Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH:9]([C:11]1[S:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OC(=O)C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:14]1[S:15][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=1
Reactant: Clc1ccccc1I
Reactant: O=Cc1ccc(B(O)O)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=Cc1ccc(-c2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-1-iodobenzene (0.25 mL) and 5-formyl-2-thiophene boronic acid (0.385 g) in DME (8 mL) were added Pd(OAc)2 (0.009 g) and Ph3P (0.021 g) followed by 2M sodium carbonate (1 mL). The mixture was stirred at rt for 1 h. The reaction was diluted with ethylacetate (20 mL) and washed with water and brine, and then dried (sodium sulfate). The crude product was purified by flash-chromatography using EtOAc-hexanes (1:5) to give the desired 5-(2-chlorophenyl)thiophene-2-aldehyde as an oil. The aldehyde (0.15 g), thus obtained, was then condensed with 2,4-thiazolidine-2,4dione in the presence of benzoic acid and piperidine under the conditions described in EXAMPLE 5 to give the title compound 5-(5-(2-chloro-phenyl)thienylidene)thiazolidine-2,4-dione.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:19]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1nc(-c2ccccc2)n2c(=O)[nH]ncc12
Solvent: c1ccncc1
Product: Cc1nc(-c2ccccc2)n2c(=S)[nH]ncc12
Temperature: 100 °C

Procedure:
To a solution of 4.5 gm. of 8-methyl-6-phenyl-imidazo-[1,5-d]-as-triazin-4(3H)-one in 100 ml. of pyridine is added 5 gm. of phosphorus pentasulfide. The reaction mixture is heated at 100° C. for 8 hours, filtered, and poured into dilute hydrochloric acid. The precipitated product is isolated by filtration, washed with water, and dried.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[C:6]([C:13]([O:15]C)=O)=[N:7][C:8]([CH3:12])=[C:9]([CH3:11])[N:10]=1.[NH2:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH2:24][CH3:25].C=O>C(Cl)(Cl)Cl.ClCCl.O>[CH2:24]([N:20]1[CH2:21][CH2:22][CH2:23][CH:19]1[CH2:18][NH:17][C:13]([C:6]1[C:5]([O:4][CH3:3])=[N:10][C:9]([CH3:11])=[C:8]([CH3:12])[N:7]=1)=[O:15])[CH3:25]
Reactant: COC(=O)c1nc(C)c(C)nc1OC
Reactant: CCN1CCCC1CN
Agent: C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCN1CCCC1CNC(=O)c1nc(C)c(C)nc1OC

Procedure:
To 20 ml. of methanol there was added 1.0 g of methyl 3-methoxy-5,6-dimethylpyrazine-2-carboxylate and 1.5 g of 2-aminomethyl-1-ethylpyrrolidine and the mixture was refluxed for 30 hours. The methanol was distilled off under reduced pressure from the reaction mixture, the residue thus obtained was added to a mixture of 20 ml. of water and 20 ml of dichloromethane and mixed well. The organic layer that was separated was acidified with an aqueous hydrochloric acid and extracted three times each time with 20 ml. of water. The aqueous extracts were combined basified with a 2 N aqueous sodium hydroxide and extracted three times each time with 20 ml. of dichloromethane. The dichloromethane extracts were combined, dried over anhydrous magnesium sulfate and then the solvent was distilled off. The residue thus obtained was applied to a silica gel column chromatography and then developed using a mixture of chloroform and methanal in a 1:1 volume ratio as the eluting solution, whereby 0.8 g. of light yellow oily N-(1 -ethylpyrrolidin-2-ylmethyl)-3-methoxy-5,6-dimethylpyrazine-2-carboxamide was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[C:6]([N:13]=1)=[N:7][CH:8]=[C:9]([CH2:11]O)[CH:10]=2.O=S(Cl)[Cl:16]>C(Cl)Cl>[Cl:16][CH2:11][C:9]1[CH:10]=[C:5]2[S:4][C:3]([S:2][CH3:1])=[N:13][C:6]2=[N:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1nc2ncc(CO)cc2s1
Solvent: ClCCl
Product: CSc1nc2ncc(CCl)cc2s1
Reaction time: 3 h
Yield: 107.7 %

