Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].ClCCl.C([O:20][C:21]([C:23]1([C:26](O)=[O:27])[CH2:25][CH2:24]1)=[O:22])C>[Cu]Cl.CCCCCC>[C:10]([O:14][C:26]([C:23]1([C:21]([OH:22])=[O:20])[CH2:25][CH2:24]1)=[O:27])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: CC(C)(C)O
Agent: Cl[Cu]
Agent: CC(C)N=C=NC(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(C(=O)O)CC1
Reaction time: 96 h

Procedure:
At room temperature under shielded light, to N,N′-diisopropylcarbodiimide (99.75 g) was added copper(I) chloride (1.57 g), and then tert-butanol (83 ml) was added dropwise over 20 minutes, followed by stirring for 4 days. The supernatant (12.7 ml) was added to a dichloromethane solution (40 ml) of 1-(ethoxycarbonyl)cyclopropanecarboxylic acid (6.37 g), and heated at reflux for 3 hours. Hexane (50 ml) was added to the reaction solution, and the precipitate was filtered off. After the filtrate was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After hexane was added to the resulting residue, the precipitate was filtered off, and the filtrate was concentrated. The resulting residue was dissolved in tetrahydrofuran (25 ml), and 1 N aqueous sodium hydroxide solution (25 ml) was added, and stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, 1 N aqueous sodium hydroxide solution (15 ml) was added to the residue, and washed with dichloromethane. A 10% aqueous citric acid solution was added to the aqueous layer to render it acidic, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1-(tert-butoxycarbonyl)cyclopropanecarboxylic acid (1.80 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[N:14]([C:7]1[N:6]=[C:5]([NH2:8])[N:4]=[C:3]([NH2:9])[C:2]=1[NH2:1])=[O:15]
Reactant: Nc1ncc(N)c(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N)c(N=O)n1
Temperature: 8 °C

Procedure:
In a 500-gallon glasslined reactor, crude damp triaminopyrimidine was dissolved in 150 gallons of deionized water with the aid of 117 pounds of acetic acid. HPLC assay showed 137 pounds of triaminopyrimidine in solution. The solution was cooled to 8° C. and treated with 80 pounds of sodium nitrite in 45 gallons of deionized water over a period of 13 minutes, with full refrigeration on the reactor jacket. A dense granular slurry of nitrosotriaminopyrimidine formed during the next 15 minutes as the temperature rose to 13° C. Analysis showed less than 0.1% of the triaminopyrimidine remaining unreacted in the filtrate, and a sample of the slurry was taken for small scale experiments. It remained a stable slurry under refrigeration for several days. The remainder of the slurry was reduced in situ to tetraaminopyrimidine sulfite by reaction with 382 pounds of sodium dithionite, filtered hot and chilled to 0°-5° C. to precipitate 609 pounds of damp cake, containing 186 pounds of tetraaminopyrimidine sulfite.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:25](C=O)=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25]1[C:24]([CH3:23])=[CH:29][C:28]([CH3:30])=[CH:27][N:26]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)NCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(N(CCCNC(=O)OC(C)(C)C)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B, reaction of [3-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-propyl]-carbamic acid tert-butyl ester, 3,5-dimethylpyridine-2-carboxaldehyde and NaBH(OAc)3 in CH2Cl2 gave {3-[(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-propyl}-carbamic acid tert-butyl ester as a pale beige sticky solid. 1H NMR (CDCl3) δ 1.75 (m, 4H), 2.18 (br t, 1H), 2.27 (s, 3H), 2.30 (s, 3H), 2.37 (br, 1H), 2.56 (t, 1H, J=10.5 Hz), 2.83 (m, 4H), 3.38 (br, 1H), 3.68 (d, 1H, J=15.0 Hz), 3.84 (br, 1H), 4.04 (d, 1H, J=15.0 Hz), 7.13 (m, 1H), 7.26 (s, 1H), 7.41 (d, 1H, J=7.0 Hz), 8.33 (s, 1H), 8.53 (d, 1H, J=4.5 Hz). Deprotection with TFA using General Procedure F gave N-(3,5-dimethyl-pyridin-2-yl)-N]-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[C:14]([S-:16])#[N:15].[K+]>CO.[O-]S([O-])(=O)=O.[Cu+2]>[NH2:15][C:14]1[S:16][C:11]2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=[C:3]([O:12][CH3:13])[C:2]=2[N:1]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: N#C[S-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(OC)c2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
