Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH2:24])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([F:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:30])[CH3:29].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:28](=[O:30])[CH3:29])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([F:25])=[CH:10][C:9]=1[F:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)sc3n2)c(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)c(F)cc3F)nc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2,4-difluorophenyl}carbamate (3.94 g, 10.0 mmol) and N,N-dimethylpyridine-4-amine (1.22 g, 10 mmol) in pyridine (20 mL) was added dropwise acetyl chloride (0.94 g, 12 mmol) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (4.36 g, quantitatively) as a pale-yellow amorphous.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]3[O:12][CH:10]([CH2:11][C:4]=2[C:3]=1[C:13]([CH:15]1[CH2:18][CH2:17][CH2:16]1)=[O:14])[CH2:9][CH2:8]3.C(N(CC)CC)C.ClC(Cl)(O[C:30](=[O:36])OC(Cl)(Cl)Cl)Cl.[CH3:38][C:39]([NH2:43])([CH2:41][CH3:42])[CH3:40]>O1CCCC1>[CH:15]1([C:13]([C:3]2[C:4]3[CH2:11][CH:10]4[O:12][CH:7]([CH2:8][CH2:9]4)[C:5]=3[S:6][C:2]=2[NH:1][C:30]([NH:43][C:39]([CH3:40])([CH3:38])[CH2:41][CH3:42])=[O:36])=[O:14])[CH2:16][CH2:17][CH2:18]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1sc2c(c1C(=O)C1CCC1)CC1CCC2O1
Reactant: CCC(C)(C)N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)(C)NC(=O)Nc1sc2c(c1C(=O)C1CCC1)CC1CCC2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a 20-mL scintillation vial containing a magnetic stir bar were added the product from Example 8A (263 mg, 1.00 mmol), anhydrous tetrahydrofuran (8 mL), and triethylamine (354 mg, 488 μL, 3.50 mmol), followed by drop-wise addition of a solution of triphosgene (0.35 mmol) in anhydrous tetrahydrofuran (2 mL). The resulting mixture was stirred at room temperature for 2 hours. A 2-mL aliquot of the mixture was removed and placed in a separate scintillation vial containing a magnetic stir bar and neat 2-methylbutan-2-amine (87 mg, 1.00 mmol) was added. The resulting mixture was stirred at room temperature overnight. The solvent and volatiles were removed by rotary evaporatory and the product was purified by flash chromatography (silica gel: 25% ethyl acetate, 75% hexanes—product Rf˜0.3) to give 42 mg (56%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 0.79 (t, J=7.4Hz, 3H), 1.22 (s, 3H), 1.23 (s, 3H), 1.54-2.30 (m, 12H), 3.13-3.20 (m, 2H), 3.67-3.77 (m, 1H), 4.67-4.70 (m, 1H), 4.95-4.97 (m, 1H), 7.68 (s, 1H), 11.39 (br s, 1H); MS (ESI+) m/z 377 (M+H)+. Anal. calcd. for C20H28N2O3S: C, 63.80; H, 7.50; N; 7.50. Found: C, 63.65; H, 7.86; N, 7.37.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH:11]([NH2:13])=[O:12]>C(OCC)(=O)C.O>[C:5]1([C:3]2[N:13]=[CH:11][O:12][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: NC=O
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(-c2cocn2)cc1
Temperature: 130 °C
Yield: 39.1 %

Procedure:
Bromoacetophenone (595 mg, 2.99 mmol) and formamide (1781 μl, 44.8 mmol) were combined and heated at 130° C. for 90 min. The reaction was cooled then dilute with ethyl acetate and water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The concentrate was purified by chromatography on a Biotage 25M column using a 5-8% ethyl acetate in heptane gradiant to yield 4-phenyl-oxazole (170 mg, 1.17 mmol). TLC (5% ethyl acetate in heptane) of product: Rf=0.28.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([F:38])[CH:36]=5)[N:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([F:38])[CH:36]=5)[N:31]=[CH:30][C:29]4=[O:39])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 3 mL of a chloroform solution containing 631 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of trifluoroacetic acid was added and stirred at room temperature for 6 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with ethyl acetate. The organic layer was washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=5:1], to give 400 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a brown solid.
