Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:15][CH2:14][C:13]([CH:16]=O)=[C:12]([Cl:18])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH2:20][OH:21]>C(O)C>[CH2:2]([N:9]1[CH2:15][CH2:14][C:13]([CH:16]=[N:20][OH:21])=[C:12]([Cl:18])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=CC1=C(Cl)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: ON=CC1=C(Cl)CCN(Cc2ccccc2)CC1

Procedure:
Prepared by reacting 1-benzyl-4-chloro-5-formyl-2,3,6,7-tetrahydro-1H-azepine hydrochloride with hydroxylamine hydrochloride in ethanol at 30° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[OH:36][NH2:37].C(=O)([O-])O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:37]/[OH:36])/[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:25][CH2:26][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:28][CH:29]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-1-(2-methylpyridin-4-yl)-3-(4-(1-(methylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3-o-tolylpropan-1-one and hydroxyl-amine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless foam, MS (ESI+): m/z=490.4 ([M+H]+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[CH:18]=[CH2:19].Cl>C1COCC1>[C:22]([O:21][C:17](=[O:20])[CH2:18][CH2:19][C:9]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: O=C(O)C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
To a 50 ml round-bottomed flask under nitrogen was added lithium diisopropylamide (10.95 mL, 21.90 mmol). The solution was cooled to −20° using a controlled dry ice/acetonitrile bath. Cyclopentanecarboxylic acid (1.187 mL, 10.95 mmol) in dry THF (10 mL) was added over 5 minutes, keeping the temperature at −20° C. The mixture was warmed to room temperature, stirred for one hour, then cooled to −78° C. Tert-butyl acrylate (1.685 mL, 10.95 mmol) in dry THF (10 mL) was added dropwise over 5 min, keeping the temperature at −70° C. After 2 hours at −70° C., the mixture was quickly warmed to 0° C., acidified with 5N HCl, and extracted with hexane. The hexane extract was washed with water and saturated sodium bicarbonate, water, and dried over MgSO4, and then recrystallized from hexanes. Recovered 1-(3-tert-butoxy-3-oxopropyl)cyclopentanecarboxylic acid (1.8 g, 7.43 mmol, 67.8% yield).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([O-:22])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:26]([O:32][CH2:33]I)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:23](=[O:24])[N:6]2[C:7]([C:20]([O:22][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:21])=[C:8]([C:11]3[S:15][C:14]4=[CH:16][N:17]=[CH:18][N:13]4[C:12]=3[CH3:19])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: Cc1c(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3[C@H]2C)sc2cncn12
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To a solution of 29.4 mg of sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate in 0.8 ml of dry DMF was added 0.017 ml of iodomethyl pivalate under the atmosphere of argon at −30° C., and the mixture was stirred for 4 hours during which the temperature was raised up to 10° C. The reaction mixture was diluted with 10 ml of ethyl acetate, separated, and the aqueous layer was extracted twice with ethyl acetate, while the organic layer was washed with 10 ml of semi-saturated aqueous saline. The combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to a volume of 1 ml. The residue thus obtained was purified by column chromatography on silica gel (chloroform:methanol=20:1) and on Sephadex LH-20 (dichloromethane:methanol=1:1) in this sequence to give 7.9 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Oc1ccccc1F
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccccc3F)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-fluoro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-fluoro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=1[NH:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)c1ccccc1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1ccccc1Nc1ccccc1N
Yield: 99.3 %

Procedure:
2-isopropyl-N-(2-nitrophenyl)aniline (22.7 g, 89 mmol) and 10% palladium on carbon (0.6 g) were mixed with 150 mL of ethanol under nitrogen in a plastic coated hydrogenation vessel. The mixture was put on a par hydrogenator and reacted under 40 psi of hydrogen until there is no pressure drop. The catalyst was filtered off through a Celite bed. The solvent was evaporated. The product was used for the next step without further purification. 20 g of desired product was obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[CH2:22][CH2:21][N:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[O:24])[CH2:19][CH2:18]1>>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[CH2:18][CH2:19][N:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([N:4]3[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]3(=[O:8])=[O:7])=[CH:27][CH:26]=2)=[O:24])[CH2:21][CH2:22]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3)CC2)c(C)c1
Yield: 25.7 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (202 mg) described in Preparation Example 4 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (420 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 1, the title compound (110 mg) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:14][CH:13]=1.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([CH:30]([CH2:32][NH2:33])[OH:31])=[CH:25][C:24]=1[Cl:34]>CN(C=O)C>[NH2:22][C:23]1[C:24]([Cl:34])=[CH:25][C:26]([CH:30]([OH:31])[CH2:32][NH:33][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([NH2:21])=[O:20])=[CH:14][CH:13]=2)=[CH:27][C:28]=1[Cl:29]
Reactant: NCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: NC(=O)Cc1ccc(CCCOCCCCCCBr)cc1
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)cc1
Yield: 38.5 %