To a solution of methyl 4-amino-3-methoxybenzoate (307 g, 1.696 mol) in anhydrous methanol (4 L) was added an intimated mixture of KSCN (1640 g, 16.9 mol) and anhydrous CuSO4 (1350 g, 8.44 mol) in one portion. The mixture was heated to reflux for 4 h. TLC (EtOAc/Petroleum ether 1:4) showed the reaction was complete. The mixture was filtered and the filtrate was diluted with water. The solution was heated to boiling until a slightly clear solution formed. The mixture was cooled to ambient temperature and left standing for 1 day. A dark yellow solid was formed, which was collected by filtration to afford the desired product (338 g, 84%) as a dark yellow solid. 1H NMR (400 MHz, CDCl3): δ 9.000-8.200 (br, 2H), 8.052 (s, 1H), 7.435 (s, 1H), 3.927 (s, 3H), 3.827 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:32]=[CH:31][C:23]4[C:24]([C:28]([OH:30])=O)=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.C(Cl)(=O)C(Cl)=O.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[CH:39]1([NH:42][C:28]([C:24]2[C:23]3[CH:31]=[CH:32][C:20]([O:19][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[CH:11]=[C:10]([C:8]([N:5]6[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]6)=[O:9])[S:18][C:17]=45)=[CH:21][C:22]=3[O:26][C:25]=2[CH3:27])=[O:30])[CH2:41][CH2:40]1
Reactant: NC1CC1
Reactant: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Agent: O=C(Cl)C(=O)Cl
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NC6CC6)c(C)oc5c4)c3s2)C1
Yield: 33.1 %

Procedure:
This material was prepared from 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic acid 89e (37 mg, 0.08 mmole) by treatment with oxalyl chloride (15 μl, 0.17 mmole) and cyclopropylamine (56 μl, 0.81 mmole) in a manner as previously described for example 16d to give a white solid (13 mg,33%). 1H NMR (DMSO-d6) δ8.57 (1H, d, J=5.1 Hz), 8.19 (1H, s), 8.06 (1H, bs), 7.74 (1H, d, J=6.1 Hz), 7.65 (1H, s), 7.24 (1H, d, J=6.1 Hz), 6.71 (1H, d, J=1.8 Hz), 4.10-3.80 (3H, m), 3.70-3.35 (2H, m), 3.25 (3H, d, J=13.1 Hz), 2.86 (1H, m), 2.59 (3H, s), 2.25-1.95 (2H, m), 0.71 (2H, m), 0.60 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][C:3]=1[F:15].[CH:16]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[C:4]([CH3:16])[C:3]=1[F:15]
Reactant: Fc1cc(OC2CCCCO2)ccc1Br
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(OC2CCCCO2)ccc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
2-(4-bromo-3-fluorophenoxy)tetrahydro-2H-pyran (1200 mg, 4.4 mmol) was dissolved in tetrahydrofuran (22 mL, 0.2M) under nitrogen and cooled to −78° C. To this was added (600 mg, 5.6 mmol) lithium diisopropylamide in solution dropwise over 5 minutes. The reaction mixture was stirred for 1 h at −78° C. Methyl iodide (948 mg, 6.5 mmol) was then added dropwise. The reaction was stirred at −78° C. for 30 min and allowed to warm to RT overnight. The mixture was quenched with water and 10 mL of saturated aqueous ammonium chloride solution. The reaction was extracted with diethyl ether (3×). The organic layer was dried over sodium sulfate, filtered and evaporated to yield 1.17 g (93%) of a light yellow mix of solid and oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57-1.78 (m, 3 H) 1.85-1.93 (m, 2 H) 1.95-2.08 (m, 1 H) 2.21 (d, J=2.34 Hz, 3H) 3.61 (m, J=11.27, 3.98, 3.98, 1.46 Hz, 1 H) 3.78-3.88 (m, 1 H) 5.41 (t, J=3.12 Hz, 1 H) 6.81 (dd, J=8.98, 1.37 Hz, 1 H) 7.27 (d, J=16.98 Hz, 1 H)
Reaction SMILES: [CH3:1][C:2]1([NH2:8])[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[OH-].[Na+].O.[Br:12][CH:13]([CH2:17][Br:18])[C:14](Cl)=[O:15]>C(Cl)Cl>[CH3:1][C:2]1([NH:8][C:14](=[O:15])[CH:13]([Br:12])[CH2:17][Br:18])[CH2:7][O:6][CH2:5][O:4][CH2:3]1
