Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=2)=[N:9][S:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[C:29]([CH3:40])[C:28]=1[CH3:41]>>[CH2:24]([C:21]1[CH:22]=[CH:23][C:18]([C:8]2[C:7]([CH2:6][O:5][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:29]([CH3:40])[C:28]=3[CH3:41])=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:10][N:9]=2)=[CH:19][CH:20]=1)[CH3:25]
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CCc1ccc(-c2nsc(-c3ccccc3)c2COS(C)(=O)=O)cc1
Product: CCc1ccc(-c2nsc(-c3ccccc3)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 2-6 by coupling of (3-(4-ethylphenyl)-5-phenylisothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.1 Hz, 2H), 7.58-7.59 (m, 2H), 7.42 (t, J=3.0 Hz, 3H), 7.22 (s, 2H), 6.94 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 4.83 (s, 2H), 2.97 (t, J=8.4 Hz, 2H), 2.60-2.70 (m, 2H), 2.28 (s, 3H), 2.24 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C29H29NO3S, 472.2 (M+H). found 472.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:23][PH:24]([O-])([O-:28])[O:25][CH2:26][CH3:27].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][C:12]([CH3:15])([S@@:10]([NH:9][C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:24]([CH3:23])(=[O:28])[O:25][CH2:26][CH3:27])=[CH:3][CH:4]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@@](=O)C(C)(C)C)c2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 68 %

Procedure:
To (S)—N—((S)-(4-bromophenyl)(4-fluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 19-b, (10 g, 0.026 mol), ethyl methylphosphite (5.6 g, 0.052 mol) and Et3N (7.88 g, 0.78 mol) in THF (100 ml) was added PdCl2(dppf) (2.2 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into dichloromethane and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel (petroleum ether:ethyl acetate=1/1) to provide the product, 19-c, (6.9 g, 68%).
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20][CH2:21][CH3:22].C1C=C(Cl)C=C(C(OO)=[O:32])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:23][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH2:18][CH3:19])[C:4]=1[S:20]([CH2:21][CH3:22])=[O:32]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SCC)c1CC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(=O)CC)c1CC

Procedure:
Prepared from product of Example 5 (7.0 g, 19.6 mmol) and MCPBA (3.98 g of an 85% mixture with MCBA, 19.6 mmol) as described above. Recrystallization (ether/petroleum ether) afforded the product as a white solid (6.56 g).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=O)=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1)[CH2:7][CH3:8].C(Cl)Cl>CN(C=O)C>[C:25]([C:24]1[CH:28]=[CH:29][C:21]([C@H:18]2[CH2:17][CH2:16][C@H:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([CH2:6][CH2:7][CH3:8])[CH2:10][CH2:11]3)[CH2:20][CH2:19]2)=[CH:22][CH:23]=1)#[N:27]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(N)=O)cc3)CC2)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)CC1

Procedure:
A solution of 32.6 g of p-(trans-4-(trans-4-propyl-cyclohexyl)-cyclohexyl)-acetophenone in 100 ml of dioxane is added dropwise to a solution of 40 g of NaOH and 48 g of bromine in 230 ml of water at 20°, while stirring. Stirring is continued for 1 hour. A solution of 14 g of NaHSO3 in 140 ml of water is added and hydrochloric acid is added until the pH is 5. Customary working up (CH2Cl2) gives p-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)-benzoic acid. The crude product is boiled with 60 ml of SOCl2 for 2.5 hours. After evaporation, the resulting crude acid chloride is dissolved in 430 ml of dioxane, 200 ml of 25% aqueous ammonia is added and the mixture is poured onto ice and filtered to give p-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)-benzamide. 65 g of POCl3 is added dropwise to a solution of 32.7 g of this amide in 500 ml of DMF at 50°, while stirring. After the mixture has been further stirred for 1 hour, it is poured onto ice and worked up in the customary manner (CH2Cl2) to give trans-1-p-cyanophenyl-4-(trans-4-propyl-cyclohexyl)-cyclohexane, m.p. 55°, c.p. 184°.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:42][C:43]([N:45]([CH2:47][CH3:48])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH2:47][CH3:48])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(C)CCOc1ccc(CN(CC)c2cc(OC)c(OC)cc2C2CCc3cc(O)ccc3C2)cc1F
Yield: 11.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-ethyl-N-methylacetamide (9.5 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.ClC1C(OC)=CC(OC)=C(Cl)C=1C1N=C2NN=C([C:50]3[CH:51]=[C:52]4[C:57](=[CH:58][CH:59]=3)[O:56][CH:55]([C:60]([N:62]([CH3:64])[CH3:63])=[O:61])[CH2:54][CH2:53]4)C2=CN=1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:50]3[CH:51]=[C:52]4[C:57](=[CH:58][CH:59]=3)[O:56][CH:55]([C:60]([N:62]([CH3:64])[CH3:63])=[O:61])[CH2:54][CH2:53]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc5c(c4)CCC(C(=O)N(C)C)O5)n[nH]c3n2)c1Cl
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CCC(C(=O)N(C)C)O5)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and N,N-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chromane-2-carboxamide (Example 2, Step 2). LCMS (M+H)+=495.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])O.[Na+]>ClCCl>[CH:19]1([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(NC3CCCCC3)nnc(Cc3ccncc3)c2c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 0.56 %

