Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:18]N(C)C=O.C(Cl)(=O)C(Cl)=O.CO>ClCCl>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:2]=1[F:1]
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)O)c1F
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: CCCS(=O)(=O)Nc1cccc(C(=O)OC)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 2-fluoro-3-(propane-1-sulfonylamino)-benzoic acid (15, 5.05 g, 19.3 mmol) in 100 mL of dichloromethane, N,N-dimethylformamide (0.075 mL, 0.97 mmol) was added under an atmosphere of nitrogen. The reaction was cooled with ice water bath, followed by slow addition of oxalyl chloride (10.8 mL, 2.00 M in dichloromethane, 21.6 mmol). The reaction mixture was stirred at room temperature for 3.0 hours, then cooled with ice water bath, followed by slowly adding 36.0 mL of methanol. The reaction was stirred at room temperature overnight, then concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a crude white solid (16, 4.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Mg].CN([CH:17]=[O:18])C>>[CH3:11][N:10]([CH3:12])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:17]=[O:18])=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: CN(C)CCc1ccc(Br)cc1
Agent: [Mg]
Product: CN(C)CCc1ccc(C=O)cc1

Procedure:
2-(4-Bromophenyl)-N,N-dimethylethylamine (6.8 g) was refluxed under heating with magnesium for 1 hr to prepare a Grignard reagent, which was reacted with DMF to give the objective 4-(2-dimethylaminoethyl)benzaldehyde as an oil (4.2 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:11][C:12]2[CH:13]=[C:14]([CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:15]#[N:16])[C:6]([CH2:9][CH3:10])=[CH:7][CH:8]=1.[N:22]([C:25]1[NH:26][C:27]([C:31](O)=[O:32])=[C:28]([Cl:30])[N:29]=1)=[N+]=[N-].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C>[NH2:22][C:25]1[NH:26][C:27]([C:31]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[C:5]([O:11][C:12]3[CH:13]=[C:14]([C:15]#[N:16])[CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:4]=2[F:21])=[O:32])=[C:28]([Cl:30])[N:29]=1
Reactant: [N-]=[N+]=Nc1nc(Cl)c(C(=O)O)[nH]1
Reactant: CCc1ccc(CN)c(F)c1Oc1cc(Cl)cc(C#N)c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(CNC(=O)c2[nH]c(N)nc2Cl)c(F)c1Oc1cc(Cl)cc(C#N)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 53.5 %