Reactant: CC1(N)COCOC1
Reactant: O=C(Cl)C(Br)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC1(NC(=O)C(Br)CBr)COCOC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Five and nine-tenths grams (g) (0.05 mole) of 5-methyl-5-amino-1,3-dioxane, 3.2 g (0.04 mole) of 50% sodium hydroxide, 8 milliliters (ml) of water and 55 ml of methylene chloride were combined in a reaction flask. The mixture was cooled to -10° C. Ten g (0.04 mole) of 2,3-dibromopropionyl chloride were added dropwise. The reaction mixture was stirred for 2 hours and then vacuum stripped. The product was recrystallized in ethanol/water. Yield was 8.7 g of 5-methyl-5-(2',3'-dibromopropionyl)amino-1,3-dioxane. m.p.=115°-119° C. Structure was confirmed by NMR spectroscopy.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]=2)[C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][N:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:25][N:26]1[CH:30]=[CH:29][C:28]([NH:31][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:17]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=2)=[N:27]1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCOCC3)c2)n1
Yield: 47.8 %

Procedure:
3-[(Phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid (3.14 g, 9.5 mmol), 1-methyl-1H-pyrazol-3-amine (1.85 g, 19.0 mmol) and HATU (4.70 g, 12.35 mmol) were dissolved in DMF (12.5 mL) and DIPEA (3.31 mL, 19.0 mmol) added. The resultant mixture was stirred at RT for 20 hours. The mixture was quenched with water (150 mL), extracted with ethyl acetate (2×75 mL), washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a pale yellow gum (1.85 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3cccc(F)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-fluoro-phenylboronic acid to give [1-(3-fluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 319(MH+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][N:17]([CH2:19][CH2:20][OH:21])[CH2:16][N:15]([CH3:22])[C:14]1=[S:23].C(OCC)C>C1(C)C=CC=CC=1>[C:1]([O:21][CH2:20][CH2:19][N:17]1[CH2:18][N:13]([C:7]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[CH3:5])[C:14](=[S:23])[N:15]([CH3:22])[CH2:16]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(N2CN(CCO)CN(C)C2=S)c(C)c1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(=O)OCCN1CN(C)C(=S)N(c2ccc(C)cc2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
Acetyl chloride (0.168 g, 1.5 mmole) was added dropwise with stirring to a cooled solution of 1-(2,4-dimethylphenyl)-5-(2-hydroxyethyl)-3-methyl-tetrahydro-s-triazin-2[1H]-thione (0.60 g, 1 mmole) in dry toluene (30 ml). After 10 minutes the solution was allowed to warm to room temperature and stirring was continued for a further 3 hours. The solution was filtered and the solvent removed under vacuum. The product was chromatographed on a column of silica eluting with dichloromethane containing 2% methanol to yield an oil. Trituration with diethyl ether gave 5-(2-acetoxyethyl)-1-(2,4-dimethylphenyl)-3-methyl-tetrahydro-s-triazin-2[1H]-thione (0.24 g, 35%), m.p. 80°-83° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].C(N(CC)CC)C.[NH:17]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:18]([C:29](ON1C(=O)CCC1=O)=[O:30])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1>CN(C=O)C>[NH:17]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:18]([C:29]([NH:1][C@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:30])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)ON1C(=O)CCC1=O
Reactant: CSCC[C@H](N)C(N)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
