Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13]>[Pd].CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[OH:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1O

Procedure:
A mixture of 2.01 g (10 mmol) 2-hydroxy-3-nitro-benzoic acid methyl ester, 0.8 g of palladium (10 wt. % on carbon powder) and 30 mL of methanol was hydrogenated at 40 psi overnight. The reaction mixture was filtered over celite. Evaporation of the solvents in vacuo gave 3-Amino-2-hydroxy-benzoic acid methyl ester. LCMS: 168 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9](N)[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4].C(#N)C.N([O-])=[O:27].[Na+]>OS(O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([OH:27])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4]
Reactant: O=N[O-]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(O)c1Cl
Reaction time: 0.17 h
Yield: 53 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-chloropyrimidine-4-carboxylic acid methyl ester (320 mg, 0.92 mmol, see U.S. Pat. No. 7,300,907 B2 for preparation) was dissolved in 10 mL 1M H2SO4 plus 4 mL acetonitrile, warmed to 75° C. and treated in portions with sodium nitrite (690 mg, 10 mmol) over 30 minutes. After stirring for 10 minutes more the mixture was cooled and the solid product was collected by filtration, washed well with water, and dried under vacuum at 80° C. to give 170 mg (53% yield) of 6-hydroxy-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-chloropyrimidine-4-carboxylic acid methyl ester MP 215-217° C.; MS m/z 346; 1H NMR (DMSO-d6): δ 7.47 (m, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.34 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSc1cccc2nccn12
Yield: 99.9 %

Procedure:
To a solution of 5-(2-hydroxy)ethylthioimidazo[1,2-a]pyridine (9.71 g, 50 mmoles) and triethylamine (10.5 ml, 75.3 mmoles) in methylene chloride (300 ml) was added methanesulfonyl chloride (4.26 ml, 55 mmoles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was washed in turn with aqueous saturated sodium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain 13.6 g of the desired product (quantitative, brown oily product).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:24]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH:24]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCCCNC(c1ccccc1)c1ccccc1
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCNC(c1ccccc1)c1ccccc1

Procedure:
Batch size: 1.9 g (12.6 mmol) 3-(3-pyridyl)-acrylic acid, 2.5 g (15.1 mmol) CDI and 3.7 g (14.5 mmol) 4-(benzhydryl-amino)-butylamine in 60 ml abs. THF.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[CH3:12][CH2:13][CH2:14][CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH:19][CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14][CH2:13][CH3:12])=[O:7]
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Yield: 57 %

Procedure:
3-amino-4-hydroxy-N-(1-propylbutyl)benzamide was prepared in a similar manner to example 4 using 3-Amino-4-hydroxybenzoic acid and 4-heptylamine. Yield 57%. 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 6H); 1.26-1.51 (m, 8H); 4.09 (m, 1H); 6.74 (m, 1H); 7.05 (s, 1H); 7.43 (m, 2H); 7.77 (m, 2H). MS: (251, M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.BrN1C(=[O:19])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(O)C>C(Cl)(Cl)(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([CH:1]=[O:19])=[CH:7][CH:6]=1
Reactant: Cc1ccc(-c2ncco2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=[N+]([O-])[O-]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1ccc(-c2ncco2)cc1
Temperature: 100 °C

Procedure:
To 2-(4-methylphenyl)oxazole (6.41 g, 40.3 mmol) and N-bromosuccinimide (14.7 g, 82.6 mmol) in carbon tetrachloride (300 mL) was added 2,2′-azobisisobutyronitrile (500 mg, 3.1 mmol) and the reaction mixture was heated at 100° C. for 12 h. The reaction mixture was cooled to 0° C., filtered through a fritted funnel, and concentrated in vacuo. To this crude reaction mixture was added 95% ethanol (300 mL) and silver nitrate (15.1 g, 88.8 mmol), and the reaction mixture was refluxed for 4 h, cooled to room temperature, filtered through a fritted funnel, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 10:1 hexanes/ethyl acetate) gave 880 mg (13%, 2 steps) of the title compound. MS 174 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=O)[C:5](=[O:15])[N:4]([CH3:16])[N:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[C:20]([N:25]([CH3:27])[NH2:26])=[N:21][CH:22]=[CH:23][CH:24]=1>C(O)C.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[N:26][N:25]([CH3:27])[C:20]2[C:19]([C:18]([F:29])([F:28])[F:17])=[CH:24][CH:23]=[CH:22][N:21]=2)[C:5](=[O:15])[N:4]([CH3:16])[N:3]=1
Reactant: CN(N)c1ncccc1C(F)(F)F
Reactant: Cn1nc(Cl)n(-c2ccccc2C=O)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CN(N=Cc1ccccc1-n1c(Cl)nn(C)c1=O)c1ncccc1C(F)(F)F
Temperature: 50 °C

