Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20](O)=[O:21])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27](OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20](=[O:21])[CH3:27])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: O=C(O)c1ccccc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1Nc1ccc(OCc2ccccc2)cc1
Reaction time: 1.25 h

Procedure:
Methyllithium (280 ml, 1M in ether) was added slowly to a solution of 31.9 g (0.1 mole) of 2-(4-benzyloxyphenylamino)benzoic acid (Example 2, part a) in 300 ml of tetrahydrofuran cooled to 0°-5° C. The reaction mixture was stirred at 0°-5° C. for 75 minutes. Ethyl acetate was then added and the mixture poured into a mixture of ice and saturated ammonium chloride solution. The aqueous suspension was extracted with ether, the ether extracts dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from isopropyl alcohol to give 24 g of 1-[2-(4-benzyloxyphenylamino)phenyl]ethanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][OH:24])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:23][O:24][CH2:29][CH:28]=[CH2:27])[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@](CO)(c2ccc(Cl)c(Cl)c2)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC[C@@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)OC(C)(C)C)CCO1
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (7S)-7-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (1.01 g) in DMF (7 mL) was added sodium hydride (129 mg) at 0° C. After stirring for 10 min, allyl bromide (0.272 mL) was added, and the mixture was stirred at room temperature for 10 min. Under ice-cooling, the reaction was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (917 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([CH2:18][F:19])[CH2:9]2)=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[NH:22]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH:10]([CH2:18][F:19])[CH2:9]2)[C:2]=1[Cl:1])[C:20]#[N:21]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(CF)C2)c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(N2CCN(C3COC3)C(CF)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
(+/−) Tert-butyl (2-chloro-5-cyano-3-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (Peak 2) (315 mg, 0.741 mmol) was taken up in DCM (4 mL) and TFA (1.142 mL, 14.83 mmol) was added. The reaction was stirred at rt for 1 h. The solvent was removed in vacuo and the material was taken up in MeOH and loaded onto an SCX column (5 g, benzenesulfonic acid sorbent). The column was rinsed with MeOH, then 7N NH3/MeOH to release the product. The solvent was removed in vacuo to give (+/−) 3-amino-4-chloro-5-(3-(fluoromethyl)-4-(oxetan-3-yl)piperazin-1-yl)benzonitrile (234 mg) as a yellow foam.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([S:18]([CH:21]5[CH2:23][CH2:22]5)(=[O:20])=[O:19])[CH2:16][CH2:17]4)[S:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(=O)(=O)C5CC5)CC4)sc3n2)cn1

Procedure:
2-Chloro-4-morpholin-4-yl-6-[4-(cyclopropane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 308. NMR (DMSO): 0.90-0.92 (2H, m), 0.97-1.00 (2H, m), 2.53-2.58 (4H, m), 2.60-2.64 (1H, m), 3.20-3.23 (4H, m), 3.74-3.77 (4H, m), 3.80 (2H, s), 3.88-3.91 (4H, m), 7.08 (2H, br), 7.52 (1H, s), 9.08 (2H, s). MS (ESI+): MH+ 517.22 (50%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](=O)[CH3:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:4](=[N:11][C:27]([CH3:28])=[C:26]([C:21]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=3)[N:9]=2)[N:3]=1
