Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19](OCC)=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:27][C:26]=1[S:39]([NH2:42])(=[O:41])=[O:40].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:27][C:26]=2[S:39](=[O:40])(=[O:41])[N:42]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CCOC(=O)C1=C(O)c2ccccc2[C@@](C)(CCC(C)C)C1=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NC(=O)OC(C)(C)C)ccc3N2)=C(O)c2ccccc21
Temperature: 100 °C

Procedure:
To a solution of the product of Example 39-4 (320 g, 1.01 mol) in toluene (1100 mL) was added product of Example 17A-4 (291 g, 1.01 mol). The solution was heated to 100° C. for 4 h then cooled to RT. The solution was transferred to a pressure bottle and triethylamine (472, 4.66 mol) was added and the solution was heated to 100° C. for 26 h. The solution was concentrated to ⅓ of the original volume and ethyl acetate (2000 mL) was added. The organic layer was washed with 10% KH2PO4 and 10% NaCl then concentrated to a thick oil then chased with CH2Cl2. The crude product of Example 39-5 (assay for 406.5 g, 74.5%) was used directly.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:31]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cccc(Cl)c4)cc23)CC1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-l-piperazinyl)-naphthalene (0.24 g, 0.995 mmol) and triethylamine (0.146 mL, 1.09 mmol) and 3-chlorobenzoyl chloride (0.138 mL, 1.09 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was isolated using flash chromatography and trituration from hexane and recrystallization from ethyl acetate (with a seed crystal) to yield 0.076g (20%) of the title compound: mp 147°-148° C. HRMS m/e calculated for C22H22ClN3O; 379.1448. Observed m/e: 379.14473. Analysis calculated for C22H22ClN3O: C, 69.56; H, 5.84; N, 11.06. Found: C, 68.95; H, 5.81; N, 10.96.
Reaction SMILES: Br[C:2]1[C:3]([C:14]#[N:15])=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.[CH3:16]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:11]([C:9]1[N:10]=[C:5]2[CH:4]=[C:3]([C:14]#[N:15])[C:2]([CH3:16])=[CH:7][N:6]2[CH:8]=1)([CH3:13])[CH3:12]
Reactant: CB(O)O
Reactant: CC(C)c1cn2cc(Br)c(C#N)cc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cn2cc(C(C)C)nc2cc1C#N
Temperature: 25 °C
Yield: 38.5 %

Procedure:
6-Bromo-2-isopropylimidazo[1,2-a]pyridine-7-carbonitrile (200 mg, 0.757 mmol) obtained in step 1 was dissolved in 1,4-dioxane-water (2/1) (1.5 mL), and the solution was stirred under heat and reflux for 3 hours after adding methylboronic acid (140 mg, 2.33 mmol), sodium carbonate (240 mg, 2.26 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (62.0 mg, 0.0759 mmol). The reaction mixture was allowed to cool to room temperature, and, after adding water, the mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL). The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=98/2) to give 2-isopropyl-6-methyl-imidazo[1,2-a]pyridine-7-carbonitrile (58.0 mg, yield 38%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1B(O)O)([CH3:9])[CH3:8].Br[C:22]1[CH:51]=[CH:50][C:25]([CH2:26][NH:27][C:28](=[O:49])[C:29]2[CH:34]=[CH:33][C:32]([C:35]3[O:36][C:37]4[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][C:41]([C:47]#[N:48])=[CH:40][C:38]=4[N:39]=3)=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:47]([C:41]1[CH:42]=[C:43]([CH:44]([CH3:46])[CH3:45])[C:37]2[O:36][C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([NH:27][CH2:26][C:25]4[CH:50]=[CH:51][C:22]([C:12]5[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=5[O:10][CH:7]([CH3:9])[CH3:8])=[CH:23][CH:24]=4)=[O:49])=[CH:30][CH:31]=3)=[N:39][C:38]=2[CH:40]=1)#[N:48]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCc4ccc(Br)cc4)cc3)oc12
Reactant: Cc1ccc(OC(C)C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(OC(C)C)c(-c2ccc(CNC(=O)c3ccc(-c4nc5cc(C#N)cc(C(C)C)c5o4)cc3)cc2)c1
Temperature: 150 °C

