Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH3:14])=[C:8]([O:15][CH3:16])[C:7]=1[OH:17])=[O:5].[K].Br[CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([O:17][C:7]1[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[CH:10]=[C:11]([CH3:12])[C:6]=1[C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:22])[CH2:26][CH2:27][CH3:28]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(O)c1OC
Reactant: CCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCOc1c(OC)c(OC)cc(C)c1C(=O)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 2,6-dichloro-3',4'-dimethoxy-2'-hydroxy-6'-methyl-benzophenone, potassium salt (1.13 g; 3 mmol), 1-bromobutane (0.69 g, 5 mmol) and dimethyl formamide (5 ml) are stirred at 100° C. for 8 h, and concentrated in vacuo. The residue is dissolved by shaking with a toluene/water mixture, after separation, the organic layer is collected washed with water and dried. After addition of silica gel (5 g), the solvent is evaporated. A flash chromatography column is packed with silica gel (25 g) and the charged silica gel is layered on top of that. Elution with petrol ether/ethyl acetate (95/5, 500 ml) gives the title compound, 0.82 g, (69% y) as colourless crystals, mp. 70° C.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19]3[CH:18]=[N:17][C:16]([C:20]([O:22]CC)=O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1.ClC1C(F)=C(C(F)=CC=1)CN1C2C=NC([C:45]([NH:47][OH:48])=O)=CC=2C2C1=CC=CC=2>>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:19]3[CH:18]=[N:17][C:16]([C:20]([N:47]([OH:48])[CH3:45])=[O:22])=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:4][CH:3]=1
Reactant: O=C(NO)c1cc2c3ccccc3n(Cc3c(F)ccc(Cl)c3F)c2cn1
Reactant: CCOC(=O)c1cc2c3ccccc3n(Cc3ccc(F)cc3)c2cn1
Product: CN(O)C(=O)c1cc2c3ccccc3n(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound can be prepared from ethyl 9-(4-fluorobenzyl)-9H-β-carboline-3-carboxylate under the similar conditions as those in steps (a) and (b) of example 7. 1H NMR (400 MHz, CD3OD): δ 8.60–8.95 (2H, m), 8.32 (1H, d, J=8 Hz), 7.60–7.75 (2H, m), 6.95–7.45 (5H, m), 5.76 (2H, s), 3.48 (3H, s). HRMS (M+H)+ found: 350.1297. Calcd for C20H17FN3O2: 350.1305.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH3:28]>>[F:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH2:28])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Product: CS(=O)(=O)c1cc(F)c2c(c1)O[C@@H](CN)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2R)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.7 g, 1.7 mmol), NH3 (6 ml, 7N in methanol) was heated under microwave radiation at 120° C. for 20 min. The product was evaporated to dryness and was purified on an SCX-3 column (TEA/MeOH) Yield 0.34 g. MS m/z (rel. intensity, 70 eV) 261 (M+, bp), 217 (49), 97 (39), 69 (55), 56 (79).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1[nH]cnc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Br)ncn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
To a solution of ethyl 4-bromo-1H-imidazole-5-carboxylate (400 mg, 1.83 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL) was added sodium hydride (100 mg, 4.17 mmol, 1.00 equiv) in portions. The reaction was stirred at room temperature for 20 min then [2-(chloromethoxy)ethyl]trimethylsilane (300 mg, 1.80 mmol, 1.00 equiv) was added. The resulting solution was stirred at room temperature for 5 h and then diluted with 50 mL of ethyl acetate. The mixture was washed with 3×10 mL of brine then the organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to give 330 mg (52%) of ethyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate as a colorless oil. 1H-NMR (300 MHz, CDCl3): δ 7.69 (s, 1H), 5.67 (s, 2H), 4.43-4.36 (m, 2H), 3.58 (t, J=10.8 Hz, 2H), 1.45-1.40 (m, 3H), 0.94 (t, J=10.8 Hz, 2H), 0.05 (s, 9H) ppm.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)[CH2:13][N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7][N:6]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:4].[OH-].[Li+].Cl>C1COCC1.CO>[C:39]([O:38][C:36]([N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=5)=[CH:22][CH:21]=4)[CH2:13][N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7]1)=[O:37])([CH3:42])([CH3:40])[CH3:41]
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)Oc2cc3c(cc21)CC(C(=O)O)N(C(=O)OC(C)(C)C)C3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester was dissolved in THF:methanol (4:1). 2 N lithium hydroxide (0.5 mL) was added and the resulting reaction mixture was stirred at room temperature for 4 hours. Excess 1N HCl was added and the mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to afford the product in pure form (122 mg).
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH:23]=[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.CCOCC>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:20][CH:21]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
tert-Butyl {(1R,3S)-3-isopropyl-3-[(4-phenyl-3,6-dihydropyridin-1(2H)-yl)carbonyl]cyclopentyl}carbamate (0.23 g, 0.56 mmol) was dissolved in a 1.0 M solution of HCl in ether (4 mL). After being stirred at room temperature for 2 h, the solution was concentrated to give a colorless oil (170 mg). MS calculated for C20H28N2O: (M+H) 313; found 313.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:12])[C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:14][CH:15]=O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:12])[C:9]2[S:10][CH:14]=[CH:15][N:11]=2)=[CH:6][CH:7]=1
Reactant: O=CCCl
Reactant: CN(C(N)=S)c1ccc(F)cc1
Solvent: CCO
Product: CN(c1ccc(F)cc1)c1nccs1

