Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[C:13]([O:17][CH3:18])=[N:14][CH:15]=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1>>[CH3:18][O:17][C:13]1[C:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:42]4[CH:41]=[N:40][N:39]([CH3:38])[CH:43]=4)[CH:7]=3)=[N:9][NH:10][C:11]=2[CH:16]=[CH:15][N:14]=1
Reactant: COc1nccc2c1c(-c1ccnc(Cl)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1nccc2[nH]nc(-c3ccnc(-c4cnn(C)c4)c3)c12
Yield: 57 %

Procedure:
Prepared according to the procedure described in Example 116, by reacting 3-(2-chloropyridin-4-yl)-4-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to give the title compound (30.5 mg, 57% over two steps). LC-MS (Method G): m/z=307.0 (M+H)+; 3.06 min. 1H-NMR (400 MHz, DMSO): δ 13.89 (br s, 1H), 8.60 (d, J=5.2, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.03 (s, 1H), 7.97 (d, J=6.0, 1H), 7.75 (dd, J=5.2, 1.5 Hz, 1H), 7.23 (d, J=6.0, 1H), 4.05 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27][CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:30]([Cu])#[N:31]>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:27][CH3:28])=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3c(C)cccc3CC)cc2c1O
Reactant: N#C[Cu]
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3CC)cc2c1O

Procedure:
The title compound was synthesized from 1-Bromo-6-(2-ethyl-6-methyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and CuCN in analogy to example 3a; MS-(−)-ion: M−1=403.5.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:26](=[O:28])[CH3:27])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)cc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-1-(4-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethyl amine. The title compound, ESI MS (m/z): 382 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(O)(c2ccc(F)cc2)CC1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 50 parts of fluorobenzene and 4.1 parts of 4-(4-fluorophenyl)-4-hydroxycyclohexanone were added portionwise 11 parts of aluminium chloride. Upon completion, stirring was continued for 2 hours while still cooling. The reaction mixture was decomposed by pouring onto a mixture of crushed ice and a hydrochloric acid solution. The product was extracted with methylbenzene. The extract was washed with water till neutralization, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 4.3 parts (75.9%) of 4,4-bis(4-fluorophenyl)-1-cyclohexanone as a residue (intermediate 19).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:43])[O:39][CH:40]([CH3:42])[CH3:41]>C(Cl)Cl>[CH2:25]([NH:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:43])[O:39][CH:40]([CH3:42])[CH3:41])[CH:7]=[N:6][CH:5]=2)=[N:9][N:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cncc(-c2nnc(NCc3ccccc3)c3c(-c4ccccc4)cccc23)c1
Reaction time: 5 h
Yield: 68.5 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-N-benzyl-8-phenylphthalazin-1-amine (60.0 mg, 0.149 mmol) in DCM (20 mL) was added pyridine (0.241 mL, 0.297 mmol) at room temperature followed by isopropyl carbonochloridate (18.2 mg, 0.149 mmol) and the reaction mixture stirred for 5 h. The volatile components were removed under reduced pressure and the resulting residue was purified by preparative HPLC (Condition 23 as described in general methods) to afford isopropyl (5-(4-(benzylamino)-5-phenylphthalazin-1-yl)pyridin-3-yl)carbamate (50.0 mg, 68.7%) as a white solid. LCMS (Condition 4): retention time 2.60 min, [M+1]=490.2. HPLC (Condition 28): retention time=7.65 min, purity 99.27%. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (d, J=6.4 Hz, 6 H), 4.51 (d, J=4.8 Hz, 2 H), 4.93 (sept, J=6.4 Hz, 1 H), 5.06 (dd, J=4.8 Hz, J=5.2 Hz, 1 H), 7.01-7.03 (m, 2 H), 7.21-7.28 (m, 3 H), 7.42-7.52 (m, 5 H), 7.69 (dd, J=1.2 Hz, J=6.8 Hz, 1 H), 7.85-7.93 (m, 2 H), 8.16 (br s, 1 H), 8.47 (d, J=1.6 Hz, 1 H), 8.80 (d, J=2.4 Hz, 1 H), 10.00 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:26])=[C:11]([C@:13]3([CH3:25])[C:19]([F:21])([F:20])[C:18]([CH3:23])([CH3:22])[O:17][CH2:16][C:15](=O)[NH:14]3)[CH:12]=2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:26])=[C:11]([C@:13]3([CH3:25])[C:19]([F:21])([F:20])[C:18]([CH3:23])([CH3:22])[O:17][CH2:16][C:15](=[S:36])[NH:14]3)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(=O)N[C@](C)(c2cc(C3=CCOCC3)ccc2F)C1(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(C3=CCOCC3)ccc2F)C1(F)F
Yield: 86.5 %

