Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=[O:8])C1C=CC=CC=1.[CH3:19][C:20]1[CH:25]2[C:26]([CH3:28])([CH3:27])[CH:23]([CH2:24]2)[CH2:22][CH:21]=1.[OH-].[Na+]>C(#N)C.CO.O>[CH3:19][C:20]1[C@@H:25]([OH:8])[CH2:24][C@H:23]([C:26]([CH3:28])=[CH2:27])[CH2:22][CH:21]=1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Reactant: CC1=CCC2CC1C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: C=C(C)[C@@H]1CC=C(C)[C@@H](O)C1
Yield: 61 %

Procedure:
A well stirred solution of benzoyl peroxide (24.0 g), cuprous chloride (0.2 g), cupric benzoate (1.5 g) and alpha-pinene (28.0 g) in acetonitrile (150 ml) is heated on an oil bath at 65° ± 5° for 24 hours. The acetonitrile is removed by evaporation under vacuum (water pressure) at 40°. Excess alpha-pinene is recovered by continuing the evaporation at 75° (3 mm). The resulting blue-green slurry is dissolved in 100 ml ether and the solution filtered to remove the cupric benzoate. The filtrate is washed with 2N HCl (2 × 30 ml), distilled water (3 × 30 ml) and then the ether removed by evaporation. This gives a straw colored oil which is dissolved in a solution of methanol (200 ml), water (50 ml), NaOH (10 g), and hydroylzed by refluxing 1 hour. Removal of the methanol affords an aqueous suspension which is diluted with water (100 ml) and steam distilled. The distillate is extracted with ether (4 × 20 ml). This organic solution is dried over magnesium sulphate and evaporated to yield crude trans-carveol (9.2 g). Distillation affords pure material, b.p. 106°-110°C (10 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH:15]=O)([CH3:14])[CH3:13].[NH:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:17]1([CH:15]([NH:8][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:12]([CH3:13])([CH3:14])[CH3:11])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1ccc(Cl)cc1)n1nnc2ccccc21

Procedure:
A suspension of 4-chlorobenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[N:9]=[C:8]([NH:24][C@H:25]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)[N:7]=1)=[O:5])C.[NH2:37]C1C(C(OCC)=O)=NC(N[C@H]2CCN(C(OC(C)(C)C)=O)C2)=NC=1NC1C=CC=CC=1OC.[CH2:71]([OH:73])C>[Pd]>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:15]1[C:71](=[O:73])[NH:12][C:11]2[C:10]1=[N:9][C:8]([NH:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1)=[N:7][C:6]=2[C:4]([NH2:37])=[O:5]
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc(Nc2ccccc2OC)c1N
Reactant: CCO
Agent: [Pd]
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CCNC3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
(S)-Ethyl 5-amino-2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-6-(2-methoxy-phenylamino)pyrimidine-4-carboxylate (S)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (0.424 g, 0.844 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.085 g) were added to the flask and flushed with fresh hydrogen gas and allowed to stir at room temperature. After 16 h, the reaction was filtered through celite and the filtrate condensed under reduced pressure. The crude oil was purified using biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.357 g, 94%). MS (ESI) m/z 473.5 [M+1]+.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([Br:11])[CH:5]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.[H][H]>N1C(C)=CC(C)=CC=1C>[Br:10][C:8]1[CH:9]=[C:4]([O:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[C:6]([Br:11])[CH:7]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: Oc1ccc(F)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1cc(C)nc(C)c1
Product: Fc1ccc(Oc2cc(Br)cc(Br)c2)cc1
Reaction time: 8 h
Yield: 32.5 %

Procedure:
Sodium hydride (3.24 g of 60% suspension in mineral oil was added portionwise to a stirred mixture of 1,3,5-tribromobenzene (76.4 g), 4-fluorophenol (18.16 g), and cuprous oxide (11.6 g) in collidine (400 ml) at room temperature. When evolution of hydrogen had ceased the mixture was heated under reflux with stirring for 8 hours. It was then cooled and filtered. The residue was washed with ethyl acetate followed by concentrated aqueous ammonia, and the combined filtrate and washings were partitioned between ethyl acetate and water. The organic layer was washed twice with brine and evaporated. The residue was dissolved in ethyl acetate, and the solution was filtered, washed several times with citric acid solution and dried (MgSO4). The solvent was evaporated, and the residue was dissolved in hot hexane. The solution was filtered and the filtrate was evaporated. The residue was chromatographed on silica using hexane as eluent to give the title compound as an oil (18.21 g), Rf 0.31(SS 2). Found: C,41.71; H,1.97. C12H7Br2FO requires C,41.66; H,2.04%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@H:15]([CH2:16][C@@H:17]([O:28]S(C)(=O)=O)[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:33])[CH2:10][CH2:9]1)[CH3:7].[CH2:35](O)[CH2:36][OH:37].N1C=CC=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([O:28][CH2:35][CH2:36][OH:37])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:33])[CH2:10][CH2:9]1)[CH3:7]
