Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14].CN(C)C=O>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]([CH2:12][N:4]([CH:1]([CH3:3])[CH3:2])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:14])=[CH:16][CH:17]=1
Reactant: CC(C)Nc1ccccc1
Reactant: O=C(CCl)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(CC(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
562.9 g. (4.08 moles) of N-isopropylaniline is rapidly added to a solution of the crude product of Step 1 in 500 ml. of dimethylformamide stirred at 50° C. under nitrogen. The reaction mixture is stirred at 100° C. under nitrogen for 10 hours and allowed to cool to room temperature overnight. The reaction mixture is heated to 60° C., 2 l of water is added, and the mixture is cooled to 10° C. The obtained solids are collected, washed twice with 500 ml. portions of water and dissolved in 550 ml. of 95% ethanol at 75° C. The solution is cooled to 0° C., and the obtained solids are collected, washed three times with 100 ml. portions of 95% ethanol and vacuum dried at 35°-40° C. for 4 hours to obtain the 95.3% pure yellow product (466 g. (80.2% (two steps))), m.p. 78°- 81° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>ClCCl>[CH2:1]([C:3]1[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1)[CH3:2]
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCN)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylamine (step 4 of EXAMPLE 3, 1.72 g, 5.9 mmol) and triethylamine (2.0 mL, 14.8 mmol) in dichloromethane (60 mL) was added phenyl chloroformate (900 μL, 7.0 mmol) at ambient temperature. After 1 h, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 3:1 to 1:1) to afford 2.0 g (83%) of the title compound as colorless amorphous: MS (ESI) m/z 412 [M+H]+, 1H-NMR (CDCl3)δ1.27 (3H, d, J=7.5 Hz), 2.73 (2H, t, J=7.5 Hz), 2.99 (2H, t, J=7.1 Hz,) 3.59 (2H, t, J=7.0 Hz), 5.12 (1H, br), 7.12 (2H, d, J=7.5 Hz), 7.18-7.25 (2H, m), 7.29-7.41 (8H, m) 7.80 (2H, dd, J=8.3, 1.3 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[C:48]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)([CH3:51])([CH3:50])[CH3:49]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:15][C:61]2[CH:62]=[CH:63][C:58]([C:55]3[CH:54]=[CH:53][C:52]([C:48]([CH3:51])([CH3:50])[CH3:49])=[CH:57][CH:56]=3)=[CH:59][CH:60]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (300 mg, 1.35 mmol) in toluene (14 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 512 mg, 2.03 mmol) at 0° C., followed by the addition of tributylphosphine (0.5 mL, 2.03 mmol) and 4′-tert butyl-biphenyl-4-ol (367 mg, 1.62 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving 4-[1-(4′-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid methyl ester. The ester product is taken into ethanol (5 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1 mL), extract with ethyl acetate. The organic layers are dried and concentrated giving 4-[1-(4′-tertbutyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid (400 mg).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.[CH:19](OCC)=[O:20].CC(C)([O-])C.[K+].Cl>C(OCC)C>[OH:20][CH2:19][CH:3]1[CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCC2=O)CC1
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(CO)C2=O)CC1
Temperature: -78 °C
Reaction time: 48 h
Yield: 51.4 %

Procedure:
tert-Butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate from Procedure 1, Step G (0.526 g, 2.08 mmol) was dried by evaporating with toluene (10 mL) three times in vacuo, dissolved in methyl-tert-butyl ether (5 mL), and cooled to −78° C. To this solution was added ethyl formate (0.336 mL, 4.15 mmol) and then potassium t-butoxide (0.466 g, 4.16 mmol). After 2 days, the reaction mixture was diluted with diethyl ether, poured into 2N HCl, and extracted three times with diethyl ether. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 0.575 g. The residue was purified by flash chromatography eluting with 45% ethyl acetate/hexanes to give the title compound (0.303 g). MS/EI (acetonitrile/water): m/z 304 (M+1+Na) retention time=2.9 min.
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.C(O[C:18]([O:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C1COCC1>C(Cl)Cl>[C:24]([O:23][C:21]([O:20][C:18]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:22])([CH3:25])([CH3:26])[CH3:27]
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Reaction time: 22 h

