Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[N:3][CH:2]=1.[ClH:19].P(Cl)(Cl)([Cl:22])=O>C(#N)C.O1CCOCC1>[ClH:22].[Cl:19][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][N:3]=2)=[N:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(Cc2ccncn2)c2ccccc12
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Clc1nnc(Cc2ccncn2)c2ccccc12
Temperature: 50 °C
Reaction time: 36 h

Procedure:
850 mg (3.57 mmol) 4-(4-pyrimidinylmethyl)-1(2H)-phthalazinone in 15 ml acetonitrile is mixed with 1.78 ml (7.14 mmol) 4N HCl solution in dioxane and finally with 1.14 ml (12.5 mmol) phosphoryl chloride. After stirring for 36 h at 50° C., the red suspension is filtered and washed with acetonitrile: FAB MS (M−H)+=255. Further product is obtainable from the evaporated filtrate by distribution between dichloromethane and sat. NaHCO3 solution.
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1.[CH2:30]([N:37]1[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH2:30]([N:37]1[CH2:42][CH2:41][C:40]([C:29]2[C:20]([Cl:19])=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)([OH:43])[CH2:39][CH2:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC1(c2cc3ccccc3nc2Cl)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 38.2 mL, 61.1 mmol) was added to a solution of diisopropylamine (8.6 mL, 61.1 mmol) in tetrahydrofuran (140 mL) at −78° C. under argon. After 1 h, a solution of 2-chloroquinoline (10.00 g, 61.1 mol) in tetrahydrofuran (30 mL) was added via syringe. After 1 h, a solution of 1-benzyl-4-piperdinone (11.3 mL, 61.1 mmol) was added, and the reaction stirred for an additional 40 min at −78° C., then allowed to warn to room temperature. The reaction was cooled to −20° C. and quenched with water. The reaction solution was extracted with ethyl acetate, and the organic phase washed with saturated brine and dried over magnesium sulfate. Chromatographic purification (silica gel,0 to 10% {5% ammonium hydroxide/methanol} in methylene chloride gradient elution) gave the title compound, 11.3 g. MS 353 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 8.00 (d, J=8 Hz, 1H), 7.82 (d, J=8 Hz, 1H), 7.72 (dt, J=1,10 Hz, 1H), 7.57 (dt, J=1,8 Hz, 1H), 7.39–7.26 (m, 5H), 3.61 (s, 2H), 2.85 (d, J=11 Hz, 2H), 2.59 (t, J=12 Hz, 2H), 2.48 (dt, J=4,13 Hz, 2H), 2.13 (d, J=12 Hz, 2H).
Reaction SMILES: [CH:1]1([C:6]2[N:7]=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:10]=3[N:16]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:28](C)=O.[Na+]>CO.[OH-].[Na+]>[CH:1]1([C:6]2[N:7]=[C:8]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:9]3[CH2:15][CH2:14][N:13]([CH3:28])[CH2:12][CH2:11][C:10]=3[N:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Fc1ccc(-c2nc(C3CCCC3)nc3c2CCNCC3)cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCc2nc(C3CCCC3)nc(-c3ccc(F)cc3)c2CC1
Yield: 85.1 %

Procedure:
To a solution of 2-cyclopentyl-4-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (0.035 g, 0.112 mmol) in MeOH (1 mL) was added formaldehyde (37% in water; 0.10 mL) and NaBH(OAc)3 (0.032 g, 0.151 mmol). After the reaction was judged complete, the mixture was diluted with 1 N NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (1-7% 2 M NH3 in MeOH/CH2Cl2) to give 0.031 g (87%) of the title compound. MS (ESI): exact mass calcd. for C20H24FN3, 325.20; m/z found, 326.4 [M+H]+. 1H NMR (CDCl3): 7.47 (dd, J=5.4, 8.8, 2H), 7.15 (t, J=8.7, 2H), 3.38-3.30 (m, 1H), 3.20 (dd, J=4.1, 6.3, 2H), 2.97 (dd, J=4.2, 5.9, 2H), 2.71-2.70 (m, 2H), 2.60 (m, 2H), 2.41 (s, 3H), 2.12-2.05 (m, 2H), 1.99-1.91 (m, 2H), 1.87-1.79 (m, 2H), 1.73-1.63 (m, 2H). The following compounds in Examples 59-62 were prepared using methods similar to those described in Example 58, starting with the corresponding unmethylated azepines from the preceding examples.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.O.[N:20]#[C:21]Br>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]3[NH:17][C:21]([NH2:20])=[N:18][C:13]=3[CH:12]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CCOc2ccc(N)c(N)c2)CC1
Reactant: N#CBr
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(CCOc2ccc3[nH]c(N)nc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 149.4 %

