Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Li+].[OH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([OH:17])[CH:11]=[CH:10][C:9]=1[C:18](=[O:20])[CH3:19].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>CN(C=O)C>[CH2:21]([O:17][C:12]1[CH:11]=[CH:10][C:9]([C:18](=[O:20])[CH3:19])=[C:8]([OH:7])[C:13]=1[N+:14]([O-:16])=[O:15])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1O
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Lithium tert-butoxide (4.06 g) was added to a stirred solution of 1-(2,4-dihydroxy-3-nitrophenyl)ethanone (example 11, step a) (10 g) in DMF (100 mL), under nitrogen, whilst maintaining the internal temperature below 30° C. After stirring for a further 10 minutes at ambient temperature, benzyl bromide (6.03 mL) was added and the mixture stirred for a further 20 h. Further benzyl bromide (3 mL) was added and the mixture stirred for 24 h. The reaction was quenched with water (300 mL), 1M aqueous sodium hydroxide (50 mL) was added and the mixture was washed with diethyl ether (2×300 mL), filtering through Celite to aid separation. The basic solution was cooled in ice/water, acidified with ice cold 2M hydrochloric acid (200 mL) and the resulting precipitate filtered off, washed with water and dried to afford a light brown solid. The solid was slurried with ethanol (100 mL) for 1 h and the solid filtered off, washed with cold ethanol (20 mL), and dried under vacuum at 40° C. to afford the subtitled compound as a light brown solid. Yield 6.8 g.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:11]([OH:13])=O.O[N:24]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[NH2:26].CCN(C(C)C)C(C)C>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[N:24]=[C:11]([C:10]2[CH:14]=[CH:15][C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:8]([CH3:7])[CH:9]=2)[O:13][N:26]=1
Reactant: COc1ccccc1C(N)=NO
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1noc(-c2ccc(N3CCOCC3)c(C)c2)n1

Procedure:
Oxalyl chloride (138 μL; 1.63 mmol; 3 eq.), Intermediate 35 (120 mg; 0.54 mmol; 1 eq.), Intermediate 1 (90 mg; 0.54 mmol, 1 eq.) and DIEA (280 μL; 1.63 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)[CH:6]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:20]([Si:17]([CH3:19])([CH3:18])[O:11][CH:9]1[CH2:8][CH:7]([N:5]2[CH:6]=[C:2]([I:1])[CH:3]=[N:4]2)[CH2:10]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CC(n2cc(I)cn2)C1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC(n2cc(I)cn2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.9 %

Procedure:
A mixture of 3-(4-Iodo-pyrazol-1-yl)-cyclobutanol (Compound 100C, 75.00 mg, 0.2840 mmol), 4-dimethylaminopyridine (6.940 mg, 0.05680 mmol), 1H-imidazole (58.01 mg, 0.8521 mmol), tert-butyldimethylsilyl chloride (0.08562 g, 0.5680 mmol) and DCM (4 mL) were stirred at room temperature for 20 minutes. The material was transferred to a separatory funnel extracting with DCM washing with aqueous saturated NaHCO3. The organic layer was dry-loaded on silica for column chromatography eluting with 3% EtOAc in hexanes to afford 59 mg (55% yield) of the title compound as colorless oil. MS (ES+): m/z 378.94 (100) [MH+]; HPLC: tR=4.35 min (Polar—5 min, ZQ3).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][S:15]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(C2N[C@H](C(=O)O)CS2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.9 %

