Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:4](=[O:13])[CH:3]=1.N1C=CC=CC=1.S(OC)(O[C:24](SC)([S:27][CH3:28])[S:25][CH3:26])(=O)=O>O1CCOCC1>[CH3:26][S:25][C:24]([S:27][CH3:28])=[C:3]1[C:2](=[O:1])[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])[C:4]1=[O:13]
Reactant: COS(=O)(=O)OC(SC)(SC)SC
Reactant: CC(C)CCn1ccc(O)cc1=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CSC(SC)=C1C(=O)C=CN(CCC(C)C)C1=O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
The product of Example 457B (2.24 g, 12.37 mmol) in pyridine (8.0 mL, 98.96 mmol) and dioxane (50 mL) at 90° C. was treated with excess tris(methylthio)methyl methyl sulfate (prepared using the procedures in Synthesis, 22-25, 1988; M. Barbero, S. Cadamuro, I. Degani, R. Fochi, A. Gatti, V. Regondi), stirred at 90° C. for 1.5 hours and cooled to about 25° C. The reaction solution was decanted from the resulting solids and the solvent was removed under reduced pressure. The residue was dissolved in hexanes and loaded onto a pad of silica gel (300 mL) and eluted with hexane followed by dichloromethane then 25% ethyl acetate in dichloromethane to provide the title compound (2.42 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[OH-].[Na+]>C1OCCOC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:25][CH:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=3[F:36])[CH2:27]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:11][CH2:12]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4F)C3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4F)C3)CC2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 41.8 %

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)nicotinamido)cyclopropyl)benzoate (D169) (12 mg, 0.024 mmol) in a mixture 1-4 dioxane/water (3 ml/1 ml), 1N NaOH (0.036 ml) was added. The reaction mixture was stirred 12 h at 60° C. Organic solvent was evaporated in vacuo and the reaction mixture was acidified with 2N HCl (pH=2) and the resulting mixture was extracted with ethylacetate (3×5 ml). Combined organics were evaporated in vacuo and the residue was loaded on SNAP-C18 gold cartridge (15 g) eluting with H2O-AcOH (0.1%)/CH3CN—AcOH (0.1%) from 10/90 to 0/100. Collected fractions were evaporated in vacuo to afford the title (E35) (5 mg)
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:22])[C:20]#[CH:21]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:22][CH2:19][C:20]#[CH:21])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: C#CCN
Solvent: O
Product: C#CCNc1nc(NCC=C)c2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.6 %

Procedure:
To 150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was added 1.61 g (29.16 mmol) of 2-propynylamine, followed by stirring at room temperature for 6 hours. After water was added to the reaction solution was water added, crystals thus precipitated were filtered and recrystallized from ethyl acetate-hexane to give 143 mg (yield: 88.6%) of the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]([N:15]1[CH:22]([CH3:23])[CH2:21][CH2:20][CH:19]2[CH:17]([O:18]2)[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CO.O>[CH2:5]([O:12][C:13]([N:15]1[CH2:16][CH:17]([OH:18])[CH:19]([N:1]=[N+:2]=[N-:3])[CH2:20][CH2:21][CH:22]1[CH3:23])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1CCC2OC2CN1C(=O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CCC(N=[N+]=[N-])C(O)CN1C(=O)OCc1ccccc1
Yield: 80.1 %

Procedure:
Sodium azide (0.56 g, 8.62 mmol) was added to a solution of racemic (1S,4R,7R)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.75 g, 2.87 mmol) and ammonium chloride (0.46 g, 8.62 mmol) in MeOH (5 ml) and H2O (0.5 ml), then was refluxed for 6 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then was diluted with water (5 ml) and extracted with EtOAc (10 ml). The organic layer was then extracted with water, brine, dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 20% EtOAc/hexanes) to yield the title compound (0.7 g, 80%): 7.39–7.30 (m, 5H), 5.15 (2H, s), 4.10–3.67 (m, 2H), 3.10 (1H, d), 1.85–1.53 (m, 4H), 1.09 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=305.2.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:8](=[C:10]([C:23]([OH:25])=[O:24])[CH:11]=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[N+:14]([O-])=O)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[C].[Pd]>[NH2:14][C:13]1[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[C:8]2[C:7]=1[O:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9]2
Reactant: CC(C)(C)c1nc2c(C(=O)O)cc(-c3ccccc3)c([N+](=O)[O-])c2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1nc2c(C(=O)O)cc(-c3ccccc3)c(N)c2o1

