Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH2:16][CH:17]([CH2:31][C:32]1([F:37])[CH2:36][CH2:35][CH2:34][CH2:33]1)[C:18]([NH:20][C:21]1([CH:26]([C:28](=[O:30])[NH2:29])[OH:27])[CH2:24][CH:23]([F:25])[CH2:22]1)=[O:19].C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]1([CH:26]([C:28](=[O:30])[NH2:29])[OH:27])[CH2:22][CH:23]([F:25])[CH2:24]1)[CH2:31][C:32]1([F:37])[CH2:36][CH2:35][CH2:34][CH2:33]1)[CH3:15]
Reactant: CCOC(=O)Cl
Reactant: NC(=O)C(O)C1(NC(=O)C(N)CC2(F)CCCC2)CC(F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(N)=O)CC(F)C1
Yield: 68.9 %

Procedure:
Diisopropylethylamine (0.087 mL, 0.5 mmol) and ethyl chloroformate (0.024 mL, 0.25 mmol) were added to a stirred solution of the amine A1-b, 2-amino-N-[1-(carbamoyl-hydroxy-methyl)-3-fluoro-cyclobutyl]-3-(1-fluorocyclopentyl)-propionamide (0.23 mmol) in DMF. After 15 min sat. aq. NaHCO3 and DCM were added and the organic layer was collected and concentrated and purified on flash silica gel column using DCM-MeOH 0-10% which gave the title compound (62 mg) [M+1]+391.9.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(Cl)CCl.CCN(CC)CC.[CH3:21][C:22](O)([CH3:24])[CH3:23]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1CCOCC1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Tetrahydro-2H-pyran-4-carboxylic acid (10 g, 77 mmol) and EDC (17.68 g, 92 mmol) were added to a flask, followed by DCM (200 ml). To the resulting suspension was added Et3N (16 ml, 115 mmol), tBuOH (16.1 ml, 169 mmol) and DMAP (9.39 g, 77 mmol). The reaction mixture was stirred at 40° C. for 18 hr. The reaction mixture was diluted with DCM (100 Ml) and washed with 1N NaOH (1×100 Ml) followed by 1M citric acid solution (1×100 Ml). The organic layer was dried over sodium sulfate, filtered and concentrated to afford tert-butyl tetrahydro-2H-pyran-4-carboxylate. 1H NMR (500 MHz, CDCl3) δ 3.90 (dt, 2H), 3.37 (dt, 2H), 2.38 (septet, 1H), 1.77-1.67 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1.[C:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:28]([N:31]1[CH2:36][CH2:35][N:34]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=4[N:18]([CH3:27])[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])=[N:5][CH:4]=2)[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CCl)s3)cc12
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(Cc2cnc(-c3cc4c(C)ccc(N(C)S(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.15 g) and N-acetylpiperazine (90 mg) in N,N-dimethylformamide (10 ml) was added potassium carbonate (120 mg) under ice-cooling, and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1-7:3), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (95 mg, yield 52%) as colorless crystals. melting point 171-172° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][C@@H:16]1[CH2:20][O:19][C:18]([CH3:22])([CH3:21])[O:17]1.N>CO>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][C@@H:16]2[CH2:20][O:19][C:18]([CH3:21])([CH3:22])[O:17]2)=[C:2]([Cl:1])[N:10]=1
Reactant: CC1(C)OC[C@@H](COn2cnc3c(Cl)nc(NC=O)nc32)O1
Agent: N
Solvent: CO
Product: CC1(C)OC[C@@H](COn2cnc3c(Cl)nc(N)nc32)O1

