Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][C:14]=3[N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.Cl.Cl.[NH:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[NH:16][C:15]3[CH2:17][O:18][CH:19]([CH3:21])[CH2:20][C:14]=3[N:13]=2)=[CH:7][C:3]=1[C:4]([N:35]1[CH2:40][CH2:39][CH:38]([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1)=[O:6]
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1cc(C)c(-c2nc3c([nH]2)COC(C)C3)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2nc3c([nH]2)COC(C)C3)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 2 h
Yield: 10.4 %

Procedure:
Into around-bottom flask, was placed a solution of 2,4-dimethyl-5-[6-methyl-3H,4H,6H,7H-pyrano[3,4-d]imidazol-2-yl]benzoic acid (50 mg, 0.17 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). EDC.HCl (67 mg, 0.35 mmol, 2.00 equiv), 4-dimethylaminopyridine (64 mg, 0.52 mmol, 3.00 equiv), and 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 39 mg, 0.18 mmol, 1.00 equiv) were added and the solution was stiffed for 2 h at room temperature. The reaction was quenched with water (20 mL) and the aqueous was extracted with ethyl acetate (2×20 mL). The combined organics was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:1) as the eluent. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, Xbridge Prep Phenyl, 5 um, 19*150 mm; mobile phase, water with 0.03% NH3H2O and CH3CN (30% CH3CN up to 60% in 9 min, up to 100% in 1 min, down to 30% in 1 min); Detector, Waters 2489 254 nm & 220 nm. The fractions containing pure product were combined and lyophilized to obtain the title compound as a white solid (8.0 mg, 10%). m/z (ES+) 455 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:20]([CH2:21][CH3:22])[CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH:12]2[C:23](OCC)=[O:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:20]([CH2:21][CH3:22])[CH2:19][C:14]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:13][CH:12]2[CH2:23][OH:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC2(CC(CC)N1S(=O)(=O)c1ccc(Cl)cc1)OCCO2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1CC2(CC(CO)N1S(=O)(=O)c1ccc(Cl)cc1)OCCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.6 %

Procedure:
Ethyl 8-(4-chlorophenylsulfonyl)-9-ethyl-1,4-dioxa-8-azaspiro[4.5]decane-7-carboxylate (110; 2.47 g, 5.92 mmol) and lithium borohydride (4.7 ml, 2.0 M in THF, 9.48 mmol) were added to THF (15 ml). The mixture was stirred for 18 hours under nitrogen at rt which led to only a 25% conversion to the desired alcohol. Solid lithium borohydride was added in equivalent portions and the reaction monitored until the starting ester was consumed. The reaction mixture was concentrated under reduced pressure, and equal portions of EtOAc and Rochelle's salt were added. The aqueous layer was washed with several more portions of EtOAc, dried with Na2SO4, and concentrated to give 2.44 g of crude oil. The material was purified by column chromatography using EtOAc/hexanes gradients to yield 1.26 g (57%) of a mixture of cis/trans isomers.
Reaction SMILES: [CH3:1][Li].CON(C)[C:6]([CH:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]1)=[O:7]>C1COCC1>[F:14][C:11]1([F:15])[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[CH3:1])[CH2:9][CH2:10]1
Reactant: [Li]C
Reactant: CON(C)C(=O)C1CCC(F)(F)CC1
Solvent: C1CCOC1
Product: CC(=O)C1CCC(F)(F)CC1
Temperature: 25 °C

Procedure:
2 ml methyl lithium (1 M in diethylether) were added into a solution of 0.593 g 4,4-difluoro-cyclohexanecarboxylic acid methoxy-methyl-amide in anhydrous 5 ml THF at 0° C. The reaction was allowed to warm to rt overnight. The reaction was quenched with sat. ammonium chloride solution (˜50 ml) and diluted with sat. sodium hydrogencarbonate solution (25 ml). The aqueous layer was extracted with diethylether (3×50 ml) and the combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 5:1→1:1 petroleum/ether (40-60).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[C:28]12([CH2:38][O:39][C:40]3[C:48]([CH:49]4[CH2:52][CH2:51][CH2:50]4)=[CH:47][C:43]([C:44](O)=[O:45])=[C:42]([F:53])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.CS(N)(=O)=O.[CH:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1>>[C:28]12([CH2:38][O:39][C:40]3[C:48]([CH:49]4[CH2:50][CH2:51][CH2:52]4)=[CH:47][C:43]([C:44]([NH:65][S:62]([CH:59]4[CH2:61][CH2:60]4)(=[O:64])=[O:63])=[O:45])=[C:42]([F:53])[CH:41]=3)[CH2:35][CH:34]3[CH2:36][CH:30]([CH2:31][CH:32]([CH2:33]3)[CH2:37]1)[CH2:29]2
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CCC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CCC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a colorless solid (0.090 g, 35%): 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J=16.3 Hz, 1H), 7.87 (d, J=9.3 Hz, 1H), 6.53 (d, J=14.71H), 3.69-3.56 (m, 1H), 3.49 (s, 2H), 3.15-3.06 (m, 1H), 2.39-2.29 (m, 2H), 2.18-1.98 (m, 6H), 1.87-1.65 (m, 13H), 1.48-1.42 (m, 2H), 1.17-1.10 (m, 2H); MS (ES−) m/z 460.2 (M−1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)CCC>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:29][C:30]=1[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4ccccn4)s3)n2)CC(C)(C)N1
Yield: 13 %

