Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)(=[NH:4])=[O:3].[OH-].[Na+].C(OCC)(=O)C>C1COCC1.Cl>[NH2:11][C:7]1[CH:6]=[C:5]([S:2]([CH3:1])(=[NH:4])=[O:3])[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=N)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=N)(=O)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 200 mg (1.00 mmol) of (RS)—S-methyl-S-(3-nitrophenyl)sulfoximide in 20 ml of THF is mixed at room temperature with 8 ml of an approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid. After 3 hours, another 2 ml of the approximately 10% solution of Ti(III)Cl in 20-30% hydrochloric acid is added and stirred overnight at room temperature. The batch is made basic with 1N NaOH solution and mixed with ethyl acetate. It is filtered, and the filter cakes are washed with ethyl acetate/MeOH (3:2). The organic solvent is drawn off in a rotary evaporator, and the residue is extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The residue that is obtained is purified by chromatography (DCM/EtOH 95:5). 82 mg (0.48 mmol, corresponding to 48% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](/[C:6](=[CH:11]/[C:12]1[CH:13]=[N:14][N:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH:16]=1)/[CH2:7][C:8]([OH:10])=O)=[O:5])[CH3:2].[CH3:23][C:24]([O-])=[O:25].[Na+]>C(OC(=O)C)(=O)C>[C:24]([O:10][C:8]1[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=[C:12]2[C:16]=1[N:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)[N:14]=[CH:13]2)(=[O:25])[CH3:23]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)/C(=C/c1cnn(C2CCCCO2)c1)CC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)c2c(cnn2C2CCCCO2)c1
Yield: 26.8 %

Procedure:
Crude (3E)-3-(ethoxycarbonyl)-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]but-3-enoic acid (45 g) was mixed with acetic anhydride (500 mL) and NaOAc (12 g, 0.146 mol). The reaction mixture was heated at reflux over a period of 5 hours and evaporated. The residue was alkalized to pH 8-9 with aqueous Na2CO3. The product was extracted with EtOAc (5×50 mL). The combined extracts were dried and evaporated. The residue was purified by chromatography (EtOAc/hexane, 1:4) to provide ethyl 7-(acetyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (13 g, 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13].[F:14][C:15]1[C:20]([O:21][CH3:22])=[C:19]([CH3:23])[CH:18]=[CH:17][C:16]=1B(O)O.[F-].[Cs+]>C(COC)OC.O>[NH2:1][C:2]1[CH:7]=[C:6]([C:16]2[CH:17]=[CH:18][C:19]([CH3:23])=[C:20]([O:21][CH3:22])[C:15]=2[F:14])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[Cl:13]
Reactant: COC(=O)c1nc(Cl)cc(N)c1Cl
Reactant: COc1c(C)ccc(B(O)O)c1F
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1nc(-c2ccc(C)c(OC)c2F)cc(N)c1Cl
Temperature: 85 °C
Yield: 18.2 %

Procedure:
A solution of 4-amino-3,6-dichloropyridine-2-carboxylic acid, methyl ester (0.24 g, 1.1 mmol), 2-fluoro-3-methoxy-4-methylphenyl boronic acid (0.30 g, 1.63 mmol) and cesium fluoride (3.0 g, 3.26 mmole) in dimethoxyethane (2 mL) and water (2 mL) was purged with a stream of nitrogen for 15 minutes before adding dichlorobis(triphenylphosphine) palladium (0.07 g, 0.1 mmol) and then heated to 85° C. for 2 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×15 mL). The combined extracts were washed with brine, dried (sodium sulfate) and concentrated. The residue was purified by chromatography (33% ethyl acetate in hexanes) to give 4-amino-3-chloro-6-(2-fluoro-3-methoxy-4-methylphenyl)pyridine-2-carboxylic acid, methyl ester (0.08 g, 0.2 mmol): mp 95-96° C.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][S:5]([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:7])=[O:6].[CH3:26]I>CN(C)C=O>[CH3:3][N:4]([CH3:26])[S:5]([CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:6])=[O:7]
