Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:13]([OH:24])=[CH:14][C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>CC(C)=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[C:13]([O:24][S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])=[CH:14][C:15]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17][C:16]=3[CH:23]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CN1CCc2cc(O)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CCc2cc(OS(=O)(=O)C(F)(F)F)c(S(=O)(=O)c3ccc(F)cc3)cc2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To an ice bath cooled solution of D6 (340 mg, 0.82 mmol) in acetone (10 mL) was added triethylamine (0.29 mL, 2.1 mmol) followed by trifluoromethanesulfonyl chloride (0.13 mL, 1.2 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue partitioned between dichloromethane and saturated sodium bicarbonate. The organic layer was removed, dried (MgSO4) and evaporated to yield the title compound D7 as a solid (270 mg). MH+ 468. 1H NMR δ (CDCl3) 2.42 (3H, s), 2.55-2.70 (4H, m), 2.95-3.15 (4H, m), 7.09 (1H, s), 7.15-7.24 (2H, t), 7.93-8.04 (3H, m).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[C:30](=[O:37])(Cl)[S:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:30](=[O:37])[S:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: CCCCSC(=O)Cl
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCSC(=O)Nc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (150.0 mg, 0.485 mmol) in dichloromethane (5 mL), under argon atmosphere, were added pyridine (0.078 mL, 0.97 mmol) and S-butyl carbonochloridothioate (133 mg, 0.87 mmol) at room temperature. After stirring at room temperature overnight, the reaction mixture was diluted with dichloromethane (50 mL), filtered through “Chem Elut” cartridge, washed with dichloromethane (50 mL) and the filtrate was concentrated in vacuo yielding to S-butyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamothioate as a honey [82 mg, yield 38%; HPLC/MS m/z=426 (M+H); logP(HCOOH)=4.25].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=O.[Cl:12][C:13]1[CH:14]=[C:15]([NH2:27])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:27][C:9](=[O:11])/[CH:8]=[CH:7]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]
Reactant: O=C(O)/C=C/c1ccccn1
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Product: CCN(CC)CCOc1ccc(NC(=O)/C=C/c2ccccn2)cc1Cl

Procedure:
Prepared analogously to Example 172 starting from (E)-3-pyridin-2-yl-acrylic acid and 3-chloro-4-(2-diethylamino-ethoxy)-phenylamine (Z2b) at RT (72 h). The crude product was purified by column chromatography (silica gel, dichloromethane/MeOH/conc. aqueous ammonia 90:10:0.1) and recrystallisation from petroleum ether.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[CH:37]=[C:38]([NH:39][C:12]([NH:11][C:4]2[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=2)=[O:20])[CH:40]=[CH:41][CH:42]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(C)n4)c3)c2cc1OC
Temperature: 50 °C
Yield: 21 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate from the previous step (0.114 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) were heated at 50° C. for 3 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.041 g, 21%). 1H NMR (300 MHz, CDCl3) δ 9.6 (br, 1H), 8.65 (s, 1H), 7.63 (m, 1H), 7.61 (s, 1H), 7.43 (t, 1H), 7.33 (m, 2H), 7.02 (dd, 1H), 6.92 (s, 1H), 6.25 (s, 1H), 4.08 (s, 6H), 3.93 (s, 3H); LC-MS (ESI) m/z 489 (M+H)+.
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].CO.C[O-].[Na+].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](OC)=O)=[CH:19][CH:18]=1>O>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[NH:5][N:6]=[C:7]([NH2:9])[N:8]=2)=[CH:19][CH:18]=1
Reactant: N=C(N)NN
Reactant: COC(=O)Cc1ccc(OC)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: O=[N+]([O-])O
Product: COc1ccc(Cc2nc(N)n[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a stirred mixture of N-aminoguanidine nitrate (5.50 g, 40 mmol) and anhydrous methanol (50 mL) cooled to 0 C was added sodium methoxide solution (25% in methanol, 9.2 mL, 40 mmol) dropwise. The resulting mixture was stirred at 0° C. for 10 min before methyl 2-(4-methoxyphenyl)acetate (1.6 mL, 10 mmol) was added. The mixture was then stirred at 0° C. for 10 min, RT for 10 min, and 75° C. for 27 hr. The reaction mixture was cooled and diluted with 20 mL of water. Methanol was removed under vacuum and the aqueous solution was acidified to pH=3-4 with 3 N aqueous HCl solution. The solid obtained was filtered, washed with water, and recrystalized in ethanol-water to give 1.65 g (81% yield) of 5-(4-methoxybenzyl)-1H-1,2,4-triazol-3-amine as a white solid. (M+H)+=205.22
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9](C#N)[CH2:10][CH2:11][C:12]([CH3:20])([CH3:19])[CH2:13][C:14]([O:16]CC)=O.Cl.C(O)(=[O:26])C.O>C(OCC)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10](=[O:26])[CH2:11][C:12]([CH3:19])([CH3:20])[CH2:13][C:14]1=[O:16]
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(C)(C)CCC(C#N)c1ccc(C)cc1C
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(C2C(=O)CC(C)(C)CC2=O)c(C)c1
Reaction time: 12 h
Yield: 32 %

