Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[O:4][C:3]=1[C@H:13]([OH:33])[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[CH3:41].N#N.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.CCOC(C)=O.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>[Si:16]([O:15][CH2:14][C@H:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:7]([C:2]=1[C:37]1[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([CH3:34])[CH:36]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)[OH:33])([C:29]([CH3:30])([CH3:31])[CH3:32])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](OC[C@@H](O)c1oc(=O)c2ccccc2c1Br)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c([C@H](O)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)oc(=O)c3ccccc23)cc1C
Yield: 62 %

Procedure:
A solution of 4-bromo-3-((1R)-2-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-1-hydroxyethyl)-1H-2-benzopyran-1-one (142 mg, 0.271 mmol) and 3,4-dimethylphenylboronic acid (61.0 mg, 0.407 mmol) in N,N-Dimethylformamide (DMF) (2.5 mL) was degassed with N2 for 10 min. The reaction mixture was treated with 2M Na2CO3 (149 μl, 0.298 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol) and irradiated in the microwave for 20 min at 120° C. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NH4Cl, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate-hexanes 0-30%) to afford the title compound (92 mg, 0.168 mmol, 62% yield) as a white solid: Rt=1.31, 1.33 (atropisomers), ES+ MS: 571 (M+23).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][C:8]([F:12])([F:11])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O>ClCCl>[Br:13][C:3]1[CH:4]=[CH:5][C:6]2[O:7][C:8]([F:12])([F:11])[O:9][C:10]=2[C:2]=1[NH2:1]
Reactant: Nc1cccc2c1OC(F)(F)O2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1c(Br)ccc2c1OC(F)(F)O2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.2 %

Procedure:
To a stirred solution of 4-amino-2,2-diflouro-1,3-benzodioxole (2.5 g, 14.4 mmol) in dichloromethane at 0° C. was added N-bromosuccinimide (2.7 g, 15.2 mmol) portion wise. The solution was stirred at 0° C. for 30 min, then at room temperature for 1 h. The reaction mixture was quenched with 1M sodium thiosulfate solution and diluted with deionized water, extracted with dichloromethane (2×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0-20% ethyl acetate in hexanes) to recover starting material 1 g and afford 5-bromo-4-amino-2,2-diflouro-1,3-benzodioxole as colorless oil (2.33 g, 9.25 mmol, 64%). MS: (ES) m/z calculated for C7H4BrF2NO [M+H]+252.0. found 252.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([C@@H:13]3[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=O)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[C:21]1[N:22]=[CH:23][C:24]2[C:29]([CH:30]=1)=[C:28]([Cl:31])[CH:27]=[CH:26][C:25]=2[F:32].C(Cl)Cl.Cl.[CH3:37][NH:38][CH3:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH3:37][N:38]([CH3:39])[C:18]([C@@H:15]1[CH2:14][C@H:13]([N:11]2[CH:12]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([C:21]4[N:22]=[CH:23][C:24]5[C:29]([CH:30]=4)=[C:28]([Cl:31])[CH:27]=[CH:26][C:25]=5[F:32])[CH:4]=3)[CH:9]=[N:10]2)[CH2:17][NH:16]1)=[O:20]
Reactant: Nc1ncc(-c2cnn([C@@H]3CN[C@H](C(=O)O)C3)c2)cc1-c1cc2c(Cl)ccc(F)c2cn1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@H](n2cc(-c3cnc(N)c(-c4cc5c(Cl)ccc(F)c5cn4)c3)cn2)CN1
Reaction time: 0.02 h

