Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][C:15]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)([SH:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].[NH2:32]OS(O)(=O)=O.[OH-].[K+]>O1CCCC1>[C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:16]([F:19])([F:18])[F:17])[S:20][N:32]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOS(=O)(=O)O
Reactant: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-methyl-benzoic acid tert-butyl ester (1.875 g) in tetrahydrofuran (6 mL) was added a solution of Hydroxylamine-O-sulfonic acid (2 equiv.) in a solution of potassium hydroxide (1.2 g in 75 mL of water). After stirring at room temperature for 30 minutes, the mixture was quenched with a solution of hydrochloric acid (1N), extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isothiazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (881 mg)
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.O[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>CO.CN1C(=O)CCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([CH2:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2c(=O)sc3cc(Br)ccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottom flask was added 6-bromo-1,3-benzothiazol-2(3H)-one (0.300 g, 1.304 mmol), tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.365 g, 1.695 mmol), triphenylphosphine (0.455 g, 1.695 mmol), diisopropyl (E)-diazene-1,2-dicarboxylate (DIAD) (0.330 mL, 1.695 mmol), and NMP (5 mL). The reaction mixture was then permitted to stir at room temperature for two hours. The crude reaction mixture was then diluted with methanol, filtered and concentrated. Purification of crude reaction mixture by reverse phase chromatography (Waters Sunfire MSC18, 30% acetonitrile/0.1% trifluoroacetic acid/water→100% acetonitrile/0.1% trifluoroacetic acid/water) tert-butyl 4-[(6-bromo-2-oxo-1,3-benzothiazol-3(2H)-yl)methyl]piperidine-1-carboxylate (11-1) as a tan solid. HRMS (M+H)+: observed=427.0691, calculated=427.0686.
Reaction SMILES: C([O:4][CH:5]([C:14](=[O:16])[NH2:15])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])(=O)C.C(OCC(C1C=CC=CC=1)CC(=O)N)(=O)C>>[C:14]([CH:5]([OH:4])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])(=[O:16])[NH2:15]
Reactant: CC(=O)OC(C(N)=O)C(C)c1ccccc1
Agent: CC(=O)OCC(CC(N)=O)c1ccccc1
Product: CC(c1ccccc1)C(O)C(N)=O

Procedure:
Except for using 3-N-morphoryl carbamoyl-2-phenyl propanol acetate, instead of 3-carbamoyl-2-phenyl propanol acetate, as the starting material, the same procedure with that of Example 8 was repeated.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[Cl:12][C:13]1[CH:22]=[C:21]([O:23][C@H:24]2[CH2:41][O:40][C@@H:26]([CH2:27][O:28]C(=O)C3C=CC([N+]([O-])=O)=CC=3)[CH2:25]2)[C:20]([Cl:42])=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][C:18]2=[O:43].[CH2:44]([O:51][C:52]1[C:57]([CH2:58]Cl)=[C:56]([CH3:60])[CH:55]=[C:54]([CH3:61])[N:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:44]([O:51][C:52]1[C:57]([CH2:58][N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[C:20]([Cl:42])[C:21]([O:23][C@@H:24]4[CH2:25][C@H:26]([CH2:27][OH:28])[O:40][CH2:41]4)=[CH:22][C:13]=3[Cl:12])[C:18]2=[O:43])=[C:56]([CH3:60])[CH:55]=[C:54]([CH3:61])[N:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(OC[C@H]1C[C@@H](Oc2cc(Cl)c3c(c2Cl)C(=O)NCC3)CO1)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CN2CCc3c(Cl)cc(O[C@H]4CO[C@@H](CO)C4)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Reaction time: 0.5 h
Yield: 25.9 %

