Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1[CH:10]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15].OS(O)(=O)=O>N1CCCCC1.N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[CH:4]=[C:3]1/[CH:10]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: Cn1cc([N+](=O)[O-])cc1C=O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cn1cc([N+](=O)[O-])cc1/C=C/C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
Alternatively, a mixture of 1-methyl-4-nitro-2-pyrrolecarboxaldehyde (0.20 g, 1.30 mmol), malonic acid (0.68 g, 6.5 mmol), piperidine (2 drops), and pyridine (2 mL) was stirred at room temperature at for 20 h and at 100° C. for 4 h, then 30% aqueous H2SO4 (10 mL) was added. The precipitate that formed was removed by filtration and washed with water to give (E)-1-methyl-4-nitro-2-pyrroleacrylic acid as fine yellow needles (0.23 g, 92%). 1H NMR [(CD3)2SO] δ 12.35 (br s, 1 H, CO2H), 8.13 (d, J=1.9 Hz, 1 H, H-5), 7.44 (d, J=15.9 Hz, 1 H, H-β), 7.41 (d, J=1.9 Hz, 1 H, H-3), 6.46 (d, J=15.9 Hz, 1 H, H-α), 3.79 (s, 3 H, NCH3); 13C NMR δ 167.4 (CO2H), 135.3, 129.9 (C-2,4), 130.6, 127.0, 118.6, 105.8 (C-3,5,α,β), 34.8 (NCH3).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1>>[C:34]([O:33][C:31]([N:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:26]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(C(=O)OC(C)(C)C)C2)cn1
Yield: 61 %

Procedure:
As described for example 34, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using (+/−)-3-amino-1-N-Boc-piperidine instead of 1-methylpiperidin-4-amine, to the title compound (96 mg, 61%) which was obtained as a white foam. MS: m/e=493.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]([O:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[CH2:24][N:29]2[C@H:28]([CH3:27])[C@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][C:30]2=[O:39])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)cc(C(F)(F)F)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)cc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-trifluoromethyl-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[N:5][S:6][C:7]=1[NH:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C:15](OC)=[O:16])=[O:10])#[N:2].S(=O)(=O)(O)[OH:29]>>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([C:4]2[C:3]([C:1]([NH2:2])=[O:29])=[C:7]([NH:8][C:9]([N:11]3[CH2:12][CH2:13][CH2:14][C:15]3=[O:16])=[O:10])[S:6][N:5]=2)=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)CCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)N1CCCC1=O
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Methyl 4-[({[4-cyano-3-(4-nitrophenyl)isothiazol-5-yl]amino}carbonyl)amino]butanoate (10.0 g) was added portion wise to concentrated sulfuric acid (50.0 mL) at ambient temperature over 20 min. The resulting suspension was heated to 45° C. over 90 min. The reaction mixture was cooled to ambient temperature. The reaction mixture was poured into ice water (600 ml), stirred for 30 min. The solid which formed was collected and washed with water then dried in vacuo to give the titlee compound as off white solid (10.2 g, 99%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=O)(C)(C)C.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C@H:25]([NH2:27])[CH3:26])[CH:22]=[CH:23][CH:24]=1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C@H:25]([NH:27][C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[O:16])[CH3:26])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Product: COc1cccc([C@@H](C)NC(=O)C2CNCCO2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Step-2 of Intermediate-2 by using 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (Step-1 of Intermediate-2) and (R)-1-(3-methoxyphenyl)ethanamine followed by deprotection of resultant Boc protected compound by following the similar procedure as described in Step-3 of Intermediate-2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.CC1C=CC(S(O[CH2:34][C@H:35]2[CH2:39][CH2:38][CH2:37][O:36]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][O:36]1
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)CCO3
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: BrCC1CCCCO1
Product: O=C1N(C[C@H]2CCCO2)c2cccc(Br)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-bromo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-bromo-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (75%) as a colorless solid: mp 137-141° C.; 1H NMR (300 MHz, DMSO-d6) (diastereomers) δ7.30-7.10 (m, 3H), 6.42-6.37 (m, 1H), 6.32 (s, 1H), 4.88 (d, J=9.63 Hz, 1H), 4.70-4.63 (m, 1H), 4.46 (t, J=8.6 Hz, 2H), 4.18-4.05 (m, 1H), 3.85-3.52 (m, 4H), 2.93 (t, J=8.5 Hz, 2H), 2.01-1.67 (m, 3H), 1.64-1.49 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ177.5 (2), 162.2, 161.8, 145.7, 130.9, 130.2 (2), 126.6, 119.9 (2), 119.0 (2), 118.9 (2), 118.1, 92.5, 77.5, 76.3, 76.1, 72.5, 67.7 (2), 65.4, 58.7, 44.5, 29.0 (2), 28.7, 25.5; MS (ES+) m/z 443.9 (M+1), 445.9 (M+1).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14].[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14]
Reactant: CSc1ccccc1B(O)O
Reactant: CC(c1nc2ccccn2c(=O)c1Br)N1C(=O)c2ccccc2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CSc1ccccc1-c1c(C(C)N2C(=O)c3ccccc3C2=O)nc2ccccn2c1=O
Temperature: 85 °C
Reaction time: 25.5 h

