Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[S-:13][C:14]#[N:15].[K+].O>C(O)(=O)C>[CH3:2][N:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:15][C:14]1=[S:13]
Reactant: CNCC(=O)c1ccccc1
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1cc(-c2ccccc2)[nH]c1=S
Temperature: 140 °C
Yield: 47.3 %

Procedure:
An adaptation of the method reported by Kjellin and Sandström, Acta Chem. Scand. 1969, 23, 2879-2887 was used. A mixture of 2-methylamino-1-phenyl-ethanone hydrochloride (0.754 g, 4.06 mmol) (see e.g. Hyde et al. J. Am. Chem. Soc. 1928, 50, 2287-2292; Shang et al. Chem. Eur. J. 2007, 13, 7780-7784) and potassium thiocyanate (0.434 g, 4.46 mmol) in acetic acid (12 mL) was heated at 140° C. for 10 minutes using a microwave synthesizer. Dilution with water (50 mL) and cooling in an ice bath caused the product to precipitate. It was collected by filtration, washed with water, and vacuum dried to yield the title compound (0.365 g, 47%) pure as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ12.66 (br s, 1H), 7.65 (d, J=7.6 Hz, 2H), 7.60 (s, 1H), 7.39 (I, J=7.8 Hz, 2H), 7.27 (t, J=7.4 Hz, 1H), 3.49 (s, 3H).
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[CH3:6][N:7]([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[CH3:6][N:7]([CH3:14])[C:8]1[CH:9]=[C:10]([S:1]([Cl:5])(=[O:3])=[O:2])[CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CN(C)c1cccc(S(=O)(=O)Cl)c1
Temperature: 0 °C
Yield: 11.3 %

Procedure:
Sulfurochloridic acid (100 g, 862.07 mmol) was cooled to 0° C. and N,N-dimethylbenzenamine (20 g, 165.29 mmol) was added dropwise with stirring, maintaining a temperature of 0° C. The resulting solution was then heated to 120° C. and stirred for 3 hours. After cooling to room temperature, dichloromethane (40 mL) was added and the resulting mixture was added dropwise to 100 mL of ice/salt water. The resulting solution was extracted with dichloromethane (3×500 mL) and the organic layers combined, dried (Na2SO4) and filtered. The filtrate was concentrated and the residue was purified by column chromatography using a 1:100 ethyl acetate/petroleum ether solvent system. The collected fractions were combined and concentrated to give 4.1 g (11%) of 3-(dimethylamino) benzene-1-sulfonyl chloride as a yellow solid. 1H NMR (CDCl3) δ 7.41 (t, 1H), 7.31 (d, 1H), 7.23 (s, 1H), 6.98 (m, 1H), 3.05 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH:9]=O)(=[O:3])[CH3:2].Br[CH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:20]([C:18]1[N:19]=[C:15]([C:14]2[O:12][C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:11][C:8]=3[CH:9]=2)[S:16][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)c1csc(CBr)n1
Reactant: CC(=O)c1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-acetyl-2-hydroxybenzaldehyde (1.68 g), 2-bromomethyl-4-tert-butylthiazole, potassium carbonate (1.24 g) and potassium iodide (0.59 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 5 hours. The resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. A mixture of the resulting syrup and acetic anhydride in xylene was stirred under reflux for 1 day. After being cooled to room temperature, the reaction mixture was concentrated under reduced -pressure. The resulting syrup was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-(5-acetylbenzofuran-2-yl)thiazole (1.83 g).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27]CC4C=CC=CC=4)[CH:23]=3)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(CCO)(O)(=O)=O>[Pd].CO.O1CCCC1>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20]3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc3cc(OCCN4CCC(Cc5ccccc5)CC4)ccc3c2)cc1
Agent: [Pd]
Agent: O=S(=O)(O)CCO
Solvent: CO
Solvent: C1CCOC1
Product: Oc1ccc2cc(OCCN3CCC(Cc4ccccc4)CC3)ccc2c1
Reaction time: 20 h
Yield: 95.3 %

