Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[C:26]([C:28]#[CH:29])[CH:27]=2)[O:24][C:23]([CH3:31])([CH3:30])[CH2:22][C:21]3([CH3:33])[CH3:32])=[O:17])=[CH:11][CH:10]=1)=[O:7])(C)(C)C.C(O)=O>O1CCOCC1.O>[C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]([C:18]2[CH:19]=[C:20]3[C:25](=[C:26]([C:28]#[CH:29])[CH:27]=2)[O:24][C:23]([CH3:31])([CH3:30])[CH2:22][C:21]3([CH3:33])[CH3:32])=[O:17])=[CH:13][CH:14]=1)([OH:7])=[O:5]
Reactant: C#Cc1cc(C(=O)Oc2ccc(CC(=O)OC(C)(C)C)cc2)cc2c1OC(C)(C)CC2(C)C
Solvent: O
Solvent: O=CO
Solvent: C1COCCO1
Product: C#Cc1cc(C(=O)Oc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Reaction time: 2 h

Procedure:
A solution of 8-ethynyl-2,2,4,4-tetramethyl chroman-6-carboxylic acid 4-tert-butoxycarbonylmethyl-phenyl ester (Compound 27, 1.5 g, 3.34 mmol) in 1,4-dioxane (30 mL) was treated with formic acid (200 mL) at ambient temperature. After 2 h, the reaction mixture was diluted with water and extracted with diethyl ether. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product. The product was further purified by recrystallization from 10-20% ethyl acetate in hexane (1.32 g, 100%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1([O:32][CH3:33])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24]CS([O-])(=O)=O)[O:21][C:20]3=[O:30])=[CH:15][CH:14]=2)[CH2:9][CH:8]1[F:31]>CN(C)C=O>[CH3:5][O:6][C:7]1([O:32][CH3:33])[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:23][C@@H:22]([CH2:24][N:1]=[N+:2]=[N-:3])[O:21][C:20]3=[O:30])=[CH:17][CH:18]=2)[CH2:9][CH:8]1[F:31]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2)CC1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2)CC1F
Temperature: 70 °C
Yield: 78 %

Procedure:
The mixture of sodium azide (88.5 mmol) and (R)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-methanesulfonate (29.6 mmol) in dimethylformamide (75 ml) was heated at 70° C. for 14 hours. The reaction mixture was poured on ice cold water, and the solid was filtered to afford title compound in 78% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.[OH-].[Na+].O>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12](=[O:14])/[CH:13]=[CH:20]/[C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)/C=C/c1ccc(C(C)C)cc1
Reactant: O=Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(/C=C/C(=O)/C=C/c2cccs2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86 %

Procedure:
A mixture of 7.9 grams (0.042 mol) of E-4-(p-isopropylphenyl)-3-butene-2-one, 4.7 grams (0.042 mol) of 2-thiophene carboxaldehyde, 2mL of 10% sodium hydroxide, 30 mL of water, and 75 mL of ethanol was stirred at ambient temperature for 15 hours. The product was collected by filtration and air dried to give 10.2 grams (86% of theoretical yield) of E,E-1-(p-isopropylphenyl)-5-(2-thienyl)-1,4-pentadien-3-one as a yellow solid. Melting point was determined to be 100°-101° C. Proton nuclear magnetic resonance (1H NMR) was conducted in CDCl3: d 7.84 (d, 1H, J=16 Hz), 7.69 (d, 1H, J=16 Hz), 7.53 (AA'BB', 2H), 7.39 (m, 1H), 7.32 (m, 1H), 7.25 (AA'BB', 2H), 7.06 (dxd, 1H, J=3.6, 5 Hz), 6.96 (d, 1H, J=16 Hz), 6.87 (d, 1H, J=16 Hz), 2.90 (septet, 1H, J=7 Hz), 1.23 (d, 6H, J=7 Hz). Infrared spectroscopy was conducted using a KBr pellet: 2960, 1650, 1585, 1180, and 705 cm-1. Field desorption mass spectral analysis (FDMS) was consistent with the proposed formula (C18H18 0S) m+ /z 316.
Reaction SMILES: [Na+].[F:2][C:3]1[C:8](C)=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-:14])=O)=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl.[CH2:23](O)C>>[F:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:14])[N:15]2[CH3:23])=[CH:7][CH:8]=1
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1F
Reactant: CCO
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CN1C(=O)CNc2ccc(F)cc21
Temperature: 25 °C

