Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20]([CH3:35])=[CH:21][C:22]([NH:27]C(=O)OC(C)(C)C)=[N:23][C:24]=2[O:25]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[Si](I)(C)(C)C>C(#N)C>[NH2:27][C:22]1[NH:23][C:24](=[O:25])[C:19]([CH2:18][NH:17][C:15]([C:4]2[C:5]3[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=[C:2]([Br:1])[CH:3]=2)=[O:16])=[C:20]([CH3:35])[CH:21]=1
Reactant: COc1nc(NC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Cc1cc(N)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
To a stirred solution of tert-butyl (5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)carbamate (0.80 g, 1.467 mmol) in acetonitrile (20 mL) was added dropwise at RT TMSI (0.50 ml, 3.67 mmol). A reflux condenser was attached and the reaction was purged with N2 and heated to 70° C. After stirring for 30 minutes LCMS indicated that the reaction was complete (89% pure with 11% possible iodinated side product as the only other impurity). After 1 hr the reaction was quenched with MeOH (5 mL) and stirred for 30 minutes. The clear brown solution was evaporated to dryness under vacuum, taken up in CH2Cl2, washed with aq. Na2S2O3, (a ppt. formed that was filtered off), dried (Na2SO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-10g, 0 to 7% (5% NH4OH/MeOH) in CH2Cl2) gave the product N-((6-amino-4-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamide (59.6 mg, 0.138 mmol, 9.4% yield) as a white solid. Note: The ppt. that was filtered off during the aq. Na2S2O3 wash was later shown to contain product. This solid was washed with water and dried under vacuum to give additional product as an off-white solid (602 mg, 1.4 mmol, 95%, 100% pure by LCMS). 1H NMR (400 MHz, DMSO-d6) δ=10.59 (br. s., 1H), 8.13 (t, J=4.4 Hz, 1H), 7.76 (d, J=1.5 Hz, 1H), 7.33 (s, 1H), 6.99 (d, J=1.5 Hz, 1H), 5.83 (br. s., 2H), 5.19 (s, 1H), 4.74 (dt, J=6.6, 13.3 Hz, 1H), 4.22 (d, J=4.8 Hz, 2H), 2.14 (s, 3H), 2.11 (s, 3H), 1.39 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 431.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].[F:14][C:15]([F:20])([F:19])[CH2:16][CH2:17]I>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:17][CH2:16][C:15]([F:20])([F:19])[F:14])[N:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: FC(F)(F)CCI
Product: CCOC(=O)c1c([N+](=O)[O-])cnn1CCC(F)(F)F
Yield: 31 %

Procedure:
The product was obtained according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and 1,1,1-trifluoro-3-iodo-propane as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 68 mg (15%) of the desired regioisomer and 141 mg (31%) of 4-nitro-2-(3,3,3-trifluoropropyl)-2H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].B(O)(O)[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCO.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[C:11]2[C:16]([C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCCCOC(=O)c1nc(Br)c2ccccc2c1OCc1ccccc1
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: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCOC(=O)c1nc(-c2ccc(C)cc2)c2ccccc2c1OCc1ccccc1
Reaction time: 4 h
Yield: 105.8 %

Procedure:
4-Benzyloxy-1-bromo-isoquinoline-3-carboxylic acid butyl ester (207 mg, 0.5 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) were dissolved in THF (3 ml) and the solution was stirred for 10 min before a solution of p-tolylboronic acid (68 mg, 0.5 mmol) in EtOH (0.5 ml) and a solution of Na2CO3 (106 mg, 1 mmol) in water (0.5 ml) were added. The resulting mixture was refluxed with stirring for 4 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (2 ml) and the mixture was extracted with EtOAc (10 ml). The organic phase was dried over MgSO4 and evaporated in vacuo to give a yellowish oil (225 mg). Purification by flash column chromatography on silica gel using hexanes:EtOAc=94:6 as the eluent gave the title compound as a colorless oil; MS-(+)-ion: M+1=426.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[O:7][C:8]=1[CH2:9]O.C(N(CC)CC)C.CS([Cl:32])(=O)=O>ClCCl>[Cl:32][CH2:9][C:8]1[O:7][C:6]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[N:5][C:4]=1[CH2:3][O:2][CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: COCc1nc(C=Cc2ccc(OC)cc2)oc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc(C=Cc2ccc(OC)cc2)oc1CCl
Temperature: 25 °C

