Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:47])[C@H:7]([CH2:26][S:27][C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH:8]C(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O)([CH3:4])[CH3:3].N1CCCCC1>CN(C=O)C>[CH3:4][C:2]([O:5][C:6](=[O:47])[C@H:7]([CH2:26][S:27][C:28]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[NH2:8])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OCc1cccc2c1Cc1ccccc1-2
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of N-fluorenylmethoxycarbonyl-S-trityl-L-cysteine 1,1-dimethylethyl ester (640 mg, 1 mmol) in 5 mL of DMF was added 2 mL of piperidine. The solution was stirred for 20 min., and the solvent was evaporated. The residual piperidine was removed by azeotroping the solid with DMF (3×20 mL) and drying under high vacuum for 1 hour to give S-trityl-L-cysteine 1,1-dimethylethyl ester as a solid. To this solid was added 5 mL of DMF followed by 1-(2-azidoethyl)cyclopentane carboxylic acid (6a) (183 mg, 1 mmol), HBTU (379 mg, 1 mmol), and DIPEA (0.18 mL, 1 mmol). The resulting solution was stirred for 5 hours, and the solvent was removed under high vacuum. The residue was purified by silica gel column chromatography usilng ethylacetate/hexanes (15/85) as eluent, to afford 500 mg (86%) of N-[[1-(2-azidoethyl)cyclopentyl]carbonyl]-S-triphenylmethyl-L-cysteinie 1,1-dimethylethyl ester.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[F:22].[C:23]1([CH3:54])[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([Sn](CCCC)(CCCC)CCCC)[CH:38]=3)[CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.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>[CH:13]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([C:36]4[CH:35]=[C:34]5[C:39](=[CH:38][CH:37]=4)[CH2:40][N:32]([S:29]([C:26]4[CH:27]=[CH:28][C:23]([CH3:54])=[CH:24][CH:25]=4)(=[O:31])=[O:30])[CH2:33]5)[C:11]=3[CH3:12])[C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8]2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(Br)c(F)cc2c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CN(S(=O)(=O)c1ccc(C)cc1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)c(F)cc2c1=O

Procedure:
In 1 ml of toluene was suspended 47 mg of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, and to this suspension were added 74 mg of 2-(p-toluenesulfonyl)-5-tributylstannylisoindoline and 1.5 mg of tetrakis(triphenylphosphine)palladium (0), after which the resulting mixture was heated under reflux for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue obtained was purified by a column chromatography (eluent: n-hexane:ethyl acetate=1:1), and diethyl ether was then added thereto, after which the crystals formed were collected by filtration, to obtain 27 mg of colorless, crystalline ethyl 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[N:14]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32]COC)=[CH:28][CH:27]=3)[N:23]=[C:22]3[N:36](C4CCCCO4)[N:37]=[C:38]([CH3:39])[C:21]=23)[CH2:13][C:12]1([CH3:47])[CH3:46])C)(C)(C)C.Cl>O1CCOCC1>[CH3:39][C:38]1[C:21]2[C:22](=[N:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[CH:25][C:20]=2[CH2:19][N:14]2[CH2:13][C:12]([CH3:46])([CH3:47])[N:11]([CH2:10][CH2:9][NH:7][CH3:6])[CH2:16][C:15]2([CH3:18])[CH3:17])[NH:36][N:37]=1
Reactant: COCOc1ccc(-c2cc(CN3CC(C)(C)N(CCN(C)C(=O)OC(C)(C)C)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CNCCN1CC(C)(C)N(Cc2cc(-c3ccc(O)cc3)nc3[nH]nc(C)c23)CC1(C)C
Reaction time: 1.5 h
Yield: 5.2 %