Procedure:
A mixture of 0.3 g (1.173 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.523 g (5.278 mmol) cyclohexylamine is stirred for 8 h at 115° C. The cooled reaction mixture is then distributed between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic solution washed with brine and dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol (19:1). Title compound (with water content of 0.56%) is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV; m.p. 137-139° C.; ESI-MS: (M+H)+=319.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:26]([O:28]CCO)C>>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:2]3[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=3[NH:9][C:26]2=[O:28])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOCCO
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCN(Cc2ccccc2)CC1

Procedure:
A solution of 38.4 g of 2,4-dichloro-1-nitrobenzene in 160 ml of 2-ethoxyethanol is heated to 100° C. A solution of 152.23 g of N-benzyl-4-aminopiperidine in 40 ml of 2-ethoxyethanol is then added slowly. The mixture is maintained at reflux for 5 hours. The solvent is evaporated off under vacuum and the residue is taken up in H2O, extracted with EtOAc, washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with isopropyl ether. 24.4 g of the expected product are obtained after crystallization from isopropyl ether, mp=84° C.
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].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[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:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([F:23])=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(F)c(C(F)(F)F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) and 4-fluoro-3-trifluoromethyl-benzoyl chloride (0.6 g, 2.8 mmol) in dry methylene chloride (60 mL), was added diisopropylethylamine (0.7 g, 5.4 mmol). After stirring at room temperature overnight, the reaction mixture was quenched with methanol (1 mL). The resulting suspension was filtered, and the solid was washed with methyene chloride to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-fluoro-3-trifluoromethyl-benzamide (0.8 g, 79%) as a white solid: mp 171-173° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=7.5 min. (99%); 1H NMR (DMSO-d6) δ 2.06-2.12 (m, 1H), 2.54-2.65 (m, 2H), 2.85-2.98 (m, 1H), 4.97 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5.4 and 12.5 Hz, 1H), 7.68 (t, J=8.9 Hz, 1H), 7.76-7.84 (m, 3H), 8.28-8.35 (m, 2H), 9.43 (t, J=5.7 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.91, 30.86, 38.43, 48.82, 116.20 (116.37, 116.64, 116.80), 117.35 (117.63), 120.50 (124.10), 121.92, 126.51 (126.56), 127.14, 130.65 (130.70), 131.48, 133.22, 134.58, 134.71 (134.77), 138.70, 158.78 (162.21), 164.19, 166.87, 167.44, 169.75, 172.68; Anal. Calcd. for C22H15N3O5F4+0.2H2O: C, 54.94; H, 3.23; N, 8.74; F, 15.80. Found: C, 54.68; H, 3.17; N, 8.63; F, 15.72.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][C:16]([O:18]C)=[O:17])[CH2:11][CH2:10]1.[OH-].[Na+].Cl>C(OCC)(=O)C.O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]1
Reactant: COC(=O)C[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1
Temperature: 40 °C
Yield: 52.6 %

