Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1I)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: COCCN(C(=O)OC(C)(C)C)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COCCN(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2-methoxy-ethyl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Colorless oil (70%). MS (ESI): m/z=363.147 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:16](=[O:17])[N:15]2[CH2:18][C@H:19]([O:21][C:22]3[C:31]([C:32]4[S:33][C:34]5[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=5[N:36]=4)=[N:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH2:20][C@H:14]2[C:13](=[O:41])[NH:12][C@:11]2([C:43]([NH:45][S:46]([CH:49]3[CH2:51][CH2:50]3)(=[O:48])=[O:47])=[O:44])[CH2:42][C@H:10]2[CH2:9][C:8]([F:53])([F:52])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[O:69][N:68]=[C:67]([C:70](O)=[O:71])[CH:66]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[C:31]1[C:22]([O:21][C@H:19]2[CH2:18][N:15]3[C:16](=[O:17])[C@@H:2]([NH:1][C:70]([C:67]4[CH:66]=[C:65]([CH3:64])[O:69][N:68]=4)=[O:71])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([F:52])([F:53])[CH2:9][C@@H:10]4[CH2:42][C@@:11]4([C:43](=[O:44])[NH:45][S:46]([CH:49]4[CH2:51][CH2:50]4)(=[O:48])=[O:47])[NH:12][C:13](=[O:41])[C@@H:14]3[CH2:20]2)=[N:23][C:24]2[C:29]([N:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: Cc1cc(C(=O)O)no1
Reactant: N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3nc4ccccc4s3)CN2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(F)(F)C[C@@H]3C[C@@]3(C(=O)NS(=O)(=O)C3CC3)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5nc4-c4nc5ccccc5s4)CN3C2=O)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To (2R,6S,13aS,14aR,16aS)-6-amino-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2-yloxy)-N-(cyclopropylsulfonyl)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide, Hydrochloric Acid (Example 14a, 16.1 mg, 0.020 mmol) was added DMF (200 μl) and diisopropylethylamine (25 μl, 0.14 mmol). To the yellow solution was added 5-methylisoxazole-3-carboxylic acid (3.85 mg, 0.030 mmol) followed by HATU (13.89 mg, 0.037 mmol). The reaction mixture was stirred at rt 2 h, cooled to 0° C. and neutralized with HCl (4 N in dioxane, 36 μl, diluted with EA). The solution was concentrated under reduced pressure and purified by prep-TLC (dichloromethane/EA=1/1, 2×) to provide the title compound N-((2R,6S,13aS,14aR,16aS)-2-(3-(benzo [d]thiazol-2-yl)quinoxalin-2- yloxy)-14a-(cyclopropylsulfonylcarbamoy1)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)-5-methylisoxazole-3-carboxamide (14.3 mg, 81% yield). MS (ESI): m/z=877.1 [M+H], 875.2 [M−H]. Example 14 provided an IC50 of between 0.1 and 0.5 nM in a 1a enzyme assay; an IC50 of between 0.1 and 0.5 nM in a 1b enzyme assay; a HLM stability value of <50 μl/min/mg; an EC50 of between 2.0 and 5.0 nM in a replicon cell line assay in a 1a-H77 background, and an EC50 of between 1.0 and 2.0 nM in a replicon cell line assay in a 1-con1 background.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=[O:36])O1>>[CH:35]([C:34]1[C:37]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:38]([C:2]2[C:16]([O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=[C:4]([CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)[CH:39]=[CH:32][CH:33]=1)=[O:36]
Reactant: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1Br
Reactant: CC1(C)OB(c2cccc(C=O)c2)OC1(C)C
Product: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1-c1cccc(C=O)c1OCOCCOC