Procedure:
Potassium tert-butoxide solution in tetrahydrofuran (1.0 M, 645 μL, 0.645 mmol) was added dropwise to a cooled (0° C.) solution of 2,5-anhydro-3-deoxy-4-O-(5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-1-O-(4-nitrobenzoyl)-L-threo-pentitol (296n, 120 mg, 0.249 mmol) in anhydrous N,N-dimethylformamide (4 mL). After stirring for 30 minutes, a solution of 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (compound Z, 71 mg, 0.273 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added and stirring continued at 0° C. for 30 more minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL) and brine (50 mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane), affording 1,4-anhydro-2-O-(2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5,8-dichloro-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-3-deoxy-L-threo-pentitol (296o, 36 mg, 26% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=7.21 Hz, 2H), 7.29-7.40 (m, 3H), 6.94 (s, 1H), 6.62 (s, 1H), 5.43 (s, 2H), 4.92 (br. s., 1H), 4.87 (s, 2H), 4.15-4.26 (m, 2H), 3.91 (dd, J=10.39, 3.91 Hz, 1H), 3.75-3.84 (m, 1H), 3.66-3.75 (m, 1H), 3.25 (t, J=6.05 Hz, 2H), 2.69 (t, J=6.05 Hz, 2H), 2.42 (s, 3H), 2.34-2.40 (m, 1H), 2.32 (s, 3H), 2.03-2.16 (m, 2H). MS: 557 [M+1].
Reaction SMILES: C([O:4][CH:5]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[CH:28]=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=[O:7])(=O)C>[OH-].[Na+].CO.O>[OH:4][CH:5]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[CH:28]=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=[O:7]
Reactant: CC(=O)OC(C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)C(O)c1ccccc1

Procedure:
A solution of 0.34 g of α-(acetyloxy)-N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]benzeneacetamide in 2 ml of 1N NaOH and 4 ml of methyl alcohol is stirred at room temperature for 30 minutes, diluted with 2 ml of water and evaporated in vacuo. The aqueous suspension is extracted with 30 ml of ethyl acetate and the extract washed with brine, dried with Na2SO4 and filtered through a pad of hydrous magnesium silicate and evaporated in vacuo to a residue. The residue is stirred with ether-hexanes to give 0.26 g of cream colored solid. MS(CI): 438(M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[N:1]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=2)[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: OCc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccc(CN2CCC3(CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.6 %

Procedure:
To a stirred solution of 2,3-dihydrospiro[indene-1,4′-piperidine] (0.4 g, 1.78 mmol) in DMF (12 mL) is added Cs2CO3 (1.4 g, 4.4 mmol) and [4-(bromomethyl)phenyl]methanol (0.36 g, 1.78 mmol) and the reaction mixture is stirred overnight at room temperature. The reaction mixture is poured into cold water and extracted with EtOAc (3×50 mL). The combined organic layer is washed with brine solution, dried over Na2SO4, and concentrated under vacuum. The crude material is purified by silica gel chromatography (gradient DCM/MeOH 8/2) to give the title compound (0.6 g, 98%). ESI/MS m/z 308.40 (M+H)+.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:9])=[N:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:10][N:11]([CH3:15])[C:12](Cl)=[O:13]>>[CH3:10][N:11]([CH3:15])[C:12]([O:2][N:1]=[C:3]1[C:8]([CH3:9])=[N:7][CH2:6][CH2:5][S:4]1)=[O:13]
Reactant: CN(C)C(=O)Cl
Reactant: CC1=NCCSC1=NO
Product: CC1=NCCSC1=NOC(=O)N(C)C

Procedure:
2-Oxo-5,6-dihydro-3-methyl-2H-1,4-thiazine oxime is reacted with dimethylcarbamoyl chloride as described in Example 2 to yield 2-oxo-5,6-dihydro-3-methyl-2H-1,4-thiazine O-(dimethylcarbamoyl)oxime, m.p. 64°-65° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[SH:26]>>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2
Reactant: Sc1cc(Br)ccc1Br
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Product: O=c1ccc2cc(OCCCCSc3cc(Br)ccc3Br)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p.: 198°-199° C.) and 2,5-dibromothiophenol.
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]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=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>[N:27]1([C:24]2[CH:25]=[CH:26][C:21]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=4[CH:18]=3)=[CH:22][CH:23]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: [O-]B([O-])Oc1ccc(N2CCCC2)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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCCC4)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-(1-pyrrolidinyl)phenyl borate (508 mg) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 17 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals were washed with diisopropylether to give yellow crystals of methyl 7-[4-(1-pyrrolidinyl)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (323 mg).
Reaction SMILES: [H][H].[OH:3][C@@H:4]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:6]([CH2:7][C@@H:8]([CH3:30])[C@@H:9]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:5]1.O[C@@H]1CC[C@@]2(C)[C@H](C[C@H](C)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(O)=O)C1>C(OCC)(=O)C.O=[Pt]=O>[OH:3][C@@H:4]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:6]([CH2:7][CH:8]([CH3:30])[C@@H:9]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH2:5]1
Reactant: [H][H]
Reactant: C[C@@H]1C[C@@H]2C[C@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@H]3[C@H]12
Agent: O=[Pt]=O
Agent: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCOC(C)=O
Product: CC1C[C@@H]2C[C@H](O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@H]3[C@H]12

