Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:38]([C:42]1[CH:43]=[CH:44][C:45]([CH2:48]Cl)=[N:46][CH:47]=1)[CH2:39][CH2:40][CH3:41]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:48][C:45]2[CH:44]=[CH:43][C:42]([CH2:38][CH2:39][CH2:40][CH3:41])=[CH:47][N:46]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCCCc1ccc(CCl)nc1
Agent: Cl
Product: CCCCc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)nc1
Yield: 80.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 5-butyl-2-chloromethylpyridine (0.66 g) as starting materials, 5-benzyloxy-N-({1-[(5-butylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained.
Reaction SMILES: N1C=CC=CC=1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1.[C:18](Cl)(=[O:29])[O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1.O>ClCCl>[C:18](=[O:29])([O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
Adapting a known procedure (P. Pasetto, et al., Anal. Chim. Acta, 2005, 542(1), 66-75), 8.03 mL of anhydrous pyridine (7.84 g, 99.3 mmol; 1.5 eq.) was added at a temperature of about 0° C. (ice bath) to a suspension of 10.00 g N-(4-hydroxyphenyl)acetamide (1) (paracetamol (INN), acetaminophen (USAN) (66.2 mmol; 1.0 eq.) in 300 mL of anhydrous dichloromethane (DCM). The reaction mixture was stirred at the same temperature for about 10 minutes. To this mixture, a solution of 13.97 g (69.5 mmol; 1.05 eq.) of commercially available 4-nitrophenyl carbonochloridate (2) in 20 mL of anhydrous DCM was then added dropwise and the reaction mixture was stirred with gradual warming to room temperature for overnight. Fifty (50) mL of water were added to the reaction mixture. A solid precipitated out of solution. The solid was filtered off and washed successively with diethylether (Et2O) (2×50 mL) and hexane (4×50 mL) to afford 9.92 g (47% yield) of the target compound 3 as a colorless solid after drying in high vacuum. The initial filtrate (DCM and water) was washed with a saturated aqueous solution of sodium chloride (NaCl/brine). The organic layer was dried using anhydrous sodium sulfate (Na2SO4) to afford an additional 7.0 g (33% yield) of the target compound 3. Rf-value: 0.35 (ethyl acetate/hexane=1:1). 1H NMR (DMSO-d6, 300 MHz): δ=10.09 (s, 1H), 8.34 (d, J=9.3 Hz, 2H), 7.68 (d, J=9.3 Hz, 2H), 7.64 (d, J=9.0 Hz, 2H), 7.31 (d, J=8.7 Hz, 2H), 2.05 (s, 3H) ppm. LC/MS (ESI): m/z=317.2 [M+H]+. The analytical data corresponded to the analytical data given in the literature.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.O(C1C=CC(C(C2C=CC(OC#N)=CC=2)(C)C)=CC=1)[C:22]#[N:23].O>C1COCC1.[Cl-].[Na+].O>[Br:3][C:4]1[N:5]([C:22]#[N:23])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1ccc(-c2c(Br)[nH]c3ccccc23)cc1
Reactant: CC(C)(c1ccc(OC#N)cc1)c1ccc(OC#N)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(Br)n(C#N)c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
NaH (18.35 mg, 0.76 mmol) was stirred in dry THF (1 ml) at 0° C. and 2-bromo-3-(4-methoxyphenyl)-1H-indole (210 mg, 0.69 mmol) dissolved in dry THF (4.5 ml) was added dropwise. The mixture was stirred at 0° C. for 5 min and then 2,2-bis-(4-cyanatophenyl)propane (251 mg, 0.90 mmol) dissolved in dry THF (4.5 ml) was added dropwise. Water was added and this mixture was stirred for 30 min Brine was added and the aqueous mixture was extracted with DCM. The solvent was concentrated and the crude product was purified on silica (EtOAc/n-Heptane 1:4). 198 mg 2-bromo-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile was obtained.
