Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:38][CH:37]=2)=[CH2:35])[N:28]=3)=[C:21]([F:50])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]2([C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:38][CH:37]=4)[CH2:1][CH2:35]2)[N:28]=3)=[C:21]([F:50])[CH:20]=1
Reactant: C=C(c1ccc(OCc2ccccc2)cc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccc(OCc5ccccc5)cc4)CC3)nc2s1
Reaction time: 4 h

Procedure:
A solution of potassium tert-butoxide (0.206 g, 1.83 mmol) and trimethylsulfoxonium iodide (0.404 g, 1.83 mmol) in 5 mL DMSO under nitrogen was added 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)vinyl)-thiazolo[5,4-b]pyridine (0.385 g, 0.734 mmol) as a solution in 6 mL THF (min volume to dissolve) slowly dropwise via addition funnel over 1 h. The cloudy reaction mixture was allowed to stir for 4 h and was quenched with ice. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water, brine, dried, and concentrated in vacuo to give an oil/solid which was purified by silica gel chromatography 0-100% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)cyclopropyl)thiazolo[5,4-b]pyridine as a yellow solid. The aqueous suspension from the extraction was further extracted with DCM, the combined org extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give additional 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)-cyclopropyl)thiazolo[5,4-b]pyridine. MS (ESI) m/z: calculated: 538.2; Observed: 539.1 (M++1).
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.O[C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23]([OH:30])=[CH:24][CH:25]=3)[C:20]([CH3:32])([CH3:31])[C:19]=2[CH:18]=1.B(O)(O)O>C1(C)C(C)=CC=CC=1>[OH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][C:17]2[CH:29]=[CH:28][C:27]3[C:26]4[C:21](=[CH:22][C:23]([O:30][C:11](=[O:12])[C:10]5[CH:14]=[CH:15][C:7]([OH:6])=[CH:8][CH:9]=5)=[CH:24][CH:25]=4)[C:20]([CH3:32])([CH3:31])[C:19]=3[CH:18]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: CC1(C)c2cc(O)ccc2-c2ccc(O)cc21
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Product: CC1(C)c2cc(OC(=O)c3ccc(O)cc3)ccc2-c2ccc(OC(=O)c3ccc(O)cc3)cc21
Yield: 85.4 %

Procedure:
In a nitrogen atmosphere, concentrated sulfuric acid (0.2 mL) was added to a mixture of 4-hydroxybenzoic acid (12.2 g), 2,7-dihydroxy-9,9-dimethylfluorene (10.0 g), boric acid (0.3 g) and xylene (120 mL), and the mixture was heated under reflux for 6 hours while removing water. A deposited matter was filtered and rinsed with toluene. It was recrystallized from a mixed solvent of ethanol (75 mL) and acetone (75 mL) to provide 2,7-bis(4-hydroxybenzoyloxy)-9,9-dimethylfluorene (compound [H2]) (17.6 g) in the form of pale rose solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.Cl[C:10]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=[C:12]([Cl:21])[CH:11]=1>Cl.C(O)C>[Cl:21][C:12]1[CH:11]=[C:10]([NH:1][C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][N:13]=1
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(Cl)cc1Nc1cccc(C)c1
Temperature: 80 °C

Procedure:
(Wallace, E., et. al., ibid.) m-toluidine (0.47 mL, 4.34 mmol) and conc. HCl (1 drop) were added to a solution of compound iii (1.00 g, 4.57 mmol) in ethanol (10 mL). The reaction mixture was heated at 80° C. for 3 h, cooled to room temperature and partitioned between water (15 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phase was dried (MgSO4) and reduced in vacuo to give the crude product as a brown oil. Column chromatography (SiO2), eluting with 12:1 Hexanes-EtOAc, gave compound iv. (0.670 g, 2.31 mmol, 51%) as a light orange oil, which solidified on standing, [M+H]+ m/z=291.0.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[C:16]([O:15][C:13](=[O:14])[CH2:12][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#CCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccccc1CC#N
Reaction time: 12 h
Yield: 97.5 %

