Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N1C[C@@H:30](O)[C@H:29]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:39][CH:38]=2)(=[O:36])=[O:35])C1)(OC(C)(C)C)=O.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:43]([C:40]1[CH:41]=[CH:42][C:37]([S:34]([N:33]2[CH2:30][CH2:29]2)(=[O:36])=[O:35])=[CH:38][CH:39]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Oc2ccccc2)cc1)N1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147 %

Procedure:
To a stirred solution of Ph3P (0.88 g, 3.35 mmol) and (±)-N-Boc-trans-3-(4-phenoxybenzenesulfonamido)-4-hydroxypyrrolidine (1.316 g, 3.04 mmol) in THF (20 mL) at 0° C. was added diethyl azodicarboxylate (DEAD) (0.58 mL, 3.33 mmol) dropwise. The reaction mixture was stirred at room temperature overnight, then it was evaporated under reduced pressure. The residue was purified by flash chromatography (30% ethyl acetate in hexane) to give the N-(4-phenoxybenzenesulfonyl)aziridine as a solid (1.23 g, 98%): mp 136-138° C.; 1H NMR (300 MHz, CDCl3) δ 7.88 (m, 2H), 7.43 (m, 2H), 7.22 (m, 1H), 7.10 (m, 4H), 3.72 (m, 2H), 3.59 (m, 1H), 3.47 (m, 1H), 3.38 (m, 2H), 1.42 (s, 9H); MS, ESI m/e 416.1 (M+); HRMS (ESI) calcd for C21H24N2O5SNa+ 439.1290. found 439.1290.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: c1ccc(CN2CC[C@@H](OC3CCCCO3)C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C1CCC(O[C@@H]2CCNC2)OC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 122.8 %

Procedure:
A mixture of 1-benzyl-3-(R)-tetrahydropyranyloxypyrolidine(8.78 g, 27.3 mmol) and Pearlman's catalyst (3.50 g) in MeOH (100 ml) was stirred under hydrogen atmosphere at rt for 4 h. After removal of the catalyst by Celite filtration, the filtrate was concentrated to give 5.74 g of clear light brown oil. This was used for the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC1(C)C(C)(C)OB(/[CH:22]=[CH:23]/[CH2:24][O:25][CH3:26])O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:13][C:10]1[CH:9]=[C:4]([CH:3]=[C:2](/[CH:22]=[CH:23]/[CH2:24][O:25][CH3:26])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(C)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C(=O)OC)cc(Br)c1C
Temperature: 100 °C

Procedure:
To a solution of methyl 3,5-dibromo-4-methylbenzoate (1 eq.) and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.1 eq.) in DMF (0.1 M) was added trans-bis(triphenylphosphine) palladium(II) bromide (0.02 eq.). The vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting mixture was heated at 100° C. for 2 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4]Br.C([O-])([O-])=[O:12].[Ca+2]>O1CCOCC1.O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH2:4][OH:12]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(Br)c(CBr)c1
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: OCc1cc(F)ccc1Br

Procedure:
2-Bromo-5-fluorobenzylbromide (2.0 g, 7.46 mmol) was dissolved in dioxane (25 mL) and H2O (25 mL), and CaCO3 (3.84 g, 38.39 mmol) was added. The mixture was heated to reflux overnight. The solution was concentrated, and the residue was partitioned between H2O and CH2Cl2. The organic phase was washed with 1N HCl and brine, dried (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (CDCl3): δ 2.00 (t, 1H), 4.72 (d, 2H), 6.85-6.92 (m, 1H), 7.26 (dd, 1H), 7.48 (dd, 1H).
Reaction SMILES: [F:1][C:2]1([F:32])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:29]C)=[CH:27][CH:28]=5)[C:20]([CH3:31])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.Cl>O1CCOCC1>[F:32][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:28]=[CH:27][C:26](=[O:29])[NH:25][CH:24]=5)[C:20]([CH3:31])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ncc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)[nH]c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-yl)cyclopropanecarboxamide (126 mg, 0.286 mmol) in 1,4-dioxane (1.50 mL), 4 M aqueous HCl (775 μL, 3.10 mmol) was added and stirred at 90° C. for one hour. The reaction was cooled to room temperature, quenched with Et3N and concentrated. The resulting mixture was dissolved in EtOAc and filtered. The solid was dissolved in water and the product was extracted using ethyl acetate (×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was dissolved in DMSO (1 mL), filtered and purified by reverse phase preparative HPLC to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(5-methyl-4-(6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 426.11. Found 427.3 (M+1)+. Retention time 1.34 minutes.
Reaction SMILES: C(OC([N:8]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=2[C:35]#[N:36])[CH2:21][CH2:20]1)[C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:37].C(OCC)C>C(Cl)Cl>[ClH:37].[ClH:37].[C:35]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:26]=1[CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:8][C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:20][CH2:21]1)[C:30]([OH:32])=[O:31])#[N:36]
Reactant: CC(C)(C)OC(=O)N(CC1CCN(Cc2ccc(C(=O)O)cc2C#N)CC1)[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: N#Cc1cc(C(=O)O)ccc1CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.9 %