Procedure:
The title compound of Step A (0.20 g, 0.80 mmol) was dissolved in absolute ethanol (7 mL) and a solution of 1-[3-(trifluoromethyl)pyridin-2-yl]-1-methylhydrazine in ethanol (3 mL) was added followed by 3 drops of glacial acetic acid. The mixture was warmed to 50° C. for 1 h, cooled to room temperature and then diluted with aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated to give 0.38 g of the title compound of Step B as a yellow solid. 1H NMR (300 MHz. CDCl3): δ 8.42 (d.1H. J=5 Hz), 8.16 (d,1H, J=8 Hz), 8.01 (d,1H, J=8 Hz), 7.51 (t,1H, J=8 Hz), 7.42 (t,1H), J=8 Hz), 7.35 (s,1H), 7.21 (d,1H, J=8 Hz), 7.03 (dd,1H, J=8, 5 Hz), 3.56 (s,6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([OH:16])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(OS(C)(=O)=O)C2
Temperature: 5 °C
Reaction time: 18 h
Yield: 100.6 %

Procedure:
Compound 1010 (7.55 g, 33.2 mmol), triethylamine (5.1 mL, 37 mmol), and 4-dimethylaminopyridine (36 mg, 0.3 mmol) were taken into 100 mL of dichloromethane and cooled to 5° C. in an ice bath. Methanesulfonyl chloride (2.6 mL, 33.2 mmol) was added to the solution dropwise and the reaction warmed to room temperature and stirred at room temperature for 18 hours. The reaction was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to afford 10.2 g of 3-methanesulfonyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester as a mixture of isomers (Compound 1011) as a clear yellow oil; 1H NMR (300 MHz, DMSO-d6): δ 5.09-5.01 (m, 1H), 4.28 (s, 1H), 4.22 (s, 1H), 3.01 (s, 3H), 2.20-1.97 (m, 6H), 1.71-1.66 (m, 2H), 1.46 (s, 9H). This compound was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](O)([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2(O)C(=O)Nc3cc(Cl)ccc32)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
rac-6-Chloro-3-hydroxy-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (from Example 4a supra) was suspended in a mixture of triethylsilane (5 mL, 31.3 mmol) (Aldrich) and trifluoroacetic acid (12.5 mL) and heated in an 90° C. oil bath for 17 hours. After cooling to room temperature, mixture was diluted with ethyl acetate (100 mL) and treated with solid sodium carbonate (10.5 g). After stirring for 30 minutes, mixture was extracted with water (2×100 mL) and brine (100 mL). Aqueous layers were back washed with ethyl acetate (100 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40M, dichloromethane then 10% ethyl acetate in dichloromethane as solvent). Fractions containing product were combined, concentrated and recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 2.26 g, 82.6% over two steps).
Reaction SMILES: [O:1]=[C:2]1[NH:21][CH2:20][CH2:19][C:4]2([CH2:8][C@H:7]([C:9]([O:11]CC3C=CC=CC=3)=[O:10])[CH2:6][CH2:5]2)[NH:3]1>CO.[Pd]>[O:1]=[C:2]1[NH:21][CH2:20][CH2:19][C:4]2([CH2:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][CH2:5]2)[NH:3]1
Reactant: O=C1NCCC2(CC[C@@H](C(=O)OCc3ccccc3)C2)N1
Agent: [Pd]
Solvent: CO
Product: O=C1NCCC2(CC[C@@H](C(=O)O)C2)N1
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a solution of (2R)-benzyl 7-oxo-6,8-diazaspiro[4.5]decane-2-carboxylate (from step E, 20 mg, 0.069 mmol) in methanol (2 mL) was added palladium (Pd/C, 10% wt., 7.38 mg, 6.94 μmol). The resulting mixture was stirred under a hydrogen balloon for 30 min. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to yield (2R)-7-oxo-6,8-diazaspiro[4.5]decane-2-carboxylic acid (10 mg, 0.050 mmol, 72.7% yield) as an oil. It was used as such for the next step without further purification. MS m/z 199 (M+H)+
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[OH:17].[CH3:18][O:19][CH2:20]Cl>CC(C)=O>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:10]([O:17][CH2:18][O:19][CH3:20])=[C:9]([O:8][CH3:7])[CH:14]=1
Reactant: COCCl
Reactant: COc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To anhydrous K2CO3 (3.55 g) in acetone (10 mL) under N2 was added 2,4-dimethoxyphenol (3.3 g, J.O.C. 1984, 49, 4740) in acetone (20 mL). Chloromethyl methyl ether (1.79 mL) was added dropwise and the mixture was stirred at room temperature for 18 h then heated to 50° C. for 24 h. Additional quantity of chloromethyl methyl ether (1.79 mL) was added and the mixture was stirred for another day at 50° C. and evaporated. The residue was taken up with water and extracted with AcOEt. The extract was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/AcOEt 20:1 to 10:1) to give 1,3-dimethoxy-4-methoxymethoxybenzene (1.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]=3)=[CH:10][C:3]=12.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[C:9]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)=[CH:10][C:3]=12.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Br)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(C3=CCNCC3)cc3c(Br)ccnc32)cc1