Procedure:
4-[3-[(6-Bromohexyl)oxy]propyl]benzeneacetamide (950 mg) was added to a stirred solution of 4-amino-α-(aminomethyl)-3,5-dichloro-benzenemethanol (900 mg) and DEA (650 mg) in DMF (10 ml) at 100° under nitrogen. After 1 h the solvent was evaporated and the residue was partitioned between 8% sodium bicarbonate (20 ml) and ethyl acetate (20 ml). The organic layer was washed with water and brine, dried and concentrated in vacuo to give a yellow solid which was triturated with ether to give the title compound as an off-white powder (510 mg) m.p. 104°-106°.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][O:1][C:2]2[CH:33]=[CH:32][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=4)[CH2:10][CH2:9][N:8]3[CH2:21][C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:4][C:3]=2[O:34][CH3:35])[CH2:38][CH2:37]1
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: BrCC1CC1
Product: COc1cc2c(cc1OC)C(Cc1ccc(OCC3CC3)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with cyclopropyl-methyl bromide
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=O>>[N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[O:1][C:12]=1[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[NH2:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: Nc1ccncc1O
Product: Nc1ccccc1-c1nc2ccncc2o1
Yield: 31.5 %

Procedure:
3-Hydroxy-4-aminopyridine (2.220 g, 20.0 mmol) and 2-aminobenzoic acid (2.740 g, 20.0 mmol) in polyphosphoric acid (40 mL) were stirred at 140° C. for 6 hrs. The reaction mixture was poured into distilled water and sodium hydroxide was added until pH=8. The precipitate was collected by filtration and further purified by chromatography on silica gel eluted with petroleum ether:ethyl acetate:Et3N (160:40:1) to give 2-(oxazolo[5,4-c]pyridin-2-yl)benzenamine as yellow solid (1.332 g, Yield: 31%). 1H NMR (400 MHz, DMSO-d6) δ: 6.70 (1H, t, J=6.8 Hz), 6.94 (1H, d, J=8.4 Hz), 7.20 (2H, s), 7.33 (1H, t, J=6.8 Hz), 7.80 (1H, d, J=5.6 Hz), 7.95 (1H, d, J=8.4 Hz), 8.53 (1H, d, J=5.6 Hz), 9.05 (1H, s); MS (ESI) calcd. for C12H9N3O (m/z): 211, found: 212 [M+1]+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:24][CH:25]=[CH:26][C:27]=1[CH2:28]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.CCOC(C)=O>[Cl:22][C:23]1[S:24][CH:25]=[CH:26][C:27]=1[CH2:28][O:20][C:17]1[CH:18]=[CH:19][N:14]([C:11]2[CH:12]=[CH:13][C:6]3[N:5]=[C:4]([CH:1]4[CH2:2][CH2:3]4)[N:8]([CH3:9])[C:7]=3[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: OCc1ccsc1Cl
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccsc4Cl)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a mixture of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), (2-chloro-3-thienyl)methanol (106 mg) and tributylphosphine (0.264 ml) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (269 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc), followed by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH) to give the title compound (42.4 mg) as an off-white solid.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@H](n2cc(I)c(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(=O)[nH]c2=O)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.4 %

Procedure:
To a solution of (34) (2.34 g, 4.71 mmol) in dry THF (40 ml) was added at 0° C. TBAF (5.2 ml, 5.2 mmol, 1 M solution in THF). The reaction mixture was allowed to warm up to room temperature and was then stirred for 16 h. The reaction was quenched by adding sat. NaCl solution (20 ml) and extracted with EtOAc three times. The combined organic layers were dried over MgSO4. The crude mixture was purified by chromatography on silica (EtOAc:petrol 7:3). Product (35) (1.4 g, 75%) was isolated as a colourless solid. 1H NMR (d6 DMSO) δ 2.02-2.39 (m, 2H, H-2′), 3.42-3.52 (m, 2H, H-5′), 3.84-3.88 (m, 3H, H-4′, CH2], 3.97-4.00 (m, 1H, H-3′), 5.02-5.09 (m, 2H, OH, ═CH2), (dd, J=1.9, 17.3 Hz, 1H, ═CH2), 5.73-5.82 (m, 1H, CH═), 5.94 (t, J=6.8 Hz, 1H, H-1′), 8.24 (s, 1H, H-6), 11.56 (s, 1H, NH). Mass (−ve electrospray) calcd for C12H16IN2O5 394.0 found 393.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=4)[CH:24]=[C:23]([C:35]([F:38])([F:37])[F:36])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:34][C:29]1[CH:28]=[C:27]([C:25]2[CH:24]=[C:23]([C:35]([F:38])([F:36])[F:37])[N:22]=[C:21]([C:17]3[CH:16]=[C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=4)[CH:20]=[CH:19][CH:18]=3)[N:26]=2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.4 %

