Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[CH2:10][C:9]2=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1.CN(C)P(N(C)C)(N(C)C)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]([CH3:15])[CH2:10][C:9]2=[S:26])=[CH:4][CH:3]=1
Reactant: CC1CC(=O)N(c2ccc(F)cc2)C(=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC1CC(=O)N(c2ccc(F)cc2)C(=S)C1
Temperature: 100 °C
Reaction time: 30 h
Yield: 57.5 %

Procedure:
A mixture of 1.02 g (4.68 mmol) of N-(4'-fluorophenyl)-3-methylglutarimide (Compound 66), 0.88 g (2.2 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (known as Lawson's Reagent), and 6 ml of hexamethylphosphoramide in a 50 ml round-bottomed flask was warmed to 95°-100° C. for 21 hours. An additional 1.05 g (2.5 mmol) of Lawson's Reagent were added and heating to 100° C. was continued for an additional 30 hours. The mixture was allowed to cool to room temperature and water (50 ml) was added. The mixture was extracted with ether (4×50 ml). The organic portions were combined, dried over MgSO4 and the solvent was removed in vacuo. The resulting 2 g of orange oil were purified via flash chromatography (silica gel, 1:1 hexanes/methylene chloride) to yield 300 mg (28% yield) of yellow oil which solidified to a solid: m.p. 84.5°-87.5° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:25]([O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:32]=O)([CH3:27])[CH3:26]>C(Cl)Cl.CCCCCC.[Zn]>[Br:2][C:1]([Br:5])=[CH:32][C:31]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:25]([CH3:27])[CH3:26])[CH:30]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(C=O)cc1OC(C)C
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(C=C(Br)Br)cc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 99.8 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PPh3 (40.5 g, 154.4 mmol) in CH2Cl2 (350 mL) maintained at 0° C. on an ice-salt bath. The resulting suspension was allowed to warm to room temperature and then stirred for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and isovanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. The resulting mixture was allowed to stir at room temperature for 1 h then diluted with hexane (200 mL) and filtered through a No. 3 porosity sintered-glass funnel. The filtrate was concentrated on to silica gel (400-200 mesh, 30 g) and the resulting solid added to the top of a flash chromatography column (20 cm long×10 cm wide) which was subjected to gradient elution with 2:1, 1:1 then 1:2 hexane/CH2Cl2. Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) afforded the title compound (27.0 g, 99%) as white crystalline masses, m.p. 67-69° C. νmax (KBr) 3009, 2975, 2929, 1597, 1572, 1508, 1463, 1441, 1429, 1373, 1301, 1276, 1260, 1233, 1144, 1110 and 999 cm−1. 1H n.m.r. δ 7.38 (s, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.4 and 2.1 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.53 (septet, J=6.0 Hz, 1H), 3.86 (s, 3H), 1.38 (d, J=6.0 Hz, 6H). 13C n.m.r. δ 150.5 (C), 146.7 (C), 136.4 (C), 127.7 (C), 122.1 (CH), 115.3 (CH), 111.3 (CH), 87.0 (C), 71.4 (CH), 55.8 (CH3), 22.0 (2×CH3). Mass spectrum m/z 352 (20) 350 (40) 348 (22) (M+·), 310 (50) 308 (100) 306 (50) [(M-C3H6)+·], 295 (30), 293 (61) 291 (33) [(M-C3H6—CH3+·)+]. Anal. Calcd for C12H14Br2O2 C, 41.2; H, 4.0; Br, 45.7. Found: C, 41.1; H, 3.7: Br, 45.3%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH:12]=O)=[C:5]([CH3:23])[O:4][N:3]=1.Cl.[NH2:25][OH:26].N1C=CC=CC=1.Cl.B(F)(F)F.S(C)C>CCO.C(Cl)Cl.CO>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:9][N:10]([CH3:14])[C:11]=2[CH:12]=[N:25][OH:26])=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: NO
Reactant: COc1ccc(-c2nn(C)c(C=O)c2-c2c(C)noc2C)cc1
Agent: Cl
Agent: FB(F)F
Solvent: CCO
Solvent: CSC
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1c(-c2ccc(O)cc2)nn(C)c1C=NO
Temperature: 100 °C
Yield: 34.5 %