Procedure:
A mixture of 2-(1-(3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione (0.9836 g, 2.470 mmol), 2-(methylthio)phenylboronic acid (0.623 g, 3.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.143 g, 0.124 mmol), and potassium carbonate (1.024 g, 7.41 mmol) in DME (12.35 mL) was stirred at 85° C. After 25.5 h, to the mixture were added 2-(methylthio)phenylboronic acid (0.623 g, 3.71 mmol), tetrakis(triphenylphosphine)palladium(0) (0.143 g, 0.124 mmol), and potassium carbonate (1.024 g, 7.41 mmol) and the mixture was stirred at 85° C. After 4 days 21 h, the mixture was cooled to rt. The insoluble solid was filtered off and the solid was washed with DCM (50 mL). The filtrate was cond under reduced pressure. The residue was dissolved in DCM (50 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and cond under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min and then 50% isocratic of EtOAc for 20 min as eluent to give 2-(1-(3-(2-(methylthio)phenyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione as a yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 (1 H, ddd, J=7.2, 1.6, 0.8 Hz), 7.98-8.05 (1 H, m), 7.77-7.84 (2 H, m), 7.68-7.75 (3 H, m), 7.43 (1 H, td, J=6.9, 1.5 Hz), 7.31 (1 H, dd, J=8.1, 0.9 Hz), 7.18-7.24 (1 H, m), 6.79-6.85 (1 H, m), 6.70-6.76 (1 H, m), 5.36-5.44 (1 H, m), 2.41 (3 H, s), 1.64 (3 H, d, J=7.2 Hz); Mass Spectrum (ESI) m/e=442.1 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15]O)=[C:12]([CH3:17])[CH:11]=1)[CH3:8].[OH-].[K+]>Cl>[CH3:8][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][S:5][CH2:4][CH2:3][NH2:2])=[C:12]([CH3:17])[CH:11]=1)[CH3:6]
Reactant: Cc1cc(CN(C)C)oc1CO
Reactant: NCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(CN(C)C)oc1CSCCN
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a solution of 2-aminoethanethiol hydrochloride (2.27 g; 20.0 mmoles) in 20 ml of concentrated HCl that was cooled in an ice-salt bath to -10° was added dropwise 5-dimethylaminomethyl-3-methyl-2-furanmethanol (3.38 g; 20.0 mmoles) [prepared in Step A], and the mixture stirred for 15 minutes then allowed to stand in the cold (0°) overnight. After 17 hours the cold solution was made strongly basic with aqueous KOH solution and then extracted with five portions of methylene chloride. The combined organic phase was dried, filtered and evaporated under reduced pressure to yield the title compound (4.16 g), bp 110°-120°/0.1 mm Hg.
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:45][C:46]3[C:47]([F:56])=[C:48]4[C:52](=[CH:53][CH:54]=3)[NH:51][C:50]([CH3:55])=[CH:49]4)=[N:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[O:57][CH3:58]>CC(N(C)C)=O>[F:56][C:47]1[C:46]([O:45][C:39]2[C:38]3[C:43](=[CH:44][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:21]4[CH2:22][CH2:23][N:18]([CH2:15][C:16]#[CH:17])[CH2:19][CH2:20]4)=[C:36]([O:57][CH3:58])[CH:37]=3)[N:42]=[CH:41][N:40]=2)=[CH:54][CH:53]=[C:52]2[C:48]=1[CH:49]=[C:50]([CH3:55])[NH:51]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCBr
Reactant: C#CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: C#CCN1CCN(CCCOc2cc3ncnc(Oc4ccc5[nH]c(C)cc5c4F)c3cc2OC)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
1-Prop-2-ynylpiperazine diTFA salt (329 mg, 0.94 mmol) and potassium carbonate (258 mg, 1.87 mmol) were added to a solution of 7-(3-bromopropoxy)-4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxyquinazoline (144 mg, 0.31 mmol), (prepared as described for the starting material in Example 7), in DMA (3.6 ml). The reaction mixture was stirred at 85° C. overnight before being filtered. The filtrate was concentrated under vacuum and the crude product was purified by column chromatography eluting with increasingly polar mixtures of ammonia/methanol in methylene chloride (1 to 7%). A second purification by column chromatography eluting with a mixture of methanol in methylene chloride (1/9) gave 4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-(3-[4-(2-propynyl)piperazin-1-yl]propoxy}quinazoline as a white solid (115 mg, 73%).
Reaction SMILES: [BrH:1].[Br:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]O>C(O)(=O)C>[Br:2][C:3]1[C:4]([OH:13])=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][Br:1]
Reactant: Br
Reactant: COc1cc(Br)c(O)c(CO)c1
Solvent: CC(=O)O
Product: COc1cc(Br)c(O)c(CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In the course of 30 minutes, at room temperature, 20 g of hydrogen bromide are introduced into a suspension of 50 g of 3-bromo-2-hydroxy-5-methoxy-benzyl alcohol in 300 ml of anhydrous acetic acid. The reaction mixture is stirred for 5 hours at room temperature and the resulting solution is concentrated by evaporation. The black-brown oily residue, which crystallises slowly when left to stand at room temperature, is crystallised from ethyl acetate/cyclohexane (5:1) with the addition of a small amount of activated charcoal. 3-Bromo-2-hydroxy-5-methoxy-benzyl bromide is thus obtained [1H-NMR (360 MHz, CDCl3): 3.75 (s, 3H, OCH3), 4.53 (s, 2H, CH2Br), 5.45 (s, 1H, OH), 6.85 (d, 1H), 7.00 (d, 1H) ppm].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>ClCCl.CC1C=CC(S(O)(=O)=O)=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][O:21]2)=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(CCO)ccc1OCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CCOC2CCCCO2)ccc1OCc1ccccc1
Yield: 90.7 %