Procedure:
1320 mg of the crude (2-{4-[6-(4-Methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-2,2,5,5-tetramethyl-piperazin-1-yl}-ethyl)-methyl-carbamic acid tert-butyl ester were dissolved in 6 ml of 1,4-dioxane and treated with 4 ml of hydrochloric acid (4M in dry dioxane). After standing at rt for 1.5 h the volatiles were removed in vacuo. The residue was purified by preparative HPLC (C18 column, acetonitrile/water gradient) and 45 mg (5%) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[O:9])[N:3]=1.C[Si](C)(C)[C:12]([F:15])([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([OH:9])[C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1nccc(Cl)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1nccc(Cl)n1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Chloropyrimidine-2-carbaldehyde (283 mg, 1.99 mmol) was dissolved in tetrahydrofuran (11.4 mL) and cooled to 0° C. Trimethyl(trifluoromethyl)silane (0.37 mL, 2.38 mmol) was added followed by 1 M tetra-n-butylammonium fluoride in tetrahydrofuran (2.38 mL, 2.38 mmol). The ice bath was removed and the reaction was stirred for 1 hour. The reaction was then diluted with water and brine and extracted with ethyl acetate three times. The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting mixture was purified via silica gel chromatography (0-5% methanol in ethyl acetate) to afford the title compound.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[Li]CCCC.[C:34]([C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]2)=[CH:38][CH:37]=1)#[N:35]>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[C:45]2[CH2:46][CH2:47][N:42]([C:39]3[CH:40]=[CH:41][C:36]([C:34]#[N:35])=[CH:37][CH:38]=3)[CH2:43][CH2:44]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC(=Cc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
A suspension of the 4-fluorobenzyl triphenylphosphonium chloride (0.737 g, 1.81 mmol) in THF (10 mL) was treated with nBuLi (724 μL of a 1.6M solution in hexanes, 1.81 mmol) at 0° C., treated with 1-(4′-cyanophenyl)-4-oxopiperidine (prepared according to the procedure described in Synthesis 1981, 606-608, 0.300 g, 1.51 mmol), and gradually warmed to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to give the desired product. (0.268 g, 61%). MS (ESI) m/e 292 (M+H)+.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1>CC1C=CC=CC=1C.O1CCCC1>[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([P:2]([C:20]2[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=[C:18]([C:17]([F:16])([F:31])[F:30])[CH:19]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[OH:3])[CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1
Reactant: FC(F)(F)c1cc([Mg]Br)cc(C(F)(F)F)c1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1C
Product: Oc1ccccc1-c1ccccc1P(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 120 °C
Yield: 97.4 %

Procedure:
23.5 g (0.1 mol) of 6-chloro-6H-dibenz[c,e][1,2]oxaphosphorine in 200 ml of anhydrous o-xylene at 80° C. are introduced, in an argon atmosphere with stirring, and a solution of 0.23 mol of 3,5-di(trifluoromethyl)phenylmagnesium bromide in 300 ml of tetrahydrofuran is added dropwise. Tetrahydrofuran is distilled off and the temperature is slowly increased to 120° C. in the course of this. The mixture is then stirred for 3 hours at 120° C., cooled to room temperature, and 100 ml of water are added. The mixture is neutralized with dilute hydrochloric acid, the organic phase is separated off, dried with sodium sulfate and concentrated under reduced pressure. 61.0 g of black solid are obtained. By recrystallization from heptane, with addition of activated carbon, and subsequent hot filtration, 37.2 g (59%) of pale yellow crystals having melting point 120° to 121° C. are obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)[C:9]2[C:10](=[O:19])[NH:11][C:12]3[C:17]=2[C:16]=1[C:15]([F:18])=[CH:14][CH:13]=3.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:15]1[C:16]2[C:17]3[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[C:9]=3[C:8]([C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[CH:7][C:6]=2[NH:5][CH2:4][CH2:3][NH:2][C:25](=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCNc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Reaction time: 2 h