Reaction SMILES: [Li+].[BH4-].[Br:3][C:4]1[C:13]([F:14])=[CH:12][C:11]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34](=[O:37])[NH:35][CH3:36])=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:10][C:5]=1[C:6](OC)=[O:7].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[Br:3][C:4]1[C:5]([CH2:6][OH:7])=[CH:10][C:11]([N:15]([C:20]2[C:39]([CH:40]3[CH2:42][CH2:41]3)=[CH:38][C:23]3[C:24]([C:34]([NH:35][CH3:36])=[O:37])=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[O:26][C:22]=3[CH:21]=2)[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:13]=1[F:14]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c(Br)c(CO)c3)S(C)(=O)=O)c(C3CC3)cc12
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of LiBH4 (1.018 mL, 2M) in THF was added dropwise to a solution of methyl 2-bromo-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorobenzoate (430 mg, 0.679 mmol) in MeOH (0.5 mL) and THF (5.0 mL) at 0° C. After 0.5 h, citric acid (4.0 mL, 5% wt) was added to the mixture. The organic solvent was then removed under reduced pressure. The residue was diluted with DCM (10 mL) and washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give 6-(N-(4-bromo-3-fluoro-5-(hydroxymethyl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (400 mg, 97% yield) as white solid. The crude was used for next step without more purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.57 (br. s., 1H), 0.71-0.88 (m, 2H), 0.93-1.06 (m, 1H), 1.96-2.02 (m, 1H), 2.63 (t, J=6.1 Hz, 1H), 2.96 (d, J=4.8 Hz, 3H), 3.25 (s, 3H), 4.67 (d, J=5.6 Hz, 2H), 5.96 (d, J=4.8 Hz, 1H), 7.08-7.21 (m, 3H), 7.31 (s, 1H), 7.42 (s, 1H), 7.56 (s, 1H), 7.82 (dd, J=8.7, 5.3 Hz, 2H). LCMS (m/z, ES+)=605, 607 (M+H+).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[C:5]([O:9][C:10](=[O:26])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=2)[CH:13]=1)([CH3:8])([CH3:7])[CH3:6].BrBr>C(O)(=O)C>[C:5]([O:9][C:10](=[O:26])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[N:20]=[C:21]3[S:1][C:2]([NH2:3])=[N:25][C:22]3=[CH:23][CH:24]=2)[CH:13]=1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc(N)cn2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(N)sc3n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Potassium thiocyanate (4.30 g, 44.2 mmol) was suspended in acetic acid (50 mL), and the suspension was stirred at room temperature for 30 min. To the obtained solution was added tert-butyl{3-[(5-aminopyridin-2-yl)oxy]phenyl}carbamate (3.33 g, 11.1 mmol), and the mixture was further stirred at room temperature for 10 min. To the obtained solution was added dropwise a solution of bromine (1.85 g, 11.6 mmol) in acetic acid (10 mL) for 10 min or more. After the completion of the dropwise addition, the mixture was stirred at room temperature for 1.5 hr. The yielded yellow solid was filtered off, and washed with acetic acid. The filtrate and the washing solution were combined, and concentrated under reduced pressure. The residue was suspended in ethyl acetate (200 mL), and the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (3.51 g, 88%) as a pale-yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:10]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:2][CH2:3][CH3:4])[C:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:10]2
Reactant: CCCBr
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(-c2ccccc2)cc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.1 %

Procedure:
1-Bromopropane (0.248 g, 2.015 mmol) was added to a solution of 95A (0.15 g, 0.672 mmol) in DMF (5 mL) followed by cesium carbonate (0.657 g, 2.015 mmol), and the mixture was stirred at 25° C. for 12 h. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using 3% ethyl acetate in hexane as eluent to afford title compound (0.1 g, 56.1%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.54-7.5 (m, 4H), 7.46-7.39 (m, 2H), 7.06 (d, J=2.0 Hz, 1H), 6.8 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H), 6.42 (s, 1H), 4.12 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 1.54 (m, 2H), 0.63 (t, J=7.2 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][C:11]([OH:13])=O)[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:16])=O>ClC(Cl)(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][C:11]([Cl:16])=[O:13])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(CC(=O)O)on1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1cc(CC(=O)Cl)on1