Procedure:
To a stirred solution of 4-((4-(((tert-butoxycarbonyl)((trans)-2-phenylcyclopropyl)amino) methyl)piperidin-1-yl)methyl)-3-cyanobenzoic acid (400 mg, 0.817 mmol) in DCM (5 mL) was added HCl in diethyl ether (5 mL, 0.817 mmol) at 0° C. and stirred at RT for 2 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether (2×10 mL) and dried to afford 3-cyano-4-((4-((((trans)-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid, dihydrochloride (250 mg, 0.538 mmol, 65.9% yield) as white solid. LCMS (ES) m/z: 390.09 (M+H)+. 1HNMR (400 MHz in D2O): δ 8.489 (bs, 1H) 8.342 (d, J=8 Hz, 1H), 7.866 (d, J=8 Hz, 1H), 7.400-7.291 (m, 3H), 7.209 (d, J=8 Hz, 2H), 4.624 (s, 2H), 3.683 (d, J=10.8 Hz, 2H), 3.269-3.214 (m, 4H), 2.979-2.997 (m, 1H), 2.526-2.577 (m, 1H), 2.107 (d, J=14.8, 3H), 1.528-1.618 (m, 3H), 1.434 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[CH3:11][O:12][Na]>CO>[CH3:11][O:12][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: CO[Na]
Reactant: O=Cc1cccc(CBr)c1
Solvent: CO
Product: COCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
3-(bromomethyl)benzaldehyde (1.00 g, 5.02 mmol) was dissolved in MeOH (100 mL) and treated with 0.5M solution of MeONa (5 equiv.) in MeOH. The mixture was stirred overnight at RT and MeOH was evaporated under reduced pressure. The residue was acidified to pH ˜6 with 1M aqueous HCl solution. DCM (100 mL) was added and the mixture was vigorously stirred overnight. The organic layer was separated, dried over Na2SO4 and the solvent was removed under reduce pressure to furnish the desired material as yellowish oil (560 mg, 3.75 mmol, 74%). 1H NMR (DMSO, 400 MHz): δ3.33 (s, 3H), 4.51 (s, 1H), 7.62 (m, 2H), 7.85 (m, 2H), 10.02 (s, 1H). MS 151 (MH1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[N:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][CH:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=3)[CH2:14][CH2:15]2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(C2CCN(c3ccncc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(C2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulphonyl chloride (0.076 g) was added dropwise to a stirred solution of the product from part (ii) above (0.152 g) in pyridine (5.0 ml) at 0°. The mixture was stirred at room temperature for 3 hours and then evaporated. The residue was dissolved in water and an excess of solid sodium bicarbonate was added. The solid was filtered off, washed with water, dried and crystallised from methanol/ethyl acetate to give the title compound, (0.065 g), m.p. 269°-271° (with decomp).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:27])[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][N:17]3[CH2:20][CH3:21])=[CH:12][C:11]=2[F:28])[S:8][CH:9]=1)=[N+]=[N-].[H][H]>C(O)(=O)C.[Pd]>[NH2:1][CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:27])[C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][N:17]3[CH2:20][CH3:21])=[CH:12][C:11]=2[F:28])[S:8][CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(CC)c2cc(-c3nc(CN=[N+]=[N-])cs3)c(F)cc2c1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(CC)c2cc(-c3nc(CN)cs3)c(F)cc2c1=O
Yield: 94.5 %