Procedure:
2-tert-Butyl-7-nitro-6-phenyl-1,3-benzoxazole-4-carboxylic acid (I-223) (6.27 mmol) was dissolved in methanol (30 ml), then at room temperature, 10% palladium-carbon (430 mg) was added. The suspension was stirred at room temperature under atmospheric pressure of hydrogen for 16 hour. The catalyst was removed by filtration with washing with methanol, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, chloroform:methanol=98:2) to obtain the entitled compound (1.274 g, 66% from I-222) as a pale brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[O:11][CH:12]=[CH:13][C:9]=2[C:8]([NH:14][C:15](=[O:17])[CH3:16])=[C:7]([Cl:18])[CH:6]=1)=[O:4].[H][H]>CC(C)=O.[Rh]>[C:15]([NH:14][C:8]1[C:9]2[CH2:13][CH2:12][O:11][C:10]=2[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[Cl:18])(=[O:17])[CH3:16]
Reactant: [H][H]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2ccoc12
Agent: [Rh]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCC2
Yield: 95.3 %

Procedure:
A solution of methyl-4-acetamido-5-chloro-benzo[b]furan-7-carboxylate (0.5 g) in acetone (300 ml) was stirred for 3 hours in presence of 5% Rh/C (0.5 g) in a hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated in vacuo to yield 0.48 g of the title product.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:3][CH2:2]1>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[CH2:3][CH2:2]1
Reactant: CC(C)Oc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)Oc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1C=O
Reaction time: 1 h
Yield: 89.5 %

Procedure:
Manganese dioxide (10.8 g) was added to a toluene (30 mL) solution of (2-cyclopropyl-2′,4′-difluoro-5-isopropoxybiphenyl-4-yl)methanol (3.97 g), and the mixture was stirred at 60 C for 1 hour in a nitrogen atmosphere. The reaction mixture was filtered, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (3.53 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:24]=1[C:25](N(OC)C)=[O:26]>O1CCCC1>[F:22][C:23]1[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:24]=1[C:25]([C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1)=[O:26]
Reactant: CON(C)C(=O)c1cc(C)cnc1F
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(Br)n2)CC1
Solvent: C1CCOC1
Product: Cc1cnc(F)c(C(=O)c2cccc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 86.7 %

Procedure:
To a solution of tert-butyl 4-(6-bromopyridin-2-yl)-1,4-diazepane-1-carboxylate (898 mg, 2.52 mmol) in tetrahydrofuran (10 ml) at −78° C. was added a 2.5M solution of nbutyllithium in hexanes (1.01 ml, 2.52 mmol) dropwise maintaining the temperature at −78° C. After complete addition, the solution was stirred at −78° C. for a further 20 minutes. A solution of 2-fluoro-N-methoxy-N,5-dimethylnicotinamide (500 mg, 2.52 mmol) in tetrahydrofuran (5 ml) was added dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 hour. The reaction was quenched with a saturated solution of ammonium chloride. The mixture was stirred at room temperature for 20 minutes and extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion□, 40 g column, 0-20% EtOAc/Petrol) to afford the title compound as a sticky green oil (906 mg, 87% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([NH2:26])=O)[N:6]2[CH2:21][O:22][CH3:23].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24](=[S:36])[NH2:26])[N:6]2[CH2:21][O:22][CH3:23]
Reactant: COCn1c(C(N)=O)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCn1c(C(N)=S)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
A mixture of 4-fluoro-1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.41 g), Lawesson's reagent (0.50 g) and tetrahydrofuran (40 mL) was stirred at 60° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-4:6) to give the title compound (0.25 g, yield 59%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][OH:16])[CH:5]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][O:16][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)[CH:5]=1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cccc(-c2ncsc2CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(-c2ncsc2COC2CCCCO2)c1

