Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-])=O>CN(C=O)C.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][CH:7]([CH:14]1[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN1CC(C(Oc2ccccc2[N+](=O)[O-])c2ccccc2)OCC1=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: CN1CC(C(Oc2ccccc2N)c2ccccc2)OCC1=O
Reaction time: 0.5 h

Procedure:
To a solution of 7 g of 2-[α-(2-nitro-phenoxy)-benzyl]-4-methyl-morpholin-5-one in 200 ml of DMF, 5% Palladium-charcoal (0.7 g) was added and the mixture was hydrogenated at 3.5 atmospheres for 0.5 hours. The catalyst was filtered off, the solution was poured into water and then extracted with ethyl acetate. After anhydrification and evaporation to dryness of the solvent, crystallization from ethyl ether gave 2-[α-(2-amino-phenoxy)-benzyl]-4-methyl-morpholin-5-one, m.p. 167°-170° C. (5.3 g; 75.2%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH:8]2[CH2:21][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=4)[N:13]=[CH:12][C:11]=3[O:10][CH2:9]2)[CH2:4][CH2:3]1.[O:23]=[C:24]1[NH:29][C:28]2[CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=[CH:33][C:27]=2[S:26][CH2:25]1>>[OH:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][C:11]1[O:10][CH2:9][CH:8]([C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][C:34]([C:31]4[CH:32]=[CH:33][C:27]5[S:26][CH2:25][C:24](=[O:23])[NH:29][C:28]=5[CH:30]=4)=[O:35])[CH2:7][CH2:6]3)[CH2:21][C:20]2=1
Reactant: N[C@H]1CC[C@H](C2COc3cnc4ccc(O)cc4c3C2)CC1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: O=C1CSc2ccc(C(=O)N[C@H]3CC[C@H](C4COc5cnc6ccc(O)cc6c5C4)CC3)cc2N1

Procedure:
The titled compound is prepared as a white lyophilizated powder following Scheme 6 and in analogy to Example 15 using 3-(trans-4-amino-cyclohexyl)-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-6-ol and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]2[CH2:6][C:5](C(OCC)=O)([C:13]([O:15]CC)=[O:14])[CH2:4][C:3]1=2.[OH-].[K+]>C(O)C.O>[CH3:11][C:8]1([CH3:12])[CH2:9][CH2:10][C:2]([CH3:1])([CH3:23])[C:3]2[CH2:4][CH:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1=2
Reactant: CCOC(=O)C1(C(=O)OCC)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(C)(C)C2=C1CC(C(=O)O)C2
Temperature: 160 °C
Yield: 51.2 %

Procedure:
18.4 g of diethyl 4,5,6,7-tetrahydro-4,4,7,7-tetramethyl-2,2-indanebiscarboxylate are dissolved in 500 ml of ethanol and treated with a solution of 64 g of potassium hydroxide in a mixture of 200 ml of ethanol and 50 ml of water. After heating at reflux temperature for 6 hours, the mixture is cooled, the majority of the alcohol is distilled off on a rotary evaporator, the residue is poured on to ice, acidified with 2N hydrochloric acid, extracted repeatedly with ethyl acetate, dried and evaporated. The thus-obtained crude product is heated to 160° C. for 5.5 hours and subsequently chromatographed on silica gel [eluting agent: hexane/ether (2:1)]. After recrystallization from pentane, there are obtained 6.5 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethyl-2-indanecarboxylic acid in the form of colourless crystals of melting point 125°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[C:34]([Mg]Cl)([CH3:37])([CH3:36])[CH3:35].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH:14]([OH:15])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:16][C:17]=2[C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: CC(C)(C)[Mg]Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(C(O)C(C)(C)C)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (95.0 mg, 0.213 mmol) was dissolved in THF (2.5 mL) and the flask was cooled in an ice water bath. Then, tert-butylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.60 mL, 0.60 mmol) was added via syringe, turning the reaction red. The reaction was stirred under nitrogen while being warmed to room temperature, and after 70 min the reaction was treated with MeOH (1.0 mL) and 5 N HCl (0.50 mL). The flask was fitted with a reflux condenser and put in a preheated oil bath (about 50° C.), and stirring was continued for 1 h. Then, the reaction was cooled to room temperature, diluted with MeOH, concentrated, and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min) to give 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)-2,2-dimethylpropan-1-ol (45.9 mg, 97.4% purity, 52% yield). 1H NMR (d6-DMSO, 400 MHz) δ 12.62 (br s, 1H), 9.61 (s, 1H), 8.63 (s, 1H), 8.53 (d, J=2.74 Hz, 1H), 8.21-8.14 (m, 2H), 6.88 (d, J=9.0 Hz, 1H), 4.31 (s, 1H), 3.86 (s, 3H), 2.85 (s, 3H), 0.91 (s, 9H). m/z (ESI, pos. ion) 420 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].CC(C)([O-])C.[K+].Cl[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][O:7][C:17]1[N:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=1
Reactant: OCCOCC(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCCOCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.8 %

