Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(#N)C.C(=O)(O)[O-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(OCC)(=O)C>[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccccc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Nc1cnc(-c2ccccc2O)cn1
Temperature: 150 °C
Yield: 255.3 %

Procedure:
To each of 8 microwave tubes was added 2-amino-5-bromopyrazine (174 mg, 1.00 mmol), 2-hydroxyphenylboronic acid (151 mg, 1.10 mmol), acetonitrile (3 mL), dichlorobis(triphenylphosphine)palladium(II) (36 mg, 0.05 mmol), and a 1M aqueous sodium bicarbonate solution (1 mL). The 8 tubes were microwave-heated at 150° C. for 15 min. The reaction mixture was cooled and then poured into a solution of ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in hot methanol (100 mL). The methanol solution was concentrated in vacuo until a precipitate was observed. The precipitate was filtered. The filtrate was further concentrated and filtered to afford 5-(2-hydroxy-phenyl)-pyrazin-2-ylamine (478 mg, 32%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20]Cl)[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][C:17](=[CH2:20])[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCC(CCl)CC2)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C1CCN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)CC1

Procedure:
2-Chloro-5-(4-chloromethylpiperidinosulfonyl)benzoic acid (0.5 g.) is dissolved in 10 ml. of 5N sodium hydroxide and refluxed for one hour. 10 ml. of water is then added and the mixture is acidified with concentrated hydrochloric acid. The precipitated solid is chromatographed on a 10 g. silica gel column with a developing solvent system of 1:7 benzene:hexane containing 5% acetic acid. 2-Chloro-5-(4-methylenepiperidinosulfonyl)benzoic acid, m.p. 157°-160° C., is isolated from the first fraction
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1F)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(F)cccc2c1=O
Yield: 87.4 %

Procedure:
Ethyl 2-butyryl-3-(2-fluorophenylamino)acrylate (37 g, 0.13 mol) was added in portions to boiling diphenyl ether (450 ml), then heated at reflux for 1.5 hours. After partial cooling the mixture was diluted with petroleum ether (50 ml). Filtration and washing with petroleum ether gave 3-butyryl-8-fluoro-4(1H)-quinolone (26.5 g), m.p. 176°-178°.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[C:4](=[O:14])[CH:5]=[CH:6][C:7]2=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[NH:15]([C:10]1[C:9](=[O:12])[C:8]2[C:3]([C:2](=[O:1])[CH:11]=1)=[C:4]([OH:14])[C:5]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:6][C:7]=2[OH:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1C=CC(=O)c2c(O)ccc(O)c21
Reactant: Nc1ccccc1
Solvent: CCO
Product: O=C1C(Nc2ccccc2)=CC(=O)c2c(O)c(Nc3ccccc3)cc(O)c21

