Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:24]3[C:19]([C:20]([NH2:25])=[N:21][CH:22]=[N:23]3)=[C:18](Br)[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:34]1[CH:42]=[C:41]2[C:36]([CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=[CH:40]2)=[N:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[N:24]3[C:19]([C:20]([NH2:25])=[N:21][CH:22]=[N:23]3)=[C:18]([C:38]3[CH:39]=[CH:40][C:41]4[C:36]([CH:37]=3)=[N:35][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:42]=4)[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(Br)c3c(N)ncnn23)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
The product from step 3 (330 mg, 0.78 mmol) and Intermediate C (337 mg, 1.01 mmol), were dissolved in 7 mL dioxane:ethanol (5:2) and the mixture was treated with 2 M sodium carbonate (7 mL) and 1,1′-bis(diphenylphosphinoferrocenyl)palladium dichloride (27 mg) was added. The mixture was heated to 80° C. with stirring for 4 h. The mixture was allowed to cool and filtered through Celite®. Ethyl acetate was added and the product was extracted from the aqueous solution. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue purified by Biotage® to provide the title compound. 1H NMR (CD2Cl2) δ 1.50 (s, 9H), 1.60-2.00 (m, 3H), 2.80 (m, 2H), 3.80 (t, 1H), 4.10 (m, 3H), 5.60 (s, 2H), 7.20 (d, 1H), 7.40 (m, 6H), 7.80 (dd, 2H), 8.10 (m, 2H). LC-MS [M+H]+=574.1, RT=3.36 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[O:15]1[C:19]2([CH2:24][CH2:23][CH:22]([NH:25][C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=3[N+:12]([O-:14])=[O:13])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1
Reactant: NC1CCC2(CC1)OCCO2
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NC2CCC3(CC2)OCCO3)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.4 g) in tetrahydrofuran (30 mL) was added 1,4-dioxaspiro[4.5]decan-8-amine (1.0 g) and diisopropylethylamine (5 mL). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[N:19][C:20]([O:23]C)=[CH:21][CH:22]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1>Cl>[CH3:1][N:2]1[CH2:26][CH2:25][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20](=[O:23])[NH:19][CH:18]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: COc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Agent: Cl
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccc(=O)[nH]c2)CCN(C)C1

Procedure:
A solution of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-(6-methoxy-pyridin-3-yl)-ethanol (200 mg, 0.569 mmol) in 3N HCl (8 mL) was stirred at 100° C. for 3 h. The reaction mixture was concentrated under reduced pressure and residue was purified by reverse phase HPLC to yield 5-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-hydroxyethyl)pyridin-2(1H)-one. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.5 (m, 1H), 7.23 (s, 1H), 7.2 (s, 1H), 7.19 (d, 1H), 6.5 (s, 1H), 4.62 (d, 1H), 4.19-4.37 (m, 3H), 3.8 (m, 1H), 3.5 (m, 1H), 3.24 (m, 2H), 3.1 (m, 4H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers II-92a-b.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][N:15]2[CH:10]([CH2:11][O:12][CH:13]([C:18]3[N:26]4[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)=[C:20]([C:28]4[CH:29]=[CH:30][C:31]5[C:35]([CH:36]=4)=[N:34][N:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:32]=5)[CH:19]=3)[CH2:14]2)[CH2:9]1)C1C=CC=CC=1>[Pd].CC(O)=O>[CH2:11]1[CH:10]2[CH2:9][NH:8][CH2:17][CH2:16][N:15]2[CH2:14][CH:13]([C:18]2[N:26]3[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]3)=[C:20]([C:28]3[CH:29]=[CH:30][C:31]4[C:35]([CH:36]=3)=[N:34][N:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:32]=4)[CH:19]=2)[O:12]1
Reactant: Nc1ncnn2c(C3CN4CCN(Cc5ccccc5)CC4CO3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Reaction time: 8 h
Yield: 29.8 %

Procedure:
Palladium on carbon (60 mg, 10% by wt.) was placed under an inert atmosphere and suspended in AcOH (5 mL). A solution of 7-(8-benzyloctahydropyrazino[2,1-c][1,4]oxazin-3-yl)-5-(2-phenyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (600 mg, 1.08 mmol) in AcOH (6 mL) was added. The reaction mixture was placed under H2 atmosphere (1 Atm pressure) and stirred overnight. Additional amounts of palladium on carbon (10% by wt.) were added as needed until the reaction was complete as observed by HPLC. The resulting mixture was filtered through a pad of Celite® and the solvent was concentrated under reduced pressure. Trituration with Et2O afforded 150 mg (29%) of the desired product as an off-white solid. 1H NMR (300 MHz, DMSO-d6) 9.16 (s, 1 H), 8.10 (d, 2 H), 7.94 (s, 1 H), 7.85 (d, 1 H), 7.68 (s, 1 H), 7.58 (t, 2 H), 7.44 (t, 1 H), 7.21 (dd, 1H), 6.78 (s, 1H), 5.14 (dd, 1H), 3.74 (dd, 1H), 3.49-3.28 (m, 1H), 2.94 (dd, 1H), 2.75-2.60 (m, 5H), 2.46-2.38 (m, 1H), 2.26-2.08 (m, 3H); LC-MS [M+H]+=467, RT=0.91 min.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=O)[C:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[CH3:22]>O1CCOCC1.C(O)C.[Ni]>[OH:1][C:2]1[CH:21]=[CH:20][C:5]2[CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[C:3]=1[CH3:22]
Reactant: Cc1c(O)ccc2c(=O)c(-c3ccc([N+](=O)[O-])cc3)coc12
Agent: [Ni]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(O)ccc2c1OCC(c1ccc(N)cc1)C2

Procedure:
7-Hydroxy-8-methyl-3-(4-nitrophenyl)-4H-1-benzopyran-4-one (440 mg), dissolved in a mixture of dioxane/ethanol 1:1 (200 ml), is hydrogenated for 15 h at room temperatutre over Raney nickel (200 mg). After filtration of the catalyst, the filtrate is evaporated under reduced pressure. The residue is dissolved in ethanol (75 ml) and hydrogenated for 15 h at room temperature over palladium 10% on active charcoal (200 mg) in the presence of p-toluenesulfonic acid monohydrate (760 mg). After filtration of the catalyst, the filtrate is evaporated under reduced pressure. The residue is dissolved in water (100 ml). The solution is neutralized to pH 7.5 by addition of a saturated solution of NaHCO3 and extracted with ethyl acetate (3×50 ml). The combined organic solutions are washed with water (2×20 ml), dried over MgSO4 and evaporated. The residue is purified by column chromatography on silica gel using dichloromethane/ethyl acetate 1:1 as eluent. The product is dried in vacuo to constant weight to yield 3,4-dihydro-7-hydroxy-8-methyl-3-(4-aminophenyl)-2H-1-benzopyran, m.p. 150°-151°.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][CH2:13]Br)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:13][CH2:12][N:9]2[C:7](=[O:8])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:10]2=[O:11])=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCNc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added n-(2-bromoethyl)phthalimide, 95% (508 mg, 1999 μmol, Aldrich), 4-fluoroaniline (193 μL, 1999 μmol, Aldrich), DMF (2 mL), sodium carbonate (336 mg, 3999 μmol). The reaction mixture was stirred at 80° C. for overnight. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with water (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give 2-(2-(4-fluorophenylamino)ethyl)iso-indoline-1,3-dione. MS (ESI pos. ion) m/z: 285 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([OH:30])=O)[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10].[NH2:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]([CH3:31])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22]1[S:23][CH:24]([CH2:27][C:28]([NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[O:30])[CH2:25][N:26]=1)=[CH:18]2)(=[O:11])=[O:10]
Reactant: Nc1nnn[nH]1
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)Nc4nnn[nH]4)S3)[nH]c12
Temperature: 25 °C
Yield: 56.6 %

Procedure:
To a mixture of (2-{7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (165 mg), 5-amino-tetrazole (37 mg), 1H-1,2,3-benzotriazol-1-ol (68 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (96 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with water, aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound (107 mg, yield 56%) as a pale-yellow amorphous solid. MS: 527 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][CH:41]=[C:42]([CH:45]=2)[C:43]#[N:44])O1>>[NH2:18][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[C:8]([C:6]2[CH:7]=[C:2]([C:38]3[CH:39]=[N:40][CH:41]=[C:42]([CH:45]=3)[C:43]#[N:44])[CH:3]=[CH:4][C:5]=2[F:29])([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=2)[N:9]=1
Reactant: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2cc(Br)ccc2F)c2cccc(F)c21
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2ccc(F)c(C3(c4ccnc(C(F)(F)F)c4)N=C(N)c4c(F)cccc43)c2)c1
Yield: 65 %

Procedure:
The title compound was synthesized as described for Example 1 in 65% yield, starting from 1-(5-bromo-2-fluorophenyl)-4-fluoro-1-(2-(trifluoromethyl)pyridin-4-yl)-1H-isoindol-3-amine (60.0 mg, 0.13 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (32.4 mg, 0.14 mmol).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=2)[N:8]=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C(Cl)Cl>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH3:18][O:17][C:11]1[CH:10]=[C:9]2[C:14]([N:15]=[CH:16][C:7]([NH2:6])=[N:8]2)=[CH:13][CH:12]=1
Reactant: COc1ccc(CNc2cnc3ccc(OC)cc3n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2ncc(N)nc2c1
Yield: 98.8 %

Procedure:
N-(2,4-Dimethoxybenzyl)-7-methoxyquinoxalin-2-amine (0.79 g, 2.428 mmol) was stirred in TFA (10 mL, 130 mmol)/CH2Cl2 (10 mL) at room temperature for 30 min. Solvents were removed on the rotary evaporator. Saturated aqueous NaHCO3 (200 mL) was added to the red residue, which precipitated a yellow solid. The mixture was extracted extensively with DCM. The organic layer was concentrated and dried under vacuum to yield 7-methoxyquinoxalin-2-amine 2,2,2-trifluoroacetate (0.70 g, 2.4 mmol, 99% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][S:8]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)(=[O:10])=[O:9].[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[CH:24]2.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C=O>[NH:26]1[C:27]2[C:23](=[CH:22][C:21]([NH:20][C:17]([CH:14]3[CH2:13][CH2:12][N:11]([S:8]([CH3:7])(=[O:9])=[O:10])[CH2:16][CH2:15]3)=[O:19])=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CS(=O)(=O)N1CCC(C(=O)O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(C(=O)Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
A catalytic amount of N,N-dimethylformamide and a solution of oxalyl dichloride (0.367 g, 2.89 mmol) in methylene chloride (3 ml) were added to a solution of 1-(methylsulfonyl)-4-piperidinecarboxylic acid (500 mg, 2.41 mmol) in methylene chloride (7 ml), and the resulting mixture was stirred at room temperature for three and a half hours. The reaction solution was distilled under reduced pressure to remove the solvent, and a solution of the resulting residue in methylene chloride (5 ml) was added to a solution of 5-aminoindazole (322 mg, 2.42 mmol) and triethylamine (0.67 ml, 4.8 mmol) in methylene chloride (10 ml) at 0° C. and stirred overnight at room temperature. Then, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and the organic solvent was distilled off under reduced pressure. The solid precipitated was collected by filtration and suspended in methanol, and the resulting suspension was stirred at 50° C., followed by filtration. The solid collected by this filtration was dried under reduced pressure to obtain N-(1H-indazol-5-yl)-1-(methylsulfonyl)-4-piperidinecarboxamide (670 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@@H:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][N:13]=[N+]=[N-])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.C1(S)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:23])[C@@H:5]1[CH2:9][CH:8]([CH2:10][CH2:11][CH2:12][NH2:13])[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(CCCN=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: Sc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CC(CCCN)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N-(tert-butoxycarbonyl)-4-(3-azidopropyl)-L-proline ethyl ester (1.17 g, 3.58 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) and dry tin chloride (1.01 g, 1.5 eq.), thiophenol (2.21 mL, 6 eq.) and triethylamine (2.24 mL, 4.5 eq.) were added. The reaction mixture was stirred at 25° C. for Ihour, poured into ethyl acetate, washed with 1 N HCl, 1 N NaOH, brine, dried (Na2SO4) and concentrated. The residue (0.96 g, 90%) was used crude in the next step: 1H NMR (400 MHz, CDCl3, 7:3 mixture of diastereomers) δ 1.29 (m, 3H), 1.40-1.56 (m, 9H), 1.84 (m, 1H), 2.10 (m, 1H), 2.39 (m, 1H), 2.42 (m, 1H), 2.72 (m, 2H), 2.99 (m, 2H), 3.76 (m, 2H) 4.18-4.38 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:33][C:34]([C@@H:36](OS(C(F)(F)F)(=O)=O)[CH3:37])=[O:35]>>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[C@@H:36]([C:34]([OH:35])=[O:33])[CH3:37])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCCN1CCCC1
Reactant: CCOC(=O)[C@H](C)OS(=O)(=O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(CCN1CCCC1)[C@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-{[(2-pyrrolidin-1-ylethyl)amino]methyl}quinazolin-4-amine (prepared as described in Example 47) was coupled with ethyl O-trifluoromethanesulfonyl-L-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-pyrrolidin-1-ylethyl)-D-alanine; 1H NMR Spectrum: (DMSO-d6) 1.27 (d, 3H); 1.83 (m, 4H); 2.86 (m, 8H); 3.44 (q, 1H); 3.84 (d, 1H); 3.94 (d, 1H); 4.01 (s, 3H); 7.25 (s, 1H); 7.33 (t, 1H); 7.53 (m, 1H); 7.63 (m, 1H); 8.42 (s, 1H); 8.48 (s, 1H); 9.78 (brs, 1H); Mass Spectrum: (M+H)+ 502.
Reaction SMILES: [C@@H:1]1(O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.C1(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C@H:1]1([NH2:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: O[C@H]1Cc2cccc3cccc1c23
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: N[C@@H]1Cc2cccc3cccc1c23
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a cooled (0° C.) and stirred solution of (S)-acenaphthenol (1.74 g, 10.2 mmol) and diphenyl-phosphorylazide in toluene (17.5 ml) was added DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (1.86 ml, 12.3 mmol) and stirring was continued at RT over a period of 20 h. The reaction mixture was extracted with toluene (2×50 ml), the combined organic phases washed with water, dried (MgSO4) and evaporated in vacuo. The crude product was dissolved in EtOH (120 ml) and hydrogenated at RT over PtO2 (0.24 g). The catalyst was filtered off, the solution evaporated in vacuo and the residue purified by column chromatography on silica gel (dichloromethane/MeOH 9:1) to yield (R)-acenaphthen-1-yl-amine (1.56 g) as a pink oil. MS: m/e=169 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[N:5]([C:13]1[CH:18]=[C:17]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:16]=[C:15]([NH2:24])[C:14]=1[N+:25]([O-])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>CO.[Ni]>[CH2:1]([O:3][C:4](=[O:28])[N:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:13]1[CH:18]=[C:17]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)[N:16]=[C:15]([NH2:24])[C:14]=1[NH2:25])[CH3:2]
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(-n2cccn2)nc(N)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCOC(=O)N(Cc1ccccc1)c1cc(-n2cccn2)nc(N)c1N
Reaction time: 1 h
Yield: 96.3 %

Procedure:
(2-Amino-3-nitro-6-pyrazol-1-yl-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (65.4 mg, 0.171 mmol) was dissolved in methanol (5 mL) and hydrogenated over Raney Nickel (25 mg) at room temperature, 80 psi for 1 hour. The reaction mixture was filtered through a short plug of Arbocel and the filtrate was then evaporated in vacuo to afford 58mg of the title compound as a brown residue.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].C(OP(O[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C:15]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])(OCC)=O)C.[NH4+].[Cl-]>C1COCC1.[Cu]I>[CH2:1]([C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][C:15]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:2]
