Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:36]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1C[C@@H](Oc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@@H](Oc2cccc(N=C(c3ccccc3)c3ccccc3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Heat a mixture of 4-(3-bromo-phenoxy)-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 23, 0.759 g), benzhydrylideneamine (0.446 g), racemic-2,2′-bis(diphenylphosphino)-1,1′ binaphthyl (50 mg) and sodium t-butoxide (0.269 g) in toluene (20 mL) at 100° C. After 10 min., add tris(dibenzylidineacetone)-dipalladium(0) (37 mg) and heat at 100° C. After 2.5 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 35 g silica gel column eluting with dichloromethane-2M NH3 in methanol gradient to give the crude title compound (0.74 g). Mass spectrum (electrospray) m/z 471 (M+1).
Reaction SMILES: [CH3:1][N:2](C)[CH3:3].Cl.CNC.[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20](OCC)=[O:21])[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10].Cl>ClCCl>[C:9]([C:11]1[C:16]2[N:17]=[C:18]([C:20]([N:2]([CH3:3])[CH3:1])=[O:21])[O:19][C:15]=2[C:14]([F:25])=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[CH3:32])#[N:10]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: CN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reaction time: 0.42 h
Yield: 67 %

Procedure:
Under nitrogen atmosphere, trimethylamine (1.03 M n-hexane solution, 2.25 ml, 2.31 mmol) was dropwise added at room temperature to a dichloromethane (3 ml) solution of dimethylamine hydrochloride (189 mg, 2.31 mmol), followed by stilling for 25 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (250 mg, 771 μmol) was dropwise added, followed by stirring for 17 hours. After the reaction, aqueous 1N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried oil anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was suspended and washed in diethyl ether to obtain the entitled compound (167 mg, 67%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13].[OH-].[Li+]>O1CCCC1.CO>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([S:12]([NH:15][C:16]2[CH:20]=[CH:19][S:18][C:17]=2[C:21]([OH:23])=[O:22])(=[O:13])=[O:14])=[C:2]([Cl:1])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(Cl)c1
Temperature: 77.5 °C
Yield: 86.8 %

Procedure:
To a solution of 22 (272.0 mg; 0.73 mmol) in tetrahydrofuran (8 mL) and methanol (2 mL) was added aqueous lithium hydroxide (4 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a white solid (237 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12]Cl)=[C:4]([CH3:14])[N:3]=1.[CH:15]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[C:18]([CH3:19])[C:16]=1[OH:17].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][O:17][C:16]2[CH:15]=[C:22]([CH:23]([CH3:24])[CH3:25])[CH:21]=[CH:20][C:18]=2[CH3:19])=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1nc(Cl)c2ccccc2c1CCl
Reactant: Cc1ccc(C(C)C)cc1O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
A solution of 1-chloro-4-chloromethyl-3-methyl-isoquinoline (150 mg, 0.66 mmol) is added to a mixture of carvacrol (199 mg, 1.33 mmol) and CsCO3 (645 mg, 1.98 mmol) in DMF (8 ml). After stirring overnight at room temperature, water is added and the mixture is extracted with ether. The combined extracts are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is chromatographed on silica gel to give 220 mg of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline. A mixture of 1-chloro-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline (220 mg, 0.65 mmol), 5-isopropylindazole-4-boronic acid (173 mg, 0.85 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol), and Na2CO3 (1.3 ml of 2M in H2O) in dioxane (8 ml) The mixture is heated for 18 h at 100° C. After cooling to room temperature, water is added and the resulting mixture is extracted with EtOAc. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel to give 133 mg of 1-(5-isopropyl-1H-indazol-4-yl)-4-(5-isopropyl-2-methyl-phenoxymethyl)-3-methyl-isoquinoline
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](O)=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]([O:41][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH:37]([CH3:38])[CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:15][CH:16]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 563.1 (M+H)+.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][CH2:15][C:16]([C:19]1[CH:23]=[C:22]([NH:24][C:25](=[O:38])[C:26]([CH3:37])([S:28]([CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)(=[O:30])=[O:29])[CH3:27])[O:21][N:20]=1)([CH3:18])[CH3:17]>CC(C)=O.ClCCl>[CH3:17][C:16]([C:19]1[CH:23]=[C:22]([NH:24][C:25](=[O:38])[C:26]([CH3:37])([S:28]([CH:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)(=[O:30])=[O:29])[CH3:27])[O:21][N:20]=1)([CH3:18])[C:15]([OH:3])=[O:14]
Reactant: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 64 %