Procedure:
Proceeding as in Reference 19, but substituting methyl-3-formyl-4-hydroxy-5-bromophenylacetate (2.47 g, 9.0 mmol) and 2-methoxymethoxy-5-fluorophenylboronic acid (2.0 g, 10.0 mmol), gave methyl 5′-fluoro-5-formyl-6-hydroxy-2′-methoxymethoxy-biphenyl-3-yl)-acetate (2.2 g, 70%) as a yellow oil which crystallized overnight Proceeding as in Reference 19, but substituting tert-butyl [3-bromo-4-(2-methoxyethoxymethoxy)-benzyl]carbamate (2.3 g, 5.9 mmol) and 2-2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (60 mL, 0.1 M in toluene), gave tert-butyl [3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]carbamate (2.96 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7](C=O)=[CH:6][C:3]=1[C:4]#[N:5].C(O)C.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>[Cl-].[NH4+]>[CH2:23]([O:22][CH:15]([O:19][CH2:20][CH3:21])[C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5])[CH3:24]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: CCOC(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1ccc(F)c(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a stirred solution of 2-fluoro-5-formylbenzonitrile (5.96 g, 40 mmol) in ethanol (5.6 g, 120 mmol) was added ammonium chloride (85.6 mg, 1.6 mmol). After the addition, the mixture was cooled to 0° C. and triethyl orthoformate (6.52 g, 44 mmol) was added dropwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was concentrated, then filtered and the cake washed with ethyl acetate (20 mL×2). The filtrate was concentrate to give the title compound (8.8 g, yield 98%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.22-1.29 (m, 6H), 3.50-3.70 (m, 4H), 5.50 (s, 1H), 7.19-7.24 (t, J=8.8 Hz, 1H), 7.70-7.74 (m, 1H), 7.76-7.78 (dd, J1=6.4 Hz, J2=2.4 Hz, 1H). LC-MS (ESI) m/z: 224 (M+1)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])#[N:2].O1CCCC1.[OH-].[Na+].Cl>CO>[C:1]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cccc(CCC#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#CCCc1cccc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a solution of methyl 3-(2-cyanoethyl)benzoate (169 mg, 893 μmol) in methanol (3 mL)/tetrahydrofuran (1 mL) was added 2N aqueous sodium hydroxide solution (893 μL, 1.79 mmol), and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was neutralized with 6N hydrochloric acid (500 μL), 1N hydrochloric acid (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (151 mg, 96%) as a white solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12]>C(O)(=O)C>[CH3:16][C:15]1[CH:14]=[CH:13][C:11]([NH:12][C:5]([CH3:6])=[O:7])=[CH:10][C:9]=1[CH3:8]
Reactant: Cc1ccc(N)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C)c(C)c1

Procedure:
95 ml of acetic anhydride was added to a stirred solution of 3,4-dimethylaniline in 300 ml of glacial acetic acid at such a rate the temperature of the mixture slowly rose to 60° C. The resulting mixture was stirred while the temperature dropped to room temperature, then evaporated to dryness. A mixture of water and ice was added to the residue, followed by methylene chloride. The resulting mixture was stirred and treated with solid sodium bicarbonate until neutral. The organic phase was separated, and dried (MgSO4), and the solvent was evaporated to give 3,4-dimethylacetanilide (4A).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:19][CH2:20][C@@H:21]([CH2:32][OH:33])[O:22][CH2:23][P:24]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:33][CH2:32][C@@H:21]([O:22][CH2:23][P:24]([CH:26]([CH3:28])[CH3:27])([CH:29]([CH3:30])[CH3:31])=[O:25])[CH2:20][O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)P(=O)(CO[C@H](CO)COCc1ccccc1)C(C)C
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](COCc2ccccc2)OCP(=O)(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
p-Tolylsulfonyl chloride (38.8 g, 204 mmol) was added to a solution of compound 6 (31 g) in dry pyridine (200 mL) cooled to 0° C. After 1 h stirring at 0° C. the mixture was stirred at room temperature (rt) for additional 24 h and evaporated in vacuo. The syrupy residue was chromatographed on a column of silica gel (1000 mL) in system toluene-ethyl acetate (5:1). After removal of rests of p-tolylsulfonyl chloride (RF 0.9) the compound 7 was eluted with system toluene-ethyl acetate (1:2), (RF 0.5). Product containing fractions were evaporated to give 18.7 g (77%) of 7 as a colorless syrup.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[C:21]#[N:22])[C:13]1=[O:23]>ClCCl>[C:21]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][CH:12]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:13]2=[O:23])#[N:22]
Reactant: N#Cc1cccc2c1CC(Br)C2=O
Reactant: CCOC(=O)c1ncc[nH]1
Solvent: ClCCl
Product: CCOC(=O)c1nccn1C1Cc2c(C#N)cccc2C1=O
Temperature: 130 °C
Yield: 35.3 %

