Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[C:9](=[CH:15][N:16](C)C)[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([S:20][CH3:21])[C:3]=1[F:22].O.[CH2:24]([OH:26])[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH:9]([CH:15]=[N:16][O:26][CH2:24][CH3:25])[C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[C:4]([S:20][CH3:21])[C:3]=1[F:22]
Reactant: CCO
Reactant: CSc1c(C(=O)C(=CN(C)C)C(=O)C2CC2)ccc(Cl)c1F
Solvent: O
Product: CCON=CC(C(=O)c1ccc(Cl)c(F)c1SC)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-chloro-3-fluoro-2-methylsulphenylphenyl)-3-cyclopropyl-2-(dimethylaminomethylene)-propan-1,3-dione (3 g) and O-ethylhydroxylaminehydrochloride (1 g) in ethanol (20 ml) was stirred at 25° C. for 2 hours. The mixture was poured into water and extracted with dichloromethane. The solution was dried (anhydrous sodium sulphate) and filtered. The filtrate was evaporated and the mixture purified by column chromatography on silica, using a mixture of ethyl acetate and hexane as eluent. The resulting solution was evaporated and 1-(4-chloro-3-fluoro-2-methylsulphenylphenyl)-3-cyclopropyl-2-(ethoxyiminomethyl)-propan-1,3-dione (compound 5) was obtained as a reddish gum (2.4 -g), NMR (CDCl3) δ 1.1-1.4(m, 7H), 2.7(m, 1H), 2.4(s, 3H), 3.9(m, 2H), 7.0(m, 1H), 7.3(m, 1H), 7.6(s, 1H), 17.4(s, 1H) ppm.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[C:18]3=[N:19][C:20](Cl)=[N:21][CH:22]=[C:17]3[CH2:16][N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=3[F:32])[C:14]2=[O:33])[CH2:9][CH2:8]1)(C)(C)C.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:25]1[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:24]=1[N:15]1[CH2:16][C:17]2[C:18](=[N:19][C:20]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)=[N:21][CH:22]=2)[N:13]([C@H:10]2[CH2:9][CH2:8][C@H:7]([OH:6])[CH2:12][CH2:11]2)[C:14]1=[O:33]
Reactant: COc1ccc(N2Cc3cnc(Cl)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)C2=O)c(F)c1
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(Nc2ncc3c(n2)N([C@H]2CC[C@H](O)CC2)C(=O)N(c2ccc(OC)cc2F)C3)cc1
Temperature: 160 °C

Procedure:
A mixture of 1-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-7-chloro-3-(2-fluoro-4-methoxy-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.20 g, 0.38 mmol) (from Example 17c supra), p-anisidine (61.5 mg, 0.50 mmol) (Aldrich) and p-toluenesulfonic acid monohydrate (95.1 mg, 0.50 mmol) (Aldrich) in 2-propanol (4 mL) was placed in a microwave reactor (SmithSynthesizer™). The reaction mixture was heated at 160° C. for 15 minutes. After cooling, it was concentrated under reduced pressure and purified by RP-HPLC (C-18, eluted with acetonitrile-water) to give 3-(2-fluoro-4-methoxy-phenyl)-1-(trans-4-hydroxy-cyclohexyl)-7-(4-methoxy-phenylamino)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one. (Yield 0.12 g, 61%).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:20][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)CN
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C

Procedure:
In a DMF solution containing 2.0 g of Boc-Val-OH, 0.92 ml of isobutylamine, 1.40 g of HOBt and 2.28 g of DCC were added under ice cooling and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 51 (Process 1) to give 1.89 g of the title compound.
Reaction SMILES: [CH2:1]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[CH2:3][CH2:2]1.[C:13](=O)([O:16]C)[O:14][CH3:15].[H-].[Na+].Cl>CO>[O:5]=[C:4]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[CH2:12][CH2:1][CH2:2][CH:3]1[C:13]([O:14][CH3:15])=[O:16]
Reactant: O=C1CCCCc2ccccc21
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCc2ccccc2C1=O
Temperature: 80 °C

