Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C@:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[CH2:14][C:15]([CH3:18])([OH:17])[CH3:16])[CH3:9])=[CH:4][CH:3]=1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:11][CH2:12][C@@:13]([OH:19])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][C:15]([OH:17])([CH3:18])[CH3:16])[C:27](=[O:28])[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NCC[C@](O)(CC(C)(C)O)c1ccccc1)c1ccc(Br)cc1
Reactant: O=C(Cl)Oc1ccccc1
Product: C[C@@H](c1ccc(Br)cc1)N(CC[C@](O)(CC(C)(C)O)c1ccccc1)C(=O)Oc1ccccc1
Temperature: 10 °C
Reaction time: 10 h

Procedure:
Preparation 2: Using a procedure similar to that described in Preparation 1 above, the reaction mixture from Step 4 above is cooled to about 10° C. and treated drop-wise with phenyl chloroformate (5.2 mL, 41.3 mmol). The reaction mixture is stirred at 20-25° C. for 2-18 hours, extracted with EtOAc, and the organic extract washed with 3N aqueous HCl. The combined organic phases are distilled to remove EtOAc and DME. The resultant solution is treated with heptane (30 mL), cooled to about 5° C., seeded with 5 (obtained from Preparation 1 immediately above), and held at about 5° C. for 3 hours. The resultant solids are collected by filtration, washed with heptane, and dried under vacuum at 25° C. for 18 hours to provide 5 as an off-white solid. Yield: 14.61 g, 78.3%; 97.2% purity by weight. Melting point: 129-131° C. LC-MS: 507.6/509.6 (95%, 100%); [M−H2O]+; calculated exact mass for M−H2O: 507.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.[Cl:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([NH:18][NH2:19])=[O:17])=[CH:14][CH:13]=1.O>CCO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[N:19][NH:18][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:21][CH:20]=1
Reactant: O=Cc1c(O)cccc1Cl
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: CCO
Solvent: O
Product: O=C(NN=Cc1c(O)cccc1Cl)c1ccc(Cl)cc1
Temperature: 60 °C
Yield: 95.5 %

