Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[K+].O1CCCC1.ClCCl.Cl>ClCCl.CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OCC(=O)OC)cc12
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OCC(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a 50 mL round-bottomed flask was added methyl 2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yloxy)acetate (132.3 mg, 0.370 mmol) and 2 equivalents of potassium trimethylsilanolate (95 mg, 0.740 mmol) along with a 1:1 solution of tetrahydrofuran/dichloromethane (10 ml) to give a yellow heterogeneous mixture. The mixture was stirred at room temperature overnight. The crude product was then cooled to 0° C., diluted further with dichloromethane, and acidified with 1 N HCl. The product was extracted, washed with water then brine, and dried over magnesium sulfate. After solvent evaporation, the product was triturated with hexane to give a 91% yield (115 mgs), a white amorphous solid after drying under vacuum. The LC/MS data was obtained on a Shimadzu analytical LC/MICROMASS® Platform LC (ESI+) at 220 nm using the following set of conditions: PHENOMENEX® 10 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 1 minute hold at a rate of 5 mL/minute. The NMR spectra was recorded at room temperature using a Bruker DRX300 spectrometer. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.82 (d, J=4.39 Hz, 3H), 4.72 (s, 2H), 7.00 (dd, J=8.78, 2.56 Hz, 1H), 7.08 (d, J=2.56 Hz, 1H), 7.35 (t, J=8.97 Hz, 2H), 7.57 (d, J=8.78 Hz, 1H), 7.92 (dd, J=8.78, 5.49 Hz, 2H), 8.34 (m, 1H). LCMS m/z 344.27 (M+H), Rt 1.450 min., 96.0% purity.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH:20]=O)[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[CH:35]([NH2:38])([CH3:37])[CH3:36].CC(O)=O.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:25]=[CH:24][C:23]([CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:22][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH2:20][NH:38][CH:35]([CH3:37])[CH3:36])[CH2:16][CH2:15]2)=[O:7])=[CH:33][CH:34]=1
Reactant: O=C[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NC[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCCCC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 12.2 %

Procedure:
A suspension of (E)-4-fluoro-N-(1-(cis-4-formylcyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (75 mg, 0.162 mmol) in MeOH (3.2 mL) was cooled to 0° C. under nitrogen atmosphere. To this mixture was added isopropylamine (0.208 mL, 2.432 mmol) followed by AcOH (0.056 mL, 0.973 mmol). The resulting mixture was stirred for 15 minutes. Solid sodium cyanoborohydride (15.28 mg, 0.243 mmol) was added in one portion, and the resulting mixture was stirred for 18 hours at RT. The reaction mixture was quenched with water (10 mL), and the aqueous layer was extracted with DCM (30 mL). The organic layer was collected, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography (10-30% of 90/10/1 DCM/MeOH/NH4OH in DCM) to afford (E)-4-fluoro-N-(1-(cis-4-((isopropylamino)methyl)cyclohexyl)-6-(piperidin-1-ylmethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (10 mg, 12.20% yield). MS m/z=506.2 [M+H]. Calc'd for C30H40FN5O: 505.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]([C:36]1[CH:40]=[C:39]([NH2:41])[NH:38][N:37]=1)([CH3:35])[CH3:34].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CC(=O)OCC>N1C=CC=CC=1.O.C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:41][C:39]3[NH:38][N:37]=[C:36]([C:33]([CH3:35])([CH3:34])[C:32]([F:43])([F:42])[F:31])[CH:40]=3)=[O:29])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Reactant: CC(C)(c1cc(N)[nH]n1)C(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)n[nH]3)c(F)c2)cnc1OCc1ccc(OC)cc1
Reaction time: 2 h
Yield: 42 %

Procedure:
To a mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (100 mg, 0.243 mmol) and 3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine (51.6 mg, 0.267 mmol) in pyridine (3 mL) was added T3P® (EA solvate) (0.3 mL, 0.243 mmol) at 25° C. Then the mixture was stirred for 2 h, the mixture was concentrated to give a residue which was distributed between DCM (20 mL) and H2O (10 mL) and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to yield a white solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide (100 mg, 0.102 mmol, 42.1% yield): 1H NMR (400 MHz, CD3OD) δ 8.52 (d, J=4.2 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.48-7.33 (m, 6H), 6.90 (d, J=8.6 Hz, 2H), 5.35 (s, 2H), 4.19-4.09 (m, 2H), 3.78 (s, 3H), 3.70-3.63 (m, 2H), 1.54-1.36 (m, 9H). ES-LCMS m/z 587 (M+H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=S.F[C:12](F)(F)C(F)=C(F)F.C=C=O>>[F:1][C:2]([F:10])([F:9])[C:3](=[CH2:12])[C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: FC(F)(F)C(=S)C(F)(F)F
Agent: C=C=O
Product: C=C(C(F)(F)F)C(F)(F)F
Temperature: 150 °C

