Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:14]2[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([C:22]([OH:24])=O)[CH:15]=2)=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.C([O:27][C:28](=[O:41])[C@H:29]([OH:40])[C@H:30]([NH2:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:28]([C@H:29]([OH:40])[C@H:30]([NH:39][C:22]([C:16]1[CH:17]=[C:18]([F:21])[C:19]([F:20])=[C:14]([C:9]2[C:8]([C:6]([OH:5])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=1)=[O:24])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:38])([OH:41])=[O:27]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1cc(C(=O)O)cc(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](Cc1ccccc1Cl)[C@@H](O)C(=O)O)c1cc(F)c(F)c(-c2ccccc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 6.6 %

Procedure:
5′,6′-Difluoro-biphenyl-2,3′-dicarboxylic acid 2-t-butyl ester (60 mg, 180 μmol, 1.0 eq.), (2R,3R)-3-amino-4-(2-chloro-phenyl)-2-hydroxy-butyric acid ethyl ester (46.3 mg, 180 μmol, 1.0 eq.), DIPEA (94 μL), and HATU (68.4 mg, 180 μmol) were combined in DCM (2 mL) and was stirred for 45 minutes at room temperature. The reaction was quenched with saturated NH4Cl and extracted with DCM, dried and evaporated. 1:1 DCM:TFA (0.5 mL each) was added and the mixture was stirred for 30 minutes. The solvent was evaporated under vacuum. THF (2 mL) and 10N NaOH (0.3 mL) were added and the mixture was stirred for 2 hours. The reaction was quenched with AcOH and the product was purified by preparative HPLC to yield the title compound (5.8 mg, 97% purity). MS m/z [M+H]+ calc'd for C24H18ClF2NO6, 490.08. found 491.
Reaction SMILES: C([S:4][CH2:5][CH:6]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][CH2:10][C@@H:9]([C:20]([O:22]CC2C=CC=CC=2)=[O:21])[NH:8][C:7]1=[O:30])(=O)C.O.[OH-].[Li+].Cl>>[SH:4][CH2:5][CH:6]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][CH2:10][C@@H:9]([C:20]([OH:22])=[O:21])[NH:8][C:7]1=[O:30]
Reactant: CC(=O)SCC1CCCCCCCCSC[C@@H](C(=O)OCc2ccccc2)NC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C1N[C@H](C(=O)O)CSCCCCCCCCC1CS
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzyl (3R)-6-(acetylthiomethyl)-5-oxo-1-thia-4-azacyclotetradecane-3-carboxylate (Isomer A), (0.11 g, 0.25 mmol) is dissolved in nitrogen degassed tetrahydrofuran (5 ml) and water (1 ml). Lithium hydroxide monohydrate (0.032 g, 0.75 mmol) is added and the mixture is stirred for 3 hours at room temperature. The mixture is poured into 1N hydrochloric acid and extracted with ethyl acetate (2×50 ml). The combined organic layers are washed with brine (1×50 ml), dried (MgSO4) and the solvent is evaporated. The product is triturated from diethyl ether/hexane (1:1) to give (3R)-6-mercaptomethyl-5-oxo-1-thia-4-azacyclotetradecane-3-carboxylic acid (Isomer A), m.p. 165°-168° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]=[C:8]([S:10][CH3:11])[N:7]=[C:6]([CH2:12][C:13](=[O:15])[CH3:14])[CH:5]=1>O1CCOCC1>[Br:1][CH:12]([C:6]1[CH:5]=[C:4]([CH3:3])[N:9]=[C:8]([S:10][CH3:11])[N:7]=1)[C:13](=[O:15])[CH3:14]
Reactant: CSc1nc(C)cc(CC(C)=O)n1
Reactant: BrBr
Solvent: C1COCCO1
Product: CSc1nc(C)cc(C(Br)C(C)=O)n1
Temperature: 25 °C

