Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)=[CH:11][N:10]=[N:9]1.Br.[OH-].[Na+]>C(O)(=O)C>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[N:9]=[N:10][CH:11]=1
Reactant: COC(=O)CCCCn1nncc1-c1ccccc1OC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CCCCn1nncc1-c1ccccc1O
Temperature: 25 °C
Yield: 80.3 %

Procedure:
Combine 5-[5-(2-methoxy-phenyl)-[1,2,3]triazol-1-yl]-pentanoic acid methyl ester (2.99 g, 10.3 mmol), hydrobromic acid (50 mL, 48% in water), and acetic acid (50 mL, glacial) and heat to reflux under N2 for 3 hours. Add hydrobromic acid (20 mL, 48% in water) and continue heating at reflux under N2 overnight. Cool to room temperature, basify to pH 4 with 5N NaOH solution. Extract from aqueous layer with EtOAc (×3), wash combined organic layers with brine, dry combined organic layers over MgSO4 and concentrate to get 2.6 yellow oil. Concentrate, adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 3-5% MeOH/CH2Cl2. Add Et2O and concentrate (×5) in order to remove solvents and afford the title compound (2.16 g, 80%). MS (IS) 262 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.C([Li])CCC.[F:24][C:25]([F:39])([F:38])[C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH3:37])[CH:29]=1)=[O:27]>C1COCC1>[F:39][C:25]([F:24])([F:38])[C:26]([C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1)([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH3:37])[CH:29]=1)[OH:27]
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: Cc1nc2cc(Br)ccc2n1-c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc2cc(C(O)(c3cn(C)c4ccccc34)C(F)(F)F)ccc2n1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-2-methyl-1H-benzimidazole (210 mg, 0.68 mmol) in anhydrous THF (3 mL) was added n-butyllithium (1 mmol, 400 μL of a 2.5 M solution in hexanes) over a 1 minute period followed by a chilled (−78° C.) solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (200 mg, 0.88 mmol) in 1 mL of anhydrous THF. After 30 minutes, the mixture was quenched with ammonium chloride solution and extracted with methylene chloride. The organic layer was concentrated to afford a yellow oil. The residue was purified by column chromatography over silica gel eluting with 0-50% ethyl acetate in hexanes. The product rich fractions were collected and concentrated in vacuo to afford a light yellow oil. A second purification by reverse phase HPLC (C-18 column) using a gradient of 20-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 15 minutes and fractions corresponding to an earlier eluting peak (M+H 455) were collected. The acetonitrile was concentrated in vacuo, the residue was made basic with aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was concentrated to afford 55 mg of the title compound as an off-white solid. MS m/z 455 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30](=[O:45])[N:31]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:27]=[C:26]([Cl:46])[CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:46][C:26]1[CH:27]=[C:28]([CH:29]=[C:24]([O:23][CH2:22][CH2:21][NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:25]=1)[C:30]([N:31]([CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:45]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCN2CCCC2)C2CCCC2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCN1CCCC1)C1CCCC1
Reaction time: 2 h
Yield: 183.8 %