Procedure:
A one-neck round bottom flask was charged with 52.50 g (0.17 mol) of ethyl 6-(2', 4'-dimethylphenyl)-6-cyano-3,3-dimethylhexanoate, 250 ml of concentrated hydrochloric acid, 250 ml of glacial acetic acid, and 100 ml of water. The reaction mixture was stirred and refluxed for 48 hours. After 12 hours and 24 hrs. of refluxing, an additional 100 ml of conc. HCl and 100 ml glacial HOAC were added. After 48 hours, the mixture was stripped to dryness under reduced pressure. To the residue were added 150 ml of water and 150 ml of ethyl ether, and the mixture shaken vigorously. A white, crystalline precipitate formed, and this was removed by suction filtration to give 13.20g (32%) of 2-(2',4'-Dimethylphenyl)-5,5-dimethyl-1, 3-cyclohexanedione as white, crystalline solid, m.p. 167°-168.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].[OH-].[K+].Cl>CC(C)=O.CO.CI>[CH3:12][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)ccc1C(=O)O
Temperature: 25 °C
Yield: 24462.6 %

Procedure:
To a solution of 2-hydroxy-4-methylbenzoic acid (25 g, 0.164 mol) in acetone (350 mL) was added K2CO3 (68 g, 0.492 mmol) followed by MeI (41 mL, 0.656 mmol) and the reaction mixture heated at reflux for 48 hrs. After cooling to r.t. the reaction mixture was filtered and the filtrate was evaporated to give the crude methyl 2-methoxy-4-methylbenzoate. KOH (11.3 g, 1.2 eq) was dissolved in MeOH (300 mL) and the crude ester was added to the mixture and the solution heated at reflux 48 hrs. After cooling the reaction mixture was acidified with aq. HCl (1N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was triturated with Ethyl acetate/Hexane to give 20 g of 2-methoxy-4-methylbenzoic acid as a cream white solid (85% yield)
Reaction SMILES: [C:1]([OH:6])(=[S:5])[CH:2](C)O.[F:7][C:8]([F:15])([F:14])[C:9](=[CH2:13])[C:10]([OH:12])=[O:11]>>[C:1]([S:5][CH2:13][CH:9]([C:8]([F:15])([F:14])[F:7])[C:10]([OH:12])=[O:11])(=[O:6])[CH3:2]
Reactant: CC(O)C(O)=S
Reactant: C=C(C(=O)O)C(F)(F)F
Product: CC(=O)SCC(C(=O)O)C(F)(F)F

Procedure:
A mixture of thiolactic acid (50 g) and 2-(trifluoromethyl)acrylic acid [M. W. Buxton, et al., J. Chem Soc., 366 (1954)] (66 g) is heated on the steam bath for one hour and then stored at room temperature for eighteen hours. The reaction mixture is distilled in vacuo to give 3-acetylthio-2-trifluoromethylpropanoic acid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]2[C:14](=[O:21])[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:4]2=[C:3]1[C:22]#[N:23].IC.[C:26](=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.CN(C)C=O>[CH3:26][N:7]1[C:2](=[O:1])[C:3]([C:22]#[N:23])=[C:4]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14](=[O:21])[C:5]2=[C:6]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1c2c(c(-c3ccccc3)[nH]c1=O)C(=O)c1ccccc1-2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(-c2ccccc2)c2c(c(C#N)c1=O)-c1ccccc1C2=O

