Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]([OH:38])[CH2:35][NH:36][CH3:37])=[CH:26]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20][N:36]([CH2:35][CH:34]([OH:38])[C:27]4[C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[NH:25][CH:26]=4)[CH3:37])=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNCC(O)c1c[nH]c2ccccc12
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 42.4 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.26 mmol), 1-(1H-indol-3-yl)-2-(methylamino)ethanol (Khim.-Farm. Zh. 1970, 4, 5-9)(75 mg, 0.39 mmol) and diisopropylethylamine (180 μL, 1.04 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with warming 5 mL of acetonitrile, then cooled to 0° C. and then diluted with 3 mL of water, left overnight) gave the title compound (59 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[O:3]1.[Si:19]([O:26][C@@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][C@@H:27]1[CH2:31][CH2:30][N:29]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]3)=[CH:17][CH:16]=2)=[O:15])[CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCNC1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(C(=O)N3CC[C@@H](O[Si](C)(C)C(C)(C)C)C3)cc2)OC1(C)C

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid and (R)-3-(tert-butyldimethylsilyloxy)pyrrolidine.
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])C=C.C[Sn](C)(C)[C:25]1[CH:34]=[CH:33][N:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][C:29](=[O:35])[NH:30]2>>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:10]1[N:11]=[C:12]([C:25]2[CH:34]=[CH:33][N:32]=[C:31]3[C:26]=2[CH2:27][CH2:28][C:29](=[O:35])[NH:30]3)[S:13][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: C[Sn](C)(C)c1ccnc2c1CCC(=O)N2
Reactant: C=CCn1ccnc1-c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Product: O=C1CCc2c(-c3nc(-c4ccc(Cl)cc4Cl)c(-c4ncc[nH]4)s3)ccnc2N1

Procedure:
The title compound was prepared from 5-(1-Allyl-1H-imidazol-2-yl)-2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole and 5-(trimethylstannyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one using procedures analogous to those described in Example 1-C, Steps 8 and 9. LCMS: (FA) ES+ 442, 444. 1H NMR (300 MHz, d6-DMSO) δ: 12.10-11.89 (bs, 1H), 10.64 (s, 1H), 8.25 (d, J=5.28 Hz, 1H), 7.74 (d, J=1.72 Hz, 1H), 7.60-7.46 (m, 2H), 7.39 (d, J=5.29 Hz, 1H), 7.23-6.94 (m, 2H), 4.11-4.06 (m, 1H), 3.38-3.30 (m, 1H), 3.16 (d, J=5.21 Hz, 2H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=1.C=O.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][C:18]=1[CH3:26].[C:27](=O)([O-])[O-].[K+].[K+]>C(O)C>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH2:9][CH2:10][N:11]([CH2:27][NH:23][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([F:16])=[C:18]([CH3:26])[CH:19]=2)[CH2:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: C1=C(c2ccccn2)CCNC1
Reactant: Cc1cc(C(N)=O)ccc1F
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1cc(C(=O)NCN2CC=C(c3ccccn3)CC2)ccc1F
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A mixture of 1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl hydrochloride (20 mg, 0.10 mmol, Saari, W. S.; et al. J. Med. Chem. 1984, 27, 1182), paraformaldehyde (30 mg, 1 mmol), 4-fluoro-3-methylbenzamide (77 mg, 0.5 mmol, Oakwood), and 42 mg of potassium carbonate (0.3 mmol) in 2.5 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 9 mg (28%) pure compound. 1H NMR (500 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.56 (m, 2H), 2.76 (m, 2H), 3.30 (m, 2H), 4.26 (d, J=5 Hz, 2H), 6.70 (m, 1H), 7.20 (m, 2H), 7.50 (d, J=6 Hz, 1H), 7.75 (m, 2H), 7.85 (d, J=6 Hz, 1H), 8.51 (m, 1H) 8.77 (t, J=5 Hz, 1 H); MS (ESI/APCI−) m/e 324 (M−H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:13][CH2:14][CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>C(Cl)Cl>[Br:36][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:13][CH2:14][CH3:15]
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1cc(C(=O)OC)ccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(C(=O)OC)ccc1CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a magnetically stirred solution of 0.405 g (1.94 mmol) of the product of Step D dissolved in 5.0 mL of methylene chloride was added 0.638 g (2.43 mmol) of triphenylphosphine followed by 0.806 g (2.43 mmol) of carbon tetrabromide at room temperature. The reaction mixture was stirred for 30 minutes at room temperature, then the magnetic stir bar was removed and the methylene chloride was evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 10% EtOAc-hexane, and evaporation of the purified fractions and solvent removal in vacuo afforded 0.496 g (94%) of the title compound.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[N:12]=1.Cl.[OH-:14].[Na+]>>[Cl:11][C:7]1[N:8]=[C:9]([Cl:10])[C:4]2[S:3][C:2](=[O:14])[NH:12][C:5]=2[N:6]=1
Reactant: Clc1nc(Cl)c2sc(Cl)nc2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=c1[nH]c2nc(Cl)nc(Cl)c2s1
Temperature: 60 °C
Yield: 50 %

