Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]5)[C:19]([CH:36]=[CH2:37])=[CH:18][CH:17]=4)=[N:14][N:13]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:10]3=[CH:11][N:12]=2)[CH:2]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:36]([C:19]1[C:20]([N:22]2[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]2)=[N:21][C:16]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[N:14]=2)=[CH:17][CH:18]=1)[CH3:37]
Reactant: [H][H]
Reactant: C=Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C

Procedure:
(S)-tert-butyl 1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-vinylpyridin-2-yl)piperidin-3-ylcarbamate (59.18 mg, 0.09426 mmol) and palladium hydroxide on carbon 20% (0.2:0.8, Palladium hydroxide:carbon black, 6.619 mg) in Ethanol (30 mL) in a round bottom flask was vacuumed and connected to a Hydrogen balloon. The mixture was stirred at room temperature over the weekend. The reaction mixture was filtered through Celite. The filtrate was concentrated to afford (S)-tert-butyl 1-(3-ethyl-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate, which was dissolved in Trifluoroacetic Acid (3 mL) and Methylene chloride (3 mL), and treated with Trifluoromethanesulfonic acid (83.4 uL, 0.943 mmol) and Triethylsilane (150.6 uL, 0.943 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 327 as an off-white solid (5.8 mg, 15%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.31 (s, 1H), 9.20 (s, 1H), 9.13 (s, 1H), 8.59 (d, J=4.5 Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.53 (dd, J=8.0, 4.8 Hz, 1H), 3.60 (d, J=11.4 Hz, 2H), 2.86 (dt, J=20.8, 9.5 Hz, 2H), 2.70 (dd, J=18.0, 10.0 Hz, 2H), 1.95 (d, J=12.5 Hz, 1H), 1.84 (d, J=13.1 Hz, 1H), 1.80-1.69 (m, 1H), 1.26 (t, J=7.5 Hz, 3H); ESI MS m/z=400.2 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[N:8]([NH:19][CH3:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[C:25](OC=O)(=[O:27])C.C(OC(=O)C)(=O)C>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]1)[N:8]([NH:19][CH2:20][CH:25]=[O:27])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: CC(=O)OC=O
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3NCC=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Fluoro-methylamino-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid (Example 1) (2.7 g) was added to mixed formic-acetic anhydride prepared from 3.9 g of 96% formic acid and 8.3 g of acetic anhydride. The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The solid residue was dissolved in 50 ml of water and the solution made basic with pyridine. The solid product was collected by filtration and recrystallized from acetonitrile to give 2.0 g of 6-fluoro-1-(N-formylmethylamino)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, cream-colored powder, m.p. 252°-253° C. (decompn.).
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([O:13][CH:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28](OCC)OCC)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]>C(Cl)(Cl)Cl>[CH2:11]([O:13][CH:14]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]2[NH:10][C:1](=[O:9])[C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=3[O:4]2)=[CH:22][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])[CH3:12]
Reactant: NC(=O)c1ccccc1O
Reactant: CCOC(COc1ccc(CC(OCC)C(=O)OC)cc1)OCC
Solvent: ClC(Cl)Cl
Product: CCOC(Cc1ccc(OCC2NC(=O)c3ccccc3O2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a stirred solution of polyphosphonate ethyl ester (PPE) (3.46 g, 8.0 mmol) in chloroform (10 mL) was added salicylamide (548 mg, 4.0 mmol) followed by addition of a solution of (±)-Methyl 2-ethoxy-3-[4-[(2,2-diethoxy)ethoxy]phenyl]propanoate (1.28 g, 4.4 mmol) obtained in preparation 2, in chloroform (10 mL) dropwise at 25-30° C. The reaction mixture was immersed in a preheated oil bath at 70° C. and refluxed 12 h. The reaction mixture was cooled to room temperature and CHCl3 was removed under reduced pressure. The resultant residue was neutralised (pH=7.0) with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude compound was chromatographed on silica gel using a gradient of 5-25% of ethyl acetate in pet ether as eluent to afford the title compound (1.15 g, 72%) as a pale yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:9].Cl.[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH:17](OC(C)C)([CH3:19])[CH3:18]>C(O)(C)C.C(OCC)(=O)C.O>[NH2:8][C:7]1[C:2]([CH3:1])=[C:3]2[C:4]([CH:18]=[C:17]([CH:11]=[O:14])[CH:19]=[N:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)OC(C)C
Reactant: O=C([O-])[O-]
Reactant: Cc1c(N)cccc1N
Agent: Cl
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(N)ccc2cc(C=O)cnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 2-methyl-1,3-benzenediamine (30.0 g, 246 mmol) and 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane bis-tetrafluoroborate (263 g, 737 mmol) in isopropanol (500 ml) was heated under reflux with stirring for 16 hrs. and allowed to cool to room temperature. To the reaction solution was added 1N hydrochloric acid (500 ml). The mixture was stirred at 70° C. for 5 hrs. with heating and allowed to cool to room temperature. The resulting precipitate was collected and washed with water, acetonitrile and isopropyl ether. A suspension of the obtained precipitate (61.6 g) and potassium carbonate (170 g, 1.23 mol) in ethyl acetate (500 ml)-water (500 ml) was vigorously stirred with heating at 90° C. and allowed to cool to room temperature. The organic layer was separated, washed with saturated brine, dried over sodium sulfate and passed through silica gel (100 g) packed in a glass filter. The solvent was evaporated under reduced pressure and the obtained crude product was treated with isopropyl ether to give the title compound (35.4 g) as a powder.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]([CH2:5][CH2:4][CH2:3][C:2]([OH:25])=[O:1])([C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:13])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)=O
Reactant: COC(=O)C1(CCCC=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COC(=O)C1(CCCC(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-(4-oxobut-1-yl)-1-(tert-butoxycarbonyl)piperidine-4-carboxylate (23.0 g, 0.0734 mol) from Step C in acetone (775 mL) at room temperature was added Jones reagent (28.2 mL, 2.6M) via syringe. After 5 min, the reaction mixture was concentrated. The residue was taken up in water and diethyl ether and extracted three times with diethyl ether. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (23.4 g) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[N:9][C:10](Cl)=[N:11][CH:12]=1.[H-].[Na+]>O1CCOCC1>[Br:6][C:7]1[CH:8]=[N:9][C:10]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:11][CH:12]=1
Reactant: OC1CCC1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Brc1cnc(OC2CCC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.42 mL (31.0 mmol) cyclobutanol and 3.00 g (15.5 mmol) 5-bromo-2-chloropyrimidine are added to 40 mL 1,4-dioxane and cooled down to 0° C. Then the reaction mixture is charged with 1.86 g (46.5 mmol) NaH. After removing of the cooling bath the reaction mixture is stirred at r.t. for 1 h. The reaction is quenched by the addition of water and sat. aq. NaHCO3 solution. The 1,4-dioxane is removed in vacuo and the aq. residue is extracted with DCM. The org. phases are combined, washed with water and dried with MgSO4. The solvent is removed under reduced pressure. The crude product is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1CCCCC1>C1(C)C=CC=CC=1>[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10](=[O:12])[CH3:11])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCOc1ccc(C=O)cc1
Reactant: COc1ccc(CC(C)=O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCCCCCOc1ccc(CC(C(C)=O)c2ccc(OC)cc2)cc1
Yield: 46 %