Procedure:
Bromine (1.46 ml, 28.5 mmol) is added to a rapidly stirred cooled (5-10° C.) solution of 1-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-propan-2-one (7.0 g, 35 mmol) in dioxane (100 ml) over 30 minutes. The reaction is allowed to warm to room temperature and the solvent is removed in vacuo to yield the titled compound which is used immediately in the next step.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([C@H:21]([N:23]2[CH2:28][CH2:27][O:26][C@@H:25]([C:29]3[CH:34]=[CH:33][C:32]([NH:35][C@@H:36]4[CH2:40][CH2:39][O:38][CH2:37]4)=[CH:31][CH:30]=3)[CH2:24]2)[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C=O>ClC(Cl)C>[CH3:1][N:35]([C:32]1[CH:33]=[CH:34][C:29]([C@@H:25]2[O:26][CH2:27][CH2:28][N:23]([C@@H:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH3:22])[CH2:24]2)=[CH:30][CH:31]=1)[C@@H:36]1[CH2:40][CH2:39][O:38][CH2:37]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N[C@@H]3CCOC3)cc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N(C)[C@@H]3CCOC3)cc2)C1
Reaction time: 2 h
Yield: 99.8 %

Procedure:
Sodium triacetoxyborohydride (2.4 g, 11.3 mmol) was added to a solution of 4-((1R)-1-phenylethyl)-(2S)-2-(4-(N-((3R)-tetrahydrofuran-3yl)amino)phenyl)morpholine (1.3 g, 3.69 mmol) and formalin (35%, 1.6 g, 18.6 mmol) in dichloroethane (50 mL) at room temperature. After stirring for 2 hours, the resulting suspension was partitioned between ethyl acetate and 1 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish (2S)-2-(4-(N-methyl-N-((3R)-tetrahydrofuran-3-yl)amino)phenyl)-4-((1R)-1-phenylethyl)morpholine (1.35 g, 100%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([NH2:11])=[O:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([N:6]1[CH2:5][C:4](=[O:7])[N:3]([CH2:8][C:9]([NH2:11])=[O:10])[C:2]1([CH3:12])[CH3:1])(=[O:15])[CH3:14]
Reactant: CC1(C)NCC(=O)N1CC(N)=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CC(=O)N(CC(N)=O)C1(C)C

Procedure:
A solution of 2,2 dimethyl-5-oxo-1-imidazolidineacetamide (1.7 g) in acetic anhydride (9 ml) was stirred at 70°-80° C. for 5 minutes. The precipitate was collected and washed with acetone, affording the title compound as a white powder, m.p. 188°-189° C. (ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:29])[CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:28])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=2)[CH:18]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:36][CH2:35]1)(=[O:33])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][C:10](=[O:11])[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:26])[NH:47][C:44]3[CH:45]=[CH:46][C:41]([CH2:40][N:37]4[CH2:36][CH2:35][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:39][CH2:38]4)=[CH:42][CH:43]=3)=[CH:21][CH:20]=2)[C:16]([Cl:28])=[CH:15][CH:14]=1)[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(CC(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(S(C)(=O)=O)CC4)cc3)cc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5′-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-2′-chloro-biphenyl-4-carboxylic acid (85 mg), 4-(4-methanesulfonyl-piperazin-1-ylmethyl)-phenylamine (81 mg) and HBTU (120 mg) in dry DMF (4 ml) containing N-methylmorpholine (65 μl) was stirred at room temp for 18 h.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C(N(CC)C(C)C)(C)C.[C:19]([O:22][C:23]1[C:24](=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:25](Cl)=[O:26])(=[O:21])[CH3:20]>C1(C)C=CC=CC=1>[C:19]([O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[CH3:9])=[O:26])(=[O:21])[CH3:20]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Cc1cc(Cl)ccc1N
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc(Cl)cc1C

