Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH:53]([CH3:56])[CH2:54][NH2:55])=[CH:49][CH:48]=1>CN(C=O)C>[CH3:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([CH:53]([CH3:56])[CH2:54][NH:55][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:22])=[CH:49][CH:48]=1
Reactant: COc1ccc(C(C)CN)cc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccc(C(C)CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Reaction time: 18 h

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (11.3 mg, 0.034 mmol), HOBT (6.0 mg, 0.044 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (8.0 mg, 0.042 mmol) and 2-(4-methoxyphenyl)propylamine (0.34 mmol) were mixed in DMF (0.7 ml) and the reaction left at room temperature for 18 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (0.4 ml) and water (0.4 ml). The organic phase was washed with aqueous sodium hydroxide (0.5M, 0.2 ml) and the DCM evaporated under vacuum. The residue was purified by mass directed HPLC to give N-[2-(4-methoxyphenyl)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide. LCMS; retention time 3.40 min, MH+ 442.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:34])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH:15]([C:20]4[CH:24]=[CH:23][N:22](S(C5C=CC=CC=5)(=O)=O)[CH:21]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:35])[C:5]([C:36]([OH:38])=[O:37])=[CH:4]1)[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:34])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH:15]([C:20]4[CH:24]=[CH:23][NH:22][CH:21]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:35])[C:5]([C:36]([OH:38])=[O:37])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4ccn(S(=O)(=O)c5ccccc5)c4)C3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4cc[nH]c4)C3)cc21
Yield: 72.9 %

Procedure:
A mixture of 538 mg of 1-ethyl-6-fluoro-1,4-dihydro-7-[4-methyl-3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid, 5 ml of 1N sodium hydroxide and 15 ml of dioxane was reacted as described in Example 56, giving 290 mg of the desired product, mp 150°-152° C.
Reaction SMILES: CO[C:3](=O)[NH:4][C:5]1[CH:27]=[CH:26][C:8]2[N:9]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)=[N:11][C:7]=2[CH:6]=1.[AlH3].OS(O)(=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1>C1COCC1>[CH:23]1([CH2:22][N:9]2[C:8]3[CH:26]=[CH:27][C:5]([NH:4][CH3:3])=[CH:6][C:7]=3[N:11]=[C:10]2[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CCOc1ccc(Cc2nc3cc(NC(=O)OC)ccc3n2CC2CC2)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [AlH3]
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2nc3cc(NC)ccc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
Methyl-1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-1H-benzimidazol-5-ylcarbamate (1.65 g, 4.35 mmol) was added portionwise to a cold (0° C.) solution of AlH3 (˜0.3 M), which was freshly prepared by adding dropwise conc. H2SO4 (0.80 g, 8.10 mmol) to 1 M LiAlH4 THF solution (16 ml, 16 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, and subsequently quenched carefully by adding EtOAc (5 mL), H2O (3 mL) and Et2O (100 mL), and then Na2SO4.5H2O (10 g). The reaction mixture was stirred until a clear solution was produced, and the solid was filtered off. The filtrate was dried over Na2SO4 and concentrated in vacuo to afford desired compound (1.21 g). The crude product was used for next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
4-Bromophenol (1.00 g) was dissolved in N,N-dimethylformamide (20 ml) to prepare a solution. Imidazole (0.95 g) and tert-butylchlorodimethylsilane (1.05 g) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform to give (4-bromo-phenoxy)-tert-butyl-dimethyl-silane (1.586 g, yield 96%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C@@H:5]2[O:6][CH:7]([OH:9])[CH2:8][C@@H:4]2[C@H:3]1[CH2:11][CH2:12][C@@H:13]([O:22]C1CCCCO1)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C1COCC1.[OH-].[K+]>O>[OH:1][C@@H:2]1[CH2:10][C@@H:5]2[O:6][CH:7]([OH:9])[CH2:8][C@@H:4]2[C@H:3]1[CH2:11][CH2:12][C@@H:13]([OH:22])[CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OC1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](O)C[C@@H]2O1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: OC1C[C@@H]2[C@@H](CC[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Temperature: 45 °C
Reaction time: 4 h
Yield: 41.7 %