Reactant: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(c2c[nH]c3ccc(CCS(=O)(=O)N(C)C)cc23)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Sodium hydride (60% w/w with paraffin; 124 mg) was added cautiously to a stirred solution the product of Example 1 in dry dimethylformamide (20 ml). The resultant mixture was stirred at room temperature under nitrogen for 0.25 h then a solution of methyl iodide (440 mg) in dry dimethylformamide (1 ml) was added in a stream. The mixture was stirred at room temperature for 2.5 h. The reaction mixture was quenched with water (3 ml), evaporated in vacuo and the residue was chromatographed on silica (150 g), eluting with dichloromethane, ethanol and ammonia (80:10:1) to give a gum. The gum was briefly triturated in diethyl ether and the title compound crystallised out as a powder (238 mg), m.p. 170°-172°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.Cl>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccnc1NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1-Benzyl-piperidin-4-yl)-(3-nitro-pyridin-2-yl)-amine (from Step A) in 10 mL of THF was added 2.4 g of SnCl2 and 1 mL of concentrated HCl at room temperature, stirred at room temperature for 2 hours. The reaction was diluted with 40 mL of EtOAc and washed with 30 mL of saturated NaHCO3 aqueous solution. After separating layers, the aqueous phase was extracted with 2×15 mL EtOAc. The combined organic phases were washed with 15 mL of brine, dried over MgSO4 and concentrated under reduced pressure to give 603 mg of yellow soid.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:29][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:30]12([C:40](Cl)=[O:41])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>C1COCC1.N1C=CC=CC=1>[C:30]12([C:40]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:29][C:11]5[CH:12]=[N:13][C:14]([NH:16][C:17]([C:19]67[CH2:26][CH:25]8[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]8)[CH2:20]6)[CH2:28]7)=[O:18])=[CH:15][C:10]=5[N:9]=4)=[CH:4][CH:3]=3)=[O:41])[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(-c2nc3cc(NC(=O)C45CC6CC(CC(C6)C4)C5)ncc3[nH]2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C45CC6CC(CC(C6)C4)C5)cc3)[nH]c2cn1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of amine 14 (0.200 g, 0.50 mmol) in dry THF-Pyridine (10 ml/0.400 ml), adamantane carbonyl chloride (0.150 g, 0.75 mmol) was added and stirred at room temperature under argon overnight. The reaction was quenched with water and stirred at room temperature for 30 min. The yellow solid was filtered and passed through SiO2 gel using CH2Cl2: MeOH (95:5) as a eluent that yielded the desired product 15 (0.150 g, 50%). M.p. 265° C.; 1HNMR (DMSO-d6, 500 MHz): δ 13.02 (1H, brs, NH), 9.48 (1H, brs, NH), 9.37 (1H, brs, NH), 8.64 (1H, s), 8.24 (1H, s), 8.08 (2H, d, J=5.0 Hz), 7.88 (2H, d, J=5.0 Hz), 2.03-1.60 (30H, m). EIMS m/z: 449.6 (M+1); Anal (C34H39N5O2×0.85 H2O) C, H, N.
Reaction SMILES: [C:1]1([C:11]#[C:12][CH:13]=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([Mg]Br)[CH:16]=[CH2:17]>O1CCCC1>[C:1]1([C:11]#[C:12][CH:13]([OH:14])[CH2:17][CH:16]=[CH2:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=CC#Cc1cccc2ccccc12
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)C#Cc1cccc2ccccc12
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A solution of naphthalen-1-yl-propynal (2.50 g, 13.88 mmol) in tetrahydrofuran (50 mL) was added to a stirred solution of allylmagnesium bromide (1M in diethyl ether, 20.81 mL, 20.81 mmol, 1.5 eq.) at 0° C. over 0.5 h under an atmosphere of nitrogen. Stirring was continued for a further 2 h at 0° C. The reaction was quenched with water (50 mL) at 0° C. To the reaction mixture was added diethyl ether (100 mL) and the reaction mixture was stirred and allowed to separate. The aqueous phase was re-extracted with diethyl ether (3×100 mL) and the combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford a yellow oil. The crude material was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether 40-60; 30%:70%) to afford the desired compound as a yellow oil (2.34 g, 76%). 1H NMR (400 MHz, CDCl3) δ ppm 2.67-2.69 (2H, m, CH2), 4.80-4.81 (1H, m, CH), 5.24-5.31 (2H, m, CH2), 5.99-6.06 (1H, m, CH), 7.40-7.64 (4H, m, Ar—H), 7.66 (1H, d, J 8.0 Hz, ArH), 7.82 (1H, d, J 8.0 Hz, ArH), 8.28 (1H, d, J 8.0 Hz, ArH).