Procedure:
A suspension of 2-chloro-6-hydroxybenzaldehyde (0.10 g, 0.64 mmol) and 4-chlorobenzoic acid hydrazide (0.10 g, 0.61 mmol) in EtOH (3 mL) was agitated and heated to 60° C. for 16 h. The reaction mixture was cooled to room temperature and H2O (1-2 mL) was added portionwise to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish the title compound as an off-white solid (0.18 g, 95%): mp 273-277° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 12.51 (s, 1H), 9.04 (s, 1H), 8.03-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.34 (t, J=8.2 Hz, 1H), 7.07 (dd, J=7.9, 0.9 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H); ESIMS m/z 309 ([M+H]+), 307 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[OH-].[Na+]>>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2cccc(C(OC)OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: COC(OC)c1cccc(-c2ccc(C(=O)O)cc2)c1
Yield: 85.3 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 3′-dimethoxymethylbiphenyl-4-carboxylate (1.91 g), which is the product of Reference example 14(b), and aqueous sodium hydroxide (1N, 10.0 ml) and the reaction mixture was treated to afford the desired compound (1.55 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]([CH3:26])([CH3:25])[C:3]([NH:5][C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)=[O:4].[CH3:27][N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33](O)=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:18]([N:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:10][C:6]([NH:5][C:3]([C:2]([NH:1][C:33]([C@@H:29]2[CH2:30][CH2:31][CH2:32][N:28]2[CH3:27])=[O:34])([CH3:26])[CH3:25])=[O:4])=[N:7]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC[C@H]1C(=O)O
Reactant: CC(C)(N)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1C(=O)NC(C)(C)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 100 mL rbf was charged DCM (14.29 ml) followed by addition of 2-amino-N-(1-benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-yl)-2-methylpropanamide (1.000 g, 2.83 mmol) and (S)-1-methylpyrrolidine-2-carboxylic acid (0.402 g, 3.11 mmol). And it was stirred at room temperature for 10 min, the clear solution save for a couple of particles, was placed in an ice bath at 2° C. Then HATU (2.152 g, 5.66 mmol) and triethylamine (0.789 ml, 5.66 mmol) were added. The yellow semi-solution was allowed to stir at 2° C. for 5 h. It was allowed to warm to room temperature over night. It was diluted with DCM (25 mL) and H2O (30 mL). The white precipitates were collected by filtration and washed with 1:1 water/sat. NaHCO3 solution. (2×60 mL), brine (2×40 mL). This afforded the title compound 1H NMR (400 MHz, DMSO-d6) d ppm 1.53 (d, J=1.52 Hz, 6H) 1.66-1.78 (m, 3H) 1.96-2.13 (m, 1H) 2.21-2.29 (m, 1H) 2.30 (s, 3H) 2.61-2.70 (m, 1H) 2.99-3.09 (m, 1H) 5.43 (s, 2H) 7.13 (d, J=6.95 Hz, 2H) 7.26-7.43 (m, 5H) 7.68-7.75 (m, 2H) 7.97 (s, 1H) 10.21 (s, 1H). Theoretical mass 464.23. found 464.23. MS (m/z) 465.00 M (+1), tR=1.23, Meth A. ee: 95%, using 30% EtOH Heptane.
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[Cl:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:10]=1[NH2:11].C(N(CC)CC)C.[Cl:24][C:25]1[C:26]2[N:27]([N:34]=[C:35]([S:37](Cl)(=[O:39])=[O:38])[N:36]=2)[C:28]([CH3:33])=[N:29][C:30]=1[O:31][CH3:32].CS(C)=O>C(#N)C>[Cl:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:10]=1[NH:11][S:37]([C:35]1[N:36]=[C:26]2[N:27]([C:28]([CH3:33])=[N:29][C:30]([O:31][CH3:32])=[C:25]2[Cl:24])[N:34]=1)(=[O:38])=[O:39]
Reactant: COc1nc(C)n2nc(S(=O)(=O)Cl)nc2c1Cl
Reactant: Nc1c(Cl)cccc1Cl
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nc(C)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2c1Cl

Procedure:
Anhydrous sodium iodide (11.7 g, 0.078 mol) was placed in 50 ml of dry acetonitrile and 8.5 g (0.078 mol) of trimethylsilyl chloride added with stirring. To this was added 6.3 g (0.039 mol) of 2,6-dichloroaniline and 7.9 g (0.078 mol) of triethylamine. The mixture was stirred at ambient temperature for 30 min and then the volatiles were carefully removed by evaporation under reduced pressure and the residue diluted with ether and filtered. The contents of this solution appeared to be N-trimethylsilyl-2,6-dichloroaniline of about 97 percent purity by GLC analysis. The ether precipitation of insolubles was repeated and the ether was removed by evaporation under reduced pressure. The residue was mixed with 50 ml of dry acetonitrile, 3.9 g (0.013 mol) of 8-chloro-2-chlorosulfonyl-7-methoxy-5-methyl-1,2,4-triazolo[1,5-c]pyrimidine, and 0.2 ml (0.003 mol) of dimethylsulfoxide and the mixture stirred overnight. The resulting mixture was concentrated under reduced pressure and the solid residue was mixed with hexane and water and filtered. The residue was then dissolved in 400 ml of methylene chloride and resulting solution was twice extracted with water, dried over sodium sulfate and filtered. It was then concentrated under reduced pressure and the residue was mixed with hexane, collected by filtration, and dried to obtain 3.3 g (60 percent of theory) of the title compound as a pale yellow powder melting at 255°-256° C. with decomposition.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Li+].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:18]=[C:13]3[C:12]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(-c3ccccc3Oc3ccccc3)cnc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccccc2)c2cc(-c3ccccc3Oc3ccccc3)cnc21
Temperature: 105 °C
Yield: 63.8 %