Procedure:
To a stirred mixture of (2-(methylthio)thiazolo[4,5-b]pyridin-6-yl)methanol (404 mg, 2 mmol) in anhydrous CH2Cl2 (20 mL) at rt was added SOCl2 (166 μL, 2.4 mmol). After 3 h, the mixture was concentrated under reduced pressure to afford 6-(chloromethyl)-2-(methylthio)thiazolo[4,5-b]pyridine (497 mg) as a white solid. The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (d, J=1.9 Hz, 1H), 8.60 (d, J=1.9 Hz, 1H), 4.95 (s, 2H), 2.83 (s, 3H); LCMS (ESI) m/z 231 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:45]=[CH:44][C:13]([CH2:14][N:15]([C:31]3[CH:43]=[CH:42][C:34]4[O:35]C(C)(C)[O:37][C:38](=[O:39])[C:33]=4[CH:32]=3)[C:16](=[O:30])[C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]([C:16](=[O:30])[C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:22]=3)[C:31]3[CH:43]=[CH:42][C:34]([OH:35])=[C:33]([CH:32]=3)[C:38]([OH:39])=[O:37])=[CH:44][CH:45]=2)=[CH:6][CH:7]=1
Reactant: CCCCCCCc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)c2ccc(O)c(C(=O)O)c2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-chlorophenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-4-heptylbenzamide and NaOH as a white solid (67%). M− (ESI): 577.8; M+ (ESI): 580.1. HPLC, Rt: 5.89 min (Purity: 92.3%).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([NH2:24])=[O:23])[N:15]=1>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([N:24]=[C:2]=[O:3])=[O:23])[N:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Solvent: ClCCl
Product: O=C=NC(=O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 94.5 %

Procedure:
Oxalyl chloride (2.5 ml, 28.2 mmol, 2.0 eq.) is then added dropwise under N2 to a suspension of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzamide (Compound A3, 4.0 g, 14.1 mmol) in anhydrous dichloromethane (20 mL) cooled to 0° C. The mixture is slowly heated to reflux and stirred for an additional 6 h. The solvent is removed on a rotary evaporator. The residue is azeotroped with anhydrous dichloromethane (20 mL) and dried under high vacuum for two hours to give 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoyl isocyanate (Compound A4) as a tan solid 4.12 g (95%) which may be used immediately without further purification.
Reaction SMILES: [NH:1]([C:5]([O:7][CH2:8][CH:9]([NH:22]C(OC(C)(C)C)=O)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:6])[C:2]([NH2:4])=[O:3].CC(O)C.Cl>CO.C(Cl)(Cl)Cl>[ClH:21].[NH2:22][CH:9]([CH2:8][O:7][C:5]([NH:1][C:2]([NH2:4])=[O:3])=[O:6])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(COC(=O)NC(N)=O)COc1noc2ccc(Cl)cc12
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: NC(=O)NC(=O)OCC(N)COc1noc2ccc(Cl)cc12

