Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]2[CH:12]=[C:13]([CH3:15])[N:14]=[C:8]2[C:7]=1I)=O.[C:19]1(C#C)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:15][C:13]1[CH2:12][N:9]2[CH:10]=[CH:11][C:6]3[C:7]([CH:2]=[C:3]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:5]=3)=[C:8]2[N:14]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1cn2ccc(NC(=O)C(F)(F)F)c(I)c2n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=Nc2c3cc(-c4ccccc4)nc-3ccn2C1
Temperature: 115 °C
Reaction time: 48 h
Yield: 56.2 %

Procedure:
A mixture of 28 (200 mg, 0.54 mmol), phenylacetylene (83 mg, 0.81 mmol), [Cu(Phen)(PPh3)2]NO3 (45 mg, 54.0 μmol), K3PO4 (230 mg, 1.08 mmol) and anhydrous DMF (5 mL) was flushed with argon and stirred for 2 days at 115° C. After removal of the solvent, the residue was diluted with H2O (25 mL) and extracted with CH2Cl2 (5×20 mL). The CH2Cl2 extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford compound 29 (75 mg, yield: 56%); mp 222° C.; IR (KBr) 3026, 3057, 2944, 2824, 1641, 1604, 1535 cm−1; 1H NMR (400 MHz, DMSO-d6) δ 2.3 (s, 3H), 6.96 (d, 1H, J=7.2 Hz), 7.15 (s, 1H), 7.29 (t, 1H, J=7.4 Hz), 7.46 (t, 2H, J=7.8 Hz), 7.50 (s, 1H), 7.85 (d, 2H, J=8.4 Hz), 8.06 (d, 1H, J=7.2 Hz), 11.98 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.2, 98.1, 100.6, 109.3, 114.2, 120.9, 124.5, 127.1, 128.9, 131.4, 131.9, 135.7, 139.1, 140.7. Anal. Calcd for C16H13N3: C, 77.71; H, 5.30; N, 16.99. Found: C, 77.69; H, 5.41; N, 16.94.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]2[CH:6]=[CH:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[N:10]([C:12](=[O:14])[CH3:13])[CH2:11][C:4]=2[N:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)([OH:23])=[O:22].C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:12]([N:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[CH:7]=[CH:6][C:5]2[CH:19]=[CH:20][C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:21]([OH:23])=[O:22])=[N:3][C:4]=2[CH2:11]1)(=[O:14])[CH3:13]
Reactant: O=C(O)c1ccccc1B(O)O
Reactant: CC(=O)N1Cc2nc(Cl)ccc2C=Cc2ccccc21
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2nc(-c3ccccc3C(=O)O)ccc2C=Cc2ccccc21