Procedure:
In 200 mL of methylene chloride was dissolved 6.91 g (0.043 m) of 4-acetoxystyrene and 13.10 g (0.060 m) of di-t-butyldicarbonate under nitrogen. To the solution at room temperature was added 14.0 g (0.101 m) of potassium carbonate and the mixture was vigorously stirred for 22 hours, following the reaction by thin layer chromatography. After 22 hours at room temperature 100 mL of THF was added and the reaction was further stirred for 142 hours. It was worked up as in the above Examples. There was a very low yield (less than 10 %) of the product, 4-(t-butoxycarbonyloxy)styrene, under these conditions as analyzed by NMR, HPLC and TLC.
Reaction SMILES: [SH:1][C:2]1[N:3]([NH2:20])[C:4]([C@H:7]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:8])=[N:5][N:6]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=S)[CH:25]=[CH:26][CH:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(O)C.CCOCC>[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][C:29]2[S:1][C:2]3=[N:6][N:5]=[C:4]([C@H:7]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH3:8])[N:3]3[N:20]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1nnc(S)n1N
Reactant: S=C=Nc1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Solvent: CCOCC
Product: C[C@@H](NC(=O)OCc1ccccc1)c1nnc2sc(Nc3cccc(Cl)c3)nn12
Temperature: 80 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
(Step 8-ii) A mixture of (R)-benzyl 1-(5-mercapto-4-amino-4H-1,2,4-triazol-3-yl)ethylcarbamate (1.32 g, 4.5 mmol) in ethanol (15 mL) was heated to 80° C. and 3-chlorophenylisothiocyanate (1.3 g, 7.65 mmol) and dicyclohexylcarbodiimide (1.11 g, 5.4 mmol) were added. After 4 hours, the reaction was cooled, diluted with an equal volume of ether, and filtered. The filter cake was washed with additional ether and the collected solids dried in vacuo to provide 0.94 g of (R)-benzyl 1-(6-(3-chlorophenylamino)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-yl)ethylcarbamate: ESMS MH+=429.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][Br:50])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(=O)OCc1ccc(Cl)cc1N([C@H](C)CCCO)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=O)OCc1ccc(Cl)cc1N([C@H](C)CCCBr)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
To a solution of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4-hydroxybutyl]benzenesulfonamide (500 mg, 1.09 mmol) in acetonitrile (2 mL) was added triphenylphosphine (571 mg, 2.18 mmol) and carbon tetrabromide (720 mg, 2.18 mmol) at 0° C. The resulting mixture was allowed to stir at 22° C. for 12 h followed by the addition of 25 mL of sat. ammonium chloride. The product was extracted with ether (2×25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:4 ethyl acetate:hexanes) of the concentrate afforded 479 mg of 4-chloro-N-[5-chloro-2-(acetoxymethyl)phenyl]-N-[(R)-1-methyl-4-bromobutyl]benzenesulfonamide as a colorless oil in 84% yield.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18](Br)[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>CCO.CCOC(C)=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[S:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH:18]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: CCC(Br)c1nc2ccsc2c(=O)n1Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC(NCCN(C)C)c1nc2ccsc2c(=O)n1Cc1ccccc1
Reaction time: 24 h

Procedure:
3-Benzyl-2-(1-bromopropyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-6, 0.032 g, 0.088 mmol) was dissolved in EtOH (2.0 mL) and treated with N,N-dimethyl ethylenediamine (0.03 mL, 0.26 mmol). The reaction was to 80° C. for 24 h. The reaction was diluted with EtOAc (20 mL), washed with 5% NH4Cl, and dried over MgSO4. The organics were concentrated under reduced pressure to provide 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[3,2-d]pyrimidin-4(3H)-one (1-7). MS 371.1 found 370.5 required.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][CH:14]=1)=[O:11])=[O:4].C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N+:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([N:12]2[C:3](=[O:4])[CH:5]3[CH2:9][CH2:8][CH2:7][N:6]3[C:10]2=[O:11])=[CH:14][CH:15]=1)([O-:25])=[O:24]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)Nc1ccc([N+](=O)[O-])c2ccccc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: O=C1C2CCCN2C(=O)N1c1ccc([N+](=O)[O-])c2ccccc12
Temperature: 80 °C
Yield: 19.9 %

