Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([OH:50])[C@@H:20]([NH:28][C:29](=[O:49])[C@H:30]([C:42]([S:45]([CH3:48])(=[O:47])=[O:46])([CH3:44])[CH3:43])[NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH2:59][C:60](O)=[O:61]>>[C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][N:9]1[CH2:18][C@@H:19]([O:50][C:60](=[O:61])[CH2:59][O:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53][O:52][CH3:51])[C@@H:20]([NH:28][C:29](=[O:49])[C@H:30]([C:42]([S:45]([CH3:48])(=[O:46])=[O:47])([CH3:44])[CH3:43])[NH:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]#[N:40])[CH:34]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cccc(C#N)c1)C(C)(C)S(C)(=O)=O
Reactant: COCCOCCOCC(=O)O
Product: COCCOCCOCC(=O)O[C@H](CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1cccc(C#N)c1)C(C)(C)S(C)(=O)=O

Procedure:
Example 160, [M+H]+ 868.5, was prepared in a manner analogous to Example 147 starting from N-tert-butyl-2-[3(S)-[[N-(3-cyanobenzoyl)-3-(methanesulfonyl)-L-valyl]amino]-2(R)-hydroxy-4-phenylbutyl]-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydro-3(S)-isoquinolinecarboxamide (Example 39) and 2-[2-(2-methoxyethoxy)ethoxy]acetic acid (Aldrich 40,7000-3).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]=1.[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15].O>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:17])[C:14]([NH:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)=[O:15]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc(C)nc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C)nc(NC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of 57% sodium hydride in mineral oil (38.0 gm, 0.90 mole) in dry toluene (600 ml) at 75° under nitrogen atmosphere is added in small portions 2-amino-4,6-dimethylpyridine (52.5 gm, 0.43 mole). The reaction is heated to 100° for one hour and then cooled to 90°. A solution of dimethyl carbamoyl chloride (47.0 g, 0.43 m) in toluene (150 ml) is added dropwise over a one and one-half hour period. Stir for two hours and then cool to ambient temperature. Water (150 ml) is added, the organic layer separated, dried over anhydrous sodium sulfate filtered through charcoal and evaporated. The residue is triturated with cyclohexane (50 ml) and filtered to give analytically pure product (74.0 g., 85% yield), m.p. 105°-108° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>CO>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: Fc1cccc(CBr)c1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3cccc(F)c3)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a mixture of 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (4.2 mg, 0.016 mmol) described in Manufacturing Example 5-1-1 and methanol (0.4 mL) was added 1 N aqueous sodium hydroxide solution (16 μL, 0.016 mmol), which was then concentrated under a reduced pressure. To a mixture of the residue and N,N-dimethylformamide (0.5 mL) was added 3-fluorobenzyl bromide (2.3 μL, 0.019 mmol), which was stirred for 1 hour at room temperature. The reaction mixture was purified directly by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (4.3 mg, 55%) as a trifluoroacetic acid salt.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl[CH2:30][CH2:31][S:32][CH3:33].[Cl-].[NH4+]>CS(C)=O>[CH3:7][C:8]1[N:12]([CH2:30][CH2:31][S:32][CH3:33])[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CSCCCl
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)c1c(-c2ccccc2)c(C(=O)OCC)n(CCSC)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Potassium t-butoxide (224 mg, 2.00 mmol) was added to a solution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (500 mg, 1.66 mmol) in dry dimethylsulfoxide (10 mL) at 10° C. over 5 min. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min before cooling again to 10° C. 1-Chloro-2-methylsulfanyl-ethane (200 mg, 1.81 mmol) was added slowly and the reaction mixture then stirred at ambient temperature for 72 h. Saturated aqueous ammonium chloride was added and the mixture extracted with diethyl ether. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. Purification by flash column chromatography over 100-200 mesh silica gel by eluting with 5%-7% ethyl acetate in petroleum ether afforded diethyl 5-methyl-1-(2-methylsulfanylethyl)-3-phenyl-pyrrole-2,4-dicarboxylate (420 mg, 68%) as a liquid.
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][NH:17][CH2:16][CH2:15][NH:14]2)=[CH:9][CH:8]=1)[CH3:6].C(N(CC)CC)C.[Cl:26][C:27]1[N:32]([CH3:33])[C:31](=[O:34])[CH:30]=[C:29]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[N:28]=1>O1CCCC1>[ClH:26].[ClH:1].[ClH:26].[CH3:6][N:5]([C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[NH:14][CH2:15][CH2:16][N:17]([C:27]3[N:32]([CH3:33])[C:31](=[O:34])[CH:30]=[C:29]([C:35]4[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=4)[N:28]=3)[CH2:18]2)=[CH:11][CH:12]=1)[CH3:4]
Reactant: CN(C)c1ccc([C@H]2CNCCN2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)c1ccc([C@H]2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCN2)cc1
Reaction time: 10 h
Yield: 163.7 %

