Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[C:14]=2[S:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH2:3][CH2:2]1
Reactant: CCCSc1c(C(=O)NC2CCOCC2)cnn1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1c(C(=O)NC2CCOCC2)cnn1-c1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
Methyl 4-[4-(oxan-4-ylcarbamoyl)-5-propylsulfanyl-pyrazol-1-yl]benzoate (Intermediate#5) (104 mg, 0.26 mmol) was dissolved in methanol (5 mL) and treated at ambient temperature with 2M aqueous sodium hydroxide solution (0.65 mL, 1.29 mmol). The mixture was stirred at ambient for 18 h. Methanol was removed by evaporation under reduced pressure and the clear solution diluted with water (25 ml). 2M HCl was added to pH4 and the mixture extracted with ethyl acetate (2×25 mL). The combined extracts were washed with water (2×10 mL) and brine (10 mL), dried (MgSO4) and evaporated to give the product as a white solid (89 mg, 85%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]2)=[CH:23][C:22]=1[CH3:39])=[O:19])=[O:12].Cl>C(OCC)(=O)C.O1CCOCC1>[NH:30]1[CH2:31][CH:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:18]([C:17]3[NH:16][CH:15]=[N:14][C:13]=3[C:11]([NH:10][C:2]3[NH:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:12])=[O:19])=[C:22]([CH3:39])[CH:23]=2)[CH2:29]1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1NC(=O)c1[nH]cnc1C(=O)Nc1nc2ccccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(OC2CNC2)ccc1NC(=O)c1[nH]cnc1C(=O)Nc1nc2ccccc2[nH]1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
1,1-dimethylethyl 3-({4-[({4-[(1H-benzimidazol-2-ylamino)carbonyl]-1H-imidazol-5-yl}carbonyl)amino]-3-methylphenyl}oxy)azetidine-1-carboxylate (155.0 mg, 0.29 mmol) was suspended in 5 mL of ethyl acetate, which was cooled with an ice-water bath. 3 mL of 4 N HCl in dioxane was added dropwise. The reaction mixture was stirred overnight. The suspension was filtered and the solid was washed with 5 mL of ethyl acetate, dried under vacuum to afford the desired product (102 mg, 0.22 mmol) as the hydrochloride salt. 1H-NMR (400 MHz, DMSO-d6): δ=10.9 (br, 1H), 9.85 (br, 2H), 8.32 (s, 1H), 7.63 (m, 2H), 7.38 (m, 3H), 6.84 (m, 1H), 6.78 (m, 1H), 5.05 (m, 1H), 4.43 (m, 2H), 3.94 (m, 2H), 2.25 (s, 3H). MS: 432 (M++1).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[F:10][C:11]([F:32])([F:31])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](OC)=[O:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[F:10][C:11]([F:31])([F:32])[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][OH:28])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OC/C=C/c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
DIBAL-H (20% w/w in toluene, 2 mL, 2.39 mmol) was added to a slurry of ester 100 (0.396 g, 1.23 mmol) in toluene (12 mL) at −78° C. The mixture was warmed to room temperature, stirred for 1 h, and then poured onto ice cold NH4Cl solution (50 mL). The mixture was diluted with CH2Cl2 (100 mL), filtered through Celite and the organic layer was dried and evaporated. Column chromatography of the residue on silica gel using gradient elution (CH2Cl2 to 95:5 CH2Cl2:EtOAc) gave (2E)-3-[4′-(trifluoromethoxy)[1,1′-biphenyl]-4-yl]-2-propen-1-ol (101) (0.195 g, 54%) as a white solid: mp 121-123° C.; NMR (CDCI3) δ 7.60 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 6.66 (d, J=15.9 Hz, 1H), 6.42 (dt, J=15.9, 5.7 Hz, 1H), 4.36 (dd, J=5.9, 5.7 Hz, 2H), 1.44 (t, J=5.9 Hz, 1H). APCI MS m/z 307 [M−H−H2O+MeOH]−.