Procedure:
A solution of 2.0 g (11 mmol) of 1-(4-fluorophenyl)-1-methylthiourea in 20 mL of EtOH was treated with 4.1 mL (33 mmol) of a 50% (w/v) aqueous solution of chloroacetaldehyde and heated at reflux for 18 h. The solvent was removed in vacuo and the residue purified by flash chromatography eluting with a linear gradient of 10% EtOAc in hexane to 100% EtOAc to deliver the title compound. MS (M+H)+ 209.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:14](=[O:16])[CH3:15])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)[CH:10]=1)=[O:16]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: CC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)cs1
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1cc(-c2ccc(C(F)(F)F)cc2)cs1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(4-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is purified by silica-gel chromatography.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[N:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[N:10]=1.CCN(C(C)C)C(C)C.O>CS(C)=O>[CH3:18][O:17][C:11]1[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:9]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])[N:10]=1
Reactant: C[C@H]1COCCN1
Reactant: COc1cc(OC)nc(Cl)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(OC)nc(N2CCOC[C@@H]2C)n1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution of (S)-3-methylmorpholine (4.86 g, 48.0 mmol), 2-chloro-4,6-dimethoxypyrimidine (6.98 g, 40 mmol) and DIPEA (8.36 mL, 48.0 mmol) in DMSO (40 mL) was heated at 100° C. in a sealed flask for 22 h, and then allowed to cool to room temperature. The reaction mixture was placed in an ice bath, and water (120 mL) was added drop-wise. The mixture was decanted and the gummy precipitate was dissolved in ethyl acetate. The ethyl acetate solution was washed with brine, dried with MgSO4, filtered and concentrated by rotary evaporation to give the title compound (8.58 g, 90%). 1H NMR (400 MHz, CDCl3) δ 5.40 (s, 1 H), 4.69 (qd, J=6.8, 3.1 Hz, 1 H), 4.33 (dd, J=13.7, 2.9 Hz, 1 H), 4.01-3.93 (m, 1 H), 3.86 (s, 6 H), 3.78-3.73 (m, 1 H), 3.73-3.66 (m, 1 H), 3.54 (ddd, J=12.2, 11.4, 3.1 Hz, 1 H), 3.25 (ddd, J=13.5, 12.4, 3.8 Hz, 1 H), 1.29 (d, J=6.8 Hz, 3 H). m/z (APCI+) for C11H17N3O3 240.0 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[CH3:25])[NH2:21]>C(O)(C)C>[ClH:2].[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[O:15][CH3:16])[N:6]=[CH:5][N:4]=[C:3]2[NH:21][C:20]1[CH:22]=[CH:23][C:24]([CH3:25])=[C:18]([OH:17])[CH:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(C)c(O)c3)c2cc1OC
Temperature: 25 °C
Yield: 56.4 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinazoline hydrochloride (130 mg, 0.5 mmol), (prepared as described for the starting material in Example 2), and 3-hydroxy-4-methylaniline (62 mg, 0.5 mmol) in isopropanol (7 ml) was heated at reflux for 2 hours. The mixture was allowed to cool to ambient temperature, the precipitated solid was collected by filtration, washed with isopropanol and ether and dried to give 6,7-dimethoxy-4-(3-hydroxy-4-methylanilino)quinazoline hydrochloride (98 mg, 56%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Nc1ccc(O)cc1C(=O)O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Nc1ccc(O)cc1C(=O)Nc1ccccc1Cl
Yield: 11.5 %

