Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2[C:37]([C:42]3[CH:47]=[CH:46]C=C(F)C=3)=[N:38]OC=2C)=NC=1>>[CH:42]1([CH2:37][NH:38][C:3](=[O:24])[C:4]2[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])=[N:6][CH:5]=2)[CH2:47][CH2:46]1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccnc3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2cccnc2)c1COc1ccc(C(=O)NCC2CC2)cn1
Yield: 67 %

Procedure:
As described for example 90, 6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (130 mg, 0.4 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted to the title compound (98 mg, 67%) which was obtained as a light yellow solid. MS: m/e=365.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[CH:27]=[CH:26][S:25][CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[N:44]1([CH2:2][CH2:3][CH2:4][S:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[C:22]4[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]5[CH:27]=[CH:26][S:25][CH:24]=5)[CH:21]=4)[NH:16][N:15]=3)[CH2:10][CH2:9]2)(=[O:7])=[O:6])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)n[nH]c12
Yield: 8.9 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-thienyl)-1H-indazole-7-carboxamide (Example 48a) (0.05 mmol) in DMF (2 mL) was reacted with K2CO3 (14 mg, 0.1 mmol), triethyl amine (42 uL, 0.3 mmol) and morpholine (22 uL, 0.25 mmol) to afford the title compound (2.3 mg, 8.8%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]\[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1>CO.[Pd]>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(/C=C\c2ccncc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
To a solution of methyl 4-[(Z)-2-(4-pyridyl)vinyl]benzoate (570 mg) in methanol (5.7 ml) was added 10% palladium on carbon, and the mixture was stirred for 4 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was crystallized with n-hexane to give methyl 4-[2-(4-pyridyl)ethyl]benzoate (539 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].C[Si]([C:16]#[N:17])(C)C.Cl.C(OCC)C>ClCCl.[I-].[Zn+2].[I-]>[OH:8][CH:7]([C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:16]#[N:17]
Reactant: C[Si](C)(C)C#N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: ClCCl
Product: N#CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
To a stirred solution of 3-nitrobenzaldehyde (5.0 g, 33.1 mmol) in dichloromethane (30 ml) at 0 ° C. was added trimethylsilyl cyanide (4.63 ml, 34.7 mmol). After stirring for 6 h at room temperature, zinc iodide (210 mg, 0.66 mmol) was added which caused the reaction mixture to warm and gently reflux. After 30 min, the reaction mixture was treated with hydrochloric acid (2M, 100 ml) and diethyl ether (150 ml) and stirred vigorously for 16 h. The phases were separated and the aqueous phase was further extracted with diethyl ether (3×100 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel eluting with hexane:ethyl acetate (3:1 and then 1:1). This gave the title compound as a clear oil (5.0 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[S:55][CH:56]=[CH:57][N:58]=1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:53][C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: Nc1nccs1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
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: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (Intermediate 4) (2.0 g) DIPEA (4-ml) and HATU (3.05 g) were dissolved in DMF (20 ml) and stirred at room temp for 15 min. 2-Aminothiazole (801 mg) was added and the mixture was stirred at room temp for 18 h. The solvent was evaporated under vacuum and the residue was partitioned between ethyl acetate (250 ml) and water (50 ml). The organic phase was washed with hydrochloric acid (2N, 50 ml) and aqueous sodium bicarbonate (1M, 50 ml) dried (magnesium sulphate) concentrated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexanelethyl acetate (4: 1) to give the title compound (1.72 g).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH2:18])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:19]1[CH:23]=[C:22]([C:24](O)=[O:25])[CH:21]=[N:20]1>>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][NH:18][C:24]([C:22]3[CH:23]=[N:19][NH:20][CH:21]=3)=[O:25])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC/C=C\COc1cc(CN2CCCC2)ccn1
Reactant: O=C(O)c1cn[nH]c1
Product: O=C(NC/C=C\COc1cc(CN2CCCC2)ccn1)c1cn[nH]c1
Yield: 34 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-[4-(1-pyrrolidinylmethyl)-2-pyridyloxy]-cis-2-butenylamine and 4-pyrazolecarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 57°-61° C., in a 34% yield.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([S:27]([O-:29])=[O:28])[CH:21]=[CH:20]3)=[CH:13][CH:12]=1.[Na+].O>CS(C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([S:27]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:29])=[O:28])[CH:21]=[CH:20]3)=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: O=Cc1cccnc1Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1cccnc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 80 °C
Yield: 55 %

