Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])=[N+:2]=[N-:3].[Cl:13][C:14]1[C:21]([F:22])=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1.[H-].[Na+].O>CN(C=O)C>[N:1]([CH2:4][C@@H:5]([O:6][C:16]1[CH:15]=[C:14]([Cl:13])[C:21]([F:22])=[CH:20][C:17]=1[C:18]#[N:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: [N-]=[N+]=NC[C@@H](O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CN=[N+]=[N-])c1ccccc1
Yield: 69.8 %

Procedure:
The product from step (a) (1.75 g) and 4-chloro-2,5-difluorobenzonitrile (1.86 g) in dry DMF (40 ml) were treated with 60% sodium hydride in mineral oil (470 mg) with stirring under nitrogen. The reaction mixture was stirred for 2.5 h, poured into water, and extracted with ethyl acetate. The extract was washed with water (5×) then brine and dried (MgSO4). The solvent was evaporated and the residue purified by chromatography (silica, 10% ether/isohexane as eluent) to give the sub-title compound (2.37 g) as a pale yellow oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5]>C1COCC1.[Br-]>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:8]([CH3:17])[CH3:7])[CH:10]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 1.3 mL 0.5M 3-N,N-dimethylanilinemagnesium bromide. Yield: 97 mg of a yellow solid. LC-MSD, m/z for C24H20BrN3O2 [M+H]+=462.0, 464.0; HPLC retention time: 2.2 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)=[CH:4][C:5](=[O:19])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([F:18])[CH:9]=2)[CH:7]=1.Cl>>[ClH:1].[Cl:1][C:2]1[C:3]([O:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][C:5](=[O:19])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:10]([F:18])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(S(C)(=O)=O)c(F)c3)cc2Cl)CC1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2cc(Cl)c(OC3CCNCC3)cc2=O)cc1F
Reaction time: 0.25 h
Yield: 199.3 %

Procedure:
A mixture of tert-butyl 4-(5-chloro-1-(3-fluoro-4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (300 mg, 0.599 mmol) and hydrogen chloride (37% in H2O, 5 mL) was stirred for 15 min and then concentrated in vacuo to yield 261 mg of the desired product as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (br. s., 2H) 8.11 (s, 1H) 7.97 (t, J=8.16 Hz, 1H) 7.78 (dd, J=10.92, 1.88 Hz, 1H) 7.57 (dd, J=8.28, 1.76 Hz, 1H) 6.30 (s, 1H) 4.80-4.91 (m, 1H) 3.39 (s, 3H) 3.05-3.26 (m, 4H) 2.10-2.20 (m, 2H) 1.85-1.98 (m, 2H). MS (ESI) 401 (M+H).
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH2:15])=[O:14])[CH3:9].C1(C)C=CC=CC=1>O>[CH2:8]([C:10]1([CH2:16][CH3:17])[CH2:12][CH:11]1[C:13]([NH:15]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4])=[O:14])[CH3:9]
Reactant: CCC1(CC)CC1C(N)=O
Reactant: CCC(=O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C/C=C(\NC(=O)C1CC1(CC)CC)C(=O)O
Yield: 9.7 %

Procedure:
A mixture of 2.3 g of 2-ketobutyric acid, 2.0 g of 2,2-diethylcyclopropanecarboxamide, and 25 ml of toluene was heated under reflux for 16 hrs with removal of H2O by a modified Dean-Stark trap containing molecular sieves (4A). No product precipitated upon cooling. Ether (25 ml) was added and the mixture was extracted with saturated NaHCO3 (3 times). The combined extracts were acidified with concentrated HCl. The gummy precipitate crystallized when triturated with water. Recrystallization from ethyl acetate gave 0.31 g of product, m.p. 129°-30°. The NMR spectrum was consistent with the desired structure.
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[CH3:11][CH:2]([S:12][C:13]#[N:14])[C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#C[S-]
Reactant: CC(Br)C(=O)c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(SC#N)C(=O)c1ccccc1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of 2-bromopropiophenone (7.14 ml, 46.9 mmol) and potassium thiocyanate (4.56 g, 46.9 mmol) in ethanol (80 ml) was stirred at 80° C. for 3 hours. After cooling to room temperature, water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 7.27 g (81.0%) of the desired product as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][NH:5][C:6]1[N:15]=[C:14]([NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[CH:12]=2)[N:7]=1.[CH2:28]([N:30]([CH2:45][CH3:46])[CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH3:44])[CH3:43])[C:35]=1[CH:36]=O)[CH3:29]>>[CH2:45]([N:30]([CH2:28][CH3:29])[CH2:31][CH2:32][O:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH3:43])[CH3:44])[C:35]=1[CH2:36][N:20]1[CH2:21][CH2:22][CH:17]([NH:16][C:14]2[C:13]3[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[CH:12]=3)[N:7]=[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:27])[N:15]=2)[CH2:18][CH2:19]1)[CH3:46]
Reactant: CCN(CC)CCOc1cccc(N(C)C)c1C=O
Reactant: COc1cc2nc(NCCN(C)C)nc(NC3CCNCC3)c2cc1OC
Product: CCN(CC)CCOc1cccc(N(C)C)c1CN1CCC(Nc2nc(NCCN(C)C)nc3cc(OC)c(OC)cc23)CC1

