Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[C:44]3[CH:45]=[CH:46][S:47][C:43]=3[CH2:42][CH2:41][NH:40]2)=[CH:35][CH:34]=1>ClCCl.CN(C)C=O.O>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:39]2[C:44]3[CH:45]=[CH:46][S:47][C:43]=3[CH2:42][CH2:41][N:40]2[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:37][CH:38]=1
Reactant: Clc1ccc(C2NCCc3sccc32)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCc2sccc2C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
Benzoic acid (46 mg, 0.38 mmol) and 1-hydroxybenzotriazole (55 mg, 0.41 mmol) were dissolved in a mixture of dichloromethane (1 mL) and N,N-dimethylformamide (0.5 mL). N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol) was added and the mixture was shaken 0.5 hour at room temperature. 4-(4-Chlorophenyl)4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.38 mmol) dissolved in dichloromethane (0.5 ml) was added and the mixture was shaken at 1000 rpm for 3 hours. Water (1 mL) was added and the mixture was shaken at 1000 rpm overnight at room temperature. The organic phase was evaporated to give 129 mg (97%) of the title compound as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:24]=[CH:25][CH:26]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[S:30][CH:31]=[C:27]([C:23]4[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[CH:22]=4)[N:28]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4cccc(F)c4)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 72 h
Yield: 40.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (273 mg, 0.835 mmol), 1-[4-(3-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 137 mg (40.8%) of the desired product as a solid.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1.O1CCOCC1.C(Cl)(Cl)Cl>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-n2cccn2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-n2cccn2)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-4-(1H-pyrazol-1-yl)benzamido)-4-phenylbenzoate (0.098 g) in ethyl acetate (2 mL), methanol (1 mL), and dioxane (1 mL), 10% palladium-carbon (49 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Chloroform was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: chloroform] to obtain tert-butyl 2-(2-hydroxy-4-(1H-pyrazol-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: C[Al](C)C.[I:5][C:6]1[N:15]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:9]2=[N:10][CH:11]=[C:12]([NH2:14])[CH:13]=[C:8]2[CH:7]=1.[F:25][C:26]1[C:35]([N:36]([S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])[S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])=[CH:34][CH:33]=[C:32]([F:49])[C:27]=1[C:28](OC)=[O:29]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:25][C:26]1[C:35]([N:36]([S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[S:43]([CH2:46][CH2:47][CH3:48])(=[O:44])=[O:45])=[CH:34][CH:33]=[C:32]([F:49])[C:27]=1[C:28]([NH:14][C:12]1[CH:13]=[C:8]2[CH:7]=[C:6]([I:5])[N:15]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:17])=[O:18])[C:9]2=[N:10][CH:11]=1)=[O:29]
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)OC)c1F)S(=O)(=O)CCC
Reactant: Nc1cnc2c(c1)cc(I)n2S(=O)(=O)c1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
Trimethylaluminum (0.51 mL, 1.01 mmol, 2.0M solution in toluene) was added dropwise via a syringe to a cold (0° C.) suspension of 2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.135 g, 0.338 mmol) in toluene (10 mL). The cold bath was removed and the mixture was stirred at room temperature for 20 minutes. Methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (0.149 g, 0.372 mmol) was added, and the reaction mixture was heated to 90° C. under N2 for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) 30% Aqueous potassium sodium tartrate solution (50 mL) was carefully added, and the resulting emulsion was stirred at room temperature for 30 minutes. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 2,6-difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(N-(propylsulfonyl)propylsulfonamido)benzamide (0.225 g, 87%) as a foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=1.P([O-])(OCC)(SCC)=[S:14]>C1COCC1.O>[C:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])(=[S:14])[NH2:11]
Reactant: COC(=O)c1cccc(C#N)c1
Reactant: CCOP([O-])(=S)SCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(C(N)=S)c1
Temperature: 80 °C
Yield: 102.4 %