Procedure:
A suspension of the trichloro compound (22: 3.0 g, 12 mmol) in 1N NaOH (35 mL) was heated at 60° C. for 1 h. The solution was treated with decolorizing carbon and then acidified with 10% aqueous HCl. The resulting precipitate was collected and reprecipitated from dilute base with glacial acetic acid to provide 24 as orange needles (1.38g, 50%): mp. 191°-192° C.: UV λmax (pH 1) 254 nm (ε 5,300), 290 (11,400): UV λmax (pH 7,11) 226 nm (ε 28,900), 300 (14,100). Anal. Calcd. for C5HCl2N3OS: C, 27.04: H, 0.45: C1, 31.93: N, 18.93. Found: C, 26.78: H, 0.61: C1, 32.15: N, 18.66. Single crystal X-ray analysis of 24 showed the structure assignment to be correct.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[Si](C)(C)[CH3:14]>CO>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[Cl:1]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1ccc(F)cc1Cl
Solvent: CO
Product: COC(=O)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
A mixture of 2-chloro-4-fluorobenzoic acid (6.5 g, 37 mmol) in methanol (100 mL) was treated with chlorotrimethylsilane (14.0 mL, 111 mmol), stirred 24 h at room temperature and evaporated. The residue was dissolved in dichloromethane, washed with sodium bicarbonate, dried (sodium sulfate) and evaporated to provide 2-chloro-4-fluoro-benzoic acid methyl ester (7.01 g, 99% yield) as a pale yellow oil. 1H-NMR (CDCl3, 500 MHz) 7.93 (m, 1H), 7.22 (m, 1H), 7.06 (m, 1H), 3.95 (s, 3H) ppm; MS (FIA) 189.1 (M+H); HPLC (Method A) 3.37 min.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C@@H:23]2[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:17][C@H:16]1[CH2:24][NH:25][CH2:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:43][O:44][C:45]1[C:50]2[O:51][C:52]([CH3:55])([CH3:54])[O:53][C:49]=2[CH:48]=[C:47]([C:56](Cl)=[O:57])[CH:46]=1.FC(F)(F)C(O)=O>ClCCl>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[CH:31]=[C:27]1[CH2:26][N:25]([CH2:24][C@@H:16]1[CH2:17][C@H:18]2[C@H:23]([CH2:22][CH2:21][CH2:20][CH2:19]2)[NH:15]1)[C:56]([C:47]1[CH:46]=[C:45]([O:44][CH3:43])[C:50]2[O:51][C:52]([CH3:55])([CH3:54])[O:53][C:49]=2[CH:48]=1)=[O:57]
Reactant: CC(C)(C)OC(=O)N1[C@H](CNCc2cc3ccccc3o2)C[C@@H]2CCCC[C@@H]21
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cc3ccccc3o2)C[C@@H]2C[C@@H]3CCCC[C@@H]3N2)cc2c1OC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of 45 mg (0.09 mmol) of (2S,3aS,7aS)-2-{[(benzofuran-2-ylmethyl)-amino]-methyl}-octahydro-indole-1-carboxylic acid tert-butyl ester trifluoroacetic acid salt in 1 mL dichloromethane, 28 μL (0.20 mmol) of triethylamine and 23 mg (0.10 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride were added at r.t. Stirring at r.t. for 1 hour was followed by the addition of 0.1 mL trifluoroacetic acid; 2 hours thereafter the solution was evaporated in vacuum and purified using reverse phase HPLC, mobile phase with a gradient 15-80% acetonitrile in 50 min. Fractions containing pure product were evaporated, the residue was dissolved in dichloromethane, which was washed with aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate and evaporated in vacuum to yield 13 mg of the product as the free base off-white Solid. LC-MSD, m/z for C29H34N2O5 [M+H]+: 491.2. 1H NMR (400 MHz, CDCl3): δ 1.2-2.3 (m, 11 H), 1.7 (s, 6 H), 3.2-3.9 (m, 4 H), 3.9 (s, 3 H), 4.7-4.9 (m, 1 H), 4.9-5.0 (m, 1 H), 6.7 (s, 1H), 6.7-6.9 (m, 2H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1 H), 7.5-7.6 (m, 1 H).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1>CN(C)C=O.O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4]
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: CN=C=O
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)Nc1ccc(C2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.4 %

