Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.C([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])[CH2:12][CH2:11]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:13]1([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][O:20][C:19]2=[O:23])[CH2:14][CH2:15][NH:10][CH2:11][CH2:12]1
Reactant: O=C1OCCN1CCN1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C1OCCN1CCN1CCNCC1

Procedure:
291 g of 3-[2-(4-benzyl-1-piperazinyl)-ethyl]-2 -oxazolidinone dihydrochloride in 7 litres of methanol are hydrogenated in the presence of 70 g of palladium/carbon (5%) at 50° C and 10 atmospheres of hydrogen. The mixture is filtered and concentrated under reduced pressure. The residue is treated with sodium hydroxide, extracted with chloroform, filtered through diatomaceous earth and concentrated. There is obtained 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone as a yellow oil. The dihydrochloride of melting point 203° C (decomposition) is obtained by treatment with an excess of hydrochloric acid in methanol/ether.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[N:24][CH:25]=[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:27]=3)[C:22]3([CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:21]1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[N:24][CH:25]=[C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:27]=3)[C:22]3([CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH2:21]1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([C:42]([NH:41][CH3:40])=[O:43])[CH2:15][CH2:14]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(N3CC4(CCOCC4)c4ncc(N5CCOCC5)cc43)c2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1′-(5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinolin-4-yl)-6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (50 mg, 0.093 mmol) was dissolved in DCM (5.0 mL), and treated with methylisocyanate (5.50 μL, 0.093 mmol) and the reaction was stirred at rt for 2.5 h. After this time the reaction was concentrated to dryness and the residue was purified using an SCX column (compound loaded in MeOH and using 2M ammonia in MeOH as eluent) to give 4-(5,7-difluoro-3-methyl-4-(6′-morpholino-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]-1′(2′H)-yl)quinolin-2-yl)-N-methylpiperazine-1-carboxamide. 1H NMR (400 MHz, chloroform-d) δ ppm 7.55 (1H, d, J=2.3 Hz), 7.34 (1H, dt, J=9.8, 1.3 Hz), 6.75 (1H, ddd, J=11.8, 9.0, 2.4 Hz), 5.65 (1H, d, J=2.3 Hz), 4.69 (1H, q, J=4.2 Hz), 4.03-4.20 (2H, m), 3.80-3.97 (2H, m), 3.68-3.80 (4H, m), 3.48-3.67 (6H, m), 3.27-3.48 (4H, m), 2.90-3.04 (4H, m), 2.85 (3H, d, J=4.5 Hz), 2.19-2.39 (5H, m), 1.78 (1H, d, J=13.5 Hz), 1.69 (1H, d, J=13.5 Hz). Mass Spectrum (ESI) m/e=594.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]=O)=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl.[NH2:29][OH:30]>C(Cl)Cl>[Cl:1][C:2]1[C:3](/[CH:17]=[N:29]/[OH:30])=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)n1c(O)nc2ncc(Cl)c(C=O)c21
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)n1c(O)nc2ncc(Cl)c(/C=N/O)c21
Temperature: 60 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
6-Chloro-2-hydroxy-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridine-7-carbaldehyde (20 mg) was dissolved in 3 mL of CH2Cl2. DIEA (130 uL, 10 eq.) and hydroxylamine hydrochloride (51.5 mg, 10 eq.) were added, and the resulting solution was stirred at 60° C. for 2 h. The solvent was evaporated, and the crude was purified by reversed phase HPLC using an acetonitrile/water gradient to give 15 mg of the desired product in 71.4% yield. m/z=283.20 [M+H]+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc2nccc(Cl)c2c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2nccc(-c3ccncc3)c2c1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of 4-chloro-6-quinolinecarbaldehyde (3.24 g, 16.92 mmol), 4-pyridylboronic acid (3.12 g, 25.38 mmol), tetrakistriphenylphosphine palladium (0) (0.978 g, 0.846 mmol), and 2M aqueous K2CO3 (7.02 g, 50.76 mmol, 25.4 mls of 2M solution) in DMF (100 mL) was heated at 100° C. for 3.0 h and cooled to room temperature. The mixture was filtered through Celite and the Celite was washed with EtOAc. The filtrate was transferred to a separatory funnel, washed with water and saturated NaCl, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% MeOH:CH2Cl2) to give the title compound (2.03 g, 51%) as a tan solid. MS (ES)+ m/e 235 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[Cl:17][S:18](O)(=[O:20])=[O:19].O>S(Cl)(Cl)=O>[Cl:17][S:18]([C:15]1[C:2]([Cl:1])=[C:3]([Cl:16])[C:4]2[O:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][C:5]=2[CH:14]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOC(=O)C1Cc2cc(S(=O)(=O)Cl)c(Cl)c(Cl)c2O1
Yield: 101.6 %

