Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:10][CH2:9]2)C=CC=CC=1.Cl.[H][H]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(CCc1cccnc1)NCCCCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Temperature: 45 °C

Procedure:
100 g (219.5 mmol) N-[4-(1-diphenylmethyl-piperidin-4-yl)-butyl]-3-(pyridin-3-yl)-propionamide (substance 54) are dissolved in 500 ml ethanol and added to 8.0 g palladium (5%) on activated carbon (moistened with 40 ml water) and 25 ml conc. hydrochloric acid. The mixture is heated to ca. 45° C. and stirred ca. five hours long under hydrogen atmosphere until the consumption of the theoretical amount of hydrogen to be taken up. After cooling, this is filtered from the catalyst and the solvent is removed under vacuum. The residue is taken up in 200 ml water and washed three times with a total of 200 ml CHCl3. The organic phases are discarded and the aqueous phase is made alkaline with 11 g sodium hydroxide and extracted three times, each with 100 ml CHCl3. After washing the organic phase with 30 ml water, the solvent is removed under vacuum. The oily residue is filtered over silica gel with CHCl3/CH3OH/NH4OH (80/20/2). Yield of a slowly hardening resin: 53.0 g (83%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12](Br)Br)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.C[N+]1([O-])CC[O:21]CC1>C(#N)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:21])=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2
Reactant: Cc1cc(=O)c2c(Cl)ccc(C(Br)Br)c2o1
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: Cc1cc(=O)c2c(Cl)ccc(C=O)c2o1

Procedure:
210 mg (0.57 mmol) of 5-chloro-8-(dibromomethyl)-2-methyl-4H-chromen-4-one are heated with 147 mg (1.2 mmol) of N-methylmorpholine N-oxide with the addition of molecular sieves in 15 ml of acetonitrile under reflux overnight. After filtration through kieselguhr, the solvent is removed in vacuo and the residue is purified by preparative HPLC. 22 mg (17% of theory) of the title compound are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:9]1)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:9]1
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(S(C)(=O)=O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN1C(=O)[C@@H](N)CN(S(C)(=O)=O)c2ccccc21
Temperature: 50 °C

Procedure:
A solution of 100 mg (0.27 mmol) of ((S)-5-methanesulfonyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 5 ml of dioxane was treated with 0.22 ml of hydrochloric acid and heated in the sealed flask at 50° C. for 1 hour. For the working-up, the solvent was evaporated under reduced pressure and the residue submitted to a azeotropic distillation with toluene. After drying under reduced pressure, the (S)-3-amino-5-methanesulfonyl-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one hydrochloride was obtained in quantitative yield as a light yellow solid; MS: m/e=270 (M+H)+.
Reaction SMILES: NC1C=CC(C(OC)=O)=CN=1.C(C1C=CC=CC=1C(O)=O)CC1C=CC=CC=1.[CH2:29]([C:37]1[CH:54]=[CH:53][CH:52]=[CH:51][C:38]=1[CH:39]=[N:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][N:42]=1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[CH2:29]([C:37]1[CH:54]=[CH:53][CH:52]=[CH:51][C:38]=1[CH2:39][NH:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][N:42]=1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(N=Cc2ccccc2CCc2ccccc2)nc1
Agent: COC(=O)c1ccc(N)nc1
Agent: O=C(O)c1ccccc1CCc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NCc2ccccc2CCc2ccccc2)nc1

Procedure:
Methyl 2-[N-(2-(phenethyl)benzyl)amino]pyridine-5-carboxylate was prepared from methyl 2-amino-5-pyridinecarboxylate and 2-phenethylbenzoic acid by a procedure similar to that described in Example 4 paragraph (G), except that the imine intermediate, methyl 2-[N-(2-(phenethyl)benzylidene)amino]-5-pyridinecarboxylate, was formed by heating methyl 2-amino-5-pyridinecarboxylate and 2-phenethylbenzoic acid in a Dean & Starke apparatus in toluene for 18 hours.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([C:4]2[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=2)[NH2:10])[O:13][CH2:12][CH2:11][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(c2cccc(N)c2)OCCO1