Procedure:
Following General Procedure H, Compound 185 (34.6 mg, 0.093 mmol) and Compound 188 (58.2 mg, 0.22 mmol) were converted into the final product AGN-221250 as a yellow solid.
Reaction SMILES: [OH:1][N:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([NH:5][C:6]1[S:10][N:9]=[N:8][CH:7]=1)=[O:4].C(N(CC)CC)C.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>O1CCCC1>[C:11]1([N:2]([O:1][C:24](=[O:27])[CH2:25][CH3:26])[C:3]([NH:5][C:6]2[S:10][N:9]=[N:8][CH:7]=2)=[O:4])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1cnns1)N(O)c1ccccc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)ON(C(=O)Nc1cnns1)c1ccccc1
Temperature: 20 °C

Procedure:
9.43 g (0.04 mole) 1-hydroxy-1-phenyl-3-(1,2,3-thiadiazole-5-yl)-urea were under addition of 6.15 ml (0.044 mole) triethylamine dissolved in 100 ml tetrahydrofuran. There were added to this solution under cooling to 20° C., a solution of 3.46 ml (0.04 mole) propionylchloride in 10 ml tetrahydrofuran within about 5 minutes in dropwise fashion and thereafter the resulting mixture was stirred for an hour. After separating off the precipitate which had formed the filtrate was concentrated and the residue taken up in 150 ml of ether. The ether phase was washed with water, dried over magnesium sulfate, again concentrated and the residue digested with diisopropylether.
Reaction SMILES: CS(O)(=O)=O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24]([O:27]C)([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.[CH2:37](O)[CH2:38][OH:39]>>[NH2:29][C@@H:17]1[CH2:16][CH2:15][C@@H:14]([C:8]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])[CH2:20][N:19]2[C:21]([C:24]([CH3:25])([O:27][CH2:37][CH2:38][OH:39])[CH3:26])=[CH:22][N:23]=[C:18]12
Reactant: COC(C)(C)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2NC(=O)OC(C)(C)C
Reactant: OCCO
Agent: CS(=O)(=O)O
Product: CC(C)(OCCO)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2N
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Methanesulfonic acid (78 μL, 1.19 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,6-difluorophenyl)-3-(1-methoxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (104 mg, 0.24 mmol) in ethylene glycol (4 mL) and the mixture heated to 60° C. After 18 h, the reaction mixture was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×), and the combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated. MS 366.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[C:5]([C:18]([F:21])([F:20])[F:19])=[CH:4][N:3]=1.[CH2:22]([O:29][C:30](=[O:40])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[C:33]([O:38][CH3:39])[CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C[Si](Cl)(C)C>CC(O)C>[CH2:22]([O:29][C:30](=[O:40])[C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:2]2[N:7]=[C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=3)[C:5]([C:18]([F:21])([F:20])[F:19])=[CH:4][N:3]=2)=[C:33]([O:38][CH3:39])[CH:32]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1N
Reactant: O=[N+]([O-])c1ccc(Oc2nc(Cl)ncc2C(F)(F)F)cc1
Agent: C[Si](C)(C)Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)OCc2ccccc2)ccc1Nc1ncc(C(F)(F)F)c(Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
b-3.) 1.0 g of 2-chloro-4-(4-nitrophenyloxy)-5-trifluoromethylpyrimidine and 0.77 g of 4-amino-3-methoxy-benzoic acid benzyl ester are suspended in 15 mL of 2-propanol. The suspension is heated to 50° C. and 0.08 mL trimethylsilylchloride (TMSCl) are added. The suspension is stirred for 16 hours at 50° C. The suspension is cooled to ambient temperature and stirred for 3 hours. The precipitate is filtered and washed with 2-propanol. After drying in a vacuum drying oven 1.38 g (85% of theory) of the corresponding 2-amino pyrimidine derivative product, i.e. 3-methoxy-4-[4-(4-nitro-phenoxy)-5-trifluoromethyl-pyrimidin-2-ylamino]-benzoic acid benzyl ester is obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:8][CH2:7]1)=[O:5].[NH2:26][CH:27]1[CH:34]2[CH2:35][C:30]3([CH2:37][OH:38])[CH2:31][CH:32]([CH2:36][CH:28]1[CH2:29]3)[CH2:33]2>>[OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:26][CH:27]2[CH:28]3[CH2:36][CH:32]4[CH2:31][C:30]([CH2:37][OH:38])([CH2:35][CH:34]2[CH2:33]4)[CH2:29]3)=[O:19])[CH2:8][CH2:7]1)=[O:5]
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Reactant: CC(C)(CO)C(=O)N1CCC(CCOc2cccc(C(=O)O)c2)CC1
Product: CC(C)(CO)C(=O)N1CCC(CCOc2cccc(C(=O)NC3C4CC5CC3CC(CO)(C5)C4)c2)CC1

