Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][CH:15]2O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12](=[CH:11][CH:10]=1)[CH2:13][CH:14]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1CCc2ccc(OCc3ccccc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=Cc2cc(OCc3ccccc3)ccc2C1
Temperature: 80 °C
Yield: 88.5 %

Procedure:
To a stirred solution of the product from Step B (15.0 g, 62.5 mmol) in toluene (200 mL) was added p-TsOH (1.0 g, 6.25 mmol) at ambient temperature and the mixture was heated at 80° C. for 1.5 hours. The mixture was concentrated and purified by column chromatography (eluted with PE:EtOAc=30:1) to give the title compound (12.3 g, 89%) as a white solid. 1H-NMR (600 MHz, CDCl3) δ 7.47-7.46 (m, 2H), 7.41-7.33 (m, 5H), 7.06-7.05 (m, 1H), 6.85-6.84 (m, 1H), 6.60-6.58 (m, 1H), 5.11 (s, 2H), 3.35 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][C@H:8]1[C@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C:9]1=O)([CH3:4])[CH3:3].Cl.[O:25]([NH2:27])[CH3:26]>N1C=CC=CC=1>[CH3:26][O:25][N:27]=[C:9]1[CH2:10][C@@H:11]([CH2:12][O:13][Si:14]([C:17]([CH3:18])([CH3:20])[CH3:19])([CH3:16])[CH3:15])[C@H:8]1[CH2:7][O:6][Si:5]([C:2]([CH3:3])([CH3:4])[CH3:1])([CH3:23])[CH3:22]
Reactant: CON
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 75.6 %

Procedure:
A solution of 12.317 g (34.9 mmol) of [2R,3R]-2,3-Bis(((1,1-dimethylethyl)dimethylsilyl)oxymethyl)cyclobutanone, from Step E, in 20 mL of pyridine was added to a solution of 3.160 g (37.8 mmol) of methoxylamine hydrochloride in 80 mL of pyridine. After stirring the reaction mixture for 70 min at ambient temperature, it was concentrated to approximately 1/4 of the original volume then diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on a 5×38 cm silica gel column eluted with 1 L of hexane and 5% acetone in hexane to give 10.228 g (75.7% yield) of the title compound as a mixture of geometrical isomers. .MS DCI-NH3M/Z: 388 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:7]([NH:9][C@H:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([OH:14])=[O:13])=[O:8])([O-:3])=[O:2].O[N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[C:7]([NH:9][C@H:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][C:12]([O:14][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34])=[O:13])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1)ON1C(=O)CCC1=O
Temperature: 2.5 °C

Procedure:
12 g of (S)-3-(3,5-dinitrobenzamido)-3-phenylpropionic acid from reaction b) were dissolved in 120 ml of tetrahydrofuran and admixed with 3.92 g of N-hydroxysuccinimide. With cooling in an icebath at 0-5° C., 7.1 g of dicyclohexylcarbodiimide was added in portions to the reaction mixture. On completion of addition, the mixture was left in the icebath with further stirring until the solution reached room temperature. After the reaction ended (HPLC monitoring >95 area % conversion), the precipitated dicyclohexylurea was filtered off and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue digested at reflux in 250 ml of 2-propanol for 2 h. The product was filtered off with suction, washed with 2-propanol and dried at 50° C. under reduced pressure. The yield was 13.87 g; HPLC purity 98.8 area %.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[NH2:21])[CH:5]=[CH:6][CH:7]=1.[N:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]2=[C:24]([C:31](Cl)=[O:32])[CH:23]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[N:11]=[CH:10][C:9]=2[NH:21][C:31]([C:24]2[CH:23]=[N:22][N:26]3[CH:27]=[CH:28][CH:29]=[N:30][C:25]=23)=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)COCCn1ncc(N)c1-c1cccc(Br)c1
Reactant: O=C(Cl)c1cnn2cccnc12
Solvent: C1CCOC1
Product: C[Si](C)(C)COCCn1ncc(NC(=O)c2cnn3cccnc23)c1-c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A mixture of 5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine (533 mg, 1.45 mmol), in tetrahydrofuran (5 mL) was added of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (262 mg, 1.45 mmol) in tetrahydrofuran (5 mL) at 0° C. After addition, the mixture was warmed to room temperature, and then stirred overnight at this temperature. The mixture was concentrated to give 742 mg (99%) of N-(5-(3-bromophenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was carried forward without purification. LCMS (ESI) m+H=513.1.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:21]([F:32])[CH:20]=2)[C:10]2[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=2[CH:8]=1)=[O:6]>CO>[C:28]([O:27][C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][C:16]2[C:10]3[CH2:11][C:12]([CH3:15])([CH3:14])[O:13][C:9]=3[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:17]=2)=[CH:20][C:21]=1[F:32])=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)OC(C)(C)C)c(F)c2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Temperature: 60 °C
Yield: 103.4 %