Procedure:
To a suspension of (S)-2-(4-(N,N-dimethylamino)phenyl)piperazine trihydrochloride (115 mg, 0.365 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.28 mL, 2.0 mmol) and then 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (74 mg, 0.33 mmol) at room temperature. After stirring for 10 h, the resulting mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and saturated sodium bicarbonate aqueous solution, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated in vacuo to yield crystals, which were washed with diisopropyl ether. After the crystals were dissolved in ethyl acetate, the solution was treated with 4 N hydrogen chloride in ethyl acetate. White precipitate was collected and dried in vacuo to afford (S)-2-(3-(4-(N,N-dimethylamino)phenyl) piperazin-1-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one trihydrochloride (135 mg, 81%).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[OH:32][C:33]1[N:34]=[N:35][C:36]([OH:39])=[CH:37][CH:38]=1.N1C=CC=CC=1>C(O)C>[OH:26][C@:24]1([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22][C:21]2[CH:30]=[CH:31][C:18]([S:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)(=[O:17])=[O:16])=[CH:19][C:20]=2[C@H:25]1[O:39][C:36]1[N:35]=[N:34][C:33]([OH:32])=[CH:38][CH:37]=1
Reactant: Oc1ccc(O)nn1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2[C@@H]2O[C@@]21C
Solvent: c1ccncc1
Solvent: CCO
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccc(O)cc3)cc2[C@@H](Oc2ccc(O)nn2)[C@]1(C)O
Yield: 44.5 %

Procedure:
(3S,4S)-6-(4-tert-Butyldimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.35 g) (see Preparation 14) and 3,6-dihydroxypyridazine (0.273 g) were suspended in absolute ethanol (3 ml), dry pyridine (0.065 ml) was added and the mixture was heated under reflux for 4 days. The solvent was then removed under reduced pressure and the residue chromatographed on silica with 1:99 methanol:ethyl acetate as the eluent to yield (3S,4R)-3,4-dihydro-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-4-(3-hydroxypyridazin-6-yl)oxy-2,2,3-trimethyl-2H-benzo[b]pyran (0.155 g) as a white solid, m.p. >200° C. Found: C,57.54; H,5.35; N,5.57. C22H22N2O7S, 0.20 ethyl acetate requires C,57.50; H,4.99; N,5.88%.
Reaction SMILES: C1C=C2N=NN(O)C2=CC=1.O.C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[NH2:35])[C:29]([OH:31])=O.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CN(C=O)C.O>[NH2:25][C:26]1[CH:27]=[C:28]([C:29]([N:40]2[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]2)=[O:31])[CH:32]=[CH:33][C:34]=1[NH2:35]
Reactant: Nc1ccc(C(=O)O)cc1N
Reactant: CN1CCNCC1
Agent: CCOC(=O)Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCN(C(=O)c2ccc(N)c(N)c2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 17.8 %

