Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B.CSC.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[N:26]([CH2:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:34]([F:46])[CH:33]=1)=[O:31])=[N+:27]=[N-:28].Cl>C1COCC1.C1(C)C=CC=CC=1>[N:26]([CH2:29][C@@H:30]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[C:34]([F:46])[CH:33]=1)[OH:31])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NCC(=O)c1ccc(OCc2ccccc2)c(F)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(F)c1
Yield: 466.7 %

Procedure:
Borane-dimethylsulphide solution in THF (2M, 0.03 mL) was added to a solution of (R)-2-methyl-CBS-oxazaborolidine in toluene (1M, 0.06 mL) at 0° C. with stirring. The reaction mixture was stirred for 15 min prior to the dropwise addition of a solution of 2-azido-1-[4-(benzyloxy)-3-fluorophenyl]ethanone (100 mg) in THF. Further Borane-dimethylsulphide in THF (2M, 0.03 mL) was added dropwise and the reaction mixture stirred at 0° C. for 2 h. 2M HCl(aq) (2 mL) was added dropwise and the reaction mixture stirred for 10 min prior to partitioning the reaction mixture between ether and water. The organic phase was washed twice with 2M HCl(aq), three times with sat. NaHCO3(aq), water and brine. The organic phase was dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with DCM to give the title compound (470 mg). LCMS RT=3.36 min.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(O)(=O)CC(O)=O.[Cl:19][C:20]1[CH:29]=[C:28]([Cl:30])C2C(=C(Cl)C(OC)=CC=2)N=1>>[Cl:19][C:20]1[CH:29]=[C:28]([Cl:30])[C:6]2[C:4](=[C:3]([CH3:2])[C:9]([O:10][CH3:11])=[CH:8][CH:7]=2)[N:5]=1
Reactant: COc1cccc(N)c1C
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1Cl
Agent: Cl
Agent: O=C(O)CC(=O)O
Product: COc1ccc2c(Cl)cc(Cl)nc2c1C
Yield: 43 %

Procedure:
2,4-Dichloro-8-methyl-7-methoxyquinoline 220b was synthesized from 2-methyl-3-methoxyaniline hydrochloride 215b and malonic acid as a white powder in 43% yield, following the procedure as described for compound 220d. 1H NMR (CDCl3, 376 MHz) δ (ppm) 2.62 (s, 3H), 4.03 (s, 3H), 7.34 (s, 1H), 7.37 (d, J=9.02 Hz, 1H), 8.05 (d, J=9.02 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([N:39]=[C:40]=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:40]([NH:39][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:41])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(NCCCCCSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CCCCCCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)N(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)c1ccccc1
Yield: 56.3 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]benzeneamine (0.41 g, 0.001 mol) in toluene (25 mL) was added n-octylisocyanate (0.23 g, 0.0015 mol). The reaction mixture was stirred at reflux for 18 hours and then the solvent was removed under vacuum. The residue (1.0 g) was chromatographed with 7:3 hexane-ethyl acetate. The resulting solid was 5 triturated with hexane to give the title compound (0.32 g, 0.00056 tool) as a white solid, mp 74°-76°. 1H NMR (CDCl3) 11.8(s,1H), 7.75-7.1(m,15H), 4.3(t,1H,J=6.0 Hz), 3.8(t,2H,J=7.0 Hz), 3.0(quintet,4H,J=6.0 Hz), 1.9-0.90(m,18H), 0.8(t,3H,J=7.0 Hz).
Reaction SMILES: C.CC.FC(F)(F)S(O)(=O)=[O:7].[N:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>FC(F)(F)C(O)=O>[N+:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:7])=[O:13]
Reactant: O=Nc1ccccc1
Reactant: O=S(=O)(O)C(F)(F)F
Agent: C
Agent: CC
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccccc1