Procedure:
2-(2,2,2-Trifluoroethoxy)ethanol (0.462 g, 3.21 mmol) was dissolved in THF (5 mL) and cooled to 0 C. Potassium tert-butoxide (0.360 g, 3.21 mmol) was added, the mixture was stirred for 5 min and methyl 6-chloronicotinate (0.500 g, 2.91 mmol) was added. The mixture was warmed to room temperature and stirred for 3 h. Brine (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield a yellow oil, which was purified by FCC to afford the title compound as a colourless oil (0.453 g, 56%). 1H NMR (500 MHZ, CDCl3) δ ppm 8.73 (1H, d), 8.10 (1H, dd), 6.74 (1H, d), 4.50 (2H, t), 3.93 (2H, t), 3.87 (2H, q) and 3.84 (3H, s).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([CH2:22][O:23][CH2:24][CH3:25])([OH:21])[CH:6]([N+:18]([O-])=O)[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:2]>[Ni].C(O)(C)C>[CH2:24]([O:23][CH2:22][C:5]([CH2:4][O:3][CH2:1][CH3:2])([OH:21])[CH:6]([NH2:18])[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[CH3:25]
Reactant: CCOCC(O)(COCC)C(Cc1ccc2ccccc2c1)[N+](=O)[O-]
Agent: [Ni]
Solvent: CC(C)O
Product: CCOCC(O)(COCC)C(N)Cc1ccc2ccccc2c1
Yield: 85.9 %

Procedure:
A mixture of α,α-diethoxymethyl-β-nitro-2-naphthalenepropanol (4.7 g) and Raney nickel in isopropanol (80 ml) was stirred under hydrogen at atmospheric pressure. When absorption of hydrogen was complete the mixture was degased in vacuo for 15 minutes and filtered through celite. Evaporation of the solvent in vacuo yielded α, α-diethoxymethyl-β-amino-2-naphthalenepropanol (3.69 g) as an oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C@H:2]1[CH2:11][C:12]([OH:14])=O.[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1.C1(CC(O)=O)C2C(=CC=CC=2)CC1.C(OC(=O)[C@@H]1CSCN1)C>>[CH3:15][O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:12](=[O:14])[CH2:11][C@@H:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(O)C[C@@H]1CCc2ccccc2C1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCOC(=O)[C@@H]1CSCN1
Agent: O=C(O)CC1CCc2ccccc21
Product: COC(=O)[C@@H]1CCCN1C(=O)C[C@@H]1CCc2ccccc2C1
Yield: 86 %

Procedure:
A colorless oil of 1-[(R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetyl]-L-proline methyl ester was prepared in the same manner as in Reference Example 1, except that (R)-(+)-1,2,3,4-tetrahydronaphthalen-2-ylacetic acid and L-proline methyl ester were used instead of 2-indanyl acetic acid and L-thioproline ethyl ester, respectively (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH:19][C:20](=[O:25])[CH2:21][NH:22][CH2:23][CH3:24])=[C:4]([F:26])[CH:3]=1.[CH3:27][OH:28].C(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][C:9]2[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:19]2[C:20](=[O:25])[CH2:21][N:22]([CH2:23][CH3:24])[C:27]2=[O:28])=[C:4]([F:26])[CH:3]=1
Reactant: CCNCC(=O)Nc1cc(Oc2ncccc2C(F)(F)F)c(Cl)cc1F
Reactant: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCN1CC(=O)N(c2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)C1=O

