Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH3:14])[N:8]=1.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18].O>CCCCC.C(OCC)C>[CH2:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[N:8]=1)[CH3:14]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCc1cccc(Br)n1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: O
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(CC)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
Add under nitrogen a solution of tert-butyllithium in pentane (1.5; M, 80.3; mL, 120.5; mmol) dropwise over 1; hour to a cooled solution of 2-bromo-6-ethyl-pyridine (10.19; g, 54.77; mmol) in anhydrous diethyl ether (101.9; mL) at −78° C. at a rate so that the internal reaction temperature does not exceed −75° C. Stir 15; min and add tri-n-butyltin chloride (16.25; mL, 57.51; mmol) dropwise at a rate so that the internal reaction temperature does not exceed −70° C. Warm to room temperature, add water and separate the layers. Extract the aqueous phase once with diethyl ether. Dry the combined organic layers over sodium sulfate, filter and concentrate to give the title compound as a pale yellow liquid (24.05; g, 94%) that is subsequently used without further purification. 1H NMR (CDCl3) δ 0.88; (t, 9H), 1.09; (m, 6H), 1.32; (m, 9H), 1.56; (m, 6H), 1.57; (m, 6H), 2.80; (q, 2H), 6.95; (m, 1H), 7.17; (d, 1H), 7.38; (t, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(Br)c2)nc(N2CCOCC2)cc1=O
Yield: 59.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 199 mg of 3-bromo-4-fluoroaniline, and 228 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 1.5 ml of pyridine and 1.5 ml of N,N-dimethylformamide. 185 mg of N-(3-bromo-4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]4[NH:27][N:26](C5CCCCO5)[CH2:25][C:14]=4[C:15](=[O:24])[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:17]=3[CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.Cl.O1CCOCC1.C(OC(C)C)(C)C>C(Cl)Cl.CO>[OH:2][C:3]1[C:8]([C:9]2[CH:10]=[CH:11][C:12]3[C:13]4[NH:27][N:26]=[CH:25][C:14]=4[C:15](=[O:24])[N:16]([CH2:19][C:20]([F:23])([F:21])[F:22])[C:17]=3[CH:18]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1-c1ccc2c3c(c(=O)n(CC(F)(F)F)c2c1)CN(C1CCCCO1)N3
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CC(C)OC(C)C
Product: O=c1c2cn[nH]c2c2ccc(-c3cccnc3O)cc2n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 240 h
Yield: 72.2 %

Procedure:
To a solution of 7-(2-methoxypyrid-3-1)-1-(tetrahydro-2H-pyran-2-1)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(2-methoxypyrid-3-yl)-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (90 mg, 0.20 mmol) in a DCM/MeOH mixture (50/50) is added a 4M solution of hydrogen chloride in anhydrous dioxane (2 mL, 2.45 mmol). The solution is stirred at room temperature for 10 days and then poured into diisopropyl ether. The precipitate formed is filtered off and washed with EtOH. 52 mg of a white solid are obtained (yield: 65%).
Reaction SMILES: Cl.[CH2:2]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)C.O>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][CH2:2]4)[CH2:16][CH2:15]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: c1cc2c(c(N3CCNCC3)c1)CCC2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3CCC4)CC2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.58 g (15 mmol) of 1-(indan-4-yl)-piperazine hydrochloride and 3.62 g (15 mmol) of trans-4-(2-oxoethyl)cyclohexyl-carbamic acid tert-butyl ester were dissolved in dichloroethane (120 ml), 2.1 ml (15 mmol) triethylamine was added, then 4.6 g (22 mmol) sodium triacetoxyborohydride was added portionswise and the reaction mixture was stirred for 20 hours at ambient temperature, then 20% potassium carbonate solution in water (40 ml) was added. The organic layer was separated, dried and evaporated to dryness in vacuo. The precipitate was recrystallized from acetonitrile to give the title compound 5.5 g (yield: 85.8%), m.p.: 115-8° C.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Solvent: CCO
Product: Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.9 %

