Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.Cl[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>CS(C)=O>[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([O:18][CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C(=O)CCl
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)C(=O)COc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 60 mg, 1.5 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (200 mg, 0.9 mmol) in dimethyl sulfoxide (10 ml). After 0.5 hours, 2-chloro-N,N-dimethyl acetamide (0.3 ml, 2.4 mmol) was added and the reaction mixture was heated to 120° C. for 6 hours. The reaction was allowed to cool, the crude mixture was applied to a SCX cartridge ion exchange (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were reduced in vacuo to afford the title compound (E68). MS (ES+) m/e 303 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](Cl)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
4'-Hydroxybiphenyl-4-carboxylic acid (3.5 g) and triethylamine (2.4 g) were dissolved in dichloromethane (30 ml). Nonanoyl chloride (4.3 g) and dimethylaminopyridine (0.2 g) were added to the solution, and the mixture was stirred at room temperature for about 20 hours. Dilute hydrochloric acid was added thereto, and the organic layer was separated in a separating funnel. The solvent was removed by evaportaion, and the residue was dried after washing with n-hexane to give the titled compound (5 g).
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:38][CH3:39]>C(#N)C>[CH2:38]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:23])=[CH:8][CH:7]=2)[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:3]([CH2:1][CH3:2])[C:4]1=[O:24])[CH3:39]
Reactant: CCI
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 96.6 %

Procedure:
To a stirred solution of (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (0.20 g, 0.61 mmol) in acetonitrile (5 mL) under nitrogen was added potassium carbonate (0.050 g, 0.36 mmol), cesium carbonate (0.11 g, 0.33 mmol) and iodoethane (0.15 mL, 0.29 g, 1.9 mmol). The reaction was stirred for 10 h at 50° C. and then 5 h at 63° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water. The organic layer was concentrated in vacuo and purified via Biotage Horizon® (SiO2, gradient from 5% EtOAc/hexane to 33% EtOAc/hexane) to yield 0.21 g (96%) of (3R)-1,3-diethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 357 ([M+H]+); HRMS: calcd for C20H21FN2O3, 356.16090; found (ESI+), 357.16057.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:28])[S:24](Cl)(=[O:26])=[O:25].O>N1C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][S:24]([N:23]([CH3:28])[CH3:22])(=[O:26])=[O:25])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: O
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,6-diamine (0.05 g, 0.18 mmol) was dissolved in pyridine (1 mL). Dimethylsulfamoyl chloride (0.02 mL) was added and stirred for 72 h at ambient temperature. Then water was added and the mixture extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography (silica gel, heptane, ethyl acetate 4:1/1:1) to yield the title compound as a brown oil (30 mg, 43%); MS: m/e=383.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].Br[CH2:15][CH2:16][C:17](Cl)([Cl:19])[Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][C:17]([Cl:19])=[CH:16][CH2:15][O:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH2:9][CH2:10][OH:11])=[C:6]([Cl:12])[CH:5]=1
Reactant: OCCOc1c(Cl)cc(O)cc1Cl
Reactant: ClC(Cl)(Cl)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 95 °C
Yield: 35.5 %

Procedure:
A solution of 7.0 grams (0.386 mole) of 3,5-dichloro-4-(2-hydroxyethoxy)phenol in 60 mL of DMF was stirred, and 2.8 grams (0.039 mole) of 3-bromo-1,1,1,-trichloropropane was added, followed by 10.0 grams (0.08 mole) of potassium carbonate. Upon completion of addition the reaction mixture was heated at 95° C. during a six-hour period. After this time the reaction mixture was cooled to ambient temperature, diluted with 250 mL of water and extracted with two 150 mL portions of ethyl acetate. The extracts were combined, washed with an aqueous 10% hydrochloric acid, solution, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 75:25 heptane:ethyl acetate as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[OH:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.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:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:43]3[CH:44]=[CH:45][C:40]([OH:39])=[CH:41][CH:42]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)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: CCO
Solvent: O
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(O)cc2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (80 mg, 0.14 mmol) in EtOH (4 mL)/H2O (1 mL) were added 4-hydroxyphenylboronic acid (38 mg, 0.28 mmol), potassium carbonate (77 mg, 0.56 mmol) and Pd(PPh3)4 (3 mg, 0.0028 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14]Br)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:32]=[C:31]([C:33](=[O:41])[CH2:34][CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:19][CH:18]=1>CN(C)C=O>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:32]=[C:31]([C:33](=[O:41])[CH2:34][CH:35]3[CH2:36][CH2:37][N:38]([CH2:14][CH2:13][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH2:39][CH2:40]3)[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2cc(C(=O)CC3CCNCC3)c3ccccc3n2)cc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)CC3CCN(CCc4ccccc4)CC3)c3ccccc3n2)cc1
Temperature: 60 °C
Yield: 89.3 %

