Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:3]=1.[Li]C(C)(C)C.CCCCC.[C:28]([O:32][C:33]([N:35]1[CH:40]2[CH2:41][CH2:42][CH:36]1[CH2:37][C:38](=[O:43])[CH2:39]2)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(O)=O.[Na+]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[CH:40]2[CH2:41][CH2:42][CH:36]1[CH2:37][C:38]([C:2]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:3]=1)([OH:43])[CH2:39]2)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)n1cc(Br)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1cn([Si](C)(C)C(C)(C)C)c3ccccc13)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To 4.8 g (15.5 mmol) 3-bromo-1-(tert-butyl-dimethyl-silanyl)-1H-indole in 60 mL THF at −78° C. is added 19.1 mL (32.5 mmol) of a 1.7M solution of t-BuLi/pentane in drops over 10 min. After stirring at −78° C. for 30 min, 3.48 g (15.5 mmol) 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in 20 mL THF is added via a cannula over 5 min. After stirring at 23° C. for 3 h, the reaction mixture is poured into sat. aqueous NaHCO3, and extracted with 2×50 mL EtOAc. The combined organics are washed with 1×100 mL H2O, 1×100 mL brine, dried over MgSO4, filtered and evaporated to an orange oil. Flash chromatography on SiO2 gel, eluting with CH2Cl2/EtOAc (80/1 to 20/1), gives 3.74 g (8.2 mmol, a 53% yield) of the title compound as an off-white wax. MS (ES) m/z 457 (MH)+.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[S:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:17]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1cccc(S(=O)(=O)N2CCN(c3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a suspension of 1-(4-chlorophenyl)piperazine dihydrochloride (539 mg) and 3-(chlorosulfonyl)benzoic acid (441 mg) in dichloromethane (50 ml) was added diisopropylethylamine (0.8 ml). After stirring overnight at room temperature the reaction mixture was washed with 2N HCl (3×25 ml) and brine (25 ml), dried over MgSO4, filtered and evaporated to give the title compound as white solid (290 mg, 38%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:15]=[C:16]([C:22]6[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=6)[S:17][C:18]=5[CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:7]=[N:6]2)[CH2:2]1.CO.C(N(CC)C(C)C)(C)C.[CH3:44][C:45]1([O:48][CH2:47]1)[CH3:46]>>[CH:28]([N:23]1[C:22]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:12]4[CH:11]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([CH:3]6[CH2:4][N:1]([CH2:44][C:45]([CH3:47])([OH:48])[CH3:46])[CH2:2]6)[CH:9]=5)[CH:32]=[CH:31][C:13]=4[C:14]=3[N:15]=2)=[N:26][C:25]([CH3:27])=[N:24]1)([CH3:29])[CH3:30]
Reactant: CC1(C)CO1
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CNC5)c4)ccc2-3)n(C(C)C)n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(C5CN(CC(C)(C)O)C5)c4)ccc2-3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a slurry of 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.232 g, 0.000519 mol) in methanol (3.0 mL, 0.074 mol) was added N,N-Diisopropylethylamine (0.108 mL, 0.000623 mol) then isobutylene oxide (0.330 mL, 0.0037 mol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and purified by reverse-phase HPLC to give 480 (24.3 mg) as a colorless solid. MS(ESI+) 520.2. 1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.31 (d, J=8.3, 1H), 8.01 (s, 1H), 7.47 (dd, J=8.3, 1.8, 1H), 7.35 (d, J=1.8, 1H), 5.86-5.68 (m, 1H), 4.97 (p, J=6.9, 1H), 4.39 (t, J=5.0, 2H), 4.11 (s, 1H), 3.79 (dd, J=8.0, 7.3, 2H), 3.49 (dd, J=8.0, 6.8, 2H), 3.44 (t, J=5.0, 2H), 2.44 (s, 2H), 2.32 (s, 3H), 1.53 (d, J=6.6, 6H), 1.08 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17].[BH4-].[Na+].C[OH:24]>CCOCC.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([OH:24])[CH:5]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CC(O)CC1(C)C
Reaction time: 1 h

