Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:21]1[C:20]([F:24])=[CH:19][C:17]2=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=[C:16]2[CH:22]=1
Reactant: C#CCCn1nc2cc(F)c(F)cc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2nc3cc(F)c(F)cc3n2)n1
Yield: 31.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.32 mmol) and 2-(but-3-ynyl)-5,6-difluoro-2H-benzo[d][1,2,3]triazole (60 mg, 0.29 mmol, Example 153(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 29 mg (92 μmol, 32%) of 5,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a grey solid (M.P.=104-105° C.).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:44]4[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOCc1nc2cnc3cc(O)ccc3c2n1CC(C)(C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c2n1CC(C)(C)O
Reaction time: 16 h
Yield: 63.4 %

Procedure:
2-(Ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (3.31 g, 10.5 mmol), triphenylphosphine (3.43 g, 13.1 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (2.64 g, 13.1 mmol) were slurried in THF (105 mL), and cooled with an ice/water bath. Diisopropyl azodicarboxylate (2.58 mL, 13.1 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred for 16 hours. The solvent was removed under reduced pressure and the residue was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 1-28% CMA in chloroform) to afford 3.32 g of tert-butyl 4-{[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a tan foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-])=O.C(#N)C.CN(C)C=[O:17]>>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:17])=[CH:6][CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Solvent: CC#N
Product: Nc1ccc(C=O)cc1

Procedure:
The procedure of Example 1 was followed except that 2.3 g (3.4 wt.% of the p-nitrotoluene) of acetonitrile were substituted for the N, N-dimethylformamide, to obtain 37.7 g (0.312 mol) of p-aminobenzaldehyde and then obtain 38.5 g (0.315 mol) of p-hydroxybenzaldehyde.
Reaction SMILES: [CH3:1][NH2:2].[N:3]1([C:8]2[N:13]=[C:12]([CH:14]3[CH:18]([C:19]([O:21]CC)=O)[CH2:17][CH2:16][N:15]3[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:11]=[C:10]([CH3:31])[N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.O>C1COCC1>[N:3]1([C:8]2[N:13]=[C:12]([CH:14]3[CH:18]([C:19](=[O:21])[NH:2][CH3:1])[CH2:17][CH2:16][N:15]3[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:11]=[C:10]([CH3:31])[N:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C1CCN(C(=O)OC(C)(C)C)C1c1cc(C)nc(-n2ccnc2)n1
Temperature: 60 °C

Procedure:
Methylamine (35 mL of a 25 wt % solution in THF) was added all at once to a solution of 1-tert-butyl 3-ethyl 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)pyrrolidine-1,3-dicarboxylate (650 mg, 1.6 mmol) in THF (30 mL). The reaction mixture was heated to 60° C. for a period 12 h then cooled to rt. Water (50 mL) was added and the resulting solution was extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to afford tert-butyl 2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)-3-(methylcarbamoyl)pyrrolidine-1-carboxylate (620 mg) as yellow oil.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]([NH:13][C:14]1[S:15][C:16]([Cl:26])=[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[Cl:25])[CH:18]=1)=[O:12])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][CH2:9][CH:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]([NH:13][C:14]1[S:15][C:16]([Cl:26])=[C:17]([C:19]2[N:23]([CH3:24])[N:22]=[CH:21][C:20]=2[Cl:25])[CH:18]=1)=[O:12]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)C(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)sc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)C(CN)Cc2ccccc2)sc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl[3-{[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]amino}-3-oxo-2-(phenylmethyl)propyl]carbamate (740 mg, 1.453 mmol) in dichloromethane (7.263 ml) at 25° C. was added TFA (1.119 ml, 14.53 mmol) in one portion. After 30 min, the solution was dry loaded onto silica and neutralized through silica (0-20% MeOH in DCM (1% NH4OH) affording the free base of the title compound. The free base was then dissolved in MeOH (10 mL) and treated with excess 4M HCl in dioxane (2 mL) providing the HCl salt of 3-amino-N-[5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]-2-(phenylmethyl)propanamide (426 mg, 0.908 mmol, 62.5% yield) as an orange solid: LCMS (ES) m/e 409, 411 (M, M+2)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (s, 1 H) 8.06 (br. s., 3 H) 7.68 (s, 1 H) 7.26-7.40 (m, 4 H) 7.24 (d, J=6.82 Hz, 1 H) 6.70 (s, 1 H) 3.94-3.96 (m, 1 H) 3.70 (s, 3 H) 3.14-3.17 (m, 1 H) 3.05 (dd, J=13.52, 6.44 Hz, 2 H) 2.85 (dd, J=14.02, 7.45 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[C:13]([F:12])([F:21])[F:22])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1ccccc1C(F)(F)F
Product: O=C(Nc1ccccc1C(F)(F)F)c1cc(Cl)ccc1O
Yield: 58 %

