Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1Cl)[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[NH:22][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH3:2]
Reactant: CCOC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: NC1CCCCC1
Solvent: CC#N
Product: CCOC(=O)c1cccc([N+](=O)[O-])c1NC1CCCCC1
Yield: 95 %

Procedure:
The crude 2-chloro-3-nitro-benzoic acid ethyl ester was dissolved in acetonitrile (100 mL) and cyclohexylamine (2.5 mL, 21.83 mmol) was added. The mixture was stirred at reflux overnight. After evaporation of solvent, water (100 mL) was added and the precipitates were collected by filtration and dried to give 2-cyclohexylamino-3-nitro-benzoic acid ethyl ester (1.168 g, 95%). MS: 293.16 (M+H+).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:28][CH2:27][N:26]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:25][CH2:24]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][N:37]=[CH:38][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].C(#N)C.O>CO.O>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH2:29][C:30]([OH:32])=[O:31])[CH2:27][CH2:28]5)=[CH:18][CH:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:35]=[CH:36][N:37]=[CH:38][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCN(Cc2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: O=C(O)CN1CCN(Cc2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Yield: 84.8 %

Procedure:
A mixture of compound 347 (50 mg, 97 μmol) and lithium hydroxide, monohydrate (14 μl, 486 μmol) in methanol (9 mL) and water (3 mL) was heated at reflux for 2 h. After cooling, the crude mixture was subjected to reverse phase preparative HPLC (acetonitrile/H2O containing 0.1% TFA each, 40 min from 10 to 40%). Lyophilization provided compound 349 (40 mg) as a light yellow solid (TFA salt). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.84 (1 H, s), 9.62 (1 H, s), 9.38 (1 H, s), 8.68 (1 H, d, J=5.9 Hz), 8.58 (1 H, d, J=6.3 Hz), 8.26-8.48 (2 H, m), 7.89-8.01 (1 H, m), 5.40 (1 H, quin, J=8.9 Hz), 2.75-4.63 (12 H, m), 2.39-2.47 (2 H, m), 2.01-2.23 (4 H, m), 1.70-1.87 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 487.3.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(=O)=O.[CH3:43][C@H:44]1[O:49][C@@H:48]([CH3:50])[CH2:47][NH:46][CH2:45]1.[I-].[Na+]>O1CCCC1>[CH3:50][C@H:48]1[O:49][C@@H:44]([CH3:43])[CH2:45][N:46]([CH2:6][CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH2:47]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCOS(C)(=O)=O)CC2)c2ncnn12
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCN3C[C@@H](C)O[C@@H](C)C3)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethyl methanesulfonate (0.3 g), cis-2,6-dimethylmorpholine (1.2 g), sodium iodide (0.015 g) and tetrahydrofuran (10 mL) was stirred at 70° C. for 5 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.3 g, 96%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([OH:12])=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2].[C:13](Br)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CC(N(C)C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=1[S:8][CH3:9])#[N:2]
Reactant: CC(C)(C)Br
Reactant: CSc1sc(C(=O)O)cc1C#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: CSc1sc(C(=O)OC(C)(C)C)cc1C#N
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 4-cyano-5-(methylthio)thiophene-2-carboxylic acid (2.0 g, 10 mmol), benzyltrimethylamonium chloride (2.25 g, 10 mmol), tertbutyl bromide (54 mL, 480 mmol), and anhydrous potassium carbonate (36 g, 260 mmol) in dimethylacetamide (100 mL) was stirred at 60° C. for 6 hours.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][CH:33]([C:36]#[N:37])[C:34]#[N:35]>O1CCCC1>[NH2:37][C:36]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)[C:8]([OH:9])=[N:32][C:33]=1[C:34]#[N:35]
Reactant: N#CC(N)C#N
Reactant: O=C=NCc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1nc(O)n(Cc2ccc(F)cc2)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.1 %