Procedure:
A solution of (S)-6-chloro-9-(2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)-2-formamidopurine (400 mg, 1.22 mmol) in methanol (10 ml) and 0.88 ammonia (10 ml) was stirred at 25° C. for 4 h. The solution was evaporated under reduced pressure and the residue chromatographed on silica, eluting with ethyl (2,2-dimethyl-1,3-dioxolan-4-ylmethoxy)purine (270 mg, 74%) as a white Solid; m.p. 118°-120° C. υmax (KBr) 3450, 3320, 3210, 1650, 1630, 1620, 1560, 1510 and 1470 cm-1 ; δH(CDCl3) 1.36(3H,S,CH3), 1.42(3H,S,CH3), 3.85(1H,m,CH2OCMe2), 4.14(1H,m,CH2OCMe2), 4.43(3H,m,CH+CH2ON), 5.51 (2H,br.s,D2O exchangeable, NH2), 8.00(1H,S,H-8). Found: C, 44.45; H, 4.69; N, 23.31%; M+ 299.0795; C11H14ClN5O3 requires C, 44.08; H, 4.71; N, 23.37%; M+ 299.0785.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O:19]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20]1.[H-].[Na+]>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:25][CH2:24][CH:21]2[CH2:22][CH2:23][O:19][CH2:20]2)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(CCl)cc1-c1ccccc1
Reactant: OCC1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCC2CCOC2)cc1-c1ccccc1
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A solution of the product of Example 287A (2.09 g, 8.00 mmol) and tetrahydro-3-furanmethanol (0.990 g, 9.60 mmol) in DMF (4 mL) was added to a mixture of NaH (6.40 g, 16.0 mmol) (rinsed with THF just prior to use), KI (1.33 g, 9.00 mmol), and Bu4NBr (2.60 g, 0.800 mmol). An exothermic reaction including gas evolution was observed. The mixture was stirred for 30 minutes and then heated at 130° C. for 3.5 hours. The reaction mixture was quenched with by the addition of a few drops of methanol and then treated with H2O (50 mL). The mixture was extracted with a 2:1 mixture of ether and ethyl acetate, followed by ether (2×). The combined organic extracts were rinsed with H2O (4×) and brine, dried (MgSO4), and concentrated under reduced pressure. Flash column chromatography (20% ethyl acetate-hexane) afforded 0.406 g (14.5%) of a 1.6:1 mixture of the methyl and tetrahydro-3-furanmethyl esters, respectively.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:13][N:14](B(N(C)C)N(C)C)[CH3:15].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC=CC=1P>[CH3:13][N:14]([CH3:15])[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CN(C)B(N(C)C)N(C)C
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)c1ccc(OC(F)(F)F)cc1
Yield: 29.3 %

Procedure:
A mixture of 1-bromo-4-(trifluoromethoxy)benzene (2.41 g), tris(dimethylamino)borane (1.43 g), sodium t-butoxide (1.34 g), tris(dibenzylideneacetone)dipallidium (18 mg), and o-tolylphosphine (12 mg) in toluene (30 ml) was heated under reflux for 4 h. The mixture was cooled, diluted with water (30 mL) and extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane/EtOAc (99:1 increasing to (95:5) to give the title compound as an oil (600 mg). 1H NMR (360 MHz, CDCl3) δ2.95 (6 H, s), 6.66 (2 H, d, J 9 Hz), and 7.08 (2 H, d, J 8.5 Hz). m/z (ES+) m/z 206 (M+1).
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19]O)=[C:9]1[CH3:21])(=[O:7])=[O:6]>CS(C)=O.O1CCCC1>[CH3:4][S:5]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][C:1]#[N:2])=[C:9]1[CH3:21])(=[O:7])=[O:6]
Reactant: COc1ccc2c(c1)c(CO)c(C)n2S(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC#N)c(C)n2S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of potassium cyanide (3.0 g, 46.1 mmol) in methyl sulfoxide (16 ml) and tetrahydrofuran (4 ml) at 0° C. was added a solution of (1-methanesulfonyl-5-methoxy-2-methyl-1H-indol-3-yl)-methanol (0.26 g,) in tetrahydrofuran (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 8 hours and then kept at 4° C. for 72 hours. The mixture was partitioned between ethyl acetate and water, and the organic extract was washed with brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 50 to 70% ethyl acetate in hexane) to give (1-methanesulfonyl-5-methoxy-2-methyl-1H-indol-3-yl)-acetonitrile as a white solid, (0.2 g, 13% in 2 steps). 1H NMR (CDCl3) δ: 2.58 (s, 3H), 3.03 (s, 3H), 3.71 (s, 2H), 3.88 (s, 3H), 6.93-6.99 (m, 2H), 7.91 (dd, 1H, J=8.9 Hz, 0.6 Hz).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.Br[C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=1[CH3:55].[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][N:66]([C:48]2[CH:53]=[C:52]([F:54])[CH:51]=[CH:50][C:49]=2[CH3:55])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:57])[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Cc1ccc(F)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.4 %

