Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:55][O:56][Si:57]([CH:64]([CH3:66])[CH3:65])([CH:61]([CH3:63])[CH3:62])[CH:58]([CH3:60])[CH3:59])=[N:43][N:44]([CH2:46][CH2:47][O:48]C3CCCCO3)[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:55][O:56][Si:57]([CH:61]([CH3:63])[CH3:62])([CH:64]([CH3:66])[CH3:65])[CH:58]([CH3:59])[CH3:60])=[N:43][N:44]([CH2:46][CH2:47][OH:48])[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](OCc1nn(CCOC2CCCCO2)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)[Si](OCc1nn(CCO)cc1-n1nc(C(C)(C)C)cc1NC(=O)N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC[C@@H]4C)n3c2)c2ccccc21)(C(C)C)C(C)C
Temperature: 45 °C
Reaction time: 24 h
Yield: 45.7 %

Procedure:
A solution of Intermediate 74h (0.34 g, 0.37 mmol) in MeOH (3.7 mL) was treated with pyridinium p-toluenesulfonate (0.28 g, 1.1 mmol) and the mixture was stirred at 45° C. for 24 h. The mixture was evaporated in vacuo and the residue was partitioned between DCM and a saturated aqueous sodium bicarbonate solution. The aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with water, a saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-8% MeOH in DCM, to give the title compound as a golden glass (142 mg, 46%). LCMS (Method 3): Rt 4.81 min, m/z 839.6 [MH+].
Reaction SMILES: C(=O)([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])=[CH:7][C:6]=1[N+:26]([O-:28])=[O:27])OC.O>C(O)C.S(=O)(=O)(O)O>[Cl:25][C:15]1[CH:16]=[C:17]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:19]([Cl:20])[C:14]=1[N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:26]([O-:28])=[O:27])=[C:5]([OH:4])[CH:13]=2)[CH:9]=[N:10]1
Reactant: COC(=O)Oc1cc2c(cnn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2cc1O
Yield: 58.8 %

Procedure:
To a solution of methyl 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitroindazol-6-yl carbonate (8 g) in ethanol (100 g), 30% sulfuric acid (20 ml) was added, and the resultant mixture was refluxed for 6 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-hydroxy-5-nitroindazole (4.1 g).
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][CH2:42][CH2:43][CH2:44][OH:45]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:41][CH2:42][CH2:43][CH2:44][OH:45])=[O:40])=[CH:11][CH:12]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: NCCCO
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NCCCO)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for example 58 using (S)-phenyl(4-(6-(5-fluoro-2-(methylsulfonyl)phenyl)-2-(3-methylmorpholino)pyrimidin-4-yl)phenyl)carbamate (intermediate 32) (140 mg, 0.25 mmol) and 3-aminopropan-1-ol (28 mg, 0.375 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound as a yellow solid. (29 mg, 21%)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:12])=[C:9]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:8]=2[CH:18]=1)([O-])=O.[H][H]>[Pt].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([CH3:12])=[C:9]([CH2:13][CH2:14][N:15]([CH3:16])[CH3:17])[C:8]=2[CH:18]=1
Reactant: Cc1oc2ccc([N+](=O)[O-])cc2c1CCN(C)C
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCOC1
Product: Cc1oc2ccc(N)cc2c1CCN(C)C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
A mixture of 2.1 gm (8.6 mMol) 5-nitro-2-methyl-3-(N,N-dimethyl-2-aminoethyl)benzofuran and 0.5 gm platinum on carbon in tetrahydrofuran was hydrogenated at an initial hydrogen pressure of 60 p.s.i. at room temperature for 15 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residual oil was subjected to flash silica gel chromatography, eluting with dichloromethane containing 10% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure to provide 1.42 gm (76%) 5-amino-2-methyl-3-(N,N-dimethyl-2-aminoethyl)benzofuran. The dihydrochloride salt was prepared and recovered as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=O)=[CH:16][CH:15]=2)=[CH:12][CH:11]=[N:10]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]3=[N:20][O:22][C:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[C:16]3[CH:15]=2)=[CH:12][CH:11]=[N:10]1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2F)cc1
Reactant: N#CCc1ccc(F)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4F)cc23)cc1

