Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[C:7]1([CH:12]=[CH:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)[N:6](CC1C=CC(OC)=CC=1)[C:5]2=[O:33]>C(O)(C(F)(F)F)=O.C(S(O)(=O)=O)(F)(F)F>[Cl:1][C:2]1[CH:3]=[C:4]2[C:20](=[C:21]([Cl:23])[CH:22]=1)[C:7]1([CH:8]=[CH:9][NH:10][CH2:11][CH2:12]1)[NH:6][C:5]2=[O:33]
Reactant: COc1ccc(CN2C(=O)c3cc(Cl)cc(Cl)c3C23C=CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2(C=CNCC2)c2c(Cl)cc(Cl)cc21
Yield: 10.3 %

Procedure:
tert-Butyl 5,7-dichloro-2-(4-methoxybenzyl)-3-oxo-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridine]-1′-carboxylate (3.5 g, 7.2 mmol) in TFA (36 mL) and CF3SO3H (4 mL) was heated to 60° C. for 5 h. The solvent was removed and satd aq NaHCO3 was added till pH=7. Then EtOAc was added, the organic layer was washed with brine, dried and concentrated to give the crude product. It was purified by preparative HPLC to give 5,7-dichloro-2′,3′-dihydro-1′H-spiro[isoindoline-1,4′-pyridin]-3-one (0.2 g, 10%). 1H NMR (CDCl3): 1.66 (m, 3H), 2.81 (m, 1H), 3.15 (m, 1H), 3.76 (m, 1H), 7.57 (m, 1H), 7.75 (m, 1H).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[CH3:21][C:22]([CH3:24])=O>>[CH3:21][C:22]1([CH3:24])[O:4][C@@H:3]2[C@@H:5]([C@@H:7]([CH2:9][OH:10])[O:8][CH:2]2[OH:1])[O:6]1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Into a suspension of D-ribose (50 g, 0.33 mol) in acetone (1500 mL) was added sulfuric acid (1 mL) dropwise. Reaction mixture was stirred overnight at room temperature and then neutralized with sat. aq. NaHCO3. Solution was decanted and concentrated. Oily residue was dissolved in EtOAc (1000 mL) and washed with water (300 mL). Aqueous layer was re-extracted with EtOAc (2×500 mL). Combined extracts were dried over Na2SO4 and concentrated to yield the target compound (42.3 g, 67.3%) as oil which was used as such for the next step.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][C:18]([C:21](=[S:23])[NH2:22])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.CO[C:28](OC)([N:30]([CH3:32])[CH3:31])[CH3:29]>>[CH3:31][N:30]([CH3:32])[C:28](=[N:22][C:21]([C:18]1[CH:19]=[N:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:4]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)=[S:23])[CH3:29]
Reactant: NC(=S)c1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nc1
Reactant: COC(C)(OC)N(C)C
Product: CC(=NC(=S)c1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nc1)N(C)C
Reaction time: 8 h

Procedure:
A mixture of intermediate 4 (0.013 mol) and 1,1-dimethoxy-N,N-dimethyl-ethanamine (0.021 mol) was allowed to stand overnight and then used without further purification, yielding N-[1-(dimethylamino)ethylidene]-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]-3-pyridinecarbothioamide (intermediate 5).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:13]([CH:16]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2ccccc2c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc2ccccc2c1
Temperature: 0 °C
Yield: 94.1 %

Procedure:
A mixture of 2-naphthaldehyde (12 g), nitromethane (13.8 g) and ammonium acetate (5 g) in acetic acid (50 ml) was refluxed for 21/2 hours. The brown mixture was poured into ice-water (100 ml) from which a yellow solid separated. Filtration and drying in vacuo afforded the title compound (14.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]#[N:28]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[CH:24]=[N:25][C:26]([C:27]#[N:28])=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: N#Cc1[nH]cnc1N
Product: Cc1cc(-c2cc(C(F)(F)F)n3cnc(C#N)c3n2)ccc1C(F)(F)F
Yield: 47.2 %