Procedure:
HOBT monohydrate (2.00 g, 13.1 mmol) was dissolved in DMF (20 mL), and the solution was added with triethylamine (2.54 mL, 18.2 mmol) and ethylchloroformate (1.24 mL, 13.0 mmol), followed by stirring at 0° C. for 3 hours. Then, the mixture was added with triethylamine (4.22 mL, 30.3 mmol) and 3,4-diaminobenzoic acid (1.86 g, 12.2 mmol), followed by stirring at the same temperature for 2 hours. The mixture was added with a solution of N-methylpiperazine (1.21 mL, 10.9 mmol) in DMF (20 mL), followed by further stirring for 30 minutes. The reaction mixture was added with water (2 mL) and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=50/0.5/0.5-7/0.5/0.5) and preparative thin-layer chromatography (chloroform/methanol/7 mol/L ammonia-methanol solution=4/0.5/0.5) to obtain (3,4-diaminophenyl)(4-methylpiperazin-1-yl)methanone (455 mg, yield 18%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([NH:37][CH2:16][O:15][C:4]1[CH:5]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:7]=[CH:2][N:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC(C)(C)OC(=O)c1ccnc(OCNCc2ccccc2)c1

Procedure:
t-Butyl 2-chloro-6-methoxypyridine-4-carboxylate (1.0 g) (D60) was heated in benzylamine (20 mL) for 16.5 h at 140° C. After cooling, the mixture was poured into citric acid solution (10% aq.) and extracted twice with ether. The combined extracts were washed with water and brine, dried (MgSO4) and evaporated to a yellow gum. This was chromatographed on silica, eluting with hexane/ether, giving the title compound (D54) as an off-white solid (0.411 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:26])=O>CN(C=O)C>[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCN(C)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCN(C)CC1
Yield: 23 %

Procedure:
A mixture of 6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (500 mg, 1.57 mmol), thionyl chloride (20 ml) and DMF (3 drops) was heated at reflux for 3 hours and allowed to cool. The excess thionyl chloride was removed by evaporation, and the residue was azeotroped with toluene. The residue was treated with aqueous sodium hydrogen carbonate and the product was extracted with methylene chloride. The combined extracts were washed with brine, passed through phase separating paper and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline (120 mg, 23%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[CH:11]=[N:10]2)[CH:6]=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:20][C:2]([F:1])([F:19])[C:3]1[N:8]=[C:7]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[N:10]2)[CH:6]=[N:5][CH:4]=1
Reactant: CCOC(=O)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cnn(-c2cncc(C(F)(F)F)n2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Under N2, ethyl 1-(6-(trifluoromethyl)pyrazin-2-yl)-1H-pyrazole-4-carboxylate (155 mg, 542 μmol, Eq: 1.00) was dissolved in DMF (9.3 ml) and Water (9.3 ml). Potassium carbonate (150 mg, 1.08 mmol, Eq: 2) was added and the RM was stirred at 70° C. overnight. Control with LC-MS: Pr/SM: 74/26. Potassium carbonate (150 mg, 1.08 mmol, Eq: 2) was added and the RM was stirred at 70° C. overnight. Control with LC-MS: SM/Pr:4/96. At RT, the RM was partitioned between 1M K2CO3 and EtOAc; extracted; the water layer was acidified with 1M HCl; extracted with EtOAc; the organic phase was dried over MgSO4; filtered; concentrated in vacuo leading to 132 mg off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH2:22].[C:23](OC(C)(C)C)(=[O:28])[CH2:24][C:25]([CH3:27])=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]2=3)(=[O:9])=[O:10])=[CH:4][C:3]=1[NH:22][C:23](=[O:28])[CH2:24][C:25](=[O:26])[CH3:27]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Yield: 79.2 %

