Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:14])=S)=[CH:7][C:5]=2[N:6]=1.[BrH:15].C1(SC([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=N)C=CC=CC=1>C(O)C.C(OCC)C>[BrH:15].[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[NH:14])=[CH:7][C:5]=2[N:6]=1
Reactant: NC(=S)Nc1ccc2sc(N)nc2c1
Reactant: N=C(Sc1ccccc1)c1cccs1
Agent: Br
Solvent: CCOCC
Solvent: CCO
Product: N=C(Nc1ccc2sc(N)nc2c1)c1cccs1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of the amino urea compound (Example 18, 35 mg, 0.21 mmol) in ethanol (1.4 mL) was added thiophene-2-carboximidothioic acid phenyl ester hydrobromide (63.7 mg, 0.21 mmol). The mixture was stirred at room temperature for 17 hours and then diluted with diethyl ether. The light yellow precipitate was collected by filtration (64.8 mg, 93%). 1H-NMR (DMSO d6) δ: 11.36 (br s, 1H), 9.72 (br s, 1H), 8.83 (br s, 1H), 8.17 (d, 1H, J=4.68 Hz).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=O)[N:5]1[CH3:11].P(Cl)(Cl)(Cl)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28]>C(Cl)(Cl)Cl>[C:24]([OH:31])(=[O:30])/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28].[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:8][N:7]([CH3:9])[C:6](=[N:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:5]1[CH3:11]
Reactant: Nc1ccccc1
Reactant: CN1CC(CCCl)N(C)C1=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CC(CCCl)N(C)C1=Nc1ccccc1
Reaction time: 2 h
Yield: 50 %

Procedure:
To 8.0 g (0.045 mole) of 4-(2-chloroethyl)-1,3-dimethyl-2-oxo-imidazolidine was added 50 ml of phosphorus oxychloride, and the solution was refluxed for 18 hours, and concentrated in vacuo. The residue was dissolved in 25 ml of methylene chloride and added dropwise to 4.2 g (0.045 mole) of aniline stirring at room temperature. Stirring was continued for two hours. The solution was diluted with chloroform and washed with dilute sodium hydroxide solution. The chloroform was dried, filtered and concentrated in vacuo. The residue was dissolved in isopropyl alcohol and treated with 5.2 g (0.045 mole) fumaric acid, and the resulting fumarate was recrystallized from isopropyl alcohol and weighed 9.0 g (50% yield); m.p. 109°-112° C.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])=[O:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[CH2:25][NH:24][C:22]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][NH:4][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]3[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])=[CH:20][CH:19]=1)=[O:23]
Reactant: NCC1CCN(S(=O)(=O)c2ccc(NC(=O)NCc3cc(F)ccc3F)cc2)CC1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Product: O=C(NCc1cc(F)ccc1F)Nc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3ccc(O)cc3)CC2)cc1
Yield: 13 %

Procedure:
N-(4-{[4-(aminomethyl)-1-piperidinyl]sulfonyl}phenyl)-N′-(2,5-difluorobenzyl)urea formate (0.433 g, 1.00 mmol) was reacted with t-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.404 g, 1.00 mmol) according to example 37 to give the title compound (0.084 g, 0.13 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Si](C=[N+]=[N-])(C)(C)[CH3:22].CCCCCC>C1COCC1.CO>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:22])=[O:8]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of 5-bromo-2-(2-fluorophenylamino)-3,4-difluorobenzoic acid (30.3 mmol, 11 g) in THF:MeOH (60:20), cooled to 0° C., was added dropwise a solution of 2M TMSCHN2 in hexane (39.39 mmol, 19.7 ml). After the addition is completed, the reaction mixture was warmed to room temperature and stirred for an additional 4 hours. The crude reaction was quenched with acetic acid and extracted with EtOAc. The organic layers are combined, washed with H2O, dry over MgSO4 and concentrated under reduced pressure. The crude material was dried under vacuum and yields to 11 g (96%) of the title product.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[CH:12](=O)/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:13](/[CH:12]1[O:1][CH:2]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:10][O:11]1)=[CH:14]\[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCC/C=C/C=C/C=O
Reactant: COC(=O)CCCC(O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCC/C=C/C=C/C1OCC(CCCC(=O)OC)O1