Procedure:
NaOH (6.20 mL, 19.0 mmol, 3N aqueous solution) was added to a solution of 4-(4-tert-butoxycarbonyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (66a) (2.56 g, 5.91 mmol) in 30 mL MeOH. The reaction mixture was heated to 60° C. for 2 hr, concentrated, diluted with H2O (100 mL), acidified with 1N aqueous HCl to pH˜1, and extracted with CH2Cl2 (2×100 mL). The combined organic layer was dried over MgSO4, concentrated in vacuo to give a white solid (2.46 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.08 (br. s., 1 H) 7.85 (t, J=8.72 Hz, 1 H) 7.11 (d, J=1.26 Hz, 1 H) 7.06 (d, J=1.01 Hz, 1 H) 6.99 (dd, J=12.13, 2.27 Hz, 1 H) 6.89 (dd, J=8.72, 2.40 Hz, 1 H) 2.87 (s, 2 H) 1.53 (s, 9H) 1.42 (s, 6 H); LCMS for C22H23FO6 m/z 425.00 (M+Na)+.
Reaction SMILES: C([O:5][C:6](=[O:25])[C@@H:7]([N:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)[CH3:13])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:12]([CH3:13])[C@@H:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:25])=[O:5])=[CH:16][CH:17]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N(C)Cc1ccc(C(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)O)N(C)Cc1ccc(C(C)(C)C)cc1
Reaction time: 1 h

Procedure:
Step, iii: (S)-2-[(4-tert-Butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid tert-butyl ester (0.5 g, 1.4 mmol) was dissolved in CH2Cl2 (10 mL) and treated with TFA (1mL). After 1 hour, 0.5 mL TFA was added, followed by another 1 mL TFA at 2.5 hours. The reaction was stirred overnight, then concentrated to give (S)-2-[(4-tert-butyl-benzyl)-methyl-amino]-4-methyl-pentanoic acid (IIc).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O.N1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1nc2cc(N)ccc2s1
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4sc(C)nc4c3)c2cc1OC
Yield: 94.4 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.237 g of 5-amino-2-methylbenzothiazole dihydrocholride, 0.158 g of pyridine, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 20 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.356 g of 6,7-dimethoxy-4-(2-methyl-benzothiazol-5-ylamino)-quinoline-3-carbonitrile as a solid, mp 118-120° C.; mass spectrum (EI, m/e): M 376.0973.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23]([C:26](Cl)=[O:27])=[CH:22][CH:21]=1>ClCCl>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=[CH:22][C:23]([C:26]([N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[O:27])=[CH:24][CH:25]=1
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccccc2)cc1)N1CCCCc2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A solution of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine of Step A (0.300 g) and N,N-diisopropylethyl amine (0.5 mL) in dichloromethane (25 mL) was cooled to 0°. To this was added a solution of 4-biphenyl carbonyl chloride (0.518 g) in dichloromethane (5 ml). The solution was stirred overnight as it warmed to room temperature, then washed with 0.1N hydrochloric acid, aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to an oil. Flash chromatography of the residue on silica gel provided the title compound as a white solid (0.490 g), m.p. 164-166° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2)([O-:3])=[O:2].[OH-].[K+].[I:15]I>CN(C=O)C.S(=O)(O)[O-].[Na+]>[I:15][C:9]1[C:8]2[C:12](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[NH:11][N:10]=1
Reactant: II
Reactant: O=[N+]([O-])c1cccc2cn[nH]c12
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c(I)n[nH]c12
Reaction time: 2 h
Yield: 88.3 %