Procedure:
Para-nitroso-diphenylhydroxylamine is a compound which may be readily obtained by means of the catalytic dimerization of nitrosobenzene. According to a recent, especially advantageous process, the foregoing compound may be obtained with practically quantitative yield, if a sulfonic acid with a pKa ≤1, for example methane-, ethane-, or trifluoromethanesulfonic acid, or perchloric or trifluoroacetic acid is used as a catalyst (German Patent Application No. P 27 03 919). The nitrosobenzene required for the preparation of para-nitroso-diphenylhydroxylamine is likewise easily accessible and may be obtained by the catalytic reduction of nitrobenzene. The reduction will proceed with a high conversion rate and high selectivity if, pursuant to another recent process, an aliphatic, cycloaliphatic, olefinic, or aromatic hydrocarbon is used as the reducing agent (German Patent Application No. P 27 13 602).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][C:17]=1[C:29]([F:32])([F:31])[F:30].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[NH:7][C:6]3=[O:14])[CH2:26][CH2:27]2)=[CH:18][C:17]=1[C:29]([F:32])([F:30])[F:31]
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Yield: 41.6 %

Procedure:
A mixture of 4.21 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 5 parts of 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is stirred and refluxed for 6 hours with water-separator. The reaction mixture is cooled and water is added. The organic phase is separated, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 3.4 parts (41.6%) of 1-[3-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 189.2° C.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:13][C:12]([F:15])([F:14])[C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc(Br)c2[nH]1
Product: O=c1[nH]c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1

Procedure:
4-Bromo-6-trifluoromethyl-1,3-dihydro-benzoimidazol-2-one 562 mg, 2.0 mmol, Example 6a) reacted with 4-trifluoromethylphenylboronic acid (760 mg, 4.0 mmol, Aldrich) under the conditions of Example 10 to give the title compound as a white solid. MS (ESI, neg. ion) m/z: 345 (M−1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15]Cl)=[CH:5][CH:4]=1.C[O:22][C:23](=[O:35])[CH2:24][C:25]1[C:26]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:27]=2[S:28][CH:29]=1.COC(=O)CC1C2C=CC(OCC3C=CC(OCC4C=CC(C(F)(F)F)=CC=4)=CC=3)=CC=2SC=1>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][O:34][C:31]2[CH:32]=[CH:33][C:26]3[C:25]([CH2:24][C:23]([OH:35])=[O:22])=[CH:29][S:28][C:27]=3[CH:30]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Reactant: FC(F)(F)c1ccc(COc2ccccc2CCl)cc1
Agent: COC(=O)Cc1csc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc12
Product: O=C(O)Cc1csc2cc(OCc3ccccc3OCc3ccc(C(F)(F)F)cc3)ccc12

Procedure:
The title compound was prepared from compounds 7B and 5C in a manner analogous to compound 5F. MS m/z 487 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH3:9][NH:10][C:11]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)=[O:12].O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.O.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.CCO>[CH3:9][NH:10][C:11](=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:2]2[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=2)[CH:18]=1
Reactant: O=c1cc(Cl)cn[nH]1
Reactant: CNC(=O)c1cccc(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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(-c2cn[nH]c(=O)c2)c1

Procedure:
5-Chloro-pyridazin-3-one (1 eq, 5.06 mmol, 660 mg) and 3-(N-Methylaminocarbonyl)phenyl boronic acid (1.1 eq, 5.56 mmol, 996 mg) are dissolved in dioxane (4 ml), water (2 ml) and EtOH (2 ml) and K2CO3 (2 eq, 10.1 mmol, 1.40 g) is added. Pd(PPh3)4 (0.1 eq, 0.5 mmol, 584 mg) is then added and the reaction mixture is heated using microwave radiation at 140° C. for 20 min. The reaction mixture is diluted with EtOAc/H2O and filtered. The organic layer is then separated and the aqueous layer is extracted with EtOAc (2×20 ml). The organic layer is washed with NaHCO3, brine, dried over MgSO4, filtered and evaporated to dryness to yield N-Methyl-3-(6-oxo-1,6-dihydro-pyridazin-4-yl)-benzamide as a white solid which did not require further purification; [M+H]+=230
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)=[O:8])[CH3:2].[ClH:23].C(OCC)(=O)C>>[ClH:23].[O:8]=[C:7]([N:9]1[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22]
Reactant: CCOC(=O)CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(=O)N1CCNCC1