Procedure:
A suspension of 2-chloronicotinaldehyde (228 mg, 1.62 mmol) and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (500 mg, 1.62 mmol) in DMSO (2.5 mL) was heated for 12 hours at 80° C. The reaction was poured into water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 35-60% ethyl acetate/isohexane, to give the title compound as solid (349 mg). 1H NMR (400 MHz, d6-DMSO): δ 11.00 (1H, s), 8.84-8.82 (2H, m), 8.40-8.34 (3H, m), 8.25 (1H, d, J=8.7 Hz), 8.06-8.02 (2H, m), 7.94-7.84 (3H, m), 7.38 (2H, t, J=8.8 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].I[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH3:42])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:42][CH2:41][CH2:40][CH2:39][C:36]3[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=3)[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: CCCCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCCc4ccccc4)CC3)C2=O)c1
Yield: 91.4 %

Procedure:
tert-Butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 1-iodo-4-butylbenzene (0.15 g, 0.593 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in N,N-dimethylformamide (8 mL) were stirred at 65° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.30 g, 90%); MS for C35H43N3O3 m/z 554 (M+H)+.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20].C(N(CC)CC)C>C(OCC)C>[CH2:22]([O:21][C:19]([O:17][C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOC(=O)OC(=CC(=O)c1ccccc1)c1ccccc1

Procedure:
The preparation is carried out as described in Example 1, using 44.8 g (0.2 mole) of dibenzoyl methane, 61.0 g (0.2 mole) of n-hexadecyl chloroformate and 200 ml of diethyl ether as well as 22 g (0.22 mole) of triethylamine. The resultant yellow viscous liquid crystallises out. The crystals melt at 39°-40° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CNC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 94 %

Procedure:
4-Bromobenzenesulphonyl chloride (4.48 g, 18 mmol) was stirred in dichloromethane, and dimethylamine (40% aqueous solution, 10 ml) was added portionwise. The mixture was stirred for 2 h, washed with dilute hydrochloric acid, dried (Na2SO4) and evaporated to give the title compound (4.38 g, 94%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19].C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:9][CH:19]=[C:18]([C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1=CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (4.7 mL) was dissolved in dichloromethane (75 mL), and the solution was cooled to 0° C. To this solution was added dropwise a solution (10 mL) of ethyl propiolate (1.55 mL) in dichloromethane, and acetic acid (0.1 mL) was further added. The mixed solution was stirred for 4 hr while gradually warming to room temperature. The reaction solution was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the object product as a pale-yellow oil (1.37 g). The obtained compound was used for the next reaction without purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[O:19]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl.O>[CH2:1]([N:8]([CH2:21][CH2:22][CH2:23][CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCN(Cc1ccccc1)C(=O)Nc1cccc(Cl)c1O

Procedure:
A solution of 1.73 g of 1-benzyl-1-(n-butyl)-3-(2-methoxy-3-chlorophenyl)urea and 1.0 ml of boron tribromide in 40 ml of methylene chloride was stirred at ambient temperature for 3 days and diluted with water. The organic layer was separated, dried, and evaporated. The residue was crystallized from hexane to yield 1-benzyl1-(n-butyl)-3-(2-hydroxy-3-chlorophenyl)urea, m.p. 59°-62° C.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH2:7][CH2:8][CH2:9][CH:4]2[CH2:3][CH:2]1O.[N+](C1C=C([N+]([O-])=O)C=CC=1C([O-])=O)([O-])=[O:12]>CCCCCC.C(O)(C)C>[O:1]1[C@@H:5]2[CH2:6][CH2:7][CH2:8][C@H:9]([OH:12])[C@@H:4]2[CH2:3][CH2:2]1
Reactant: OC1CC2CCCC=C2O1
Reactant: O=C([O-])c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCCCCC
Product: O[C@H]1CCC[C@H]2OCC[C@@H]12