Procedure:
420 mg {4-Methoxymethyl-2-[2-(4-methoxy-phenyl)-vinyl]-oxazol-5-yl}-methanol were dissolved in 5 ml dichloromethane and cooled in an ice bath. 0.32 ml triethylamine were added, followed by the addition of 141 μl methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. 50 ml dichloromethane were added and the reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 491 mg 5-chloromethyl-4-methoxymethyl-2-[2-(4-methoxy-phenyl)-vinyl]-oxazole as an oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.[CH2:11]1CCCCC1.CI>C1COCC1>[Br:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[CH3:11]
Reactant: C1CCCCC1
Reactant: Brc1csc2cccnc12
Solvent: CI
Solvent: C1CCOC1
Product: Cc1sc2cccnc2c1Br
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
674 mg of 3-Bromo-thieno[3,2-b]pyridine (3.15 mmol) is dissolved in 12 ml of dry THF and cooled to −78° C. 2.3 ml of LDA-mono-tetrahydrofuran (1.5 M) solution in cyclohexane (3.46 mmol) is added to the mixture at −78° C. and stirred at −78° C. for 20 min. 0.22 ml of methyliodide (3.46 mmol) is added to the mixture and stirred at −78° C.→room temperature for 2 h. the reaction mixture is quenched by sat. NH4Cl and extracted with CH2Cl2. The separated CH2Cl2 is dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt:2 M NH3 in MeOH=20:4:1) to give 618 mg of the title compound. Yield 86%. mass spectrum (m/e): 230 (M+1); 1H-NMR (CDCl3): 8.78 (dd, 1H, J=4.8 Hz, 1.4 Hz), 8.10 (dd, 1H, J=8.2 Hz, 1.4 Hz), 7.30 (dd, 1H, J=8.2 Hz, 4.8 Hz), 2.67 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8](I)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1.[CH:22]([N:25]1[C:29](B(O)O)=[CH:28][CH:27]=[N:26]1)([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[C:3]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([C:29]3[N:25]([CH:22]([CH3:24])[CH3:23])[N:26]=[CH:27][CH:28]=3)=[C:7]([C:11]([NH:13][CH3:14])=[O:12])[C:6]=2[CH:15]=1
Reactant: CC(C)n1nccc1B(O)O
Reactant: CNC(=O)c1c(I)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccnn2C(C)C)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Temperature: 100 °C
Yield: 44.4 %