Procedure:
To a solution (2.5 ml) of 1 g (3.83 mmol) of ethyl 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate (1) in 2.5 ml of thionyl chloride is dropwise added 1.25 g of chlorosulfonic acid under ice-cooling and the mixture allowed to react at room temperature for 2 hours. The reaction mixture is poured into iced water and extracted with 60 ml of ethyl acetate. The organic layer is dried and evaporated to give about 1.4 g of ethyl 5-chlorosulfonyl-6,7-dichloro-2,3-dihydrobenzofuran-carboxylate (2) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]1[CH2:9][O:8][C:7](=[O:10])[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:17][CH:18]([N:26]1[C@H:29]([SH:30])[C@H:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]1=[O:42])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O.C(OCC)(=O)C>[OH:17][CH:18]([N:26]1[C@H:29]([S:30][CH2:2][C:3]([CH:5]2[CH2:9][O:8][C:7](=[O:10])[CH2:6]2)=[O:4])[C@H:28]([NH:31][C:32](=[O:41])[CH2:33][O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:27]1=[O:42])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: O=C1CC(C(=O)CCl)CO1
Reactant: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(O)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SCC(=O)C1COC(=O)C1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
(RS)-4-Chloroacetyltetrahydrofuran-2-one (2.060 g, 12.6 mmol), followed by potassium carbonate (0.690 g, 5 mmol) were added to crude t-butyl (2RS)-2-hydroxy-[(3R,4R)-4-mercapto-3-phenoxyacetamidoazetidin-2-on-1-yl]acetate (3.866 g) (prepared as described in Example 1c) in acetone (10 ml). The reaction was stirred 1 h. then diluted with ethyl acetate, washed with water (x2) and brine, dried, concentrated and flash chromatographed on silica gel eluting with 50,60,75,90% ethyl acetate in hexane to provide the title compound as a foam (3.458 g, 68%), νmax (CH2Cl2) 3380, 1780, 1680, 1235, 1150 cm-1 ; [Mass spectrum: +ve ion (thioglycerol) MH+ (509)].
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OCC)(OCC)([O:19][CH2:20][CH3:21])[CH2:17][CH3:18]>CCCCCC>[CH2:20]([O:19][C:16](=[N:15][S:12]([C:10]1[S:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=1)(=[O:14])=[O:13])[CH2:17][CH3:18])[CH3:21]
Reactant: NS(=O)(=O)c1nc(-c2ccccc2)ns1
Reactant: CCOC(CC)(OCC)OCC
Solvent: CCCCCC
Product: CCOC(CC)=NS(=O)(=O)c1nc(-c2ccccc2)ns1
Temperature: 25 °C

Procedure:
A mixture of 3.0 g of 3-phenyl-1,2,4-thiadiazole-5-sulfonamide and 11 ml of triethyl orthopropionate was warmed in an oil bath at 80° for 4 hours. The mixture was cooled to room temperature and diluted with hexane (35 ml) and the precipitated solid was collected, washed with hexane and dried to give 3.3 g of solid, m.p. 98°-100°.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:7]([CH2:8][O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[N:6](C2C=CC(OC)=CC=2)[C:5]1=[O:23])=[N+:2]=[N-:3]>C(#N)C.O>[N:1]([C@H:4]1[C@@H:7]([CH2:8][O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH:6][C:5]1=[O:23])=[N+:2]=[N-:3]
Reactant: COC(=O)COC[C@@H]1[C@H](N=[N+]=[N-])C(=O)N1c1ccc(OC)cc1
Solvent: CC#N
Solvent: O
Product: COC(=O)COC[C@H]1NC(=O)[C@H]1N=[N+]=[N-]
Yield: 79.7 %