Procedure:
A mixture of of 4-benzyl-1-[2-(6-benzyloxy-naphthalen-2-yloxy)-ethyl]-piperidine (0.67 g, 1.48 mmol) and 20% palladium on carbon (0.06 g) in methanol (8 ml) and tetrahydrofuran (8 ml) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for 20 h. After removal of the catalyst, the filtrate was evaporated and the white solid (0.51 g, 95%) was dissolved in tetrahydofuran (5 ml). A solution of isethionic acid in methanol (4.6 ml, 1.28 mmol) was added, and the solid precipitate was filtered off. The solid was washed with tetrahydofuran, and dried in vacuo overnight to give the title compound (0.51 g, 82%), mp139-141° C. Analysis calculated for C24H27NO2 ·C2H6O4S: C, 64.04; H, 6.82; N, 2.87; S, 6.58. Found: C, 63.88; H, 6.77; N, 2.70; S, 6.60.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[N:13]([CH3:18])[N:14]=[C:15]([C:16]#[N:17])[C:7]1=[CH:6]2.[OH2:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[N:13]([CH3:18])[N:14]=[C:15]([C:16]([NH2:17])=[O:19])[C:7]1=[CH:6]2
Reactant: O
Reactant: COc1ccc2nc3c(cc2c1)c(C#N)nn3C
Product: COc1ccc2nc3c(cc2c1)c(C(N)=O)nn3C

Procedure:
A mixture of 6.20 g 6-methoxy-1-methyl-1H-pyrazolo[3,4-b]quinoline-3-carbonitrile (Example 33), 250 ml water and 13.5 ion exchange resin (Amberlite IRA-100, OH- form) was stirred and heated at reflux until hydrolysis was complete. The product was isolated and recrystallized from ethyl acetate-hexane to give 2.7 g 6-methoxy-1-methyl-1H-pyrazolo[3,4-b]quinoline-3-carboxamide, yellow solid, m.p. 268°-270° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH3:26])=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1.[CH:29]1(N=C=O)[CH2:33]C[CH2:31][CH2:30]1.CN=C=O>>[O:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@@H:16]2[O:20][C@H:19]([CH2:21][NH:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:33]3)=[O:24])[C@@H:18]([OH:27])[C@H:17]2[OH:28])[CH2:2]1
Reactant: O=C=NC1CCCC1
Reactant: CNC(=O)NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O
Agent: CN=C=O
Product: O=C(NC[C@H]1O[C@@H](n2cnc3c(N[C@@H]4CCOC4)ncnc32)[C@H](O)[C@@H]1O)NC1CCCC1

Procedure:
Compound 76 was prepared in the manner of compound 24 substituting cyclopentyl isocyanate for methyl isocyanate and refluxing for 16 h [MS 448.3 (M+1)].
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11]2)([O-:5])=[O:4].[CH3:20][O:21][CH2:22]Cl.O>CN(C)C=O>[CH3:20][O:21][CH2:22][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[N+:3]([O-:5])=[O:4])[CH:11]=[C:12]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2n1COC
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a suspension of sodium hydride (60%, in oil, 0.51 g) in N,N-dimethylformamide (15 ml) was slowly added ethyl 7-nitro-1H-indole-2-carboxylate (2.50 g) at 0° C., and the mixture was stirred for 30 min. Chloromethyl methyl ether (1.00 ml) was added to the reaction mixture over 20 min at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.29 g, yield 77%) as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). melting point 62-63° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(Cl)c3)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1cccc(-c2csc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.5 %

