Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH3:15])[C:12](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:16]1([C:22]2[N:27]=[N:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C([O-])(O)=O.[Na+]>[C:16]1([C:22]2[CH:23]=[CH:24][C:25]3[N:26]([C:12]([CH:11]([C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH3:15])=[N:29][N:28]=3)[N:27]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C(=O)O)c1ccc2ncccc2c1
Reactant: NNc1ccc(-c2ccccc2)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(c1ccc2ncccc2c1)c1nnc2ccc(-c3ccccc3)nn12
Temperature: 160 °C
Yield: 54.5 %

Procedure:
To a 2-5 ml Personal Chemistry microwave vial was added 2-(quinolin-6-yl)propanoic acid (0.25 g, 1.2 mmol), 1-(6-phenylpyridazin-3-yl)hydrazine (0.42 g, 2.2 mmol) and conc. HCl (2 mL). The mixture was heated in the microwave at 160° C. for 8 h. After cooling to rt, the mixture was poured into sat. NaHCO3 (100 mL) and then extracted with EtOAc (4×75 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (1.0 to 4.5% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as an off-white solid (0.23 g, 53% yield). MS (ESI, pos. ion) m/z: 352 (M+1).
Reaction SMILES: [CH2:1]([N:4]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15](B(O)O)=[C:14]([O:23][CH3:24])[CH:13]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].[CH3:25][O:26][C:27](=[O:55])[C@H:28]([CH2:40][C:41]1[CH:46]=[CH:45][C:44](OS(C(F)(F)F)(=O)=O)=[CH:43][CH:42]=1)[NH:29][C:30](=[O:39])[C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:38]>>[CH3:25][O:26][C:27](=[O:55])[C@H:28]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:15]2[C:16]([O:18][CH3:19])=[CH:17][C:12]([N:4]([CH2:1][CH:2]=[CH2:3])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[CH:13][C:14]=2[O:23][CH3:24])=[CH:45][CH:46]=1)[NH:29][C:30](=[O:39])[C:31]1[C:32]([Cl:38])=[CH:33][CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: C=CCN(C(=O)OC(C)(C)C)c1cc(OC)c(B(O)O)c(OC)c1
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Product: C=CCN(C(=O)OC(C)(C)C)c1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c(OC)c1

Procedure:
4-(N-Allyl-N-tert-butoxycarbonylamino)-2,6-dimethoxybenzeneboronic acid and N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester were coupled by a similar method as described in Example 7-2) to give N-(2,6-dichlorobenzoyl)-4-[4-(N-allyl-N-tert-butoxycarbonylamino)-2,6-dimethoxyphenyl]-L-phenylalanine methyl ester.
Reaction SMILES: [Na].[CH:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[CH:3]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C.C(OCC)C>[Br:9][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:2][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)COc1ccc(Br)cc1

Procedure:
2.76 g of sodium are dissolved in 100 ml of anhydrous ethanol and 20.8 g (0.120 mol) of p-bromophenol are added. 22.1 g (0.132 mol) of ethyl bromoacetate are run into this solution over the course of 20 minutes and the mixture is then heated under reflux for 1 hour. The ethanol is driven off under reduced pressure and the residue is dissolved in diethyl ether; after washing with water and then with a potassium carbonate solution, and evaporating the solvent, 30.2 g of a white powder are obtained. After purification of this product by crystallisation from petroleum ether, 23 g of a white, water-insoluble powder are obtained.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C@H:37]([C:40](O)=[O:41])[CH2:38][OH:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:19][C:20](=[O:35])[C@H:21]([CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:22][C:38](=[O:39])[C@H:37]([CH2:40][OH:41])[NH:36][C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.3 %

Procedure:
To a solution of L-glutamic acid 1,5-dibenzyl ester p-toluenesulfonate (10.0 g), Boc-Ser (4.1 g) and TEA (2.0 g) in DMF (200 ml) are added with stirring WSC (5.0 g) and HOBt (4.0 g) under ice-cooling. The mixture is stirred at room temperature for 20 hours, and thereto is added ethyl acetate (200 ml). The mixture is washed successively with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried, and concentrated under reduced pressure. The precipitated solid is collected by filtration, and washed with ether to give N-tert-butoxycarbonyl-L-seryl-L-glutamic acid 1,5-dibenzyl ester (9.7 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[C:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:32]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:30]=[C:29]([CH3:42])[CH:28]=2)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:42][C:29]1[CH:30]=[C:31]([C:2]2[S:6][C:5]([CH:7]=[C:8]3[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:4][CH:3]=2)[CH:32]=[C:27]([NH:26][C:22]2[N:21]=[C:20]([CH3:19])[CH:25]=[CH:24][N:23]=2)[CH:28]=1
Reactant: CCOC(=O)C1CCC(=Cc2ncc(Br)s2)CC1
Reactant: Cc1cc(Nc2nccc(C)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(=Cc2ncc(-c3cc(C)cc(Nc4nccc(C)n4)c3)s2)CC1
Temperature: 80 °C

