Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1OC)[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:15]1([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:3]=2)[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:5]1[C:4](=[O:22])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]1[CH2:12][S:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[N:27]=[CH:28][NH:29]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1-c1ccccc1
Yield: 168.3 %

Procedure:
Prepared according to Procedure C using Intermediate 21 (400 mg, 1.05 mmol), 6-mercapto-purine monohydrate (196 mg, 1.15 mmol), K2CO3 (159 mg, 1.15 mmol), and DMF (5 mL). The crude product was chromatographed in MeOH/CH2Cl2 and subsequently recrystallized from EtOH to provide 439 mg of a pale yellow crystalline solid (84%), mp 222.0-222.5° C. (dec). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.55 (s, 1H); 8.45 (s, 1H); 7.73 (t, J=8.0 Hz, 1H); 7.64 (d, J=7.7 Hz, 1H); 7.50-7.59 (m, 4H); 7.41-7.48 (m, 1H); 7.25-7.38 (m, 5H); 4.41 (d, J=16 Hz, 1H); 4.16 (d, J=16 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.2, 157.0, 153.7, 151.5, 149.7, 149.3, 143.5, 139.9, 137.8, 135.1, 134.1, 133.3, 131.5, 130.5, 130.3, 130.1, 129.1, 128.9, 128.4, 128.4, 126.9, 117.5, 32.3. MS (ES): m/z 497.0 (M+). Anal. calcd. for C26H17ClN6OS: C, 62.84; H, 3.45; Cl, 7.13; N, 16.91; S, 6.45. Found: C, 62.60; H, 3.47; Cl, 7.15; N, 16.65; S, 6.41.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[N:8]([CH2:13][C:14]#[CH:15])[Si](C)(C)C.[CH3:18][N:19]1[C:27]2[N:26]=[CH:25][N:24]([CH2:28][CH2:29][CH3:30])[C:23]=2[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH2:34][CH2:35][C:36](=[O:38])[CH3:37])[C:20]1=[O:39]>CCCCCC.O1CCCC1>[NH2:8][CH2:13][C:14]#[C:15][C:36]([OH:38])([CH3:37])[CH2:35][CH2:34][CH2:33][CH2:32][N:21]1[C:22](=[O:31])[C:23]2[N:24]([CH2:28][CH2:29][CH3:30])[CH:25]=[N:26][C:27]=2[N:19]([CH3:18])[C:20]1=[O:39]
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reactant: C#CCN([Si](C)(C)C)[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CCN)c(=O)n2C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
29 ml (46.5 mmol) of a 15% strength butyllithium solution in n-hexane were slowly added dropwise to a stirred solution of 9.26 g (46.5 mmol) of N,N-bis(trimethylsilyl)-2-propynylamine from stage C1 in 50 ml of tetrahydrofuran at -40° C. under argon. The mixture was then warmed to room temperature and again cooled to -40° C., and a solution of 14.25 g (46.5 mmol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 40 ml of tetrahydrofuran was slowly added. After removal of the cooling bath, the mixture was stirred at room temperature for 6 hours. The reaction mixture was then added to saturated ammonium chloride solution at 0° C., the aqueous phase was extracted with ether, the organic phase was dried over sodium sulfate, the desiccant was filtered off, and the solvent was removed under reduced pressure. The crude product was subjected to flash chromatography first with the mobile phase mixture dichloromethane/methanol/saturated ammonia solution=19/1.5/2.5 and then with 9/1/2.5. Yield: 9.79 g (58% of theory); yellowish oil
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1>N1C=CC=CC=1.CCOCC>[C:7]1([CH3:8])[CH:9]=[CH:10][C:4]([S:1]([O:19][CH2:18][CH:16]2[CH2:15][O:14][C:13]([CH3:20])([CH3:12])[O:17]2)(=[O:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 8 h

