Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N.[Na].[CH:3]#[CH:4].[C:5]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[Cl-].[NH4+]>C1COCC1.C(Cl)(Cl)Cl.CO.ClCCl.CO.C(Cl)(Cl)Cl>[C:5]([N:8]1[CH2:13][CH2:12][C:11]([C:3]#[CH:4])([OH:14])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: C#C
Reactant: CC(=O)N1CCC(=O)CC1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: C#CC1(O)CCN(C(C)=O)CC1

Procedure:
To 350 ml of liquid ammonia was added 0.06 g of ferric nitrate. When the ferric nitrate dissolved, 1.0 g of sodium was added. The mixture was stirred until a black precipitate formed. To the mixture was then added 3.25 g of sodium. The solution was stirred until the mixture turned gray after which acetylene was bubbled through the reaction for 2 hrs. To the mixture was then added 25 g (0.177 mol) of N-acetyl-4-piperidone in 100 ml of dry THF. The mixture was subsequently stirred for 3 hrs. during which time acetylene was bubbled through. The reaction was then quenched by addition of 10 g (0.187 mol) of ammonium chloride. The ammonia was allowed to evaporate overnight. To the mixture was then added 75 ml of saturated ammonium nitrate and 40 ml of 25% ammonium hydroxide. The mixture was then extracted twice with chloroform, dried over potassium carbonate, filtered and the solvent evaporated to provide a white solid. The solid was washed with anhydrous ether and dried. The crude yield of 1-acetyl-4-ethynyl-4-piperidinol was 17.9 g (0.107 mol, 60.6%). Recrystallization from ethyl acetate provided analytically pure material, m.p. 132°-134° C. The material appeared pure by TLC (silica; 2% methanol/chloroform), Rf =0.2; (silica; 10% methanol/dichloromethane), Rf =0.4, IR (chloroform), 1H-NMR (CDCl3) and MS (MH+ =168) are consistent with the assigned structure.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26]>C[O-].[Na+].CO>[OH:22][C:7]1[C:8]2[S:14][C:13]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(Nc3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(Nc3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of 7-hydroxy-2-phenylamino-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (39 mg, 0.12 mmol) and glycine (186 mg, 2.48 mmol) in 0.5 M sodium methoxide/methanol (4.7 mL) was refluxed for 22 h before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (20 mL) and extracted twice with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.5 mL). The suspension was extracted with ethyl acetate (2×30 mL) and chloroform/isopropanol (3:1, 40 mL). The organic layer was combined and dried in vacuo to give the title compound as a brown solid (35 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.99 (br s, 1H), 11.00 (s, 1H), 9.25 (t, 1H), 8.47 (s, 1H), 7.77 (m, 2H), 7.39 (t, 2H), 7.09 (t, 1H), 4.00 (d, J=6.3 Hz, 2H); MS: (+) m/z 345.07 (M+1).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:5]=1[OH:11].[Li+].[BH4-]>C1COCC1>[OH:11][C:5]1[CH:6]=[C:7]([I:10])[CH:8]=[CH:9][C:4]=1[CH2:3][OH:2]
Reactant: COC(=O)c1ccc(I)cc1O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(I)cc1O

Procedure:
Methyl-2-hydroxy-4-iodo-benzoate from Step 2 (17.8 g, 64 mmol) was dissolved in THF. LiBH4 (3.07 g, 144 mmol) was added portionwise. The reaction mixture was heated at 50° for 16 hours. The reaction mixture was quenched carefully with 1N HCl and then extracted with EtOAc (3×). The organic layers were combined, washed with brine, dried (MgSO4) filtered and concentrated to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[O:3]1.[Br:13]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:12][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][Br:13])=[CH:10][C:4]=2[O:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)OC(F)(F)O2
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: FC1(F)Oc2ccc(CBr)cc2O1
Yield: 96.6 %

