Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[C:3]=1[CH:16]1[CH2:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[CH2:17]1.C(O[C:29](=[O:32])[CH2:30]C)(=O)CC.C[N:34]([C:36]1[CH:41]=[CH:40]C=CN=1)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:13][CH3:14])([CH3:12])[CH2:8]2)=[C:4]([CH3:15])[C:3]=1[CH:16]1[CH2:21][C:20](=[O:22])[C:19]([C:36](=[N:34][O:32][CH2:29][CH3:30])[CH2:41][CH3:40])=[C:18]([OH:23])[CH2:17]1
Reactant: CCC1(C)Cc2c(C)c(Cl)c(C3CC(=O)CC(=O)C3)c(C)c2C1
Reactant: CN(C)c1ccccn1
Reactant: CCC(=O)OC(=O)CC
Solvent: Cc1ccccc1
Product: CCON=C(CC)C1=C(O)CC(c2c(C)c3c(c(C)c2Cl)CC(C)(CC)C3)CC1=O

Procedure:
To a solution of 9.3 g of the 5-(6-chloro-2-ethyl-2,4,7-trimethylindan-5-yl)-cyclohexane-1,3-dione in 50 ml of absolute toluene was added 15 ml of propionic anhydride. After refluxing for 4 hours, toluene and excess propionic anhydride were evaporated under reduced pressure to afford a residue. To the solution of the residue in 50 ml of toluene was added 0.6 g of dimethylaminopyridine and refluxed for 20 hours. The reaction mixture was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 4.96 g of the title compound as yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:19]2[CH2:22][CH:21]([C@@H:23]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([C:35]#[N:36])[CH:29]=3)[C:24]([F:27])([CH3:26])[CH3:25])[CH2:20]2)[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][NH2:15])=[O:13])=[CH:4][CH:3]=1.[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:9]2[CH:18]=[CH:17][CH:16]=[C:11]([C:12]3[O:13][C:37](=[O:38])[NH:15][N:14]=3)[CH:10]=2)[N:19]2[CH2:22][CH:21]([C@@H:23]([C:28]3[CH:29]=[C:30]([CH:31]=[C:32]([F:34])[CH:33]=3)[C:35]#[N:36])[C:24]([F:27])([CH3:26])[CH3:25])[CH2:20]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(F)[C@H](c1cc(F)cc(C#N)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C(=O)NN)c2)C1
Solvent: ClCCl
Product: CC(C)(F)[C@H](c1cc(F)cc(C#N)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(-c3n[nH]c(=O)o3)c2)C1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3.0 g (5.85 mmol) of 3-((S)-(4-chlorophenyl){3-[(1S)-1-(3-cyano-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzohydrazide in 100 mL of CH2Cl2 was added 3.73 mL (7.1 mmol) of phosgene solution (20% in toluene). The solution was stirred for 1.5 h at 0° C., The solution was concentrated ,and to the residue was added 6 mL of 2N NH3 in MeOH, and the mixture was concentrated again. The residue was purified by silica gel chromatography with CH2Cl2/acetone to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.26 (d, 3H, J1=22.1 Hz), 1.30 (d, 3H, J1=21.7 Hz), 2.39(t, 1H, J=8.0 Hz), 2.93-3.0(m, 2H), 3.12(t, 1H, J=7.3 Hz), 3.33(m, 1H), 3.69 (t, 1H, J=6.8 Hz), 4.35(s, 1H), 7.20 (d, 1H, J=9.7 Hz), 7.23 (d, 1H, J=7.3 Hz), 7.29-7.40(m, 7H), 7.48 (d, 1H, J=7.8 Hz), 7.68 (d, 1H, J=7.8 Hz), 7.97 (s, 1H); Mass Spectrum: m/e=535, (M+1, 35Cl), 537 (M+1, 37Cl).
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH3:25])[C:10]([NH:12][C@@H:13]([CH3:24])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:11])=O)(C)(C)C.[ClH:27]>O1CCOCC1>[Cl-:27].[CH2:17]([O:16][C:14]([C@@H:13]([NH:12][C:10]([C@@H:9]([NH2+:8][CH3:6])[CH3:25])=[O:11])[CH3:24])=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cl
Reactant: C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: C[NH2+][C@@H](C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.80 g (21.4 mmol) of the compound from example 4A are dissolved in 4N hydrogen chloride solution in dioxane (80 ml). After a few minutes, precipitate formation commences. The mixture is stirred for a further 1 h at RT, and the solid is filtered off with suction and washed with diethyl ether. After drying in vacuo, 5.96 g (93% of th.) of the product are obtained.
Reaction SMILES: [O:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[N+:2]([O-:4])=[O:3].[CH:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12]>C(OCC)(=O)C>[CH:11]([NH:14][C:15]([N:8]1[CH2:9][CH2:10][CH:5]([O:1][N+:2]([O-:4])=[O:3])[CH2:6][CH2:7]1)=[O:16])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])OC1CCNCC1
Reactant: CC(C)N=C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)N1CCC(O[N+](=O)[O-])CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
7 g. 4-Nitroxypiperidine are dissolved in 25 ml. ethyl acetate and mixed with 5.2 ml. isopropyl isocyanate while cooling with ice water to 0°to 5° C. The reaction mixture is stirred for 2 hours at 10° C. and then evaporated in a vacuum. The residue is taken up in diethyl ether and the precipitated crystals are filtered off with suction. There are obtained 6.6 g. of the title compound; m.p. 93°-95° C., 60% of theory.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O>C(O)C.ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: NC1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reaction time: 24 h

