Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[C:16]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]2=3)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2].[NH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[C:16]([S:19]([NH:36][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][N:38]=4)(=[O:20])=[O:21])[CH:17]=[CH:18][C:10]2=3)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2]
Reactant: Nc1ccncn1
Reactant: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Nc3ccncn3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
To a solution of perfluorophenyl 4-(4-cyano-2-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (180 mg, 0.351 mmol) and 4-amino pyrimidine (50 mg, 0.527 mmol) in THF (5 mL) was added LiHMDS (1M in THF, 0.7 mL, 0.703 mmol) at −78° C. The reaction mixture was stirred at same temperature for 5 minutes and at 0° C. for 1 h. After completion, reaction mixture was quenched with 2-3 drops of acetic acid and concentrated under reduced pressure. The crude mass was purified by prep purification to obtain 4-(4-cyano-2-methoxyphenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (13 mg, 11.3%) as a white solid. m/z (ESI) 423.0 (M+H)+. 1H NMR (400 MHz, DMSO) δ 11.88 (s, 1H), 8.64 (s, 1H), 8.36 (d, J=5.8 Hz, 1H), 7.65 (s, 1H), 7.55-7.43 (m, 2H), 7.35-7.15 (m, 2H), 7.00 (d, J=5.9 Hz, 1H), 6.34 (d, J=8.6 Hz, 1H), 4.30 (t, J=4.0 Hz, 2H), 3.81 (s, 3H), 3.67-3.65 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([OH:23])=O.[NH2:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1>CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1)=[O:23]
Reactant: Cc1nnc(N)s1
Reactant: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Solvent: CCOCC
Product: COc1cccc(-c2ccc3c(C(=O)Nc4nnc(C)s4)c(OC)ccc3c2)c1

Procedure:
The compound was prepared by reaction of 2-methoxy-6-(3-methoxyphenyl)-1-naphthoic acid (450 mg, 1.46 mmol, 1 eq) with 2-amino-5-methyl-1,3,4-thiadiazole (0.6 eq) according to method E. Characterization of the compound was not effected. The raw product was directly employed for ether cleavage.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:65])([CH3:64])[C@H:42]([N:50]1[CH2:54][CH2:53][N:52]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH3:62])[N:57]=2)[C:51]1=[O:63])[C:43](OC(C)(C)C)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:65])([CH3:64])[C@H:42]([N:50]1[CH2:54][CH2:53][N:52]([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([CH3:62])[N:57]=2)[C:51]1=[O:63])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
A solution containing the product from Example 2C (1.0 g, 1.88 mmol) in THF (19 mL) was treated with the product from Example 10B (0.83 g, 1.98 mmol), DEPBT (0.84 g, 2.8 mmol), and N,N-diisopropylethylamine (1.6 mL, 9.2 mmol), stirred at 25° C. for 16 hours, and partitioned between a mixture of dichloromethane and ethyl acetate (2:1, respectively) and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by elution with 0-5% methanol in ethyl acetate to give the title compound (1.15 g, 75% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.83 (s, 9 H), 0.90 (s, 9 H), 1.55 (m, 2 H), 2.38 (q, J=9.44 Hz, 1 H), 2.46 (s, 3 H), 2.57 (m, 1 H), 2.67 (d, J=7.35 Hz, 2 H), 2.79 (m, 1 H), 2.97 (m, 1 H), 3.09 (q, J=8.95 Hz, 1 H), 3.21 (m, 1 H), 3.50 (s, 3 H), 3.67 (m, 1 H), 3.85 (d, J=9.93 Hz, 1 H), 4.12 (m, 3 H), 4.35 (m, 2 H), 4.54 (d, J=7.72 Hz, 1 H), 6.63 (d, J=9.56 Hz, 1 H), 7.09 (m, 7 H), 7.22 (d, J=8.09 Hz, 2 H), 7.31 (m, 1 H), 7.49 (d, J=9.56 Hz, 1 H), 7.69 (t, J=7.54 Hz, 1 H), 7.86 (m, 5 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Reactant: CCCCCCCCO
Agent: Cl
Product: CCCCCCCCOC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-octanol and the suspension is saturated with hydrogen chloride gas for 4 hours at 70°. The mixture is concentrated in vacuo at 70° to half its volume, 50 ml of diethyl ether and 15 ml of propylene oxide are added and the whole is filtered. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid octylester, m.p. 161°-162°.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][CH:5]=[C:6]([CH2:8][C:9]([OH:11])=O)[N:7]=1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[CH2:33]([O:32][CH2:31][C@H:13]([NH:12][C:9](=[O:11])[CH2:8][C:6]1[N:7]=[C:3]([CH3:2])[NH:4][CH:5]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: Cc1nc(CC(=O)O)c[nH]1
Agent: Cl