Procedure:
Reaction of 1-(3-methyl-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (224 mg, 0.75 mmol), prepared from 3-methyl-4-trifluoromethyl-acetophenone (synthesis: see part acetophenone derivatives) according to general procedure A, and 4-amino-5-cyano-1H-imidazole (81 mg, 0.75 mmol) according to general procedure B yielded the title compound as a yellow solid (131 mg, 47%). MS (ISP) 371.1 [(M+H)+]; mp 217° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N+:16]([O-])=O)=[CH:7][C:6]=2[N:5]([C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][C:26]([O:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:25][CH:24]=3)=[O:20])[CH2:4]1>C1COCC1.O=[Pt]=O>[NH2:16][C:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:3]([CH2:2][Cl:1])[CH2:4][N:5]([C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][C:26]([O:30][CH2:31][CH2:32][N:33]([CH3:34])[CH3:35])=[CH:25][CH:24]=4)=[O:20])[C:6]=2[CH:7]=1
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3ccccc43)cc2c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc(N)c3ccccc43)cc2c1
Yield: 99.4 %

Procedure:
A solution of 14e (125 mg, 0.25 mmol) in THF (10 mL) was hydrogenated over PtO2 at 50 psi for 2 h. After removal of the catalyst, the solution was concentrated to a small volume under reduced pressure below 25° C. and diluted with iPr2O to give 15e (115 mg, 98%): mp >250° C.; 1H NMR [(CD3)2SO] δ 11.56 (d, J=1.4 Hz, 1 H, NH), 8.08 (d, J=8.5 Hz, 1 H, H-6), 7.76 (d, J=8.2 Hz, 1 H, H-9), 7.70 (s, 1 H, H-4), 7.46 (t, J=7.4 Hz, 1 H, H-8), 7.39 (d, J=8.9 Hz, 1 H, H-7'), 7.28 (t, J=7.7 Hz, 1 H, H-7), 7.17 (d, J=2.2 Hz, 1 H, H-4'), 7.07 (d, J=1.8 Hz, 1 H, H-3'), 6.91 (dd, J=8.9, 2.4 Hz, 1 H, H-6'), 5.98 (s, 2 H, NH2), 4.73 (dd, J=10.6, 9.1 Hz, 1 H, H-2), 4.51 (dd, J=10.9, 1.4 Hz, 1 H, H-2), 4.16-4.08 (m, 1 H, H-1), 4.06 (t, J=5.9 Hz, 2 H, OCH2), 3.98 (dd, J=10.9, 3.0 Hz, 1 H, CHHCl), 3.75 (dd, J=10.9, 8.1 Hz, 1 H, CHHCl), 2.65 (t, J=5.9 Hz, 2 H, OCH2CH2), 2.24 (s, 6 H, N(CH3)2).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:18])=[C:11]([N+:15]([O-])=O)[CH:12]=2)[CH2:7][N:6]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C=C(C=CC=1Cl)C[O:50][C:51](=O)[CH:52]([C:54]1[CH:59]=[CH:58][C:57]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=2)=[CH:56][CH:55]=1)O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl.C1COCC1.[Fe].CCOC(C)=O>[C:22]([O:21][C:19]([N:6]1[C@H:5]([C:3]([OH:2])=[O:4])[CH2:14][C:13]2[CH:12]=[C:11]3[C:10]([O:18][CH:52]([C:54]4[CH:59]=[CH:58][C:57]([O:60][CH2:61][C:62]5[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=5)=[CH:56][CH:55]=4)[C:51](=[O:50])[NH:15]3)=[CH:9][C:8]=2[CH2:7]1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: O=C(OCc1ccc(Cl)c(Cl)c1)C(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reactant: COC(=O)[C@@H]1Cc2cc([N+](=O)[O-])c(O)cc2CN1C(=O)OC(C)(C)C
Agent: [Fe]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)NC(=O)C(c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of (S)-7-hydroxy-6-nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (3.0 g, 8.5 mmol), resin-bound triphenylphosphine (17 mmol), [4-(3,4-dichloro-benzyloxy)-phenyl]-hydroxy-acetic acid 3,4-dichloro-benzyl ester (13.0 mmol) in DCM-THF (1-1, 80 mL) was cooled to 0° C. To this solution was added DIAD (13.0 mmol) and the mixture was agitated for 10 min at 0° C. and the mixture was slowly allowed to warm up to r.t. and agitated for 16 h. The reaction mixture was filtered, concentrated and the residue passed over a plug of silica-gel hexanes-ethyl acetate (9:1). The resulting residue was dissolved in glacial acetic acid (65 mL) and iron powder (170 mmol) added. The resulting mixture was heated at 100° C. for 1 h. The mixture was poured onto water and EtOAc. The organic layer was washed with water, brine, saturated sodium bicarbonate solution and dried over sodium sulfate. The solution was concentrated under reduced pressure to give the desired product. This crude product was purified by silica gel column chromatography using hexanes-ethyl acetate (7:3) to afford (7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (1.6 g). LC-MS (m/z) 614.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:7][CH:8]=1.[C:15]1([C@H:25]([NH2:27])[CH3:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O.C(O)(=O)C.ClCCl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][NH:27][C@@H:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH3:26])[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: O=CCCc1cccc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](NCCCc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2.12 g of 3-(3-trifluoromethylphenyl)propanal synthesized in the Step 2, 2.0 ml of (R)-1-(1-naphthyl)ethylamine, 3.42 g of sodium triacetoxyborohydride, and 150 ml of dry dichloromethane was added 0.750 ml of glacial acetic acid, and the mixture was stirred at room temperature for 5 hours. After 100 ml of water had been added and the mixture had been stirred for 3 hours, 100 ml of 2M sodium hydroxide aqueous solution was added, and the resultant was separated into an aqueous layer and an organic layer. The aqueous layer was extracted with dichloromethane, and the extract was combined with the separated organic layer, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with column chromatography (silica gel/hexane:ethyl acetate of 4:1 to 1:1) and then concentrated to afford 3.41 g of (R)—N-(3-(3-trifluoromethylphenyl)propyl)-1-(1-naphthyl)ethylamine as an oil. The compound was dissolved in 10 ml of dichloromethane, 5 ml of 4M hydrochloric acid/dioxane and 20 ml of toluene were added, and the mixture was concentrated under reduced pressure to pureness. The residue was recrystallized from 40 ml of ethanol and 200 ml of heptane to afford 1.71 g of the captioned compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][NH:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][N:9]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:10]([CH3:11])[CH3:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NCCC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
A solution of 0.935 g (0.005 mole) of 3-isopropylamino-propanoic acid tert-butyl ester in 20 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.6 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (IV-43).
Reaction SMILES: [ClH:1].[CH:2](=[N:9][CH2:10][CH2:11][NH:12][S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[ClH:1].[CH2:2]([NH:9][CH2:10][CH2:11][NH:12][S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)S(=O)(=O)NCCN=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)S(=O)(=O)NCCNCc1ccccc1
Yield: 92.8 %