Reaction SMILES: [F:1][CH:2]1[CH:7](OC(C)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].Cl>>[F:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[NH:6][CH:7]=1
Reactant: CC(C)OC1NC(=O)NC(=O)C1F
Agent: Cl
Product: O=c1[nH]cc(F)c(=O)[nH]1
Yield: 74.9 %

Procedure:
0.41 g of 5-fluoro-6-isopropoxy-5,6-dihydrouracil was placed in a reflux flask and then 1 ml of concentrated HCl was added to the flask. Precipitation of a solid occurred a few minutes after reaching reflux conditions, yielding 0.21 g of 5-fluorouracil.
Reaction SMILES: [CH:1]1([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CS(C)=O.CO>[CH:1]1([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2c(cnn2C2CCCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(cnn2C2CCCCCC2)c1
Yield: 103.7 %

Procedure:
Methyl 3-(1-cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate (393 mg, 0.97 mmol) was hydrolyzed by heating with 10 equiv NaOH in 3:1 DMSO/MeOH (10 mL). Purified by HPLC to give 393 mg of 3-(1-cycloheptyl-1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid. (M+H)+=391.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[CH:15]=1)([O-:4])=[O:3].C=O.[CH:18](O)=O.[OH-].[Na+]>O>[ClH:1].[CH3:18][N:11]1[CH2:10][C:9]2[CH:15]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=[CH:7][C:8]=2[O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCCO2
Reactant: O=CO
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1CCOc2ccc([N+](=O)[O-])cc2C1
Temperature: 80 °C
Yield: 61.5 %

Procedure:
A mixture of 7-nitro-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (11.53 g, 50 mmol), 37% formaldehyde (25 ml, 335 mmol) and 88% formic acid (15 ml, 340 mmol) was heated at 80° C. for 24 h, cooled and poured into water (150 ml). The suspension was Is basified with 25% aqueous sodium hydroxide to give a brown solid (7.52 g). The aqueous layer was extracted with methylene chloride (3×200 ml), washed with saturated brine solution, and dried over magnesium sulphate to give yellow crystals (1.02 g). This sample was combined with the solid obtained earlier and suspended in isopropanol (750 ml), refluxed for several hours and then filtered. The filtrate was acidified to give the title compound (9.51 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 42.5 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (99 mg, 0.21 mmol) obtained in step 2 and ethanesulfonamide (110 mg, 1.05 mmol), the title compound (50 mg, 42%) was obtained.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=O)[CH:7]=1)C.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(O)(C)C.C(#N)C>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][CH2:12][C:8]1[CH:7]=[C:6]([CH2:5][CH2:4][OH:14])[CH:11]=[CH:10][CH:9]=1
Reactant: NCc1ccccc1F
Reactant: CCOC(=O)Cc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CC#N
Product: OCCc1cccc(CNCc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of (3-formyl-phenyl)-acetic acid ethyl ester (400 mg), (2-fluorobenzyl)amine (410 mg) and acetic acid (130 mg) in methanol (5 mL) was stirred at room temperature. After 1 h, sodium triacetoxyborohydride (700 mg) was added. After 5 hours, the reaction mixture was neutralised with aqueous ammonia (0.880) and the solution evaporated to dryness. The residue was diluted with toluene and the mixture evaporated. The resulting gum was dissolved in methanol and applied to a SCX cartridge (70 g, varian). The cartridge was eluted with methanol (250 mL) and then 20% ammonia in methanol to collect the reductive amination product. The solution was evaporated and the gum dissolved in ethanol. Anhydrous calcium chloride (730 mg) was added followed by careful portionwise addition of sodium borohydride (500 mg). After 16 hours, the reaction mixture was quenched with 2M aqueous potassium carbonate (20 mL). The solid was removed by filtration, the