Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][NH:20][C:21](=[O:33])[CH:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:23][CH2:24]O)=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.P(Cl)(Cl)([Cl:36])=O>>[Cl:36][CH2:24][CH2:23][CH:22]([C:21]1[O:33][C:17](/[CH:16]=[CH:15]/[C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:19][N:20]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(/C=C/C(=O)NNC(=O)C(CCO)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Product: COc1cc(/C=C/c2nnc(C(CCCl)c3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C

Procedure:
A solution of 2-(4-fluorophenyl)-4-hydroxybutyric acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (224 mg) in phosphorus oxychloride (1 mL) was stirred at 120° C. for two hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: ethyl acetate→ethyl acetate:methanol=3:1) to obtain 87 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9](O)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.Cl.[CH2:33]([N:35]1[CH2:40][C:39]2([CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[O:38][CH2:37][C:36]1=[O:46])[CH3:34]>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([N:43]2[CH2:44][CH2:45][C:39]3([O:38][CH2:37][C:36](=[O:46])[N:35]([CH2:33][CH3:34])[CH2:40]3)[CH2:41][CH2:42]2)[C:10]([NH2:12])=[O:11])=[C:4]([F:14])[CH:3]=1
Reactant: NC(=O)C(O)c1c(F)cc(Br)cc1F
Reactant: CCN1CC2(CCNCC2)OCC1=O
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1CC2(CCN(C(C(N)=O)c3c(F)cc(Br)cc3F)CC2)OCC1=O
Temperature: 40 °C
Reaction time: 3 h
Yield: 121.8 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-hydroxyacetamide (0.86 g, 3.2 mmol) and triethylamine (1.4 mL, 9.7 mmol) in anhydrous acetonitrile (5 mL) was added neat methanesulfonyl chloride (0.33 mL, 4.2 mmol). The reaction mixture was stirred vigorously at 40° C. for 3 h, at which point the reaction had progressed to completion. To this mesylate intermediate mixture was added more triethylamine (1.4 mL, 9.7 mmol) followed by 4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (0.11 g, 0.48 mmol). The reaction mixture was heated at 90° C. for 3 h until the starting material was consumed. The reaction was diluted with water and was extracted with ether (3×35 mL). The combined ether phases were dried over sodium sulfate, filtered, and evaporated under reduced pressure. Purification of the residue by flash chromatography (65-100% of 10% methanol in dichloromethane:dichloromethane) afforded the title product (261 mg, 18% yield). MS(ES)+ m/e 446 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 1.64-1.71 (m, 1 H) 1.73 (dd, J=4.17, 2.65 Hz, 1 H) 1.90-1.99 (m, 2 H) 2.19-2.27 (m, 1 H) 2.54-2.66 (m, 1 H) 2.67-2.73 (m, 1 H) 2.75-2.81 (m, 1 H) 3.15 (s, 2 H) 3.41 (q, J=6.91 Hz, 2 H) 3.98 (s, 2 H) 4.69 (s, 1 H) 5.68 (br. s., 1 H) 7.15-7.25 (m, 2 H) 7.36 (br. s., 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.Cl.[NH2:24][CH2:25][C:26]1[C:27](=[O:37])[NH:28][C:29]([CH3:36])=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:24][CH2:25][C:26]1[C:27](=[O:37])[NH:28][C:29]([CH3:36])=[CH:30][C:31]=1[C:32]([F:33])([F:34])[F:35])=[O:9]
Reactant: CCN(c1cc(Cl)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: Cc1cc(C(F)(F)F)c(CN)c(=O)[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C(F)(F)F)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 23 °C
Reaction time: 7 h
Yield: 41.5 %