Procedure:
To 2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenylamine (1.0 g, 3 mmol, step 4B) in dry toluene (60 mL) was added tert-butyl acetoacetate (0.75 mL, 4.5 mmol) and 4-dimethyl-aminopyridine (0.37 g, 3 mmol). The mixture was refluxed under N2 for 16 hrs. After the removal of toluene, the reaction residue was repartitioned with ethyl acetate (100 mL) and water (50 mL). The organic layer was washed with sat. NH4Cl (2×50 mL) and brine (2×50 mL) and was dried over MgSO4. Concentration and purification by silica gel column chromatography eluting with hexane/ethyl acetate (3/1 to 1/1) yielded N-[2-chloro-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-3-oxo-butyramide as yellowish solid (1.0 g). MS: 421.0 (M+H)+; tR=2.74 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:23][C@@H:24]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]1.C(Cl)Cl>CN(C=O)C.[I-].[K+]>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:23][C@@H:24]3[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[CH3:15]
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: Cc1c(Cl)c2c(=O)[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(Cl)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc2n(C)c1=O
Temperature: 120 °C
Reaction time: 12 h
Yield: 38.4 %

Procedure:
5-Chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (8.3 g, 36.8 mmol, 1 eq, compound 8D), cesium carbonate (47.9 g, 147.5 mmol, 4e q) and potassium iodide (30 mg, cat) were stirred in anhydrous DMF (180 mL, 0.4 M) containing 4 Å molecular sieves (2.49 g) under N2. After 15 minutes (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (25.1 mL, 184 mmol, 5 eq) was added and the mixture stirred at 120° C. for 12 hours. DCM (150 mL) was added and the organic layer washed with water (150 mL) dried over magnesium sulfate and evaporated. The residue was purified by silica chromatography using 0-70% EtOAc/Hexane as eluent to give 4.8 g of product. [M+H] calc'd for C15H18ClN3O4, 340; found, 340.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[O:18][C@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[O:7])[CH2:3]1.F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1>>[CH3:17][S:14]([C:12]1[CH:11]=[CH:10][C:9]([O:18][C@H:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])=[C:8]([C:6]([N:4]2[CH2:3][CH:2]([O:1][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:5]2)=[O:7])[CH:13]=1)(=[O:15])=[O:16]
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1)C(F)(F)F
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Yield: 9 %

Procedure:
Prepared in analogy to Example 21(b) from (3-hydroxy-azetidin-1-yl)-[5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone and 4-fluorobenzotrifluoride. The crude material was purified by flash chromatography (methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 9%). MS (m/e): 512.3 (M+H+, 100%).
Reaction SMILES: OC1C(C(C)(C)C)=CC(C=NO)=CC=1C(C)(C)C.Cl[C:20](=[N:33][OH:34])[C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([Cl:32])[CH:22]=1.[CH2:35]([N:38]=[C:39]=[S:40])[CH:36]=[CH2:37]>>[Cl:32][C:23]1[CH:22]=[C:21]([C:20]2[CH2:37][CH:36]([CH2:35][N:38]=[C:39]=[S:40])[O:34][N:33]=2)[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]=1[OH:31]
Reactant: CC(C)(C)c1cc(C(Cl)=NO)cc(Cl)c1O
Reactant: C=CCN=C=S
Agent: CC(C)(C)c1cc(C=NO)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C2=NOC(CN=C=S)C2)cc(Cl)c1O

Procedure:
A 25 g. portion of 4-hydroxy-3,5-bis(t-butyl)benzaldoxime was chlorinated as in Example 1 to produce 1 g. of α,3-dichloro-4-hydroxy-5-(t-butyl)benzaldoxime by chlorination and rearrangement. The intermediate was reacted with an excess of allylisothiocyanate to produce 1 g. of product, an oily liquid, NMR singlets at 1.41 and 6.18 ppm., multiplets at 2.92-3.93, 4.68-5.23 and 7.5-7.63 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]2[O:9][C:4]3[CH:3]=[C:2]([Br:1])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:25][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: Nc1ccc(Br)cc1O
Product: Brc1ccc2nc(-c3ccc(OCc4ccccc4)cc3)oc2c1