Procedure:
In ethanol (300 ml) was dissolved 4-(4-nitrobenzyl)-morpholine (25.8 g), and to the mixture was added dried 10% palladium on carbon (Pd--C) (1.00 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate) to give 4-(4-aminobenzyl)-morpholine (430 mg) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:31](C1C=C2C(=CC=1)NC=C2CC(O)=O)#[N:32]>>[C:31]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:2]=1)[NH:8][CH:7]=[C:6]2[CH2:11][C:12]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=1)=[O:13])#[N:32]
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Reactant: N#Cc1ccc2[nH]cc(CC(=O)O)c2c1
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3ccc(C#N)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(5-cyano-1H-indol-3-yl)acetic acid (preparation H) in step 23 (A), the title compound was prepared. 1H-NMR (500 MHz, CD3OD) δ ppm 2.19 (s, 3 H) 4.03 (s, 2 H) 4.56 (s, 2 H) 7.45 (m, 4 H) 7.55 (d, J=8.55 Hz, 1 H) 8.06 (s, 1 H)
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([CH:26]=[CH:27][CH2:28][CH2:29][CH3:30])=[C:6]([CH:31]([CH3:33])[CH3:32])[N:5]=1)([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH:1]([C:4]1[C:9]([CH:10]=[O:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:7]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[C:6]([CH:31]([CH3:32])[CH3:33])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
2,6-Diisopropyl-3-hydroxymethyl-4-(2-benzyloxyphenyl)-5-(pent-1-enyl)-pyridine (Example 162) (680 mg, 1.53 mmol) was dissolved in 15 mL of methylene 25 chloride under an argon atmosphere and treated with a mixture of Celite (661 mg) and pyridinium chlorochromate (“PCC”) (661 mg, 2 eq). The reaction was stirred at room temperature for 1.5 h. The suspension was filtered through a pad of silica and the pad was washed with 50 mL CH2Cl2 and the filtrate was combined and concentrated in vacuo to afford 572.4 mg of product (84%). 1H NMR (300 MHz, CDCl3): δ 0.70 (t, J=7.2 Hz, 3 H), 1.08-1.35 (m, 61 H), 4.9-1.93 (m, 1 H), 3.26-3.45 (m, 1 H), 3.87-3.97 (m, 1 H), 4.97-5.06 (m, 2 H), 5.27-5.50 (m, 1 H), 6.01-6.10 (m, 1 H), 6.94-7.34 (m, 9 H), 9.82 (d, J=3.6 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1.[N:13]([O-])=[O:14].[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][N:7]([N:13]=[O:14])[C:6]=2[CH:12]=1
Reactant: Fc1ccc2c(c1)NCCCS2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCCSc2ccc(F)cc21
Yield: 92 %

Procedure:
7-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (423 mg, 2.3 mmol) was dissolved in acetic acid (1.15 mL) at 0° C. in an ice bath. 2.7 M aqueous sodium nitrite (1 mL) was added and this was stirred over night. Water was added (100 mL) and extracted with dichloromethane (3×50 mL), the organics were combined and concentrated to give 7-fluoro-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (449 mg, 92%). 1H NMR (CDCl3, 300 MHz): δ 7.43 (t, 1H, J=7.1 Hz), 7.30 (dd, 1H, J=9.1 Hz, J=9.2 MHz), 7.26–7.00 (m, 1H), 4.18 (t, 2H, J=5.8 Hz), 2.86 (t, 2H, J=7.2 Hz), 2.17–2.04 (m, 2H) ppm.
Reaction SMILES: [C:1]1([NH:11][C:12](=[S:15])[NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([OH:26])[C:18]=1[CH:19]=O>C(O)(=O)C>[C:1]1([NH:11][C:12](=[S:15])[NH:13][N:14]=[CH:19][C:18]2[C:17]([OH:16])=[CH:24][C:23]([OH:25])=[CH:22][C:21]=2[OH:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c(O)cc(O)cc1O
Reactant: NNC(=S)Nc1cccc2ccccc12
Solvent: CC(=O)O
Product: Oc1cc(O)c(C=NNC(=S)Nc2cccc3ccccc23)c(O)c1
Yield: 47.9 %

Procedure:
A solution of 4-(naphth-1-yl)thiosemicarbazide (572 mg, 2.63 mmol) and 2,4,6-trihydroxybenzaldehyde (405 mg, 2.63 mmol) in acetic acid (5 mL) was heated under reflux for 20 min, then cooled. The precipitate was filtered, washed (acetic acid) and dried to give the title compound (445 mg, 54%) as a solid. MS (ES+) m/e 354 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:53][CH2:54][F:55]>O1CCCC1.O>[F:55][CH2:54][CH2:53][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]([NH:20][C:21]([C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25]([C:29](=[O:45])[CH2:30][CH2:31][CH:32]4[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:36][CH2:37]4)[CH2:24]3)=[O:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(O)c2)c1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2cccc(OCCF)c2)c1
Temperature: 25 °C
Reaction time: 70 h
Yield: 71.2 %