Procedure:
Ethyl 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxylate can be obtained in the following way: a mixture of 3.92 g of ethyl imidazole-2-carboxylate and 3.4 g of 2-bromo-4-cyano-1-indanone is heated at 130° C. for 20 minutes, cooled to 20° C. and dissolved in 20 ml of dichloromethane. The mixture is then concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40° C. The residue thus obtained is purified by flash chromatography on a silica column, under a nitrogen stream at medium pressure (0.5 bar), with a dichloromethane/methanol (95/5 by volume) mixture as eluent. 1.5 g of ethyl 1-[(4-cyano-1-oxoindan-2-yl)]imidazole-2-carboxylate are thus obtained, which product melts at 159° C.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10]CC)=[O:9])=[C:4]([C:15]([C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)=[O:16])[CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:22]1([N:20]2[CH:21]=[C:17]([C:15]([C:4]3[CH:3]=[C:2]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:14]=[CH:13][C:5]=3[O:6][CH2:7][C:8]([OH:10])=[O:9])=[O:16])[CH:18]=[N:19]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Reactant: OB(O)c1ccccc1
Product: O=C(O)COc1ccc(-c2ccccc2)cc1C(=O)c1cnn(-c2ccccc2)c1

Procedure:
Prepared from ethyl [4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxy]acetate and phenylboronic acid according to GP4: LC/MS (an 10p8): Rt 1.05 min, m/z 398.6 [M−H]−; 1H NMR (CDCl3): δ 4.86 (s, 2H), 7.17 (d, J=8.6 Hz, 1H), 7.35-7.57 (m, 8H), 7.70-7.75 (m, 2H), 7.78 (dd, J=8.6, 2.3 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 8.20 (s, 1H), 8.54 (s, 1H); 13C NMR (CDCl3): δ 67.7, 115.8, 120.1, 124.8, 127.1, 128.0, 128.3, 129.1, 129.3, 129.4, 129.9, 132.3, 136.2, 139.3, 139.3, 143.5, 155.8, 170.4, 189.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([CH2:25][O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])[CH:22]=[CH:21][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[O:10][C:11]=1[CH3:12].C[Sn]([N:41]=[N+:42]=[N-:43])(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([CH2:25][O:26][Si:27]([CH:28]([CH3:29])[CH3:30])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH:22]=[CH:21][C:4]=1[O:5][CH2:6][C:7]1[N:8]=[C:9]([C:13]2[CH:14]=[C:15]([C:16]3[NH:43][N:42]=[N:41][N:17]=3)[CH:18]=[CH:19][CH:20]=2)[O:10][C:11]=1[CH3:12]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Solvent: Cc1ccccc1
Product: COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OCc1nc(-c2cccc(-c3nnn[nH]3)c2)oc1C
Yield: 63.8 %

Procedure:
A mixture of 3-{4-[(2-methoxy-4-{[(triisopropylsilyl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (0.52 g), trimethyl tin azide (0.62 g) and toluene (10 mL) was heated under reflux for 15 hrs. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography to give 5-(3-{4-[(2-methoxy-4-{[(triisopropylsilyl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)-1H-tetrazole as colorless crystals (0.36 g, yield 65%), from a fraction eluted with ethyl acetate-methanol (95:5, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: C([O:5]O)(C)(C)C.[CH2:7]([OH:17])/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:10]([C@@H:9]1[O:5][C@H:8]1[CH2:7][OH:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC/C=C/CO
Reactant: CC(C)(C)OO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CCCCCCC[C@@H]1O[C@H]1CO
Reaction time: 0.5 h