Procedure:
Prepared according to Procedure A using 2-amino-5-hydroxybenzoic acid (5.0 g, 32.7 mmol) and SOCl2 (6.0 mL, 81.6 mmol) in benzene (150 mL), followed by 2-chloroaniline (6.9 mL, 65.4 mmol) and CHCl3 (150 mL). The product was purified by two chromatographies in MeOH/CH2Cl2 to provide 990 mg of a brown solid (12%). 1H NMR (MeOH-d4) δ: 7.92 (dd, J=1.6, 8.1 Hz, 1H); 7.48 (dd, J=1.5, 7.7 Hz, 1H); 7.34 (dt, J=1.5, 7.7 Hz, 1H); 7.20 (dt, J=1.7, 7.7 Hz, 1H); 7.16 (d, J=2.7 Hz, 1H); 6.83 (dd, J=2.7, 8.7 Hz, 1H); 6.76 (d, J=8.7 Hz, 1H); [6.24 (br s, 2H)). MS (ES): m/z 263.0 (M+).
Reaction SMILES: [C:1]([NH:8][C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.N1C=CC=CC=1.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:26]([O:14][C:13]([C:9]1([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:12][CH2:11][CH2:10]1)=[O:15])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1(C(=O)OCc2ccccc2)CCC1
Reaction time: 16 h

Procedure:
To a solution of 2.0 g N-Boc-1-aminocyclobutane carboxylic acid in 100 ml dichloromethane were added 2.1 g EDC, 1.4 g DMAP, 2.2 ml pyridine and 4.8 ml benzyl alcohol. After stirring for 16 h the mixture was diluted with dichloromethane and washed with 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by chromatography on silica using heptane/ethyl acetate 2/1 as eluent.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:11](=[O:13])[CH3:12])=[CH:6][N:5]=1.Br>C(O)(=O)C>[Br:1][CH2:12][C:11]([C:7]1[CH:8]=[C:9]([Cl:10])[C:4]([NH2:3])=[N:5][CH:6]=1)=[O:13]
Reactant: CC(=O)c1cnc(N)c(Cl)c1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: Nc1ncc(C(=O)CBr)cc1Cl
Reaction time: 2 h
Yield: 74.2 %

Procedure:
16 g (0.1 mol) of bromine are added dropwise to a solution of 17.05 g (0.1 mol) of 2-amino-3-chloro-5-acetylpyridine in a mixture of 19.3 g of hydrogen bromide (47% strength aqueous solution; 0.11 mol) and 500 ml of glacial acetic acid. The mixture is subsequently stirred for two hours, brought to pH 8 and extracted with ethyl acetate. Drying and evaporation gives 18.5 g (74%) of the title compound, melting point 134° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16](I)=[N:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)CO.[C:34]1([SH:44])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>C(OCC)(=O)C.[Cu]I.CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([S:44][C:34]2[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH:37]=[CH:36][CH:35]=2)=[N:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(I)c23)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(Sc4cccc5ccccc45)c23)CC1
Temperature: 25 °C
Yield: 45 %

