Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C.O>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([O:5][C:4]1[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
Orcinol monohydrate (1.42 g, 10.0 mmol) and 2,3-dichlorobenzenesulfonyl chloride (2.46 g, 10.0 mmol) were mixed in saturated aqueous NaHCO3 (30 mL) and diethyl ether (30 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted into ethyl acetate (3×50 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (1.45 g, 45%). 1H-NMR (300 MHz, CDCl3) δ 7.91 (d, J=8.0 Hz, 1 H), 7.75 (d, J=8.0 Hz, 1 H), 7.33 (t, J=8.0 Hz, 1 H), 6.55 (s, 2 H), 6.44 (s, 1 H), 5.27 (s, 1 H), 2.24 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25](O)=O)[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([CH2:25][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Reactant: CN1CCNCC1
Product: CN1CCN(Cc2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(F)cc4F)cc2CO3)CC1

Procedure:
Following the procedure of Examples 25 and 70 and General Procedure E, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and 1-methylpiperazine were coupled to give 136bp.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1>CCO.Cl.O=[Pt]=O>[OH:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: OCc1ccc(C2CCCCN2)cc1
Reaction time: 40 h
Yield: 90.7 %

Procedure:
To a solution of 4-pyridin-2-yl-benzaldehyde (1.036 g, 5.65 mmol) in EtOH (95%, 3.1 mL) and conc. HCl (0.48 mL) in a Parr hydrogenation flask was added PtO2 (57 mg, 0.251 mmol) and the mixture hydrogenated at 50 psi H2 for 40 h. The mixture was filtered through celite, the cake washed with MeOH and the solvent was removed from the eluent under reduced pressure. The resultant yellow solid was dissolved in 1 N NaOH (30 mL) and extracted with ether (4×50 mL). The combined organic phases were dried (Na2SO4), filtered and concentrated under reduced pressure to give crude 1-(hydroxymethyl)-4-(piperidin-2-yl)-benzene (0.98 g) as white solid. To a solution of the solid in THF (25 mL), triethylamine (10 drops) and water (10 drops) was added di-tert-butyl dicarbonate (1.51 g, 6.92 mmol) and the reaction stirred at room temperature for 20 h. The mixture was concentrated under reduced pressure and the residue taken up in CH2Cl2 (100 mL) and washed with brine (3×75 mL). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give crude 1-(hydroxymethyl)-4-[(1-butoxycarbonyl)-piperidin-2-yl]-benzene (1.87 g) as an oil.
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][N:7]=CC1C2C(=CC=CC=2)C=CC=1O)=[O:5].[C:24](C1C=CC(C(O)=O)=CC=1)([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C1C=CC=CC=1.NN>>[C:24]([C:22]1[CH:23]=[CH:2][C:3]([C:4]([NH:6][NH2:7])=[O:5])=[CH:20][CH:21]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: Nc1ccccc1C(=O)NN=Cc1c(O)ccc2ccccc12
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: NN
Agent: O=C(O)c1ccccc1
Product: CC(C)(C)c1ccc(C(=O)NN)cc1

