Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1>C(Cl)Cl>[CH3:12][O:13][CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1
Reactant: COC1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC1CCC(=O)CC1
Reaction time: 3 h
Yield: 89.5 %

Procedure:
To methylene chloride there was added 11 g of pyridinium chlorochromate, and a solution consisting of 4.2 g of 4-methoxycyclohexanol and 30 ml of methylene chloride was then added. The reaction was carried out at room temperature for 3 hours. The product was purified on Florisil column. After distillation, there was obtained 3.7 g of 4-methoxycyclohexanone.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([C:23]1[C:28]([C:29]2[O:33][N:32]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[CH:30]=2)=[CH:27][C:26]([C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH:50]([CH3:52])[CH3:51])(=[O:49])=[O:48])=[CH:43][N:42]=2)=[CH:25][N:24]=1)C(=O)OC(C)(C)C)=O)(C)(C)C>C(Cl)Cl>[CH:50]([S:47]([C:44]1[CH:45]=[CH:46][C:41]([C:26]2[CH:27]=[C:28]([C:29]3[O:33][N:32]=[C:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)[CH:30]=3)[C:23]([NH2:15])=[N:24][CH:25]=2)=[N:42][CH:43]=1)(=[O:48])=[O:49])([CH3:52])[CH3:51]
Reactant: Cc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3N)on2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.2 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(5-isopropylsulfonyl-2-pyridyl)-3-[3-(p-tolyl)isoxazol-5-yl]-2-pyridyl]carbamate (90 mg, 0.1418 mmol) in DCM (5 mL) and the reaction stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was redissolved in MeCN/water and passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a pale yellow solid (26 mg, 39% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.22 (d, J=6.8 Hz, 6H), 2.40 (s, 3H), 3.56 (sept, 1H), 7.05 (s, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.61 (s, 1H), 7.88 (d, J=8.1 Hz, 2H), 8.24-8.31 (m, 2H), 8.74 (d, J=2.2 Hz, 1H), 8.99 (d, 1H) and 9.02 (d, 1H) ppm; MS (ES+) 435.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C2CCCCO2)=[O:26])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[ClH:35]>CCO>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:3]=[C:4](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(CN2CCC(Nc3ncc(/C=C/C(=O)NOC4CCCCO4)cc3Cl)CC2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(CN2CCC(Nc3ncc(/C=C/C(=O)NO)cc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (470 mg) in EtOH (2 ml) was treated with 2N HCl in EtOH (2.42 ml) and was stirred at 25° C. for 1 hour. The precipitate was collected, washed with EtOH, dried under reduced pressure to give (2E)-3-(5-chloro-6-{[1-(4-methylbenzyl)-4-piperidyl]amino}-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (308 mg).
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[O:34]1[CH2:35][CH:36]=[C:37]([C:2]2[C:3]([O:8][C@H:9]3[CH2:14][CH2:13][C@H:12]([N:15]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[CH2:11][CH2:10]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:38][CH2:39]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](Oc3nccnc3Cl)CC2)cc1
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: [Na+]
Solvent: COCCOC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](Oc3nccnc3C3=CCOCC3)CC2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
trans-4-(3-Chloropyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine (0.810 g, 1.73 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.455 g, 2.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.087 mmol) were mixed in DME (2 mL) under a nitrogen atmosphere. Sodium carbonate (2.60 mL, 5.19 mmol, 2 M in water) was added via syringe, and the reaction mixture was then heated to 80° C. and stirred for 5 h. The mixture was cooled to RT and partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2×). The extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel chromatography to give trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OO.S([O-])([O-])(=[O:31])=S.[Na+].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][C:16]([C:17](=[O:31])[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)cc(C#N)c2C1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)cc(C(N)=O)c2C1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
A solution of 8-cyano-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (3.87 g, Reference Example 4(a)) in methanol (200 mL) was treated with a 10M aqueous solution of sodium hydroxide (10.45 mL), then with a 27.5% w/w aqueous solution of hydrogen peroxide (0.74 mL). After stirring at 50° C. for 0.75 hour the reaction mixture was further treated with a 27.5% w/w aqueous solution of hydrogen peroxide (0.74 mL). After further stirring at 50° C. for 2 hours the reaction mixture was then further treated with a 27.5% w/w aqueous solution of hydrogen peroxide (0.74 mL). After further stirring at 50° C. for 1.5 hours the reaction mixture was allowed to cool to room temperature and treated with a saturated aqueous solution of sodium thiosulfate (20 mL). After stirring at room temperature for 15 minutes the reaction mixture was evaporated and then treated with ethyl acetate (650 mL) and water (150 mL). The organic phase was separated, washed with water (150 mL) and then dried over sodium sulfate. The organic phase was then evaporated to give the title compound (4.06 g) as a white solid, m.p. 208–210° C. MS: 342 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.O.[Sn](Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[NH2:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1F
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
The mixture of 2-fluoro-4-nitrobenzonitrile (8.31 g, 50 mmol) and tin (II) chloride dihydrate (56.4 g, 250 mmol) in 250 mL of EtOAc was stirred at 25° C. overnight. LCMS (78109-084) indicated the reaction was completed. 25 mL of sat. K2CO3 was added to the reaction. The resulting mixture was stirred at room temperature for 2 h and was followed by addition of 100 g of solid K2CO3. The mixture was stirred at room temperature for 2 hours. Solid was removed by filtration and further washed with EtOAc (50 mL×2). The filtrate was concentrated to yield 6.81 g (100%) of 4-amino-2-fluorobenzonitrile as an off white solid. 1H NMR (400 MHz, CDCl3) δ ppm 4.30 (s, 2H) 6.29-6.51 (m, 2H) 7.27-7.40 (m, 1H). MS (ESI) 137 (M+H).
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=[O:4])[CH3:2].CO.[OH-].[K+].[CH3:10][C:11]1[C:15]([CH3:17])([CH3:16])[CH:14]([CH2:18][CH:19]=O)[CH2:13][CH:12]=1.S(=O)(=O)(O)O>O>[CH3:2][C:1](=[CH:19][CH2:18][CH:14]1[CH2:13][CH:12]=[C:11]([CH3:10])[C:15]1([CH3:17])[CH3:16])[C:3](=[O:4])[CH3:5]
Reactant: CCC(C)=O
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)C(C)=CCC1CC=C(C)C1(C)C
Reaction time: 21 h