Procedure:
Methyl 5,6-dihydroxyhexanoate (0.32 g, 2.0 mmol), 2E,4E-dodecadienal and catalytic pyridinium p-toluenesulfonate (PPTS) were refluxed in 10 ml of benzene for 39 hours with a Dean-Stark trap. Molecular sieves were added after 19 hours. The reaction mixture was cooled, filtered and concentrated. Flash chromatography on silica gel with 25:1 hexane/ethyl acetate as eluent gave the product (0.10 g, 0.31 mmol), 15%.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=3[CH:22]=[O:23])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Na+]>CO>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:21]=3[CH2:22][OH:23])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1CO
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzaldehyde (99.3 mg, 0.199 mmol) in MeOH (5 mL) was added excess NaBH4. The reaction was stirred for 30 minutes, and then quenched with saturated NH4Cl solution (10 mL), diluted with EtOAc (60 mL), and washed with brine (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 50% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(hydroxymethyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.54 (75% EtOAc/hexanes). LCMS=502.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.87 (s, 1H), 7.75 (s, 2H), 7.62 (s, 2H), 7.51 (s, 1H), 5.79 (d, J=8.0 Hz, 1H), 5.06 (d, J=15.5 Hz, 1H), 4.83 (d, J=5.1 Hz, 2H), 4.25 (d, J=15.6 Hz, 1H), 4.01-3.99 (m, 1H), 0.79 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[C:19](\[CH3:25])/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[S:8](=O)[C:7]=2[CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si](Cl)(C)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[C:19](\[CH3:25])/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[S:8][C:7]=2[CH:35]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC2=C(c3ccc(OC)cc3)S(=O)c3cc(OC)ccc32)cc1
Agent: C[Si](C)(C)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Temperature: 75 °C
Yield: 76.5 %

Procedure:
To a solution of (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)-1-oxidobenzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate (144 mg, 0.294 mmol) in THF (6.0 mL) was added triphenylphosphine (285 mg, 1.086 mmol) and TMS-Cl (0.375 mL, 2.94 mmol). The reaction was heated to 75° C. for 7 h after which time the mixture was cooled to room temperature, quenched with sat. aq. NaHCO3 and extracted with EtOAc, the combined organic layers were collected (phase separator) and concentrated in vacuo to afford the crude product which was purified by column chromatography (SiO2, 0-40% EtOAc/Heptane) to afford (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-2-methylacrylate (107 mg, 0.225 mmol, 77% yield). LC/MS (m/z, MH+): 475.3.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])#[N:2].S(=O)(=O)(O)[OH:24]>>[NH2:2][C:1]([C:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:22])[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4])=[O:24]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C(=O)Nc2ccc(C(C)(C)C#N)cc2)cc1
Product: COc1ccc(C(=O)Nc2ccc(C(C)(C)C(N)=O)cc2)cc1

Procedure:
5 g. N-[4-(1-Cyano-1-methylethyl)-phenyl]-4-methoxybenzamide (Example 27) are stirred for 20 hours at ambient temperature in 100 ml. concentrated sulphuric acid, poured on to ice, the precipitate is filtered off with suction, dissolved in hot glacial acetic acid, water added thereto until the commencement of turbidity and then left to cool. There are obtained 2.2 g. (42% of theory) of the title compound in the form of colourless crystals; m.p. 234°-235° C.
Reaction SMILES: C([C:3]1([C:21]([O-:23])=[O:22])[CH:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:10]([CH3:12])[CH2:11][N:6]2[N:5]=[C:4]1[I:20])C.[OH-].[Na+]>CCO.O>[C:16]([O:15][C:13]([N:9]1[CH:10]([CH3:12])[CH2:11][N:6]2[N:5]=[C:4]([I:20])[C:3]([C:21]([OH:23])=[O:22])=[C:7]2[CH2:8]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCC1(C(=O)[O-])C(I)=NN2CC(C)N(C(=O)OC(C)(C)C)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1Cn2nc(I)c(C(=O)O)c2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.7 %

Procedure:
To a stirred solution of Intermediate 340D (0.85 g, 1.953 mmol) in EtOH (2.0 mL) was added a solution of NaOH (0.391 g, 9.76 mmol) in water (1.0 mL) and the resulting solution was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was acidified by the addition of a 1N aq. solution of HCl (5 mL) which was allowed to stir for 10 min. The generated precipitate was filtered and dried to afford Intermediate 340E as a white solid (0.65 g, 82%). MS(ES): m/z=408 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 5.05 (d, J=18.89 Hz, 1H), 4.67 (br. s., 1H), 4.36 (d, J=18.13 Hz, 1H), 4.13-4.25 (m, 1H), 3.93-4.13 (m, 2H), 1.44 (s, 9H), 1.08 (t, J=6.99 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[NH:7][CH3:8].[CH3:13][C:14]1[N:19]=[C:18]([OH:20])[CH:17]=[C:16]([OH:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][C:14]1[N:19]=[C:18]([OH:20])[CH:17]=[C:16]([O:21][C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:7][CH3:8])[CH:9]=2)[CH:15]=1
Reactant: Cc1cc(O)cc(O)n1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNc1cc(Oc2cc(C)nc(O)c2)ccc1[N+](=O)[O-]
Yield: 89 %