Procedure:
A solution of 3-{[3-(aminomethyl)-6-ethyl-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.075 g, 0.246 mmol), 2-azido-4-chloro-1H-imidazole-5-carboxylic acid (0.051 g, 0.271 mmol), EDC (0.052 g, 0.271 mmol) and HOBT (0.041 g, 0.271 mmol) in DMF (4 ml) was stirred at RT under an atmosphere of nitrogen for 16 h then ethyl acetate (100 mL) and saturated aqueous NaHCO3 solution (100 mL) were added. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (100 mL), water (100 mL), dried over MgSO4, filtered and concentrated. Ethyl acetate (20 mL) and Lindlar Catalyst (0.026 g, 0.247 mmol) were added and the mixture was stirred at RT under an atmosphere of hydrogen (55 psig) for 19 h. The vessel was carefully vented and the mixture was filtered thru Celite, concentrated purified by Reverse Phase HPLC (MeCN/water+0.1% TFA) to give the title compound (0.059 g, 51%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (s, 1H), 7.77 (t, 1H), 7.70 (t, 1H), 7.39 (s, 1H), 7.33 (t, 1H), 7.18-7.29 (m, 2H), 5.81 (s, 2H), 4.47 (d, 2H), 2.47-2.54 (m, 2H), 1.08 (t, 3H). LCMS m/z 450.1 (M+H).
Reaction SMILES: [C:1]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)(=O)[CH3:2].[CH2:9]([C-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[CH3:10].[Fe+2:16].[Li+].CC([N-]C(C)C)C.P(Cl)(OCC)(OCC)=O>C1COCC1>[CH2:1]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:2].[C:9]([C-:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)#[CH:10].[Fe+2:16]
Reactant: CC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Solvent: C1CCOC1
Product: C#C[c-]1cccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
Following a general procedure (Doisneau et al. (1992) J. Organomet. Chem. 425: 113–117), to a solution of 12 (2.0 g, 7.8 mmol) in dry THF (50 mL) at −78° C. were added dropwise 1.1 equiv of freshly prepared LDA (40 mL, 8.0 mmol) in THF. After 1 h at −78° C., diethyl chlorophosphate (1.1 equiv, 1.2 mL, 8.0 mmol) was added at −78° C. for 1 h. The reaction mixture was allowed to warm to rt for an additional 1 h and then was recooled to −78° C. and an additional 2.3 equiv of LDA (80 mL, 20 mmol) was added. The reaction mixture was warmed to rt and stirred overnight then hydrolyzed at 0° C. The reaction mixture was extracted with ether (3×50 mL) and the combined organic layers were washed with water (3×50 mL) and satd NaCl (3×50 mL) and dried (MgSO4). The resulting residue after evaporation was purified by column chromatography (silica, petroleum ether) to afford 1.7 g (90%) of a yellow oil. 1H NMR δ 1.19 (t, J=7.5 Hz, 3H), 2.36 (q, J=7.5 Hz, 2H), 2.73 (s, 1H), 4.10 (m, 4H), 4.15 (t, J=2.1 Hz, 2H), 4.37 (t, J=2.1 Hz, 2H); 13C NMR δ 15.3, 21.9, 66.5, 69.7, 69.8, 70.0, 72.9, 74.3; FAB-MS obsd 238.0466, calcd exact mass 238.0445; Anal. Calcd for C14H14Fe: C, 70.62; H, 5.93; Found: C, 70.65; H, 5.92.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)[SH:21])C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][SH:21])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: C=C1CC(CC)C(C(=O)OCC)C1
Reactant: S[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CC(CS)CC1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Ethyl 2-ethyl-4-methylenecyclopentanecarboxylate (0.720 g, 3.95 mmol), triphenylsilanethiol (1.329 g, 4.54 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.195 g, 1.185 mmol) in toluene (3.95 mL) was heated at reflux for about 6 h. The reaction mixture was cooled to ambient temperature and then concd under reduced pressure. The material was purified by silica gel (40 g) chromatography eluting with a gradient of 0-10% EtOAc in heptane to give a colorless oil. The resulting oil was dissolved in DCM (4 mL) and TFA (1.52 mL, 19.7 mmol) was added. After stirring at ambient temperature for about 1 h, the solvent was removed under reduced pressure. The material was purified by silica gel (40 g) chromatography eluting with a gradient of 0-15% EtOAc in heptane to provide ethyl 2-ethyl-4-(mercaptomethyl)cyclopentanecarboxylate (0.620 g, 72%) as a colorless oil: 1H NMR (DMSO-d6) δ 4.13-4.01 (m, 2H), 2.50-2.30 (m, 3H), 2.24 (m, 1H), 2.15-1.87 (m, 3H), 1.66-1.54 (m, 1H), 1.50-1.37 (m, 2H), 1.31-1.23 (m, 2H), 1.17 (t, 3H), 0.83 (m, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH:7]([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9])[C:3]([O:5][CH3:6])=[O:4].N1C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CCOC(C)=O>C(Cl)Cl>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][CH:2]([CH:7]([C:8]([F:11])([F:10])[F:9])[C:12]([F:13])([F:14])[F:15])[C:3]([O:5][CH3:6])=[O:4])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(NS(=O)(=O)c1ccc(Cl)cc1)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
A solution of methyl 2-amino-3-(trifluoromethyl)-4,4,4-trifluorobutanoate (2.12 g, 8.87 mmol) in CH2Cl2 (10 mL) was stirred under nitrogen at 25° C. Pyridine (10 mL, 126 mmol) was added dropwise followed by 4-chloro-benzenesulfonyl chloride (2.81 g, 13.3 mmol) in one portion, and the resulting solution stirred for 18 hours at 25° C. After this time period, the reaction was complete by TLC (20:80 EtOAc:PE). After quenching with H2O, the mixture was diluted with Et2O (200 mL). The organic layer was washed with 1 N aq. HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL), and then dried (MgSO4). After concentration, the crude product was purified by Biotage Flash™ 40 chromatography, eluent: 5:95 to 20:80 EtOAc:PE, to obtain methyl 2-[(4-chloro-phenyl)sulfonylamino]-3-trifluoromethyl-4,4,4-trifluorobutanoate as a solid (1.53 g, 42%). Mass Spectrum
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:11]([F:29])[C:10]=1[Cl:30].CS(O[CH2:36][CH:37]1[CH2:51][C@@H:40]2[CH2:41][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:43][C@@H:39]2[CH2:38]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.CO.C(OCC)(=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:36][CH:37]4[CH2:51][C@@H:40]5[CH2:41][N:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:43][C@@H:39]5[CH2:38]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:11]([F:29])[C:10]=1[Cl:30]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(COS(C)(=O)=O)C[C@H]2C1
Reactant: COc1cc2c(Nc3ccc(Br)c(Cl)c3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc2c(Nc3ccc(Br)c(Cl)c3F)ncnc2cc1OCC1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C1