Reaction SMILES: CS[C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[S:4].[NH2:11][CH2:12][C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].C(N(CC)CC)C>CO.C(OCC)(=O)C>[CH:16]1([NH:15][C:13](=[O:14])[CH2:12][NH:11][C:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)=[S:4])[CH2:18][CH2:17]1
Reactant: NCC(=O)NC1CC1
Reactant: CSC(=S)c1cccnc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CNC(=S)c1cccnc1)NC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a solution of methylpyridine-3-carbodithioate (2.97 g, 17.52 mmol) in methanol (10 mL) was added a solution of 2-amino-N-cyclopropylacetamide (2 g, 17.52 mmol) (HCl salt) and triethylamine (3.55 g, 35.0 mmol). The mixture was stirred at room temperature for 1 hour and then diluted with ethyl acetate and washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-cyclopropyl-2-(pyridine-3-carbothioamido)acetamide as a yellow solid (3.60 g, 83%): mp 152-153° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.91 (ddd, J=7.0, 2.3, 0.7 Hz, 1H), 8.76-8.56 (m, 1H), 8.10 (m, 2H), 7.57-7.32 (m, 1H), 4.26 (m, 2H), 2.73-2.57 (m, 1H), 0.77-0.61 (m, 2H), 0.50-0.29 (m, 2H); ESIMS (m/z) 234 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH:25]([C:27]1[CH:32]=[CH:31]C(B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:1]3[CH:31]=[CH:32][C:27]([CH:25]=[O:26])=[CH:28][CH:29]=3)[C:10]=12
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1nn([C@H]2CC[C@@H](N3CCN(C)CC3)CC2)c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN1CCN(C2CCC(n3nc(-c4ccc(C=O)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 54.3 %

Procedure:
cis-3-Methyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3.0 g, 6.80 mmol), 4-formylphenylboronic acid (1.22 g, 8.16 mmol), palladium tetrakistriphenyphosphine (0.47 g, 0.41 mmol) and sodium carbonate (1.73 g, 16.31 mmol) were mixed with ethylene glycol dimethyl ether (70 mL) and water (35 mL). The reaction mixture was heated at reflux overnight under nitrogen. Organic solvent was removed under reduced pressure and the aqueous layer was filtered and washed with water. After drying on the lyophilizer, the residue was purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase to give 4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde (1.55 g, 54%). 1H NMR (DMSO-d6) δ 1.60 (m, 2H), 1.72 (m, 2H). 2.07 (m, 2H), 2.15 (s, 3H), 2.22-2.46 (m, 1H), 4.83 (m, 1H), 7.88 (d, J=8.13 Hz, 2H), 8.07 (d, J=8.10 Hz, 2H), 8.21 (s, 1H), 10.11 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=420.2, Rt=0.70 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[C:20]([CH3:32])[CH:19]=3)([CH2:16][CH3:17])[CH2:14][CH3:15])[S:10][C:9]=2[CH:33]=1)=[O:4].[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([CH2:14][CH3:15])([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([OH:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[C:20]([CH3:32])[CH:19]=3)[CH2:16][CH3:17])[S:10][C:9]=2[CH:33]=1)=[O:4]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)OC)cc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2ccc(C(=O)OC)cc2s1
Yield: 86.3 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-6-carboxylic acid methyl ester (4.50 g, 9.64 mmol) in THF (100 mL) is reacted with NaBH4 (0.37 g, 9.64 mmol) analogous to Example 2 to obtain the title compound (3.90 g, 86%).