Procedure:
Prepared from 3-{2-[1-(3-hydroxy-2,2-dimethyl-propionyl)-piperidin-4-yl]-ethoxy}-benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 7.31-7.38 (m, 2H), 7.24-7.29 (m, 1H), 7.02 (d, 1H), 6.31-6.43 (m, 1H), 4.33-4.45 (m, 2H), 4.17-4.24 (m, 1H), 4.07 (t, 2H), 3.49 (s, 2H), 3.26 (d, 2H), 2.74-2.87 (m, 2H), 2.12-2.19 (m, 2H), 2.01-2.05 (m, 1H), 1.42-1.93 (m, 15H), 1.27 (s, 6H), 1.14-1.23 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[NH:26][N:25]=[N:24][N:23]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:6][CH:5]=1)([O-])=O.O.NN.[H][H]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[NH:26][N:25]=[N:24][N:23]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:6][CH:5]=1
Reactant: CCCn1c(=O)c2[nH]c(Cc3nnn[nH]3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3nnn[nH]3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 1H-tetrazole-5-acetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.
Reaction SMILES: [H-].[K+].C([O:7][C:8](=[O:18])[CH2:9][CH:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=O)(C)(C)C>C1COCC1>[CH2:14]([CH:10]1[CH2:11][O:18][C:8](=[O:7])[CH2:9]1)[CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)CC(CC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CC1COC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.6 %