filtrate evaporated and the residue partitioned between ethyl acetate and brine. The organic solution was dried over magnesium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with ethyl acetate:dichloromethane 1:3, then ethyl acetate:dichloromethane 1:3 containing 5% triethylamine, to give 2-{3-[(2-fluoro-benzylamino)-methyl]-phenyl}-ethanol (320 mg). Without further purification the 2-{3-[(2-fluoro-benzylamino)-methyl]-phenyl}-ethanol was dissolved in dichloromethane (5 mL) and di-tert-butyl dicarbonate (300 mg) added. After 3 hours, the solution was applied to a silica gel column eluting with ethyl acetate:dichloromethane 1:9 to give the subtitle compound (300 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH:13]=2)[NH2:12])[CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:13]=[C:11]([NH2:12])[C:10]([NH2:14])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: Nc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCOCC2)cc1N
Yield: 86.6 %

Procedure:
5-Morpholino-2-nitroaniline (200 mg, 0.896 mmol) was added to the 10% Pd/C (25 mg) in ethanol (25 mL) and then hydrogen gas (60 psi) was applied for overnight at room temperature. The reaction mixture was filtered through Celite, and the solvent was removed in vacuum. Purification by flash chromatography (5% CH3OH/CH2Cl2) afforded the title compound (150 mg). 1H NMR: (400 MHz, DMSO-d6): δ 6.38 (d, 1H, J=8.0 Hz), 6.18 (d, 1H, J=2.4 Hz), 5.99 (dd, 1H, J=2.4 and 8.4 Hz), 4.35 (bs, 2H), 3.97 (bs, 2H), 3.66 (m, 4H), 2.81 (m, 4H).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([S:14]([N:17]2[CH:21]=[C:20](Br)[C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:18]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:29][C:30]1[CH:31]=[C:32](/[CH:36]=[CH:37]/B(O)O)[CH:33]=[CH:34][CH:35]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[C:8]1([S:14]([N:17]2[CH:21]=[C:20]([CH:37]=[CH:36][C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)[C:19]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:18]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c(-c2cccnc2)n1
Reactant: OB(O)/C=C/c1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1cc(C=Cc2cccc(F)c2)c(-c2cccnc2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To toluene (20 ml) containing 36A (0.48 g, 1.32 mmol) (see Scheme 7), was added 1.5 eq of (E)-2-(3-fluorphenyl)-vinyl boronic acid (0.33 g). The resulting mixture was stirred for 2 hours under N2. Successively were added 2 eq of K3PO4 (0.56 g), 4 mol % of Pd(OAc)2 (8.8 mg) and 8 mol % of S-Phos (32 mg). After the addition, the resulting solution was warmed at 90° C. for 18 hours under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-(1-phenylsulfonyl-4-[2-(3-fluoro-phenyl)-vinyl]-1H-pyrazol-3-yl)-pyridine (46B) as an oil (0.39 g, 73%). 1H-NMR (400 MHz, CDCl3): δ 8.85 (d, J=2 Hz, 1H), 8.65 (dd, J=5 Hz, 2 Hz, 1H), 8.36 (s, 1H), 8.13-8.08 (m, 2H), 7.95 (dt, J=8 Hz, 2 Hz, 1H), 7.72-7.67 (m, 1H), 7.58 (bt, J=8 Hz, 2H), 7.41-7.37 (m, 1H), 7.33-7.27 (m, 1H), 7.16 (bd, J=7 Hz, 1H), 7.12-7.07 (m, 1H), 7.0-6.94 (m, 1H), 6.92 (d, J=16 Hz, 1H), 6.82 (d, J=16 Hz, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][CH2:43][C@@H:42]5[CH2:46][O:47][Si](C(C)C)(C(C)C)C(C)C)=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([N:41]5[CH2:45][CH2:44][CH2:43][C@@H:42]5[CH2:46][OH:47])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@@H]5CO[Si](C(C)C)(C(C)C)C(C)C)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@@H]5CO)n4c3)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a solution of Intermediate 27d (27 mg, 0.034 mmol) in THF (1 mL) at −30° C. was added TBAF (1M in THF, 36 μL, 0.036 mmol) and the mixture was allowed to warm to RT over 1 h. The reaction mixture was applied to an SCX-2 cartridge (2 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. Purification by HPLC (C6-Ph column, 10-70% MeCN in H2O, 0.1% HCO2H) gave the title compound as a white powder after freeze-drying (10.0 mg, 45%). LCMS (Method 5): Rt 4.18 min, m/z 635 [MH+]. 