Procedure:
A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(3-chlorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (5.15 g, 13.6 mmol) in ethyl acetate (100 ml), the mixture was stirred at room temperature for 6 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 3.29 g (86.8%) of the desired product as an oil.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][C:4]#[CH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:1][CH:2]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCC(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(+/−)-4-Pentyn-2-ol (5.58 ml, 59.4 mmol) and 3,4-dihydro-2H-pyran (8.08 ml, 89 mmol) were dissolved in DCM (100 ml). 4-Toluenesulfonic acid pyridine salt (1.494 g, 5.94 mmol) was added and the resulting mixture was stirred for 4 h at RT with CaCl2-tube. The mixture was concentrated. 50 ml of diethyl ether was added, extracted with brine and dried with MgSO, filtered and evaporated. The product was used in the subsequent steps without further purifications. LC-MS: [M+1]=169.23.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH2:16])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][C:4]1[CH:17]=[C:7]2[C:8]([C@H:12]3[CH2:14][C@@H:13]3[CH2:15][NH:16][C:25](=[O:27])[CH3:26])=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c([C@H]3C[C@@H]3CN)cccn2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1C[C@@H]1c1cccn2nc(C)cc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.5 %

Procedure:
To a suspension of 1-[(1S,2S)-2-(2-methylpyrazolo[1,5-a]pyridin-4-yl)cyclopropyl]methanamine dihydrochloride (750 mg, 2.74 mmol) and triethylamine (1.52 mL, 10.9 mmol) in tetrahydrofuran (27 mL) was added acetic anhydride (388 μL, 4.10 mmol), and the mixture was stirred at room temperature for 14 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (623 mg, yield 93%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Na+].[I-]>C1(C)C=CC=CC=1.CN(C=O)C>[C:21]1([CH2:20][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a mechanically stirred DMF (260 mL) suspension of 1-[4-hydroxy-3-nitrophenyl]ethanone (51 g, 282 mmol) and K2CO3 (17 g, 847 mmol) was added benzyl bromide (68 mL, 572 mmol) followed by NaI (47 g, 313 mmol). After stirring overnight at 20° C., an additional 10 mL of benzyl bromide was added and stirred 15 minutes. The reaction was quenched by the addition of 1.6 L water. The resulting suspension was stirred overnight and then filtered. The collected solids were washed 3×250 mL=750 mL water and dried in vacuo at ~55° C. to give 75 g crude product which was slurried in 1.3 L toluene at ~75° C., filtered hot through a 5.0 μm membrane, concentrated in vacuo to a volume of ~300 mL, diluted with 250 mL heptane, and the suspension cooled from ~60° C. to ambient. After filtration, the collected solids were washed with heptane and dried in vacuo at ~55° C. to give 64 g (84%) of the title compound.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36]/[N:37]=[C:38](\[CH3:46])/[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:26]([NH:28][CH3:29])=O.O>C1(C)C=CC=CC=1>[CH3:23][O:24][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36]/[N:37]=[C:38](\[CH3:46])/[C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:26]([NH:28][CH3:29])=[S:10]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=S)C(OC)c1ccccc1O/N=C(\C)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 137.8 %

Procedure:
Lawesson's reagent (40 mg, 0.1 mmol) was added to a solution of (E)-α-methoxy-N-methyl-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylacetamide (73 mg, 0.2 mmol) in toluene (3 ml), and the mixture was heated at 80° C. for 1.5 hours with stirring. The mixture was cooled to room temperature. Water was added, and the mixture was extracted with ether and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give the desired compound (E)-α-methoxy-N-methyl-2-(α-methyl-4-chlorobenzylideneaminooxy)phenylthioacetamide (50 mg, 66%) as an oil.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].Cl[CH2:8][CH2:9][C@H:10]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:22])[CH:17]=2)[C:12]([CH3:24])([CH3:23])[CH2:11]1.Cl>O1CCCC1>[CH2:9]([C@H:10]1[C:19]([CH3:21])([CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:22])[CH:17]=2)[C:12]([CH3:23])([CH3:24])[CH2:11]1)[CH3:8]
Reactant: Cc1ccc2c(c1)C(C)(C)[C@H](CCCl)CC2(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC[C@@H]1CC(C)(C)c2ccc(C)cc2C1(C)C
Yield: 95.3 %

