Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH3:14])[CH:7]=1>CO.O1CCCC1>[CH3:14][O:13][CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[C:5]([OH:15])=[O:4]
Reactant: COCc1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cccc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
1 N Sodium hydroxide (3.6 ml, 3.6 mmol) was added to a 3-methoxymethyl-benzoic acid methyl ester (436 mg, 2.4 mmol) in methanol (5 ml) and tetrahydrofuran (5 ml). The reaction was stirred at 70° C. for 30 min. and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH about 2) by the addition of 1 N HCl (aq.). Following extraction of the aqueous layer with ethyl acetate, the organic layer was then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 395 mg (98%) of 3-methoxymethyl-benzoic acid as a white solid. 1H NMR (DMSO), δ (ppm): 7.90 (s, 1H), 7.87 (d, 1H), 7.56 (d, 1H), 7.48 (t, 1H), 4.48 (s, 2H), 3.31 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=2)[CH:7]=1.[CH3:16][O:17][C:18]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([NH:21][CH2:20][C:19]3[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:18]=3[O:17][CH3:16])=[O:13])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cnc2ccc(Br)cn12
Reactant: COc1ccc(CN)c(OC)c1
Solvent: Cc1ccccc1
Product: COc1ccc(CNC(=O)c2cnc3ccc(Br)cn23)c(OC)c1
Temperature: 120 °C
Yield: 20 %

Procedure:
To a solution of ethyl 6-bromoimidazo[1,2-a]pyridine-3-carboxylate (1.0 g, 3.7 mmol) in toluene (5 mL) was added 2,4-dimethoxybenzylamine (0.93 g, 5.6 mmol). The reaction mixture was heated at 120° C. for 2 days in a sealed tube, allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-100% gradient of ethyl acetate in hexanes to afford 6-bromo-N-(2,4-dimethoxybenzyl)imidazo[1,2-a]pyridine-3-carboxamide as a yellow oil in 20% yield (0.29 g): 1H NMR (300 MHz, CDCl3) δ9.70-9.67 (m, 1H), 7.91 (s, 1H), 7.53 (dd, J=9.5, 0.7 Hz, 1H), 7.38 (dd, J=9.5, 1.9 Hz, 1H), 7.27-7.21 (m, 2H), 6.48-6.38 (m, 2H), 4.54 (d, J=5.8 Hz, 2H), 3.85 (s, 3H), 3.78 (s, 3H); MS (ES+) m/z 389.8 (M+1), 391.8 (M+1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+:10].[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:15][CH:14]=1.[C:25]([O:32][CH2:33][CH3:34])(=[O:31])[C:26]([O:28]CC)=O>CC1CCCCC1>[CH2:33]([O:32][C:25]([C:26](=[O:28])[CH:20]([CH3:21])[CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:23])[F:24])=[CH:18][CH:17]=1)[O-:22])=[O:31])[CH3:34].[Li+:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=O)c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC1CCCCC1