Procedure:
Compound 61A was prepared from 55C (17 mg, 0.060 mmol) and 2-carboxyphenylboronic acid (10 mg, 0.060 mmol) by a route analogous to that used for the preparation of 2B.
Reaction SMILES: C(OC([N:8]1[C:12]2=[CH:13][N:14]=[CH:15][C:16]([C:17]3[CH:22]=[C:21]([C:23]([C:25]4[NH:52][C:28]5=[N:29][C:30]([N:33]6[CH2:38][CH2:37][CH:36]([O:39][P:40]([O:47]C(C)(C)C)([O:42]C(C)(C)C)=[O:41])[CH2:35][CH2:34]6)=[CH:31][CH:32]=[C:27]5[N:26]=4)=[O:24])[CH:20]=[CH:19][C:18]=3[C:53]#[N:54])=[C:11]2[CH:10]=[CH:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[C:53]([C:18]1[CH:19]=[CH:20][C:21]([C:23]([C:25]2[NH:52][C:28]3=[N:29][C:30]([N:33]4[CH2:38][CH2:37][CH:36]([O:39][P:40](=[O:41])([OH:42])[OH:47])[CH2:35][CH2:34]4)=[CH:31][CH:32]=[C:27]3[N:26]=2)=[O:24])=[CH:22][C:17]=1[C:16]1[CH:15]=[N:14][CH:13]=[C:12]2[NH:8][CH:9]=[CH:10][C:11]=12)#[N:54]
Reactant: CC(C)(C)OC(=O)n1ccc2c(-c3cc(C(=O)c4nc5ccc(N6CCC(OP(=O)(OC(C)(C)C)OC(C)(C)C)CC6)nc5[nH]4)ccc3C#N)cncc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccc(C(=O)c2nc3ccc(N4CCC(OP(=O)(O)O)CC4)nc3[nH]2)cc1-c1cncc2[nH]ccc12
Temperature: 23 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
To a solution of 4-(2-Cyano-5-{5-[4-(di-tert-butoxy-phosphoryloxy)-piperidin-1-yl]-3H-imidazo[4,5-b]pyridine-2-carbonyl}-phenyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.132 mmol) (Step 1) in anhydrous CH2Cl2 (5 mL) at 0° C. was added 4M HCl in Dioxane (0.331 mL, 1.32 mmol, 10 eq) and the solution warmed to 23° C. and stirred for 16 hr. The resulting suspension was concentrated under reduced pressure to afford Phosphoric-acid-mono-(1-{2-[4-cyano-3-(1H-pyrrolo[2,3-c]pyridin-4-yl)-benzoyl]-3H-imidazo-[4,5-b]pyridin-5-yl}-piperidin-4-yl)ester as a red-orange solid (75 mg, 0.122 mmol, 92%). HRMS m/z 544.1523 (M+H)+. 1H NMR (400 MHz, MeOD) δ: 9.24 (1H, s), 8.90 (s, 1H), 8.81 (d, J=8 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J=3 Hz, 1H), 8.23 (d, J=8 Hz, 1H), 8.11 (d, J=9 Hz, 1H), 7.29 (d, J=9.5 Hz, 1H), 6.98 (d, J=2.5 Hz, 1H), 4.63 (m, 1H), 3.98 (m, 2H), 3.77 (m, 2H), 2.08 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]2[O:30][CH2:29][O:28][C:27]=12)[CH:20]=[CH:21][C:22](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[C:26]4[O:30][CH2:29][O:28][C:27]4=[C:17]([O:16][CH3:15])[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: COc1cc(C=CC(=O)O)cc2c1OCO2
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(OC)c4c(c3)OCO4)nc2n(CC)c1=O
Yield: 12.4 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.31 g (14.9 mmol) of 3-methoxy-4,5-methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from tetrahydrofuran/water to give 600 mg (yield 53%) of Compound 169 as a white powder.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][C:28]#[N:29])=[CH:24][CH:23]=1)=O>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:20][C:22]4[CH:31]=[CH:30][C:25]([O:26][CH2:27][C:28]#[N:29])=[CH:24][CH:23]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: N#CCOc1ccc(C=O)cc1
Product: N#CCOc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-(4-formylphenoxy)acetonitrile was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 2-[4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]phenoxy]acetonitrile.
Reaction SMILES: [Si]([O:18][C:19]1[CH:64]=[CH:63][C:22]([O:23][CH2:24][C@@H:25]([OH:62])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:61]=[CH:60][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([S:41]([C:44]4[CH:49]=[CH:48][C:47]([NH:50][C:51]([NH:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:52])=[CH:46][CH:45]=4)(=[O:43])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:54]([NH:53][C:51]([NH:50][C:47]1[CH:48]=[CH:49][C:44]([S:41]([N:38]2[CH2:37][CH2:36][CH:35]([NH:34][C:33]3[CH:60]=[CH:61][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:62])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:64][CH:63]=4)=[CH:31][CH:32]=3)[CH2:40][CH2:39]2)(=[O:43])=[O:42])=[CH:45][CH:46]=1)=[O:52])[CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1

Procedure:
N-[4-({4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N′-hexylurea (0.18 g, 0.199 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound as the hydrochloride salt (0.1 g, 0.142 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N+:21]([O-])=O)=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:21])=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1N
Yield: 93.8 %