Procedure:
A mixture of 1.9 g of 5,8-dihydroxy-1,4-naphthoquinone and 40 ml of aniline is heated at 100° for 8 hours. After the mixture has been cooled and diluted with ethanol, 2,6-bis-anilino-5,8-dihydroxy-1,4-naphthoquinone is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].ClC(F)C(N(CC)CC)(F)[F:17]>C(Cl)Cl>[F:1][C:2]1[C:7]([CH2:8][F:17])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: OCc1c(F)c(F)c(F)c(F)c1F
Reactant: CCN(CC)C(F)(F)C(F)Cl
Solvent: ClCCl
Product: FCc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of pentafluorobenzyl alcohol (3.0 g) and dry methylene dichloride (50 ml) was cooled to a temperature of 0° C. in an ice-bath and 2-chloro-1-diethylamino-1,1,2-trifluoroethane (4.3 g) was slowly added to the cooled, stirred mixture over a period of ten minutes. After standing for a period of 18 hr. at 0° C. the reaction mixture was poured into ice and the organic layer was separated and washed with IM aqueous sodium carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation and the product was distilled under reduced pressure to give pentafluorobenzyl fluoride, b.p. 51° C. at 30 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][C:5]([O:13][CH3:14])=[C:4]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH:3]=1.C(O)(=O)C.[CH:28](N)=[NH:29]>COCCO>[CH3:14][O:13][C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][C:4]=1[O:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)[N:1]=[CH:28][NH:29][C:8]2=[O:10]
Reactant: N=CN
Reactant: CCOC(=O)c1cc(OC)c(OCC2CCN(C)CC2)cc1N
Solvent: CC(=O)O
Solvent: COCCO
Product: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(C)CC1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A solution of ethyl 6-amino-3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)benzoate (16.1 g, 50 mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (5.2 g, 50 mmol) was heated at 115° C. for 2 hours. Formamidine acetate (10.4 g, 100 mmol) was added in portions every 30 minutes over 4 hours. Heating was prolonged for 30 minutes after the last addition. After cooling, the volatiles were removed under vacuum. The solid was dissolved in ethanol (100 ml) and methylene chloride (50 ml). The precipitate was removed by filtration and the filtrate was concentrated to a final volume of 100 ml. The suspension was cooled to 5° C. and the solid was collected by filtration, washed with cold ethanol followed by ether and dried under vacuum overnight at 60° C. to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-3,4-dihydroquinazolin-4-one (12.7 g, 70%).
Reaction SMILES: [N:1]1([C:10]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>C1COCC1>[N:1]1([CH2:10][C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=4)=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2c[nH]c3ncc(C(=O)N4CCc5ccccc54)cc23)cn1
Solvent: C1CCOC1
Product: Cn1cc(-c2c[nH]c3ncc(CN4CCc5ccccc54)cc23)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
A mixture of 1.0 M BH3 in THF (1.0 mL, 1.0 mmol) and amide 58 (80.7 mg, 0.235 mmol) in THF (2.0 mL) was refluxed under N2 for 20 min. The reaction mixture was cooled to r.t., quenched with MeOH (5 mL) and concentrated. The residual solid was treated with 10% aqueous HCl (2.0 mL) and MeOH (2.0 mL). After 1 h stirring at r.t. the mixture was concentrated, basified with NaHCO3 and extracted with AcOEt (3×10 mL). Combined extracts were dried (MgSO4), concentrated and purified by means of preparative LCMS (column LUNA 10 μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give 59 as a white solid (14.0 mg, 18%); 1H NMR (400 MHz, CDCl3) δ 2.97 (t, J=8.3 Hz, 2H), 3.30 (t, J=8.3 Hz, 2H), 3.98 (s, 3H), 4.40 (s, 2H), 6.66 (d, J=7.8 Hz, 1H), 6.72 (td, J=7.4, 0.8 Hz, 1H), 7.08-7.15 (m, 2H), 7.43 (d, J=1.6 Hz, 1H), 7.61 (s, 1H), 7.75 (s, 1H), 8.08 (d, J=1.8 Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 9.90 (bs, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=1.[K+].[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[N:27][CH:28]=1)([CH3:22])[CH3:21]>CS(C)=O.O>[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:32][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([CH3:18])[N:3]=2)(=[O:31])=[O:30])=[N:27][CH:28]=1)([CH3:22])[CH3:21]
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.1 %

Procedure:
To a solution of 2.15 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine in 40 ml of DMSO was added 3.59 g of 5-isopropyl-2-pyridine sulfonamide potassium salt. The mixture was stirred for 72 h at room temperature. The solution was diluted with 350 ml of water and extracted twice with 200 ml of diehtyl ether. The organic layers were extracted twice with water. The combined aqueous layers were acidified to pH 4 with 5 ml of acetic acid and extracted twice with DCM. The organic layers were washed with water, and dried over Na2SO4. The solution was treated with activated charcoal, filtered over Celite and evaporated. The residue was suspended in 30 ml of diethyl ether, filtered off and dried to give 3.15 g of 5-isopropyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide as a pale beige powder. LC-MS: tR=5.18 min, [M+1]+=449.25, [M−1]−=447.31.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[S:24][C:23]([CH3:25])=[N:22][C:21]=1[CH3:26]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[S:24][C:23]([CH3:25])=[N:22][C:21]=2[CH3:26])[CH:11]=1
Reactant: Cc1nc(C)c(Br)s1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1nc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)O)s1