Product: CCOC(=O)C(=O)C(C)C([O-])c1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 118 ml of lithium bis(trimethylsilyl)amide (Lithium Hexamethyldisilazide; 0.9 M in methylcyclohexane) was added dropwise over 15 min 20 g of 1-(4-Trifluoromethyl-phenyl)-propan-1-one in 51 ml methylcyclohexane at while maintaining the reaction mixture at 15-25° C. After stirring for 2 h, 15 ml of diethyl oxalate were added dropwise over 30 min and the reaction mixture was stirred for 16 h. Then, the precipitated product was collected by filtration and washed with n-heptane. The isolated crude product was used in the next reaction step after drying in vacuo. Yield: 19 g.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][CH2:7][C:8]#[N:9].[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[NH:25][C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:13][C:14]1[S:18][C:17]([C:19]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[C:24](=[O:32])[N:25]([CH2:2][C:3]2[CH:12]=[CH:11][CH:10]=[C:5]([O:6][CH2:7][C:8]#[N:9])[CH:4]=2)[C:26]3=[O:31])=[O:20])=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc2c1C(=O)NC2=O)c1ccc(Cl)s1
Reactant: N#CCOc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CCOc1cccc(CN2C(=O)c3cccc(NC(=O)c4ccc(Cl)s4)c3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.46 g (8.94 mmol) of 2-[3-(hydroxymethyl)phenoxy]acetonitrile, 2.5 g (8.15 mmol) of 5-chloro-N-(1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-2-thiophenecarboxamide and 4.28 g (16.3 mmol) of triphenylphosphine are, under argon, dissolved in 250 ml of tetrahydrofuran. 2.84 g (16.3 mmol) of DEAD (diethyl azodicarboxylate) are added, and the mixture is stirred at room temperature overnight. 10 g of silica gel are added and the mixture is concentrated under reduced pressure and chromatographed on a silica gel column (gradient: toluene->toluene/ethyl acetate=4:1). This gives 2.37 g (64.4% of theory) of the target compound of melting point 164° C. Rf (SiO2, toluene/ethyl acetate=4:1): 0.45.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2>CCO.Cl.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[NH2:8][C:7]1[C:2]([Cl:1])=[C:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]([Cl:11])=[CH:5][CH:6]=1
Reactant: Cn1c(=O)c(-c2c(Cl)ccc([N+](=O)[O-])c2Cl)cc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1c(=O)c(-c2c(Cl)ccc(N)c2Cl)cc2ccccc21
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
To a suspended solution of 3-(2,6-dichloro-3-nitro-phenyl)-1-methyl-1H-quinolin-2-one (50 mg, 0.143 mmol) in EtOH (3.0 mL) is added a solution of Sn(II)Cl2 (122 mg, 0.644 mmol) in concentrated HCl (2.0 mL) at 75° C. After the mixture is stirred for 30 minutes at 75° C., the mixture is diluted with EtOAc and neutralized with K2CO3 until a pH of 8 is achieved. The organic layer is washed with saturated K2CO3, brine and dried, filtered and concentrated to give crude product (44.2 mg, 96.7%).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][CH2:17][NH:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[C:21]=4[C:11]=3[CH:10]=[N:9]2)=CC=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([NH:34][C:35]([N:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[C:21]3[C:11]4[CH:10]=[N:9][NH:8][C:12]=4[N:13]=[CH:14][C:15]=3[CH2:16][CH2:17]2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CCNc2ccccc2-4)cc1
Product: O=C(Nc1ccccc1)N1CCc2cnc3[nH]ncc3c2-c2ccccc21
Yield: 31 %

