Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=O)=[CH:4][CH:3]=1.[C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)(=[O:22])[CH3:21]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCOCC1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)cc1OC
Solvent: Cc1ccccc1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(Cl)cc2)cc1OC
Temperature: 50 °C

Procedure:
4-Chloro-3',4'-dimethoxy benzophenone (6.29 g, 25 mmol), sodium tert.-amylate (5.50 g, 50 mmol), acetyl morpholine (23.90 g, 185 mmol), and anhydrous toluene (50 ml) were stirred under reflux for 8 hours. After cooling, the solution was washed twice with water, dried, and the toluene distilled off on a rotary evaporator. The viscous residue was stirred at 50° C. with diisopropyl ether (40 ml), whereupon the substance solidified. After it had cooled to room temperature, the crude product was crushed, filtered by suction, washed with diisopropyl ether (2×5 ml) and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:14]([CH3:15])[C@@H:13]([O:16][Si](C(C)(C)C)(C)C)[CH2:12][C:11]2=[O:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@@H:14]([CH3:15])[C@@H:13]([OH:16])[CH2:12][C:11]2=[O:24])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 2-chloro-4-[(4S,5S)-4-(tert-butyldimethylsilyloxy)-5-methyl-2-oxopyrrolidin-1-yl]benzonitrile (1.2 g) and tetrabutylammonium fluoride-THF solution (4 mL, 1 mol/L), and in the same manner as in Example 15, the title compound was obtained as a colorless solid (yield: 690 mg, 62%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([C:20]1[O:24][NH:23][C:22](=O)[CH:21]=1)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:16][O:17][C:18]([C:20]1[O:24][N:23]=[C:22]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:21]=1)=[O:19]
Reactant: Cc1onc(-c2ccc(F)cc2)c1CO
Reactant: COC(=O)c1cc(=O)[nH]o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
To a solution of [3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (1.0 g, 4.8 mmol) in THF (70 mL) was added 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (0.69 g, 4.8 mmol) and triphenylphosphine (1.65 g, 6.3 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (2.7 mL, 6.3 mmol) was added at 4° C. and the reaction mixture was stirred for 3 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 7:3) afforded the title compound (958 mg, 60%) as a white solid. MS: m/e=333.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:31](I)=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33].[CH3:34][CH2:35]N(CC)CC.C([B-](F)(F)F)=C.[K+]>C(O)CC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Ar].Cl[Pd]Cl>[NH2:1][C:2]1[C:31]([CH:34]=[CH2:35])=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)[C:13](=[O:16])[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(I)c4)CS(=O)(=O)C[C@@H]32)c1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=C[B-](F)(F)F
Solvent: CCCO
Product: C=Cc1cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc(F)c1N
Temperature: 90 °C

Procedure:
To a solution of (3aR,7S,7aS)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexahydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (0.65 g, 1.1 mmol), NEt3 (0.54 mL, 3.9 mmol) and potassium vinyltrifluoroborate (0.39 g, 2.7 mmol) in n-propanol (20 mL) was added after degassing with argon (1,1′-bis(diphenylphosphino)ferrocene)-dichloro-palladium (0.063 g, 0.078 mmol) and the reaction mixture was heated at 90° C. for 3.5 h. After dilution with saturated NaHCO3 solution the product was extracted with EtOAc. Combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. The title compound was obtained after chromatographic purification (Combi Flash, 40 g, hexane-EtOAc 5:95 to 0:100) as a yellow solid: TLC (toluene-EtOAc 3:1) Rf=0.38; UPLC RtD=1.756 min; ESIMS [M+NH4]+=504; 1H NMR (400 MHz, CDCl3): δ 7.38 (d, 1H), 7.30 (m, 2H). 7.09 (d, 1H), 6.80 (s, 1H), 6.72 (dd, 1H), 6.66 (d, 1H), 5.64 (d, 1H), 5.39 (d, 1H), 4.53 (d, 1H), 4.33 (d, 1H), 3.7-3.9 (m, 4H), 3.05 (m, 3H), 2.82 (dd, 1H), 2.72 (m, 1H), 2.60 (m, 2H), 1.31 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])([OH:12])[C:4]([F:11])([F:10])[C:5](OCC)=[O:6].[NH3:21].C(O)C.C(OCC)(=O)C.Cl>C(O)C.O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:3]1([O:12][CH2:2]1)[C:4]([F:11])([F:10])[C:5]([NH2:21])=[O:6]
Reactant: CCOC(=O)C(F)(F)C(O)(CCl)c1ccc(Cl)cc1Cl
Reactant: N
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)C(F)(F)C1(c2ccc(Cl)cc2Cl)CO1