Procedure:
The title compound was prepared as described for Example 25, using [4-(5-bromo-thiophen-2-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Step C of Example 5) and 3-tributylstannylpyridine. Yield: 13%.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:18]3[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=O)=[CH:11][CH:10]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[S:20][C:19]3[CH:30]=[CH:31][CH:32]=[CH:33][C:18]=3[C:17]=2[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=2)=[CH2:1])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(c1ccc(OC)cc1)c1c(-c2ccc(OC)cc2)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 170.6 %

Procedure:
A solution of 1.20 g (3.36 mmol) of methyltriphenylphosphonium bromide in 50 mL of THF was treated with 0.45 g (4.01 mmol) of potassium tert-butoxide and the mixture stirred at room temperature for 0.5 h. To this was added dropwise 0.80 g (2.14 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-methoxyphenyl ketone (Example 3, Part B) in 10 mL of THF and the reaction was stirred at room temperature for 18 h and then heated at gentle reflux for 48 h. The reaction was quenched by 100 mL of brine. The two layers were separated and the organic layer was dried over Na2SO4. Concentration in vacuo gave 1.36 g of an oil which was purified by radial chromatography (SiO2; 10% EtOAc in hexanes) to afford 0.610 g (1.64 mmol; 77%) of the desired product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH2:15]O)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>>[Cl:19][CH2:15][C:14]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2ncccc2CO)cc1
Product: COc1ccc(-c2ncccc2CCl)cc1
Reaction time: 2 h
Yield: 55 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of [2-(4-methoxyphenyl)pyridin-3-yl]methanol (1 g, 4.65 mmol, 1.00 equiv) in thionyl chloride (20 mL). The resulting solution was stirred for 2 h at reflux. The resulting mixture was concentrated under vacuum to yield 600 mg (55%) of 3-(chloromethyl)-2-(4-methoxyphenyl)pyridine as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11](=[O:14])[CH:10]=[CH:9]2)[CH:2]=C.[O:15]1CCOCC1>O.O=[Os](=O)(=O)=O>[O:14]=[C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:4]([CH2:1][CH:2]=[O:15])[CH:5]=[CH:6][CH:7]=2)[O:12]1
Reactant: C=CCc1cccc2ccc(=O)oc12
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=CCc1cccc2ccc(=O)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
To a solution of 8-(2-propen-1-yl)-2H-chromen-2-one (390 mg, 2.0 mmol) in dioxane (10 mL) and water (5 mL) was added OsO4 (4% solution in H2O, 0.5 mL, 10 mol %) and NaIO4 (430 mg, 4.0 mmol). The reaction was stirred at RT for 2 h and NaIO4 (430 mg, 4.0 mmol) was added and the reaction was allowed to stir another 2 h. The reaction was diluted with 20 mL of H2O and was extracted with ethyl acetate (3×50 mL). The combined extracts were dried (Na2SO4), and concentrated to give the title compound (350 mg, 93%) as a dark oil which was used without further purification: MS (ES) m/e 188.9 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]1([CH2:33][CH:34]([OH:38])[CH2:35][CH:36]=[CH2:37])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.I[C:40]1[CH:49]=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(=O)OCC>[OH:38][CH:34]([CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:35]/[CH:36]=[CH:37]/[C:40]1[CH:49]=[CH:48][CH:47]=[CH:46][C:41]=1[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)c1ccccc1I
Reactant: C=CCC(O)Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1/C=C/CC(O)Cc1ccccc1
Yield: 56 %