Procedure:
The title compound, light grey solid (22 mg, 17%), MS (ISP) m/z=392.2 [(M+H)+], mp 149° C., was prepared in accordance with the general method of example 1 from 1-(2,4-difluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate I) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:9]1.[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25](Cl)[N:24]=1>C(O)(C)(C)C>[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[C:25]([O:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[N:9]2)[N:24]=1
Reactant: NC(=NCC(F)(F)F)Nc1ccn(CCCCO)n1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: NC(=NCC(F)(F)F)Nc1ccn(CCCCOc2cncc(Cl)n2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.4 %

Procedure:
Sodium hydride (46 mg. of a 61% w/w dispersion in oil) was added to a hot solution of 1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (279 mg.) in dry t-butanol (10 ml.). 2,6-Dichloropyrazine (180 mg.) was added and the mixture was stirred at room temperature for two hours, followed by evaporation in vacuo to dryness. The residue was treated with dilute aqueous 0.5N HCl (10 ml.), and then extracted with EtOAc (4×10 ml.). The combined extracts were dried (MgSO4) and evaporated. The residue was purified by preparative t.l.c. on silica gel plates using triethylamine/EtOH/EtOAc 1:1:9 v/v/v as developing solvent to give 2-chloro-6-[4-(3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazol-1-yl)butoxy]pyrazine (170 mg.; 43%) having the following n.m.r. in d6DMSO: 8.25 (s, 2H); 7.4 (d, 1H); 5.6 (d, 1H); 4.25 (t, 2H); 3.9 (m, 4H); 1.7 (br m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[O:11][CH3:12].B.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(CC#N)ccc1Br
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(CCN)ccc1Br

Procedure:
4-Bromo-3-methoxyphenylacetonitrile (22.6 g, 0.1 m) dissolved in tetrahydrofuran (100 ml) is added to 1M borane in tetrahydrofuran (300 ml) stirred at 25°. The mixture is refluxed, cooled to 0° and treated cautiously with 2N hydrochloric acid to give 4-bromo-3-methoxyphenethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:39][CH2:40][C:41]#[N:42].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C(OCC)(=O)C>[C:41]([CH2:40][CH2:39][N:19]1[CH2:20][CH2:21][CH:16]([C:14]([N:12]2[CH2:13][CH:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH:10]([N:22]([CH3:37])[C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=3)[CH2:11]2)=[O:15])[CH2:17][CH2:18]1)#[N:42]
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CCC#N)CC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.090 mmol) in dichloromethane (1 mL) was added 3-bromopropionitrile (11 μL, 0.13 mmol) and an aqueous saturated solution of sodium carbonate (1000 μL). The resulting suspension was stirred for 18 h at ambient temperature. After the addition of dichloromethane (1 mL) and further 3-bromopropionitrile (11 μL, 0.13 mmol) it was stirred for 6 h at 40° C. After diluting with ethyl acetate (10 mL) the mixture was washed with an aqueous solution of sodium carbonate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate:(ethyl acetate:triethylamine=95:5):methanol=20:80:0:0 to 0:0:90:10) afforded the title compound (51 mg, 93%) as an light brown foam. MS m/e: 611.2 [M]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)[CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.N(C(C)C)C(C)C>ClCCl.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:8][C:9]#[C:10][C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(I)cc1
Reactant: C#CCN(Cc1ccc(F)c(F)c1)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N(CC#Cc1ccc(Cl)cc1)Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
A mixture of (3,4-difluoro-benzyl)-prop-2-ynyl-carbamic acid tert-butyl ester (3.2 g, 11.4 mmol), 4-chloroiodobenzene (4.1 g, 17.2 mmol, 1.5 eq.), Pd(PPh3)2Cl2 (0.4 g. 0.57 mmol, 5 mol %), iPr2NH (4 mL, 28.5 mmol, 2.5 eq.) and CuI (0.435 g, 2.3 mmol, 0.2 eq.) in 100 mL dichloromethane was stirred overnight at room temperature. The solution was diluted with 300 mL ether and filtered through a CELITE pad to remove the insoluble components. The filtrate washed with 2×100 mL 1N HCl, 100 mL brine, dried over MgSO4, filtered, concentrated and chromatographed with 6% ethyl acetate in hexanes to provide 2.6 g of [3-(4-chloro-phenyl)-prop-2-ynyl]-(3,4-difluoro-benzyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[F:21][C:22]([F:29])([F:28])[CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][C:25](=[O:26])[CH2:24][CH2:23][C:22]([F:29])([F:28])[F:21])=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: O=C(Cl)CCC(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCC(F)(F)F)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 176 mg, 4.4 mmol, 1.1 eq.), and the mixture was stirred at a room temperature for 40 minutes. Then, 4,4,4-trifluorobutyryl chloride (4.4 mmol, 1.1 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 2 hours. Thereafter, a sodium hydrogencarbonate aqueous solution and water were added to the reaction solution, and the precipitate was separated by filtration and dried to give 1-phenyl-4-(4,4,4-trifluorobutyryloxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (955 mg, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:9]2)=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([CH2:33]Br)[CH:30]=[CH:29][C:28]=1[O:35][CH3:36])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:37])[C:27]1[CH:32]=[C:31]([CH2:33][N:20]2[CH2:19][CH2:18][CH:17]([C:10]3[C:11]4[C:12](=[CH:13][N:14]=[CH:15][CH:16]=4)[N:8]([CH2:7][C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:9]=3)[CH2:22][CH2:21]2)[CH:30]=[CH:29][C:28]=1[O:35][CH3:36])[CH3:24]
Reactant: Clc1ccc(Cn2cc(C3CCNCC3)c3ccncc32)s1
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Product: CCOC(=O)c1cc(CN2CCC(c3cn(Cc4ccc(Cl)s4)c4cnccc34)CC2)ccc1OC
Yield: 43.4 %