Procedure:
In 17 ml of ethanol was dissolved 1.7 g of ethyl 4-chloro-3-(2,4-dichlorophenyl)-2,2-difluoro-3-hydroxybutyrate. To the resulting solution was added 16.3 ml of a 3N ammonia-ethanol solution. The solution was subjected to reaction at 25°-30° C. for 24 hours. Then, the solvent was removed by distillation under reduced pressure. To the residue obtained were added 20 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform) to obtain 0.88 g of 3-(2,4-dichlorophenyl)-3,4-epoxy-2,2-difluorobutanamide.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21]([O:23][C:24](=[O:28])[CH:25]([F:27])Br)[CH3:22]>CN(C)C=O.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:28])[CH:25]([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[F:27])[CH3:22]
Reactant: CCOC(=O)C(F)Br
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)Oc1cccc2c1cc(C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
1-Benzyl-2-methyl-1H-indol-4-ol 3 (0.3 g 1.26 mmole) was dissolved in anhydrous dimethylformamide (50 mL). To the solution sodium hydride 60% in mineral oil (66 mg 1.65 mmole) was added. The mixture was stirred at room temperature for 1 h. To the mixture ethyl-2-bromofluoroacetate (0.2 mL, 1.65 mmole) was added. The mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (500 mL) and washed with H2O (5×100 mL) and brine (1×100 mL). The organic layer was separated, dried with magnesium sulfate and concentrated. The residue was purified by column chromatography (6:1 Hexane:EtOAc) to afford 6 (0.14 g, 32%) as an yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)=[C:14]([C:26]([O:28][CH3:29])=[O:27])[N:15]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:16]2=[O:19])=[CH:11][C:10]=1[O:42][CH3:43])C1C=CC=CC=1.CO>[C].[Pd].CN(C)C=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)=[C:14]([C:26]([O:28][CH3:29])=[O:27])[N:15]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:16]2=[O:19])=[CH:11][C:10]=1[O:42][CH3:43]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OCc3ccccc3)cc2c(=O)n1N1CCOCC1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To the compound obtained in Example 1 (2.8 g) are added methanol (100 ml), dimethylformamide (100 ml) and palladium-carbon (100 mg), and the mixture is stirred under hydrogen atmosphere (1 atm) at room temperature for 1.5 hour. The catalyst is removed by filtration, and the filtrate is concentrated. The precipitated crystals are collected by filtration, and washed with diethyl ether to give 7-hydroxy-6-methoxy-3-methoxycarbonyl-2-morpholino-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (2.26 g) as listed in Table 1.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH3:22]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:20])[C:17](=[CH2:22])[CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CNC
Reactant: CCCC(=O)c1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(CC)C(=O)c1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 2-(2,3-dichloro-4-butyrylphenoxy)-2-methylpropionic acid (10 g, 0.031 mole), dimethylamine hydrochloride (15 g, 0.18 mole), paraformaldehyde (3 g, 0.10 equiv.) and acetic acid (0.6 ml) was stirred and heated on a steam bath for two hours. N,N-dimethylformamide (30 ml) was added and stirring and heating was continued for another two hours. The mixture was poured into ice water which was then extracted with ether. The ether extract was washed with water, then brine and finally dried over MgSO4. The ether was evaporated in vacuo and the residue recrystallized from cyclohexane to give 6.3 g 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]-2-methylpropionic acid, m.p. 88°-89° C.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)[N:3]=1.C(O)C.O.C(N(CC)CC)C>[H][H].[Pd]>[CH3:9][O:8][C:7]1[CH:6]=[N:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[N:3][CH:2]=1
Reactant: CCCCCCCCc1ccc(-c2nc(Cl)c(OC)c(Cl)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCCCCCCc1ccc(-c2ncc(OC)cn2)cc1

