Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:24]=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][C:15]=3[CH3:25])=[CH:7][C:6]=2[C:5]2[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:4]=2[N:3]=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:24]=[CH:23][C:17]([CH2:18][OH:19])=[CH:16][C:15]=3[CH3:25])=[CH:7][C:6]=2[C:5]2[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CO)cc3C)cc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of ethyl 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoate (from Example 74) (1.0 eq.) in THF (0.1M) at −78° C. was added 1.0 M DIBAL-H in toluene (10 eq.) and warmed to room temperature over 2 hours. 1.5 M Rochelle salt aqueous solution was added slowly to quench the reaction followed by addition of EA, and the mixture was stirred for 45 minutes. The two phases were separated, and the aqueous layer was extracted twice with EA. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by RP-HPLC using a 10-50% MeCN in water gradient followed by extraction in DCM to give (4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)methanol. 1H NMR (Acetone-d6): δ 8.77 (s, 1H), 8.71 (s, 1H), 8.25 (d, 1H), 7.41 (s, 1H), 7.10-7.15 (m, 4H), 6.5 (br, 2H), 4.54 (s, 2H), 4.05 (br, 1H), 3.08-3.18 (m, 4H), 2.44 (s, 3H), 2.31 (s, 3H). LRMS [M+H]=358.2
Reaction SMILES: [Si]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:39])[C:19]([NH:21][CH2:22][C:23]3[N:27]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=4)[N:26]=[C:25]([C:35]([F:38])([F:37])[F:36])[CH:24]=3)=[O:20])=[CH:14][C:13]=2[F:40])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:34][C:30]1[CH:29]=[C:28]([N:27]2[C:23]([CH2:22][NH:21][C:19](=[O:20])[CH:18]([C:15]3[CH:16]=[CH:17][C:12]([C:9]4([OH:8])[CH2:10][CH2:11]4)=[C:13]([F:40])[CH:14]=3)[CH3:39])=[CH:24][C:25]([C:35]([F:38])([F:36])[F:37])=[N:26]2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(C2(O[Si](C)(C)C(C)(C)C)CC2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(C2(O)CC2)c(F)c1
Yield: 49.2 %

Procedure:
To a stirred solution of 2-(4-(1-(tert-butyldimethylsilyloxy)cyclopropyl)-3-fluorophenyl)-N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-propanamide (103 mg, 0.173 mmol, 1 eq) in THF (5 mL) was added TBAF (90 mg, 0.346 mmol, 2 eq) at room temperature and the mixture was stirred for 2 h after which THF was evaporated and the residue was dissolved in ethyl acetate (15 mL), washed with water (10 mL×2), brine (10 mL) and the solvent evaporated. The residue was purified by CC using methanol/CHCl3 (1:9) as eluent to give N-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-2-(3-fluoro-4-(1-hydroxycyclopropyl)phenyl)propanamide (41 mg, 49%) as off white solid (TLC system: methanol/CHCl3 (1:9) Rf: 0.5).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:20]=[CH:21][S:22][CH:23]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: ClCc1cscn1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cscn1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 4-(chloromethyl)-1,3-thiazole: 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J=2.0 Hz, 1H), 7.50 (m, 2H), 6.75 (s, 1H), 6.64 (s, 1H), 5.50 (s, 2H), 2.53 (s, 3H); MS (ES) m/z 322 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27](=[O:30])[NH:28][CH3:29])[CH:22]=3)=[CH:16][C:15]=2[F:31])=[O:12])[N:7]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH2:38][N:37](C(OCC2C=CC=CC=2)=O)[CH2:36][CH2:35]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)=O>CO.[Pd]>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27](=[O:30])[NH:28][CH3:29])[CH:22]=3)=[CH:16][C:15]=2[F:31])=[O:12])[N:7]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[CH2:38][NH:37][CH2:36][CH2:35]3)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc4c(c3)CCN(C(=O)OCc3ccccc3)C4)c(F)c2)ccn1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc4c(c3)CCNC4)c(F)c2)ccn1
Reaction time: 1.5 h
Yield: 57.9 %

