Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4]([OH:6])=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:7][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:2])[C:4]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:6]
Reactant: C1COCCN1
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Agent: Cl
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)N3CCOCC3)ccc21

Procedure:
The above compound was prepared from 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride and morpholine using a procedure analogous to that of Example 128.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(O)[O-].[Na+].[C-:24]#[N:25].[K+]>O.C(OCC)(=O)C>[C:24]([CH:9]([OH:10])[C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)#[N:25]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)CC1CCCCC1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of Example 1B (19.7 g, 77.1 mmol) and sodium bisulfite (8.0 g, 77.1 mmol) in water (500 mL) at 5° C. was stirred for 24 hours, warmed to room temperature, treated with a solution of potassium cyanide (5.1 g, 78.8 mmol) in ethyl acetate (350 mL), and stirred for 5 hours. The aqueous phase was separated and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide tert-butyl (1R)-2-cyano-1-(cyclohexylmethyl)-2-hydroxyethylcarbamate.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[N:11][C:10]([OH:13])=[N:9]2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[P:20](=[S:28])(Cl)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>C(#N)C>[P:20](=[S:28])([O:13][C:10]1[N:11]=[CH:12][N:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)[N:9]=1)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]
Reactant: Oc1ncn(-c2cccc(F)n2)n1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(OCC)Oc1ncn(-c2cccc(F)n2)n1
Temperature: 70 °C
Yield: 88.3 %

Procedure:
Into a 500 milliliter (ml) flask equipped with a stirrer and a reflux condenser were placed 9 grams (g) (0.05 mole (m)) of 1-(6-fluoro-2-pyridinyl)-1H-1,2,4-triazol-3-ol, 7 g (0.05 m) of potassium carbonate, 1 g of mercuric chloride and 200 mls of acetonitrile. This mixture was stirred and heated to 70° C. for two hours and allowed to cool. To this mixture was added 9 g (0.05 m) of O,O-diethyl phosphorochloridothioate and the mixture heated to 70° C. for 16 hours and allowed to cool. The insolubles were removed by filtration and the solvent was removed from the filtrate by distillation at 60° C. under reduced pressure. The oil which remained was taken up in 300 mls of methylene chloride, washed twice with 150 ml portions of water, separated, dried over anhydrous sodium sulfate, filtered and the methylene chloride was removed by distillation leaving 14 grams (84 percent of theoretical) of the desired O,O-diethyl O-(1-(6-fluoro-2-pyridinyl)-1H-1,2,4-triazol-3-yl) phosphorothioate. The product was a white solid melting at 80°-82° C. Upon analysis, the compound was found to have carbon, hydrogen and nitrogen contents of 39.33, 4.19 and 16.73 percent, respectively, as compared with the theoretical contents of 39.76, 4.25 and 16.86 percent, respectively, calculated for the above named compound. (Compound 1).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20]([OH:22])=O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@H:19]([C:20](=[O:22])[NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: Nc1ccccc1
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)Nc1ccccc1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 45 %

Procedure:
The title compound (25 mg, 45%) was prepared from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid and aniline as in Example 1, Part C. HPLC: RT=10.81 min. MS (ESI−): mass calcd. for C28H20Cl3N5O4S2, 660.98; m/z found, 658/660 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.54 (s, 1H), 8.39 (dd, J=7.1, 1.0, 1H), 8.19 (dd, J=8.8, 0.8, 1H), 7.75-7.67 (m, 2H), 7.67-7.62 (m, 1H), 7.47-7.42 (m, 2H), 7.42-7.33 (m, 4H), 7.26-7.23 (m, 1H), 7.11-7.09 (m, 1H), 6.96-6.90 (m, 2H), 4.84-4.77 (m, 1H), 3.23-3.10 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:16])=[CH:9][CH:8]=1)[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:15]2[O:14][CH2:13][CH2:12][C:11]=2[C:10]([O:16][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1OCC2)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2c1OCC2)OCC

Procedure:
In analogy to the procedure described in example 120 f], [rac]-2-ethoxy-3-(4-hydroxy-2,3-dihydro-benzofuran-7-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2,3-dihydro-benzofuran-7-yl]-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-2,3-dihydro-benzofuran-7-yl]-propionic acid as white solid.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[C:13](OCC)(=[O:16])[CH:14]=[CH2:15]>C(O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:11][C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: C=CC(=O)OCC
Reactant: CC(=O)Cc1ccc(F)cc1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(F)cc2)C(=O)C1
Yield: 10.4 %

