Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[C:10]([CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH:11]=[CH:12][C:13]=13)[C:8]([CH2:24][CH3:25])=[C:7]2[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)(=[O:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>O1CCCC1>[C:1]([C:4]1[CH:5]=[C:6]2[N:14]3[C:9](=[C:10]([CH2:15][OH:16])[CH:11]=[CH:12][C:13]=13)[C:8]([CH2:24][CH3:25])=[C:7]2[C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3ccc(CO[Si](C)(C)C(C)(C)C)c1n32
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2cc(C(C)=O)c3ccc(CO)c1n32
Reaction time: 24 h
Yield: 59.2 %

Procedure:
4-Acetyl-2-(4-benzyloxyphenyl)-7-(tert-butyldimethylsilanyloxymethyl)-1-ethylpyrrolo[2,1,5-cd]indolizine (1.5 g, 2.79 mmol) and tetrabutylammoniumfluoride hydrate (2.92 g. 11.16 mmol) was dissolved in 20 ml of dry tetrahydrofuran and stirred for 24 hours. Diethyl ether (100 ml) was added and the organic layer was extracted with 100 ml of 15% acetic acid, 100 ml of saturated sodium hydrogen carbonate, 100 ml of water, washed with brine, dried over sodium sulfate, and evaporated to a red-brown solid. The crude product was purified by column chromatography over silica gel 60, using 10% of ethyl acetate in toluene as the eluent. Fractions containing the product were combined an the solvent was evaporated. The remaining solid was crystallised from toluene and petroleum ether to afford 0.7 g (59%) of the title compound. M.p. 190-191° C. MS(SP): m/z 423 (M+). 1H--NMR (DMSO-d6, 200 MHz) δ: 1.39 (t, 3 H); 2.64 (s, 3 H); 3.20 (q, 2 H); 5.18 (s, 2 H); 5.22 (s, 2 H); 7.25 (d, 2 H); 7.31-7.55 (m, 5 H); 7.75 (d, 2 H); 8.01 (d, 1 H); 8.20 (s, 1 H); 8.36 (d, 1 H). Analysis: Calculated for C28H25N1O3 : C, 79.41; H, 5.95; N, 3.31%; Found: C, 79.2; H, 5.7; N, 3.2%.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][CH3:18])=[O:16])[CH:10]=2)=[CH:4][CH:3]=1.[I-:19].[K+].C(ON=O)(C)(C)C>C(I)I.CCOC(C)=O>[I:19][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH:17][CH3:18])=[O:16])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Reactant: [I-]
Agent: CC(C)(C)ON=O
Agent: [K+]
Solvent: ICI
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(I)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A mixture of 4-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide (0.4 g, 1.64 mmol) and potassium iodide (1.36 g, 8.19 mmol) in methylene iodide (5.46 mL) was treated dropwise with t-butylnitrite (1.95 mL, 16.4 mmol). The mixture was stirred overnight at RT, diluted with EtOAc (75 mL), and washed with 10% sodium carbonate (50 mL), 10% thiosulfate (50 mL), and brine (50 mL). The organics were dried over sodium sulfate, evaporated to dryness and purified by silica gel chromatography ((EtOAc/Hex) to afford 4-((6-iodopyridin-3-yl)oxy)-N-methylpicolinamide (0.214 g, 36.8%). 1H NMR (400 MHz, DMSO-d6): δ 8.78 (br d, J=5.6 Hz, 1H), 8.54 (d, J=5.6 Hz, 1H), 8.40 (d, J=3.0 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.50 (dd, J=8.6, 3.1 Hz, 1H), 7.45 (d, J=2.6 Hz, 1H), 7.23 (dd, J=5.6, 2.7 Hz, 1H), 2.78 (d, J=4.9 Hz, 3H); MS (ESI) m/z: 356.0 (M+H+).
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:33][NH2:34]>C(O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:15]2[CH2:14][CH2:13][C:12]3([C:3]4[CH:2]=[N:34][NH:33][C:4]=4[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[O:11]3)[CH2:17][CH2:16]2)=[O:31])=[CH:20][C:21]=1[C:27]([F:28])([F:29])[F:30]
Reactant: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2C(=O)C3=CO)cc1C(F)(F)F
Reactant: NN
Solvent: CCO