Procedure:
To a solution of (2S,4S)-4-{4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-2-carboxylic acid (5.00 mg, 0.00889 mmol) in DCM (2 mL, 0.02 mol) was added dimethylamine hydrochloride (20 mg, 0.2 mmol) and DIPEA (0.2 mL, 1.0 mmol), and stirred for 1 min. TBTU (5.71 mg, 0.0178 mmol) was then added, and the solution was stirred at rt for 10 min. The material was transferred to a separatory funnel. The organic layer was washed with water, and concentrated in vacuo. The material was loaded onto a prep TLC plate, eluting with 6% (7N NH3 in MeOH/DCM. The band containing the product was collected and the product was eluted with 1:1 MeOH/DCM. The solution was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.15-2.22 (m, 1H), 2.82-2.90 (m, 1H), 2.99 (s, 3H), 3.10-3.13 (m, 3H), 3.21-3.26 (m, 1H), 3.49 (dd, J=12.3, 3.2 Hz, 1H), 4.15 (t, J=8.2 Hz, 1H), 4.99-5.05 (m, 1H), 7.38 (dd, J=9.6, 8.3 Hz, 1H), 7.84-7.91 (m, 2H), 8.13-8.17 (m, 2H), 8.27 (d, J=2.3 Hz, 1H), 8.43 (s, 1H), 9.60 (s, 1H). MS (ES+): m/z=480.13/482.11 (100/36) [MH+]. HPLC: tR=1.89 min (ZQ2, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[CH2:26][CH2:27]Br>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:27][CH2:26][C:25]4[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1cccc(CCBr)c1
Product: COc1cccc(CCN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)c1
Yield: 34 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-methoxyphenethyl bromide. Yield: 34%. MS M+H calculated 410.18; found 410.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.16 μM.
Reaction SMILES: C(O[C@H:5]1[C@H:9]([CH2:10][CH2:11][CH3:12])[CH2:8][C:7](=[O:13])[CH2:6]1)(=O)C.C1CCN2C(=NCCC2)CC1>CCOCC>[CH2:10]([C@@H:9]1[CH2:8][C:7](=[O:13])[CH:6]=[CH:5]1)[CH2:11][CH3:12]
Reactant: CCC[C@@H]1CC(=O)C[C@H]1OC(C)=O
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CCC[C@H]1C=CC(=O)C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
The acetoxy cyclopentanone 1 (approx. 28.5 mmol) in ether (40 ml) was added dropwise over 1 hr to a stirred solution of DBU (4.27 ml, 28.5 mmol) in ether (50 ml) at −40° C. under argon. The mixture was allowed to warm to −30° C. and stirred for 30 minutes before being quenched with dilute hydrochloric acid (20 ml). The reaction mixture was partitioned between ether (100 ml) and 1N HCl (150 ml). The organic layer was separated and the aqueous layer was further extracted with ether (2×100 ml). The combined ether layers were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane-ether, 1:0 to 8:2) to give the propylcyclopentenone 2 (2.4 g, 68% from (R)-4-acetoxycyclopent-2-enone). νmax(film)/cm−1 1708 (C═O).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:34]1([CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[OH:47][C:46]1[CH:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[O:18][C:43](=[O:44])[C:42]=1[S:41][CH2:40][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCCN2CCOCC2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCN3CCOCC3)cc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-[2-(4-morpholinyl)ethoxy]acetophenone (1.31 g, 5.29 mmol), lithium bis(trimethylsilyl)amide (0.972 g, 5.81 mmol), chlorotrimethylsilane (0.738 mL, 5.81 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.35 g, 4.80 mmol). m.p. dec. 207° C.; 1H NMR (250 MHz, DMSO-d6) δ2.54 (s, 2 H), 6.89 (m, 4 H), 2.83 (t, 2 H), 3.55 (m, 4 H), 3.96 (s, 2 H), 4.22 (t, 2 H), 6.58 (s, 1 H), 7.08 (d, 2 H), 7.23 (m, 5 H), 7.73 (d, 2 H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](=O)([O-])[O-].[K+].[K+].P(OC)(OC)(OC)=O>>[CH:2](=[O:1])[C:3]1[CH:11]=[CH:10][C:8]([O:9][CH3:12])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COP(=O)(OC)OC
Product: COc1ccc(C=O)cc1OC
Temperature: 35 °C
Yield: 111.2 %