Procedure:
A suspension of compound 2A (410 mg, 1.29 mmol) and DBU (0.2 mL, 1.33 mmol) in toluene (10 mL) was heated at 80° C. for 2 hours. HPLC check of the reaction showed little product formed. Additional DBU (0.1 mL) was added and the reaction heated at 90° C. overnight. After cooling to RT, the reaction mixture was filtered. The filtrate was diluted with EtOAc, washed with 1 N aqueous HCl, water, brine, dried over MgSO4 and concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with CH2Cl2, 0.2% to 0.4% MeOH in CH2Cl2 to give the title compound (racemate) (80 mg) as a brown solid. mp. 215-217° C. HPLC: 97.5% at 2.51 min (retention time) (YMC S5 ODS column 4.6×50 mm; 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nM), MS (ES): m/z 312 [M+1]+.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([C:21]([N:23]2[CH2:27][CH:26]([CH:28]=O)[CH:25]([CH2:30][N:31]3[CH2:36][CH2:35][CH:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH2:33][CH2:32]3)[CH2:24]2)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]1([C:21]([N:23]2[CH2:27][CH:26]([CH:28]=[CH2:1])[CH:25]([CH2:30][N:31]3[CH2:32][CH2:33][CH:34]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH2:35][CH2:36]3)[CH2:24]2)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=CC1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.08 g (0.22 mmol) of methyltriphenyl phosphonium bromide (Ph3PCH3Br) in 4 mL of THF at rt was added 0.36 mL of potassium bis(trimethylsilyl)amide and the reaction mixture was stirred for 30 min. The reaction mixture was cooled to 0° C. and to it was added a solution of 0.04 g (0.089 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-formylpyrrolidine in 2 mL of THF. The reaction mixture was warmed to rt and stirred for 1.2 h. The reaction mixture was filtered through a thin pad of silica eluting with acetone:hexanes, 1:2, then concentrated. The residue was purified by chromatography (silica, acetone:hexanes, 1:2) to give the title compound. Mass Spectrum (ESI) m/e=444 (M+1).
Reaction SMILES: S(O[CH2:12][C@H:13]1[O:17][C:16](=[O:18])[NH:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[C-:19]#[N:20].[Na+]>CO.O>[C:19]([CH2:12][CH:13]1[O:17][C:16](=[O:18])[NH:15][CH2:14]1)#[N:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CNC(=O)O2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CCC1CNC(=O)O1
Yield: 70 %

Procedure:
To a stirring solution of (S)-5-tosyloxymethyl-1,3-oxazolidine-2-one (0.54 g, 1.99 mmol) in MeOH-water (15-3 mL) was added NaCN (0.39 g, 8.00 mmol) at room temperature and then heated to reflux for 4 h. After completion of the reaction, solvent in the reaction mixture was completely evaporated and the residue was purified by column chromatography employing EtOAc-hexane (70:30) as eluent to afford pure 5-cyanomethyl-1,3-oxazolidine-2-one in 70% yield. [α]26D=+4.5 (c 1.0, MeOH); IR (Neat) 3349, 2918, 2839, 2243, 1710, 1255, 1051 cm1; 1HNMR (200 MHz, CD3OD) δ 2.57 (d, 2H, J=6.6 Hz), 3.20-3.55 (m, 2H), 4.00-4.18 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N.C[OH:30]>Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:30])[N:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CO
Reactant: Nc1nc(NCCc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Agent: Cl
Agent: N
Product: Nc1nc(NCCc2ccccc2)nc2c1nc(O)n2Cc1ccccc1
Yield: 77 %

