Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][C:9]2([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][CH:24]=2)[CH3:22])[CH:5]=[CH:6][CH:7]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][Cl:38].[OH-].[Na+].O>CC(C)=O>[Cl:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][C:9]2([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:27][CH:28]=2)[CH3:22])[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCBr
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2cccc(OCCCCCl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
(3RS,4RS)-4-(3-Hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (260 mg, 0.59 mmol), 1-bromo-4-chlorobutane (0.8 ml, 2.98 mmol) and aqueous 2N-NaOH solution (0.8 ml) were dissolved in acetone (10 ml) and then stirred for 4 hours at 50° C. The reaction mixture was cooled to room temperature and then water was added thereto. The reaction solution was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to remove the organic solvent. The concentrate was separated by column chromatography (n-hexane:ethyl acetate=4:1) to obtain 300 mg (yield: 96%) of the title compound as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]([C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH2:24])[C:22]=2[N:23]=1)[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10])(=[O:5])[CH3:4].Cl>C1COCC1.CO.C(Cl)Cl>[OH:5][CH:3]([C:6]1[N:7]([C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH2:24])[C:22]=2[N:23]=1)[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10])[CH3:4]
Reactant: CC(=O)c1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(O)c1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
NaBH4 (0.19 g, 5.05 mmol) was added to a solution of 8-acetyladenosine (17l) (0.78 g, 2.52 mmol) in THF (35 ml) and MeOH (4 ml) under argon and the mixture stirred at room temperature for 18 h. The mixture was treated dropwise with 1 M HCl until neutral pH and the mixture applied on top of a flash chromatography column which was developed by 30% MeOH in CH2Cl2; yield 0.46 g (59%). The product was a mixture of the two alcohol epimers, ratio 1:1.
Reaction SMILES: [C:1]1(=[S:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11]>CC(C)=O>[Br-:8].[OH:11][C:10]1[N+:6]2[CH2:5][CH2:4][CH2:3][CH2:2][C:1]=2[S:7][C:9]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: S=C1CCCCN1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CC(C)=O
Product: Oc1c(-c2ccccc2)sc2[n+]1CCCC2
Product: [Br-]

Procedure:
An acetone solution of 3.51 g. (0.03 mole) δ-thiovalerolactam and 6.75 g. (0.03 mole) α-bromophenylacetic acid was heated until the solid started to form. After the solution was cooled, the solid was collected which weighed 6.5 g. Recrystallization could be done with acetonitrile. The purified material had a melting point of 188°-192° (dec.).
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:5][CH:4]=1)#[CH:2].[BH4-].[Na+].O>CO>[C:1]([C:3]1[N:7]([CH3:8])[C:6]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[N:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1cnc(C(=O)c2ccccc2)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C#Cc1cnc(C(O)c2ccccc2)n1C
Reaction time: 2 h
Yield: 37.2 %

Procedure:
A solution of 200 mg (0.951 mmol) of (5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone in 1 mL of MeOH was added dropwise to a 0° C. solution of 54 mg (1.43 mmol) of NaBH4 in 5 mL of MeOH. After stirring for 2 h, 10 mL of water was added and the mixture was extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, concentrated, and chromatographed (0–80% EtOAc in hexanes) to give (5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanol as a white solid (75 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:23]1[C:27]([NH2:28])=[CH:26][NH:25][N:24]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]=[C:15]1[C:23]1[C:27]([NH:28][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])=[CH:26][NH:25][N:24]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: O=C(O)c1cccc2cccnc12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Nc1c[nH]nc1-c1nc2ccccc2[nH]1)c1cccc2cccnc12
Yield: 6.2 %

Procedure:
A mixture of quinoline-8-carboxylic acid (104 mg, 0.60 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.50 mmol), EDC (116 mg, 0.60 mmol) and HOBt (81 mg, 0.60 mmol) was stirred at room temperature in DMF (1.5 ml) for 20 h. The reaction mixture was purified by preparative LC/MS to give quinoline-8-carboxylic acid [3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide (11 mg, 6%) as a brown solid. (LC/MS: Rt 3.85, [M+H]+ 355.11).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1/[CH:13]=[CH:14]/[C:15](=[O:17])[CH3:16].O.[C:19]([OH:23])(=[O:22])[CH:20]=O>C(O)(=O)C.O>[O:17]=[C:15](/[CH:14]=[CH:13]/[C:4]1[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])/[CH:16]=[CH:20]/[C:19]([OH:23])=[O:22]
Reactant: O=CC(=O)O
Reactant: COc1ccc(/C=C/C(C)=O)c(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)c(OC)c1OC