Procedure:
4-Cyanobenzaldehyde (500 mg, 3.8 mmol) was dissolved in 5 ml of ethanol (96%) and L-(+)-cysteine hydrochloride (460 mg, 3.8 mmol) and natriumacetate trihydrate (468 mg, 5.7 mmol) dissolved in 5 ml of water was added. The reaction mixture was stirred for 16 hours at room temperature and the white crystals were collected by filtration and washed twice with 15 ml of water:ethanol (1:1), to afford 400 mg of 2-(RS)-(4-cyanophenyl)thiazolidine-4-(R)-carboxylic acid (48) in 44% yield. 1H-NMR (MEOH, 300 MHz) δ: 7.69 (m, 4H); 5.81 (s, ½H); 5.60 (s, ½H); 4.23 (dd, ½H); 4.02 (dd, ½H); 3.52-3.17 (m, 2H).
Reaction SMILES: [CH:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])=[O:12])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:40]([N:4]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([NH:13][C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)=[O:24])=[O:12])[CH2:9][CH2:10]1)[CH:1]([CH3:3])[CH3:2])(=[O:42])[CH3:41]
Reactant: CC(C)N[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)N(C(C)C)[C@H]1CC[C@H](C(=O)Nc2c(C(=O)Nc3ccc(Cl)cn3)oc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trans-3-[4-(isopropylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 310 and triethylamine (61 μl) is dissolved in chloroform (5 ml), and thereto is added acetyl chloride (24 μl). The mixture is stirred at room temperature for one hour, and thereto is poured a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is washed successively with water and a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then ethyl acetate). The resulting residue is suspended in n-hexane, and collected by filtration to give the title compound (60 mg).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]1.[CH2:23]([NH:26][C:27]1[CH2:31][S:30][C:29](=[O:32])[N:28]=1)[C:24]#[CH:25].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][CH:16](/[CH:19]=[C:31]2/[C:27]([NH:26][CH2:23][C:24]#[CH:25])=[N:28][C:29](=[O:32])[S:30]/2)[CH2:15][CH2:14]1
Reactant: O=CC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)phenyl]piperidine-4-carbaldehyde (1.61 g) in 2-propanol (20 mL) were added 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (1.15 g) and piperidinium acetate (0.72 g). The reaction mixture was stirred at 80° C. for 1 hr, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from ethyl acetate/heptane to give the title compound (1.45 g).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([CH3:39])=[C:20]([CH:37]=[O:38])[C:21]4[O:25][C:24]([CH3:27])([CH3:26])[CH:23]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)[C:22]=4[C:35]=3[CH3:36])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.O>C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]([CH3:39])=[C:20]([CH:37]([OH:38])[CH3:1])[C:21]4[O:25][C:24]([CH3:27])([CH3:26])[CH:23]([C:28]5[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=5)[C:22]=4[C:35]=3[CH3:36])[CH2:14][CH2:13]2)=[CH:10][CH:11]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C=O)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C(C)O)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Reaction time: 0.33 h
Yield: 1.3 %

Procedure:
To a solution of methyl magnesium bromide (THF solution 3.0 M, 1.0 mL, 3.0 mmol) in THF (5 ml) at −30° C. was added 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6-tetramethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-7-carbaldehyde (310 mg, 640 mmol) obtained in Example 105. The reaction mixture was stirred for 20 minutes under the same temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from hexane-ethyl acetate to obtain 19.5 mg (yield 61%) of the title compound. mp. 149–151° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CN(C1C=CN=CC=1)C.O>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:3]([CH2:2][CH:1]=[O:7])[C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(CO)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(COC(CC=O)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of succinic anhydride (10 g, 0.1 mol) in CH3CN (200 mL) were added (4-methoxyphenyl)methanol (69.0 g, 0.5 mol) and DMAP (12.2 g, 0.1 mol). The reaction mixture was stirred for 3 h at about 30° C. and then diluted with water (700 mL). The resulting mixture was adjusted to pH=10 with saturated Na2CO3 solution and washed with ethyl acetate (300 mL×4) to remove an excess of (4-methoxyphenyl)methanol. The aqueous phase was adjusted to pH=2 with saturated citric acid solution and then extracted with ethyl acetate (200 mL×2). The combined extracts were dried over anhydrous Na2SO4 and concentrated to give product (21.0 g. 88% yield) as a white solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([NH:15][C:16](=[O:54])[CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][C@H:23]1[C@@H:27]([OH:28])[CH2:26][C@@H:25]([O:29]C2CCCCO2)[C@@H:24]1/[CH:36]=[CH:37]/[C@@H:38]([O:47]C1CCCCO1)[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:14]>CO>[CH3:14][CH2:13][NH:15][C:16]([CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][C@@H:23]1[C@@H:24](/[CH:36]=[CH:37]/[C@@H:38]([OH:47])[CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:25]([OH:29])[CH2:26][C@@H:27]1[OH:28])=[O:54]
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](OC2CCCCO2)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.03 g, 0.17 mmol) was added to a stirred solution of (5Z)-N-ethyl-7-((1R,2R,3R,5S)-5-hydroxy-2-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enamide (2.0 g, 3.4 mmol) in methanol (20 mL). The mixture was stirred for 2 hours at room temperature. Then, the reaction mixture was washed with saturated aqueous solution of sodium bicarbonate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was crystallized from hexane and ethyl acetate to give Bimatoprost in a white crystalline form (77.5% yield). UPLC (ACQUITY UPLC BEH C18) analysis of the crude product showed that no 5,6-trans isomer, 15β-isomer or any other isomers were found.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]2[C:5]([CH:6]([NH:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][NH:23]4)=[O:17])[CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[H-].[Na+].S(OC)(O[CH3:34])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:14]=[C:13]2[C:5]([CH:6]([NH:15][C:16]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[N:22][N:23]4[CH3:34])=[O:17])[CH2:7][C:8]3([O:12]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(Nc1cccc2[nH]ncc12)NC1CC2(CCC2)Oc2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(NC(=O)NC3CC4(CCC4)Oc4cc(F)ccc43)cccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of Example 3D (483 mg, 1.32 mmol) in N,N-dimethylformamide (5 mL) was treated with 60% NaH (65 mg, 1.63 mmol), and the mixture was stirred at room temperature for 45 min. Dimethyl sulfate (0.14 mL, 1.48 mmol) was then added, and the reaction was allowed to stir for 1 h. Concentration in vacuo, followed by silica gel chromatography (98:2 CH2Cl2-methanol, eluent), afforded the title compound as an off-white solid, 121 mg (24%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.74 (s, 1H), 8.03 (s, 1H), 7.72 (d, J=7.1 Hz, 1H), 7.29 (m, 2H), 7.16 (d, J=8.5 Hz, 1H), 6.77 (m, 2H), 6.66 (dd; J=10.5, 7.8 Hz; 1H), 4.97 (m, 1H), 4.01 (s, 3H), 2.40 (m, 1H), 2.12-2.30 (m, 4H), 1.65-1.99 (m, 3H). MS (ESI+) m/z 381 (M+H).
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>>[N+:12]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([CH2:9][C:10]#[N:11])=[O:8])([O-:14])=[O:13]
Reactant: N#CCC(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Product: N#CCC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
Benzoylacetonitrile (14.5 g, 10 mmol) was added to cold fuming nitric acid (50 ml) portionwise over 10 min. The reaction mixture was stirred for 15 min., and then poured into ice. The solid was filtered off and recrystallised from ethanol to give 2-(3-nitrobenzoyl)acetonitrile (5.4 g) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8]([CH3:10])=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][C:15]([CH3:18])=[N:14]2)[N:3]=1.SC[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][C:15]([CH3:18])=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([S:8][CH2:10][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: Cc1ccn(-c2nc(N)nc(S(C)=O)c2C#N)n1
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccn(-c2nc(N)nc(SCCc3ccccn3)c2C#N)n1