Procedure:
To a solution of 2-[4-(4-benzyl-1-piperazinyl)cyclohexyl]-1H-isoindole-1,3(2H)-dione (5.00 g, 12.4 mmol) in ethanol-dichloromethane (10:3/65 ml) was added NH2NH2-water (2.4 ml /50.0 mmol) and the mixture was stirred for 1 day. After filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil (2.82 g/89%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=1
Reactant: O=Cc1cc(C(F)(F)F)ccc1O
Reactant: ClCc1ccncc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2oc(-c3ccncc3Cl)cc2c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 59 %

Procedure:
A mixture of 0.78 g of 2-hydroxy-5-(trifluoromethyl)benzaldehyde, 0.89 g of 3-chloro-4-(chloromethyl)pyridine, 1.94 g of potassium carbonate and 15 ml of DMF was stirred at 80° C. for 3 hours and subsequently at 150° C. for 4 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.72 g of 3-chloro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 6”).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH2:7][C:8]#[N:9].[CH3:10][C:11](O)([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:12].S(=O)(=O)(O)[OH:20]>C(O)(=O)C>[NH2:9][CH2:8][C:7]([NH:6][C:11]([CH3:12])([CH3:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:20]
Reactant: N#CCN
Reactant: CCCCCC(C)(C)O
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCCCCC(C)(C)NC(=O)CN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of aminoacetonitrile bisulphate (15.4 g, 0.1 mol) and 2-methylheptan-2-ol (13.0 g, 0.1 mol) in acetic acid (60 ml) was treated with concentrated sulphuric acid (12 ml) with the temperature held at 40°-45° C. After stirring for 1 hour the mixture was poured into ice-water (300 ml) and washed with ether (2×200 ml). The aqueous phase was basified with 10 N sodium hydroxide solution, extracted with ether (3×200 ml) and the combined extracts were dried over magnesium sulphate then distilled to give 2-amino-N-(1,1-dimethylhexyl)acetamide as a colourless oil, b.p. 104°-110° C. at 0.2 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([S:15]([CH3:18])(=[O:17])=[O:16])[N:10]=2)=[C:4]([F:19])[CH:3]=1.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:23][C:13]1[C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[CH:3][C:4]=2[F:19])=[N:10][N:11]([S:15]([CH3:18])(=[O:17])=[O:16])[C:12]=1[CH3:14]
Reactant: Cc1cc(-c2cc(C)n(S(C)(=O)=O)n2)c(F)cc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(-c2nn(S(C)(=O)=O)c(C)c2Cl)c(F)cc1Cl

Procedure:
0.8 g (2.7 mmol) of 3-(4-chloro-2-fluoro-5-methylphenyl)-5-methyl-1-methylsulfonyl-1H-pyrazole and 0.4 g (3.0 mmol) of sulfuryl chloride were reacted in 50 ml of carbon tetrachloride by the method of Example 2. Yield: 0.1 g.
Reaction SMILES: [CH:1]1([C@@H:7]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:28][C:29](=O)[CH2:30][CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[CH:1]1([C@@H:7]([C:9]2[NH:10][CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[N:13]=2)[NH:8][CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(C)=O
Reactant: N[C@H](c1nc(-c2ccc(F)cc2)c[nH]1)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2c[nH]c([C@@H](NC3CCC3)C3CCCCC3)n2)cc1
Temperature: 23 °C
Yield: 12 %