Procedure:
Racemic alcohol 12 (70 mg, 0.5 mmol) was dissolved in THF (5 mL), vinyl acetate (120 μL, 1.25 mmol) was added. Amano lipase PS-30 (30 mg) was added and the resulting suspension was stirred at 15-17° C. After 48 h, 30 mg additional enzyme was added and the mixture was left for additional 48 h until which ca. 54% conv. was reached (NMR and GC). The resulting suspension was diluted with Et2O and filtered on celite, the filter cake rinsed with Et2O. After evaporation of the remaining solvent, the residue was purified by column chromatography using hexanes/EtOAc (5:1, 3:1 then 2:1) as the eluent to yield acetyl furanol 13 (38 mg, 41%) and the desired enantioenriched (−)-hexahydrobenzofuranol (−)-12 (24 mg, 35%). The enantiomeric excess of the 2,4-dinitrobenzoate derivative of (−)-12 was determined to be 98.8% ee by chiral HPLC, Column ChiralPak IA, hexane/isopropanol (90/10 to 50/50, 40 min), 1 mL/min, 35° C., λ=254 nm, Rt Major=16.54 min, Rt minor=37.1 min.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])[CH:8]=[CH:9][C:2]=12.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([N:16]([CH3:20])[CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])[CH:8]=[CH:9][C:2]=12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CNc1ccc(-c2ccc3nonc3c2)c(OC)c1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(N(C)C)ccc1-c1ccc2nonc2c1
Temperature: 25 °C

Procedure:
200 mg (0.8 mmol) of (4-benzo[1,2,5]oxadiazol-5-yl-3-methoxy-phenyl)-methyl-amine are stirred at 0 to 5° C. in 5 mL of DMF, then over 1 minute treated with 1 mL NaHMDS-solution (1.0 M, 1.25 eq.) and stirred another minute. Then, 0.5 mL (7.8 mmol, 10 eq.) of methyliodide is added and stirred 2 minutes under warming to rt. Then, the mixture is extracted with ethyl acetate/aqueous NaHCO3, the combined organic layers dried with sodium sulfate and concentrated. This yields the desired product as a reddish-yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:46]=[CH:45][C:6]2[CH:7]([C:17]3[C:18](=[O:44])[NH:19][C:20](=[O:43])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH2:30]C(NC5SC=C(CC(O)=O)N=5)=O)[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].N1C[CH:49]([C:51]([OH:53])=[O:52])[CH2:48]1>>[CH2:1]([C:3]1[CH:46]=[CH:45][C:6]2[CH:7]([C:17]3[C:18](=[O:44])[NH:19][C:20](=[O:43])[N:21]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([N:29]5[CH2:48][CH:49]([C:51]([OH:53])=[O:52])[CH2:30]5)[N:24]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C(O)C1CNC1
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Product: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(N3CC(C(=O)O)C3)n2)c(=O)[nH]c1=O

Procedure:
The title compound was prepared from the product of example 15 step (viii) (0.2 g) and 3-azetidinecarboxylic acid (0.045 g) by the method of example 7 step (i). Purification was by precipitation with ethyl acetate/isohexane and filtration. Yield 0.14 g.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[CH:16]=[CH:15][S:14][N:13]=1>>[N+:6]([C:16]1[C:12]([O:11][CH3:10])=[N:13][S:14][CH:15]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: COc1ccsn1
Agent: O=S(=O)(O)O
Product: COc1nscc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
To a solution of 10 ml. of concentrated sulfuric acid and 2 g. (0.022 mole) of 70% nitric acid was added over several minutes 2.3 g. (0.02 mole) of 3-methoxyisothiazole. The temperature rose to 40° C. and was controlled at that point by cooling. After stirring for 5 hours the reaction solution was poured into 30 ml. of ice-water to precipitate 0.5 g. (16%) of 4-nitro-3-methoxyisothiazole as a white solid, m.p. 118°-122° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([Cl:19])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(O)C.[H][H]>[Pd].[O-]S([O-])(=O)=O.[Ba+2].C1COCC1>[Cl:19][C:12]1[CH:11]=[C:10]([O:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[CH:15]=[CH:14][C:13]=1[NH2:16]
Reactant: [H][H]
Reactant: CSc1nccc(Oc2ccc([N+](=O)[O-])c(Cl)c2)n1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1nccc(Oc2ccc(N)c(Cl)c2)n1
Yield: 32.4 %