Procedure:
57.2 g (300 mmol) of tosyl chloride are added to a solution of 39.6 g (300 mmol) of (2,2-dimethyl[1,3]dioxolan-4-yl)methanol in 170 ml of pyridine at 0° C. The mixture is stirred overnight, diluted with ether, washed with a 1N hydrochloric acid solution until the aqueous phase is at acid pH, and then washed with a saturated sodium hydrogen carbonate solution.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[N:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([NH:32][C:33]([NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=3)=[O:34])[N:31]=2)=[CH:23][CH:22]=1>C(Cl)(Cl)(Cl)Cl>[Br:8][C:29]1[S:28][C:27]([C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)=[N:31][C:30]=1[NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[N:37]=1)=[O:34]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(NC(=O)Nc2nc(-c3ccncc3)sc2Br)n1
Temperature: 25 °C

Procedure:
NBS (686 mg, 3.85 mmol) and AIBN (158 mg, 0.96 mmol) were added to a heterogeneous solution of 1-((2-pyridin-4-yl)thiazol-4-yl)-3-(6-methylpyridin-2-yl)urea (600 mg, 1.93 mmol, Example. 6) in CCl4 (25 mL) and the resulting mixture was heated at reflux for 2 h. After cooling to RT, a precipitate formed and was collected, rinsing with hexane to give a white solid. MS m/z: 392.0 (M+2H). Calc'd for C15H12BrN5OS-390.26.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](OC)[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH3:2].[CH:20]([Li])([CH2:22][CH3:23])[CH3:21]>>[CH:20]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1/[CH:11]=[N:12]/[CH:13]([CH:14]([CH3:15])[CH3:16])[CH:17]([CH3:19])[CH3:18])([CH2:22][CH3:23])[CH3:21]
Reactant: CCc1cccc(OC)c1/C=N/C(C(C)C)C(C)C
Reactant: [Li]C(C)CC
Product: CCc1cccc(C(C)CC)c1/C=N/C(C(C)C)C(C)C

Procedure:
rac-(E)-[1-(2-sec-Butyl-6-ethyl-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine was prepared from (E)-[1-(2-ethyl-6-methoxy-phenyl)-methylidene]-(1-isopropyl-2-methyl-propyl)-amine (Example 3 a) and sec.-butyl lithium in analogy to procedure Example 5 a): colourless liquid: MS (ISP): 288.1 ((M+H)+.).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 66 %

Procedure:
As described for example 162b, 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200 mg, 0.65 mmol) was converted using 4-amino-tetrahydropyran instead of ethanolamine to the title compound (trituration with tert-butylmethylether, 168 mg, 66%) which was obtained as a white solid. MS: m/e=393.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1C2C(=CC=CC=2)C=N1.N([O-])=O.[Na+]>[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12]([CH:13]=[N:22][N:17]2[CH2:18][CH:19]([OH:21])[CH3:20])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)CNc1cc(OCc2ccccc2)ccc1C=O
Reactant: c1ccc2[nH]ncc2c1
Agent: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Product: CC(O)Cn1ncc2ccc(OCc3ccccc3)cc21
Yield: 60 %

Procedure:
The product of Step C (202.7 g, 0.71 mol) was treated as described for Steps C and D of Preparation 3. After the nitrosamine intermediate had been converted to a mixture of the desired indazole product and unreacted starting material (5:1), sodium nitrite (29.5 g, 0.43 mol) was added to renitrosate the starting material. Zinc dust (84 g, 1.28 mol) was then added in portions with cooling as described. When the starting material was consumed, the reaction mixture was worked up as described and combined with the product from another batch that started with 176 g of the product of Step C. The combined crude products were purified by chromatography (Biotage Kiloprep-250) to give a solid (226 g, 60%): 99% purity by HPLC.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C:10](=[CH2:17])[C:11]([O:13][CH2:14][CH2:15][NH2:16])=[O:12].[F:18][C:19]([F:25])([F:24])[S:20](F)(=[O:22])=[O:21]>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C(#N)C>[CH3:17][C:10](=[CH2:9])[C:11]([O:13][CH2:14][CH2:15][NH:16][S:20]([C:19]([F:25])([F:24])[F:18])(=[O:22])=[O:21])=[O:12]
Reactant: O=S(=O)(F)C(F)(F)F
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=C(C)C(=O)OCCNS(=O)(=O)C(F)(F)F
Temperature: -30 °C
Yield: 68.9 %