Procedure:
A mixture containing (S)-cyclohexyl[4-(4-fluorophenyl)-1H-imidazol-2-yl]methanamine (prepared in Stage 5.2; 519 mg; 0.0015 mol), triethylamine (0.4 ml; 0.003 mol) and butanone (140 mg; 0.002 mol) in 10 ml of methanol is stirred for thirty minutes at 23° C. Sodium triacetoxyborohydride (630 mg; 0.003 mol) is then added. The reaction mixture is stirred for sixteen hours then poured into water. After extraction with ethyl acetate, the organic phase is washed with a saturated solution of sodium chloride then dried over magnesium sulphate. The solvent is evaporated off and the residue is purified on a silica column (eluent: CH2Cl2-MeOH mixture/95-05). A white-coloured powder is obtained with a yield of 12%. Melting point: 170-172° C.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[O:23])[N:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:10]=1[C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])C1C=CC=CC=1>CO.C(Cl)Cl.[Pd]>[CH2:42]([N:39]([CH2:40][CH3:41])[C:37]([C:10]1[N:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:12]([C:22]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])=[O:23])=[C:13]([OH:14])[C:9]=1[OH:8])=[O:38])[CH3:43]
Reactant: CCN(CC)C(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(CC)CC)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)C(=O)c1c(O)c(O)c(C(=O)N(CC)CC)n1-c1ccc(OC)cc1
Yield: 93 %

Procedure:
A solution of 3,4-bis(benzyloxy)-N2,N2,N5,N5-tetraethyl-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxamide UL1-046 (50 mg, 0.086 mmol) in methanol/DCM (4 mL/4 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford N2,N2,N5,N5-tetraethyl-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxamide (UL1-003) (32 mg, 93%) as a light yellow solid: m/z 404 (M+H)+ (ES+); 402 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 2H), 6.96-6.88 (m, 2H), 6.87-6.81 (m, 2H), 3.72 (s, 3H), 3.27 (q, J=7.1 Hz, 8H), 0.96 (t, J=7.0 Hz, 12H).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3][CH2:4][O:5][CH2:6]Cl.[Cl:10][C:11]1[C:16]([S:17]([NH:20][C:21]2[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=2)(=[O:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>CN(C=O)C>[Cl:10][C:11]1[C:16]([S:17]([N:20]([C:21]2[C:26]([O:27][CH3:28])=[N:25][C:24]([CH3:29])=[CH:23][N:22]=2)[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:18])=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1Cl
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(C)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccnc1Cl
Reaction time: 0.67 h