Procedure:
The reaction and post-treatment were carried out according to Example (16c) using 5-fluoro-N-methyl-2-nitroaniline (US2003-675927, 6.30 g, 37.0 mmol), 6-methylpyridine-2,4-diol (5.09 g, 40.7 mmol), potassium carbonate (5.63 g, 40.7 mmol) and DMF (100 mL) to obtain the title compound (9.06 g, 89%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[SiH:5]1[N:9]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=[CH:7][N:6]1[C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21]>CCCCCC>[CH3:24][C:18]([N:6]1[CH:7]=[CH:8][N:9]([C:10]([CH3:17])([CH3:16])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[SiH:5]1[NH:3][CH2:1][CH3:2])([CH3:25])[CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CCN
Reactant: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1Cl
Solvent: CCCCCC
Product: CCN[SiH]1N(C(C)(C)CC(C)(C)C)C=CN1C(C)(C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
In an argon atmosphere, 6.80 g (151 mmol) of ethylamine was dissolved in 20 mL of hexane, and a solution obtained by dissolving 5.26 g (15.2 mmol) of Si(tOctNCHCHNtOct)(H)Cl in 10 mL of hexane was added thereto at −20° C. After stirring at room temperature for 12 hours, insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 128° C./1.4×102 Pa) to obtain 1,3-bis(1,1,3,3-tetramethylbutyl)-2-ethylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tOctNCHCHNtOct)(H)NHEt) as a pale yellow liquid (yielded amount: 5.22 g, yield: 97%).
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:5]=1)(=[O:3])[NH2:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:49][C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][C@@H:56]1[CH2:60][CH2:59][CH2:58][NH:57]1>CN(C=O)C.C(Cl)Cl>[CH3:49][C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][C@@H:56]1[CH2:60][CH2:59][CH2:58][N:57]1[C:13]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[S:8][CH:7]=2)=[CH:17][CH:16]=1)=[O:15]
Reactant: NC(=O)c1cc(-c2ccc(C(=O)O)cc2)cs1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2csc(C(N)=O)c2)cc1
Yield: 14.4 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 10 mL 30% DMF/CH2Cl2 using 4-(5-Carbamoyl-thiophen-3-yl)-benzoic acid (360 mg, 1.6 mmol), EDC-HCl (439 mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol), DIEA (0.70 mL, 4.0 mmol) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (236 mg, 1.4 mmol) to give the title compound (80 mg, 14% yield). MS (ES+) 398.3 (M+H)+
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)=[O:11].O.ON1C2C=CC=CC=2N=N1.[C:33]1([CH2:39][CH2:40][CH2:41][NH2:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[C:33]1([CH2:39][CH2:40][CH2:41][NH:42][C:17]([C:16]2[CH:20]=[CH:21][C:13]([NH:12][C:10]([N:2]3[CH2:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3]3)=[O:11])=[CH:14][CH:15]=2)=[O:19])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCc1ccccc1)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Isoindoline-2-carboxamido)benzoic acid (150 mg, 0.531 mmol) and 1-hydroxybenzotriazole hydrate (122 mg, 0.797 mmol) were dissolved in dimethylformamide (3 ml) followed by addition of 3-phenylpropan-1-amine (110 mg, 0.797 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (153 mg, 0.797 mmol). The homogeneous solution was stirred at ambient temperature overnight. The solution was diluted with water to give a precipitate which was filtered, washed with cold ethyl acetate then ether and dried under vacuum to provide the title compound. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ ppm 8.27-8.34 (bs, 1H), 7.93-7.98 (m, 1H), 7.73-7.76 (m, 2H), 7.61-7.64 (m, 2H), 7.32-7.36 (m, 2H), 7.27-7.32 (m, 2H), 7.24-7.28 (m, 2H), 7.19-7.24 (m, 2H), 7.13-7.18 (m, 1H), 4.79 (s, 4H), 3.30 (q, J=6.5 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 1.86 (p, J=7.3 Hz, 2H); MS (ESI(+)) m/e 400 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19].[Cl-].[Ca+2].[Cl-]>>[Cl:17][S:18]([C:7]1[C:6]2[C:5](=[O:16])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:20])=[O:19]
Reactant: O=c1c2ccccc2oc2ccc(Cl)cc12
Reactant: O=S(=O)(O)Cl
Agent: [Ca+2]
Agent: [Cl-]
Product: O=c1c2cc(Cl)ccc2oc2cccc(S(=O)(=O)Cl)c12
Temperature: 120 °C