Procedure:
A mixture of 2,2-difluoro-5-methyl-1,3-benzodioxole (29.0 g, 0.169 mole), N-bromosuccinimide (30.1 g, 0.169 mole), benzoyl peroxide (0.5 g) and carbon tetrachloride (50 ml) is refluxed for 2.5 hours. Carbon tetrachloride (50 ml) is then added to the hot reaction mixture and the solids are filtered off. The filtrate and washings are evaporated to yield 41.0 g of title product, a brown oil; nmr (CCl4) δ 4.38 (S, 2H), 6.8-7.4 (m, 3H). The product is used without further purification in the next step.
Reaction SMILES: ClC1C=NC=C(Cl)C=1.[CH3:9][O-:10].[Na+].O.Cl[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1>CS(C)=O.C(OCC)C>[CH3:9][O:10][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1
Reactant: COc1cncc(Cl)c1
Reactant: C[O-]
Agent: Clc1cncc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1cncc(OC)c1

Procedure:
50 g of 3,5-dichloro-pyridine are dissolved in 250 ml dimethylsulfoxide. 15 g sodium methylate are added to this solution under stirring. It is stirred under exclusion of moisture at 60°-80° C. 15 g sodium methylate are further added after each of 8 and 16 hours. After a total of 72 hours' stirring, the reaction mixture is reacted with a little water and shaked out with diethylether. The ether phase, after drying, is distilled in a vacuum, resulting in 24 g (51% of theoretical amount) of 3,5-dimethoxy-pyridine in the boiling range 90°-120° C. at 1.6·103Pa. The product is polluted with a small amount of 3-chloro-5-methoxypyridine. It can, however, be employed directly in the next stage for nitrification, since the chloro-compound is not dinitrified and therefore can easily be removed upon crystallization of the 3,5-dimethoxy-2,6-dinitro-pyridine.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][C:14](OC)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[CH2:12][CH2:13][CH2:14][OH:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1cnoc1-c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of methyl 3-(5-phenyl-4-isoxazolyl)propionate (18.13 g) in tetrahydrofuran (300 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 160 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-(5-phenyl-4-isoxazolyl)propan-1-ol (15.72 g, yield 99%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). NMR (CDCl3) δ: 1.82–2.00 (2H, m), 2.72–2.88 (2H, m), 3.66–3.78 (2H, m), 7.41–7.56 (3H, m), 7.68–7.78 (2H, m), 8.21 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[NH:8][C:7](=S)[CH2:6][CH2:5]2.[C:14]([NH:17][NH2:18])(=O)[CH3:15].C(OCC)(=O)C.O>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:17][N:18]=[C:7]1[CH2:6][CH2:5]2
Reactant: Fc1cc(Br)cc2c1NC(=S)CC2
Reactant: CC(=O)NN
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: O
Product: Cc1nnc2n1-c1c(F)cc(Br)cc1CC2
Temperature: 25 °C

Procedure:
A suspension of 6-bromo-8-fluoro-3,4-dihydroquinoline-2(1H)-thione (1-4, 1.71 g, 6.57 mmol) and acetohydrazide (0.58 g, 7.89 mmol) in n-butanol (7 mL) was refluxed for 18 h under inert atmosphere. After cooling down to ambient temperature, ethyl acetate (10 mL) and water (10 mL) were added. The organic phase was then separated and the water phase was extracted with ethyl acetate (5×10 mL). The combined organic phases were washed with brine and dried over Na2SO4; the combined organic layers were then evaporated under reduced pressure to yield the crude product. The crude compound was purified by flash chromatography on silica gel to obtain the title compound as a white solid; 1H NMR (DMSO-D6, 500 MHz) δ=7.79 (dd, J=2.0 Hz, JHF=11.0 Hz, 1H), 7.63 (s, 1H), 2.95 (br s, 4H), 2.46 (d, JHF=8.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][NH:30][CH2:31][CH2:32][O:33][Si](C)(C)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([N:30]([CH3:29])[CH2:31][CH2:32][OH:33])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: CNCCO[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CN(CCO)c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 125 °C
Reaction time: 0.12 h
Yield: 25.9 %