Procedure:
Jones reagent (1.28 mL, 10.24 mmol) is added dropwise to a solution of N-[3-(2-Hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (560 mg, 1.50 mmol) in a mixture of acetone (4 mL) and dichloromethane (4 mL) at 0° C. The reaction mixture is stirred at 0° C. for 3 minutes then room temperature for 2.5 h. After this time, the reaction mixture is diluted with acetone and filtered through celite and the celite is washed with acetone. The filtrate is concentrated under reduced pressure. The residue is dispersed in water and filtered to yield the title compound. Yield: 64%; m/z 389 [M+H].
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]2)=[O:23])[CH:36]=[CH:35][CH:34]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (10%).
Reaction SMILES: C1(OC([N:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH:13]([CH2:26][CH3:27])[C:12]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:11]2)=O)C=CC=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[CH2:31]([O:30][C:28](=[O:29])[C:12]1[C:13]([CH2:26][CH3:27])=[C:14]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:15]=[N:10][CH:11]=1)[CH3:32]
Reactant: CCOC(=O)C1=CN(C(=O)Oc2ccccc2)C=C(OCCc2cccc(Cl)c2)C1CC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)c1cncc(OCCc2cccc(Cl)c2)c1CC
Temperature: 25 °C

Procedure:
The title compound of step 2 (80 mg, 0.175 mmol)) was dissolved in dichloromethane. 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (80 mg, 0.35 mmol) was added and the mixture was stirred over night at room temperature. The mixture was partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution with addition of some sodium sulfit. The combined organic extracts were dried over sodium chloride and evaporated to dryness in vacuo. The material was titured with diethyl ether, the solid material was separated by suction filtration, the filtrate was evaporated to dryness, again, to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[CH:18]=2)[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#C/C(=C\c1cccc(Br)c1)c1ccc(Cl)cc1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 40.1 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-bromo-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (2 g, 5.9 mmol) prepared in Example 66a, AgF (1.5 g, 12 mmol), and triethylamine (2.7 mL, 20 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.3 g, 40%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]([CH3:19])[C:10]=2[CH3:20])[CH:6]=[CH:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH3:19])[C:10]([CH3:20])=[C:9]2[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)([CH3:29])[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)c2cc(O)ccc2n1C
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1cccc(C(F)(F)F)c1)c(C)n2C

Procedure:
The above compound was prepared from 3-(3-trifluoromethyl-phenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3]1.[NH:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:14]1([C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)=[O:13])[CH2:19][CH2:18][CH2:17][C@@H:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH2:26][C@H:15]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Cn1cc(C(=O)O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)c2ccccc21
Yield: 26 %