Procedure:
To a stirred solution of 4-chloro-2-methylaniline, 1-1, (10.0 g 0.071 moles) in toluene was added (24.7 mL 0.014 moles) of N,N-diisopropylethylamine, followed by slow addition of acetylsalicyloyl chloride. The mixture was stirred until complete by TLC. Reaction was filtered and dried under vacuum to afford 9.4 grams of 1-2. Analytical LCMS: (CH3CN/H2O/1% TFA, 4 min gradient), 88% pure, M+1 peak m/e 304.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([OH:31])[CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1>>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([O:31][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)[CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc4c(c3)CCC4)CC2)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc3c(c2)CCC3)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(2,3-dihydro-1H-inden-5-yl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenol: ESMS m/e: 527.3 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:22])[C:17]=2Br)[CH:12]1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30])=O)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][O:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[CH:12]1[C:13]2[C:18](=[CH:17][C:16]([F:22])=[CH:15][CH:14]=2)[CH2:19][CH2:20][NH:11]1)[CH3:43]
Reactant: O=C(OCc1ccccc1)N1CCc2c(ccc(F)c2Br)C1c1cc(F)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(F)cc1C1NCCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-5-bromo-6-fluoro-1-(5-fluoro-2-hydroxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (50 mg, 0.11 mmol, 1.0 eq.) and Cs2CO3 (104 mg, 0.32 mmol, 3.0 eq.) in DMF (1 mL), ethyl bromoacetate (18 μL, 0.16 mmol, 1.5 eq.) was added. The resulting solution was stirred at r.t. for 18 hours. The solvent was evaporated and the mixture was poured into water and extracted with DCM (3×). The combined extracts were washed with water and dried over MgSO4. To a solution under N2 of the residue in EtOH (4 mL), palladium on activated carbon (10 wt. %, 10 mg) was added. The flask was evacuated and backfilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with EtOH, and the filtrate was concentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-bridge, 19×50 mm, 10 um, UV/MS, basic conditions) to give the title amine.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].CC(C)([O-])C.[K+].Cl[CH2:12][C:13]([N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].O>CN(C=O)C>[OH:3][CH2:2][CH2:1][O:4][CH2:12][C:13]([N:15]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(C)CN(C(=O)CCl)c1ccccc1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CN(C(=O)COCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of ethylene glycol (12.4 g, 200 mmol) in DMF (50 ml) was carefully added potassium tert-butoxide (16.8 g, 150 mmol) while the temperature was kept below 70° C. The resulting mixture was stirred at ambient temperature for 30 min, then a solution of the above acetamide (11.3 g, 50 mmol) in DMF (5 ml) was added in one portion and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured into iced water (400 ml) and extracted with dichloromethane (2×50 ml). The combined organic phases were dried (MgSO4) and the solvent was evaporated in vacuo to give 12.5 g of 2-(2-hydroxyethoxy)-N-(2-methyl-1-propyl)-N-phenylacetamide.
Reaction SMILES: [CH2:1]([N:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)N)[CH:2]=[CH2:3].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[CH2:31])[CH2:21][C:22]2([CH3:30])[C:27](=O)[CH2:26][CH2:25][N:24]([CH3:29])[CH2:23]2)=[CH:16][CH:15]=1.FC(F)(F)C(O)=O>O1CCOCC1>[CH2:1]([N:4]1[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:26]2[CH2:25][N:24]([CH3:29])[CH2:23][C:22]([CH2:21][C:20]([C:17]3[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=3)=[CH2:31])([CH3:30])[C:27]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN(N)c1ccc(C)cc1
Reactant: C=C(CC1(C)CN(C)CCC1=O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C=CCn1c2c(c3cc(C)ccc31)CN(C)CC2(C)CC(=C)c1ccc(F)cc1
Temperature: 100 °C
Yield: 20.2 %