Procedure:
2-(Trimethylsilyl)ethoxymethyl chloride (0.315 ml) was added dropwise to a stirred solution of 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.47 g) and N,N-diisopropylethylamine (0.347 ml) in dry DMF (7 ml) at -15° C. Stirring was continued for 40 minutes at this temperature after the addition was complete. Ethyl acetate (40 ml) was added and the mixture was washed with water (3×15 ml) and saturated sodium chloride solution and then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 0-30% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-chloro-N-(3-methoxy-5-methylpyrazin-2-yl)-N-[2-(trimethylsilyl)ethoxymethyl]pyridine-3-sulphonamide (0.462 g) as an oil; 1H NMR (CDCl3): 0.0 (s, 9 H), 0.85 (t, 2 H), 2.5 (s, 3 H), 3.75 (t, 2 H), 3.8 (s, 3 H), 5.3 (s, 2 H), 7.3 (dd, 1 H), 7.8 (s, 1 H), 8.4 (dd, 1 H), 8.5 (dd, 1 H); mass spectrum (+ve ESP): 403 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)N.[CH2:19]([N:21](CC)CC)[CH3:20].C([S:28](Cl)(=[O:30])=[O:29])C>O1CCCC1>[CH2:19]([NH:21][S:28]([C:14]1[CH:16]=[CH:17][CH:18]=[C:12]([O:11][CH2:10][C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:13]=1)(=[O:30])=[O:29])[CH3:20]
Reactant: CCS(=O)(=O)Cl
Reactant: CCN(CC)CC
Reactant: Nc1cccc(OCc2nc3ccccc3s2)c1
Solvent: C1CCOC1
Product: CCNS(=O)(=O)c1cccc(OCc2nc3ccccc3s2)c1
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a solution of 3-[(2-benzothiazolyl)methoxy]aniline (2.0 g) and triethylamine (0.79 g) in tetrahydrofuran (50 ml) at room temperature is slowly added a solution of ethane sulfonyl chloride (1.0 g) in tetrahydrofuran. The reaction is stirred for 1 hour. The mixture is filtered through a pad of Celite and silica gel and the solvent is removed in vacuo giving an oil. The oil is purified by HPLC and crystallized from hexane to give 1.4 g (51% yield) of product, m.p. 111°-113° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][NH:5][C:4]2=[N:8][C:9]([Br:13])=[C:10]([C:11]#[N:12])[C:3]=12.C(O[CH:18]1[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:24]([CH3:37])[C@H:19]1[O:20][C:21](=[O:23])[CH3:22])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[C:9]([Br:13])[N:8]([C@@H:18]3[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C@@H:24]([CH3:37])[C@H:19]3[O:20][C:21](=[O:23])[CH3:22])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)[C@@H](C)[C@H]1OC(C)=O
Reactant: N#Cc1c(Br)nc2[nH]cnc(N)c1-2
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(Br)c(C#N)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
BSA (0.29 mL, 2.0 mmol) was added into a stirred suspension of 4-amino-6-bromo-5-cyano-1H-pyrrolo[2,3-d]pyrimidine (0.24 g, 1 mmol; prepared according to Nucleic Acid Chemistry, Part IV, Townsend, L. B. and Tipson, R. S.; Ed.; Wiley-Interscience: New York, 1991, pp. 16-17 and Synthetic Commun. 1998, 28, 3835) in dry acetonitrile (10 mL) at room temperature under argon. After 15 min, 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-methyl-D-ribofuranose (J. Med. Chem. (1976), 19, 1265) (0.36 g, 1.0 mmol) was added along with TMSOTf (0.54 g, 3 mmol). The mixture was stirred at room temperature for 5 min and then at 80° C. for 0.5 h. The solution was cooled, diluted with ethyl acetate (50 mL) and poured into ice-cold saturated aqueous NaHCO3 (15 mL). The layers were separated. The organic layer was washed with brine (15 mL), dried (Na2SO4) and then evaporated. The residue was purified on silica gel column using a solvent system of hexanes/EtOAc: 3/1. Appropriate fractions were collected and evaporated to provide the title compound as colorless foam (0.21 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=C(C)C=C(C)N=1.ClC(OC(C)(C)C(Cl)(Cl)Cl)=O.[NH2:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[CH:48]=[N:47][CH:46]=[CH:45]2.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:10]([C:11]([NH:41][C:42]2[CH:43]=[C:44]3[C:49](=[CH:50][CH:51]=2)[CH:48]=[N:47][CH:46]=[CH:45]3)=[O:13])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: Nc1ccc2cnccc2c1
Agent: CC(C)(OC(=O)Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To (S)-3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoic acid (28) (8.5 g, 28.4 mmol) in DMF cooled to 0° C. was added 2,4,6-trimethylpyridine and 2,2,2-trichloro-1,1-dimethylethyl chloroformate in DMF. Then, 6-aminoisoquinoline in DMF was added and the solution stirred for 2 h at 0° C. The mixture was poured into NaHCO3 (sat) and extracted with EtOAc. The organic layers were washed with H2O, dried (Na2SO4), filtered and evaporated to give crude 29. Column chromatography (30% EtOAc-Hexanes) and recrystallization (EtOAc/Hexanes) gave pure (S)-tert-butyl 2-(4-chlorophenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (29, 7.8 g, 64%, >99% S enantiomer).
Reaction SMILES: C(OCC)C.C([Mg]Br)C.[C:10]1([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[C:21](I)=[CH:20]2)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:31]([N:38]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:39]([CH3:42])[CH:40]=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[CH2:43]([N:38]([CH:39]([CH3:42])[CH:40]([C:21]1[C:22]2[C:27](=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[N:19]([S:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH:20]=1)[OH:41])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)cc(F)c21
Reactant: CC(C=O)N(Cc1ccccc1)Cc1ccccc1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C(O)c1cn(S(=O)(=O)c2ccccc2)c2c(F)cc(F)cc12)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
A 3.0 M diethyl ether solution of ethylmagnesium bromide (7.3 ml, 21.8 mmol) is added under N2 at 0° C. to a 95 ml tetrahydrofuran solution of N-benzenesulfonyl-3-iodo-5,7-difluoro-indole (8.4 g, 20 mmol). The resulting mixture is stirred for 20 minutes at 0° C., allowed to warm to room temperature over 20 minutes, then recooled to 0° C. A 20 ml tetrahydrofuran solution of (S) N,N dibenzyl-2-aminopropanal (Syn. Lett., 1997,2, 223–224, 5.1 g, 22 mmol) is added to the reaction mixture and the resulting mixture is stirred 1 hour as it warmed to room temp. The reaction is quenched with aqueous NH4Cl, extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, concentrated, and the residue is purified by flash chromatography (SiO2, ethyl acetate/hexane gradient) to yield 8.4 g of 2-(N,N-dibenzylamino)-1-(1-benzenesulfonyl-5,7-difluoro-1H-indol-3-yl)-propan-1-ol. (77%)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[O:3]1.[NH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])(=[O:14])=[O:13])[CH:8]=2)[O:3]1
Reactant: CC1(C)CCc2cc(S(=O)(=O)Cl)ccc2O1
Reactant: CC(C)(C)OC(=O)CN
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To the solution of 2,2-dimethylchroman-6-sulfonyl chloride (3.165 g, 10.92 mmol) in DCM (50 mL) at −30° C. was added tert-butyl 2-aminoacetate (2.308 mL, 16.39 mmol), Hunig'sBase (3.82 mL, 21.85 mmol), and catalytic amount of DMAP. The mixture was stirred at 25° C. overnight while the reddish orange color of the reaction mixture turned bright yellow. The crude reaction mixture was diluted with EtOAc, washed with dilute aqueous hydrochloric acid solution, then aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4 and removed on a rotavapor to give a creamy powder. The crude material was purified by silica chromatography (15-30% EtOAc/Hexanes) to yield 3.6 grams of an off white powder (88%). 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J=2.1 Hz, 1H), 7.55 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (t, J=10.6 Hz, 1H), 4.90 (s, 1H), 3.64 (d, J=5.1 Hz, 2H), 2.81 (t, J=6.7 Hz, 2H), 1.81 (t, J=6.7 Hz, 2H), 1.35 (s, 9H), 1.34 (s, 6H). LRMS [ESI, (M−H)−] m/z calcd for C17H24NO5S 354.14, found 354.2.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N+:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(CCCCBr)cc1
Reactant: Cc1ccncc1
Solvent: CC#N
Product: CCCCc1ccc(CCCC[n+]2ccc(C)cc2)cc1
Product: [Br-]
Yield: 72 %