Procedure:
Ethyl 4-[(5-bromo-1,3-thiazol-2-yl)methylidene]cyclohexanecarboxylate (223 mg, 0.676 mmol), 4-methyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (220 mg, 0.676 mmol) and 1,1′-bis(diphenylphosphino)-ferrocenedichloro palladium(II) dichloromethane complex (49.5 mg, 0.068 mmol) were combined in a flask that was then sealed and flushed with nitrogen (2×). Dioxane (4 mL) and sodium carbonate (2 M in water, 1.015 mL, 2.029 mmol) were added, and the reaction was flushed again with nitrogen (2×). The mixture was heated to 80° C. for 1 hour and then cooled to room temperature, diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by chromatography on silica gel (5-60% EtOAc in hexanes) afforded ethyl 4-[(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)methylidene]cyclohexanecarboxylate as a yellow foam. MS ESI calc'd. for C25H29N4O2S [M+H]+ 449. found 449. 1H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.34 (d, J=5.0, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.51 (s, 1H), 7.07 (s, 1H), 6.74 (d, J=5.0 Hz, 1H), 6.46 (s, 1H), 4.06 (q, J=7.1 Hz, 2H), 3.55-3.47 (m, 1H), 3.31 (s, 2H), 2.66-2.57 (m, 1H), 2.44-2.24 (m, 7H), 2.04-1.97 (m, 2H), 1.61-1.46 (m, 2H), 1.17 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11](OS(C)(=O)=O)[CH2:10]2)[S:7][CH:8]=1)(=[O:3])[NH2:2].[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>CN(C)C=O>[C:18]([S:20][CH:11]1[CH2:10][N:9]([C:6]2[S:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:12]1)(=[O:21])[CH3:19]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(N)=O)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(N)=O)cs2)C1
Temperature: 80 °C
Reaction time: 10 h
Yield: 69.6 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (3.04 g, 11.0 mmol) (obtained as described in Reference Example 3(3)) in dimethylformamide (152 ml) was added potassium thioacetate (7.5 g, 65.8 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 10 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→4% methanol in ethyl acetate as the eluant to afford 3-acetylthio-1-(4-carbamoyl-1,3-thiazol-2-yl)azetidine (1.97 g, yield 70%) as a pale brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[NH2:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:30][CH:29]=1)(=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (2.50 g, 0.012 mol) in dry toluene (40 ml) was treated with 4-aminobenzophenone (2.43 g, 0.012 mol) and a catalytic amount of p-toluenesulfonic acid (0.25 ml of an anhydrous 0.1M solution of p-toluenesulfonic acid in benzene). The mixture was heated under nitrogen at 80° C. overnight. The reaction was worked up as described in Preparation 5. Purification on a silica gel column using a graded eluant of 5-40% ethyl acetate in petroleum ether 40/60 afforded the title compound as a yellow foam (3.65 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH2:22][CH2:23][CH2:24][N:25]([CH3:29])[S:26](=[O:28])(=[O:27])[C:20]=4[CH:19]=[CH:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[C:22](=[N:31][OH:32])[CH2:23][CH2:24][N:25]([CH3:29])[S:26](=[O:28])(=[O:27])[C:20]=4[CH:19]=[CH:18]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: CN1CCCc2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCC(=NO)c2c(ccn2CCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Yield: 66.2 %