Procedure:
To a solution of 4a (13.7 g, 47.2 mmol) in 100 mL of methanol at 0°-5° C. was added NaBH4 (2.68 g, 70.9 mmol). The mixture was stirred for 1 hr, diluted with ether and H2O. The organic layer was washed with H2O and brine and dried (MgSO4). Removal of the volatiles in vacuo provided a quantitive yield of product which was taken forward without further purification.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:36]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([CH2:28][CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:36][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:7][CH:8]=1)[C:14]([N:16]([CH2:28][CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21)OCC
Solvent: C1CCNCC1
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Yield: 112.9 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (S)-(9H-fluoren-9-yl)methyl 3-(4-tert-butoxyphenyl)-1-((2,2-diethoxyethyl)(naphthalen-1-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-2) (740 mg, 1.0 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (556.1 mg, 112%).
Reaction SMILES: C[O:2][CH:3](OC)[C:4](=O)[CH3:5].[CH2:9]([C:16]1[C:17]([NH2:28])=[N:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C:16]1[NH:21][C:20]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:19][N:18]2[C:3](=[O:2])[C:4]([CH3:5])=[N:28][C:17]=12)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Cc1ccccc1
Reactant: COC(OC)C(C)=O
Product: Cc1nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn-2c1=O

Procedure:
Synthesized using method B with 1,1-dimethoxypropan-2-one and 3-benzyl-5-phenylpyrazin-2-amine as starting materials. Exact mass calculated for C20H18N30+ m/z+316.14, found m/z+316.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH3:18]>CCO>[Cl:11][C:4]1[N:3]=[C:2]([NH2:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To an ice-cooled solution of 2,6-dichloro-3-nitropyridine (55.65 g, 288 mmol) in EtOH (500 ml) was added sodium carbonate (76.32 g, 720 mmol) followed by aqueous ammonia (35%, 21 ml). The reaction was then allowed to warm to rt, stirred at rt for 1 h, then at 50° C. for 1 h and then at 90° C. for 1 h. Another 20 ml of aqueous ammonia was added and heating continued at 90° C. for a further 1 h. Another 50 ml of aqueous ammonia was added and heating continued at 90° C. for a further 1 h. The reaction was cooled to rt, and the solid was filtered, washed with water (500 ml) and dried in vacuo to give the title compound as a yellow solid (37.25 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1.[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11]([N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:19])[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1ccccc1Nc1nc(Cl)c2sccc2n1
Reactant: CNc1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1Nc1nc(N(C)c2ccccc2)c2sccc2n1
Yield: 40.1 %

Procedure:
2-(2-Methylphenylamino)-4-chlorothieno[3,2-d]-pyrimidine (1.5 g, 0.0054 mol) and N-methylaniline (1.16 g, 0.0054 mol) were heated in an oil bath at 140° for 2 hours. The reaction mixture was diluted with dichloromethane (100 ml) and washed with 2N hydrochloric acid (3×100 ml), then sodium carbonate solution. The dichloromethane extracts were dried over magnesium sulphate, filtered and evaporated to give a solid. Recrystallization from methanol gave the title compound, (0.75 g) m.p. 198°-200°.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[CH3:15])=[CH:5][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:18])=[O:17].CCN(C(C)C)C(C)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:38]([NH:37][CH2:35][CH3:36])=[O:39])=[N:11][C:10]=2[CH3:15])=[CH:5][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: CCN=C=O
Reactant: Cc1nc(N)sc1-c1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(Cl)c(S(=O)(=O)N3CCN(C)CC3)c2)s1
Temperature: 120 °C