Product: Cc1nc(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)c[nH]1
Yield: 7 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-methyl-1H-imidazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 162, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(2-methyl-1H-imidazol-4-yl)acetamido)propanamide (52 mg, 7%). 1H-NMR (400 MHz, DMSO-D6): σ 10.19 (s, 1H), 8.40-8.36 (m, 2H), 7.61 (d, 2H), 7.32-7.18 (m, 6H), 7.04-6.97 (m, 3H), 6.74 (br s, 1H), 4.69-4.64 (m, 1H), 4.52 (s, 2H), 3.67-3.54 (m, 4H), 2.20 (s, 3H). MS (EI) for C28H27FN4O4. found 503.2 (MH+).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[S:15])[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][C:21]([CH:23]=[CH2:24])=[O:22].C(N(CC)CC)C>C(O)C>[CH2:1]([N:5]1[C:14](=[S:15])[C:13]2[N:12]([CH2:24][CH2:23][C:21](=[O:22])[CH3:20])[CH:11]=[N:10][C:9]=2[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=S)c2[nH]cnc2n(CCCC)c1=O
Reactant: C=CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCn1c(=S)c2c(ncn2CCC(C)=O)n(CCCC)c1=O
Reaction time: 1 h

Procedure:
1,3-di-n-butyl-6-thioxanthine (8,3 g), methylvinylketone (2,9 ml) and triethylamine (1 ml) were dissolved in ethanol (10 ml) and the mixture was slowly heated with stirring at 40°-50° C. for one hour. After cooling of the clear solution, the 1,3-di-n-butyl-7-(3-oxobutyl)-6-thioxanthine precipitated in the form of yellow needles.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(NCc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(NCc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 13.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-benzylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Manufacturing Example 68-1-4 and 3-ethynyl-pyridin-2,6-diamine (46.4 mg, 0.348 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (190 μL, 1.37 mmol). The mixture was stirred for 6.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (17 mg, 8.4%).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Br.[C:17](O)(=O)C>O>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:17])=[O:6]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: Br
Solvent: O
Product: COC(=O)CCC(=O)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
A mixture of the compound from Step 1 (77.3 g), 48% HBr (310 ml), and acetic acid (620 ml) was heated under reflux for 18 hours. The resulting mixture was cooled to room temperature and poured into 3 liters of water. The resulting solution was extracted with ethyl acetate (3×500 ml). The combined organic layers were washed with water (4×200 ml), dried over Na2SO4, the solvents were removed by evaporation and the residue was dissolved in 10% HCl/methanol (500 ml). After 10 hours at room temperature the volatile components were removed by evaporation in vacuo. The resulting residue was triturated with hexane to yield the title compound, m.p. 115°-116°.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:30][CH2:29]2)=[C:24]([CH:31]=O)[CH:23]=1>COCCOC.C(OCC)C>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:30][CH2:29]2)=[C:24]([CH:31]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:23]=1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2Cl)ccc1C1CC1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3Cl)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102450.9 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (15.70 g, 0.11 mol) in anhydrous 1,2-dimethoxyethane (285 ml) is added sodium methoxide (6.50 g, 0.12 mol) in one portion, and the mixture is stirred at this temperature for 30 minutes. A solution of 2′,4′-dichloro-4-cyclopropylbiphenyl-3-carbaldehyde (13.70 g, 0.047 mmol) is then added dropwise over 20 minutes, maintaining temperature below 10° C. The reaction mixture is stirred at this temperature for 2 hours, then allowed to warm to room temperature before diluting with diethyl ether and distilled water. The two phases are separated, and the aqueous phase is extracted again with diethyl ether (×2). Organic fractions are combined, washed with brine, then dried over magnesium sulphate. The suspension is filtered and filtrate concentrated in vacuo. The aqueous phase is further acidified with 2M hydrochloric acid then extracted again with diethyl ether (×2), dried over magnesium sulfate and concentrated in vacuo. All organics are combined, then diluted with toluene and azeotroped (×4) to afford 4-[1-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (20.0 g) which is of sufficient purity to use directly in the next step.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[O:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:16][C:15]=1[O:21][CH3:22])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccc(O)cc1OC)C(=O)OCC