Procedure:
4-Fluorobenzylisocyanate (1.37 g, 10 mmol) and N,N-diisopropylethylamine (1.29 g, 10 mmol) were added to aminomalononitrile p-toluenesulfonate (2.53 g, 10 mmol) suspended in tetrahydrofuran (50 ml). The mixture was stirred at room temperature for 24 hours and then the solvent was removed in vacuo. To the residue was added ethyl acetate and the solution was washed and the organic layer was extracted with 1N aqueous sodium hydroxide. The extract was neutralized with 10% aqueous potassium hydrogen sulfide and extracted with ethyl acetate. The organic layer was dried on sodium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (1.93 g, yield 89%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:18])[CH:15](Br)[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[C:1]([N:4]1[C:12]2[C:11]([Cl:13])=[CH:10][CH:9]=[C:8]3[C:14](=[O:18])[CH:15]([N:23]=[N+:24]=[N-:25])[CH2:16][C:6]([C:7]=23)=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)C(Br)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)n1cc2c3c(ccc(Cl)c31)C(=O)C(N=[N+]=[N-])C2
Reaction time: 1.5 h

Procedure:
To a solution of 1-acetyl-4-bromo-8-chloro-3,4-dihydrobenz[cd]-indol-5(1H)-one (8.3 g., 0.029 mole) in dimethylformamide (70 ml.) containing 5 ml of acetic acid and cooled in an ice bath, is added a solution of sodium azide (3.8 g. in 17 ml. of H2O) at such a rate that the reaction temperature does not exceed 25° C. Stirring is continued for 1.5 hours with cooling. The reaction mixture is poured into water (200 ml.) and the dark solid that separates is recovered by filtration and dried. The yield of crude 1-acetyl-4-azido-8-chloro-3,4-dihydrobenz[cd]-indol-5(1H)-one is 7.0 g. (97%).
Reaction SMILES: Br.C[O:3][C:4]1[C:5](=[O:23])[C:6]2[C:14](=[CH:15][C:16]=1[O:17]C)[C:13]1[C:8](=[CH:9][C:10]([O:21]C)=[C:11]([O:19]C)[CH:12]=1)[CH:7]=2>C(O)(=O)C>[OH:3][C:4]1[C:5](=[O:23])[C:6]2[C:14](=[CH:15][C:16]=1[OH:17])[C:13]1[C:8](=[CH:9][C:10]([OH:21])=[C:11]([OH:19])[CH:12]=1)[CH:7]=2
Reactant: COC1=C(OC)C(=O)C2=Cc3cc(OC)c(OC)cc3C2=C1
Agent: Br
Solvent: CC(=O)O
Product: O=C1C2=Cc3cc(O)c(O)cc3C2=CC(O)=C1O
Yield: 76.9 %