Procedure:
49.2 g of 3-(4-methoxyphenyl)-2-propanone and 61.8 g of 4-hexyloxybenzaldehyde were added to 100 ml of toluene containing 4 ml of piperidine. The resultant mixture was heated at reflux temperature overnight after which the solvent was removed in vacuo to afford the desired subtitled intermediate (46% yield), b.p. 230°-235° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CN(C=O)C>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:8][CH:7]([O:9][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])=[O:17]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C

Procedure:
To a solution of trans-N-Boc-4-hydroxy-L-proline methyl ester (7) in pyridine and dry DCM at 0° C. is added 4-methyl-benzenesulfonyl chloride. After adding, the mixture is refluxed overnight. The solvent is evaporated and then the residue is dissolved in CH2Cl2. After removal of solvent, the crude 4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is obtained, which is used in the following reaction without further purification. To a solution of 4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester thus obtained above in dry DMF is added NaN3 in one portion, and the reaction mixture is stirred at about 50° C. for 5 h. The resulting mixture is purified to give 4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (8).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:11]=[CH:12][C:13]=1[CH3:14].O.NN>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([NH2:15])[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccn(N2C(=O)c3ccccc3C2=O)c1-c1ccc(Cl)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccn(N)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a suspension of 2-[2-(2,4-dichlorophenyl)-3-methyl-1H-pyrrol-1-yl]-1H-isoindole-1,3(2H)-dione (3.71 g, 10.0 mmol) in EtOH (60.0 mL) is added hydrazine monohydrate (1.21 mL, 1.25 g, 25.0 mmol) at room temperature. The reaction mixture is heated at reflux for 2 h. After cooling down to room temperature, the mixture is filtered. The filtrate is concentrated in vacuo to dryness and the residue is subjected to column chromatography (silica gel, 1/4 EtOAc/heptane) to give 2.36 g (98%) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=2.1 Hz, 1H), 7.37 (dd, J=2.1, 8.2 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 6.82 (d, J=2.8 Hz, 1H), 6.01 (d, J=2.8 Hz, 1H), 2.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 136.5, 135.0, 134.6, 130.0, 129.9, 127.6, 127.3, 122.8, 117.0, 106.9, 12.3; IR (liq.) 2422, 2350, 2327, 2286, 2211, 1563, 1547, 1484, 1102, 1001, 868, 826, 806, 724, 708 cm-−1; MS (EI) m/z 243 (M++H), 241 (M++H); HRMS (FAB) calcd for C11H10Cl2N2+H 241.0299, found 241.0291.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH2:13][CH:12]([C:14](OC)=[O:15])O[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O:21]CC)C>CO.O=[Pt]=O>[C:1]([O:5][C:6](=[O:18])[CH:7]([OH:21])[CH2:8][CH:9]1[CH2:13][CH2:12][C:14](=[O:15])[NH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CC(CCC(=O)OC(C)(C)C)=NO1
Reactant: CCOCC
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)C(O)CC1CCC(=O)N1