Procedure:
The reaction of (R)-5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepan-3-one (72 mg, 195 μmol) with Lawesson's reagent (79 mg, 195 μmol) in 1,4-dioxane (5 ml) yielded the (R)-5-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-1,4-oxazepane-3-thione (65 mg, 87% yield) as a white foam. MS (ISP): m/z=386.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10](Br)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21]1(B(O)O)[CH2:23][CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[C:10]([CH:21]2[CH2:23][CH2:22]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1cccc2c1c(Br)nn2Cc1ccccc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2c1c(C1CC1)nn2Cc1ccccc1
Temperature: 100 °C
Yield: 68.5 %

Procedure:
To a reaction vial was added 1-benzyl-3-bromo-4-nitro-1H-indazole (100 mg, 0.301 mmol), cyclopropylboronic acid (33.6 mg, 0.391 mmol) and potassium phosphate (192 mg, 0.903 mmol). Toluene (1.5 mL) and water (0.1 mL) were added. The mixture was purged with argon for 30 minutes. Palladium (II) acetate (3.38 mg, 0.0151 mmol) and tri-cyclohexyl phosphine (8.44 mg, 0.0301 mmol) were added. The reaction vessel was purged with argon and sealed. The mixture was heated at 100° C. for 24 hours. The mixture was filtered through glass fiber filter paper, washing with ethyl acetate and methanol followed by concentration under reduced pressure. The material was purified by preparative chromatography on silica, eluting with hexane/ethyl acetate (5:1). The band containing the desired product was isolated and concentrated under reduced pressure to give 1-benzyl-3-cyclopropyl-4-nitro-1H-indazole (60.5 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11](=[O:47])[C@H:12]([CH2:33][CH2:34][CH2:35][NH:36]C(OCC1C=CC=CC=1)=O)[NH:13][C:14](=[O:32])[C@H:15]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:16]C(OC(C)(C)C)=O.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11](=[O:47])[C@H:12]([CH2:33][CH2:34][CH2:35][NH2:36])[NH:13][C:14](=[O:32])[C@H:15]([CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)Sc1nc2ccccc2s1
Solvent: O=C(O)C(F)(F)F
Product: NCCC[C@H](NC(=O)[C@@H](N)CCc1ccccc1)C(=O)Sc1nc2ccccc2s1

Procedure:
A solution of Boc-homophenylalanyl-Nδ-Cbz-ornithinyl 2-benzothiazolyl thioether (B) (35 mg) and trifluoroacetic acid (10 ml) was kept at 25° C. for 2 hrs and concentrated in vacuo. After HPLC purification (method A, retention time=42.1 min), there was obtained a white solid (33 mg): 1H NMR (400 MHz, D2O) δ1.78-1.90 (m, 4H), 2.04 (m, 2H), 2.62 (m, 2H), 3.11 (m, 2H), 3.44 (dd, J=13.3; 9.6 Hz, 1H), 3.79 (dd, J=13.0; 2.7 Hz, 1H), 4.06 (t, J=5.9 Hz, 1H), 4.41 (m, 1H), 7.03 (m, 2H), 7.24 (m, 3H), 7.42 (t, J=8.5 Hz, 1H), 7.55 (t, J=9.4 Hz, 1H), 7.81 (d, J=9.5 Hz, 1H), and 7.85 (d, J=8.6 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.CCN(CC)CC>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>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[C:11]([C:35]2[CH:36]=[CH:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=c1c(-c2ccc(F)cc2)c(OS(=O)(=O)C(F)(F)F)cnn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(-c2cnn(Cc3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 100 °C
Yield: 67.6 %

Procedure:
A mixture of the product from Example 8 (154 mg, 0.36 mmol), 4-(methylthio)benzeneboronic acid (67 mg, 0.4 mmol), Et3N (0.11 mmol; 0.8 mmol) and Pd(Ph3P)4 (30 mg, 0.025 mmol) in 15 mL of toluene was heated at reflux, about 100° C. for about 45 minutes. The mixture was concentrated in vacuo and the residue purified by column chromatography (hexanes-ethyl acetate 3:1) to provide the title compound (yield: 98 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 2.47 (s, 3H), 5.38 (s, 2H), 6.98 (m, 4H), 7.12 (m, 2H), 7.20 (m, 2H), 7.35 (m, 3H), 7.54 (m, 2H), 7.86 (s, 1H). MS (DCI/NH3) m/z 403 (M+H)+, 420 (M+NH4)+.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([CH3:25])([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:12][CH:11]=1.[OH-].[K+]>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)[CH2:17][C:18]([CH3:25])([CH3:24])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C)(C)C=Cc1ccc(Cl)cc1
Reactant: COc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(C(CC(C)(C)C(=O)O)c2ccc(Cl)cc2)cc1

