Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([NH:31][C:32]([NH:34][C:35](=[O:44])[CH2:36][C:37]2C=CC(F)=C[CH:38]=2)=S)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:16]2=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[CH:19][N:15]2[N:14]=[CH:13][N:12]=1.Cl.FC1C=C(C(C(NC2C=CC(F)=CC=2)=O)C(N)=O)C=CC=1[O:53]C1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1>>[CH:36]1([C:35]([NH:34][C:32]([NH:31][C:6]2[CH:7]=[CH:8][C:9]([O:10][C:11]3[C:16]4=[C:17]([CH3:30])[C:18]([O:20][CH2:21][CH2:22][N:23]5[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]5)=[CH:19][N:15]4[N:14]=[CH:13][N:12]=3)=[C:4]([F:3])[CH:5]=2)=[O:53])=[O:44])[CH2:37][CH2:38]1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)NC(=O)C4CC4)cc3F)c12

Procedure:
Prepared in a similar manner as Example 264 using Compound B of Example 45 and Compound A of Example 280 (20.3 mg, 64%). 1H NMR (CD3OD) δ 10.85 (s, 1H), 7.70 (s, 1H), 7.76–7.72 (m, 2H), 7.22–7.14 (m, 2H), 4.14 (t, 2H, J=5.5 Hz), 2.94 (t, 2H, J=5.5 Hz), 2.89–2.60 (m, 4H), 2.78 (s, 3H), 2.34 (s, 4H), 1.70–1.67 (m, 1H), 0.99–0.95 (m, 2H), 0.91–0.86 (m, 2H); MS(ESI+) m/z 512.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5]2.[CH2:28](Br)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>CCOCC>[F:1][C:2]1[C:3]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:6][CH2:5]2
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCC1CCc2c(cc(F)c(F)c2-c2ccc(O)cc2)C1
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2c(F)c(F)cc3c2CCC(CCCCCCCC)C3)cc1

Procedure:
From 6,7-difluoro-5-(4-hydroxyphenyl)-2-octyl-1,2,3,4-tetrahydronaphthalene and 1-octyl bromide by means of the Williamson ether synthesis.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N+:10]([CH3:18])[N:9]([CH3:19])[C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+].[CH3:28]I.O>CS(C)=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:28][O:6][C:7]1[C:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N+:9]([CH3:19])[N:10]([CH3:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: Cn1c(-c2ccccc2)c(O)c(-c2ccccc2)[n+]1C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1c(-c2ccccc2)n(C)[n+](C)c1-c1ccccc1
Temperature: 60 °C
Yield: 53 %

Procedure:
4-Hydroxy-1,2-dimethyl-3,5-diphenylpyrazolium perchlorate (7 g, 0.02 mole) in DMSO (2.5 ml) is added to 5% sodium hydroxide (0.84 g, 0.02 mole) in DMSO (100 ml), dropwise with stirring. The mixture is warmed to 60° C for 5 minutes, then stirred at room temperature for 4 hours. The reaction mixture (75 ml) is treated with methyl iodide (0.43 g, 0.013 mole) and the mixture is stirred at room temperature for 16 hours, then heated at 40° C for 2 hours. On pouring into water, a solid precipitates with melting point 88° C. One crystallization from methanol gives the product with melting point 132°-132.5° C in 53% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:24])[CH2:13][NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][OH:17])=[CH:11][C:5]=2[CH2:4][O:3]1.[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C:2]1([CH3:25])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:24])[CH2:13][N:14]([C@@H:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][OH:17])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: O=CCCCCCOCCCCc1ccccc1
Reactant: CC1(C)OCc2cc([C@@H](O)CN[C@H](CO)c3ccccc3)ccc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCCCc3ccccc3)[C@H](CO)c3ccccc3)ccc2O1
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a cloudy mixture of (1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanol (500 mg) and crude 6-(4-phenylbutoxy)hexanal (400 mg) in CH2Cl2 (3 ml) under nitrogen was added sodium triacetoxyborohydride (433 mg) in one portion. A gelatinous mixture formed initially which thinned over a 15 min period. The resulting light yellow solution was stirred for 18 h before it was partitioned between ethyl acetate (10 ml) and saturated aqueous NaHCO3 (30 ml). The aqueous layer was extracted with ethyl acetate (3×20 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo to give the title compound (725 mg).
Reaction SMILES: Cl.C(OC([N:9]1[C@H:14]([CH2:15][NH:16][C:17]2[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=2)[C@@H:13]2[CH2:24][C@H:10]1[CH2:11][CH2:12]2)=O)(C)(C)C>O1CCOCC1>[C@H:10]12[CH2:24][C@H:13]([CH2:12][CH2:11]1)[C@@H:14]([CH2:15][NH:16][C:17]1[N:22]=[CH:21][C:20]([Br:23])=[CH:19][N:18]=1)[NH:9]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNc1ncc(Br)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Brc1cnc(NC[C@H]2N[C@@H]3CC[C@H]2C3)nc1