Procedure:
A mixture of Example 5C (8 g, 15.02 mmol) and trifluoroacetic acid (11.58 mL, 150 mmol) in dichloromethane (100 mL) was stirred at 20° C. for 12 hours and the mixture was concentrated to provide the title compound as a trifluoroacetic acid salt. MS (CI) m/z 432 (M+H)+.
Reaction SMILES: [CH2:1](Cl)[C:2]#[CH:3].[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CO>[CH2:1]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:2]#[CH:3]
Reactant: C1CCNCC1
Reactant: C#CCCl
Solvent: CO
Product: C#CCN1CCCCC1

Procedure:
With stirring, a solution of 2-propynyl chloride (40.31 g) in dry methanol (50 ml) was added dropwise to a solution of piperidine (92.14 g) in dry methanol (100 ml). The mixture was stirred at 25° C. for 3 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue was distilled (boiling point: 163–165° C./atmospheric pressure).
Reaction SMILES: [H-].[Na+].[CH:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:21]S(C)=O>>[O:4]1[CH2:21][CH:3]1[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CCC(C2CO2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of NaH (10.4 g, 60% dispersion in mineral oil) in DMSO was added (CH3)3SOI (57 g). The reaction mixture was stirred for 30 min at room temperature followed by the dropwise addition at 0° C. of phenylmethyl 4-formyl-1-piperidinecarboxylate (43 g, which can be purchased from AstaTech, Inc., Bristol, Pa.). The mixture was allowed to stir at room temperature for 1 hour and then quenched with water and extracted with Et2O. The organic layer was washed with H2O, brine, dried over MgSO4, filtered and concentrated to yield a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:6]=[C:5]2[I:11]
Reactant: Clc1ccc2[nH]nc(I)c2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Product: Clc1ccc2c(c1)c(I)nn2CCN1CCCC1
Yield: 60 %

Procedure:
The title compound was prepared from 5-chloro-3-iodo-indazole and 1-(2-chloroethyl)pyrrolidine hydrochloride in 60% yield according to the procedure for Preparation 50A. 1H NMR (400 MHz, CDCl3): δ 1.75-1.80 (4H, m), 2.54-2.59 (4H, m), 2.99 (2H, t, J=7.3 Hz), 4.52 (2H, t, J=7.1 Hz), 7.35-7.39 (2H, m), 7.45 (1H, s). [M+H] Calc'd for C13H15ClN3, 376; Found, 376.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3.[C:18]([NH:28][NH2:29])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>CN(C)C=O>[CH2:21]([O:20][C:18]([NH:28][NH:29][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cc2c(c3c1NC(=O)CC3)OC(CBr)C2
Reactant: NNC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CNNC(=O)OCc1ccccc1)C2
Temperature: 150 °C
Reaction time: 5 h
Yield: 38.2 %

Procedure:
The compound obtained in Example 338 (1.5 g, 5.1 mmol) was dissolved in dimethylformamide (40 ml), to which carbobenzoxy hydrazine (4.2 g, 25.3 mmol) was added, and stirred at 150° C. for 5 hours. The reaction mixture was poured into water, and then extracted with chloroform. The organic phase was washed with water, dried, and condensed under reduced pressure. As a result, 0.744 g of the title compound was obtained as a colorless solid (40.0%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH:25]1([C:28]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:29])[CH2:27][CH2:26]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)C1CC1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.006 mL (0.061 mMol) cyclopropanecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(Cl)cc1

Procedure:
The procedure of Example 13 is followed, but the endcapper is 4-chloro-N,N-dimethylbenzamide (0.20 g, 1.09 mmol) to yield the amido-functionalized macromonomer. 4-Chloro-N,N-dimethylbenzamide is prepared by reacting 4-chlorobenzoyl chloride with dimethylamine in toluene with some pyridine (1 mol equivalent per acid chloride) to trap the HCl that is evolved. After aqueous extraction of the pyridinium salt and any excess starting materials, the product is crystallized from the toluene solution.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17]C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH3:20]>B(Br)(Br)Br.C(Cl)Cl>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:19][CH3:20]
Reactant: CCc1cc2c(OC)cccc2n1Cc1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Yield: 69.3 %