Procedure:
3.45 g of potassium carbonate and 1.39 g of 2-phenylethyl bromide are added to a solution of 1.72 g of 1-[2-(4-methyl-phenyl)-4-quinolyl]-2-(4-piperidyl)-ethanone, prepared as indicated in Example 8, in 25 ml of dimethylformamide. The suspension, well stirred, is heated for 5 hours at 60° C., then poured into 1 liter of ice-water. The oil which separates is decanted, washed with water, then 100 ml of ether and 100 ml of a 1N aqueous solution of hydrochloric acid are added. The precipitate formed is filtered, washed with water and then with acetone. 2 g of 1[2-(4-methyl-phenyl)-4-quinolyl]-2-[1-(2-phenyl-ethyl)-4-piperidyl]-ethanone are obtained in the form of dihydrochloride melting at 195° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C@@H:9]([CH2:18][CH2:19][CH3:20])[C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12].[C:21](OC=O)(=[O:23])C>N1C=CC=CC=1>[CH:21]([N:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C@@H:9]([CH2:18][CH2:19][CH3:20])[C@@H:10]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:13])=[O:12])=[O:23]
Reactant: CC(=O)OC=O
Reactant: CCC[C@H](NOC1CCCCO1)[C@@H](CC(C)C)C(=O)O
Solvent: c1ccncc1
Product: CCC[C@@H]([C@@H](CC(C)C)C(=O)O)N(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
A solution of (2R,3S)-3-(2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)hexanoic acid (7.90 g, 27.5 mmol) in 100 mL of anhydrous pyridine is cooled to 0° C. and treated with formic acetic anhydride (4.0 mL, 46 mmol). The reaction mixture is allowed to warm to 25° C., stirred for 6 h, and then concentrated to dryness under reduced pressure. The resulting gum is dissolved in 150 mL of EtOAc and washed successively with two 50-mL portions of 1 M aqueous sodium bisulfate and two 50-mL portions of saturated aqueous sodium chloride. The combined organic extracts are dried over sodium sulfate and filtered, and the solvents are removed under reduced pressure affording 8.67 g (99%) of (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)hexanoic acid obtained as a viscous oil.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:60][O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:5][C:6](=[O:59])[C@H:7]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:47][CH:46]=1)[NH:8][C:9](=[O:43])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:42])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:41])[C@H:22]([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[CH2:70]([NH2:72])[CH3:71]>CO>[CH2:70]([NH:72][C:3](=[O:2])[C@H:4]([CH2:60][O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[NH:5][C:6](=[O:59])[C@H:7]([CH2:44][C:45]1[CH:46]=[CH:47][C:48]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[CH:49][CH:50]=1)[NH:8][C:9](=[O:43])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:42])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21](=[O:41])[C@H:22]([CH2:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34][CH:33]=1)[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH3:71]
Reactant: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C
Reactant: CCN
Solvent: CO
Product: CCNC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C

Procedure:
Nα -t-Butoxycarbonyl-L-tryptophyl-L-prolyl-L-prolyl-O-benzyl-L-tyrosyl-O-benzyl-L-serine methyl ester, 1.0 g., is dissolved in 50 ml. of a mixture of methyl alcohol and ethylamine (50:50). The solution is let stand at room temperature for one day. After removal of the solvent, the crude product is purified by chromatography over silica gel in ethyl acetate-methanol (90:10) solution to give 0.6 g. of the above named product as a white glass [α]D23 -70° (c. 1.02 in methanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[CH3:19][NH:20][C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])=[O:22]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][NH:15]3)=[CH:11][CH:10]=2)=[N:7][C:2]([NH:26][C:25]2[CH:27]=[CH:28][CH:29]=[C:23]([C:21]([NH:20][CH3:19])=[O:22])[CH:24]=2)=[N:3][CH:4]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2cc[nH]c2c1
Reactant: CNC(=O)c1cccc(N)c1
Product: CNC(=O)c1cccc(Nc2ncc(F)c(Nc3ccc4cc[nH]c4c3)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-[(1H)indol-6-yl]-4-pyrimidineamine and 3-[(N-methylamino)carbonyl]aniline were reacted to provide 5-fluoro-N4-[(1H)indol-6-yl]-N2-[3-[(N-methylamino)carbonyl]phenyl]-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.99 (t, 1H, J=1.8 Hz), 7.89 (d, 1H, J=3.6 Hz), 7.78-7.76 (m, 1H), 7.70 (ddd, 1H, J=1.2, 2.4, and 8.4 Hz), 7.50 (d, 1H, J=9.0 Hz), 7.31 (td, 1H, J=1.2 and 7.5 Hz), 7.23-7.17 (m, 3H), 6.43 (dd, 1H, J=1.2 and 3.6 Hz), 2.73 (s, 3H); 19F NMR (282 MHz, CD3OD): −47513; LCMS: purity: 99%; MS (m/e): 377(MH+).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]([O:13]C)=O)=[CH:7][N:6]=1)=[O:4].[NH2:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18]>C(O)C>[OH:18][CH2:17][CH:16]([NH:15][C:11]([C:8]1[CH:7]=[N:6][C:5]([C:3]([NH:15][CH:16]([CH2:19][OH:20])[CH2:17][OH:18])=[O:4])=[CH:10][N:9]=1)=[O:13])[CH2:19][OH:20]
Reactant: COC(=O)c1cnc(C(=O)OC)cn1
Reactant: NC(CO)CO
Solvent: CCO
Product: O=C(NC(CO)CO)c1cnc(C(=O)NC(CO)CO)cn1
Yield: 84.4 %