Procedure:
A solution of 18 g (76 mmol) of (E)-4-(2,3,4-trimethoxyphenyl)but-3-en-2-one and 7 g (76 mmol) of glyoxylic acid monohydrate in 19 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from ether/methylene chloride yielded (E,E)-4-oxo-6-(2,3,4-trimethoxyphenyl)-2,5-hexadienoic acid of melting point 125°-127°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.Cl[CH2:45][C:46]1[O:47][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[CH:52]=2)=[CH:49][CH:50]=1.BrCC1OC(C(F)(F)F)=CC=1>>[Cl:57][C:53]1[CH:52]=[C:51]([C:48]2[O:47][C:46]([CH2:45][N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]4([C:13]5=[CH:14][C:15]6[O:19][CH2:18][O:17][C:16]=6[CH:20]=[C:12]5[O:11][CH2:10]4)[C:2]3=[O:21])=[CH:50][CH:49]=2)[CH:56]=[CH:55][CH:54]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: ClCc1ccc(-c2cccc(Cl)c2)o1
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ccc(-c3cccc(Cl)c3)o2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-(chloromethyl)-5-[3-chlorophenyl]furan to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (22%) as a colorless solid: mp 205-207° C.; 1H NMR (300 MHz, CDCl3) δ 7.55 (t, 1H), 7.46 (dt, 1H), 7.28 (d, 2H), 7.21-7.14 (m, 2H), 7.09-7.04 (m, 2H), 6.59 (d, 1H), 6.50 (s, 1H), 6.40 (d, 1H), 6.10 (s, 1H), 5.84 (dd, 2H), 4.98 (ABq, 2H), 4.80 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.2, 155.9, 152.5, 149.2, 148.9, 142.4, 141.7, 134.8, 132.1, 132.0, 130.1, 128.9, 127.5, 124.0, 123.7, 123.6, 121.7, 119.4, 110.8, 109.2, 106.9, 103.0, 101.5, 93.6, 80.4, 58.2, 37.3; MS (ES+) m/z 472.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](SC)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.O[O:17][S:18]([O-:20])=O.[K+].[C:22]([O-])(O)=O.[Na+]>CO>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:18]([CH3:22])(=[O:20])=[O:17])[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CSc1nccc(-c2sc(C)nc2C)n1
Reactant: O=S([O-])OO
Reactant: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C)c(-c2ccnc(S(C)(=O)=O)n2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 4-(2,4-dimethyl-thiazol-5-yl)-2-methylsulfanyl-pyrimidine (342 mg, 1.44 mmol) in MeOH (12 ml) was cooled at 0° C., then an aqueous solution of oxone (2.65 g, 4.32 mmol in 12 ml of water) was slowly added. After stirring 2 hours at room temperature, the mixture was basified with 5% NaHCO3 and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 288 mg of the title compound that was used in the next step without further purification (75% yield).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[CH:16]12[CH:21]([N:22]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]1[CH2:19][NH:18][CH2:17]2.N12CCCN=C1CCCCC2>O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:18]3[CH2:19][CH:20]4[CH:16]([CH:21]4[NH2:22])[CH2:17]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:18]3[CH2:17][CH:16]4[CH:20]([CH:21]4[N:22]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:19]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: c1ccc(CN(Cc2ccccc2)C2C3CNCC32)cc1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: NC1C2CN(c3ccc(C(=O)NCCC4CC4)nn3)CC12
Product: O=C(NCCC1CC1)c1ccc(N2CC3C(C2)C3N(Cc2ccccc2)Cc2ccccc2)nn1