Procedure:
A solution of 3.0 g (0.011 mole) of N-benzylidene-2-[N'-[(dimethylamino)sulfonyl]amino]ethylamine hydrochloride in 100 ml of methanol was hydrogenated, at 40 psi, over 0.3 g of 10% Pd-C catalyst until hydrogen uptake ceased (20 min.). The mixture was filtered and concentrated under reduced pressure to provide 3.0 g of crude product. The NMR spectrun was consistent with the assigned structure and the crude product was utilized directly without further purification.
Reaction SMILES: C[O:2][CH2:3][C:4]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2[C:21]([N:23]2[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]2)=[O:22])=[O:14])[CH:8]=1)([CH3:6])[CH3:5].[Cl-].[Al+3].[Cl-].[Cl-]>C(S)C>[OH:2][CH2:3][C:4]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][CH2:17][N:16]2[C:21]([N:23]2[CH2:28][CH2:27][S:26](=[O:29])(=[O:30])[CH2:25][CH2:24]2)=[O:22])=[O:14])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: COCC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCS(=O)(=O)CC2)no1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Product: CC(C)(CO)c1cc(NC(=O)[C@@H]2CCCCN2C(=O)N2CCS(=O)(=O)CC2)no1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(S)-1-(1,1-Dioxo-1λ6-thiomorpholine-4-carbonyl)-piperidine-2-carboxylic acid [5-(2-methoxy-1,1-dimethyl-ethyl)-isoxazol-3-yl]-amide (110 mg; 0.249 mmol) is dissolved in ethanethiol (2 mL) and cooled to 0° C. Aluminum chloride (498 mg; 3.735 mmol) is added to the solution and the reaction mixture is stirred at room temperature for 2 hours. The mixture is quenched with water (10 mL) and 3 drops of concentrated HCl aqueous solution and extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated. Purification by preparative HPLC affords title compound, m/z 429 [M+H+].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[C:16]([CH3:20])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc2occ(-c3ccc(C(C)C)cc3)c2c(C)c1C
Solvent: CO
Product: Cc1cc2c(c(C)c1C)C(c1ccc(C(C)C)cc1)CO2
Yield: 74 %

