Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[NH:26][CH:25]([C:27]([OH:29])=O)[CH2:24][S:23]2)[CH:17]=1.ON1C2C=CC=CC=2N=N1.[CH2:40]([NH2:59])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]>O1CCCC1.C(OCC)(=O)C>[CH2:40]([NH:59][C:27]([CH:25]1[CH2:24][S:23][CH:22]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[NH:26]1)=[O:29])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58]
Reactant: CCCCCCCCCCCCCCCCCCCN
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCNC(=O)C1CSC(c2cccnc2)N1
Reaction time: 1 h
Yield: 21.9 %

Procedure:
A solution of 500 mg of dicyclohexylcarbodiimide in 3 ml of tetrahydrofuran was added dropwise to a mixture of 510 mg of 2-(3-pyridyl)thiazolidine-4-carboxylic acid, 490 mg of 1-hydroxybenzotriazole, 680 mg of nonadecylamine and 12 ml of tetrahydrofuran with ice cooling, and the resulting mixture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) and recrystallized from ethyl acetate to give 250 mg of N-nonadecyl-2-(3-pyridyl)thiazolidine-4-carboxamide. Melting point 108°-110° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:13]2[CH2:17][NH:16][C:15](=[O:18])[CH:14]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29]Cl>CN(C)C=O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][C:14]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:17][NH:16][C:15]1=[O:18]
Reactant: COc1ccc(CCl)cc1OC
Reactant: CCOC(=O)C1C(=O)NCC1c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccc(OC)c(OC)c2)C(=O)NCC1c1ccc(OC)c(OC)c1
Reaction time: 1 h
Yield: 77 %

Procedure:
5.3 g of a 50% suspension of sodium hydride in mineral oil is added to a solution of 29.3 g of ethyl 4-(3,4-dimethoxyphenyl)-2-oxo-3-pyrrolidinecarboxylate in 180 ml of anhydrous dimethylformamide at 0°-5°C with stirring. The resulting mixture is held at 0°-5°C with stirring for 30 minutes and then at room temperature for an additional one hour. To the mixture is added 20.5 g of 3,4-dimethoxybenzyl chloride at 0°-5°C, and the whole mixture is stirred at room temperature for one hour. The reaction mixture is then concentrated under reduced pressure. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual oil is crystallized with ethanol to give 34.1 g of ethyl 3-(3,4-dimethoxybenzyl)-4-(3,4-dimethoxyphenyl)-2-oxo-3-pyrrolidinecarboxylate as white crystals, melting at 146°-149°C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)[CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1.Cl>C(O)CCC>[NH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:2]2[CH:3]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Clc1cc(Nc2cccc(Oc3ccccc3)c2)ncn1
Reactant: Nc1cccc(N)c1
Agent: Cl
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3cccc(Oc4ccccc4)c3)ncn2)c1
Yield: 33.8 %

Procedure:
A solution of 6-chloro-N-(3-phenoxyphenyl)pyrimidine-4-amine (0.25 g, 0.8 mmol), 1,3-diaminobenzene (0.36 g, 3.3 mmol), n-butanol (10 mL) and conc. HCl (61 mg, 1.6 mmol) was subjected to microwave irradiation (160° C., 15 min). The reaction mixture was cooled, was concentrated under reduced pressure and the residue was taken in EtOAc (10 mL). The EtOAc solution was washed with water (5 mL) and brine (5 mL), and was dried over Na2SO4. Concentration under reduced pressure gave a residue that was purified by column chromatography (SiO2, 60-120, hexane/ethyl acetate, 6/4) to give N4-(3-aminophenyl)-N6-(3-phenoxyphenyl)pyrimidine-4,6-diamine (0.1 g, 32%) as a brown solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:35](OC(OCC)OCC)C>[Pt].C1(C)C=CC=CC=1>[N:14]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:1]=[CH:35]1
Reactant: O=C(NCCCCCNc1c([N+](=O)[O-])cnc2ccccc12)c1ccccc1
Reactant: CCOC(OCC)OCC
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: O=C(NCCCCCn1cnc2cnc3ccccc3c21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