Procedure:
A mixture of N-(4-fluoro-5-methyl-2-nitrophenyl)glycine sodium salt(0. 125 g, 0.548 mmol) and tin (II) chloride dihydrate (0.370 g, 1.64 mmol, Aldrich, used as received) in ethanol (3.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water (4.0 mL) and basified with saturated NaHCO3 to pH ˜8. The resulting. suspension was extracted with ethyl acetate (30 mL). The extract was dried over Na2SO4 and evaporated to yield 0.032 g of the tide compound as a yellow powder, which was used for the next reaction; 1H NMR (DMSO-d6): 2.024 (s, 3H), 3.607 (s, 2H), 5.751 (s, 1H), 6.453 (d, 1H, J=9.9 Hz), 6.456 (d, 1H, J=8.1 Hz), 10.162 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH3:10].[F:11][C:12]([F:29])([F:28])[C:13](=[O:27])[CH2:14][C:15](C1C=C(C)C=CC=1OC)([CH3:17])[CH3:16]>>[F:11][C:12]([F:29])([F:28])[C:13](=[O:27])[CH2:14][C:15]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([CH3:10])=[CH:5][C:6]=1[CH3:9])([CH3:17])[CH3:16]
Reactant: COc1ccc(C)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: COc1ccc(C)cc1C
Product: COc1cc(C(C)(C)CC(=O)C(F)(F)F)c(C)cc1C

Procedure:
The title product was prepared from 1-methoxy-2,4-dimethylbenzene according to the same procedure described in the synthesis of 1,1,1-trifluoro-4-(2-methoxy-5-methylphenyl)-4-methylpentan-2-one.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].[CH3:15][O:16][C:17]1[CH:18]=[C:19](OB(O)O)[CH:20]=[CH:21][CH:22]=1>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:16][CH3:15])[CH:22]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1ccc2cc(Br)ccc2c1Br
Reactant: COc1cccc(OB(O)O)c1
Product: COc1cccc(-c2ccc3c(Br)c(OC)ccc3c2)c1
Yield: 81 %

Procedure:
The compound is prepared by the reaction of 1,6-dibromo-2-methoxy-naphthalene (5.75 g, 18.20 mmol, 1 eq) with 3-methoxyphenylboric acid (2.77 g, 18.20 mmol, 1 eq) according to method A. Purification by column chromatography with hexane as the eluent yielded the desired compound in a yield of 81%, 5.1 g.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=2)=[CH:31][CH:30]=1
Reactant: OC(c1ccc(F)cc1)c1cccc(F)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OC(c1ccc(F)cc1)c1cccc(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-(4-fluoro-phenyl)-methanol.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([Cl:33])[CH:29]=2)[N:24]=1)=[O:22])=[O:7])(C)(C)C.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][C:39]2[N:42]=[C:43](C([O-])=O)[S:44][C:38]=2[CH2:37]1.[Li+]>C(O)C>[ClH:33].[Cl:33][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]([C:21]([NH:20][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:14][C@H:9]1[NH:8][C:6]([C:43]1[S:44][C:38]3[CH2:37][N:36]([CH3:35])[CH2:41][CH2:40][C:39]=3[N:42]=1)=[O:7])=[O:22])[CH:32]=[CH:31]2
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2ccc3cc(Cl)ccc3n2)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3ccc4cc(Cl)ccc4n3)sc2C1

Procedure:
(1S,2R,4S)—N2-(tert-Butoxycarbonyl)-N1-[(6-chloroquinolin-2-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(-c2cnn(C(C)(C)C)c2-c2ccc(F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)n1ncc(-c2nc(C(=O)O)cs2)c1-c1ccc(F)cc1
Yield: 94.6 %