Procedure:
Using 5-chlorosalicylic acid and 2-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:23](#[N:26])[CH:24]=[CH2:25]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:24](=[CH2:25])[C:23]#[N:26])=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:8][N:9]=1
Reactant: C=CC#N
Reactant: CCCCCc1cnc(Cl)c(C=O)c1
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1cc(CCCCC)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-pentylnicotinaldehyde (10 mmol, 2.11 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.62 g.).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:13]([CH2:15][CH3:16])=[N:14][C:9]2=[C:8]([CH3:35])[CH:7]=1)=O)C.[H-].CC(O)=O>C1COCC1>[CH2:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:10]2=[N:11][C:6]([CH2:4][OH:3])=[CH:7][C:8]([CH3:35])=[C:9]2[N:14]=1)[CH3:16]
Reactant: CCOC(=O)c1cc(C)c2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1
Agent: [H-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(CO)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To 5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (50 mg) in THF (1 mL) at -78° C. was added Diisobutylahminum hydride (0.534 mL, 1M/THF). After 1 hour at -78° C, the mixture was warmed to RT and 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), and purification (SiO2, 80/20/1 CH2Cl2 /MeOH/NH4OH) gave 28 mg of a solid. 1H NMR (300 MHz, CD3OD) δ 7.57 (t, 2H, J=7.5 Hz), 7.48 (t, 2H, J=7.5 Hz), 7.26 (s, 1H), 7.08-7.02 (AB quartet, 4H), 5.54 (s, 2H), 4.74 (s, 2H), 2.85 (q, 2H, J=7.5 Hz), 2.66 (s, 3H), 1.26 (t, 3H, J=7.5 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([OH:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](F)[C:25]=1[Cl:31].CCO>CN(C=O)C.Cl>[Cl:23][C:24]1[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=1[O:20][C@@H:13]([CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@@H](O)C2CCOCC2)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Clc1cccc(O[C@@H](C2CCOCC2)[C@@H]2CCNC2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-3-[(S)-Hydroxy(tetrahydropyran-4-yl)methyl]pyrrolidine-1-carboxylic acid t-butyl ester (30 mg, 0.1 mmol) was dissolved in DMF (380 μL). NaH (3.0 mg, 126 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluorobenzene (34.7 mg, 210 μmol) was added and the mixture was stirred at 100° C. overnight. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (510 μL, 610 μmol) and stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (10.8 mg, purity 100%). MS m/z: [M+H]+ calcd for C16H21Cl2NO2, 330.10. found 330.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH2:22][CH2:23][NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C(O)C>[O:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=2)=[CH:15][CH:16]=1)[C:1]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1cccc(CCN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(CCNCc2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of 4-benzoxybenzaldehyde (2.5 g, 12.6 mmol), 3-methoxyphenethylamine (1.9 g, 12.6 mmol), a catalytic amount of p-toluenesulfonic acid monohydrate in absolute ethanol (12 mL) was stirred at 80° C. for 1.5 hours. After cooling to room temperature, NaBH4 (0.49 g, 13.0 mmol) was added in portions. The reaction mixture was stirred at 80° C. for 1 hour, then cooled to room temperature, and the ethanol was removed in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The combined extracts were washed with saturated NaCl, dried over MgSO4, filtered, and the solvent removed in vacuo to afford a colorless oil which was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane saturated with NH3 to afford the title compound (3.2 g, 76%) as a colorless oil. MS (DCl/NH3) m/e 334 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 2.82 (t, 2H), 2.92 (t, 2H), 3.77 (s, 2H), 3.80 (s, 3H), 6.80 (m, 3H), 6.98 (m, 3H), 6.08 (t, 1H), 7.22 (m, 3H), 7.32 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([OH:15])=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2ccc(O)cc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccc(OCc3ccccc3)cc2c1
Reaction time: 2 h
Yield: 36 %