Procedure:
A solution of HCl in dioxane (4.0 M, 30 mL) is added to a solution of (1R,3S,4S)-3-[(5-bromo-pyrimidin-2-ylamino)-methyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (6.63 mmol) in dioxane (30 mL). After 4 h the solvents are removed in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.64 min; [M+H]+=283.0.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([O-])(=[O:10])[CH:8]=C>C(O)(=O)C>[C:7]([O:3][CH:2]([CH3:4])[C:1]([OH:6])=[O:5])(=[O:10])[CH3:8]
Reactant: CC(O)C(=O)O
Reactant: C=CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)OC(C)C(=O)O

Procedure:
In one aspect the invention pertains to a process of forming an acrylate without utilizing an anhydride reagent. Lactic acid or a lactic acid ester is introduced into a first vessel with an excess of acetic acid (as measured by molar value). The lactic acid or lactic acid ester is reacted with a first portion of the acetic acid in the presence of a first catalyst to produce the corresponding 2-acetoxy propionic acid or ester. A non-reacted portion of the acetic acid is recycled and can be re-used for further reaction without converting to an anhydride. The 2-acetoxy propionic acid or ester is transferred to a second vessel where, in the presence of a second catalyst, acetic acid is liberated from the 2-acetoxy propionic acid or ester to produce a corresponding acrylic acid or first acrylate ester. After removing the liberated acetic acid by distillation, the acetic acid or first acrylate ester is mixed with an alcohol and the acrylic acid is esterified, or the first acrylate ester is trans-esterified, by reaction with the alcohol to form a second acrylate ester.
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:26]2[C:34]3[C:29](=[N:30][CH:31]=[C:32]([Br:35])[CH:33]=3)[NH:28][CH:27]=2)OC)=[CH:19][N:18]=1)[CH2:8][C:9]1[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:35][C:32]1[CH:33]=[C:34]2[C:26]([CH2:23][C:20]3[CH:21]=[CH:22][C:17]([NH:7][CH2:8][C:9]4[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=4)=[N:18][CH:19]=3)=[CH:27][NH:28][C:29]2=[N:30][CH:31]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(OC)c3c[nH]c4ncc(Br)cc34)cn2)cn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Br)cc34)cn2)cn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 61.8 %

Procedure:
To {5-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methoxy-methyl]-pyridin-2-yl}-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (154, 0.35 g, 0.63 mmol) in 20.0 mL of acetonitrile, triethylsilane (1.0 mL, 6.3 mmol) and trifluoroacetic acid (0.50 mL, 6.5 mmol) were added and the reaction stirred at 80° C. for 4 hours. The reaction was concentrated under vacuum and combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-2017, 165.1 mg). MS (ESI) [M+H+]+=423.8, 425.8
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12]I.[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:12][N:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]1[CH3:1]
Reactant: CI
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(C)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 10 g of ethyl 2-methyl-1H-pyrrole-3-carboxylate (65.3 mmol) and 8.95 mL (130.6 mmol) of methyl iodide in 70 mL of dimethylformamide placed at 0° C. there are added, in three portions, 2.61 g (65.3 mmol) of sodium hydride 60%. The batch is then stirred at 0° C. for 1 hour. Then, the reaction mixture is hydrolysed by the addition of 420 mL of ice-cold water. The reaction mixture is then diluted with ethyl acetate, successively washed with 0.1M HCl solution, saturated aqueous LiCl solution and then brine. The organic phase is then dried over MgSO4, filtered, concentrated to dryness and purified by chromatography over silica gel (petroleum ether/AcOEt gradient).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2F)[CH2:10][CH2:9]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O>C1COCC1>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:6]=[CH:5][C:4]([C:26](=[O:28])[CH3:27])=[CH:3][CH:2]=3)[CH2:9][CH2:10]2)=[O:25])[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)c(F)c1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCN(C)CC3)CC2)cc1
Temperature: 800 °C