Procedure:
A mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (300 mg, 0.72 mmol), Pd(OAc)2 (20 mg, 0.1 mmol), Methyl-(2-trimethylsilanyloxy-ethyl)-amine (211 mg, 1.44 mmol), X-phos (70 mg, 0.144 mmol), tert-butoxide (140 mg, 1.44 mmol) in dioxane (2 mL) was bubbled N2 for 10 min and then stirred at 125° C. for 7 min under the irradition of microwave. The mixture was filtered over ceilite. The filtrate was concentrated to dryness and purified by pre-TLC(EtOAc:PE=2:1) to afford 85 mg of 242. (yield=26%). 1H NMR (CDCl3, 400 MHz): δ8.01-8.00 (m, 1H), 7.50-7.45 (m, 1H), 7.13-7.00 (m, 4H), 6.36 (d, J=9.2 Hz, 1H), 4.17-4.15 (m, 2H), 3.78-3.75 (m, 1H), 3.63-3.59 (m, 2H), 3.07-3.05 (m, 2H), 2.98 (s, 3H), 2.30-2.26 (m, 1H). LC-MS (ESI): m/z=456 [M+H]+
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]1[O:19][CH2:18][CH:17]([N:26]3[CH:30]=[C:29]([NH2:31])[CH:28]=[N:27]3)[CH2:16][C:15]2=1.C(N(CC)CC)C>C(#N)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][C:20]1[O:19][CH2:18][CH:17]([N:26]3[CH:30]=[C:29]([NH:31][CH2:2][CH2:3][S:4][C:5]4[S:6][CH:7]=[CH:8][CH:9]=4)[CH:28]=[N:27]3)[CH2:16][C:15]2=1
Reactant: COc1ccc2ncc3c(c2c1)CC(n1cc(N)cn1)CO3
Reactant: BrCCSc1cccs1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2ncc3c(c2c1)CC(n1cc(NCCSc2cccs2)cn1)CO3
Temperature: 80 °C
Reaction time: 72 h
Yield: 15.8 %

Procedure:
2-(2-Bromo-ethylsulfanyl)-thiophene (317 mg, 0.13 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-1H-pyrazol-4-ylamine (50 mg, 0.13 mmol, 1.0 eq) in acetonitrile (6 mL), followed by triethylamine (19 μL, 0.13 mmol, 1.0 eq). After 72 hours stirring at 80° C., the reaction mixture is concentrated to give a residue that is purified by column chromatography (silica gel, eluent:cyclohexane:ethyl acetate:methanol, 1:3:0 to 0:1:0 to 0:9:1, v/v/v) to afford [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-yl)-1H pyrazol-4-yl]-[2-(thiophen-2-ylsulfanyl)-ethyl]-amine as a brown viscous oil (9 mg, 14% yield).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[CH:7]=1.[BrH:17]>>[Br:17][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[CH:7]=1
Reactant: Br
Reactant: O=c1cc(CCCCO)c2ccccc2[nH]1
Product: O=c1cc(CCCCBr)c2ccccc2[nH]1
Yield: 61.3 %

Procedure:
4-(4-hydroxybutyl)-2(1H)-quinolinone (1 g, 4.60 mmol) was suspended in 47%hydrobromic acid solution (20 ml) and the mixture was refluxed for 16 hours. The reaction mixture was cooled in ice bath and the separated solid was filtered off by aspiration. The residue was washed with water and recrystallized with methanol (with treatment with activated carbon) to give the entitled compound (II-4) as white crystals (790 mg, yield 61.3%, mp 156°-158 ° C. (methanol)).
Reaction SMILES: O[CH2:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]([NH2:15])=[O:14])=[C:6]2[N:5]=[N:4]1.BrC[C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21].C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[O:9]=[C:8]1[N:3]([CH2:2][C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:4]=[N:5][C:6]2=[C:12]([C:13]([NH2:15])=[O:14])[N:11]=[CH:10][N:7]12
Reactant: NC(=O)c1ncn2c(=O)n(CO)nnc12
Reactant: C[Si](C)(C)C#CCBr
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)C#CCn1nnc2c(C(N)=O)ncn2c1=O
Reaction time: 0.5 h