5.78 g (0.039 mole) of H-Met-NH2 was dissolved in 50 ml of DMF, then 5.46 ml of triethylamine and further 18.70 g (0.047 mole) of Boc-Trp-OSu were added under cooling with ice, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and extracted with ethyl acetate. The extract was washed with 1N citric acid, saturated saline solution, saturated sodium bicarbonate solution, and saturated saline solution in series. The resulting organic layer was dried over anhydrous sodium sulfate, distilled in vacuo to remove the solvent, and solidified with hexane. The solid was recrystallized from ethyl acetate-hexane, giving 12.45 g of Boc-Trp-Met-NH2 ; yield 73.5%, m.p. 155°-157° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[Cl:11][C:9]1[CH:10]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:6]=[N:7][C:8]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2CCCC2)c(Cl)c1
Temperature: 130 °C
Yield: 91.2 %

Procedure:
A mixture of 5,6-dichloronicotinic acid ethyl ester (1.00 g, 4.57 mmol), pyrrolidine (325 mg, 4.57 mmol), potassium carbonate (632 mg, 4.57 mmol) and copper powder (34 mg) in DMF (6.8 mL) was heated at 130° C. in the microwave for 20 min. Further pyrrolidine (163 mg, 2.29 mmol) was added and the reaction heated at 130° C. for 20 min. Water (7 mL) was added and the mixture extracted with ethyl acetate (2×14 mL). The combined organic extracts were washed with water (7 mL) and brine (7 mL) before being dried (phase separator) and concentrated in vacuo to give the title compound as an orange oil (1.06 g, 4.17 mmol). δH (methanol-d4, 400 MHz): 8.45 (1H, d), 7.98 (1H, d), 4.31 (2H, q), 3.82-3.75 (4H, m), 2.0-1.93 (4H, m), 1.36 (3H, t) ppm. MS (ES): C12H15ClN2O2 requires 254, 256; found 255, 257 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[OH:24])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH3:25][S:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:31][C:30]2[CH:33]=[CH:34][C:27]([S:26][CH3:25])=[CH:28][CH:29]=2)=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: CSc1ccc(CCl)cc1
Reactant: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: C=CCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(SC)cc2)cc1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 86(b)] with 4-methylthio-benzyl chloride [J.Org.Chem. (1988),53(3), 561-569] there was obtained tert-butyl (3RS,4RS)-4-(4-allyloxy-phenyl)-3-(4-methylsulphanyl-benzyloxy)-piperidine-1-carboxylate, from which by cleavage of the allyl group by means of bis-(triphenylphosphine)-palladium(II) diacetate analogously to Example 152(e) there was obtained tert-butyl (3RS,4RS)-4-(4-hydroxy-phenyl)-3-(4-methylsulphanyl-benzyloxy)-piperidine-1-carboxylate. Subsequent alkylation with 5-bromomethyl-3-(2-methoxy-phenyl)-[1,2,4]oxadiazole analogously to Example 44(e) gave tert-butyl (3RS,4RS)-4-{4-[3-(2-methoxy-phenyl)-[1,2,4]oxadiazol-5-ylmethoxy]-phenyl}-3-(4-methylsulphanyl-benzyloxy)-piperidine-1-carboxylate as a pale yellow, viscous oil; MS: 618 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH2:13]([N:15]([CH2:29][CH3:30])[CH2:16][CH2:17][O:18][CH:19]1[C:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:23][CH2:22][NH:21][CH2:20]1)[CH3:14].C(N(CC)CC)C.[I-].[K+]>CN(C)C=O>[CH2:29]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][O:18][CH:19]1[C:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH2:20]1)[CH3:30]
Reactant: CCN(CC)CCOC1CNCCC1(OC)OC
Reactant: Fc1ccc(OCCCCl)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCOC1CN(CCCOc2ccc(F)cc2)CCC1(OC)OC
Temperature: 60 °C
Reaction time: 17 h
Yield: 75 %

Procedure:
A mixture of 7.5 parts of 1-(3-chloropropoxy)-4-fluorobenzene, 10.5 parts of N,N-diethyl-2-[(4,4-dimethoxy-3-piperidinyl)oxy]ethanamine, 7 parts of N,N-diethylethanamine, 1 part of potassium iodide and 90 parts of N,N-dimethylformamide was stirred for 17 hours at 60° C. The reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in acetonitrile and 2-propanol. The whole was evaporated and the residue was taken up in acetonitrile. The solution was evaporated, yielding 14 parts (75%) of N,N-diethyl-2-[[1-[3-(4-fluorophenoxy)propyl-]-4,4-dimethoxy-3-piperidinyl]oxy]ethanamine as a residue (intermediate 115).