Procedure:
To a stirred solution of 400 g (6.1 moles) of methyl ethyl ketone, 1025 g (32 moles) of methanol, 30.5 g (0.54 mole) of potassium hydroxide and 380 g of water cooled to -5° to -10° C was added 152 g (1.0 mole) of campholenic aldehyde over 15-30 minutes. The mixture was maintained at 0° to -10° C for 24-36 hours and then at 25°-35° C for 18-24 hours. The mixture was neutralized by addition of 36.8 g of 62.5% sulfuric acid and the unreacted methyl ethyl ketone and excess methanol were removed by atmospheric distillation. The residual liquid was added to 200 ml of hexane and 200 ml of water. The aqueous layer was drawn off and the hexane layer was washed with 200 ml of brine. The hexane was removed by atmospheric distillation and the oil fractionally distilled under vacuum to give 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl) pent-3-en-2-one and two other isomers in a ratio of ca. 86:6:8 by glc. Yield 140.3 g (85% theory); bp 102°-105° C (1.3 mm); nD20 1.4888; mol wt. 206 (ms); nmr, 0.8δ (3H, s), 1.0 (3H, s), 1.6 (3H, broad s), 1.8 (3H, broad s), 2.3 (3H, s, acetyl CH3), 5.3 (1H, broad multiplet, olefinic H), 6.7 (1H, complex, β-olefinic H of an α,β-unsaturated carbonyl system); ir, 3030, 1670, 1635, 790 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12]S(C(F)(F)F)(=O)=O)=[C:7]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:31])=[CH:5]2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[C:7]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:31])=[CH:5]2
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1O
Reaction time: 1 h

Procedure:
To a solution of (S)-ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (260 mg, 0.5 mmol) in anhydrous THF (4 mL) at 0° C. was added a 1N tetrabutylammonium fluoride in THF (0.6 mL, 0.6 mmol) and stirred for 1 hour. The reaction was quenched by the addition saturated NaHCO3 solution and extracted using EtOAc. The organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give the desired compound. LCMS-ESI− (m/z): [M−H]− calcd for C19H22BrO4: 394.29. Found: 394.0.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4]OS1(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:37]>C1COCC1>[F:37][CH2:4][C:5]1([OH:1])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)COS(=O)(=O)O2
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CF)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
1,1-dimethylethyl 1,3-dioxa-2-thia-8-azaspiro[4.5]decane-8-carboxylate 2,2-dioxide (500 mg, 1.7 mmol) was taken into THF (5 mL) followed by addition of TBAF (1M in THF, 1.8 mL) and the resulting solution was stirred for 3 h at 40° C. The mixture was then cooled and partitioned with ethyl acetate and 20% aqueous citric acid. The organic solution was washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to afford tert-butyl 4-(fluoromethyl)-4-hydroxypiperidine-1-carboxylate (350 mg, 88% yield). GC-MS (EI) for C11H20FNO3: 233 (M+). BOC-group deprotection was carried out in a manner well established in the literature (see, Greene and Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience) to give 4-(fluoromethyl)piperidin-4-ol hydrochloride salt as a colorless solid.
Reaction SMILES: CS(O[CH2:6][CH:7]([CH3:31])[CH:8]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(=O)=O.Br[C:33]1SC(C(C2C3C(=C(CSC)C=CC=3)NC=2)CCC#N)=C[N:37]=1>CS(C)=O>[CH3:31][CH:7]([CH:8]([C:19]1[C:27]2[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=1)[CH2:6][C:33]#[N:37]
Reactant: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C(C)COS(C)(=O)=O)c[nH]c12
Reactant: CSCc1cccc2c(C(CCC#N)c3cnc(Br)s3)c[nH]c12
Solvent: CS(C)=O
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3)C(C)CC#N)c[nH]c12