Procedure:
To a cooled (0° C.) suspension of potassium hydride (1.58 g, 39.5 mmol) (previously washed 3 times with pentane) in tetrahydrofuran (22 mL) was added, under an argon atmosphere, a solution of methyl methylthiomethyl sulfoxide (1.36 mL, 13.04 mmol, previously dried over molecular sieves for 3 hours) in tetrahydrofuran (3 mL) over 1 hour. After stirring for a further 30 minutes, a solution of 3 (3.17 g, 13.1 mmol) in THF (2 mL) was added, at 0° C., over 1 hour. The reaction mixture was then allowed to warm up to room temperature and was stirred overnight. The mixture was quenched by addition of aqueous ammonium chloride (6 mL, 25%). After 10 minutes, the solid was filtered off and the filtrate concentrated. The residue was taken up in ether (20 mL) and 9N sulfuric acid (0.05 mL) was added. After stirring for 30 hours, saturated sodium hydrogen carbonate was added. The ether phase was separated and concentrated to 5 mL. Saturated sodium hydrogen sulphite (1.5 g) solution was added and the mixture stirred for 30 minutes. The phases were separated. The ethereal phase was stirred for further 30 minutes with a saturated sodium hydrogen sulphite (0.5 g) solution. The phases were separated, and the collected aqueous phases were treated with aqueous sodium hydroxide (5 mL, 20%) and extracted with ether. The ether phase was dried (MgSO4) and evaporated under reduced pressure to give 4 as a yellow liquid (0.16 g, 11%). δH (400 MHz; CDCl3): 3.0 (2H, m), 2.15–2.45 (6H, m), 1.65 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH2:18][OH:19])=[N:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[N:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(CO)nc2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(C=O)nc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (5-((6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)methanol (0.266 g, 0.676 mmol) in DCM (3.38 mL) was added manganese dioxide (1.176 g, 13.52 mmol) and the reaction was stirred at room temperature for 48 h. Upon completion the reaction was filtered over Celite™ and concentrated in vacuo to afford crude 5-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)picolinaldehyde which was used without further purification. LC/MS (m/z, MH+): 392.2.
Reaction SMILES: [F:1][C:2]1[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])[CH:7]=1.[Si:19]([O:36][CH2:37][CH2:38][C@@H:39](O)[CH2:40][CH3:41])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[Si:19]([O:36][CH2:37][CH2:38][C@H:39]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([F:1])[C:3]([C:15]([O:17][CH3:18])=[O:16])=[N:4][CH:5]=1)[CH2:40][CH3:41])([C:32]([CH3:33])([CH3:34])[CH3:35])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC[C@H](O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: COC(=O)c1ncc(-c2ccccc2O)cc1F
Product: CC[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1cnc(C(=O)OC)c(F)c1

Procedure:
In accordance with the method of Example 5-2, the compound of Example 38-2 was used instead of the compound of Example 1-3, and (3S)-1-{[tert-butyl(diphenyl)silyl]oxy}pentane-3-ol (Tetrahedron Letters, 2006, 47(7), 1213-1215) was used instead of the compound of Example 5-1 to afford methyl 5-(2-{[(1R)-3-{[tert-butyl(diphenyl)silyl]oxy}-1-ethylpropyl]oxy}phenyl)-3-fluoropyridine-2-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]([SH:18])[CH2:16][SH:17])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH2:10]OC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([I:31])[C:28]=1[O:29][CH3:30])[CH:24]=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C@H:24]2[S:18][C@H:15]([C:5]3[CH:6]=[C:7]([O:13][CH3:14])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:16][S:17]2)[CH:26]=[C:27]([I:31])[C:28]=1[O:29][CH3:30]
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Reactant: COc1cc(C=O)cc(I)c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(I)c1OC

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (1.404 g,5.40 mmole), 3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (1.30 g, 4.45 mmole) and 0.542 g of pyridinium para-toluenesulfonate was added to 50 ml dry benzene and refluxed with Dean-Stark removal of the benzene- water azeotrope for 12 hours. The benzene was removed in vacuo, and the remaining oil redissolved in ethyl acetate. The organic layer was washed with 10% NaHCO3 and H2O. The organic layer was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.0 cis/trans ratio (2.38 g, 100%). The trans isomer can be isolated by recrystallization from methanol.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccc(F)c(F)c4)c3O2)cc1
Product: CNCC1Cc2cc(Cl)cc(-c3ccc(F)c(F)c3)c2O1

Procedure:
The title compound was prepared (0.09 g, 79%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(3,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.149 g, 0.33 mmol) and methylamine (0.102 g, 3.3 mmol). mp 235-237° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C:7]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[C:10]([CH2:21][C:22]2([CH3:25])[CH2:24][O:23]2)=[C:9]([O:26]CC2C=CC=CC=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>CO.[Pd]>[C:1]([O:5][C:6]([C:7]1[CH:12]=[C:11]([OH:13])[C:10]2[CH2:21][C:22]([CH2:24][OH:23])([CH3:25])[O:26][C:9]=2[CH:8]=1)=[O:34])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1cc(OCc2ccccc2)c(CC2(C)CO2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(C)(CO)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.7 %