Procedure:
0.8 ml (13.4 mmol) of methyl isocyanate was added to a solution containing 1.0.g (3.41 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 8 ml of dimethylformamide (DMF), then the reaction mixture was stirred at 25° C. for 24 hours. After diluting with 80 ml of water, filtering at 5° C. and drying at 60° to 100° C., 1.06 g of raw product, m.p.: 204°-207° C. (sintering from 160° C.) were obtained which, when recrystallized from 5 ml of ethanol, gave 0.85 g (71.4%) of the aimed product, m.p.: 223°-224° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.CN([CH:13]=[O:14])C.C([Li])CCC.C(NC(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:13]=[O:14])=[C:4]([F:9])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)cc(Br)cc1F
Yield: 58.9 %

Procedure:
Using analogous reaction condition and reagents as described in Example 20 for the preparation of I-20a above, 1-bromo-3,5-difluoro-benzene (2 g, 2.10.36 mmol) in THF was reacted with DMF (1.43 g, 19.68 mmol), n-butyl lithium (1.56 ml, 12.4 mmol) and diisopropyl amine (0.57 mL, 15.5 mmol) to afford crude product. Purification by column chromatography on silica gel (2% ethyl acetate in hexane) afforded 1.35 g of the product (61% yield).
Reaction SMILES: C(N(CC)CC)C.C(O[C:13]([NH:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[F:25])C)=O)(C)(C)C.[CH3:26][C@:27]12[C:33]([CH3:35])([CH3:34])[C@H:30]([CH2:31][CH2:32]1)[CH:29]([C:36](Cl)=[O:37])[C:28]2=O.Cl.O1CCOCC1>ClCCCl>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([N:16]2[C:36](=[O:37])[C:29]3[C@@H:30]4[C:33]([CH3:35])([CH3:34])[C@@:27]([CH3:26])([CH2:32][CH2:31]4)[C:28]=3[N:15]2[CH3:13])[CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CN(NC(=O)OC(C)(C)C)c1cccc(Cl)c1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1cccc(Cl)c1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 6.9 %

Procedure:
Triethylamine (1 mL, 7.2 mmol) was added dropwise to a solution of N′-(3-chloro-2-fluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (434 mg, 1.6 mmol) in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 800 mg, 3.7 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was heated in an oil bath at 50° C. for 1 h. The solution was allowed to cool and a solution of HCl in dioxane (4 M; 6 mL, 24 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. The solvent was evaporated and the residue was purified on an ISCO system, eluting with 30-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and co-evaporated with methanol. The residue was triturated with ether/hexane and the solvent was removed with a pipet. The solid was drie under high vacuum at 90° C. to give (4S,7R)-2-(3-chloro-2-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (37 mg, 7%) as a white solid. ES(+)-MS (M+H) 335.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].C(O[C:16](=[O:18])[CH3:17])(=O)C>N1C=CC=CC=1>[C:2]([O:4][C@@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[O:10][C:16](=[O:18])[CH3:17])[O:8][C:9](=[O:10])[CH3:11])[O:6][C:5](=[O:6])[CH3:7])[CH:2]=[O:1])(=[O:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]([C@H](OC(C)=O)[C@H](C)OC(C)=O)[C@@H](C=O)OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 173.9 %

