Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16](=[O:36])[C:17](C(C)C)([NH2:32])C1C=CC(OCC3C=CC=CC=3)=CC=1)[CH:12]=[CH:11][C:10]=2[OH:37])=[O:6])[CH3:3].[CH3:38][OH:39]>[C].[Pd]>[ClH:1].[CH2:2]([O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([CH:16]([OH:36])[CH2:17][NH:32][CH:9]([CH3:10])[CH2:14][C:13]1[CH:16]=[CH:17][C:38]([OH:39])=[CH:11][CH:12]=1)[CH:12]=[CH:11][C:10]=2[OH:37])=[O:6])[CH3:3]
Reactant: CO
Reactant: CCOC(=O)c1cc2c(C(=O)C(N)(c3ccc(OCc4ccccc4)cc3)C(C)C)ccc(O)c2[nH]1
Agent: [Pd]
Agent: Cl
Product: CCOC(=O)c1cc2c(C(O)CNC(C)Cc3ccc(O)cc3)ccc(O)c2[nH]1

Procedure:
209 mg of 4-[2-(4-benzyloxyphenyl)-1-methylethyl-aminoacetyl]-7-hydroxyindole-2-carboxylic acid ethyl ester hydrochloride is hydrogenated in 20 ml of methanol for 2.5 hours at room temperature and under normal pressure in the presence of 42 mg of 10% palladium-carbon. The mixture is filtered, the filtrate is concentrated under vacuum, and the residue is recrystallized from acetone/diethyl ether, thus obtaining 115 mg of 4-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1-methylethylamino]ethyl}-7-hydroxy-indole-2-carboxylic acid ethyl ester hydrochloride, decomposition point 110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:26]N[CH2:24]3)[N:9]=2)=[CH:4][CH:3]=1.NC1(C(O)=O)C[O:30]C1.NC1(C(O)=O)CN(C(OC(C)(C)C)=O)C1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]3([CH2:26][O:30][CH2:24]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC1(C(=O)O)COC1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(CNC1)c1nnc(C)n1-2
Agent: CC(C)(C)OC(=O)N1CC(N)(C(=O)O)C1
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC1(COC1)c1nnc(C)n1-2

Procedure:
A procedure analogous to the scheme set forth for the synthesis of Compound 224 was followed, with the exception that 3-aminooxetane-3-carboxylic acid was used as starting material instead of 3-amino-1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:22]1([CH3:32])[CH2:27]C[CH:25]([CH:28](C)[CH3:29])[CH:24](O)[CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH:23]([CH:22]([CH3:32])[CH3:27])[CH2:24][CH2:25][CH:28]([CH3:29])[CH2:8]1)=[O:5])#[N:2]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1CCC(C(C)C)C(OC(=O)C(C#N)=C(c2ccccc2)c2ccccc2)C1
Reaction time: 6 h
Yield: 56.8 %

Procedure:
55.4 g (0.2 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 62.5 g of menthol and 4 g of Na2CO3 were reacted with one another at 185-200° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 6 h, the reaction mixture was cooled and distilled under reduced pressure, giving 44 g (57%) of menthyl 2-cyano-3,3-diphenylacrylate [λmax=300 nm, E11=351].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:14]([N+:23]([O-])=O)=[C:13]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[N:12]=2)=[CH:5][CH:4]=1.[Cl-].[Ca+2].[Cl-]>C(#N)C.O.[Zn]>[NH2:23][C:14]1[C:13]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[N:12][C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:16][C:15]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: COc1ccc(C=Cc2nc(N3CCOCC3)c([N+](=O)[O-])c(N3CCOCC3)n2)cc1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CC#N
Product: COc1ccc(C=Cc2nc(N3CCOCC3)c(N)c(N3CCOCC3)n2)cc1
Yield: 74.8 %