Procedure:
3-(5-Hydroxymethyl-thiazol-4-yl)-benzoic acid methyl ester (1.25 g), dihydropyrane (0.84 mL) and p-toluenesulfonic acid hydrate (0.10 g) in AcOEt (12 mL) was stirred at 20° C. for 3 h. The solution was diluted AcOEt, washed with 5% NaHCO3 solution and with brine, dried and evaporated. The residual oil was purified by chromatography on silica gel using AcOEt/hexane (1:3) as eluent to give 3-[5-(tetrahydro-pyran-2-yloxymethyl)-thiazol-4-yl]-benzoic acid methyl ester (1.60 g) as a pale-yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[C:20]1(=[O:24])[CH2:23][CH2:22][CH2:21]1>C1COCC1>[Br:13][C:14]1[C:19]([C:20]2([OH:24])[CH2:23][CH2:22][CH2:21]2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=C1CCC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OC1(c2cccnc2Br)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.9 %

Procedure:
To a solution of diisopropylamine (3.0 mL, 21.40 mmol) in THF (10 mL) at −78° C. was added n-BuLi (7.6 mL, 17.84 mmol). After 30 min, a solution of 2-bromopyridine (1.1 mL, 11.89 mmol) in THF (30 mL) was added and stirring was continued at −78° C. After 45 min, cyclobutanone (1.0 g, 14.27 mmol) was added and the mixture was stirred at −78° C. for 1.5 h. After warming to room temperature, the mixture was quenched with water (20 mL), diluted with saturated NH4Cl (15 mL), and extracted with Et2O (3×30 mL). The combined organic layer was dried (MgSO4), filtered, and concentrated to afford an orange oil. Purification by flash column chromatography on silica gel using hexanes/EtOAc (2:1) afforded 1-(2-bromo-pyridin-3-yl)-cyclobutanol as an orange oil (1.0 g, 37%). 1H NMR (CDCl3) δ 1.69-1.73 (m, 1H), 2.19-2.22 (m, 1H), 2.49-2.55 (m, 2H), 2.61-2.68 (m, 2H), 3.01 (s, 1H), 7.29 (dd, 1H, J=5.1, 4.8 Hz), 7.68 (dd, 1H, J=7.7, 2.1 Hz), 8.28 (dd, 1H, J=4.7, 1.8 Hz).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[CH:18][CH:17]=1)[CH3:2].CO.[H][H]>[Pd].C(O)(=O)C>[CH2:1]([C:3]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[CH3:2]
Reactant: CCc1nc(C(F)(F)F)nc2c1ncn2-c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1nc(C(F)(F)F)nc2c1ncn2-c1ccc(O)cc1
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A mixture of 6-ethyl-9-(4-benzyloxyphenyl)-2-trifluoromethylpurine (0.1 mmol), palladium on active carbon (0.001 mol, methanol (50 mL) and acetic acid (3 mL) was shaken under 30 psi hydrogen. After 5 hours, the reaction mixture was filtered through celite and the filtrate was concentrated under vacuum. The resulting residue was dissolved in 30 mL of ethyl acetate and washed with 5% aqueous sodium bicarbonate (1×30 mL). Concentration and Chromatography (5% methanol in dichloromethane) gave 6-ethyl-9-(4-hydroxyphenyl)-2-trifluoromethylpurine (21 mg, 93%). 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.45 (d, J=7.2 Hz, 2H), 6.96 (d, J=7.2 Hz, 2H), 3.29 (q, J=7.5 Hz, 2 H), 3.11 (s, 1H), 1.41 (t, J=7.5 Hz, 3H). [ESMS m/z (309.4 (M+H)+)]
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[O:11]C.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[OH:11]
Reactant: COc1cccc2cc(C)[nH]c12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2cccc(O)c2[nH]1
Reaction time: 3 h
Yield: 99 %