Procedure:
A mixed solution of the compound (0.57 g, 1.53 mmol) obtained in step 1 and 1N aqueous sodium hydroxide solution (2.289 ml, 2.29 mmol) in ethanol (5 mL) and THF (5 mL) was stirred at 60° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue. The precipitate was collected by filtration to give 2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid (0.50 g, 1.448 mmol, 95%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([OH:14])=O)=[O:9])=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12]([NH:35][C@H:36]([CH2:40][OH:41])[CH:37]([CH3:39])[CH3:38])=[O:14])=[O:9])=[CH:18][CH:19]=1
Reactant: Cc1ccc(COC(=O)N2CCC[C@H]2C(=O)O)cc1
Reactant: CC(C)[C@H](N)CO
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Product: Cc1ccc(COC(=O)N2CCC[C@H]2C(=O)N[C@H](CO)C(C)C)cc1

Procedure:
The subject compound was prepared from 3.9 g (14.8 mmol) p-methylbenzyloxycarbonyl-L-proline, 2.0 g (14.6 mmol) isobutyl chloroformate, 1.5 g (14.8 mmol) N-methylmorpholine, and 1.5 g (14.5 mmol) L-valinol, using a procedure described in Example 1. The product, N-(p-methylbenzyloxycarbonyl)-L-prolyl-L-valinol, obtained after recrystallization from ethyl acetate/ n-hexane, melted at 122°-123.5°, α25D -61.9° (C=1.00 g/100 mL in acetone).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([O-])([O-])=O.[Na+].[Na+].CC([O-])=O.[K+].[Cl-].[NH4+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Fe].O.C(O)C.C(#N)C>[NH2:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[C:23]1[CH:24]=[C:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(B(O)O)c1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Fe]
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: Cn1ncc(N)c1-c1cccc(NC(=O)OC(C)(C)C)c1
Reaction time: 1 h

Procedure:
To a 10 mL microwave vial was added 5-chloro-1-methyl-4-nitro-1H-pyrazole (150 mg, 0.93 mmol), 3-(tert-butoxycarbonylamino)phenylboronic acid (440 mg, 1.86 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (152 mg, 0.019 mmol), a 1:1 M solution of Na2CO3/KOAc (1 mL) and acetonitrile (4 mL). The mixture was irradiated to 130° C. with a microwave for 40 min and the mixture was cooled, concentrated and purified via flash chromatography, heptane/ethyl acetate 20% to 95% to afford a yellow oil. To a 50 mL round bottom flask was added the nitro compound (120 mg, 0.90 mmol), iron (156 mg, 2.8 mmol), ammonium chloride (200 mg, 3.7 mmol), ethanol (10 mL) and water (1.5 mL). The mixture was stirred for 1 h and the reaction was monitored by LCMS. Upon completion of the reaction, the mixture was filtered through a pad of Celite and was washed with ethyl acetate (30 mL) and a 10% aqueous solution of K3PO4 (30 mL). The organic layer was washed with water (30 mL), dried over Na2SO4 and the organic solvent was distilled off to yield tert-butyl 3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenylcarbamate as a brown oil with a purity of >98% (120 mg, 45%) over two steps. ESIMS m/z=289.1 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Al](Cl)(C)C.[CH3:13][N:14]([CH3:42])[C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26](OCC)=[O:27])[CH:23]=[C:22]([O:31][C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)[C:20]=2[CH:21]=1)=[O:16]>ClCCCl>[CH3:13][N:14]([CH3:42])[C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:27])[CH:23]=[C:22]([O:31][C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=3)[C:20]=2[CH:21]=1)=[O:16]
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C(=O)N(C)C)oc2c1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(C(=O)N(C)C)oc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.9 %