Procedure:
A stirred mixture of 150 mg (0.39 mmol) 1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone, 200 mg (2.0 mmol) 1-methylpiperazine in 4 ml THF was heated to 800° C. for 1 h. Water was added to the reaction mixture, the precipitate isolated, dried and purified by flash-chromatography on silica gel with heptane/AcOEt as eluent. The title compound was obtained as a light yellow powder, MS (m/e): 471.2 (MH+, 100%).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[CH:14]=[C:13]([N:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH3:23])[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:8][C:2]([O:30][C:27]1[CH:26]=[CH:25][C:24]([N:22]([C:13]2[N:12]=[C:11]([Cl:10])[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=3)[CH3:23])=[CH:29][CH:28]=1)([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Temperature: 100 °C
Yield: 54.7 %

Procedure:
A mixture of ethyl 2-bromo-2-methylpropionate (0.54 g), 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (0.74 g), potassium carbonate (0.38 g) dimethylformamide was heated at 100° C. for 28 hrs. The mixture was cooled, diluted with dichloromethane, washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated to give an oil, which was purified by column chromatography over silica gel (eluent dichloromethane) to give ethyl 2-methyl-2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]-phenoxy}propionate (0.55 g) as a yellow oil.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O)([O-:17])=[O:16].[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[OH-].[Na+]>C(Cl)Cl>[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)([O-:17])=[O:16]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(CNC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaB(OAc)3H (11.87 mmol, 2.52 g) was added to a mixture of 3-nitrobenzaldehyde Compound 6a (9.89 mmol, 1.49 g) and 4-amino-tetrahydro-pyran Compound 3d (9.89 mmol, 1.00 g) in CH2Cl2 (50 mL) and the resulting suspension was stirred overnight at r.t. The reaction mixture was made basic with a 2N NaOH solution and extracted with CH2Cl2. The organic layer was washed with brine, then separated and dried over MgSO4. The drying agent was filtered and the solvent was removed in vacuo. The product was purified by flash column chromatography (9:1 CH2Cl2:MeOH) to yield (3-nitro-benzyl)-(tetrahydro-pyran-4-yl)-amine Compound 6b as a yellow oil (1.91 g, 82%). (This portion of Example 6 was adapted from Shiroshi, et al., J. Med. Chem., 2000, 43, 2049). MS m/e 237 (M+H, 100%); 1H NMR (300 MHz, CDCl3) δ 1.35-1.53 (m, 4H), 1.82-1.95 (d, 2H), 2.65-2.8 (m, 1H), 3.38 (dt, J=3.2 Hz, J=11.2 Hz, 2H), 3.92-4.05 (m, 4H), 7.45-7.54 (t, 1H), 7.65-7.72 (d, 1H), 8.07-8.15 (d, 1H), 8.22 (s, 1H).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14](O)=[CH:15][C:16](=[O:18])[CH3:17])=[CH:7]2.O.C([O-])(=O)C.[Na+].C([O-])(=O)C.[Na+].[H][H]>O.[Pd].CO>[CH3:13][O:12][C:11]1[CH:2]=[C:3]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])[CH:5]=[CH:4]2
Reactant: [H][H]
Reactant: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc2cc(CCC(C)=O)ccc2c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
48 Grams (0.150 moles) of 4-(5-bromo-6-methoxy-2-naphthyl)-4-hydroxybut-3-en-2-one, 6.1 g of sodium acetate hydrate containing 32.4% of water, equivalent to 0.050 moles of sodium acetate, 4 g of a 50% suspension in water of 10% palladium on carbon, equivalent to 0.0019 moles of palladium, and 500 ml of methanol are put in a hydrogenator. The hydrogenator is washed with nitrogen in order to eliminate the oxygen and then hydrogen is introduced at the pressure of 2 atmospheres. The temperature of reaction is kept at 40° C. for a period of time of 6 hours, then the hydrogen is let off, the hydrogenator is washed with nitrogen and the reaction mixture is filtered to eliminate the catalyst. The solution is brought to pH 6 with a 5% aqueous solution of sodium hydroxide and concentrated under vacuum. The oily residue is dissolved into 130 ml of isopropanol and 30 ml of N,N-dimethylformamide and the solution is added with 45 ml of water and 17.6 g of sodium bisulfite obtaining a suspension that is stirred for one hour at 60° C., then is cooled to 5° C. and is filtered. The obtained solid is washed with 75 ml of methanol, suspended in 200 ml of a 5% aqueous solution of sodium hydroxide and kept under stirring at room temperature for three hours. The suspension is then filtered, the solid is washed with water until neutrality and dried in oven under vacuum obtaining 18 g of product with a yield equal to 52.8%.
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)Cl.C1(C)C=CC=CC=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH2:1]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:3]1[O:5][CH2:4]1
Reactant: Oc1ccccc1
Reactant: ClC[C@@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(OC[C@H]2CO2)cc1
Reaction time: 50 h
Yield: 68.7 %