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2nc(N)nc(N)c2nc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A stirred solution of 1.0 gram (0.007 mole) of 2,4,6-triamino-5-nitrosopyrimidine and 2.7 grams (0.020 mole) of potassium carbonate in 30 mL of N,N-dimethylformamide was heated to 95°-100° C., and 2.0 grams (0.010 mole) of (3,4-dichlorophenyl)acetone was added in one portion. Upon completion of addition, the reaction mixture was allowed to cool to ambient temperature, where it was allowed to stir for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure. The residue was triturated with 250 mL of water, and the remaining solid was collected by filtration. The solid was further triturated with 50 mL of 20% methanol in methylene chloride. The remaining solid was collected by filtration, yielding 0.5 gram of 2,4-diamino-6-(3,4-dichlorophenyl)-7-methylpteridine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CS([O:5][C:6](=O)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=O)=O.[Br-:29].[Mg+2].[Br-]>CCOCC>[C:6]([Br:29])(=[O:5])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)OS(C)(=O)=O
Reactant: [Br-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Br
Reaction time: 8 h

Procedure:
A mixture of docosahexaenoyl methane sulfonate (2.0 g, 5.1 mmol) and magnesium bromide (4.3 g, 23 mmol) in anhydrous ether (100 mL) was stirred under argon overnight. The resulting suspension was filtered and the solid washed with ether (2×30 mL). The filtrate and wash were combined and solvent evaporated. The resulting residual was purified by column chromatography on silica gel (230-400 mesh, 40 mL) eluted with hexanes. This gave 2.2 g of docosahexaenoyl bromide (II) as colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19]([C:21]4([NH:25]C(=O)OC(C)(C)C)[CH2:24][CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C:21]1([C:19]([NH:18][C:15]2[CH:16]=[N:17][C:12]([O:11][C:7]3[C:6]4[C:2]([CH3:33])([CH3:1])[CH2:3][O:4][C:5]=4[CH:10]=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)=[O:20])[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)Nc2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)COc2cccc(Oc3ccc(NC(=O)C4(N)CCC4)cn3)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a solution of 1,1-dimethylethyl {1-[({6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}amino)carbonyl]cyclobutyl}carbamate (Intermediate 69, 23.5 mg) in dry dichloromethane (3.5 ml), TFA (159 μl, 2.07 mmol) was slowly added at 0° C. and the reaction mixture was stirred for 2 hours at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified with an SCX cartridge. The cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). This afforded the title compound (18 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.CN(C)[CH:27]=[O:28].[Cl-].[NH4+]>O1CCCC1>[CH3:13][O:12][CH2:11][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:27]=[O:28])=[CH:3][CH:4]=1
Reactant: COCOCCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCCc1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
Next, to a mixture of bromo-4-(2-methoxymethoxyethyl)benzene (12.0 g, 49.0 mmol) and tetrahydrofuran (75 ml), a 1.58 mol/L n-butyllithium n-hexane solution (34 ml, 53.7 mmol) was added dropwise at −78° C. over 10 minutes. After stirring at −78° C. for 1 hour, a solution of N,N-dimethylformamide (11.4 mL, 147 mmol) in tetrahydrofuran (5 mL) was added and stirred at −78° C. for 1.5 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After concentration, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to give 4-(2-methoxymethoxyethyl)benzaldehyde (7.0 g, 74%).
Reaction SMILES: S(=O)(=O)(O)O.[C:6](OC(=O)C)(=[O:8])[CH3:7].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([CH:27]=2)[NH2:26])=[CH:17][CH:16]=1>C(OCC)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([N+:28]([O-:30])=[O:29])=[C:25]([NH:26][C:6](=[O:8])[CH3:7])[CH:27]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2ccc([N+](=O)[O-])c(N)c2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COc1ccc(-c2ccc([N+](=O)[O-])c(NC(C)=O)c2)cc1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
A catalytic amount of concentrated sulfuric acid was added dropwise to an acetic anhydride (55 ml) suspension of 5-(4′-methoxyphenyl)-2-nitroaniline (2.02 g), followed by 3 hours and 20 minutes stirring at 40° C. After cooling to room temperature, diethyl ether (200 ml) was added thereto and the precipitated powder was collected by filtration to obtain N-(4′-methoxy-4-nitrobiphenyl-3-yl)acetamide (596 mg).