Procedure:
A solution of N-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenyl]-2-ethylaminoacetamide (0.82 g) and 1,11 -carbonyldiimidazole (0.43 g) in toluene (20 ml) was heated at reflux for 2 hours, cooled and processed. Column chromatography on silica gel eluting with 2.5% methanol-methylene chloride gave a buff colored solid (0.8 g), mp 162-3° C. 1H NMR (CDCl3, TMS): 1.24(3H, t, J=7 Hz), 3.53(2H, q, J=7 Hz), 4.05(2H, s), 7.13(1H, m), 7.30(1H, d, J=7 Hz), 7.38(1H, d, J=9 Hz), 8.01(1H, m), 8.24(1H, m).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O-:10])=O)=[CH:6][N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[Na].[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH3:21][C:20]1[CH:19]=[CH:18][C:17]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)=[CH:16][C:15]=1[NH:14][C:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([S:11][CH3:12])=[N:5][CH:6]=1)=[O:10]
Reactant: CSc1ncc(C(=O)[O-])c(N)n1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C(=O)Nc2cc(NC(=O)c3cccc(C(F)(F)F)c3)ccc2C)c(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 4-amino-2-methylsulfanyl-5-pyrimidinecarboxylate in a sodium salt form (1.28 g, 6.2 mmol), N-(3-Amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide (1.82 g, 6.2 mmol), and DIEA (3.22 mL, 18.5 mmol) in DMF is added HATU (2.82 g, 7.42 mmol), and the mixture is stirred for 1 h at room temperature. The reaction mixture is diluted with EtOAc and washed with 5% aqueous Na2S2O3 solution, saturated aqueous NaHCO3 solution, and brine. The organic layer is dried over MgSO4 and concentrated in reduced pressure. The crude product is crystallized from MeOH to give 4-amino-2-methylsulfanyl-pyrimidine-5-carboxylic acid [2-methyl-5-(3-trifluoromethyl-benzoylamino)-phenyl]-amide (1.79 g, 61%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl.O>[Cl:21][CH2:22][C:23]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[C:2]([CH3:13])([CH3:1])[CH2:3]1)=[O:24]
Reactant: CC1(C)CNc2cc(C#N)ccc21
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN(C(=O)CCl)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a solution of 3,3-dimethylindoline-6-carbonitrile (0.35 g, 2.0 mmol) and triethylamine (0.56 mL, 4.0 mmol) in DCM (10 mL) at 0° C. was added chloroacetyl chloride (0.16 mL, 2.0 mmol) dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was then diluted with water. The organic phase was then separated, dried over magnesium sulfate and concentrated to give the title compound (0.39 g). 1H NMR (CDCl3): 8.47 (s, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 4.14 (s, 2H), 3.94 (s, 2H), 1.42 (s, 6H).
Reaction SMILES: [CH3:1]O.S(=O)(=O)(O)O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:25]=[C:24]([O:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])[C:23]=2[O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>O>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:21][C:22]2[N:27]=[C:26]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:25]=[C:24]([O:34][CH2:35][CH2:36][C:37]([O:39][CH3:1])=[O:38])[C:23]=2[O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[O:47][CH3:48])(=[O:20])=[O:19])=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CO
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CCOc1nc(N2CCOCC2)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Methanol (0.5 ml) and concentrated sulfuric acid (two droplets) were added to 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid (50 mg), and the mixture was stirred for 4 hours at room temperature, then poured into water, and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (chloroform-methanol (30:1)), to thereby obtain 46 mg (yield: 90%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]#[C:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[CH:14]=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:14][C:13]2[CH:12]=[C:11]([C:10]#[C:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=Cc1cccc(C#CCCN2CCOCC2)c1
Product: CN1CCN(Cc2cccc(C#CCCN3CCOCC3)c2)CC1

Procedure:
May be prepared analogously to Example 15 using the product of Example 10 and 1-methylpiperazine.
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9]CC)=[O:8])[CH:3]=1.Br[CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl>C(#N)C.CO.O>[N:5]1[N:6]2[C:2]([O:1][CH2:13][CH2:14][CH2:15]2)=[CH:3][C:4]=1[C:7]([OH:9])=[O:8]
Reactant: BrCCCBr
Reactant: CCOC(=O)c1cc(O)[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cc2n(n1)CCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (0.5 g, 3.20 mmol), 1,3-dibromopropane (0.358 mL, 3.52 mmol) and potassium carbonate (1.770 g, 12.81 mmol) were heated at reflux in acetonitrile (20 mL) for 20 h then cooled to RT, filtered and evaporated in vacuo. The residue was dissolved in a mixture of MeOH (10 mL) and water (20 mL), NaOH (0.384 g, 9.61 mmol) added and stirred for 2 h. The reaction mixture was adjusted to pH5 with 2M HCl and purified by reverse phase HPLC with MeCN/aqTFA as eluent. The solvent was evaporated in vacuo to ˜15 mL and freeze dried to give the sub-title compound as a white solid. Yield: 440 mg
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH3:17][CH:18]([NH2:21])[CH2:19][CH3:20].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH:18]([NH:21][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1)([CH2:19][CH3:20])[CH3:17]
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CCC(C)N
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)Nc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 200 °C
Yield: 38 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 22 mg of butan-2-amine and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N4-sec-Butyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1>>[CH3:12][C:7]1([CH3:13])[C:8]([CH3:11])([CH3:10])[O:9][B:5](/[CH:4]=[CH:3]/[CH2:2][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)[O:6]1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CC1(C)OB(/C=C/CCl)OC1(C)C
Product: CC(C)(C)OC(=O)NC1CCCN(C/C=C/B2OC(C)(C)C(C)(C)O2)C1
Yield: 34.9 %