Procedure:
To a solution of the iodide 27 (2.00 g, 3.62 mmol) in toluene (40 mL) and EtOH (40 mL) was added lithium chloride (0.46 g, 10.86 mmol), dichlorobis(triphenylphosphine) palladium (II) (0.127 g, 0.18 mmol), phenylboronic acid (0.662 g, 5.43 mmol) and 1 M sodium carbonate (9.05 mL, 9.05 mmol). The mixture was refluxed under N2 (oil bath temp. 105° C.) for 2.5 h and then concentrated in vacuo. The resulting residue was co-evaporated once from xylene and purified by silicagel chromatography (gradient elution, hexanes to dichloromethane) to afford the azaindole 28 (1.16 g, 64%) as pale yellow solid. 1H NMR (400 MHz; CDCl3) δ6.91-6.94 (m, 2H), 7.04-7.08 (m, 2H), 7.22-7.30 (m, 3H), 7.31-7.41 (m, 4H), 7.44-7.53 (m, 5H), 7.60 (tt, J=7.4, 1.3 Hz, 1H), 7.87 (s, 1H), 8.23-8.26 (m, 3H) and 8.66 (d, J=1.9 Hz, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:15]2[CH:19]=[C:18]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:17]=[N:16]2)[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:35][Si:33]([CH3:34])([CH3:36])[CH2:32][CH2:31][O:30][CH2:29][N:26]1[C:22]2[N:23]=[CH:24][N:25]=[C:20]([C:18]3[CH:17]=[N:16][N:15]([C:4]4([CH2:3][C:1]#[N:2])[CH2:5][NH:6][CH2:7]4)[CH:19]=3)[C:21]=2[CH:28]=[CH:27]1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (5.36 g, 10.5 mmol) in 1,4-dioxane (100 mL) was added 4.00 M of hydrogen chloride in 1,4-dioxane (40 mL, 160 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction was poured into saturated sodium bicarbonate solution sufficient to neutralize. The product was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to afford product which was used without further purification (3.0 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29](O)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:68][CH2:69][CH2:70][CH2:71][CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:68][CH2:69][CH2:70][CH2:71][CH2:72][C:73]([O:75][CH2:76][CH3:77])=[O:74])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Reactant: CCOC(=O)CCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCNC(=O)c1c[nH]c(-c2cc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (300 mg, 0.67 mmol), HATU (281 mg, 0.74 mmol) and N,N-diisopropylethylamine (258 mg, 2.0 mmol) in anhydrous DMF (10 ml) was stirred at room temperature for 10 minutes, followed by addition of ethyl 5-aminovalerate hydrochloride (145 mg, 0.80 mmol). The mixture was stirred for another 10 minutes and poured into 100 ml of water. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% of methanol in chloroform to give ethyl 5-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}pentanoate as white solid. Yield: 288 mg, 75%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=1.[CH3:18][C:19]([CH3:25])([CH2:23][CH3:24])[CH2:20][Mg]Br>O1CCCC1>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([OH:15])[CH2:24][CH2:23][C:19]([CH3:25])([CH3:20])[CH3:18])=[CH:10][CH:9]=1
Reactant: CCC(C)(C)C[Mg]Br
Reactant: COC(=O)CCNC(=O)c1ccc(C=O)cc1
Solvent: C1CCOC1
Product: COC(=O)CCNC(=O)c1ccc(C(O)CCC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-(4-Formyl-benzoylamino)-propionic acid methyl ester (4.8 g, 20.43 mmol) is dissolved in the anhydrous tetrahydrofuran (THF) (75 mL) and cooled to 0° C. under nitrogen. 2,2-Dimethyl-butyl magnesium bromide (16.3 mL, 1.5M solution in THF, 24.5 mmol) is then added slowly to the solution by addition funnel. The reaction is allowed to stir at 0° C. for 1 hour and the ice bath is removed. The reaction is monitored by TLC or HPLC to determine complete consumption of the aldehyde. The reaction is cooled back down to 0° C. and 1.0N hydrogen chloride solution is dropped in to quench. The solids are dissolved with enough water and the solution is diluted with ether. The two phases are separated and the organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated. The alcohol (1.6 g, 4.98 mmol) is purified by column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:3]=1[O:4][CH2:5][C@H:6](OS(C)(=O)=O)[CH2:7][O:8][S:9]([CH3:12])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][C:2]1[C:3]2[O:4][CH2:5][C@H:6]([CH2:7][O:8][S:9]([CH3:12])(=[O:10])=[O:11])[O:22][C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)OC[C@H](COc1c(O)cccc1O)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)(=O)OC[C@H]1COc2c(O)cccc2O1
Yield: 40.6 %