Procedure:
To a solution of 5-bromo-2-iodo-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.12 mmol), (1-isopropyl-1H-pyrazol-5-yl)boronic acid (23 mg, 0.12 mmol) and Na2CO3 (22 mg, 0.25 mmol) in 1,4-dioxane (0.5 mL) and water (0.05 mL) was added Pd (dppf)Cl2 (10 mg) under nitrogen. The mixture was heated at 100° C. for 4 hour and filtered through the Celite pad. The filtrate was extracted with EtOAc, and then the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by the prep-TLC (PE:EA=1:1) to give 5-bromo-2-(1-isopropyl-1H-pyrazol-5-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (25 mg, yield: 50%). 1H-NMR (CDCl3, 400 MHz) δ 8.50 (s, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 6.58 (d, J=2.0 Hz, 1H), 5.74 (d, J=3.6 Hz, 1H), 4.45˜4.52 (m, 1H), 3.28 (s, 3H), 3.04 (s, 3H), 2.82 (d, J=4.8 Hz, 3H), 1.51 (s, 6H). MS (M+H)+: 469/471.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1>C1COCC1>[OH:1][C:2]1[C:3]([C:12]([N:28]2[CH2:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27]2)=[O:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc2cccnc2c1O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (189 mg, 1.0 mmol) and di(1H-imidazol-1-yl)methanone (162.2 mg, 1.0 mmol) in THF (10 mL) was heated to reflux for 4 h, under nitrogen. The reaction mixture was allowed to cool to RT and isoindoline (95.3 mg, 0.80 mmol) was added. The resulting mixture was stirred at RT for 3 h and then left to stand at RT overnight. The reaction mixture was then quenched with H2O and an aqueous saturated solution of sodium hydrogen carbonate, and twice extracted with DCM. The separated organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by SPE-SI cartridge (2 g, DCM to DCM:MeOH 99:1) affording the title compound (123 mg, 0.42 mmol) as a light brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:14]=O>>[CH2:14]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]([C:10]([OH:12])=[O:11])[NH:1]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cl
Product: O=C(O)C1Cc2ccccc2CN1

Procedure:
Phenylalanine (75 g) was refluxed with 488 ml of concentrated HCl and 165 ml of formalin for 30 minutes. Then a further 165 ml of HCl and 75 ml of formalin were added and the mixture refluxed for six more hours. After cooling, it was filtered, washed with a small amount of methanol, and dried overnight in a vacuum oven. This material was then treated for an hour with refluxing isopropanol and filtered after cooling to give 28 gms.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:21][CH2:20]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C1CCN(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: C1CCNC1
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NC(=O)N1CCC(N2CCCC2)CC1

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-(4-oxopiperidin-1-ylcarbonyl)aminobenzamide (100 mg, 0.268 mmol) and pyrolidine (0.045 mL, 0.54 mmol) yielded the title compound.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-])=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:14]=1[NH:20][CH:2]=[CH:1]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(Cl)ccc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc(OCc2ccccc2)c2[nH]ccc12
Temperature: -40 °C
Reaction time: 2 h