Product: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2[nH]ncc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(hydroxymethylene)-1′-[4-methoxy-3-(trifluoromethyl)-benzoyl]spiro[chromane-2,4′-piperidine]-4-one (54 mg, 0.12 mmol) and hydrazine (3.8 μL, 0.12 mmol) in ethanol (1.7 mL) was allowed to stir for 1 h at 25° C., then for 2.5 h at 50° C. The mixture was cooled and then concentrated in vacuo. The residue was taken up in DMF and was purified by reverse phase HPLC to give (4-methoxy-3-(trifluoromethyl)phenyl)(1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z talc. 443.2, found 444.1 (M+1)+; Retention time: 2.40 minutes (4 min run). 1H NMR (400 MHz, CDCl3) δ 9.15-8.90 (m, 1H), 7.73 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.33-7.18 (m, 1H), 7.04 (dd, J=18.8, 8.3 Hz, 2H), 6.91 (t, J=7.5 Hz, 1H), 6.05-5.60 (m, 1H), 4.50-4.05 (m, 2H), 4.08-3.55 (m, 3H), 3.97 (s, 3H), 2.50-2.32 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([F:18])=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=2)=[C:4]([F:19])[CH:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([NH:1][C:2]2[C:17]([F:18])=[CH:16][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[CH:8]=3)=[C:4]([F:19])[CH:3]=2)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
To a solution of 4-(4-amino-2,5-difluorophenoxy)picolinamide (200 mg, 0.76 mmol), and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (165 mg, 0.75 mmol) in DCM (10 mL) was added EDCI (175 mg, 0.93 mmol), and HOAT (26 mg, 0.15 mmol). The reaction was stirred at 45° C. for 16 hours, cooled to rt and diluted with EtOAc (20 mL). The solid was collected through filtration, dried at 45° C. in vacuo overnight to give the title compound as a white solid (230 mg, 63.7%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@:5]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10](=[O:15])[C@@H:11]([O:13][CH3:14])[CH3:12])[N:8]=[C:7]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:6]1.[N:30]#[C:31]Br.C(N(CC)CC)C.[ClH:40].[CH3:41][O:42][NH2:43]>ClCCl>[ClH:40].[F:23][C:17]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=1[C:7]1[S:6][C@@:5]([CH2:4][CH2:3][CH2:2][NH:1][C:31]([NH2:30])=[N:43][O:42][CH3:41])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]([C:10](=[O:15])[C@@H:11]([O:13][CH3:14])[CH3:12])[N:8]=1
Reactant: N#CBr
Reactant: CON
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C(N)NCCC[C@@]1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)[C@H](C)OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
To a solution of (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one (Example 5, Steps A-C, 52.1 mg, 0.106 mmol) and cyanogen bromide (13.4 mg, 0.127 mmol) in dichloromethane (1 mL) was slowly added triethylamine (35.3 mg, 0.349 mmol). After stirring for 20 minutes at room temperature, the mixture was concentrated under reduced pressure and dissolved in ethanol (2 mL). To this solution was added methoxyamine hydrochloride (600 mg, 7.18 mmol) and triethylamine (642 mg, 6.35 mmol). The reaction vessel was sealed and heated to 70° C. for 24 hours. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The precipitate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed (3% methanol in dichloromethane with 0.5% NH4OH), and the isolated material was treated with excess HCl in MeOH then concentrated to afford the product as a white solid (7.3 mg, 13% yield). MS APCI (+) m/z 492 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ 7.65-7.60 (m, 1H), 7.47-7.45 (m, 2H), 7.42-7.37 (m, 2H), 7.35-7.29 (m, 3H), 4.79 (q, 1H, J=7.0 Hz), 3.73 (s, 3H), 3.45-3.37 (m, 2H), 3.36 (s, 3H), 3.28-3.19 (m, 1H), 2.60-2.51 (m, 1H), 2.19-2.08 (m, 1H), 1.71-1.60 (m, 1H), 1.43 (d, 3H, J=7.0 Hz).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:12][C@@H:13]([C@H:22]([CH3:25])[CH2:23][CH3:24])[C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15].[P:26](Cl)(Cl)(=[O:38])[O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(Cl)[Cl:42]>>[Cl:42][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[O:27][P:26](=[N:12][C@@H:13]([C@H:22]([CH3:25])[CH2:23][CH3:24])[C:14]([O:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:15])=[O:38]
Reactant: O=P(Cl)(Cl)Oc1cccc2ccccc12
Reactant: CC[C@@H](C)[C@H](N)C(=O)OCC(C)(C)C
Reactant: ClCCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC[C@@H](C)[C@H](N=[P+]([O-])Oc1c(Cl)ccc2ccccc12)C(=O)OCC(C)(C)C
Yield: 37 %