Procedure:
128 mg (0.21 mmol) tert-butyl 4-{3-[(3R)-3-({1-[5-(3-hydroxyphenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate were dissolved in 2.25 ml tetrahydrofurane. 134 mg (0.41 mmol) cesium carbonate and 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added. The mixture was stirred at room temperature for 70 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 48 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 70 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane, 2 ml tetrahydrofurane and 134 mg (0.41 mmol) cesium carbonate were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 24 hours. 68 mg (0.39 mmol) 1-iodo-2-fluoroethane were added and the mixture stirred at room temperature for 70 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-90/10) gave 100 mg (65%) tert-butyl 4-{3-[(3R)-3-{[1-{5-[3-(2-fluoroethoxy)phenyl]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(OCC)C.O1CCCC1>[O:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([OH:23])[CH2:3][CH:2]=[CH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CCCCCCCCCCOc1ccccc1
Reactant: C=CC[Mg]Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC(O)CCCCCCCCCOc1ccccc1
Temperature: 0 °C
Yield: 42 %

Procedure:
To 85 ml of a 1M solution of allyl magnesium bromide in diethyl ether cooled in ice bath was added dropwise, under nitrogen, a solution of 20 g of 10-phenoxydecanal in 200 ml of dry tetrahydrofuran. The mixture was poured into 400 ml of ice and 30 ml of 9M sulfuric acid was added. Upon standing the mixture formed aqueous and organic layers. The organic layer was stirred for 15 min with solid sodium bicarbonate and concentrated. The aqueous layer was extracted with diethyl ether (2×200 ml) and the extracts were combined with the concentrated organic layer. The combined organics were washed with 300 ml of water and 300 ml of a half-saturated aqueous solution of sodium chloride, filtered, and concentrated. The residue was flash chromatographed utilizing as successive eluents 5% diethyl ether/hexane, 10% diethyl ether/hexane, and 25% diethyl ether/hexane to give 18.51 g (42%) of 13-phenoxy-1-tridecen-4-ol as a solid, m.p. 50°-52°.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][NH:13][C:12]1=[S:16].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].Cl>C(O)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[S:16][CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C=CC(=O)OCC
Reactant: S=c1[nH]ccn1C1CCc2ccccc2C1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCSc1nccn1C1CCc2ccccc2C1
Temperature: 80 °C
Yield: 95.3 %

Procedure:
A mixture of 1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydro-imidazole-2-thione (1 g, 4.3 mmol), prepared as in Example 9, ethyl acrylate (4.7 mL, 43 mmol) and hydrochloric acid (1N in ether, 8.7 mL, 8.7 mmol) in 20 mL of ethanol was heated at 80° C. under nitrogen for approximately 5 hours. The mixture was allowed to cool, concentrated and partitioned between saturated sodium bicarbonate solution and methylene chloride. The organic layer was separated and dried (K2CO3), filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (99:1) to give ethyl 3-[1-(1,2,3,4-tetrahydronaphthalen-2-yl)imidazol-2-yl-thio]propionate (1.36 g, 4.1 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:37][C:38](=[O:48])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:24][O:25][C:26](=[O:36])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:13]([O:15]C(C)(C)C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][S:21][CH2:22][C@H:23]([O:37][C:38](=[O:48])[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:24][O:25][C:26](=[O:36])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C)OC(=O)NCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCC

Procedure:
A solution of (R)-tert-butyl 2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(octylcarbamoyloxy)propylthio)propanoate in 30% TFA in DCM (0.3 M) was stirred at room temperature until complete deprotection of the tert-butyl group (4 hours). The reaction was diluted with DCM and concentrated with a stream of nitrogen. The reaction mixture was then diluted in MTBE and washed once with 1M citric acid (adjusted to pH3). The organic layer was dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting waxy solid was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C@@H:6]([CH3:17])[C@@H:7]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)[OH:8])[CH3:4].[NH2:18][S:19]([C:22]1[C:23]([Cl:44])=[CH:24][C:25]([NH:37][CH2:38][C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[C:26]([CH:36]=1)[C:27]([O:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34])=[O:28])(=[O:21])=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:18][S:19]([C:22]1[C:23]([Cl:44])=[CH:24][C:25]([NH:37][CH2:38][C:39]2[O:40][CH:41]=[CH:42][CH:43]=2)=[C:26]([CH:36]=1)[C:27]([O:29][CH2:30][CH2:31][CH2:32][C:33]([O:1][CH2:2][C@H:3]([NH:5][C@H:6]([CH3:17])[C@H:7]([C:9]1[CH:10]=[C:11]([F:16])[CH:12]=[C:13]([F:15])[CH:14]=1)[OH:8])[CH3:4])=[O:34])=[O:28])(=[O:20])=[O:21]
Reactant: NS(=O)(=O)c1cc(C(=O)OCCCC(=O)O)c(NCc2ccco2)cc1Cl
Reactant: C[C@H](CO)N[C@@H](C)[C@H](O)c1cc(F)cc(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C[C@H](COC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)N[C@H](C)[C@@H](O)c1cc(F)cc(F)c1