Procedure:
Following the method of Rudenko et al*, anisole was alkylated with ethyl 4-(4-chlorophenyl)-2,2-dimethylbut-3-enoate. Hydrolysis of the ester with potassium hydroxide gave 4-(4-chlorophenyl)-4-(4-methoxyphenyl)-2,2-dimethylbutanoic acid, purified by washing with sodium bicarbonate solution and water. Recrystallization from ethyl acetate-light petrol (b.p. 60°-80°) afforded the acid as white prisms, m.p. 139°-142° (63%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([NH:20][CH2:21][CH3:22])[C:17]([C:23]([OH:25])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].S(Cl)(Cl)=O.C(NCC)C>O.C(Cl)(Cl)Cl>[CH2:26]([N:28]([CH2:29][CH3:30])[C:23]([C:17]1[C:18]([NH:20][CH2:21][CH3:22])=[N:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[N:15][CH:16]=1)=[O:25])[CH3:27]
Reactant: CCNc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)O
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Solvent: O=S(Cl)Cl
Product: CCNc1nc(N2CCN(Cc3ccccc3)CC2)ncc1C(=O)N(CC)CC
Yield: 65.3 %

Procedure:
A mixture of 0.5 g (1.46 mmol) of 2-(4-benzylpiperazino)-4-ethylaminopyrimidine-5-carboxylic acid (the compound synthesized in Referential Example 67) and 20 ml of chloroform was added with 0.2 ml (1.43 mmol) of triethylamine, followed by a further addition of 0.22 ml (3.02 mmol) of thionyl chloride. The resultant mixture was stirred at room temperature for 1 hour. After adding 1.0 ml (9.67 mmol) of diethylamine and stirring the resultant mixture for 1 hour, water was added. The resultant mixture was extracted with chloroform. After drying the chloroform layer with MgSO4, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.37 g of the above-identified compound (yield: 64%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1>CS(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:13]=[C:12]([Cl:17])[N:11]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1cc(N2CCOCC2)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A mixture of morpholine (0.604 g, 6.04 mmol) in dry DMSO and NaH (0.251 g, 6.6 mmol) was stirred for 30 minutes at 0° C., after which time 2,4,6-trichloropyridine (1.0 g, 5.50 mmol) was added. This reaction mixture was stirred at room temperature for 4 hours, after which time ice cold water was added to quench the reaction (100 mL). The reaction mixture was then extracted with ethyl acetate, and the extract was washed with 3-4 times water. The organic layer was dried over sodium sulphate and concentrated under vacuum. The residue was purified by column chromatography over 100-200 mesh silica gel. Elution of the column with 20% acetone in hexanes gave the pure product as a colorless solid (0.565 g, yield 44%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: O=Cc1cc(Br)ccn1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Br)ccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
4-Bromo-pyridin-2-carbaldehyde (10.0 g, 53.5 mmol), malonic acid (12.5 g, 120.5 mmol), and piperidine (4.4 mL, 44.4 mmol) were added to pyridine (32.5 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 6.3 g of the titled compound as a white solid.
Reaction SMILES: Cl[CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C=O)C>[C:16]1(=[O:26])[N:20]([CH:2]([CH3:15])[CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[O:6])[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(C(=O)CCC(C)Cl)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CCC(C)N2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Yield: 80.9 %

Procedure:
To a solution of 4-chloro-4′-methoxyvalerophenone (Rieke Metals) (2.26 g, 10.0 mmol) in DMF (10 mL) was added potassium phthalimide (1.85 g, 10 mmol mmol). The solution was heated under N2 (g) at 70° C. overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (70 mL) and water (50 mL). The organic layer was washed with another portion of water (50 mL), followed by saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried (sodium sulfate) and concentrated to give a tan solid (2.73 g, 81% yield). MS m/e 220; HPLC retention time 3.52 min (Method A).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[CH2:11][NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH2:5][CH2:4]1.O[C:27]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(Cl)Cl>[O:25]=[C:10]([NH:9][C@H:6]1[CH2:5][CH2:4][C@@H:3]([NH:2][CH:37]2[CH2:38][CH2:39][C:34]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:35][CH2:36]2)[CH2:8][CH2:7]1)[CH2:11][NH:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1
Reactant: N[C@H]1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C1CCC(O)(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CC[C@@H](NC2CC=C(c3ccccc3)CC2)CC1
Reaction time: 0.17 h
Yield: 6.4 %