Procedure:
A mixture of compound [11a] (0.55 g), acetic acid (2 ml), THF (2 mL) and water (2 mL) was stirred at 40-50° C. for 4 hours (TLC monitoring). The mixture was basified with 1 N aq. potassium hydroxide to pH 10-11 and the product was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (elution with gradient ethyl acetate/hexane from 1:2 to 3:1 v/v) to give 0.18 g (43%) of the compound [11b] as a colorless oil. 1H NMR (CD3OD) is compatible with literature data.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][O:14][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CCC(c2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
The compound (III) (50 g, 0.268 mol) obtained in the first step was dissolved in dry pyridine (110 ml) and the solution was cooled to 5° C. or lower. To this solution was dropwise added a solution of p-toluenesulfonic acid chloride (50.1 g, 0.263 mol) dissolved in dry toluene (70 ml), in small portions through a dropping funnel so that the reaction temperature did not exceed 10° C. After completion of the dropwise addition, the cooling bath was removed and the reaction mixture was agitated at room temperature for 4 hours, followed by adding water (100 ml) and toluene (300 ml) and stirring. The mixture was transferred into a separating funnel and the toluene layer was washed twice with 6N-HCl aqueous solution (100 ml), then once with water (200 ml), further twice with 2N-NaOH aqueous solution (100 ml) and then four times with water (200 ml). Toluene was distilled off under reduced pressure and the resulting crystals were recrystallized from toluene (90 ml), followed by separating the crystals by filtration to obtain p-toluenesulfonic acid (trans-4-phenylcyclohexylmethyl) ester (IV) (77 g) having a melting point of 108.0°~108.7° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@@:5]1([CH3:29])[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1.COC[C@H]1[C@@H](/C=C/C(/C)=C/C(OCC)=O)[C@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@:5]1([CH3:29])[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1
Reactant: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CCOC(=O)/C=C(C)/C=C/[C@@H]1[C@H](COC)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC[C@H]1[C@@H](/C=C/C(C)=C/C(=O)O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 85 %

Procedure:
Following a procedure similar to that for the preparation of Compound 20a but using Compound 17a as the starting material afforded the title compound (42 mg, 85% yield) as a white solid:
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[OH-].[Li+]>O1CCCC1>[F:27][C:2]([F:1])([F:26])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@H:14]3[CH2:15][CH2:16][C@H:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19]3)=[CH:12][CH:13]=2)[CH:4]=1
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with the product from Example 26B (0.520 g, 1.36 mmol) and 6 mL of 20% aqueous tetrahydrofuran. Lithium hydroxide was added (114 mg, 2.72 mmol), and the reaction stirred at room temperature overnight. After 16 hours, the reaction was quenched with 1 N HCl, and the mixture filtered over a bed of celite. Evaporation of the solvents and purification via silica gel chromatography (10-30% ethyl acetate/hexanes with 1% acetic acid) afforded the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.23 (m, 2 H), 1.41-1.57 (m, 2 H), 1.58-1.67 (m, 1 H), 1.69-1.77 (m, 1 H), 1.78-1.88 (m, 4 H), 2.12-2.20 (m, 2 H), 7.05-7.17 (m, 1 H), 7.26-7.41 (m, 2 H), 7.62-7.82 (m, 2 H), 12.00 (s, 1 H), 13.89-14.07 (m, 1 H); MS (ESI) m/z 354 [M+H]+.
Reaction SMILES: Cl[O-].[Na+].[CH:4]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH2:5]1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]=[N:21][OH:22])=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[CH:8]3[CH2:9][CH2:10][CH:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:5][CH2:6][CH:7]3[O:22][N:21]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)C1CCC=CCC1
Reactant: ON=Cc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)C1CCC2ON=C(c3ccc(Cl)cc3)C2CC1
Reaction time: 48 h
Yield: 36.3 %