Procedure:
A solution of (2-{3-chloro-5-[cyclopentyl-(3-pyrrolidin-1-yl-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate (0.080 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure to give the title compound (0.075 g) as a colourless gum.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)[CH3:6]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)[CH3:6]
Reactant: COCCN(C)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: COCCN(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
In acetic acid (100 ml) was dissolved N-(2-methoxyethyl)-N-methyl-4-nitrobenzylamine (5.9 g), and to the mixture was added reduced iron (7.5 g) little by little. The mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added ethyl acetate, and precipitates were filtered off. The filtrate was washed with sodium hydroxide solution, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4-((N-(2-methoxyethyl)-N-methylamino)methyl)aniline (3.4 g) as red oil.
Reaction SMILES: C[O:2][C:3](=[O:22])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:21])[CH:12]=1)=[N:5]/[O:6][CH2:7][CH:8]([CH3:10])[CH3:9].[OH-].[Li+]>CO>[Cl:21][C:13]1[CH:12]=[C:11](/[C:4](=[N:5]\[O:6][CH2:7][CH:8]([CH3:10])[CH3:9])/[C:3]([OH:22])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: COC(=O)/C(=N/OCC(C)C)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CO/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid methyl ester (326 mg, 0.94 mmol) was dissolved in methanol (9.4 mL) and cooled to 0° C. A 2.0 N aqueous solution of lithium hydroxide (1.41 mL, 2.82 mmol) was added dropwise and the cooling bath was removed. After stirring 25 min, the reaction mixture was diluted with chloroform (175 mL) and washed with 0.2 M aqueous potassium bisulfate solution (50 mL). The aqueous phase was extracted with chloroform (75 mL) and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford (E)-(3-chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid as a faintly yellow semi-solid (352 mg, >100%), which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][NH:18][CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][N:18]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1C2CNCC1COC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound X) (100 mg, 0.33 mmol) in CH2Cl2 (5 mL) was added DIPEA (0.23 mL, 1.32 mmol) and methanesulfonyl chloride (57 mg, 0.49 mol). The reaction mixture was stirred at room temperature for 1 hour, and then quenched with sat. NH4Cl, then diluted with EtOAc (60 mL). The mixture was washed with sat. NH4Cl, sat. NaHCO3 and brine (20 mL) respectively. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure to give 7-methanesulfonyl-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound Y) (105 mg, 95%) as yellowish oil. MS: calc'd (MH+) 341, measured (MH+) 341.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[N:14]=[N:15][NH:16][N:17]=2)=[CH:5][CH:4]=1.Br.[OH-].[Na+]>>[N:17]1[NH:16][N:15]=[N:14][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: COc1ccc(CCCCc2nn[nH]n2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(CCCCc2nn[nH]n2)cc1
Yield: 52 %

Procedure:
450 mg (1.94 mmol) 5-(4-(4-methoxy-phenyl)-butyl)-2H-tetrazole and 1.5 ml 48% aqueous hydrobromic acid were stirred at 80° C. for 17 h. The reaction mixture was adjusted to pH=4 by addition of conc. NaOH and the aqueous phase discarded. Purification of the undissolved residue by HPLC-MS (methanol/water 7:3, pH=2.3) gave 220 mg (52%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH:5][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19])[CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCc1cccc(CC)c1NS(=O)(=O)c1ccc(C)cc1
Reaction time: 3 h

Procedure:
To a solution of 149.0 g (1.0 mole) of 2,6-diethylaniline in pyridine (500 ml) is added in portions at 0° C. 209.6 g (1.1 moles) of p-toluenesulfonyl chloride. The reaction mixture is allowed to come to room temperature and stir for three hours. The mixture is poured into cold aqueous 10% HCl and the crude sulfonamide solidified. The sulfonamide is filtered, washed with water and crystallized from acetic acid to give N-(2,6-diethylphenyl)-p-toluenesulfonamide m.p. 130°-131° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:17]1[N:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:6][CH2:7][N:8]([C:17]2[N:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[N:21][CH:22]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(2-bromo-5-fluorophenoxy)piperidine from Step 2 (1.90 g, 6.95 mmol), methyl 5-chloropyrazine-2-carboxylate (1.00 g, 5.79 mmol) and potassium carbonate (1.60 g, 11.59 mmol) in dioxane (30 mL) was heated at 100° C. After a period of 2 h, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The solvent was separated, dried over sodium sulfate and evaporated. The title compound was purified by flash chromatography (50% ethyl acetate in hexane) to provide the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:17][CH2:18][CH2:19][O:20][Si](C(C)C)(C(C)C)C(C)C.[H-].[Na+].O>CN(C=O)C>[OH:20][CH2:19][CH2:18][CH2:17][O:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CC(C)[Si](OCCCBr)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCOCC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.5 g (2.3 mmol) of 1-t-butoxycarbonyl-4-hydroxymethylpiperidine and 1.4 g (4.6 mmol) of 1-bromo-3-(triisopropylsilyloxy)propane in 3 mL of DMF was added 0.12 g (4.1 mmol) of NaH (60% dispersion in mineral oil) and the reaction mixture was stirred at rt for 16 h. To the reaction mixture was added 10 mL of H2O and it was extracted with ether. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=19:1) to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([C:15]([N:17]([C@H:21]([CH3:38])[C@:22]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])([OH:29])[CH2:23][N:24]3[CH:28]=[N:27][CH:26]=[N:25]3)[CH2:18][CH2:19]O)=[O:16])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].C(P(CCCC)CCCC)CCC>C1COCC1>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C@:22]1([CH2:23][N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[O:29][CH2:19][CH2:18][N:17]([C:15]([C:11]2[S:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:13][C:12]=2[CH3:14])=[O:16])[C@@H:21]1[CH3:38]
Reactant: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)N(CCO)[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)N1CCO[C@@](Cn2cncn2)(c2ccc(F)cc2F)[C@H]1C