Procedure:
Sodium (0.3 g, 0.013 moles) was dissolved in ethanol (50 ml) and 4-Fluorophenylacetone (2.0 g, 0.013 moles) was added in ethanol (10 ml). Ethyl acrylate (1.3 g, 0.013 moles) was and the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool and evaporated under reduced pressure to give a brown gum. Dissolved in water and washed with diethyl ether. The aqueous layer was acidified to pH2 with conc. Hydrochloric acid and extracted with dichloromethane. The extracts were combined and washed with water. Dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated to give an orange oil. (1.7 g) This was purified using a silica column eluted with dichloromethane:ethyl acetate 8:2 and then dichloromethane:ethyl acetate 2:1 to give a colorless gum. (0.428 g) This was triturated with diethyl ether/isohexane to give 4-(4-Fluorophenyl)cyclohexane-1,3-dione (0.28 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([N+:14]([O-])=O)[NH:12][CH:13]=2)[CH2:4][CH2:3]1.CO.C1COCC1.CO.C(N1CCN(C2C=C(N[C:41]([C:43]3[C:44]4[N:45]=[CH:46][CH:47]=[N:48][C:49]=4[C:50]([C:53]4[C:62]5[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=5)[CH:56]=[N:55][CH:54]=4)=[CH:51][CH:52]=3)=[O:42])C=CC=2)CC1)C>[Ni].C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:10]=[C:11]([NH:14][C:41]([C:43]3[C:44]4[N:45]=[CH:46][CH:47]=[N:48][C:49]=4[C:50]([C:53]4[C:62]5[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=5)[CH:56]=[N:55][CH:54]=4)=[CH:51][CH:52]=3)=[O:42])[NH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(Cc2c[nH]c(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)n2)CC1

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3, Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 8-isoquinolin-4-yl-quinoxaline-5-carboxylic acid (Example 52) in Step 14.1. Title compound: ESI-MS: 479.0 [M+H]+; TLC: Rf=0.16 (DCM/MeOH, 9:1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:44])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:43])[CH2:9][CH2:10][C@@:11]3([C:27]([NH:29][C@@H:30]4[CH2:34][CH2:33][C@H:32]([CH2:35][N:36]5[CH2:41][CH2:40][CH2:39][CH:38]([CH3:42])[CH2:37]5)[CH2:31]4)=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:46])[CH3:45].N1C=CC=CC=1.[CH3:53][C:54]1([CH3:61])[CH2:58][C:57](=[O:59])[O:56][C:55]1=[O:60]>C(OCC)(=O)C>[CH3:53][C:54]([CH3:61])([CH2:58][C:57](=[O:59])[O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:44])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:43])[CH2:9][CH2:10][C@@:11]3([C:27](=[O:28])[NH:29][C@@H:30]4[CH2:34][CH2:33][C@H:32]([CH2:35][N:36]5[CH2:41][CH2:40][CH2:39][CH:38]([CH3:42])[CH2:37]5)[CH2:31]4)[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:45])[CH3:46])[C:55]([OH:60])=[O:56]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCCC(C)C4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)CC(=O)OC1=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCCC(C)C4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-N-((1R,3S)-3-((3-methylpiperidin-1-yl)methyl)cyclopentyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example −50, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and 3,3-dimethyldihydrofuran-2,5-dione (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.80-0.95 (m, 16H) 1.23-1.90 (m, 41H); 2.03-3.08 (m, 16H), 4.13-4.18 (m, 1H), 4.46 (s, 1H), 4.58 (s, 1H), 4.72 (s, 1H); 5.61-5.63 (m, 1H); ES Mass: [M+1] 778 (100%); HPLC: 78.4%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28](OC(N[C@H](C(O)=O)CC(C)C)=O)[C:29]1C=CC=C[CH:30]=1.Cl.COC(=O)[C@H](CC(C)C)N>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][C:22]1[CH:23]=[CH:30][CH:29]=[CH:28][CH:24]=1)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
N-Benzyloxycarbonyl-L-leucyl-L-leucine (m.p. 70°-76° C.) from N-benzyloxycarbonyl-L-leucine and L-leucine methyl ester hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.F[C:21](F)(F)[S:22](O[Si](C(C)(C)C)(C)C)(=[O:24])=[O:23].CS(Cl)(=O)=O>O1CCCC1>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[C:3]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: Nc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
A solution of 4-amino-7-chloro-3-phenyl-2(1H)-quinolone (0.55 g, 2 mmol) (Example 2) and potassium (bistrimethylsilyl) amide (4 ml, 0.5M solution in toluene) in 50 ml tetrahydrofuran were stirred for 10 mins prior to the addition of tert-butyldimethylsilyl trifluoromethanesulfonate (6.1 ml). After a further 10 mins a further portion of potassium(bistrimethylsilyl)amide (6.1 ml) was added followed after 10 mins by methanesulfonyl chloride (0.48 ml). The solvent was removed in vacuo after one hour and the residue was suspended in 5N HCl (30 ml), and treated with ultrasound for 5 mins before being filtered. The solid was suspended in 1N NaOH and re-exposed to ultrasound then filtered to give the title compound (0.077 g); mp 222°-224° C. (DMF-water-diethyl ether); δ (360 MHz, DMSO-d6) 2.17 (3H, s, CH3), 7.34-7.67 (8H, m, aromatics), 9.60 (1H, br s, NHSO2), 12.16 (1H, br s, NHCO); m/z (EI) 348 (M+).
Reaction SMILES: O[C@H:2]1[C@H:9]2[C@H](O[C:7]([CH3:11])(C)[O:8]2)O[C@H]1C(O)=O.C[N:16]([C:18]([O:22]N1N=NC2C=CC=CC1=2)=[N+:19](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.N1CCOCC1>C1COCC1>[N:16]1([C:18]([NH2:19])=[O:22])[CH2:11][CH2:7][O:8][CH2:9][CH2:2]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC1(C)O[C@@H]2O[C@@H](C(=O)O)[C@@H](O)[C@@H]2O1
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: NC(=O)N1CCOCC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 134.9 %