Procedure:
To a suspension of 5-(2-amino-ethylamino)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one hydrochloride salt (from Example 10 above) (35.5 mg, 0.1 mmol) in CH2Cl2 (2 mL) were added acetic anhydride (Fisher Scientific, 10.2 mg, 0.1 mmol) and triethylamine (Aldrich, 20.2 mg, 0.2 mmol) at room temperature. The reaction mixture was stirred for 2 hours at the same temperature and then quenched with a saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were successively washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate and hexanes, filtered, and dried to give N-[2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-ylamino]-ethyl]-acetamide as a brown solid. (Yield 13.5 mg, 38.4%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:26](=[O:27])[N:12]2[C:13]([C:23]([OH:25])=[O:24])=[C:14]([CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8].C(Cl)Cl.[C:31]1([C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N+]=[N-])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.CCOCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:26](=[O:27])[N:12]2[C:13]([C:23]([O:25][CH:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:24])=[C:14]([CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylic acid (stereoisomer A: 88 mg) in mixture (5 ml) of methanol and methylene chloride (1:1) is added a solution of diphenyldiazomethane in ether until the red color of the solution does no more disappear at 55° C on standing. After 3 hours, the reaction mixture is concentrated to give the residue which is stirred in a mixture of ether and petroleum ether. The supernatant is removed, and resulting precipitate is recrystallized from petroleum ether to give diphenylmethyl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylate (stereoisomer A: 85 mg). m.p. 161-163° C. Yield: 70%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCOCC3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-morpholino-2-phenylquinoxaline-6-carboxylate (136.4 mg, 0.39 mmol, 1.00 equiv) in methanol (12 mL), a solution of sodium hydroxide (78.2 mg, 1.96 mmol, 5.00 equiv) in water (2 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The resulting mixture was sent for prep-HPLC. This resulted in 56 mg (41%) of 3-morpholino-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>>[CH3:18][N:19]([CH3:23])[C:20]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CN(C)C(=O)Cl
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)N(C)C)cc23)CC1
Yield: 78.5 %

Procedure:
Beginning with 13.0 mg (0.056 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 6.4 mg (0.059 mMol) dimethyl carbamoyl chloride, 13.2 mg (79%) of the title compound were recovered.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:10]#[CH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:17]([SnH:21]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>>[Si:1]([O:8][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])/[CH:10]=[CH:11]/[Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC(CCCCC)O[Si](C)(C)C(C)(C)C
Product: CCCCCC(/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C(C)(C)C

Procedure:
Irradiation of 3-(tert-butyldimethylsilyloxy)-1-octyne (48, 2.05 g, 8.53 mmol) and tributyltin hydride (2.30 mL, 8.53 mmol) under the conditions described above yielded 50: 1H NMR (CDCl3) δ 6.04 (d, J=19.0 Hz, 1H), 5.93 (dd, J1 =19.0 Hz, J2 =5.2 Hz, 1H), 4.04 (dd, J1 =6.1 Hz, J2 =5.6 Hz, 1H), 1.52, 1.34 (2m, 26H), 0.94 (m, 21H), 0.07 (s, 3H), 0.05 (s, 3H). 1H NMR analysis revealed that 50 was only 85% pure and presumably contained the same isomeric impurities as did 49.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:22])[C:16]=1[CH3:32].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH3:62][C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[C:65]([NH2:70])[CH:64]=1>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:69][C:66]2[CH:67]=[CH:68][C:63]([CH3:62])=[CH:64][C:65]=2[NH2:70])=[O:31])=[O:22])[C:16]=1[CH3:32]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Reactant: Cc1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)CCCCCNC(=O)c2c(C)[nH]c(C=NN=C3C(=O)Nc4ccc(F)cc43)c2C)c(N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (441 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-methyl-o-phenylenediamine (146 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (376 mg, 69% yield) as a red solid. LC-MS (m/z) 546 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1.[OH-].[Na+].[BrH:13]>>[BrH:10].[NH2:1][C:2]1[C:7]([CH2:8][Br:13])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1CO
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Br)cc1CBr

Procedure:
A solution of 2-amino-5-bromo-3-hydroxymethylpyridine (5.00 g, 24.6 mmole), from Preparation 14 (b), in 48% aqueous HBr (50 mL), was heated at reflux for 12 hrs. The reaction was concentrated and toluene was used to azeotrope the residual H2O. The resulting light brown solid was placed under high vacuum overnight and used directly.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1Cl)=[O:4].[CH:15]1([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([F:25])[CH:19]=2)[CH2:17][CH2:16]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]2[C:6]=1[NH:22][C:21]1[CH:23]=[CH:24][C:18]([CH:15]2[CH2:16][CH2:17]2)=[CH:19][C:20]=1[F:25])=[O:4]
Reactant: COC(=O)c1ccn2cncc2c1Cl
Reactant: Nc1ccc(C2CC2)cc1F
Agent: [Pd]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 100 °C
Yield: 41.8 %