Procedure:
A solution of 4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol trifluoroacetate (salt) (0.217 g, 0.425 mmol), 1,1-dimethylethyl(3aR,6aS)-5-{[(methylsulfonyl)oxy]methyl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (0.163 g, 0.510 mmol), potassium carbonate (0.290 g, 2.12 mmol) in N,N-dimethylacetamide (1.6 mL) was heated in a sealed reaction tube at 90° C. for 12 h. The crude reaction mixture was diluted with 100 mL of 10% methanol in ethyl acetate and washed with water (5×30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (SiO2, 3:1 hexanes: acetone) provided 1,1-dimethylethyl(3aR,6aS)-5-({[4-[(4-bromo-3-chloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate which was used directly in the next step. MS (EI) for C28H31N4O4FClBr: 623 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OC)(O[CH3:22])(=O)=O.CO>>[CH3:22][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: COS(=O)(=O)OC
Solvent: CO
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 200 °C
Yield: 975.6 %

Procedure:
As in Example 2, a melt consisting of 10 g (0.0455 mol) of 3,5-diphenylpyrazole and 0.057 g (0.00455 mol) of dimethyl sulfate was prepared at 200° C. Over the course of 5 hours, 435 g (13.6 mol) of methanol were vaporized at 155° C. and passed through the melt which was maintained at 200° C. 10.4 g (96.9%) of 1-methyl-3,5-diphenylpyrazole were obtained, boiling point 190° C./3 mbar, with a content of 99.2% (GC).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][C:9](=O)[NH:8]2)[CH:2]=1.[Cl:13]C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O>[Cl:13][C:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=1
Reactant: Clc1ccccc1
Reactant: O=C1CCN(c2cccnc2)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: ClC1=NN(c2cccnc2)CC1
Temperature: 80 °C
Yield: 75 %

Procedure:
To the paste-like solid obtained from Step 1 in a 4-neck round bottomed flask (500 mL) was added chlorobenzene (120 mL). Phosphoryl chloride (10.2 mL, 0.110 mol) was added dropwise to the thick mixture over 10 minutes. The temperature of the mixture went from 22° C. to 27° C. The slurry was heated at 80° C. for 1 hour. The mixture was cooled to 25° C., water (120 mL) was added to dissolve the solids, and the temperature rose to 28° C. The two phase mixture was brought to pH ˜12 with sodium hydroxide (50% in water, 42.8 g) using an ice-bath cooling to keep the temperature below 40° C. After cooling to 30° C., the mixture was transferred to a separatory funnel. The phases separated rapidly, and the bottom aqueous layer (containing some suspended solids) was removed from the dark organic phase. Attempted re-extraction of the aqueous phase with chlorobenzene (30 mL) resulted in an emulsion with solids present. The mixture was filtered through Celite®, the phases allowed to settle, and the organics added to the above organic phase to give a solution of the title compound as a dark amber liquid containing a small amount of fine solids (319 g, LC internal standard analysis indicated 4.3 wt % (75.4 mmol) 3-chloro-4,5-dihydro-1-(3-pyridinyl)-1H-pyrazole in the solution, for an in-pot yield of 75% starting from 3-hydrazinopyridine).
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(OCC)OCC)C.[CH:17]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@@H:33]([CH3:38])[C:34]([NH:36][NH2:37])=[O:35])[N:27]=1)([CH3:19])[CH3:18].C(OCC)(=O)C>CCCCCCC>[CH:17]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C@H:33]([C:34]2[O:35][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:37][N:36]=2)[CH3:38])[N:27]=1)([CH3:19])[CH3:18]
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)C(=O)NN)n1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2nnc(-c3ccccc3)o2)n1
Yield: 17.9 %