Procedure:
A mixture of Example 69B (0.89 g, 3.27 mmol), 3,4-dihydro-2H-pyran (1.49 mL, 16.34 mmol) and p-TsOH.H2O (5 mg) in dichloromethane (20 mL) were stirred at room temperature overnight. The reaction solution was dried with silica gel powder (15 g). 20% ethyl acetate in hexanes (1 L) was used to run flash chromatography to give the title compound (1.06 g, 91%). MS (DCI) m/z 375.13 (M+NH4)+; 1H NMR (400 MHz, CDCl3) δ ppm 1.42–1.62 (m, 4 H) 1.68 (m, 1 H) 1.79 (m, 1 H) 2.88 (t, J=6.60 Hz, 2 H) 3.45 (m, 1 H) 3.59 (m, 1 H) 3.70 (m, 1 H) 3.94 (m, 1 H) 4.58 (t, J=3.38 Hz, 1 H) 5.21 (s, 2 H) 7.03 (d, J=8.59 Hz, 1 H) 7.28–7.48 (m, 6 H) 7.77 (d, J=2.15 Hz, 1 H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[CH:11][C:12]([OH:14])=[O:13]>CC(O)=O.[Zn]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)C=C1Cc2ccccc2C1=O
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)CC1Cc2ccccc2C1=O
Yield: 83.2 %

Procedure:
To a solution of 1.9 g (0.031 mol) of zinc dust suspended in 10 mL of HOAc was added 2.3 g (0.012 mol) of the product from Step A. The reaction mixture was refluxed for 1 hour, cooled, filtered and rinsed wtih acetic acid. The acetic acid solution was poured into 200 mL of H2O and extracted with ethyl acetate (3 ×50 mL), washed with H2O (2×50 mL), dried over anhydrous magensium sulfate, filtered and concentrated under vacuum to afford 1.9 g of a yellow solid. 1H NMR (CDCl3) δ: 2.6-3.5 (m, 5H), 7.4-7.8 (m, 4H), 12.2 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH:28]=[CH:27][CH:26]=[N:25]1.[I-].[Na+]>C1COCC1>[N:24]1([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:23])=[CH:16][CH:17]=2)[CH:28]=[CH:27][CH:26]=[N:25]1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: c1cn[nH]c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cn2cccn2)cc1
Yield: 84.9 %

Procedure:
4-((1H-Pyrazol-1-yl)methyl)-N-(2-(5-Chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.069 g; 0.199 mmol), pyrazole (0.062 g; 0.893 mmol) and sodium iodide (0.150 g; 0.994 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 20 minutes. Flash chromatography on silica gel (eluent 7 to 60% ethyl acetate in dichloromethane) furnished 0.064 g (85%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])=[O:30])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: CN1C(=O)[C@@H](NC(=O)Nc2ccccc2Cl)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(S)-(-)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 212°-214° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl>C(OCC)C.O>[CH2:21]([O:20][C:18]([NH:11][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)cc1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1ccc(O)cc1C(=O)O)OCc1ccccc1
Yield: 96.6 %