Procedure:
A mixture of benzosuberone (8 g, 50 mmol) and neat dimethyl carbonate (45 mL) at ambient temperature under nitrogen was treated with sodium hydride (60% in mineral oil, 4 g, 100 mmol) in 0.1 mL of dry methanol, heated at 80° C. for 3 hours, cooled to ambient temperature, treated with 2 N hydrochloric acid (55 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate) and concentrated to provide the title compound as an oil, as a 3:1 mixture of enol and keto forms of product determined by NMR spectroscopy. The NMR of the main enol form was: 1H NMR (CDCl3) δ 2.03-2.16 (m, 4H), 2.64 (m, 2H), 3.82 (s, 3H), 7.23 (m, 1H), 7.33 (m, 2H), 7.62 (m, 1H), 12.6 (br s, 1H); MS (ESI+) m/z 219 (M+H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([CH2:9][OH:10])[NH:7]1)=[O:5])[CH3:2].[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH:8]([CH2:9][O:10][Si:15]([C:12]([CH3:14])([CH3:13])[CH3:11])([CH3:17])[CH3:16])[NH:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H]1N[C@@H]1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1NC1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In a flame dried flask equipped with a magnetic stirring rod and a rubber septum with a N2 inlet was added (S,S) 3-hydroxymethylaziridine-2-carboxylic acid ethyl ester (296 mg, 2.04 mmol) and 12 ml of CH2Cl2. The reaction vessel was cooled to 0° C. then TBDMSCl (377 mg, 2.50 mmol) and DMAP (623 mg, 5.1 mmol) was added. The reaction was allowed to stir for 1 hour at 0° C. then at room temperature until the reaction was completed according to TLC (Rf=0.65; 7:3 hexanes/EtOAc). The reaction was diluted with CH2Cl2 then water was added. The organic layer was extracted three times, and the combined organic layers were washed first with saturated NaHCO3, then water, then brine and dried over solid Na2SO4. The mixture was filtered and dried under reduced pressure to afford a pale yellow oil, which was subjected to flash column chromatography (silica gel; 8:2 hexanes/EtOAc) to afford the title compound as a thick colourless oil in 99% yield. 1H NMR (CDCl3, 400 MHz) δ: 4.21 (q, J=3.6 Hz, 2H), 3.66 (dd, J=11.2 Hz, 5.2 Hz, 1H), 3.56 (dd, 10.8 Hz, 4.8 Hz, 1H), 2.42 (m, 2H), 1.37 (bt, 1H), 1.29 (t, J=7.2 Hz, 3H) ppm. 13C NMR (CDCl3, 100 MHz) δ: 172.6, 64.8, 61.7, 40.3, 33.7, 26.1, 18.5, 14.4, −5.1 ppm. HRMS (ESI) [M+H]+ calcd. for C12H25NO3Si 260.1676, found 260.1675.
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=[O:3].[CH2:7]([N:9]1C(=O)C(O)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:10]1(=[O:27])=[O:26])[CH3:8].CN(C=O)C>C(Cl)Cl>[Cl:6][C:1]1[C:2](=[O:3])[N:9]([CH2:7][CH3:8])[S:10](=[O:27])(=[O:26])[C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=1
Reactant: CCN1C(=O)C(O)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN1C(=O)C(Cl)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Yield: 60.5 %

Procedure:
Oxalyl chloride (0.379 g, 2.99 mmol) was added dropwise to a solution of 2-ethyl-4-hydroxy-5-[4-(trifluoromethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide (0.480 g, 1.49 mmol) and DMF (0.109 g, 1.49 mmol) in DCM (12 mL). The mixture was refluxed for 1 h. It was evaporated and water was added. The resulting mixture was extracted with EtOAc, and the combined organic layers were washed with brine and evaporated to give the title compound (0.306 g, 71%) as a solid; 1H NMR (500 MHz, DMSO-d6): δ 8.07-8.11 (m, 4H), 3.81 (q, 2H), 1.33 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29](O)=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.[NH2:50][NH:51][C:52]([NH2:54])=[O:53]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:11](=[O:26])[C@:10]([CH2:28][C:29]([NH:50][NH:51][C:52]([NH2:54])=[O:53])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(N)=O
Reactant: CCC(CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(CC)N1C(=O)[C@@](C)(CC(=O)NNC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 320 mg (0.69 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic acid (Example 71, Step F) and 921 mg (2.42 mmol) of HOBt in DMF (13 mL) was added 0.58 mL (4.15 mmol) of triethylamine. After stirring at room temperature for 40 min, added 270 mg (2.42 mmol) of semicarbazide hydrochloride. The resulting dark red solution was stirred at room temperature for 2.5 h, and then was concentrated under reduced pressure. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 90% MeCN in water over a 30 min period, where both solvents contain 0.1% TFA) provided the title compound as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[O:3]1.[NH4+:15].[OH-]>S(Cl)(Cl)=O.C(Cl)Cl>[O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:4]([CH2:11][C:12]([NH2:15])=[O:14])[O:3]1
Reactant: [NH4+]
Reactant: O=C(O)CC1OC(=O)c2ccccc21
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: NC(=O)CC1OC(=O)c2ccccc21