Procedure:
Using the general procedure for synthesizing naphthyl (aminoacid ester) phosphorochloridates the tosylate salt of (2S,3R)-neopentyl 2-amino-3-methylpentanoate (2.5 g), naphthalen-1-yl phosphorodichloridate (1.75 g), TEA (1.86 mL) and DCM (50 mL) were combined to give (2S,3R)-neopentyl 2-(chloro(naphthalen-1-yloxy)phosphorylamino)-3-methylpentanoate in a 37% yield (1.06 g) as a pale yellow thick oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([OH:14])[CH:5]=2)[CH2:3][CH2:2]1.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:13]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]([OH:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(C2CC2)cc1O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1cc(Br)c(C2CC2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of methyl 4-cyclopropyl-2-hydroxybenzoate (1.80 g) in acetic acid (15.0 mL) was added dropwise bromine (1.57 g) under ice-cooling. The mixture was stirred at room temperature for 2 hr, to the reaction mixture was added water, and the resulting solid was collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (2.28 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:19][CH2:18][CH2:17][CH:13]([C:14]([OH:16])=O)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)=[O:4].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([CH2:34][NH:35][C:14]([CH:13]3[CH2:17][CH2:18][CH2:19][N:11]([C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:3]([O:2][CH3:1])=[O:4])[CH2:12]3)=[O:16])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc(N2CCCC(C(=O)O)C2)c1
Reactant: NCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: Cl
Product: COC(=O)c1cccc(N2CCCC(C(=O)NCc3ccc(-c4ccc(Cl)cc4)cc3)C2)c1
Yield: 69.3 %

Procedure:
Using 1-[3-(methoxycarbonyl)phenyl]nipecotic acid (108 mg, 0.410 mmol) and (4′-chlorobiphenyl-4-yl)methylamine hydrochloride (95.0 mg, 0.374 mmol), the same procedure was followed as in Step 3a of Example 3 to give 120 mg (69%) of the desired compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To acetone 40 mL solution of 4-bromo-2-nitrobenzoic acid 4.0 g were added potassium carbonate 3.4 g and dimethylsulfate 2.3 mL at room temperature, and it was stirred at 50° C. for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure. Water and ethyl acetate were added to the obtained residue. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with saturated sodium hydrogen carbonate aqueous solution,1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure to give methyl 4-bromo-2-nitrobenzoate 4.1 g of white solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH:46]([OH:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2].[N-:67]=[N+:68]=[N-:69].[Na+].O>CN(C)C=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:67]=[N+:68]=[N-:69])[CH:46]([OH:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(S(=O)(=O)c4ccccc4[N+](=O)[O-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 80 °C

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-{2'-[4"-(o-nitrobenzenesulfonyl)-3"-hydroxycyclohexyl]-1'-methylvinyl}-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (87 mg) in dry dimethylformamide (1 ml) is added sodium azide (16.7 mg) in one portion. The reaction is heated at 80° C. under nitrogen atmosphere for 3 hr. The reaction mixture is cooled, poured into water (5 ml) and extracted with ethyl acetate. Normal work-up followed by preparative tlc on silica gel gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:35])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1>>[NH2:1][C:2]1[C:3](=[O:35])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:29]3[CH2:34][CH2:33][N:32]([CH2:39][CH:36]4[CH2:38][CH2:37]4)[CH2:31][CH2:30]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: O=CC1CC1
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCNCC4)n3)cccc2[nH]c1=O
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCN(CC5CC5)CC4)n3)cccc2[nH]c1=O

Procedure:
The reaction of 3-amino-5-(2-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (27 mg, 0.056 mmol, Example 135) with cyclopropanecarboxaldehyde (59 mg, 0.279 mmol, Aldrich) under the conditions of Example 36 provided the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 538 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:13]([F:16])([F:15])[C:12](=[O:17])[CH:11]=[CH:10][C:9]=2[N:8]=[CH:7][C:6]=1[OH:18])=[O:4].[C:19](OC(=O)C)(=[O:21])[CH3:20].C(OCC)(=O)C>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:13]([F:16])([F:15])[C:12](=[O:17])[CH:11]=[CH:10][C:9]=2[N:8]=[CH:7][C:6]=1[O:18][C:19](=[O:21])[CH3:20])=[O:4]
Reactant: COC(=O)c1c(O)cnc2c1C(F)(F)C(=O)C=C2
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(OC(C)=O)cnc2c1C(F)(F)C(=O)C=C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.2 %