Procedure:
The compound N-phenyl-6,7-dihydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine-8(3H)-carboxamide was prepared using 3-(4-methoxybenzyl)-3,6,7,8-tetrahydropyrazolo[4′,3′:5,6]pyrido[3,4-d][1]benzazepine and phenyl isocyanate as described in the two step general procedure L to give the desired compound as an off-white solid (0.048 g, 31%). M.p.>140° C.; 1H NMR (CDCl3, 400 MHz) δ 11.35 (brs, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.99 (m, 1H), 7.68-7.60 (m, 2H), 7.46 (dd, J1=1.6 Hz, J2=7.2 Hz, 1H), 7.15-7.06 (m, 4H), 6.90 (m, 1H), 5.97 (s, 1H), 4.75 (m, 1H), 3.77 (m, 1H), 2.90 (m, 2H); LCMS [M+H]: 356.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH2:28])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1>N1C=CC=CC=1>[CH3:13][C:14]1[CH:29]=[C:17]2[N:18]=[C:19]([NH:28][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:16]2[N:15]=1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)[C@@H]3C[C@H]3c3ccccc3)cc(-c3ccccc3)n2n1
Temperature: 25 °C

Procedure:
In a round-bottomed flask was a mixture of (1R,2R)-2-phenylcyclopropanecarbonyl chloride and cis (+/+, −/−)-2-phenylcyclopropanecarbonyl chloride (200 mg, 1.1 mmol) added in Pyridine (5 mL) to give a yellow suspension. 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 124 mg, 0.554 mmol) was added portionwise at 0° C. The temperature was slowly raised to room temperature. The reaction was quenched with saturated sodium bicarbonate and partitioned between ethyl acetate and water. The separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure (3×100 mL). The reaction mixture was filtered and purified by preparatory HPLC (70-80% MeCN/H2O gradient+0.01% TFA). Received 62 mg (30%) of yellow solid. Melting point (208.2-208.3° C.). 1H NMR (DMSO-d6) δ: 11.28 (s, 1H), 7.93-8.10 (m, 2H), 7.90 (s, 1H), 7.55-7.68 (m, 3H), 7.28-7.34 (m, 2H), 7.17-7.25 (m, 3H), 6.33 (s, 1H), 2.42-2.48 (m, 1H), 2.37 (s, 4H), 1.34-1.63 (m, 2H); [α]D20=−238° (c=1.058, MeOH). ESI-MS: m/z 369.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]2)=[CH:12][CH:13]=1)=[O:7].C1(CCNC(C2N=NC(N3CC4C(C4N)C3)=CC=2)=O)CC1.[F:42][C:43]([F:54])([F:53])[C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](Cl)=[O:47]>>[CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:18][CH2:17][CH:16]([NH:19][C:46](=[O:47])[C:45]3[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=3[C:43]([F:42])([F:53])[F:54])[CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCC(N)C2)nn1
Agent: NC1C2CN(c3ccc(C(=O)NCCC4CC4)nn3)CC12
Product: CC(C)CCNC(=O)c1ccc(N2CCC(NC(=O)c3ccccc3C(F)(F)F)C2)nn1
Yield: 99 %

Procedure:
Following the procedure as described in Example 4, making variations only as required to use 6-(3-aminopyrrolidin-1-yl)pyridazine-3-carboxylic acid (3-methylbutyl)-amide to replace 6-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide to react with 2-trifluoromethylbenzoyl chloride, the title compound was obtained as a white powder in 99% yield. 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J=9.3 Hz, 1H), 7.85 (t, J=5.6 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.52-7.61 (m, 3H), 6.72 (d, J=9.4 Hz, 1H), 6.07 (d, J=7.0 Hz, 1H), 4.86-4.89 (m, 1H), 3.94-3.97 (m, 1H), 3.64-3.73 (m, 3H), 3.47 (dd, J=6.7 and 13.6 Hz, 2H), 2.42-2.49 (m, 1H), 2.20-2.26 (m, 1H), 1.64-1.75 (m, 1H), 1.47-1.51 (m, 2H), 0.93 (d, J=6.7 Hz, 6H). MS (ES+) m/z 450.4 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[C:13]([F:21])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: CC1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Temperature: 75 °C
Reaction time: 60 h
Yield: 22.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75° C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H](C=O)CCS(C)=O.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:16]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17]
Reactant: CS(=O)CC[C@@H](C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: C1CCNCC1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCCC1
Reaction time: 4 h