1H NMR (400 MHz, CDCl3): 1.25 (9H, s), 1.63-1.75 (1H, m), 1.81-1.95 (3H, m), 1.97-2.01 (3H, m), 2.26 (1H, m), 2.31 (3H, s), 3.17-3.26 (1H, m), 3.32-3.47 (2H, m), 3.57 (1H, dd, J 11.6, 3.2), 4.07-4.15 (1H, m), 4.99-5.07 (1H, m), 5.15 (1H, t, J 4.1), 5.57 (1H, d, J 8.9), 6.25 (1H, s), 6.61 (1H, s), 6.91 (1H, d, J 10.2), 7.16 (2H, d, J 8.3), 7.20-7.29 (4H, m), 7.32 (2H, d, J 8.0), 7.35-7.41 (2H, m).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=[O:25].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[F:20][C:21]1[CH:22]=[C:23]([CH:24]([C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[F:13])[OH:25])[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Fc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cccc(F)c1)c1ccncc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under nitrogen atmosphere, a solution of 6.1 mL of diisopropylamine in 100 ml of dehydrated tetrahydrofuran was cooled to −70° C., added with 28 mL of 1.56 M n-butyllithium in hexane, and stirred at 0° C. for 15 minutes. After cooling to −70° C., 3.4 mL of 3-fluoropyridine was added dropwise, stirred at the same temperature for 4 hours, and then added dropwise with 4.8 mL of 3-fluorobenzaldehyde. After stirring for 1 hour, aqueous ammonium chloride and ethyl acetate were successively added, and the reaction solution was recovered to room temperature. The organic layer was extracted, washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was recrystallized from diisopropyl ether, to afford 7.1 g of the title compound as colorless cubic crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][C:12]=2[CH3:26])[CH:5]=[CH:6][N:7]=1.[C:33](O)(=[O:37])[C:34]#[C:35][CH3:36]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[C:33](=[O:37])[C:34]#[C:35][CH3:36])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][C:12]=2[CH3:26])[CH:5]=[CH:6][N:7]=1
Reactant: CC#CC(=O)O
Reactant: Cc1cc(C(=O)Nc2ccccn2)ccc1-c1nc([C@@H]2CCCCN2)n2ccnc(N)c12
Product: CC#CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2C)c2c(N)nccn12
Yield: 59.1 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from 4-(8-amino-3-((S)-piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-3-methyl-N-(pyridin-2-yl)benzamide (intermediate 43) and 2-butynoic acid, to afford the title compound (13.7 mg, 59.1%). Data: UPLC(C) Rt: 2.28 min; m/z 494.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]12[CH2:22][CH:6]([N:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:13][CH:12]=3)=[O:10])[CH2:8]1)[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]2.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCO>[N:25]1([CH2:20][CH2:19][C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([C:9]([N:7]3[CH2:8][C:2]4([CH3:1])[CH2:22][CH:6]3[CH2:5][C:4]([CH3:24])([CH3:23])[CH2:3]4)=[O:10])=[CH:16][CH:15]=2)=[O:21])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: C=CC(=O)Nc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Solvent: CCO
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)CCN3CCCCC3)cc2)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
To a mixture of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acrylamide (0.2 g, 0.613 mmol) and piperidine (120 μl, 1.23 mmol) in EtOH (10 ml) was added two drops of TEA. The resulting mixture was heated in a microwave oven at 100° C. for 25 min. The volatiles were evaporated in vacuo and the residue purified on column chromatography (silicagel) using first EtOAc followed by 4% TEA in EtOAc-EtOH 9:1 as eluents. Semi pure fractions were collected, the solvent evaporated in vacuo and the residue dissolved in 1 N HCl (2.5 ml). Water (5 ml) was added followed by diethyl ether (10 ml) and the mixture was stirred for 30 min. The organic phase was discarded and the pH of the aqueous phase adjusted to 10 with 1 N NaOH followed by extraction with diethyl ether (2×10 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo affording 55 mg (22%) of the title compound as an oil.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](O)[CH2:9][CH2:10][OH:11]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:7]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:11][CH2:10][CH2:9][CH2:8]1