Procedure:
To a stirred solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.225 g, 1.00 mmol) in 1,4-dioxane (10 mL) was added (3-aza-bicyclo[3.1.0]hex-6-yl)dibenzyl-amine (0.440 g, 1.200 mmol), 1,8-diazabicyclo-[5.4.0]undec-7-ene (0.5 mL, 3.00 mmol) and tetrabutyl ammonium bromide (0.032 g, 0.10 mmol). The resulting mixture was stirred at reflux for 18 hours. 1,4-Dioxane was removed in vacuo and the obtained crude product was purified by column chromatography to yield the desired product, 6-(6-dibenzylamino-3-azabicyclo[3.1.0]hex-3-yl)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide in 89% yield (0.415 g). 1H NMR (300 MHz, CDCl3) δ 8.00-7.96 (m, 1H), 7.94 (d, J=9.6 Hz, 1H), 7.33-7.21 (m, 10H), 6.56 (d, J=8.5 Hz, 1H), 3.65 (s, 5H), 3.55-3.48 (dd, J=7.0 and 6.3 Hz, 3H), 3.44 (s, 2H), 1.57-1.48 (m, 5H), 0.76-0.67 (m, 1H), 0.46-0.40 (m, 2H), 0.09-0.04 (m, 2H). MS (ES+) m/z 468 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([CH3:19])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11]C)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+].O>O1CCCC1>[CH:1]1([CH2:7][C:8]([CH3:19])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C(C)(CC1CCCCC1)c1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CC1CCCCC1)(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of Example 41A (4.02 g, 15.4 mmol) and potassium trimethyl silanolate (11.0 g, 77.2 mmol) in tetrahydrofuran (80 mL) was heated to reflux for 18 hours. The mixture was cooled to 25° C., treated with water (10 mL), and concentrated in vacuo to remove the tetrahydrofuran. The residue was dissolved in water and washed with hexane. The aqueous layer was acidified to pH 1 with 1N hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound (3.80 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 1.10 m, 6 H) 1.57 m, 8 H) 1.82 m, 1 H) 2.04 m, 1 H) 7.32 m, 5 H).
Reaction SMILES: [CH3:1][O-].[Na+].[Br:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9]P(=O)(OCC)OCC)=[CH:7][CH:6]=1.[CH3:20][N:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1C=O)[CH3:22].O>CN(C=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:1]/[C:28]2[CH:27]=[CH:24][C:23]([N:21]([CH3:20])[CH3:22])=[CH:30][CH:29]=2)=[CH:18][CH:19]=1
Reactant: CN(C)c1ccccc1C=O
Reactant: C[O-]
Reactant: CCOP(=O)(Cc1ccc(Br)cc1)OCC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(/C=C/c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DMF (anhydrous) (10.5 mL) was added to sodium methoxide (176 mg, 3.26 mmol) and the color was changed to pink. To the above solution diethyl 4-bromobenzylphosphonate (1.0 g, 3.26 mmol) in DMF (6.5 ml) was added dropwise over 2 minutes, followed by 4 (dimethylamino)benzaldehyde (486 mg, 3.26 mmol). The reaction mixture was stirred at room temperature for 24 hours. Deionized water (17 mL) was added. The product was filtered out through vacuum filtration and recrystallized with DCM/hexane to give compound 17. 17: 74%. Yield; tan solid; 1H NMR (400 MHz, CDCl3) δ 7.47-7.32 (m, 6H), 7.04 (d, 1H, J=12.5 Hz), 6.83 (d, 1H, J=16.3 Hz), 6.71 (d, 2H, J=8.9 Hz), 2.99 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 150.5, 137.4, 136.1, 132.1, 131.8, 129.7, 128.3, 128.2, 127.9, 127.7, 125.5, 123.2, 120.3, 112.6, 40.7; HRMS Calc for C16H16BrN 302.0541 found 302.0539.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:20])=O>C(OCC)(=O)C.CN(C=O)C>[Cl:20][C:9]([CH:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCCC1)C(=O)Cl
Temperature: 0 °C

Procedure:
A solution comprised of 3-cyclohexyl-2-ethoxycarbonylpropionic acid (8.52 g, 37 mmol) in ethyl acetate (80 mL) was cooled to 0° C. was treated sequentially with 2 drops of DMF and oxalyl chloride (3.93 mL) added dropwise over five minutes. The mixture was allowed to warm slowly and after approximately 2 hours concentrated to provide ethyl 2-chlorocarbonyl-3-cyclohexylpropionate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([O-])=O.[Na+].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>Cl.O.[OH-].[Na+]>[C:2]1([N:1]=[N:8][C:15]2[CH:14]=[C:13]([CH3:12])[CH:18]=[CH:17][C:16]=2[SH:19])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: Nc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S)c(N=Nc2ccccc2)c1
Reaction time: 8 h
Yield: 61.4 %

