Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:32][CH3:33])[C:23]=3[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:18]2=[O:34])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:32][CH3:33])[C:23]=3[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:18]2=[O:34])=[CH:11][CH:10]=1
Reactant: CCCCCOc1c(OC)ccc2c1CN(CCc1ccc(OCc3ccccc3)cc1)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCOc1c(OC)ccc2c1CN(CCc1ccc(O)cc1)C2=O
Yield: 4.9 %

Procedure:
2-[2-(4-Benzyloxyphenyl)ethyl]-5-methoxy-4-pentyloxy-2,3-dihydroisoindol-1-one (125.9 mg, 0.274 mmol, 1.0 eq) was dissolved in ethyl acetate (10 ml), and 100% palladium-carbon catalyst (80 mg, water content 50%) was added. The mixture was stirred in a stream of hydrogen for 3 hours. After the completion of the reaction, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give 2-[2-(4-hydroxyphenyl)ethyl]-5-methoxy-4-pentyloxy-2,3-dihydroisoindol-1-one (5 mg, 74.1%) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH3:10])=[CH:15][CH:14]=1
Reactant: Cc1cc(C#N)ccc1Br
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C#N)cc2C)cc1
Yield: 80 %

Procedure:
4-Bromo-3-methylbenzonitrile and 4-methoxyphenylboronic acid were processed as described in Example 164A to provide the title compound (80% yield). 1HNMR (300 MHz, CDCl3) δ2.40 (3H), 3.73 (s, 3H), 6.84-7.60 (m, 7H); MS (DCI) m/z 224 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>CC(O)=O>[Br:19][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([NH2:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(Br)cc1[N+](=O)[O-]
Temperature: 110 °C
Yield: 46.8 %

Procedure:
A mixture of 5-chloro-2-nitrobenzenamine (6.0 g, 34.9 mmol) and NBS (6.06 g, 34.0 mmol) in HOAc (240 mL) was heated at 110° C. for 1 h. The solution was cooled to RT and the reaction mixture was poured into an ice-water (800 mL). The resulting solid was filtered, washed with water (50 mL×3), and dry under vacuum to afford 4.0 g (44%) of 4-bromo-5-chloro-2-nitrobenzenamine (246) as yellow solid: MS (ESI) m/z=250.9 (M−1).
Reaction SMILES: [CH2:1]([O:3][P:4]([O:19][CH2:20][CH3:21])([O:6][C:7]1[CH:12]=[CH:11][C:10](/[C:13](/[CH3:18])=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:22][C:23]1[C:28](O)=[C:27]([Cl:30])[C:26]([Cl:31])=[C:25]([Cl:32])[C:24]=1[Cl:33].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:1]([O:3][P:4]([O:19][CH2:20][CH3:21])([O:6][C:7]1[CH:8]=[CH:9][C:10](/[C:13](/[CH3:18])=[CH:14]/[C:15]([O:17][C:28]2[C:27]([Cl:30])=[C:26]([Cl:31])[C:25]([Cl:32])=[C:24]([Cl:33])[C:23]=2[Cl:22])=[O:16])=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(OCC)Oc1ccc(/C(C)=C/C(=O)O)cc1
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)Oc1ccc(/C(C)=C/C(=O)Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)cc1
Yield: 72.2 %