Procedure:
A 100 mL flasked was charged with 4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene-1,2-diamine (4.35 mmol), water (50 mL) and acetic acid (2 mL) and stirred at room temperature for 15 minutes. The reaction mixture was placed in an ice bath and then charged with cyanogen bromide (0.526 g, 5 mmol). The reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was concentrated under reduced pressure and redissolved in acetone, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 1.79 g of 5-(2-(4-methylpiperazin-1-yl)ethoxy)-1H-benzo[d]imidazol-2-amine. This material was used without any further purification. MS (EI): 276 (MH+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][CH:12]=[CH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH3:10]>ClC(Cl)(Cl)Cl>[Br:1][C:13](=[CH:12][O:11][CH2:9][CH3:10])[C:14](=[O:19])[C:15]([F:17])([F:18])[F:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC=CC(=O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC=C(Br)C(=O)C(F)(F)F
Yield: 78.5 %

Procedure:
9.8 g (0.055 mole) of N-bromosuccinimide and 100 mg azoisobutyronitrile are added to a solution of 8.4 g (0.05 mole) of 4-ethoxy-1,1,1-trifluoro-but-3-en-2-one in 50 ml of tetrachloromethane. The mixture is then refluxed for 8 hours, the cooled solution is filtered and the filtrate is concentrated. 13.4 g of a crude product are obtained whiose distillation under reduced pressure gives 9.7 g of 3-bromo-4-ethoxy-1,1,1-trifluorobut-3-en-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[N+:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][NH2:37])=[CH:31][CH:30]=1)([O-:28])=[O:27].Cl>C1COCC1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:37][CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:34][CH:33]=1)=[O:9]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A solution of 8.8 g (47.2 mmol) of 5-chloro-2-methoxybenzoic acid and 8.5 g (51.9 mmol) of carbonylbisimidazole in 180 ml of absolute THF was stirred at room temperature for 2 h. 10 g (49.7 mmol) of 2-(4-nitrophenyl)ethylamine hydrochloride and 9.4 ml of triethylamine were added and the resulting solution was then stirred overnight at room temperature. The reaction solution was then slowly poured onto 1.2 l of 1N hydrochloric acid, and the deposited precipitate was filtered off and washed with water. Drying of the precipitate in a high vacuum yielded 13.8 g of the title compound as a white solid. M.p.: 159-160° C. Rf (silica gel, EA/heptane 4:1)=0.46. MS (ESI): m/z=334 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[N:30]1[C:37](Cl)=[N:36][C:34]([Cl:35])=[N:33][C:31]=1[Cl:32].C([O-])([O-])=O.[Na+].[Na+].O>CC(C)=O>[Cl:35][C:34]1[N:33]=[C:31]([Cl:32])[N:30]=[C:37]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:37]4[N:36]=[C:34]([Cl:35])[N:33]=[C:31]([Cl:32])[N:30]=4)=[CH:18][CH:17]=3)([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:37]4[N:36]=[C:34]([Cl:35])[N:33]=[C:31]([Cl:32])[N:30]=4)=[CH:25][CH:24]=3)[C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:37]4[N:36]=[C:34]([Cl:35])[N:33]=[C:31]([Cl:32])[N:30]=4)=[CH:13][CH:14]=3)=[CH:6][CH:7]=2)[N:36]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(C(c2ccc(N)cc2)(c2ccc(N)cc2)c2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Nc2ccc(C(c3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)(c3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)c3ccc(Nc4nc(Cl)nc(Cl)n4)cc3)cc2)n1
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A solution of tetrakis(4-aminophenyl)methane (4.57 grams, 12.0 mmol; prepared as described in Example C) in acetone (96 milliliters) was added dropwise at 0° C. to a stirred solution of cyanuric chloride (9.06 grams, 49.1 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) in acetone (144 milliliters). The resulting mixture was kept at 0° C. for 1 hour, treated with Na2CO3 (5.21 grams, 49.2 mmol), and poured into water (960 milliliters). The precipitate was separated by filtration, washed with water, and dried to give the tetrakis[4-[(2,4-dichloro-1,3,5-triazin-6-yl)amino]phenyl]methane (7.97 grams, 8.20 mmol, 68 percent yield) as a colorless solid: mp>310° C.; 1H NMR (400 MHz, DMSO-d6, 25° C.) δ7.18 (d, 8H, 3J=8.7 Hz), 7.55 (d, 8H, 3J=8.7 Hz), 11.18 (s, 4H); 13C NMR (75.4 MHz, DMSO-d6, 25° C.)δ64.1, 121.7, 131.7, 135.8, 143.8, 164.6, 169.7, 170.7; MS (FAB, 2-nitrobenzyl alcohol) m/e 969. Anal. Calcd for C37H20Cl8N16: C, 45.71; H, 2.07; N, 23.05. Found: C, 46.03; H, 2.09; N, 22.61.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:35])[C:12]([CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:42]([OH:45])(=[S:44])[CH3:43]>>[CH2:8]([O:10][C:11](=[O:35])[CH:12]([CH2:13][S:44][C:42](=[O:45])[CH3:43])[CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:9]
Reactant: C=C(C(=O)OCC)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Reactant: CC(O)=S
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 45 °C
Yield: 73 %