Procedure:
A flame-dried 100 mL round bottom 3-necked (RB3N) flask (note 1) filled with thermometer, stopcock, septum, and stirbar was purged with argon, charged with 4 A molecular sieves (300 mg; note 2) and 30 mL of dichloromethane (note 3), and cooled to -22° (30% ethylene glycol/water/dry ice). R,R-(+)-diethyl tartrate (97 mg; 47 mmol; note 4) and titanium(IV)isopropoxide (91 mg; 0.32 mmol; note 5) were added, and the mixture was stirred at -22±2° for 10 min. t-Butyl hydroperoxide (2.2 mL of a 5.8M dichloromethane solution; note 6) was added, and the mixture was stirred at -22±2° for 30 min. A solution of trans-2-decen-1-ol (1.00 g; 6.4 mmol; note 7) in dichloromethane, was then added. The mixture was stirred under argon at -22±2° until analysis (note 8) indicated >95% reaction (2.5 hr).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][O:23][CH3:24])[C:17](=[O:20])[NH:18][N:19]=2)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][N:18]1[C:17](=[O:20])[N:16]([CH2:21][CH2:22][O:23][CH3:24])[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)=[N:19]1)[CH3:7]
Reactant: CCOC(=O)CCl
Reactant: COCCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCOC)c1=O

Procedure:
527 mg (4.30 mmol) of ethyl chloroacetate are added to 1.09 g (4.30 mmol) of 5-(4-chlorophenyl)-4-(2-methoxyethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one from Example 49A and 1.19 g (8.59 mmol) of potassium carbonate in 20 ml acetonitrile and the mixture is heated under reflux for 3 hours with stirring. After purification of the resulting crude product by preparative HPLC [Method 9] 810 mg (42% of theory) of the target compound are obtained.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:6][NH:7][NH2:8].C([O:17][C:18](=O)[C:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:18](=[O:17])[C:19]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(CNN)cc1C(F)(F)F
Reactant: CCOC(=O)C(=C(N)OCC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cn2[nH]c(N)c(-c3ccccc3)c2=O)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
31.5 g of 3-trifluoromethyl-4-methylbenzylhydrazine were added dropwise under nitrogen to a solution of 35.3 g of α-phenyl-β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 150 ml of ethanol. After stirring overnight, the solvent was distilled off in vacuo and the residue was recrystallized from dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.S(=O)(O)[O-].[Na+].C(Cl)[Cl:33]>>[Cl:33][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]=1[O:12][CH3:13]
Reactant: ClCCl
Reactant: COC(=O)c1nc(Cl)ccc1OC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1nc(Cl)cc(Cl)c1OC
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
Methyl 6-chloro-3-methoxypicolinate (prepared as in Van Heertum, J. C. et al. U.S. Pat. No. 5,571,775 A, Nov. 5, 1996; 4.0 g, 20 mmol) was dissolved in dry CH2Cl2 (20 mL), treated with urea hydrogen peroxide complex (4.0 g, 43 mmol), cooled to 0-5° C., stirred and treated in portions with trifluoroacetic anhydride (5.6 mL, 40 mmol). The mixture was allowed to warm to 20° C. and stirred for 20 h. An additional portion of the urea hydrogen peroxide complex (2.0 g) and trifluoroacetic anhydride (2.8 mL) were added and stirring was continued for 4 h. The mixture was stirred with 10% sodium bisulfite (NaHSO3) solution until negative to starch-iodide paper. The organic phase was washed with H2O (10 mL), dried (Na2SO4) and evaporated. This material was dissolved in phosphorus oxychloride (POCl3; 30 mL) and heated at 70° C. for 2 h and then at reflux for 3 h to produce a 1:1 mixture of the isomeric 4,5- and 4,6-dichloropicolinates. After cooling, the volatiles were removed under vacuum, the residue was combined with ice and the product was taken up in EtOAc. This solution was washed with H2O, dried (Na2SO4) and evaporated. The crude mixture was purified by reverse-phase high performance liquid chromatography (RP-HPLC; eluting with 60% acetonitrile (CH3CN)—H2O) to provide the title compound (1.1 g, 23%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); EIMS m/z 235.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[CH:13]=O)=[CH:4][CH:3]=1.[NH2:15]OS(O)(=O)=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[C:13]#[N:15])=[CH:4][CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: O=Cc1[nH]ccc1-c1ccc(Cl)cc1
Solvent: O
Product: N#Cc1[nH]ccc1-c1ccc(Cl)cc1
Yield: 63.7 %