Reaction SMILES: [C:1]([C@@:4]12[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([OH:14])[CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:3])[CH3:2].[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl.C(N(CC)CC)C>C1COCC1>[C:1]([C@@:4]12[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[CH2:8][CH2:7][CH2:6][CH2:5]2)(=[O:3])[CH3:2]
Reactant: CC(=O)[C@]12CCCC[C@@]1(O)CCCC2
Reactant: COCCOCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCO[C@]12CCCC[C@@]1(C(C)=O)CCCC2

Procedure:
A mixture of 100 mmol of 4a-acetyl-8a-hydroxy-cis-decalin, 110 mmol of 2-methoxyethoxymethyl chloride, 110 mmol of triethylamine, and 200 ml of THF was refluxed for 3 hours. The resulting reaction mixture was subjected to column chromatography on a silica gel to yield 4a-acetyl-8a-(2-methoxyethoxymethoxy)-cis-decalin represented by the following formula (yield: 90.3%). The conversion rate from 4a-acetyl-8a-hydroxy-cis-decalin was 95%.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]1[CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Br[CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C>CN(C=O)C.[H-].[Na+]>[OH:31][CH2:30][CH2:29][N:10]1[C:9]2[C:4](=[N:5][C:6]([C:11]3[CH:12]=[N:13][N:14]4[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][C:15]=34)=[N:7][CH:8]=2)[N:3]([CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:2]1=[O:1]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n(C5CCOCC5)c4n3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccn2ncc(-c3ncc4c(n3)n(C3CCOCC3)c(=O)n4CCO)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
To a solution of example 1 (50 mg, 0.14 mmol) in DMF (8 mL), 55-65% NaH dispersion in mineral oil (6 mg, 0.15 mmol) was added. The resulting solution was stirred at room temperature for 10 min. Then (2-bromoethoxy)-tert-butyldimethylsilane (0.074 mL, 0.34 mmol) was added and the reaction was stirred at 50° C. for 14.5 h. The reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The crude product thus obtained was chromatographed over silica gel using hexanes/EtOAc mixtures of increasing polarity as eluent, to afford 55 mg of the desired compound (76% yield).
Reaction SMILES: [NH:1]1[C:9](=O)[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.[NH3:11]>P(Cl)(Cl)(Cl)=O.C1COCC1>[N:1]1[C:9]([NH2:11])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1
Reactant: O=c1[nH]cnc2nc[nH]c12
Reactant: N
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncnc2nc[nH]c12
Temperature: 60 °C
Yield: 90.5 %

Procedure:
1.27 g (2.8 mM) of the above hypoxanthine (C.) was heated in 13 ml of phosphorus oxychloride to 70° C. for 30 min. Evaporation in vacuo and twice repetition with toluene gave the crude 6-chloro intermediate, which was dissolved in 40 ml of THF and added at 0-5° C. to 12 ml of 32% aqueous ammonia. After the addition of 50 g of liquid ammonia the solution was heated to 60° C. in a 450 ml pressure reactor (340 psi). After 3.5 hr the solid was filtered off and the solution evaporated in vacuo to dryness. The residue was dissolved in dichloromethane, extracted with 1 n NaOH and evaporated again to dryness. The residue was dissolved in 20 ml of methanol, treated with 2.9 ml of 1 m methanolic HCl and evaporated to dryness. Crystallization from ethyl acetate gave 1.24 g (90.5%) of title adenine with mp 172-175° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]3[O:20][C:19]([CH3:22])([CH3:21])[CH:18]=[CH:17][C:14]=3[CH:15]=2)[C:10](=O)[C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CN(C=O)C.O.NN>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]3[O:20][C:19]([CH3:21])([CH3:22])[CH:18]=[CH:17][C:14]=3[CH:15]=2)[CH2:10][C:9]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)C=Cc2cc3c(cc2O1)C(=O)C(=O)N3Cc1ccccc1