Procedure:
A solution of (triethoxymethyl)benzene (360 mg, 1.6 mmol, 5.0 equiv. in 5 mL of benzene and 0.5 mL of glacial AcOH) was added to (S)-2-((4-((S)-4-isopropyl-2-oxooxazolidin-3-yl)pyrimidin-2-yl)amino)propanehydrazide (99 mg, 0.30 mmol, 1.0 equiv.), the reaction mixture was stirred at reflux for 1.5 hours, the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 90%) to yield (S)-4-isopropyl-3-(2-(((S)-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (21.2 mg, white solid) in 15.9% yield. HRMS(B) m/z 395.1820, (M+H)+, RT=2.42 min
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=3)[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:31][C:32]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)=[O:33]>CN(C=O)C>[N:34]1([C:32](=[O:33])[CH2:31][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]4[S:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=4)[CH:8]=3)[CH2:2][CH2:3]2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: O=C(CBr)N1CCOCC1
Reactant: N#Cc1cnc(Nc2cc(N3CCNCC3)ncn2)s1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(Nc2cc(N3CCN(CC(=O)N4CCOCC4)CC3)ncn2)s1
Temperature: 0 °C

Procedure:
2-[(6-Piperazin-1-ylpyrimidin-4-yl)amino]-1,3-thiazole-5-carbonitrile 12-3 (0.10 g, 0.35 mmol) and diisopropylethylamine (0.049 g, 0.38 mmol) were dissolved in DMF. After cooling to 0° C., a DMF solution of 4-(bromoacetyl)morpholine 12-4 (0.08 g, 0.38 mmol) was added slowly via addition funnel. The product was purified on a C18 preparative LC column and isolated via lyophilization. Hi-Res MS: calc: 415.1655 found: 415.1663. 1H-NMR (CD3OD): 8.49 ppm (s, 1H); 8.03 ppm (s, 1H); 6.27 ppm (s, 1H); 4.34 ppm (s, 2H); 3.70 ppm (m, 4H); 3.65 ppm (m, 4H); 3.42 ppm (t, 2H); 3.33 ppm (m, 6H).
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C@@H:13]([O:14][CH2:15][C:16](=[O:27])[C:17](=[N+]=[N-])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:12][C:11]1=[O:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1C=CC=CC=1.O1CCCC1.[Hg]>[C:1]([NH:9][C@H:10]1[C:11](=[O:28])[N:12]2[C@@H:13]1[O:14][CH2:15][C:16]([OH:27])=[C:17]2[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)CO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Agent: [Hg]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)C1=C(O)CO[C@@H]2[C@@H](NC(=O)c3ccccc3)C(=O)N12
Yield: 16.6 %

Procedure:
An anhydrous and degassed solution of 78 mg (0.2 mmol) of tert.-butyl 4-[3(R)-benzoylamino-2-azetidinon-4-(R)-yloxy]-2-diazo-3-oxo-butyrate in 25 ml of benzene:tetrahydrofuran 3:1 was irradiated in a nitrogen atmosphere at 20° C. for 1 hour with a 450 W mercury vapour lamp with a Pyrex filter. The solvent was evaporated off in vacuo and the residue was purified by chromatography on 8 g of silica gel (toluene:ethyl acetate 35:65). 12 mg (17%) of the title compound were obtained as a colorless rigid foam.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1>CO.[Fe]>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Product: COC(=O)c1cnc(Cl)c(N)c1
Temperature: 75 °C
Yield: 56 %

Procedure:
A suspension of methyl 6-chloro-5-nitronicotinate (1 eq), iron powder (5.2 eq), and NH4Cl3 (5.3 eq) in MeOH was heated at 75° C. for 2 h. The mixture was passed through a pad of celite while hot and concentrated in vacuo to give methyl 5-amino-6-chloronicotinate (56% yield).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:14]=[CH:15][C:16]=3[C:17](O)=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[CH:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[CH:24]=[CH:23]5)[CH:14]=[CH:15][C:16]=3[CH2:17][OH:18])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(C(=O)O)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(-c3ccc(CO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1