Procedure:
A mixture of 25 parts of 3,9-dihydro-3,9-dioxo-1-phenyl-2H-indeno[2,1-c]pyridine-4-carbonitrile, 114 parts of iodomethane, 115 parts of potassium carbonate, and 475 parts of N,N-dimethylformamide is heated at 85° for 11/4 hours, then diluted with 1500 parts of water, followed by 100 parts of aqueous 5% sodium hydroxide. The deep tan precipitate which forms is filtered off, dried in air, and consecutively recrystallized from a mixture of chloroform and hexane, ethyl acetate, a mixture of ethyl acetate and chloroform, and acetonitrile to give 3,9-dihydro-2-methyl-3,9-dioxo-1-phenyl-2H-indeno-[2,1-c]pyridine-4-carbonitrile melting at approximately 255°-256°. The product has the formula ##STR15##
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](O)([CH3:9])[CH3:8])=[N:4][CH:3]=1.[SH:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]>ClCCCl.O.[I-].[Zn+2].[I-]>[Br:1][C:2]1[S:6][C:5]([C:7]([S:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([CH3:9])[CH3:8])=[N:4][CH:3]=1
Reactant: COC(=O)CCS
Reactant: CC(C)(O)c1ncc(Br)s1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: O
Product: COC(=O)CCSC(C)(C)c1ncc(Br)s1
Yield: 95.8 %

Procedure:
The product of Step 2 (9.00 g, 40.5 mmol) was taken up in 1,2-DCE (400 mL) before adding methyl 3-mercaptopropionate (9.74 g, 81 mmol) and zinc iodide (38.8 g, 122 mmol). The reaction was stirred at reflux for 5 h. The suspension was diluted with water and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-15% ethyl acetate in hexanes) provided methyl 3-{[2-(5-bromo-1,3-thiazol-2-yl)propan-2-yl]sulfanyl}propanoate (12.58 g, 96%) as a colorless oil. ESI: [M+H]+ m/z 323.9/326.0.
Reaction SMILES: Br[C:2]1[C:6]2[O:7][C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:9][C:10](=[O:11])[C:5]=2[S:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O=C1CCCCC1C(OCC)=O.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>[Cu]I>[O:15]1[CH2:16][CH2:17][N:12]([C:8]2[O:7][C:6]3[C:2]([N:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:3][S:4][C:5]=3[C:10](=[O:11])[CH:9]=2)[CH2:13][CH2:14]1
Reactant: O=c1cc(N2CCOCC2)oc2c(Br)csc12
Reactant: C1CCNCC1
Agent: [Cu]I
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Product: O=c1cc(N2CCOCC2)oc2c(N3CCCCC3)csc12
Temperature: 150 °C

Procedure:
A 0.5 mL microwave vial was charged with a magnetic stirring bar, 3-bromo-5-morpholino-7H-thieno[3,2-b]pyran-7-one (103) (50 mg, 158 μmol), cesium carbonate (103 mg, 316 mop, copper (1) iodide (3 mg, 31 μmol), ethyl 2-oxocyclohexanecarboxylate (10 μL, 63 μmol), and piperidine (200 μL). The reaction mixture was sealed, and the reaction mixture was magnetically stirred and heated via microwave irradiation to 150° C. for 15 minutes to give 5-morpholino-3-(piperidin-1-yl)-7H-thieno[3,2-b]pyran-7-one (71).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17](=[O:18])[NH2:19])=[C:14]([O:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1)(=[O:36])=[O:35]
Reactant: CC(Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 900 mg of 5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide, 423.8 mg of methanesulfonyl chloride, and 393.6 mg of triethylamine in 32 ml dichloromethane give [1-(5-carbamoyl-4-{1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.N1(C2C=CN=CC=2)CCCC1>C1(C)C(C)=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Oc1ccc(F)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: c1cc(N2CCCC2)ccn1
Solvent: Cc1ccccc1C
Product: Fc1ccc(Oc2ccnc3cc(Cl)ccc23)cc1
Reaction time: 18 h
Yield: 649.9 %