Procedure:
A mixture of 4 g (0.029 mol) of 3-aminoacetophenone and 2.47 ml (0.044 mol; 1.5 equivalents) of ethylene glycol and a small amount of 4-toluenesulphonic acid in 60 ml of anhydrous benzene are heated to reflux with azeotropic removal of water for 4 hours. The solution is left to cool, washed successively with 20% aqueous sodium carbonate and water and then dried (MgSO4). The solvent is evaporated off under reduced pressure to leave a yellow oil, which is purified by chromatography on a column of silica gel using a diethyl ether/petroleum ether (1:1) mixture as eluent, and then crystallized in hexane to yield 3-(2-methyl-1,3-dioxolan-2-yl)aniline, m.p. 75-77° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:15])[NH:9][C@H:10]1[CH2:13][C@H:12]([OH:14])[CH2:11]1)([CH3:6])([CH3:5])[CH3:4].Cl[C:17]1[N:21]([CH3:22])[C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]=1>CN(C=O)C.O>[C:3]([O:7][C:8](=[O:15])[NH:9][C@H:10]1[CH2:13][C@H:12]([O:14][C:17]2[N:21]([CH3:22])[C:20]3[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=3[N:18]=2)[CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(O[C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydride, 60% in oil (0.141 mL, 6.70 mmol) was added portionwise to a solution of tert-butyl(trans-3-hydroxycyclobutyl)carbamate (0.57 g, 3.04 mmol) and 2-chloro-1-methyl-1H-benzoimidazole (0.558 g, 3.35 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature for 3 h, diluted with water and extracted with EtOAc. EtOAc extract was concentrated and residue purified with ISCO eluting with 0-40% EtOAc/hexanes to give the desired product tert-butyl(trans-3-((1-methyl-1H-benzo[d]imidazol-2-yl)oxy)cyclobutyl)carbamate (0.388 g, 1.222 mmol, 40.2% yield). m/z: 318.2 (M+1)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2].[CH2:29]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:29])[CH:15]([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cccs4)C3)cc21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4cccs4)C3)cc21

Procedure:
A mixture of 200 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-(2-thienyl)-1-piperazinyl]-3-quinolinecarboxylic acid, 0.3 ml of 37% formalin and 0.35 ml of 90% formic acid was refluxed for 2 hours, then evaporated. A ml portion of water was added and the mixture neutralized with 1N sodium hydroxide. The solid was collected, washed with water, methanol, ether and dried, giving mg of the desired product, mp 238°-240° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:37])[C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][C:25]5[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]#[N:36])=[CH:28][C:26]=5[N:27]=4)=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:38][NH:39][CH3:40]>>[C:35]([C:29]1[CH:30]=[C:31]([CH:32]([CH3:34])[CH3:33])[C:25]2[O:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:16]([NH:15][CH2:14][CH:11]4[CH2:12][CH2:13][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([N:39]([CH3:40])[CH3:38])[N:7]=5)[CH2:9][CH2:10]4)=[O:37])=[CH:18][CH:19]=3)=[N:27][C:26]=2[CH:28]=1)#[N:36]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccnc(Cl)n5)CC4)cc3)oc12
Reactant: CNC
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5ccnc(N(C)C)n5)CC4)cc3)oc12
Yield: 48 %