Procedure:
3-(3-Ureidocarbonyloxy-2-tert-butoxycarbonylaminopropoxy)-5-chloro-1,2-benzoisoxazole is suspended in 10 ml of methanol and 5 ml of chloroform, and 12.8 ml of a 2-propanol solution (7.5N) of hydrogen chloride is added, after which they are subjected to reaction at 20°-25° C. overnight. The crystals precipitated are collected by filtration, to obtain 0.62 g of colorless, crystalline 3-(2-amino-3-ureidocarbonyloxypropoxy)-5-chloro-1,2-benzisoxazole hydrochloride having a melting point of 203°-204° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.F[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38]>>[CH2:2]1[C:35]2[C:41](=[CH:40][CH:39]=[C:37]([NH:38][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:5][CH2:4][NH:3]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: Nc1cccc(F)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 3-fluoroaniline in a manner analogous to Example 27, Step D. 1H NMR (400 MHz, DMSO-d6) δ 6.58 (d, 1H, J=5.3 Hz), 6.71 (m, 1H), 7.12 (m, 1H), 7.23 (m, 3H), 7.31 (d, 1H, J=7.7 Hz), 7.44 (m, 3H), 7.53 (m, 1H), 7.76 (m, 2H), 8.00 (s, 1H), 8.29 (d, 1H, J=5.3 Hz), 8.45 (d, 1H, J=9.0 Hz), 8.84 (d, 1H, J=7.0 Hz), 9.83 (s, 1H), 10.92 (s, 1H); ESIMS (M+H)+=537.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][C:3]=1[O:27]C.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:19]=[C:18]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[O:9])=[CH:4][C:3]=1[OH:27]
Reactant: COc1cc(C(=O)c2nc(Nc3cc(C)[nH]n3)c3ccccc3n2)ccc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(O)c3)nc3ccccc23)n[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a stirred suspension of (4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone from Example 76 (100 mg, 0.265 mmol) in DCM (4 mL) at 0° C., was added dropwise 1.0 M boron tribromide/DCM (2.12 mL, 2.12 mmol). The mixture was stirred at 0° C. for 30 min. Additional 1.0 M boron tribromide/DCM (1.50 mL, 1.50 mmol) was added and the mixture was allowed to warm to rt and stir for a further 2.5 h. Water (10 mL) was added, and the mixture was extracted with 25% 2-propanol/DCM (2×). T The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the resulting solid was collected by filtration and dried. The solid was further purified by reverse-phase HPLC eluting with a mixture of water and acetonitrile to afford (4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone as a yellow solid (20 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H), 6.51 (s, 1H), 7.28 (dd, J=10.8, 8.4 Hz, 1H), 7.39 (m, 1H), 7.58 (dd, J=8.7, 1.8 Hz, 1H), 7.67 (ddd, J=8.1, 8.1, 1.5 Hz, 1H), 7.83-7.92 (m, 2H), 8.73 (d, J=8.4 Hz, 1H), 10.65 (br s, 1H), 12.22 (br s, 1H); LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[C:40]([N:44]([CH3:49])[C:45](=O)[CH2:46]Cl)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([N:44]([CH3:49])[CH2:45][CH2:46][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C(=O)CCl)C(C)(C)C
Product: COc1cc(NCCCc2ccc(OCCN(C)C(C)(C)C)cc2)c(C2CCc3cc(O)ccc3C2)cc1OC
Yield: 24.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and N-tert-butyl-2-chloro-N-methylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.4 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH:9]=[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]2=[O:26].S(=O)(=O)(O)O.[N+:34]([O-])([O-:36])=[O:35].[K+]>>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:13]=[C:14]([O:19][CH3:20])[C:15]([F:18])=[CH:16][C:17]=1[N+:34]([O-:36])=[O:35])[CH:9]=[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]2=[O:26]
Reactant: CCOC(=O)c1cn(-c2ccc(F)c(OC)c2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(-c2cc(OC)c(F)cc2[N+](=O)[O-])c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 57.3 %

Procedure:
Ethyl 8-chloro-6,7-difluoro-1-(4-fluoro-3-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (830 mg) was added to concentrated sulfuric acid (4 ml), and anhydrous potassium nitrate (250 mg) was added portionwise to the mixture while stirring under ice cooling. The resultant mixture was stirred for 15 minutes under ice cooling and for 50 minutes at room temperature. The reaction mixture was poured into ice water (50 ml) and then extracted with chloroform (50 ml). After a chloroform layer was washed with distilled water (20 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Deposits were dispersed in ethanol, collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (528 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:40][CH2:39][CH:38]([C:41]([OH:43])=[O:42])[CH2:37][CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)C1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(C(=O)O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylic acid was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.F[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[N+:28]([O-:30])=[O:29]>C(O)C>[N+:28]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:19]=1[NH:15][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:17][CH:16]=1)[C:23]([OH:25])=[O:24])([O-:30])=[O:29]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(OCCOc2ccccn2)cc1
Solvent: CCO
Product: O=C(O)c1ccc(Nc2ccc(OCCOc3ccccn3)cc2)c([N+](=O)[O-])c1

Procedure:
4-[2-(Pyridin-2-yloxy)ethoxy]aniline (4.50 g, 19.50 mmol) and 4-fluoro-3-nitrobenzoic acid (3.60 g, 19.50 mmol) were dissolved in ethanol (100 mL) and refluxed under nitrogen for 18 h. The reaction mixture was filtered and washed with cold ethanol (×2) to give 3-nitro-4-({4-[2-(pyridin-2-yloxy)ethoxy]phenyl}amino) benzoic acid as a reddish orange solid. 1H NMR (d6-DMSO, 400 MHz): δ 9.77 (brs, 1H), 8.64 (d, J=2.4 Hz, 1H), 8.18 (ddd, J=5.2, 2.0, 0.8 Hz, 1H), 7.88 (dd, J=9.6, 2.0 Hz, 1H), 7.73 (ddd, J=8.8, 6.8, 2.0 Hz, 1H), 7.29 (ddd, J=6.4, 3.2, 3.2 Hz, 1H), 7.08 (ddd, J=5.6, 3.2, 3.2 Hz, 1H), 7.01 (ddd, J=7.4, 5.2, 1.2 Hz, 1H), 6.97 (d, J=9.2 Hz, 1H), 6.87 (ddd, J=8.4, 0.8, 0.8 Hz, 1H), 4.60 (m, 2H), 4.37 (m, 2H), 4.15 (m, 2H). MS(ES+): m/z 396.45 (100) [MH+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]1[S:26][CH:27]([CH2:30][C:31](OCC)=[O:32])[CH2:28][N:29]=1)=[CH:9]2.O1CCCC1.CO.[BH4-].[Li+]>O>[OH:32][CH2:31][CH2:30][CH:27]1[S:26][C:25]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:24])[S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:18])=[N:29][CH2:28]1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OCCOC)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CCO)S3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.2 %