Procedure:
6.2 g (0.014 mol) of the acid obtained in Example 10 are dissolved in 30 ml of THF and treated with 49 ml of BH3 (1M) in THF. The reaction medium is refluxed for 12 h, it is then evaporated, taken up in 900 ml of water and treated with 35 ml of 1N HCl. It is extracted with 800 ml of ethyl acetate, and the organic phase is washed with water and evaporated. The residue is chromatographed on silica in dichloromethane to give 4.45 g (75%) of the expected derivative which melts at 212° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:10](Cl)(=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.FC1C=CC=CC=1C(C1C=CC(OC)=C(OC)C=1)=O.C(O)C#C.C1C2C(=CC=CC=2)C=CC=1O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>[Cl-].[Al+3].[Cl-].[Cl-].C1C=CC=CC=1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][C:7]=1[C:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:19]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cccc(C)c1
Agent: C#CCO
Agent: COc1ccc(C(=O)c2ccccc2F)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COc1ccc(C(=O)c2ccc(OC)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-methyl-4,4'-dimethoxybenzophenone was prepared from the Friedel-Crafts reaction of 3-methyl anisole with anisoyl chloride using aluminum chloride as catalyst and hexane as the solvent. The benzophenone product (6.1 grams, 0.02 mole) was converted to the propargyl alcohol according to the procedure of Example 1, Step 2. The resulting crude oil was taken up in 150 milliliters of benzene and 2.8 grams (0.01 mole) of 2-naphthol and 0.1 grams of p-toluene sulfonic acid were added to the benzene solution. The resulting mixture was stirred at room temperature for about 30 minutes and then poured into an equal volume of 5 percent aqueous sodium hydroxide. The organic layer was washed with water and the benzene solvent removed on a rotary evaporator. The remaining crude product was subjected to column chromatography using a 1:1 mixture of chloroform and hexane as elutant. The photochromic fractions were combined and the product crystallized from a mixture of hexane and ether. The product had a melting range of 112-114C. Nuclear Magnetic Resonance (NMR) analysis of the product confirmed it to be, 3(2-methyl-4-methoxyphenyl)-3-(4methoxyphenyl)-3H-naphtho-[2,1-b]pyran.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][N:33]1[CH2:38][CH2:37][O:36][CH:35]([CH2:39][NH2:40])[CH2:34]1>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:40][CH2:39][CH:35]4[O:36][CH2:37][CH2:38][N:33]([CH3:32])[CH2:34]4)=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN1CCOC(CN)C1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CN(C)CCO3)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (4-methylmorpholin-2-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.44 (s, 3H) 2.78-2.94 (m, 4H) 2.98-3.15 (m, 1H) 3.31-3.58 (m, 4H) 3.68 (t, J=11.75 Hz, 1H) 3.78-3.95 (m, 1H) 4.08 (dd, J=12.88, 3.03 Hz, 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 1H) 7.78 (br. s., 1H) 8.21 (d, J=6.32 Hz, 1H) 8.44 (d, J=7.07 Hz, 2H) 8.85-9.06 (m, 2H) 9.93 (br. s., 1H) 12.57-13.73 (m, 1H). MS m/z [M+H]+ 433.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 99.4 %

Procedure:
8.51 g (61.57 mmol) of potassium carbonate are added to a solution of 10.0 g (58.64 mmol) of 4-hydroxy-2-nitrobenzaldehyde in 70 ml of DMF. The solution is briefly stirred, then 10.53 g (61.57 mmol) of benzyl bromide are added and the reaction mixture is stirred at room temperature for 3 h. The resulting solid is then filtered off, 250 ml of water are added to the filtrate and the aqueous phase is extracted 3× with ethyl acetate. The organic phase is washed twice with water, dried over sodium sulphate, concentrated in vacuo and the residue is dried. 15.0 g (99%) of 4-benzyloxy-2-nitrobenzaldehyde are obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[O:8])[NH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(O)(=O)C>[Br:10][C:7]1[NH:6][C:5](=[O:8])[C:4]([OH:9])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]cc(Cl)cc1O
Solvent: CC(=O)O
Product: O=c1[nH]c(Br)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
To 5-chloro-3-hydroxypyridin-2(1H)-one (500 mg) was added acetic acid (20 ml), and N-bromosuccinimide (734 mg) was added at room temperature. The reaction mixture was stirred at room temperature for 5 hr. The obtained solid was collected by filtration and washed with ethyl acetate. The obtained residue was purified by reversed-phase column chromatography (methanol-0.1% aqueous formic acid solution) and solidified by dimethylformamide to give 6-bromo-5-chloro-3-hydroxypyridin-2(1H)-one (40 mg).