Procedure:
Treat a solution of 7-hydroxynaphthalene-2-carboxylic acid methyl ester (2.84 g, 14.0 mmol) and benzyl bromide (1.84 mL, 15.5 mmol in DMF (14 mL) with cesium carbonate (9.10 g, 27.9 mmol). Stir the mixture for 2 h and concentrate. Dissolve the crude residue in EtOAc (150 mL) and 1 N HCl (50 mL). Wash the organic layer with brine (3×100 mL), dry over Na2SO4, and filter. Concentrate the filtrate and purify using medium pressure silica gel chromatography (10:90 EtOAc:hex) to give the title compound as a white solid (1.47 g, 36%). MS (ES) m/e 293 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:19]#[N:20])[CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cccc(C#N)c3)cccc2c1N
Yield: 85.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 3-cyanophenylboronic acid (147 mg, 1.000 mmol) were reacted to afford the title compound (138 mg, 86% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.54 (br, 1H), 8.06-7.89 (m, 3H), 7.85-7.69 (m, 3H), 7.65-7.57 (m, 1H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=332 M+H) HPLC 1.93 min.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH3:41][O:42][CH:43]1[CH2:46][CH:45]([NH2:47])[CH2:44]1>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:47][CH:45]4[CH2:46][CH:43]([O:42][CH3:41])[CH2:44]4)=[O:40])=[CH:11][CH:12]=3)[CH:21]=2)[CH:27]=1
Reactant: COC1CC(N)C1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Product: COC1CC(NC(=O)Nc2ccc(-c3cc(-c4cc(F)ccc4S(C)(=O)=O)nc(N4CCOC[C@@H]4C)n3)cc2)C1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) 3-methoxycyclobutanamine (22 mg, 0.213 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (37 mg, 30%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>Cl.O1CCOCC1.O>[CH3:27][S:28]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[N:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]([O:2][CH3:1])=[O:26])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)(=[O:30])=[O:29]
Reactant: COC(=O)C(=O)Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C(=O)Nc1ccc(N2CCN(S(C)(=O)=O)CC2)nc1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 4-(5-{[methoxy(oxo)acetyl]amino}pyridin-2-yl)piperazine-1-carboxylate (Intermediate 16, 4 g, 11 mmol) in 4N HCl/dioxan (25 mL) was stood for 16 h then concentrated by evaporation. The residue was dissolved in a mixture of DMF (20 mL) and pyridine (7 mL) then methanesulphonyl chloride (1.28 mL, 16.48 mmol) was added. The mixture was stirred for 3 hours then was diluted with water (50 mL) and extracted with dichloromethane (2×100 mL). The organic extracts were dried and concentrated by evaporation to give the title compound as a solid that was used without further purification; MS m/e MH+ 343.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4O[CH:21]=[N:20][C:19]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([NH2:26])=O>O>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:26]=[CH:21][NH:20][C:19]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncoc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Reactant: NC=O
Solvent: O
Product: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O