Procedure:
A suspension of 174 mg (0.4 mmol) of Compound 26, 56 mg (0.8 mmol) of hydroxylamine hydrochloride and 66 mg (0.8 mmol) of sodium acetate in 20 ml of methanol was refluxed for 17 hours. Post-treatment and purification were conducted in a similar manner as in Example 20, whereby 119 mg of the title compound were obtained (yield: 66%).
Reaction SMILES: CN(C)C=O.[CH2:6]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=1)[CH2:7][CH2:8][CH3:9].CS(O[CH2:25][CH2:26][C:27]([CH3:31])=[C:28]([F:30])[F:29])(=O)=O.C(=O)([O-])O.[Na+]>O>[CH2:6]([O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH2:25][CH2:26][C:27]([CH3:31])=[C:28]([F:30])[F:29])=[O:16])=[CH:13][N:12]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOc1ccc(C(=O)O)cn1
Reactant: CC(CCOS(C)(=O)=O)=C(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C(=O)OCCC(C)=C(F)F)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.39 g (2.0 mmol) of 6-butoxynicotinic acid, synthesized by a method in accordance with one used in Intermediate Production Example 1, and 0.40 g (2.0 mmol) of 4,4-difluoro-3-methyl-3-butenyl methanesulfonate, followed by the addition of 0.34 g (4.0 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:7) to obtain 0.45 g (yield: 75%) of 4,4-difluoro-3-methyl-3-butenyl 6-butoxynicotinate.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[C:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:32][C:27]2[CH:28]=[CH:29][C:30]([F:31])=[C:25]([F:24])[CH:26]=2)[N:9]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To the product of Example 131 (250 mg, 0.6984 mmol) was added 3,4-difluorophenol (273 mg, 2.095 mmol), Cs2CO3 (683 mg, 2.096 mmol) and toluene (4.5 mL) before heating to 100° C. After stirring 16 hours the reaction solution was filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 10% ethyl acetate/hexane affording the product. MS (electrospray) m/e 453.0 MH+ (Rt=4.4 min LC/MS).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Li+].[OH-]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]3[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3cccc([N+](=O)[O-])c3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a solution of ethyl 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (2.00 g, 4.52 mmol) in methanol (5 mL) was added LiOH (500 mg, 20.9 mmol). The resulting solution was stirred for 17 hours at 60° C., concentrated in vacuo, and extracted with ethyl acetate (×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid as a yellow solid. LRMS (ESI) calc'd for C19H23N4O5Si [M+H]+: 415, found 415.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][CH3:19])=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1C2C(=CC([B:31]3[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]3)=CC=2)N=C(C2C=CC=CC=2)N=1>>[CH3:19][O:18][C:6]1[C:5]2[C:10](=[CH:11][C:2]([B:31]3[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]3)=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: Cc1nc(-c2ccccc2)nc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: COc1nc(-c2ccccc2)nc2cc(Cl)ccc12
Product: COc1nc(-c2ccccc2)nc2cc(B3OC(C)(C)C(C)(C)O3)ccc12

Procedure:
Synthesized from of 7-chloro-4-methoxy-2-phenylquinazoline (189 mg, 0.7 mmol) as 4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline; off-white solid. MS (ES+): m/z 347.2 (20) MS (ES+): m/z 281.2 (100) [MH+-82]; HPLC: tR=3.19 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@:26](Br)([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:33])[CH:22]=[CH:23]2)[C@@H:18]([CH3:34])[CH2:17]3)[CH2:14][C@@H:13]1[CH3:35])[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C([SnH](CCCC)CCCC)CCC>>[C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:33])[CH:22]=[CH:23]2)[C@@H:18]([CH3:34])[CH2:17]3)[CH2:14][C@@H:13]1[CH3:35])[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@@]3(Br)[C@@H](O)C[C@@]21C
Agent: CCCC[SnH](CCCC)CCCC
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 101.5 %

Procedure:
As described in Example 1(G), 460 mg of 17α,21-diacetoxy-9α-bromo-11β-hydroxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione is debrominated with tributyltin hydride and worked up, thus obtaining 400 mg of 17α,21-diacetoxy-11β-hydroxy-6α,16β-dimethyl-1,4-pregnadiene-3,20-dione, mp 124°-126° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6]#[N:7])[CH3:2].[NH2:10][OH:11]>CCO>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6](=[N:10][OH:11])[NH2:7])[CH3:2]
Reactant: NO
Reactant: CCN(CC)CCC#N
Solvent: CCO
Product: CCN(CC)CCC(N)=NO
Yield: 92.6 %

Procedure:
A solution of 3-(diethylamino)propanenitrile (1 g, 8 mmol) and NH2OH (50% in water, 0.73 cm3, 11.9 mmol) in EtOH (10·cm3) were heated to reflux for 24 hours, after which the solvent and excess hydroxylamine were removed by rotary evaporator. The residue was freeze-dried and kept in high vacuum line until it slowly solidified to give give 3-(diethylamino)-N′-hydroxypropanimidamide (1.18 g, 92.6%) as a white solid, mp 52-54° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1cnccn1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1cnccn1