Procedure:
To a suspension of aluminum lithium hydride (6.5 g; 0.171 mol) in tetrahydrofuran (100 ml), a solution of (S)-3-(2-chloroethyl)-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene ([α]546 --33.4° (C=1.17 in ethanol)) (44.8 g; 0.169 mol) in tetrahydrofuran was dropwise added thereto. The resultant mixture was heated with reflux for 12 hours and then cooled. The cooled mixture was treated with dilute hydrochloric acid and extracted with n-hexane. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give (R)-3-ethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (37.0 g; 0.161 mol; 94%). B.P., 79°-80° C./0.15 mmHg. [α]546 +2.2° (C=0.95 in ethanol).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][N:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.N1C2C(=CC=CN=2)C=C1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(OCC)(=O)C>C(=O)([O-])[O-].[K+].[K+].O.O1CCCC1.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>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:10]=[CH:9][N:8]=[C:7]3[NH:6][CH:5]=[CH:4][C:3]=23)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Clc1ccnc2[nH]ccc12
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: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccnc3[nH]ccc23)cc1OC
Temperature: 150 °C

Procedure:
In a microwave reaction tube, 4-chloro-7-azaindole (49, 1.362 g, 8.926 mmol), prepared from 7-azaindole following published procedure (Schneller, S. W.; Luo, Jiann-Kuan. J. Org. Chem. 1980, 45, 4045-4048), 3,4-dimethoxyphenyl boronic acid (4.06 g, 22.3 mmol), and tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.45 mmol) were mixed in 1.0 M potassium carbonate in water (27 mL) and tetrahydrofuran (43 mL). The resulting mixture was heated at 150° C. in a CEM Discover microwave unit for 20 minutes. Ethyl acetate and water were added, and the two layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded the crude material, which was purified by column chromatography (40-70% ethyl acetate in hexane) to yield the desired product in light yellow solid (50, 974 mg, 3.83 mmol). MS(ESI) [M+H+]+=255.2.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:37])[C:12]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:19]([CH3:21])[CH:20]=1)=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:44]([OH:47])(=[S:46])[CH3:45]>>[CH2:8]([O:10][C:11](=[O:37])[CH:12]([CH2:13][S:46][C:44](=[O:47])[CH3:45])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:19]([CH3:21])[CH:20]=1)[CH3:9]
Reactant: CC(O)=S
Reactant: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Triethylamine (0.234 mL, 1.68 mmol) was added to a solution of 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.68 g, 1.61 mmol) in thioacetic acid (3 mL) at 0° C. The mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic phase was washed with water, saturated NaHCO3 and brine and dried. The crude product was purified by flash chromatography (toluene/ethyl acetate, 3:1→1:2) to give pure 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (489 mg, 61%) and slightly impure 2-acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (0.34 g, 43%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11](OB(O)O)=[CH:10][CH:9]=1.[Cl-].[Li+].C[O:21][CH2:22][CH2:23][O:24][CH3:25]>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:8]2[CH2:13][CH2:12][C:25]3([O:21][CH2:22][CH2:23][O:24]3)[CH2:10][CH:9]=2)=[CH:10][CH:9]=1
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: COCCOC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Li+]