Procedure:
A mixture of 4-(3,5-dimethylisoxazol-4-yl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde (9.1 mg, 0.029 mmol), hydroxylamine hydrochloride (54.9 mg, 0.79 mmol) and pyridine (69 μL, 0.85 mmol) in dry EtOH (1 mL) was heated at 100° C. for 3 minutes in the microwave. 1 mL 2 M HCl and 5 mL DCM were added and the phases were separated. The organic phase was filtered through a phase separator and concentrated to give a raw product, that was dissolved in DCM (0.5 mL). BF3.Me2S (1 M solution in DCM, 0.5 mL, 0.5 mmol) was added and the mixture was stirred at room temperature over night. Methanol was added to quenched the reaction and the mixture was purified on preparative HPLC to give E12 4-(3,5-dimethylisoxazol-4-yl)-3-(4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbaldehyde oxime (3.0 mg, 0.01 mmol, 32%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 313.22 (M+H), 311.21 (M−H); 1H NMR (acetone-d6, 500 MHz): 7.92 (s, 1H), 7.31 (m, 2H), 6.79 (m, 2H), 4.08 (s, 3H), 2.15 (s, 3H) and 1.86 (s, 3H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:25][C:26](=[O:37])[CH:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH3:28])[C:16]1=[O:38])[C:11]([NH:13][CH3:14])=[O:12])(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[Cl:36][C:31]1[CH:30]=[C:29]([CH:27]([CH3:28])[C:26]([NH:25][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]=2[CH:23]=[CH:24][N:15]([C@H:10]([CH2:9][OH:8])[C:11]([NH:13][CH3:14])=[O:12])[C:16]3=[O:38])=[O:37])[CH:34]=[CH:33][C:32]=1[Cl:35]
Reactant: CNC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(NC(=O)C(C)c3ccc(Cl)c(Cl)c3)cccc2c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(=O)[C@@H](CO)n1ccc2c(NC(=O)C(C)c3ccc(Cl)c(Cl)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A round bottom flask was charged with (2R)-3-(tert-butyldimethylsilyloxy)-2-(5-(2-(3,4-dichlorophenyl)propanamido)-1-oxoisoquinolin-2(1H)-yl)-N-methylpropanamide (60 mg, 0.0001 mol), tetrahydrofuran (3 mL, 0.04 mol) and tetra-n-butylammonium fluoride (0.037 mL, 0.00012 mol) and the reaction stirred at room temperature for 30 minutes during which time the reaction was complete. The solvent was removed under reduced pressure and the residue purified by preparative HPLC (reverse phase) to yield the product as a white solid. MS m/z=463.3 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 10.02 (s, 1H), 8.12 (m, 1H), 8.06 (d, J=8.26 Hz, 1H), 7.74 (t, J=7.29 Hz, 1H), 7.68 (d, J=1.82 Hz, 1H), 7.64 (d, J=8.43 Hz, 1H), 7.51 (dd, J=7.97&3.17 Hz, 1H), 7.46-7.42 (m, 2H), 6.37 (dd, J=5.04&2.04 Hz, 1H), 5.47 (t, J=6.94 Hz, 1H), 5.15-5.13 (m, 1H), 4.05 (q, J=7.24 Hz, 1H), 3.95-3.92 (m, 2H), 2.57 (d, J=4.25 Hz, 3H), 1.47 (d, J=7.22 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[C:8]([OH:10])=O)[CH3:2].C(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:4]=[CH:5][S:6][C:7]=1[C:8]([Cl:13])=[O:10])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CCc1ncsc1C(=O)O
Solvent: Cc1ccccc1
Product: CCc1ncsc1C(=O)Cl
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1,7.9 g (0.05 mole) of 4-ethylthiazole-5carboxylic acid were suspended in 100 ml of toluene. Under heating and reflux, phosgene was blown at a rate of 220 ml/hr for 15 hours (0.15 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 8.5 g of 4-ethylthiazole-5carboxylic acid chloride. Its purity and yield were 95.0% and 92.0%, respectively. NMR (δCDCl 3/TMS, ppm): 1.28(3H,t,J=7Hz), 3.10(2H,q,J=7Hz).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[S:8][S:7][CH2:6]1>C(Cl)Cl>[S:7]1[CH2:6][CH2:5][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([Cl:3])=[O:16])[S:8]1
Reactant: O=C(O)CCCC[C@@H]1CCSS1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)CCCCC1CCSS1
Reaction time: 3 h