Procedure:
5 mmoles of 3(t-butyl)isoxazole-5 yl acetylchloride were prepared from 3(t-butyl)isoxazole-5-yl-acetic acid and thionylchloride in tetrachloromethane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][C@H:11]1[C:20]([O-:22])=[O:21].CO.[OH-].[Li+].Cl>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][C@H:11]1[C:20]([OH:22])=[O:21]
Reactant: O=C([O-])[C@@H]1CC2(CC[C@H]1c1cc(F)c(F)cc1F)OCCO2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H]1CC2(CC[C@H]1c1cc(F)c(F)cc1F)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of trans 8-(2,4,5-trifluorophenyl)-1,4-dioxaspiro[4.5]decane-7-carboxylate from Step E (1.82 g, 5.5 mmol) dissolved in tetrahydrofuran (11 mL) and methanol (22 mL) was treated with aqueous lithium hydroxide solution (1.0M, 18.5 mL) and the mixture was stirred at room temperature overnight. The reaction solution was acidified with hydrochloric acid (1N) to pH 1 and extracted with ethyl acetate. The organic phase was washed by saturated brine solution, dried over anhydrous sodium sulfate and evaporated to yield the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)([CH3:3])[CH3:2].[NH2:12][C@@H:13]([CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:28])[CH:21]=2)=[N:16]1>>[Cl:28][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][N:15]([CH2:14][C@@H:13]([NH:12][C:9]([C:7]3[N:6]([C:9]([C:7]4[NH:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=4)=[O:11])[N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)=[O:11])[CH3:29])[N:16]=2)[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: CC(C)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(C)c1cc(C(=O)n2nc(C(C)C)cc2C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 1.88 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-isopropyl-1-(3-isopropyl-1H-pyrazole-5-carbonyl)-1H-pyrazole-5-carboxamide was prepared using the method of Example 34(d) starting from 3-isopropyl-1H-pyrazole-5-carboxylic acid (0.284 g, 1.841 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 1.534 mmol). Yield 1.883%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (dd, 6H), 1.27 (d, 3H), 1.32 (dd, 6H), 2.94 (m, 1H), 3.81 (m, 1H), 4.32 (dd, 1H), 4.47 (dd, 1H), 4.63 (m, 1H), 6.63 (d, 1H), 6.81 (s, 1H), 7.08 (s, 1H), 7.44 (d, 1H), 7.51 (d, 1H), 7.64 (dd, 1H), 7.78 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [C:1]([O:7][CH:8]([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.N1CCCCC1.[CH2:17]([C:24]1[CH:25]=[N:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]([CH:34]=O)[C:32]=2[CH:33]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH2:36]/[C:37](/[CH3:41])=[CH:38]\[C:39]#[N:40]>C(Cl)Cl.C(O)(=O)C>[C:39]([C:38]1[CH:34]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:32]=2[CH:33]=[C:24]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:25]=[N:26]3)[C:2]([C:1]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])=[C:3]([CH3:5])[NH:36][C:37]=1[CH3:41])#[N:40]
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: O=Cc1cccc2ncc(Cc3ccccc3)cc12
Reactant: C/C(N)=C/C#N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC1=C(C#N)C(c2cccc3ncc(Cc4ccccc4)cc23)C(C(=O)OC(C)C)=C(C)N1

Procedure:
0.72 g of isopropyl acetoacetate, 0.025 ml of acetic acid and 0.05 ml of piperidine are added to 1.24 g (5 mmol) of 3-benzylquinoline-5-aldehyde in 20 ml of methylene chloride and the mixture is heated at the boiling point overnight. It is cooled, diluted with methylene chloride, extracted twice by shaking with water, dried and concentrated. The resulting intermediate product is suspended in 15 ml of isopropanol, 0.41 g (5 mmol) of 3-aminocrotononitrile are added and the mixture is stirred at 80° C. for 20 hours. It is concentrated and the residue is purified by flash chromatography with toluene/ethyl acetate mixtures. After crystallization from ethanol/ether 1:1, 1.0 g of colourless crystals of melting point 188°-190° C. is obtained.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:5]([C:10]#N)=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].S(=O)(=O)(O)[OH:13].[OH-:17].[Na+]>O>[CH2:1]([S:3][C:4]1[C:5]([C:10]([OH:13])=[O:17])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: [OH-]
Reactant: CCSc1cccnc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCSc1cccnc1C(=O)O
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of 1.4 g of 3-ethylsulfanylpyridine-2-carbonitrile, 15 mL of concentrated sulfuric acid and 5 mL of water was stirred at 130° C. for 2 hours. Water was poured to the reaction mixture cooled to room temperature, sodium hydroxide was added thereto, and the mixture was extracted with ethyl acetate. Concentrated hydrochloric acid was added to the aqueous layer, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.15 g of 3-ethylsulfanylpicolinic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[C:15]([NH:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:14]=[CH:13][N:12]=1)([O-:3])=[O:2].[H-].[Na+].[Cl:27][C:28]1[C:33]([N:34]=[C:35]=[O:36])=[C:32]([Cl:37])[C:31]([O:38][CH3:39])=[CH:30][C:29]=1[O:40][CH3:41].O>C1COCC1>[Cl:27][C:28]1[C:29]([O:40][CH3:41])=[CH:30][C:31]([O:38][CH3:39])=[C:32]([Cl:37])[C:33]=1[NH:34][C:35](=[O:36])[N:17]([C:15]1[CH:16]=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:12]=[CH:13][N:14]=1)[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(OC)c(Cl)c(N=C=O)c1Cl
Reactant: O=[N+]([O-])c1ccccc1Nc1cc(NCc2cccnc2)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(NC(=O)N(Cc2cccnc2)c2cc(Nc3ccccc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of N-(2-nitro-phenyl)-N′-pyridin-3-ylmethyl-pyrimidine-4,6-diamine (150 g, 0.467 mmol) in THF (15 mL) was added NaH (60%, 48 g, 1.2 mmol) at 0° C., and the mixture was stirred for 30 minutes at room temperature. A solution of 2,4-dichloro-3-isocyanato-1,5-dimethoxy-benzene (procedure 2A, steps a-d; 180 g, 0.73 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 2 hours. Water (2 mL) was added to quench the reaction. The mixture was concentrated, and the residue was purified by flash chromatography on silica to obtain the title compound (85 mg, yield: 32%). MS (ESI): 570 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C@H:6]1[C@@H:10]2[C@@H:11]3[C@@:24]([CH3:27])([CH2:25][CH2:26][C@@:9]2([CH2:33][OH:34])[CH2:8][CH2:7]1)[C@@:23]1([CH3:28])[C@@H:14]([C@:15]2([CH3:32])[C@@H:20]([CH2:21][CH2:22]1)[C:19]([CH3:30])([CH3:29])[C@@H:18]([OH:31])[CH2:17][CH2:16]2)[CH2:13][CH2:12]3)=[CH2:5].O.[O:36]1[CH2:40]CC[CH2:37]1>IC>[CH3:5][C:4]([C@H:6]1[C@@H:10]2[C@@H:11]3[C@@:24]([CH3:27])([CH2:25][CH2:26][C@@:9]2([CH2:33][OH:34])[CH2:8][CH2:7]1)[C@@:23]1([CH3:28])[C@@H:14]([C@:15]2([CH3:32])[C@@H:20]([CH2:21][CH2:22]1)[C:19]([CH3:30])([CH3:29])[C@@H:18]([OH:31])[CH2:17][CH2:16]2)[CH2:13][CH2:12]3)=[CH2:3].[CH3:37][O:36][CH3:40]
Reactant: C1CCOC1
Agent: C=C(C)[C@@H]1CC[C@]2(CO)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: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: COC

Procedure:
The alkylated betulinol derivatives can be prepared in a variety of ways. Keto-derivatives can be acquired by treating betulinol with suitable oxidizing reagent, such as Jone's reagent or pyridinium chlorochromate (PCC) (Kim et al., Synthetic Communications 27:1607-1612 (1997); Komissarova et al., Chemistry of National Compounds 38:58-61 (2002); Ito et al., J. Nat. Prod. 64:1278-1281 (2001), which are hereby incorporated by reference in their entirety). In a preferred method, betulinol is first dissolved in acetone, and then oxidized with oxidizing reagent at 0° C. to synthesize carbonyl derivatives of betulinol, such as betulone aldehyde, betulin aldehyde, betulonic acid, and