:69][CH:70]([CH3:72])[CH3:71].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].CC(OC(C)C)C>C(O)CCC>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=2)([CH:45]2[CH2:46][CH2:47][N:48]([CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=3[O:69][CH:70]([CH3:71])[CH3:72])[CH2:49][CH2:50]2)[OH:44])=[CH:39][CH:38]=1
Reactant: CC(C)Oc1ccccc1OCCCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)OC(C)C
Solvent: CCCCO
Product: CC(C)Oc1ccccc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 58.5 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 g (0.01 mole) of [α,α-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.3 g (0.01 mole) of 1-chloro-3-[2-(1-methylethoxy)phenoxy]propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 2.9 g (58%) of the title compound as a fluffy, white solid, mp 75°-79° C. (2-propyl ether).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:51]([O:58][C:59](=[O:69])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH2:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>CN(C=O)C>[CH2:51]([O:58][C:59](=[O:69])[C@H:60]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:61][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:16])=[CH:6][CH:5]=1)(=[O:8])=[O:9])[C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40.3 %

Procedure:
To N-(toluene-4-sulfonyl)-L-alanine (2.0 mmoles) in DMF (10 mL) was added BOP (2.1 mmoles) and N-methylmorpholine (4.0 mmoles) and the reaction stirred at room temperature for 45 minutes. L-Phenylalanine benzyl ester (2.0 mmoles) was added and the reaction stirred for 16 hours at room temperature. The reaction mixture was extracted with water (100 mL) and diethyl ether (3×50 mL) The combined organic layers were successively washed with 0.2 N HCl (2×50 mL), sat. NaHCO3 (50 mL), and sat. NaCl (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to yield a colorless oil (387 mg, 40%). The crude product was purified by silica gel chromatography (50% EtOAc/Hexane, Rf=0.61). The title compound was crystalized from CHCl3/Hexane to yield a white solid, mp=109–110° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9]\[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)c1ccc(O)cc1
Reaction time: 0.03 h
Yield: 60.1 %

Procedure:
A 500 mL par shaker charged with ethyl (2Z)-3-(4-hydroxyphenyl)-3-phenylprop-2-enoate (1 g, 3.7 mmol) in Ethanol/Ethyl acetate was degasified with nitrogen for 2 min. Added 10% of Pd/C (0.4 g, 10%) and applied 50 psi of H2 pressure for 3 h. Reaction mixture was filtered through celite pad and washed the pad with excess Ethanol. Organic phase was dried over anhydrous Na2SO4 and concentrated to afford oil as product. (0.6 g, Yield: 60.1%); 1H NMR (300 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.07-7.29 (m, 7H), 6.63-6.66 (d, 2H), 4.29-4.34 (t, 1H), 3.89-3.96 (q, 2H), 3.02-3.03 (d, 2H), 0.99-1.04 (t, 3H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:29]([O-])=[O:30])[C:5]([C:12](=[O:28])/[C:13](/[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][N:23]=2)=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>CO.[Pd]>[F:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]2[C:12](=[O:28])[CH:13]([C:22]3[N:26]([CH3:27])[N:25]=[CH:24][N:23]=3)[CH:14]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[N:29]([OH:30])[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C(=O)/C(=C/c1ccc(F)cc1)c1ncnn1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(F)cc2c1C(=O)C(c1ncnn1C)C(c1ccc(F)cc1)N2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a solution of (E)-Methyl 5-fluoro-2-(3-(4-fluorophenyl)-2-(1-methyl-1H-1,2,4-triazol-5-yl)acryloyl)-3-nitrobenzoate (9) (200 mg, 0.467 mmol) in methanol (20 mL) was added 10% Pd/C (24 mg). After the addition, the mixture was stirred under H2 (1 atm) at room temperature for 0.5 h. The reaction system was then filtered and evaporated under reduced pressure. The residue was purified by chromatography (ethyl acetate:petroleum ether=1:1) to give the title compound (10) (110 mg, yield 57%) as an off-white foam. LC-MS (ESI) m/z: 415 (M+H)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.53 (s, 3H), 3.73 (s, 3H), 5.08 (d, 2H), 5.27 (d, 2H), 6.95 (dd, 1H), 7.08 (dd, 2H), 7.15 (dd, 1H), 7.42 (dd, 2H), 7.77 (s, 1H), 9.92 (s, 1H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) with diethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol). Methane sulfonyl chloride (43 μL, 0.55 mmol) was added and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E72); MS (ES+) m/e 379 [M+H]+.