Procedure:
The particularly preferred substituted aromatic hydrazone 2-hydroxy-1-naphthaldehyde-p-(t-butyl)-benzoyl hydrazone is prepared in a manner similar to the preparation of 2-hydroxy-1-naphthaldehyde-o-aminobenzoyl hydrazone, Equations (1) through (3) above. Since the ester of p-(t-butyl)-benzoic acid is not available the preparation of this hydrazone requires the additional step of esterification of the benzoic acid. The ester of p-(t-butyl)-benzoic acid is reacted with hydrazine to produce p-(t-butyl)-benzhydrazide. This hydrazide is then reacted with 2-hydroxy-1-naphthaldehyde to yield 2-hydroxy-1-naphthaldehyde-p-(t-butyl)-benzoyl hydrazone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2.C([Sn](CCCC)(CCCC)[C:26]1[N:27]=[CH:28][N:29](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=1)CCC>C1(C)C=CC=CC=1.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>[Cl:11][C:9]1[CH:10]=[C:2]([C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1Cc1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(-c3c[nH]cn3)cc2CN1Cc1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
A mixture of 5-Bromo-7-chloro-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (127 mg, 0.343 mmol), 4-Tributylstannanyl-1-trityl-1H-imidazole (300 mg, 0.514 mmol), and Pd(PPh3)4 (79 mg, 0.0514 mmol) in toluene (15 mL) stirred overnight at 110° C. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue (7-Chloro-2-(4-chloro-benzyl)-5-(1-trityl-1H-imidazol-4-yl)-2,3-dihydro-isoindol-1-one) was dissolved in formic acid (5 mL) and stirred at room temperature for 18 hrs. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organics were washed with 3N HCl (2×30 ml) and the aqueous washes were combined, neutralized with 1N NaOH, and extracted with ethyl acetate. The organics were washed with brine, and dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (100% Ethyl acetate—5% 2M NH3 in MeOH/CH2Cl2) provided the title compound (22 mg, 18%). 1H NMR (300 MHz, CDCl3): δ 7.80 (s, 2H), 7.7.75 (s, 1H), 7.46 (s, 1H), 7.35-7.30 (m, 4H), 4.77 (s, 2H), 4.27 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C@@H:10]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:22]([C:25]([CH3:31])([CH3:30])[C:26](OC)=[O:27])=[C:23]=[O:24]>C1COCC1>[CH2:1]([O:8][NH:9][C@@H:10]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH2:11][N:12]1[C:26](=[O:27])[C:25]([CH3:31])([CH3:30])[NH:22][C:23]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)N=C=O
Reactant: NC[C@H](COc1ccc(Br)cc1)NOCc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)NC(=O)N(C[C@H](COc2ccc(Br)cc2)NOCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of Example 3G (19.7 g) in THF (100 mL) at room temperature was treated with the solution of the methyl 2-isocyanato-2-methylpropanoate in THF, stirred for 25 minutes, and concentrated to a volume of 170 mL. The concentrate was treated with THF (80 mL) and 6M HCl (95 mL), heated to reflux, stirred for 6 hours, cooled to room temperature, concentrated, and extracted with isopropyl acetate. The extract was washed sequentially with water, saturated NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated to provide 24.2 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ8.33 (s, 1H), 7.47 (m, 2H), 7.35 (m, 5H), 6.90 (m, 2H), 6.78 (d, 1H, J=5 Hz), 4.65 (m, 2H), 4.00 (m, 2H), 3.68 (m, 1H), 3.55 (m, 2H), 1.30 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[N:37]([CH2:40][CH3:41])=[C:38]=[O:39]>>[NH2:36][C:15]1[N:16]=[C:17]([N:19]2[CH:28]([CH3:29])[CH2:27][C:26]3[C:21](=[CH:22][C:23]([CH:30]4[CH2:31][CH2:32][N:33]([C:38]([NH:37][CH2:40][CH3:41])=[O:39])[CH2:34][CH2:35]4)=[CH:24][CH:25]=3)[CH2:20]2)[CH:18]=[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]2)[N:14]=1
Reactant: CCN=C=O
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CCNC(=O)N1CCC(c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and isocyanatoethane. LCMS (M+H)+: m/z=493.4.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH2:6].Br[CH2:15][C:16]([CH3:18])=[CH2:17].O>C1COCC1>[Br:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH:6][CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CNc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a suspension of NaH 60% dispersion in oil (97 mg, 0.0023 mol) in 2 mL of anhydrous THF at 0° C. was added 2-bromo-5-nitroaniline (500 mg, 0.0023 mol) in 2 mL of THF dropwise, the temperature was raised to rt to complete deprotonation then lowered to 0° C. 3-bromo-2-methylpropene (232 mL, 0.0023 mol) was added very slowly and the reaction mixture was stirred at 0° C. for 3 h then neutralized with water (5 mL). The mixture was extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give 200 mg (32%) of 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline (structure 55A of Scheme XLVII, where R1 =methyl, R2 =H). Data for 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline: 1H NMR (400 MHz, CDCl3) 7.55 (d, J=8.5, 1H), 7.40 (dd, J=8.5, 2.8, 1H), 7.39 (d, J=2.8, 1H), 4.96 (s, 2H), 4.95 (bs, 1H), 3.82 (d, J=5.9, 2H), 1.81 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:24]([F:26])[F:25])=[N:8][N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[O:5])C.[OH-].[Na+]>C(O)C>[C:18]1([N:9]2[C:10]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH:24]([F:25])[F:26])=[N:8]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1c(C(F)F)nn(-c2ccccc2)c1C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(C(F)F)nn(-c2ccccc2)c1C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
N-Phenyl-3-difluoromethyl-5-pentafluoroethyl-4-pyrazolecarboxylic acid ethyl ester (3.0 g, 7.81 mmol) in ethanol (15 ml) was admixed gradually with an 8N aqueous sodium hydroxide solution (3.0 ml) and stirred at room temperature for 3 h. The solvent was removed by rotary evaporation; the residue was taken up in water (40 ml) and extracted with diethyl ether (20 ml). Acidification to pH 1 with 6M HCl was followed by extraction with ethyl acetate (3×30 ml). The combined organic phases were dried over sodium sulphate and filtered, and the solvent was removed by rotary evaporation. N-Phenyl-3-difluoromethyl-5-pentafluoroethyl-4-pyrazolecarboxylic acid (2.71 g, 7.61 mmol, 98%) was isolated as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:79])[C:71]1[CH:76]=[CH:75][C:74]([NH2:77])=[CH:73][C:72]=1[F:78])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:79])[C:71]1[CH:76]=[CH:75][C:74]([NH:77][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[CH:73][C:72]=1[F:78])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1F
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich, 147 mg, 0.39 mmol) was added followed by the addition of DIPEA (0.225 mL, 1.29 mmol) and 4-amino-2-fluoro-benzoic acid t-butyl ester (Aldrich, 44 mg, 0.32 mmol). The mixture was stirred at rt for 5.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 0-15% EtOAc/hexanes) to give a white solid. 19 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]3[C:10](=[N:11][N:12]=[C:13]3[C@H:15]3[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]3)[CH2:9][N:8]([C:25](=[O:31])[CH2:26][O:27]C(=O)C)[CH2:7][C:6]=2[CH:32]=1.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:14]3[C:10](=[N:11][N:12]=[C:13]3[C@H:15]3[CH2:20][CH2:19][C@H:18]([O:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]3)[CH2:9][N:8]([C:25](=[O:31])[CH2:26][OH:27])[CH2:7][C:6]=2[CH:32]=1
Reactant: CC(=O)OCC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](OC(C)C)CC2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)O[C@H]1CC[C@H](c2nnc3n2-c2ccc(Cl)cc2CN(C(=O)CO)C3)CC1
Reaction time: 0.67 h