Procedure:
To a reaction vessel were added (S)-epichlorohydrin (99% ee, 2.64 g, 29 mmol), toluene (6 ml) and water (6 ml), and the mixture was cooled with ice. After adding phenol (1.78 g, 19 mmol), thereto 24% aqueous NaOH solution (4.75 g, 29 mmol) was dropped under stirring over a ten minute period. The mixture was stirred for 30 minutes under ice-cooling and then for 50 hours at room temperature. The aqueous layer was removed and the organic layer was neutralized with 5% HCl and washed with water twice. The solvent was removed to give objective crude (R)-glycidylphenyl ether (1.96 g, yield 69%, optical purity 98% ee) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([O:16]CC)=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:19]=1.[OH-].[K+].Cl.O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:19]=1
Reactant: CCOC(=O)C1CCc2sc3ccc(F)cc3c2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCc2sc3ccc(F)cc3c2C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 8-fluoro-1,2,3,4-tetrahydrodibenzo[b,d]thiophene-2-carboxylate (2.5 g, 9 mmol) in EtOH (60 mL) was added KOH (0.81 g, 15 mmol). The reaction was stirred at 40° C. overnight. After cooling in an ice-water bath, the mixture was acidified to pH 2-3 with 1 N HCl. Water was added and the resulting white solid precipitate was collected and dried to afford 2.15 g (96%) of the title compound: mp 245° C. (dec.), MS (−) 249 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([Cl:10])=[C:5]([Cl:11])[N:4]=1.S(Cl)([Cl:15])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:15][CH2:1][O:2][C:3]1[C:8]([Cl:9])=[CH:7][C:6]([Cl:10])=[C:5]([Cl:11])[N:4]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1nc(Cl)c(Cl)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClCOc1nc(Cl)c(Cl)cc1Cl

