Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[C:4]([C:11]2[N:16]=[C:15]3[N:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=4)[C:14]3=[N:13][CH:12]=2)=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9].CO.CC[O:38]C(C)=O>OS(O)(=O)=O>[F:33][C:2]([F:1])([F:32])[C:3]1[C:4]([C:11]2[N:16]=[C:15]3[N:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][N:23]=4)[C:14]3=[N:13][CH:12]=2)=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]([NH2:9])=[O:38]
Reactant: CCOC(C)=O
Reactant: N#Cc1cnc(-c2cnc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)c(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: NC(=O)c1cnc(-c2cnc3c(Nc4ccc(C(F)(F)F)cn4)ccnc3n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Dissolve 5-(trifluoromethyl)-6-(8-(5-(trifluoromethyl)pyridin-2-ylamino)pyrido[2,3-b]pyrazin-3-yl)nicotinonitrile (25 mg, 0.0542 mmol) in 1 mL of conc. H2SO4 and stir at 25° C. for 20 hours under N2 atmosphere. Monitor the reaction by TLC (1% MeOH/EtOAc) and LC/MS for the disappearance of starting material. Quench the reaction mixture with ice (5 g), adjust the pH to 9.0 using 10.0 N aq. NaOH, extract the aq. layer with EtOAc (3×5.0 ml) and dry combined organic layers with MgSO4. Filter the dried extract and concentrate under vacuum. Purify by column chromatography using 1% MeOH/EtOAc as eluent to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.4 (s, 1H), 9.36 (d, 1H, J=0.6 Hz), 9.18 (s, 1H), 9.09 (d, 1H, J=1.4 Hz), 8.95 (d, 1H, J=1.3 Hz), 8.73 (s, 1H), 8.70(d, 1H, J=0.5 Hz), 7.89 (dd, 1H), 7.13 (d, 1H, J=2.2 Hz). MS=480.01 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[F:15][C:16]([F:31])([F:30])[C:17]([NH:19][C:20]1[CH:21]=[C:22]([CH3:29])[C:23]2[O:27][CH2:26][CH2:25][C:24]=2[CH:28]=1)=[O:18]>C(Cl)(Cl)(Cl)Cl>[F:31][C:16]([F:15])([F:30])[C:17]([NH:19][C:20]1[CH:21]=[C:22]([CH3:29])[C:23]2[O:27][CH:26]=[CH:25][C:24]=2[CH:28]=1)=[O:18]
Reactant: Cc1cc(NC(=O)C(F)(F)F)cc2c1OCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(NC(=O)C(F)(F)F)cc2ccoc12

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (1.3 g) was added to a solution of 2,2,2-trifluoro-N-(7-methyl-2,3-dihydro-benzofuran-5-yl)-acetamide (600 mg) in carbon tetrachloride (30 ml) and the resulting mixture heated at reflux for 4.5 hours. The reaction mixture was filtered, the filtrate adsorbed on to silica and the residue purified by FCC eluting with ether-hexane (1:1) to give the title compound as a peach solid (590 mg), m.p. 96-97°.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=[C:5]([C:18]#[N:19])[N:4]=1)#[N:2].[C:20](OC)(=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)[SH:23].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:7][CH:6]=[C:5]([C:18]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[C:20](=[O:28])[N:19]=2)[N:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCc1ccc(C#N)nc1C#N
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(-c2nc(=O)c3ccccc3s2)nc1C#N
Yield: 25.4 %

Procedure:
tert-Butyl 3-(2,6-dicyano-3-pyridyl)propanoate (0.31 g, 1.20 mmol) and methyl thiosalicylate (0.40 g, 2.40 mmol) were dissolved in toluene (30 ml), and triethylamine (0.75 ml, 5.41 mmol) was added thereto. The mixture was refluxed for 18 hrs, and the solvent was evaporated. The residue was washed with hexane-ethyl acetate to give the titled compound (0.12 g, 25%) as white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][C:3]=1[Cl:11].[CH3:12][NH2:13]>C(O)C>[Cl:11][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:13][CH3:12])=[S:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CN
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: CNC(=S)Nc1ccc(Cl)c(Cl)c1
Temperature: 80 °C