Reaction SMILES: C([O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([C:16]2[S:17][CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[C@H:13]([OH:26])[C@@H:12]1[OH:27])(=O)C1C=CC=CC=1.[NH3:28]>C(O)C>[C@@H:14]1([C:16]2[S:17][CH:18]=[C:19]([C:21]([NH2:28])=[O:22])[N:20]=2)[O:15][C@H:11]([CH2:10][OH:9])[C@@H:12]([OH:27])[C@H:13]1[OH:26]
Reactant: N
Reactant: CCOC(=O)c1csc([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](O)[C@H]2O)n1
Solvent: CCO
Product: NC(=O)c1csc([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
Ethyl 2-(5′-O-Benzoyl-β-D-ribofuiranosyl)thiazole-4-carboxylate (11, 3.7 g, 942 mmol) was placed in a steel bomb and mixed with freshly prepared cold methanolic ammonia (70 ml, saturated at 0° C. The mixture was protected from moisture and stirred at room temperature for 12 hr. The steel bomb was cooled to 0° C., opened carefully and evaporated to a sticky foam. The residue was triturated with dry toluene (3×50 ml) and the toluene layer was discarded. The residue that obtained was treated with anhydrous ethanol (60 ml) and triturated to give light yellow solid. The solid was filtered, washed with ethyl acetate and dried. The solid was crystallized from ethanol-ethyl acetate to provide 2.25g (90%) of pure product: mp 145-147° C. 1H NMR (DMSO-d6): δ 3.57 (M,2 H), 3.89) (s,2 H), 4.07(m, 1 H), 4.83 (t, 1H), 4.92 (d, 1H), 5.05 (d, 1 H), 5.36 (d, 1 H), 7.56 (s, 1), 7.69 (s, 1) and 8.20 (s,1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:16])[CH2:12][CH2:13][CH2:14]Cl)[C:5]([Cl:9])=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[C:5]([Cl:9])=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1cc(NC(=O)CCCCl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc(N2CCCC2=O)c(Cl)cc1Cl

Procedure:
13.5 g (0.05 mol) of N-(3-amino-4,6-dichlorophenyl)-γ-chlorobutyramide, 200 ml of tetrahydrofurane and 100 ml of 1 N NaOH solution are stirred for 5 hours at 50° C. After the mixture has been allowed to cool, it is extracted three times with 300 ml of ethyl acetate and the extracts are washed with water, dried with magnesium sulphate and concentrated. The resulting product is recrystallised from toluene/ethyl acetate. Yield: 8.5 g; melting point 168°-170° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Br[CH2:12][CH2:13][OH:14].C([O-])([O-])=O.[Ca+2]>O>[OH:14][CH2:13][CH2:12][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: OCCBr
Reactant: CNc1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CN(CCO)c1cccc(C#N)c1
Yield: 76.2 %

Procedure:
3-methylaminobenzonitrile (11.36 g, 86 mmol, 1.0 eq), 2-bromoethanol (43.00 g, 344 mmol, 4.0 eq) and CaCO3 (34.40 g, 344 mmol, 4.0 eq) are added into water (150 ml) at room temperature, and the resulting mixture is refluxed with elevated temperature for 13.5 h, then cooled and filtered, and the aqueous solution is extracted with ethyl acetate (100 ml*3). The organic phases are combined, washed with water (20 ml*2), washed with saturated brine twice, dried over anhydrous sodium sulfate, and concentrated to give a light yellow oily crude product (11.55 g, crude yield: 76.2%). The crude product can be used directly in next step without purification.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([F:21])[C:19]=1[F:20])[CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12][CH3:13])=[O:11]>CO.[Pt](=O)=O>[ClH:1].[F:21][C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([F:2])[C:19]=1[F:20])[CH2:6][CH:7]1[CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[CH2:14][CH2:15][NH:16]1
Reactant: COC(=O)c1ccnc(Cc2cc(F)c(F)c(F)c2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(Cc2cc(F)c(F)c(F)c2)C1
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Methyl 2-(3,4,5-trifluorobenzyl)isonicotinate hydrochloride (4 g, 12.59 mmol) was dissolved in MeOH (45 mL) and platinum(IV) oxide (0.143 g, 0.63 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 3 h. Additional platinum(IV) oxide (0.029 g, 0.13 mmol) was added and the hydrogenation continued for 20 min. The catalyst was filtered off and washed with MeOH. The filtrate was evaporated in vacuo to yield methyl 2-(3,4,5-trifluorobenzyl)piperidine-4-carboxylate hydrochloride (3.96 g, 97%) as a brown solid. MS m/z 288 (M+H)+
