Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:22])=[CH:17][C:16]=1[N+:32]([O-:34])=[O:33].C([O-])(=O)CC([O-])=O>CS(C)=O.O>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:22])[C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[CH:17][C:16]=1[N+:32]([O-:34])=[O:33])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])CC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
NaH, 60% dispersion in mineral oil, (1.27 g, 31.7 mmol) was washed with petroleum ether then suspended in anhydrous DMSO (30 mL). Diethyl malonate (4.85 mL, 31.7 mmol) was dissolved in 8 mL of anhydrous DMSO and added dropwise to the NaH suspension. The mixture was allowed to stir for 15 min at 100° C., during which time the reaction mixture became homogeneous. (4-Bromo-3-nitro-phenyl)-(-4-nitro-phenyl)-methanone (5.15 g, 14.4 mmol) was dissolved in anhydrous DMSO (15 mL) and subsequently added via syringe to the malonate solution. The mixture was allowed to stir at 100° C. for 2 h after which the reaction was cooled to room temperature and poured into water (˜300 mL). The mixture was extracted with EtOAc (3×300 mL) and dried over anhydrous Na2SO4. The organic layers were then concentrated in vacuo affording a crude black oil. The crude oil was then flashed through a plug of silica with 30% EtOAc/Hexanes. The solution was then concentrated in vacuo yielding a pale yellow solid that contained the desired product contaminated with excess diethyl malonate. The impure solid was washed with Hexanes, filtered and dried affording diethyl [2-nitro-4-(4-nitrobenzoyl)phenyl]malonate in 75% yield (4.64 g, 10.8 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].N1C=CC=CC=1.[F:19][CH:20]([F:24])[C:21](Cl)=[O:22]>O1CCOCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:21](=[O:22])[CH:20]([F:24])[F:19])=[C:3]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=1
Reactant: O=C(Cl)C(F)F
Reactant: Nc1ccc(Cl)cc1S(N)(=O)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(Cl)ccc1NC(=O)C(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 1 g of 2-amino-5-chlorobenzenesulphonamide (obtained in accordance with J. Chem. Soc. Perkin I 1979, 1043-1047) dissolved in 4 ml of dioxane there are added, in the cold state (+5° C.), 0.6 ml of pyridine and 0.6 ml of difluoroacetic acid chloride. The flask is hermetically closed immediately and subjected to vigorous stirring at ambient temperature for 10 minutes. The solvents are then removed under reduced pressure. The solid residue is taken up in water (12 ml), and the insoluble material is collected by filtration, washed with water and dried to yield the expected compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][CH:15]=[CH2:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](F)[C:27]=1[CH3:33].Cl.CCO>>[Cl:25][C:26]1[C:27]([CH3:33])=[C:28]([CH:29]=[CH:30][CH:31]=1)[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH:15]=[CH2:16]
Reactant: C=CC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1c(F)cccc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C=CC[C@H](Oc1cccc(Cl)c1C)[C@H]1CCNC1
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxy-but-3-enyl)pyrrolidine-1-carboxylic acid t-butyl ester (31 mg, 130 μmol) was dissolved in DMF (470 μL, 6.1 mmol). 60% Sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 10.1 mg, 169 μmol) was carefully added, and the mixture allowed to stand for 15 minutes. 2-Chloro-6-fluorotoluene (47.0 μL, 390 μmol) was added. The mixture was stirred at 70° C. for 3 hours. The reaction was quenched with MeOH, and the solvent was removed. 1.2M HCl in EtOH (630 μL, 760 μmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (1 mg, 100% purity). MS m/z: [M+H]+ calcd for C15H20C1NO, 266.12. found 266.0.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>[Pd].C(O)C>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:17]=3)[CH:12]=[CH:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: O=[N+]([O-])c1ccc2ccn(CCCN3CCOCC3)c2c1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2ccn(CCCN3CCOCC3)c2c1)c1cccs1
Reaction time: 15 h
Yield: 92.2 %