Procedure:
A 5-ml microwave vial was charged with N-{[1-(2-chloropyrimidin-4-yl)piperidin-4-yl]methyl}-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (31 mg, EXAMPLE 7) and dimethylamine (2M in tetrahydrofuran, 3 ml). The resultant mixture was heated to 130° C. for 15 min in a microwave reactor. The mixture was concentrated in vacuo and the residue purified via flash chromatography on a Biotage Horizon 25M column, eluting with 10 column volumes of 100% ethyl acetate, to provide the title compound (15 mg, 48%). Mass spectrum (ESI) 524.3 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.34 (d, J=8.2 Hz, 2H), 7.94 (m, 5H), 7.52 (s, 1H), 6.30 (t, J=5.8 Hz, 1H), 5.84 (d, J=6.0 Hz, 1H), 4.43 (d, J=10.8 Hz, 2H), 3.48 (sept, J=6.8 Hz, 1H), 3.45 (t, J=6.4 Hz, 2H), 3.13 (s, 3H), 2.84 (t, J=11.2 Hz, 2H), 1.93, (m, 3H), 1.46 (d, J=7.0 Hz, 6H), 1.37 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([C:16]([O:18]C(C)(C)C)=[O:17])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O.O>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O[C@@H](C)C(=O)OC(C)(C)C)cc1)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(O[C@@H](C)C(=O)O)cc1)OCC
Yield: 97.7 %

Procedure:
A solution of (S,S)-3-[4-(1-tert-butoxycarbonyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (1.10 g, 3.00 mmol) in CH2Cl2 (5.0 ml) and TFA (4.0 ml) and water (0.2 ml) was stirred for 12 hours. The mixture was concentrated to a residue and purified by silica gel chromatography with EtOAc/Hexanes (50%) to afford the acid product (0.91 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Yield: 97.4 %

Procedure:
A mixture of 2-fluoro-4-nitrophenol (15 gr, 95.5 mmol) and benzyl bromide (18 g, 105 mmol) in acetone (125 ml) containing potassium carbonate (26.5 gr, 190 mmol) was refluxed for 2 hours. The volatiles were removed and the residue was partitioned between 2N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed under vacuum. The solid was triturated with petroleum ether to give 2-fluoro-4-nitro-benzyloxybenzene (23 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[C:17]([CH3:18])=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=2[CH3:19])[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-].[Na+].Cl.O>C(O)C.C(OCC)(=O)C>[CH3:7][C:4]1[N:3]([C:8]2[C:9]([CH3:19])=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:16][C:17]=2[CH3:18])[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: COC(=O)c1cc(C)c(-n2c(C)ccc2C)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)cc(C)c1-n1c(C)ccc1C
Temperature: 25 °C

Procedure:
Methyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)-3,5-dimethylbenzoate of Step A (1.55 g, 6 mmol) was dissolved in ethanol (100 mL) and treated with 1M sodium hydroxide (9 mL). The solution was refluxed overnight, cooled to room temperature, acidified with 1N hydrochloric acid, and diluted into water and ethyl acetate. The organic layer was washed with water until neutral, dried with anhydrous sodium sulfate, filtered and evaporated in vacuo to yield the title compound as a a cream colored solid (1.36 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:17]=[CH:16][C:6]2=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:8][N:9]=[C:5]2[CH:4]=1.[C-:18]#[N:19].[K+].O1CCOCC1.O>C(Cl)Cl>[C:10]1([C:7]2[O:8][N:9]=[C:5]3[CH:4]=[C:3]([CH2:2][C:18]#[N:19])[CH:17]=[CH:16][C:6]=23)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccc2c(-c3ccccc3)onc2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: N#CCc1ccc2c(-c3ccccc3)onc2c1

Procedure:
A mixture of 10.9 g (0.038 mole) of slightly impure 6-(bromomethyl)-3-phenyl-2,1-benzisoxazole, 9.8 g (0.15 mole) of potassium cyanide, 80 ml of dioxane, and 50 ml of water was heated at reflux under a nitrogen atmosphere for 2.5 hr. The mixture was diluted with 200 ml of methylene chloride and the layers were separated. The organic layer was washed twice with water, once with brine, and dried over sodium sulfate, and concentrated to give 7.5 g of gray solid as residue. The solid was chromatographed on 150 g of silica gel and the title compound was eluted with 1% methanol in benzene to yield 3.3 g (37%) of product, m.p. 148°-155° C.
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13](=[O:26])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-])=O)[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)(=O)C.[Fe]>[CH3:1][CH:2]([NH:12][C:13](=[O:26])[CH:14]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1)[CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCCC(C)NC(=O)C=C(C)c1cccc(N)c1