Procedure:
In a 50 ml round bottom flask equipped with a magnetic stir bar and fitted with a nitrogen inlet, the XPhos (210.80 mg, 0.44 mmol) and the cesium carbonate (1.80 g, 5.52 mmol) were combined dry. This mixture was taken up in 1,4-dioxane (10.00 ml, 116.91 mmol) and the 2-bromo-4-fluoro-1-methyl-benzene 16a (1.04 g, 5.53 mmol) was added followed by the piperazine-1-carboxylic acid tert-butyl ester 16b (514.80 mg, 2.76 mmol). The mixture was stirred together under vacuum at room temperature for 10 min and then the system was flushed with nitrogen. The palladium(II) acetate (62.10 mg, 0.28 mmol) was added to the reaction in one portion and the reaction was warmed to 100° C. and was allowed to stir under nitrogen overnight. The reaction was cooled to room temperature and filtered through Celite, washing with ethyl acetate. The collected product solution was then concentrated under reduced pressure and the product was purified from the resultant dark brown oil using silica gel column chromatography, eluting a gradient of 100% heptanes to 50% ethyl acetate in heptanes. 4-(5-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 16c (451.00 mg, 1.53 mmol) was isolated as an off-white solid. LCMS (m/e)=295 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH2:11]>C1COCC1>[CH3:10][NH:11][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(Cl)n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nccc(C#N)n1
Reaction time: 8 h

Procedure:
2-Chloro-4-pyrimidinecarbonitrile (14.1 g, 101 mmol, prepared according to the procedure of Daves et. al J. Het. Chem. 1964, 1, 130-132) in 100 ml THF was cooled to 0° C. Reaction progress was monitored as aliquots of methylamine solution (in THF, 2.0 M, Aldrich) were added dropwise over the course of 1 h (58 ml +15 ml +15 ml). The mixture was stirred overnight. Additional methylamine solution (15 ml) was added very slowly, and the reaction was stirred 10 min. After concentration, the residue was extracted with EtOAc (400 ml) and saturated aqueous NaHCO3 (15 ml), and the organic layer was washed with 100 ml brine. The combined aqueous layers were extracted with EtOAc again (200 ml), and this organic layer was washed with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The orange solid was packed into a filtration apparatus, and submerged in just enough MeOH to cover the material (15 ml). Orange liquid was allowed to drain by gravity, then under high vacuum. The solid was washed in the same manner with t-BuOMe (15 ml). 2-Methylamino-pyrimidine-4-carbonitrile was obtained as peach-colored “fly-away” crystals. MS: 135.0 (M+1); Calc'd. for C6H6N4—134.14.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[C:39]2[CH:43]=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO.N1CCCCC1>[CH2:26]([O:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[NH:41][CH:40]=[C:39]2/[CH:43]=[C:7]1\[O:8][C:4]2[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2c(OCc3ccccc3)cccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4c(OCc5ccccc5)cccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.050 g, 0.14 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 7-benzyloxy-1H-indole-3-carboxaldehyde (0.035 g, 0.14 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with a mixed solvent of chloroform and methanol to obtain tert-butyl (Z)-4-[(2-{[7-(benzyloxy)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.049 g, 61%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1>>[CH:13]1([CH2:16][CH2:17][NH:18][C:19]([C:21]2[N:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([C:7]4[CH:6]=[CH:5][O:4][C:3]=4[C:2]([F:1])([F:12])[F:11])=[O:10])[CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[O:20])[CH2:15][CH2:14]1
Reactant: O=C(O)c1ccoc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccoc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-trifluoromethylfuran-3-carboxylic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (71% yield). 1H NMR (300 MHz, CDCl3) δ 8.04, 7.96, 7.56, 7.00, 6.54, 3.9-3.7, 3.6-3.5, 1.49, 0.79-0.66, 0.47-0.41, 0.09-0.04. 13C NMR (300 MHz, CDCl3) δ 161.78, 160.01, 145.60, 145.05, 138.14, 137.57, 127, 15, 121.74, 120.54, 112.54, 110.88, 46.33, 44.59, 41.43, 39.67, 34.52, 8.64, 4.23. MS (ES+) m/z 438.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:14][CH2:15][Cl:16]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:14][CH2:15][Cl:16])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: ClCCn1cc(Br)cn1
Temperature: 60 °C
Yield: 87.1 %