Procedure:
A solution of compound 149 (2.0 g, 6.912 mmol) in abs. ethanol (20 mL) was treated with Pd—C (0.25 g), purged with hydrogen gas and stirred for overnight (15 h) under hydrogen atm. (balloon pressure). The reaction mixture was filtered through a celite pad and washed with abs. ethanol (2×20 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (3.94 g, 13.824 mmol) and the resulting mixture was stirred for overnight (16 h) at room temperature. The solvent was evaporated and the product was precipitated with ether (250 mL). The solid was dissolved into sat. NaHCO3 sol.: CH2Cl2 (100 mL, 1:1). The org. layer was separated and aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined CH2Cl2 layer was washed with brine (25 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography (2M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 150 (2.348 g, 92%) as a foam. 1H-NMR (DMSO-d6) δ 1.83-1.91 (m, 2H), 2.19 (t, 2H, J=6.6 Hz), 2.30 (brs, 4H), 3.56 (t, 4H, J=4.8 Hz), 4.14 (t, 2H, J=6.6 Hz), 6.34-6.35 (m, 3H), 6.58 (dd, 1H, J=1.2, 8.2 Hz), 6.95 (brs, 1H), 7.09 (dd, 1H, J=3.9, 5.1 Hz), 7.21 (d, 1H, J=3.0 Hz), 7.44 (d, 1H, J=8.1 Hz), 7.59 (d, 1H, J=3.9 Hz), 7.72 (dd, 1H, J=0.9, 3.6 Hz).
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9].[NH2:29][C@H:30]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:40])[NH:36][N+:37]([O-:39])=[O:38].ON1C2C=CC=CC=2N=N1.C1(N=C=N)CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([NH:29][C@H:30]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:40])[NH:36][N+:37]([O-:39])=[O:38])=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[Cl:14])=[O:9]
Reactant: N=C(NCCC[C@H](N)C(=O)OCc1ccccc1)N[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)O
Agent: N=C=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Boc-Lys(Cl-Z)-OH (4.15 g), H-Arg(NO2)OBzl.2TsOH (6.54 g) and 1-hydroxybenzotriazole (1.35 g) were dissolved in methylene chloride (70 ml) and then triethylamine (2.02 g) was added, followed by addition of cyclohexylcarbodiimide (2.06 g) under ice-cooling. The temperature was raised to room temperature. The mixture was stirred for 4 hours and then filtered. The filtrate was concentrated and extracted with ethyl acetate. The extract was washed with water, dilute sodium hydrogen carbonate, water and sodium chloride in that order, dried over magnesium sulfate, and concentrated to give Boc-Lys(Cl-Z)-Arg(NO2)-OBzl (7.29 g) as an amorphous solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]=[C:11]=[S:12])[CH3:2].[CH:13]([NH:16][CH2:17][C:18](O)=[O:19])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]1[C:18](=[O:19])[CH2:17][N:16]([CH:13]([CH3:15])[CH3:14])[C:11]1=[S:12])[CH3:2]
Reactant: CC(C)NCC(=O)O
Reactant: CCc1cccc(C)c1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C)c1N1C(=O)CN(C(C)C)C1=S
Yield: 47.1 %

Procedure:
The title compound was prepared by the procedure described in Example 18 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 21.2 g of N-isopropyl glycine, 21.0 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethanol afforded the title compound (13.0 g) as a light yellow solid, m.p. 132°-134° C. Anal. Calcd. for. C15H20N2OS: C, 65.18; H, 7.29; N, 10.14. Found: C, 65.06; H, 7.37; N, 10.20. Mass spectrum (EI, M.+) m/z 276.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][C:30](O)=[O:31])[CH:24]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:30](=[O:31])[CH2:29][C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)=[CH:17][N:16]2[CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Reactant: O=C(O)Cc1cccnc1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)Cc3cccnc3)ccc2n1
Yield: 42 %

Procedure:
As described for Example 56, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (96 mg, 0.33 mmol) was converted, using 3-pyridylacetic acid instead of cyclopropylacetic acid, to the title compound (26 mg, 42%) which was obtained as a light brown solid. MS: m/e=410.0 [M+H]+.
Reaction SMILES: F[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[S:10]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:28][O-:29].[Na+]>>[F:27][C:24]1[CH:23]=[CH:22][C:21](/[CH:20]=[CH:19]/[C:16]2[CH:17]=[CH:18][C:13]([S:10]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=3[O:29][CH3:28])(=[O:11])=[O:12])=[CH:14][CH:15]=2)=[CH:26][CH:25]=1
Reactant: C[O-]
Reactant: COc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1F
Agent: [Na+]
Product: COc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1OC
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-fluoro-1-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)-3-methoxybenzene (Example 192, 45 mg, 0.116 mmol) and sodium methoxide (0.5M in methanol, 1 mL) was heated to 150° C. for 10 minutes in a microwave reactor. A further 0.5 mL sodium methoxide was added and heating continued at 150° C. for 30 minutes. The cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 20% ethyl acetate/isohexane, to give the title compound. δH (500 MHz, d6 DMSO): 7.91 (2H, d, J=8.5 Hz), 7.76 (2H, d, J=8.4 Hz), 7.67 (2H, dd, J=5.7, 8.7 Hz), 7.52 (1H, dd, J=2.2, 8.5 Hz), 7.39 (2H, d, J=2.3 Hz), 7.28 (1H, s), 7.25–7.19 (2H, m), 7.14 (1H, d, J=8.6 Hz), 3.82 (3H, s), 3.80 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35]>C1COCC1>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=[C:16]([NH:32][C@@H:33]([CH3:36])[CH2:34][OH:35])[N:17]=2)=[C:20]([CH3:26])[CH:21]=1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: C[C@H](N)CO
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(N[C@@H](C)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 240 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and (S)-2-amino-1-propanol (75 mg, 1 mmol) were dissolved in THF (10 ml) and stirred under Ar at 230 for 10 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-15% EtOAc/CH2Cl2 gave the title compound as an off-white amorphous solid. mp 96-101°, LC MS m/z=441 (MH+). Retention time=2.04 min.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[C:28]([O:32][C:33]([N:35]([CH2:41][CH2:42][OH:43])[CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:38](=[O:39])[CH2:37][CH2:36][N:35]([CH2:41][CH2:42][OH:43])[C:33](=[O:34])[O:32][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(CCO)CCC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 3-[(tert-butoxycarbonyl)(2-hydroxyethyl)amino]propanoic acid (0.038 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.034 g, 0.000175 mol), N,N-diisopropylethylamine (0.034 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous dichloromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-oxopropyl)-N-(2-hydroxyethyl)carbamate (0.040 g, 0.000070 mol).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]#[N:13])[CH:4]=[CH:3]1.CN1C2C(=CC=CC=2C=[O:25])C=C1.[Li]C#N.C(OP(C#N)(=O)OCC)C.C(O)(C)(C)C>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:13])=[O:25])[CH:4]=[CH:3]1
Reactant: Cn1ccc2cccc(C=O)c21
Reactant: Cn1ccc2cccc(CC#N)c21
Agent: CCOP(=O)(C#N)OCC
Agent: [Li]C#N
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Cn1ccc2cccc(CC(N)=O)c21
Reaction time: 0.5 h