Procedure:
A suspension of 105 of 4,5-dihydro-5-methoxycarbonyl-3-isoxazolepropanoic acid t-butyl ester and 2.0 g of PtO2 /C in 1 L of methanol is placed under a hydrogen atmosphere with agitation. After H2 absorption is complete, the solution is filtered and the solvent removed under reduced pressure to give an oil. The oil is titurated with anhydrous diethyl ether and filtered to yield 5-oxo-alpha-hydroxy-2-pyrrolidinepropanoic acid t-butyl ester as a white solid with mp 110°-112° C. NMR (CDCl3) and 6.38 (s, 1H), 4.13 (m, 1H), 3.87 (m, 1H), 3.27 (d, 1H), 2.47-1.60 (m, 6H), 7.53 (s, 9H). IR (KBr) 3460, 3245, 2978, 2938, 1723, 1686, 1426, 1392, 1372, 1318, 1277, 1256, 1209.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:11][CH:12]([CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:13]([CH3:15])[CH3:14]>CS(C)=O.ClCCl>[CH:9]([CH:10]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH2:11][CH:12]([CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:13]([CH3:14])[CH3:15])=[O:8]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(CO)NC(=O)OC(C)(C)C)C(C)C)cc12
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCc1cn(C)c2ccc(CC(CC(C=O)NC(=O)OC(C)(C)C)C(C)C)cc12
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
1.27 ml of triethylamine and then (over 20 minutes) a solution of 1.60 g of sulphur trioxide-pyridine complex in 6 ml of dimethyl sulphoxide are added dropwise at 0° C. to the solution of 1.44 g of tert-butyl {1-hydroxymethyl-3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methylpentyl}carbamate in 10 ml of dichloromethane. After 40 minutes, 10 ml of ice-water are added dropwise and the reaction mixture is stirred at 10° C. for a further 10 minutes. The reaction mixture is extracted with dichloromethane (3×)—the combined organic phases are washed successively with 10% aqueous sodium hydrogensulphate solution, water, 10% sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and concentrated by evaporation. The crude title compound is obtained as a yellowish foam from the residue. Rf=0.73 (2:1 EtOAc-heptane). Rt=5.48 (gradient I).
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[I:10]C.[CH2:12](O)C>CCOCC>[IH:10].[N:1]1([C:7]([S:9][CH3:12])=[NH:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: CI
Reactant: NC(=S)N1CCOCC1
Solvent: CCOCC
Product: CSC(=N)N1CCOCC1
Product: I
Reaction time: 48 h

Procedure:
A solution of 4.65 g. of 4-morpholinethiocarboxamide [W. G. Finnegan, et al., J. Org. Chem. 18, 779 (1952)] and 4.54 g. of iodomethane in 50 ml. of ethanol is allowed to stand 48 hours at room temperature, then diluted with 250 ml. of ether to give a colorless crystalline precipitate of methyl 4-morpholinethiocarboximidate hydroiodide. A solution of 5.76 g. of this product and 1.1 g. of hydrazine hydrate in ethanol is heated under reflux for about 2 hours and then treated with 2.1 g. of 9,10-anthracenedicarboxaldehyde in 200 ml. of ethanol and 2 ml. of glacial acetic acid by heating under reflux for 3.5 hours. The solution is filtered and then evaporated to give an orange solid which is recrystallized from ethanol-ether to give the title compound, m.p. 280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[N:6][CH:7]=1.Cl.[C:15]([O:19][C:20](=[O:31])[C@@H:21]([NH2:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH3:18])([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:15]([O:19][C:20](=[O:31])[C@@H:21]([NH:30][C:11]([C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)c1cc2cc(Cl)cnc2[nH]1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)c1cc2cc(Cl)cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Preparation 57, 500 mg, 2.54 mmol) in DMF (20 mL) was added 2-(S)-amino-3-(4-fluorophenyl)propionic acid tert-butyl ester hydrochloride (Preparation 114, 701 mg, 2.54 mmol), HOBt (344 mg, 2.54 mmol) and DIPEA (1.4 mL, 7.88 mmol). After 5 min, EDCI (634 mg, 3.31 mmol) was added and the reaction mixture stirred at rt for 72 h. The solvent was removed in vacuo and the solid partitioned between water (50 mL) and ethyl acetate (3×40 mL). The combined organic phase was washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography on silica gel eluting with methanol:dichloromethane (1:99) to give the title compound. δH (CD3OD): 1.42 (9H, s), 3.09 (1H, dd), 3.22 (1H, dd), 4.76 (1H, m), 6.98 (2H, m), 7.07 (1H, s), 7.27 (2H, m), 8.06 (1H, d), 8.28 (1H, d); m/z (ES+)=418 [M+H]+.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].F[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18].O>C(O)C>[CH2:2]([O:1][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH3:3]
Reactant: CC[O-]
Reactant: C[Si](C)(C)CCOCOc1cnccc1F
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccncc1OCOCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.6 %