Procedure:
To a stirred solution of thionyl chloride (1.4 mL, 7.5 mmol) in CH2Cl2 (30 ml) at 0° C. was added a solution of lipoic acid (3.0 g, 5 mmol), dissolved in dichloromethane, dropwise over 1 h. The mixture was allowed to stir for additional 3 h. at the same temperature. After completion of the reaction the solvent was removed under vacuum using a dry-ice collection trap being very careful not to heat the reaction mixture since this will decompose the product. Reaction proceeds with quantitative yield.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.[Cl:38][C:39]1[C:40]([C:49]([F:52])([F:51])[F:50])=[N:41][N:42]([CH2:45][C:46](O)=[O:47])[C:43]=1[CH3:44]>>[Cl:38][C:39]1[C:40]([C:49]([F:51])([F:50])[F:52])=[N:41][N:42]([CH2:45][C:46]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)[CH2:33][CH2:34]2)=[O:47])[C:43]=1[CH3:44]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chlorophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 7.22 (d, 2H), 6.83 (d, 2H), 4.99 (s, 2H), 3.77 (m, 2H), 3.72 (m, 2H), 3.19 (m, 2H), 3.16 (m, 2H), 2.28 (s, 3H) ppm; MS (ES) M+Na expected=443.0, found 443.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@H:34]([C:38](O)=[O:39])[CH:35]([CH3:37])[CH3:36])[O:10][C:9]1([CH3:42])[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:45][C:46](=[O:54])[C:47]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:48][NH2:49])C>>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:11]([CH2:33][C@H:34]([C:38](=[O:39])[NH:49][CH2:48][C:47]([C:46]([OH:45])=[O:54])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH:35]([CH3:36])[CH3:37])[O:10][C:9]1([CH3:41])[CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(CC)(CC)CN
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C(=O)O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Product: CCC(CC)(CNC(=O)[C@@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](Cc1ccc(OC)c(OCCCOC)c1)C(C)C)C(C)C)C(=O)O

Procedure:
The starting material is prepared analogously to Example 124 b) from 3-tert-butoxycarbonyl-5(S)-(2(S)-carboxy-3-methyl-butyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine (Example 124 c) and 3-amino-2,2-diethylpropionic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([N:36]4[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[N:38]([CH3:45])[C:37]4=[O:46])[CH2:32][CH2:31]3)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(Cl)Cl>FC(F)(F)C(O)=O>[CH3:45][N:38]1[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[N:36]([CH:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][N:14]3[C:11]4[CH2:12][CH2:13][NH:8][CH2:9][C:10]=4[C:16]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=4)=[N:15]3)[CH2:31][CH2:32]2)[C:37]1=[O:46]
Reactant: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCN(C(=O)OC(C)(C)C)C4)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(C2CCN(CCCn3nc(-c4ccc(C(F)(F)F)cc4)c4c3CCNC4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
1-{3-[4-(3-Methyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (1.19 g, 1.86 mmol) was dissolved in trifluoroacetic acid (5 mL) and CH2Cl2 (5 mL) and allowed to stir at room temperature for 2 h. The reaction mixture was concentrated, diluted with CH2Cl2, and washed with saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to afford 1-methyl-3-(1-{3-[3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin4-yl)-1,3-dihydro-benzoimidazol-2-one (0.955 g, 96%) as a white foam. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.19. MS (electrospray) calculated for C29H33F3N6O, 539.3 ([M+H]+), m/z found, 539.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)n(C)c1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1=CCCC=CCC1
Solvent: O
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(S(N)(=O)=O)cc1