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[N:18]#CN>ClCCl>[NH2:18][C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: N#CN
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: Nc1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.7 %

Procedure:
To a cooled solution of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (2.00 g, 8.08 mmole) in 25 mL dichloromethane, cyanamide (0.728 g, 16.2 mmole) was added in one portion and the mixture was stirred for 48 h at room temperature. The resulting precipitate was filtered, slurried in methanol and subsequently washed with dichloromethane to give 1.01 g (66%) of 3-amino-1,2,4-thiadiazolo[4,5-a]benzimidazole as colourless crystals: mp 255-256 ° C.; 1H NMR (DMSO-d6) δ 8.23 (d, 1H), 7.71 (d, 1H), 7.43 (t, 1H), 7.54 (s, 2H), 7.32 (t, 1H) ppm; IR (KBr) ν 3302, 3151, 1661, 1577, 1487, 1473, 1251, 1207, 810 cm-1 ; HRMS calcd for C8H6N4S 190.0313, found 190.0293. Anal. Calcd for C8H6N4S: C, 50.51; H, 3.18; N, 29.45. Found: C, 50.26; H, 3.26; N, 29.38.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.6 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3-S)3-dimethylamino-pyrrolidine-1 carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-Chloro-phenyl)3-[3-[(3S)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (60.1 mg, 5%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([CH:16]=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])(O)(O)=[O:19].[Na+].Cl([O-])=O.[Na+].C=C(C)C>C(O)CCC.O>[CH2:1]([O:8][C:9]([C:11]1[NH:12][C:13]([C:16]([OH:19])=[O:17])=[CH:14][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)[nH]1
Reactant: O=P([O-])(O)O
Agent: C=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCCCO
Solvent: O
Product: O=C(O)c1ccc(C(=O)OCc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 5-formyl-1H-pyrrole-2-carboxylic acid benzyl ester (8.0 g) in n-butanol (300 mL) and water (112 mL) was added sodium dihydrogen phosphate (6.28 g), sodium chlorite (9.47 g) and isobutene (58g). The mixture was stirred for 20 h at RT after which it was concentrated. After purification of the residue by flash column chromatography on silica (DCM/MeOH 15:1 to 1:1) 10.0 g of 1H-pyrrole-2,5-dicarboxylic acid monobenzyl ester were obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1.C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:13]3[CH:21]=[CH:20][C:16]4[O:17][CH2:18][O:19][C:15]=4[CH:14]=3)[OH:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: Brc1ccc2c(c1)OCO2
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Yield: 82.6 %

Procedure:
Benzo[1,3]dioxole-5-carbaldehyde (1.80 g, 11.96 mmol), 5-bromobenzo[1,3]dioxole (2.65 g, 13.16 mmol), and n-butyl lithium (5.26 ml, 13.16 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 40% EtOAc in hexane in about 40 min.) to give bis-benzo[1,3]dioxol-5-yl-methanol as a light brown oil (2.69 g, 83%): 1HNMR (CDCl3) 6.86-6.74 (m, 6H, Ar), 5.93 (s, 4H, 2CH2), 5.68 (d, J=3 Hz, 1H, CHOH), 2.16 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.