Procedure:
Preparation is carried out analogously to 4.1.a from 4-bromo-2-hydroxy-aniline and 4-benzyloxybenzoic acid.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21](B(O)O)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:20]=[N:19][CH:18]=[C:17]([Cl:16])[CH:22]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cncc(Cl)c1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(Cl)c2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 3-chloropyridine-5-boronic acid (0.381 g, 2.42 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 19.5 h to give 4-chloro-2-(5-chloropyridin-3-yl)-5,7-difluoro-3-methylquinoline as an off white solid. Mass Spectrum (ESI) m/e=325.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:28][C:29]([NH:31][C@H:32]([C:41](O)=[O:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:41](=[O:42])[C@H:32]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[NH:31][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 59.5 %

Procedure:
In 15 ml of dichloromethane were dissolved 1.65 g of (S)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid tert-butyl ester and 1.9 g of N-benzyloxycarbonyl-L-tyrosine. To the solution was added, while stirring for one hour, 1.44 g of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, and the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure to leave an oily substance, which was dissolved in ethyl acetate. The organic layer was washed with a 5% aqueous solution of potassium hydrogen carbonate and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (eluent: ethyl acetate: hexane=7:3) to afford 2.0 g of (S)-4-(N-benzyloxycarbonyl-L-tyrosyl)-3-methoxycarbonylmethyl-2-oxopiperazine-1-acetic acid tert-butyl ester as a colorless oily product. IR γmax cm-1 : 3332, 2952, 1740, 1646, 1613, 1514, 1444, 1367, 1227, 1153. NMR(CDCl3) δ: 1.46(9H,s), 2.30-2.53(1H,m), 2.72-3.13(5H,m), 3.50-3.72(2H,m), 3.63(3H,s), 3.85(1H,d,J=12 Hz), 4.07(1H,d,J=12 Hz), 4.70-4.90(1H,m), 4.90-5.05(1H,m), 5.11(2H,s), 5.50-5.67(2H,m), 6.76(2H,d,J=8.2 Hz), 7.03(2H,d,J=8.2 Hz), 7.36(5H,s).
Reaction SMILES: [C:1]1(C)[C:2](C)=CC=C[CH:6]=1.C(Br)CBr.[C:13]1(/[CH:19]=[CH:20]/[CH2:21][CH2:22][CH2:23][OH:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+]>O.CCOCC>[CH3:2][C:1]([CH:23]([OH:24])[CH2:22][CH2:21]/[CH:20]=[CH:19]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH2:6]
Reactant: OCCC/C=C/c1ccccc1
Reactant: Cc1ccccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: BrCCBr
Product: C=C(C)C(O)CC/C=C/c1ccccc1
Temperature: 25 °C

Procedure:
Magnesium (a) (12.5 g) was flame dried in a 250 ml 3-necked flask equipped with mechanical stirrer, reflux condenser, and addition funnel. The magnesium was covered with 52 ml of dry tetrahydrofuran (b) and reaction was initiated by the addition of ca. 0.5 ml of ethylene dibromide under a nitrogen atomosphere. To the stirred mixture was added 30.9 g of 2-bromopropene (c) dropwise at a rate which maintained reflux without external heating. After the addition, the Grignard solution was stirred until it had cooled to room temperature (0.5-1 hour) and then cooled to -15°. Then 27.35 g of trans-5-phenyl-4-pentenal (d) was added dropwise over 15 minutes. After the resultant green mixture was stirred at room temperature for 2 hours, 130 ml of a saturated solution of ammonium chloride was added followed by 200 ml of water. The layers were separated and the aqueous portion extracted with ether (3×200 ml). The organic layer were worked up in the usual manner to give after evaporation, the alcohol as an orange liquid (33 g). TLC; silica gel HF254 ; ethyl acetate/benzene 2:8 Rf 0.45.