Procedure:
A mixture of 1.10 g (3.69 mmol) 2-methylsulfanyl-4-(3-chloro-4-nitrophenoxy)-pyrimidine, 20 ml ethanol, 20 ml THF, and 300 mg palladium/BaSO4 is hydrogenated at 50 mbar hydrogen pressure at r.t. for 8 h. The catalyst was removed by filtration, washed with 20 ml ethanol and evaporated. The residue was purified by chromatography on silica (ethyl acetate/isohexane 2:7) to give 320 mg (32%) 2-chloro-4-(2-methylsulfanyl-pyrimidin-4-yloxy)-phenylamine.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:33][CH:30]1[CH2:31][CH2:32][N:28]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=4[N:18]([CH3:27])[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])=[N:5][CH:4]=2)[CH2:29]1
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CCl)s3)cc12
Reactant: OC1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CN4CCC(O)C4)s3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.13 g) and 3-pyrrolidinol (60 mg) in N,N-dimethylformamide (8 ml) was added potassium carbonate (110 mg) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-7:3), and the obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (85 mg, yield 59%) as pale-yellow prism crystals. melting point 190-191° C. MS: 489(MH+).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[I:12].[CH2:13](O)[CH2:14][OH:15].Cl[Si](C)(C)C>ClCCl>[O:7]1[CH2:13][CH2:14][O:15][CH:6]1[C:5]1[CH:8]=[C:9]([O:10][CH3:11])[C:2]([OH:1])=[C:3]([I:12])[CH:4]=1
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: OCCO
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: COc1cc(C2OCCO2)cc(I)c1O
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of 4-hydroxy-3-iodo-5-methoxybenzaldehyde (20 g, 72 mmoles), ethylene glycol (8.0 mL, 144 mmoles), and chlorotrimethylsilane 36.5 mL, 0.29 moles) in dichloromethane (300 mL) was heated at reflux for 16 hours. The mixture was cooled to room temperature and washed with saturated sodium hydrogencarbonate (3×200 mL). The combined aqueous phases were; extracted with dichloromethane (3×150 mL). The combined organic extracts were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evaporated in vacuo to afford 22.1 g (95%) of 4-[1,3]dioxolan-2-yl-2-iodo-6-methoxy-phenol. M.p. 120-121° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[OH:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH3:23])=[C:18]([CH:21]=1)[CH:19]=[O:20]>C(#N)C>[CH3:23][O:22][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1ccc(O)cc1C=O
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(OC2CCCC2)cc1C=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
5.45 g of potassium carbonate (39.4 mmol) and 4.2 ml of bromocyclopentane (39.4 mmol) are added to a solution of 4 g of 5-hydroxy-2-methoxybenzaidehyde (26.3 mmol) in 27 ml of acetonitrile. The mixture is stirred for 16 hours at 80° C. and is then poured into ice-cold water and extracted with ether, and the organic phase is washed with normal aqueous sodium hydroxide solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under vacuum. The title product is isolated by bulb-to-bulb oven distillation (T=200° C., P=10 mbar). 4.13 g of a pale yellow oil are obtained:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[S:16](Cl)(=[O:18])=[O:17]>>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:13])[F:15])=[CH:8][C:7]=1[S:16]([NH:1][CH2:2][CH2:3][OH:4])(=[O:18])=[O:17]
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Product: O=S(=O)(NCCO)c1cc(C(F)(F)F)ccc1Br

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate EU using 2-aminoethanol and 2-bromo-5-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (500 MHz, CD3OD) δ 8.35-8.30 (m, 1H), 8.07-7.98 (dd, J=8.2, 0.9, 1H), 7.82-7.76 (m, 1H), 3.59-3.50 (t, J=5.9, 2H), 3.10-3.02 (t, J=5.9, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]3[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: C1CCCNCC1
Product: Cc1nc2ccc(N3CCCCCC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 14 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and azepane according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 14%; MS: m/z=413 (M+H).