Procedure:
In a 1 L three-neck flask equipped with a thermometer and a reflux condenser were placed 350 g of acetonitrile, 70.7 g (0.699 mol) of triethylamine, 33.1 g (0.200 mol) of 2-aminoethyl 2-methylacrylate hydrochloride, and 0.2 g of phenothiazine, followed by cooling to −30° C. with stirring. After the inner temperature reached −30° C., 36.5 g (0.240 mol) of trifluoromethanesulfonyl fluoride was introduced into the slurry as a gas over a period of 1 hour. After completion of the introduction, the mixture was continued to stir for further 1 hour and then warmed to room temperature. The solvent acetonitrile and unreacted trifluoromethanesulfonyl fluoride were removed by evaporation from the reaction solution under reduced pressure. One litter of diisopropyl ether was added thereto to form a suspension and the precipitated triethylamine hydrochloride and triethylamine hydrofluoride were removed by filtration. To the filtrate was added 200 mL of an 18% aqueous calcium chloride solution, followed by washing and separation into two layers. Furthermore, the organic layer was washed with 200 g of a 10% aqueous sodium chloride solution three times. The organic layer was dried over 40 g of magnesium sulfate. After removal of the magnesium sulfate by filtration, 0.2 g of phenothiazine was added thereto and the solvent was removed by evaporation to obtain 44.2 g of a crude organic matter. The crude organic matter was distilled under reduced pressure and a fraction of 105 to 115° C./13 Pa was collected, whereby 36.0 g of 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate was obtained. Gas chromatographic investigation of composition thereof revealed that objective 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate was 97.5%. The resulting organic matter was crystallized from diisopropyl ether/n-hexane to obtain 32.4 g of white crystals. Gas chromatographic investigation of composition thereof revealed that objective 2-{[(trifluoromethyl)sulfonyl]amino}ethyl 2-methylacrylate was 99.0%. The yield was 61.4%.
Reaction SMILES: ClCCl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([OH:20])=[C:18]([O:21][CH3:22])[C:17]([O:23][CH3:24])=[CH:16][C:15]=1[CH3:25].N1C=CC=CC=1.[O:32]=O>C1C=C(C=NCCN=CC2C([O-])=CC=CC=2)C([O-])=CC=1.[Co+2]>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19](=[O:20])[C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:16](=[O:32])[C:15]=1[CH3:25]
Reactant: COc1cc(C)c(CCCCCCCCCO)c(O)c1OC
Reactant: O=O
Agent: [Co+2]
Agent: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=C(OC)C(=O)C(CCCCCCCCCO)=C(C)C1=O

Procedure:
To a dichloromethane solution (30 ml) of 6-(9-hydroxynonyl)-2,3-dimethoxy-5-methylphenol (1.8 g) are added pyridine (0.5 ml) and bis(salicylidene)ethylenediiminocobalt(II) (32 mg). The mixture is stirred in oxygen streams at atmospheric temperature and pressure. The reaction product is isolated as in Example 7 and recrystallized from hexane. The above procedure yields 6-(9-hydroxynonyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone (1.2 g) as orange-yellow needles melting at 45° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH2:9]([SH:13])[CH2:10][CH2:11][SH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>ClCCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[S:13][CH2:9][CH2:10][CH2:11][S:12]1
Reactant: SCCCS
Reactant: O=Cc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: c1ccc(C2SCCCS2)nc1
Temperature: 5 °C
Yield: 85.2 %