Procedure:
The title compound is prepared from 1-methyl-1H-indole-3-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 26% of theory; LC (method 4): tR=2.02 min; Mass spectrum (ESI+): m/z=331 [M+H]+.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28]([OH:30])=[O:29])[CH:18]=[CH:19][CH:20]=1.[C:31]1([C:37]([CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)O)=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[C:28]([O:30][CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:37](=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:29])[CH:18]=[CH:19][CH:20]=1
Reactant: COc1cccc(CC2CCCCC2C(=O)O)c1
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc(CC2CCCCC2C(=O)OC(C(=O)c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (501 mg) was added to a stirred solution of 2-[(3-methoxyphenyl)methyl]cyclohexanecarboxylic acid (500 mg), benzoin (427 mg), and 4-dimethylaminopyridine (12.2 mg) in dichloromethane (10 ml) under ice cooling. The resulting mixture was stirred at the same temperature for 2 hours and at room temperature for 1 hour, and then a mixture of ethyl acetate and 1N hydrochloric acid was added thereto. The organic layer was separated, washed successively with 1N hydrochloric acid, sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed over silica gel using n-hexane--toluene as an eluent to afford 2-oxo-1,2-diphenylethyl 2-[(3-methoxyphenyl)-methyl]cyclohexanecarboxylate (455 mg) as a colorless oil.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:9][CH:8]=1)(C)C.[OH-].[Na+]>ClCCl.CO>[C:6]([C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(CN2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.75 g (2.91 mmol) of 1-(4-trimethylsilanylethynylbenzyl)pyrrolidine in 10 mL of dichloromethane and 10 mL of methanol is combined with 2.4 mL of a 1M sodium hydroxide solution and stirred for 3 hours at ambient temperature. The reaction mixture is evaporated down and the residue is extracted with water and ethyl acetate. The organic phase is stirred with activated charcoal, filtered, and then dried over sodium sulfate. Yield: 0.4 g (74.1% of theory); C13H15N (M=185.27); calc.: molecular ion peak (M+H)+: 186; found: molecular ion peak (M+H)+: 186.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O-:12])=[O:11])=[C:7]([N:13]([CH:23]2[CH2:28][CH2:27][P:26]([O:30][CH3:31])(=[O:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.[Li+].[OH-].Cl>CO.C1COCC1>[CH3:32][C:2]([CH3:1])([CH3:33])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([CH:23]2[CH2:28][CH2:27][P:26]([O:30][CH3:31])(=[O:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1
Reactant: COP1(=O)CCC(N(c2cc(C#CC(C)(C)C)sc2C(=O)[O-])C(=O)[C@H]2CC[C@H](C)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COP1(=O)CCC(N(c2cc(C#CC(C)(C)C)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(1-methoxy-1-oxo-1λ5-phosphinan-4-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylate (36 mg, 0.07 mmol) was dissolved in 1 mL of methanol and 1 mL of THF, and to the solution was added 0.2 mL of 1 N LiOH. The reaction mixture was stirred at room temperature for 5 hours, and then cooled to 0° C. and neutralized with 0.4 mL of 0.5 N HCl. After removal of solvent, the residue was purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid), resulting in 20 mg (57%) of the title compound. MS (m/z): 494.2 [M+H]+; HPLC retention time: 4.144 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])=[CH:24][CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:25]4[S:26][C:22]([C:20](=[O:21])[C:19]([F:18])([F:36])[F:37])=[CH:23][CH:24]=4)[CH:28]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 5 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described in example 8 step 6 (8 mg, yield 5%). 1H NMR (400 MHz, DMSO-d6) δ 8.53-8.50 (t, J=6.2 Hz, 1H), 8.21 (m, 1H), 8.17-8.16 (m, 1H), 8.03-7.98 (m, 4H), 7.93-7.91 (m, 1H), 7.88-7.87 (d, J=4.3 Hz, 1H), 7.63-7.59 (t, J=7.8 Hz, 1H), 7.34-7.30 (t, J=8.8 Hz, 2H), 3.52-3.50 (d, J=6.4 Hz, 2H), 1.29 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13]Br)[N:8]=2)[N:3]=1.[Cl:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][Cl:21]>CN(C)C(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:18]([CH2:19][CH2:20][Cl:21])[CH2:17][CH2:16][Cl:15])[N:8]=2)[N:3]=1
Reactant: ClCCNCCCl
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CN(CCCl)CCCl)cnc2n1
Reaction time: 5 h

Procedure:
To a stirred solution of 2.4 g (9.4 mmol) of 2,4-diamino-6-(bromomethyl)pteridine in 50 ml of N,N-dimethylacetamide was added 6 g (0.04 mol) of bis-(2-chloroethyl)amine, and the mixture was stirred at 50°-55° C. for 5 hours and then for 18 hours at room temperature. After filtering from a small amount of dark insoluble matter, the filtrate was diluted with 200 ml of water whereupon 2,4-diamino-6-bis(2-chloroethyl)-aminomethylpteridine separated as a light tan solid which was filtered, washed thoroughly with water and air dried; yield, 0.92 g (31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C1(S)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:44])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN(c2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cs1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ccc(-c3ccc(F)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
2-{[4-(2-{(4′Fluorobiphenyl-4-yl)[(2-nitrophenyl)sulfonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (675 mg) synthesized in Example 256-2 and thiophenol (169 mg) were dissolved in N,N-dimethylformamide (5 mL), potassium carbonate (425 mg) was added, and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (454 mg) as a colorless oil.
Reaction SMILES: [BrH:1].[C:2]([C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([C:21](=[O:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@@H:15]2[O:24][C@@H:16]2[CH2:17]1)[CH2:12][CH2:11]3)#[N:3]>C(Cl)(Cl)Cl>[Br:1][C@H:16]1[CH2:17][C@@:18]2([CH3:19])[C@@H:13]([CH2:12][CH2:11][C@@H:10]3[C@@H:20]2[C:21](=[O:23])[CH2:22][C@@:5]2([CH3:6])[C@H:7]3[CH2:8][CH2:9][C@@H:4]2[C:2]#[N:3])[CH2:14][C@@H:15]1[OH:24]
Reactant: Br
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Solvent: ClC(Cl)Cl
Product: C[C@]12C[C@H](Br)[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C#N)[C@@]3(C)CC(=O)[C@@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous 48% hydrobromic acid (60 ml.) was added to a solution of 17β-cyano-2α,3α-epoxy-5α-androstan-11-one (3.03g.) in chloroform (175ml.) and the mixture stirred at room temperature for 1 hr. The organic phase was separated, washed with aqueous 10% sodium bicarbonate and water and dried. Filtration and evaporation followed by preparative t.l.c. afforded the pure title compound as a white froth (2.16g.); [α]D + 68.5°, (c 0.6).