Product: Fc1ccc(C2=CCC3(CC2)OCCO3)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In an argon-charged flask, 2M sodium carbonate (4.8 mmol), 1,2-dimethoxyethane (8 ml), 4-fluorophenylboric acid (2.8 mmol), lithium chloride (6 mmol), 1,4-dioxaspiro[4.5]dec-7-en-8-yl-trifluormethane-sulphonic acid ester (2 mmol) and tetrakis(triphenyl-phosphine)palladium (0.1 mmol) are combined and stirred overnight at 80° C. The reaction mixture is concentrated in a vacuum and the residue is dispersed in dichloromethane/2M aqueous sodium carbonate solution. The aqueous phase is extracted with dichloromethane. The combined organic phases are then dried over sodium sulphate and the solvent is evaporated off in a vacuum. From the residue, after column chromatography using silica gel (ethyl acetate/heptane 1:4), pure 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene is isolated (Synthesis 1993, 735-762): tR 3.61 min (LC-1); ESI-MS(+): m/z 235.34 [M+H]+. 1H NMR (ppm,CDCl3): 7.35 (2H); 6.95 (2H); 5.9 (1H); 4.05 (4H); 2.65 (2H); 2.45 (2H); 1.9 (2H).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=O)[NH:5][C:4]=2[CH:3]=[CH:2]1.B.CSC.CO>O1CCCC1>[S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCCc2sccc2N1
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: c1cc2c(s1)CCCCN2
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a mixture of 21.2 g of 5,6,7,8-tetrahydro-4H-thieno[3 2-b]azepin-5-one in 100 ml of tetrahydrofuran under argon, chilled to 0° C. is added 25.2 ml of a 10.0 molar solution of borane-dimethylsulfide in tetrahydrofuran. The solution is stirred at room temperature for 16 hours and is refluxed for 5 hours. The mixture is cooled to room temperature and 85 ml of methanol added dropwise (exotherm). The solvent is removed and 100 ml of methanol is added (2 times) and after each addition the solvent is removed. To the residual solid (dried under vacuum) is added 126 ml of 2N NaOH and the mixture refluxed 3 hours. The mixture is chilled (2 hours) and extracted with dichloromethane. The extract is dried (Na2SO4) and the solvent removed to give 15.4 g of brown solid, m.p. 55°-57° C. A sample (3 g) is sublimed to give 2.6 g of crystals, m.p. 64°-65° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C@H:11]([NH:19][C:20](=O)OC(C)(C)C)[C:12]([N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)=O)[CH2:10][CH2:9][CH2:8]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:7]1([C@H:11]([NH:19][CH3:20])[CH2:12][N:14]2[CH2:17][CH:16]([OH:18])[CH2:15]2)[CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC(O)C1)C1CCC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CN[C@H](CN1CC(O)C1)C1CCC1
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A 1 M solution of LAH in THF (66.8 mL, 66.8 mmol) under nitrogen was heated to 45° C. A solution of (S)-tert-butyl 1-cyclobutyl-2-(3-hydroxyazetidin-1-yl)-2-oxoethylcarbamate (Compound Y2.1) (3.80 g, 13.4 mmol) in THF (20 mL) was added dropwise over 30 min. The resultant mixture was stirred at 47° C. over night. The mixture was cooled on an ice-bath and NaHCO3 (8% aq., 16 mL) was carefully added dropwise. The stirring was continued for 2 h at rt. The precipitate was filtered off and washed with DCM. The filtrate was concentrated and the residue dissolved in DCM and filtered through a 0.45 μm syringe filter. The filtrate was concentrated to give the title compound (2.23 g, 91%, 92% pure) as an oil. 1H NMR (400 MHz, CD3OD) δ 1.69-2.13 (6H), 2.2-2.38 (7H), 2.79 (1H), 2.89 (1H), 3.56-3.66 (2H), 4.26-4.34 (1H). Expected Number of protons: 20. OH- and NH-protons are exchanged with CD3OD.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:9][C:10]2[C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][N:13]=[C:12]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:11]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.O>C(O)C>[CH:3]1([NH:9][C:10]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=[C:12]3[N:21]([CH2:24][CH3:25])[N:22]=[CH:23][C:11]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(NC3CCCCC3)c(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sodium hydroxide solution (4.09 gm in 20 ml water) was added to a solution of ethyl 4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (9.32 gm, 0.0294 mole) (example 4) in ethanol. The reaction mixture was stirred for about 14 h at room temperature and then warmed for about 1 h at 60° C. Water was added and the reaction mixture was extracted with ethyl acetate. Aqueous layer was acidified by using hydrochloric acid (2N) to pH of about 4-5. White solid, which was obtained, was filtered and dried in vacuo.