Procedure:
Sodium carbonate (100 μl of a 2M aqueous solution), (2-isopropoxy-5-methylphenyl)boronic acid (19 mg), and N-(4-bromobenzyl)-4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzamide (24 mg, EXAMPLE 1) were dissolved in toluene (2.1 ml), water (0.6 ml) and ethanol (0.3 ml). To this solution was added tetrakis(triphenylphosphine)palladium(0) (9 mg). The mixture was heated to 150° C. for 25 min via microwave. Upon cooling, the mixture was concentrated in vacuo and then dissolved in dichloromethane (5 ml). The sample was transferred to a Biotage 40M column and purified via flash chromatography, eluting 1 column volume of 100% hexanes followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volume, followed by 100% ethyl acetate for 4 column volumes, to provide the title compound. Mass spectrum (ESI) 544.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.2 Hz, 2H), 7.94 (s, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.52 (s, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.13 (s, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.90 (d, J=8.4 Hz, 2H), 6.47 (t, J=4.6 Hz, 1H), 4.73 (d, J=5.5 Hz, 3H), 4.40 (sept, J=6.2 Hz, 1H), 3.48 (sept, J=7.1 Hz, 1H), 2.32 (s, 3H), 1.46 (d, J=6.9, 6H), 1.24 (d, J=5.9, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=O)=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:32]([NH2:34])[CH3:33].C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[N:25][C:24]([C:27](=[O:29])[NH:34][CH2:32][CH3:33])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccc(C(=O)O)nc3)cc2)OC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCNC(=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]3CF)cc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.9 %

Procedure:
To a stirred solution of 5-[4-((4S,5R)-3-tert-Butoxycarbonyl-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl)-phenyl]-pyridine-2-carboxylic acid (0.3 g, 0.697 mmol) in dry tetrahydrofuran (5 mL) is added ethyl amine (0.038 g, 0.837 mmol), diisopropylamine (0.27 g, 2.092 mmol) and 50% solution of triphenyl phosphine in ethyl acetate (0.332 g, 0.66 mL, 1.046 mmol) and stirred at room temperature for 14 hours. Diluted with water and ethyl acetate, organic layer is separated and aqueous layer is extracted with ethyl acetate. Combined organic layer is dried over sodium sulphate, solvent is evaporated in vacuo to obtained crude material purified by column chromatography eluting in 3% methanol in CH2Cl2 to afford title compound (0.21 g): 1H-NMR (400 MHz, DMSO-d6): δ: 1.13 (t, 3H, J=6.98 Hz), 1.44 (s, 9H), 1.51 (s, 3H), 1.64 (s, 3H), 3.34-3.37 (m, 2H), 3.84-3.91 (m, 1H), 4.47-4.59 (m, 1H), 4.76-4.95 (m, 2H), 5.15 (d, 1H, J=7.24 Hz), 7.61 (d, 2H, J=8.28 Hz), 7.83 (d, 2H, J=8.24 Hz), 8.09 (d, 1H, J=8.20 Hz), 8.29 (dd, 1H, J=8.08 Hz, J=2.2 Hz), 8.84 (t, 1H, J=5.68 Hz), 8.93 (d, 1H, J=1.88 Hz) LC-MS (m/z): [M+H]=458.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH:31]=[CH:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH:40]([F:42])[F:41])=[CH:35][CH:34]=2)[O:29][CH:30]=1.[I-].[K+]>CC(=O)CC>[F:42][CH:40]([F:41])[O:39][C:36]1[CH:37]=[CH:38][C:33]([CH:32]=[CH:31][C:28]2[O:29][CH:30]=[C:26]([CH2:25][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[N:27]=2)=[CH:34][CH:35]=1
Reactant: FC(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Cc1cc(O)ccc1COCCn1ccnn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: Cc1cc(OCc2coc(C=Cc3ccc(OC(F)F)cc3)n2)ccc1COCCn1ccnn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
A mixture of 201 mg (0.86 mmol) 3-methyl-4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol and 169 mg (0.52 mmol) cesium carbonate in 10 ml 2-butanone was stirred at 60° C. for 30 minutes, then 246 mg (0.86 mmol) 4-chloromethyl-2-[2-(4-difluoromethoxy-phenyl)-vinyl]-oxazole and 143 mg (0.86 mmol) potassium iodide were added and stirring was continued overnight. After evaporation, the residue was mixed with aqueous NaOH (1N) and extracted with ethyl acetate. The combined extracts were dried, evaporated and the product purified on silica (ethyl acetate) to yield 242 mg (59%) 1-[2-(4-{2-[2-(4-Difluoromethoxy-phenyl)-vinyl]-oxazol-4-ylmethoxy}-2-methyl-benzyloxy)-ethyl]-1H-[1,2,3]triazole as a white solid melting at 119-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.[C:23]1([N:29]2[C:33]([N:34]3[CH2:37][C:36]4([CH2:40][NH:39][CH2:38]4)[CH2:35]3)=[N:32][N:31]=[N:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:39]3[CH2:40][C:36]4([CH2:37][N:34]([C:33]5[N:29]([C:23]6[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=6)[N:30]=[N:31][N:32]=5)[CH2:35]4)[CH2:38]3)=[O:21])[C:4]=12
Reactant: c1ccc(-n2nnnc2N2CC3(CNC3)C2)cc1
Reactant: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(-n2cnc(C)n2)c2[nH]cc(C(=O)C(=O)N3CC4(C3)CN(c3nnnn3-c3ccccc3)C4)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
2-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.050 g), 2-(1-phenyl-1H-tetrazol-5-yl)-2,6-diazaspiro[3.3]heptane (0.044 g), BOP reagent (0.080 g) and Hunig's base (0.2 mL) were mixed in dry DMF (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with methanol (10 mL) and volatiles were removed under reduced pressure. The resulting oil was diluted with ethyl acetate (50 mL), washed with 10% NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by silica gel column chromatography using MeOH/CHCl3 (1:9) as an eluent to afford 1-(4-methoxy-7-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(6-(1-phenyl-1H-tetrazol-5-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethane-1,2-dione (30 mg). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.47-2.49 (s, 3H), 3.93 (s, 4H), 4.08-4.13 (m, 2H), 4.20-4.36 (d, 2H), 7.54-7.62 (m, 5H), 7.84 (s, 1H), 8.30-8.32 (s, 1H), 9.22 (s, 1H), 12.26 (bs, 1H). LCMS MS (M+H)+ Calcd.: 526, Observ.: 526.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH3:19][CH:20]1[CH2:25][CH:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>>[CH3:19][CH:20]1[CH2:25][CH:24]([CH3:26])[CH2:23][N:22]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:21]1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: CC1CNCC(C)C1
Product: CC1CC(C)CN(C(=O)c2cnoc2-c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3,5-dimethylpiperidine (6.8 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (2.2 mg). Calcd for C18H19F3N2O2: 352.1399, found 352.1399.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:9]2[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:15][C:14]=1[F:20]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(Cl)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde and 4-chloro-3-fluorophenol.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3(O)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3c(Cl)cccc3s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccc2sc(C3=CCNCC3)cc12
Temperature: 23 °C
Reaction time: 4 h
Yield: 88.7 %