Procedure:
Hexafluorothioacetone is a known compound (b.p. 6° C.) and is a relatively reactive and unstable monomer. It is convenient to handle this compound in the form of its dimer 2,2,4,4-tetrakis (trifluoromethyl)-1,3-dithietane which is a stable liquid (b.p. 110° C.). Hexafluorothioacetone may be conveniently generated from its dimer by thermal cracking which may be readily accomplished by passng the dimer through a hot tube at about 590°-600° C. The dimer, in turn, is rapidly formed from hexafluorothioacetone at about room temperature and the dimerization is catalyzed by bases. Alternatively, hexafluorothioacetone may be prepared by reacting sulfur and hexafluoropropene over a carbon bed at about 400° C. and the hexafluorothioacetone produced can be used immediately after it has been prepared. The effluent gases from such reaction containing hexafluorothioacetone, unreacted hexafluoropropene and by-products should be passed through traps maintained at 150° C. to remove unreacted sulfur. The presence of sulfur lowers the yield of hexafluoroisobutylene from the reaction of ketene with hexafluorothioacetone. These gases are then contacted with ketene to form hexafluoroisobutylene. The total effluent should then be passed through caustic traps to remove residual amounts of ketene and hexathioacetone. This procedure eliminates the need to isolate and purify the hexafluorothioacetone dimer.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3([C:18]([CH3:20])([CH3:19])[O:17][C:12]4([CH2:16][CH2:15][CH2:14][CH2:13]4)[C:11]3=[O:21])[O:9]2)=[C:4]([CH2:22][CH3:23])[CH:3]=1.BrC1C=CC(C2C3(C(=O)C(C)(C)OC43CCCC4)O2)=C(CC)C=1.S(=O)(=O)(O)O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:11](=[O:21])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[O:17][C:18]([CH3:19])([CH3:20])[C:10]2=[O:9])=[C:4]([CH2:22][CH3:23])[CH:3]=1
Reactant: CCc1cc(Br)ccc1C1OC12C(=O)C1(CCCC1)OC2(C)C
Agent: CCc1cc(Br)ccc1C1OC12C(=O)C(C)(C)OC21CCCC1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCc1cc(Br)ccc1C1C(=O)C(C)(C)OC2(CCCC2)C1=O
Temperature: 7.5 °C
Reaction time: 0.92 h

Procedure:
To an ice cold solution of a mixture of 2-(4-bromo-2-ethylphenyl)-11,11-dimethyl-1,10-dioxadispiro[2.1.4.2]undecan-4-one and 2-(4-bromo-2-ethylphenyl)-10,10-dimethyl-1,9-dioxadispiro[2.0.4.3]undecan-11-one (7 g, 0.0185 mol) in dichloromethane (3.5 ml) is added concentrated sulphuric acid (21 ml), dropwise over 50-60 minutes, maintaining the temperature of the reaction mixture at 5-10° C. The reaction mixture is maintained at 5-10° C. for 10-15 minutes, quenched into crushed ice (100 g) and extracted with dichloromethane (3×75 ml). The organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 9-(4-bromo-2-ethyl-phenyl)-7,7-dimethyl-6-oxaspiro[4.5]decane-8,10-dione (1.1 g) as a white solid.
Reaction SMILES: [CH2:1]([C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]#[N:17])[CH2:5]1)[CH:2]=C.[O:18]=[O+][O-]>ClCCl>[O:18]=[CH:2][CH2:1][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]#[N:17])[CH2:5]1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H]1C[C@H](CC#N)OC2(CCCCC2)O1
Solvent: ClCCl
Product: N#CC[C@H]1C[C@@H](CC=O)OC2(CCCCC2)O1
Temperature: 25 °C

Procedure:
A solution of (±)-cis-4-(2-propenyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile 4.26 g (19.42 mmol), in 100 mL of dichloromethane is cooled to -78° C. under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage=90 V) is then passed through a fritted gas inlet tube into the solution until the blue color of ozone appears. The current is turned off, and oxygen bubbled through until the blue color is discharged. Triphenylphosphine, 5.6 g (21.36 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography provides after concentration in vacuo 4.04 g of pure (±)-cis-4-(2-oxoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH2:10])=[S:9])=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:19])[C:15](=O)[CH2:16]Br)[CH3:12]>CO>[CH2:11]([O:13][C:14]([C:15]1[N:10]=[C:8]([NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[S:9][CH:16]=1)=[O:19])[CH3:12]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1ccncc1
Solvent: CO
Product: CCOC(=O)c1csc(Nc2ccncc2)n1
Yield: 79.8 %