Procedure:
1-(4-Bromo-butyl)-4-butyl-benzene (1 mmol) was added to a solution of 4-picoline (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in a vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (72%). 1HNMR (300 MHz, CDCl3, ppm), 9.22 (d, J=6.6, 2H), 7.79 (d, J=6.6, 2H), 7.05 (d, J=8.4, 2H), 7.02 (d, J=8.4, 2H), 4.90 (t, J=7.5, 3H), 2.51-2.63 (m, 7H), 1.96-2.06 (m, 2H), 1.58-1.68 (m, 2H), 1.51-1.61 (m, 2H), 1.31-1.37 (m, 2H), 0.89 (t, J=7.2, 3H); 13CNMR, 158.91, 144.31, 140.83, 138.30, 128.92, 128.66, 128.45, 61.26, 35.54, 34.95, 34.04, 31.61, 27.95, 22.73, 22.57, 14.33.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:18]([O:20]CC)=O)[CH2:10][CH:9]2[CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:2]1([C:8]2([C:18]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:20])[CH2:10][CH:9]2[CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CCOC(=O)C1(c2ccccc2)CC1CN1CCOCC1
Agent: Cl
Product: O=C(N1CCCC1)C1(c2ccccc2)CC1CN1CCOCC1

Procedure:
In a manner similar to that described in Example 1, but hydrolyzing the hydrochloride of 1-phenyl 1-ethoxycarbonyl 2-morpholinomethyl cyclopropane (Z) and then treating the intermediate acid chloride with pyrrolidine, there is obtained the product of the formula ##STR15##