Procedure:
In an apparatus similar to Example 1, 15.0 g (0.099 mol) of vanillin and 10.0 g (0.072 mol) of anhydrous potassium carbonate were heated under nitrogen to 90° C. To this clear slurry was added over about 10 minutes 13.5 ml (0.112 mol) of trimethyl phosphate while holding the temperature below 110° C. The mixture was stirred and heated to 65°-75° C. for three hours then cooled to 35° C. and quenched with 80 ml of water to precipitate an oil. On stirring a light powder precipitated which was filtered, washed with three 100 ml portions of water, and dried to give 13.3 g (81%) of veratraldehyde.
Reaction SMILES: [CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].CN(C)[CH:18]=[O:19]>>[CH2:1]([N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([CH:18]=[O:19])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccccc1
Reactant: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C=O)cc1
Temperature: 90 °C

Procedure:
A 20 ml sample of N,N-dimethylformamide (DMF) was cooled to 0° C. for 1 hour and at 25° C. for 1 hour, then N,N-dibutylaniline was added slowly. The reaction mixture was heated at 90° C. for 16 hours, then cooled and poured onto 50 g of ice. A brown oil separated which was taken up in dichloromethane. The extract was washed with saturated aqueous bicarbonate then with water containing a little ammonium chloride, dried (MgSO4), and the solvent was removed at reduced pressure. The brown, oily residue was distilled in vacuo to product 6.65 g (58%) of a yellow liquid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH:18]([CH3:20])[CH3:19])=[CH:11][C:12]([CH3:17])([CH3:16])[O:13]2)=[CH:8][C:7]=1/[C:21](/[CH3:26])=[C:22](/[F:25])\[CH2:23][OH:24])[CH2:2][CH2:3][CH3:4].C[N+]1([O-])CCOCC1>>[CH2:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH:18]([CH3:19])[CH3:20])=[CH:11][C:12]([CH3:17])([CH3:16])[O:13]2)=[CH:8][C:7]=1/[C:21](/[CH3:26])=[C:22](/[F:25])\[CH:23]=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc2c(cc1/C(C)=C(/F)CO)C(C(C)C)=CC(C)(C)O2
Agent: C[N+]1([O-])CCOCC1
Product: CCCCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure M, (2E)-3-(7-butoxy 4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-en-1-ol (Compound 87, 109 mg, 0.30 mmol) and 4-methylmorpholine N-oxide (70 mg, 0.60 mmol) were reacted to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:12][CH2:11][CH2:10][NH2:13])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: NCCN
Product: NCCNCc1ccc(Cl)nc1
Reaction time: 8 h
Yield: 100 %

Procedure:
Next, 20 mL of ethylenediamine was added to 2.0 g (12.4 mmol) of 2-chloro-5-chloromethylpyridine, and the mixture was stirred overnight. Following reaction completion, the reaction mixture was concentrated under reduced pressure, after which acetonitrile was added and insoluble matter were removed by filtration. The filtrate was concentrated under reduced pressure, giving 2.45 g (yield, 100%) of N-((6-chloropyridin-3-yl)methyl)ethane-1,2-diamine.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].C[Al](C)C.C([O:11][C:12](=O)[CH2:13][O:14][C:15]1[CH:44]=[CH:43][C:18]([CH2:19][C:20]2[C:21]3[CH:42]=[CH:41][CH:40]=[CH:39][C:22]=3[S:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)C.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:4])[NH:3][C:12](=[O:11])[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][C:20]2[C:21]3[CH:42]=[CH:41][CH:40]=[CH:39][C:22]=3[S:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)=[CH:29][CH:30]=2)=[CH:43][CH:44]=1
Reactant: CN(C)N
Reactant: CCOC(=O)COc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)NC(=O)COc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A solution of 1,1-dimethyl hydrazine (0.1 mL, 1.3 mmol) in toluene (5 mL) was added to a solution of trimethyl aluminum (1.3 mL, 1.0M/toluene) in toluene (20 mL) at 0-5° C. The cooling bath was removed and the mixture stirred for 60 minutes. A solution of 3-[4-(2-ethoxy-2-oxoethoxy)benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophene (310 mg, 0.6 mmol) in toluene (5-10 mL) was added and the mixture refluxed for 60 minutes, cooled, decomposed with water, and extracted with CH2Cl2:i-PrOH (3:1). The organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient (CH2Cl2/5% MeOH/0-1% Et3N) to give the title compound as an amorphous solid (205 mg, 65%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl[C:12]1[C:16]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=2[S:14](=[O:23])(=[O:22])[N:13]=1>>[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]=3[CH3:1])=[N:13][S:14](=[O:23])(=[O:22])[C:15]=2[CH:20]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=S1(=O)N=C(Cl)c2ccc(F)cc21
Product: Cc1[nH]c2ccccc2c1C1=NS(=O)(=O)c2cc(F)ccc21