Procedure:
To a mixed solution of acetic acid (20 ml) and 47% hydrobromic acid (10 ml), 2,3,6,7-tetramethoxyfluorenone (8.0 g) was added and the mixture was refluxed for 15 hours. After cooling, the precipitated crystals were filtered, washed with water and then recrystallized from water-containing ethanol to give 5.0 g of 2,3,6,7-tetrahydroxyfluorenone as a claret powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[CH3:16].[CH:17](N1CCCCC1)=[O:18]>O1CCCC1.BrCBr>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:17]=[O:18])[C:10]=1[CH3:16]
Reactant: O=CN1CCCCC1
Reactant: Cc1c(Br)cccc1COC1CCCCO1
Solvent: C1CCOC1
Solvent: BrCBr
Product: Cc1c(C=O)cccc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.2 g of Mg (magnesium shavings) in 15 ml of absolute tetrahydrofuran are initially introduced under a nitrogen atomsphere. A few drops of dibromomethane are added at 65° C. A solution of 14.25 g of 3-bromo-2-methylbenzyl tetrahydro-2-pyranyl ether in 50 ml of tetrahydrofuran is added dropwise while the temperature is kept at 65° C. The refluxed mixture is then stirred for 2 hours. A solution of 5.65 g of N-formylpiperidine in 10 ml of absolute tetrahydrofuran is added dropwise to the reaction mixture after the latter has been cooled to 0° C. Stirring is carried out for 20 hours at room temperature, the mixture is rendered slightly acidic with about 50 ml of 5% strength hydrochloric acid and extraction is carried out several times with ether. The combined ether extracts are washed with water, dried and evaporated down. The crude product (11 g) can be purified by column chromatography over silica gel using 97.5:2.5 toluene/acetone.
Reaction SMILES: [N+:1]([C:4]1[C:5](C(C)(C)C)=[C:6]([CH:10]=[CH:11][C:12]=1Cl)[C:7]([O-:9])=[O:8])([O-:3])=[O:2].Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][O:27][C:26]2=[O:35])[CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][O:27][C:26]2=[O:35])[CH2:23][CH2:24]1)[C:7]([O:9][C:6]([CH3:10])([CH3:7])[CH3:5])=[O:8])([O-:3])=[O:2]
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Reactant: CC(C)(C)c1c(C(=O)[O-])ccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
The product was prepared from 3-nitro-4-chloro-t-butylbenzoate (0.96 g) and 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (1.0 g) using the method of example 115 step (ii). Purification was by chromatography eluting with 50% ethyl acetate/isohexane. Yield 2.1 g as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([C:15](O)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[C:1]([O:5][C:6]([CH:8]1[CH:14]([CH2:15][OH:16])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(C(=O)O)C2C(=O)OC(C)(C)C)cc1
Agent: B
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCCCC(CO)C2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(4-Methoxy-benzenesulfonyl)-azepane-2,3-dicarboxylic acid 2-tert-butyl ester (1.06 g, 2.56 mmoL) in 12.8 mL THF at 0° C. was added a Borane-THF solution (1M, 6.4 mL) dropwise. The reaction was warmed to ambient temperature after 30 minutes and allowed to stir for 20 hours before cooling to ice bath temperature and carefully quenching with a 1:1 solution of acetic acid and water. This solution was stirred for 1 hour after which the majority of the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with brine. This solution was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure and purified by column chromatography (silica: 25% to 30% ethyl acetate in hexanes) to yield 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester as a clear oil; MS: (M+H)+ =400, (M+NH4)+ =417; and the cooresponding aldehyde (31 mg, 3%) as a clear oil; MS: (M+H)+ =398, (M+NH4)+ =415.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:20])=[C:10]2[C:18]([CH3:19])=[N:17][S:16][C:11]2=[C:12]([CH2:14][CH3:15])[N:13]=1)=[O:7])CCC.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[CH2:14]([C:12]1[N:13]=[C:8]([C:6]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:7])[C:9]([OH:20])=[C:10]2[C:18]([CH3:19])=[N:17][S:16][C:11]=12)[CH3:15]
Reactant: CCCCOC(=O)c1nc(CC)c2snc(C)c2c1O
Reactant: NCC(=O)O
Product: CCc1nc(C(=O)NCC(=O)O)c(O)c2c(C)nsc12