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)C(=CNc1ccc(OC(=O)c2ccccc2)cc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
Ethyl 2-butyryl-3-(4-hydroxy-2-methoxyphenylamino)acrylate (34.5 g) and pyridine (100 ml) were stirred in dichloromethane (500 ml) at 0°-5°. Benzoyl chloride (20 ml) in dichloromethane (100 ml) was added dropwise (below 10°) and the mixture was stirred overnight at room temperature. The reaction mixture was washed successively with water, 2M HCl (×2) and sodium hydrogen carbonate solution (×2). The organic layer was dried, filtered and evaporated to an oil which crystallized on standing to give ethyl 2-butyryl-3-(4-benzoyloxy-2-methoxyphenyl-amino)acrylate (24 g, 52%) m.p. 85°-87°.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.C1COCC1.[C:28]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[OH:35][C@@H:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](O)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
To a dry 250 mL round bottom flask were added (S)-Me-CBS (5 mL, 1.0 M in toluene, 5.0 mmol) and 50 mL of THF under argon. The solution was cooled to −5° C. To this solution were added simultaneously BH3.THF (50 mL, 1.0 M in THF, 50 mmol) and ketoester 1 in neat (9.6 g, 50 mmol) via syringe. The addition was completed in 30 min. The reaction mixture was stirred at the same temperature for another 30 minutes and worked up by addition of aqueous K2CO3 solution. After stirring for 30 minutes, the organic layer was separated, and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with brine and dried over (Na2SO4). Revomal of solvent gave a pale yellow oil, containing the hydroester 5 and the CBS catalyst (ca. 11 g). The crude product could be used directly for next reaction. A sample was purified by hydrolysis with 3 N NaOH, and converted into lactone 2 by azeotropically reflux with toluene. E.e was measured by HPLC on lactone 2 (95.6%)
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.Cl[CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:26][CH2:27][OH:28])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
To a solution of benzhydryl piperazine (7.28 gm) in toluene (35 ml) at room temperature, dimethyl formamide (70 ml), 2-chloroethanol (5 ml) and potassium carbonate (5 gm) were added. The reaction mass was heated to reflux with constant stifling for 14-16 hours. Reaction mass was cooled, filtered, and concentrated under vacuum to get 2-(4-benzhydryl piperazine-1-yl) ethanol (yield: 7.5 gm).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11](C1C=CC=CC=1Cl)[N:12]1[CH2:17][CH2:16][C:15]2[O:18][CH:19]=[CH:20][C:14]=2[CH2:13]1)C.C(O)C.[OH-].[Na+]>O>[O:18]1[C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([CH3:29])([CH3:28])[C:4]([OH:30])=[O:3])[CH2:13][C:14]=2[CH:20]=[CH:19]1
Reactant: CCOC(=O)C(C)(C)CCCCCC(c1ccccc1Cl)N1CCc2occc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCCCN1CCc2occc2C1)C(=O)O
Yield: 73.5 %

Procedure:
8-(2-Chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid ethyl ester (0.5 g, 1.16 mmol) was added to a mixture of ethanol (20 mL) and sodium hydroxide (0.32 g, 8.0 mmol) in water (6.6 mL). The mixture was heated to reflux for 6.5 hours. Evaporated solvent under reduced pressure and water (20 mL) was added to the residue. The aqueous solution was washed with a mixture of ethyl acetate/heptane 1/10 (10 mL), and the extract was discarded. The aqueous fraction was acidified with concentrated hydrochloric acid to pH=6 and the product was extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 842-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid (0.25 g, 46.9%) as a yellow oil. The material was dissolved in diethyl ether (5 mL) and added to hydrochloric acid solution (2N HCl in diethyl ether, 0.34 mL). Water (12 mL) was added and after mixing the aqueous portion was separated and freeze dried to provide 8-(2-chlorophenyl)-8-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-yl)-2,2-dimethyloctanoic acid, hydrochloride salt (Compound Io hydrochloride, 0.16 g, light yellow powder, 59.3% yield). 