Procedure:
The sub-title compound was prepared as described for example 1, step b) using 2-methyl indole and the product from step b). The product did not crystallize upon quenching, and was instead purified by partitioning between DCM and water.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C:11]3[CH:12]=[C:13]([CH:16]=O)[S:14][CH:15]=3)=[CH:9][O:10][C:4]=2[C:3]=1[O:18][C@@H:19]([C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=1[Cl:29])[CH3:20].Cl.[NH2:31]O.C([O-])(=O)C.[K+].C(O)C.Cl.C1COCC1>O.[Zn]>[NH2:31][CH2:16][C:13]1[S:14][CH:15]=[C:11]([C:8]2[C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[C:3]([O:18][C@@H:19]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=4[Cl:29])[CH3:20])[C:4]=3[O:10][CH:9]=2)[CH:12]=1
Reactant: NO
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3csc(C=O)c3)coc12)c1c(Cl)ccc(F)c1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C[C@@H](Oc1c(N)ncc2c(-c3csc(CN)c3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-{6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-3-yl}thiophene-2-carbaldehyde (10.0 mg, 0.0222 mmol), hydroxylamine hydrochloride (1.85 mg, 0.0266 mmol), potassium acetate, (2.61 mg, 0.0266 mmol) and ethanol (1.0 mL, 17 mmol) was stirred at room temperature for 20 minutes. The solution was concentrated in vacuo and extracted with DCM and sat. NaHCO3. The organic layer was concentrated in vacuo. Zinc (14.5 mg, 0.222 mmol), 2 M of HCl in H2O (0.5 mL) and THF (1.0 mL, 12 mmol) were added. The mixture was refluxed at 70° C. for 3 hours. The solution was concentrated in vacuo and extracted with DCM and sat. NaHCO3. The organic layer was concentrated in vacuo and dissolved in DMSO. The sample was purified by the MDPS to afford the title compound as white solid. MS (ES+): m/z 452.08/454.05 (100/75) [MH+]. HPLC: tR=0.62 min (HPLC-ACQUITY, Analytical). 1H NMR (400 MHz, CD3OD): δ=1.91 (d, J=6.6 Hz, 3H), 4.33 (s, 2H), 6.55 (q, J=6.8 Hz, 1H), 7.23 (t, J=8.6 Hz, 1H), 7.41 (dd, J=9.0, 4.9 Hz, 1H), 7.51 (s, 1H), 7.77 (d, J=1.3 Hz, 1H), 7.89 (s, 1H), 8.24 (s, 1H).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])C(=O)C2=CC=CC=C12.O.NN.Cl>C(O)C>[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 72 %

Procedure:
A mixture of methyl 20-phthalimidoeicosanoate (5.0 g, 10.6 mmoles), 100 ml of ethanol, 80% hydrazine hydrate (1.0 ml, 15.9 mmoles) was refluxed for 9 hours. After the addition of 26.5 ml of 6N aqueous hydrochloric acid, the reaction mixture was further refluxed for 1 hour. The insoluble matter that formed was removed by filtration. The liltrate was concentrated under reduced pressure. To the residue were added 70 ml of ethanol and 42.4 ml of 1N aqueous sodium hydroxide solution, and the obtained reaction mixture was refluxed for 16 hours. The reaction mixture was neutralized by adding 6N aqueous hydrochloric acid solution under ice-cooled condition. The precipitates that formed were collected by filtration and recrystallized from ethanolacetic acid-water, to give 20-aminoeicosanoic acid (2.50 g, 72%) having the following properties.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:11]([C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: Nc1ccc2c(c1)CCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Nc2ccc3c(c2)CCO3)cc1
Temperature: 25 °C