Procedure:
To a 50 mL flask equipped with a condenser, drying tube and thermometer, was added 1.98 g (0.01 moles) of 4,7-dichloroquinoline, 1.57 g (0.0014 moles) of 4-fluorophenol, 0.22 g (0.0015 moles) of 4-pyrrolidinopyridine and 20 mL of xylene. The reaction mixture was heated to reflux and reaction progress was monitored by TLC. After 18 hr, the mixture was cooled and washed with 50 mL of 5 N NaOH. The caustic layer was extracted with 3×20 mL of diethyl ether. The xylene and the ether layers were combined and dried over Na2SO4. Removal of the solvent provided 2.49 g (91 percent yield) of product, mp=88°-91° C.
Reaction SMILES: C([O:5][C:6](=[O:29])[N:7]([C@H:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=2)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)[CH3:8])(C)(C)C.C(=O)([O-])N.FC1C(OC(=O)N([C@H]2[C@H](C3C=CC(Cl)=C(Cl)C=3)CN(C(C3CCN(C(C4(C)CC4)=O)CC3)=O)C2)C)=CC=CN=1.[F:73][C:74]1[CH:79]=[CH:78][C:77](O)=[CH:76][CH:75]=1.C(OC(=O)N([C@@H]1[C@@H](C2C=CC(Cl)=C(Cl)C=2)CNC1)C)(C)(C)C>>[F:73][C:74]1[CH:79]=[CH:78][C:77]([O:5][C:6](=[O:29])[N:7]([C@H:9]2[C@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([F:21])[CH:15]=3)[CH2:12][NH:11][CH2:10]2)[CH3:8])=[CH:76][CH:75]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Reactant: Oc1ccc(F)cc1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CN(C(=O)Oc1cccnc1F)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: NC(=O)[O-]
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)c(F)c1