Procedure:
The title compound was prepared starting from 620 mg (1.32 mmol) of the compound from Example 70A in analogy to the synthesis of the compound from Example 53 but with dimethyl sulfoxide as solvent. 492 mg (93% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.C([O:15][C:16]([C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:21]=[C:20]([CH3:31])[N:19]=1)=O)C>O1CCOCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]([C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:21]=[C:20]([CH3:31])[N:19]=2)=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)cc(C)n1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cc1cc(-c2ccc(F)cc2)cc(C(=O)Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.9 %

Procedure:
To a solution of 113 μl (138 mg, 1.08 mmol, 4.0 equiv.) of 3-Chloroaniline in 7 ml of dry dioxane were added 540 μl (1.08 mmol, 4.0 equiv.) of a 2M solution of trimethylaluminium in hexane. The solution was stirred for 45 min at room temperature. Then a solution of 70.0 mg (0.27 mmol) of 4-(4-Fluoro-phenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in 1 ml of dry dioxane was added and the reaction was heated to 100° C. for 1 h. The reaction was quenched by cautious addition of 0.7 ml of water. Then approximately 1 g of anhydrous sodium sulfate were added to bind the water and the mixture was stirred vigorously for 5 min. The mixture was diluted by addition of 10 ml of methylenene chloride and filtered over Speedex filter aid which was washed with methylene chloride. The filtrate was concentrated in vaccuo and the residue (248 mg orange solid) was purified by flash chromatography (heptane/ethyl acetate 4:1) to yield the title compound (68.0 mg, 74%) as a crystalline white solid, MS (ISP): m/e=341.0, 343.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].Cl[C:20]1[N:25]=[CH:24][N:23]2[N:26]=[CH:27][C:28]([C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])=[C:22]2[CH:21]=1>CN(C=O)C>[CH:32]([NH:31][C:29]([C:28]1[CH:27]=[N:26][N:23]2[CH:22]=[CH:21][C:20]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:25][C:24]=12)=[O:30])([CH3:34])[CH3:33]
Reactant: CC(C)NC(=O)c1cnn2cnc(Cl)cc12
Reactant: OCc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cnn2ccc(OCc3cccnc3)nc12
Reaction time: 0.17 h
Yield: 67.7 %

Procedure:
To a degassed solution of 3-pyridylcarbinol (17.6 mg, 0.16 mM, 1.5 equiv) in 0.8 mL of DMF was added a one molar solution of lithium hexamethyldisilazide (215 uL, 0.22 mM, 2.0 equiv). This mixture was stirred for 10 minutes then added dropwise to a stirred solution of 5-chloro-N-isopropylpyrazolo[1,5-c]pyrimidine-3-carboxamide (25.7 mg, 0.11 mM, 1.0 equiv) in one mL of DMF. The reaction mixture was purified using reversed phase HPLC (5 to 30% acetonitrile/water, 0.1% formic acid) and the product lyophilized to give 22.7 mg (68%) of N-isopropyl-5-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=312.2, 1H NMR (400 MHz, DMSO-d6) δ: 9.09 (d, 1H), 8.76 (d, 1H), 8.59 (dd, 1H), 8.38 (s, 1H), 7.95 (d, 1H), 7.45 (dd 2H), 6.81 (d, 1H), 5.61 (s, 1H), 4.08 (m, 1H), 1.19 (d, 6H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[CH2:10][CH2:9]2.Cl[C:17]1[CH:22]=[C:21]([Cl:23])[N:20]=[CH:19][C:18]=1[C:24]#[N:25]>C1COCC1.CCOC(C)=O>[Cl:23][C:21]1[N:20]=[CH:19][C:18]([C:24]#[N:25])=[C:17]([NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[N:11]([CH3:15])[CH2:10][CH2:9]3)[CH:22]=1
Reactant: N#Cc1cnc(Cl)cc1Cl
Reactant: CN1CCc2cccc(N)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCc2cccc(Nc3cc(Cl)ncc3C#N)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.2 %