Procedure:
80 g (0.347 moles) of 2-chloroxanthone (DHAR, J. Chem. Soc. 117, 1068) are suspended in 210 ml of chlorosulfonic acid (368.1 g; 3.16 moles) in a 500 ml one neck flask provided with refluxing coolant and calcium chloride valve. The mixture is slowly heated in an oil bath up to 120° C. under magnetic stirring. It is maintained at 120°-130° C. until the gas development ceases (2-3 h). The cool reaction mixture is carefully dropwise added to a becker containing ground ice under mechanical stirring. A heavy crystalline product is separated which is filtered on Buchner and washed with iced H2O. It is dried in air. There are obtained 112 g (98%) of raw 2-(chlorosulfonyl-7-chloroxanthone. After TLC monitoring (silica gel F245 ; toluene, acetic acid 14:1, visualizer UV) the product is used as such for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:36])(=[O:35])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[CH:33]=[CH:32][N:31]([CH3:34])[C:28]2=[N:29][CH:30]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:35])(=[O:36])[N:23]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:24][C:25]1[CH:26]=[C:27]2[CH:33]=[CH:32][N:31]([CH3:34])[C:28]2=[N:29][CH:30]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2cnc3c(ccn3C)c2)c(Cl)c1
Reactant: Fc1ncc(Cl)cc1Cl
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2cnc3c(ccn3C)c2)c2ncc(Cl)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and ethyl 3-chloro-4-(N-((1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 35).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH:30]([OH:32])[CH3:31])=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([CH:30]([OH:32])[CH3:31])=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1C(C)O
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C(C)O

Procedure:
The title compound was prepared in the same manner described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 1-(6-chloro-2-methylpyridin 3-yl)ethanol (82 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])(CC)C.[CH:29]([CH:31]=[CH2:32])=[O:30]>CCCCCC.O.O1CCCC1>[C:2]1([CH:1]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH:29]([OH:30])[CH:31]=[CH2:32])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: CC(C)(C)OC(=O)NCc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=CC(O)C(NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 78 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
4.2 g (20.3 mmol) of t-butyl benzylcarbamate, 40 cm3 of anhydrous tetrahydrofuran and 6.5 cm3 (5.0 g, 43 mmol) of tetramethylethylenediamine (TMEDA) are introduced successively into a 250 cm3 single-necked flask placed under argon and equipped with a magnetic stirring system. The solution obtained is cooled to 78° C. and 60 cm3 (60 mmol) of a 1M solution of secondary butyllithium in hexane are then added dropwise. The reaction is left to proceed for 3 hours at this temperature and the mixture is then cooled to -100° C. 3 cm3 (2.5 g, 44.9 mmol) of freshly distilled acrolein are then added and the reaction is left to proceed for 3 to 4 minutes at this temperature and then for 1 hour at -78° C. The resulting reaction mixture is hydrolyzed at -78° C. with 20 cm3 of water and then extracted with 2 times 30 cm3 of ether. The organic phases are combined and then washed twice with 20 cm3 of water and once with 10 cm3 of a saturated aqueous solution of sodium chloride. They are then dried over anhydrous sodium sulphate. After filtration, the solvents are driven off under reduced pressure. The residue obtained (11.6 g) is purified on a column of silica gel using a methylene chloride/ether mixture (95/5 by volume) as the eluent. 2.606 g (9.91 mmol) of 1-phenyl-1-t-butoxycarbonylamino-2-hydroxybut-3-ene are obtained with a yield of 49% in the form of a mixture of the syn and anti diastereoisomers in a ratio of 6/1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=O)[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[S:22])[NH2:10])[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)nc(C(N)=O)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COc1cc(Cl)nc(C(N)=S)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of compound 18 (9 mmol) in THF (30 mL) was added Lawesson reagent (5.4 mmol). The reaction mixture was stirred at 90° C. for 2 hrs. After cooling at room temperature, the solution was concentrated under reduced pressure and the residue was triturated in DCM to give compound 19 as a yellow solid in 71% yield. MS (ESI, EI+): m/z=203 (MH+).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].O>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1cc(S(C)(=O)=O)ccc1C(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A solution of 1.0 M boron tribromide (44.0 ml, 44.0 mmol) in DCM (20 ml) was cooled to 0° C. 2-methoxy-4-(methylsulfonyl)benzoic acid (4.0 g, 17.4 mmol) dispergated in DCM (120 ml) was slowly added to the tribromide-solution during 20 minutes. The reaction mixture was vigorously stirred for 1.5 h at 0° C. Water was added and the organic phase was separated. The aqueous phase was extracted with DCM and EtOAc. The combined organic phases was dried (Na2SO4) and evaporated under reduced pressure to give a white powder (3.6 g). 1H-NMR (400 MHz, MeOH): δ 8.07 (1H, d, J 8.0 Hz), 7.42 (1H, d, J 2.0 Hz), δ 7.38 (1H, dd, J1 8.4 Hz, J2 1.6 Hz), δ 3.11 (3H, s).