Procedure:
The resin was deprotected using a 20% solution of piperidine in DMF (1×3 min, 1×7 min, 20 ml each) and subsequently washed with DMF (1×20 ml). Acylation was carried out by addition of FmocMetOH (2.4 g, 3 eq), DMF (10 ml), HOBt (990 mg, 3 eq), and DIC (1.01 ml, 3 eq) and DMAP (260 mg, 0.1 eq). The coupling was left for 4 h and the resin was washed with DMF (7×20 ml). A small sample was dried carefully and deprotected with DCM/piperidine (1:1) for 30 min. Photometric determination of the resulting Fmoc-piperidine adduct (absorption at 301 nm) gave a resin loading of 0.43 m mol/g. The remaining resin was capped using a solution of acetic anhydride (2 M) and DMAP (0.1 M) in DMF (20 ml, 1×10 min) and subsequently washed with DMF (12×20 ml), methanol (3×40 ml) and diethyl ether (3×40 ml), and dried in vacuo to yield 3.9 g FmocMet-Rinkamide resin.
Reaction SMILES: Cl.Cl[C:3]1[S:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.C([O-])([O-])=O.[K+].[K+].[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>CC#N>[S:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:11]=[C:3]1[O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][OH:18])=[CH:21][CH:22]=1
Reactant: OCc1ccc(O)cc1
Reactant: Clc1nc2ncccc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
To a suspension of 2-chloro[1,3]thiazolo[4,5-b]pyridine hydrochloride (1.0 equiv.) in CH3CN (0.25 M), was added K2CO3 (powder, 325 mesh; 2.1 equiv.). The mixture was stirred at 50° C. under N2 for 3 h prior to the addition of 4-hydroxymethyl-phenol (1.0 equiv.). The reaction mixture was heated at reflux for 3 h and cooled to rt. Some product precipitated out from the reaction solution and was dissolved by adding CH2Cl2. The insoluble inorganic salt was then filtered off and washed with CH2Cl2. The filtrate solution was concentrated to give the title compound (99%), which was used without further purification. MS (ESI): mass calcd. for C13H10N2O2S, 258.1; m/z found, 258.9 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (ddd, J=4.9, 1.7, 0.4, 1H), 8.02 (ddd, J=7.9, 1.7, 0.4, 1H), 7.48-7.38 (m, 4H), 7.21 (ddd, J=7.9, 4.8, 0.4, 1H), 4.74 (s, 2H).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]=[N+]=[N-])=[CH:12][CH:11]=1)=[O:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[O:27]1CC[CH2:29][CH2:28]1>>[OH:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:28](=[O:27])[CH3:29])=[CH:12][CH:11]=1)[CH3:7]
Reactant: CC(=O)c1ccc(CN=[N+]=[N-])cc1
Reactant: C1CCOC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Product: CC(=O)NCc1ccc(C(C)O)cc1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a suspension of aluminum lithium hydride (5.31 g) in tetrahydrofuran (500 ml) was added dropwise a solution of (4-azidomethylphenyl) methyl ketone (8.18 g) in tetrahydrofuran (100 ml) at below 5° C. over 30 min. The mixture was stirred at 30° C. for 2 hr. A saturated aqueous sodium sulfate solution (30 ml) was added and the mixture was stirred for 1 hr. The insoluble matter was filtered off and the solvent was evaporated. The obtained residue was dissolved in ethyl acetate (100 ml), 2N aqueous sodium hydroxide solution (30 ml) and water (70 ml). Thereto was added dropwise acetic anhydride (4.8 ml) with vigorous agitation at 10-15° C. over 10 min. The mixture was stirred at room temperature for 1 hr. The organic layer was separated and the aqueous layer was extracted with ethyl acetate and combined with the organic layer. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (elution solvent; methanol:chloroform=3:97, later 5:95) to give the title compound (5.37 g) as a rather brown oil.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17]C(O)=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH2:33])[CH:27]=1.ClCCl.[OH-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:23][O:24][C:25]([C:26]1[CH:31]=[CH:30][C:29]2[O:32][C:17]([CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([C:1]45[CH2:10][CH:5]6[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]6)[CH2:2]4)[CH2:8]5)=[CH:22][CH:21]=3)=[N:33][C:28]=2[CH:27]=1)=[O:34]
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: O=C(O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 140 °C
Yield: 64.1 %

Procedure:
A mixture of (4-adamantan-1-yl-phenoxymethyl)-acetic acid (200.0 mg, 0.70 mmol) and 3-amino-4-hydroxy-benzoic acid methyl ester (164.3 mg, 0.98 mmol) in PPSE (3 mL) was heated at 140° C. for 2 h. At the end of the reaction period, the mixture was taken to dichloromethane and neutralized with 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtoAc:MeOH=6:3:1) to afford 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester as a white solid (187.3 mg, 64.1% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([Cl:14])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:15](#[N:19])[CH2:16][C:17]#[N:18]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([Cl:14])[C:12]=1[OH:13])[CH:8]=[C:16]([C:15]#[N:19])[C:17]#[N:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCC#N
Reactant: CC(C)(C)c1cc(C=O)cc(Cl)c1O
Product: CC(C)(C)c1cc(C=C(C#N)C#N)cc(Cl)c1O

Procedure:
In a similar manner as described in Example 2 reaction of 3-tert-butyl-5-chloro-4-hydroxybenzaldehyde and malononitrile gave 3-tert-butyl-5-chloro-4-hydroxybenzylidenemalononitrile m.p. 173°.
Reaction SMILES: [CH3:1][C@H:2]([C:9]([OH:11])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]1([CH:19]=[CH:18][CH:17]=[C:15]([OH:16])[CH:14]=1)[OH:13].Cl.O>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[OH:13][C:12]1[CH:14]=[C:15]([OH:16])[CH:17]=[CH:18][C:19]=1[C:9](=[O:11])[CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH3:1]
Reactant: Oc1cccc(O)c1
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C(=O)c1ccc(O)cc1O)c1ccccc1
Temperature: 110 °C
Yield: 41.3 %