Procedure:
To 4,6-dichloro-5-methoxy-2-(4-octylphenyl)pyrimidine (74.2 g, 0.202 mol) were added ethanol (310 ml), water (15.5 ml), 5% Pd-activated carbon (5.7 g) and triethylamine (61.3 g, 0.606 mol), followed by agitating the mixture at about 40° C. in hydrogen current, filtering off the Pd-activated carbon adding toluene, sufficiently washing the mixture with 2N-NaOH aqueous solution, further washing it with water, distilling off toluene and recrystallizing the residue from ethanol (70 ml) to obtain 5-methoxy-2-(4-octylphenyl)pyrimidine in the form of colorless acicular crystals (54.9 g) having a m.p. of 40.1-41.8° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:28])[NH:14][C:15](=[O:27])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[S:29]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:16]2[C:15](=[O:27])[NH:14][C:13](=[O:28])[C:12]=2[C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:31]4[CH:32]=[CH:33][S:29][CH:30]=4)=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[CH:18]1
Reactant: OB(O)c1ccsc1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(Br)ccc34)C(=O)NC2=O)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(C2=C(c3cn(C)c4cc(-c5ccsc5)ccc34)C(=O)NC2=O)c2ccccc21
Reaction time: 24 h
Yield: 72.3 %

Procedure:
Argon was bubbled through a solution of 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (160 mg, 0.37 mmol) in dioxane (15 mL) for 10 min. Tetrakis(triphenylphosphine)palladium (0) (8.5 mg, 0.007 mmol) and thiophene-3-boronic acid (52 mg, 0.41 mmol) and aqueous Na2CO3 (0.37 mL, 2M) were added. The mixture was refluxed for 2 h and more tetrakis(triphenylphosphine)palladium (0) (20 mg, 0.01 mmol) was added. Refluxing was continued for 24 h. The mixture was cooled and evaporated. Chromatography of the residue over silica using 50% EtOAc in hexane gave 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-thiophen-3-yl-1H-indol-3-yl)pyrrole-2,5-dione (117 mg, 72%).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:10][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])C=C.FC(F)(F)S(O[C:41]1[CH:46]=[CH:45][N:44]=[C:43]2[S:47][CH:48]=[CH:49][C:42]=12)(=O)=O>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]1[CH:12]=[C:11]([C:41]2[CH:46]=[CH:45][N:44]=[C:43]3[S:47][CH:48]=[CH:49][C:42]=23)[S:10][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: O=S(=O)(Oc1ccnc2sccc12)C(F)(F)F
Reactant: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Product: Clc1ccc(-c2cc(-c3ccnc4sccc34)sc2-c2ncc[nH]2)c(Cl)c1

Procedure:
The title compound was prepared from 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole and thieno[2,3-b]pyridin-4-yl trifluoromethanesulfonate using procedures analogous to those described in Example 8-A, Steps 2 and 3. LC/MS (AA) ES+ 428, 430. 1H NMR (400 MHz, d6 DMSO) δ: 11.97-11.69 (m, 1H), 8.73 (d, J=4.97 Hz, 1H), 8.27 (d, J=5.56 Hz, 1H), 7.88 (s, 1H), 7.77-7.73 (m, 2H), 7.68 (d, J=5.56 Hz, 1H), 7.52-7.43 (m, 2H), 7.22-6.89 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=O)=[N:6][CH:7]=1.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]2[C:25]3[CH:26]=[N:27][CH:28]=[C:29]([F:30])[C:24]=3[N:23]([CH:31]([CH3:34])[CH2:32][OH:33])[CH:22]=2)=[O:20])[CH:16]=[N:17][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([C:19]([C:21]3[C:25]4[CH:26]=[N:27][CH:28]=[C:29]([F:30])[C:24]=4[N:23]([CH:31]([CH3:34])[CH2:32][OH:33])[CH:22]=3)=[O:20])[CH:14]=2)=[O:11])=[N:6][CH:7]=1
Reactant: CC(CO)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Reactant: O=C(O)Cc1ccc(Cl)cn1
Product: CC(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cn3)c2)c2cncc(F)c21