Procedure:
To a round 25 ml bottomed flask containing cis-methyl [4-(2,4-dihydroxyphenyl)cyclohexyl]acetate (10 mg, 0.038 mmol) and water (4 ml) was added sodium hydroxide (5 mg, 0.13 mmol) and the solution heated to 40° C. for 1 hr. The solution was poured into a separating funnel containing ethyl acetate (15 ml) and water (10 ml). To the aqueous layer was then added aqueous hydrochloric acid (10 ml, 1.0M) and ethyl acetate (20 ml). The layers were separated and the aqueous layer extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (15 ml), dried over magnesium sulfate, filtered and concentrated in vacuo affording the title compound (5 mg, 55%) as a solid. m/z (ES+) 251 (M+H+); δH(CD3OD) 1.61-1.77 (8H, m), 2.30 (1H, m), 2.49 (2H, d), 2.84 (1H, m), 6.27 (2H, m), 6.96 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[CH3:16][C:17]([CH3:19])=O>C(O)C.[Pd]>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][CH:17]([CH3:19])[CH3:16])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Reactant: CC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(NC(C)C)ccc21

Procedure:
To a solution of 4.1 g (20.0 mmol) of compound obtained in Example 4 in 4 ml of acetone and 96 ml of anhydrous ethanol there is added 10% Pd—C catalyst. The mixture is hydrogenated under a hydrogen pressure of 3-3.5 kg/cm2. After the absorption of hydrogen is complete, the catalyst is filtered off and the filtrate is concentrated in vacuo to dryness. The residue is crystallised from dilute ethanol to give the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:17]([NH:21][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH3:7])=[N:9][CH:10]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(C(=O)O)cn1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)NC(C)(C)C)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
3.5 ml (40 mMol) Oxalylchloride and 57.4 □l (0.74 mMol) DMF were added to a suspension of 5.0 g (36.5 mMol) 6-methyl-nicotinic acid in 25 ml toluene and the system was heated to 40° C. for one hour. After diluting with 20 ml toluene and cooling to 0° C., 11.5 ml (109 mMol) tert.-butylamine were slowly added. After 30 minutes stirring at room temperature, 25 ml aqueous NaOH 2N were added and stirring pursued for 30 minutes. The phases were separated and the aqueous phase was extracted with toluene. The combined organic extracts were washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (eluent: ethyl acetate/n-heptan 1:1) to yield 5.4 g (77%) N-tert.-butyl-6-methyl-nicotinamide as a light beige solid of m.p. =103.5-104.8° C.
Reaction SMILES: [Cl-:1].[K+].O=O.[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[C:6]1[CH3:7].CC1CC(=O)OC1=O>O>[Cl:1][CH2:7][CH:6]1[CH2:8][C:9](=[O:10])[O:11][C:5]1=[O:12]
Reactant: CC1=CC(=O)OC1=O
Reactant: [Cl-]
Agent: CC1CC(=O)OC1=O
Agent: O=O
Agent: [K+]
Solvent: O
Product: O=C1CC(CCl)C(=O)O1
Reaction time: 2 h

Procedure:
Next, the reacted gas was passed through a layer in a Pyrex tube (diameter: 2.5cm) packed with 20cc of an oxychlorinating catalyst comprising silica-alumina carrying 5% by weight of potassium chloride and 5% by weight of cupric chloride, at a temperature of 250°C while introducing oxygen in an amount of 1000cc/hour. The water generated was trapped in a vessel and the chlorine gas recovered was circulated, whereby the reaction was carried out for 2 hours. After completion of the reaction, the product was analyzed using gas chromatography, and it was confirmed that the product contained 7.4g of citraconic acid anhydride and 1.8g of methylsuccinic acid anhydride. In addition, a small amount of chloromethylsuccinic acid anhydride was formed.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[CH2:3]1.[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C.CCN(CC)CC.CCOC(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>[F:10][C:11]1[C:12]([C:9]#[C:8][CH2:7][N:4]2[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: C#CCN1CC[C@@H](O)C1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CC[C@@H](O)C3)c21