Procedure:
3.0 g (20 millimols) of S-(+)-2-phenylpropionic acid was mixed with 3.3 g (24 millimols) of anhydrous zinc chloride and heated to 110° C. to dissolve the latter in the former. 2.64 g (24 millimols) of resorcinol was added to the solution and further heated to 150° C. over a period of 20 minutes while stirring the reaction mixture. The reaction mixture was then cooled to the room temperature. 10 ml of concentrated hydrochloric acid solution and 50 ml of water was added to the reaction mixture, and the reaction product was extracted for 3 times while using 50 ml of ethyl ether in each extraction operation. The extract in ethyl ether was rinsed with an aqueous solution of NaHCO3 for two times, and then rinsed with water for three times. The extract in ethyl ether was then dried by adding anhydrous Na2SO4. The drying agent was removed by filtration and ethyl ether was removed by distillation to obtain 3.6 g of a crude product. The crude product was refined through silica gel column chromatography while using chloroform as the eluent. As a result, 2.0 g of 3-hydroxy-4-(1-oxo-2-phenylpropyl)phenol was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([O:17]CC3C=CC=CC=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C>[Pd].[Hg].CO>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=2[CH:10]=[C:9]1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Agent: [Pd]
Agent: [Hg]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reaction time: 6 h
Yield: 48.1 %

Procedure:
1-Benzyl-4-benzyloxy-2-methyl-1H-indole 2 (86 g, 0.263 mole) was dissolved with ethyl acetate (1.5 L) and methanol (300 mL). To the mixture 10% Pd/C wet (18 g) was added to the solution. The reaction was then subjected to H2 gas passed through a mercury bubbler at room temperature and 1 atm. The mixture was left to stir for 6 h. The reaction mixture was filtered through Celite and concentrated. The residue was purified by column chromatography (3:1 Hexane:EtOAc) to afford 3 (30 g, 49%) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:17]([C:19]1([CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:22][O:21][CH2:20]1)[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:23][C:19]2([CH2:17][CH3:18])[CH2:22][O:21][CH2:20]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1(COc2ccc(Br)cc2C=O)COC1
Temperature: 140 °C
Yield: 47.8 %

Procedure:
To a mixture of 5-bromo-2-hydroxy-benzaldehyde (14 g, 70 mmol), KI (5 g) and K2CO3 (19 g, 140 mmol) in DMF (100 mL) was added toluene-4-sulfonic acid 3-ethyl-oxetan-3-ylmethyl ester (19 g, 70 mmol). The mixture was heated at 140° C. for 2 h, and then cooled to room temperature, partitioned between water and ethyl acetate. The organic layer was washed with water for 3 times, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound (10 g).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].CC#N.[F:13][C:14]([F:32])([F:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH:22][C:23]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].[OH-].[Na+]>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:28]2[CH2:29][CH2:30][CH:25]([C:23]([NH:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]([F:13])([F:31])[F:32])=[O:24])[CH2:26][CH2:27]2)[N:7]=1
Reactant: O=C(NCc1ccccc1C(F)(F)F)C1CCNCC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(NCc1ccccc1C(F)(F)F)C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of cyanuric chloride (1.00 g, 5.42 mmol, 1.00 equiv) in 1:1 CH3CN:H2O (9.0 mL) at 0° C. was added N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidinecarboxamide (1.55 g, 5.42 mmol, 1.00 equiv). This mixture was treated with 1 N NaOH to maintain a pH of 9-10, and the resulting suspension was stirred for 10 min at 0° C. This material was used in the next step without workup or purification. MS (ES+): m/e 433.8 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][S:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:16]([O-])=O.[Na+]>C(O)(=O)C.Cl.O>[C:10]1([C:3]2[C:2]3[N:1]=[N:16][NH:9][C:7](=[O:8])[C:6]=3[S:5][N:4]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(=O)c1snc(-c2ccccc2)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]nnc2c(-c3ccccc3)nsc12
Reaction time: 8 h
Yield: 71.3 %

Procedure:
219 mg of 4-amino-3-phenyl-5-isothiazolecarboxamide in 7.2 ml of glacial acetic acid and 4 ml of concentrated hydrochloric acid were stirred at 0° C. during the addition of a solution of 80 mg of sodium nitrite in 1.2 ml of water. The mixture was held at below room temperature overnight and the precipitated product was filtered off and recrystallized from methanol to give 164 mg of 7-phenylisothiazolo[4,5-d]-1,2,3-triazin-4(3H)-one. A sample recrystallized from aqueous methanol melted at 179°-180° C. (dec.).