Procedure:
A mixture of 3,5-bis-benzyloxy-4-(2-methyl-oxiranylmethyl)-benzoic acid tert-butyl ester (227b) (158 g, 0.343 mol), 10% Pd/C (15 g), Et3N (57.3 mL, 0.412 mol) and K2Co3 (56.94 g, 0.412 mol) in MeOH (1.5 L) was stirred under 760 mmHg of H2 at room temperature overnight. TLC (EtOAc/petroleum ether=1/3) showed that the reaction was complete. The mixture was filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (EtOAc/petroleum ether=1/3) to give a brown oil. The brown oil was further purified by prep. HPLC to give the title compound (18 g, 18.7% yield) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 6.98 (s, 1H), 6.82(s, 1H), 3.67 (d, 1 H), 3.56 (d, 1H), 2.80 (d, 1H), 1.48 (s, 9H), 1.35 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:43])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17]2[N:16]=[C:15]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:14]3=[CH:13][C:12]=2[C:11](=[O:23])[N:10]([CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28](C(NCCN(C)C)=O)[CH:27]=2)[CH:9]=1)=[O:7].[OH-].[Na+]>C(O)C>[CH3:43][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:17]2[N:16]=[C:15]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:14]3=[CH:13][C:12]=2[C:11](=[O:23])[N:10]([CH2:24][CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)[CH:9]=1)=[O:7]
Reactant: Cc1cccc2cc3c(=O)n(CCc4cn(C(=O)NCCN(C)C)c5ccccc45)cc(C(=O)NCCN(C)C)c3nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc2cc3c(=O)n(CCc4c[nH]c5ccccc45)cc(C(=O)NCCN(C)C)c3nc12
Yield: 89.8 %

Procedure:
To a hot solution of the bisamide 21b (0.58 g, 1.00 mmol) in ethanol (10 mL) was added 10% sodium hydroxide (10 mL), and the whole was heated at reflux for 40 min. The reaction mixture was then evaporated to dryness under reduced pressure, water was added and the solid was filtered and washed with water to give 20v as a gold solid (0.42 g, 90%), mp 105-107° C. (from acetonitrile). 1H NMR (CDCl3): δ 2.31 [s, 6H, N(CH3)2], 2.64 (t, J=6.4 Hz, 2H, CH2CH2NMe2), 2.82 (s, 3H, ArCH3), 3.21 (t, J=7.7 Hz, 2H, CH2CH2Indole), 3.73 (q, J=6.1 Hz, 2H, CH2CH2NMe2), 4.30 (t, J=7.8 Hz, 2H, CH2CH2Indole), 6.99 (d, J=2.0 Hz, 1H, H-2′), 7.06-7.14 (m, 2H, H-5′, H-6′), 7.30 (d, J=7.7 Hz, 1H, H-7′), 7.46 (t, J=7.6 Hz, 1H, H-8), 7.66-7.70 (m, 2H, H-4′, H-7), 7.82 (d, J=8.2 Hz, 1H, H-9), 8.51 (s, 1H, H-3), 8.62 (s, 1H, H-1′), 9.24 (s, 1H, H-10), 10.98 (br t, J=5.3 Hz, 1H, CONH). 13C NMR (CDCl3): δ 18.2 (ArCH3), 24.8 (CH2CH2Indole), 37.2 (CH2CH2NMe2), 45.0 [N(CH3)2], 50.2 (CH2CH2Indole), 58.4 (CH2CH2NMe2), 109.0 (C), 110.9 (CH, C-7′), 111.1 (C), 118.2 (CH, C-4′), 119.2 (CH, C-5′), 121.7 (CH, C-6′), 122.0 (CH, C-2′), 125.6 (C-9a), 126.2 (CH, C-8), 126.8 (C-3a′), 127.0 (CH, C-9), 132.5 (CH, C-7), 135.5 (C-6), 136.0 (C-7a′), 139.5 (CH, C-3), 142.7 (CH, C-10), 147.8 (C-5a), 148.4 (C-4a), 162.1 (C-1), 164.4 (CONH). Indole C-3′ was not observed.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Br:27]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:27])[N:6]2[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1nc(NCCc2ccccc2)nc2c1ncn2Cc1ccccc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(NCCc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
6-Amino-9-benzyl-2-(N-benzylmethylamino)purine (77 mg, 0.22 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (91 mg, yield 96%).