Reactant: CC[Mg]Br
Reactant: CCOC(=O)C1=C(OP(=O)(OCC)OCC)CCN(C(=O)OC(C)(C)C)C1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(CC)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a slurry of CuI (4.21 g, 22.12 mmol) in THF (61.4 mL) at about 0° C. was added ethylmagnesium bromide (1.0 M in THF, 44.2 mL, 44.2 mmol) dropwise. After about 30 min, the reaction mixture was cooled to about −78° C. and a solution of 1-tert-butyl 3-ethyl 4-(diethoxyphosphoryloxy)-5,6-dihydropyridine-1,3(2H)-dicarboxylate (7.51 g, 18.43 mmol) in THF (61 mL) was added slowly. The reaction mixture was stirred at about −78° C. for about 1 h then warmed to about 0° C. The reaction mixture was stirred at about 0° C. for about 1.5 h, then warmed to ambient temperature and stirred for about 1 h. The reaction mixture was cooled to about −78° C. and saturated aqueous NH4Cl (100 mL) was slowly added. The reaction mixture was allowed to warm to ambient temperature and stirred for about 16 h. The mixture was extracted with Et2O (100 mL). The aqueous layer was further extracted with Et2O (2×50 mL). The organic layers were combined, washed with saturated aqueous NH4Cl (50 mL), dried over anhydrous Na2SO4, filtered, concd under reduced pressure and purified by silica gel chromatography eluting with a gradient of 0-30% EtOAc in heptane to yield 1-tert-butyl 3-ethyl 4-ethyl-5,6-dihydropyridine-1,3(2H)-dicarboxylate (0.785 g, 15%) as a clear oil: 1H NMR (CDCl3) δ 4.23 (d, J=7.1 Hz, 2H), 4.12 (s, 2H), 3.48 (t, J=5.8 Hz, 2H), 2.52 (q, J=7.5 Hz, 2H), 2.28 (t, J=5.8 Hz, 2H), 1.51 (s, 9H), 1.32 (t, J=7.1 Hz, 3H), 1.09 (t, J=7.5 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[CH:4]=O.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH3:13])[C:3]=1[CH2:4][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(Cl)c(C=O)c(OC)c1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(Cl)c(CN2CCCCC2)c(OC)c1
Yield: 90.6 %

Procedure:
To a pre-stirred solution of 2-chloro-4,6-dimethoxybenzaldehyde (2.7 g, 13.5 mmol) and piperidine (1.46 mL, 14.9 mmol) in DCM (50 mL) at 0° C. was added sodium triacetoxyborohydride (4.29 g, 20.0 mmol) in portions. The reaction mixture was then allowed to warm to ambient and stirred for an additional 3 h before the addition of water (50 mL). The pH of the aqueous phase was adjusted to 2 by the addition of hydrochloric acid and then washed with DCM (50 mL). The pH of the aqueous phase was then adjusted to 9 by the addition of saturated aqueous sodium carbonate and then the organic component was extracted into DCM (50 mL), dried over sodium sulfate and evaporated under reduced pressure to afford the title compound as a beige solid (3.3 g, 91%) that was used without further purification. 1H NMR (CDCl3, 300 MHz): 6.60 (d, J=2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.35 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 3.6-2.57 (ν br m, 4H), 2.29-1.88 (br m, 4H), 1.71-1.40 (br m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:20](=[O:22])[CH3:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: CC(=O)O
Product: CC(=O)Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-ylamine and acetic acid as starting materials, MS (LC/MS): 317.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH3:21]>>[CH2:19]([O:18][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:21])=[CH:10][C:9]([O:12][CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=2)=[O:17])[CH3:20]
Reactant: N
Reactant: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1Cl
Product: CCOC(=O)c1cnc2ccc(OC(C)C)cc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-6-isopropoxyquinoline-3-carboxylate (Example 10b) and ammonia as an off white solid (75%). MS 275 (MH+.