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Ethyl-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 296.2 (M+1).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28](/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[C:43]([F:51])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>>[F:51][C:43]1[CH:42]=[C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)[CH:46]=[CH:45][C:44]=1[C:47]([F:50])([F:48])[F:49]
Reactant: Fc1cc(/C=C/c2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)ccc1C(F)(F)F
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Product: O=c1[nH]nc(CCc2ccc(C(F)(F)F)c(F)c2)cc1O
Yield: 60 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[(E)-2-[3-fluoro-4-(trifluoromethyl)phenyl]ethenyl]pyridazine (Intermediate 79) in 60% yield. The solid was purified by reverse phase chromatography, eluting with 5-100% acetonitrile in water with acid modifier to yield 6-{2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([Cl:26])[N:20]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:5]=[N:6][CH:7]=1.O1CCCC1.C([O-])(=O)C.[Na+]>COCCOC.O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([Cl:26])[N:20]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)cc1/C=C/c1cncc(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(Cl)ncc2Cl)cc1CCc1cncc(N)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a solution of N-{3-[(E)-2-(5-aminopyridin-3-yl)vinyl]-4-methoxyphenyl}-2,5-dichloropyrimidin-4-amine (2.25 g, 5.80 mmol) in 1,2-dimethoxyethane (2.0 mL), and tetrahydrofuran (100 mL) was added p-toluenesulfonylhydrazide (16.2 g, 86.9 mmol). The reaction mixture was heated to 90° C. when a solution of sodium acetate (11.4 g, 139 mmol) in water (120 mL) was added dropwise over 4 h. The reaction mixture was stirred at 90° C. for 3 h. The reaction mixture was diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate twice. The combined organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the desired product as a yellow foam (1.75 g, 77%). LCMS for C18H18Cl2N5O (M+H)+: m/z=390.1
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O>ClCl>[Cl:1][C:2]1[C:3]([C:4]([NH:6][CH2:7][CH3:8])=[O:5])=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:16])[C:10]([N+:17]([O-:19])=[O:18])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: ClCl
Agent: O=S(=O)(O)O
Product: CCNC(=O)c1c(Cl)ccc([N+](=O)[O-])c1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of the amide of example 45 (1.28 g, 5 mmol) in CH2 Cl2 (20 mL) at 0° C. was added dropwise a cold mixture of 70% nitric acid (0.64 mL, 10 mmol) and concentrated sulfuric acid (5 mL) dropwise. The mixture was stirred at 0° C. for 10 min and was poured onto ice. The mixture was extracted with ether, the combined organic layers washed with sat NaHCO3, brine, dried (MgSO4) and concentrated to a solid (1.52 g, 101%). The title compound was obtained by recrystallization from ethyl acetate/hexanes in 83% yield as a white solid. m.p. 147°-149° C.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH2:17][CH2:16]1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH3:14][C:10]1[N:9]=[C:8]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCC2CCNCC2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCC(CCCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
In an argon atmosphere, sodium tert-butoxide, (0.52 g), tris(dibenzylideneacetone)dipalladium (100 mg) and 2-(dicyclohexylphosphino)biphenyl (76 mg) were added to a Tol (22 ml) solution of 2-chloro-6-methylpyridine (0.56 g) and tert-butyl 4-[3-(4-piperidinyl)propyl]-1-piperidinecarboxylate (1.1 g), followed by heating with stirring at 100° C. for 1 hour. This was cooled to room temperature, diluted with EtOAc, and washed with aqueous saturated sodium hydrogencarbonate solution. This was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: hexane:EtOAc=10:1 (v/v)) to obtain tert-butyl 4-{3-[1-(6-methyl-2-pyridinyl)-4-piperidyl]propyl}-1-piperidinecarboxylate (1.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:31])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.COCCOC.CC1(C)C(C)(C)OB([C:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[CH3:31][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[CH:22][C:14]=2[NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:46]4[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH:47]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=2)[N:17]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(Br)ccn45)cccc32)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(C6=CCN(C(=O)OC(C)(C)C)CC6)ccn45)cccc32)n1
Temperature: 90 °C