Procedure:
7-Nitroindazole (1.60 g, 9.80 mmol) was dissolved in DMF (100 mL), and thereto potassium hydroxide (2.20 g, 39.20 mmol) and iodine (4.98 g, 19.61 mmol) were added in drops. The mixture was stirred for 2 hours, and diluted with 10% sodium bisulfite solution. The resulting solid was collected and dried to give 3-iodo-7-nitro-1H-indazole (2.50 g, Yield 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([F:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:28])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([F:21])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCCC(F)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCCC(F)C1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(3-fluoropiperidin-1-yl)quinolin-7-yl]ethanone (0.0287 g, 0.0936 mmol) and ammonium acetate (0.0721 g, 0.936 mmol) in methanol (1.0 mL) and acetonitrile (1.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.234 mL, 0.234 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C16H20ClFN3 (M+H)+: m/z=308.1; Found: 308.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:27])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[C:15](Cl)=[N:14][CH:13]=1)[CH3:8]>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:27])[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[C:15]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:14][CH:13]=1)[CH3:8]
Reactant: CCOC(=O)Cc1cnc(Cl)c2cc(OC)c(OC)cc12
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1cnc(N2CCOCC2)c2cc(OC)c(OC)cc12

Procedure:
Excess morpholine is added to a suspension of (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid ethyl ester (0.200 g, 0.65 mmol) in toluene (1 ml) and the mixture heated to reflux until the starting material is consumed. After evaporation, the residue is partitioned between water and dichloromethane, the organic phase is dried over magnesium sulfate and evaporated. to afford (6,7-dimethoxy-1-morpholin4-yl-isoquinolin4-yl)-acetic acid ethyl ester [MH]+ 361. The crude ester (0.240 g, 0.66 mmol) is dissolved in ethanol (20 ml), treated with 2M sodium hydroxide (3 ml) and stirred at room temperature overnight. After adjustment to pH 1 with concentrated hydrochloric acid, the solvent is evaporated and the crude acid used directly for formation of the xanthine derivative.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:4]([CH3:21])[C:5](=O)[NH:6][C@H:7]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:43]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C@@H:3]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:4]([CH3:21])[C:5]([NH:6][C@H:7]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[S:43]
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CO[C@H]([C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 33.2 %

Procedure:
A mixture of #16 (350 mg, 0.739 mmol, 1 eq.) and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson's reagent) (324 mg, 0.776 mmol, 1.05 eq.) in toluene (6 mL, 0.1 M) was warmed to 100° C. After 10 minutes, the mixture was cooled to room temperature. Insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 12% to 80% ethyl acetate in heptane) and then by reverse phase chromatography (Method E2) to give #17 (120 mg, 33%); HPLC (Protocol J): m/z 490.2 [M+H+], retention time=10.069 minutes; [α]20D−110 (c 0.24, MeOH); 1H NMR (400 MHz, CD3OD), characteristic signals: δ 7.78 (d, J=3.3 Hz, 1H), 7.51 (d, J=3.3 Hz, 1H), 7.32-7.37 (m, 2H), 7.24-7.30 (m, 2H), 7.17-7.23 (m, 1H), 6.52-6.61 (br m, 1H), 3.62 (br dd, J=15, 4 Hz, 1H), 3.37 (s, 3H), 2.98-3.09 (br m, 1H), 2.53-2.64 (br m, 1H), 1.60-1.78 (m, 2H), 1.49 (s, 9H), 1.27 (d, J=6.5 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[F:13][C:14]1[CH:15]=[C:16](OB(O)O)[CH:17]=[CH:18][C:19]=1[F:20].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>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.C(O)C>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OB(O)Oc1ccc(F)c(F)c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Oc1ccc2cc(-c3ccc(F)c(F)c3)ccc2c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
To 25.0 g of 6-bromo-2-naphthol and 22.0 g of 3,4-difluorophenylboric acid were added 100 ml of toluene, 50 ml of ethanol, 50 ml of a 2 N aqueous solution of potassium carbonate and 1.3 g of tetrakis(triphenylphosphine)palladium (0). The reaction mixture was heated under reflux for 3 hours. The reaction solution was then allowed to cool to room temperature. The resulting organic phase was separated, washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was purified through silica gel column chromatography (dichloromethane) to obtain 25.3 g of 6-(3,4-difluorophenyl)-2-naphthol.
Reaction SMILES: COC([CH2:5][CH:6](C1CO1)[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=O.C([Mg]Cl)C=C.C(Cl)/C=C(/CCC=C(C)C)\C.[NH4+].[Cl-]>CCOCC.C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:17]/[C:10](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:9]\[CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: COC(=O)CC(CC/C=C(\C)CCC=C(C)C)C1CO1
Agent: C=CC[Mg]Cl
Agent: CC(C)=CCC/C(C)=C/CCl
Agent: [Cl-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC/C=C(\C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 78 %