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:33][CH:32]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]([CH2:30][CH2:31]3)[CH2:28]2)[C:9]=1Br.C([Sn](CCCC)(CCCC)[C:58]([O:60][CH2:61][CH3:62])=[CH2:59])CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][Si:2]([CH3:52])([CH3:51])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:43][O:44][CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:33][CH:32]3[N:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:29]([CH2:30][CH2:31]3)[CH2:28]2)[C:9]=1[C:58]([O:60][CH2:61][CH3:62])=[CH2:59]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1nc3c(-c4ccc(C(C)(C)O)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c1Br)C2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(OCC)c1c(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(C(C)(C)O)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
tert-butyl 3-{7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-6-bromo-3-[6-(1-hydroxy-1-methylethyl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-5-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate (0.550 g, 0.672 mmol), tributyl[1-(ethyloxy)ethenyl]stannane (681 μL, 2.02 mmol) and tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.067 mmol) were placed in a 3-neck 25-mL round bottom flask equipped with a reflux condenser and rubber septa. Then, the flask was evacuated and back-filled with nitrogen three times before adding 1,4-dioxane (20 mL). The resulting solution was sparged with nitrogen for 15 minutes and then lowered into an oil bath that was heated at 100° C. and the resulting solution stirred overnight at the same temperature. Another portion of tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.067 mmol) was added after 14 h, and the reaction allowed to progress for another 24 h, at which point, analysis showed consumption of the starting material and formation of the desired product. The reaction was cooled to ambient temperature and concentrated in vacuo. The crude dark oil was purified by flash chromatography (40 g silica gel, 0 to 8% methanol in chloroform) to afford the title compound (476 mg).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[C:15]1[N:16]=[N:17][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:20]=1>O1CCCC1.C(OCC)(=O)C>[O:7]([C:15]1[N:16]=[N:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: Clc1ccc(Oc2ccccc2)nn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc(Oc2ccc(Oc3ccccc3)nn2)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 83.5 %

Procedure:
Phenol (Aldrich, 1.88 g, 20 mmol) in tetrahydrofuran (50 mL) was treated with potassium tert-butoxide (Aldrich, 2.24 g, 20 mmol) at ambient temperature for 10 minutes. The product of Example 27A (3.0 g, 14.5 mmol) was then added and the reaction mixture was stirred at 60° C. for 10 hours. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (100 mL), and washed with brine (2×10 mL). The organic phase was concentrated affording the title compound as a solid (3.2 g, yield, 84%). 1H NMR (MeOH-d4, 300 MHz) δ 7.14–7.28 (m, 6H), 7.38–7.48 (m, 6H) ppm. MS (DCl/NH3) m/z 265(M+H)+.
Reaction SMILES: COCCOC[O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.CCOC(C)=O.[Zn+2].[Br-].[Br-]>[CH2:21]([O:20][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([OH:7])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCOc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a stirred solution of (2′-methoxyethoxymethoxy-[1,1′;3′1″]terphenyl-5′-yloxy)butane (0.237 g, 0.583 mmol) in CH2Cl2 (6 mL) at room temperature was added anhydrous ZnBr2 (0.656 g, 2.92 mmol). After 18 h at this temperature, the resulting mixture was diluted with EtOAc (100 mL). The organic layer was washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by preparatory plate chromatography (10% EtOAc/petroleum ether) to afford the product (0.172 g, 92%) as a solid; 1H NMR (CDCl3) δ0.97 (t, J=10.9 Hz, 3H), 1.39-1.60 (m, 2H), 1.68-1.87 (m, 2H), 3.97 (t, J=9.5 Hz, 2H), 5.05 (s, 1H), 6.87 (s, 2H), 7.32-7.62 (m, 10H); mass spectrum [(+) ESI], m/z 319 (M+H)+, 341 (M+Na)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][CH3:13])([O-])=O>C(O)C.[Pt]>[NH2:1][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[O:12][CH3:13]
Reactant: COc1c(C)cc(Cl)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: COc1c(C)cc(Cl)cc1N
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A suspension of 2-nitro-4-chloro-6-methylanisole (16 g) and 10% Pt(S)/C (1.6 g) in ethanol was hydrogenated at 50 psi for 3 hours. After filtration and concentration, purification by flash chromatography over silica gel (eluted with 10% ethyl acetate in hexanes) gave 12.3 g (90%) of 2-amino-4-chloro-6-methylanisole. 