Procedure:
In analogy to example 203, step 1, 5-[(E)-3-(4-chloro-2-methyl-phenyl)-acryloyl]-1-methyl-1H-pyridin-2-one (example 323, step 3) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a colourless solid, MS (ESI+): m/z=445.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc21

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (46 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (68 mgs) were converted to the title compound (64 mgs as a tan solid). 1H-NMR (CDCl3, 400 MHz): 9.82 (s, 1H), 8.95 (broad s, 1H); 8.41 (d, J=8.4 Hz, 1H), 8.10 (s, 1H), 7.92 (d, J=7.8 Hz, 1H); 7.83 (s, 1H); 7.53 (t, J=7.6 Hz, 1H); 7.34 (t, J=7.8 Hz, 1H), 6.78 (s, 1H), 3.91 (s, 3H); 3.5 (s, 2H), 2.78 (s, 6H), 2.65-2.0 (broad m, 6H), 1.17 (t, 7.1 Hz, 3H); LC/MS: found (M+H)+=545.21; MP: 147-153° C.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14](=[O:24])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[CH:7]=1.CO.Cl>O>[C:22]([C:18]1[CH:17]=[C:16]([NH:15][C:14]([CH2:13][O:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:5]([OH:25])=[O:4])=[O:24])[CH:21]=[CH:20][CH:19]=1)#[N:23]
Reactant: COC(=O)c1cccc(OCC(=O)Nc2cccc(C#N)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1cccc(NC(=O)COc2cccc(C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.8 %

Procedure:
Add lithium hydroxide (0.15 g, 6.3 mmol) to a suspension of 3-[(3-cyano-phenylcarbamoyl)-methoxy]-benzoic acid methyl ester (0.94 g, 3.1 mmol) in a 1:1 mixture of MeOH:water (30 mL). Stir the mixture at room temperature for 15 h then adjust the pH of the reaction to slightly acidic by the addition of a 2 N solution of hydrochloric acid. A solid precipitates from solution. Collect by filtration, wash with water, and dry on the filter pad to provide 0.650 g of 3-[(3-cyano-phenylcarbamoyl)-methoxy]-benzoic acid as a solid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[C:15]1([NH:21][C:22](=[S:25])[NH:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([NH:21][C:22](=[S:25])[NH:23][N:24]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=S)Nc1ccccc1
Agent: Cl
Product: O=c1c(=NNC(=S)Nc2ccccc2)c(=O)c2ccccc12

Procedure:
ninhydrin, 4-phenyl thiosemicarbazide hydrochloride
Reaction SMILES: C([C@@:4]1([OH:37])[C@@:9](C(=O)C)([OH:10])[C@@:8](C(=O)C)([OH:14])[C@@H:7]([CH:18](C(=O)C)[OH:19])[O:6][C@H:5]1[O:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=1[N+:34]([O-:36])=[O:35])[C:27]([O:29][CH3:30])=[O:28])(=O)C.CO>C(N(CC)CC)C>[C@@H:5]1([O:23][C:24]2[CH:25]=[C:26]([CH:31]=[CH:32][C:33]=2[N+:34]([O-:36])=[O:35])[C:27]([O:29][CH3:30])=[O:28])[O:6][C@H:7]([CH2:18][OH:19])[C@H:8]([OH:14])[C@H:9]([OH:10])[C@H:4]1[OH:37]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O[C@@H]2O[C@H](C(O)C(C)=O)[C@@](O)(C(C)=O)[C@@](O)(C(C)=O)[C@]2(O)C(C)=O)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([N+](=O)[O-])c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1