Procedure:
A solution of 10b (2.0 g, 6.4 mmol), pentachlorophenol (1.9 g, 7.0 mmol), DCC (1.6 g, 7.7 mmol) and DMAP (0.08 g, 0.64 mmol) in 100 mL of EtOAc was stirred at room temperature for 24 h. The mixture was filtered through celite and the solvent removed in vacuo. The crude product was purified by silica gel chromatography eluting with 25% EtOac-hexanes to give 2.6 g (72%) of 11b1 as white solid. 1H NMR (CDCl3, 300 MHz) δ 1.26-1.32 (m, 6H), 2.54 (d, J=1.2 Hz, 3H), 4.12-4.21 (m, 4H), 6.34 (d, J=1.2 Hz, 1H), 7.2 (d, J=8.7 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H). 11C NMR (CDCl3, 75.0 MHz) δ 16.0, 16.1, 18.4, 64.8, 64.8, 68.9, 113.4, 120.2, 120.3, 128.0, 128.1, 131.2, 131.9, 137.8, 141.9, 144.3, 152.1, 160.6, 161.9. HRMS (M+H) calc, 560.9362; found, 560.9197.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C@@H:18]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:50]([C:51]#[N:52])=[C:49]([S:53][CH2:54][C:55]3[N:56]=[C:57]([C:60]4[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][CH:61]=4)[O:58][CH:59]=3)[N:48]=[C:47]([NH2:67])[C:46]=2[C:68]#[N:69])=[CH:41][CH:40]=1)[CH2:19][O:20][C:21](=[O:36])[CH2:22][CH2:23][NH:24][C:25](=[O:35])[CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:16])=[O:11])=O)(C)(C)C.[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73]>ClCCl>[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73].[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73].[NH2:27][CH2:26][C:25]([NH:24][CH2:23][CH2:22][C:21]([O:20][CH2:19][C@@H:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH2:8])[CH2:37][O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[C:50]([C:51]#[N:52])=[C:49]([S:53][CH2:54][C:55]3[N:56]=[C:57]([C:60]4[CH:61]=[CH:62][C:63]([Cl:66])=[CH:64][CH:65]=4)[O:58][CH:59]=3)[N:48]=[C:47]([NH2:67])[C:46]=2[C:68]#[N:69])=[CH:41][CH:40]=1)=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](COC(=O)CCNC(=O)CN)OC(=O)CCNC(=O)CN)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An amount of 79 mg (0.080 mmol) of the compound from example 32A was introduced in 0.5 ml of dichloromethane, admixed with 0.061 ml (0.798 mmol) of trifluoroacetic acid and stirred at RT. After 3 hours, again, the same amount of trifluoroacetic acid was added and the mixture was stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 54 mg (65% of theory) of the target compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Br:25][C:26]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH:33]=[CH:32][C:27]=1[O:28][CH2:29][CH:30]=O>C(Cl)Cl.[Zn]>[Br:25][C:26]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH:33]=[CH:32][C:27]=1[O:28][CH2:29][CH:30]=[C:20]([Br:24])[Br:21]
Reactant: BrC(Br)(Br)Br
Reactant: O=CCOc1ccc(Oc2cccc(Cl)c2)cc1Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cccc(Oc2ccc(OCC=C(Br)Br)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
First, 0.38 g of zinc dust, 1.54 g of triphenylphosphine, 1.94 g of carbon tetrabromide and 20 ml of methylene chloride were charged into a reaction vessel, and stirred at room temperature. After 24 hours, a solution prepared by dissolving 1.0 g of (2-bromo-4-(3-chlorophenoxy) phenoxy)acetaldehyde in 5 ml of methylene chloride was added dropwise to the solution with stirring. After stirring at room temperature for 6 hours, the reaction solution was concentrated to give a residue. This residue was subjected to silica gel column chromatography to give 0.48 g of 2-bromo-4-(3-chlorophenoxy)-1-(3,3-dibromo-2-propenyloxy)benzene, yield 33%; nD24.0 1.6282.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:8]2)=[CH:4][CH:3]=1.Cl.Cl[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]1([C:9]2[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)=[CH:26][CH:25]=3)[N:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc4ccccc4n3)cc2)nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 83.2 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (600 mg), 2-chloromethylquinoline hydrochloride (380 mg), potassium carbonate (360 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(2-quinolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (660 mg, yield: 83%). This was recrystallized from acetone-hexane. Melting point: 147–148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>C1COCC1.C(N(CC)C(C)C)(C)C>[F:15][C:16]([F:26])([F:27])[C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1)=[O:20]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1cc(N)cc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]cnc12
Temperature: 0 °C

Procedure:
To a solution of methyl 6-amino-1H-benzimidazole-4-carboxylate (266 mg) in dehydrated THF (12 mL), N,N-diisopropylethylamine (284 μL) was added, and the solution was stirred under ice-cooling. To this solution, 2-(trifluoromethyl)benzoyl chloride (284 μL) in dehydrated THF (5 mL) was added slowly dropwise, and stirred at the same temperature for 3 hours. After ice water was added, THF was removed under reduced pressure, and aqueous saturated sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on NH silica gel column chromatography (ethyl acetate→ethyl acetate/MeOH) to obtain the titled compound (309 mg) as pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[C:13]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=1[Cl:11]
Reactant: COc1ccc(CS)c(Cl)c1
Reactant: C#Cc1cccc(C)c1C
Agent: [Na]
Product: COc1ccc(C(/C=C\c2cccc(C)c2C)SC(/C=C\c2cccc(C)c2C)c2ccc(OC)cc2Cl)c(Cl)c1