Procedure:
To a solution of 2-methyl-7-methoxy indole (814 mg, 5.0 mmol) in CH2Cl2 (20 mL) at 0° C. was added BBr3 (15 mL, 15 mmol, 1M in CH2Cl2), and then the ice bath was removed and stirring was continued for 3 h. Ice was added and the reaction mixture diluted with water (30 mL). The aqueous layer was extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via passage through a short silica gel column (20% then 50% EtOAc/hex) to afford 2-methyl-7-hydroxy indole as an unstable solid (99% yield).
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[H][H].[CH2:13]([O:15][C:16](=[O:22])[CH2:17][CH:18]([NH2:21])[C:19]#[CH:20])[CH3:14]>CCO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:13]([O:15][C:16](=[O:22])[CH2:17][CH:18]([NH2:21])[CH:19]=[CH2:20])[CH3:14]
Reactant: C#CC(N)CC(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: C=CC(N)CC(=O)OCC
Reaction time: 2.5 h

Procedure:
A mixture of 5% Pd/BaSO4 (0.025 g) and quinoline (0.30 mL) was stirred under a balloon of hydrogen for 30 minutes. 3-Amino-pent-4-ynoic acid ethyl ester (18-1) (for preparation, see J. A. Zablocki, et al., J. Med. Chem., 1995, 38, 2378-2394) (1.77 g, 10.0 mmol) in EtOH (15 mL) was added and the solution stirred for an additional 2.5 hours. The solution was filtered through a pad of celite and concentrated in vacuo to provide 2.65 g of crude product 18-2. 1H NMR (CDCl3, 300 MHz): δ 8.40-7.60 (br s, 2H), 6.11-5.96 (m, 1H), 5.58-5.53 (d, 1H), 5.44-5.41 (d, 1H), 4.31-4.16 (m, 3H), 3.12-2.86 (m, 2 H), 1.29-1.25 t, 3H). ##STR30##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]2[CH2:22][O:21]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:37])([F:36])[C:25]1[CH:35]=[CH:34][C:28]([CH2:29][C:30]2([NH2:33])[CH2:32][CH2:31]2)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:20]([OH:21])[CH2:22][NH:33][C:30]2([CH2:29][C:28]3[CH:34]=[CH:35][C:25]([C:24]([F:23])([F:36])[F:37])=[CH:26][CH:27]=3)[CH2:31][CH2:32]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2c(C3CO3)ccc(OCc3ccccc3)c2[nH]1
Reactant: NC1(Cc2ccc(C(F)(F)F)cc2)CC1
Product: O=c1ccc2c(C(O)CNC3(Cc4ccc(C(F)(F)F)cc4)CC3)ccc(OCc3ccccc3)c2[nH]1

Procedure:
Reaction of 587 mg (2.0 mmol) 8-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 710 mg (3.3 mmol) 1-(4-trifluoromethyl-benzyl)-cyclopropylamine is carried out analogously to Example 40a43a). Yield: 322 mg (32%); mass spectroscopy: [M+H]+=509.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]([NH2:21])[CH2:8][S:9][S:10][CH2:11][C@H:12]([NH2:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])([CH3:3])[CH3:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:16]([O:15][C:13](=[O:14])[C@@H:12]([N:20]([S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[S:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:31])=[O:30])[CH2:11][S:10][S:9][CH2:8][C@H:7]([NH2:21])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CSSC[C@H](N)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@@H](N)CSSC[C@@H](C(=O)OC(C)(C)C)N(S(=O)(=O)c1ccccc1)S(=O)(=O)c1ccccc1