Procedure:
(1-Methyl-1H-indol-7-yl)-acetonitrile (adapted from the procedure described in YONEDA, R.; HARUSAWA, S.; KURIHARA, T. Tetrahedron Lett. 1989, 30, 3681–3684; YONEDA, R.; HARUSAWA, S.; KURIHARA, T. J. Org. Chem. 1991, 56, 1827–1832). A solution of 1-methyl-1H-indole-7-carboxaldehyde (137 mmol, crude material prepared as described above), LiCN 1.5 THF complex (1.94 g, 13.7 mmol), and diethylcyanophosphonate (27.1 mL, 179 mmol) in THF (400 mL) was stirred at room temperature overnight. Tert-butanol (13.1 mL, 137.7 mmol) was introduced and the mixture was transferred via cannula into a 0.1 M solution of SmI2 in THF (3.6 L, 360 mmol) and the mixture stirred for 30 minutes. The mixture was concentrated to dryness, the residue was taken up in EtOAc (2 L), and the solution was washed with 1N HCl (3×500 mL), saturated aq NaHCO3, and brine. The solution was dried (MgSO4), passed through a pad of silica gel, and concentrated to give the title compound in sufficient purity for use in the next step. Flash chromatography (90% hexane/EtOAc) can be used to afford the title compound pure, as an off-white crystalline solid. 1H (400 MHz, DMSO-d6) 7.51 (d, J=7.5 Hz, 1H), 7.28 (d, J=3 Hz, 1H), 7.09 (d, J=7.5 Hz, 1H), 6.99 (dd, J=7.5, 7.5 Hz, 1H), 6.43 (d, J=3 Hz, 1H), 4.58 (s, 2H), 4.07 (s, 3H). 13C NMR (75.5 MHz, DMSO-d6) 133.56, 131.89, 130.06, 122.38, 120.74, 119.53, 119.16, 114.47, 100.59, 35.86, 20.43. IR (CHCl3, cm−1) 2252. MS (electrospray, m/z) 171 (M++1). Anal. Calcd for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C, 77.62; H, 5.96; N, 16.38.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1.N([O-])=O.[Na+].[ClH:21]>O.[Cu]Cl>[Cl:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]1
Reactant: Cl
Reactant: CC(=O)N1CCC(c2ccccc2N)CC1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCC(c2ccccc2Cl)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-[4-(2-Amino-phenyl)-piperidin-1-yl]-ethanone (0.3 g, 1.38 mmol) was dissolved in a solution of hydrochloric acid (6 N, 6 mL) and cooled to 0° C. A solution of sodium nitrite (0.097 g, 1.4 mmol) in water (1 mL) was added drop wise and the mixture stirred for 1 hour. The resulting solution was added drop wise to a solution of copper (I) chloride (0.35 g, 3.5 mmol) in hydrochloric acid (6 N, 6 mL). The mixture was allowed to warm to room temperature, and was then diluted with water (20 mL) and the products extracted into ethyl acetate. The organic solution was washed with water (20 mL) then dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as an orange oil (0.2 g). LCMS m/z 238.2 [M+H]+. R.T.=4.30 min (Analytical Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Br:22][CH2:23][C:24](=O)[CH2:25][Br:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:24]([CH2:25][Br:26])[CH2:23][Br:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: O=C(CBr)CBr
Solvent: C1CCOC1
Product: Fc1ccccc1C1=NCC(NN=C(CBr)CBr)=Nc2ccc(Cl)cc21