Procedure:
A solution of 392 mg of 2,5-dimethoxycarbonylpyrazine and 364 mg of 2-amino-1,3-propanediol in 5 cm3 of ethanol is heated at a temperature in the region of the reflux temperature for 3 hours. The reaction mixture is filtered while hot. The white solid is washed with 3 times 10 cm3 of boiling ethanol. 530 mg of N,N′-bis(1,3-dihydroxy-2-propyl)pyrazine-2,5-dicarboxamide are thus obtained in the form of a white solid melting at 218° C. [1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): from 3.45 to 3.65 (mt, 8H: 4×CH2O); 4.02 (mt, 2H: 2×NCH); 4.85 (t, J=5.5 Hz, 4H: 4×OH); 8.48 (d, J=9 Hz, 2H: 2×CONH); 9.25 (s, 2H: ═CH at 3 and ═CH at 6)].
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:4]=2[N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:2]1[C:3]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:4]=2[N:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CN(Cc1ccccc1)CC2
Agent: [Na+]
Solvent: CO
Product: COc1nc(C(F)(F)F)nc2c1CCN(Cc1ccccc1)C2

Procedure:
4-Chloro-7-(phenylmethyl)-2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (98 mg, 0.30 mmol) and 1.5 mL of 0.5 M sodium methoxide in methanol was warmed to 60° C. overnight. The mixture was concentrated under nitrogen and partitioned between ether and water. The ether layer was washed with brine, dried and concentrated to give 94 mg of the title compound as a yellow oil. LC-MS 324.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:18])[CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH3:19][O:20][C:21]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.O>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:18])[C:7]([CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:21]=1[O:20][CH3:19])([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: COc1cccc(CCl)c1OC
Reactant: CCCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(Cc1cccc(OC)c1OC)(C(=O)OCC)C(=O)OCC
Yield: 73.1 %

Procedure:
To a suspension of 60% sodium hydride (440 mg, 11 mmol) in 5 ml of dimethylformamide was added a solution of 2.30 g (10 mmol) of n-pentylmalonic acid diethyl ester in 5 m of dimethylformamide under stirring and ice cooling, and the resultant mixture was stirred for 30 minutes. A solution of 1.86 g (10 mmol) of 2, 3-dimethoxybenzyl chloride in 5 ml of dimethylformamide was dropwise added to the mixture, which was stirred at 70° C. for 1 hour. After cooling, the reaction mixture was mixed with water and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline in this order, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was chromatographed on a silica gel column, eluting with ethyl acetate/hexane (1/12) to give 2.78 g of 2, 3-dimethoxybenzyl-n-pentylmalonic acid diethyl ester as a colorless oil. Yield, 73%.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:19][CH3:20].CCOC(C)=O>CN(C)C=O>[CH2:19]([N:4]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]2[C:2]([I:1])=[N:3]1)[CH3:20]
Reactant: CCI
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1nc(I)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 72 h
Yield: 51.9 %