Procedure:
Preparation in analogy to example 6a from 1 g (2.35 mmol) of (R)-cystine-bis-tert-butylester and 0.83 g (4.7 mmol) benzenesulfonic acid chloride. Yield: 1.5 g.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH:30]([S:33](Cl)(=[O:35])=[O:34])([CH3:32])[CH3:31]>>[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][N:19]([S:33]([CH:30]([CH3:32])[CH3:31])(=[O:35])=[O:34])[CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
7-(3-Piperidin-1-yl-propoxy)-2-(propane-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt3 (0.25 mL, 1.8 mmol), and isopropylsulfonyl chloride (0.07 mL, 0.60 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (93 mg, 49% yld). MS(ES+) 381.1(M+H)+.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:11])[CH2:7][CH2:8][CH2:9][CH3:10].Cl>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:11][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCO
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: CCCCCOP(=O)(Cl)Cl
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
Phosphoryl trichloride (306 g; 2 moles) is placed in a 2-liter flask fitted with a condenser and mechanical stirrer, and cooled down to about 10° C. (external ice bath). Pentanol (159 g; 1.8 moles; 0.9 equivalents with respect to POCl3) is added at a rate such that the reaction temperature remains below 15° C. The reaction is exothermic and the HCl gas that evolves during this reaction is vented out with a flow of nitrogen using an aspirator operated at a slight vacuum (about 0.5 inches of mercury). When addition of alcohol is completed (about 1.5 hours), the ice bath is removed and the reaction mixture is allowed to warm to room temperature and then warmed to 60°-70° C. and stirred at this temperature for 1.5 hours to drive out most of the HCl gas. The product, pentyl phosphorodichloridate, is obtained as a clear light yellow free-flowing liquid.
Reaction SMILES: [C:1]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.ClC(OCC)=O.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH2:33][CH3:34])[CH:27]=1>C(#N)C>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:9]([C:6]2([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:7][CH2:8]2)=[O:11])=[C:28]([CH2:33][CH3:34])[CH:27]=1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: CCc1cc(Cl)ccc1N
Agent: CCOC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2ccc(Cl)cc2CC)CC1
Temperature: 25 °C
Yield: 40 %

Procedure:
To a stirred solution of 1.54 grams (0.01 mole) of 1-carboethoxycyclopropanecarboxylic acid (the monocarboxylic acid intermediate described in Example XVIII) and 0.99 gram (0.01 mole) of triethylamine in 75 milliliters of acetonitrile was added a solution of 1.06 grams (0.01 mole) of ethyl chloroformate in 25 milliliters of acetonitrile dropwise with cooling to 0° C.-5° C. After stirring at ice temperature for 30 minutes a solution of 1.52 grams (0.01 mole) of 4-chloro-2-ethylaniline in 20 milliliters of acetonitrile was fed dropwise with stirring and continued cooling. The reaction mixture was allowed to warm to room temperature, then stirred for approximately sixteen hours following which it was filtered and the filtrate freed of solvent by evaporation. The residue was dissolved in dichloromethane and extracted, successively, with water (2×50 milliliters), 2N HCl (2×50 milliliters) and water (1×50 milliliters). After drying (MgSO4), solvent was removed by evaporation and the solid recrystallized from hexane to give 1.15 grams (0.004 mole) of ethyl 1-(4-chloro-2-ethylphenylaminocarbonyl)cyclopropanecarboxylate as cream colored prisms having a melting point of 77° C.-80° C. Elemental analysis of the product indicated the following:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[K+].[Br-]>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:3])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN1CCNCC1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: CN1CCN(C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-chlorophenyl chloroformate and 1-methylpiperazine, yield 81%. White crystals, m.p. 237-240° C.; 1H NMR (DMSO-d6): δ11.67 (br s, 1H), 7.50, 7.45, 7.24, 7.20 (AB-system, d=7.47 and 7.22; J=8.84 Hz, 4H), 4.40-3.91 (br, 2H, 3.77-2.92 (br m, 6H+water), 2.77 (s, 3H); IR (KBr): ν 1717 (C═O) cm −1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22](I)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[N:10]=3)[CH:23]=2)=[CH:35][CH:34]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(I)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)cc1

Procedure:
N-tert-Butyl-4-{1-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3,4-dichloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.74) (0.485 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.08 g) which was subsequently deprotected.