Procedure:
A solution of methyl 5-tert-butoxycarbonylaminomethyl-2-nitrophenylacetate (6.8 g, 21 mmol) in methanol (250 mL) in the presence of 10% Pd/C was hydrogenated under atmospheric pressure of hydrogen at room temperature. The catalyst was removed by filtration through celite and the filtrate was concentrated to give 5.8 g of the title compound.
Reaction SMILES: [O-2].[Zn+2:2].[CH3:3][S:4]([OH:7])(=[O:6])=[O:5].NCCNCCNCCNCCN.C1C=CC(C(C(C2C(=O)C3C(=CC=CC=3)C2=O)=O)C2C=CC=CC=2)=CC=1>O>[CH3:3][S:4]([O-:7])(=[O:6])=[O:5].[Zn+2:2].[CH3:3][S:4]([O-:7])(=[O:6])=[O:5]
Reactant: CS(=O)(=O)O
Agent: NCCNCCNCCNCCN
Agent: O=C1c2ccccc2C(=O)C1C(=O)C(c1ccccc1)c1ccccc1
Agent: [O-2]
Solvent: O
Product: CS(=O)(=O)[O-]

Procedure:
A solution of zinc methanesulfonate was prepared from 7 parts zinc oxide, 22.6 parts of a 70% aqueous solution of methanesulfonic acid and 41.4 parts water. To this solution was added 15.5 parts tetraethylenepentamine over a one hour period. A solution of 375.5 parts Example 1 product in 176.7 parts Promar oil was added, and the materials were reacted at 150° C. for two hours under a vacuum of 2 mm of mercury. The product, after dilution with 160.7 parts Promar oil, and filtration, contained 0.40% nitrogen, 0.45% zinc and 0.36% sulfur.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].CC1C=CC(S([CH2:26][N+:27]#[C-:28])(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:9]=[C:6]([C:7]2[O:8][CH:28]=[N:27][CH:26]=2)[CH:5]=[N:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Brc1cncc(-c2cnco2)c1
Temperature: 85 °C
Yield: 53.3 %

Procedure:
To a solution of 5-bromonicotinaldehyde (0.2 g, 1 mmol) in MeOH (5 mL) was added K2CO3 (0.3 g, 2 mmol) followed by TOSMIC (0.27 g, 1.39 mmol). The mixture was heated to 85° C. for 2 h. Methanol was evaporated under reduced pressure and the residue was dissolved in DCM then washed with water. The organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 2.1% MeOH in DCM as the eluent to provide 5-(5-bromopyridin-3-yl)oxazole (0.12 g. 50%). LCMS Method Y: retention time 1.39 min; [M+1]=225.0.
Reaction SMILES: [BH4-].[Li+].Cl[Si](C)(C)C.Cl.[NH2:9][CH:10]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:11](O)=[O:12].CO>C1COCC1>[NH2:9][CH:10]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:11][OH:12]
Reactant: NC(CC(F)(F)F)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: NC(CO)CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
12.9 ml of 2 M lithium borohydride solution in THF (25.8 mmol, 2.5 equivalents) were initially charged in 20 ml of THF, 6.5 ml of chlorotrimethylsilane (51.1 mmol, 5 equivalents) were added and the mixture was stirred at RT for 5 min. 2.0 g of rac-2-amino-4,4,4-trifluorobutanoic acid hydrochloride (10.3 mmol, 1 equivalent) were then added a little at a time, and the mixture was stirred at RT overnight. 20.4 ml of methanol were then added dropwise, and after the addition had ended the mixture was concentrated. 12 ml of a 20% strength aqueous potassium hydroxide solution were added to the residue, and the mixture was extracted three times with dichloromethane. The combined organic solutions were dried over sodium sulphate, filtered and concentrated. This gave 1.58 g (96% of theory; purity 90%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10]Cl)=[N:5][N:4]=[N:3]1.[I-].[Na+].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>CN(C)C=O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][N:16]([CH2:17][CH3:18])[CH2:14][CH3:15])=[N:5][N:4]=[N:3]1
Reactant: CCNCC
Reactant: Cn1nnnc1SCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCCSc1nnnn1C
Reaction time: 3 h
Yield: 24.3 %