Procedure:
To a stirred solution of 5-chloro-3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methylbenzoic acid (crude material, ˜0.7 mmol) and 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-1,2-dihydropyridin-2-one hydrochloride HCl salt (200 mg, 0.91 mmol) in DMSO (5.3 mL) was added PyBOP (550 mg, 1.05 mmol) and hunig base (366 ul, 2.10 mmol). The reaction mixture was stirred at 23° C. for 7 hours. The reaction mixture was quenched with water and diluted with ethylacetate. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (SiO2 Ethylacetate/MeOH=10/1+5% triethylamine). The crude compound was triturated with ethylacetate/hexane, and dried to give the titled compound as a white solid (145 mg, 42% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.08 (d, J=2.4 Hz, 1H), 7.03 (d, J=2.4 Hz, 1H), 6.81-6.85 (m, 1H), 6.35 (s, 1H), 4.71 (d, J=5.2 Hz, 2H), 3.03 (q, J=6.8 Hz, 2H), 2.81-2.85 (m, 2H), 2.68-2.72 (m, 1H), 2.39 (s, 3H), 2.27 (s, 3H), 2.24 (s, 3H), 1.88-1.94 (m, 2H), 1.67-1.72 (m, 4H), 0.85 (t, J=6.8 Hz, 3H); MS (ES) [M+H] 499.1, [M+Na] 521.1; HPLC 96.0% purity.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.[F-].[K+]>C1COCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:15]1[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccccc1Br
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 97.6 %