Procedure:
The N-(1-methyldecyl)-3-(3-nitrophenyl)-2-butenamide from Preparation 23 (6.5 g.) was reduced with iron powder (5.0 g.) in glacial acetic acid (80 ml.) in a manner analogously to Preparation 27. After chromatography, 4.5 g. of the title compound was obtained, as an amber oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[N:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:42][C:43]1[CH:44]=[CH:45][C:46]([O:52][CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[C:47]([CH:51]=1)[C:48](O)=[O:49]>CN(C)C=O>[Br:42][C:43]1[CH:44]=[CH:45][C:46]([O:52][CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[C:47]([CH:51]=1)[C:48]([NH:17][C:13]1[CH:14]=[N:15][CH:16]=[C:11]([F:10])[CH:12]=1)=[O:49]
Reactant: Nc1cncc(F)c1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cncc(F)c1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.28 ml, 1.63 mmol), 5-fluoro-3-pyridinamine (73.0 mg, 0.65 mmol) and HATU (371 mg, 0.98 mmol) were added to a solution of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5; 200 mg, 0.651 mmol) in N,N-dimethylformamide (50 ml) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was then purified by chromatography on silica using 0-100% ethyl acetate/hexane. However a number of impurities persisted and the residue was re-purified by MDAP to yield the title compound. 45 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH:24]1([Mg]Br)[CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: Br[Mg]C1CCCC1
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 15 %

Procedure:
To a stirred solution of 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 100 mg, 0.29 mmol) in 2 ml THF, was added cyclopentyl magnesium bromide (2 M solution in diethyl ether) (0.72 ml, 1.44 mmol) drop wise at 25° C. under nitrogen. The resulting reaction mixture was stirred for 40 min at 50° C. in a microwave. The reaction mixture was then quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (2% ethyl acetate in hexane) to afford 6-chloro-2-cyclopentyl-4-phenyl-quinoline-3-carboxylic acid ethyl ester (16.5 mg, 15%) as pale yellow sticky solid. LC-MS: 380 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN([C:14]([O:18][N:19]1N=NC2C=CC=N[C:20]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CONC.O>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:19]([O:18][CH3:14])[CH3:20])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1ccc(O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a suspension of 5-hydroxypicolinic acid (1.0 eq), HATU (1.2 eq) and N-methoxymethanamine hydrochloride (1.2 eq) in dry DMF was added DIEtOAc (2.5 eq) dropwise at rt. The mixture was then stirred overnight at rt. After addition with water, the mixture was extracted with CH2Cl2. The extract was dried, concentrated, and purified by column chromatography to give the desired product (87% yield).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:19][CH:18]=1)=[O:22]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1ccc([N+](=O)[O-])cc1O
Yield: 32.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 4-trifluoromethyl phenyl isocyanate (1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (111 mg, 32%). EI-MS m/z 340 (M-H)-
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][C:24]1[S:25][C:26]([CH:30]([C:32]2[N:36]([CH3:37])[N:35]=[N:34][CH:33]=2)[OH:31])=[C:27]([CH3:29])[N:28]=1>C(Cl)Cl>[CH3:23][C:24]1[S:25][C:26]([C:30]([C:32]2[N:36]([CH3:37])[N:35]=[N:34][CH:33]=2)=[O:31])=[C:27]([CH3:29])[N:28]=1
Reactant: Cc1nc(C)c(C(O)c2cnnn2C)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)c2cnnn2C)s1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A flask containing Dess-Martin reagent (7.50 g, 17.7 mmol) in DCM (200 mL) was cooled to 0° C. and then a solution of (2,4-dimethylthiazol-5-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (3.00 g, 13.4 mmol, Intermediate 45, step a) in 100 mL of DCM was added. After 5 min, the ice bath was removed and the reaction was allowed to stir at room temperature for 45 min, at which time TLC (30% acetone-DCM) indicated the reaction was complete. The reaction was quenched with saturated NaHCO3 solution and about 2 mL of 1 N NaOH and the aqueous portion (pH˜9) was extracted with DCM (3×75 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give an amber oil. Flash chromatography on silica gel (10-40% EtOAc-DCM) afforded the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]2[CH:15]=[N:14][CH:13]=[C:12](C(O)=O)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:35]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN1C(=O)CCC1>[NH2:35][C:12]1[CH:13]=[N:14][CH:15]=[C:16]2[C:11]=1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(cncc2C(=O)O)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCc2c(N)cncc2C1
Temperature: 90 °C