Procedure:
1-Methyl-5-(3-chloropropylthio)-1,2,3,4-tetrazole (3.8 g) is dissolved in dimethylformamide (50 ml). To the mixture are added sodium iodide (3 g) and diethylamine (4.4 g) and the mixture is stirred at 60°-70° C. for 3 hours. Dimethylformamide is distilled off under reduced pressure, and the residue is purified by alumina column chromatography (basic alumina, made by Merk & Co.), followed by eluting with n-hexane to give 1-methyl-5-[3-(N,N-diethylamino)propylthio]-1,2,3,4-tetrazole (1.1 g), colorless liquid, nD25 =1.5040.
Reaction SMILES: [O:1]([NH2:3])[CH3:2].Cl[C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@@:15]1([CH3:23])[OH:16]>>[CH3:23][C@@:15]1([OH:16])[C@H:17]([OH:18])[C@@H:19]([CH2:21][OH:22])[O:20][C@H:14]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][CH:12]=[N:13][C:5]=2[NH:3][O:1][CH3:2]
Reactant: CON
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Product: CONc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O

Procedure:
The above compound was synthesized from methoxylamine and 6-chloro-9-(2′-C-methyl-β-D-ribofuranosyl)purine as described in Example 1, Step 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][C:9]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([F:18])[CH:3]=1.OP([O-])([O-])=O.[K+].[K+].[C:26](S(Cl)(=O)=O)([F:29])([F:28])[F:27].CCOC(C)=O>C1C=NC2C3N=CC=CC=3C=CC=2C=1.C1C=NC2C3N=CC=CC=3C=CC=2C=1.C1C=NC2C3N=CC=CC=3C=CC=2C=1.O.[Cl-].[Cl-].[Ru+2].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:26]([F:29])([F:28])[F:27])[NH:10][C:9]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([F:18])[CH:3]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCOC(=O)c1[nH]ccc1-c1ccc(Cl)cc1F
Agent: [Ru+2]
Agent: O=P([O-])([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c(C(F)(F)F)cc1-c1ccc(Cl)cc1F
Temperature: 27.5 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
To a mixture of ethyl 3-(4-chloro-2-fluorophenyl)-1H-pyrrole-2-carboxylate (2.00 g, 7.47 mmol), K2HPO4 (3.90 g, 22.4 mmol) and dichlortris(1,10-phenanthroline)-ruthenium(II) hydrate (106 mg, 0.149 mmol) in argon degassed dry MeCN (24 mL) was added CF3SO2Cl (1.59 mL, 14.9 mmol). The reaction mixture was stirred for 18 h at a temperature of 25-30° C. adjacent to a fluorescent light bulb (E27-32W, 4000K, 65 mA). The reaction mixture was diluted with argon degassed dry MeCN (24 mL). Extra reagents were added: CF3SO2Cl (398 μL, 3.73 mmol) and dichlortris(1,10-phenanthroline)-ruthenium(II) hydrate (106 mg, 0.149 mmol). The reaction mixture was stirred for 3 d at a temperature of 25-30° C. adjacent to a fluorescent light bulb. Subsequently, EtOAc (100 mL) and H2O (100 mL) were added. The aqueous layer was extracted with EtOAc (50 mL). The combination of organic layers was washed with saturated aqueous NaHCO3 and with brine, dried (Na2SO4) and the solvent was evaporated. The crude product was purified by flash chromatography (silica, gradient heptane/EtOAc, 1:0→4:1) to give a yellow solid, which was crystallised from hot heptane to provide 1.01 g (40%) of the desired product as colourless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:19]=O)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][NH:25][C@H:26]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:28][O:29][CH3:30]>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH2:19][N:25]([CH3:24])[C@H:26]([C:31]([NH2:33])=[O:32])[CH2:27][CH2:28][O:29][CH3:30])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: CN[C@@H](CCOC)C(N)=O
Product: COCC[C@@H](C(N)=O)N(C)Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC

Procedure:
4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazoline-6-carbaldehyde was coupled with N2,O-dimethyl-L-homoserinamide analogously as for the equivalent step in Example 1 to give N2-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N2,O-dimethyl-L-homoserinamide; 1H NMR spectrum: (DMSO d6) 1.91 (m, 2H), 2.25 (s, 3H), 3.23 (s, 3H), 3.27 (t, 1H), 3.39 (m, 1H), 3.48 (m, 1H), 3.66 (d, 1H), 3.81 (d, 1H), 3.96 (s, 3H), 7.07 (brs, 1H), 7.20 (s, 1H), 7.29 (t, 1H), 7.38 (brs, 1H), 7.49 (t, 1H), 7.55 (t, 1H), 8.35 (s, 1H), 8.43 (s, 1H), 9.77 (s, 1H); Mass Spectrum: (M+H)+ 462.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14](O)=[O:15])=[CH:11][C:10]=2[NH:17][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[N:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:4][CH:3]=1.[CH3:31][C@@H:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:33][NH2:34].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CS(C)=O.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:13][C:12]([C:14]([NH:34][CH2:33][C@H:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:31])=[O:15])=[CH:11][C:10]=2[NH:17][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[N:24][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)sc3Sc3ccc(N)cc3)ncnc2n1
Reactant: C[C@H](CN)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC[C@@H](C)c4ccccc4)sc3Sc3ccc(N)cc3)ncnc2n1
Yield: 85.2 %

Procedure:
The product of Example 430F (62 mg, 0.142 mmol) in dimethyl sulfoxide (2 mL) under a nitrogen atmosphere was reacted with (S)-(−)-β-methylphenethylamine (23 mg, 0. 170 mmol), N,N-diisopropylethylamine (0.123 mL, 0.708 mmol), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (55 mg, 0.170 mmol at room temperature for 20 hours. The reaction mixture was diluted with water (10 mL), and extracted with ethyl acetate (50 mL). The organic extract was washed sequentially with water (3×10 mL), saturated aqueous sodium hydrogencarbonate (20 mL), and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. Purification of the residue by silica gel flash chromatography eluting with 4:96 methanol/methylene chloride afforded the title compound (67 mg, 0.121 mmol, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.19 (d, J=6.99 Hz, 3 H) 1.33 (d, J=6.99 Hz, 6 H) 2.91-3.07 (m, 1 H) 3.14-3.29 (m, 1 H) 5.50 (s, 2 H) 6.51 (d, J=8.46 Hz, 2 H) 7.12 (d, J=8.82 Hz, 2 H) 7.16-7.34 (m, 5 H) 7.63 (d, J=8.46 Hz, 1 H) 7.77 (s, 1 H) 8.50 (t, J=5.88 Hz, 1 H) 8.62 (s, 1 H) 8.82 (d, J=8.82 Hz, 1 H) 9.97 (s, 1 H); MS (ESI+) m/z 555 (M+H)+, 1109 (2M+H)+, MS (ESI−) m/z 553 (M−H)−.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1>Cl.CC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([S:5][CH2:4][CH:3]=[O:2])=[CH:7][CH:8]=1
Reactant: COc1ccc(SCC(OC)OC)cc1
Agent: Cl
Solvent: CC(C)=O
Product: COc1ccc(SCC=O)cc1
Yield: 96.8 %

Procedure:
1-[(2,2-Dimethoxyethyl)thio]-4-methoxybenzene (11.0 g) was dissolved in 1% aqueous hydrochloric acid (60 mL) and acetone (30 mL). The reaction mixture was refluxed for 2 h. Acetone was removed under reduced pressure and the residue was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel with 20% ethyl acetate in hexanes to afford the desired product (8.5 g, 97%). 1H-NMR (400 MHz, CDCl3): 9.55 (t, J=4.2 Hz, 1H), 7.36 (m, 2H), 6.84 (m, 2H), 3.79 (s, 3H), 3.40 (d, J=4.2 Hz, 2H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)#[N:21]>>[C:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:27])=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Product: N#Cc1ccc(C(=O)NC2N=C(c3ccccc3)c3ccccc3NC2=O)cc1