Procedure:
Using Method C above, (R)-3-Hydroxy-1-prop-2-ynyl-pyrrolidine (60 mg, 0.48 mmol) (Example 92A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.16 mmol) (Starting Material 6) using (Ph3P)4Pd (18 mg, 0.02 mmol) and a catalytic amount of Cul in a mixture of DMF (4 mL) and Et3N (4 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-[3-(3-hydroxy-pyrrolidin-1-yl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-20% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 45 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH2:27])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:28])[CH2:26][NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH3:23]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.396 g (10 mmol) of glycine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](Cl)(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].O>CN(C=O)C>[CH3:14][CH:13]([CH3:15])[CH2:12][C:11]([NH:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:16]
Reactant: Nc1cnccc1C(=O)O
Reactant: CC(C)CC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(=O)Nc1cnccc1C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-aminoisonicotinic acid 1-1 (3.89 g, 28.16 mmol) in DMF at 0° C. was added isovaleryl chloride (3.73 g, 30.97 mmol) and the reaction was stirred at 0° C. After 2.5 h, water was added to the reaction mixture and a precipitate formed which was collected by filtration and washed with ether to afford the title compound as a bone colored powder. 1H NMR (500 MHz, CDCl3) δ 0.95 (d, J=7 Hz, 6H), 2.06-2.13 (m, 1H), 2.27 (d, J=7 Hz, 2H), 7.73 (d, J=4.5 Hz, 1H), 8.41 (d, J=5 Hz, 1H), 9.37 (s, 1H). MS [M+H] C11H14N2O3=223.1.
Reaction SMILES: O[C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19]CCBr>>[CH:12]1[C:13]2[C:8](=[N:7][C:6]3[C:15]([N:14]=2)=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH:9]=[CH:10][CH:11]=1.[CH:12]1[C:13]2[C:8](=[N:7][C:6]3[C:15]([N:14]=2)=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH:9]=[CH:10][CH:11]=1.[CH3:19][CH2:18][O:17][CH2:16][CH3:2]
Reactant: Oc1cccc2nc3ccccc3nc12
Reactant: COCCCCBr
Product: CCOCC
Product: c1ccc2nc3ccccc3nc2c1

Procedure:
Scheme 6 illustrates the synthesis of N-ethyl phenazine 1-hydroxybutyl methyl ether. The phenazine ether (21) is prepared by the alkylation of the 1-hydroxyphenazine (1) with 4-methoxybutylbromide (Aldrich Chemical Company, USA) to give phenazine derivative (21). N-ethyl phenazine (22) is prepared by reaction of compound (21) with diethyl sulfate in the presence of potassium carbonate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].CN(C(OC)OC)C.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[NH:35][CH2:36][CH2:37][NH:38][C:39]1[N:44]=C(C2C=CC(C(N)=O)=CC=2)C=[CH:41][N:40]=1.[O-]CC.[Na+]>C(O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:41][N:40]=[C:39]([NH:38][CH2:37][CH2:36][NH:35][C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:25]=3)[N:44]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CC(=O)c1ccc(C#N)cc1
Reactant: NC(=O)c1ccc(-c2ccnc(NCCNc3ccc4ccccc4n3)n2)cc1
Agent: CC[O-]
Agent: COC(OC)N(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cnc(NCCNc2ccc3ccccc3n2)nc1-c1ccc(C#N)cc1
Temperature: 80 °C

Procedure:
Ethyl 3-(4-cyanophenyl)3-oxopropanoate (64 mg, 0.3 mmol) was heated with DMFDMA (50 μl) and dry THF (1 ml) at 70° C. for 3 hours. The cooled mixture was then added to a suspension of amino[2-(2-quinolylamino)ethyl]carboxamidinium 4-methylbenzenesulfonate (prepared according to Example 12), (120 mg, 0.3 mmol) in ethanol (2 ml) containing 0.35 mmol of sodium ethoxide. The reaction was then heated at 80° C. overnight and then concentrated in vacuo. The residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was concentrated in vacuo. The residue was taken up in acetonitrile. Addition of water gave a precipitate which was filtered off and dried to give the title compound.