Procedure:
2-Amino-5-methylpyridine (226 mg, 2.09 mmol) was dissolved in DCE (10 mL) at 0° C., and Al(CH3)2Cl (2.09 mL, 1M in hexanes) was then added drop-wise. After stirring the mixture at room temperature for 30 minutes, ethyl 2-(dimethylcarbamoyl)-4-(4-(methylsulfonyl)phenoxy)-benzofuran-6-carboxylate (90 mg, 0.21 mmol) was then added and the stirring was continued for another 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine, and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (61 mg, 61%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 2.32 (s, 3 H) 3.08 (s, 3 H) 3.15 (s, 3 H) 3.34 (s, 3 H) 7.12-7.18 (m, 2 H) 7.19 (s, 1 H) 7.52 (s, 1 H) 7.58 (dd, J=8.48, 2.26 Hz, 1 H) 7.87-7.98 (m, 2 H) 7.99 (s, 1 H) 8.11 (s, 1 H) 8.24 (d, J=8.48 Hz, 1 H) 8.64 (s, 1 H). LCMS m/z 494.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([NH:39]O)=[NH:38])[CH:35]=2)[N:30]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:29]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:38]=[C:37]([C:34]3[CH:35]=[C:36]4[C:31](=[CH:32][CH:33]=3)[N:30]([CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH:29]=[C:28]4[Cl:27])[N:39]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C(=O)O)cc1Br
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(C(=N)NO)ccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1cc(Cl)c2cc(-c3noc(-c4ccc(OC)c(Br)c4)n3)ccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The 3-bromo-4-(methyloxy)benzoic acid (commercial: ICN) (243 mg, 1.05 mmol) stirring in DMF (10 ml) was treated with EDC (219 mg, 0.1.14 mmol) followed by HOBt (156 mg, 0.1.14 mmol). The resultant solution was stirred for 10 minutes. Added ethyl 3-{3-chloro-5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D96) (324 mg, 1.05 mmol) and stirred at RT for 45 minutes. The solution was heated at 80° C. for 4 hours then left standing overnight. The solution was heated at 80° C. for a further 4 hours to give one major product. Evaporated off the DMF, added EtOAc (50 ml) and washed with water (50 ml). The EtOAc was washed with sat. aqueous sodium hydrogen carbonate (50 ml) and water (50 ml) then dried over MgSO4. Evaporated off the solvent and crystallised from ethanol to yield the title compound as 280 mg of cream solid. δH (400 MHz, d6-DMSO) 1.10 (3H, t), 2.90 (2H, t), 3.99-4.05 (5H, m), 4.49 (2H, t), 7.38 (1H, d), 7.74 (1H, s), 7.80 (1H, d), 7.97 (1H, d), 8.21-8.23 (2H, m), 8.36 (1H, d). MS (ES) C22H1981Br35ClN3O4 requires 505; found 506 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-])=O>CO.[C].[Pd]>[NH2:13][C:3]1[C:4]([CH3:12])=[C:5]([CH:10]=[CH:11][C:2]=1[F:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(F)c(N)c1C
Reaction time: 4 h
Yield: 41.3 %

Procedure:
A mixture of a crudely purified product (6.00 g, purity 50%) of methyl 4-fluoro-2-methyl-3-nitrobenzoate and wet palladium carbon (10 wt %, 300 mg, 2.81 mmol) in methanol (100 mL) was stirred under hydrogen atmosphere for 4 hr. The catalyst was filtered off through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/20→1/10) to give the title compound (2.13 g, yield 42%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O.CN(C=O)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([Cl:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)Cc1cccc([N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
A mixture of commercially available 2-(3-nitrophenyl)acetic acid [CAS no. 1877-73-2] (25.8 g, 142 mmol, Eq: 1.00) and thionyl chloride (25.4 g, 15.5 ml, 214 mmol, Eq: 1.5) in toluene (141 ml) and DMF (208 mg, 221 μl, 2.85 mmol, Eq: 0.02) was stirred at 80° C. for 2 h. The hot solution was filtered through a Sartorius filter, the filtrate was evaporated and dried in HV to give the 2-(3-nitrophenyl)acetyl chloride (28.12 g, 141 mmol, 98.9% yield) as a yellow solid, which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].Cl.[Cl:10][C:11]([C:13]1[C:17]([CH3:18])=[CH:16][N:15]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[N:24]3)[CH:14]=1)=[O:12]>CO>[ClH:10].[NH:4]([C:11]([C:13]1[C:17]([CH3:18])=[CH:16][N:15]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[CH:21]=[CH:22][CH:23]=[N:24]3)[CH:14]=1)=[O:12])[C:3]([NH2:5])=[NH:2]
Reactant: Cc1cn(-c2cccc3ncccc23)cc1C(=O)Cl
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cn(-c2cccc3ncccc23)cc1C(=O)NC(=N)N
Reaction time: 2 h
Yield: 40.8 %