Procedure:
To a solution of 92.2 g. (0.434 mole) 2-methoxy-3,5,6-trichloropyridine in 400 ml. carbon tetrachloride, which is illuminated and heated to reflux by a G.E. sunlamp, add dropwise over a period of 5 hours a solution of 58.6 g. (0.434 mole) sulfuryl chloride in 400 ml. carbon tetrachloride. The mixture is allowed to reflux for 1 hour, then is cooled and the solvent is evaporated in vacuum. The residue is a colorless liquid which is distilled through a 4-inch fractionating Claisen head to afford a pure fraction of 2-chloromethoxy-3,5,6-trichloropyridine, 52.5 g. (49%), b.p. 106°-110° C. at 1.3 mm. Hg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:16]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:16])=[C:7]([CH3:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc([N+](=O)[O-])c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
4-tert-Butyl-2-methyl-6-nitro-phenol (209 mg, 1 mmol) was dissolved in 3 mL acetone. 552 mg K2CO3 (4 eq) was added, followed by addition of MeI (0.33 mL, 5 mmol). The reaction mixture was stirred vigorously at 60° C. overnight. After removal of the acetone, the residue was shaken with DCM. Filtration and evaporation of the solution yielded 221 mg product which was used as such.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25](OC(C)(C)C)(N(C)C)[N:26]([CH3:28])[CH3:27]>C1COCC1>[CH2:1]([NH:8][C:9]([C:11]1[NH:12][CH:13]=[C:14]([C:16](=[O:24])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:25][N:26]([CH3:28])[CH3:27])[CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1c[nH]c(C(=O)NCc2ccccc2)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=C(C(=O)c1c[nH]c(C(=O)NCc2ccccc2)c1)c1ccccc1
Reaction time: 24 h

Procedure:
To a solution of compound 2 (1 equivalent) in THF, at ambient temperature, was added (Me2N)2CHOt-Bu (3 equivalents). After 24 hours, the solvent was evaporated and the crude product 3 was utilized without purification. 1H NMR (CDCl3) δ 4.4 (s, 2H), 4.8 (s, NH), 6.8-7.4 (m, 13H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][C:4]2[CH:15]=[N:16][NH:17][C:3]1=2.[H-].[Na+].I[CH3:22]>CN(C=O)C>[CH3:22][N:17]1[C:3]2[C:2]([CH3:18])([CH3:1])[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:5][C:4]=2[CH:15]=[N:16]1
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C(C)(C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c1C(C)(C)CN(C(=O)OC(C)(C)C)C2
Reaction time: 0.5 h

Procedure:
2.10 g (8.36 mmol) tert. butyl 7,7-dimethyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylate were placed in 25 mL DMF. While cooling with ice, 350 mg (8.75 mmol) sodium hydride (55%) were added. The reaction mixture was stirred for 30 min, then 0.540 mL (8.67 mmol) iodomethane were added and the mixture was stirred for 1 h at 0° C. The reaction mixture was concentrated to dryness by rotary evaporation and the residue was mixed with water and extracted with EtOAc. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation. The residue was purified by HPLC. The product-containing fractions were combined and organic solvent was eliminated by rotary evaporation. The aqueous residue was extracted with DCM. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:22])[CH:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1N
Yield: 98.7 %

Procedure:
[1-(3-Methyl-4-nitrophenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (1.744 g, Example 35a), iron powder (1.52 g), ammonium chloride (1.45 g), ethanol (50 ml) and water (50 ml) were refluxed together under nitrogen for 2 h. The mixture was cooled and the iron was filtered off. Water (200 ml) was added to the residue and the product extracted into ethyl acetate (3×200 ml), dried (MgSO4), and concentrated to give the subtitle compound (1.56 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16](O)=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[N:15][C:16]([Cl:28])=[C:11]2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2nn(Cc3ccccc3)c3ncnc(O)c23)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cccc(-c2nn(Cc3ccccc3)c3ncnc(Cl)c23)c1
Temperature: 0 °C

Procedure:
A mixture of 2.48 g (7.46 mmol) of 1-benzyl-4-hydroxy-3-(3-methoxy-phenyl)-pyrazolo[3,4-d]pyrimidine and 30 ml of phosphorus oxychloride is heated under reflux for 10 hours and then, with stirring, poured slowly into ice-water. The reaction mixture is stirred for a further 2 hours at 0-10° C. and filtered and the filter residue is washed with water. The crude product is dissolved in methylene chloride and the organic phase is washed with brine, dried over sodium sulfate and concentrated by evaporation in vacuo. Purification of the residue by flash chromatography on silica gel (230-400 mesh) using methylene chloride and methylene chloride/methanol mixtures (99:1 and 49:1) yields the title compound; m.p. 99-101° C.; FAB-MS: (M+H)+ =351.