Procedure:
5 g (53.7 mmoles) of aniline is dissolved in conc. HCl (13 ml)/water (90 ml) and diazotized with 3.89 g (56.4 mmoles) of sodium nitrite (dissolved in water (8 ml)), at 0-5° C. The resulting solution is slowly added to a solution of 7.52 g (53.7 mmoles) of 4-methylthiophenol in 2N NaOH (54 ml). After stirring overnight the mixture is neutralised with 2N HCl, the precipitate is filtered off, dried, and dissolved in toluene (800 ml). The solution is dried over anhydrous sodium sulfate, filtered through silica gel, and evaporated. Recrystallisation from methanol gives 7.53 g (57%) of dark brown crystals, m.p. 70-80° C.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH:11]1([CH2:14][CH:15]([C:17]2[CH:18]=C(O)[CH:20]=[C:21]([CH:23]=2)[OH:22])[CH3:16])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH:15]([C:17]2[CH:23]=[C:21]([OH:22])[C:20]3[C:2]4[CH2:6][CH2:5][S:4][C:3]=4[C:7](=[O:8])[O:9][C:10]=3[CH:18]=2)[CH3:16])[CH2:12][CH2:13]1
Reactant: CC(CC1CC1)c1cc(O)cc(O)c1
Reactant: COC(=O)C1SCCC1=O
Product: CC(CC1CC1)c1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-(3-cyclopropyl-2-propyl)resorcinol to give 7-(3-cyclopropyl-2-propyl)-1,2-dihydro-9-hydroxy-4-oxo-4H-thieno[2,3-c][1]benzopyran.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:13](=[O:18])[NH:14][NH:15][C:16]=2[CH3:17])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:19][C:20]([O:22][CH2:23][C@H:24]1[O:29][C@H:28](Br)[C@H:27]([O:31][C:32]([CH3:34])=[O:33])[C@@H:26]([O:35][C:36]([CH3:38])=[O:37])[C@@H:25]1[O:39][C:40]([CH3:42])=[O:41])=[O:21]>O1CCCC1.C(=O)([O-])[O-].[Ag+2]>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]2[C:13]([O:18][C@@H:28]3[O:29][C@H:24]([CH2:23][O:22][C:20](=[O:21])[CH3:19])[C@@H:25]([O:39][C:40](=[O:41])[CH3:42])[C@H:26]([O:35][C:36](=[O:37])[CH3:38])[C@H:27]3[O:31][C:32](=[O:33])[CH3:34])=[N:14][NH:15][C:16]=2[CH3:17])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1[nH][nH]c(=O)c1Cc1ccc(OC(C)C)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C)c2Cc2ccc(OC(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 39 %

Procedure:
To a suspension of 1,2-dihydro-4-[(4-isopropoxyphenyl)methyl]-5-methyl-3H-pyrazol-3-one (46 mg), acetobromo-α-D-glucose (99 mg) and 4A molecular sieves in tetrahydrofuran (3 mL) was added silver carbonate (66 mg), and the mixture was stirred under shading the light at 65° C. overnight. The reaction mixture was purified by column chromatography on aminopropyl silica gel (eluent: tetrahydrofuran). Further purification by preparative thin layer chromatography on silica gel (developing solvent: ethyl acetate/hexane=2/1) afforded 4-[(4-isopropoxy-phenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (42 mg).
Reaction SMILES: [CH:1]1([O:7][C:8]2[N:13]=[C:12](S(C)(=O)=O)[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:10]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:33]([Li])CCC.[CH:38]([OH:41])([CH3:40])[CH3:39]>>[CH:2]1([CH2:1][O:7][C:8]2[N:13]=[C:12]([O:41][CH:38]([CH3:40])[CH3:39])[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:10]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[N:9]=2)[CH2:33][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1nc(OC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)O
Reactant: [Li]CCCC
Product: CC(C)Oc1nc(OCC2CCCCC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2-Cyclohexyloxy-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (HRf product, Example 51, Step A),(24 mg, 0.1 mmol) was reacted with 1 equivalent each of n-butyl lithium and isopropanol by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 95/5 hexanes/ethyl acetate) afforded 2-cyclohexylmethyloxy-4-isopropoxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine. HPLC/Rt=5.47 min. 1H-NMR 500 MHz (CDCl3): δ 0.8 (m, 1H), 1.1 (m, 2H), 1.20-1.35 (m, 3H), 1.37 (d, J=6 Hz, 6H), 1.7-1.8 (m, 3H), 1.90 (m, 2H). 4.20 (d, J=6 Hz, 1H), 5.50 (qn, J=6 Hz, 1H), 7.03 (d, J=7 Hz, 1H), 7.10 (d, J=8 Hz, 1H), 7.18 (m, 4H), 7.32 (d, J=2 Hz, 1H).
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](Cl)=[O:20])[CH:13]=2)[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][NH:3]1.[ClH:22].[CH2:23]([O:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH2:28])[CH3:24].N1C=CC=CC=1>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:2]2[C:7]([Cl:22])=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)=[CH:13][C:14]=1[C:19]([NH:28][C@@H:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:25][CH2:23][CH3:24])=[O:32])=[O:20]
Reactant: O=C(Cl)c1cc(C2(Cl)C=CC(C(F)(F)F)=CN2)ccc1Cl
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](NC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl)C(C)C
Reaction time: 60 h