Procedure:
1.06 g (11.18 mmol) of guanidine hydrochloride is added to a solution of 0.604 g (11.18 mmol) of sodium methoxide in 50 mL of methanol at a temperature in the region of 20° C. under an argon atmosphere. After stirring for 2 hours at this temperature, the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 25 mL of 1,2-dimethoxyethane, and 0.57 g (1.86 mmol) of 3-chlorocarbonyl-4-methyl-1-(quinolin-5-yl)-1H-pyrrole hydrochloride is added. After stirring for 2 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in 25 mL of water and then filtered, giving a gum, which is triturated again in 20 mL of water and filtered. The residue is purified by chromatography on silica gel [eluent: chloroform/methanol (80/20 by volume)]. After the fractions containing the expected product have been concentrated to dryness under reduced pressure, the residue is dissolved in ethyl acetate, and excess 4 M hydrochloric ether is added. After the reaction mixture has been stirred at room temperature for one hour, the precipitate formed is isolated by filtration, giving 0.25 g of 3-guanidinocarbonyl-4-methyl-1-(quinolin-5-yl)-1H-pyrrole hydrochloride in the form of a yellow solid melting at 240° C. Mass spectrum (EI): m/e 293 (M+.) (base peak).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[Cl:17])[NH:13][CH:12]=[C:11]2[CH2:18][C:19]([O:21]CCCC)=[O:20]>O.CO>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[Cl:17])[NH:13][CH:12]=[C:11]2[CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCCCOC(=O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1c[nH]c2cc(Cl)c(Cl)cc12
Yield: 33.2 %

Procedure:
An aqueous solution prepared by dissolving 280 mg of potassium carbonate in 2.5 ml of water was added to a solution of 100 mg of n-butyl 5,6-dichloroindole-3-acetate in 10 ml of methanol. After 1.5 hours of refluxing, the methanol was removed from the reaction solution under reduced pressure, and the aqueous solution thus obtained was extracted with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed with distilled water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by a silica gel thin-layer chromatography to obtain 27 mg of 5,6-dichloroindole-3-acetic acid.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:9]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]([O:6]CC)=[O:5].[OH-].[K+].CCCCCC>O.C(O)C.C(O)(=O)C.CC(O)C>[ClH:1].[NH2:2][CH:3]([CH:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(N)C1c2ccccc2Oc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: NC(C(=O)O)C1c2ccccc2Oc2ccccc21
Reaction time: 13 h

Procedure:
Ethyl α-amino-9H-xanthene-9-acetate hydrochloride (5.33 g, 17 mmol) is combined with 45 mL of absolute ethanol and 27 mL of 1.25M ethanolic potassium hydroxide solution (2 equivalents). The progress of the reaction is monitored by thin layer chromatography (TLC), silica gel (SiO2), hexane:2-propanol/3:7 with 1% of acetic acid. After 13 hours and an additional two equivalents of the potassium hydroxide solution (in three portions) most of the starting material is consumed. Ethanol is stripped off, the residue is taken up in 100 mL of water, and extracted with diethyl ether. The aqueous portion is acidified with 0.5N hydrochloric acid (~100 mL) to pH 2 and cooled overnight. A white precipitate is collected by filtration, washed with cold water, diethyl ether, and dried at 50° C./10 mm Hg. This provides 3.18 g of the title compound; mp 264°-269° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[C:8]([O:15][CH3:16])=[C:7]([CH3:17])[C:4]=1[CH:5]=O.[CH3:18][C:19]([CH3:21])=[O:20].C[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH:5]=[CH:18][C:19](=[O:20])[CH3:21])=[C:7]([CH3:17])[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: CC(C)=O
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C)c(C=CC(C)=O)c(OC)c(OC)c1OC
Yield: 59.8 %

Procedure:
To a solution of 2,3,4,5-tetramethoxy-6-methylbenzaldehyde (1.56 g, 6.5 mmol) and acetone (1.13 g, 19.5 mmol) in methanol (15 ml) was added 28% methanolic sodium methoxide (1.88 g). The mixture was refluxed for 1.5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column elution being carried out with isopropyl ether. The fractions containing the desired compound were concentrated to give 1,2,3,4-tetramethoxy-5-methyl-6-(3-oxo-1-butenyl)benzene (Compound 21, 1.09 g, 60% Oily substance) δ 2.28 (3H), 2.36 (3H), 3.77 (3H), 3.79 (3H), 3.89 (3H), 3.95 (3H), 6.70 (1H), 7.57 (1H),