Procedure:
A mixture of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(4-methyloxazol-5-yl) methyl]-1H-pyrido[4,3-b]indol-1-one (180 mg) and formamide (20 ml) was heated at 180° for 18 h. The solution was then cooled (0°), diluted with water (100 ml) and extracted with dichloromethane (3×100 ml). The combined extracts were concentrated in vacuo and purified by FCC eluting with System A (100:8:1) to give the title compound (110 mg), m.p. 230°-233°.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C@@H:6]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:8]([CH2:9][CH2:10][C@@H:11]4[C@@H:27]3[CH2:26][CH2:25][C@@:24]3([CH3:32])[C@H:12]4[CH2:13][CH2:14][C@@H:15]3[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]2)[CH2:3]1.C(N(CC)CC)C.[CH2:40]([S:56](Cl)(=[O:58])=[O:57])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C1C=CC=CC=1>[CH2:40]([S:56]([O:1][CH:2]1[CH2:3][N:4]([C@@H:6]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:8]([CH2:9][CH2:10][C@@H:11]4[C@@H:27]3[CH2:26][CH2:25][C@@:24]3([CH3:32])[C@H:12]4[CH2:13][CH2:14][C@@H:15]3[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]2)[CH2:5]1)(=[O:58])=[O:57])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](N5CC(O)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)OC1CN([C@@H]2CC[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]43)C2)C1
Temperature: 25 °C
Reaction time: 480 h

Procedure:
To a stirred suspension of 1.5 g 3α-(3-hydroxy-1-azetidinyl)-5α-cholestane (prepared as described in Example 1 and purified by column chromatography, m.p. 191.5°-195.5° C.) and 0.34 g triethylamine in 33 ml dry benzene, add a solution of 0.78 g 98% hexadecanesulfonyl chloride in 7 ml dry benzene. Stir the resultant cloudy solution at room temperature for 20 days. Concentrate the reaction mixture in vacuo to about one-third the original volume and filter the resultant precipitate. Remove the solvent in vacuo from the filtrate. Dissolve the resultant residue in 80 ml ethyl ether and filter through a column of 45-50 g silica gel eluting with additional ethyl ether as needed to afford the title compound, m.p. 64.5°-68.0° C.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](C(C)(C)C)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O(CCCNC(C)(C)CC1C=CC(OC)=CC=1)[C:32]1[CH:37]=CC=C[CH:33]=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:33][CH2:32][CH3:37])[CH2:4][NH:5][C:6]([CH3:16])([CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Agent: Cl
Product: CCCc1ccccc1OCC(O)CNC(C)(C)Cc1ccc(OC)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M-15,1), 251(17), 250 (100), 163 (6), 121 (34), 114 (9), 107 (6), 90 (17), 78 (9), 77 (10), 71 (17).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.C(N(CC)CC)C.[C:19]1([C:25](Br)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1c[nH]cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 72 h

Procedure:
To a suspension of 1H-imidazole-4-acetic acid methyl ester hydrochloride (1, 7.48, 42.4 mmol) in methylene chloride (200 ml) was added triethylamine (17.7 ml, 127 mmol) and triphenylmethyl bromide (16.4 g, 50.8 mmol) and stirred for 72 h. After this time, reaction mixture was washed with sat. aq. sodium bicarbonate (100 ml) and water (100 ml). The organic layer was evaporated in vacuo and purified by flash chromatography (30-100% ethyl acetate/hexanes gradient elution) to provide 23 as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[S:3]1.C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([Pb+3])=[C:32]([CH2:37][CH3:38])[CH:31]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH:6]2[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[S:3][C:4]([CH3:11])([CH3:10])[C:5]2=[O:9])=[C:32]([CH2:37][CH3:38])[CH:31]=1
Reactant: CCc1cc(Br)ccc1[Pb+3]
Reactant: CC1(C)SC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)SC(C)(C)C1=O
Temperature: 80 °C
Yield: 40.9 %

Procedure:
2,2,6,6-Tetramethylthiopyran-3,5-dione (10 g, 0.053 mol) (described in Helvetica Chimica Acta, 1992, 75(7), 2265-69) and 4-dimethylaminopyridine (32 g, 0.26 mol) are added to a mixture of chloroform (200 ml) and toluene (50 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (34 g, 0.06 mol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×100 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-(4-bromo-2-ethylphenyl)-2,2,6,6-tetramethylthiopyran-3,5-dione as a white solid (8 g).