Procedure:
A solution of 3.55 g of 2-chloro-2-(4-chloro-3-chloroformylphenyl)-5-trifluoromethylpyridine in 10 ml of methylene chloride was added dropwise to a mixture of 3.63 g of L-valine ethyl ester hydrochloride, 7.9 g of pyridine and 30 ml of methylene chloride at 23° C. After stirring for 60 hours, 160 ml of methylene chloride were added. The mixture was washed three times with 150 ml of water each time, dried over sodium sulfate and then concentrated. The crude product was purified by chromatography on silica gel with cyclohexane/ethyl acetate (10:1). Yield: 2.2 g (48%) of colorless crystals; melting point: 90°-92° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:9][C:8]([N:10]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:18]=1.[CH2:20]=O.Cl.[H][H]>CO.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:9][C:8]([N:10]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:20])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:18]=1
Reactant: C=O
Reactant: Cc1cc(C)c2oc(N3CCCCNCC3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Cc1cc(C)c2oc(N3CCCCN(C)CC3)nc2c1

Procedure:
5,7-Dimethyl-2-(1,4-diazacyclooctanyl)benzoxazole (135 mg) was dissolved in methanol (3 ml), and the solution was mixed with 37% formaldehyde solution (1 ml) and 1 N hydrochloric acid (0.5 ml). This was further mixed with 10% palladium-carbon (10 mg) and stirred overnight in an atmosphere of hydrogen. After removing the catalyst by celite filtration, the filtrate was washed with ethyl acetate and then the solvent was evaporated. The thus obtained residue was extracted with 1 N hydrochloric acid and ethyl acetate, and the resulting water layer was adjusted to pH 8 with potassium carbonate and extracted with methylene chloride. The organic layer was dried with magnesium sulfate and the solvent was evaporated to obtain the title compound 5,7-dimethyl-2-(4-methyl-1,4-diazacyclooctanyl)benzoxazole (50 mg).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][O:8][C:4]=2[CH:3]=1.[N:17]1C=CC=C[CH:18]=1>Cl>[C:18]([C:2]1[CH:16]=[CH:15][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:7][O:8][C:4]=2[CH:3]=1)#[N:17]
Reactant: c1ccncc1
Reactant: Clc1ccc2c(-c3ccccc3)coc2c1
Agent: Cl
Product: N#Cc1ccc2c(-c3ccccc3)coc2c1
Temperature: 200 °C

Procedure:
A mixture of 76.2 g of 6-chloro-3-phenylbenzofuran, 34.1 g of cuprous cyanide and 28 ml of pyridine is heated for about 125 hours at a temperature of 200° C. The mixture is then poured into a solution of 100 g of ferric chloride in 60 ml of concentrated hydrochloric acid and 300 ml of ice water. The mixture is extracted twice with diethyl ether, the ether extracts are washed with saturated sodium chloride solution and dried. The solvent is evaporated to provide the desired product, 6-cyano-3-phenylbenzofuran.