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added 2,3-dihydro-1-benzofuran-5-amine (11.6 grams, 85.8 mmoles, prepared as in Example 23 of U.S. Pat. No. 20040029932), 4-tert-butyl bromobenzene (18.1 grams, 85 mmoles), tris(dibenzylideneacetone)dipalladium (0) (1.6 grams, 1.7 mmoles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (2.1 grams, 3.4 mmoles), sodium tert-butoxide (16.4 grams, 0.17 moles) and anhydrous toluene (100 mL). The contents of the flask were refluxed for three days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (150 mL). The combined organic layers were concentrated in vacuo to yield a dark solid. The solid was chromatographed on silica gel, eluting with hexane/ethyl acetate (20:1) to afford 10 grams of the desired product as a white solid. 1H NMR (CDCl3) δ 7.25 (d, 2H), 6.95 (s, 1H), 6.85 (d, 3H), 6.7 (d, 1H), 5.4 (bs, 1H), 4.5 (t, 2H), 3.15 (t, 2H), 1.3 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[CH2:15][CH:14]2[N:16]([CH3:17])[CH:10]([CH2:11][N:12]([CH3:18])[CH2:13]2)[CH2:9]1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH3:18][N:12]1[CH2:11][CH:10]2[N:16]([CH3:17])[CH:14]([CH2:15][CH:8]([OH:7])[CH2:9]2)[CH2:13]1
Reactant: CN1CC2CC(=O)CC(C1)N2C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CC2CC(O)CC(C1)N2C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 93.3 %

Procedure:
To a suspension of lithium aluminum hydride (0.95 g, 25.0 mmol) in dry THF (40 ml) was added dropwise at room temperature while stirring a solution of 7-oxo-3,9-dimethyl3,9-diazabicyclo[3.3.1)nonane (2.78 g, 16.5 mmol) in dry THF (50 ml). After stirring at room temperature for 4.5 hrs, water (1 ml), 40% aqueous sodium hydroxide solution (1 ml) and water (3 ml) were added successively to a reaction solution. Further anhydrous magnesium sulfate was added and stirred, and thereafter the reaction was filtered. The filtrate was concentrated under reduced pressure to afford the title compound (2.62 g) as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[F:33]>>[F:33][C:27]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:10])=[O:11]
Reactant: Fc1cccc(CBr)c1F
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2cccc(F)c2F)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)-benzoate (Example 5-10b) and 1-(bromomethyl)-2,3-difluorobenzene. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.30 (s, 3H), 4.29 (s, 2H), 4.32 (s, 2H), 6.87 (d, 2H, J=8 Hz), 7.02-7.20 (m, 5H), 7.95 (d, 2H, J=8 Hz). 8.05 (d, 2H, J=8 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:27][CH2:28][NH2:29])=[CH:22][CH:21]=1>C1C=CC=CC=1>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([S:26][CH2:27][CH2:28][NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: Clc1ncnc2ccccc12
Reactant: NCCSc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Brc1ccc(SCCNc2ncnc3ccccc23)cc1
Reaction time: 3 h
Yield: 55.5 %

Procedure:
To a solution of 2.5 g (0.015 mol) of 4-chloroquinazoline in 50 ml of benzene were added 1.5 g (0.015 mol) of triethylamine and 3.5 g (0.015 mol) of 2-(p-bromophenylthio) ethylamine, and the mixture was heated, with stirring, at 70°~80° C. for 3 hours. After completion of the reaction, the benzene was evaporated under reduced pressure and the resulting crystals were washed with water, collected by filtration and recrystallized from ethanol, giving 3.0 g of 4-[2-(4-bromophenylthio)ethyl]aminoquinazoline in the form of colorless granules.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:5]=[CH:6][CH:7]=1.C[O:28][C:29](=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]=O)=[CH:33][CH:32]=1>>[C:19]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:37][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C:29]([OH:39])=[O:28])=[CH:36][CH:35]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:20])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(Cl)cccc23)c1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Product: O=C(O)Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(Cl)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-chloro-quinolin-3-yl]-phenyl-methanone and (4-formyl-phenyl)-acetic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 507.