Procedure:
After acidic cleavage of the Boc-protecting group from [(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester the intermediately built carbamate was prepared in analogy to the procedure described for the synthesis of {(3S,4R)-4-(3,4-Dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 2-fluoro-pyridin-3-yl ester (example 293, c) with 4-fluorophenol. In analogy to the procedure described for the synthesis of rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (example 1, e) the title compound was prepared from the intermediately built [(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester through cleavage of the benzyl group. MS m/e: 367.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH3:18])[C:11]=2[CH:19](O)[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(S(F)(F)[F:33])CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH3:18])[C:11]=2[CH:19]([F:33])[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(O)c1ccncc1
Solvent: ClCCl
Product: Cc1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C(F)c1ccncc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of 200 mg of 4-[[5-(3,5-dichloro-phenylsulfanyl)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-hydroxy-methyl]-pyridine in 5 mL of dichloromethane was added 68 μL of diethylamino sulfur trifluoride. The reaction mixture was stirred for 1 hour at −78° C. then quenched with saturated aqueous sodium hydrogen carbonate. The aqueous phase was extracted three times with 10 mL of dichloromethane and combined extracts were washed with brine, dried, filtered and evaporated to give a blue gum which was purified by flash chromatography on silica gel using diethyl ether/hexane (1:2 then 1:1) for the elution to give 118 mg of 4-[[5-(3,5-Dichloro-phenylsulfanyl)-1-isopropyl-3-methyl-1H-pyrazol-4-yl]-fluoro-methyl]-pyridine as a colourless oil. Mass spectrum (ES) m/z 410 [M+H]+, 451 [M+H+MeCN]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(Cl)Cl.O=S(Cl)Cl.C(N(C(C)C)CC)(C)C.[F:30][C:31]([F:40])([F:39])[CH2:32][NH:33][CH2:34][C:35]([F:38])([F:37])[F:36]>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:33]([CH2:32][C:31]([F:30])([F:39])[F:40])[CH2:34][C:35]([F:38])([F:37])[F:36])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: FC(F)(F)CNCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluoro-3-nitrobenzoic acid (2.50 g, 13.5 mmol) was refluxed in a 2:1 mixture of CH2Cl2/SOCl2 (150 mL) for 5 h. The solvent was concentrated and the residue was dissolved in CH2Cl2 (50 mL). Another CH2Cl2 solution (50 mL) of diisopropylethylamine (DIPEA) (3.50 mL, 20.3 mmol) and bis(2,2,2-trifluoroethyl)amine (4.90 g, 27.0 mmol) was then added dropwise to the cold stirring solution (0° C.) of the acid chloride. The solution was stirred at rt overnight. The solution was then washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 3:1/hexanes:EtOAc to afford the title product. Yield: 3.08 g (66%). 1H NMR (400 MHz, CDCl3) δ 4.17 (brs, 4H), 7.40 (t, J=8.59 Hz, 1H), 7.66 (m, 2H), 8.10 (d, J=6.84 Hz, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]([C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:17][C:18]([OH:20])=[O:19])(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:29][C:30]([NH2:32])=[NH:31])=[N:5][CH:4]=1.Cl.NC(N)=N.[C:38](OC(=O)CN(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)[C@H](C1C=CC=CC=1)C)([CH3:41])([CH3:40])[CH3:39]>COCCOC>[C:38]([O:19][C:18](=[O:20])[CH2:17][N:16]([S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:11][CH:10]=1)(=[O:14])=[O:15])[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22])([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@@H](c1ccccc1)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Reactant: C[C@@H](c1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: COCCOC
Product: C[C@@H](c1ccccc1)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 60 °C
Yield: 57.5 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1S)-1-phenylethyl]glycine hydrochloride ##STR29## NaH (30 mg, 80% dispersion by wt in mineral oil, 1.01 mmol) was added in one portion to a stirred suspension of guanidine hydrochloride (154 mg, 1.61 mmol) in DME (6.0 mL) and the mixture was heated at 60° C. under N2 for 30 min. A solution of N-[(1,4-dichloro-7-isoquinolinyl)sulphonyl]-N-[(1S)-1-phenylethyl]glycine t-butyl ester (200 mg, 0.40 mmol) in DME (3.0 mL) was added and the mixture heated at 95° C. for 5 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using pentane-EtOAc (50:50 to 33:66) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1S)-1-phenylethyl]glycine t-butyl ester (128 mg, 0.23 mmol) as pale yellow foam after repeated evaporation from CH2Cl2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:23])[CH3:22]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc(OC)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
3-Methoxyphenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:18]N1C(=O)CCC1=O>C(Cl)Cl>[Br:18][C:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C:7]=1[N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=c1cc(N2CCOCC2)oc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=c1c(Br)c(N2CCOCC2)oc2ccccc12
Yield: 91.5 %

Procedure:
2-(4-morpholinyl)-4H-benzopyran-4-one (2.0 g, 8.0 mmol) is dissolved in CH2Cl2 (20 mL). N-Bromosuccinimide (1.6 g, 8.2 mmol) is added and the reaction mixture waned slightly and the starting material disappears immediately as evidenced by TLC. The solvent is removed in vacuo and the colorless residue is taken up in EtOAc (200 mL) and washed with water (4×30 mL), brine (50 mL) and dried (MgSO4). Rotary evaporation gives the desired product (2.27 g, 92%) as colorless crystals. mp: 145°-6° c ; IR (mull) 3337, 3016, 2922, 2871, 2855, 1698, 1609, 1585, 1502, 1462, 1378, 1367, 1341, 1303, 1295, 1260, 1234, 996, 812 cm-1 ; 1H NMR (CDCl3, δ) 8.22 (dd, J=7.9, 1.8 Hz, 1H), 7.63 (ddd, J=8.2, 7.4, 1.4 Hz, 1H), 7.44-7.28 (m, 2H), 3.90-3.84 (m, 4H), 3.76-3.69 (m, 4H); LRMS m/e (rel intensity) 311 (55), 309 (55), 253 (14), 231 (17), 230 (100), 172 (21), 121 (20), 120 (15), 110 (61), 41 (16); UV (EtOH) λ max (ε) 216 (18,400), 238 (18,600), 317 (17,040); High resolution MS calc'd. for C13H12 NO3Br: 309.0001. Found: 308.9990. Anal. calc'd. for C13 H12NO3Br: C, 50.34; H, 3.90; N,4.52. Found: C, 50.40; H,4.05; N, 4.46.