Procedure:
A solution of 4-chloro-2-(4-hydroxy-N-t-butoxycarbonyl-piperidin-4-yl)benzo[b]thiophene (0.290 g, 0.79 mmol) in methylene chloride (4.0 ml) was treated with 1.5 ml of trifluoroacetic acid and stirred at 23° C. for 4 hours. The reaction was concentrated to a foam under reduced pressure and the residue chromatographed (silica gel, chloroform/methanol 95:5) to give 0.175 g (88%) of a tan powder. FDMS m/e=250 (M+ of free base)
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[CH3:11][C:9]1[O:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[C:7]=2[CH:8]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1cc2c(O)cccc2o1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc2c(OCc3ccc(C#N)cc3)cccc2o1

Procedure:
4-Hydroxy-2-methylbenzofuran (5.18 g, 0.035 M), 4-bromomethylbenzonitrile (6.86 g, 0.035 M), anhydrous potassium carbonate (5.2 g), sodium iodide (0.21 g) and 95% ethanol (50 ml) were reacted together in an analogous manner to that described in Example 5(A) to give 4-(2-methyl-4-benzofuranyloxymethyl)benzonitrile, m.p. 84°-85° C. (Found: C, 77.57; H, 5.02; N, 5.22. C17H13NO2 requires C, 77.55; H, 4.98; N, 5.32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O:33]C)=[O:32])=[C:5]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:4]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([OH:33])=[O:32])=[C:5]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:4]=1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)O)C2c1ccc2c(c1)OCO2
Yield: 57.4 %