Procedure:
A mixture of methanesulfonic acid (S)-3-(2,6-dihydroxy-phenoxy)-2-methanesulfonyloxy-propyl ester (253 g, 7.10 mmol) and potassium carbonate (1.14 g, 8.30 mmol) in acetone (30 ml) was refluxed under nitrogen atmosphere for 3.5 h. The reaction mixture was cooled down, filtered and evaporated to dryness. The crude product was purified with flash chromatography using dichloromethane and ethyl acetate as eluents to give 0.75 g of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH:11]([OH:14])[CH2:12][CH3:13].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH:11]([O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:12][CH3:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCC(O)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCC(Oc1ccc([N+](=O)[O-])cc1)c1c(Cl)cccc1Cl

Procedure:
1,3-Dichloro-2-[1-(4-nitrophenoxy)propyl]benzene was prepared according to the method described in Example 20f but from 0.236 g of sodium hydride (at 60% in the oil), 1.1 g of 1-(2,6-dichlorophenyl)propan-1-ol and 0.832 g of 1-fluoro-4-nitrobenzene. We thus obtain 1.18 g of 1,3-dichloro-2-[1-(4-nitrophenoxy)propyl]benzene in the form of a colorless oil which crystallizes, having the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[C:12](Cl)=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)([O-:10])=[O:9]>N1C=CC=CC=1.CCOC(C)=O>[N+:8]([C:11]1[C:12]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2)([O-:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)ccc2cccnc12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=[N+]([O-])c1c(Nc2ccccc2)ccc2cccnc12
Temperature: 170 °C
Yield: 90.3 %

Procedure:
Aniline (2 ml, 21 mmol) was added to a solution of 8-nitro-7-chloroquinoline 40 (200 mg, 0.96 mmol) in pyridine (1 ml) and the mixture was heated in a microwave at 170° C. under nitrogen for 3 h. The residue was dissolved in EtOAc (50 ml) and the organic phase was washed with sat. NaHCO3 (30 ml) and concentrated in vacuo to give the title compound (230 mg, 89%) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:9][C@H:4]([CH3:3])[C@@H:25]([OH:26])[C:24]4[CH:23]=[CH:27][CH:7]=[CH:6][CH:5]=4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: C1CCOC1
Product: C[C@@H](Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1)[C@@H](O)c1ccccc1
Temperature: 140 °C
Yield: 18.7 %