1H NMR (Field: 300 MHz, Solvent: CD3OD/TMS) δ (ppm): 7.77 (br s, 1H), 7.63-7.48 (m, 5H), 6.37 (br s, 1H), 5.05 (m, 1H), 4.18 (m, 1H), 3.62 (m, 1H), 3.02 (m, 2H), 2.36-2.24 (m, 2H), 1.42-1.40 (m, 2H), 1.32 (m, 2H), 1.20-1.18 (m, 4H), 1.11 (s, 6H), 1.08-0.92 (m, 1H). 13C NMR (Field: 75 MHz, Solvent: CD3OD/TMS) δ (ppm): 181.70, 147.11, 144.55, 137.40, 132.15, 131.89, 130.08, 128.21, 129.87, 112.37, 109.71, 66.34, 52.10, 50.05, 43.07, 41.60, 35.10, 31.67, 30.56, 26.64, 25.85, 22.31. HRMS (FIR, DIP-CI): Calculated for C23H30ClNO3 (M+H)+: 404.1987. Found 404.2009. CHN analysis: Calculated; 62.73; C, 7.09; H, 3.18; N, 16.10; Cl. found; 59.13; C, 7.04; H, 3.03; N, 13.58; Cl.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][C:6]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16](C(F)(F)F)[CH:15]=3)=[CH:5][C:4]=2[CH2:3]1.Cl>>[CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][C:6]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:5][C:4]=2[CH2:3]1
Reactant: CN1CCc2ncc(NC(=O)c3cccc(C(F)(F)F)c3)cc2C1
Agent: Cl
Product: CN1CCc2ncc(NC(=O)c3ccccc3)cc2C1

Procedure:
N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-trifluoromethyl benzarnide and its monohydrochloride
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:16]1[CH2:19][CH:18]([CH:20]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH3:24][O:23][C:21](=[O:22])[CH:20]([CH:18]1[CH2:17][N:16]([CH:2]([C:3]2[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:19]1)[C:25]1[CH:26]=[C:27]([F:32])[CH:28]=[C:29]([F:31])[CH:30]=1
Reactant: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Reactant: Clc1ccc(C(Br)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccc(Cl)cc2)C1

Procedure:
A solution of 0.042 g (0.15 mmol) of 1-[bromo(phenyl)methyl]-4-chlorobenzene, 0.028 g (0.1 mmol) of methyl azetidin-3-yl(3,5-difluorophenyl)acetate (Example 25, Step 1) and 0.298 g (0.3 mmol) of Cs2CO3 in 5 mL of acetonitrile was heated at 45° C. for 18 h. The solution was concentrated and the residue was dissolved in 5 mL of ethyl acetate. This solution was washed with 1 mL water and the aqueous layer was washed with a second aliquot of 3 mL ethyl acetate. The organic extracts were washed with brine, combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography on a Waters RCM column (5 micron silica gel, 20 mm×10 cm) using a 2:1 mixture of hexane and 5:4:1 hexane-methyl tert-butyl ether-acetonitrile. Homogenous fractions were pooled and concentrated to afford the title compound. 1NMR(CDCl3) δ 2.65-2.69 (m, 1H), 2.88-2.93 (m, 1H), 3.05-3.16 (m, 2h). 3.41-3.46 (m, 1H), 3.67 (s, 3H), 3.81-3.86 (m, 1H), 4.30 (s, 1H), 6.69-6.74 m, 1H), 6.80-6.85 (m, 2H), 7.19-7.37 (m, 9H). Mass Spectrum: m/e=442 (M+1 35Cl) and 444 (M+1 37Cl).
Reaction SMILES: C1([O:7][S:8](=O)(=[O:10])[NH2:9])C=CC=CC=1.[F:12][C:13]([F:20])([F:19])[C:14]1([OH:18])[CH2:17][CH2:16][CH2:15]1>>[F:12][C:13]([F:20])([F:19])[C:14]1([O:18][S:8](=[O:10])(=[O:7])[NH2:9])[CH2:17][CH2:16][CH2:15]1
Reactant: NS(=O)(=O)Oc1ccccc1
Reactant: OC1(C(F)(F)F)CCC1
Product: NS(=O)(=O)OC1(C(F)(F)F)CCC1

Procedure:
Sulfamic acid 1-trifluoromethyl-cyclobutyl ester was synthesized according to the method presented in the synthesis of sulfamic acid phenyl ester in Example 1 with the exception of utilizing 1-trifluoromethyl-cyclobutanol to obtain sulfamic acid 1-trifluoromethyl-cyclobutyl ester: 1H NMR (CDCl3, 300 MHz) δ 5.85 (s, 2H), 3.40 (t, 1H), 3.01 (m, 1H), 2.56 (m, 1H), 2.42 (t, 1H), 2.04 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[N+:15]([O-])=O)[CH3:5].O1CCCC1.[BH4-].[Na+].[Cl-].[Cl-].[Cl-].[Al+3]>O>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[NH2:15])[CH3:5]
Reactant: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc(N)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
The obtained 2,4-dinitrophenylpropanoic acid methyl ester (2.29 g) was added into tetrahydrofuran (50 ml), and was dissolved by stirring at room temperature. Sodium borohydride (0.76 g, 0.02 mole) and aluminum trichloride (1.33 g, 0.01 mole) were then added, and reaction was conducted for 2 hours at room temperature. After the reaction, water (10 ml) was added to completely react with the remaining reductant. Solvent was removed by distilling under a reduced pressure to obtain 2,4-diaminophenylpropanoic acid methyl ester (1.67 g, yield: 86%).