Procedure:
A solution of (±)-(cis)-[(3-azido-1-(4-methoxyphenyl)-2-oxo-4-azetidinyl)methoxy]acetic acid, methyl ester (2.054 g, 6.44 mmole) in acetonitrile (40 ml) was cooled to -5° C. A solution of ceric ammonium nitrate (10.62 g, 19.32 mmole) in water (30 ml) was added rapidly over ca. forty-five seconds. The reaction was warmed to +10° C. over fifteen minutes, diluted with water (100 ml), and extracted with ethyl acetate (two 80 ml portions). Sodium chloride was added to the aqueous layer which was again extracted with ethyl acetate (ca. 150 ml). The organic extracts were washed with saturated potassium bicarbonate, saturated sodium sulfite solution, brine, and dried (sodium sulfate). Filtration followed by solvent removal yielded 1.56 g of crude product which was chromatographed on silica gel (55 g, 230-400 mesh). Elution with 70% ethyl acetate-hexane yielded 1.1 g of the title compound as a heavy oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH2:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[N:11]1[CH:21]=[C:14]2[CH:15]=[N+:16]([O-])[CH:17]=[C:18]([F:19])[C:13]2=[N:12]1.P(Br)(Br)([Br:24])=O>C(Cl)Cl>[Br:24][C:15]1[C:14]2=[CH:21][N:11]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([CH:8]=[CH2:9])=[CH:5][C:4]=3[Cl:10])[N:12]=[C:13]2[C:18]([F:19])=[CH:17][N:16]=1
Reactant: O=P(Br)(Br)Br
Reactant: C=Cc1cc(Cl)c(-n2cc3c[n+]([O-])cc(F)c3n2)c(Cl)c1
Solvent: ClCCl
Product: C=Cc1cc(Cl)c(-n2cc3c(Br)ncc(F)c3n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.3 %

Procedure:
To a suspension of 2-(2,6-dichloro-4-vinylphenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5 oxide (1.0 g, 3.1 mmol) in DCM (15 mL) under an atmosphere of nitrogen at 0° C., was added phosphorus oxybromide (2.6 g, 9.0 mmol). The reaction mixture was stirred at 0° C. for 1 hour and then allowed to reach room temperature over 30 minutes. The resultant mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and diluted with DCM. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (304 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.41 (d, J=2.5 Hz, 1H), 8.19 (d, J=3.3 Hz, 1H), 7.99 (s, 2H), 6.85 (dd, J=17.6, 11.0 Hz, 1H), 6.25 (d, J=17.6 Hz, 1H), 5.60 (d, J=11.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:31])[C:13]2[CH:18]=[N:17][C:16](S(C)(=O)=O)=[N:15][C:14]=2[N:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:24]=1)=[O:10])[CH3:7]>>[CH2:6]([O:8][C:9]([C:11]1[C:12](=[O:31])[C:13]2[CH:18]=[N:17][C:16]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:14]=2[N:23]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:24]=1)=[O:10])[CH3:7]
Reactant: COCCN
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCOC)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 2-methoxy-ethylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (27 mg, 0.07 mmol). 8-Cyclohexyl-5-oxo-2-(2-methoxy-ethylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (20 mg, 80%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C19H26N4O4: 375.2 (M+H). Found: 375.2.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[N:9]([C:13]([C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][N:15]=2)[CH:10]=[CH:11][CH:12]=1)(=O)=O.[CH3:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[CH3:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:7]2[C:8]3[N:9]([C:13]([C:16]#[C:17][Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:14][N:15]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:30][CH:29]=1)(=[O:26])=[O:27]
Reactant: C[Si](C)(C)C#Cc1cnc2c(OS(=O)(=O)C(F)(F)F)cccn12
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: C[Si](C)(C)C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Temperature: 80 °C