Procedure:
2-(Pyridin-4-ylamino)-thiazole-4-carboxylic acid ethyl ester (200 mg) was prepared according to General Procedure B using pyridin-4-yl-thiourea (154 mg) and 3-bromo-2-oxo-propionic acid ethyl ester (200 mg) in methanol (2 mL). The crude product was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([OH:6])[C:4]#[CH:5].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C>[CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH:3]([O:6][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)[C:4]#[CH:5]
Reactant: C#CC(O)C(C)(C)CCCC
Reactant: C1=COCCC1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: C#CC(OC1CCCCO1)C(C)(C)CCCC
Temperature: 25 °C

Procedure:
To a solution of 23.1 g. (0.150 mole) of 4,4-dimethyl-1-octyn-3-ol (Example 994) in 126 g. of freshly distilled dihydropyran is added 1 drop of phosphorus oxychloride and the solution is maintained at ambient temperature in a tightly stoppered flask for 20 hours. Five drops of triethylamine are then added and the mixture is evaporated in vacuo to an oil. The oil is chromatographed on 600 g. of silica gel and the product is eluted with 5% ethyl acetate in benzene yielding a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:27])[C:15]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[CH:18]=1)=[O:16])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]#[N:37]>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:35][C:36]#[N:37])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:27])[C:15]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[CH:18]=1)=[O:16])=[CH:7]2
Reactant: CN(Cc1ccc2c(Br)c(O)ccc2c1)C(=O)c1cn(C)c2ccccc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc2c(Br)c(OCC#N)ccc2c1)C(=O)c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A mixture of 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (2.0 g, 4.72 mmol), prepared in the previous step, potassium carbonate (3.26 g, 23.6 mmol) and bromoacetonitrile (0.39 mL, 5.67 mmol) in 60 mL of DMF was stirred under nitrogen at room temperature for 24 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted five times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (2.06 g, 94.5%) as a tan solid, mp 148-150° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Br:20])[CH:19]=3)=[N:11][CH:12]=2)[CH2:3]1.C=O.[C:25](O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH:4]3[CH2:5][N:2]([CH3:25])[CH2:3]3)=[CH:12][N:11]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: CC(=O)O
Reactant: Cn1cc(Br)cc(Nc2ccc(OC3CNC3)cn2)c1=O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CO
Product: CN1CC(Oc2ccc(Nc3cc(Br)cn(C)c3=O)nc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
A mixture of 206e (1.24 g, 3.2 mmol), 37% aqueous formaldehyde solution (15 mL), acetic acid (1 mL), and NaBH(OAc)3 (1.36 g, 6.4 mmol) in methanol (10 mL) was stirred at room temperature for 4 h. The solvent was evaporated in vacuo and the residue was extracted with ethyl acetate (3×20 mL). The combined extract was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on reverse-phase Combiflash to afford 206f (940 mg, 80%). MS-ESI: [M+H]+ 365.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([N:12]2[CH2:27][CH2:26][C:15]3([CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[ClH:28].CO>O1CCOCC1>[ClH:28].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:12]2[CH2:13][CH2:14][C:15]3([CH2:18][NH:17][CH2:16]3)[CH2:26][CH2:27]2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)N2CCC3(CC2)CN(C(=O)OC(C)(C)C)C3)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(CC(=O)N2CCC3(CC2)CNC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 7-[(4-methoxyphenyl)acetyl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (2.75 g, 11.2 mmol) in 15 mL of anhydrous dioxane was added 4N HCl in dioxane (3.8 mL). The reaction mixture was stirred at room temperature overnight. Methanol (3 mL) was added to dissolve the solids and the mixture was stirred at ambient temperature for another 2 hours. The reaction was concentrated to dryness and dried on high vacuum overnight to provide the product as a light yellow foam (2.31 g). MS (ES+) 275.4 (M+H)+. 1H NMR (D2O) δ 1.58 (t, 2H), 1.75 (t, 2H), 3.39 (t, 4H), 3.63 (s, 2H), 3.70 (s, 3H), 3.72-3.82 (m, 4H), 6.86 (d, 2H), 7.08 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:37](=[O:39])[CH3:38])[CH2:12]1)[CH2:10][C:9]2=[O:26]
Reactant: CC(=O)Cl
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(C)=O)C1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A suspension of Intermediate 4 (280 mg, 0.90 mmol) in DCM (7.5 ml) was treated with DIPEA (0.32 ml, 1.8 mmol) and acetyl chloride (0.09 ml, 1.35 mmol). The reaction mixture was stirred at RT for 1 h and the solution was then evaporated under vacuum to give (E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester as a light brown solid (280 mg).
Reaction SMILES: [NH4+].[Cl-].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[C:17]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:16][CH2:15]3)=[N:10][CH:11]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[C:17]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:23][C:24]([F:27])([F:25])[F:26])[CH2:16][CH2:15]3)=[N:10][CH:11]=1
Reactant: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(-c3ccc([N+](=O)[O-])cn3)ccc2C1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(-c3ccc(N)cn3)ccc2C1=O
Yield: 75.7 %