Procedure:
To a mixture of 2.92 g of (2-hydroxyphenyl)acetonitrile, 4.71 g of tert-butyl bromoacetate and 110 mL of DMF was added 6.06 g of potassium carbonate at room temperature, followed by stirring for 12 hours. To the reaction solution was added water, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexane/ethyl acetate as an eluent solvent to obtain 5.29 g of tert-butyl[2-(cyanomethyl)phenoxy]acetate as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.C(N(CC)CC)C.C(O[CH:20]=[C:21]([C:27](=O)[C:28]([F:31])([F:30])[F:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:8]2[C:27]([C:28]([F:29])([F:30])[F:31])=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=[N:9]2)[CH:5]=[CH:6][N:7]=1
Reactant: NNc1ccnc(Cl)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnn(-c2ccnc(Cl)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution 2-chloro-6-hydrazinopyrimidine (1.00 g, 6.92 mmol) and triethylamine (0.964 mL, 6.92 mmol) in acetonitrile (35 mL) was added ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (1.35 mL, 6.97 mmol). After 45 min, the reaction mixture was placed in a 90° C. oil bath. After 1 h, the reaction mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 60% EtOAc in hexanes, then 60 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 321.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.80 (d, J=5.5 Hz, 1H), 8.12 (s, 1H), 7.76 (d, J=5.5 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.N#N.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]2[CH3:25])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCN(C)CC3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 56.7 %

Procedure:
To a solution of 3-fluoro-4-(4-methylpiperazin-1-yl)aniline (11.01 g, 52.60 mol) in anhydrous CH2Cl2 (200 mL) was added trimethylaluminum (158 mL, 158 mmol, 1.0 M in toluene) slowly under N2. The mixture was stirred at rt for 20 min, followed by the addition of a solution of methyl 3-acetaminocrotonate (9.92 g, 63.10 mmol) in anhydrous CH2Cl2 (20 mL). The reaction mixture was stirred at rt for another 5 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (CH2Cl2/MeOH (V/V)=5:1) to give the title compound as a white solid (11.31 g, 68%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCSCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCSCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-thiopyran-4-yl)amino)benzoate (2.5 g, 5.83 mmol) and acetaldehyde (513 mg, 11.66 mmol) in dichloroethane (50 mL), acetic acid (2.0 ml, 34.9 mmol) was added and reaction was stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (3.7 g, 17.49 mmol) was added and stirred at room temperature for overnight. The mixture was neutralized with sat. NaHCO3 and compound was extracted in DCM, dried over Na2SO4, concentrated under reduced pressure. The crude material was purified by column chromatography to afford methyl 5-bromo-3-(ethyl(tetrahydro-2H-thiopyran-4-yl)amino)-2-methylbenzoate (2.0 g, 74.0%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:21][C:22]=1[CH3:23].O>CN(C)C=O>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2c1ccn2Cc1nc(-c2ccccc2)oc1C
Reaction time: 0.5 h

Procedure:
Methyl indole-4-carboxylate (700 mg) was dissolved in 7 ml of dimethylformamide, then 160 mg of sodium hydride (content 60%) was added to the resulting solution at room temperature and the mixture was stirred for 30 minutes. After adding 830 mg of 4-chloromethyl-5-methyl-2-phenyloxazole to the mixture and stirring them for 2 hours, the reaction solution was added to 70 ml of water and extracted with ethyl acetate (50 ml×2). The resulting organic phase was washed with, in order, water (50 ml×2) and 50 ml of a saturated common salt aqueous solution and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the residue was crystallized in 50 ml of hexane to thus give 1.18 g of methyl 1-[(5-methyl-2-phenyloxazol-4-yl)methyl]indole-4-carboxylate as pale brown crystals. The yield thereof was found to be 85%.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:15][Si](C=[N+]=[N-])(C)C.O>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:15][CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1CCC(c2cccnc2F)CC1
Solvent: ClCCl
Solvent: O
Product: O=C1CCCC(c2cccnc2F)CC1

Procedure:
To a solution of boron trifluoride-diethyl etherate (0.64 g, 4.50 mmol) and 4-(2-fluoropyridin-3-yl)cyclohexanone (0.79 g, 4.09 mmol) in DCM (8 mL) at −25° C. under argon was added (trimethylsilyl)diazomethane (2.25 mL, 5.18 mmol, 2.0 M in hexanes). The reaction was stirred for 2 h at that temperature, water was added, and the mixture was extracted with DCM (2×). The combined organic extracts were washed with 10:1 saturated ammonium chloride/ammonium hydroxide mixture (1×), water (1×), saturated aqueous sodium chloride (1×), and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 4-(2-fluoropyridin-3-yl)cycloheptanone. MS (ESI, pos. ion) m/z: 208.1 (M+1).
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.C[O:19][B:20](OC)[O:21]C>C1COCC1>[B:20]([OH:21])([OH:19])[CH:5]1[N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][CH2:3][CH2:4]1
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1B(O)O