Procedure:
To a mixture of 5-hydroxyanthranilic acid (50 g, 0.33 mol), sodium hydrogen carbonate (109 g, 1.3 mol) and water (200 ml) was added dropwise a solution of benzyl chloroformate (52 ml, 0.36 mol) in diethyl ether (200 ml) with stirring, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was acidified by adding conc. hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained crystals were washed with diisopropyl ether and hexane to give 2-{[(benzyloxy)carbonyl]amino}-5-hydroxybenzoic acid (91.6 g, yield 98%) as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCCC(CCCNS(=O)(=O)c1ccc(Cl)cc1)CCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.083 g (0.18 mmol) of methyl 8-(p-chlorophenylsulfonamido)-5-[2-(3-pyridyl)ethyl]-octanoate (example 8), 2 ml dioxane and 0.4 ml (0.4 mmol) 1N aqueous sodium hydroxide is stirred for 16 h at room temperature. The solvent is evaporated and the residue taken up in water and the pH is adjusted to 5. The aqueous mixture is then extracted with methylene chloride (4×10 ml). Combined organic extract is dried (MgSO4), filtered and evaporated to give an oil which is crystallized from ether to give 8-(p-chlorophenylsulfonamido)-5-[2-(3-pyridyl)ethyl]-octanoic acid, m.p. 83°-85°.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:7](=[O:9])[CH3:8])(=[O:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>[Zn]>[OH:9][C:7]([CH3:8])([CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CC(=O)CC(CCc1ccccc1)OC(C)=O
Reactant: CCOC(=O)CBr
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)CC(CCc1ccccc1)OC(C)=O

Procedure:
Using 1.48 g of 4-acetoxy-6-phenylhexan-2one, 1 ml of ethyl bromoacetate and 0.62 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 1.03 g of ethyl 3-hydroxy-3-methyl-5-acetoxy-7-phenylheptanoate. The ester (0.90 g) thus obtained was dissolved in 5 ml of methanol and 2 ml of 4 N sodium hydroxide was added thereto. The mixture was stirred for 4 hours at room temperature, acidified by the addition of 4 N hydrocholoric acid, 5 ml of ethyl acetate was added and the mixture was stirred for 3 days. The usual treatment of the organic solvent layer afforded 400 mg of the desired compound.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(OCC)(=O)C>[N+:1]1([O-:19])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1cnc2c(c1)CCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: [O-][n+]1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.3 %

Procedure:
5,6,7,8-Tetrahydroquinoline (3.0 g, 22.5 mmol) was dissolved in ethyl acetate (15 ml), and 3-chloroperbenzoic acid (ca. 70%, 5.6 g, 22.5 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 days, subjected to a silica gel column chromatography and eluted with ethyl acetate-ethanol (5:1, v/v) to give the titled compound (3.4 g, 97%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][CH3:3].[Br:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13](Cl)[S:14][C:10]=2[CH:9]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([CH:2]([CH3:3])[C:1]([O:5][CH3:6])=[O:4])[S:14][C:10]=2[CH:9]=1
Reactant: CCC(=O)OC
Reactant: Clc1nc2ccc(Br)cc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)c1nc2ccc(Br)cc2s1
Reaction time: 0.17 h
Yield: 74 %

Procedure:
To a solution of methyl propionate (0.088 mL, 0.89 mmol) and 6-bromo-2-chlorobenzo[d]thiazole (221 mg, 0.89 mmol) in degassed toluene (5 mL) at brine/ice bath temperature was slowly added 1.0 M NaHMDS in THF (2.22 mL, 2.22 mmol). After the addition was complete, the reaction was stirred for 10 min. The mixture was then quenched with satd. NH4Cl (15 mL) then extracted with EtOAc (2×20 mL). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexane to give Compound R3a (198 mg, 0.66 mmol, 74% yield) as a yellow solid. LCMS=1.0 min using analytical method (M), 302.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=1.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.7, 1.9 Hz, 1H), 4.30 (q, J=7.3 Hz, 1H), 3.78 (s, 3H), 1.75 (d, J=7.3 Hz, 3H).
Reaction SMILES: [OH:1]O.[C:3]1([CH3:12])[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[OH:11]>>[CH3:12][C:3]1[CH2:8][C:7]([CH3:9])([OH:1])[CH:6]=[C:5]([CH3:10])[C:4]=1[OH:11]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: OO
Product: CC1=CC(C)(O)CC(C)=C1O

Procedure:
If this procedure is not adopted, but instead a solvent rendered alkaline is admixed with a mixture of hydrogen peroxide and mesitol, then the yields of product 2,4,6-trimethylquinol obtained are not as high as can be seen in example 31.