Procedure:
By using 1.2 g of tert-butyl 4-(4-ethoxy-4-oxobutanoyl)piperazine-1-carboxylate and 1.0 mL of 4.0 M hydrogen chloride/ethyl acetate solution, the reaction similar to Preparation Example 35 was performed, thereby obtaining 900 mg of ethyl 4-oxo-4-(piperazin-1-yl)butanoate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[CH3:27][C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[NH2:37])[NH:30][N:29]=1>>[NH2:37][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[N:30]([CH:8]([C:6]3[C:5]([O:11][CH3:12])=[C:4]([CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)[C:3]([CH3:26])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:29]=[C:28]([CH3:27])[C:36]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared according to the procedure of Example 139 step 5, using of tert-butyl 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as the starting materials. LCMS calculated for C26H36ClN6O3 (M+H)+: m/z=515.3; Found: 515.2.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)[CH:2]=[CH2:3].CC(C)([O-])C.[K+].O>O1CCOCC1>[CH:1]([O:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[CH:2][CH3:3]
Reactant: C=CCOCC1CNCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC=COCC1CNCCO1
Yield: 101.8 %

Procedure:
2-(Allyloxymethyl)morpholine (39.5 g, 0.25 mol) was dissolved in 1,4-dioxane (500 ml), and potassium tert-butoxide (28.2 g, 0.25 mol) was added to the solution at room temperature, followed by heating under reflux for 3 hours. After completion of the reaction, water was added to the reaction mixture at room temperature, and the reaction mixture was extracted with chloroform (3×1000 ml). The extract was washed with a saturated aqueous solution of sodium chloride (1000 ml) and dried over magnesium sulfate. The solvent was evaporated to give crude 2-(1-propenyloxymethyl)morpholine (40.0 g) as a pale yellow oily substance.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:38])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH:18]([CH3:22])[NH:19][CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C(Cl)Cl>[F:38][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:17]=[C:16]2[CH:18]([CH3:22])[N:19]([S:49]([CH3:48])(=[O:51])=[O:50])[CH2:20][CH2:21][C:15]2=[N:14][C:13]=1[N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:25][CH2:24]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CS(=O)(=O)Cl
Reactant: CC1NCCc2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1c2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CCN1S(C)(=O)=O

Procedure:
A solution of N-(2,2-difluoroethyl)-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (15 mg, 0.027 mmol), DIPEA (14.2 μL, 0.081 mmol), and methanesulfonyl chloride (3.2 μL, 0.041 mmol) in DCM (271 μL) was stirred overnight. Purification by HPLC Method A gave the title compound as a TFA salt (6.4 mg) as a white film. 1H NMR (500 MHz, methanol-d4) δ ppm 1.54 (d, J=6.8 Hz, 3H), 1.91-2.02 (m, 2H), 2.07-2.19 (m, 2H), 2.66 (dd, J=16.8, 3.2 Hz, 1H), 2.91 (s, 3H), 2.93-3.06 (m, 3H), 3.34-3.48 (m, 3H), 3.68-3.88 (m, 2H), 3.98 (dd, J=14.2, 6.4 Hz, 1H), 4.45 (dt, J=7.4, 3.8, Hz, 1H), 4.77 (q, J=6.8 Hz, 1H), 5.87-6.21 (m, 1H), 6.82-6.92 (m, 1H), 6.98 (ddd, J=11.4, 8.7, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 518.80.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:3]=1[NH2:4].B(Cl)(Cl)Cl.C(Cl)Cl.Cl[CH2:19][C:20]#N.[Cl-].[Al+3].[Cl-].[Cl-].[BH4-].[Na+]>ClCCCl>[O:9]([C:6]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]2[C:5]=1[CH:19]=[CH:20][NH:4]2)[CH3:10]
Reactant: COc1ccc(Br)c(N)c1
Reactant: N#CCCl
Agent: ClB(Cl)Cl
Agent: [Al+3]
Agent: [BH4-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(Br)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.3 %