Procedure:
A solution of 0.87 g (2.17 mmol) ethyl 7-[4-(azidomethyl)-2-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 125 ml acetic acid was stirred with 0.10 g 10% palladium on carbon catalyst and hydrogen gas bubbled through for 1.5 hours. After filtration, evaporation of solvent and trituration with ether gave 0.77 g of ethyl 7-[4-(aminomethyl)-2-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=2[C:24]([NH2:26])=[O:25])[C:5]2[CH:10]=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:41]=[C:40]2[C:36]([CH2:37][CH2:38][N:39]2[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[CH:35][C:34]=1[O:48][CH3:49]>>[CH3:47][N:45]([CH3:46])[C:43](=[O:44])[CH2:42][N:39]1[C:40]2[C:36](=[CH:35][C:34]([O:48][CH3:49])=[C:33]([NH:32][C:2]3[NH:7][C:6]4=[N:8][CH:9]=[CH:10][C:5]4=[C:4]([NH:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:23]=4[C:24]([NH2:26])=[O:25])[N:3]=3)[CH:41]=2)[CH:37]=[CH:38]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Reactant: COc1cc2c(cc1N)N(CC(=O)N(C)C)CC2
Product: COc1cc2ccn(CC(=O)N(C)C)c2cc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccnc-2[nH]1
Yield: 5.7 %

Procedure:
In a manner analogous to General Protocol III, 2-[(2-{[1-[2-(dimethylamino)-2-oxethyl]-5-(methyloxy)-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide was prepared from 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (0.25 g, 0.54 mmol) and 2-[6-amino-5-(methyloxy)-2,3-dihydro-1H-indol-1-yl]-N,N-dimethylacetamide (0.16 g, 0.64 mmol) to afford the title compound (0.016 g, 6% over 3 steps) as a grey solid. LCMS (ESI+) and 1H NMR indicate oxidation of the indoline to the indole. ESIMS (M+H)+=517. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.78 (s, 3 H) 2.98 (s, 3 H) 3.80 (s, 3 H) 4.93 (s, 2 H) 6.19-6.20 (m, 1 H) 6.29-6.30 (m, 1 H) 6.82-6.91 (m, 1 H), 6.94-7.01 (m, 1 H) 7.04-7.11 (m, 2 H) 7.25-7.35 (m, 1 H) 7.60 (s, 1 H) 7.98 (s, 1 H) 8.04 (s, 1H) 8.09 (s, 1 H) 8.45 (d, J=8.42 Hz, 1 H) 10.48 (s, 1 H) 11.23 (s, 1 H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:36])([CH3:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C(C)(C)CCCCBr
Reactant: Oc1ccc(OCCCCCn2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)CCCCOc1ccc(OCCCCCn2ccnc2)cc1
Temperature: 60 °C

Procedure:
After 300 ml of ethanol was added to 35 g of p-[5-(1-imidazolyl)pentyloxy]phenol and 39 g of potassium carbonate, the mixture was heated at 60° C. with stirring and then cooled to room temperature. A solution of 43 g of ethyl 6-bromo-2,2-dimethylhexanoate in 50 ml of ethanol was added to the reaction mixture, and then the mixture was stirred under reflux overnight. The solvent was removed from the reaction mixture by distillation under reduced pressure and the residue was dissolved in chloroform. The solution was successively washed with a 1N aqueous sodium hydroxide solution, water, a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After drying, the solvent was removed by distillation under reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted out using a chloroform-methanol liquid mixture (30:1) as an eluant. The solvent was removed from the eluate by distillation. The residue was recrystallized from a mixture of ethyl acetate-n-hexane to give the desired product, ethyl 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoate.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]#[N:16])=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].C(=O)([O-])[O-].[K+].[K+].Cl[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=1>CS(C)=O>[C:15]([C:14]1[CH:17]=[CH:18][C:19]([O:21][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]#[N:40])[CH:34]=2)=[CH:20][C:13]=1[C:9]1[N:8]=[C:7]2[N:6]([CH3:22])[C:5](=[O:23])[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[C:12]2=[CH:11][CH:10]=1)#[N:16]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(O)ccc3C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cc(Oc4ccnc(C#N)c4)ccc3C#N)nc21

Procedure:
A solution of 2-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-hydroxybenzonitrile (16-2, 100 mg, 0.30 mmol) in DMSO (4 ml) was charged with Potassium carbonate (82 mg, 0.59 mmol, 2.0 equiv) and 4-Chloro-pyridine-2-carbonitrile (82 mg, 0.59 mmol, 2.0 equiv). The reaction was irradiated at 160° C. for 20 min. The dark mixture was purified via reverse-phase HPLC (Acetonitrile/Water gradient with 0.1% TFA present) to afford the title compound, 4-{4-cyano-3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]phenoxy}pyridine-2-carbonitrile (3), as a pure yellow-tan solid-oil. 1H NMR (500 MHz, CDCl3) δ 8.64 (d, 1H, J=5.6 Hz), 7.91 (d, 1H, J=8.3 Hz), 7.62 (bs, 1H), 7.54 (d, 1H, J=8.1 Hz), 7.36-7.33 (m, 2H), 7.21-7.15 (m, 2H), 3.71 (s, 2H), 3.58 (s, 3H), 1.06 (s, 9H). LRMS m/z: Calc'd for C25H22N6O2 (M+H) 439.0. found 439.1.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:30][NH:29][C:21]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)=[O:28])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccncc1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccncc1