Procedure:
N-Allyl-N-p-tolyl-hydrazine (600 mg, 3.70 mmol) and 3-[2-(4-fluoro-phenyl)-allyl]-1,3-dimethyl-piperidin-4-one (970 mg, 3.71 mmol) were dissolved in 1,4-dioxane (4 mL). Trifluoroacetic acid (1 mL) was added and the reaction mixture was heated to 100° C. for 3 h. 1,4-Dioxane was removed under reduced pressure, the residue was basified with aqueous sodium bicarbonate, and extracted with EtOAc (2×30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (100-200 mesh, eluent as 5% EtOAc in hexane) to obtain 290 mg of 5-allyl-4-[2-(4-fluoro-phenyl)-allyl]-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[N:21]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([N:21]2[CH:22]=[CH:23][CH:24]=[CH:25]2)=[N:27][CH:28]=1
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(-n2cccc2)nc1
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2cccc2)nc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 6-pyrrol-1-yl-nicotinic acid. MS: 444.5 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[N:11]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C@H:5]([OH:6])[C:10]#[N:11]
Reactant: Cc1cccc(C=O)c1
Reactant: C#N
Product: Cc1cccc([C@H](O)C#N)c1
Reaction time: 0.75 h

Procedure:
60 mg (0.5 mmol) of meta-methylbenzaldehyde were reacted at pH 3.25 with 475 μl of 4.2M aqueous HCN solution and 500 μl of oxynitrilase solution in accordance with Example 14. The reaction was complete after about 45 minutes. The work-up was carried out analogously to Example 1 to give (S)-3-methylmandelonitrile.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])([CH2:13][CH2:14][CH3:15])[C:8]2=O)=[CH:4][C:3]=1[CH2:21][C:22]([OH:24])=[O:23].Cl>[OH-].[Na+].O>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]([CH2:21][C:22]([OH:24])=[O:23])[CH:4]=[C:5]2[C:9]=1[C:8]1[C:7]([CH2:13][CH2:14][CH3:15])([CH2:6]2)[CH2:16][CH2:17][C:18](=[O:20])[CH:19]=1
Reactant: CCCC1(CCC(C)=O)Cc2cc(CC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC12CCC(=O)C=C1c1c(cc(CC(=O)O)c(Cl)c1Cl)C2

Procedure:
[6,7-Dichloro-2,3-dihydro-1-oxo-2-(3-oxo-butyl)-2-propyl-1H-inden-5-yl]acetic acid (3.0 g, 0.00808 mole) was dissolved in 25 ml 1N sodium hydroxide and 6 ml water, stirred at room temperature for 70 hours and then the reaction was diluted with water and acidified with hydrochloric acid. The product was extracted with methylene chloride, the organic extracts were washed with water, dried over MgSO4, concentrated under vacuum and the residue recrystallized from acetonitrile to obtain the product, mp 206°-8°C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[N:22]=[C:21]([OH:23])[CH:20]=[C:19]([CH3:24])[N:18]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[N:22]=[C:21]([OH:23])[CH:20]=[C:19]([CH3:24])[N:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cc(O)nc(N)n1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Product: Cc1cc(O)nc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)n1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 2-amino-6-methylpyrimidin-4-ol (25 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 313.1, found 314.1 (M+1)+. Retention time 2.31 minutes.
Reaction SMILES: [F:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[C:19]([CH3:25])[CH:18]=1>>[F:1][C:2]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][C:19]=1[CH3:25])=[O:5]
Reactant: COc1ccc([Mg]Br)c(C)c1
Reactant: CON(C)C(=O)c1cccc(C)c1F
Product: COc1ccc(C(=O)c2cccc(C)c2F)c(C)c1