Procedure:
To a solution of trans-acetic acid 2-[8-chloro-1-(4-isopropoxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzoazulen-5-yl]-2-oxo-ethyl ester in methanol (5 ml) was added one drop of a 30% methanolic sodium methoxide solution at room temperature. Stirring for 40 minutes was followed by quenching with water. The mixture was extracted with three portions of tert-butyl methyl ether. The combined org layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/2-propanol as eluent gave the title compound (0.033 g, 49%) as white solid. MS m/e: 419 (M+H+).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[C:15]([F:23])[CH:16]=[CH:17][CH:18]=3)[C:13]([F:25])([F:24])[C:12]([F:27])([F:26])[C:11]=2[C:10]=1[F:28])[CH3:7].[I:29]I>C1COCC1>[CH2:6]([O:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[C:15]([F:23])[C:16]([I:29])=[CH:17][CH:18]=3)[C:13]([F:24])([F:25])[C:12]([F:27])([F:26])[C:11]=2[C:10]=1[F:28])[CH3:7]
Reactant: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c(F)cccc1-2
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc2c(c1F)C(F)(F)C(F)(F)c1c-2ccc(I)c1F
Temperature: -60 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
Under a nitrogen atmosphere, n-butyllithium (1.65 M, 14.1 mL, 23.26 mmol) was slowly added dropwise, at −60° C. or lower, to a THF (50 mL) solution of compound (87) (6.44 g, 19.38 mmol). The reaction mixture was agitated at −60° C. or lower for 1 hour, and then a THF (30 mL) solution of iodine (5.9 g, 23.26 mmol) was added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with a saturated aqueous solution of ammonium chloride, and extracted with 50 mL of toluene three times. Combined organic layers were washed with a sodium thiosulfate aqueous solution, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 2-ethoxy-1,8,9,9,10,10-hexafluoro-7-iodo-9,10-dihydrophenanthrene (88) (6.7 g, yield 74.5%) was obtained.
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[C-:13]#[N:14].[K+]>CN1CCCC1=O.[Cu]I>[C:13]([C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:10])[C:4]=2[CH:3]=1)#[N:14]
Reactant: [C-]#N
Reactant: O=c1[nH]cnc2cnc(Cl)cc12
Agent: [Cu]I
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc2c(=O)[nH]cnc2cn1
Reaction time: 70 h
Yield: 25.3 %