Procedure:
The synthesis method shall be explained concretely, and in order, below. A mixed solution of 2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholino-5-nitropyrimidine (1.35 g, 3.16 mmol), zinc dust (6.19 g, 94.8 mmol), and calcium chloride (224 mg, 2.02 mmol) in acetonitrile (80 ml) and water (20 ml) was refluxed under heating for 1 hour. The undissolved matter was separated out by celite filtering, the filtrate was distilled away under reduced pressure, water was added to the residue, the precipitated crystals were taken out by filtering, and 5-amino-2-[2-(4-methoxyphenyl)vinyl]-4,6-dimorpholinopyrimidine (940 mg, yield 75%) was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 131 are shown below.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:15][C:16](O)=[O:17])[C:9](=[O:10])[C:8]2=[CH:30][CH:31]=1)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:15][C:16]([NH:45][OH:46])=[O:17])[C:9](=[O:10])[C:8]2=[CH:30][CH:31]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC
Yield: 85.5 %

Procedure:
3-(4-tert-Butylphthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(4-tert-butylphthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (800 mg, 4.93 mmol) and hydroxylamine hydrochloride (377 mg, 5.43 mmol) in tetrahydrofuran (10 mL) to afford 3-(4-tert-butylphthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a white solid (1.77 g, 85% yield): mp, 127.5-129.5° C.; 1H NMR (DMSO-d6) δ1.24-1.44 (m, 12H, 4CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.66 (t, J=7.8 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.76-7.87 (m, 3H, Ar), 8.79 (br s, 1H, OH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.73, 30.76, 34.29, 35.48, 50.14, 55.46, 63.72, 111.69, 112.27, 119.59, 119.98, 123.07, 128.75, 131.28, 131.45, 131.55, 147.69, 148.49, 158.32, 166.07, 167.53, 167.85; Anal Calcd for C24H28N2O6: C, 65.44; H, 6.41; N, 6.36. Found: C, 64.34; H, 6.29; N, 7.04.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)=[CH2:6])[CH3:2].[CH:22]([Br:25])(Br)[Br:23].[OH-].[Na+]>C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[CH2:6][C:22]1([Br:25])[Br:23])=[O:21])[CH3:2]
Reactant: C=C(C(=O)OCC)c1cccc(OCc2ccccc2)c1
Reactant: BrC(Br)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(c2cccc(OCc3ccccc3)c2)CC1(Br)Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.6 %

Procedure:
Intermediates d-e were prepared following the procedure of Kirmse, W.; Rode, J. Chem. Ber. 1986, 119, 3694-3703. To absolution of 2-(3-benzyloxy-phenyl)-acrylic acid ethyl ester (250 mg, 0.89 mmol) in methylene chloride (283 uL) was added bromoform (100 uL, 1.1 mmol), benzyltriethyl ammonium chloride (2.6 mg), and sodium hydroxide (50% aqueous solution, 167 uL). The reaction was stirred at room temperature for 48 hours and then the product was extracted into diethyl ether, dried (MgSO4), and evaporated. This material was further purified by filtration through a plug of silica gel using diethyl ether as the eluant to give 358 mg (89% yield) of the title compounds as a white solid. MS (ESI) 454.8 (M+H+).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([C:52]3[CH:57]=[CH:56][C:55]([Cl:58])=[C:54]([N+:59]([O-])=O)[CH:53]=3)=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:45]=[CH:46][C:47]([S:50]([C:52]3[CH:57]=[CH:56][C:55]([Cl:58])=[C:54]([NH2:59])[CH:53]=3)=[O:51])=[CH:48][CH:49]=2)=[CH:42][CH:43]=1
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccc(-c3ccc(Br)cc3)cc2)ccc1Cl
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1cc(S(=O)c2ccc(-c3ccc(Br)cc3)cc2)ccc1Cl
Yield: 88 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 1-(4-bromophenyl)-4-(4-chloro-3-nitrophenylsulfinyl)-benzene, the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9](Cl)=[O:10])[CH2:5][CH2:4]1.[CH2:12]([O:14][C:15]#[CH:16])[CH3:13]>>[CH2:15]([O:14][C:12]1[C:6]2([CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]2)[C:9](=[O:10])[CH:13]=1)[CH3:16]
Reactant: COC1CCC(C(=O)Cl)CC1
Reactant: C#COCC
Product: CCOC1=CC(=O)C12CCC(OC)CC2