Procedure:
The title compound (0.18 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.54 g) and 2-chloropyrazine according to the method of D20.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[I:10]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[I:10][C:7]1[C:2]([NH2:1])=[CH:3][CH:4]=[C:5]([O:8][CH3:9])[N:6]=1
Reactant: COc1ccc(N)cn1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: COc1ccc(N)c(I)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-methoxypyridine (10.0 g, 0.081 mol) was dissolved in EtOH (50 mL), and silver sulfate (27.6 g, 0.089 mol) and iodine (22.5 g, 0.089 mol) were added. The reaction was stirred at room temperature overnight, and then the mixture was filtered over Celite to remove solids. The filtrate was concentrated and purified on silica gel (0-50% EtOAc in hexanes) to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1/[CH:4]=[N:5]\[OH:6].[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[OH:6]/[N:5]=[C:4](\[Cl:11])/[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1]
Reactant: O/N=C\c1ccccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 250.9 %

Procedure:
To a solution of (E)- and/or (Z)-2-fluoro-benzaldehyde oxime (66.8 g, 480 mmol) in DMF (334 mL) was added N-chlorosuccinimide (29.4 g, 211 mmol) portionwise and after 10 min, keeping the temperature below 50° C., N-chlorosuccinimide (44.1 g, 317 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 2 h and then extracted with tert-butyl methyl ether to afford the title compound (91.9 g, 91%) which was obtained as a yellow oil. 1H-NMR (CDCl3): 7.10-7.25 (m, 2H), 7.40-7.50 (m, 1H), 7.64-7.70 (m, 3H), 8.99 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([OH:20])[CH2:19][CH2:18][C:13]4([O:17]CCO4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[CH3:22]O>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([O:20][CH3:22])[CH2:11][CH2:12][C:13](=[O:17])[CH2:18][CH2:19]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CO
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Agent: Cl
Product: COC1(c2ccc3c(c2)OCO3)CCC(=O)CC1
Yield: 70 %

Procedure:
A solution of 8-(1,3-Benzodioxol-5-yl)-1,4-dioxa-spiro[4.5]decan8-ol (5.0 g, 1.8 mmole) in 100 mL methanol with 1 mL conc. hydrochloric acid was stirred for 22 hr and the solution concentrated in vacuo. The residue was purified by chromatography on silica eluting with ethyl acetate-hexane (1:19) to give the product (70%, mp: 84°-85 ° C.).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=[S:28])[CH2:24][C:25](=O)[CH3:26])=[O:4].[C:29]([O:33][C:34]([N:36]([CH3:38])[NH2:37])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23](=[S:28])[CH2:24][C:25](=[N:37][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH3:38])[CH3:26])=[O:4]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(C)=NN(C)C(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-oxo-thiobutyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192 g) was reacted with N-methyl-hydrazinecarboxylic acid tert-butyl ester (CAS Reg. No. 21075-83-2) to give the title compound as off-white solid. MS (ESI): m/z=566.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:12])[NH:6][C:7](=[O:11])[N:8]([CH3:10])[CH:9]=1)([O-:3])=[O:2].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O>[C:18]([O:17][C:15](=[O:16])[CH2:14][N:6]1[C:5](=[O:12])[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]([CH3:10])[C:7]1=[O:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cn1cc([N+](=O)[O-])c(=O)[nH]c1=O
Solvent: O
Product: Cn1cc([N+](=O)[O-])c(=O)n(CC(=O)OC(C)(C)C)c1=O
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
Sodium hydride (0.51 g of a 60% dispersion in mineral oil, 13 mmol) was washed with pentane three times (4 mL each). The compound of Example 109 (2.00 g, 12 mmole) was added portionwise. After the addition was complete, the reaction mixture was stirred for 30 minutes under a nitrogen atmosphere. t-Butyl bromoacetate (1.73 g, 12 mmole) was added in one portion, and the solution was stirred for 3 hours. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water (3×50 mL), then brine, dried over magnesium sulfate. The solvent was concentrated, hexanes were added and the solvent was removed in vacuo to afford the title compound (1.97 g) in 59% yield. Rf=0.38 (silica gel, 20% ethyl acetate in dichloromethane.