Procedure:
6-Amino-9-benzyl-2-benzylmethylamino-8-bromopurine (85 mg, 0.20 mmol) in concentrated hydrochloric acid (30 ml) and methanol (20 ml) were refluxed for 5 hours under heating. The reaction mixture was made basic with 28% aqueous ammonia, and the resulting crystals were filtered, washed with water and dried to give the subject compound (56 mg, yield 77%).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH:9][C:10]([C:12]1[C:21]2[C:16](=[C:17]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:11].C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>ClCCl>[CH2:43]([O:42][C:40]([N:27]1[CH2:26][CH2:25][CH:24]([NH:23][S:22]([C:17]2[C:16]3[C:21](=[C:12]([C:10](=[O:11])[NH:9][CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]4[CH3:2])[CH:13]=[CH:14][CH:15]=3)[CH:20]=[CH:19][CH:18]=2)(=[O:31])=[O:30])[CH2:29][CH2:28]1)=[O:41])[CH3:44]
Reactant: CC1CCCCC1NC(=O)c1cccc2c(S(=O)(=O)NC3CCNCC3)cccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)NC4CCCCC4C)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(Piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid (2-methyl-cyclohexyl)-amide hydrochloride 48 (190 mg, 0.41 mmol) was dissolved in dichloromethane (1 mL). Triethylamine (0.13 g, 0.18 mL, 1.28 mmol) was added followed by ethyl chloroformate (65 mg, 0.068 mL, 0.60 mmol). The reaction was stirred overnight at room temperature. The crude reaction mixture was charged to a flash column. Elution with 99:1 dichloromethane:methanol afforded H-24 (66 mg, 59%) as a white solid. 1H NMR (300 MHz, CDCl3) (1:1 mixture of diastereomers) δ 8.65 (d, 1H), 8.48 (d, 1H), 8.25 (d, 1H), 7.55 (m, 3H), 6.20 (d, 1H), 5.47 (m, 1H), 5.26 (s, 1H), 4.00 (m, 2H), 3.75 (m, 3H), 3.20 (m, 1H), 2.75 (m, 2H), 2.15 (m, 1H), 1.78 (m 3H), 1.57 (m 2H), 1.38 (m, 2H), 1.05 (m, 10H); LC/MS m/z 502 (M+H)+.
Reaction SMILES: [C:1]([O:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])(=O)[CH:2]([CH3:4])C.[C:12]1([CH3:19])[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[C:7]([O:6][C:1]1[CH2:2][CH2:4][CH2:19][CH2:12][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:18][CH2:16][CH2:17][C@@H:12]([CH3:19])[CH:13]=1)(=[O:11])[CH:8]([CH3:9])[CH3:10]
Reactant: CC(C)C(=O)OC(=O)C(C)C
Reactant: Cc1ccccc1C
Product: CC(C)C(=O)OC1=C[C@H](C)CCCCCCCCCCCC1
Yield: 81 %