betulonic acid. Betulin acetate derivatives betulin diacetate, 3-acetoxy betulin, and 28-acetoxy betulin were prepared by acylation reaction (Kim et al., Bioorg. Med. Chem. Lett., 8:1707-1712 (1998); Hiroya et al., Bioorg. Med. Chem. 10:3229-3236 (2002), which are hereby incorporated by reference in their entirety). In particular, a dry pyridine solution of betulinol was treated with anhydrous acetic anhydride and stirred for 6 hrs. The workup of the resulting mixture was done by diluting with ethyl acetate and washed with 10% HCl and saturated NaHCO3 to yield betulin diacetate, 3-acetoxy betulin, and 28-acetoxy betulin. Betulin dimethyl ether was prepared by alkylation. To a solution of NaOH and betulinol in dry tetrahydrofuran, iodomethane was added and the resulting mixture was refluxed for 40 hrs. Distilled water was added drop wise to stop the reaction. Betulin dimethylether was obtained after column chromatography. Chlorocarbonyl betulin was obtained by treatment with oxalyl chloride (Sun et al., J. Med. Chem. 45:4271-4275 (2002), which is hereby incorporated by reference in its entirety). A solution of oxalyl chloride was added to betulinic acid and stirred for 2 hrs. Most of the solvent was removed under vacuo. Additional dry CH2Cl2 was added and subsequently concentrated to yield chlorocarbonyl betulin.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:13](=[O:16])([O-])[O-:14].[K+].[K+]>CN(C)C=O>[C:13]([CH:3]1[CH2:2][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][S:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)([OH:14])=[O:16]
Reactant: CC(C(=O)O)c1cccc(S)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1cccc(SCC2CCCCC2C(=O)O)c1
Temperature: 170 °C
Reaction time: 3 h
Yield: 192.6 %

Procedure:
To 2-(3-mercaptophenyl)propionic acid (2.7 g) were added cis-2-(hydroxymethyl)cyclohexanecarboxylic acid lactone (2.5 g), potassium carbonate (2.5 g) and dimethylformamide (25 ml). The mixture was heated with stirring for 3 hours in an oil bath maintained at 170° C. and evaporated to dryness under reduced pressure. The residue was dissolved in water, acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers were washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give the title compound (4.6 g) as an oil. IR νmaxfilm cm-1 : 1700 (C=O). MS m/e: 322 (M+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6])#[N:2].[CH3:12][N:13]([C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[S:16])[NH2:14].N1C=CC=CC=1.O>C(COC)OC>[NH:2]=[C:1]1[C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[N:14]1[N:13]([CH3:12])[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[S:16]
Reactant: CN(N)C(=S)Nc1ccccc1
Reactant: N#Cc1ccccc1C(=O)Cl
Solvent: O
Solvent: COCCOC
Solvent: c1ccncc1
Product: CN(C(=S)Nc1ccccc1)N1C(=N)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 166.9 %

Procedure:
A solution of crude 2-cyanobenzoylchloride (2.2 g; 0.013 mole) in 20 ml of dimethoxyethane was added dropwise to a solution of 2-methyl-4-phenylthiosemicarbazide 0.35 g; 0.013 mole) and pyridine (1.1 g; 0.013 mole) in 35 ml of dimethoxyethane. The resulting red solution was allowed to stir at room temperature overnight. The reaction mixture was poured into a large volume of water to give a reddish gummy precipitate. The water was decanted and the gummy material dissolved in a small amount of ethyl acetate. Upon standing a solid crystallized from solution. Filtration gave 1 g of the desired product, mp: 165-167. The IR and NMR spectra were consistent with the cyclic tautomer structure, as illustrated in the foregoing reaction scheme. Under basic conditions, as in the exemplified synthesis procedure, existence of the tautomeric ortho-cyanobenzoyl compound is probably negligible. It is conceivable, however, that in some chemical environments the tautomeric form can be detected, or that reaction products derived from the tautomeric form will be produced when identification by preparation of chemical derivatives is attempted.