Procedure:
2-Bromoanisole (98 mg, 0.52 mmol) reacted with 4-trifluoromethylphenylboronic acid (145 mg, 0.76 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (90 mg, 1.55 mmol) in THF at room temperature for 3 h to give the title compound (128 mg, 97%). 1H-NMR (300 MHz, CDCl3): δ 13C{1H}-NMR (100 MHz, CDCl3): δ. GC/MS(EI): m/z (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[NH2:12][C:13](=[N:19]O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)C(C)C)(C)C.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[O:10][N:19]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1noc(Cc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
2-(4-chlorophenyl)acetyl chloride (0.554 mL; 3.78 mmol) was added to a mixture of ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (15 mL) at −15° C. The reaction mixture was stirred at room temperature overnight and poured into a mixture of ice and water. The formed precipitate was filtered off, suspended in pyridine (18 mL) and refluxed in a sealed tube for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica (eluent to 100% ethyl acetate in heptane) to yield 0.506 g (50%) of ethyl 5-(4-chlorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:15]1[O:23][CH:16]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:14][CH2:15][CH:16]([OH:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: c1ccc(C2CO2)cc1
Reactant: COc1ccc(CC(C)N)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(CC(C)NCC(O)c2ccccc2)cc1OC
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 20 g. (0.102 mol) of 1-(3,4-dimethoxyphenyl)-2-aminopropane and 12.01 ml. (0.102 mol) of styrene oxide is heated and stirred at 100° C. under argon for 18 hours. The cooled reaction mixture is dissolved in a minimum amount of benzene and petroleum ether is then added to precipitate a solid which turned to a liquid upon standing. Fractional vacuum distillation yields N-[2-(3,4-dimethoxyphenyl)-1-methylethyl]-2-hydroxy-2-phenylethylamine, b.p. 205°-225° C./0.2 mm.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:15]1([C:21]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:29]3[C@H:25]([CH2:26][NH:27][CH2:28]3)[C@@H:24]([OH:30])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[CH3:13][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:27]1[CH2:26][C@H:25]2[C@H:29]([C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:22][CH2:23][C@@H:24]2[OH:30])[CH2:28]1)=[O:12]
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Reactant: CN(C)c1ccccc1CC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
0.49 g of N,N'-carbonyldiimidazole is added to a solution of 0.52 g of 2-dimethylaminophenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 30 minutes at +5° C. and then a solution of 0.93 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride and 0.84 cm3 of triethylamine in 10 cm3 of dichloromethane is added. The reaction mixture is stirred for 2 hours at +5° C. and then washed with 10 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (0.04 mm -0.06 mm, diameter 2 cm, height 35 cm), eluting with ethyl acetate and collecting fractions of 30 cm3. Fractions 8 to 27 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from a mixture of 4 cm3 of acetonitrile and 20 cm3 of ethyl ether. The crystals are drained and dried under reduced pressure (2.7 kPa). 0.70 g of (3aR,4S,7aR)-2-[(2-dimethylaminophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolol is obtained in the form of a white solid; melting point 160° C., [α]20D =-162° (c =0.5, methanol).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH:6]1([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH2:8][CH2:7]1>C(OCC)C>[CH:6]1([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:14]([OH:15])[CH2:3][CH:2]=[CH2:1])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1
Reactant: C=CC[Mg]Br
Reactant: O=Cc1ccc(CC2CC2)cc1
Solvent: CCOCC
Product: C=CCC(O)c1ccc(CC2CC2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of allylmagnesium bromide (1.0M in diethyl ether, 3 ml) in diethyl ether (5 ml) was added dropwise 4-(cyclopropylmethyl)benzaldehyde (240 mg) in diethyl ether (2 ml) at 0° C. After 15 minutes, the reaction mixture was quenched by aqueous ammonium chloride and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column eluting with a mixture of hexane and ethyl acetate (85:15) to give 1-[4-(cyclopropylmethyl)phenyl]-3-buten-1-ol (229 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].C=O.[C:12]([BH3-])#N.[Na+]>CO>[CH3:12][N:6]1[CH2:7][CH2:8][CH2:9][CH:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: [BH3-]C#N
Reactant: COC(=O)C1CCCN1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCN1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl pyrrolidine-2-carboxylate 10b crude product (5 g) was dissolved in 100 mL of methanol. The solution was cooled to 0˜5° C. in an ice-water bath, followed by addition of 13 mL of 40% formaldehyde. The reaction mixture was warmed up to room temperature and stirred for 2 hours, then cooled to 0˜5° C. in an ice-water bath, and sodium cyanoborohydride (5.45 g, 87.20 mmol) was added in batches. The reaction mixture was warmed up to room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure and added with 5 mL of water, extracted with dichloromethane (5 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain methyl 1-methylpyrrolidine-2-carboxylate 10c (4.7 g, yield 70.1) crude product as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]([OH:15])=O)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(C1NC=CN=1)([C:18]1[NH:19]C=CN=1)=O.CN.Cl>O1CCCC1>[CH3:18][NH:19][C:13]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)=[O:15]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)c1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
250 mg 6-nitro-1H-indole-3-carboxylic acid are dissolved in 10 ml of tetrahydrofuran, combined with 240 mg carbonyl-diimidazole and stirred for 30 minutes at 60° C. Then 750 μl of a 2 M solution of methylamine in tetrahydrofuran is added and the mixture is stirred overnight at 60° C. Then 1 N hydrochloric acid is added and the precipitated solid is suction filtered. Then the solid is extracted from ethyl acetate, suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18](=O)[CH3:19])[CH2:13][C:12]=3[C:21](=[O:23])[O:22][C:5]=2[CH:4]=1.[CH3:24][NH2:25]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH:18]([NH:25][CH3:24])[CH3:19])[CH2:13][C:12]=3[C:21](=[O:23])[O:22][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CC(C)=O)C3
Reactant: CN
Product: CNC(C)CN1CCc2c(c(=O)oc3cc(OC)c(OC)cc23)C1
Yield: 291.4 %