Procedure:
4-bromopyrazole (700 mg, 4.76 mmol, available from Aldrich), cesium carbonate (2328 mg, 7.14 mmol) and 1-bromo-2-chloroethane (0.592 ml, 7.14 mmol, available from Acros) were suspended in N,N-Dimethylformamide (DMF) (14 ml) and heated to 60° C. under microwave conditions in an Emrys Optimiser for 1 hour. The mixture was partitioned between water (20 ml) and ethyl acetate (60 ml). The aqueous layer was run off and the organic washed (water 3×10 ml), brine (10 ml)), dried (magnesium sulfate) and evaporated to dryness to give the desired product (868 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:10]=3[NH:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[C:13]2[O:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:17][C:10]=3[N:9]=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc2c(c1)NCc1cccc(OC)c1O2
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc2c(c1)N=Cc1cccc(OC)c1O2
Yield: 90.6 %

Procedure:
A mixture of 2 g of ethyl 10,11-dihydro-4-methoxydibenz-[b,f][1,4]oxazepine-8-carboxylate, 2 g of chloranil and 30 ml of xylene was refluxed for 3 hours, and the solvent was distilled off under vacuum. The residue was subjected to chromatography on silica gel to give 1.8 g of ethyl 4-methoxydibenz[b,f][1,4]oxazepine-8-carboxylate. The melting point and elemental analysis of the product were the same as those of a mixture with the product obtained in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](OC)=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13].[H-].[Na+].BrC1C=CC(OC)=CC=1O.C[O:27][CH2:28][Br:29]>CN(C=O)C>[Br:29][CH2:28][O:27][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH2:11][O:12][CH3:13]
Reactant: COCBr
Reactant: COCOc1cc(OC)ccc1Br
Agent: COc1ccc(Br)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1OCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
1-Bromo-4-methoxy-2-methoxymethoxybenzene. To a suspension of NaH (2.5 g, 0.06 mol) in dry DMF (100 mL) at 0° C. was added solution of 1-bromo-2-hydroxy-4-methoxybenzene (10.6 g, 0.05 mol). After stirring at 0° C. for 30 min. bromomethyl methyl ether (7.8 g, 0.06 mmol) were dropwise added. The mixture was warmed to room temperature over 20 min. and then stirred for 2 h, it was then quenched cautiously by the addition of cold dilute HCl and extracted with EtOAc. The EtOAc extract was washed successively with; H2O, 5% aqueous NaHCO3, H2O and finally brine. After drying (MgSO4) filtration and evaporation gave liquids. The product was purified by distillation (85° C., 0.2 mm Hg) to give the title compound as a colorless oil (13.7 g, 97%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:13][CH2:12][CH2:11][C:7]2[N:6]=[C:5]3[CH2:4][O:3][C:2](=[O:1])[C:10]3=[CH:9][CH:8]=2)[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: CN1CCN(CCCc2ccc3c(n2)COC3=O)CC1
Yield: 83.6 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (63 mg, 0.33 mmol) and 1-methylpiperazine (33 mg, 0.33 mmol) are reacted to provide the title compound as white solid (76 mg, 84%).
Reaction SMILES: [N+:1](C1C=C(S(Cl)(=O)=O)SC=1)([O-])=O.[N+:13]([C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1)([O-])=O.N>CC(C)=O>[NH2:13][C:16]1[S:20][C:19]([S:21]([NH2:1])(=[O:23])=[O:22])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1csc(S(=O)(=O)Cl)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Agent: N
Solvent: CC(C)=O
Product: Nc1ccc(S(N)(=O)=O)s1
Reaction time: 0.5 h