Procedure:
A suspension of 8-chloro-imidazo[1,5-a]pyridine-7-carboxylic acid methyl ester (105 mg, 0.50 mmol), 4-cyclopropyl-2-fluoroaniline (101 mg, 0.60 mmol), Pd2dba3 (18 mg, 0.02 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl (37 mg, 0.08 mmol) and K3PO4 (148 mg, 0.70 mmol) in toluene (2 mL) was degassed and then heated to 100° C. for 24 hours. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate. The resultant solution was washed with water and brine, then loaded onto a 10 g Isolute® SCX-2 cartridge which was eluted with methanol followed by a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, ethyl acetate in dichloromethane) to afford the title compound as a yellow oil (68 mg, 42%). LCMS (method B): RT=3.45 min, [M+H]+=326.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2.C(OC([N:31]1[CH2:36][CH2:35][CH:34]([CH2:37]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][CH2:32]1)=O)(C)(C)C.[Na+].[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC.O>[F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH2:37][CH:34]1[CH2:35][CH2:36][NH:31][CH2:32][CH2:33]1)[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(OCC3CCNCC3)cc21
Temperature: 70 °C
Yield: 39.3 %

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.06 g, 0.19 mmol) and 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.20 mmol) in DMF (3 mL) was added NaI (0.014 g, 0.009 mmol) and K2CO3 (0.08 g, 0.56 mmol). The reaction mixture was heated to 70° C. for 20 hours. The mixture was diluted with ether and water and the layers were separated. The aqueous layer was extracted with ether (2×) and the combined organic layers were washed with water and brine, and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and purified by reverse phase HPLC. The desired fraction was concentrated to 0.037 g that was then treated with HCl (4N in dioxane) for 7 hours. The solvent was removed under reduced pressure and the final product was dried under high vacuum to obtain 0.031 g solid (37% yield). MS (APCI+) m/z 416 (M+1) detected.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[CH3:22]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c([N+](=O)[O-])ccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(COCC[Si](C)(C)C)c2nccc([N+](=O)[O-])c12

Procedure:
A solution of 80 mg (210 μmol) of 3-bromo-4-nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine, 27 mg (210 μmol) of trimethylboroxine, 25 mg (20 μmol) of tetrakis(tri-phenylphosphine)palladium and 103 mg (640 μmol) of potassium carbonate in 2.00 ml of degassed DMF is stirred in a sealed pressure vessel at 110° C. for 6 h and then at RT overnight. The suspension is then filtered through an Extrelut silica gel cartridge, the cartridge is washed with a mixture of dichloromethane/methanol 1:1 and the filtrate is concentrated under reduced pressure. The residue is purified by preparative RP-HPLC.
Reaction SMILES: [OH:1][CH:2]([PH:4](=[O:6])[OH:5])[CH3:3].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C1C=CC=CC=1>[OH:1][CH:2]([PH:4](=[O:5])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:3]
Reactant: OCc1ccccc1
Reactant: CC(O)[PH](=O)O
Solvent: O
Solvent: c1ccccc1
Product: CC(O)[PH](=O)OCc1ccccc1
Yield: 87.2 %

Procedure:
A solution of α-hydroxyethylphosphinic acid (5.5 g) and benzyl alcohol (2.26 g) in benzene (50 ml) was heated for 8 hours with removal of water through a Dean-Stark apparatus. After cooling, the reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo to give 3.65 g (91.2%) of benzyl α-hydroxyethylphosphinate (Compound No. 36).
Reaction SMILES: O.[OH-].[Na+:3].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([O:18]CC)=[O:17])[CH:12]=2)[CH:7]=[CH:6][N:5]=1>CO>[Na+:3].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([O-:18])=[O:17])[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CCCC(Oc1ccc2ccncc2c1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(Oc1ccc2ccncc2c1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 42 h

Procedure:
10 ml of water and 840 mg (21.0 mmol) of sodium hydroxide are added to a solution of 5.20 g (19.0 mmol) of ethyl 2-(isoquinolin-7-yloxy) -pentanoate in 50 ml of methanol, and the mixture is stirred at room temperature for 42 hours. The solvent is removed by distillation, giving 2-(isoquinolin-7-yloxy)pentanoic acid sodium salt as a colourless solid; ESI 246.