Reaction SMILES: [Li]CCCC.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].FC1C([O:20][C:21](=O)[C@@H:22]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23]([CH3:26])([CH3:25])[CH3:24])=C(F)C(F)=C(F)C=1F.[NH4+].[Cl-]>C1COCC1>[C:31]([O:30][C:28](=[O:29])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21](=[O:20])[CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)C(C)(C)C
Reactant: Cc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Cc1ccccn1)C(C)(C)C
Temperature: -40 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
The reaction was carried out under argon in flame dried apparatus. n-BuLi (1.6 M in hexanes, 11.3 mL, 18.1 mmol) was added dropwise to a cooled (−40° C.) solution of 2-picoline (1.64 mL, 16.6 mmol) in THF (30 mL). When addition was complete the solution was stirred at −40° C. for 1 hour before cooling to −78° C. A solution of 2(S)-tert-butoxycarbonylamino-3,3-dimethyl-butyric acid pentafluorophenyl ester (3.00 g, 7.6 mmol) in THF (30 mL) was added via a cannula, maintaining the reaction temperature below −65° C. After stirring for 1 hour at −78° C. saturated NH4Cl solution (10 mL) was added and the reaction mixture was allowed to warm to room temperature before it was partitioned between EtOAc (200 mL) and saturated NH4Cl solution (200 mL). The organic extract was washed with water (200 mL) and brine (200 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 25% Et2O in hexanes) to give the title product as a bright yellow solid (1.01 g, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11]Br)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C-:13]#[N:14].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:13]#[N:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: BrCC1(c2ccc(Br)cc2)CC1
Agent: [K+]
Product: N#CCC1(c2ccc(Br)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 2, using 1-bromo-4-(1-bromomethyl-cyclopropyl)-benzene and potassium cyanide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=O.[C:11]([CH2:13]P(=O)(OCC)OCC)#[N:12].CC(C)([O-])C.[K+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:11]#[N:12])[CH:7]=[C:8]([CH3:10])[CH:9]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1cc(C)cc(C=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C=CC#N)c1
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a stirred mixture of 3,5-dimethyl benzaldehyde (13.4 g, 0.1M), diethyl cyanomethylphosphonate (19.4 g, 0.11M) in anhydrous THF (200 ml) under nitrogen at 0° C. (ice bath), was added potassium t-butoxide (12.3 g, 0.11M). After stirring for 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then partitioned between ether and water. The ether layer was taken, dried with anhydrous magnesium sulfate, filtered, evaporated in vacuo, and the residue was purified by silica gel column chromatography (eluent, ether:hexanes (1:20)) to afford 14.8 g (86%) of a white solid. m.p. 67-68° C.; 1H NMR (200 MHz, CDCl3) δ 2.33 (6H, s), 5.83 (1H, d, J=16.6 Hz), 7.05 (3H, s), 7.28 (1H, d, J=16.6 Hz).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](O)(=[O:11])[CH3:10]>>[C:9]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1)(=[O:11])[CH3:10]
Reactant: Cc1ccc(O)cc1
Reactant: CC(=O)O
Product: CC(=O)Oc1ccc(C)cc1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of p-cresol (1.08 g (10 mmole)) and acetic acid (25 ml) was stirred for 5 hours at 110° C. to produce p-acetoxytoluene. N-hydroxyphthalimide (0.16 g (1 mmole)) and cobalt(II) acetylacetonate (0.018 g (0.05 mmole)) were added to this reaction mixture, and this mixture was stirred for 6 hours at 100° C. under an oxygen atmosphere. The product in the resultant reaction mixture was analyzed by gas chromatography and, as a result, p-acetoxybenzoic acid (yield 92%) was formed. The conversion of p-cresol was 95%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC#N.C(N(CC)CC)C.[C]=O>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CO>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([C:6]([O:5][CH3:1])=[O:7])=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 143.2 %

Procedure:
To a Parr autoclave with mechanical stirring, add Pd(OAc)2 (120 mg, 0.53 mmol), 1,1′-bis(diphenylphosphino)ferrocene (355 mg, 0.64 mmol), (S)—N-tert-butoxycarbonyl-1-(4-bromophenyl)ethylamine (1.50 g, 5.0 mmol), anhydrous CH3CN (45 mL), anhydrous CH3OH (30 mL), and triethylamine (1.9 mL, 13.63 mmol). Seal the vessel and pressurize with carbon monoxide to 724 kPag. Heat the vessel to 85° C. and stir the mixture overnight. Vent the reaction vessel (Caution—poison gas!) and transfer to a round-bottomed flask, rinsing with CH3OH. Concentrate the mixture under reduced pressure to furnish an orange residue. Add water (50 mL), then extract with EtOAc (2×50 mL). Wash the combined organic phases with saturated aqueous NaCl (25 mL), then separate the layers, dry the organic phase over MgSO4, filter to remove the solids, and concentrate the filtrate under reduced pressure to give crude product. Purify the product by flash chromatography on silica gel eluting with a gradient of 0% to 60% EtOAc/hexanes. Concentrate the fractions containing the desired product under reduced pressure to furnish the title compound as a white solid (1.00 g, 72% yield). Mass spectrum (m/z) 224 (M+2H−t-Bu)+, 302 (M+Na)+, 581 (2M+Na)+. 1H NMR (400 MHz, DMSO-d6): δ 7.89 (d, =8.4 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 4.64 (dq, J=7.4, 6.8 Hz, 1H), 3.82 (s, 3H), 1.34 (br s, 9H), 1.28 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:9])[CH2:7]Br)=[CH:4][CH:3]=1.[C:12]([OH:15])(=[O:14])[CH3:13]>>[C:12]([O:15][CH2:7][C:6]([C:5]1[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9])(=[O:14])[CH3:13]
Reactant: CC(=O)O
Reactant: Cc1ccc(C(=O)CBr)cc1
Product: CC(=O)OCC(=O)c1ccc(C)cc1

Procedure:
Following the procedure of Example 1, 5 grams of 4-methylphenacyl bromide reacted with 5 grams of acetic acid to obtain 4-methylphenacyl acetate, m.p. 85°-85° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Cl.C(O[C:14]([SH:16])=[S:15])C.[K]>CN(C=O)C>[SH:16][C:14]1[S:15][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: CCOC(=S)S
Reactant: N#Cc1ccc(N)c(Cl)c1
Agent: [K]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(S)sc2c1
Yield: 97 %

Procedure:
The title compound was prepared using the method of example 239, starting with 4-amino-3-chloro-benzonitrile (Lancaster, 5.0 g, 32.7 mmol), O-ethylxanthic acid, potassium salt (Lancaster, 11.8 g, 73.7 mmol) in DMF (40 mL). The mercaptobenzothiazole (241) (6.1 g, 97%) was obtained as a pale brown solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:35])([F:34])[C:25]1[C:29]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:28][NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[OH:33][C:30]([C:29]1[C:25]([C:24]([F:35])([F:34])[F:23])=[N:26][N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[CH:28]=1)([CH3:32])[CH3:31]
Reactant: CC(C)(O)c1c[nH]nc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3cc(C(C)(C)O)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (30 mg, 0.11 mmol) was dissolved in DCM (5 mL) and thionyl chloride (66 mg, 0.57 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) and 2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)propan-2-ol (21.6 mg, 0.11 mmol) was added followed by potassium carbonate (30.8 mg, 0.22 mmol). The reaction mixture was stirred at room temperature overnight before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative basic HPLC gave (R)—N-(5-((4-(2-hydroxypropan-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (9.6 mg, 0.022 mmol, 19.4%). MS (ESI): m/z [M+H]+ 446.5
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6]N(C2C([N+]([O-])=O)=CC=CN=2)[CH2:4][CH2:3]1.[Li].C[Si]([N-][Si](C)(C)C)(C)C.[Li].[O:28]1[C:32]2(CCC(=O)CC2)[O:31][CH2:30][CH2:29]1.[N+](C1C(N2CCC(=O)CC2)=NC=CC=1)([O-])=O>>[CH2:1]=[C:2]1[CH2:3][CH2:4][C:32]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:6][CH2:7]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Agent: [Li]
Product: C=C1CCC2(CC1)OCCO2

Procedure:
The title compound was prepared following the method reported here for Compound 2a, but using lithium-bis-trimethylsilylamide instead of buthyl lithium and carrying out the reaction at −20° C. As starting material 1,4-dioxaspiro[4.5]decan-8-one replaced 1-(3-nitro-2-pyridyl)-4-oxopiperidine. After the usual work-up procedure the residue was purified by means of automated flash chromatography (Horizon®TM-Biotage; Petroleum Ether EtOAc 95:5) to give the title compound as fluid colourless oil. Yield: 99.3%.