Procedure:
The procedure of Example 134 was carried out employing equivalent amounts of 1,3-dihydro-3-(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-cyanobenzoylchloride. The product was purified by chromatography on silica gel (5% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)C.ClC(N(C)C)=C(C)C.N1C=CC=CC=1.[NH2:37][C:38]1[N:42](C(OC(C)(C)C)=O)[N:41]=[C:40]([O:50][CH2:51][C:52]2[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[C:54]([O:60][CH3:61])[CH:53]=2)[CH:39]=1.Cl.O1CCOCC1>C1COCC1>[CH3:59][O:58][C:56]1[CH:57]=[C:52]([CH2:51][O:50][C:40]2[CH:39]=[C:38]([NH:37][C:20]([C:17]3[CH:18]=[N:19][C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)=[CH:15][CH:16]=3)=[O:22])[NH:42][N:41]=2)[CH:53]=[C:54]([O:60][CH3:61])[CH:55]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Reactant: COc1cc(COc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCNCC4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
6-[4-[(2-Methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]pyridine-3-carboxylic acid (150 mg, 0.412 mmol) was dissolved in dry THF (10 ml), 1-chloro-N,N,2-trimethyl-prop-1-en-1-amine (65 μl, 0.412 mmol) was added and the mixture was stirred at room temperature under nitrogen overnight. Pyridine (40 μl, 0.412 mmol) and tert-butyl 5-amino-3-[(3,5-dimethoxyphenyl)methoxy]pyrazole-1-carboxylate (142 mg, 0.343 mmol) were added and the mixture was stirred at 65° C. for 18 h. The mixture was then cooled to room temperature and stirred overnight with 4 M HCl in dioxane (1.8 ml, 7.20 mmol). The mixture was then filtered and the solid was washed with hexane. The product was purified on acidic prep. HPLC, eluting with a gradient of 16-26% MeCN in water (containing 0.1% TFA). The product containing fractions were neutralised with aq. NaHCO3 and the acetonitrile removed under vacuum. The product precipitated out and was collected by filtration. This was further washed with water and dried in vacuo to give the title compound (39 mg, 26%) as a white solid; 1H NMR (399.902 MHz, DMSO) δ 2.82 (t, J=5.1 Hz, 4H), 3.61 (t, J=4.8 Hz, 4H), 3.80 (s, 6H), 5.13 (s, 2H), 5.62 (bs, 1H), 6.50 (s, 1H), 6.65 (d, J=2.2 Hz, 2H), 6.92 (d, J=8.9 Hz, 1H), 8.09 (d, J=9.3 Hz, 1H), 8.76 (d, J=2.3 Hz, 1H), 10.74 (bs, 1H), 11.64 (bs, 1H). MS: m/z=439 (MH+)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][C:6]=1[OH:28])(=[O:3])[CH3:2].[C:29](Cl)([CH3:32])([CH3:31])[CH3:30]>[Cl-].[Zn+2].[Cl-].ClC(Cl)(Cl)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][C:6]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CC(C)(C)Cl
Reactant: CCCCCCCCCCCCCCCCOc1ccc(NC(C)=O)c(O)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCOc1cc(O)c(NC(C)=O)cc1C(C)(C)C
Yield: 81.3 %

Procedure:
A mixture composed of 19.6 g (0.05 mol) of 2-acetylamino-5-hexadecyloxyphenol, 20 g of tertbutyl chloride, 6 g of anhydrous zinc chloride and 60 ml of 1,1,1-trichloroethane was stirred with heating at a temperature range between 70° C. and 75° C. for 5 hours. After cooling, the excess amount of tert-butyl chloride and the solvent were removed under reduced pressure. The residue was washed with water and recrystallized from acetonitrile to obtain 18.2 g of 2-acetylamino-4-tert-butyl-5-hexadecyloxyphenol.