Procedure:
To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0 g, 24.5 mmol) in THF (100 mL, 20×) was added TBTU (11.8 g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20° C. for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20° C. for an additional 6 h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2× ×2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), δ 6.02 (d, J=3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J=3.2 Hz, 1H), 4.58 (d, J=3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21]([O:23]CC)=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O>CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([C:21]([OH:23])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
Added to a 1 l flask were 40 g (0.128 mol) of the ethyl 2-(4-benzylpiperazino)-4-methylpyrimidine-5-carboxylate, 11 g of KOH, 200 ml of H2O and 500 ml of EtOH. The contents were stirred at 100° C. for 0.5 hr. Thereafter, the solvent was distilled off under reduced pressure. One liter of H2O was then added to the residue and the resulting mixture was adjusted to pH 4 with conc. hydrochloric acid. The precipitated crystals were filtered off and the filtrate was dried under reduced pressure, thereby obtaining 36 g of the intended compound as a white solid substance (yield: 98%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[CH3:35][N:36]([CH3:46])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>>[CH3:35][N:36]([CH3:46])[C:37]1[CH:42]=[C:41]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:3])=[O:34])[CH:11]=[C:12]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=3)[CH:13]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CN(C)c1cccc(B(O)O)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(N(C)C)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-dimethylamino-phenylboronic acid under the conditions described in Example 1; 1H NMR (300 MHz, MeOD) δ ppm 0.99 (dd, J=6.59, 2.45 Hz, 6H), 1.58 (dt, J=13.28, 6.73 Hz, 1H), 1.78 (ddd, J=13.75, 7.16, 6.97 Hz, 1H), 2.03-2.13 (m, 1H), 3.32 (s, 6H), 3.88 (t, J=7.72 Hz, 1H), 7.49 (d, J=7.91 Hz, 1H), 7.68-7.83 (m, 7H), 7.86-7.94 (m, 3H); Calcd for C27H28F3NO2 (M+H) 456.21, Found 456.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:50])[CH2:23][C:24]1([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])[CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:26][CH2:25]1)[CH3:20]>C(#N)C>[CH2:19]([O:21][C:22](=[O:50])[CH2:23][C:24]1([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)[CH2:25][CH2:26]1)[CH3:20]
Reactant: CCOC(=O)CC1(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)CC1
Reactant: BrCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1(CCC(/C=C/c2ccccc2OCCCCCc2ccccc2)Cc2ccc(C(=O)OC)cc2)CC1