A catalytic amount of platinum on carbon was added to a suspension of N1-{5-[(3-nitroquinolin-4-yl)amino]pentyl}benzamide (5 g, 13.2 mmol) in toluene (250 mL). The reaction mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus. After about 2 hours an oily ball had formed in the bottom of the Parr bottle. Magnesium sulfate and additional catalyst were added and the hydrogenation was continued overnight. The reaction mixture was filtered to remove the catalyst. The residue in the Parr bottle was combined with isopropyl alcohol (150 mL), heated on a steam bath and then filtered. HPLC analysis indicated that both filtrates contained product so they were combined and concentrated under vacuum to provide crude N1-{5-[(3-aminoquinolin-4-yl)amino]pentyl}benzamide. This material was combined with toluene (250 mL). Triethylorthoformate (4 g, 26.4 mmol) was added and the reaction mixture was heated at reflux with a Vigreux column for 2 hours. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration to provide 3.4 g of N1-[5-(1H imidazo[4,5-c]quinolin-1-yl)pentyl]benzamide as a solid, m.p. 171.5-172.5° C. 1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.43 (t, J=6.0 Hz, 2H), 8.38 (m, 1H), 8.18 (m, 1H), 7.80 (d, J=7.0 Hz, 2H), 7.73 (m, 2H), 7.51 (t, J=7.0 Hz, 11H), 7.45 (t, J=7.0 Hz, 2H), 4.72 (t, J=7.5 Hz, 2H), 3.25 (q, J=6.0 Hz, 2H), 1.94 (quintet, J=7.5 Hz, 2H), 1.58 (quintet, J=7.5 Hz, 2H), 1.40 (quintet, J=8.5 Hz, 2H).
Reaction SMILES: [CH2:1]([C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[C@@H:5]1[N:17]1C(=O)C2=CC=CC=C2C1=O)[CH:2]=[CH2:3].CN(C)CCCN>C(Cl)Cl.CO>[NH2:17][CH:5]1[C@@H:4]([CH2:1][CH:2]=[CH2:3])[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6]1=[O:16]
Reactant: C=CC[C@@H]1[C@@H](N2C(=O)c3ccccc3C2=O)C(=O)N1C(C(=O)OC)=C(C)C
Agent: CN(C)CCCN
Solvent: ClCCl
Solvent: CO
Product: C=CC[C@@H]1C(N)C(=O)N1C(C(=O)OC)=C(C)C
Reaction time: 24 h
Yield: 51.1 %

Procedure:
To a solution of methyl 2-[(3R,4R)-4-allyl-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (2.64 g) in a mixture of methylene chloride (20 ml) and methanol (10 ml) was added N,N-dimethyl-1,3-propanediamine (1.98 ml) and the mixture was left in a refrigerator for 3 days and at room temperature for 24 hours. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate (50 ml), washed with water, dried over magnesium sulfate and evaporated to give an oil, which was chromatographed on silica gel eluting with a mixture of methylene chloride and acetone (6-5:1) to give methyl 2-[(4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (873 mg) as an oil.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[CH2:35]1[C:43]2[C:38](=[CH:39][C:40]([NH:44][C:45](=[O:72])[NH:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:61]=[C:60]5[C:56]([CH2:57][N:58]([C@@H:63]([CH:68]([CH3:70])[CH3:69])[C:64]([O:66]C)=[O:65])[C:59]5=[O:62])=[CH:55][CH:54]=4)=[CH:49][C:48]=3[F:71])=[CH:41][CH:42]=2)[CH2:37][CH2:36]1>>[CH2:35]1[C:43]2[C:38](=[CH:39][C:40]([NH:44][C:45](=[O:72])[NH:46][C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:61]=[C:60]5[C:56]([CH2:57][N:58]([C@@H:63]([CH:68]([CH3:69])[CH3:70])[C:64]([OH:66])=[O:65])[C:59]5=[O:62])=[CH:55][CH:54]=4)=[CH:49][C:48]=3[F:71])=[CH:41][CH:42]=2)[CH2:37][CH2:36]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc5c(c4)CCC5)c(F)c3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc5c(c4)CCC5)c(F)c3)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 438 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 437.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[O:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[CH2:11][CH2:10]1>ClCCl>[Cl:1][C:19]1[CH:20]=[C:15]([CH:12]2[CH2:11][CH2:10][O:9][CH2:14][CH2:13]2)[C:16]([OH:22])=[CH:17][C:18]=1[OH:21]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc(C2CCOCC2)c(O)c1
Solvent: ClCCl
Product: Oc1cc(O)c(C2CCOCC2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