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,3-dibromopropanone under nitrogen to give 7-chloro-2-[[2-bromo-1-(bromomethyl)ethylidene]hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [F:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:11]1[C:2]([F:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C)c1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(CBr)c1F
Yield: 56.6 %

Procedure:
To a solution of methyl 2-fluoro-3-methylbenzoate (13.8 g, 82.3 mmol) from Step A above and N-bromosuccinimide (16.0 g, 90.6 mmol) in carbon tetrachloride (82 mL) at room temperature was added a catalytic amount of benzoyl peroxide. The yellow mixture was heated under reflux until the reaction was complete by TLC (overnight) and then it was concentrated and purified by column chromatography (silica gel, 9:1 hexanes/ethyl acetate) to afford methyl 3-(bromomethyl)-2-fluorobenzoate as a light yellow oil (11.5 g, 56%): 1H NMR (500 MHz, CDCl3) δ 7.90 (t, J=8.0 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 7.19 (t, J=7.5 Hz, 1H), 4.53 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:19]2[CH2:20][CH2:21][O:22][CH2:23][CH:24]=2)[C:5]2C[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][C:6]=2[N:7]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>>[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:2]2[N:3]=[C:4]([CH:19]3[CH:20]=[CH:21][O:22][CH2:23][CH2:24]3)[C:5]3[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][C:6]=3[N:7]=2)=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(Cl)nc2C2=CCOCC2)C1
Reactant: Nc1ncc(B(O)O)cn1
Product: CC(C)(C)OC(=O)N1Cc2nc(-c3cnc(N)nc3)nc(C3C=COCC3)c2C1

Procedure:
Compound de was synthesized according to general procedure described in step 2 of Example 1 by reacting tert-butyl 2-chloro-4-(3,6-dihydro-2H-pyran-4-yl)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate with 2-aminopyrimidin-5-ylboronic acid. LC-MS: m/z=397 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>>[C:1]([O:6][CH2:7][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCCCCCCCCCCCO
Reactant: C=C(C)C(=O)OC
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCCCCCCCCCCC
Reaction time: 6 h

Procedure:
Two hundred six grams of a reaction mix containing a 5:1 mole ratio of methyl methacrylate, 1-dodecanol, and 100 ppm phenothiazine as inhibitor were added to a 500 ml flask equipped with an agitatior, thermocouple, and a 10-tray Oldershaw fractional distillation column. Thirty grams of the heterogeneous zirconium vinylbenzyl acetylacetonate/styrene/divinylbenzene catalyst was added. The mixture was heated to reflux at atmospheric pressure while an azeotropic mixture of methyl methacrylate and methanol was removed from the upper portion of the fractionating column. The reaction was continued in this manner for 6 hours while the temperature at the column was 64°-67° C. and the temperature in the pot was 101°-107° C. Gas liquid chromatography (GLC) analysis showed 30% conversion of 1-dodecanol with a selectivity to dodecyl methacrylate of 95%.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([N:12]1[C:16]2[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=2[N:14]=[C:13]1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)C.O.[OH-].[Li+]>O1CCOCC1.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:13]2[N:12]([CH:5]([CH:6]3[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]3)[C:4]([OH:30])=[O:3])[C:16]3[CH:17]=[C:18]([F:22])[C:19]([F:21])=[CH:20][C:15]=3[N:14]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
To the solution of 24 g (0.055 mol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid ethyl ester in 240 ml dioxan, 240 ml water and 7.0 g (0.166 mol) lithium hydroxide monohydrate were added. The solution was stirred for 2 h at 100° C. After cooling to room temperature the organic solvent was evaporated. Under stirring 162 ml 1M hydrochloric acid were added. The resulting suspension was filtered, the filter cake washed with water and dried under high vacuum to give 21.7 g (95%) of the desired compound as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[CH3:24]>C1COCC1>[F:17][C:18]1[CH:19]=[C:20]([CH:1]([OH:2])[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: N#Cc1cccc(-c2ccncc2C=O)c1
Reactant: Cc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2cnccc2-c2cccc(C#N)c2)cc1F

Procedure:
To a solution of 3-(3-formyl-pyridin-4-yl)-benzonitrile (41 mg, 0.20 mmol) in THF (2 mL) at −78° C. was added 0.5 M 3-fluoro-4-methylphenylmagnesium bromide in THF (0.8 mL). The reaction mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash chromatography eluted with 5% methanol in dichloromethane to yield 3-{3-[(3-fluoro-4-methyl-phenyl)-hydroxy-methyl]-pyridin-4-yl}-benzonitrile as a colorless oil.