Procedure:
A mixture of triethylamine (7.6 mL, 54.7 mmol), triphenylphosphine (0.778 g, 2.97 mmol) and palladium acetate (0.35 g, 1.56 mmol) in 1,4-dioxane (50 mL) was refluxed to form a homogeneous dark-red solution. The reaction temperature was then reduced to just below reflux. Compound 30b (4.56 g, 28 mmol), methyl 2-iodobenzoate (4.10 g, 15.6 mmol) and triethylamine (2.88 mL, 10.2 mmol) were added subsequently with stirring. The reaction mixture was then refluxed for about 30 min until TLC showed the SM had disappeared. The reaction mixture was filtered hot through celite, which was washed with 1,4-dioxane. The combined filtrate and washings were evaporated in vacuo to a small volume and purified by CC using PE:EA=5:1 as mobile phase to give the desired product (2.59 g, 56% yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[CH:36]=[CH:35][CH:34]=[C:33](B3OC(C)(C)C(C)(C)O3)[C:27]=1[CH2:28][O:29]C(=O)C)[N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20]([C:26]1[C:27]([CH2:28][OH:29])=[C:33]([C:2]3[N:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=3)[CH:34]=[CH:35][CH:36]=1)[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cn1cc(Br)nc1C(N)=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)ccc2c1=O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)ccc4c3=O)c2CO)nc1C(N)=O
Yield: 33 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid amide (intermediate-1) and acetic acid 2-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 4). The desired compound was prepared in two steps (33% yield). 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J=8.5 Hz, 1H), 8.36 (s, 1H), 7.95-7.91 (m, 2H), 7.77 (d, J=1.6 Hz, 1H), 7.70 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.36 (dd, J=7.9, 1.3 Hz, 1H), 4.42 (br s, 2H), 4.14 (s, 3H), 1.46 (s, 9H). LC-MS calcd for C24H25N5O3 (m/e) 431.20, obsd 432 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:9]1([C:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[OH:8][CH2:7][C:2]1([NH:1][C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NC1(CO)CCCC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: OCC1(NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCCC1

Procedure:
A mixture of 1-amino-1-cyclopentanemethanol (3.00 g; 26.05 mmol) and triphenylmethylchloride (7.26 g; 26.05 mmol) in 70 ml CH2Cl2 is heated overnight. The reaction mixture is cooled and flash chromatographed twice using 5:1; hexane:EtOAc to obtain 1-hydroxymethyl-1-triphenylmethylaminocyclopentane as a thick yellow oil which is used directly in the next step.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[S:33])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:33])[CH:28]=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(C(F)(F)F)c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 3-(trifluoromethyl)phenyl isothiocyanate (12.5 μL, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 11 in Table 1, below (31 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.72 (s, 1H), 7.41-7.35 (m, 1H), 7.29-7.21 (m, 2H), 7.21-7.16 (m, 1H), 4.37 (q, J=7.10 Hz, 2H), 4.27-3.93 (m, 8H), 1.50 (t, J=7.04 Hz, 3H) ppm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2].Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1>N1C=CC=CC=1>[C:19]([O:17][C:6]1[CH:7]=[CH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][CH:21]=1
Reactant: CC(C)(C)c1cc(C2CCCCC2)ccc1O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C2CCCCC2)ccc1OC(=O)c1cccnc1
Temperature: 35 °C
Reaction time: 48 h

Procedure:
12 g (52 mmol) of 2-t-butyl-4-cyclohexylphenol and 10 g (56 mmol) of nicotinic acid chloride hydrochloride was mixed with 150 ml of dry pyridine and stirred for 48 hours at 35° C. After cooling precipitated pyridine hydrochloride was sucked off and the filtrate mixed with 75 ml of water. The precipitated raw product was freed from pyridine by washing with water and recrystallized from alcohol.
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][O:9][C:10](=[O:35])/[CH:11]=[CH:12]/[C:13]1[CH:14]=[C:15]2[C:31](=[CH:32][CH:33]=1)[O:30][C:18]1([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)[CH2:17][C:16]2=[O:34]>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:35])/[CH:11]=[CH:12]/[C:13]1[CH:14]=[C:15]2[C:31](=[CH:32][CH:33]=1)[O:30][C:18]1([CH2:22][CH2:21][NH:20][CH2:19]1)[CH2:17][C:16]2=[O:34]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)C1)O2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 M HCl in dioxane (10 ml, 80 mmol) was added to a solution of (±)-(E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (4.30 g, 11.2 mmol) in DCM (15 ml) and the mixture was stirred at RT for 1 h. The precipitate was filtered off, washed with DCM, dried under vacuum and collected (3.3 g) as a white solid (hydrochloride salt). Y=92%
Reaction SMILES: C1([C:7]2[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[CH:10][C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[CH:12][CH:7]=2)=[CH:14][CH:15]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: c1ccc(-c2ccccc2-c2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)c1ccc(-c2ccc(-c3ccccc3)cc2)cc1
Temperature: -5 °C
Yield: 119 %