Reactant: OCCO
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@@H](OCCO)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Temperature: 120 °C
Yield: 37 %

Procedure:
A pressure vessel (250 mL flask) containing the compound of Example 1A (10.0 g, 20 mmol) was charged with ethylene glycol (20 mL) and pyridine (4 mL) at ambient temperature, sealed and then heated at 120° C. for 4 hours. The reaction was cooled to ambient temperature, diluted with EtOAc (50 mL), and quenched with 1N HCl (30 mL). The layers were separated and the organic layer was washed with 1N HCl (2×30 mL), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (10%—>40% acetone/hexanes) provided the title compound (3.5 g, 37%). MS (ESI) m/e 484 (M+NH4)+
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.C1COCC1>O>[CH2:1]([O:8][C:9]([N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc(CNCC2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CNCc2ccccc2)CC1
Reaction time: 3 h
Yield: 49.7 %

Procedure:
Under ice-cooling, 3.46 g of benzyloxycarbonyl chloride was added dropwise to a mixed solution of 4.15 g of N-(4-piperidylmethyl)-N-benzylamine, 2.10 g of triethylamine and 200 ml of THF. After stirring the mixture at the same temperature for 3 hours and then at room temperature for 2 hours, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed and dried, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; chloroform:methanol=19:1) to give 3.41 g of N-(1-benzyloxycarbonylpiperidin-4-ylmethyl)-N-benzylamine (yield: 50%, IR: 1702 cm-1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[CH:6])[CH3:2].[CH:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=1.CN1CCOCC1>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])/[CH:5]=[CH:6]/[O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: C#CC(=O)OCC
Reactant: OCCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: CCOC(=O)/C=C/OCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
The reaction was performed in standard glassware under an atmosphere of N2. To 100 ml of diethylether were added 9.8 g (0.1 mol) of propiolic acid ethyl ester, 12.2 g (0.1 mol) phenylethanol and 10.1 g (0.1 mol) of N-methylmorpholine. This solution was kept without stirring at room temperature for 24 hours. The mixture was evaporated under vacuum and the residue purified by bulb to bulb distillation (bp: 70-75° C., 0.006 mbar) to yield 15.7 g (88%) of an oil.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:58]=[CH:57][C:29]3=[N:30][N:31]([C:33]4[CH:38]=[C:37]([C:39]([CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:47]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([CH3:49])[CH3:48])[C:34]=4[OH:56])[N:32]=[C:28]3[CH:27]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:10][C:3]1([CH3:11])[CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[N:2]1[O:1][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:58]=[CH:57][C:29]3=[N:30][N:31]([C:33]4[CH:38]=[C:37]([C:39]([CH2:42][C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:47]([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)([CH3:48])[CH3:49])[C:34]=4[OH:56])[N:32]=[C:28]3[CH:27]=2)=[CH:24][CH:25]=1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccc(N)cc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccc(ON5C(C)(C)CCCC5(C)C)cc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Yield: 87.3 %

Procedure:
The title compound is prepared reacting 0.59 g (3.75 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 1.0 g (10 mmol) of tert-butyl nitrite, 2.3 mg (0.0037 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 120 mL of pyridine and 24.0 g (75 mmol) of 5-(4-aminophenyl)-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole, prepared in Example 17, in 10 mL of pyridine at 70° C. The crude product obtained is purified by vacuum flash chromatography (2% ethyl acetate/heptane) to give 2.20 g of the title compound as a colorless oil in 87.3% yield. M/S [M+1]673.