Procedure:
Triethylamine (0.105 g, 1.04 mmol) was added to a solution of 2-[(6tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-acrylic acid ethyl ester (0.36 g, 0.94 mmol) in thioacetic acid (4 mL) at 0° C. under argon. The mixture was heated at 45° C. for 24 h. Ethyl acetate was added and the organic phase was washed with aqueous saturated sodium bicarbonate and brine and dried. After filtration and evaporation in vacuo the crude product was purified by flash chromatography (toluene/ethyl acetate, 1:0→5:1) to give 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-3-phenyl-propionic acid ethyl ester (0.314 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1Cl
Temperature: 105 °C
Yield: 97.5 %

Procedure:
57 g (363.96 mmol) of 2-chloro-5-methylanisole is dissolved in 800 ml of carbon tetrachloride and mixed at room temperature with 69.9 g (393.08 mmol) of N-bromosuccinimide. After 174.6 mg of benzoyl peroxide is added, it is refluxed for five hours (bath temperature 105° C.). The reaction mixture is suctioned off through a glass-pleated filter, rewashed, and the solution is spun in in a rotary evaporator. 83.6 g (97.5%) of the desired product (contains traces of starting material and dibromide) is obtained, which is incorporated in crude form into the next stage.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:11][C:10]=1[Cl:24])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[Cl:24][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][C:17]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: O=C(CCc1ccc(OCc2ccccc2)c(Cl)c1)C1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCc1ccc(O)c(Cl)c1)C1CCCC1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)-3-chlorophenyl]-1-cyclopentylpropan-1-one (48 g, 0.140 mole), from Step 1, and 10% palladium-on-carbon (11.52 g of 50 wt % wet, 0.005 mol, 3.5 mole %) in ethyl acetate (500 mL) was degassed and purged with hydrogen three times. The reaction was stirred with 1 atm H2 for 4 h, resulting in complete conversion. The mixture was filtered through a fine fritted glass funnel and the filtrate concentrated in vacuo, affording a yellow oil which crystallized on cooling. This material was recrystallized from two parts of isopropyl ether, affording 22 g (62%) of the title product. mp 88–90° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12](O)=[O:13])=[CH:2]1.OC1C2N=NNC=2C=CC=1.Cl.[CH3:27][NH:28][CH3:29]>O1CCCC1.CN1CCOCC1.[Au].C(Cl)Cl>[CH3:27][N:28]([CH3:29])[C:12](=[O:13])[C:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:15]
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Reactant: CNC
Agent: [Au]
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CN(C)C(=O)C(=O)Cc1c[nH]c2ccccc12