Procedure:
The compounds obtained from fractions 2 and 3 from Example 2, above, were dissolved in ethyl acetate and reduced with hydrogen in the presence of a PtO2 catalyst to yield a mixture of 3α-hydroxy-7α-methyl-5β-cholanic acid and 3α-hydroxy-7β-methyl-5β-cholanic acid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[N:11]1([CH2:17][C:18]2[CH:19]=[C:20]([C:24]3[O:25][C:26](=[O:37])[C:27]4[C:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=5[S:30][C:28]=4[N:29]=3)[CH:21]=[CH:22][CH:23]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH:38]1([C:41]2[S:45][C:44]([NH2:46])=[N:43][N:42]=2)[CH2:40][CH2:39]1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.C1COCC1>[CH:38]1([C:41]2[S:45][C:44]([NH:46][C:26]([C:27]3[C:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=4[S:30][C:28]=3[NH:29][C:24](=[O:25])[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH:19]=3)=[O:37])=[N:43][N:42]=2)[CH2:40][CH2:39]1
Reactant: O=c1oc(-c2cccc(CN3CCOCC3)c2)nc2sc3c(c12)CCCC3
Reactant: Nc1nnc(C2CC2)s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1sc2c(c1C(=O)Nc1nnc(C3CC3)s1)CCCC2)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 0.07 mL of lithium hexamethyldisilazide (1.0M in THF) and 0.2 mL of THF was added to a mixture of 11.5 mg of 2-[3-(morpholin-4-ylmethyl)phenyl]-5,6,7,8-tetrahydro-4H-[1]benzothieno[2,3-d][1,3]oxazin-4-one, 4.9 mg of 5-cyclopropyl-1,3,4-thiadiazol-2-amine, and 0.8 mL of THF, followed by stirring overnight at room temperature. Chloroform and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was separated. After the solvent was removed under reduced pressure, the obtained residue was purified, thereby obtaining 11.4 mg of N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-2-{[3-(morpholin-4-ylmethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]([CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[CH2:10][N:9]=2)=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][NH:12][C:11]([C:10]1[NH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:14]2[C:15]=1[CH:16]=[CH:17][CH:18]=[CH:13]2)=[O:26])[CH3:23]
Reactant: CCN(CC)CCN1C(=O)CN=C(c2ccc(Cl)cc2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCNC(=O)c1[nH]c(-c2ccc(Cl)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 11.1 g. of 5-(p-chlorophenyl)-1-[2-(diethylamino)ethyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one in 100 ml. of dimethylformamide is treated under an atmosphere of argon at room temperature with 0.035 mol. of sodium hydride (1.55 g. of a 55% dispersion in mineral oil). The mixture is first warmed to 60° C. over a period of about 30 minutes, then stirred at this temperature for 1 hour and thereafter at 70° C. for 1 hour. After cooling, 4 ml. of water are added dropwise and the mixture is then poured on to 800 ml. of ice-water. After the addition of 30 g. of sodium chloride, the precipitated product is extracted with methylene chloride. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. The oily residue obtained crystallizes upon trituration with hexane. Recrystallization from ethyl acetate yields 3-(p-chlorophenyl)isoindole-1-carboxylic acid [2-(diethylamino)ethyl]amide in the form of felt-like greenish crystals having a melting point of 145°-147° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C:22]3[CH:34]=[CH:33][O:32][C:23]=3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].BrC1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C([C@H]3CCO[C@H]3CO2)=CC=1)(=O)=O.C(N(CC)C/C=C\[Sn](CCCC)(CCCC)CCCC)C>>[CH2:35]([N:3]([CH2:1][CH3:2])[CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([C@H:22]3[CH2:34][CH2:33][O:32][C@H:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:36]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCc1occc1-2
Agent: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@@H]1OCC[C@H]21
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@@H]1OCC[C@H]21
Temperature: 80 °C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 9, starting from methyl cis-(3aRS,9bRS)-7-(2-bromo-4-fluorobenzenesulfonylamino)-1,3a,4,9b-tetrahydro-2H-furo[2,3-c]chromene-6-carboxylate (Intermediate 18) and N,N-diethyl-N—((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 11) and heating at 80° C. for 2 hours.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[C:17]1([C:16]([NH:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCNC(=O)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a suspension of methyl 4-(2-amino-ethoxy)benzoate hydrochloride (0.232 g, 1 mmol) in THF (6 ml) was added benzoyl chloride (0.140 g, 1 mmol) followed by triethylamine (0.121 g, 1.2 mmol). The reaction mixture was stirred for 1 h and then diluted with ethyl acetate. The organic layer was washed with 0.5 M aqueous HCl, saturated sodium bicarbonate solution, and brine. The organic layer was concentrated in vacuo to give methyl 4-(2-benzenecarbonylamino-ethoxy)benzoate which was directly used in the next step.
Reaction SMILES: [CH:1]1([CH:4]([OH:21])[CH2:5][O:6][C:7]2[C:8](Cl)=[N:9][C:10]([Cl:19])=[N:11][C:12]=2[N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[H-].[Na+]>C1COCC1>[Cl:19][C:10]1[N:11]=[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:7]2[O:6][CH2:5][CH:4]([CH:1]3[CH2:3][CH2:2]3)[O:21][C:8]=2[N:9]=1
Reactant: OC(COc1c(Cl)nc(Cl)nc1N1CCOCC1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc2c(c(N3CCOCC3)n1)OCC(C1CC1)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-cyclopropyl-2-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-ethanol (196 mg, 0.59 mmol) in THF (10 mL) was added sodium hydride (65 mg, 1.77 mmol, 65% dispersion in mineral oil) and the reaction mixture stirred at RT for 4 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (15 mL) then extracted with ethyl acetate (3×20 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo giving 2-Chloro-7-cyclopropyl-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine as a white solid (205 mg, quantitative). LCMS: RT=3.19 min, [M+H]+=298/300.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:37][C:36](=[O:38])[NH:35][N:34]=2)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][N:35]=[C:36]([O:38][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:37]=2)=[CH:31][CH:32]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Product: COc1ccc(-c2cc(Oc3ncnc4cc(OCCCN5CCN(C)CC5)c(OC)cc34)n[nH]2)cc1
Yield: 0 %