Procedure:
A solution of 2,3-dimethylphenylacetylene (0.02 mol), 2-chloro-4-methoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,3-dimethylstyryl-2-chloro-4-methoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[O:25])[NH2:24])=[N:9][C:8]=2[N:7]=[C:6]1[N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)[C:2]#[C:3][CH3:4].[ClH:39].C(OCC)(=O)C>CO>[ClH:39].[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([NH2:24])=[O:25])=[N:9][C:8]=2[N:7]=[C:6]1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Oc3ccccc3C(N)=O)n(C)c(=O)c21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC#CCn1c(N2CCNCC2)nc2nc(Oc3ccccc3C(N)=O)n(C)c(=O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
210 mg of t-butyl 4-[7-(2-butynyl)-2-(2-carbamoylphenoxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was combined with 3.5 ml of methanol and 2.1 ml of 4N hydrochloric acid-ethyl acetate solution. After the mixture had been stirred at room temperature for 4 hours, the reaction solution was concentrated by flushing with nitrogen gas. The resulting residue was washed with ethanol and ethyl acetate to give 177 mg of the title compound (96%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34](=O)[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=5)[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(C=O)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)cc1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-[1-(4-methoxy-benzyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with p-anisaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.91-1.94 (m, 2H), 2.13-2.23 (m, 4H), 2.93-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.47 (s, 2H), 3.74 (s, 3H), 4.74-4.80 (m, 1H), 6.89-6.91 (m, 2H), 7.24-7.26 (m, 2H), 7.62-7.64 (m, 2H), 8.04-8.06 (m, 2H), 8.36 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=494.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[NH2:19][CH2:20][CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:19][CH2:20][CH2:21][OH:22])[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:5]=1
Reactant: COc1ccc(CNc2nc(Cl)nc(Cl)n2)cc1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc(CNc2nc(Cl)nc(NCCO)n2)cc1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A 1.43 g (5.01 mmol) portion of 2,4-dichloro-6-(4-methoxybenzylamino)-1,3,5-triazine was suspended in 100 ml of ethanol, mixed with 303 μl (5.01 mmol) of 2-aminoethanol and 693 mg of potassium carbonate and stirred at 45° C. for 1 day. After evaporation of the solvent under a reduced pressure, water was added to the residue and the resulting precipitate was collected by filtration to obtain 1.56 g (quantitative) of the title compound as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[CH2:12]([NH:16][OH:17])[CH2:13][CH2:14][CH3:15]>>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:16]([CH2:12][CH2:13][CH2:14][CH3:15])[O-:17])[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: CCCCNO
Product: CCCC[N+]([O-])=Cc1ccccc1OCC

Procedure:
The title compound was prepared according to the procedures described in Examples 11 using 2-ethoxybenzaldehyde and N-n-butylhydroxylamine. The title compound was isolated in 44.5% yield as a liquid.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[C:11]([CH:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[O:14][SiH:15]([CH3:17])[CH3:16])[CH:10]=[C:9]([CH:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[O:23][SiH:24]([CH3:26])[CH3:25])[CH:8]=1.[CH3:31][C:32]([CH3:34])=[O:33].[NH4+].[Cl-]>CCCCCC.C1COCC1>[OH:33][C:32]([C:7]1[CH:12]=[C:11]([CH:13]([C:18]([CH3:20])([CH3:19])[CH3:21])[O:14][SiH:15]([CH3:17])[CH3:16])[CH:10]=[C:9]([CH:22]([C:27]([CH3:30])([CH3:28])[CH3:29])[O:23][SiH:24]([CH3:25])[CH3:26])[CH:8]=1)([CH3:34])[CH3:31]
Reactant: CC(C)=O
Reactant: C[SiH](C)OC(c1cc(Br)cc(C(O[SiH](C)C)C(C)(C)C)c1)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[SiH](C)OC(c1cc(C(O[SiH](C)C)C(C)(C)C)cc(C(C)(C)O)c1)C(C)(C)C
Temperature: -71 °C

Procedure:
10.5 ml of n-BuLi as a 1.6M solution in hexane are added dropwise to 4.32 g of 1-bromo-3,5-bis[(tert-butyl)dimethylsilanyloxymethyl]benzene (G. T. Crisp and P. D. Turner, Tetrahedron, 2000, 56 (42), 8335) in solution in 150 ml of THF cooled to −71° C. After 1 h 30, 4.27 ml of acetone are added dropwise. The mixture is allowed to return to AT and then hydrolysed with a saturated aqueous NH4Cl solution. The aqueous phase is extracted with 100 ml of AcOEt, the combined organic phases are dried over MgSO4 and concentrated under RP, and the residue is purified by flash chromatography on silica (Biotage 65+M) using a gradient from 0 to 20% AcOEt in heptane. 2.48 g of 1-(1-hydroxy-1-methylethyl)-3,5-bis[(tert-butyl)dimethylsilanyloxymethyl]benzene are thus obtained.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[Se:8][C:7]=1[C:15]([O:17]CC)=[O:16])[CH3:3].[OH-].[Na+]>>[CH3:3][N:2]([N:4]=[N:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[Se:8][C:7]=1[C:15]([OH:17])=[O:16])[CH3:1]
Reactant: CCOC(=O)c1[se]c2ncccc2c1N=NN(C)C
Agent: [Na+]
Agent: [OH-]
Product: CN(C)N=Nc1c(C(=O)O)[se]c2ncccc12