Procedure:
To a stirred solution of 1,2-dichloro-4-isothiocyanatobenzene (1 g, 4.9 mmol) in ethanol (30 mL) was added 8M methyl amine in ethanol (0.613 mL, 4.9 mmol) and the reaction was heated at 80° C. overnight. The solvent was removed under vacuum and the residue was washed with diethyl ether (10 mL) and dried to give crude 1-(3,4-dichlorophenyl)-3-methylthiourea as an off white solid (0.8 g, 69%). 1HNMR: 400 MHz, DMSO-d6: δ 2.93 (d, J=4.40 Hz, 3H), 7.37 (d, J=7.60 Hz, 1H), 7.55 (d, J=8.40 Hz, 1H), 7.86 (d, J=2.40 Hz, 1H), 7.92 (bs, 1H), 9.74 (bs, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][NH2:7])=[O:5])#[N:2].[OH-].[Na+].Cl.[CH2:11](O)[CH3:12].O>O>[O:5]=[C:4]1[C:3]([C:1]#[N:2])=[CH:12][CH:11]=[N:7][NH:6]1
Reactant: N#CCC(=O)NN
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1ccn[nH]c1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
To a mixture of glyoxal bis(sodium hydrogen sulfite) monohydrate (25.24 g, 88.8 mmol) in water (80 ml) was added slowly a solution of cyanoacetohydrazide (8 g, 80.7 mmol) in ethanol/water 2:1 (120 ml). The mixture was then heated to 40° C. for 30 min. The pH was adjusted to 12-13 by addition of 10 N NaOH and stirring was continued for 3 h at 40° C. and for 1 h at 60° C. The reaction mixture was then allowed to cool to ambient temperature over night. The pH was then adjusted to 1-2 by addition of conc. HCl and the resulting mixture was evaporated. The remaining solid was extracted with CHCl3 in a soxhlet-extractor for two days to obtain the title compound as a light brown solid (2.019 g, 16.67 mmol, 21%). 1H NMR (d6-DMSO): 8.07 (d, J=4 Hz, 1H), 8.12 (d, J=4 Hz, 1H), 13.91 (s br, 1H).
Reaction SMILES: [O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:1]=[C:2]([CH3:20])[CH2:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)CCCOc1ccc(CCC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)CCc1ccc(OCCCC(=O)O)cc1
Yield: 59.9 %

Procedure:
4-[4-(3-Oxobutyl)phenoxy]butanoic acid, ethyl ester (716 mg, 2.57 mmol) is dissolved in 5 mL of methanol/water (3:2) and treated with 1.24 g (9.0 mmol) of potassium carbonate according to the procedure described for Example 4 to give 385 mg (60%) of 4-[4-(3-oxobutyl)phenoxy]butanoic acid as a white powder: m.p. 97°-99°; the 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 1730, 1700, 1620, 1520 cm-1 ; Analysis calculated for C14H18O4 : C, 67.18; H, 7.25; found: C, 66.55; H, 7.09.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH:13]([C:15]1[O:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OC)(C)(C)C.O>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[C:2]([C:18]2[O:19][C:15]([CH:13]=[O:14])=[CH:16][CH:17]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)c1ccc(O)c(-c2ccc(C=O)o2)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 7.4 %

Procedure:
A reaction flask was flushed with nitrogen and charged with 2-bromo-4-tert-butyl-phenol (2.019 g, 8.81 mmol), 5-formyl-furan-2-boronic acid (1.831 g, 13.09 mmol) and sodium carbonate (2.783 g, 26.26 mmol). A mixture of 1,2-dimethoxyethane (40 mL) and water (13 mL) was added and the reaction mixture was stirred for 10 min under a nitrogen atmosphere. Dichlorobis(triphenylphosphine) palladium(II) (0.193 g, 0.27 mmol) was added and the mixture was stirred and heated to 65° C. for 17 h. The mixture was cooled to room temperature, diluted with methyl tert-butyl ether (MTBE) (250 mL) and washed successively with 5% aq. potassium carbonate (100 mL), water (100 mL) and brine. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on flash Silica (100 g, 5 to 10% ethyl acetate in hexanes) to afford 5-(5-tert-butyl-2-hydroxy-phenyl)-furan-2-carbaldehyde (160 mg, 7%). 1H NMR (400 MHz, CDCl3): δ 1.33 (9H, s) 6.51 (1H, bs), 6.90 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=4.0 Hz), 7.32 (1H, dd, J=8.8, 2.4 Hz), 7.36 (1H, d, J=3.6 Hz), 7.73 (1H, d, J=3.2 Hz), 9.64 (1H, s). ESI-MS: 243.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([N:14]([CH2:29][CH3:30])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=O)[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:13]>N1CCCCC1.C(O)C>[CH2:29]([N:14]([CH2:12][CH3:13])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[C:24]([CH3:25])=[C:23]([CH:26]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:22][C:21]=1[CH3:28])=[O:19])[CH3:30]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c1C
Temperature: 90 °C
Yield: 68.1 %