Procedure:
A solution of benzyl 6-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (93 mg, 0.13 mmol) in methanol (3 mL) was treated with 10% Pd/C (50% wet, 74 mg, 0.03 mmol) and formic acid (88%, 0.60 mL, 14 mmol). The resultant reaction mixture was stirred for 90 min and filtered through Celite, washing forward with methanol. The filtrate was concentrated in vacuo and purified on silica gel to provide 1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea (42 mg, 56% yield). The product was treated with aqueous HCl (0.1 M, 0.75 mL) to provide 1-(3-tert-butyl-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 9.38 (br s, 2H), 9.10 (d, J=1.8 Hz, 1H), 9.05 (s, 1H), 8.80 (m, 1H), 8.53 (d, J=5.4 Hz, 1H), 8.15 (t, J=9.1 Hz, 1H), 7.46-7.34 (m, 4H), 7.32 (dd, J=11.6, 2.8 Hz, 1H), 7.18 (m, 1H), 7.05 (m, 1H), 6.39 (s, 1H), 4.33 (br s, 2H), 3.40 (2H obscured by H2O), 3.09 (t, J=6.0 Hz, 2H), 2.79 (d, J=5.0 Hz, 3H), 1.28 (s, 9H); MS (ESI) m/z: 558.3 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([OH:25])=O)=[CH:18]3)[CH:10]=[N:9]1.Cl.[NH2:27][C:28]([NH2:30])=[NH:29].[OH-].[Na+]>ClCCl.CN(C)C=O>[CH3:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([C:23]([NH:29][C:28]([NH2:30])=[NH:27])=[O:25])=[CH:18]3)[CH:10]=[N:9]1
Reactant: N=C(N)N
Reactant: Cn1cc(-c2cccc3cc(C(=O)O)ccc23)cn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc3cc(C(=O)NC(=N)N)ccc23)cn1
Temperature: 25 °C
Reaction time: 4.25 h
Yield: 83.2 %

Procedure:
Oxalyl chloride (1.1 mL, 13 mmol) was added to a solution of 5-(1-methyl-1H-pyrazol-4-yl)-2-naphthoic acid (1.19 g, 4.71 mmol) in anhydrous dichloromethane (200 mL (which was added in portions during the reaction to effect dissolution)) containing dimethylformamide (2 drops) under nitrogen and the mixture was stirred at room temperature for 4.25 hours. The reaction mixture was then heated for 1 hour at 40° C., before being concentrated under reduced pressure. The resulting crude acid chloride was suspended in anhydrous tetrahydrofuran (50 mL) and this mixture was added dropwise to a solution of guanidine hydrochloride (2.09 g, 21.9 mmol) in 2M aqueous sodium hydroxide (15 mL, 30 mmol) and the reaction mixture was then stirred for 30 minutes. The organic phase was separated, and the aqueous phase was extracted with chloroform (3×30 mL) followed by ethyl acetate (3×30 mL). The combined organic extracts were washed sequentially with 1M aqueous sodium hydroxide (60 mL) and water (40 mL), then dried (Na2SO4) and concentrated in vacuo to give a glassy solid (1.45 g after drying under high vacuum). This solid was dissolved in dichloromethane which was then allowed to evaporate slowly to give 5-(1-methyl-1H-pyrazol-4-yl)-2-naphthoylguanidine as a yellow solid (1.15 g, 83%).
Reaction SMILES: [OH-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:10][C:11]1[CH:22]=[CH:21][C:14]2[C:15](=O)[O:16]C(=O)[NH:18][C:13]=2[CH:12]=1.O1CCCC1>C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([NH2:18])[C:14](=[CH:21][CH:22]=1)[C:15]([O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:16]
Reactant: Oc1ccccc1
Reactant: O=c1[nH]c2cc(F)ccc2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cc(F)ccc1C(=O)Oc1ccccc1

Procedure:
Sodium hydroxide (2 pellets; approx 0.15 g) was added to a mixture of phenol (1.08 g) and 7-fluoro-1H-3,1-benzoxazine-2,4-dione (2 g) followed by tetrahydrofuran (4 ml). The mixture was heated on a steam bath until gas evolution ceased. It was then cooled, diluted with ethyl acetate (100 ml), the liquid collected and washed with aqueous sodium carbonate, dried, treated with charcoal and evaporated. The crude product was recrystallised from diisopropyl ether/light petroleum to give phenyl 4-fluoroanthranilate, m.p. 69°-70°. (Compound 3).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]3[O:30][CH2:31][O:32][C:26]=3[CH:25]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12][C:11]=2[O:17][CH2:18][CH:19]([F:21])[F:20])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[O:36])=[CH:29][C:25]=1[C:26](O)=[O:27]>C1COCC1>[F:21][CH:19]([F:20])[CH2:18][O:17][C:11]1[C:10]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[O:22])=[CH:15][C:14]([NH:16][C:26](=[O:27])[C:25]2[CH:29]=[C:30]([CH2:33][NH:34][C:35]([C:37]([CH3:38])([CH3:40])[CH3:39])=[O:36])[CH:31]=[CH:32][C:24]=2[Cl:23])=[CH:13][N:12]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: Nc1cnc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)c1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cnc(OCC(F)F)c(C(=O)Nc3ccc(Br)cc3)c2)c1