Procedure:
N-(2-(cis-4-Amino-cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide hydrochloride (120 mg, 0.315 mmol, 1 eq), 4-hydroxy-4-phenylcyclohexanone (60 mg, 0.315 mmol, 1 eq) and sodium triacetoxyborohydride (134 mg, 0.631 mmol, 2 eq) were stirred in 2% acetic acid/methylene chloride (10 mL) at room temperature for 20 hours. Worked up by adding saturated sodium bicarbonate (10 mL). Stirred 10 minutes then extracted 3 times with methylene chloride (10 mL). The organic layers were combined, dried (sodium sulfate) and stripped to give an oil. Purified over silica gel in 100% ethyl acetate to 4:1 methylene chloride/methanol to give N-(2-oxo-2-(cis-4-(4-phenylcyclohex-3-enylamino)cyclohexylamino)ethyl)-3-(trifluoromethyl)benzamide (10 mg) as a tan solid. MS found: (M+H)+=500.33.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([OH:15])=O)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CC(=O)N2CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the product of EXAMPLE 30B (1 g, 4.74 mmol) in thionyl dichloride (20 mL) was stirred at reflux for 3 hours. The solution was concentrated and the residue was diluted with dry dichloromethane (20 mL) and dropped into a solution of pyrrolidine (0.63 mL, 7.1 mmol) and diisopropyl ethylamine (1.7 mL, 9.5 mmol). The mixture was stirred at room temperature overnight and the mixture was washed with 1N aqueous hydrochloric acid (20 mL) and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated and the residue was purified by flash chromatography on silica gel eluting with 1/100 methanol/dichloromethane to give the title compound.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[F:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH:21]([CH:23]=[O:24])[CH2:20][CH2:19][C:18]=2[CH:25]=1>CS(C)=O>[CH2:20]1[CH:21]([CH:23]2[O:24][CH2:7]2)[O:22][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:25][C:18]=2[CH2:19]1
Reactant: CC(C)(C)[O-]
Reactant: O=CC1CCc2cc(F)ccc2O1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1ccc2c(c1)CCC(C1CO1)O2
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To 234 ml of dimethyl sulfoxide was added 32 g of trimethyl sulfoxonium iodide. To it, potassium tertiary butoxide (16 g) was added and stirred for 1 h at 20-40° C. The reaction mixture was cooled and to it was added a solution of the compound obtained in Example 2 in dimethyl sulfoxide (26 ml.) while maintaining the temperature between 20°-40° C. for 1.5 hr. The reaction mixture was quenched in cold water. The aqueous layer was extracted with ethyl acetate, washed with water, concentrated under reduced pressure followed by product distillation to give 19.6 g of 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII) in the form of a mixture of A and B as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][C@H:12]1[NH:17][CH2:16][C@@H:15]([CH2:18][OH:19])[O:14][CH2:13]1.[NH2:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[C:23]([Cl:28])[N:22]=1>CC#N>[NH2:20][C:21]1[N:26]=[C:25]([N:17]2[C@H:12]([CH3:11])[CH2:13][O:14][C@H:15]([CH2:18][OH:19])[CH2:16]2)[CH:24]=[C:23]([Cl:28])[N:22]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CO[C@H](CO)CN1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CO[C@H](CO)CN1c1cc(Cl)nc(N)n1
Temperature: 160 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
In a 2-5 mL microwave vessel Hunig's base (0.59 mL, 3.35 mmol) was added to [(2S,5R)-5-methyl-2-morpholinyl]methanol hydrochloride (208 mg, 1.12 mmol) in CH3CN (3 mL), and then 2-amino-4,6-dichloropyrimidine (174 mg, 1.06 mmol) was added. The mixture was heated with stirring in a microwave reactor at 160° C. for 1 hour. HPLC indicated complete conversion. The mixture was filtered through a 0.45 um filter disc, evaporated, and the product was purified further by chomatography (Analogix SF25-40 g silica column) eluting with 2-5% CH3OH—CHCl3 to afford the title compound (258 mg) as a white foam. LC-MS (ES) m/z=260 [M+H]+.
Reaction SMILES: [ClH:1].C(OC(N1C=CC=C(C(OC(C)(C)C)=O)N1)=O)C1C=CC=CC=1.[CH3:25][O:26][C:27](=[O:49])[CH2:28][N:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][CH2:32][C@H:31]([NH:40]C(OC(C)(C)C)=O)[C:30]1=[O:48]>C(Cl)Cl>[ClH:1].[CH3:25][O:26][C:27](=[O:49])[CH2:28][N:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][CH2:32][C@H:31]([NH2:40])[C:30]1=[O:48]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Agent: CC(C)(C)OC(=O)C1=CC=CN(C(=O)OCc2ccccc2)N1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Anhydrous HCl was bubbled into a solution of 3S) -2-oxo-3-tert-butoxycarbonylamino-2, 3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester (600a/103, 4.0 g, 11.4 mmol) in 20 ml of CH2Cl2 for 20 min then stirred for 1 h at RT. The reaction was evaporated to give (3S)-2-oxo-3-amino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester hydrochloride as a white solid.