Procedure:
Preparation H1, Step 2: A solution of 2 g (0.01 mol) of methyl-3-cyanobenzoate in 32 ml of THF and 8 ml of water was charged with 2.3 g (0.012 mol) of diethyl dithiophosphate and heated at 80° C. for 24 h. THF was removed and the residue was taken in ethyl acetate. The extract was washed with water and concentrated to afford methyl 3-carbamothioylbenzoate (2.0 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C(NC(C)C)(C)C.[O:13]=[C:14]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:19]=2[CH:18]=[CH:17][C:16]2[CH:30]=[CH:31][CH:32]=[CH:33][C:15]1=2.C(I)C>CCCCCC.CO.O.CCOCC.CN(C)P(=O)(N(C)C)N(C)C.O1CCCC1>[O:13]=[C:14]1[C:20]2[CH:21]=[CH:22][C:23]([CH:25]([CH2:1][CH3:2])[C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:19]=2[CH:18]=[CH:17][C:16]2[CH:30]=[CH:31][CH:32]=[CH:33][C:15]1=2
Reactant: [Li]CCCC
Reactant: COC(=O)Cc1ccc2c(=O)c3ccccc3ccc2c1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(C(=O)OC)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
1.075 Ml. of 1.6 molar n-butyllithium in hexane is added to a solution of 0.242 ml. of diisopropylamine in 15 ml. of dry tetrahydrofuran. 0.300 Ml. of hexamethylphosphoric triamide is added and the mixture is cooled to about -60° C. 0.465 G. of methyl (5-oxo-5H-dibenzo[a,d]-cyclohepten-2-yl)acetate is added, and after 15 minutes, 0.137 ml. of ethyl iodide is added. The mixture is warmed slowly to room temperature and a further 0.05 ml. of ethyl iodide is added. After 30 minutes an additional 0.05 ml. of ethyl iodide is added. After 30 minutes, a few drops of methanol are added, and then ether and water are added. The organic layer is washed with water, dilute hydrochloric acid and saturated sodium chloride solution, then dried and evaporated to yield the impure product, which, after chromatography on 40 g. silica gel, eluting with hexane:ether (5:1) affords methyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyrate. 0.326 G. of methyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyrate is refluxed for 4 hours in 10 ml. of methanol and 20 ml. of water containing 0.5 g. of sodium hydroxide. The mixture is cooled, washed with ether and acidified with dilute hydrochloric acid. The product is extracted with ether and the extract washed, dried and evaporated to yield 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyric acid.
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH3:11][C:12]1[N:19]2[C:15]([S:16][CH:17]=[CH:18]2)=[CH:14][N:13]=1.[OH-].[Na+]>ClCCl.O>[CH:4]([C:14]1[N:13]=[C:12]([CH3:11])[N:19]2[CH:18]=[CH:17][S:16][C:15]=12)=[O:5]
Reactant: Cc1ncc2sccn12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1nc(C=O)c2sccn12
Temperature: 0 °C

Procedure:
DMF (8 ml) was added to 40 ml of dichloromethane. The mixture was cooled in an argon atmosphere to 0° C. A solution of 9 ml of phosphorus oxychloride in 40 ml of dichloromethane was added dropwise thereto. Further, a solution of 1.2 g of 5-methylimidazo[5,1-b]thiazole in 20 ml of dichloromethane was added dropwise thereto. The mixture was heated under reflux for 5 hr. The reaction solution was poured into iced water, and then adjusted to pH 10 by the addition of an aqueous sodium hydroxide solution. The mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate. The solvent was then concentrated under the reduced pressure. The residue was purified by chromatography on silica gel to give 1.5 g of 7-formyl-5-methylimidazo[5,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>C(Cl)Cl>[Br:35][CH2:14][CH2:13][CH2:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1cc(C(F)(F)F)ccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Cl)c(CCCBr)c1
Yield: 94.3 %

Procedure:
Compound 57-2 (6.32 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (7.64 g) and N-bromosuccinimide (5.18 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (7.53 g) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=5)=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:29][N:27]1[CH:28]=[C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@H:10]4[O:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:42]6[CH:41]=[N:40][N:39]([CH2:38][CH2:37][O:36][CH:31]7[CH2:32][CH2:33][CH2:34][CH2:35][O:30]7)[CH:43]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)[CH:25]=[N:26]1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCOC
Product: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(CCOC7CCCCO7)c6)cn5)CCO4)c3n2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
(S)-4-(5-bromopyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine 300 mg (0.66 mmol) was dissolved in dimethoxymethane 12 ml, and 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole 450 mg (1.39 mmol) was added. Cesium carbonate 641 mg (1.97 mmol) was dissolved in distilled water 3 ml, which was then added to the reaction solution. PdCl2(dppf)2 27 mg (0.03 mmol) was added, and the mixture was purged with N2 (g), followed by stirring at 80° C. for 4 hours. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate and brine, and the organic layer was dried over Na2SO4. Prep LC with 5% MeOH/MC gave a product 290 mg (77%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][C:3]=1[CH:12]=O.[SH:14][CH:15]([CH2:19][C:20]([OH:22])=[O:21])C(O)=O.C(N(CC)CC)C.Cl>CS(C)=O.O>[S:14]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:5][CH2:4][C:3]=2[CH:12]=[C:15]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=CC1=C(Cl)c2ccccc2SC1
Reactant: O=C(O)CC(S)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)Cc1cc2c(s1)-c1ccccc1SC2
Reaction time: 0.5 h