Procedure:
The free base of (rac)-(R*,S*)-2-((2-hydroxy-(R)-1-methylethyl)amino)-1-(3,5-difluorophenyl)propanol (21) (0.023 mole) and benzene (30 mL) (or toluene) is added to a round-bottomed flask. 4-(5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoic acid (0.025 mole), benzene (30 mL), and p-toluenesulfonic acid (0.026) catalyst is added to the flask. A Dean-Stark trap is filled with benzene, and the contents of the flask is refluxed with stirring for several hours or until no additional water is collected in the trap. The reaction is cooled, extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give (rac)-(R*,S*)-2-((2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl)amino)-(R)-2-methylethyl 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoate. See eg., Sandler et al., Organic Functional Group Preparations, p. 249 (1968).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[Mg].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16](Br)[CH:17]=[CH:18][CH:19]=1.[Cl-].[NH4+]>CCOCC>[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[C:1]([CH2:2][CH3:3])([OH:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccccc1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC(O)(c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 37.5 g. of propiophenone in 200 ml. of dry ether is added dropwise to a -10° C Grignard solution prepared from 13.6 g. of magnesium turnings and 126 g. of 3-trifluoromethyl-bromobenzene in 182 ml. of dry ether. The reaction mixture is stirred at 0° C for 30 minutes, thereafter refluxed for 1 hour. The mixture is cooled to 0° C, and the Grignard complex is decomposed with a 10% aqueous ammonium chloride solution. The ethereal phase is separated, washed until neutral, and dried over anhydrous sodium sulfate. The solvent is evaporated, and the residual oil is subjected to fractional distillation in vacuo. This way 57.3 g. of 3-trifluoromethyl-α-ethyl-benzhydrol are obtained: b.p.: 106°-108° C/0.03mmHg.
Reaction SMILES: [Cl:1][CH:2]([Cl:23])[C:3]1[C:12]([C:13]([O:15]CC)=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:21])[F:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH-].[Na+]>C(O)C>[Cl:23][CH:2]([Cl:1])[C:3]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([OH:18])[C:10]2[C:5](=[C:6]([C:19]([F:22])([F:20])[F:21])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)c1c(C(Cl)Cl)nc2c(C(F)(F)F)cccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(C(Cl)Cl)nc2c(C(F)(F)F)cccc2c1O
Yield: 88.6 %

Procedure:
A solution of 22 g of the product of Step A, 220 ml of ethanol and 110 ml of sodium hydroxide was stirred at room temperature for 36 hours and the ethanol was then evaporated at less than 40° C. under reduced pressure. The solution was diluted with 200 ml of water and ice and the pH was adjusted to 1 by addition of concentrated hydrochloric acid. The mixture was vacuum filtered and the product was washed with water and then was dissolved in ether. The solution was filtered and the filtrate was dried and evaporated to dryness under reduced pressure to obtain 18 g of 2-dichloromethyl-4-hydroxy-8-trifluoromethyl-3-quinoline-carboxylic acid which was used as is for the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:9]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][O:14][Si:15]([C:18]([CH3:20])([CH3:21])[CH3:19])([CH3:17])[CH3:16])[CH2:11][C@@H:10]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:9]1=[O:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C2=C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc([C@@H]2C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C2=O)cc1

Procedure:
A solution of (5R)-5-(tert-butyl-dimethylsilanyloxymethyl)-3-(4-methoxyphenyl)-2-oxo-2,5-dihydropyrrole-1-carboxylic acid tert-butyl ester (1.7 grams, 3.9 mmol) in ethanol (100 mL) was treated with palladium black (300 mg) and hydrogenated in a Parr™ shaker at 3 atmospheres pressure overnight. The catalyst was removed by filtration and the solvent was evaporated to provide crude (3S, 5R)-5-(tert-butyl-dimethylsilanyloxymethyl)-3-(4-methoxyphenyl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester as an oil. This was dissolved in tetrahydrofuran (40 mL) and treated with aqueous 0.5M hydrochloric acid solution (7.2 mL). The resulting mixture was stirred at room temperature overnight, quenched with saturated sodium carbonate solution and extracted twice with methylene chloride. The combined organic extracts were dried over magnesium sulfate and concentrated to an oil. The title compound (551 mg, 48%) was isolated by flash chromatography on silica gel eluting with 20% hexane in ethyl acetate.