2.4 g of N-chlorosuccinimide are added to a solution of 2 g of 4-(tetrahydropyran-4-yl)benzene-1,3-diol (Example 1) in 30 ml of dichloromethane at 0° C. The reaction mixture is stirred at ambient temperature for 16 hours. The reaction mixture is extracted with dichloromethane and then washed with water. The organic phases are combined and then dried over sodium sulphate. The residue is chromatographed on silica gel (75/25 heptane/ethyl acetate). 400 mg of 4-chloro-6-(tetrahydropyran-4-yl)benzene-1,3-diol are obtained. Yield=17%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.ClCC(OC(=O)CCl)=O.[S:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>ClC(Cl)C>[CH3:1][O:2][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:24]1[S:23][CH:27]=[CH:26][CH:25]=1)=[O:12])=[O:13]
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: c1ccsc1
Agent: O=C(CCl)OC(=O)CCl
Solvent: CC(Cl)Cl
Product: COC(=O)CCCCCCC(=O)c1cccs1
Temperature: 60 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
In 50 ml of dichloroethane were dissolved 9.41 g (0.05 mole) of suberic acid monomethyl ester and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 5.47 g (0.065 mole) of thiophene and 0.71 g of boron trifluoride-diethyl ether complex and the resulting mixture was then stirred at 60° C. for 5 hours. After completion of the reaction, the reaction solution was cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain 11.5 g of 2-(7-methoxycarbonyl-1-oxoheptyl)thiophene.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8](Cl)=[O:9].O>C1COCC1>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:7]=1[C:8]([N:2]([CH3:3])[CH3:1])=[O:9]
Reactant: CNC
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC)c1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of dimethylamine (2M in THF, 3 mL) and THF (2 mL) is added 2,6-dimethoxybenzoyl chloride (200.6 mg, 1 mmol) in THF (2 mL) dropwise. After the addition, the solution is stirred at RT for 1 h. Water is added and the suspension is extracted with EtOAc. The organic layer is washed with water and brine, and dried over sodium sulfate. The solvent is removed under reduced pressure to afford the title compound: 1H NMR (CDCl3) δ 7.26-7.22 (t, J=8.34 Hz, 1H), 6.56-6.53 (d, J=8.33 Hz, 2H), 3.79 (s, 6H), 3.12 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][O:3][C:4]2[C:12]([O:13][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([O:8][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)=[O:7])=[CH:18][CH:17]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=C(O)c1cccc(O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2cccc(OCc3ccc(OC)cc3)c2OCc2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
Sodium hydride (60%, 4.69 g, 0.117 mol) was added in portions to 18 (5.47 g, 35.5 mmol) in DMF (150 mL) with ice bath cooling, and the mixture was stirred at 0° C. for 45 min and at room temperature for 1 h. A solution of 4-methoxybenzyl bromide (25.0 g, 0.124 mol) in DMF (50 mL) was added to the reaction mixture over 30 min. After stirring for 20 h, quenching with H2O (30 mL) at 0° C. was performed, and solvents were removed under high vacuum. The concentrate was dissolved in EtOAc (200 mL), which was washed with H2O (100 mL) and saturated NaCl (100 mL); solvent was removed in vacuo. Flash chromatography, eluting with 5:1 hexanes/EtOAc, gave 11.33 g (62%) of 19 as a white solid, mp 108° C.: 1H NMR δ 3.77 (s, 3H), 3.79 (s, 3H), 3.81 (s, 3H), 4.95 (s, 2H), 5.03 (s, 2H), 5.25 (s, 2H), 6.76 (d, 2H, J=8.8), 6.86 (d, 2H, J=8.8), 6.89 (d, 2H, J=8.4), 7.04 (t, 2H, J=7.8), 7.11 (dd, 2H, J=8.0, 2.0), 7.18 (d, 2H, J=8.8), 7.33-7.36 (m, 4H); 13C NMR δ 55.32, 55.37, 55.40, 66.81, 71.20, 75.31, 112.97, 113.61, 114.02, 118.16, 123.93, 127.08, 128.19, 128.75, 129.51, 129.73, 130.31, 130.41, 148.43, 152.95, 159.43, 159.62, 159.70, 166.44; HRMS m/z calcd for C31H30NaO7, 537.1889 (M+Na). found, 537.1884.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCCN1CCC(NC(=O)c2ccccc2)CC1
Yield: 80.9 %

Procedure:
An intimate mixture of 4-benzamidopiperidine (2.0g.), methyl 4-bromobutyrate (2.0g.) and potassium carbonate (1.5 g.) was stirred and heated on a steam bath for 15 minutes. An exothermic reaction occurred and the semi-molten mixture set solid. Trituration with water (20 ml.) and filtration provided the title compound (2.41 g., 82%), m.p. 116° (Found: C, 67.10; H, 8.00; N, 9.39; C17H24N2O3 requires C, 67.08; H, 7.95; N, 9.20%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[C:5]2[C:14]([F:17])([F:16])[F:15].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1>CN(C=O)C>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])=[CH:11][CH:10]=2)[C:5]([C:14]([F:17])([F:15])[F:16])=[CH:6][C:7]1=[O:13]
Reactant: O=C=Nc1ccccc1
Reactant: Cn1c(=O)cc(C(F)(F)F)c2cc(N)ccc21
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(=O)cc(C(F)(F)F)c2cc(NC(=O)Nc3ccccc3)ccc21
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A solution of 6-amino-1-methyl-4-trifluoromethyl-1H-quinolin-2-one (Preparation 1, 48 mg, 200 μmol) in anhydrous DMF (2 mL) was treated with PhNCO (33 μL, 300 μmol) & pyridine (16 μL, 20 μmol). The mixture was stirred for 16 h & then partitioned between EtOAc (30 mL) & H2O (20 mL). The organic layer was washed with H2O (20 mL) & brine (20 mL), before being dried (MgSO4). After filtration, the solution was concentrated & a precipitate formed. This precipitate was collected by filtration & washed with cold EtOAc to give the title compound (58 mg, 80%): δH ((CD3)2SO)=3.60 (s, 3H), 7.00 (t, 1H), 7.10 (s, 1H), 7.30 (t, 2H), 7.45 (d, 2H), 7.65 (d, 1H), 7.75 (dd, 1H), 8.15 (d, 1H), 8.70 (s, 1H), 9.00 (s, 1H); m/z (ES+)=362.2
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].ClC(Cl)(Cl)C(=N)O[CH2:13][CH:14]=[CH2:15].FC(F)(F)S(O)(=O)=O>C1CCCCC1>[CH2:15]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH:14]=[CH2:13]
Reactant: CCOC(=O)[C@H](C)O
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Product: C=CCO[C@@H](C)C(=O)OCC
Reaction time: 16 h
Yield: 72.7 %

Procedure:
7.08 g (60 mmol) of ethyl (S)-(−)-lactate are introduced into 120 ml of cyclohexane, and 25.0 g (120 mmol) of allyl trichloroacetimidate, dissolved in 30 ml of cyclohexane, are added thereto. 0.55 ml (6 mmol) of trifluoromethanesulfonic acid are then added and the mixture is stirred for 16 h. When the reaction is complete, the precipitated trichloroacetamide is filtered off with suction and washed with cyclohexane. The filtrate is washed with saturated NaHCO3 solution, after which the organic phase is dried over Na2SO4, filtered and evaporated on a rotary evaporator. Flash-chromatographic purification (cyclohexane/EtOAc=10:1; Rf=0.27) gives 6.9 g (72%) of a colorless liquid.
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[O:9]=[C:10]1[C@@H:16]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14][S:13][C@H:12]2[CH2:24][CH2:25][CH2:26][C@@H:27]([C:28]([O:30][CH3:31])=[O:29])[N:11]12>CN(C=O)C>[O:9]=[C:10]1[C@@H:16]([N:17]([CH3:3])[C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH2:15][CH2:14][S:13][C@H:12]2[CH2:24][CH2:25][CH2:26][C@@H:27]([C:28]([O:30][CH3:31])=[O:29])[N:11]12
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)C(F)(F)F)C(=O)N21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N(C)C(=O)C(F)(F)F)C(=O)N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Iodomethane (77 mg, 0.54 mmol) and K2CO3 (150 mg, 1.08 mmol) were added to a solution of (4S,7S,10aS)-methyl 5-oxo-4-(2,2,2-trifluoroacetamido)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (64 mg, 0.18 mmol) in DMF (1 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give (4S,7S,10aS)-methyl 5-oxo-4-(2,2,2-trifluoro-N-methylacetamido)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (47.6 mg, 0.129 mmol, 72% yield) of a yellow oil. Anal. Calcd. for C14H19F3N2O4S m/z 368.3. found: 391.1 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[O:25]3)=[CH:20][CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[O:25]3)=[CH:20][CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A mixture of tert-butyl 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoate (290 mg, 0.689 mmol) and trifluoroacetic acid (10 mL) in DCM (10 mL) was stirred at room temperature for 16 hrs. The solvents were removed and the residue was extracted with EtOAc (150×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash (15%-19% MeCN in 0.5% NH4HCO3) to give target product of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (100 mg, 49%) as a white solid. LCMS (ESI) m/z: 364.9 [M+H]+.