Procedure:
6-Chloro-pyrido[3,4-d]pyrimidin-4one (10 g) in 1-methyl-2-pyrrolidinone (100 ml) was treated with copper (I) iodide (10.52 g) and potassium cyanide (7.10 g) at 215° C. for 72 hours under N2. Further potassium cyanide was added (3.58 g) and heating continued at 230° C. for 70 hours. The 1-methyl-2-pyrrolidinone was removed by distillation at reduced pressure and the residue absorbed onto silica. Chromatography gave the title compound (2.4 g) as a beige solid; δH [2H6]DMSO 13.0(1H,bs), 9.25 (1H,s), 8.55 (1H,s), 8.50 (1H,s); m/z (M-1+) 171.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C[N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[C:14](=[O:16])[NH2:18])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O

Procedure:
To a solution of N-Boc-L-pipecolinic acid (200 mg, 0.87 mmol) in DMF (3.5 mL) was added TBTU (336 mg, 1.05 mmol), ammonium chloride (93 mg, 1.74 mmol) then DIPEA (182 μL, 1.05 mmol) and the reaction stirred for 16 h. The mixture was partitioned between ethyl acetate (2×30 mL) and water (30 mL), and the organics combined before being washed with 1M sodium hydroxide (3×30 mL) and brine (3×30 mL). The organic solution was dried (MgSO4) and solvent removed in vacuo to give the title compound as a white solid. δH (d6 DMSO): 7.23 (1H, s), 6.97 (1H, s), 4.56–4.39 (1H, br m), 3.43–3.74 (1H, d), 3.14–2.90 (1H, br m), 2.09–2.00 (1H, d), 1.63–1.47 (3H, m), 1.30–1.17 (2H, m).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][NH:4][C:5]([NH:7][C:8]([NH2:10])=[S:9])=[NH:6].Cl[CH2:14][C:15](=O)[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>CCO>[F:12][C:2]([F:1])([F:11])[CH2:3][N:4]=[C:5]([NH2:6])[NH:7][C:8]1[S:9][CH:14]=[C:15]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[N:10]=1
Reactant: COC(=O)CCCC(=O)CCl
Reactant: N=C(NCC(F)(F)F)NC(N)=S
Solvent: CCO
Product: COC(=O)CCCc1csc(NC(N)=NCC(F)(F)F)n1