Procedure:
A mixture of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-3-iodo-1H-indazole (0.068 g, 0.159 mmol), copper(I) iodide (0.005 g, 0.024 mmol) and potassium carbonate (0.044 g, 0.318 mmol) are added to a screw-capped test tube with a Teflon-lined septum. The tube is evacuated and backfilled with argon and this procedure repeated twice more. The reaction mixture is treated sequentially with 2-propanol (1.5 mL), ethylene glycol (19 μL, 0.318 mmol) and 1-naphthalenethiol (0.051 g, 0.318 mmol), heated at 130°–140° C. for 8 h, cooled to room temperature, diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure. The resultant crude material is purified by flash chromatography (silica gel, 40:60 ethyl acetate/hexanes) to afford the title compound as a colorless oil, 0.033 g (45% yield), identified by NMR and mass spectral analyses.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:34][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:30][CH:31]=[CH:32][N:33]=5)[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.C(N(CC)CC)C.[C:43]([N:47]=C=O)([CH3:46])([CH3:45])[CH3:44]>CO>[C:43]([NH:47][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:34][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:33][CH:32]=[CH:31][N:30]=5)[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)NC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into the solution of 4-{4-[3-(1H-imidazol-2-yl)-phenylamino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (59.4 mg, 0.118 mmol) in methanol (1.0 mL) was added HCl in methanol (9 M, 11.0 mL). The above mixture was stirred at rt for 4 h. After that time, the mixture was concentrated in vacuo and was then suspended in DMF (2 mL). Into the above suspension were added triethylamine (159 μL, 1.18 mmol) and tert-butyl isocyanate (14.8 μL, 0.130 mmol). The above mixture was stirred at rt under an atmosphere of N2 for 1 h. After that time, the mixture was concentrated in vacuo to obtain brown oil that was purified by HPLC to yield the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.35 (s, 9H), 2.55 (brs, 2H), 3.59 (t, 2H, J=4.2 Hz), 4.05 (brs, 2H), 6.28 (brs, 1H), 6.65 (s, 1H), 7.13 (d, 2H, J=1.2 Hz), 7.42 (t, 1H, J=8.4 Hz), 7.55 (dd, 1H, J=0.8 & 7.6 Hz), 7.74 (dd, 1H, J=0.8 & 8.0 Hz), 7.75-8.19 (m, 1H), 8.23 (d, 1H, J=1.2 Hz). MS (ES+): m/z 457.12 (100) [MH+]. HPLC: tR=2.00 min (ZQ2000, polar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.Cl.[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([NH:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:7][C:4]2[S:5][CH:6]=[C:2]([Br:1])[CH:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)NC(=O)C1CCNCC1
Reactant: O=Cc1cc(Br)cs1
Agent: Cl
Product: CC(C)(C)NC(=O)C1CCN(Cc2cc(Br)cs2)CC1

Procedure:
The title compound is prepared according to the reaction 3.01c described above using 4-bromo-thiophene-2-carbaldehyde and piperidine-4-carboxylic acid tert-butylamide hydrochloride as in 3.01c: LC-MS A: tR=0.65 min; [M+H]+=360.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:22])=[C:8]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:22])=[C:8]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH:9]([OH:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C)c(-c3ccc(OC)nc3)c(=O)oc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)OC(O)C(c1ccc(OC)nc1)=C2C
Reaction time: 1 h