Reaction SMILES: [C:1](=[S:7])([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH:8]([CH:10](Cl)[C:11](OCC)=O)=[O:9].O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[OH:9][CH2:8][C:10]1[S:7][C:1]([CH2:2][CH:3]([CH3:5])[CH3:4])=[N:6][CH:11]=1
Reactant: CCOC(=O)C(Cl)C=O
Reactant: CC(C)CC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cc1ncc(CO)s1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
Isovalerothioamide (6.0 g, 51 mmol) and ethyl formylchloroacetate (Heterocycles 32 (4), 693–701, (1991), 5.0 g, 33 mmol) are dissolved in dry DMF (20 mL), and heated to 95 degrees C. for 4 hours. The reaction is subsequently cooled to 0 degrees C., and cold water (50 mL) is added. The mixture is basified to pH=8 with solid sodium bicarbonate, then extracted with ether (3×35 mL). The combined organic extracts are washed with water, then saline and dried over magnesium sulfate, filtered, and concentrated. The residue is purified by flash chromatography (ethyl acetate/hexanes 4–10% elution) to give the desired product. NMR (CDCl3, 300 MHz) δ 8.27, 4.45–4.30, 3.70–3.50, 3.00–2.80, 2.30–2.10, 1.40–1.20, and 1.10–0.90.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:18])=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13].F[C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][C:21]=1[N+:33]([O-:35])=[O:34].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(Cl)(Cl)Cl.O>[Br:1][C:2]1[C:3]([O:18][C:20]2[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[CH:22][C:21]=2[N+:33]([O-:35])=[O:34])=[C:4]([Cl:17])[CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH2:8][CH:7]2[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(O)c2Br
Reactant: CC(C)(C)OC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a stirred solution of ethyl 8-bromo-6-chloro-7-hydroxychroman-4-carboxylate (4.00 g, 11.9 mmol) and tert-butyl 4-fluoro-3-nitrobenzoate (3.16 g, 13.1 mmol) in N,N-dimethylformamide (66 mL) at ambient temperature was added solid potassium carbonate (2.64 g, 19.1 mmol). The resulting mixture was stirred in an oil bath set to 90° C. for 30 minutes. The mixture was cooled to ambient temperature and poured into a reparatory funnel containing water (600 mL). Chloroform (300 mL) was added, followed by 1M hydrochloric acid (100 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 90/10 hexanes/ethyl acetate to afford ethyl 8-bromo-7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6-chlorochroman-4-carboxylate as a light yellow glass (4.33 g, 65% yield).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:19][CH2:20][CH2:21][O:22][C:23]=4[CH:24]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.CC(C)([O-])C.[K+].CN1CCCC1=O>[Cu]Br.O>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:16]4[C:15](=[CH:24][C:23]5[O:22][CH2:21][CH2:20][O:19][C:18]=5[CH:17]=4)[O:14][CH2:13]2)[C:5](=[O:12])[N:6]3[CH3:11])=[CH:29][CH:28]=1
Reactant: COc1ccc(O)cc1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21
Agent: [Cu]Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3C)cc1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A 10 mL microwave reaction vessel was charged with 4′-bromo-1′-methyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one (0.19 g, 0.5 mmol), 4-methoxyphenol (0.12 g, 1.0 mmol), potassium tert-butoxide (0.11 g, 1.0 mmol), copper (I) bromide (0.012 g, 0.08 mmol) and anhydrous 1-methylpyrrolidin-2-one (2 mL). The reaction mixture was irradiated at 250° C. for 75 min in a microwave reactor and was allowed to cool to ambient temperature. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (50 mL). The combined organic extracts were washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes afforded 4′-(4-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.084 g, 39%) as an off-white solid: mp 55-58° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ7.27-7.14 (m, 1H), 6.78-6.59 (m, 5H), 6.44 (d, J=8.48 Hz, 1H), 6.31 (d, J=1.08 Hz, 1H), 6.22 (d, J=1.08 Hz, 1H), 4.86 (ABq, 2H), 4.16-4.03 (m, 4H), 3.74 (s, 3H), 3.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.6, 155.8, 155.6, 154.3, 149.6, 144.8, 144.3, 137.7, 130.0, 120.2, 120.1, 119.5, 114.5, 112.7, 111.0, 103.1, 99.1, 64.4, 63.9, 57.4, 55.6, 27.0; MS (ES+) m/z 432.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1>C(O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(N)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Solvent: CCO
Product: COc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 72.6 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 3.0 ml (26.0 mmol) m-anisidine was heated to reflux under N2. Removed heat at 4.5 hours and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried with hexane and collected crystals. Washed with water, dried in vacuo. Dissolved 5.94 g of crude product in 320 ml boiling ethyl acetate, stirred with Darco, filtered, stripped solvent, and dried in vacuo, giving about 5 g of yellow-orange solid: mass spectrum (electrospray m/e): M+H=291.1.
Reaction SMILES: [ClH:1].CCOCC.[CH2:7]([N:14]1[C:20](=[O:21])[CH:19]([NH:22][C:23](=[O:35])[C@@H:24]([N:26](C)[C:27](=O)OC(C)(C)C)[CH3:25])[CH2:18][S:17][C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]1=2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[ClH:1].[CH2:7]([N:14]1[C:20](=[O:21])[CH:19]([NH:22][C:23](=[O:35])[C@@H:24]([NH:26][CH3:27])[CH3:25])[CH2:18][S:17][C:16]2[CH:36]=[CH:37][CH:38]=[CH:39][C:15]1=2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[C@@H](C(=O)NC1CSc2ccccc2N(Cc2ccccc2)C1=O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)NC1CSc2ccccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
1 M HCl in Et2O (2 mL, 2.00 mmol, Eq: 26.7) was added to a solution of tert-butyl (S)-1-(5-benzyl-4-oxo-2,3,4,5-tetrahydro-benzo[b][1,4]thiazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (35 mg, 75 μmol, Eq: 1.00) in MeOH (1 mL). After 2 h at RT, the mixture was stored in a freezer overnight, removed from the freezer and stirred an additional 2 h at RT. The mixture was concentrated, the residue dissolved in MeCN/H2O, and lyophilized to afford the title compound (25 mg, 83%). MS m/z 370.0 (MH+)
Reaction SMILES: [CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([CH:19]4OCCCO4)=[CH:15][CH:14]=3)=[CH:9][C:8]=2[C:27]([F:30])([F:29])[F:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:32]1[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]1.[BH3-]C#N.[Na+]>C1COCC1.C(OCC)C.C(N(CC)CC)C>[CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([CH2:11][S:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][N:32]4[CH2:35][CH:34]([C:36]([OH:38])=[O:37])[CH2:33]4)=[CH:17][CH:18]=3)=[CH:9][C:8]=2[C:27]([F:30])([F:28])[F:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: FC(F)(F)c1cc(CSc2ccc(C3OCCCO3)cc2)ccc1C1CCCCC1