Procedure:
A cooled (0° C.) solution of (1R,2R)-2-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N-(2-hydroxyethyl)-4-methylthiazole-5-carboxamide (0.45 g, 0.83 mmol, obtained in example 82) in THF (10 mL) was treated with diethylazadicarboxylate (0.20 mL, 1.25 mmol) and tributylphosphine (0.31 mL, 1.25 mmol) for 20 h at room temperature. The mixture was evaporated to dryness and the residue was purified by flash chromatography to give the title compound as a white solid: mp 150°-160° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.06 (d, J=8.4, 2H, arom), 7.76 (s, 1H, triazole), 7.76 (d, J=8.4, 2H, arom), 7.30 (s, 1H, triazole), 7.4-7.2 (m, 1H, arom), 7-6.7 (m, 2H, arom), 5.53 (br), 5.17 (d, J=15.1, 1H, TrCH(H)), 4.7 (br d, 1H), 4.6-4.4 (m, 1H), 4.0 (br d), 3.6 (br s), 2.57 (s, 3H, Me-thiazole), 1.13 (d, J=6.8, 3H, MECH); GC--MS 293 (M+ -acyl, C14H15N4F2O), 227 (acyl group, C12H7N2OS); [α]D =-80.5° (c 1, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-])=[C:4]([CH3:9])[C:3]=1[CH3:10].S(OC)(OC)(=O)=O.[C-:18]#[N:19].[K+]>CC#N.O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[N:5]=[C:6]([C:18]#[N:19])[CH:7]=1
Reactant: Cc1c(Br)cc[n+]([O-])c1C
Reactant: [C-]#N
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Solvent: O
Product: Cc1nc(C#N)cc(Br)c1C
Temperature: 70 °C
Reaction time: 3.25 h

Procedure:
A mixture of 4-bromo-2,3-dimethyl-1-oxido-pyridin-1-ium (15.8 g, 78.2 mmol) (which may be prepared as described in Description 5) and dimethyl sulfate (8.88 mL, 93.84 mmol) in MeCN (36 mL) was stirred at block temp of 70° C. under N2 for 3.25 h. The reaction mixture was evaporated to an oil which was stirred with Et2O (2×50 ml) and the solvent was decanted from the oil. The oil was dried in vacuo and dissolved in water (105 mL) and then was added over 25 mins to a stirred solution of potassium cyanide (20.37 g, 312.79 mmol) in water (75 mL), cooled in a salt-ice Dewar bath (range during addition −5 to 0° C.). The turbid mixture was stirred in the ice/salt bath whilst it warmed slowly to ambient temperature overnight. The beige precipitate was then filtered under suction and washed with water (3×50 ml) and pressed dry. This moist solid was then dissolved in DCM (300 ml), dried (Na2SO4), filtered and evaporated to a beige solid, approximately 90% pure 4-bromo-5,6-dimethyl-pyridine-2-carbonitrile (D144) by NMR;
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1)([CH3:13])[CH3:12].C(=O)([O-])O.[Na+]>ClCCl.O.C(N(CC)CC)C>[CH:11]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCC(C=O)CC1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 39.8 %