Procedure:
A mixture of 3-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyridin-8-yl trifluoromethanesulfonate (0.329 g, 0.91 mmol), 0.186 (1.09 mmol) of 4-(methylsulfonyl)aniline, 0.083 g (0.091 mmol) of Pd2(dba)2, 0.087 g (0.181 mmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, and 0.385 g (1.81 mmol) of potassium phosphate in 8 mL of DME was heated at 80° C. in a sealed tube overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (triethylamine-treated silica gel; eluted with 0-80% EtOAc/hexanes) to provide 0.058 g of product: 384 m/z (M+H).
Reaction SMILES: [CH2:1]([C@@H:3]([C@@H:9]([OH:11])[CH3:10])[C:4](OCC)=[O:5])[CH3:2].[NH3:12]>C(O)C>[CH2:1]([C@@H:3]([C@@H:9]([OH:11])[CH3:10])[C:4]([NH2:12])=[O:5])[CH3:2]
Reactant: N
Reactant: CCOC(=O)[C@@H](CC)[C@H](C)O
Solvent: CCO
Product: CC[C@H](C(N)=O)[C@H](C)O
Yield: 85.5 %

Procedure:
(2S,3S)-Ethyl 2 ethyl-3-hydroxybutyrate (1 gram) was dissolved in 5 ml of absolute ethanol, followed by the addition of 0.5 gram of gaseous ammonia. The solution was kept in a stoppered flask, and the progress of the reaction was followed by thin layer chromatography. After the reaction was judged complete, the ethanol was evaporated and the resulting residue redissolved in ethyl acetate. Ammonia was removed by extraction with 1% HCl, and the ethyl acetate solution was dried over MgSO4, filtered, and rotary evaporated to leave 0.7 grams of (2S,3S)-2 ethyl-3-hydroxybutyramide.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH:18]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]4[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=4[CH:34]=3)[CH2:19]2)=[N:14]1.CCN(CC)CC.Br[CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45]>CN(C=O)C>[C:47]([O:46][C:44](=[O:45])[CH2:43][N:22]([CH:18]1[CH2:17][CH2:16][C:15]2[C:20](=[CH:21][N:13]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[N:4]=4)[N:9]=[CH:8][CH:7]=3)[N:14]=2)[CH2:19]1)[CH2:23][C:24]1[CH:25]=[CH:26][C:27]2[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1)([CH3:50])([CH3:49])[CH3:48]
Reactant: COc1ccc2nccc(-n3cc4c(n3)CCC(NCc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(N(CC(=O)OC(C)(C)C)Cc3ccc5c(c3)NC(=O)CS5)C4)c2n1
Temperature: 50 °C
Yield: 25.6 %

Procedure:
To a solution of 6-{[2-(6-methoxy-[1,5]naphthyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-5-ylamino]-methyl}-4H-benzo[1,4]thiazin-3-one (50 mg, 0.1 mmol) in DMF (600 μL) was added Et3N (19 μL, 0.13 mmol) and tert-butyl bromoacetate (19 μL, 0.13 mmol). The reaction mixture was heated at 50° C. overnight. The crude was purified directly by basic reverse phase HPLC to afford 15 mg (24%) of the title compound. MS (ESI): exact mass calculated for C31H34N6O4S, 586.24; m/z found, 587.23 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]2[C:22](=[O:25])[NH:23][N:24]=[C:14]2[C:13]2[CH:26]=[CH:27][CH:28]=[N:29][C:12]1=2)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[H-].[Na+].Cl[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36]>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:36][N:35]([CH2:34][CH2:33][N:23]1[C:22](=[O:25])[N:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:11]([C:9](=[O:10])[CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[C:12]3[N:29]=[CH:28][CH:27]=[CH:26][C:13]=3[C:14]2=[N:24]1)[CH3:37]
Reactant: CCCN(CCC)CC(=O)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CCCN(CCC)CC(=O)N1c2ccccc2-n2c(nn(CCN(C)C)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 21, to 2,9-dihydro-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling with (2-chloroethyl)dimethylamine in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-[(dimethylamino)ethyl]-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.
Reaction SMILES: [CH3:1][NH2:2].Cl.C[Al](C)C.[N:8]1[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:9]=1[C:18]([O:20]C)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][NH:2][C:18]([C:9]1[N:8]=[CH:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=1)=[O:20]
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Yield: 104.6 %