Procedure:
7-Bromo-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 50, Steps A-B; 0.0815 g, 0.171 mmol) was dissolved in 2 mL of 1:1 (DME:DMF). To this was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.0795 g, 0.257 mmol), Pd(dppf)Cl2 (5 mol %), and 2M aqueous sodium carbonate (256 μL, 0.513 mmol). Nitrogen was bubbled through the solution for 5 minutes and the reaction mixture was then heated to 90° C. for 16 hours. The reaction mixture was then diluted with EtOAc and the precipitate formed was filtered and the filtrate was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography to provided tert-butyl 4-(3-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-5,6-dihydropyridine-1-(2H)-carboxylate, which was treated 4M HCl/dioxane to give the title product. MS (APCI), positive scan, m/z=478.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[Br:9].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[Br:9])[O:10][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: COc1cc(O)ccc1Br
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Br)c(OC)c1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
3-Methoxy-4-bromophenol D8 (6.95 g, 34 mmoles) in dry dimethylformamide (100 ml) at 0° C. was treated with sodium hydride (80% dispersion in oil) (1.13 g, 37 mmoles). After 30 mins ethyl bromoacetate (3.8 ml, 34 mmoles) was added and the mixture allowed to warm to room temperature over 1 hr. The mixture was concentrated in vacuo and the residue partitioned between water and diethyl ether. The organic layer was washed several times with water and then dried (Na2SO4) and evaporated to dryness. Flash chromatography on TLC silica gel eluting with dichloromethane gave the title compound (D9) (7.43 g, 75%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:26]1[O:27][C:19]2[CH:18]=[CH:17][C:22]([C@@H:23]3[C:8]4[NH:9][C:10]5[C:15]([C:7]=4[CH2:6][C@H:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]3)=[CH:14][CH:13]=[CH:12][CH:11]=5)=[CH:21][C:20]=2[O:25]1
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1
Reaction time: 96 h
Yield: 36.8 %

Procedure:
To a stirred solution of D-tryptophan methyl ester (11 g) and piperonal (7.9 g) in anhydrous CH2Cl2 (400 mL) cooled at 0° C. was added dropwise trifluoroacetic acid (7.7 mL) and the solution was allowed to react at ambient temperature. After 4 days, the yellow solution was diluted with CH2Cl2 (200 mL) and washed with a saturated aqueous solution of NaHCO3, then with water (3×200 mL) and dried over Na2SO4. The organic layer was evaporated under reduced pressure and the residue containing the two geometric isomers was purified by flash chromatography eluting with dichloromethane/ethyl acetate (97/3) to give as the first eluting product the title compound (6.5 g).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6]1)[CH:2](C)C.[CH3:31]OC(C1C=C2C(C(C3OCCNC3)=CN2)=CC=1)=O.IC(C)C.COC(C1C=C2C(C(C3OCCN(C(C)C)C3)=CN2)=CC=1)=O.N1(C(N)=O)CCNCC1.O[Li].O.CC(N1CCNCC1)C>>[CH:1]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH2:6]1)([CH3:31])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CNCCO3)c[nH]c2c1
Reactant: CC(C)CN1CCOC(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)C1
Agent: CC(C)N1CCNCC1
Agent: COC(=O)c1ccc2c(C3CN(C(C)C)CCO3)c[nH]c2c1
Agent: NC(=O)N1CCNCC1
Solvent: O
Solvent: CC(C)I
Product: CC(C)N1CCN(C(=O)c2ccc3c(C4CN(C(C)C)CCO4)c[nH]c3c2)CC1

Procedure:
According to the procedure described for the synthesis of [3-(4-isobutyl-morpholin-2-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 90) the title compounds was synthesized in consecutive steps from 3-morpholin-2-yl-1H-indole-6-carboxylic acid methyl ester and 2-iodopropane (commercially available) leading to 3-(4-isopropyl-morpholin-2-yl)-1H-indole-6-carboxylic acid methyl ester (MS (m/e): 303.4 (MH+)) which was converted to the title compounds according to the procedure described for the conversion of an ester functionality to a piperazine amide functionality like in example 72, step 2. The title compound was prepared from 3-(4-isopropyl-morpholin-2-yl)-1H-indole-6-carboxylic acid methyl ester and (after ester cleavage with LiOH.H2O), 1-(2-propyl)-piperazine (commercially available). The title compound was obtained as light yellow foam. MS (m/e): 399.3 (MH+).