Procedure:
Prepared analogously to Example 2f from N-(4-bromophenyl)-2-(2,2-difluoroethyl)oxy-5-amino-nicotinic acid amide and 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid with PPA and TEA in THF. Purification via HPLC (Method A)
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][C:29]2=[O:35])[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][C:29]5=[O:35])[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cccc(N)c2)C(=O)C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)C(=O)C1

Procedure:
204 c) 1-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-4-methyl-piperazin-2-one was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 1-(3-amino-phenyl)-4-methyl-piperazin-2-one (75.0 mg, 0.365 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (27.0 mg, 0.0494 mmol) as the ligand in a manner analogous to Example 2d. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.91 (s, 1H), 8.89 (d, J=6.6 Hz, 1H), 8.44 (d, J=8.2 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.99 (d, J=7.3 Hz, 1H), 7.86 (s, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.19 (t, J=7.0 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 3.68-3.63 (m, 2H), 3.29 (s, 3H), 3.13 (s, 2H), 2.77-2.72 (m, 2H), 2.31 (s, 3H). MP=234-236° C. MS=477 (MH)+.
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH:4]([CH3:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][CH2:11][C:12]1[C:13]([CH2:18]Cl)=[CH:14][CH:15]=[CH:16][CH:17]=1.Cl>C1COCC1.CS(C)=O.CCOCC>[Cl:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][N:6]1[CH:4]([CH3:5])[CH2:3][CH2:2][C:1]1=[O:7]
Reactant: ClCc1ccccc1CCl
Reactant: CC1CCC(=O)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1CCC(=O)N1Cc1ccccc1CCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.4 %

Procedure:
A solution of γ-valerolactam (7 g, 70.5 mmol) in THF (150 mL) and DMSO (20 mL) was treated with NaH (2.83 g of a 60% oil dispersion) at 0° C. under nitrogen atmosphere. After a total of 15 min, α,α'-dichloro-o-xylene (25 g, 140 mmol) was added and the solution was allowed to warm and stir at room temperature. After 4 h, 100 mL of ether and 100 mL of 0.2 N HCl were added. The water was withdrawn, and the organic layer was washed 2× more with water, dried (MgSO4), filtered and concentrated. This material was purified on ca. 400 g of silica gel (flash chromatography; EtOAc/hexane 7:3) to yield N-[2-(chloromethyl)benzyl]-γ-valerolactam (6.6 g, 40%). 1H NMR and mass spectral analysis supported the assigned structure. A solution of this lactam (5.0 g, 21.09 mmol), 2-(isopropoxy)phenylpiperazine fumarate (6.38 g, 18.99 mmol), and triethylamine (8.82 mL, 62.37 mmol) in DMF (75 mL) was heated for 3 h at 50°-60° C. After 3 h, the solution was added to a 3:1 solution of ether/ethyl acetate (ca. 100 mL) and extracted 3X with water, dried (MgSO4), filtered and concentrated. The residual oil was purified on ca. 400 g of silica gel (flash chromatography, EtOAc/hexane, 6:4) to give 5.41 g of white semi-solid, pure by thin layer chromatography. It was then dissolved in iPrOH, filtered through a Millipore filter, treated with 2.44 mL of conc. aqueous HCl (ca. 26 mmol), and then triturated out of solution by the addition of ether. The resultant white solid was recrystallized in MeOH/ether to give 1-[[2-[[1-[2-(methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidin-2-one hydrochloride(3:2)as a white powder (5.50 g, 61%), m.p. 249.5°-252.5° C. 1H NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)C.[OH-].[Li+]>C1COCC1.CO.O>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[O:21][CH:5]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.6 %

Procedure:
(2,4-Difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.3 gm, 2.98 mmol) was dissolved in THF (5 ml) and methanol (0.5 ml). To this was added a solution of lithium hydroxide (0.62 gm, 14.90 mmol) in water (5 ml) and stirred for 18 hours at 25° C. Organic solvents were evaporated from the reaction mixture and aqueous layer was acidified with 1N HCl, precipitated product was filtered off and residue was washed with water. Solid product was dried under vacuum to provide (2,4-difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid (1 gm).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:21]1[CH:26]=CC=C[CH:22]=1>CNC.C(O)C>[CH3:12][C:11]1([CH3:13])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[N:21]([CH3:26])[CH3:22]
Reactant: CC1(C)C(Cl)=Nc2ccccc2C1(O)c1ccccc1
Reactant: c1ccncc1
Agent: CNC
Solvent: CCO
Product: CN(C)C1=Nc2ccccc2C(O)(c2ccccc2)C1(C)C
Reaction time: 24 h
Yield: 75.7 %