Procedure:
To a cooled and stirred solution of 3′-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.43 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.26 g, 53%). MS (ISP) 492.1 [(M+H)+]; mp 211° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>CN(C)C=O>[CH3:1][C:2]1[N:3]([CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CC(Br)c1ccccc1
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
A mixture of ethyl 2-methyl-1H-indole-3-carboxylate (400 mg, 1.97 mmol) and sodium hydride (47 mg, 2.0 mmol) in N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 0.5 hours, and then (1-bromoethyl)benzene (361 mg, 2.0 mmol) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. Organic layers were combined and concentrated to give a residue. The residue was purified by chromatography (petroleum ether/ethyl acetate=5:1) to give ethyl 2-methyl-1-(1-phenylethyl)-1H-indole-3-carboxylate (340 mg, 56%). LRMS (M+H+) m/z: calcd 307.16. found 307.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C@H:32]3[CH2:37][CH2:36][C@@H:35]([O:38][CH3:39])[CH2:34][CH2:33]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]#[N:42])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:31][C@H:32]3[CH2:33][CH2:34][C@@H:35]([O:38][CH3:39])[CH2:36][CH2:37]3)[C:17]([NH:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:40])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(C[C@H]2CC[C@@H](OC)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: COc1cn(C(C[C@H]2CC[C@@H](OC)CC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.5 h

Procedure:
2.10 g (3.55 mmol) of ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(cis-4-methoxycyclohexyl)propanoyl}amino)benzoate (racemate) in 129 ml of ethanol/water (2.6/1) were reacted with 5.89 g (18.1 mmol) of caesium carbonate according to General Method 4. After complete conversion, the pH was adjusted to 5-6 with hydrochloric acid (1N) and the mixture was stirred for another 30 min. The precipitate was filtered off with suction, washed with a little water and dried under high vacuum and it corresponded to the title compound. Yield: 1.24 g (60% of theory)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:21]=[C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[N:12]=[C:13]([NH2:14])[N:8]2[N:7]=1.[Cl:22][C:23]1[C:32]([CH:33]=O)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:35])[CH:29]=2)[N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:22][C:23]1[C:32]([CH2:33][N:18]2[CH2:17][CH2:16][N:15]([C:11]3[N:12]=[C:13]([NH2:14])[N:8]4[N:7]=[C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)[CH:21]=[C:9]4[N:10]=3)[CH2:20][CH2:19]2)=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH3:35])[CH:29]=2)[N:24]=1
Reactant: Cc1ccc2nc(Cl)c(C=O)cc2c1
Reactant: Nc1nc(N2CCNCC2)nc2cc(-c3ccco3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccc2nc(Cl)c(CN3CCN(c4nc(N)n5nc(-c6ccco6)cc5n4)CC3)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
7-Furan-2-yl-2-piperazin-1-yl-pyrazolo[1,5-a][1,3,5]triazin-4-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 2-chloro-6-methyl-quinoline-3-carbaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 7.4-8.0 (m, 4H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.2 (s, 1H) 3.8 (br s, 2H), 2.2-3.2 (m, 8H), 2.35 (br s, 3 H). MS: m/z: 476 [M+H]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH2:16]([S:19](Cl)(=[O:21])=[O:20])[CH2:17][CH3:18].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH2:16]([S:19]([N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1)(=[O:21])=[O:20])[CH2:17][CH3:18]
Reactant: OC1CNC1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CC(O)C1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
To a cooled solution (0-5° C.) of azetidin-3-ol hydrochloride (1 g, 9.13 mmol) in 10 ml dichloromethane containing diisopropyl ethyl amine (2,391 ml, 13.69 mmol) was added dropwise a solution of propane-1-sulfonyl chloride (1,126 ml, 10.04 mmol) dissolved in 5 ml dichloromethane over an 1 h period. The mixture was allowed to warm up to room temperature and was stirred over night. Citric acid (10%) was added, extracted with dichloromethane, dried over MgSO4, filtered and the solvent was evaporated to obtain 597 mg of a yellow oil, which was purified by chromatography (yield 470 mg)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](C(OC)=O)[C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([O:5][C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1

Procedure:
To a solution of dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate (4.00 g, 13.0 mmol) in THF (30 mL) and MeOH (10 mL) was added NaOH (2N, 19.5 mL, 38.9 mmol). After stirring the reaction for 45 minutes at room temperature, it was diluted with 1 M citric acid and extracted with EtOAc. The organic layer was washed (water, brine), dried (MgSO4), and concentrated to a yellow residue. The residue was redissolved in EtOAc (50 mL) and H2O (50 mL) and stirred for 2 h at 80° C. The mixture was extracted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated to give [4-tert-butoxycarbonyl)phenyl]acetic acid as an off-white solid. MS (ESI) calcd [M+Na]+ 259.1, found 259.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28]([O:30]C)=O)[C:15](=[O:27])[N:16]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:33][NH2:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:28]([NH:34][CH3:33])=[O:30])[C:15](=[O:27])[N:16]3[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(-c2ccc(OC)cc2)c1=O
Yield: 97 %

Procedure:
In a similar manner to that described in example 196, from methyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.115 mmol) and methylamine was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-methyl-1-[4-(methyloxy)phenyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (48 mg, 97% yield) as a white solid. 1H NMR (CDCl3) δ 9.96 (s, 1 H), 8.48 (s, 1 H), 7.11-7.05 (m, 4 H), 7.01-6.98 (m, 4 H), 6.77 (s, 1 H), 3.92 (s, 2 H), 3.87 (s, 3 H), 2.95 (d, J=4.8 Hz, 3 H); HRMS m/z calcd for C24H21FN3O4: 434.1511 Found: 434.1512.