Procedure:
Oxalyl chloride (3.15 ml) was dissolved in 30 ml of dichloromethane, a solution of 3.20 ml of dimethyl sulfoxide in 6 ml of dichloromethane was added thereto at −70° C., the mixture was stirred for 15 minutes, a solution of 2.93 g of (1-isopropyl-4-piperidyl)methanol in 15 ml of dichloromethane was added thereto at −70° C. and the mixture was stirred for 1 hour. After 12.5 ml of triethylamine were added at −70° C., the mixture was raised to room temperature, then water and a saturated aqueous solution of sodium hydrogen carbonate were added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and ethyl acetate was added to the resulting residue. After removing the insoluble matter by filtration, the solvent was evaporated in vacuo to give 1.15 g of 1-isopropylpiperidine-4-carbaldehyde. This compound was used for the next reaction without purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)#[N:2].[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:13]1([CH2:12][CH2:11][CH2:10][S:9][C:5]2[N:4]=[C:3]([C:1]3[S:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[C:19](=[O:27])[N:2]=3)[CH:8]=[CH:7][CH:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(SCCCc2ccccc2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(SCCCc3ccccc3)n2)sc2ccccc12
Yield: 37.6 %

Procedure:
2-Cyano-6-(3-phenylpropylthio)pyridine (1.84 g, 7.22 mmol) and methyl thiosalicylate (1.21 g, 7.22 mmol) were dissolved in toluene (30 ml), and triethylamine (1.52 ml, 10.8 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (1.06 g, 38%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[Mg]Br.Br[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([CH3:20])[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl>[CH3:20][C:14]1[CH:13]=[C:12]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: Cc1cc(Br)ccc1C#N
Reactant: Cc1ccc(C)c([Mg]Br)c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C)c(-c2ccc(C#N)c(C)c2)c1
Yield: 90 %

Procedure:
2,5-dimethylphenylmagnesium bromide (84 g, 20% solution in tetrahydrofuran) is added dropwise over five hours to a refluxing solution of 4-bromo-2-methylbenzonitrile (16 g), palladium (II) chloride (0.57 g) and triphenylphosphine (1.7 g) in tetrahydrofuran (100 ml). [HPLC: yield 90-95%]. After cooling to room temperature tetrahydrofuran is removed under vacuum. The residue is taken up in toluene/water (1:1) (200 ml) and filtered. The aqueous phase is separated off, and the solvent removed by distillation. The crude product is recrystallised from ethanol to give 3,2',5'-trimethylbiphenyl-4-carbonitrile as a solid, m.pt. 96-97° C. 1H NMR (CDCl3): 2.19(s,3H), 2.34(s,3H), 2.58(s,3H), 6.99(s,1H), 7.08-7.25(m,3H), 7.62(d,1H).
Reaction SMILES: [CH:1]1([C:6]2[CH:35]=[CH:34][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:16]5=[C:15]([CH2:32][CH3:33])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:36]([F:39])([F:38])[F:37])[CH2:5][CH2:4][CH2:3][CH2:2]1.NC(CS)C(O)=O>C(O)(C(F)(F)F)=O>[CH:1]1([C:6]2[CH:35]=[CH:34][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[C:15]([CH2:32][CH3:33])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:36]([F:39])([F:37])[F:38])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1c2n(c3ccc(OCc4ccc(C5CCCC5)c(C(F)(F)F)c4)cc13)CCC2CC(=O)OC(C)(C)C
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCc1c2n(c3ccc(OCc4ccc(C5CCCC5)c(C(F)(F)F)c4)cc13)CCC2CC(=O)O
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 13.7 %