Procedure:
A mixture of 5-Chloro-1,3-dihydro-indol-2-one (335 mg, 2 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (530 mg, 2 mmol) and piperidine (1 drop) in ethanol was heated at 90° C. for 2 hours. The reaction was cooled to room temperature, the resulting precipitate was collected by vacuum filtration, washed with ethanol and dried to give 565 mg (68%) of the title compound as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[O:21]([C:28]([NH:30][C:31]1[CH:32]=[C:33]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[O:34][CH:35]1[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1)=O)C1C=CC=CC=1.O.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:16]1([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([NH:1][C:28]([NH:30][C:31]4[CH:32]=[C:33]([CH:46]=[C:47]([C:49]([F:51])([F:52])[F:50])[CH:48]=4)[O:34][CH:35]4[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]4)=[O:21])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(NC(=O)Oc3ccccc3)cc(C(F)(F)F)c2)C1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(NC(=O)Nc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3)cc(C(F)(F)F)c2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 69.3 %

Procedure:
Dissolve N-[4-(4-aminophenoxy)-2-pyridyl]cyclopropanecarboxamide (186 mg, 0.69 mmol), tert-butyl 3-[3-(phenoxycarbonylamino)-5-(trifluoromethyl)phenoxy]azetidine-1-carboxylate (312 mg, 0.69 mmol) and DMAP (17 mg, 0.14 mmol) in DMF (10 mL), stir at 100° C. for 16 hrs. Cool the reaction, pour the mixture to water (50 mL), adjust pH=7 with saturated NaHCO3 solution, extract with EtOAc (15 mL×3). Combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the target compound (300 mg, 69%). MS: (M+1): 628.3.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[CH:15]=[C:16]([F:19])[CH:17]=3)[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.C([O:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38])(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>ClCCl.N1C=CC=CC=1.CO.CO.CS(C)=O>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:37](=[O:38])[C:36]([OH:35])([CH3:41])[CH3:40])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: COc1cc(F)cc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: COc1cc(F)cc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)O)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
N-[1-{[3-(Aminomethyl)phenyl]methyl}-6-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 54) (100 mg, 0.208 mmol) (intermediate) was dissolved in dichloromethane (0.5 mL) and pyridine (0.5 mL), and then treated with 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.031 mL, 0.218 mmol). The mixture was stirred for 2 h. LCMS showed starting material remaining so more 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.021 mL, 0.146 mmol) was added to the reaction mixture and stirred for 1.5 hr. LCMS showed starting material remaining so a further portion of 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.015 mL, 0.104 mmol) was added to the reaction and stirred for 1.25 h. The reaction mixture was concentrated under a stream of nitrogen to leave a yellow residue, which was dissolved in methanol (1 mL) and potassium carbonate (86 mg, 0.624 mmol) was added to the solution. The reaction mixture was heated to 40° C. for 1 hand then neutralised with 2M HCl and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed three times with water (50 mL) and once with brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate before being evaporated in vacuo to leave a yellow residue. The sample was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (60 mg, 51%). LCMS (System A) RT=1.04 min, ES+ve m/z 481/483 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[C:19]([CH:54]=[CH:55][CH:56]=1)[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[CH:25][C:24]=1[C:34]1[CH:35]=[C:36]([CH:51]=[CH:52][N:53]=1)[C:37]([NH:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:50])([F:49])[F:48])[CH:42]=1)=[O:38])=[O:21].C(N(CC)CC)C.Cl[S:65]([C:68]1[CH:76]=[CH:75][C:71]([C:72]([OH:74])=[O:73])=[CH:70][CH:69]=1)(=[O:67])=[O:66]>ClCCl>[CH2:32]([N:29]([CH2:30][CH3:31])[C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20]([C:19]2[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:65]([C:68]3[CH:69]=[CH:70][C:71]([C:72]([OH:74])=[O:73])=[CH:75][CH:76]=3)(=[O:67])=[O:66])[CH:56]=[CH:55][CH:54]=2)=[O:21])=[C:24]([C:34]2[CH:35]=[C:36]([C:37](=[O:38])[NH:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]([F:48])([F:49])[F:50])[CH:42]=3)[CH:51]=[CH:52][N:53]=2)[CH:25]=1)[CH3:33]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCN)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(NC(=O)c2cccc(CCCOCCOCCOCCOCCNS(=O)(=O)c3ccc(C(=O)O)cc3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 270 (200 mg, 0.25 mmol, 1.0 eq) and triethylamine (50.5, 0.50 mmol, 2.0 eq) in dichloromethane (5 mL) under N2 was cooled to 0° C. 4-(chlorosulfonyl)benzoic acid (55.15 mg, 0.25 mmol, 1.0 eq) was added and the reaction warmed to room temperature and monitored by LCMS. After 2 hours, the resulting solution was diluted with dichloromethane (20 mL) and washed with water (2×20 mL). The organic layer was acidified to pH 5 with 1N HCl and washed with water (20 mL), brine, and dried over Na2SO4. Removing the solvent resulted in 172 mg of 4-(N-(15-(3-(4-(diethylamino)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)phenyl)-3,6,9,12-tetraoxapentadecyl)sulfamoyl)benzoic acid as an oil.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C:18](O)=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:21])[O:5][N:4]=1)[CH3:2].S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C:18]([Cl:24])=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:21])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1CC(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1CC(=O)Cl