Procedure:
A stirred solution of 5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-ylamine hydrobromide (174d) (0.1 g, 0.26 mmol) in DMF (1 ml) at room temperature is treated with DIPEA (0.07 g, 0.52 mmol) and ethyl isocyanate (0.025 ml, 0.33 mmol). The reaction mixture is heated to 120° C. for 1 hour and then allowed to cool to room temperature. Purification by preparative LC-MS affords the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=O)[CH2:13][CH2:12]3)[CH:7]=1.Cl.[NH2:28][OH:29]>>[F:1][C:2]1[CH:3]=[C:4]([C:19]2([O:25][CH3:26])[CH2:23][CH2:22][O:21][CH:20]2[CH3:24])[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)/[C:14](=[N:28]/[OH:29])/[CH2:13][CH2:12]3)[CH:7]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc4c(c3)CCC4=O)c2)CCOC1C
Reactant: NO
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc4c(c3)CC/C4=N\O)c2)CCOC1C
Yield: 48 %

Procedure:
Using an analogous procedure to that described in Example 66, 5-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenylthio}indan-1-one was reacted with hydroxylamine hydrochloride to give (E)-5-{5-fluoro-3-[(2RS,3SR)-3-methoxy-2-methyltetrahydrofuran-3-yl]phenylthio}indan-1-one oxime in 48% yield, m.p. 136°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](I)=[CH:14]2)[C@H:9]([OH:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])=[CH:14]2)[C@H:9]([OH:12])[CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)n1cc(I)c2ccccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC[C@@H](O)[C@H](c1cccc(F)c1)n1cc(-c2ccccc2F)c2ccccc21
Temperature: 90 °C
Yield: 60.5 %

Procedure:
A mixture of (2S,3S)-3-(3-fluorophenyl)-3-(3-iodo-1H-indol-1-yl)propane-1,2-diol (0.25 g, 0.61 mmol), 2-fluorobenzeneboronic acid (0.12 g, 0.85 mmol), and potassium phosphate (0.39 g, 1.83 mmol) in N,N-dimethylformamide (10 mL) was degassed with nitrogen for 5 minutes then a catalytic amount (0.02 g) of [1,4-bis-(diphenylphosphine)butane]palladium (II) dichloride was added. The solution was heated to 90° C. for 3 hours then cooled and poured into 100 mL of water. The aqueous mixture was extracted 3 times with ethyl acetate and the combined extracts were then washed 2 times with water. The ethyl acetate was dried by filtration through a plug of silica gel then concentrated. The residue was purified by Biotage chromatography (FlasH40i, silica, 40% ethyl acetate/hexane) to yield 0.14 g of (2S,3S)-3-(3-fluorophenyl)-3-{3-[2-fluorophenyl]-1H-indol-1-yl}propane-1,2-diol as an oil, which was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]([CH2:19][CH2:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][C:26]2[CH:40]=[CH:39][C:29]([O:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11])=O)(C)(C)C.Cl.O1CCCC1>O1CCOCC1>[ClH:18].[Cl:18][C:14]1[CH:13]=[C:12]([C@@H:10]([OH:11])[CH2:9][NH:8][CH2:19][CH2:20][C:21]2[CH:42]=[CH:41][C:24]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:39][CH:40]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)COc1ccc(Cc2ccc(CCNC[C@H](O)c3cccc(Cl)c3)cc2)cc1
Reaction time: 0.08 h
Yield: 75.1 %