Procedure:
2-Bromo-5-methoxy-aniline (4.4 g, 21.8 mmol) was added dropwise to a solution of boron trichloride in methylene chloride (1.0 M, 24 mL, 24 mmol) cooled with ice water. The reaction mixture was warmed to room temperature, stirred for 30 min, and chloroacetonitrile (4.01 mL, 26.2 mmol) and aluminum chloride (4.01 g, 24.0 mmol) were added, followed by 1,2-dichloroethane (28.5 mL). The reaction mixture was heated to 70° C. to distill off methylene chloride, and then heated to reflux for 24 hrs. After cooling to 0–5° C., the mixture was treated with 2.5 M HCl (38.4 mL) carefully, and then heated to 80° C. for 1 h until all solids dissolved. The aqueous layer was separated, extracted with methylene chloride and the combined extracts washed with water and brine, dried (sodium sulfate) and evaporated to a yellow solid, which was used without further purification. The crude product was taken into dioxane (37 mL) and water (4.2 mL), and treated with sodium borohydride (0.91 g, 24.0 mmol) in portions. After stirring at room temperature for 30 min, all the starting material was consumed and the reaction mixture was then heated to reflux for 14 hrs. After cooling to room temperature, the mixture was treated with concentrated HCl, and extracted with ethyl acetate. The organic extract was washed with water and brine; dried (sodium sulfate), and concentrated. Column chromatography on silica gel (hexanes/ethyl acetate) gave 4-methoxyl-7-bromoindole (1.2 g, 24%). 1H NMR (400 MHz, CDCl3) 3.94 (s, 3H), 6.44 (d, J=8.21 Hz, 1H), 6.73 (m, 1H), 7.17 (t, J=2.74 Hz, 1H), 7.22˜7.26 (m, 1H), 8.32 (br, 1H); MS (ES, m/z): C9H8BrNO: 227.99 (M+(79Br)+1), 230.0(M+(81Br)+1).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][C:17]#[N:18].C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C.N[C@H](C(O)=O)CO>C1COCC1>[C:1]1([CH2:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH2:16][C:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:18]
Reactant: N#CCBr
Agent: CC(C)[N-]C(C)C
Agent: CCOC(=O)C(C)Cc1ccccc1
Agent: N[C@@H](CO)C(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CC#N)Cc1ccccc1
Yield: 135.9 %

Procedure:
The reaction of ethyl 2-phenylmethylpropanoate (9.60 g, 50 mmol) with bromoacetonitrile (9.0 g, 75 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (6.06 g, 60 mmol) with butyllithium in hexanes (2.5 M, 24 mL, 60 mmol)) in THF (150 mL) and HMPA (4.3 mL, 25 mmol), as described above in the preparation of Example 4, gave 11.95 g of the crude product as a pale yellow colored liquid. Ethyl 2-phenylmethylpropanoate was prepared as in Spencer R W, Tam T F, Thomas E, Robinson V J, Krantz A (1986) "Ynenol lactones: Synthesis and investigation of reactions relevant to their inactivation of serine proteases" J. Am. Chem. Soc., 108 5589-5597. Flash chromatography over silica gel (hexanes-CH2Cl2, 3:2) afforded 7.86 g (68%) of the nitrile as a colorless viscous liquid. Analytical sample was prepared by bulb-to-bulb distillation (pot temp. 110-115° C. (0.9 mmHg)).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C.O>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[N:17][OH:18])[NH2:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NO
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)C(c1ccccc1)c1ccccc1
Yield: 30.5 %

Procedure:
A mixture of diphenylacetonitrile (7.0 g), hydroxylamine hydrochloride (3.03 g), and sodium acetate (6.67 g) in 150 ml of 5:1 ethanol-water was refluxed for 4 h. The mixture was concentrated under reduced pressure. The residue was triturated with water, filtrated, and dried to give the title compound (2.5 g) having the following physical data.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[CH:10]1([C:2]2[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: OB(O)C1CC1
Reactant: OCc1ccnc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1ccnc(C2CC2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 30 %