Procedure:
A solution of 500 mg 3-indolepyruvic acid in 25 ml anhydrous tetrahydrofuran on an ice-salt bath, under argon atmosphere and under stirring was additioned in swift succession with: 400 mg hydroxybenzotriazole (HOBt) and 570 mg 1-(3-dimethylaminopropyl)-3-ethylcarbimdie.HCl (EDC.HCl). After dissolving and still maintaining the ice-salt bath, 240 mg dimethylamine.HCl were added dissolved in 10 ml anhydrous tetrahydrofuran and 325 microliters 4-methylmorpholine (NMM). The yellowish gold solution was maintained under stirring for one night, leaving the bath temperature to rise up to room temperature. The volume was then tripled adding CH2Cl2 and the organic solution was washed in sequence with 5% NaHCO3 (10×25 ml), saturated NaCl solution (3×25 ml), 5% KHSO4 (10×25 ml) and saturated NaCl solution up to neutrality. After standing for one night on anhydrous Na2SO4, this was filtered off, the mixture was purified by flash chromatography (silica gel, eluent CH2Cl2 25/n-propanol 1,5).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]([CH3:21])[CH2:18][C:19]#[CH:20])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[N:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]([CH3:21])[CH2:18][C:19]#[CH:20])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:31][N:30]=2)[CH:26]=[CH:27]1
Reactant: Oc1cnc2[nH]ccc2c1
Reactant: C#CCN(C)CCOc1cc2ncnc(Cl)c2cc1OC
Product: C#CCN(C)CCOc1cc2ncnc(Oc3cnc4[nH]ccc4c3)c2cc1OC
Yield: 47.3 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 5, 4-chloro-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)ethoxy]quinazoline (0.25 g, 0.817 mmol) was reacted with 5-hydroxy-7-azaindole (0.12 g, 0.899 mmol), (prepared as described for the starting material in Example 2), to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-[2-(N-methyl-N-prop-2-yn-1-ylamino)ethoxy]quinazoline (0.156 g, 47%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[CH:45]=[CH:44][N:43]([CH2:46][C:47](O)=[O:48])[C:42](=[O:50])[N:41]=1)=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:47](=[O:48])[CH2:46][N:43]1[CH:44]=[CH:45][C:40]([NH:39][C:37]([O:36][CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])=[N:41][C:42]1=[O:50])[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Yield: 88.4 %

Procedure:
The title compound (2.45 g, 88%) was synthesized by the reaction of N-[2-(2-nitro-benzenesulfonylamino)-ethyl]-glycine ethyl ester (1.33 g, 4 mmol) and 2-[4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid (1.51 g, 4 mmol) as per the procedure of example 46. 1H-NMR (500 MHz; DMSO-d6) δ 10.99 (s, 0.6H,), 10.98 (s, 0.4H), 8.30˜7.80 (m, 5H), 7.50˜7.25 (m, 10H), 6.94 (t, 1H), 6.79 (s, 1H), 4.79 (s, 1.2H), 4.61 (s, 0.8H), 4.33 (s, 0.8H), 4.15 (q, 0.8H), 4.05 (q, 1.2H), 4.01 (s, 1.2H), 3.52 (t, 1.2H), 3.36 (t, 0.8H), 3.24 (q, 1.2H), 3.02 (q, 0.8H), 1.23 (t, 1.2H), 1.15 (t, 1.8H).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[O:9].[F:14][C:15]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][NH:35][CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:16]=1[O:17][CH:18]1[CH2:19][CH2:20][N:21]([C:24]2[N:25]=[C:26]3[CH2:37][CH2:36][N:35]([C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH2:34][C:27]3=[N:28][C:29]=2[NH:30][CH:31]([CH3:33])[CH3:32])[CH2:22][CH2:23]1.[C:8]([OH:9])([C:10]([F:13])([F:12])[F:11])=[O:7]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)N(C)C)C2
Reaction time: 1 h

Procedure:
Dimethylcarbamic chloride (5.2 mg, 0.049 mmol) was added to a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (12.6 mg, 0.024 mmol) and triethylamine (10 μL, 0.073 mmol) in DCM (240 μL) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (8.0 mg, 55.8%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.28 (d, J=6.6 Hz, 6H), 1.90-2.00 (m, 2H), 2.08-2.17 (m, 2H), 2.77-2.84 (m, 2H), 2.91 (s, 6H), 2.99-3.08 (m, 2H), 3.35-3.44 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 4.09-4.17 (m, 1H), 4.29 (s, 2H), 4.44-4.51 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (s, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 475.4.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N+:22]([O-:24])=O)[C:7]([NH:14][C:15]([C:17](OCC)=[O:18])=[O:16])=[C:8]2[C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9]2)(=[O:3])[CH3:2].CN(C)C=O>C(O)C.[Pt]>[C:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]2[NH:14][C:15](=[O:16])[C:17](=[O:18])[N:22]([OH:24])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(C(C)=O)c2c1CCCC2
Agent: [Pt]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)c1cc2c([nH]c(=O)c(=O)n2O)c2c1CCCC2
Yield: 72.9 %