Procedure:
Iron powder (0.218 g, 3.9 mmol) and NH4Cl (0.208 g, 3.9 mmol) was added to a solution of 1I (1.7 g, 3.9 mmol) in 15 mL of ethanol-water (2:1) mixture. The reaction mixture was refluxed for 3 h, and solvent was removed under reduced pressure. The crude product was purified by flash chromatography using 25% ethyl acetate in hexane to afford the title compound (1.2 g, 53%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J=2.8 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 7.88-7.78 (m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.06 (dd, J1=2.9 Hz, J2=8.5 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.86 (s, 2H), 3.20-3.02 (m, 2H), 2.98-2.81 (m, 2H), 2.72-2.53 (m, 2H), 2.51-2.28 (m, 2H), 1.24 (t, J=7.6 Hz, 3H). ESI-MS m/z: 407 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:22])[CH:18]=[N:19][O:20][CH3:21]>CN(C)C=O>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH3:21][O:20][N:19]=[CH:18][CH:17]([NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])[CH3:22]
Reactant: CON=CC(C)Br
Agent: Cc1cccc(C)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CON=CC(C)Nc1c(C)cccc1C
Yield: 72.4 %

Procedure:
42.4 g (0.35 mol) of 2,6-dimethylaniline and 25 g (0.17 mol) of powdered potassium carbonate in 100 ml of dimethylformamide were heated to 80° C., whilst stirring, and 29 g (0.17 mol) of 2-bromo-1-methoxyimino-propane were added dropwise. During this addition, the temperature rose to 95° C. The mixture was stirred for a further 2 hours at 80° C., the inorganic salt was filtered off and the filtrate was distilled. After distilling off the solvent and the excess 2,6-dimethylaniline, 25.4 g (72.5% of theory) of N-(1-methoxyimino-prop-2-yl)-2,6-dimethylaniline of boiling point 107°-109° C./0.1 mm Hg were obtained. ##STR175## Process variant (a)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=1[Cl:24]>>[Cl:24][C:15]1[CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=[CH:19][C:14]=1[CH2:13][N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Product: CS(=O)(=O)c1ccc(Cn2ncc3cc(C=O)ccc32)c(Cl)c1

Procedure:
1-(2-Chloro-4-methanesulfonyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 1-Bromomethyl-2-chloro-4-methanesulfonyl-benzene following General Procedure A.
Reaction SMILES: C([Li])CCC.[OH:6][C:7]([C@H:10]1[C@@H:13]([CH2:14][CH:15]=[CH2:16])[N:12]([C:17](=[C:22]([CH3:24])[CH3:23])[C:18]([O:20][CH3:21])=[O:19])[C:11]1=[O:25])([CH3:9])[CH3:8].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:28].C(O)(=O)C>O1CCCC1>[CH3:23][C:22]([CH3:24])=[C:17]([N:12]1[C@H:13]([CH2:14][CH:15]=[CH2:16])[C@H:10]([C:7]([CH3:9])([O:6][C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:28])[CH3:8])[C:11]1=[O:25])[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: C=CC[C@@H]1[C@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=CC[C@@H]1[C@H](C(C)(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A solution of n-butyl lithium (0.46 ml of 1.38 M solution in hexane) was added to a solution of methyl 2-[(3R, 4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (150 mg) in tetrahydrofuran (3 ml) at -70° C. and the mixture was stirred for 15 minutes at -70° C. A solution of p-nitrobenzyl chloroformate (161 mg) in tetrahydrofuran (3.2 ml) was added to the reaction mixture at -70° C. and the mixture was stirred for 10 minutes at -70° C. The mixture was allowed to warm to 0° C. during 30 minutes and stirred at 0° C. for 1.5 hours. Acetic acid (0.043 ml) was added to the mixture at 0° C. and the mixture was evaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and the solution was washed with brine, aqueous sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of hexane and ethyl acetate (10:1-3:1) to give methyl 3-methyl-2-[(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate (123 mg) as an oil.