Procedure:
M Vinyl magnesium bromide solution in tetrahydrofuran (80 ml) was added to a stirred solution of 2-benzyloxy-5-chloronitrobenzene (5.28 g, 20 mmol) in tetrahydrofuran (160 ml) at -40° C. The mixture was stirred for 2 hours at -40° C. then poured onto saturated ammonium chloride solution (500 ml) and extracted with ether. The extract was dried and evaporated and the residue was chromatographed on silica in ethyl acetate-hexane (1:8) to give a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:25]([O-])([N+]([O-])=O)=[O:26]>>[Cl:1][CH2:2][CH2:3][N:4]([N:25]=[O:26])[C:5]([N:7]([CH2:19][CH:20]1[O:24][CH2:23][CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(CC1CCCO1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: O=NN(CCCl)C(=O)N(CC1CCCO1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 72.7 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-tetrahydrofurfuryl-3-(D-galactopyranosyl)urea and 6 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.9 g of 1-(2-chloroethyl)-1-nitroso-3-tetrahydrofurfuryl-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:23]1[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=1.O1CCOCC1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:23]2[S:27][C:26]([S:28](=[O:30])(=[O:29])[NH2:31])=[CH:25][CH:24]=2)[CH:6]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc(S(N)(=O)=O)s2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (272 mg, 0.33 mmol), 3-methoxycarbonylphenylboronic acid (898 mg, 4.99 mmol), and tripotassium phosphate (1.41 g, 6.64 mmol) were added to a solution of commercially available 5-bromothiophene-2-sulfonamide (805 mg, 3.33 mmol) in mixture of 1,4-dioxane (10 mL) and DMF (1 mL), followed by stirring at 85° C. overnight in an argon atmosphere. The reaction solution was concentrated. A saturated aqueous solution of sodium chloride was added to the residue, followed by extraction with methylene chloride and drying over anhydrous sodium sulfate. The solvent was distilled off, and methanol was added to the residue. The precipitated solid was filtered off. The residue obtained by distilling the solvent off was subjected to purification by silica gel column chromatography to obtain 3-(5-sulfamoyl-2-thienyl)benzoic acid methyl ester (529 mg, 1.78 mmol) (yield: 53%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[CH:6])[CH3:2].[CH:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][OH:16])=[CH:12][CH:13]=1.CN1CCOCC1>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])/[CH:5]=[CH:6]/[O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: OCCc1ccccc1
Reactant: C#CC(=O)OCC
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: CCOC(=O)/C=C/OCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
The reaction was performed in standard glassware under an atmosphere of N2. To 100 ml of diethylether were added 9.8 g (0.1 mol) of propiolic acid ethyl ester, 12.2 g (0.1 mol) phenylethanol and 10.1 g (0.1 mol) of N-methylmorpholine. This solution was kept without stirring at room temperature for 24 hours. The mixture was evaporated under vacuum and the residue purified by bulb to bulb distillation (bp: 70-75° C., 0.006 mbar) to yield 15.7 g (88%) of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[CH2:12]([O:14][C:15]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[C:16]#[CH:17])[CH3:13].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.ClCCl>[CH3:11][S:8]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:17]#[C:16][C:15]([O:18][CH2:19][CH3:20])([O:14][CH2:12][CH3:13])[O:21][CH2:22][CH3:23])[CH:7]=1)(=[O:10])=[O:9]
Reactant: C#CC(OCC)(OCC)OCC
Reactant: CS(=O)(=O)c1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1cncc(S(C)(=O)=O)c1)(OCC)OCC
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A solution of 3-bromo-5-methanesulfonyl-pyridine (1.00 g, 4.20 mmol), 3,3,3-triethoxypropyne (1.75 g, 9.4 mmol), dichlorobis(triphenylphospine)palladium(II) (0.15 g, 0.21, mmol), copper(I)iodide (0.08 g, 0.42 mmol), triethylamine (1.80 mL, 12.7 mmol) and dichloromethane (40 mL) was heated at reflux for 48 h. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The crude product was chromatographed on silica (30% ethyl acetate/hexanes) to give the title compound (1.2 g, 87% yield) as yellow solid. 1H NMR (CDCl3) δ 9.08(d, 1H, J=2.4 Hz), 8.91 (d, 1H J=2.0), 8.28 (t, 1H, J=2.0 Hz), 3.75 (q, 6H, J=7.2), 3.13 (s, 3H), 1.29 (t, 9H, J=7.2).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH:5]([C:8]2[N:9]=[CH:10][C:11]([NH:14]C(=O)OC(C)(C)C)=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Cl>CO>[NH2:14][C:11]1[N:12]=[CH:13][C:8]([CH:5]2[CH2:6][NH:7][C:2](=[O:1])[CH2:3][CH2:4]2)=[N:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(C2CCC(=O)NC2)cn1
Agent: Cl
Solvent: CO
Product: Nc1cnc(C2CCC(=O)NC2)cn1
Temperature: 70 °C

Procedure:
A mixture of tert-butyl 5-(6-oxopiperidin-3-yl)pyrazin-2-ylcarbamate (60 mg, 0.205 mmol) and conc HCl (1 mL) in methanol (2 mL) was heated with 70° C. oil bath for 1 hour and the reaction mixture was cooled down, concentrated to dryness and the residue was redissolved in methanol (3 mL), and to it was added NaHCO3 (200 mg), and the mixture was heated with 70° C. oil bath for 2 h. The solid suspension of reaction mixture was removed by filtration, and the filtrate was concentrated and a light yellow solid was obtained as crude 5-(5-aminopyrazin-2-yl)piperidin-2-one which was used directly in next step without further purification. LCMS (m/z): 193.1 (MH+), 0.22 min.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:25]([F:31])=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27]>O1CCOCC1.C(#N)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[C:24]([Cl:23])[C:25]=3[F:31])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Nc1cccc(Cl)c1F
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OCc1ccccc1
Temperature: 80 °C
Yield: 95.7 %