Procedure:
A mixture of 10.3 g. (0.036 mole) 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetic acid and 22.0 g. (0.185 mole) thionyl chloride in 100 ml. toluene is stirred at room temperature for 18 hours. The toluene is removed in vacuo to give 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:23]=[C:22]2[C:9]([C:10]3[CH:11]=[CH:12][N:13]=[C:14]([CH:34]=3)[C@@H:15]([NH:26]C(=O)OC(C)(C)C)[CH2:16][CH2:17][CH2:18][C:19](=[O:25])[C:20](=[O:24])[NH:21]2)=[CH:8][CH:7]=1)=[O:4].[CH3:35][Mg]Br>C1COCC1>[NH2:26][C@@H:15]1[C:14]2[CH:34]=[C:10]([CH:11]=[CH:12][N:13]=2)[C:9]2[C:22](=[CH:23][C:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])=[CH:7][CH:8]=2)[NH:21][C:20](=[O:24])[C:19]([OH:25])([CH3:35])[CH2:18][CH2:17][CH2:16]1
Reactant: C[Mg]Br
Reactant: COC(=O)Nc1ccc2c(c1)NC(=O)C(=O)CCC[C@H](NC(=O)OC(C)(C)C)c1cc-2ccn1
Solvent: C1CCOC1
Product: COC(=O)Nc1ccc2c(c1)NC(=O)C(C)(O)CCC[C@H](N)c1cc-2ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A solution of 123C (345 mg, 0.736 mmol) in THF (7 mL) was cooled to 0° C. and treated with methylmagnesium bromide (0.245 mL, 0.736 mmol), then stirred at rt for 1 hr. The reaction was cooled to 0° C. again and treated with methylmagnesium bromide (0.491 mL, 1.473 mmol), then stirred at rt for 1 hr. LCMS still showed starting material. The reaction was cooled to 0° C., treated with methylmagnesium bromide (0.491 mL, 1.473 mmol), then stirred at rt overnight. The reaction was quenched with sat. NH4Cl, then diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (3×), and the organic extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by prep HPLC. The pure material was dissolved in DCM and treated with TFA, then stirred at rt for 2 hrs. The solvent was removed in vacuo and 123D (135 mg, 0.220 mmol, 29.9% yield) was obtained as a yellow solid. The material was used in future steps without purification. MS (ESI) m/z: 385.1 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9](CC(C)(C)C)(C)[CH3:10]>ClC(Cl)C>[CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10])=[CH2:1]
Reactant: CC(C)CC(C)(C)C
Reactant: C=Cc1ccccc1
Solvent: CC(Cl)Cl
Product: C=Cc1ccccc1C=C