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:9]=[CH:10][CH:11]=1.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1>CCO>[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][N:23]1[CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: c1cc(OC[C@H]2CO2)cc(-c2cccc3cccnc23)c1
Solvent: CCO
Product: O[C@@H](COc1cccc(-c2cccc3cccnc23)c1)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 26.8 %

Procedure:
The mixture of compound (R)-8-(3-(oxiran-2-ylmethoxy)phenyl)quinoline (270 mg, 1 mmol), 1,2,3,4-tetrahydroisoquinoline (133 mg, 1 mmol) in EtOH (5 mL) was stirred at 120° C. under microwave heating for 30 min. The solvent was then removed by concentration and the crude product was purified by HPLC separation to yield the desired (R)-1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(quinolin-8-yl)phenoxy)propan-2-ol (110 mg, Yield 26.8%). 1H NMR (400 MHz, METHANOL-d4): 8.82 (dd, J1=4.0 Hz, J2=1.6 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.69 (dd, J1=J2=7.6 Hz, 1H), 7.56-7.53 (m, 1H), 7.43 (dd, J1=J2=7.6 Hz, 1H), 7.24 (s, 1H), 7.20-7.01 (m, 6H), 4.30 (br.s, 1H), 4.17-4.06 (m, 2H), 3.77 (s, 2H), 2.90-2.74 (m, 6H). LCMS (m/z): 412.2 (M+1).
Reaction SMILES: [S:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[CH2:10]([O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15][CH2:16][CH2:17][CH:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:29])[C:14]([CH3:28])([CH3:27])[CH2:15][CH2:16][CH2:17][CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25])[N:6]1[CH2:7][CH2:8][C:9]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:5]1)[CH3:11]
Reactant: CCOC(=O)C(C)(C)CCCC(Br)c1ccccc1Cl
Reactant: c1cc2c(s1)CCNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)CCCC(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 70 °C
Yield: 34.1 %

Procedure:
4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride (2.5 g, 8.8 mmol) was mixed with sodium hydroxide (2.7 g) in water (80 mL). The corresponding free amine was extracted with dichloromethane (3×20 mL), which was dried over Na2SO4, filtered, and concentrated to provide 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (1.22 g). 4,5,6,7-Tetrahydro-thieno[3,2-c]pyridine (1.22 g, 8.8 mmol) and 6-bromo-6-(2-chlorophenyl)-2,2-dimethylhexanoic acid ethyl ester (2.5 g, 8.8 mmol) were combined in DMF (90 mL) and potassium carbonate (1.82 g, 13.2 mmol) was added. The mixture was heated to 70° C. for 1 h and then 60° C. overnight. The mixture was cooled to room temperature and water (100 mL) was added. The product was extracted with diethyl ether (3×150 mL). The combined ether extracts were washed with water (3×80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, ethyl acetate/heptane=1/10) to provide 6-(2-chlorophenyl)-6-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5yl)-2,2-dimethylhexanoic acid ethyl ester (Compound Ie, 1.26 g, 42.04%) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.49 (d, 1H, J=7.8 Hz), 7.37 (d, 1H, J=8.1 Hz), 7.26-7.14 (m, 2H), 7.05 (d, 1H, J=5.4 Hz), 6.70 (d, 1H, J=5.4 Hz), 4.19 (dd, 1H, J=8.7, 4.5 Hz), 4.02 (q, 2H, J=7.2 Hz), 3.81 (d, 1H, J=14.4 Hz), 3.47 (d, 1H, J=14.4 Hz), 2.88-2.66 (m, 1.95-1.74 (m, 2H), 1.52-1.46 (m, 2H), 1.13 (t, 3H, J=7.2 Hz), 1.15-1.08 (m, 2H), 1.07 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.63, 139.16, 134.91, 134.21, 133.55, 129.53, 129.03, 128.03, 126.81, 124.46, 122.65, 63.47, 60.33, 50.73, 48.04, 42.31, 41.04, 33.48, 26.14, 25.58, 25.12, 21.07, 14.44. MS (GC-CI): Calculated for C23H30ClNO2S (MH)+: 420.1758; found 420.1725.