Procedure:
To a cooled solution of 3-(Hydroxymethyl)-4-oxo-3,4-dihydroimidazo[5,1-][1,2,3,5]tetrazine-8-carboxamide (MM-001) (1 equiv) in acetonitrile (0.17 M concentration substrate in solvent) was added 3-bromo-1-(trimethylsilyl)-1-propyne (4 equivs) and DBU (1.4 equivs). The mixture was stirred at this temperature for 30 minutes whereupon it was acidified with 1 N HCl. The mixture was extracted with EtOAc (3×1 reaction volume). The combined organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo to give an oily residue which was then precipitated from Et2O and washed with further Et2O to give the title compound. 1H NMR (400 MHz, d6-DMSO) □ ppm: 8.87 (1H, s), 7.86 (1H, s), 7.72 (1H, s), 5.18 (2H, s), 0.16 (9H, s). LCMS: rt=3.24 min.; m/z: 313.4 (M+Na)+, 291.2 (MH)+, 151.4 (100).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7].OCCN1C[CH2:38][O:37][CH2:36]C1>>[N:2]1([CH2:3][CH2:4][N:5]([CH2:18][CH2:19][NH:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=2)[S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH2:30][CH2:38][O:37][CH2:36][CH2:1]1
Reactant: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: OCCN1CCOCC1
Product: O=[N+]([O-])c1ccc(NCCN(CCN2CCOCC2)S(=O)(=O)c2ccccc2[N+](=O)[O-])nc1

Procedure:
Made using the same procedure as for polymer-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine except that 4-(2-hydroxyethyl)morpholine (5.1 mL, 42 mmol) was used.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([OH:31])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([CH:36]1[O:38][CH2:37]1)Cl>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:31][CH2:34][C@H:36]5[CH2:37][O:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCC1CO1
Reactant: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OC[C@H]1CO1
Yield: 8.9 %

Procedure:
1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-hydroxy-7-methoxyquinazolin-4-yloxy)phenyl)urea (320 mg, 0.712 mol) and (R) (−) epichlorohydrin (288 μL, 3.56 mmol) were reacted using the same procedure as described before from Example 111A to afford (R)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(oxiran-2-ylmethoxy)quinazolin-4-yloxy)phenyl)urea (160 mg, 44%). LC-MS (ESI) m/z 506 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17]>>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9](=[O:18])[CH2:6][C:2]#[N:1]
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccc(F)cc1Cl
Product: N#CCC(=O)c1ccc(F)cc1Cl
Yield: 60 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 2-chloro-4-fluoro-benzoic acid methyl ester (0.7 g, 3.7 mmol, 1.0 eq). The crude product was extracted with DCM and used in the following step without further purification (0.4 g, yield: 60%).
Reaction SMILES: CS(O[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[C:16](=[O:31])[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20]1)[NH:12][C:11](=[O:32])[CH2:10][CH2:9]2)(=O)=O.[H][H]>C(O)C.[Pd]>[O:31]=[C:16]([C:15]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=[O:32])[NH:12]2)=[CH:7][CH:6]=1)[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1
Reactant: [H][H]
Reactant: CS(=O)(=O)Oc1cc2c(cc1C(=O)CCN1CCC(c3ccccc3)CC1)NC(=O)CC2
Agent: [Pd]
Solvent: CCO
Product: O=C1CCc2ccc(C(=O)CCN3CCC(c4ccccc4)CC3)cc2N1

Procedure:
2.0 Grams of 6-methylsulfonyloxy-7-[1-oxo-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril and 0.5 g of palladium black were dispersed in 50 ml of ethanol and the mixture was catalytically reduced under 3 atmospheric pressure of hydrogen gas for 5 hours. The reaction mixture was filtered and the mother liquor was concentrated under a reduced pressure to obtain a residue. Then the residue was recrystallized from ethanol to obtain 1.1 g of 7-[1-oxo-3-(4-phenyl-1-piperidyl)-propyl]3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: C(Cl)(=O)C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:15]([CH2:26][CH3:27])=[N:14][C:13]=1[C:28]#[N:29]>C(O)C>[NH2:29][C:28]1[C:13]2[N:14]=[C:15]([CH2:26][CH3:27])[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:12]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: CCc1nc(C#N)c(-c2ccccc2N)n1CCCCNS(C)(=O)=O
Solvent: CCO
Solvent: CC(=O)Cl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Temperature: 25 °C