Procedure:
Following the procedure outlined for Example 488, (E)-2-(3-chloroprop-1-enyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.5 mmol) was reacted with tert-butyl piperidin-3-ylcarbamate (740 mg, 3.7 mmol) to afford the desired product (320 mg, 24%) as a yellow oil: ESI MS m/z 367 [C19H35BN2O4+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][CH2:55][C:56]([NH:58][CH2:59][C:60]([NH:62][CH2:63][C:64](O)=[O:65])=[O:61])=[O:57])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[C:44]([NH:54][CH2:55][C:56]([NH:58][CH2:59][C:60]([NH:62][CH2:63][C:64]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:65])=[O:61])=[O:57])([O:46][CH2:47][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45]
Reactant: O=C(O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-glycyl-glycyl-glycine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23](=O)[C:24]#[C:25][CH3:26])[CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:12][CH2:13][NH:14][CH:23]([C:24]#[C:25][CH3:26])[CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC#CC(=O)CN(CCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC#CC1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.2 %

Procedure:
To a solution of tert-butyl (2-(((6-chloro-3-pyridinyl)sulfonyl)(2-oxo-3-pentyn-1-yl)amino)ethyl)carbamate (1.0 g, 2.40 mmol) in CH2Cl2 (40 mL) at 0° C. was added TFA (4.0 mL, 51.9 mmol). After 20 min, additional TFA (4.0 mL, 51.9 mmol) was added and the cooling bath was removed. After 50 min at room temperature, solid sodium triacetoxyborohydride (2.1 g, 9.91 mmol) was added. The mixture was stirred at room temperature for 20 min then MeOH (5 mL) was added. The mixture was concentrated to about ⅕ its original volume and then saturated aqueous NaHCO3 (20 mL) was added. The pH of the aqueous layer was adjusted to about 8 with NaOH (1 N) and then the mixture was extracted with CHCl3 (containing 10% iPrOH) (3×10 mL). The combined organic extracts were dried with Na2SO4, filtered, and concentrated. The resulting orange oil was purified by chromatography on silica gel using (1 to 5% MeOH in EtOAc) to give 1-((6-chloro-3-pyridinyl)sulfonyl)-3-(1-propyn-1-yl)piperazine as a light-yellow solid (0.39 g)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([F:21])=[CH:14][C:15]([N+:18]([O-])=O)=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[C:13]([F:21])[C:12]2[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]=[N:10][C:11]=2[C:16]=1[CH3:17]
Reactant: Cc1c([N+](=O)[O-])cc(F)c2c1ncn2C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(N)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-nitrobenzimidazole (0.776 g) in methanol (100 mL)/ethyl acetate (50 mL) is added palladium-on-carbon (10%, 0.1 g) and ammonium formate (0.663 g). The mixture is stirred at room temperature for 5 hours, then filtered on Celite, with methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between water and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 25% ethyl acetate/hexane to afford 5-amino-1-tert-butoxycarbonyl-7-fluoro-4-methylbenzimidazole as a yellow oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:14]=[N+]=[N-].[Na+].[OH-].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O>[C:1]1([N:7]2[CH:12]=[CH:11][NH:14][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCN(c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C1C=CN(c2ccccc2)C=CN1
Temperature: 25 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
To the product from Step A (12.54 g, 71.56 mmols) in glacial acetic acid (60 mL) and concentrated sulfuric acid (30 mL) at 0° C. was added sodium azide (5.12 g, 78.7 mmols) in five portions of 1.024 g over a period of 4 hours. The resultant pale yellow mixture was allowed to warm to room temperature with stirring under nitrogen for 17 hours. The mixture was poured onto ice and neutralized to pH 7 with 5 M aq. NaOH. The product was extracted into methylene chloride (2×400 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated to a pale yellow solid. Flash chromatography purification eluting with EtOAc gradient to EtOAc/MeOH (95:5) yielded 12.37 g (91%) of the title intermediate as a pale yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[O:16]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C1C=CC=CC=1>C(O)(C)C>[ClH:2].[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[CH:5][N:4]=[C:3]2[NH:27][C:26]1[CH:25]=[CH:24][C:23]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CN(C)c1ccccc1
Product: Nc1ccc2ncnc(Nc3ccc(Oc4ccccc4)cc3)c2c1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A suspension of crude 4-chloro-6-nitroquinazoline hydrochloride (5 mmol) (Morley J. S. and Simpson J. C. E., J. Chem. Soc., 1948:360) was refluxed under nitrogen with stirring in isopropanol (10 mL) containing 4-phenoxyaniline (926 mg, 5 mmol) and N,N-dimethylaniline (1.215 g, 10 mmol) for 3 hours. The mixture was allowed to cool to 25° C., and the precipitate was collected by Buchner filtration, rinsed with isopropanol (2×10 mL) and dried at 60° C. in a vacuum oven to give 6-amino-4-(4-phenoxyanilino)quinazoline hydrochloride (1.702 g, 86%) as an orange solid; mp 293-294° C.