1H NMR (300 MHz, CDCl3) δ6.58 (d, J=2.4 Hz, 1 H), 6.53 (d, J=2.4 Hz, 1 H), 3.77 (s, 3 H), 2.22 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1(=[O:41])[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][O:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:12]1[CH2:11][CH2:10][C@@H:9]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:38]3[CH2:39][CH2:40][C:35]4([C:31](=[O:41])[O:32][CH2:33][CH2:34]4)[CH2:36][CH2:37]3)=[O:27])=[CH:24][CH:23]=2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: O=C1OCCC12CCNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCC4(CCOC4=O)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 30 mg (0.07 mmol) 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 1 ml anhydrous DMF at ambient temperature was added 20 mg (0.1 mmol) 2-oxa-8-azaspiro[4.5]decan-1-one, followed by 20 mg (0.1 mmol) EDCl, 15 mg (0.10 mmol) HOBt, and 0.070 ml (0.35 mmol) diisopropylethylamine. The solution was stirred for 2 h. It was then filtered and purified by reverse-phase HPLC (TMC Pro-Pac C18; 35-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give 28 mg (70%) of the title compound as a white solid. LC/MS 549.2 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](Cl)=[O:39])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:1][CH:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:13]=3)[CH2:10][CH2:11]2)=[O:39])=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(O)c3ccccc3)CC2)c1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(OC(=O)Cc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(4-hydroxy-4-phenylbutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: 1H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.34–7.19 (m, 8H) 7.11 (m, 1H), 6.98 (m, 3H), 5.75 (t, 1H, J=6.8 Hz) 3.61 (s, 2H), 2.92 (d, 2H, J=8.1 Hz), 2.48 (m, 2H) 2.31 (m, 2H), 1.99–1.84 (m, 4H), 1.84–1.67 (m, 5H) 1.55–1.35 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 531.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)[CH2:10][C:9]2=[O:25])=[CH:4][CH:3]=1.[CH2:26](Br)[CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:26]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=3)[CH2:10][C:9]2=[O:25])=[CH:4][CH:3]=1)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CBr
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(O)cc3)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OCC(C)C)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Methyl 4-[1-(4-hydroxyphenyl)-2-pyrrolidon-4-yl]methoxybenzoate (2.00 g), isobutyl bromide (2.58 ml) and potassium carbonate (3.24 g) are dissolved and suspended in dimethylformamide (20 ml) and the mixture is heated with stirring at 80° C. for 24 hours. The solvent is distilled off under reduced pressure and water is added to the resulting residue. The resulting precipitate is collected by filtration and recrystallized from about 20% aqueous methanol to give the desired product (2.11 g}, m.p. 117.5°-118.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[Br-:15].[Br-:16].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])([O-])=O.[Ca+2]>CO.C(Cl)Cl>[Br:15][C:6]1[C:5]([C:11]([F:12])([F:13])[F:14])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([Br:16])[C:7]=1[OH:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1cc(Br)c(O)c(Br)c1C(F)(F)F
Yield: 15.5 %

Procedure:
2-Nitro-5-hydroxybenzotrifluoride (2.0 g, 9.7 mmol) was dissolved in a mixture of MeOH and CH2Cl2 (80 mL, 1:1) at 0° C. Benzyltrimethylammoniumtribromide (7.53 g, 19.3 mmol) and CaCO3 (2.0 g, 19.3 mmol) was added. The reaction mixture was heated at reflux for three days. The reaction was deemed complete by HPLC and LC/MS analysis and quenched by the addition of 1N HCl. The reaction mixture was washed with brine, dried with MgSO4 and purified on column (silica gel, with gradient elution of CHCl3/MeOH). This gave to 550 mg (16%) of 2,6-dibromo-3-trifluoromethyl-4-nitrophenol.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)(=[O:18])=[O:17].[F-].[Cs+].O1CCOCC1>[Pd].O>[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1nc(Br)ns1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc(S(C)(=O)=O)cc2)ns1
Temperature: 80 °C

Procedure:
To a mixture of tert-butyl 3-bromo-1,2,4-thiadiazol-5-ylcarbamate (1.90 g, 6.78 mmol), 4-(methylsulfonyl)phenylboronic acid (2.07 g, 10.3 mmol), cesium fluoride (2.09 g, 13.8 mmol), and the palladium catalyst (0.271 g, 0.383 mmol) was added dioxane (20 mL) and water (2 mL). The reaction mixture was degassed by bubbling nitrogen through the solution for 5 min and the reaction mixture was heated to 80° C. for 3 h. The reaction mixture was diluted with EtOAc, and the organic phase was washed with saturated NH4Cl (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 10% to 50% EtOAc in hexanes) gave tert-butyl 3-(4-(methylsulfonyl)phenyl)-1,2,4-thiadiazol-5-ylcarbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>N1C=CC=CC=1>[CH2:31]([O:30][C:28]([N:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[N:11]=[C:10]1[S:20][C:21]([F:26])([F:25])[CH:22]([F:23])[F:24])=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: Fc1ccc(-c2nc(SC(F)(F)C(F)F)[nH]c2-c2ccc(F)cc2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1c(SC(F)(F)C(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 0 °C
Yield: 67.5 %

Procedure:
To an ice-cooled mixture of 4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylthio)imidazole (1.5 g) in pyridine (20 ml) was added ethyl chloroformate (1.3 g). The progress of the reaction was monitored by thin layer chromatography. Additional ethyl chloroformate (7.0 g, added in three portions) and warming to room temperature were required to force the reaction to completion. The reaction mixture was poured into water, and the crystalline solid was collected and washed with water. There was obtained 1.2 g of colorless product, mp 137°-139°.