Procedure:
A solution of pyridine-2-carboxaldehyde (26.7 g), propane-1,3-dithiol (94.4 g) and paratoluenesulphonic acid (3.7 g) in 1,2-dichloroethane (2500 cc) is kept at the boil for 20 hours so that the water formed is removed by azeotropic distillation. After cooling to 5° C., the reaction mixture is washed twice with an approximately 7 N aqueous solution of potassium hydroxide (540 cc in total) and then four times with distilled water (1400 cc in total). The organic solution is dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 2-(Pyrid-2-yl)-1,3-dithiane (41.9 g) is thus obtained.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[C:42]2[CH:43]=[CH:44][C:45](B(O)O)=[CH:46][C:41]=2[O:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:45]2[CH:44]=[CH:43][C:42]3[O:37][CH2:38][CH2:39][O:40][C:41]=3[CH:46]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)n1c(C(=CC2CCCC2)c2ccc3c(c2)OCCO3)cc2cccnc21
Yield: 95.4 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 1,4-benzodioxane-6-boronic acid (0.13 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (130 mg, 96%) as a white solid: LC/MS m/e calcd for C28H26N2O4S [M+H]+ 487.59, observed 487.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:15][NH2:16]>CN(C=O)C.CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1
Reactant: CC(C)c1csc2c(Cl)nc(Cl)nc12
Reactant: CN
Solvent: CO
Solvent: CN(C)C=O
Product: CNc1nc(Cl)nc2c(C(C)C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To 10 ml of a solution of 100 mg (0.41 mmol) of 2,4-dichloro-7-isopropylthieno[3,2-d]pyrimidine in DMF was added 40% methylamine solution in methanol under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 2 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/2) to give 90 mg (yield: 92.0%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24]Cl)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:33][NH:34][CH3:35]>C(O)C>[Cl:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23](=[O:26])[CH2:24][N:34]([CH3:35])[CH3:33])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: CNC
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CCl
Solvent: CCO
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CN(C)C
Yield: 58 %

Procedure:
Using a procedure similar to that described for the preparation of Example 43, 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[(2S)-1-(chloroacetyl)pyrrolidin-2-yl]methoxy}quinazoline (0.28 g) was reacted with 33% dimethylamine in ethanol (5 ml) to give the title product as a foam (0.165 g, 58%); 1H NMR Spectrum: (CDCl3) 1.91-2.01 (m, 1H), 2.04-2.11 (m, 2H), 2.14-2.22 (m, 1H), 2.33 (s, 6H), 3.02-3.22 (dd, 2H), 3.40-3.50 (m, 1H), 3.59-3.66 (m, 1H), 4.02 (s, 3H), 4.05-4.09 (m, 1H), 4.51-4.55 (d, 1H), 4.66-4.72 (m, 1H), 7.09-7.21 (m, 2H), 7.23 (s, 1H), 8.00-8.06 (m, 1H), 8.47 (bs, 1H), 8.62 (s, 1H), 8.68 (s, 1H); Mass Spectrum: (M−H)− 486.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:15][CH3:16])[CH2:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[O:6]1)=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32]I>>[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH:21]=[CH:20][C:19]=1[O:29][CH2:30][CH2:31][CH2:32][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C@:5]([CH2:15][CH3:16])([C:3]([OH:2])=[O:4])[CH2:9][C:8]=2[CH:10]=1
Reactant: CC(C)(C)Cc1ccc(OCCCI)c(Cl)c1
Reactant: CCC1(C(=O)OC)Cc2cc(O)ccc2O1
Product: CC[C@@]1(C(=O)O)Cc2cc(OCCCOc3ccc(CC(C)(C)C)cc3Cl)ccc2O1