Procedure:
To 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.766 mmol) in N,N-Dimethylformamide (DMF) (5 mL) was added cesium carbonate (300 mg, 0.919 mmol) followed by iodoethane (0.065 mL, 0.805 mmol), and the reaction mixture was stirred over the weekend (3 days) at 80° C. into a sealed vessel. The reaction was allowed to cool down to room temperature. The mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% CH2Cl2 to 90:10:1 CH2Cl2:CH3OH:NH4OH) afforded 1-ethyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (115 mg) as a white solid.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.CCN(CC)CC>C1(C)C=CC=CC=1>[CH2:4]([O:3][C:1]([N:15]1[CH:14]=[C:13]([I:12])[CH:17]=[N:16]1)=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)n1cc(I)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
CbzCl (95% grade, 2.9 mL, 20 mmol) is added to a solution of 4-iodo-1H-pyrazole (2.97 g, 15.3 mmol) and Et3N (3.2 mL, 23 mmol) in toluene (30 mL) at 0° C. The mixture is stirred at 0° C. for 1 h and partitioned between EtOAc and aq. NaHCO3. The organic layer is dried over MgSO4, concentrated and chromatographed to afford the title compound as a white solid: 1H NMR (CDCl3) δ 8.20 (s, 1H), 7.72 (s, 1H), 7.50-7.31 (m, 5H), 5.46 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:3].[O:34](C(C)=O)[C:35]([CH3:37])=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:3][C:2]([CH:4]1[CH:8]2[CH:9]3[C:22]([CH3:25])([CH2:23][CH2:24][C:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C:21]1([CH3:26])[CH:12]([C:13]2([CH3:30])[CH:18]([CH2:19][CH2:20]1)[C:17]([CH3:27])([CH3:28])[CH:16]([O:29][C:35]([CH3:37])=[O:34])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C1CCC2(C(=O)O)CCC3(C)C(CCC4C5(C)CCC(OC(C)=O)C(C)(C)C5CCC43C)C12

Procedure:
Betulinic acid, 100 mg (0.22 mmoles) was added to a solution containing 4 mg of 4-dimethylaminopyridine (DMAP) and 0.5 ml of (CH3CO)2O in 5 ml of CH2Cl2. After 2 hrs CH2Cl2 was removed in vacuo, and the remaining residue stirred with 25 ml of water. During the stirring enough of K2CO3 was added to decompose an excess of acetic anhydride, after which the reaction mixture was extracted with 25 ml of CH2Cl2. The extract was evaporated to dryness and the resulting solid crystallized from MeOH to give 104 mg of acetylbetulinic acid as white crystals, m.p. 285° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([S:16]C(Cl)(Cl)Cl)=[CH:12][CH:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:21])[C:10]2[CH:11]=[CH:12][C:13]([SH:16])=[CH:14][CH:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(c1ccc(SC(Cl)(Cl)Cl)cc1)c1cc(Cl)cc(Cl)c1
Solvent: CO
Product: O=C(c1ccc(S)cc1)c1cc(Cl)cc(Cl)c1
Yield: 73.5 %

Procedure:
In a 100 ml three-neck flask, said 3′,5′-dichloro-4-(trichloro methyl sulfenyl)benzophenone is added into 80 g methanol. The solution is heated with stirring under nitrogen protection to reflux for 5 h, and then is distilled to remove the methanol and all low-boiling-point substances. The residue is recrystallized in a mixed solvent consisting of ethyl acetate and petroleum ether in a weight ratio 1:1 to obtain 21 g yellow-green needle-like crystals with a purity of 98.8%, the yield is 73.5%, and the melting point is 98-99° C. 1H-NMR data (solvent CDCl3): δ3.6808 ppm, s, 1H, δ7.3431, 7.3700 ppm, d, 2H, δ7.5665, 7.5702 ppm, d, 1H, δ7.6033, 7.6065 ppm, d, 2H, 7.6489, 7.6758 ppm, d, 2H.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].CN(C=O)C.[CH3:12][O:13][C:14]([CH2:16][CH2:17][C:18]12[CH2:25][CH2:24]C(C(O)=O)([CH2:22][CH2:23]1)[CH2:20][CH2:19]2)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:15])[CH2:16][CH2:17][C:18]12[CH2:23][CH2:22][C:1]([C:2]([Cl:4])=[O:3])([CH2:24][CH2:25]1)[CH2:20][CH2:19]2
Reactant: COC(=O)CCC12CCC(C(=O)O)(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCC12CCC(C(=O)Cl)(CC1)CC2
Reaction time: 2 h

Procedure:
Oxalyl chloride (794 mg, 6.25° mmol) in methylene chloride (5 ml) plus a drop of DMF is slowly added to a mixture of 4-(2-Methoxycarbonylethyl)-bicyclo[2.2.2]octane 1-carboxylic acid (XXI, Example 96, 1.2 g, 5 mmol) in methylene chloride (20 ml). The reaction mixture is stirred for 2 hr and concentrated to give the title compound, NMR (400 MHz, CDCl3) δ3.66, 2.29, 1.95, 1.54 and 1.46.