Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=C(Cc1ccc(OCc2ccccc2)cc1)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(Cc1ccc(O)cc1)c1cccnc1
Reaction time: 4 h
Yield: 66.2 %

Procedure:
A mixture of ethyl 4-(4-benzyloxyphenyl)-3-(pyridin-3-yl)but-2-enoate (1.73 mmole) and 10% Pd/C (200 mg) in EtOH (10 mL) was shaken under H2 (50 psi) on a Parr apparatus. After 4 hr, the mixture was filtered through celite®d and the filtrate was concentrated. Flash chromatography on silica gel (50% EtOAc/hexanes) gave the impure title compound (327 mg, 66% over three steps) as a yellow oil: MS (ES) m/e 286 (M+H)+. This material was used without further purification.
Reaction SMILES: [O-]S([O-])(=O)=O.[Ca+2].O=P(Cl)(Cl)Cl.[C:12]([OH:24])(=[O:23])[CH2:13][C:14]1[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:16]([OH:18])=O.[CH3:25][N:26]([CH:28]=O)[CH3:27]>>[CH3:25][N:26]([CH:28]=[C:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[O:24][C:12]1=[O:23])[CH3:27]
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: CN(C)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C1C(=O)OC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
100 ml of anhydrous DMF in a 1 liter round-bottomed, three necked flask (fitted with a drying tube containing drierite, and a 125 ml dropping funnel) is cooled in an ice-salt bath, and 31 ml of POCl3 is subsequently added over a period of half an hour while stirring the DMF. The 125 ml dropping funnel is replaced with a 150 ml dropping funnel, and a solution of 54 g of homopthalic acid in 100 ml of DMF is added to the flask over a period of one hour at <10° C. The reaction mixture is then stirred at room temperature until a yellow paste was formed, and then poured into ice water. The solid is collected by filtration, washed with water and dried to give 54 g of the title compound as a yellow solid, m.p. 137-40° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23]OS(C)(=O)=O)[O:20][C:19]2=[O:29])=[CH:14][C:13]=1[F:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.O>[N:37]([CH2:23][CH:21]1[O:20][C:19](=[O:29])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:10]3[CH:31]=[CH:32][C:33]([CH2:35][CH3:36])=[CH:34][C:9]=3[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:13]([F:30])[CH:14]=2)[CH2:22]1)=[N+:38]=[N-:39]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1ccc(Oc2ccc(N3CC(COS(C)(=O)=O)OC3=O)cc2F)c(OCc2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)c(OCc2ccccc2)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of methanesulfonic acid 3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl ester (120 mg, 0.23 mmol) in 2 ml of dry DMF under nitrogen was added sodium azide (57 mg, 0.88 mmol). The reaction mixture was stirred at 75° C. overnight. The reaction mixture was diluted with 15 ml water and extracted with ethyl acetate. The combined organic phase was washed with water, saturated brine solution, dried over anhydrous Na2SO4 and concentrated in vacuo to get 100 mg of the title compound which was used as such for the next step.
Reaction SMILES: C([Sn](CC)(CC)[C:4]1[S:5][CH:6]=[CH:7][N:8]=1)C.[CH3:13][O:14][N:15]=[C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1Br)[C:17]([O:19][CH3:20])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl>[CH3:13][O:14][N:15]=[C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: CC[Sn](CC)(CC)c1nccs1
Reactant: CON=C(C(=O)OC)c1ccccc1Br
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON=C(C(=O)OC)c1ccccc1-c1nccs1