Procedure:
The hydrolysis of ethyl 3-[(dimethylamino)diazenyl]selenopheno[2,3-b]pyridine-2-carboxylate with sodium hydroxide gave the required 3-[(dimethylamino)diazenyl]selenopheno[2,3-b]pyridine-2-carboxylic acid (compound 10).
Reaction SMILES: [N:1]1([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CO.O1CCOCC1>[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)N2CCCC2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C([C@@H]1CCCNC1)N1CCCC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-tert-butyl 3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate in methanol (120 mL) was slowly added a solution of hydrogen chloride in 1,4-dioxane (30 mL, 4M). The mixture was stirred at 30° C. for 2 h. The solvent was removed under reduced pressure to afford (R)-piperidin-3-yl(pyrrolidin-1-yl)methanone, which was used in the next step without further purification.
Reaction SMILES: [O-]CC.[Na+].[Na].[CH2:6]([O:8][C:9](=[O:24])[CH:10]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:11]#[N:12])[CH3:7].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(O)C>[CH2:6]([O:8][C:9](=[O:24])[C:10]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([C:11]#[N:12])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C(C#N)NC(=O)OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(C#N)(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
To a sodium ethoxide solution, which was prepared from sodium (2.11 g) and ethanol (400 ml), were added in turn 2-benzyloxycarbonylamino-2-cyanoacetic acid ethyl ester (24.0 g) and ethyl bromoacetate (15.3 g). The resulting mixture was stirred at 25° C. for 3 hours and concentrated under reduced pressure. The residue was diluted with water and extracted with chloroform. The extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give the title compound (31.6 g, 99%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][OH:11])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[F:19][C:20]([F:28])(S(F)(=O)=O)C(O)=O>CC#N.[Cu]I>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][O:11][CH:20]([F:28])[F:19])[CH2:7][N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: COC(=O)C1CC(CO)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: COC(=O)C1CC(COC(F)F)CN1C(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
4-Hydroxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (584 mg, 2.25 mmol) and CuI (86 mg, 0.45 mmol) were suspended in MeCN (10 mL). The reaction mixture was heated to 45° C. and difluoro-fluorosulfonyl-acetic acid (0.465 mL, 4.5 mmol) was added dropwise over the course of 30 min. Stirring was continued for another 3 h, after which the reaction mixture was cooled to RT and concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 and brine then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (19% to 40% EtOAc/Hex) to afford the title compound (394 mg, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1.[C:22](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:23]>C(Cl)Cl>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:18])[CH:12]=3)[CH:7]=1)=[C:22]=[S:23]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Cc1cc2c(cn1)cc(-c1cc(N=C=S)ccc1C)c(=O)n2C

Procedure:
To a solution of 3-(5-amino-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 15 (280 mg, 1 mmol) in DCM (5 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (233 mg, 1 mmol) at rt. The solvent was removed in vacuo after 1 h. The crude white solid of 3-(5-isothiocyanato-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one 19 was used without further purification. 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 7.18 (d, J=8.0 Hz, 1H), 7.09 (dd, J=2.4, 8.0 Hz, 1H), 7.05 (d, J=2 Hz, 1H), 7.04 (s, 1H), 3.66 (s, 3H), 2.64 (s, 3H), 2.16 (s, 3H). MS m/z 322.2 (M+1).
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.C[O:19][B:20](OC)[O:21]C>C1COCC1>[B:20]([OH:21])([OH:19])[CH:5]1[N:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: COB(OC)OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1B(O)O

Procedure:
N-acetyl-gly-boroproline 5 was prepared from tert-butyl 1-pyrrolidinecarboxylate (N-t-BOC-pyrrolidine, Aldrich), according to the synthetic route of FIG. 1 and Example 6. Metallation of N-t-BOC-pyrrolidine in THF with sec-butyllithium was followed by addition of trimethylborate to give 1-(tert-butoxycarbonyl)pyrrolidin-2-yl-2-boronic acid 1. Borate esterification with the single enantiomer, (+)-pinanediol in tert-butyl methyl ether (MTBE) gave pinane ester 2 (Coutts et al (1994) Tetrahedron Letters 35(29):5109-5112; Kelly et al (1993) Tetrahedron 49:1009-1016). Acid hydrolysis of the BOC group and selective crystallization gave (+)-pinane 1-pyrrolidin-2-yl-2-boronate 3. Coupling of 3 and N-acetyl glycine with EDC (N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide), and HOBt (1-hydroxybenzotriazole) gave the pinane borate of N-acetyl-gly-boroproline 4. Borate exchange of 4 with phenylboronic acid gave N-acetyl-gly-boroproline 5.