Procedure:
180 ml of 16.38% (w/v) aqueous solution of sodium hypochlorite were added slowly at 5° C. over a period of 6 hours while stirring well to a solution of 61.6 g (0.4 mol) of methyl cyclohept-4-enecarboxylate, 62.0 g (0.4 mol) of 4-chlorobenzaldehyde oxime and 0.5 g of tetrabutylammonium bromide in 800 ml of ethyl acetate. The mixture was held at 20° C. for 2 days. The mixture was then filtered and the organic phase was separated and dried over magnesium sulfate. The solvent was removed by evaporation and the residue was crystallized from diethyl ether/hexane to give 44.65 g of methyl 3-(4-chlorophenyl)-3a,5,6,7,8,8a-hexahydro-4H-cyclohept[d]isoxazole-6-carboxylate as a mixture of two diastereoisomers of melting point 150°-185° C. Isomer A has a melting point of 237°-239° C. and isomer B has a melting point of 162°-166° C.
Reaction SMILES: [N:1]1[C:2]([CH:13]=O)=[CH:3][N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=12.[Cl-].[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1.N12CCCN=C1CCCCC2>C1COCC1>[CH3:16][C:17]1[N:22]2[N:23]=[C:24]([CH:26]=[CH:13][C:2]3[N:1]=[C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH2:12][N:4]4[CH:3]=3)[N:25]=[C:21]2[C:20]([CH3:46])=[N:19][CH:18]=1
Reactant: O=Cc1cn2c(n1)-c1ccccc1C2
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1ncc(C)n2nc(C=Cc3cn4c(n3)-c3ccccc3C4)nc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5H-imidazo[2,1-a]isoindole-2-carbaldehyde (150 mg, 0.81 mmol) in dry THF (5.3 mL) was added to (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium chloride (374 mg, 0.81 mmol) under argon and 1,8-diazabicyclo [5,4,0]undec-7-ene (120 micro L, 0.81 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours after which it was evaporated onto silica gel (2 g). Silica gel chromatography (gradient elution; A:B 100:0 to 0:100, where A is ethyl acetate and B 10% MeOH in ethyl acetate) afforded the title compound as a mixture of the cis and trans isomers (139 mg, 52%). LC-MS: m/z=329.3 (MH+), tR=0.96 minutes.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl.[OH:35][C:36]1[C:41]([NH:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[C:49]3[C:54]=2[N:53]=[C:52]([O:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:51]=[CH:50]3)=O)=[C:40]([OH:62])[CH:39]=[CH:38][N:37]=1>C(Cl)Cl>[O:55]([C:52]1[CH:51]=[CH:50][C:49]2[C:54](=[C:45]([C:43]3[O:62][C:40]4[CH:39]=[CH:38][NH:37][C:36](=[O:35])[C:41]=4[N:42]=3)[CH:46]=[CH:47][CH:48]=2)[N:53]=1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: O=C(Nc1c(O)ccnc1O)c1cccc2ccc(Oc3ccccc3)nc12
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]ccc2oc(-c3cccc4ccc(Oc5ccccc5)nc34)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of triphenylphosphine (421 mg, 1.607 mmol), Et3N (597 μl, 4.29 mmol), and perchloroethane (317 mg, 1.339 mmol) in DCM (5357 μl) was stirred at RT for 5 min before a slurry of N-(2,4-dihydroxypyridin-3-yl)-2-phenoxyquinoline-8-carboxamide (200 mg, 0.536 mmol) in DCM (3 ml) was added to make a light yellow solution; this was stirred for 1 h at RT. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 100% DCM to 4% MeOH/DCM) to provide 2-(2-phenoxyquinolin-8-yl)oxazolo[4,5-c]pyridin-4(5H)-one (179, 38% yield over two steps) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 6.46 (d, J=7.04 Hz, 1H) 7.22-7.30 (m, 2H) 7.36-7.47 (m, 5H) 7.55 (t, J=7.73 Hz, 1H) 7.95 (d, J=7.24 Hz, 1H) 8.22 (d, J=8.80 Hz, 1H) 8.64 (d, J=6.26 Hz, 1H) 12.51 (br. s., 1H). MS (ESI, pos. ion) m/z: 356.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[CH2:11])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: C=C1CCc2ccc(Br)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1CCc2ccc(Br)cc21
Yield: 62.7 %

Procedure:
6-Bromo-1-methylene-indan 38c (4.91 g, 23.5 mmol) was dissolve in ethyl acetate followed by addition of palladium on carbon (0.98 g). The reaction mixture was reacted at room temperature for 4 hours under hydrogen atmosphere. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-1-methyl-indan 38d (3.11 g, yield 62.7%) as a colourless oil.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]=[N+:9]=[N-:10].[C:17]([O:23][CH3:24])(=[O:22])[CH2:18][C:19]([CH3:21])=O.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:19]([CH3:21])=[C:18]([C:17]([O:23][CH3:24])=[O:22])[N:10]=[N:9]1
Reactant: COC(=O)CC(C)=O
Reactant: [N-]=[N+]=NCc1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1nnn(Cc2ccccc2-c2ccccc2)c1C
Temperature: 40 °C
Reaction time: 48 h
Yield: 68.8 %

Procedure:
To a solution of 2-biphenylylmethyl azide (Intermediate 2) (1.1 g, 5.2 mmol) and methyl acetoacetate (0.9 g, 7.8 mmol) in DMSO (10 mL) was added potassium carbonate (2.9 g, 20 mmol). The reaction mixture was stirred at 40° C. for 48 hours. After cooling, water was added and the mixture was extracted with ethyl acetate, the organic layer was dried on sodium sulphate and after filtration was evaporated to dryness. The residue was purified by flash column chromatography eluting with DCM and DCM/MeOH: 98/2 to give the title compound as an oil (1.1 g, 68.7%). LC/MS: m/z 308 (M+H)+, Rt: 3.14 min.
Reaction SMILES: C([N:4]1[CH2:11][C:10]2([CH3:12])[CH:6]([CH2:7][O:8][N:9]2[CH3:13])[CH2:5]1)(=O)C.[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>O>[CH3:12][C:10]12[CH2:11][NH:4][CH2:5][CH:6]1[CH2:7][O:8][N:9]2[CH3:13]
Reactant: CC(=O)N1CC2CON(C)C2(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CN1OCC2CNCC21C