Procedure:
273 mg (1.2 mmol) of (5-bromopentyl)benzene and 222 mg (1.6 mmol) of anhydrous potassium carbonate are added to a solution of 350 mg (0.8 mmol) of methyl 4-[(3E)-2-{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 10 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1). This gives 275 mg (58% of theory) of a solid.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.N1CCCCC1.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH2:37][C@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43](=[O:47])[CH2:44][C:45]#[N:46])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=4)=[CH:24][CH:23]=3)[C:14]=12>CO>[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH2:37][C@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43]([C:44](=[CH:4][CH:1]3[CH2:2][CH2:3]3)[C:45]#[N:46])=[O:47])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]4[CH:30]=[C:31]([F:36])[CH:32]=[C:33]([F:35])[CH:34]=4)=[CH:24][CH:23]=3)[C:14]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cc(F)cc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
Into a 10-mL round-bottom flask, was placed cyclopropanecarbaldehyde (28.7 mg, 0.41 mmol, 2.00 equiv), piperidine (17.4 mg, 0.20 mmol, 1.00 equiv), 3-[(2R)-2-([4-amino-3-[4-(3,5-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile (100 mg, 0.20 mmol, 1.00 equiv), and methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 53.12 mg (45%) of the title compound as an off-white solid. LC-MS: (ES, m/z):MS (ESI, pos. ion) m/z: 541 (M+1). H-NMR: (CDCl3, ppm): 1HNMR (300MHz, CD3OD, ppm), 8.28 3(1H, s), 7.777˜7.806 (2H,t), 7.269˜7.298 (2H,t), 6.703˜6.754 (3H,t), 6.455˜6.600 (1H,d), 4.400˜4.878 (3H,m), 3.338˜3.618(2H,m), 1.700˜2.188 (4H,m), 1.280˜1.305 (4H,m), 0.710˜0.912 (2H,m).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([O:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:8][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Solvent: Cc1ccccc1
Product: ClCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 4-(2-phenyl-4-oxazolylmethoxy)benzylalcohol (2.39 g), thionyl chloride (0.69 ml) and toluene (50 ml) was stirred at 40° C. overnight, and then the reaction mixture was concentrated. Saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 4-(4-chloromethylphenoxymethyl)-2-phenyloxazole (2.34 g, yield 92%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 129–130° C.
Reaction SMILES: C(COC1C2N=NNC=2C=CC=1)(=O)C=C.[C:16]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[C:28](C)[C:23]=2[N:22]=[N:21]1)(=[O:19])[CH:17]=[CH2:18].C(N1C(=O)CCC1=O)(=O)C=C.C(N)(=O)C=C>>[C:16]([N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)n1nnc2c(C)cccc21
Agent: C=CC(=O)COc1cccc2[nH]nnc12
Agent: C=CC(=O)N1C(=O)CCC1=O
Agent: C=CC(N)=O
Product: C=CC(=O)n1nnc2ccccc21

Procedure:
1-acryloyl methoxybenzotriazole; 1-acryloyl methylbenzotriazole; 1-acryloyl imidazolide; N-acryloyl-succinimide; N-2,4,5-trichlorophenil acrylamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1ccnc(Br)c1
Solvent: C1CCOC1
Product: CC(O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled (−78° C.) solution of 2-bromo-pyridine-4-carbaldehyde (10.0 g, 53.8 mmol) in THF (100 mL) was added a 3 M solution of methylmagnesium chloride in THF (18 mL, 54 mmol) over a 10 minute period. After 1 hour, the yellow solution was allowed to warm gradually to room temperature over a 3 hour period. The reaction was quenched by the slow addition of saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford a brown oil. The crude material was purified by silica gel chromatography eluting with a gradient of 10-45% EtOAc in hexanes to afford 1-(2-bromo-pyridin-4-yl)-ethanol.