Procedure:
From 2-amino-4-methanesulfinyl-6-(3-methyl-pyrazol-1-yl)-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 338 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=O)[O:10]2)=[CH:5][CH:4]=1.CO[CH2:16][N:17](CC1C=CC=CC=1)[CH2:18][Si](C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C@@H:7]3[CH2:18][NH:17][CH2:16][C@@H:8]3[CH2:9][O:10][C:11]=2[CH:12]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COc1ccc2ccc(=O)oc2c1
Product: COc1ccc2c(c1)OC[C@H]1CNC[C@@H]21

Procedure:
From 7-methoxycoumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C: 1H NMR (300 MHz, CDCl3), δ 1.92 (br s, 1H), 2.60 (m, 1H), 2.81 (m, 2H), 3.17 (q, 1H), 3.29 (dd, 1H), 3,40 (dd, 1H), 3.77 (s, 3H), 3.78 (t, 1H), 4.10 (dd, 1H), 6.43 (d, 1H), 6.52 (dd, 1H), 7.03 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:18]/[OH:19])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[O:9])[N:6]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:18]/[O:19][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])=[O:9])[N:6]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCS(=O)(=O)CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)(=O)CCOC(=O)/C(=N\OCC(=O)OC(C)(C)C)c1csc(N)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
In 180 ml of acetone was suspended 6 g (0.019 mole) of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 9 followed by a serial addition of 5.7 g (0.0292 mole) of t-butyl bromoacetate, 0.9 ml of water and 10.8 g of anhydrous potassium carbonate. The mixture was stirred at 40° C. for 2 hours and the insoluble matter was filtered off. To the filtrate was added 200 ml of water and 200 ml of ethyl acetate was added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with water and concentrated to dryness under reduced pressure to give 6.0 g of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate as white crystals. (Yield, 73.0%)
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=2)[C:4](=O)[NH:3][CH:2]=1.P(Cl)(Cl)([Cl:25])=O>CN(C)C1C=CC=CC=1>[Cl:25][C:4]1[C:5]([CH2:7][CH2:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2cnc[nH]c2=O)cc1
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2cncnc2Cl)cc1
Temperature: 100 °C
Yield: 78.5 %