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C=Cc2cc3c(cc2O1)CC(=O)N3Cc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
To a solution of N-benzyl-6,6-dimethyl-1H-pyrano[2,3-f]indole-2,3-dione (500 mg, 1.57 mmol) in DMF (5 mL), hydrazine monohydrate (2.5 mL) was added, and the resulting mixture was stirred at 100° C. for 1.5 hour. Water was added thereto, and the resulting solution was extracted with ethyl acetate. The resulting organic phase was washed with saturated ammonium chloride aqueous solution and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column (hexane/ethyl acetate=3/1) to obtain the aimed product (yield: 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:23])[C:20](Cl)=[O:21].Cl>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][N:10]3[C:20](=[O:21])[C:19](=[O:23])[O:12][C:11]32[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:7]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)C1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCCl
Product: O=C1OC2(C3CCCCC3)c3cc(Cl)ccc3CCN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[2-(4-chlorophenyl)ethyl]cyclohexanecarboxamide (2.03 g) was dissolved in 1,2-dichloroethane (15 mL), and oxalyl chloride (0.8 mL) was added thereto under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and then cooled to −20° C. Ferric chloride (1.49 g) was added to the mixture, followed by stirring at room temperature for 16 hours. An aqueous 1 M HCl solution was added to the mixture which was then stirred at room temperature for 30 minutes, followed by extraction with chloroform. The extract was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was dried to obtain 9-chloro-10b-cyclohexyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione (2.38 g).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:12]#[N:13])[CH2:2]1.S(=O)(=O)(O)[OH:22]>O>[S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[C:12]([NH2:13])=[O:22])[CH2:2]1
Reactant: O=S(=O)(O)O
Reactant: N#CC(=C1CSc2ccccc2N1)c1ccc(Cl)cc1
Solvent: O
Product: NC(=O)C(=C1CSc2ccccc2N1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 30 parts of (2H-1,4-benzothiazin-3(4H)-ylidene)(4-chlorophenyl)acetonitrile, 180 parts concentrated sulfuric acid and 18 parts water is stirred at room temperature for 11/2 hours. The mixture is cooled to 0°-5° and diluted with 1 to 2 volumes of water which results in a crystalline solid which is filtered, dried and crystallized from methanol to afford crystalline 2-(2H-1,4-benzothiazin-3(4H)-ylidene)-2-(4-chlorophenyl)acetamide melting at about 188°-191°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].N1([CH:22]=[O:23])C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][CH:22]=[O:23]
Reactant: O=Cn1nnc2ccccc21
Reactant: Nc1ccc(C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Product: O=CNc1ccc(C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-4-(trifluoromethyl)aniline (500 mg, 2.56 mmol) in tetrahydrofuran (THF) (8 mL) was added 1H-1,2,3-benzotriazole-1-carbaldehyde (489 mg, 3.32 mmol, Sigma-Aldrich). The reaction mixture was heated to 70° C. and stirred for 18 hours. To the reaction mixture was added 1H-1,2,3-benzotriazole-1-carbaldehyde (1.16 mmol, 245 mg) and the reaction mixture heated to 70° C. for a further 5 hours. The reaction mixture was concentrated under vacuum and the residue partitioned between DCM (20 mL) and 2N HCl (10 mL). The organic layer was collected via a hydrophobic frit and the solvent removed under vacuum.