Procedure:
To a stirred solution of sodium ethoxide (0.9 g, 13 mmol) in ethanol (10 mL) was added all at once 10 (1.07g, 4.4 mmol). The resulting mixture was stirred at room temperature for 48 hours, then poured into water (100 mL). The resulting mixture was extracted with ether (3×50 mL). The ether extracts were combined, dried (MgSO4) and concentrated. The resulting amber oil was chromatographed (silica gel, hexane-acetone, 4:1) to give 11 as a yellow oil (0.6 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)\[C:12]2[N:13]([CH3:18])[O:14][C:15](=[O:17])[N:16]=2)[CH:5]=[CH:4][CH:3]=1.[C:25]1([C:31]#[CH:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.[Cu](I)I>[CH3:18][N:13]1[C:12](/[C:11](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10]\[O:9][CH2:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:32]#[C:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:7]=2)=[N:16][C:15](=[O:17])[O:14]1
Reactant: Cn1oc(=O)nc1/C(=N\OCc1cccc(Br)n1)c1ccccc1
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: Cn1oc(=O)nc1/C(=N\OCc1cccc(C#Cc2ccccc2)n1)c1ccccc1
Temperature: 120 °C
Yield: 54.5 %

Procedure:
To a solution of 3-[(Z)-{[(6-bromopyridin-2-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (200 mg, 0.514 mmol, 1 eq) in degased THF (2 mL) was added in a microwave tube under argon tetrakis(triphenylphosphine)palladium (0) (59.4 mg, 0.051 mmol, 0.1 eq), copper iodide (14.6 mg, 0.077 mmol, 0.15 eq) N,N-diisopropylethylamine (0.358 ml, 2.06 mmol, 4 eq) and phenylacetylene (157 mg, 1.54 mmol, 3 eq). The mixture was heated in the microwave at 120° C. for 15 min. The mixture was concentrated, diluted with ethyl acetate and filtered over a celite cartridge. The solvent was evaporated and the residue was purified by chromatography on silica gel to afford 2-methyl-3-[(Z)-phenyl({[6-(phenylethynyl)pyridin-2-yl]methoxy}imino)methyl]-1,2,4-oxadiazol-5(2H)-one (115 mg, 52% yield).
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([Cl:19])=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.CC[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:19].[CH:2]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:24]4[CH2:25][C:29]5[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:27]4)=[O:18])=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(OC2CCN(C3CCC3)CC2)cc1
Reactant: CCN(CC)Cc1ccccc1
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: O=C(c1ccc(OC2CCN(C3CCC3)CC2)cc1)N1Cc2ccccc2C1
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A stirred mixture of 4-[(1-cyclobutyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D25) (0.25 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.13 g) in DCM (10 ml) at rt was treated with isoindoline (0.098 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E59) as a white powder (220 mg). MS electrospray (+ion) 377 (MH+). 1H NMR δ (DMSO-d6): 10.62 (1H, s), 7.62 (2H, m), 7.40-7.25 (4H, m), 7.08 (2H, m) 4.82 (4H, m), 4.64 (1H, m), 3.81-3.58. (1H, m), 3.45-3.20 (2H, m), 2.95 (2H, m), 2.38-1.62 (10H, m).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.B.C1COCC1>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1-c1cc(OC)ncc1F
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1-c1cc(OC)ncc1F
Temperature: 23 °C
Reaction time: 46 h
Yield: 105.4 %

Procedure:
To a stirred solution of 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(methoxycarbonyl)benzoic acid T37.2 (0.416 g, 1 mmol) in THF (14 mL) at 0° C. was added borane-THF (3 mL, 3 mmol, 1.0M). The reaction was warmed to 23° C. and stirred for 46 hours. The reaction was then concentrated in vacuo. The reaction was diluted with 1N HCl and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-40% EtOAc in hexanes) to yield T37.3 as a colorless solid (0.307 g, 77% yield).