Procedure:
After a mixture of 172 g of terphenyl, 860 ml of benzene, and 353 g of acetyl chloride was cooled to -5° C., it was added with a total of 200 g of anhydrous aluminium chloride in few instalments, and subjected to reaction at -5° C. for 1 hour and further at 10° C. for 1 hour. The solid materials thus formed were separated by filtration, washed with a total of 4 liter of methanol in few instalments, and then recrystallized from chloroform to obtain 121 g of 4-acetyl-p-terphenyl, 2. The yield was 59%.
Reaction SMILES: [I:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.P([O-])([O-])(O)=O.[Na+].[Na+].CC(N(C)C)=O>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[C:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)[N:7]=1
Reactant: Nc1ccc(I)nn1
Reactant: CC(C)(C)OC(=O)NC(=O)CCl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1cn2nc(I)ccc2n1
Temperature: 120 °C
Yield: 39.3 %

Procedure:
A mixture containing compound 7A (2.5 g, 11.3 mmol), tert-butyl 2-chloroacetylcarbamate (2.4 g, 12.4 mmol), sodium hydrogen phosphate (3.2 g, 22.6 mmol) and DMA (23 mL) was heated at 120° C. for two hours. The mixture was cooled to room temperature, poured into a flask containing 400 mL of water and sonicated. The solids were filtered, rinsed with water then dried under vacuum. The solids were then taken up in 600 mL ethyl acetate and filtered over short plug of silica gel. The filtrate was concentrated down to give compound 7B (1.6 g, 39%), as a dark green solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.21 (br. s., 1 H), 8.06-8.00 (m, 1 H), 7.69 (d, J=9.9 Hz, 1 H), 7.46 (d, J=9.3 Hz, 1 H), 1.48 (s, 9 H) ESI-MS:m/z 361.1 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N:10][CH:9]=[CH:8]2)=[N+]=[N-].CN(C)C=O>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([NH:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[N:10][CH:9]=[CH:8]2
Reactant: [N-]=[N+]=NCc1ccc2c(NC(=O)c3ccccc3)nccc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: NCc1ccc2c(NC(=O)c3ccccc3)nccc2c1

Procedure:
A solution of 6.4 g of N-[6-(azidomethyl)-1-isoquinolinyl]benzamide in 300 mL of ethanol and 60 mL of N,N-dimethylformamide containing 3.8 g of 5% palladium/calcium carbonate was hydrogenated for 20 hours. Filtration and concentration i. vac. yielded the title compound as an oil. MS (m/e)=277.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[C:20]([C:25]([O:27][CH3:28])=[O:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)OC)c3)cs2)cc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc(-c3ccc(OCC(=O)OC)c(C(=O)OC)c3)cs2)cc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
In 10 ml of dimethylformamide were suspended 1 g of 2-(3,4-diethoxyphenyl)-4-(4-hydroxy-3-methoxycarbonylphenyl)thiazole and 0.35 g of potassium carbonate. The suspension was stirred at room temperature for 30 minutes. Thereto was added 0.46 g of methyl bromoacetate. The mixture was stirred at the same temperature for 4 hours. The solvent was removed by distillation. The residue was extracted with 40 ml of dichloromethane. The extract was washed with 10 ml of water and 10 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and subjected to distillation to remove the solvent. The residue was recrystallized from diisopropyl ether to obtain 1.1 g of 2-(3,4-diethoxyphenyl)-4-(4-methoxycarbonylmethoxy-3-methoxycarbonylphenyl)thiazole.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:27])[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=1.S(=O)(=O)(O)O.[OH-].[Na+].O>C(O)C.[Pd]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[CH3:27]
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: [Pd]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(c2ccc(N)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 1 h

Procedure:
[1-Oxo-2-methyl-2-(4-nitrophenyl)-6,7-dichloro-5-indanyloxy]acetic acid (6.11 g., 0.015 mole) in absolute ethanol (250 ml.)-36 N sulfuric acid (2 ml.) is catalytically hydrogenated over 5% palladium on carbon (500 mg.) in a Parr apparatus. After one hour, the reaction mixture is filtered, then concentrated in vacuo to a 50 ml. volume. Water (200 ml.) is added to precipitate the ethyl ester which is hydrolyzed by refluxing in ethanol (200 ml.), 10 N sodium hydroxide solution (4.5 ml., 0.045 mole) and water (100 ml.) for 1.5 hours. The reaction mixture is cooled, concentrated to 1/3 its volume, filtered, then neutralized with 6 N hydrochloric acid to precipitate 1.09 g. of [1-oxo-2-(4-aminophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which melts at 235°-236° C. dec.