Procedure:
Using a procedure analogous to that described in Example 14, 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (350 mg, 1 mol), (prepared as described for the starting material in Example 14), was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (380 mg, 2 mol), (prepared as described for the starting material in Example 10), to give 4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (215 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1([C:20]([OH:22])=[O:21])[C:11]2[C:6](=[CH:7][C:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[C:9]([Cl:12])[CH:10]=2)[C:5](=O)[CH2:4][CH2:3]1.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH3:1][C:2]1([C:20]([OH:22])=[O:21])[C:11]2[C:6](=[CH:7][C:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[C:9]([Cl:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CCC(=O)c2cc(C3CCCCC3)c(Cl)cc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CC1(C(=O)O)CCCc2cc(C3CCCCC3)c(Cl)cc21
Temperature: 195 °C
Yield: 92.1 %

Procedure:
A mixture of 6.7 g of 1-methyl-4-oxo-6-cyclohexyl-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid, 4 g of hydrazine hydrate, 6.7 g of potassium hydroxide and 40 ml of triethyleneglycol is heated for 2 hours at 130°-140°C. Then, while distilling off a mixture of hydrazine and water, the temperature is raised to 195°C and the batch is stirred until nitrogen is no longer being given off, then diluted with 50 ml of water, acidified with concentrated hydrochloric acid and the mixture is extracted with ethyl acetate. The ethyl acetate is evaporated and the residual crude product recrystallized from acetone, to yield 5.9 g of 1-methyl-6-cyclohexyl-7-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid melting at 167°-168°C, of the formula ##SPC7##
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[CH:4]=[N:5]O>CC(OC(C)=O)=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(F)c1C=NO
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(F)c1C#N
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2-fluoro-6-methoxybenzaldoxime (714 mg, 4.2 mmol) in Ac2O (3.6 mL) is heated at reflux for 4 hr. The reaction is cooled to r.t. and the volatiles are stripped off to give a beige solid, which is dried at 50° C. in a vacuum oven to give 2-fluoro-6-methoxybenzonitrile (635 mg, 84%). 1H NMR (DMSO) δ7.8-7.7 (1H, m), 7.14-7.07 (2H, m),3.95 (3H, s).