Procedure:
A solution of acetyl chloride (0.15 mL, 2 mmol) in ethanol (2 mL) was added to a solution of N-{4-[5-(2-aminophenyl)-4-cyano-2-ethyl-1H-imidazo 1-yl]butyl}methanesulfonamide (0.19 g) in ethanol (4 mL). The mixture was heated at reflux for two hours, allowed to cool to room temperature, and concentrated under reduced pressure. The resulting off-white solid was dissolved in water (2.0 mL) with heating to 60° C. The resulting solution was adjusted to pH 12 with the addition of 10% w/w sodium hydroxide (about 0.2 mL). The mixture was cooled overnight at 5° C. The crystals were collected by filtration, washed with water, and dried under vacuum at 40° C. for two hours to provide N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as beige crystals, mp 202° C. to 204° C., having a 1H NMR spectrum consistent with an authentic sample.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH:1]([N:14]1[CH2:17][C:16]([O:18][S:21]([CH3:20])(=[O:23])=[O:22])([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Product: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a 0° C. solution of 1-benzhydryl-3-methylazetidin-3-ol (70 g, 276 mmol) and TEA (53.1 g, 525 mmol) in DCM (700 mL) was added drop-wise methanesulfonyl chloride (57 g, 497 mmol). The reaction mixture was stirred for 2 h then filtered and the filter cake was washed with DCM (3×50 mL). The filtrate was washed with water (3×100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (90 g, 98%) as a brown solid, which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 4H), 7.33 (m, 4H), 7.26 (m, 2H), 4.55 (brs, 1H), 3.46 (m, 4H), 3.07 (s, 3H), 1.94 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([CH3:10])[C:5]([O:7]CC)=O.[C:12](#[N:14])[CH3:13]>C1COCC1>[F:11][C:4]([F:3])([CH3:10])[C:5](=[O:7])[CH2:13][C:12]#[N:14]
Reactant: CC#N
Reactant: CCOC(=O)C(C)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)C(=O)CC#N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
In a round bottomed flask flushed with argon, a suspension of sodium hydride 60% in mineral oil (1.30 g, 34 mmoles) was rinsed twice with hexane, and suspended in 20 mL of dry THF. The solution was heated to 75° C., and ethyl difluoropropionate (3.00 g, 22 mmoles) and acetonitrile (1.78 mL) in 5 ml of dry THF was added dropwise over 30 minutes. The temperature of the reaction was lowered to 65° C. and stirred overnight. The mixture was then concentrated to an oil and partitioned between water and ether, and extracted twice to remove any mineral oil and other impurities. The aqueous layer was acidified to pH=1 with 10% HCl, and the solution extracted twice. These extracts were dried over magnesium sulfate, filtered and concentrated to a crude oil. The crude product was purified using silica gel chromatography using a gradient of 10-40% ethyl acetate/hexane to afford 4,4-difluoro-3-oxo-pentanenitrile 1H (300 MHz, CDCl3) δ 3.95 (s, 2H), 1.86 (m, 3H).
Reaction SMILES: [F:1][C:2]1([F:56])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)[CH2:4][CH2:3]1.[CH:57](N(C(C)C)CC)(C)[CH3:58].CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl.C(O)C>[F:56][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH2:57][CH3:58])=[CH:38][N:37]=4)[CH2:34][CH2:35]3)[C:9]=2[CH:44]([F:55])[C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:53])([F:52])[F:54])=[CH:49][CH:50]=2)[CH2:4][CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(CO)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
To a solution of 78 mg (0.10 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-[5-(hydroxymethyl)pyrimidin-2-yl]piperidin-4-yl]-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 17, in 2 ml of dichloromethane, 340 μl (2.0 mmol) of diisopropylethylamine and 77 μl (1.0 mmol) of methanesulfonyl chloride were added, and 2 ml of ethanol was added thereto immediately after initiation of stirring at room temperature and the reaction solution was further stirred at room temperature for 0.25 hour. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=98/2-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 68 mg of the title compound as a foam (yield: 85%).