Procedure:
To a solution of 7-tert-butoxycarbonyl-6,8-dihydro-5H-2,7-naphthyridine-4-carboxylic acid (440 mg, 1.581 mmol) in NMP (6 mL) was added TEA (207.9 mg, 286.4 μL, 2.055 mmol) followed by diphenylphosphoryl azide (478.6 mg, 374.8 μL, 1.739 mmol) at rt under nitrogen. The reaction was heated to 90° C. for 2 hours. At RT, the reaction mixture was partitioned between an aqueous saturated solution of NaHCO3 and EtOAc. Combined organic extract was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica, eluting with 1-15% MeOH:DCM to yield tert-butyl 5-amino-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate. (397 mg, 100.7%). MS (2ES+) 501.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(=O)=O.CC(C)=O.[Li]CCCC.[CH:21](=[O:25])[CH2:22][CH2:23][CH3:24]>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([CH:21]([OH:25])[CH2:22][CH2:23][CH3:24])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCC=O
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCC(O)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A solution of 2,6-dibromopyridine (1.00 g, 4.22 mmol) in THF (40 mL) was cooled to −78° C. (dry-ice/acetone bath) and treated with nBuLi (2.64 mL of a 1.6M solution in hexanes, 4.22 mmol) drop-wise over 10 minutes under nitrogen. After 30 minutes at this temperature the pale yellow/green solution was treated with butyraldehyde (400 μL, 4.44 mmol) drop-wise over 5 minutes and the resulting orange/red solution stirred at this temperature for 1 hour. The solution was then allowed to warm slowly to 0° C. (ice/water bath) over 20 minutes and was then quenched by the drop-wise addition of aqueous HCl (2M, 4 mL). The resulting pale yellow solution was reduced to an oil, partitioned between EtOAc (100 mL) and aqueous HCl (2M, 100 mL), and the layers separated. The aqueous was re-extracted with EtOAc (100 mL) and the combined organic layer washed with water (150 mL), brine (150 mL), dried (MgSO4), filtered and reduced to an orange/yellow oil. Purification by SPE (silica) eluting with cyclohexane:EtOAc (gradient 100:1 to 2:1) afforded the title compound (626 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1.C1(=O)O[C:27](=[O:28])[CH2:26]C1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[CH:1]1([NH:4][C:5]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:27](=[O:28])[CH3:26])[CH:18]=4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)O1
Reactant: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
N1-Cyclopropyl-5-[(2-amino-4-pyridyl)oxy]-1H-1-indolecarboxamide (830 mg), succinic anhydride (270 mg) and toluene (30 ml) were refluxed together for 30 minutes. After adding 50 ml of acetic anhydride and 82 mg of sodium acetate to the reaction solution, the mixture was stirred at 80° C. for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate). The second eluted substance was N1-cyclopropyl-5-{[2-(2,5-dioxotetrahydro-1H-1-pyrrolyl)-4-pyridyl]oxy}-1H-1-indolecarboxamide, of which 440 mg was obtained as a colorless powder.