Procedure:
4.0M HCl in Dioxane (4.0 ml) was added to a stirred suspension of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline (60 g, 0.2 mol) [prepared as described in WO98/13354, Example 1] and 3-chloro-2-fluoroaniline (31.96 g, 0.22 mol) in acetonitrile (1200 mL). The reaction mixture was heated at 80° C. for 1 hour then left to stand O/N. Acetonitrile (500 mL) was added and the resulting precipitate filtered, washed with Acetonitrile (3×500 mL) and dried under vacuum to give 7-(benzyloxy)-N-(3-chloro-2-fluorophenyl)-6-methoxyquinazolin-4-amine hydrochloride 2 as a beige solid (85.45 g, 96%); 1H NMR Spectrum: (DMSO d6) 4.02 (s, 3H), 5.35 (s, 2H), 7.30-7.60 (m, 9H), 7.65 (m, 1H), 8.38 (s, 1H), 8.85 (s, 1H), 11.8 (s, 1H); Mass Spectrum: (M+H)+ 410.27.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[NH3:15]>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]2[C:5](=[C:7]([S:11]([NH2:15])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: Cc1nc2c(S(=O)(=O)Cl)cccc2s1
Reactant: N
Solvent: C1CCOC1
Product: Cc1nc2c(S(N)(=O)=O)cccc2s1
Temperature: 25 °C

Procedure:
A solution of 18 g of the product from Example 1 in 170 mL of tetrahydrofuran was cooled to 0° C. under an atmosphere of nitrogen and treated with 5 mL of anhydrous ammonia. The mixture was stirred at room temperature for about an hour, filtered to remove the ammonium chloride, and the filtrate concentrated in vacuo to give an off-white solid. This crude product was purified by silica gel chromatography; elution with ethyl acetate-hexanes (3:1) gave 1.9 g of 2-methyl-4-benzothiazolesulfonamide as a white powder, m.p. 236°-239° C.; NMR (DMSO-d6 /CDCl3): δ 2.95 (3H, s), 7.0 (2H, br s, SO2NH2), 7.55 (1H, t, J=8 Hz), 8.0 (1H, dd, J=2, 8 Hz), 8.2 (1H, dd, J=2, 8 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([CH3:7])[NH2:6])=[O:4].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>>[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26](/[C:29](=[N:6]/[N:5]([CH3:7])[C:3]([NH:2][CH3:1])=[O:4])/[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1
Reactant: CNC(=O)N(C)N
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: CNC(=O)N(C)/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 21 %

Procedure:
The title compound was prepared from N,1-dimethylhydrazine carboxamide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 21% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (dd, 1H), 8.31 (d, 1H), 8.06 (m, 2H), 7.97 (d, 1H), 7.77 (d, 1H), 7.73 (s, 1H), 7.47 (q, 1H), 6.90 (q, 1H), 4.59 (s, 2H), 3.19 (s, 3H), 2.68 (d, 3H), 2.37 (s, 3H). LCMS (method B): [MH]+=406, tR=2.27 min.
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NCCC)[N:3]1[CH:22]([C:27]([CH3:29])=[CH2:28])[C:23]([O:25][CH3:26])=[O:24].[ClH:30]>C(Cl)Cl>[Cl:30][C:27]1([CH3:29])[CH:22]([C:23]([O:25][CH3:26])=[O:24])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17][CH2:28]1
Reactant: Cl
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNCCC
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-propylaminothio-α-isopropenylazetidine-1-acetate (0.43 g) was dissolved in dried methylene chloride. To this solution was added 5% methanolic hydrochloric acid (2 ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off and the residue was subjected to column chromatography on silica gel using chloroform as developing solvent to give oily methyl 3-chloro-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (310 mg).