Procedure:
Using 3-(4-isopropylphenyl)-4,5,6-trimethyl-1-benzofuran obtained in Reference Example 194, the title compound was synthesized in the same manner as in Reference Example 199. Yield 74%. Melting point: 70-71° C. (methanol).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[K].[NH:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CC(C)([O-])C.[K+].O.C(O)(C)(C)C>[C:4]([O:22][C:19]1[CH:18]=[CH:17][C:16]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:21][CH:20]=1)(=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7]
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: O=C1C=CC(=O)O1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)/C=C\C(=O)Oc1ccc(Nc2ccccc2)cc1
Reaction time: 2 h

Procedure:
4-Anilinophenyl hydrogen maleate was prepared by adding 10 grams of maleic anhydride to a solution of the potassium salt of 4-anilinophenol which was prepared by dissolving 18.5 grams of 4-anilinophenol in a solution of potassium tert.butoxide prepared by reacting 3.9 grams of potassium with 75 milliliters of tert.butyl alcohol. The reaction mixture was stirred for 2 hours at 65°-70° C. and was then poured into a solution of 12 milliliters of concentrated hydrochloric acid in 138 milliliters of water. The organic layer was separated by extraction with benzene. The extract was washed twice with water and then allowed to evaporate. The residue was recrystallized twice from benzene yielding 1.3 grams of product which melted at 139°-142° C.
Reaction SMILES: [C:1]1([NH:11][C:12]#[N:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([I:22])[CH:17]=1.[ClH:23]>>[ClH:23].[C:1]1([NH:11][C:12]([N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([I:22])[CH:17]=2)[CH3:14])=[NH:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CNc1cccc(I)c1
Reactant: N#CNc1cccc2ccccc12
Agent: Cl
Product: CN(C(=N)Nc1cccc2ccccc12)c1cccc(I)c1

Procedure:
N-(1-naphthyl)-N'-(3-iodophenyl)-N'-methyl guanidine HCl was prepared from 1-naphthyl cyanamide and N-methyl-3-iodo aniline.HCl by the method similar to the one described in Example 10.C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[O-]CC.[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][N:27]=[C:28](Br)[C:29]([F:32])([F:31])[F:30])=[CH:22][CH:21]=1>C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:28]([C:29]([F:30])([F:31])[F:32])=[N:27]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(NN=C(Br)C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)c1ccco1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nn(-c2ccc(OC)cc2)c1-c1ccco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
To a solution of ethyl 3-(2-furyl)-3-ketopropionate (2.45 g, 13.4 mmol) in 20 mL of absolute ethanol was added sodium ethoxide (4.6 mL of a 21% weight solution in ethanol, 12.2 mmol) followed by 2,2,2-trifluoroacetoyl bromide-N-(4-methoxyphenyl)hydrazone (1.82 g, 6.1 mmol). This mixture was stirred at ambient temperature for 4 h. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by recrystallization from hexane/ethyl acetate to afford 1.4 g (61%) of the title compound. LRMS (ES+): 381.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:21][CH:22]=O)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CC(O)=O>[C:16]([O:15][C:14]([N:13]([CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:21][CH2:22][NH:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N(CC=O)C1CCc2ccc(C#N)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)CNCCN(C(=O)OC(C)(C)C)C1CCc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-Butyl (7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)(2-oxoethyl)carbamate (260 mg, 0.83 mmol) in 10 mL of anhydrous DCM was added Gly-OMe (150 mg, 1.7 mmol), 2 drops of HOAc and NaBH(OAc)3 (180 mg, 0.83 mmol) and the mixture was stirred at ambient temperature overnight. Then DCM was added, and the mixture was washed with brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to the title compound. MS m/z: 388 [M+1]+.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=O)[CH3:13].[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])=[N+:26]=[N-:27].O>CN(C=O)C>[CH:19]1([C:17]2[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[N:26]=[N:27][C:16]=2[C:15]([O:14][CH2:12][CH3:13])=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)CC(=O)C1CCCC1
Reactant: [N-]=[N+]=Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1nnn(-c2ccccc2F)c1C1CCCC1
Reaction time: 0.25 h