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]2[O:30][CH:29]([CH2:31]Br)[CH2:28][C:27]=2[CH:33]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:31][CH:29]2[CH2:28][C:27]3[CH:33]=[C:23]([O:22][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:24]=[CH:25][C:26]=3[O:30]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Product: OC1(Cc2ccccc2)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=430.6 (M+H+) was prepared from 4-(benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N+:11]([O-:23])=[CH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-tert-butylquinoline (400 mg, 2.16 mmol, Journal of the Indian Chemical Society, 1998, 823) and mCPBA (639 mg, 2.59 mmol) in chloroform (10 ml) was stirred for 2 hours at room temperature. The mixture was concentrated and the crude residue was applied to a silica gel (NH silica) column chromatography and eluted with dichloromethane/methanol (20:1) to furnish the title compound (433 mg, quant.) as pale orange oil. 1H NMR (300 MHz, CDCl3) δ 1.43 (9H, s) 7.26-7.30 (1H, m), 7.73 (1H, d, J=8.1 Hz), 7.78 (1H, s), 7.85 (1H, dd, J=1.5, 8.8 Hz), 8.49 (1H, d, J=5.9 Hz), 8.67 (1H, d, J=8.8 Hz). MS (ESI): m/z 202 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O>>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6]
Reactant: COC(=O)CN
Reactant: COCCOc1cccc(C=O)c1
Product: COCCOc1cccc(CNCC(=O)OC)c1
Yield: 55 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 3-(2-methoxyethoxy)benzaldehyde. Yield 55%. MS M+H calculated 254.1; found 254.1.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[N:4]1[C:9](P(OC(C)C)(=O)OC(C)C)=[N:8][C:7]([P:20]([O:26][CH:27]([CH3:29])[CH3:28])(=[O:25])[O:21][CH:22]([CH3:24])[CH3:23])=[N:6][C:5]=1[P:30]([O:36][CH:37]([CH3:39])[CH3:38])(=[O:35])[O:31][CH:32]([CH3:34])[CH3:33]>>[CH3:1][N:2]([CH3:3])[C:9]1[N:8]=[C:7]([P:20]([O:26][CH:27]([CH3:28])[CH3:29])(=[O:25])[O:21][CH:22]([CH3:24])[CH3:23])[N:6]=[C:5]([P:30]([O:31][CH:32]([CH3:34])[CH3:33])(=[O:35])[O:36][CH:37]([CH3:39])[CH3:38])[N:4]=1
Reactant: CC(C)OP(=O)(OC(C)C)c1nc(P(=O)(OC(C)C)OC(C)C)nc(P(=O)(OC(C)C)OC(C)C)n1
Reactant: CNC
Product: CC(C)OP(=O)(OC(C)C)c1nc(N(C)C)nc(P(=O)(OC(C)C)OC(C)C)n1

Procedure:
Following the procedure of Example 20, aqueous dimethylamine (40% w/w, 50.63 g, 20.25 g (CH3)2NH, 0.450 mol) was reacted with hexaisopropyl 1,3,5-triazine-2,4,6-triphosphonate (42.98 g) to produce tetraisopropyl 2-dimethylamino-1,3,5-triazine-4,6-diphosphonate.
Reaction SMILES: [CH2:1]([N:8]1[CH2:20][C@@H:19]2[C@H:10]([NH:11][C:12](=[O:22])[C:13]3[C:14]([CH3:21])=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:9]1)C1C=CC=CC=1.[C:23]1([CH2:29]C=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO.[Pd]>[CH3:21][C:14]1[C:13]2[C:12](=[O:22])[NH:11][C@@H:10]3[CH2:9][N:8]([CH2:1][CH2:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][C@H:19]3[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=CCc1ccccc1
Reactant: Cc1cccc2c1C(=O)N[C@@H]1CN(Cc3ccccc3)C[C@@H]21
Agent: [Pd]
Solvent: CO
Product: Cc1cccc2c1C(=O)N[C@@H]1CN(CCc3ccccc3)C[C@@H]21

Procedure:
To a solution of (±)-trans-2-benzyl-6-methyl-2,3,3a,4-tetrahydro-1H-pyrrolo[3,4-c]isoquinolin-5(9bH)-one, from Example 101, Part A (57 mg, 0.2 mmol) in 10 mL of methanol was added phenylacetaldehyde (24 mg, 0.2 mmol) and 10% Pd/C catalyst (6 mg). The reaction mixture was purged several times with hydrogen and stirred under 1 atm of hydrogen, maintained by a balloon, for 18 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified (ISCO, elution with 0-8% methanol/methylene chloride) to afford the title compound of Example 102 as a solid. 1H NMR (CDCl3): δ 7.36-7.20 (m, 6H), 7.18 (d, 1H, J=7.7 Hz), 6.88 (d, 1H, J=7.7 Hz), 6.22 (broad s, 1H), 3.66-3.58 (m, 1H), 3.41 (app t, 1H, J=8.3 Hz), 3.30-3.22 (m, 1H), 3.14 (app t, 1H, J=7.7 Hz), 3.05-2.93 (m, 4H), 2.88-2.81 (m, 2H), 2.70 (s, 3H). LRMS (ESI): 307.3 (M+H)+.