Procedure:
A solution of 5,5-difluoro-3-hydroxy-6-oxo-5,6-dihydro-quinoline-4-carboxylic acid methyl ester (11.1 g, 43.50 mmol, 1.0 eq) in acetone (100 mL) is cooled to 0° C. before the addition of acetic anhydride (8.2 mL, 87.0 mmol, 2.0 eq). After 3 hours stirring at room temperature, solvent is evaporated and the crude product is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 3-acetoxy-5,5-difluoro-6-oxo-5,6-dihydro-quinoline-4-carboxylic acid methyl ester as a white solid (5.2 g, 40% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:30][CH2:31][CH3:32]>C(OCC)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:30][CH2:31][CH3:32])=[O:11]
Reactant: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CN
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CNC(=O)Cc1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 103 mg of the acid) in 2 ml of diethyl ether was added to a solution of 140 mg of 5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in 2.5 ml of 0.2M sodium hydroxide solution, the mixture was shaken vigorously for 10 minutes and then filtered. The solid was washed with 5 ml of water and 50 ml of diethyl ether, and then recrystallized from acetone to give 60 mg of 5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in the form of a white solid of melting point 249°-250° C.
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)([O-:5])=[O:4].O>C(O)(=O)C>[Br:1][C:10]1[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[C:8]([C:13]([F:14])([F:15])[F:16])[C:9]=1[NH2:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 120 °C
Yield: 91 %

Procedure:
Bromine (0.60 mL) dissolved in acetic acid (11 mL) was added dropwise to a solution of 4-nitro-2-trifluoromethyl-phenylamine (2.4 g) in acetic acid (12 mL). The reaction mixture was heated to 120° C. for 2½ hours, poured into water (400 mL) and filtered. The collected solid was washed with water (200 mL) and dried in vacuo to furnish 3.03 g (91% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 7.08 (s, 2H), 8.23 (d, 1H), 8.51 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[C:6]=2[CH:10]=1
Reactant: Fc1ccc(Oc2cc3nn[nH]c3cc2Br)c(F)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(Oc2cc3nnn(C4CCCCO4)c3cc2Br)c(F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 6-bromo-5-(2,4-difluorophenoxy)-1H-1,2,3-benzotriazole (0.047 g, 0.14 mmol) and p-toluenesulfonic acid monohydrate (0.0027 g, 0.014 mmol) in chloroform (0.65 mL) was treated with dihydropyran (0.0197 mL, 0.216 mmol) and stirred at 60° C. for 1 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was separated and re-extracted with dichloromethane. The combined organic layers were separated, washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude oil. Purification by flash column chromatography (100% hexanes to 60% EtOAc/hexanes) gave the desired product as a mixture of isomers that was used without further purification.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:26]([CH:28]=1)[NH2:27]>CN(C)C1C=CN=CC=1.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[C:26]([NH:27][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:28]=1
Reactant: Nc1cc(Cl)ccc1N1CCCCC1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1N1CCCCC1)c1ccncc1
Reaction time: 19 h
Yield: 31.8 %

Procedure:
Isonicotinoyl chloride hydrochloride (350 mg, 1.96 mmol, commercially available product), triethylamine (740 μl, 5.30 mmol), and a catalytic amount of 4-(dimethylamino)pyridine were sequentially added at room temperature to a dichloromethane (10 ml) solution of 5-chloro-2-(1-piperidinyl)aniline (378 mg, 1.79 mmol), obtained as described in Referential Example 15-2. The resulting mixture was stirred for 19 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (200 g, hexane/ethyl acetate=1/1). Thus, N-[5-chloro-2-(1-piperidinyl)phenyl]isonicotinamide (GIF-0341) (180 mg, 31.8%) was yielded as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)=CCBr
Reactant: Sc1ccc(Br)cc1
Product: CC(C)=CCSc1ccc(Br)cc1
Yield: 91.5 %

Procedure:
In a manner similar to that of Example 34(h), by reaction of 30.00 g (159.0 mmol) of 4-bromo-thiophenol with 26.00 g (175.0 mmol) of 1-bromo-3-methyl-2-butene, 37.40 g (93%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)[CH:19]=1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:22]([C:21]4[CH:25]=[CH:26][C:18]([F:17])=[CH:19][C:20]=4[N:27]4[N:31]=[CH:30][CH:29]=[N:28]4)=[O:23])[CH2:14]3)[CH2:10]2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: O=C(O)c1ccc(F)cc1-n1nccn1
Reactant: Cc1cnc(C)c(N2CC3CNCC3C2)n1
Product: Cc1cnc(C)c(N2CC3CN(C(=O)c4ccc(F)cc4-n4nccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 34 and Intermediate 4. MS (ESI): mass calculated for C21H22FN7O, 407.45; m/z found 408.2 [M+H]+. 1H NMR (400 MHz, CDCl3) 7.83-7.72 (m, 4H), 7.42 (dd, J=8.5, 5.8, 1H), 7.14 (ddd, J=8.5, 7.8, 2.5, 1H), 3.94-3.86 (m, 1H), 3.82-3.74 (m, 1H), 3.73-3.60 (m, 2H), 3.56-3.47 (m, 1H), 3.42-3.31 (m, 2H), 3.10-2.82 (m, 3H), 2.50 (s, 3H), 2.36 (s, 3H).