Reactant: O=C(O)C1CNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(O)C1CN(Cc2ccc(SCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[4-(4-cyclohexyl-3-trifluoromethyl-benzylsulfanyl)-phenyl]-[1,3]dioxane (90 mg, 0.2 mmol) in THF (10 mL), is added aqueous HCl (2N, 0.7 mL). The solution is stirred at room temperature for 4 h. The solution is diluted with diethyl ether (30 mL), and washed with saturated aqueous NaHCO3 (3×10 mL). The organic layer is washed with saturated aqueous NaCl, dried over Na2SO4, and partially concentrated followed by dilution with MeOH (10 mL). To the resulting solution is added triethyl amine (0.5 mL) and azetidine-3-carboxylic acid (46 mmol, 0.4 mmol). The resulting mixture is stirred at 50° C. for 30 min. The reaction is cooled to room temperature and NaCNBH3 (63 mg, 1 mmol) is added. The resulting mixture is stirred for 30 min followed by concentration to dryness. The crude product is purified by preparative RP LC-MS to give 1-[4-(4-cyclohexyl-3-trifluoromethyl-benzylsulfanyl)-benzyl]-azetidine-3-carboxylic acid as a colorless oil. 1HNMR (400 MHz, CD3OD) δ7.55–7.54 (m, 2H), 7.52–7.35 (m, 5H), 4.39 (s, 2H), 4.35 (m, 4H), 4.17 (s, 2H), 3.68 (tt, 1H), 2.90 (tt, 1H), 1.87–1.75(m, 5H), 1.72–1.48 (m, 5H); MS (ES+): (464.2, M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=3)=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:16](=[O:36])[N:15]2[CH3:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:38][C@H:39]([CH2:41][O:42][CH3:43])[CH3:40]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:38][C@@H:39]([CH3:40])[CH2:41][O:42][CH3:43])[N:20]=3)=[C:17]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:16](=[O:36])[N:15]2[CH3:37])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@H](C)N
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)c(-c2ccnc(S(C)(=O)=O)n2)n1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Product: COC[C@H](C)Nc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n(C)n2C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[4-(4-fluorophenyl)-2-methyl-5-(2-methanesulfonyl-pyrimidin-4-yl)-3-oxo-2,3-dihydro-pyrazol-1-yl]-piperidine-1 carboxylic acid tert-butyl ester, 12, (6 g, 12 mmol) in toluene (30 mL) is added (S)-2-amino-3-methoxypropane (2.14 g, 24 mmol). After stirring at 90° C. for 2 hours, the reaction mixture is cooled to room temperature and then concentrated in vacuo. Purification over silica (50% EtOAc/hexane) affords the desired product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][C@@H:18]1[CH2:19][CH2:20][C:21](=[O:23])[O:22]1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CC[C@@H](CO)O1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C1CC[C@@H](COS(=O)(=O)C(F)(F)F)O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Trifluoromethanesulfonic anhydride (0.97 g, 3.4 mmol) was added dropwise to a 0° C. solution of (S)-5-(hydroxymethyl)-dihydrofuran-2(3H)-one (0.20 g, 1.7 mmol) and lutidine (0.41 g, 3.8 mmol) in CH2Cl2 (2 mL). The reaction was stirred at 0° C. for 1.5 hours, then diluted with 1:4 EtOAc/hexanes and passed through a plug of silica gel. The volatiles were removed under reduced pressure to yield a yellow oil which was used immediately without purification (0.38 g, 89%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].CCN(C(C)C)C(C)C.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[C@H:3]1[C:7]([OH:9])=[O:8])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H]1[C@@H](O)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(2S,3S)-3-Hydroxy-pyrrolidine-2-carboxylic acid (254.5 mg, 1.9 mmol) was dissolved in DMF (15 mL) and distilled water (6 mL). The solution was cooled to 0° C., and DIEA (500 μL, 2.9 mmol) was added followed by benzyl chloroformate (410 μL, 2.9 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.