Procedure:
A solution of tert-butyl [4-[4-[2-[N-(tert-butoxycarbonyl)-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-amino]ethyl]benzyl]phenoxy]acetate (240 mg) and 4N hydrochloride in 1,4-dioxane (3.0 ml) was stirred at room temperature for 24 hours. The mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol/acetic acid/chloroform=10/1/100) to give a product. To a tetrahydrofuran (2.0 ml) solution of the product, 4N hydrogen chloride in 1,4-dioxane (1.0 ml) was added. The mixture was stirred for 5 minutes and evaporated under reduced pressure to give [4-[4-[2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]benzyl]phenoxy]acetic acid hydrochloride (72 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=[O:6].[CH3:14][N:15](C=O)C.Cl>CCOC(C)=O>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH3:13])=[C:2]([CH:3]=1)[C:14]#[N:15])=[O:6]
Reactant: CN(C)C=O
Reactant: CCCOc1ccc(C=O)cc1Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C=O)cc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
To a stirred solution of 3-bromo-4-propoxybenzaldehyde (0.6 g, 2.47 mmol) in anhydrous DMF (5 ml) CuCN (0.67 g; 7.4 mmol) was added and the mixture was stirred for 4 h at reflux. After cooling to room temperature, the mixture was treated with EtOAc (50 ml) and 1M HCl (10 ml) and stirred for 15 min. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give 5-formyl-2-propoxybenzonitrile (0.41 g; 88%), as yellow oil 1H NMR (CDCl3) 9.87 (s, 1H); 8.07 (d, 1H, J=1.95 Hz); 8.03 (dd, 1H, J=8.67, 2.1 Hz); 7.06 (d, 1H, J=8.7 Hz); 4.13 (t, 2H, J=6.45 Hz); 1.97-1.85 (m, 2H); 1.1 (t, 3H, J=7.35 Hz). The above benzaldehyde was oxidised via a similar procedure as described in Example 47 Step A, to give the title compound (0.29 g; 68%), as white solid. 1H NMR (CDCl3) 8.3 (d, 1H, J=1.71 Hz); 8.23 (dd, 1H, J=8.88, 2.1 Hz); 7.00 (d, 1H, J=7.62 Hz); 4.12 (t, 2H, J=6.48 Hz); 1.97-1.85 (m, 2H); 1.09 (t, 3H, J=7.38 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:19]3[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=3)[C:13]([O:12][CH3:11])=[O:14])[CH:3]=[C:4]2[CH:10]=[N:9]1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: Brc1cnc2[nH]ncc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(-c2cnc3[nH]ncc3c2)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (2.00 g, 10.10 mmol), 3-(methoxycarbonyl)phenylboronic acid (2.20 g, 12.12 mmol), sodium bicarbonate (2.2 g, 6.00 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.250 g, 0.202 mmol) in dioxane/water (40 mL/10 mL) was stirred at 110° C. for 15 hours. The mixture was then poured into ice water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded methyl 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (8) (1.65 g, 65% yield) as yellow solids. S: m/z 254.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1.[C:48]1([N:54]=[C:55]=[O:56])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][C@@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:55]([NH:54][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:56])[CH2:41]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 40 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide bis(trifluoroacetate) and phenyl isocyanate as the starting materials in 40% yield. LCMS for C32H33ClN7O2 (M+H)+: m/z=582.2.
Reaction SMILES: C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:5].[Mg+2].[CH3:15][N:16]1[C:21](=[O:22])[C:20]2[CH2:23][N:24]([CH2:27][CH2:28][S:29][CH3:30])[CH2:25][CH2:26][C:19]=2[NH:18][C:17]1=[O:31]>C(O)C>[CH3:15][N:16]1[C:21](=[O:22])[C:20]2[CH2:23][N:24]([CH2:27][CH2:28][S:29]([CH3:30])=[O:5])[CH2:25][CH2:26][C:19]=2[NH:18][C:17]1=[O:31]
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CSCCN1CCc2[nH]c(=O)n(C)c(=O)c2C1
Agent: [Mg+2]
Solvent: CCO
Product: Cn1c(=O)[nH]c2c(c1=O)CN(CCS(C)=O)CC2
Temperature: 55 °C
Reaction time: 2 h