Procedure:
A mixture of 0.63 g (3.1 mmol) of 3-(p-chlorophenyl)-pyrrole-2-carboxaldehyde in 10 mL of water is stirred and ice-cooled while 0.52 g (4.6 mmol) of hydroxylamine-O-sulfonic acid in 10 mL of water is slowly added. After the addition, the cooling bath is removed and the mixture is heated for 25 minutes. On cooling, the resulting solid is collected and shown, by NMR, to be a mixture of product and starting aldehyde. This mixture is reacted in the same manner with an additional 0.49 g (4.2 mmol) of hydroxylamine-O-sulfonic acid in a total of 30 mL of water. The mixture is heated at 60°-70° C. for 2 hours. The mixture is cooled and the resulting solids are collected and purified by chromatography or silica gel using 1:1 ethyl acetate hexane to give 0.40 g of pink solid, m.p. 114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:15]=[C:16]([OH:19])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:28].[N:29]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18]2[C:13](=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])[CH:15]=[C:16]([O:19][CH2:36][CH2:35][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:28]
Reactant: O=C1CCc2c(-c3ccc(F)cc3F)cc(O)cc2N1c1c(Cl)cccc1Cl
Reactant: OCCN1CCNCC1
Product: O=C1CCc2c(-c3ccc(F)cc3F)cc(OCCN3CCNCC3)cc2N1c1c(Cl)cccc1Cl

Procedure:
1-(2,6-Dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-[2-(1-piperazinyl)ethoxy]-2(1H)-quinolinone was prepared from 1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-3,4-dihydro-7-hydroxy-2(1H)-quinolinone (INTERMEDIATE 3) and 1-piperazine ethanol by a procedure analogous to that described in EXAMPLE 2. Mass spectrum (ESI) 532.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J=8.5 Hz, 2H); 7.36 (t, J=8 Hz, 1H); 7.29 (q, J=6 Hz, 1H); 6.96 (m, 2H); 6.52 (s, 1H); 5.90 (s, 1H); 3.96 (t, J=5.5 Hz, 2H); 2.88 (m, 4H); 2.70 (m, 4H); 2.47 (br, 4H); 2.10 (br, 2H).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1>CS(C)=O>[Cl:8][C:9]1[N:10]=[N:11][C:12]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[CH:13][CH:14]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ccc(OCC2CC2)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.016 ml cyclopropanemethanol in 10 ml dimethylsulfoxide was added 0.564 g sodium hydride 55% in mineral oil and the mixture was stirred at room temperature for 15 min. The resulting solution was added drop wise to a solution of 2.0 g 3,6-dichloropyridazine in 20 ml dry dimethylsulfoxide at room temperature and stirred at this temperature for 1 h. The reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane: ethyl acetate=95:5 to 40:60 to yield 1.88 g of the title compound as white solid. MS (EI): 185.05 (M+H).
Reaction SMILES: [Cl:1][CH:2]([CH2:27][O:28][CH3:29])[C:3]([NH:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[C:16](=[O:26])[CH2:17][C:18]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:19])=O.O1CCCC1.Cl>CN(C)C1C=CN=CC=1.O>[Cl:1][CH:2]([C:3]1[C:17]([C:18]([NH:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[O:19])=[C:16]([OH:26])[C:7]2[C:6](=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:9][CH:8]=2)[N:5]=1)[CH2:27][O:28][CH3:29]
Reactant: COCC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COCC(Cl)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A mixture of 33.35g of the product of Step A, 10g of 4-dimethylamino-pyridine and 300ml of tetrahydrofuran was refluxed for 30 minutes and was then cooled to room temperature and poured into a mixture of water and 2N hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was washed, dried and evaporated to dryness. The residue was empasted with ether, vacuum filtered, washed and dried under reduced presssure at 60° C. to obtain 28.2g of 2-(1-chloro-2-methoxyethyl)-4-hydroxy-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide melting at 186° C.