Procedure:
Under a nitrogen blanket, 1.7 g of 2-triethylstannylthiazole is added to a mixture of 1.4 g (5.19 mmol) of the bromo compound (Compound E), 100 mg of palladium(II) chloride and 310 mg of triphenylphosphine in 30 ml of tetrahydrofuran, and the whole is refluxed for 2 hours. The mixture is then filtered and evaporated down. After chromatography on silica gel using cyclohexane/ethyl acetate there remains 700 mg (49%) of compound 1, Tab. I, as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28]>>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 3-t-butoxycarbonylamino-3-methylbutanoic acid (Example 31, Step E) and 3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (Example 1, Step A) by the procedure described in Example 1, Step F. 1H NMR (300 MHz, CDCl3): 1.34 (s,6H), 1.41 (s,9H), 1.90 (m,1H), 2.45 (d,15 Hz,1H), 2.56 (d,15 Hz,1H), 2.65 (m,1H), 2.76 (m,1H), 2.92 (m,1H), 4.53 (m,1H), 5.20 (br s,1H), 6.62 (d,7 Hz,1H), 6.97 (d,8 Hz,1H), 7.10-7.25 (m,3H), 7.35 (br s,1H). FAB-MS: calculated for C20H29N3O4 375; found 376 (M+H,45%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([Cl:19])[CH:5]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:12]([O:11][C:7]1[C:6]([Cl:19])=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][C:8]=1[Cl:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-benzyloxy-3,5-dichloro-benzoic acid methyl ester (CAB02115, 7.20 g, 23.14 mmol) in THF (20 mL) was added slowly with a syringe to a suspension of lithium aluminium hydride (1.50 g, 39.5 mmol) in THF (40 mL). The reaction mixture was stirred for 30 minutes at room temperature and then carefully quenched by addition of 2N sodium hydroxide solution in water. After 20 minutes stirring the colour of the mixture turned from grey to white. The white precipitate was filtered off, the filtrate was dried over sodium sulphate and concentrated under reduced pressure. The residue was recrystallised from dichloromethane/hexane. Yield: 5.83 g (89%) white powder. 1H-NMR (400 MHz, CDCl3) δ=1.85 (t, J=5.9 Hz, 1H, —OH), 4.63 (d, J=5.9 Hz, 2H), 5.04 (s, 2H), 7.33 (s, 2H), 7.35-7.44 (m, 3H), 7.55-7.59 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ=64.05, 75.03, 127.36, 128.70, 128.75, 129.91, 136.39; 138.64, 150.32.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)[nH]c1ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)[nH]c1ccccc12

Procedure:
2-Nitrocarbazole [Mendenhall, G. D.; Smith, P. A. S. Org. Syn. Coll. Vol. 5 1973, 829, the disclosure of which is herein incorporated by reference] (structure 14 of Scheme IV, where R1-6 =H, X=NH) (1.0 g, 4.7 mmol) in 50 mL of ethyl acetate was hydrogenated over 10% Pd/C (50 mg) under an atmosphere of hydrogen for 1.5 h at rt giving, after filtration through Celite™, 840 mg (100%) of 2-aminocarbazole. Data for 2-aminocarbazole: 1H NMR (400 MHz, CDCl3) 7.94 (d, J=9.0, 1H), 7.83 (d, J=8.0, 1H), 7.80 (br s, 1H), 7.35 (m, 2H), 7.15 (dd, J=8.2, 1H), 6.67 (d, J=1.8, 1H), 6.58 (dd, J=9.0, 1.8, 1H), 3.73 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:36])(=[O:35])[NH:23][CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2)[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[S:22](=[O:36])(=[O:35])[N:23]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(Cl)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and ethyl 3-chloro-4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 8).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:13][N:14]([CH3:22])[CH2:15][CH2:16][C:17]([CH:19]1[CH2:21][CH2:20]1)=[O:18]>CCOCC>[CH:19]1([C:17]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)([OH:18])[CH2:16][CH2:15][N:14]([CH3:22])[CH3:13])[CH2:21][CH2:20]1
Reactant: CN(C)CCC(=O)C1CC1
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Mg]
Solvent: CCOCC
Product: CN(C)CCC(O)(c1cccc(C(F)(F)F)c1)C1CC1
Temperature: 25 °C