Procedure:
21.8 g of magnesium monoperoxyphthalate (85% pure) were added at 55° C. over a period of 15 min to a solution of 19.5 g of 3-methyl-6-(2-methylsulfanylethyl)-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione in 200 ml of ethanol and the mixture was stirred for 2 h at 55° C. After the pH had been adjusted to 7.5, the mixture was concentrated under reduced pressure. The residue was boiled up several times with methanol, the combined methanol phases were concentrated and the residue was purified by chromatography in a medium-pressure column with silica gel using dichloromethane/methanol (volume ratio 95:5) as the eluent and by recrystallization from isopropanol.
Reaction SMILES: [CH3:1][CH2:2][C:3]([CH2:5][CH2:6]/[CH:7]=[C:8](/[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])\[CH3:9])=[CH2:4].[CH:16]([CH:18]=[CH2:19])=[O:17]>>[CH:16]([CH:18]1[CH2:19][CH:4]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[CH2:2][CH2:1]1)=[O:17]
Reactant: C=CC=O
Reactant: C=C(CC)CC/C=C(\C)CCC=C(C)C
Product: CC(C)=CCCC(C)=CCCC1=CCC(C=O)CC1
Temperature: 100 °C
Yield: 50 %

Procedure:
The (E)-β-farnesene-containing product of Example 1 (5.0 g) and acrolein (3.0 g) are heated together at 100° C. for two hours. The mixture is then distilled under reduced pressure to give 1-formyl-4-(4,8-dimethyl-3,7-nonadienyl)-cyclohex-4-ene as a yellow oil (2.2 g, 50%); b.p. 140°-150°/0.5τ; nD20 1.5033; M+ (m/z as % base peak): 260 (3.6); δ (CCl4) 1.70 (M, 9H), 1.90-2.30 (m, 15H), 5.16 (m, 2H), 5.50 (br, t, 1H), 9.84 (br, s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:28])=[C:18]([CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([OH:31])C>[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:28])=[C:18]([CH2:20][C:21]([N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[O:31])[N:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCN1CCC[C@H]1C
Reactant: CCO
Agent: [Pd]
Product: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Reaction time: 18 h
Yield: 94 %

Procedure:
A mixture of 2-(4-Benzyloxy-phenyl)-5-methyl-4-[2-(2-(R)-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (See Example 55) (0.48 g, 1.3 mmol) and 5% Pd/C (0.046 g) in absolute ethanol (25 mL) is shaken under a hydrogen atmosphere (65 psi) for 18 h. The mixture is filtered and concentrated to provide the title compound (0.35 g, 94%) as a yellow oil, which was used without purification. MS (m/e): 287.3 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([C:25]([OH:27])=O)[CH2:17]2)(=[O:15])=[O:14])=[CH:5][CH:4]=1.ON1C2C=CC=CC=2N=N1.CC(C)N=C=NC(C)C.[CH3:47][N:48]1[CH2:52][CH2:51][CH2:50][CH:49]1[CH2:53][CH2:54][NH2:55]>ClCCl.O>[CH3:47][N:48]1[CH2:52][CH2:51][CH2:50][CH:49]1[CH2:53][CH2:54][NH:55][C:25]([CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([S:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:14])=[O:15])[CH2:17]1)=[O:27]
Reactant: COc1ccc(S(=O)(=O)N2CC(C(=O)O)c3ccccc32)c2ccccc12
Reactant: CN1CCCC1CCN
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC(C(=O)NCCC3CCCN3C)c3ccccc32)c2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.9 %

Procedure:
To a solution of 1-(4-methoxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-indole-3-carboxylic acid (C) (900 mg, 2.35 mmol) in dichloromethane (20 cm3) was added 1-hydroxybenzotriazole (HOBT, 0.48 g, 3.53 mmol) and 1,3-diisopropylcarbodidiimide (DIC, 0.55 cm3, 3.53 mmol). This was left to stir at room temperature for 5 min, before adding 2-(1-methyl-pyrrolidin-2-yl)-ethylamine (0.342 cm3, 2.35 mmol). The reaction was stirred for 16 h at room temperature before water (60 cm3) was added followed by dichloromethane (60 cm3). The resulting mixture was then shaken and the organic layer was washed with water (40 cm3), saturated aqueous sodium bicarbonate solution (40 cm3), water again (40 cm3) and then saturated aqueous sodium chloride solution (50 cm3) before the organic portion was dried over sodium sulfate, It was then evaporated under reduced pressure to afford the title compound (1) (800 mg, 1.62 mmol, 69%), positive ion ESI (M+H)+ 494.6.