Procedure:
By the method used in Example 1, Part D, 911 mg (2.6 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-4-methoxy-1H-indole was O-demethylated by treating it with 10 mL of 1M BBr3 /CH2Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 590 mg (69% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-2-ethyl-4-hydroxy-1H-indole as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:51])[NH:7][C@H:8]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:19][CH2:18]2)=[CH:13][N:12]([CH2:32][C:33]2[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:34]=2[F:43])[C:11]1=[O:44])([CH3:4])([CH3:3])[CH3:2].[N:52]([Sn](CCCC)(CCCC)CCCC)=[N+:53]=[N-:54]>C1(C)C=CC=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:51])[NH:7][C@H:8]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[NH:54][N:53]=[N:52][N:31]=4)[CH:25]=3)[CH2:19][CH2:18]2)=[CH:13][N:12]([CH2:32][C:33]2[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:34]=2[F:43])[C:11]1=[O:44])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc(C#N)c3)CC2)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCN(Cc3cccc(-c4nnn[nH]4)c3)CC2)cn(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
{(R)-2-[5-[4-(3-cyano-benzyl)-piperazin-1-yl]-3-(2-fluoro-6-trifluoromethyl-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (35 mg, 0.049 mmol), and azidotributyl tin (IV) (16 μl, 0.059 mmol) were dissolved at 120° C. for 10 hrs in toluene (1 mL) with stirring. The solution was cooled to room temperature, followed by the addition of azidotributyl tin (IV) (20 μl, 0.074 mmol) thereto and stirring at 120° C. for an additional 2 hrs. The solution was cooled to room temperature, diluted in dichloromethane, and washed with an aqueous saturated ammonium chloride solution and an aqueous saturated sodium chloride solution in the order. The organic layer thus formed was separated and concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 6/1) and dried in a vacuum to afford 20 mg of the compound as a colorless oil (yield 54%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][NH:12][CH2:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:17]([O:20][C@@H:21]([C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1)[CH3:22])(=[O:19])[CH3:18].C(N(CC)CC)C>C(O)(C)C>[C:17]([O:20][C@@H:21]([C:23]1[N:24]=[C:25]([N:12]2[CH2:11][CH2:10][C:9]3[C:14](=[CH:15][C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=3)[CH2:13]2)[CH:26]=[CH:27][N:28]=1)[CH3:22])(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CNCC2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)c1nccc(N2CCc3ccc(S(=O)(=O)N(C)C)cc3C2)n1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 92 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-isoquinoline-7-sulfonic acid dimethylamide (prepared according to the method of Example 247, Step B, 210 mg, 0.88 mmol) in isopropanol (5 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl acetate (prepared according to the method of Preparation Five, 175 mg, 0.88 mmol) followed by triethylamine (0.24 mL, 1.75 mmol). This mixture was stirred at room temperature for 1.75 h then heated to reflux for 1.5 h, cooled to room temperature, evaporated, and purified by flash column chromatography (1% methanol/chloroform) to give 327 mg (92%) of the title compound of Example 247, Step C as a white solid. 1H NMR (CDCl3, 250 MHz) δ 8.28 (d, 1H), 7.68-7.58 (c, 2H), 7.47 (d, 1H), 6.44 (d, 1H), 5.72 (q, 1H), 4.86 (s, 2H), 3.92 (t, 2H), 3.05 (t, 2H), 2.73 (s, 6H), 2.19 (s, 3H), 1.62 (d, 3H); MS (TS) 431 (MH+).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.C(N1CCN([C:45]2[CH:46]=C[C:48]3[N:49]([C:51]([C:54](F)(F)[CH:55](F)F)=NN=3)[N:50]=2)CC1)(C1C=CC=CC=1)C1C=CC=CC=1>>[F:25][CH:2]([F:1])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:55][CH2:54][C:51]5[N:49]([CH3:48])[N:50]=[CH:45][CH:46]=5)=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)cc1
Reactant: FC(F)C(F)(F)c1nnc2ccc(N3CCN(C(c4ccccc4)c4ccccc4)CC3)nn12
Product: Cn1nccc1CCOc1ccc(N2CCN(c3ccc4nnc(C(F)F)n4n3)CC2)cc1

Procedure:
The 4-[4-[3-(difluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol used as starting material was prepared in 95% yield by an analogous method to Example 514, preparation of starting materials, starting from 3-(difluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in General Synthetic Method 1, preparation of starting materials).