Procedure:
To a solution of L-fucose (1.03 g, 6.09 mmol) in 60 mL of pyridine at room temperature is added acetic anhydride (4.6 mL, 4.96 g, 48.7 mmol). The solution is stirred at room temperature for 20 h and concentrated in vacuo. The residue is then dissolved in 50 mL of CH2Cl2 and washed with 5% HCl (4×60 mL), dried over anhydrous Na2SO4 and concentrated to afford 1.76 g (85%) of L-fucose tetraacetate 1 as a white foam, a 5:2 (α:β) mixture of anomers: Rf 0.38 (40% petroleum ether/EtOAc); 1H NMR (CDCl3, 270 MHz, mixture of anomers) δ 6.33 (d, J=2.0 Hz, 1H, H-1α), 5.67 (d, J=8.2 Hz, 1H, H-1β), 5.26-5.38 (m, 5H), 5.06 (dd, J=10.4, 3.4 Hz, 1H, H-3b), 4.27 (q, J=6.6 Hz, 1H, H-5α), 3.95 (q, J=6.3 Hz, 1H, H-5β), 2.23 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 2.04 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.22 (d, J=6.6 Hz, 3H, H-6β), 1.16 (d, J=6.6 Hz, 3H, H-6α).
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:15])[N:5]=1)[CH3:3].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O.CCOC(C)=O>CN(C=O)C>[Cl:14][C:13]1[C:4]([CH:2]([N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[CH3:3])=[N:5][C:6]2[C:11]([N:12]=1)=[C:10]([Cl:15])[CH:9]=[CH:8][CH:7]=2
Reactant: CC(Br)c1nc2cccc(Cl)c2nc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(c1nc2cccc(Cl)c2nc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
To a solution of 2-(1-bromoethyl)-3,5-dichloroquinoxaline (1.00 Kg, 3.27 mol) in DMF (8.2 L) was added potassium phthalimide (1.21 Kg, 6.54 mol). The reaction mixture was stirred for 3 h. At this time LC-MS analysis showed that the reaction was complete. The mixture was transferred to a 50 L separatory funnel and water (12 L) and EtOAc (6 L) were added to it with stirring. A large amount of white solid crashed out and was collected by filtration. The aqueous. phase was separated and extracted again with EtOAc (2×4 L). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and the volume was reduced to 5 L under reduced pressure. After cooling to rt, the product was obtained as a white solid. The white solid was filtered, triturated with hexane and dried under vacuum to give 2-(1-(3,5-dichloroquinoxalin-2-yl)ethyl)isoindoline-1,3-dione (1.24 Kg). 1H NMR (DMSO-d6) δ ppm 8.02-8.21 (2H, m), 7.83-8.02 (m, 5H), 5.89 (q, J=6.8 Hz, 1H), 1.87 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI) m/z=372.0 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:18][CH3:19])[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)[CH:6]=[CH:5]2)[CH2:3][CH2:2]1.[Cl:20]N1C(=O)CCC1=O>C1COCC1.CCOC(C)=O>[CH2:16]([O:15][C:13]([C:10]1[CH:11]=[C:12]2[C:7]([C:6]([Cl:20])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[C:8]([O:18][CH3:19])[CH:9]=1)=[O:14])[CH3:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC)c2c(Cl)cn(C3CC3)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirred solution of 1.29 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate in 13 ml of THF was added 801 mg of N-chlorosuccinimide and the mixture was stirred at 60° C. for 2 hrs. After diluted with EtOAc, the mixture was washed successively with water and saturated brine, dried over Na2SO4, and concentrated. The residue was purified on SiO2 column chromatography to afford 1.03 g of ethyl-3-chloro-1-cyclopropyl-4-(methoxy)-1H-indole-6-carboxylate as a colorless solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]3[N:13]([CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC=CC=1.[C:22](Cl)(=[O:26])[C:23]([Cl:25])=[O:24]>C1COCC1>[CH:1]1([C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:22](=[O:26])[C:23]([Cl:25])=[O:24])[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1c(C2CCCC2)cn2c1CCCC2
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)C(=O)c1c(C2CCCC2)cc2n1CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
2-Cyclopentyl-5,6,7,8-tetrahydro-indolizine (0.24 g, 1.27 mmol) was dissolved in THF (1 mL) and toluene (1.5 mL) and cooled to 0° C. Oxalyl chloride (0.14 mL, 1.52 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min, then at room temperature for 1 hour. Concentration in vacuo afforded (2-cyclopentyl-5,6,7,8-tetrahydro-indolizin-3-yl)-oxo-acetyl chloride (0.31 g, 88%) as a semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C:28]1[O:32][N:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[O:32][N:31]=[CH:30][CH:29]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: Nc1ccno1
Product: O=C(Nc1ccno1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 5-aminoisoxazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(isoxazol-5-yl)terephthalamide. MS (Q1) 463 (M)+.
Reaction SMILES: [C:1](=O)(OC(Cl)(Cl)Cl)[O:2]C(Cl)(Cl)Cl.[F:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[CH:33]([NH:35][C:36]1[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([NH2:46])[CH:42]=3)[N:37]=1)[CH2:32][CH2:31][CH2:30]2>>[F:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:1]([NH:46][C:41]2[CH:42]=[C:43]3[C:38](=[CH:39][CH:40]=2)[N:37]=[C:36]([NH:35][CH:33]2[C:34]4[C:29](=[CH:28][CH:27]=[CH:26][C:25]=4[O:24][CH3:23])[CH2:30][CH2:31][CH2:32]2)[CH:45]=[CH:44]3)=[O:2])[CH2:18][CH2:17]1
Reactant: NC1CCN(CCF)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)NC4CCN(CCF)CC4)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 1-(2-fluoroethyl)-piperidin-4-ylamine and rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine; MS: m/e=492.5 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH2:44][CH2:45][O:46][CH2:47][CH3:48])[CH2:42][CH3:43])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:47]([O:46][CH2:45][CH2:44][N:41]([C:38]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH2:42][CH3:43])[CH3:48]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCN(CC)c1ccc(OB([O-])[O-])cc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl borate (410 mg) and potassium carbonate (400 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (50 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give yellow crystals of 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 69) (260 mg).