Procedure:
Prepared by the method described for Example 51 from 1,2,3,4-tetrahydro-8,9-dimethoxy-3-(2-oxopropyl)-5H-[1]benzopyrano[3,4-c]pyridin-5-one (25.0 g, 0.08 moles) and methylamine (5 g, 0.016 moles). Recrystallization from acetonitrile gave the product (15.5 g), mp 137°-139° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:7]=1[F:8]
Reactant: Oc1cc(F)c(Br)cc1F
Reactant: OB(O)c1ccccc1
Solvent: ClCCl
Product: Fc1cc(Oc2ccccc2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Bromo-2,5-difluorophenol (500 my, 0.002 mol), phenylboronic acid (0.73 g, 0.0060 mol), TEA (2.0 mL, 0.014 mol), cupric acetate (0.70 g, 0.0038 mol) and DCM (20 mL) were added to a 100 mL oven dried flask and the reaction was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=6.81 (dd, J=8.84, 7.07 Hz, 1H), 6.98-7.08 (m, 2H), 7.19 (t, J=7.45 Hz, 1H), 7.31-7.48 (m, 3H).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(OC(=O)C)(=O)C.[CH2:12]1[O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@@H:14]2[C@@H:13]1O>C(Cl)Cl>[N+:1]([O-:4])([O:3][C@@H:13]1[CH2:12][O:16][C@@H:15]2[C@H:17]([OH:20])[CH2:18][O:19][C@H:14]12)=[O:2]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 0 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a solution of fuming nitric acid (0.92 mL, 22.2 mmol) in CH2Cl2 (44 mL) and acetic anhydride (2.10 mL, 22.2 mmol) cooled to −20° C., 1,4:3,6-dianhydro-D-mannitol (2.50 g, 17.1 mmol) was added as solid. After the reaction mixture was stirred at 0° C. for 3 hours, it was slowly poured into ice/NaHCO3. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography (Biotage SP1, column SNAP 100, EtOAc/n-hexane from 30 to 100%), affording the title product as a white solid (1.35 g, yield 41%). 1H-NMR (300 MHz, CDCl3); δ 5.39 (1H, q), 4.89 (1H, t), 4.49 (1H, t), 4.35-4.27 (1H, m), 4.10-4.04 (2H, m), 3.58 (2H, t), 2.40 (1H, d).
Reaction SMILES: [CH2:1]([SH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9](=[O:13])[CH:10]=[CH:11][CH3:12]>C(O)C>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:1][S:7][CH:11]([CH3:12])[CH2:10][C:9](=[O:13])[CH3:8]
Reactant: SCc1ccco1
Reactant: CC=CC(C)=O
Solvent: CCO
Product: CC(=O)CC(C)SCc1ccco1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.8 %

Procedure:
10 g of furfurylmercaptan and 15 g of 3-penten-2-one were dissolved in 100 ml of ethanol. The solution was stirred at room temperature for 48 hours. The solvent was then distilled off in vacuo at 50° C. The residue (18 g) was purified by preparative high pressure liquid chromatography (HPLC). 9 g of 4-[(furylmethyl)thio]-2-pentanone (purity 95%) were obtained. The IR, NMR and mass spectra of the compound agree with the structure described for it.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:11]2)(=O)=O)C=CC=CC=1>CO.[OH-].[K+]>[C:19]1([C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccccc2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(-c2c[nH]c3ccccc23)cc1
Yield: 34 %

Procedure:
A mixture of 245 mg (0.73 mmol) of 1-benzenesulfonyl-3-phenyl-1H-indole in 10 mL of methanol and 5 mL of 2 N aqueous KOH was warmed at reflux for 2 hours. The mixture was then cooled and concentrated in vacuo and diluted with water and extracted with ethyl acetate. The combined organic layers were washed with two 10 mL portions of 2 N aqueous KOH solution, 10 mL of brine, three 10 mL portions of saturated aqueous ammonium chloride solution, and 10 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was triturated with hexanes afford 48 mg (33%) of 3-phenyl-1H-indole.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[CH2:7][C@@:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]2[CH2:10][CH2:9][C@:8]([CH2:7][C:6]3[S:40][C:1]([CH3:2])=[N:4][N:5]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:13][C:12]2=[O:14])[CH3:16])=[CH:18][CH:19]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NNC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Solvent: C1CCOC1
Product: Cc1nnc(C[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(Br)cc3)C(=O)O2)s1
Yield: 20.2 %