Procedure:
The title compound was prepared following the general procedure described in Example 1, Step 4 employing the chiral phenol prepared in Example 10, Step 2 and the iodide prepared in Step 1.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[C:4]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:18]#[N:19].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(N(CC)CC)C.C[O-].[Na+]>C(O)C>[NH2:19][C:18]1[C:3]2[C:4]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[C:5]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]3=[N:7][C:2]=2[S:1][C:21]=1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: N#Cc1c(S)nc2c(c1-c1cccs1)CCCCC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)c1sc2nc3c(c(-c4cccs4)c2c1N)CCCCC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-mercapto-4-thien-2-yl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carbonitrile (143 mg, 0.5 mmol), tert-butyl bromoacetate (97 mg, 0.5 mmol) and triethyl amine (51 mg, 0.5 mmol) in ethanol (20 mL) was stirred at room temperature overnight, followed by the addition of NaOMe (30 mg, 0.56 mmol). The mixture was then refluxed for 30 min., and poured onto ice. The precipitate is filtered and washed with water to furnish pure t-butyl 3-amino-4-thiophen-2-yl-6,7,8,9-tetrahydro-5H-1-thia-10-aza-cyclohepta[f]indene-2-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[C:17]([CH:28]=[CH2:29])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2cc(Br)ncc2cc1NC(=O)OCc1ccccc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: O
Solvent: C1COCCO1
Product: C=Cc1cc2nc(C(=O)OCC)c(NC(=O)OCc3ccccc3)cc2cn1
Temperature: 95 °C
Yield: 52 %

Procedure:
A mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromo-1,6-naphthyridine-2-carboxylate (22 mg, 0.051 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (43 μL, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.004 mmol), and potassium carbonate (21 mg, 0.15 mmol) in 1,4-dioxane (500 μL) and water (50 μL) in a vial was deoxygenated and purged with nitrogen several times. The vial was sealed under nitrogen and then heated at 95° C. for 3 h. The crude reaction mixture was filtered through a pad of diatomaceous earth and the inorganics were washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (24 g silica gel column, eluting with 0-50% EtOAc/hexanes) to afford the sub-title compound (10 mg, 50%). LCMS (ESI) calc. for C21H20N3O4 [M+H]+: m/z=378.1. found: 378.1.
Reaction SMILES: C(N(CC)CC)C.C(O[CH:11]=[C:12]([C:18]#[N:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])C.C(O)(=O)C(O)=O.[CH2:26]([NH:28][NH2:29])[CH3:27]>C(O)C>[CH2:16]([O:15][C:13]([C:12]1[CH:11]=[N:29][N:28]([CH2:26][CH3:27])[C:18]=1[NH2:19])=[O:14])[CH3:17]
Reactant: CCNN
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnn(CC)c1N
Yield: 80.1 %

Procedure:
Triethylamine (19.6 ml, 144 mmol) was added cautiously to a solution of ethyl (ethoxymethylene)cyanoacetate (10.1 g, 60 mmol) and ethyl hydrazine oxalate (9.9 g, 66 mmol) in ethanol (200 ml). The mixture was heated at reflux for 24 h then concentrated in vacuo. The residue was redissolved in EtOAc, washed with 5% KHCO3 solution then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 25% pet. ether:75% EtOAc) to yield the title compound (8.8 g, 80%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([O:27]CC)=[O:26])C3C=CC=CC=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH2:41]C(N)=O)C3CCCCC3)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-:45].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]([OH:27])=[O:26])[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:16]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:41])[C:5]([NH:6][CH:7]3[CH2:8][CH2:30][CH2:31][CH2:32][CH2:33]3)=[O:45])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(CC(N)=O)C3CCCCC3)cc2n1Cc1ccc(OC(C(=O)OCC)c2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc2ccc(N(C)C(=O)NC3CCCCC3)cc2n1Cc1ccc(OC(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)benzyloxy]benzyl]-6-(N-cyclohexyl-aminocarbonylmethylamino)benzimidazole and 1N sodium hydroxide solution in ethanol.