Procedure:
Prepared according to Method A step B from 2- fluoro-3-methyl-N-methoxy-N-methyl-benzamide (3.10 g, 15.7 mmol) and 4-methoxy-2-methyl-phenylmagnesium bromide (40 mL, 0.5 M in THF) to give 1.17 g of the title compound as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[N:23]([CH3:48])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:27]=[C:26]([N:37]2[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=[C:38]2[CH2:46][CH3:47])[N:25]=3)[CH2:17][C:16]1([CH3:50])[CH3:49])=O)(C)(C)C>C(Cl)Cl>[CH3:50][C:16]1([CH3:49])[NH:15][CH2:20][CH2:19][N:18]([CH2:21][C:22]2[N:23]([CH3:48])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:27]=[C:26]([N:37]2[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=[C:38]2[CH2:46][CH3:47])[N:25]=3)[CH2:17]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)n(C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNC(C)(C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (530 mg, 1.35 mmol), 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.63 mmol) and molecular sieves (4 Å, powdered, 2.5 g) in DCE (30 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (427 mg, 2.02 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; 100:0 to 95:5 to 90:10) to give 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH before the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 98:2 to 95:5 to 90:10 to 80:20) to afford 552 as a cream solid (144 mg, 22%). LCMS (Method I): RT=2.56 min, M+H+=490. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H); 7.75 (m, 1 H); 7.29 (m, 2 H); 4.35 (m, 4 H); 3.92-3.83 (m, 7 H); 3.70 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 2.97 (m, 2 H); 2.47 (m, 2 H); 2.28 (s, 2 H); 1.49-1.42 (m, 3 H) and 1.19 (s, 6 H)
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH2:10]Cl)([CH3:9])[CH3:8])=[CH:3][CH:2]=1.[Na].[CH3:19][C:20]1[NH:21][CH:22]=[CH:23][N:24]=1>>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7]([CH3:9])([CH3:8])[CH2:10][N:21]2[CH:22]=[CH:23][N:24]=[C:20]2[CH3:19])=[CH:3][CH:2]=1
Reactant: Cc1ncc[nH]1
Reactant: C[Si](C)(CCl)c1ccc(-c2ccccc2)cc1
Agent: [Na]
Product: Cc1nccn1C[Si](C)(C)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound is prepared by applying the procedure of Example 23 to (1,1'-biphenyl-4-yl)chloromethyldimethylsilane and the sodium salt of 2-methylimidazole.
Reaction SMILES: [N:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[CH:9]=[O:10].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:8]1[CH2:11][CH2:12][O:13][CH:7]1[C:6]1[N:1]=[C:2]([CH:9]=[O:10])[CH:3]=[CH:4][CH:5]=1
Reactant: O=Cc1cccc(C=O)n1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=Cc1cccc(C2OCCO2)n1
Yield: 60.3 %

Procedure:
To a solution of pyridine-2,6-dicarbaldehyde (5 g, 37.4 mmol) in benzene (100 mL) was added ethylene glycol (1.1 g, 18.5 mmol) and p-toluenesulfonic acid (0.3 g, 1.8 mmol). The reaction mixture was equipped with a dean stark condenser and refluxed for 15 min. The reaction mixture was concentrated under reduced pressure and the resulting crude was purified via column chromatography to afford 6-(1,3-dioxolan-2-yl)picolinaldehyde (2 g, 30%). MS (ES+) (M+H) 180.0495
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:23]3[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([O:20][CH3:19])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Reactant: COc1cc(-c2ocnc2C(=O)O)ccc1C
Product: COc1cc(-c2ocnc2C(=O)Nc2cnn(Cc3ccc(C(C)=O)s3)c2)ccc1C

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-methoxy-4-methyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.75 min; [M+H]+=437.25.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:9]=1[C:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22].[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:9]=1[CH:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[OH:22]
Reactant: O=C(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a solution of 80 mg (0.19 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)carbonyl]isoxazole in 3 mL of ethanol at 0° C. was added 40 mg (1.06 mmol) of sodium borohydride. The mixture was stirred for 2 hrs and then diluted with ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride solution and dried over magnesium sulfate. The drying agent was filtered off, and the ethyl acetate was removed by rotoevaporation. The crude product was purified by prep TLC to give 65 mg (0.15 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole. 1H NMR (CDCl3): δ 5.80 (br s, 1), 6.97 (m, 1), 8.23 (br s, 1), and 8.28 ppm (br s, 1). MS m/z: 431.0 (M+H).