Procedure:
The Grignard reagent prepared from 64 g. (0.28 mole) of 3-bromobenzotrifluoride and 7 g. (0.28 mole) of magnesium in ether was cooled to -30° C., and 20 g. (0.14 mole) of cyclopropyl 2-dimethylaminoethyl ketone in 100 ml. of ether was added dropwise to the stirred mixture at a rate sufficient to maintain a temperature below -20° C. The mixture was allowed to warm to room temperature and then worked up as described in Preparation I. Distillation of the crude product gave 10 g. of oil which distilled at 78°-83° C./0.12 mm.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[C:19]1([CH2:29][CH2:30][NH2:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[C:19]1([CH2:29][CH2:30][NH:31][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Reactant: NCCc1cccc2ccccc12
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccc4ccccc34)cc2)cn1
Yield: 26.7 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366 g, 0.151 mmol) and 2-naphthalen-1-ylethylamine (0.0285 g, 0.166 mmol) gives the title compound (0.0160 g, 26.7%): TOF MS ES+ 398.2 (M+H)+, HRMS calcd for C25H24N3O2 398.1869 (M+H)+, found 398.1855, time 0.39 min; TLC [silica gel 60 F254, 4% (2.0 M NH3 in methanol) in ethyl acetate] Rf=0.26.
Reaction SMILES: [C:1]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([C:31]([OH:33])=O)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@@H:15]([NH:22]C(OC(C)(C)C)=O)[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[O:40]1[CH2:45][CH2:44][CH:43]([CH2:46][NH2:47])[CH2:42][CH2:41]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:40]1[CH2:45][CH2:44][CH:43]([CH2:46][NH:47][C:31]([C:8]2([CH2:7][C:4]3[CH:3]=[CH:2][C:1]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:6][CH:5]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C@@H:15]([NH2:22])[CH2:16][C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:9]2)=[O:33])[CH2:42][CH2:41]1
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(-c3ccccc3)cc2)(C(=O)NCC2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-biphenyl-4-ylmethyl-1-[2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl]-piperidine-4-carboxylic acid (0.24 mmol; 0.13 g) in DMF (5 mL) was added C-(tetrahydro-pyran-4-yl)-methylamine (0.28 mmol; 0.027 g), N,N-diisopropyl-N-ethylamine (0.48 mmol; 0.084 mL) and HBTU (0.28 mmol; 0.108 g), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then purified via reverse phase HPLC and the desired fractions were combined and lyophilized. The resulting residue was dissolved in THF (5 mL) and a 4N HCl solution in 1,4-dioxane (15 mL) was added. The resulting solution was stirred for 7 hours at room temperature and evaporated. The residue was triturated with diethyl ether and dried under vacuum to yield 1-[2-(S)-amino-3-thiophen-2-yl-propionyl]-4-biphenyl-4-ylmethyl-piperidine-4-carboxylic acid(tetrahydro-pyran-4-ylmethyl)-amide as a hydrochloride salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[NH:35][C:34]([C@@H:36]4[CH2:40][CH2:39][CH2:38][N:37]4[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:33][CH:32]=3)=[CH:27][CH:26]=2)O1.C([O-])(O)=O.[Na+]>COCCOC.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>[C:14]([NH:13][C:11]1[NH:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4[NH:35][C:34]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[N:33][CH:32]=4)=[CH:29][CH:30]=3)=[CH:3][CH:4]=2)=[CH:9][N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)Nc1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 125 °C

Procedure:
A mixture of N-(5-(4-bromophenyl)-1H-imidazol-2-yl)acetamide (0.604 g, 2.16 mmol), (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.950 g, 2.16 mmol), NaHCO3 (0.636 g, 7.57 mmol) in DME (20 mL) and H2O (5 mL) was degassed by evacuating and back-filling with N2 (×3). To this solution Pd(PPh3)4 (0.125 g, 0.11 mmol) was added and the suspension heated at 125° C. for 24 h. The mixture was evaporated to dryness in vacuo and the residue was purified by column chromatography (Biotage) eluting with a gradient of 0 to 10% MeOH in CH2C2. The material was then purified by prep HPLC (CH3CN—H2O—NH4OAc) to afford the title compound as a colorless solid. 7.76 (app dd, J=8.4, 2.2 Hz, 4H), 7.69 (app d, J=8.4 Hz, 2H), 7.66 (app d, J=8.4 Hz, 2H), 7.45 (s, 1H), 7.23 (s, 1H), 3.66-3.72 (m, 1H), 3.48-3.53 (s, 1H), 2.34-2.46 (m, 1H), 2.18 (s, 3H), 1.96-2.10 (m, 3H), 1.46, 1.25 (s, 9H, rotamers, 1:2 ratio). LCMS: Anal. Calcd. for C29H32N6O3: 512; found: 513, 282 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=O)[CH2:4][CH2:3]1.[C:21]([C:25]1[CH:26]=[C:27]([NH2:32])[C:28]([NH2:31])=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:30]=[CH:29][C:28]2[NH:31][C:16]([C:15]3[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:14]=3)=[N:32][C:27]=2[CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CN1CCN(CCCCOc2cccc(C=O)c2)CC1
Product: CN1CCN(CCCCOc2cccc(-c3nc4cc(C(C)(C)C)ccc4[nH]3)c2)CC1
Yield: 93.9 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzaldehyde (53 mg, 0.19 mmol, 1.0 equiv), 4-tert-butyl-benzene-1,2-diamine (32 mg, 0.19 mmol, 1.0 equiv), and Na2S2O5 (48 mg, 0.25 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 75 mg (92%) of the title compound. MS (electrospray): mass calculated for C26H36N4O, 420.29; m/z found, 421.2 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.68-7.56 (m, 3H), 7.54 (br d, J=8.2 Hz, 1H), 7.44-7.36 (m, 2H), 7.02 (dd, J=8.2, 2.2 Hz, 1H), 4.07 (t, J=6.1 Hz, 2H), 3.00-2.26 (m, 10H), 2.26 (s, 3H), 1.85-1.75 (m, 2H), 1.75-1.65 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[N:25]=[N:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[N:16]1>>[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[N:25]=[N:24][C:23]([N:26]3[CH2:31][CH2:30][CH:29]([N:9]4[C:10]5[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:11]=5)[CH2:7][CH2:8]4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[N:16]1
Reactant: FC(F)(F)c1ccc2c(c1)NCC2
Reactant: Cn1cc(-c2ccc(N3CCC(=O)CC3)nn2)cn1
Product: Cn1cc(-c2ccc(N3CCC(N4CCc5ccc(C(F)(F)F)cc54)CC3)nn2)cn1