Procedure:
To a stirred solution of 21 g 4-chloro-3-formyl-thiochrom-3-ene in 80 ml dry dimethylsulfoxide under nitrogen is added 15 g mercaptosuccinic acid. 36 ml triethylamine is then added dropwise and subsequently the reaction mixture is kept at 90°-100° C. for 30 minutes. The mixture is then diluted with water, acidified with hydrochloric acid and extracted with diethylether. The organic layer is then extracted with aqueous sodium bicarbonate solution. After acidification of the aqueous layer the product precipitates as a tar. It is taken up in chloroform. After evaporation of the solvent the residue is recrystallized from a mixture of chloroform and cyclohexane. Pure (4H-thieno[3,2-c][1]benzothiopyran-2-yl)acetic acid is obtained; m.p. 106°-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12](=[O:15])[CH2:13][CH3:14].Cl.[NH2:21]O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]1[C:16]([CH2:17][CH3:18])=[N:21][O:15][C:12]=1[CH2:13][CH3:14]
Reactant: CCC(=O)C(Cc1ccc(OC)cc1Cl)C(=O)CC
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc(CC)c1Cc1ccc(OC)cc1Cl

Procedure:
4-[(2-Chloro-4-methoxyphenyl)methyl]-3,5-diethylisoxazole [I; Ar is 2-Cl-4-CH3OC6H3, Y is CH2, R is C2H5 ] was prepared from 30.9 g. of 4-[(2-chloro-4-methoxyphenyl)methyl]-3,5-heptanedione and 7.96 g. of hydroxylamine hydrochloride in 65 ml. of pyridine according to the procedure of Example 2, part (b), and was obtained in the form of a pale yellow oil, b.p. 144°-147° C. (0.08 mm.); yield 21.6 g.; MIC=12 μg/ml (herpes 2).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:11]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:12][CH2:13][S:14]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:34]3[C:29]([CH:30]=[CH:31][CH:32]=[CH:33]3)=[C:28]([O:35][CH3:36])[C:27]=2[CH3:37])=[O:25])=[CH:20][C:19]=1[O:38][CH3:39])(=[O:16])=[O:15])[CH2:8][CH2:9][CH3:10].Br[CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47].O>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([N:11]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:12][CH2:13][S:14]([N:17]([CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[N:34]3[C:29]([CH:30]=[CH:31][CH:32]=[CH:33]3)=[C:28]([O:35][CH3:36])[C:27]=2[CH3:37])=[O:25])=[CH:20][C:19]=1[O:38][CH3:39])(=[O:16])=[O:15])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCN(CCCC)CCS(=O)(=O)Nc1ccc(C(=O)c2c(C)c(OC)c3ccccn23)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)CCS(=O)(=O)N(CC(=O)OCc1ccccc1)c1ccc(C(=O)c2c(C)c(OC)c3ccccn23)cc1OC
Temperature: 60 °C

Procedure:
125 mg (0.906 mmol) of potassium carbonate are added to 400 mg (0.755 mmol) of 2-(dibutylamino)-N-{2-methoxy-4-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]phenyl}-1-ethanesulphonamide, a compound of Example 207, in solution in 10 ml of dimethylformamide, followed by 142 μl (0.906 mmol) of benzyl bromoacetate, and the medium is heated at 60° C. for 1 hour. The reaction medium is poured over water and ethyl acetate.
Reaction SMILES: C(OC[O:5][CH:6]1[CH2:23][CH:22]2[CH:8]([C:9](=[O:35])[N:10]([CH3:34])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]3[C:19]([C:25]([NH:27][S:28]([CH:31]4[CH2:33][CH2:32]4)(=[O:30])=[O:29])=[O:26])([NH:20][C:21]2=[O:24])[CH2:18]3)[CH2:7]1)C.C([O-])(O)=O.[Na+]>C1COCC1.CO.O.Cl>[OH:5][CH:6]1[CH2:23][CH:22]2[CH:8]([C:9](=[O:35])[N:10]([CH3:34])[CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH:16][CH:17]3[C:19]([C:25]([NH:27][S:28]([CH:31]4[CH2:32][CH2:33]4)(=[O:30])=[O:29])=[O:26])([NH:20][C:21]2=[O:24])[CH2:18]3)[CH2:7]1
Reactant: CCOCOC1CC2C(=O)NC3(C(=O)NS(=O)(=O)C4CC4)CC3C=CCCCCN(C)C(=O)C2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CC2C1=O