Procedure:
tert-Butyl 4-[2-(pyrimidin-4(3 H)-on-5-yl)ethyl]benzoate (0.6 g,) was dissolved in N,N-dimethylaniline (5 ml) and treated with phosphorous-oxy-chloride (1.53 g 10 mmol). The reaction was heated to 100° C. for 2.5 hours and then evaporated at reduced pressure. The residue was diluted with EtOAc, washed (1N HCl 2×, H2O, saturated brine), dried over MgSO4 and evaporated to give tert-butyl 4-[2-(4-chloropyrimidin-5-yl)ethyl]benzoate as a brown oil (0.5 g, 64%) which was used without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[C:28]1([CH2:27][CH2:26][CH2:25][N:17]([CH2:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]2)[C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CN(CCCc2ccccc2)C(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, 0.25 g (6.25 mM) of a 60% suspension of sodium hydride in liquid paraffin was added to a solution of 1.73 g (5.57 mM) of N-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)trifluoroacetoamide in N,N-dimethylformamide (20 ml) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. To this mixture was added 1.0 ml (6.58 mM) of 1-bromo-3-phenylpropane and the mixture was stirred at room temperature for 2.5 hours and further at 60° C. for one hour. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (ethyl acetate-hexane 30%) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[O:11][N:10]=1.O.O.[Sn](Cl)Cl.[Sn](Cl)Cl>C(OCC)(=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[O:11][N:10]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(-c3c(Cl)cccc3Cl)no2)c1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cccc(-c2nc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The nitro oxadiazole prepared in Step 1 (200 mg) was dissolved in ethyl acetate (20 mL) and tin (II) chloride dihydrate (162 mg, 1.2 molar equivalent) was added. The mixture was stirred at room temperature for 1 h. An additional 1.2 molar equivalents of tin (II) chloride was added. After a further 4 h at room temperature, the reaction mixture was diluted with ethyl acetate and washed three times with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the desired 3-(2,6-dichlorophenyl)-5-(3-aminophenyl)-1,2,4-oxadiazole as a white solid in quantitative yield. NMR (300 MHz, DMSO-d6): 7.70 (m, 3H), 7.36 (s, 1H), 7.24 (d, 2H), 6.91 (m, 1H), 5.57 ppm (broad s, 2H). LC-MS tr=33.1 min (Method W) MH+=307
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:13]=[CH:12]2)C1C=CC=CC=1.B(Br)(Br)Br.O>ClCCl>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([F:22])([F:20])[F:21])[CH:13]=[CH:12]2
Reactant: FC(F)(F)Cn1ccc2cc(OCc3ccccc3)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2c(ccn2CC(F)(F)F)c1
Reaction time: 2 h
Yield: 13.4 %

Procedure:
A solution of 5-benzyloxy-1-(2,2,2-trifluoroethyl)indole (1.56 g, 4.09 mmol) in dichloromethane (10 mL) at 0° C. was treated dropwise with 1M BBr3 in dichloromethane(5.73 mL, 5.73 mmol), stirred for 2 hours, transferred to 2:1:1 water/10% NaHCO3/brine (100 mL), and extracted with ethyl acetate (100 mL). The extract was washed with brine (40 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography with 9:1 hexane/ethyl acetate to provide 118 mg of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])=[C:7]3[CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([C:22](=[O:27])[C:23]([F:25])([F:24])[F:26])=[C:7]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][N:8]3[C:9]=2[CH:10]=1
Reactant: O=C(c1c2n(c3cc(Br)ccc13)CCN(C(=O)C(F)(F)F)CC2)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(c1c2n(c3cc(Br)ccc13)CCNCC2)C(F)(F)F
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
A solution of 1-[8-bromo-11-(2,2,2-trifluoroacetyl)-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,7-a]indol-3-yl]-2,2,2-trifluoro-1-ethanone (105 mg, 0.23 mmol) in methanol (3 mL) is treated with 1M sodium hydroxide (1 mL, 1 mmol). After 30 min, the reaction is diluted with water (15 mL) and extracted twice with dichloromethane (20 mL). The combined organics are washed with brine (15 mL), dried over MgSO4, filtered, and concentrated to give a crude solid. This material is recrystallized from ethyl acetate/heptane to afford 48 mg of a white solid. IR (drift) 1666, 1508, 1464, 1426, 1282, 1248, 1211, 1201, 1181, 1130, 1060, 1043, 956, 939, 757 cm−1.