Procedure:
Following the general method as outlined in Example 8, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 5-bromo-2,4-dimethyl-1,3-thiazole (Acros), the title compound was obtained as a white solid after purification by preparative HPLC.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH2:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])=[C:8]([O:16][CH2:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH3:15][C@@H:12]([CH2:13][CH3:14])[CH2:11][O:10][C:9]1[C:2]([O:1][CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23])=[C:3]([CH:6]=[CH:7][C:8]=1[O:16][CH2:17][C@@H:18]([CH3:21])[CH2:19][CH3:20])[CH:4]=[O:5]
Reactant: C=CCCCBr
Reactant: CC[C@H](C)COc1ccc(C=O)c(O)c1OC[C@@H](C)CC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCOc1c(C=O)ccc(OC[C@@H](C)CC)c1OC[C@@H](C)CC
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere, a mixture of 2-hydroxy-3,4-bis-[(S)-2-methyl-butoxy]-benzaldehyde (0.74 9, 2.51 mmol), 5-bromo-1-pentene (0.45 g, 3.02 mmol) and potassium carbonate (0.41 g, 3 mmol) in dry DMF (5 ml) was stirred at 80° C. for 3 h. The cooled reaction mixture was gently poured into HCl 3N (15 ml) and extracted with diethylether (3×20 ml). The combined organic extracts are washed with 30 ml of saturated NaCl solution, dried over magnesium sulphate and evaporated under reduced pressure. The obtained oily residue was chromatographed on silica (diethylether/petroleumether: 1/3) to give 3,4-bis-[(S)-2-methyl-butoxy]-2-(pent-4-enyloxy)-benzaldehyde as a slightly yellow oil (Yield: 0.82 g, 90%).
Reaction SMILES: [N:1]1([CH:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)=[CH:10][N:9]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1>C(OCC)(=O)C.[Pd]>[N:1]1([CH:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH3:7])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1)n1ccnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(c1ccc(-c2ccc(N)cc2)cn1)n1ccnc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-(1-(1H-imidazol-1-yl)ethyl)-5-(4-nitrophenyl)pyridine (255 mg, 0.86 mmol) in ethyl acetate (10 mL) was added 10% Pd/C (about 50 mg), under nitrogen. The reaction was stirred at rt for about 6 h under hydrogen. The reaction mixture was filtered through a Celite® bed and the filtrate was concentrated under vacuum to obtain crude product. The crude product was purified by prep TLC method using 3% methanol in DCM to provide 4-(6-(1-(1H-imidazol-1-yl)ethyl)pyridin-3-yl)aniline as off white solid (160 mg, 70% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.71 (d, 1H), 7.87 (dd, 1H), 7.78 (s, 1H), 7.36 (d, 2H), 7.24 (s, 1H), 7.14 (d, 1H), 6.88 (s, 1H), 6.61 (t, 2H), 5.60-5.54 (m, 1H), 5.29 (s, 2H), 1.79 (d, 2H), LC-MS m/z calcd for [M+H]+ 265.14. found 265.4.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C>[OH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: NCCOCCO
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21
Yield: 72.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (220 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (250 mg), 2-(2-aminoethoxy)ethanol (71 mg), HBTU (279 mg), and DIEA (160 uL). LC/MS: m/z 496.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.47 (t, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.61 (t, 1H), 3.64 (s, 3H), 3.57 (t, 2H), 3.51 (t, 2H), 3.49-3.41 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][OH:13])=[O:11].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[O:13][NH:12][C:10]1=[O:11]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NO)Nc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: O=c1[nH]oc(=O)n1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A solution of 4.2 g (19 mmol) of the compound of step A in tetrahydrofuran (20 mL) was treated with carbonyldiimidazole (3.2 g, 19 mmol). The mixture was stirred at 25° C. for 16 h. Some precipitated imidazole was filtered off and the filtrate was concentrated under reduced pressure. The residue was partitioned between 1N HCl (20 mL) and ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate and concentrated to an oil which solidified to give 3.8 g of the title compound of Step B as a solid melting at 104-107° C. It was used directly for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]O[CH2:39][CH2:38]1.IC(CC)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH:37]([CH3:41])[CH2:38][CH3:39])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: CCC(C)I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(C)C(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Yield: 51.2 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.183 g; 0.5 mmol), LHMDS 1N in THF (0.75 mL; 0.75 mmol), 2-iodobutane (0.115 mL; 1 mmol) in DMF (2.5 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-30%) in heptane furnished 0.108 g (51%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21]2)=[O:19])[C:13](OC)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[NH2:37][C@H:38]([C:51](=[O:64])[N:52]1[CH2:57][CH2:56][N:55]([C:58]2[CH:63]=[CH:62][N:61]=[CH:60][CH:59]=2)[CH2:54][CH2:53]1)[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([C:26]3[C:27](=[O:36])[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:24][CH2:25]2)=[O:19])[C:13]([NH:37][C@H:38]([C:51](=[O:64])[N:52]2[CH2:57][CH2:56][N:55]([C:58]3[CH:59]=[CH:60][N:61]=[CH:62][CH:63]=3)[CH2:54][CH2:53]2)[CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCN(c2ccncc2)CC1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(c2cc3ccccc3[nH]c2=O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of (R)-methyl 3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanoate (95 mg, 0.2 mmol) in DMF (2.0 mL) was added (S)-tert-butyl 5-amino-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate (78 mg, 0.2 mmol) followed by 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol) and triethylamine (1 mL). After stirring at room temperature for 2 h, the solvent was removed and the crude product was purified by flash chromatography using 7% methanol in dichloromethane containing 2% ammonium hydroxide (ammonia content 28-30%) to give tert-butyl (S)-5-((R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanamido)-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate in 87% yield as white solid. 1H-NMR (CD3OD) δ 8.11-8.10 (m, 2H), 7.97 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.50-7.44 (m, 3H), 7.32-7.30 (d, J=7.5 Hz, 2H), 7.23-7.20 (m, 1H), 7.13 (s, 1H), 6.77 (d, J=6.5 Hz, 1H), 4.83-4.81 (m, 1H), 4.67-4.65 (m, 1H), 4.14-4.08 (m, 2H), 3.82-3.78 (m, 2H), 3.69-3.62 (m, 1H), 3.60-3.53 (m, 1H), 3.48-2.80 (m, 10H), 2.52 (s, 3H), 1.84-1.78 (m, 2H), 1.69-1.61 (m, 1H), 1.40 (s, 9H), 1.49-1.11 (m, 8H); MS (ESI) 847 (M+H) ; Rf=2.34.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH3:20])[CH2:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21]([CH2:23][C:24]([NH2:26])=[S:25])#[N:22]>C(O)C>[NH2:26][C:24]1[C:23]([C:21]#[N:22])=[C:16]([C:15]2[CH:18]=[CH:19][C:12]([O:11][CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:20])=[CH:13][CH:14]=2)[C:23]([C:21]#[N:22])=[C:24]([SH:25])[N:26]=1
Reactant: CC(COc1ccc(C=O)cc1)O[Si](C)(C)C(C)(C)C
Reactant: N#CCC(N)=S
Solvent: CCO
Product: CC(COc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1.77 g (5.99 mmol) of the compound from Example 41A and 1.26 g (12.59 mmol) of cyanothioacetamide in 25 ml of ethanol is stirred at +78° C. for 6 h. The mixture is then cooled to RT and stirred at this temperature for a further 20 h. The resulting precipitate is filtered off with suction and washed with cold diethyl ether. Further product is obtained from the concentrated filtrate solution by chromatographic purification on silica gel 60 (mobile phase gradient cyclohexane/ethyl acetate 1:1→1:4).
Reaction SMILES: [SH2:1].[CH3:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]#[N:12])[CH:6]=[CH:7][C:8]=1[CH3:9].C(N(CC)CC)C>N1C=CC=CC=1>[CH3:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([NH2:12])=[S:1])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: S
Reactant: Cc1ccc(CC#N)cc1C
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1ccc(CC(N)=S)cc1C