Procedure:
The tetracetate IV (119 g, 0.226 mole) was added to methanol (1000 ml). The mixture was heated at 60° until the solid dissolved. Triethylamine (25 ml) was then added, and the solution was heated at 60° for an additional two hours. The crude solid product was obtained in several crops by evaporation of the solution, the final crop being taken from a 20 ml volume. The crude material was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:5]2[NH:6][C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[F:12][C:11]1[C:2]([F:1])=[CH:3][C:4]2[NH:8][C:7]([S:9][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:6][C:5]=2[CH:10]=1
Reactant: Fc1cc2[nH]c(=S)[nH]c2cc1F
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc(F)c(F)cc3[nH]2)o1
Temperature: 25 °C
Yield: 77.1 %

Procedure:
5,6-Difluoro-1,3-dihydro-benzimidazole-2-thione (1.0 g, 5.37 mmol) is suspended into 50 mL of tetrahydrofuran under argon. Then, 0.39 g (8.06 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (0.76 g, 5.37 mmol) is then added and the reaction mixture is stirred at room temperature for 16 h, upon which it is poured on ice and extracted 3 times with ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 200 g 15-40 μm silica gel cartridge (eluting solvent: dichloromethane/methanol 95/5 v/v; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is recrystallized from ethyl acetate/n-heptane, filtered, washed with n-heptane and dried under reduced pressure. 1.16 g of 5-(5,6-difluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a crystalline brown powder. mp: 133° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](Br)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH:17]=[C:16]([C:28]2[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(OC)c1OC
Reactant: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
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: O
Solvent: CCO
Product: COc1cc(-c2cn(Cc3ccccc3)c(=O)c3ccccc23)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 17 h
Yield: 55.4 %

Procedure:
A mixture of 2-benzyl-4-bromoisoquinolin-1(2H)-one (0.420 g, 1.34 mmol), 4,4,5,5-tetramethyl-2-(3,4,5-trimethoxyphenyl)-1,3,2-dioxaborolane (0.511 g, 1.74 mmol) and Na2CO3 (0.425 g, 4.01 mmol) in toluene (20 mL), ethanol (10 mL) and water (3 mL) was degassed under nitrogen. Pd(PPh3)4 (0.154 g, 0.13 mmol) was then added and the reaction mixture was stirred at 100° C. for 17 h under nitrogen. After that time, the mixture was cooled to rt and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 hexanes/ethyl acetate to 75:25 hexanes/ethyl acetate) to give 2-benzyl-4-(3,4,5-trimethoxyphenyl)isoquinolin-1(2H)-one (0.298 g, 55%) as an off white solid: mp 166-168° C.; 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J=7.8 Hz, 1H), 7.49-7.66 (m, 3H), 7.28-7.41 (m, 5H), 7.08 (s, 1H), 6.57 (s, 2H), 5.28 (s, 2H), 3.91 (s, 3H), 3.85 (s, 6H); ESI MS m/z 402 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH2:12].Cl[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24](=[O:28])[O:25]2)=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN1CCCC1=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:22]=[CH:23][C:24](=[O:28])[O:25][C:26]=2[CH:27]=1
Reactant: NCC1COc2ccccc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=c1ccc2ccc(OCCCNCC3COc4ccccc4O3)cc2o1
Temperature: 80 °C
Yield: 29.9 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine (1.7 g, 10 mmole), 7-(3-chloropropoxy)coumarin (2.4 g, 10 mmole), diisopropylethylamine (1.3 g, 10 mmole) and sodium iodide (5.0 g, 33 mmole) were combined in 100 ml of N-methylpyrrolidinone and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with 300 ml of dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was column chromatographed on 100 g of silica gel using chloroform as eluant. The product-containing fractions (Rf=0.15 on silica gel tlc with 1% methanol/chloroform) were combined and concentrated in vacuum and the residue crystallized from isopropanol with the addition of 4N isopropanolic HCl to give 1.1 g of title compound as a tan solid, monohydrochloride, m.p. 213°-215° C.