Procedure:
N-acetyl-gly-boroproline 5 was prepared according to the synthetic route of FIG. 1. Metallation of tert-butyl 1-pyrrolidinecarboxylate (N-t-BOC-pyrrolidine, Sigma-Aldrich Co.) in THF with sec-butyllithium, followed by addition of trimethylborate gave 1-(tert-butoxycarbonyl)pyrrolidin-2-yl-2-boronic acid 1 after quenching with aqueous NaOH and extraction. Borate esterification with the (1S, 2S, 3R, 5S), (+)-pinanediol in methyl, tert-butyl ether (MTBE) gave borate ester 2. Acid hydrolysis of the BOC protecting group and selective crystallization in isopropyl alcohol gave (+)-pinane 1-pyrrolidin-2-yl-2-boronate 3. Coupling of 3 and N-acetyl glycine with EDC (N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide), HOBt (1-hydroxybenzotriazole), and DiPEA (diisopropylethylamine gave the pinane borate of N-acetyl-gly-boroproline 4. Borate exchange of 4 with phenylboronic acid in MTBE and water gave N-acetyl-gly-boroproline 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:55]=[CH:54][CH:53]=[CH:52][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH:32]2[CH2:37][N:36](S(C3C=CC(C)=CC=3)(=O)=O)[C:35]3[CH:48]=[CH:49][CH:50]=[CH:51][C:34]=3[O:33]2)=[CH:13][CH:12]=1.[Mg]>CO.C(OCC)(=O)C>[O:33]1[C:34]2[CH:51]=[CH:50][CH:49]=[CH:48][C:35]=2[NH:36][CH2:37][CH:32]1[CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:52]=[CH:53][CH:54]=[CH:55][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CN(S(=O)(=O)c3ccc(C)cc3)c3ccccc3O2)cc1
Agent: [Mg]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCC2CNc3ccccc3O2)cc1

Procedure:
A solution of 0.66 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[4-(toluene-4-sulphonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2(R,S)-ylmethoxy]piperidine-1-carboxylate in 10 ml of methanol is treated in an ultrasound bath in the presence of 0.5 g of magnesium turnings over 30 minutes. The reaction mixture is decantered off from the magnesium, diluted with ethyl acetate, washed with 1N HCl (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (1:2 EtOAc-heptane); Rt=5.62.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC([O-])=O.[Na+].[N:29]#[C:30]Br.O>CO>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:30]#[N:29])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C#N)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of COMPOUND 249 (0.5021 g, 1.6 mmol) and anhydrous NaOAc (0.3775 g, 4.6 mmol) in MeOH (16 mL) was added at 0° C. cyanogen bromide (0.2315 g, 2.2 mmol), and stirred at for 2 hours at 0° C., then for another 3 hours at room temperature. Distilled water (20 mL) was added and extracted with CH2Cl2 (3×150 mL). The combined organic extracts were washed with brine (2×75 mL), dried (Na2SO4), filtered, and concentrated to provide 0.5137 g (96%) of 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carbonitrile as a beige solid. 1H NMR (CDCl3) δ 1.77-1.90 (m, 2H), 1.95-1.99 (m, 2H), 2.11 (s, 6H), 2.66 (t, 1H, J=12.0 Hz), 2.88-2.97 (m, 2H), 3.45-3.49 (m, 2H), 3.87 (s, 4H), 7.09-7.13 (m, 2H), 7.39 (d, 2H, J=6.0 Hz), 8.36 (d, 2H, J=3.0 Hz).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:13][N:12]([C:14]([C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[O:15])[CH2:11]2)=[CH:5][CH:4]=1.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:13][N:12]([C:14]([C:16]3[O:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:19][N:20]=3)=[O:15])[CH2:11]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CO)cc2)C1
Solvent: ClCCl
Product: O=C(c1nnc(-c2ccccc2)o1)N1CC(Sc2ccc(CCl)cc2)C1
Yield: 80.2 %

Procedure:
5A (3.48 g, 9.47 mmol) was dissolved in dichloromethane (150 mL) and the mixture was cooled in an ice bath. While stirring, thionyl chloride (0.76 mL, 10.4 mmol) was added dropwise. The cooling bath was removed after 30 min. The mixture was stirred for 2.5 h and then evaporated to dryness. The residue was purified by column chromatography eluting with dichloromethane. There was obtained 2.93 g (80%) of 5B as a solid. 1H NMR (500 MHz, CDCl3): δ 4.22 (m, 2H), 4.57 (s, 2H), 4.65 (m, 2H), 5.14 (m, 1H), 7.29 (d, 2H), 7.36 (d, 2H), 7.53 (t, 2H), 7.59 (t, 1H), 8.16 (d, 2H), MS (APCI+) m/z 386 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].[Cl:10][C:11]1[CH:12]=[C:13]([SH:18])[CH:14]=[CH:15][C:16]=1[Cl:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([S:18][CH2:2][CH2:3][CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[CH3:9])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CN1CCCC1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCCC1CCSc1ccc(Cl)c(Cl)c1
Yield: 43 %