Procedure:
To a solutionof Methyl (1RS,2RS,3RS)-3-(4-Methoxy-2-phenylphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (80 mg, 0.12 mmol) in dioxane (2 mL) was added 1M aqueous NaOH (0.3 mL, 0.3 mmol). The resulting mixture was heated to reflux for 48 h, then concentrated under reduced pressure. The residue was partitioned between dilute aqueous HCl and ethyl acetate. The ethyl acetate extract was washed with water and dried (MgSO4 anhydrous). The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, 20% ethyl acetate/hexane containing 5% of acetic acid) to afford the title compound (36 mg, 46%). m.p. 199-200° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].CO.O.CC#N.O>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC(=O)O)CC1
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 4-(4-(2-tert-butylphenyl)-piperazin-1-yl)-4-oxobutanoate obtained in Example 52 (0.245 g, 0.74 mmol) in THF (2.0 mL) was added a solution of lithium hydroxide (0.053 g, 2.20 mmol) in 4:1 MeOH/H2O (2.5 mL) at room temperature. After 2 h the reaction mixture was concentrate under reduced pressure. The residue was acidified to pH 1-2 with 1.0 M hydrochloric acid and extracted with ethyl acetate (3×20 mL). The combined organics were washed with saturated sodium chloride (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a residue. Trituration of the residue with 1:3 CH3CN/H2O provided 4-(4-(2-tert-butylphenyl)piperazin-1-yl)-4-oxobutanoic acid (0.217 g, 92%) as a white solid, mp 175-176° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([S:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:19]=[N:20][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:40].[Na+].CO>O.C(OCC)(=O)C>[C:1]1([CH:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[C:18]([S@:32]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:40])[N:19]=[N:20][C:21]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Nc1nccc(-c2cc(Sc3ccccc3)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC(Nc1nccc(-c2cc([S@@](=O)c3ccccc3)nnc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
Compound 86 (70 mg, 0.132 mmol), sodium periodate (28 mg, 0.132 mmol), methanol (2 mL) and water (250 μL) were combined at 0° C. under Argon. After 0.5 h, the mixture was warmed to room temperature and stirred for 24 h. An additional portion of sodium periodate (28 mg, 0.132 mmol) was added and heated to 60° C. for 48 h. Ethyl acetate and water were added. The layers were separated and the organic portion was dried with anhydrous sodium sulfate. The solvent was removed in vacuo and the remaining residue was purified by flash column chromatography (hexane:ethyl acetate 50:50) to give 20 mg (0.036 mmol, 28%) of Compound 87 as a foam.
Reaction SMILES: C(N(CC)CC)C.F[B-](F)(F)F.[C:13]([C:15](=NOC(N(C)C)=[N+](C)C)[C:16](OCC)=O)#[N:14].[CH2:30]([O:32][C:33]([C:35]([CH3:46])=[CH:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([OH:41])=O)=[O:34])[CH3:31].C(N)CC>CN(C)C=O>[CH3:46][C:35](=[CH:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](=[O:41])[NH:14][CH2:13][CH2:15][CH3:16])[C:33]([O:32][CH2:30][CH3:31])=[O:34]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCCN
Product: CCCNC(=O)c1ccccc1C=C(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of 0.69 cm3 (5.0 mmol) of triethylamine and 1.64 g (5.0 mmol) of O-[(cyano-(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide is added at 0° C. to a solution of 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide. After stirring for 30 minutes at 0° C. and then for 30 minutes at a temperature in the region of 20° C., this solution is introduced dropwise into a second solution consisting of 296 mg (5.0 mmol) of n-propylamine and 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide, and the mixture is stirred for a further 6 hours at a temperature in the region of 20° C. After leaving the solution to stand overnight, the solvent is removed under vacuum and the residue is dissolved in ethyl acetate. After washing twice with sodium bicarbonate solution and then once with sodium chloride solution, the organic phase is dried over sodium sulfate and then concentrated. 1.10 g of ethyl 2-methyl-3-(2-propylcarbamoylphenyl)acrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:36]([NH:40][S:41]([C:44]1[S:48][C:47](Cl)=[N:46][CH:45]=1)(=[O:43])=[O:42])([CH3:39])([CH3:38])[CH3:37].[F-].[K+].O>C1(C)C=CC=CC=1>[C:36]([NH:40][S:41]([C:44]1[S:48][C:47]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=3)[CH:22]=2)=[N:46][CH:45]=1)(=[O:42])=[O:43])([CH3:39])([CH3:37])[CH3:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
A stirred mixture of 4-(4-chloro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.2) (0.28 g, 0.46 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.128 g, 0.5 mmol), tetrakis(triphenyl-phosphine)palladium (0.032 g, 0.028 mmol) in toluene (5 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (5 mL), water (20 mL) was added and the water layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.094) as a light brown solid. Mp 261° C.