Procedure:
This compound was prepared following the procedure described in example 24, part E, starting with 0.44 g (1.32 mmol) of 1-(5-chlorothiophen-2-ylmethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-c]pyridine and 0.36 g (1.32 mmol) of 5-bromomethyl-2-methoxybenzoic acid ethyl ester. After standard work-up and purification, 0.3 g (43% yield) of 5-{4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-ylmethyl}-2-methoxy-benzoic acid ethyl ester were obtained.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22](O)=[O:23].O.[NH2:39][NH2:40]>CS(C)=O>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:28]=[N:27][CH:26]=[C:25]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])[C:21]=1[C:22]([NH:39][NH2:40])=[O:23]
Reactant: NN
Reactant: O=C(O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CS(C)=O
Product: NNC(=O)c1c(Nc2ccc(I)cc2F)cncc1-c1ccccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
1,1′-carbonyldiimidazole (21 mg, 0.13 mmol) was added to a solution of 3-(2-fluoro-phenyl)-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid (40 mg, 0.09 mmol) in DMSO (1 mL), and stirred overnight at 60° C. Hydrazine hydrate (13 mg, 0.27 mmol) was added, and the reaction solution was stirred for an additional 4 h at 60° C. The reaction solution was quenched with H2O, diluted with EtOAc, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 0 to 70% EtOAc in hexanes to afford the desired product (22 mg, 53%). LC-MS (M+H=467, obsd.=467).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][NH:15]C(OC(C)(C)C)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23]>>[ClH:23].[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][NH2:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NNC1CCCN(Cc2ccccc2)C1
Agent: Cl
Product: NNC1CCCN(Cc2ccccc2)C1
Yield: 146.3 %

Procedure:
A solution of tert-butyl 2-(1-benzylpiperidin-3-yl)hydrazinecarboxylate (1.25 g, 4.10 mmol) in aqueous HCl (6 N, 6.83 mL, 41.0 mmol) was stirred at ambient temperature for about 8 h. The solvent was removed under reduced pressure to give crude 1-benzyl-3-hydrazinylpiperidine hydrochloride (1.45 g, 112%) as a white solid which was used without further purification: LC/MS (Table 1, Method b) Rt=0.66 min; MS m/z: 206 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:19])[N:8]([CH3:18])[C:9]2[C:14]([C:15]=1[N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c2ccc(C)nc2n(C)c1=O
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCCC2)c2ccc(C)nc2n(C)c1=O