Procedure:
To a solution of N′-acetyl-2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetohydrazide (50 mg, 0.105 mmol) in anhydrous THF (2 mL) was added Lawesson's Reagent (50 mg, 0.126 mmol) at rt. The mixture was heated to reflux for 3 h. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((5-methyl-1,3,4-thiadiazol-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 20%). 1H NMR (400 MHz, CDCl3): δ=1.39 (d, 3H), 2.02 (m, 1H), 2.22 (m, 1H), 2.39 (m, 1H), 2.69 (s, 3H), 2.81 (m, 1H), 3.58 (m, 1H), 5.52 (q, 1H), 6.66 (m, 2H), 7.16 (m, 2H), 7.21 (m, 2H), 7.32 (m, 3H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=3[O:21][CH3:22])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]([O:21][CH3:22])=[C:12]([N:9]2[CH2:10][CH2:11][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:7][CH2:8]2)[CH:17]=1
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)C2CC2)CC1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1N1CCN(C(=O)C2CC2)CC1
Yield: 91 %

Procedure:
A solution of the cyclopropyl-[4-(2-methoxy-5-nitrophenyl)-piperazin-1-yl]methanone (D17) (1.8 mmol) in ethanol was hydrogenated over 10% Palladium on charcoal catalyst for 2 hrs at room temperature to give the title compound in 91% yield. Found MH+ 276.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.[I-]>[C:8]1([C:6]2[N:7]=[C:3]([CH2:2][O:20][C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])[O:4][C:5]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
A mixture of 2-bromomethyl-4,5-diphenyloxazole (26.72 g, 85 mmol) obtained according to D. L. Aldous, et al., J. Org. Chem. 2, 228-334 (1937), 3-hydroxybenzaldehyde (9.34 g, 76 mmol), potassium carbonate (12.92 g, 93 mmol), potasssium iodide (0.5 g) and dimethylformamide (250 mL) was stirred at 110° C. After 45 minutes, the mixture was cooled, diluted with water and extracted with diethyl ether (3×). The combined extracts were washed with water (3×), dried over sodium sulfate and concentrated in vacuo to give an oil which was chromatographed on a column of silica gel. Elution with a mixture of hexanes and diethyl ether (2:1) afforded 3-[(4,5-diphenyl-2-oxazolyl)methoxy]benzaldehyde (21.16 g, 70%). An analytical sample was recrystallized from a mixture of CH2Cl2 and hexanes and had mp 72°-75° C.
Reaction SMILES: COC1C=CC=CC=1C([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=O.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=1>>[N:10]12[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11]1)[C@H:8]([NH:7][C:26]([C:25]1[CH:24]=[N:23][C:22]([C:21]([F:20])([F:32])[F:31])=[CH:30][CH:29]=1)=[O:28])[CH2:9]2
Reactant: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccc(C(F)(F)F)nc1

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 19S, using 6-(trifluoromethyl)nicotinic acid in place of o-methoxybenzoic acid. 1H NMR (400 MHz, CDCl3) S (ppm): 8.84 (s, 1H), 8.34 (dd, J=8 Hz, 1H), 8.23 (s, 1H), 8.12 (dd, J=8 Hz, 1H), 4.18 (m, 1H), 3.39 (ddd, J=10, 14 Hz, 1H), 2.96-2.87 (m, 4H), 2.68 (ddd, J=16 Hz, 1H), 2.06 (m, 1H), 1.82 (m, 1H), 1.74 (m, 1H), 1.55 (m, 1H). C14H16F3N3O=299.12 LCMS (M+H): m/z 300
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])C.[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>C(O)C>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:5])[C:7]1=[O:20])[CH3:19]
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(CC)c1=O
Solvent: CCO
Product: CCn1c(=O)c(C(=O)NCCOC)c(O)c2ccc(C)nc21
Reaction time: 8 h

Procedure:
A stirred mixture of 1.38 g. (0.005 mole) of 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared as in Example 1) and 0.75 g. (0.01 mole) of 2-methoxyethylamine in 20 ml. of ethanol was heated under reflux for 5 hours. The solution was left at room temperature overnight. The precipitate which formed was collected and was stirred in 100 ml. of a 20% aqueous acetic acid solution for 30 minutes. The insoluble material was collected, air dried and was recrystallized from heptane to give 0.9 g. of the title compound, m.p. 118°-20° C.