Procedure:
Was prepared from 4-methoxy cyclohexanecarbonyl chloride (10 g, 52.1 mmol) and ethoxyacetylene (7.5 g, 0.10 mol) according to the method of Intermediate 1 to give the title compound as an approx. 1:1 mixture of isomers, as a pale yellow oil (7.2 g, 34.4 mmol, 65%). δH (CDCl3, 300K) 4.81-4.79 (1H, s), 4.22-4.20 (2H q, J 7.1 Hz), 3.34-3.32 (3H, s), 3.31-3.22 (1H, m), 2.04-1.56 (8H, m), 1.44-1.43 (3H t, J 7.1 Hz); m/z (ES+, 70V) 211.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9](B(O)O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[C:19]([O-:22])(=[O:21])[CH3:20].[C:23]([O-:26])(=[O:25])[CH3:24].[C:27]([O-:30])(=[O:29])[CH3:28].C([O-])(=O)C.[Pb+4:35].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:19]([O-:22])(=[O:21])[CH3:20].[C:23]([O-:26])(=[O:25])[CH3:24].[C:27]([O-:30])(=[O:29])[CH3:28].[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]2[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([Pb+3:35])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Temperature: 25 °C
Yield: 58.3 %

Procedure:
4′-Chloro-3-ethylbiphen-4-ylboronic acid (4.2 g, 0.016 mol) is added in one portion to a mixture of lead tetraacetate (7.86 g, 0.017 mol) and mercuric acetate (0.25 g, 5 mol %) in chloroform (23 ml) under an atmosphere of nitrogen. The reaction mixture is stirred at ambient temperature until dissolution is complete, and then heated at 40° C. for 4 hours. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and the filtrate is concentrated under reduced pressure to give an orange solid. Trituration with hexane (50 ml) affords a yellow solid which is dried under high vacuum. This solid is then dissolved in chloroform (100 ml), anhydrous potassium carbonate (26.7 g, 0.19 mol) is added and the suspension is stirred rapidly for 10 minutes. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 4′-chloro-3-ethylbiphen-4-yllead triacetate (5.6 g) as a cream solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH:6]=[N:7]O.Cl.[H][H].[OH-].[Na+]>CO.[Pd].CCOCC>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1)[CH2:6][NH2:7]
Reactant: ON=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 94.2 %

Procedure:
The second step of the process of the present invention was conducted as follows. At first, 5.03 g (19.6 mol) of 3,5-bis(trifluoromethyl)benzaldehyde oxime were dissolved in methanol followed by the addition of 3.0 g (82.3 mmol) of hydrogen chloride gas and 252 mg of a catalyst (i.e., activated carbon carrying thereon 5% palladium) and stirring for 5.5 hours in a hydrogen atmosphere at 10 atm and room temperature (approx. 25° C.). After removing the catalyst, ether was added to the reaction liquid, and the reaction liquid was neutralized with aqueous sodium hydroxide solution. As a result of analyzing the separated ether layer by gas chromatography, 3,5-bis(trifluoromethyl)benzylamine was formed at a yield of 94.2%.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]2[O:26][CH3:27])(=O)=O)=CC=1.[NH3:28]>C1COCC1>[NH2:28][CH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[O:26][CH3:27]
Reactant: N
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1COS(=O)(=O)c1ccc(C)cc1
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1CN