Procedure:
Sodium hydride (2.78 g, 69.46 mmol) was added portionwise to 8-amino-2-methyl-3,4-dihydroisoquinolin-1-one (3.06 g, 17.37 mmol), in THF (8 mL) under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 20 minutes and then 4,6-dichloropyridine-3-carbonitrile (3.00 g, 17.37 mmol) was added portionwise and the mixture heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (100 mL). The mixture was washed sequentially with water (100 mL), a saturated solution of NaHCO3 (100 mL), and finally with a saturated solution of NaCl (100 mL). The organic layer was dried over MgSO4 and then evaporated. The residue was loaded onto an SCX column and the product was eluted using a mixture of MeOH in CH2Cl2. Fractions containing product were combined and evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 50-70% EtOAc in isohexane. Fractions containing the required product were combined and evaporated to afford 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.149 g, 21% yield). The mixed fractions were combined and repurified by silica chromatography, eluting with a gradient of 0-20% EtOAc in CH2Cl2. Fractions containing the required product were combined and evaporated to leave 6-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridine-3-carbonitrile (1.287 g, 24% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.98 (2H, t), 3.06 (3H, s), 3.58 (2H, t), 7.07 (1H, dd), 7.36 (1H, s), 7.48-7.52 (2H, m), 8.63 (1H, s), 12.00 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=313.34 and 315.33.
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([F:17])[CH:6]=1.[C:18](=[O:20])=[O:19].Cl>O1CCCC1>[F:17][C:7]1[CH:6]=[C:5]([C:18]([OH:20])=[O:19])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=O
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 65 °C

Procedure:
Few crystals of iodine are added to tetrahydrofuran (1400 mL) containing magnesium turnings (25.17 g, 1.035 mol). The mixture is heated at 60-70° C. A solution of 4-bromo-2-fluorobiphenyl (200 g, 0.797 mol) in tetrahydrofuran (600 mL) is added dropwise to the reaction mixture and refluxed for 1 hr. Reaction mixture is brought to room temperature and then cooled to −20° C. Carbon dioxide gas is passed through the reaction mixture for 45 minutes. The reaction mixture is treated with 3N HCl (500 mL) and extracted with ethyl acetate (2×500 mL). Combined organic layer is dried over sodium sulphate. Removal of solvent under reduced pressure gives a solid which is washed with diethyl ether (2×200 mL) and then dried to furnish 2-fluorobiphenyl-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH2:11][CH3:12])[C:3]1=[S:4].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:22]=1.Cl>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:28](=[O:29])[NH:27][C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][C:23]=2[O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:6](=[O:7])[N:5]([CH2:11][CH3:12])[C:3]1=[S:4]
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccc(Cl)cc1
Reactant: CCN1C(=O)CC(=O)N(C)C1=S
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: CCN1C(=O)C(C(=O)Nc2ccc(Cl)cc2Oc2ccc(Cl)cc2)C(=O)N(C)C1=S
Temperature: 40 °C

Procedure:
3.4 g (20 mmol) of 1-methyl-3-ethyl-2-thiobarbituric acid are suspended in 80 ml of xylene. 1 g (8 mmol) of triethylamine is added, the mixture is heated to 40° C. and a solution of 5.6 g (20 mmol) of 4-chloro-2-(4-chlorophenoxy)phenylisocyanate in 30 ml of xylene is added dropwise with stirring at 40° C. The mixture is subsequently stirred for 2 hours at 40° C. and then cooled. 50 ml of 2N HCl are added, the crystalline precipitate is isolated by filtration, washed with water and dried at 80° C., affording a product with a melting point of 250°-251° C.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].C[Al](C)C.C([O:11][C:12](=O)[CH2:13][O:14][C:15]1[CH:44]=[CH:43][C:18]([CH2:19][C:20]2[C:21]3[CH:42]=[CH:41][CH:40]=[CH:39][C:22]=3[S:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)C.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:4])[NH:3][C:12](=[O:11])[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][C:20]2[C:21]3[CH:42]=[CH:41][CH:40]=[CH:39][C:22]=3[S:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)=[CH:29][CH:30]=2)=[CH:43][CH:44]=1
Reactant: CCOC(=O)COc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Reactant: CN(C)N
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)NC(=O)COc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Reaction time: 1 h
Yield: 64.5 %

Procedure:
A solution of 1,1-dimethyl hydrazine (0.1 mL, 1.3 mmol) in toluene (5 mL) was added to a solution of trimethyl aluminum (1.3 mL, 1.0M/toluene) in toluene (20 mL) at 0-5° C. The cooling bath was removed and the mixture stirred for 60 minutes. A solution of 3-[4-(2-ethoxy-2-oxoethoxy)benzyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-benzo[b]thiophene (310 mg, 0.6 mmol) in toluene (5-10 mL) was added and the mixture refluxed for 60 minutes, cooled, decomposed with water, and extracted with CH2Cl2:i-PrOH (3:1). The organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with a gradient (CH2Cl2/5% MeOH/0-1% Et3N) to give the title compound as an amorphous solid (205 mg, 65%).