Procedure:
Under argon atmosphere, (2-bromopyridin-4-yl)methanol (2.53 g), cyclopropylboronic acid (3.6 g), tripotassium phosphate (10 g), tricyclohexylphosphine (750 mg), toluene (60 ml), and water (3 ml) were mixed, and palladium acetate (II) (300 mg) were added thereto, followed by stirring at 100° C. for 5 hours. Cyclopropylboronic acid (1.8 g) was added thereto, followed by stirring at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and water were added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain (2-cyclopropylpyridin-4-yl)methanol (602 mg).
Reaction SMILES: [CH2:1]([O:3]C1C=C(C=O)C=C(O)C=1C(OC)=O)[CH3:2].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22].BrCCO>>[OH:3][CH2:1][CH2:2][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCOc1cc(C=O)cc(O)c1C(=O)OC
Agent: OCCBr
Product: COc1ccc(C=O)cc1OCCO
Yield: 62.5 %

Procedure:
Followed procedure described in Intermediate 8, step 1 starting from 3-hydroxy-4-methoxybenzaldehyde and 2-bromoethanol with the reaction conditions of 90° C. overnight. Isolated 400 mg, yield 62.5%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:14]1[S:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][N:18]=1.O>C(#N)C>[N+:19]([C:16]1[S:15][C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:18][CH:17]=1)([O-:21])=[O:20]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(N2CCNCC2)s1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74.3 %

Procedure:
To a solution of piperazine (18.2 g) and potassium carbonate (12.6 g) in acetonitrile (150 ml) was added 2-bromo-5-nitrothiazole (14.7 g) at 40° C. and the mixture was stirred at 60° C. for 40 min. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (11.2 g). The obtained brown solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give the title compound (4.8 g) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11]1[S:17][C:16]([CH3:19])([CH3:18])[CH:15]([C:20](O)=[O:21])[N:14]=[C:13]([C:23]2[C:24](=[O:31])[O:25][C:26]([CH3:30])=[CH:27][C:28]=2[OH:29])[CH2:12]1.CN1CCOCC1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:72]([O:76][C:77](=[O:81])[CH:78]([NH2:80])[CH3:79])([CH3:75])([CH3:74])[CH3:73]>CN(C=O)C>[C:72]([O:76][C:77](=[O:81])[CH:78]([NH:80][C:20]([CH:15]1[N:14]=[C:13]([C:23]2[C:24](=[O:31])[O:25][C:26]([CH3:30])=[CH:27][C:28]=2[OH:29])[CH2:12][CH:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[S:17][C:16]1([CH3:18])[CH3:19])=[O:21])[CH3:79])([CH3:75])([CH3:74])[CH3:73]
Reactant: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NC(C(=O)O)C(C)(C)S2)c(OC)c1
Reactant: CC(N)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(C2CC(c3c(O)cc(C)oc3=O)=NC(C(=O)NC(C)C(=O)OC(C)(C)C)C(C)(C)S2)c(OC)c1
Yield: 46.7 %

Procedure:
7-(2,4-Dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepine-3-carboxylic acid (0.03 g), prepared as in Example 2, was dissolved in DMF (2 mL) and 2-amino-propionic acid tert-butyl ester (0.012 g), N-methylmorpholine (0.2 ml) and PyBOP (0.034 g) were added to the solution at room temperature. The mixture was stirred while the progress of the reaction was followed by analytical HPLC and when complete (16 hours) the solvent was removed in vacuo. Purification of product by preparative HPLC (RPC18 column, 2-70% acetonitrile/water containing 0.1% HCl) provided 2-({1-[7-(2,4-dimethoxy-phenyl)-5-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-2,2-dimethyl-2,3,6,7-tetrahydro-[1,4]thiazepin-3-yl]-methanoyl }-amino)-propionic acid tert-butyl ester (18 mg) as an off-white powder. LCMS: M+ 575.0.