Procedure:
The 3,4-dimethylphenyl(thioacetamide) was prepared by passing a slow stream of hydrogen sulphide through a solution of 3,4-dimethylphenylacetonitrile (56.6 g.) in pyridine (60 ml.) and triethylamine (39.4 g.) during 12 hours. The reaction mixture was evaporated under reduced pressure and the residue was recrystallised from a mixture of benzene and light petroleum (b.p. 60°-80°) to give 3,4-dimethylphenyl (thioacetamide), m.p. 91°-94°.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([C:13]1([CH2:36][CH2:37][CH3:38])[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)#N.C[OH:40]>CCCCCC>[CH:11]([C:13]1([CH2:36][CH2:37][CH3:38])[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:40]
Reactant: CCCCCc1ccc(-c2ccc(C3CCC(C#N)(CCC)CC3)cc2)cc1
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: CCCCCc1ccc(-c2ccc(C3CCC(C=O)(CCC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
55 ml of a 1M solution of diisobutyl-aluminium hydride (DIBAH) in n-hexane are added to a solution of 8.6 g (0.05 mole) of 4-(4-cyano-4-propyl-cyclohexyl)-4'-n-pentylbiphenyl (Example 1) in 100 ml of hexane at 0°, under a nitrogen atmosphere and with exclusion of moisture. The mixture is stirred at room temperature for one hour and 5 ml of methanol are then carefully added. The reaction mixture is poured into 200 ml of ice-cold 10% H2SO4 and stirred for 30 minutes. The organic phase is then separated off and the aqueous phase is extracted twice more with hexane. The combined organic phases are neutralised with NaHCO3 solution and then dried. Purification by chromatography gives 4-(4-formyl-4-propylcyclohexyl)-4'-pentylbiphenyl.
Reaction SMILES: [C:1]([CH:5]1[C:9](=[O:10])[CH2:8][S:7][CH2:6]1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[C:18]1([O:24][P:25](Cl)([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH3:4][O:3][C:1]([C:5]1[CH2:6][S:7][CH2:8][C:9]=1[O:10][P:25]([O:24][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([O:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:26])=[O:2]
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)C1CSCC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)CSC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 108.1 %

Procedure:
To a solution of 3-carbomethoxytetrahydrothiophene-4-one (Gianturco M. A., Friedel P., Giammarino A. S., Tetrahedron, 20:1772 (1964)) (4.0 g, 25 mmol) and triethylamine (6.6 g, 65 mmol) in 50 mL dry THF at 0° was added, over a 15 minute period, diphenylchlorophosphate (17.5 g, 65 mmol). The reaction mixture was stirred at room temperature for 2 days, then treated with ice-cold water and extracted with diethyl ether. The extracts were washed with saturated NaHCO3, brine, dried with Na2SO4, and evaporated to yield an oil (10.6 g).