Procedure:
To a mixture of ethyl (2-{5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (200 mg), tetrahydrofuran (5 mL) and methanol (1 mL) was added lithium borohydride (16 mg), and the mixture was stirred at room temperature for 1 hr. Lithium borohydride (16 mg) was added to the mixture, and the mixture was further stirred at room temperature for 1 hr. Lithium borohydride (16 mg) was added to the mixture, and the mixture was further stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:9, volume ratio) to give yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (100 mg, yield 56%) as a pale-yellow powder. melting point 122-123° C.
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.[CH:33]1(B(O)O)[CH2:35][CH2:34]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:33]1([C:2]2[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:29])[CH3:30])[CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][C:5]3[N:6]([CH3:15])[C:7](=[O:14])[C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[N:10][CH:9]=4)[CH2:35][CH2:34]1
Reactant: OB(O)C1CC1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C[C@@H](COc1cc2c(cc1C1CC1)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 50.5 %

Procedure:
A mixture of (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.297 mmol) (as prepared in Ex. 3, Part A), cyclopropylboronic acid (28.1 mg, 0.327 mmol), tetrakis(triphenylphosphine)palladium (17.2 mg, 0.015 mmol) and Cs2CO3 (291 mg, 0.892 mmol) in toluene (5 mL) and water (0.43 mL) mixture was purged with nitrogen for 5 min then heated at 90° C. overnight (16 h). After cooling, toluene was removed under reduced pressure and the product was extracted with ethyl acetate (20 mL). The organic phase was washed with brine (2×20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (EtOAc-hexane) to afford (S)-tert-butyl (1-((9-cyclopropyl-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (70 mg, 0.150 mmol, 51% yield) as an off-white gummy solid. LC/MS (ESI) m/z 466.4 [(M+H)+, calcd for C27H36N3O4 466.3]; LC/MS retention time (method E): tR=1.19 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:33])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=3)[CH2:17][C:16](=[O:33])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(F)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1-c1cccc(C2=Nc3ccc(F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (4-fluoro-2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M15) (250 mg, 0.539 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (143 mg).
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH:13]([NH:16][CH3:17])[CH:12]=[CH:11][C:10]=2[CH:18]=1)([O-])=O.[OH-].[NH4+]>O>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]2[CH2:15][CH2:14][CH:13]([NH:16][CH3:17])[CH:12]=[CH:11][C:10]=2[CH:18]=1
Reactant: CNC1C=Cc2cc([N+](=O)[O-])ccc2CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CNC1C=Cc2cc(N)ccc2CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.1 %

Procedure:
A mixture of 26 ml of fuming hydrochloric acid, 3.9 g of stannous chloride dihydrate and 1.3 g of 2-nitro-7-methylamino-6,7-dihydro [5H] benzocycloheptene hydrochloride was stirred at room temperature for 16 hours and was then cooled to 10° C. for the addition of 100 ml of water. The mixture was made alkaline at 10° C. with concentrated ammonium hydroxide and was then extracted 3 times with 50 ml of methylene chloride. The organic extracts were washed with water, dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 1 g of 2-amino-7-methylamino-6,7-dihydro [5H] benzocycloheptene in the form of a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A stirred solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (134.8 g) in N,N-dimethylformamide (850 m) was cooled in an ice bath under a nitrogen atmosphere. Potassium tert butoxide (75.2 g) was added in portions such that the temperature did not exceed 22° C. and the resulting mixture was maintained at 0° C. for a further 1.5 hours when 4-fluorobenzotrifluoride (100 g) was added dropwise over 15 minutes. The reaction mixture was allowed to warm to room temperature and stirred overnight. Water (200 ml) was added and the mixture was extracted with tert butyl methyl ether (1×400 ml, 1×300 ml, 1×200 ml). The combined organic extracts were washed with water (2×400 ml), brine (200 ml) and then dried over magnesium sulphate and evaporated in vacuo to leave the title compound as an off-white/pale yellow solid (206.4 g)