Procedure:
A solution of (3-oxo-1,3-dihydro-isobenzofuran-1-yl)-acetic acid (5.0 g, 26 mmol) in thionyl chloride (10 ml) was heated at 75° C. for 15 minutes. The excess thionyl chloride was removed under vacuum to give a red oil. The red oil was dissolved in CH2Cl2 (10 ml) and then the solution was slowly added to concentrated NH4OH (40 ml) at 0° C. The resultant solid was filtered and washed with water and hexane, followed by addition of toluene. Removal of the solvent led to 2-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)acetamide as a cream solid (4.2 g, 84%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:14][O:15][C:16](=[O:41])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:25](=[O:34])[C:26]#[C:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:18]=1>>[CH3:14][O:15][C:16](=[O:41])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)/[C:26](=[C:27](/[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)\[C:2]3[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=3)/[C:25]2=[O:34])[CH:18]=1
Reactant: COc1cc(I)cc(OC)c1OC
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cc(OC)c(OC)c(OC)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 5-Iodo-1,2,3-trimethoxy-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.76 (s, 6H), 3.91 (s, 3H), 3.94 (s, 3H), 4.96 (s, 2H), 6.55 (s, 2H), 6.61-6.71 (m, 4H), 7.06 (t, 1H), 7.38-7.40 (m, 5H), 7.53 (d, 1H), 7.91 (d, 1H), 8.02 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[C@@H:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:19][CH2:20][N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH3:43][S:44]([O:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([C@@H:18]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:19][CH2:20][N:21]([CH:25]([CH3:26])[CH3:27])[CH:22]([CH3:23])[CH3:24])[CH:11]=1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCO)ccc1OCc1ccccc1)C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOS(C)(=O)=O)ccc1OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl}ethanol (Prepared according to WO1998/43942, 1.0 g, 2.25 mmol) was dissolved in dichloromethane (20 ml) and N,N-diisopropyl ethylamine (1.8 ml, 10 mmol) added. The solution was then cooled to 0° C. and methanesulphonyl chloride (0.42 ml, 5.4 mmol) was added. After stirring for 2 hours at 0° C. the mixture was diluted with dichloromethane (20 ml) and washed with water (50 ml), brine (50 ml) and then dried (magnesium sulphate) and the solvent removed in vacuo to yield the title compound as a yellow oil, 1.56 g.
Reaction SMILES: O.OO.N[C:5]([NH2:7])=[O:6].[OH-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:42][CH2:41][C:20]2([CH2:23][N:22]([C@H:24]3[C:32]4[C:27](=[CH:28][C:29]([C:33]5[CH:34]=[N:35][C:36](C#N)=[CH:37][CH:38]=5)=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CCO>[C:10]([O:14][C:15]([N:17]1[CH2:42][CH2:41][C:20]2([CH2:23][N:22]([C@H:24]3[C:32]4[C:27](=[CH:28][C:29]([C:33]5[CH:34]=[N:35][C:36]([C:5](=[O:6])[NH2:7])=[CH:37][CH:38]=5)=[CH:30][CH:31]=4)[CH2:26][CH2:25]3)[CH2:21]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: NC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C#N)nc4)ccc31)C2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C(N)=O)nc4)ccc31)C2
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a solution of water (150 mL) and urea hydrogen peroxide (916 mg, 9.45 mmol) was added sodium hydroxide (220 mg, 5.51 mmol) and the reaction was stirred at room temperature. Once a clear solution was obtained, the reaction was placed in an ice bath and fitted with an addition funnel. A solution of 2-[(R)-5-(6-cyano-pyridin-3-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (4-1c, 700 mg, 1.58 mmol) in 50 mL EtOH was added dropwise via the funnel over 30 minutes. The reaction was warmed to room temperature and was stirred overnight. The reaction mixture (a white suspension) was filtered and the solids were washed with 50 mL water and air-dried to give 440 mg (60%) of the title compound as an off-white powder. MS (ES+) 463.1 (M+H)+. 1H NMR (DMSO-d6) δ 1.39 (s, 9H), 1.54-1.62 (m, 4H), 1.81-1.91 (m, 1H), 2.06 (dd, 1H), 2.76-2.87 (m, 1H), 2.94-3.02 (m, 3H), 3.10 (d, 2H), 3.24 (br s, 4H), 3.86 (dd, 1H), 7.40 (d, 1H), 7.55 (d, 1H), 7.62-7.68 (m, 2H), 8.09 (d, 1H), 8.12 (br s, 1H), 8.22 (dd, 1H), 8.89 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/B(O)O>>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/c1ccc(F)cc1F
Reactant: COC(=O)c1ccccc1S(=O)(=O)c1ccc(Br)cc1
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2F)cc1