Procedure:
DBU (2.99 ml; 20.06 mmol; 1.10 eq.) was dissolved in DMF (25 ml) and put under nitrogen atmosphere. 3-Cyclopentyl-3-oxo-propionic acid ethyl ester (Pharmacore, 3.695 g; 20.06 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (2.5 g; 18.23 mmol; 1 eq.) in DMF (5 mL) was added dropwise to the solution at room temperature. The mixture was stirred at 90° C. for 2 hours. Water (50 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×50 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 304.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1>[F:1][C:2]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[S:13][C:6]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5)cc4)sc23)c(F)c1
Reaction time: 0.25 h
Yield: 108.7 %

Procedure:
To a solution of the nitro compound 53 (256 mg, 0.57 mmol) in a mixture of MeOH (12 mL) and THF (4 mL) at 0° C. was added NiCl2.6H2O (279 mg, 1.14 mmol), followed by portion wise addition of NaBH4 (87 mg, 2.27 mmol). The reaction mixture turned black after 15 min, and was filtered through a celite pad; the filtrate concentrated under reduced pressure. The residue was suspended in 2N HCl and the solids were removed by filteration. The filtrate was basified with NH4OH to pH˜10 then extracted with EtOAc. The organic phase was concentrated to afford the title compound 54 (260 mg, crude, >100% yield, HPLC pure) as yellowish foam. MS (m/z): 420.1 (M+H).
Reaction SMILES: N[C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].CS(O)(=O)=O.C(ON=O)(C)(C)C.[OH-].[Na+]>C(O)CO>[Cl:8][C:3]1[C:2]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: OCC(F)(F)F
Reactant: Nc1cccnc1Cl
Agent: CC(C)(C)ON=O
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: OCCO
Product: FC(F)(F)COc1cccnc1Cl
Yield: 65.8 %

Procedure:
A reactor vessel is charged with 3-amino-2-chloropyridine (15.0 g, 117 mmol), 2,2,2-trifluoroethanol (21 g, 210 mmol), and methanesulfonic acid (11.2 g, 117 mmol). The solution is heated to the range 50° C. to 60° C. and then t-butylnitrite (14.7 g of a 90% solution, 128 mmol) is added drop-wise to the vessel while maintaining the temperature at 50° C. to 60° C. After nitrogen evolution ceases, the solution is cooled and ethylene glycol is charged to the reactor. The vessel is put under vacuum and the solvent and other volatiles are distilled off. The reaction mass is then neutralized with aqueous saturated sodium bicarbonate solution and extracted with MTBE. The solvent is removed to leave an oil which is stirred several hours with 10% aqueous NaOH (23 g) followed by extraction with MTBE. MTBE is removed under vacuum to obtain 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (16.83 g) with an actual yield of 65.8%. Analysis by GC indicates the purity of the 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine to be 91.4%. Recovery of the 2,2,2-trifluoroethanol solvent is 88.9% by weight.