Procedure:
Prepared according to Method M (Example 206) using (5-chloropyridin-2-yl)acetic acid (Preparation 80) and (5-aminopyridin-3-yl)[7-fluoro-1-(2-hydroxy-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 2, Preparation 26). The residue was purified using preparative TLC eluting with 5% MeOH in EtOAc.
Reaction SMILES: C([O:5][C:6](=[O:47])[CH:7]([NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]2[C:25](=[O:26])[N:24]([CH3:27])[C:23]3[CH:28]=[CH:29][C:30]([C:32](=[O:43])[NH:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)=[CH:31][C:22]=3[S:21]2(=[O:45])=[O:44])=[CH:15][CH:14]=1)[CH:8]([CH3:10])[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][NH:33][C:32]([C:30]2[CH:29]=[CH:28][C:23]3[N:24]([CH3:27])[C:25](=[O:26])[N:20]([CH2:19][C:16]4[CH:17]=[CH:18][C:13]([C:12]([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:47])=[O:5])=[O:46])=[CH:14][CH:15]=4)[S:21](=[O:45])(=[O:44])[C:22]=3[CH:31]=2)=[O:43])=[CH:40][CH:39]=1
Reactant: COc1ccc(CNC(=O)c2ccc3c(c2)S(=O)(=O)N(Cc2ccc(C(=O)NC(C(=O)OC(C)(C)C)C(C)C)cc2)C(=O)N3C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNC(=O)c2ccc3c(c2)S(=O)(=O)N(Cc2ccc(C(=O)NC(C(=O)O)C(C)C)cc2)C(=O)N3C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of 0.18 g 2-{4-[7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1l6-benzo[1,2,4]thiadiazin-2-ylmethyl]-benzoylamino}-3-methyl-butyric acid tert butyl ester (0.27 mmol, Step 1) was added 10 mL 50% trifluoroacetic acid in CHCl3 The resulting mixture was stirred 2 hours at room temperature, then concentrated. Obtained 0.14 g of the title compound as a solid from EtOAc/hexane. Anal. (C30H32N4O8S1) C,H,N. MS: M++1=609.4 Da
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CNc1ccc(C(F)(F)F)cc1Br

Procedure:
Prepared analogously to Example 166a starting from 2-bromo-4-trifluoromethyl-phenylamine and ethyl bromoacetate.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[N:1]1([CH:6]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[CH:14][CH:15]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCCC(c1ccc(C(C)O)cc1)n1ccnc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCC(c1ccc(C(C)=O)cc1)n1ccnc1
Yield: 50.4 %

Procedure:
200 mg of the alcohol of example 7 is stirred in 10 ml of methylene chloride with 1 g of manganese dioxide overnight. It is suctioned off, concentrated by evaporation and the residue is distilled at 180° C./0.03 hPa. 100 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ncccc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ncccc2F)c1-c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
0.63 g of 5-(4-chlorophenyl)-4-(3-fluoro-2-pyridyl)-6-methyl-2H-pyrida zin-3-one and 7.2 g of phosphorus oxychloride were mixed. The mixture was stirred for 1.5 hours on an oil bath of 120° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.64 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.51 g of 3-chloro-5-(4-chlorophenyl)-4-(3-fluoro-2-pyridyl)-6-methylp yridazine (hereinafter, described as compound (16) of the present invention.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:28][S:29]([O:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:19][N:20]=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=[O:31])=[O:30]
Reactant: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)=NNc1ccc(Oc2ccc(S(C)(=O)=O)cc2)cc1OS(C)(=O)=O
Temperature: 4 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To an ice-cooled and stirred solution of ethyl 2-({2-hydroxy-4-[4-(methylsulfonyl)phenoxy]phenyl}hydrazono)propanoate (5.8 g) in pyridine (60 mL) was added methanesulfonyl chloride (1.4 mL), and the mixture was stirred at 4° C. for 1 h and then at room temperature for 3 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed successively with aqueous citric acid solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by short silica gel chromatography (ethyl acetate) to give light orange crystals, which were washed with ethyl acetate-hexane to give the title compound (6.49 g, 93%) as light orange crystals. MS 471 (MH+).
Reaction SMILES: [Na+].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([O-:13])=O.[C:14]([O:18][C:19](=[O:41])[C@@H:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH:21]([CH3:23])[CH3:22])([CH3:17])([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[C:14]([O:18][C:19](=[O:41])[C@@H:20]([NH:24][S:25]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:11]([C:3]3[O:2][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[O:13])=[CH:38][CH:39]=2)=[CH:32][CH:33]=1)(=[O:27])=[O:26])[CH:21]([CH3:23])[CH3:22])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Reactant: O=C([O-])c1nc2ccccc2o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3nc4ccccc4o3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
To benzooxazole-2-carboxylic acid sodium salt (161 mg, 1 mmol) was added (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (405 mg, 1 eq), BOP (550 mg, 1.2 eq), N,N-diisopropylethylamine (155 mg, 1.2 eq) and 4 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine, and extracted with ethyl acetate. The combined organic layers were washed with brine and water. Removal of solvent gave the crude product, which was purified by column chromatography on silica gel to give 126 mg of (S)-3-methyl-2-{4′-[(benzoxazole-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-butyric acid tert-butyl ester as a white solid.