Procedure:
For the synthesis of the (E)-6,10-dimethyl-2-oxiranylundeca-5,9-dienecarboxylic acid methyl ester, 27.00 ml (54.00 mmol) of a 2 M solution of allylmagnesium chloride in ether is added dropwise within 30 minutes to a solution of 1.10 g (6.40 mmol) of geranyl chloride in 50 ml of THF/HMPT (v/v=1/1). The resulting mixture is stirred at room temperature for 15 hours, and then 20 ml of saturated aqueous NH4Cl solution is added. The organic phase is separated off, and the aqueous phase is extracted four times with 25 ml each of dichloromethane. The combined organic phases are concentrated under reduced pressure. The remaining residue is taken up with 50 ml of ether, successively washed with 2 M aqueous hydrochloric acid, saturated aqueous NaCl solution and distilled water, dried over MgSO4 and concentrated under reduced pressure. The vacuum distillation of the thus obtained residue yields 0.89 g (4.99 mmol, 78%) of (E)-6,10-dimethyl-undeca-1,5,9-triene.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][N:5]=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[CH:19](=O)[CH3:20].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[CH2:19]([N:8]([CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)[C:7]1[C:2]([CH3:1])=[C:3]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[N:5][CH:6]=1)[CH3:20]
Reactant: COC(=O)c1cncc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: O
Product: CCN(c1cncc(C(=O)OC)c1C)C1CCOCC1
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a stirred solution of methyl 4-methyl-5-[(oxan-4-yl)amino]pyridine-3-carboxylate (600 mg, 2.40 mmol) in DCE (20 ml) under a nitrogen atmosphere was added acetaldehyde (1.07 ml, 19.2 mmol) followed by trifluoroacetic acid (367 μl, 4.79 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (3.05 g, 14.4 mmol). The reaction was stirred for 16 h at room temperature after which time more acetaldehyde (500 μl) and sodium triacetoxyborohydride (1.0 g) were added and the reaction stirred for a further 16 h. Distilled water (20 ml) was added and solid NaHCO3 was added until pH8. The phases were separated and then the aqueous phase was washed with DCM (2×50 ml), the combined organics were washed with brine (50 ml), dried using Na2SO4, filtered and evaporated. The residue was purified using a 25 g Isolute silica column using a gradient of 0% to 50% EtOAc in heptane to afford the title compound as a pale yellow oil (418 mg, 60%). LC-MS 96%, m/z=279.1, 1H NMR (500 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.44 (s, 1H), 3.97 (d, J=11.0 Hz, 2H), 3.93 (s, 3H), 3.33 (td, J=11.6, 2.1 Hz, 2H), 3.13 (q, J=7.1 Hz, 2H), 3.04 (tt, J=10.9, 4.0 Hz, 1H), 2.54 (s, 3H), 1.76-1.59 (m, 4H), 0.89 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]=[C:5]([C:9]#[N:10])C(O)=O.C(=O)=O>[Cu]>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1/[CH:4]=[CH:5]\[C:9]#[N:10]
Reactant: N#CC(=Cc1ccccc1Cl)C(=O)O
Agent: [Cu]
Agent: O=C=O
Product: N#C/C=C\c1ccccc1Cl

Procedure:
o-Chlorobenzalcyanoacetic acid (40 g; 0.193 m) was intimately mixed with copper powder (3 g) and cuprous oxide (1 g) and heated in vacuo at a temperature of 240° C. with vigorous evolution of carbon dioxide. The distillate was a pale yellow oil which was shown to contain 71% cis-nitrile by NMR assay. Fractional distillation of the mixture was carried out collecting early fractions containing pure cis-isomer, b.p. 90°-92° C. at 1.2 mm/Hg.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Na+].Br[CH2:14][CH:15]([CH2:20]Br)[C:16]([O:18][CH3:19])=[O:17].O>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:18][C:16](=[O:17])[C:15]([CH2:20][N:2]1[C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)=[CH2:14]
Reactant: COC(=O)C(CBr)CBr
Reactant: O=c1[nH]nc2ccccn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C=C(Cn1nc2ccccn2c1=O)C(=O)OC
Reaction time: 0.5 h

Procedure:
After dissolving 2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (CAS 6969-71-7) (1.0 g) in N,N-dimethylformamide (50 ml), sodium hydride (60% in oil) (355 mg) was added while stirring on ice. After stirring for 20 minutes, methyl 3-bromo-2-(bromomethyl)propionate (2.11 ml) was added dropwise. Stirring was continued for 1 hour and 30 minutes, and then sodium hydride (60% in oil) (200 mg) was added and the mixture was stirred for 3 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (400 mg).