Procedure:
To 2,2,2-trifluoroethylamidinothiourea (2.1 g.) in hot EtOH (20 ml.) was added a solution of methyl 6-chloro-5-oxohexanoate (2.0 g.) in hot EtOH (20 ml.). The mixture was heated under reflux for 1 hour and then evaporated to dryness. The residue was partitioned between ether (20 ml.) and water (60 ml.). The aqueous layer was separated, basified with sodium bicarbonate and extracted with EtOAc. The organic layer was evaporated to dryness to give a gum which was recrystallised from EtOAc/ether/acetone to give methyl 4-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-yl]butyrate which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[C:3](=[O:6])[CH2:4][Cl:5].C(O)CO.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.CO>[CH3:1][N:2]([CH2:7][CH:8]1[O:11][CH2:12][CH2:10][O:9]1)[C:3](=[O:6])[CH2:4][Cl:5]
Reactant: COC(CN(C)C(=O)CCl)OC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: OCCO
Product: CN(CC1OCCO1)C(=O)CCl
Temperature: 25 °C

Procedure:
N-Methyl-N-(2,2-dimethoxyethyl)-α-chloroacetamide (19.5 grams; 0.10 mole), ethylene glycol (6.82 grams; 0.11 mole) and 10 drops of a solution of toluene sulfonic acid (1 gram) in ether (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and distillation head. The mixture was heated at 100° to 110° C. with stirring and the methanol removed as it was formed. After no more methanol was given off the reaction mixture was cooled to room temperature and was stirred with about 2 grams of sodium carbonate for a period of about 1 hour. After this time the reaction mixture was filtered and the filtrate was distilled under reduced pressure to yield the desired product N-methyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide having a boiling point of 119° to 124° C. at a pressure of 0.15 to 0.30 mm of Hg.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]3[CH2:14][C:11]3([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.O1CCCC1.[Pd]>[CH3:14][C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[NH:10][C:9]2=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=[C:8]2[O:13][CH2:12]1
Reactant: O=[N+]([O-])c1cccc2c1N1CC1(c1ccccn1)CO2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(c2ccccn2)COc2cccc(N)c2N1
Reaction time: 6 h
Yield: 31.1 %

Procedure:
A mixture of 7-nitro-1a-pyridin-2-yl-1a,2-dihydro-1H-azireno[2,1-c][1,4]benzoxazine (100 mg, 0.4 mmol) in methanol (6 mL) and tetrahydrofuran (2 mL) was degassed with nitrogen in a Parr bottle followed by addition of palladium (10% on carbon) (30 mg, 0.28 mmol). The reaction was charged with hydrogen to 40 psi and shaken for 6 hrs. The reaction was filtered and concentrated to give crude 3-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (0.030 g. 30%). LCMS calculated for C14H16N3O (M+H)+: m/z=242.1. found: 242.1.
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([O:11]C)=O)=[C:2]=[S:3].[CH3:13][C:14]1[N:18]([CH2:19][CH2:20][CH2:21][NH2:22])[CH:17]=[N:16][CH:15]=1>>[CH3:13][C:14]1[N:18]([CH2:19][CH2:20][CH2:21][N:22]2[C:9](=[O:11])[C:5]3[S:6][CH:7]=[CH:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:17]=[N:16][CH:15]=1
Reactant: COC(=O)c1sccc1N=C=S
Reactant: Cc1cncn1CCCN
Product: Cc1cncn1CCCn1c(=S)[nH]c2ccsc2c1=O

Procedure:
The compound was synthesized starting from methyl 3-isothiocyanatothiophene-2-carboxylate (0.22 g, 1.08 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.15 g, 1.08 mmol) as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:15]#[N:16])[CH2:10][C:11](OC)=[O:12]>[Ni]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]1[CH2:15][NH:16][C:11](=[O:12])[CH2:10]1
Reactant: COC(=O)CC(C#N)Cc1ccccc1Cl
Agent: [Ni]
Product: O=C1CC(Cc2ccccc2Cl)CN1

Procedure:
In the same manner as Example 1-(d), 10 g of methyl 4-(2-chlorophenyl)-3-cyanobutyrate was catalytically reduced with the aid of Raney's nickel to obtain 4-(2-chlorobenzyl)-2-pyrrolidinone.