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and isonicotinic acid hydrazide (580.1 mg, commercially available), the title compound was afforded (quantitative).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].C([N-]C(C)C)(C)C.[Li+].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][O:4][C:15]1([N+:21]([O-:23])=[O:22])[CH:16]=[CH:17][C:18]([F:20])=[CH:19][CH2:14]1
Reactant: OCCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])C1(OCCCl)C=CC(F)=CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A solution of 2-chloro-ethanol (1) (8.3 ml, 120 mmoles) in THF, under nitrogen, was cooled to 0° C., treated dropwise with lithium diisopropylamide (LDA) (60 ml, 120 mmoles, while maintaining the temperature constant at 0° C. The mixture was stirred at 0° C. for 15 minutes, treated with 2,4-difluoro-1-nitro-benzene (1) (11 ml, 100 mmoles), stirred at room temperature overnight, diluted with water and extracted with EtOAc. The extracts were combined, washed with brine, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off-white solid (20.0 g, 91 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:5](=[O:9])[CH2:6][CH2:7][CH:8]1[CH2:1][CH2:2][C:3](=[O:10])[NH:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: OCc1ccccc1
Agent: Cl
Product: O=C1CCC(CCC(=O)OCc2ccccc2)N1
Temperature: 98 °C

Procedure:
Twenty-eight grams of dihydro 1H-pyrrolizine-3,5 (2H, 6H) dione is dissolved in 76 g of benzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 98° C. for 104 hours. The mixture is cooled and excess benzyl alcohol is distilled at 0.1 mm pressure to a maximum bath temperature of 100° C. The residual oil is dissolved in 1 l of anhydrous diethylether, 1 g of activated charcoal is added and the resulting suspension is filtered through filter aid. The filtrate is concentrated at reduced pressure and the resulting crystals are isolated by filtration. Recrystallization from cyclohexane containing 12% methylene chloride yields 5-oxo-2-pyrrolidinepropanoic acid benzyl ester with a melting point of 79°-80° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:26]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27]1>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:30]([CH:26]3[CH2:29][CH2:28][CH2:27]3)=[O:31])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: O=C(Cl)C1CCC1
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Product: CC(NC(=O)c1ccnc(NC(=O)C2CCC2)n1)c1cnc(OCC(F)(F)F)c(Cl)c1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1 of Example 210, single enantiomer) and cyclobutanecarbonyl chloride (32 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][NH:13][CH:12]=1)=[O:10].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:15]=[CH:14][N:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]=1)=[O:10]
Reactant: Clc1ccnc2ccccc12
Reactant: COC(=O)c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccn(-c2ccnc3ccccc23)c1
Temperature: 100 °C
Reaction time: 23 h
Yield: 59.5 %

Procedure:
1.73 g (12.5 mmol) of potassium carbonate are added at 20° C. under an argon atmosphere to 0.625 g (5 mmol) of 3-methoxycarbonyl-1H-pyrrole and 0.82 g (5 mmol) of 4-chloroquinoline dissolved in 10 mL of dimethyl sulphoxide. After stirring at 100° C. for 23 hours, the reaction mixture is poured into 30 mL of water and then allowed to crystallise at 20° C. for 1 hour. After filtering off and air-drying the solid residue, 0.75 g of 3-methoxycarbonyl-1-(quinol-4-yl)-1H-pyrrole is obtained in the form of a beige-coloured solid melting at 156° C.
Reaction SMILES: F[C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:18][O-:19].[Na+]>CO>[CH3:18][O:19][C:2]1[C:11]([S:12][CH3:13])=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C(F)(F)F)c(SC)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)c(SC)c1OC
Yield: 18.3 %

Procedure:
A mixture of 19.9 g (74.2 mmol) of methyl 2-fluoro-3-methylthio-4-(trifluoromethyl)benzoate and 40.1 g (30% by weight, 223 mmol) of sodium methoxide in 250 ml of methanol was heated under reflux for 6 h. For work-up, the mixture was concentrated, the residue was taken up in water and the mixture was extracted with dichloromethane. The organic phase was dried and the filtrate was freed from the solvent. This gave 15.9 g of methyl 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoate as residue. The aqueous phase from the extractive work-up was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and the filtrate was freed from the solvent. This gave an additional 3.80 g of methyl 2-methoxy-3-methylthio-4-(trifluoromethyl)benzoate as residue.