Procedure:
2-(2-Chloroethyl)-1-methylpyrrolidine (1.50 g, 10.26 mmole), 3,4-dichlorobenzenethiol (1.82 g, 10.1 mmole), potassium carbonate (14.03 g, 101.6 mmole) and DMF (20 mL) were combined, yielding 0.46 g (4.34 mmole, 43%) of the desired compound.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Br[CH2:22][CH2:23]Br>C1COCC1>[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:23][CH2:22]1
Reactant: BrCCBr
Reactant: CC(C)(C)OC(=O)Cc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(c2nccs2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Sodium hydride (702 mg, 17.56 mmol) was suspended in THF (7 mL)/DMF (7 mL) under nitrogen and cooled to 0° C. The product from Step 1 (875 mg, 4.39 mmol) in THF (3 mL)/DMF (3 mL) was added dropwise. The ice bath was removed, and the yellow-orange suspension was stirred at room temperature for 30 min. The mixture was then cooled back down to 0° C., and 1,2-dibromoethane (2.475 g, 13.17 mmol) was added in one portion. The reaction was allowed to warm to room temperature and stirred for 2 h. It was then quenched with saturated NH4Cl and water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated. Flash chromatography (0-20% ethyl acetate in hexanes) afforded tert-butyl 1-(1,3-thiazol-2-yl)cyclopropanecarboxylate (866 mg, 88%) as a colorless oil. MS ESI: [M+H]+ m/z 226.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>ClCCl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][Cl:14]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cccnc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-chloronicotinic acid (500 mg, 3.17 mmol) in anhydrous dichloromethane (10 ml) was added dropwise oxalyl chloride (0.407 ml, 4.76 mmol) at a room temperature. A drop of anhydrous N,N-dimethylformamide was added and the reaction mixture stirred for 2 hours at a room temperature. Once the reaction was completed, intermediate product, i.e., 2-chloronicotinyl chloride was obtained with vacuum-concentration. Anhydrous dichloromethane (10 ml) was added, and then 3-anisidine (0.390 ml, 3.49 mmol) in anhydrous dichloromethane (5 ml) was added dropwise at 0° C. to a solution of the above mixture. Triethylamine (0.885 ml, 6.347 mmol) was added and the mixture was stirred for one hour at 0° C. Once the reaction was completed, water was added and the resultant mixture was extracted with dichloromethane. The separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain the title compound (970 mg, ivory oil).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)C=CC=CC=1.[C:39]([C:41]1[NH:45][C:44]([CH2:46][CH2:47][CH3:48])=[N:43][C:42]=1[N:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](=[O:59])[C:55]([F:58])([F:57])[F:56])#[N:40].CN(C)C=O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[C:39]([C:41]1[N:45]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[NH:8][N:9]=[N:10][N:11]=3)=[CH:20][CH:21]=2)[C:44]([CH2:46][CH2:47][CH3:48])=[N:43][C:42]=1[N:49]1[CH:53]=[CH:52][CH:51]=[C:50]1[C:54](=[O:59])[C:55]([F:58])([F:56])[F:57])#[N:40]
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C#N)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 26, 2.1 g), 5-cyano-4-[2-(1-oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]-2-propylimidazole (Example 18, 0.89 g), N,N-dimethylformamide (10 mL), and anhydrous K2CO3 (0.5 g) were stirred at room temperature under nitrogen atmosphere for 24 hours. Ethyl acetate (50 mL) was added and inorganic solids were removed by filtration. The filtrate was evaporated at reduced pressure and the major product was isolated by flash chromatography on silica gel (toluene acetonitrile 96:4) to afford the title compound in its triphenylmethyl-protected form (1.3 g). This material was dissolved in methanol (50 mL), treated with aqueous 10% citric acid (1.5 mL) and heated at reflux for 90 minutes. After cooling to room temperature, water (10 mL) and hexanes (100 mL) were added and the mixture was shaken vigorously. The methanol layer was separated, washed again with hexanes and evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated. The resulting gum was dissolved in ether, concentrated and allowed to stand overnight to give some seed crystals. The remaining gum was dissolved in tertbutyl methyl ether, seeded and diluted with diisopropyl ether. Crystallization gave the title product after filtration. MS (CI, CH4 +NH3) 531 (m+1).