Procedure:
A mixture of intermediate (23) (0.065 mol) in THF (250 ml) was treated with liquid NH3 in an autoclave at 125° C. during 16 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between a 5% aqueous NaOH solution and DCM. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 16 g of 1,1-dimethylethyl (trans)4-(aminomethyl)-3-methoxy-1-piperidinecarboxylate (intermediate (24).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:10]2[CH2:13][C:12]([CH3:22])([CH2:14][NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:29](I)[CH3:30]>O1CCOCC1.CN(C)C=O>[C:23]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:10]2[CH2:13][C:12]([CH3:22])([CH2:14][N:15]([C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[CH2:29][CH3:30])[CH2:11]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCI
Reactant: CC1(CNC(=O)C(F)(F)F)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCN(CC1(C)CN(C(c2ccccc2)c2ccccc2)C1)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
0.16 g (3.6 mmol) of 55% strength sodium hydride is added to a solution of 1.3 g (3.6 mmol) of 1-diphenylmethyl-3-methyl-3-trifluoroacetylaminomethylazetidine in 40 ml of dioxane and 10 ml of dimethylformamide, and the mixture is stirred for two hours at 60°-70° C. The solution is cooled to room temperature, 0.73 g (4.6 mmol) of ethyl iodide is added, the mixture is stirred for 4 hours at 70° C. and evaporated to dryness, the residue is dissolved with chloroform, the organic phase is washed with water, dried with anhydrous sodium sulphate and evaporated and 1.1 g (79%) of 1-diphenylmethyl-3-methyl-3-[N-(ethyl)trifluoroacetylaminomethyl]azetidine are obtained. This compound is dissolved in ethanol, and ethyl ether saturated with hydrochloric acid is added. The product is allowed to crystallize and is filtered off, and 1-diphenylmethyl-3-methyl-3-[N-(ethyl)trifluoroacetylaminomethyl]azetidine hydrochloride, melting point 191°-4° C., is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH:18]2[CH2:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1.OS(O)(=O)=O.CCOC(C)=O>CN1C(=O)CCC1>[Cl:22][C:23]1[N:24]=[CH:25][N:26]([C:28]2[CH:34]=[CH:33][C:31]([NH:32][C:2]3[N:3]=[C:4]([NH:17][CH:18]4[CH2:19][CH2:20][CH2:21]4)[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:6]=4[N:7]=3)=[CH:30][C:29]=2[O:35][CH3:36])[CH:27]=1
Reactant: Clc1nc(NC2CCC2)c2c(n1)C(c1ccccc1)CC2
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(NC3CCC3)c3c(n2)C(c2ccccc2)CC3)ccc1-n1cnc(Cl)c1
Temperature: 97 °C
Reaction time: 20 h
Yield: 71.6 %

Procedure:
To a mixture of 2-chloro-N-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (165 mg, 0.55 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (135 mg, 0.605 mmol) in NMP (2 mL) was added Conc. H2SO4 (0.041 mL, 0.771 mmol). The mixture was stirred at 97° C. for 20 hours. After cooled down to room temperature, 100 mL of EtOAc was added, washed with saturated NaHCO3/water and water, dried over Na2SO4, and finally removed. The residue was purified via Biotage (12 g, hexanes-80% EtOAc) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4-cyclobutyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (202 mg, 0.394 mmol, 71.6% yield). LC-MS (M+H)+=487.14. 1H NMR (500 MHz, CDCl3) δ ppm 7.92 (1H, d, J=1.8 Hz), 7.51 (1H, d, J=1.2 Hz), 7.28-7.33 (2H, m), 7.18-7.24 (3H, m), 7.13 (1H, s), 7.03 (1H, d, J=8.5 Hz), 7.01 (1H, d, J=1.2 Hz), 6.74 (1H, dd, J=8.5, 2.1 Hz), 4.64-4.80 (2H, m), 4.17-4.23 (1H, m), 3.49 (3H, s), 2.72-2.81 (1H, m), 2.61-2.71 (2H, m), 2.43-2.53 (2H, m), 2.09 (1H, td, J=8.0, 2.3 Hz), 1.92-2.04 (2H, m), 1.70-1.88 (2H, m).
Reaction SMILES: CS(O[C@H:6]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]1)(=O)=O.[Si]([N:37]=[N+:38]=[N-:39])(C)(C)C.B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:37]([C@H:6]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:7]1)=[N+:38]=[N-:39]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OS(C)(=O)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 22 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of 3β-cholest-5-en-3-yl methanesulfonate (9.30 g, 20.0 mmol) in anhydrous CH2Cl2 (100 mL), TMSN3 (2.95 mL, 22.0 mmol) was added, followed by boron trifluoride etherate (5.0 mL, 40.0 mmol). The reaction was stirred at 22° C. for 2 h. When the starting material was no longer visible by TLC analysis (hexanes), the reaction was slowly poured into saturated aqueous NaHCO3 (100 mL) and vigorously stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with diethyl ether (60 mL×2). The organic layers were combined, washed with deionized water (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product as light yellow solid. Flash column chromatography (hexanes) afforded the product (7.75 g, 94.1%) as white solid, mp 84-86° C.; 1H NMR (300 MHz, CDCl3) δ 5.38 (s, 1H), 3.26-3.15 (m, 1H), 2.28 (d, J=7.9 Hz, 2H), 2.05-0.85 (m, 38H), 0.68 (s, 3H); 13C NMR (75.4 MHz, CDCl3) δ 139.8, 122.5, 61.1, 56.7, 56.1, 50.1, 42.3, 39.7, 39.5, 38.1, 37.6, 36.6, 36.2, 35.8, 31.8, 31.7, 28.2, 28.0, 27.9, 24.2, 23.8, 22.8, 22.5, 21.0, 19.2, 18.7, 11.8; IR (film) ν max 2934, 2896, 2861, 2097, 1464, 1443, 1377, 1367, 1243, 1231 cm−1; APCI m/z 411.3607 (M+, C27H45N3 requires 411.3613).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[C:17]([CH2:18]Br)=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[C-:22]#[N:23].[Na+]>>[Br:1][C:2]1[O:3][C:4]2[C:17]([CH2:18][C:22]#[N:23])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13]
Reactant: COc1ccc(CBr)c2oc(Br)c(-c3ccccc3F)c12
Reactant: [C-]#N
Agent: [Na+]
Product: COc1ccc(CC#N)c2oc(Br)c(-c3ccccc3F)c12