Procedure:
A solution of 11.3 g (49.6 mmol) of a mixture that consists of 4-nitro-thiophene-2-sulfonyl chloride and 5-nitro-thiophene-2-sulfonyl chloride (ratio: 1.4/1.0) in acetone is added while being stirred to a saturated solution of ammonia in 170 ml of acetone at −35° C. After 30 minutes, the batch is filtered and concentrated by evaporation. The crude product is dissolved without further purification in 100 ml of ethanol. It is mixed with 6 g of Raney nickel and hydrogenated for 8 hours under low pressure at room temperature. The batch is filtered and concentrated by evaporation. 11.7 g of a mixture that consists of 4-amino-thiophene-2-sulfonic acid amide and 5-amino-thiophene-2-sulfonic acid amide is obtained at a ratio of 2:1, which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7](=[O:13])[N:8]([CH3:12])[S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][Si:23]([CH2:26][CH2:27][O:28][CH2:29]Cl)([CH3:25])[CH3:24].O>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:29][O:28][CH2:27][CH2:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[C:7](=[O:13])[N:8]([CH3:12])[S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CN1C(=O)Nc2ccc(Br)cc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(COCC[Si](C)(C)C)c2ccc(Br)cc2S1(=O)=O
Temperature: 75 °C
Reaction time: 4 h

Procedure:
To a solution of compound 42a (616 mg, 2.10 mmol) in DMF (5 mL) was added K2CO3 (1.0 g, 7.2 mmol) and SEM-Cl (563 μL, 3.17 mmol). The resulting mixture was stirred at 75° C. for 4 h, allowed to cool to rt and treated with water (20 mL). The reaction mixture was then extracted with DCM (3×20 mL). The combined DCM layers were dried over Na2SO4, filtered, and concentrated to obtain a residue which was purified by flash column chromatography on silica gel (0-50% EtOAc/hexanes) to obtain compound 42b. 1H-NMR (400 MHz, CDCl3) δ (ppm): 7.99 (d, J=2.0 Hz, 1H), 7.74 (dd, J=9.1, 2.5 Hz, 1H), 7.51 (d, J=9.1 Hz, 1H), 5.42 (s, 2H), 3.71-3.77 (m, 2H), 3.35 (s, 3H), 0.91-0.98 (m, 2H), 0.01 (s, 9H).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:10]([CH:12]([CH:14]([C:24]([NH2:26])=[O:25])[C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH3:13])[CH:11]=1.[OH-].[Na+].[BrH:35]>O.[Cu]Br>[Br:35][C:6]1[CH:7]=[CH:8][C:9]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:10]([CH:12]([CH:14]([C:24]([NH2:26])=[O:25])[C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH3:13])[CH:11]=1
Reactant: Br
Reactant: CC(c1cc(N)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(c1cc(Br)ccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 0.072 gm (1.05 m mol) of sodium nitrite in 0.5 ml of water was added dropwise at an internal temperature of 0° to 5° C. to 0.40 gm (1.05 m mol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid in 2 ml of semi-concentrated aqueous hydrobromic acid. The thus obtained diazonium salt solution was then added dropwise to 0.196 gm of copper-(I) bromide in 2 ml of 48% hydrobromic acid, whereby strong formation of gas occurred. The reaction mixture was stirred for 1.5 hours at an internal temperature of 45° to 50° C., cooled, and adjusted to pH 4 by means of 4N sodium hydroxide solution. After extraction with warm ethyl acetate, the extract was washed with water, dried, and filtered. After evaporation in vacuo, the residue obtained was purified by column chromatography on silica gel (chloroform/methanol=7:1).