Procedure:
A stirred mixture of 2.8 g. (0.01 mole) of 4-chloro-1,7-dimethyl-1,2-dihydro-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester, 0.7 g. (0.01 mole) of pyrrolidine and 1.06 g. (0.01 mole) of sodium carbonate in 30 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was cooled in ice. The precipitate which formed was collected and was recrystallized from heptane to give 1.7 g. of product, m.p. 108°-111° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].C(N(CC)CC)C.Br[CH:13]([CH2:19]Br)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[NH:1]1[CH2:2][CH2:3][S:4][CH2:19][CH:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NCCS
Reactant: CCOC(=O)C(Br)CBr
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CSCCN1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A warm solution of 2-aminoethanethiol (10.0 g, 0.130 mol) and triethylamine (36 mL, 0.260 mol) in chloroform is added over 5 minutes to a solution of ethyl 2,3-di-bromopropionate (33.9 g, 0.130 mol) in a chloroform/toluene (1:1.6) solution. The reaction mixture is stirred at room temperature for 2.5 hours, filtered and concentrated in vacuo to obtain an orange liquid. The liquid is vacuum distilled to give the title product as a colorless liquid, bp 121°-124° C. at 3 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].CN(C)C1C=CC=CC=1.O1CCCC1.Br[CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](Cl)=[O:30]>C(OCC)(=O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]2[O:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11]([C:2]=3[NH:1][C:29]2=[O:30])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:33][CH:34]=1
Reactant: O=C(Cl)C(Br)c1ccc(Cl)cc1
Reactant: Nc1c(O)ccc2ccccc12
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C1Nc2c(ccc3ccccc23)OC1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a mixture of 1-amino-2-naphthol (9.4 g), N,N-dimethylaniline (17.87 g) and tetrahydrofuran (160 ml) is added dropwise α-bromo-4-chlorophenylacetyl chloride (18.97 g) under ice cooling, and the mixture is stirred for one hour. To the reaction mixture is added ethyl acetate, and the ethyl acetate layer is washed, dried and distilled to remove the solvent. The resulting oil is dissolved in acetone (500 ml) and thereto is added potassium carbonate (40.8 g), and the mixture is refluxed for 2 hours, and acetone is distilled off. To the residue is added water, and the precipitate is separated by filtration, washed, dried and recrystallized from tetrahyrofuran to give 3-(4-chlorophenyl)-1H-naphtho[2,1-b][1,4]oxazin-2(3H)-one (13.29 g, yield 72.8%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=1)[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][CH2:28][C:27]3[CH:36]=[CH:37][CH:38]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1cccc(COCCCCCBr)c1
Agent: Cl
Product: COc1cccc(COCCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 5-(3-methoxybenzyloxy)pentyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-2-methoxy-N-((1-(5-(3-methoxybenzyloxy)pentyl)-piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [C:1]([N:4]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]2[CH3:23])=[CH:13][CH:12]=1)[CH3:10])[O:5]C(=O)C)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([N:4]([CH:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:18]([CH3:23])=[CH:19][CH:20]=[C:21]2[CH3:22])=[CH:13][CH:12]=1)[CH3:10])[OH:5])(=[O:3])[CH3:2]
Reactant: CC(=O)ON(C(C)=O)C(C)c1ccc(-n2c(C)ccc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N(O)C(C)c1ccc(-n2c(C)ccc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.4 g of N-acetyl-N-acetyloxy-1-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-ethylamine and 7.0 g of potassium carbonate in 70 ml of methanol is stirred at room temperature overnight and then evaporated to dryness. The residue is suspended in water and the product is extracted with ethyl acetate. The ethyl-acetate extract is washed with brine, dried and evaporated to dryness. The residue is purified by chromatography on silica gel to yield N-acetyl-N-hydroxy-1-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-ethylamine; NMR (DMSO-d6): δ7.15, 7.45, 5.85, 2.0, 2.15.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].[C:31](OC(=O)C)(=[O:33])[CH3:32].S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:29]=[C:28]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:25]=[CH:24][C:10]([C:11]([N:13]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ccc(C(=O)Nc2ccc(C(=O)N3CCCCc4ccccc43)cc2)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc(C(=O)N3CCCCc4ccccc43)cc2)c(Cl)c1

Procedure:
A mixture of 1-[4-(2-chloro-4-aminobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g), acetic anhydride (15 ml), acetic acid (5 ml) and a drop of sulfuric acid is stirred at room temperature for 1 hour. To the reaction mixture is added aqueous 2N aqueous sodium hydroxide solution and the mixture is extracted with chloroform. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is concentrated and the resulting residue is recrystallized from methanol/diethyl ether to give 1-[4-(2-chloro-4-acetylaminobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.28 g) as white powder, m.p. 214°-243° C.