Procedure:
Following the procedure described above in Example 51, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.10 g, 0.32 mmol) was reacted with (1S, 2R)-(+) norephdrine (0.96 g, 6.32 mmol) in 2 mL of THF. The reaction mixture was heated in a sealed vial in a microwave reactor at 140° C. for 50 min, then heated to 160° C. for 30 min. The crude product was purified by preparative HPLC and lyophilized to give a fluffy, yellow solid (26.4 mg, 18.7% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 1.03 (d, J=6.32 Hz, 3 H) 3.87-4.02 (m, 1 H) 4.67 (t, J=4.67 Hz, 1 H) 5.46 (d, J=4.29 Hz, 1 H) 6.43 (d, J=9.35 Hz, 1 H) 6.93 (s, 1 H) 7.12 (t, J=7.33 Hz, 1 H) 7.18-7.46 (m, 6 H) 7.48-7.55 (m, 1 H) 8.19 (s, 1 H) 8.75 (s, 1 H) 9.54 (s, 1 H); HRMS (ESI+) calcd for C24H19ClFN5O 448.13349, found (MH+), 448.1334.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
0.1 g (0.26 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are dissolved in 10 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of DMAP, 80 mg (0.784 mmol) of N-methylpiperazine are added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is chromatographed over silica gel (dichloromethane/methanol 9:1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:23])[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3.[OH-].[Na+].[CH2:26]([OH:29])[CH2:27][OH:28]>O>[OH:28][CH2:27][CH2:26][O:29][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:23])[N:7]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[C:8](=[O:15])[C:9]3[C:14]=2[C:13]=1[CH:12]=[CH:11][CH:10]=3
Reactant: OCCO
Reactant: Cc1ccc(N2C(=O)c3cccc4c(Br)ccc(c34)C2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(N2C(=O)c3cccc4c(OCCO)ccc(c34)C2=O)cc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of 6-bromo-2-p-tolyl-benzo[de]isoquinoline-1,3-dione (4.0 g), sodium hydroxide (0.65 g), and 1,2-ethylene glycol (50 ml) was maintained under reflux with stirring at 120° C. for 10 hrs. The reaction mixture was then cooled to room temperature and water (100 ml) was added to the mixture. The solid that separated out was filtered, washed with water, and dried at 100° C. for 8 hours (Yield=2.71 g). The crude product was purified using 120 ml monochlorobenzene and 0.25 g activated charcoal to obtain pure product weighing 1.32 g. H1-NMR: 2.39 δ (s, 3 protons); 3.92 δ (m, 2 proton); 4.35 δ (t, 2 protons); 5.13 δ (t, 1 proton); 7.22 δ (m, 2 protons); 7.31 δ (m, 3 protons); 7.83 δ (t, 1 proton); 8.44δ (m, 2 protons); 8.68 δ (d, 1 proton).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[OH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[OH:16][C:17]1[CH:18]=[C:19]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:20]=[CH:21][C:22]=1[CH3:23]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: Cc1ccc(B(O)O)cc1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(-c3cc(C#N)ccn3)ncn2C)cc1O
Temperature: 120 °C
Yield: 68.9 %

Procedure:
To a microwave vessel was added 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (79 mg, 0.3 mmol), 3-hydroxy-4-methylphenyl boronic acid (55 mg, 0.36 mmol), PdCl2(dppf) (22 mg, 0.03 mmol), 2M Na2CO3 (0.3 mL, 0.6 mmol) in 2 mL dioxane. The reaction mixture was heated in a microwave oven at 120° C. for 1 hr. It was then purified by ISCO flash column (MeOH/DCM=0-5%) to give 60 mg product (69%). 1H NMR (400 MHz, DMSO-d6): δ 2.11 (3H, s), 3.46 (3H, s), 6.71 (1H, d, J=7.6 Hz), 6.75 (1H, s), 7.12 (1H, d, J=7.7 Hz), 7.52 (1H, d, J=4.9 Hz), 7.85 (1H, s), 8.06 (1H, s), 8.50 (1H, d, J=5 Hz), 9.36 (1H, s). [M+H] Calc'd for C17H14N4O, 291. Found, 291.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)O)[C:6]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26][C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[OH-].[K+]>C(Cl)Cl.O.CN1C(=O)CCC1>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:12]=[CH:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22][C:6]2=3)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(O)Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)cc1
Agent: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(C=Cn2c3c(c4cc(Cl)ccc42)CCN(C)CC3)cc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 6. To a solution of 2-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-1-(4-methoxyphenyl)ethanol (100 mg, 0.25 mmol) in DCM (2 mL), triethylamine (0.053 mL, 0.38 mmol) was added and stirred for 10 min., methane sulfonyl chloride (0.02 mL, 0.27 mmol) was added slowly at 0° C. and stirred at the same temperature for 1 h and stirred at RT for 2 h. The reaction mixture was diluted with water, extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography. Pure product was taken into NMP (2.0 mL), KOH powder (72 mg, 1.2 mmol) was added at RT and heated at 80° C. for 24 h. The product was detected by LCMS, the reaction mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and crude product was purified by reverse phase chromatography to get 6 mg of pure product as the TFA salt.