Procedure:
A solution of 7-methoxy-3-(6-methoxy-pyridin-3-yl)-4-methyl-chromen-2-one (430 mg, 1.45 mmol, 1 eq) in toluene (5 mL) was cooled to −78° C. in a 100 mL 3-neck round bottom flask under nitrogen. To the reaction mixture was slowly added a toluene solution of diisobutylaluminum hydride (1.5 mL of 1.0 M, mmol, 1.1 eq), with the temperature of the reaction mixture maintained at less than −70° C. The reaction was stirred for 1 hour, quenched with addition of methanol (0.5 mL). The resulting solution was diluted with dichloromethane, the solution washed with a saturated solution of Rochelle salt, then washed with brine, dried on anhydrous sodium sulphate, filtered and evaporated to yield the crude compound as a yellow solid. The solid was purified by column chromatography using a hexane:ethyl acetate mixture (1:1) to yield the title product as a yellow solid.
Reaction SMILES: C(O[Si](OCC)(OCC)CCC[S:8][S:9][CH2:10][CH2:11][CH2:12][Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C.[S]>>[CH2:21]([O:20][Si:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[CH2:12][CH2:11][CH2:10][S:9][S:8][S:8][S:9][CH2:10][CH2:11][CH2:12][Si:13]([O:14][CH2:15][CH3:16])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])[CH3:22]
Reactant: CCO[Si](CCCSSCCC[Si](OCC)(OCC)OCC)(OCC)OCC
Agent: [S]
Product: CCO[Si](CCCSSSSCCC[Si](OCC)(OCC)OCC)(OCC)OCC

Procedure:
47.5 g of bis-[γ-(triethoxysilyl)-propyl]-disulfide (0.1 mole) was heated together with 6.2 g of sulfur (0.2 mole) in a nitrogen gas atmosphere for about 50 hours at 160°C, until all of the sulfur had gone into solution and did not crystallize out again when the solution was cooled. A dark red, viscous solution was formed, which a thin-layer chromatograph shows to contain no more free sulfur, and which, according to mass spectrometric analysis, contains a small amount of pentasulfide in addition to disulfides and trisulfides.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.Br[CH2:16][CH:17]1[CH2:19][CH2:18]1>>[CH:17]1([CH2:16][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH2:19][CH2:18]1
Reactant: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Reactant: BrCC1CC1
Product: Cc1cc2c(C(F)(F)F)cccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.2 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.16 (t, J=8.2 Hz, 1H), 6.45 (s, 1H), 4.02 (d, J=6.4 Hz, 2H), 2.48 (s, 3H), 1.18 (m, 1H), 0.56 (m, 2H), 0.34 (m, 2H); MS (ES) m/z 254 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])N(C)[C:3]=1[C:11](NC)=[O:12].CC1OC=C(O)C(=[O:19])C=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO>[OH-].[Na+].O>[OH:12][CH2:11][C:3]1[O:19][C:5]([CH3:9])=[CH:6][C:7](=[O:8])[C:2]=1[O:1][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CNC(=O)c1c(O)c(=O)cc(C)n1C
Reactant: Cc1cc(=O)c(O)co1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1

Procedure:
3-Hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide has been prepared by the method, described in examples 45 to 48, 53, and 58 of WO98/54318. Allomaltol (1) is converted to 2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) according to the procedure described in FR1516463. The 2-(1-hydroxymethyl)-6-methylpyromeconic acid (2) is reacted with benzyl bromide in sodium hydroxide in a 10:1 mixture of methanol and water to give the 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (3) which is then oxidized with diemthyl sulfoxide and sulfur trioxide.pyridine complex to give 2-formyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (4). Oxidation of the 2-formyl derivative with sulfamic acid and sodium hypochlorite in acetone and water affords 2-carboxyl-3-benzyloxy-6-methyl-pyran-4(1H)-one (5). The 2-carboxyl derivative is reacted with dicyclohexyldiimide and 2-mercaptothiazoline and 4-dimethylaminopyridine to give the 3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione (6) which is reacted with methylamine in tetrahydrofuran to give 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7). The 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (7) is converted to 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide (8) with methylamine in alcohol. The 3-benzyloxy derivative was deprotected with hydrogenation using Pd/C in dimethylformamide as illustrated in Scheme 1 to give 1,6-dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-)N-methyl)-amide (9):