Procedure:
The ethoxy ether 1g was dissolved in a mixture of THF/MeOH/water (1:1:1, total volume 30 ml) whereafter 2.5 ml conc. hydrochloric acid was added while stirring. The reaction was stirred overnight at room temperature and was monitored by LC-MS. The reaction mixture was then poured into sat. aq. NaHCO3 (50 ml) and concentrated to half of the volume by rotary evaporation. The resulting mixture was acidified with 10% citric acid and extracted into DCM (3×20 ml). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated by rotary evaporation and dried at high vacuum overnight. The product was used without additional purification.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[N:6]=[CH:7][N:8]=[N:9][C:10]=1[CH2:11][NH2:12].[O:13]=[C:14]1[CH2:17][CH:16]([C:18](ON2C(=O)CCC2=O)=[O:19])[CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>O.[Cl-].[Na+].O.C1COCC1>[CH3:3][O:4][C:5]1[N:6]=[CH:7][N:8]=[N:9][C:10]=1[CH2:11][NH:12][C:18]([CH:16]1[CH2:17][C:14](=[O:13])[CH2:15]1)=[O:19]
Reactant: COc1ncnnc1CN
Reactant: O=C1CC(C(=O)ON2C(=O)CCC2=O)C1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ncnnc1CNC(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A flask filled with N2 was charged with 1-(5-methoxy-1,2,4-triazin-6-yl)methylamine (3.0 g, 0.021 mol), 1-{[(3-oxocyclobutyl)carbonyl]oxy}pyrrolidine-2,5-dione (5.0 g, 0.024 mol) and THF (50 mL). Sodium carbonate (20 g, 0.2 mol) dissolved in water was added to the reaction mixture slowly at 0° C. The reaction was then stirred at rt for 3 h. The reaction mixture was then concentrated under reduced pressure to give a residue. To this residue brine (500 mL) was added and the mixture was extracted with EtOAc (100 mL×3). The organics were combined, dried (Na2SO4) and concentrated under reduced pressure to give a crude residue, which was then purified by flash chromatography on silica gel using hexanes:EtOAc (2:1) as the eluent. 1H NMR (400 MHz, Chloroform-d) δ 3.12-3.33 (m, 3H), 3.44-3.58 (m, 2H), 4.11 (s, 3H), 4.75 (d, J=4.80 Hz, 2H), 7.11 (br. s., 1H), 9.08 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([CH3:15])[C:13]=1I)(C)(C)C.[C:17]([O:21][C:22](=[O:45])[NH:23][C:24]([C:26]1[S:27][C:28]([S:43][CH3:44])=[C:29]([S:31]([C:34]2[CH:39]=[CH:38][C:37](O)=[C:36](B)[C:35]=2O)(=[O:33])=[O:32])[CH:30]=1)=[NH:25])([CH3:20])([CH3:19])[CH3:18].C(O)C.C1(C)C=CC=CC=1>C([O-])([O-])=O.[Na+].[Na+].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.CCOC(C)=O>[C:17]([O:21][C:22](=[O:45])[NH:23][C:24]([C:26]1[S:27][C:28]([S:43][CH3:44])=[C:29]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:13]3[C:12]([CH3:15])=[CH:11][N:10]=[CH:9][C:8]=3[NH2:7])[CH:35]=2)(=[O:33])=[O:32])[CH:30]=1)=[NH:25])([CH3:20])([CH3:19])[CH3:18]
Reactant: Bc1c(O)ccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1O
Reactant: Cc1cncc(NC(=O)OC(C)(C)C)c1I
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: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cncc2N)c1

Procedure:
(4-Iodo-5-methyl-pyridin-3-yl)-carbamic acid tert-butyl ester (106 mg, 0.32 mmol, Example 139: step b), {[4-(3-Boranyl-dihydroxy-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (145 mg, 0.32 mmol, Example 140: step a) and Pd(PPh3)4 (74 mg, 0.06 mmol) were combined in aqueous Na2CO3 (2M, 1.2 mL), ethanol (1.2 mL) and toluene (2.4 mL) and was heated to 80° C. overnight. The reaction mixture was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and solvents were removed in vacuo. Purification by flash column chromatography (40% EtOAc/hexanes) afforded the title compound. ESI-MS (m/z): Calcd. for C28H34N4O6S3: 619.2 (M+1); found: 618.8.