Procedure:
tert-Butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-ethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (6.6 mg, 0.012 mmol) was added to a solution of 2-amino-3-mercaptopropanoic acid (1.476 mg, 0.012 mmol) in TFA (1 mL). The reaction was stirred at 23° C. for 15 min in a 20 mL sealed scintillation vial. The mixture was poured into about 4 mL of ice water. The precipitate was collected by vacuum filtration through a glass fiber paper, washed with n-hexane (3×5 mL), and dried (vacuum oven) to give the title compound (0.8 mg) as a tan solid. LCMS m/z=486.3 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.09 (t, J=7.52 Hz, 3H), 1.48-1.59 (m, 2H), 1.60-1.69 (m, 2H), 1.74-1.82 (m, 2H), 1.93-2.00 (m, 2H), 2.17-2.27 (m, 1H), 2.39-2.49 (m, 1H), 2.55-2.63 (m, 2H), 2.66-2.81 (m, 2H), 3.21-3.32 (m, 1H), 3.54-3.63 (m, 1H), 3.82-3.89 (m, 1H), 3.92-4.00 (m, 1H), 5.05 (s, 2H), 6.70 (dd, J=8.72, 2.40 Hz, 1H), 6.96 (d, J=2.27 Hz, 1H), 7.03 (d, J=8.72 Hz, 1H), 7.49 (d, 1H), 7.57 (d, J=9.35 Hz, 1H), 7.64 (d, J=1.14 Hz, 1H), 8.95 (bs, 1H).
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH3:5])#[N:2].[C:9]([C:11]1[CH:25]=[CH:24][C:14]2[O:15][C:16]([CH3:23])([CH3:22])[C@@H:17]([OH:21])[C@H:18]([NH:19][CH3:20])[C:13]=2[CH:12]=1)#[N:10]>C(OCC)(=O)C>[C:9]([C:11]1[CH:25]=[CH:24][C:14]2[O:15][C:16]([CH3:22])([CH3:23])[C@@H:17]([OH:21])[C@H:18]([N:19]([C:4](=[N:3][C:1]#[N:2])[CH3:5])[CH3:20])[C:13]=2[CH:12]=1)#[N:10]
Reactant: CN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reactant: CCOC(C)=NC#N
Solvent: CCOC(C)=O
Product: CC(=NC#N)N(C)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h

Procedure:
To 2.80 g of ethyl N-cyanoacetimidate, 4.65 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-methylamino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 2.34 g of the above identified compound in the form of crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17][CH3:18])[NH:10][C:9]=2[C:19]([O:21]CC)=[O:20])=[CH:4][CH:3]=1.[OH-].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[S:17][CH3:18])[NH:10][C:9]=2[C:19]([OH:21])=[O:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1[nH]c2cccc(SC)c2c1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1cccc2[nH]c(C(=O)O)c(-c3ccc(Cl)cc3)c12
Yield: 101.6 %

Procedure:
To a solution of the ester of Step 4 (1.5 g) in EtOH (15 mL) was added 1N KOH solution (13 mL). The reaction mixture was stirred at reflux for 1 hour. The organic solvent was removed by evaporation and the aqueous solution was acidified with 3N HCl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give the title compound as a white solid (1.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2([C:18]#N)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]2)=[C:4](I)[CH:3]=1.[Li]CCCC.C1C[O:31]CC1>>[Br:1][C:2]1[CH:21]=[C:20]2[C:5]([CH2:6][C:7]3([CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]3)[C:18]2=[O:31])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(Cc2ccc(Br)cc2I)C1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=O)C1
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of tert-butyl 3-(4-bromo-2-iodobenzyl)-3-cyanoazetidine-1-carboxylate (4.2876 g, 8.99 mmol) in THF (120 mL) was added n-BuLi (2.5 Min hexane, 3.8 mL, 9.5 mmol) at −78° C. dropwise over 10 min under nitrogen. After 1 h, the reaction mixture was quenched with saturated NH4Cl, diluted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 1.7020 g (54%) of tert-butyl 6′-bromo-1′-oxo-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate as a solid. LC-MS tR=1.90 min in 3 min chromatography, m/z 352, 354 (MH+), 337, 339 (MH+-15), 296, 298 (MH+-56); 1H NMR (400 MHz, CDCl3) δ 7.91 (m, 1H), 7.74-7.71 (m, 1H), 7.35 (d, J=7.9 Hz, 1H), 4.23 (d, J=8.2 Hz, 2H), 3.88 (d, J=8.2 Hz, 2H), 3.40 (s, 2H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 204.38, 156.03, 150.44, 138.17, 137.24, 127.88, 127.29, 122.19, 80.05, 57.88, 44.70, 39.67, 28.35.