Procedure:
A solution of 8-acetyl-5-ethoxalylamino-1,2,3,4-tetrahydro-6-nitronaphthalene (0.67 g, 2 mmol) in 100 ml of ethanol was hydrogenated at room temperature and atmospheric pressure over 50 mg of 5% platinum on carbon for 1 h. Then 50 ml of N,N-dimethylformamide was added to dissolve the precipitated solid, and the catalyst was removed by filtration. The filtrate was concentrated and the residue was washed with 50 ml of ethanol to give 0.40 g (73%) of the title compound. M.p. >200° C. decomp. (DSC); IR (KBr): 1709, 1677 cm-1, 1H-NMR (DMSO-d6): 1.43-1.93 (m, 4H, 2CH2), 2.57 (s, 3H, COCH3), 2.53-3.07 (m, 4H, 2CH2), 7.57 (s, 1H, H-7), 11.4 (very broad s, 2H, OH and NH); MS (m/e: 274 (M+, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=[C:6]([CH:26]=1)[C:7]([NH:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][N:16]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][CH:11]=1)=[O:8].N1C=CC=CC=1.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl.C1COCC1>[C:19]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:26]=[C:2]([NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH:3]=[CH:4][C:5]=3[NH:27][C:28](=[O:39])[C:29]3[CH:30]=[CH:31][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[CH:18]=2)[CH:14]=[N:15]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3cc(N)ccc3NC(=O)c3ccc(C(C)(C)C)cc3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3cc(NS(C)(=O)=O)ccc3NC(=O)c3ccc(C(C)(C)C)cc3)cc21
Reaction time: 24 h
Yield: 83 %

Procedure:
To a stirring solution of 5-amino-N-(1-Boc-6-indazolyl)-2-[(4-t-butylbenzoyl)amino]benzamide (144 mg, 0.27 mmol) and pyridine (0.066 mL, 0.82 mmol) in dichloromethane (5 mL) and THF (5 mL) was added methanesulfonyl chloride (0.023 mL, 0.30 mL). After stirring for 24 h, the solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with 1 M citric acid, water, satd aq NaHCO3, and brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo and the resulting solid was recrystallized from dichloromethane/hexanes to give 137 mg (83%) of tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12].FC(F)(F)C(O)=O.CO[CH2:23][N:24]([CH2:29][Si](C)(C)C)[C:25]([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([N:24]1[CH2:29][C@@H:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[C@@H:10]([C:11]([OH:13])=[O:12])[CH2:23]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)/C=C\c1ccc(F)cc1F
Reactant: COCN(C[Si](C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1C[C@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (2Z)-3-(2,4-difluorophenyl)acrylic acid, from preparation 35 (400 mg, 2.17 mmol) and trifluoroacetic acid (17 μL, 0.2 mmol) in dichloromethane (1 mL) was added N-(methoxymethyl)-2-methyl-N-[(trimethylsilyl)methyl]propan-2-amine, from preparation 23 (882 mg, 4.35 mmol) over 30 minutes at 0° C. The reaction mixture was warmed to room temperature and stirred for 24 hours. The solvent was removed in vacuo and the white residue formed was triturated with diethyl ether (5 mL) and the solid filtered off to give the desired product, 400 mg (65%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:16])[CH3:15].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:14]([NH:16][CH2:4][C:3]1[CH:6]=[C:7]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:8]=[CH:9][C:2]=1[OH:1])[CH3:15]
Reactant: CCN
Reactant: CS(=O)(=O)c1ccc(O)c(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNCc1cc(S(C)(=O)=O)ccc1O
Reaction time: 1 h

Procedure:
2-Hydroxy-5-methanesulfonyl-benzaldehyde (0.200 g, 1.0 mmol), ethylamine (2M in THF; 0.75 mL, 1.5 mmol), and sodium cyanoborohydride (0.095 g, 1.5 mmol) were combined in MeOH (10 mL). 4 Å Molecular sieves were added, followed by acetic acid (0.09 mL, 1.5 mmol), and the reaction was stirred for 1 hour. The mixture was filtered, and H2O (0.5 mL) was added and the solution was concentrated. The residue was partitioned between EtOAc (100 mL) and brine (20 mL), and the mixture was neutralized with 1N aqueous HCl (1 mL) and extracted six times with EtOAc, until minimal product was seen in the aqueous layer by analytical tlc. The combined organic layers were dried, filtered, and concentrated to give the title compound.