Procedure:
A crude product was prepared under the same condition as that in Example 6 except that isobutanoic anhydride was used instead of n-butanoic anhydride and xylene was used in an amount of 14 g, and was purified and isolated by silica gel column chromatography to give 2.5 g (8.14 mmol) of the title compound (R)-3-methyl-1-cyclopentadecenyl isobutyrate (yield: 81%). Gas chromatographic analysis thereof gave E/Z=1.4/98.6.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([O:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[O:26][C:27]=1[CH3:28]>>[CH2:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[O:26][C:27]=1[CH3:28])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:20])[CH2:17][CH:18]=[CH2:19]
Reactant: Cc1oc(-c2ccccc2Cl)nc1CCl
Reactant: C=CCCOC(Cc1ccc2[nH]ccc2c1)C(=O)OC
Product: C=CCCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccccc3Cl)oc2C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-but-3-enyloxy-3-(1H-indol-5-yl)-propionic acid methyl ester (preparation 9) was reacted with 4-chloromethyl-2-(2-chloro-phenyl)-5-methyl-oxazole to give rac-2-but-3-enyloxy-3-{1-[2-(2-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid as light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]>>[CH:19]([C:18]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)[CH:23]=[CH:22][CH:21]=1)=[O:20]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2cccc(C=O)c2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (102 mg, 0.54 mmol) and 3-bromobenzaldehyde (0.09 mL, 0.62 mmol) according to the general procedure IC to give 93 mg (59%) of an orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:3). Rf: 0.16 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 10.01 (s, 1H), 8.02 (s, 1H), 7.84-7.74 (m, 2H), 7.54-7.46 (m, 3H), 7.26-7.19 (m, 2H), 3.67 (s, 3H), 3.00-2.95 (t, 2H, J=7.8 Hz), 2.67-2.62 (t, 2H, J=7.8 Hz); 13CNMR (CDCl3) δ 191.6, 173.0, 141.4, 137.0, 136.5, 132.9, 131.8, 129.1, 128.8, 128.4, 124.6, 120.6, 90.9, 87.6, 51.6, 35.3, 30.8; EI-MS m/z 292 (M+).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl>CN(C)C=O>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][N:5]1[CH2:6][CH2:7][O:3][C:4]1=[O:8]
Reactant: O=C1NCCO1
Reactant: ClCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OCCN1CCCCCl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Following the procedure of Piper et al. [J. Het. Chem. 4, p. 298 (1967)], sodium hydride (4.8 g of 50% dispersion in oil, 0.1 mole) was washed with pentane and suspended in 20 ml of dimethylformamide. A solution of 2-oxazolidinone (8.7 g, 0.10 mole) and 1,4-dichlorobutane (66 g, 0.52 mole) in 100 ml of dimethylformamide was then added dropwise over 30 minutes, maintaining the reaction temperature at 25°-30° C. The reaction was stirred for 18 hours at ambient temperature, then evaporated to an oil, and the oil taken up in ethyl acetate, treated with activated carbon, filtered over diatomaceous earth, and reevaporated in vacuo to yield the title product as an oil [16.5 g, contaminated with mineral oil from incompletely washed sodium hydride; pnmr/CDCl3 /delta: 0.67-1.0 and 1.03-1.4 (mineral oil), 1.4-1.83 (m, 4H), 3.03-3.72 (m, 6H), 4.10-4.43 (t, 2H)].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([O:33][CH2:34][C@@H:35]1[CH2:37][O:36]1)[CH:27]=[CH:26]2>>[Br:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[CH:29]=[C:28]([O:33][CH2:34][C@@H:35]([OH:36])[CH2:37][N:1]1[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]1)[CH:27]=[CH:26]2
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: Brc1ccc2cc(OC[C@@H]3CO3)ccc2c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc4cc(Br)ccc4c3)CC1)O2

Procedure:
Compound 216 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-{[(6-bromo-2-naphthyl)oxy]methyl}oxirane and conditions outlined in procedure Y. M.p.=183-184° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=7.7, 0.7 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.69-7.64 (m, 2H), 7.60 (d J=8.8 Hz, 1H), 7.52-7.47 (m, 2H), 7.20 (dd, J=9.2, 2.6 Hz, 1H), 7.12 (d, J=2.6 Hz, 1H), 4.25-4.18 (m, 1H), 4.12 (d, J=4.8 Hz, 2H), 3.04-2.92 (m, 1H), 2.96 (s, 2H), 2.90-2.80 (m, 2H), 2.78-2.68 (m, 2H), 2.57 (t, J=10.4 Hz, 1H), 2.25-2.12 (m, 2H), 1.98-1.84 (m, 2H); LCMS: 580 [M+H].
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1>C(O)C.C1COCC1.[Ni]>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)C2CC2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)C2CC2)cc1
Yield: 92 %

Procedure:
A solution of 1.60 g (7.0 mmol) of 1-cyclopropanesulphonyl-4-nitrobenzene in 50 ml of ethanol and 50 ml of THF was admixed with 3.2 g of Raney nickel (50% moisture) and hydrogenated for 1.5 hours under atmospheric pressure at 0° C. The mixture was filtered and concentrated by evaporation. This gave 1.28 g (6.5 mmol; yield: 92%) of the product.