Procedure:
Swell 2.8 kg of styrene copolymer with 40 mol. percent of divinylbenzene, obtained in the presence of 100 percent by weight of isooctane, in 9 liters of dichloroethane, add a mixture of 2.0 kg of KNO3 and 5 liters of concentrated sulphuric acid, and keep for six hours at a temperature of -5° to 0° C. Proceed as in Example 1. The obtained textured nitro polymer contains 5.4 percent by weight of nitrogen.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:27][CH2:28][CH:29]=O>>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH2:29][CH2:28][CH2:27][N:23]3[CH2:24][CH2:25][CH2:26][C:22]3=[O:21])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=CCCN1CCCC1=O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCCN1CCCC1=O

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and 3-(2-oxo-1-pyrrolidinyl)propanal employing methods similar to those described in Example 265 and was obtained as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=1.6 Hz, 1 H), 7.71 (br, 1 H), 7.07 (dd, J=8.5, 5.4 Hz, 2 H), 6.92 (t, J=8.6 Hz, 2 H), 6.74 (d, J=1.3 Hz, 1 H), 4.35 (q, J=7.1 Hz, 2 H), 3.86 (s, 2 H), 3.35-3.29 (m, 4 H), 3.10 (m, 2 H), 2.33 (t, J=8.2 Hz, 2 H), 1.96 (m, 2 H), 1.79 (m, 2 H), 1.35 (t, J=7.2 Hz, 3 H); MS m/z 400 (M+H)+.
Reaction SMILES: [C:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]=1>S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[C:1]12[CH2:5][CH2:4][CH2:3][C:2]=1[C@@H:13]1[C@@H:9]([CH2:10][CH2:11][CH2:12]1)[C:6]2=[O:8]
Reactant: O=C(O)C1=CCCC1
Reactant: C1=CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: O=C1C2=C(CCC2)[C@H]2CCC[C@@H]12
Temperature: 75 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 1-cyclopentene carboxylic acid (11.2 g, 100 mmol) and cyclopentene (13.6 g, 200 mmol) was added slowly to stirring polyphosphoric acid (Aldrich, 300 g) at 60° C. in a 250 mL flask. The reaction mixture was stirred at 70-80° C. for 4 hours under nitrogen. The dark brown reaction mixture was cooled to 30° C. and poured on 300 g of ice and vigorously stirred in a cooling bath. The brown mass was then neutralized with a saturated solution of ammonium sulfate (200 ml). The resulting mixture was then extracted with Et2O (5×200 mL). The combined organic layers were washed successively with water, saturated sodium bicarbonate solution and water. The washed organic extract was then dried over anhydrous MgSO4 and concentrated in vacuo. The residue was distilled at 130-135° C. at 4 mmHg to yield 3.5 g, 25%, about 90% purity. This product was chromatographed on silica gel using hexane and ethyl acetate as eluent to obtain pure cis-tricyclo[6.3.0.03,7]undec-1(8)-en-2-one. 1H-NMR (CDCl3): δ3.2 (m, 1 H), 3.1 (m, 1H), 2.5 (m, 2H), 2.4 (m, 4H), 1.9 (m, 1H), 1.6 (m, 4H), 1.3 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)[CH:3]=1>CO.[C].[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][CH2:13][O:12][CH2:11]2)[C:5]([OH:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)cc(-c2ccoc2)c1O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(F)cc(C2CCOC2)c1O
Reaction time: 24 h
Yield: 76.5 %

Procedure:
4-fluoro-2-(furan-3-yl)-6-methylphenol (Compound 6-11) (471 mg, 2.45 mmol) were dissolved in methanol. Palladium carbon (64.3 mg, 5 wt %) was added thereto, followed by stirring under hydrogen balloon for 24 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The concentrate was purified by column chromatography (silica gel; hexane/ethyl acetate, 9/1) to obtain 4-fluoro-2-methyl-6-(tetrahydrofuran-3-yl)phenol (368 mg, 76%) as a white solid.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[NH:32][CH2:31][CH2:30][CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NCCCCc1ccccc1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCCCc3ccccc3)cc2c1=O
Yield: 19 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 4-phenyl-butylamine according to the GPA but purified, due to low solubility, by preparative TLC (eluent: hexane/ethyl acetate/acetic acid, 3/7/0.1) affording 5.4 mg (19%) of a red powder. Rt=5.93 min.