Procedure:
2-Chloro-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (1.0g., 0.0035 mole) was dissolved in a mixture of a 33% w/v solution of dimethylamine in ethanol (15 ml.) and pyridine (0.6 ml. 0.0075 mole). The solution was stirred for 24 hours, then partially evaporated and allowed to crystallise to give the title compound (0.78g., m.p. 170° - 173° C) [Found: C, 77.4; H, 7.75; N, 9.5% C19H22N2O requires: C, 77.5; H, 7.5; N, 9.5%].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=3)=[CH:13][CH:12]=2)=[N:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([OH:27])[CH:19]=4)=[CH:13][CH:12]=3)=[N:6][CH:7]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Product: COc1ccc(-c2ccc(NC(=O)Cc3ccc(Oc4ccc([N+](=O)[O-])c(O)c4)cc3)nc2)cc1
Yield: 45 %

Procedure:
The resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide (120 mg, 0.1 mmol) was reacted with 4-methoxy-phenyl boronic acid (45 mg, 0.3 mmol) as described in example 208 to afford 21.2 mg (45%) of the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21].N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:26]3[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH2:20][CH3:21])[CH2:25]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
A mixture of 22.50 g (83.03 mmole) 1-ethyl-1,4-dihydro-4-oxo-6,7,8-trifluoro-3-quinolinecarboxylic acid, 225 ml acetonitrile, 11.25 g (87.08 mmole) N-ethyl-3-pyrrolidinemethanamine and 12.6 g (83.03 mmole) 1,8-diazabicyclo[5.4.0]undec-7-ene was refluxed 1 hour then was stirred at room temperature overnight. The solid was filtered and washed with ether to give 26.33 g of 1-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 208°-210° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:29][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([O:26]CC)=[O:25])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[NH:29][C:13]4=[N:14][C:15]([N:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([OH:26])=[O:25])[CH2:19]5)=[CH:16][CH:17]=[C:12]4[N:11]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4cccc(C5CC5)n4)[nH]c3n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.8 %

Procedure:
To a solution of (R)-ethyl 1-(2-(6-cyclopropylpyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylate (150 mg, 0.383 mmol) in ethanol (15 mL) was added a 2N sodium hydroxide solution (5 mL) at 0° C. The mixture was stirred at room temperature for 2 h, then was neutralized with a 2M hydrochloric acid solution and was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford (R)-1-(2-(6-cyclopropylpyridin-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (150 mg). MS (ES+APCI) (M+H) 364.2; LCMS retention time 2.974 min (Method J).
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:12]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:13])([CH3:11])([CH3:10])[CH3:9].[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[C:28](O)=[O:29].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:8]([N:12]([C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:13][C:28]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][N:22]=1)=[O:29])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(O)c1cnccn1
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)N(NC(=O)c1cnccn1)C(=O)c1ccccc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Triethylamine (1.0 g, 0.01 mol) was added to a solution of N'-t-butyl-N'-benzoylhydrazine (0.86 g, 0.0031 mol) and pyrazine carboxylic acid (0.56 g, 0.0045 mol) in 10 ml of methylene chloride at 23° C. This mixture was added to a solution of methanesulfonyl chloride (0.6 g, 0.0052 mol) in 10 ml of methylene chloride at 0° C. The mixture was stirred at 23° C. for 3 hours and then allowed to stand at 23° C. overnight. Aqueous sodium bicarbonate was added and the layers were separated. The organic extracts were evaporated to give crude product which was triturated with ether to afford N'-t-butyl-N-(pyrazinecarbonyl)-N'-benzoylhydrazine as a white solid: m.p. 181°-183° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[C:12]([F:17])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:23]([OH:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[C:23]([O:25][C:13]2[CH:14]=[CH:15][C:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[F:17])[CH:24]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of example 24 step (i) and the product of example 18 step (iv).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][C:2]=12.[ClH:14]>O=[Pt]=O.C(O)C>[NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][C@H:2]12.[ClH:14]
Reactant: c1ccc2c(c1)Cc1ncccc1-2
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 9H-indeno[2,1-b]pyridine (0.20 g), PtO2 (70 mg), concentrated aqueous hydrochloric acid (0.1 mL), and ethanol (10 mL) is shaken under hydrogen atmosphere (2 bar) at room temperature for 16 h (in case the transformation is not complete after this time another portion of PtO2 (30 mg) is added and shaking under hydrogen is continued until complete). The catalyst is separated by filtration and the solvent is evaporated to give the crude title compound as its hydrochloric acid salt that is used without further purification. Yield: 0.25 g (crude); Mass spectrum (ESI+): m/z=174 [M+H]+.