Procedure:
Using the method of Example 17, 2-bromo-7-bromomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran is reacted with sodium cyanide to provide 2-bromo-7-cyanomethyl-3-(2-fluorophenyl)-4-methoxybenzofuran as a brown solid after isolation by column chromatography.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([N:17]([CH3:25])[C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@:28]1([CH3:35])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@:28]1([CH3:35])[C:29]([NH:20][C@H:19]([C:18]([N:17]([C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:25])=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:30]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CN1CCC[C@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Yield: 106.2 %

Procedure:
According to the general procedure D, from #6 (7.75 g, 21.6 mmol, 1 eq.), #152 (3.88 g, 21.6 mmol, 1 eq.), dichloromethane (100 mL), HATU (9.8 g, 25.9 mmol, 1.2 eq.), and diisopropylethylamine (11.1 g, 86.4 mmol, 4 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 20 to 55% ethyl acetate in petroleum ether) to afford #195 (11.1 g, quantitative yield) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[CH:23][C:24]3[C:28]([C:29]([O:31]C)=[O:30])=[C:27]([CH3:33])[S:26][C:25]=3[CH:34]=2)[CH:12]=1)=[O:10].O[Li].O>>[CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([C:11]1[S:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][C:17]=2[O:20][C:21]2[CH:22]=[CH:23][C:24]3[C:28]([C:29]([OH:31])=[O:30])=[C:27]([CH3:33])[S:26][C:25]=3[CH:34]=2)[CH:12]=1)=[O:10]
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)OC)c(C)sc4c3)c2s1
Agent: [Li]O
Solvent: O
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)O)c(C)sc4c3)c2s1
Yield: 73.3 %

Procedure:
This material was prepared by the hydrolysis of methyl 6-[(2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridin-7-yl)oxy]-2-methylbenzo[b]thiophene-3-carboxylate 122a (63 mg, 0.13 mmole) with LiOH.H2O (54 mg, 13 mmole) in a manner as previously described for example 11c to give a white solid (46 mg, 75%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H, d, J=5.46 Hz), 8.44 (1H, d, J=8.85 Hz), 8.03 (1H, s), 8.00 (1H, d, J=2.26 Hz), 7.38 (1H, dd, J=2.45, 9.04 Hz), 6.78 (1H, d, J=5.84 Hz), 4.35-4.25 (1H, m), 3.93-3.76 (2H, m), 3.59-3.50 (2H, m), 3.27, 3.15 (3H, s), 2.81 (3H, s), 2.11-1.83 (4H, m).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[N:10]=[C:9]([C:11]([O:14][CH3:15])([CH3:13])[CH3:12])[S:8][C:6]=2[N:7]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[CH3:15][O:14][C:11]([C:9]1[S:8][C:6]2[N:7]=[C:2]([C:26]3[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=3)[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:5]=2[N:10]=1)([CH3:13])[CH3:12]
Reactant: COC(C)(C)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: COC(C)(C)c1nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc2s1

Procedure:
Crude 4-(5-chloro-2-(2-methoxypropan-2-yl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine (60 mg) was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester via general procedure A with to get 55 mg 104 following reverse phase HPLC purification. MS (Q1) 388.2 (M)+.