Reactant: OCCCO
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1CCC2(CC1)OCCCO2
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Cyclohexanone (7.94 g) was dissolved in toluene (200 mL), 1,3-propanediol (12.3 g) and p-toluenesulfonic acid monohydrate (0.1 g) were added thereto, and the mixture was heated under reflux for 1.5 hr while removing water being produced. The temperature was allowed to cool to room temperature, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (12.4 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1Br.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH3:10]
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccccc1Br
Product: COc1ccccc1-c1ccccc1OC
Yield: 71 %

Procedure:
From 2-methoxy-bromobenzene and 2-methoxyphenyl boronic acid, yield 71%; mp 155-157° C. (lit.,4 155° C.); IR: 1590, 1501, 1481, 1455 and 1238; 1H NMR (400 MHz; CDCl3): 7.34 (2H, m), 7.25 (2H, d, J 8), 7.02-6.97 (4H, m) and 3.77 (6H, s); 13C NMR (CDCl3): 157, 131.4, 128.5, 127.8, 120.3, 111.1 and 55.6; m/z (EI) 214 (100%, M+), 184 (50) and 69 (40)(Found: M+, 214.099. C12H14O2 requires M, 214.099).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1.[S-:19][C:20]#[N:21].[K+].BrBr>CO>[NH2:1][C:2]1[S:3][C:4]([S:19][C:20]#[N:21])=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCSCc1csc(N)n1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCSCc1nc(N)sc1SC#N
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2-amino-4-(2-t-butyloxycarbonylaminoethylthiomethyl)-1,3-thiazole (4.27 g, 14.8 mmol) and potassium thiocyanate (2.87 g, 29.5 mmol) in methanol (30 mL) cooled to 0° C. was added dropwise bromine (3.55 g, 0.022 mol) and stirring was continued for 45 min. Reaction mixture was partitioned between ethyl acetate and water. Organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford solid residue of title product in quantitative yield. Crude product was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:25])=[CH:22][Mg]Br>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:17]([O-:19])=[O:18])=[C:13]([CH:14]([OH:15])[CH:20]=[C:21]([CH3:25])[CH3:22])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CC(C)=C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)=CC(O)c1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 51 %

Procedure:
In an analogous manner to the procedure of Example II, 2.88 g (11.20 mmol) of 5-benzyloxy-2-nitrobenzaldehyde in 30 ml of THF are reacted at −78° C. with 31.7 ml (15.67 mmol) of a 0.5 M 2-methyl-propenylmagnesium bromide soln in THF to give 1.8 g (51%) of 1-[5-(benzyloxy)-2-nitrophenyl]-3-methyl-2-buten-1-ol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][C:10](=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[CH:33]=[C:10]1[CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 1450.6 %

Procedure:
To a solution of (3-oxo-cyclobutyl)-carbamic acid tert-butyl ester (5.6 g, 30 2 mmol) in anhydrous toluene (100 mL) was added methyl (triphenylphosphoranylidene)acetate (10.7 g, 45.4 mmol) and heated to reflux overnight under N2. After cooling to room temperature, the mixture was poured into water and extracted with EA. The organic phase was dried over Na2SO4, concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with PE:EA=20:1) to give the title compound (7 g, yield 96%) as a white solid.