Procedure:
The title compound was prepared following the procedure as described in Example 5, STEP 4, reacting 6-trifluoromethylindoline and 1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-one.
Reaction SMILES: CN(C)[C:3](=[O:5])[CH3:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH2:30])[CH:24]=1.N1C(C)=CC(C)=CC=1C>ClCCCl>[Br:22][C:23]1[CH:24]=[C:25]([CH:29]2[CH2:30][C:3](=[O:5])[CH2:4]2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)N(C)C
Reactant: C=Cc1cccc(Br)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCCl
Product: O=C1CC(c2cccc(Br)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
N,N-Dimethylacetamide (9.0 g, 103 mmol) was dissolved in 1,2-dichloroethane (200 mL). The solution was cooled to 0° C. before trifluoromethanesulfonic anhydride (63 g, 223 mmol) was added. The reaction was stirred for an additional 60 min at 0° C. Then 1-bromo-3-vinylbenzene (15 g, 81.9 mmol) and 2,4,6-collidine (10.5 g, 86.6 mmol) were added. The reaction was heated to reflux overnight, quenched by addition of water (300 mL) and stirred for 2 hr at rt. The mixture was extracted with DCM (300 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by CC (EA/PE=1:20) gave the title compound 2a (5.0 g, 27%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:12]I.[H-].[Na+].Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:11][CH3:12])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(O)c1ccc(Br)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.6 %

Procedure:
2-(4-Bromo-phenyl)-propan-2-ol (Preparation 39, 1.77g, 8.2 mmol) and methyl iodide (0.5 mL, 8.2 mmol) in tetrahydrofuran (100 mL) were treated with sodium hydride (60% dispersion in mineral oil, 328 mg, 8.2 mmol). The mixture was stirred for 24 hours at room temperature, was poured into 0.5 M aqueous hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and the solvent was removed in vacuo. The residue was purified by silica gel chromatography (200:1 hexanes-ethyl acetate) to afford 500 mg (27% yield) of the title compound. 13C NMR (100 MHz, CDCl3) d 145.4, 131.5, 127.9, 121.0, 76.7, 50.9, 28.1; MS (AP/Cl) 197.0, 199.0 (M+H—OMe)+.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:26])[CH2:24][NH2:25])[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>C(Cl)Cl>[C:28]([NH:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:27])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)[CH3:22])=[O:26])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylquinoline (100 mg), acetic anhydride (35 ml), pyridine (60 μl) and methylene chloride (2 ml) was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated and the residue was purified by preparative thin-layer chromatography (ethyl acetate-methanol) to give 8-[3-[N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (138 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[O:13])OC(=O)[NH:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21].C(Cl)Cl>C1(C)C=CC=CC=1>[NH2:9][C:8]1[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[C:12]([NH:21][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[O:17][CH3:16])=[O:13]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Reactant: COc1ccccc1CN
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)c1ccc([N+](=O)[O-])cc1N
Reaction time: 0.5 h

Procedure:
A mixture of 9.3 g 7-nitro-1H-benzo[d][1.3]oxazine-2,4-dione (45 mmol) and 12.3 g 2-methoxybenzylamine (90 mmol) in 200 mL toluene was stirred for 30 minutes at reflux, then mixed with methylene chloride and washed repeated with water. The organic phase was dried, concentrated and the solid residue was dried and reacted further without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:30]([CH:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:31])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C4CCCCC4)nc3cc21

Procedure:
Cyclohexanecarboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (200 mg, 0.64 mmol) and cyclohexanecarbonyl chloride (258 μl, 1.93 mmol). The title compound was obtained as light brown powder (64 mg, 23%).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([CH2:9][P:10](=[O:15])([O:13]C)[O:11]C)(O)=[O:7].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([NH:5][C:6]([CH2:9][P:10](=[O:11])([OH:15])[OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(=O)(CC(=O)O)OC
Reactant: CC(C)(C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)CP(=O)(O)O

Procedure:
Tertiary butyl amine (0.045 mole) and dimethyl (carboxymethyl)phosphonate (0.04 mole) were dissolved in 100 ml. of methylene chloride. As the solution was stirred, dicyclohexylcarbodiimide was added portionwise. The solution was stirred overnight and the mixture filtered. The filtrate was concentrated to a solid. It was recrystallized from an appropriate solvent such as methanol. m.p. 163°-5° C., yield, 61%.