Procedure:
To a stirred solution of MeNH2.HCl (173 mg, 5.12 mmol) in toluene (5 mL) at 0° C., was added AlMe3 (2 M solution in Hexanes, 1.28 mL, 2.56 mmol). After 30 minutes the solution was canulated into a stirred solution dimethyl pyridine-2,5-dicarboxylate (500 mg, 2.56 mmol) in DCM (5 mL) at 0° C. before stirring over night at room temperature. An aliquot was taken and analysed by NMR, indicating that there was a 0.8:1 ratio of product to starting material. MeNH2.HCl (173 mg, 5.124 mmol) and AlMe3 (2M solution in Hexanes, 1.28 mL, 2.56 mmol) were added and the reaction stirred for 12 hours. The reaction was quenched by addition of H2O (2 mL) and extracted with EtOAc (2×10 mL). The organics were combined, dried (MgSO4), filtered and concentrated at reduced pressure to give the title compound (520 mg, quant. yield) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:15])=[N:4][CH:5]=[C:6]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O[CH:38](OCC)[CH2:39][NH2:40])C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:15])=[N:4][CH:5]=[C:6]([N:8]2[CH:38]=[CH:39][N:40]=[C:9]2[C:10]([F:13])([F:12])[F:11])[CH:7]=1
Reactant: CCOC(CN)OCC
Reactant: O=C(Nc1cnc(Cl)c(Br)c1)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1nccn1-c1cnc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
3-Bromo-2-chloro-5-trifluoroacetamidopyridine (0.53 g, 1.75 mmol) and triphenylphosphine (550 mg, 2.10 mmol) in carbon tetrachloride (50 ml) was refluxed for 16 hrs and then cooled to 0° C. Aminoacetaldehyde diethyl acetal (0.25 ml, 1.72 mmol) was added and the mixture stirred at 0° C. for 1 hr, then at 22° C. for 2 hrs. After concentration in vacuo, acetic acid (4 ml) was added and the mixture refluxed for 7 hrs, then cooled. Ethyl acetate (20 ml) was added and the resulting solution was washed with sodium hydroxide solution (50 ml, 2M) and brine (50 ml) before being dried (MgSO4) and concentrated. The residue was purified by silica chromatography to give the product as yellow solid (104 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:9]([C:11]3[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12.[CH:28](=[C:30](/[C:38]1[C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][N:40]([CH2:52][CH2:53][N:54]([CH3:62])[C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[N:39]=1)\[CH:31]=[CH:32]/[C:33]([N+:35]([O-:37])=[O:36])=C)\[CH3:29]>>[OH:18][CH2:17][C:13]1[CH:12]=[C:11]([C:9]2[N:8]([S:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)(=[O:20])=[O:21])[C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:42]4[C:38]([C:30]5[CH:31]=[CH:32][C:33]([N+:35]([O-:37])=[O:36])=[CH:29][CH:28]=5)=[N:39][N:40]([CH2:52][CH2:53][N:54]([CH3:62])[C:55](=[O:61])[O:56][C:57]([CH3:59])([CH3:58])[CH3:60])[CH:41]=4)=[C:3]3[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: C=C(/C=C\C(=C/C)c1nn(CCN(C)C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1)[N+](=O)[O-]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2cccc(CO)c2)cc2c(Br)ccnc21
Product: CN(CCn1cc(-c2ccnc3c2cc(-c2cccc(CO)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1)C(=O)OC(C)(C)C

Procedure:
Following the procedure described for Intermediate 100 using {3-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methanol and 1,1-dimethylethyl {2-[3-[(1E,2Z)-1-ethylidene-4-nitro-2,4-pentadien-1-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}methylcarbamate provided the title compound. ESMS [M+H]+: 709.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([O:17][CH2:16][C:13]1[CH:12]=[C:11]([C:18]([OH:20])=[O:19])[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][CH:14]=1)=[O:32]
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(=O)O)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2C(=O)O)c1
Temperature: 12.5 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a 0° C. mixture of 29.1 (2.2 g, 7.9 mmol) in THF (20 mL) was added pyridine (1.56 g, 19.8 mmol) followed by pivaloyl chloride (0.96 g, 7.9 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The resulting solution was stirred at 0-25° C. overnight and was then quenched with water and treated with 2.0 N HCl (15 mL). The mixture was extracted with EtOAc (3×30 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL). After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-65% EtOAc/hexanes for elution gave 29.2 as white solid (1.60 g, 56%).