Procedure:
The title compound was prepared according to the method described in Example 138, Step 3 using methyl 2-[(4-bromophenyl)sulfonyl]benzoate (Step 1) in place of (1S)-1-[2-({4-bromo-3-methylphenyl}sulfonyl)phenyl]ethanol and [(E)-2-(2,4-difluorophenyl)vinyl]boronic acid (Step 2) in place of [(E)-2-(4-fluorophenyl)vinyl]boronic acid. δH (500 MHz, d6 DMSO): 8.22-8.20 (1H, m), 7.94-7.80 (7H, m), 7.69-7.63 (1H, m), 7.44 (1H, d, J 16.4), 7.39 (1H, d, J 16.4), 7.35-7.30 (1H, m), 7.19-7.15 (1H, m), 3.87 (3H, s). m/z (ES+) 383 [(M-MeO)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH:42]([NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([CH3:44])[CH3:43]>C(Cl)Cl>[CH:42]([N:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:44])[CH3:43]
Reactant: CC(C)Nc1ccccc1
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCN(c1cc(Cl)cnc1C(=O)N(c1ccccc1)C(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (229 mg, 0.50 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 2 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-isopropylaniline (135 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), then quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-isopropyl-N-phenylamide. MS m/z 576.0 (M+H); 544.0 (M+H-MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=CN(C)C)[C:5]#[N:6].I([O-])(=O)(=O)=[O:16].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:16])[C:5]#[N:6]
Reactant: CN(C)C=Cc1ccc(C#N)cc1Cl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude 3-chloro-4-[2-(dimethylamino)vinyl]benzonitrile obtained in this way is taken up in 500 ml of THF/water (1:1), and 77.6 g (362.9 mmol) of sodium periodate are added. The mixture is stirred at room temperature for 18 h, and then the precipitate which has separated out is removed by filtration. The filtrate is mixed with saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases are dried with sodium sulfate, and the solvent is removed in a rotary evaporator. The crude product is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 7:3). 3.0 g (15% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH2:17].[C:19](Cl)(Cl)=[O:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N:17]=[C:19]=[O:20]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Solvent: Cc1ccccc1
Product: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N=C=O
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester (100 mg, 0.379 mmol) in dry toluene (1.5 mL) was added a solution of phosgene in toluene (20%, 1.5 mL) at −15° C. After warming to r.t., a stream of phosgene was introduced into the suspension and simultaneously heating was started. At reflux, the stream of phosgene was maintained for one hour, then replaced by a stream of argon for an additional hour. The toluene was distilled off leaving 2-isocyanato-5-nitro-4-trifluoromethyl-benzoic acid methyl ester (110 mg, 100%) as a beige solid. IR (CHCl3): 2260 cm−1 (s). 1H-NMR (CDCl3, 360 MHz): 4.05 (s, 3H), 7.55 (s, 1H), 8.65 (s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[N:33]=[C:34]=[O:35].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:34]([NH:33][C:24]3[CH:25]=[CH:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=3)=[O:35])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccc5ccccc5c4)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 63 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 2-naphthyl isocyanate (0.26 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 96:4 methylene chloride-methanol, to provide 0.46 g of the product in 70% yield: mp 201-203° C.; 1H NMR (DMSO-d6) δ 2.07-2.11 (m, 1H), 2.54-2.66 (m, 2H), 2.85-2.91 (m, 1H), 4.75 (d, J=6.0 Hz, 2H), 5.18 (dd, J=12.6 Hz, d=5.4 Hz, 1H), 6.88 (t, J=6.0 Hz, 1H), 7.28-7.34 (m, 1H), 7.38-7.45 (m, 2H), 7.70-7.88 (m, 6H), 8.05 (d, J=1.6 Hz, 1H), 9.05 (s, 1H), 11.20 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 31.0, 38.8, 48.9, 112.7, 119.4, 121.9, 123.6, 126.2, 126.8, 127.2, 127.4, 128.3, 128.8, 131.7, 133.8, 134.8, 137.9, 140.2, 155.3, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C25H20N4O5.0.5H2O: C, 64.51; H, 4.54; N, 12.03. Found: C, 64.87; H, 4.88; N, 11.59.
Reaction SMILES: C[NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Br:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40]([OH:42])=O)[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23>>[Br:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40](=[O:42])[NH:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=3[CH2:18][C:19]([O:21][CH3:22])=[O:20])[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CNc1ccc(CNC(=O)OC(C)(C)C)cc1CC(=O)OC
Product: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 60.8 %

Procedure:
A procedure similar to that described in Example 9-7) was performed with methyl 4-tert-butoxycarbonylaminomethyl-2-methoxycarbonylmethylaniline (7.63 g, 22.51 mmol) and (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (6.03 g, 21.43 mmol) to give 8.02 g of the title compound (61%).