Procedure:
11.8 g (64mmol) of 7-acetyl-1,2-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane are heated under reflux with 12 g of NaOH in 36 ml of water overnight. The mixture is saturated with K2CO3 and extracted several times with CHCl3, the extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.O1CCOCC1.[CH:37]1([CH2:40][Mg]Br)[CH2:39][CH2:38]1>C1COCC1>[CH:37]1([CH2:40][CH:22]([C:20]2[CH:19]=[C:18]([CH2:24][O:25][CH2:26][C:27]([F:29])([F:30])[F:28])[N:17]=[C:16]([NH:15][C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[N:21]=2)[OH:23])[CH2:39][CH2:38]1
Reactant: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reactant: Br[Mg]CC1CC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(O)CC3CC3)n2)ccc1-n1cnc(C)c1

Procedure:
2-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carbaldehyde (92 mg, 0.22 mmol) was coevaporated with dioxane and dissolved in THF (5 mL). The solution was cooled on an ice bath and (cyclopropylmethyl)magnesium bromide was added over 30 min. The mixture was quenched by addition of an ammonium chloride (aq, sat). The organic phase was separated and aquous phase was extracted with ethyl acetate (2×5 mL). The combined organic phase was dried over sodium sulfate and filtered through a short pad of silica. The solvents were removed and the residue was purified by preparative HPLC to give the title compound as a dry film 17 mg (16%).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].O>C1COCC1>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14]4=[N:19][S:25](=[O:27])(=[O:26])[CH2:24][CH2:23][N:15]4[CH:16]=[CH:17][CH:18]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ncccc1-c1ccc(C2CCCCC2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(C4CCCCC4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
A mixture of 3-(4-cyclohexylphenyl)pyridin-2-amine (57 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 45.2 mg) and 2-chloroethanesulfonyl chloride (110 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (40.3 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:15]=[C:14]([C:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[S:18][CH:17]=3)[CH:13]=[CH:12][C:11]=2[OH:25])=[CH:2]1.C(Cl)Cl.C(N(CC)CC)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>O>[C:36]([O:25][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18][CH:17]=2)=[CH:15][C:10]=1[C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH:2]=1)(=[O:39])[CH:37]=[CH2:38]
Reactant: C=CC(=O)Cl
Reactant: Oc1ccc(-c2csc3ccccc23)cc1-c1csc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Oc1ccc(-c2csc3ccccc23)cc1-c1csc2ccccc12
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1.96 g of the thus obtained 2,4-bis(3-benzothiophenyl)phenol is placed in a round bottom flask; 10 mL of methylene chloride is added to form a transparent solution; after ice cooling the flask, 0.66 g of triethylamine is added; 0.59 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=90/10 (volume ratio)) to concentrate a component having an Rf of 0.20, thereby obtaining 1.43 g (yield: 63%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.78 (dd=1.2 & 10.8 Hz, 1H), 6.01 (dd=10.8 & 17.2 Hz, 1H), 6.26 (dd=1.2 & 17.2 Hz, 1H), 7.38 to 7.47 (m, 7H), 7.65 to 7.75 (m, 3H), 7.88 to 7.96 (m, 3H)
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH2:3]1.[CH3:13]O>S(=O)(=O)(O)O>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:4]=[CH:3]1
Reactant: CO
Reactant: O=C(O)CCC1=CCC(=O)CC1
Agent: O=S(=O)(O)O
Product: COC(=O)CCC1C=CC(=O)CC1

Procedure:
A solution of 3.5 g of 4-oxocyclohex-1-enepropionic acid in 16.5 ml of methanol and 0.9 ml of concentrated sulfuric acid was refluxed for 30 minutes. The mixture was cooled and the solvent was evaporated under reduced pressure. The resulting residue was partitioned between 50 ml of 5% aqueous sodium bicarbonate and 100 ml of ether. The separated aqueous layer was washed twice with 100-ml portions of ether and the washings were combined with the original organic layer and dried over magnesium sulfate. The solvent was evaporated to give a crude product which was found to be a 1:1 mixture of double bond isomers by NMR analysis. Flash chromatography of this crude product (silica gel, 3:7 ethyl acetate-hexane) separated the compounds and gave methyl 4-oxocyclohex-2-enepropionate as a clear oil. 1H NMR (CDCl3) δ 3.60 (s, 3H); 5.70-6.00 (dd, 1H); 6.60-6.95 (d of m, 1H).