Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:21][CH:22]=3)[N:17](COCC[Si](C)(C)C)[N:16]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F>ClCCl>[CH2:1]([NH:8][C:9]1[N:14]=[C:13]([C:15]2[C:23]3[C:18](=[N:19][C:20]([NH:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:21][CH:22]=3)[NH:17][N:16]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccccc3)n2)c2cnc(NCCN3CCCCC3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(CNc2cccc(-c3n[nH]c4nc(NCCN5CCCCC5)ncc34)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of [3-(6-benzylamino-pyridin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-piperidin-1-yl-ethyl)-amine (133 mg, 0.24 mmol) in dichloromethane (2 mL) was added CF3CO2H (3 mL). This mixture was stirred at room temperature for 3 hours. The reaction was quenched by adding saturated aqueous NaHCO3 to pH about 9, and then extracted with dichloromethane (3×20 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was washed with EtOAc (4 mL) and dried to give [3-(6-benzylamino-pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-piperidin-1-yl-ethyl)-amine as a white solid. (Yield 78 mg, 76%).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH:34][P:35]([OH:38])([OH:37])=[O:36])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[OH-].[Ca+2:40].[OH-]>O>[Ca:40].[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH:34][P:35]([OH:37])([OH:38])=[O:36])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3]
Reactant: [Ca+2]
Agent: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NP(=O)(O)O)n1
Agent: [OH-]
Solvent: O
Product: [Ca]

Procedure:
A suspension of 7-[2-allyloxyimino-2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (5.81 g) in water (150 ml) was adjusted to pH 6.0 with calcium hydroxide (760 mg). After a small amount of insoluble material was filtered off, the filtrate was lyophilized to give calcium salt of 7-[2-allyloxyimino-2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (6.2 g), mp. >230° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:14]=1[CH3:15].[OH:25][C:26]1[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][O:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:25][C:26]2[CH:27]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:29]=[CH:30][CH:31]=2)=[CH:22][C:7]=1[O:8][CH2:9][C:10]1[N:11]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:13][C:14]=1[CH3:15]
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: COc1ccc(CCl)cc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2ccc(OC)c(OCc3nc(-c4ccccc4)oc3C)c2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(5-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (400 mg), methyl 3-hydroxyphenylacetate (195 mg), potassium carbonate (320 mg) and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals of methyl 3-[4-methoxy-3-[(2-phenyl-5-methyl-4-oxazolyl)methoxy]benzyloxy]phenylacetate from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals (470 mg, 85%). melting point: 88-89° C.
Reaction SMILES: C[O:2][C:3]1[C:8]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:7][CH:6]=[C:5]([O:20]C)[N:4]=1.[BrH:22].CCOCC>C(O)(=O)C>[BrH:22].[O:19]=[C:10]1[C:11]2[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:14])[N:9]1[C:8]1[C:3]([OH:2])=[N:4][C:5]([OH:20])=[CH:6][CH:7]=1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2=O)c(OC)n1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccc(O)nc1O
Temperature: 70 °C
Reaction time: 54 h
Yield: 71 %

Procedure:
1,3-Dioxo-2-(2,6-dihydroxypyridin-3-yl)-isoindoline hydrobromide (7) was prepared and isolated as follows. To a flask were added 2,6-dimethoxy-3-phthalimidopyridine (150 mg, 0.528 mmol) and hydrogen bromide solution in acetic acid (30%, 6 ml). The mixture was stirred at an 70° C. oil bath under N2 for 54 h. The mixture was cooled to room temperature, dry ether was added, and the supernatant liquid was decanted. Then ethyl acetate was added, solid precipitated, filtered and washed with ethyl acetate to afford 7 (126 mg, 71%) as a white solid: 1H NMR (CD3OD) δ 7.83-7.77 (m, 4H), 6.37 (d, J=8.1 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H); MS (CI/CH4) 256 [M]+; HRMS (DEI) m/z calcd for C13H8N2O4 256.0484. found 256.0483.
Reaction SMILES: C([O:8][C:9](=[O:25])[CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1)C1C=CC=CC=1.[Li+].[OH-]>C1COCC1.CO>[F:22][C:21]([F:23])([F:24])[O:20][C:16]1[CH:15]=[C:14]([C:13]#[C:12][CH2:11][CH2:10][C:9]([OH:25])=[O:8])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCC#Cc1cccc(OC(F)(F)F)c1)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCC#Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 5-(3-trifluoromethoxy-phenyl)-pent-4-ynoic acid benzyl ester (500 mg, 1.4 mmol) in THF/methanol 2/1 (13.5 ml) was added 1 N aqueous LiOH solution (8.6 ml). The reaction mixture was stirred for 2 h at ambient temperature and concentrated under reduced pressure. The residue was dissolved in 1 N NaOH/ice water 1/1 and ethyl acetate and the layers were separated. The aqueous layer was brought to pH 1 with 1 N HCl and extracted two times with ethyl acetate. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (370 mg, 1.4 mmol, quant.) as colorless crystals.
Reaction SMILES: [NH2:1][C@H:2]([CH2:20][C:21]1[N:22]=[CH:23][N:24](CC2C=CC=CC=2)[CH:25]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])=[C:8]([CH3:19])[CH:7]=1)=[O:4].[H][H]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[NH2:1][C@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:13])=[C:8]([CH3:19])[CH:7]=1)=[O:4]
Reactant: [H][H]
Reactant: Cc1cc(NC(=O)[C@H](N)Cc2cn(Cc3ccccc3)cn2)ccc1C(=O)N1CCCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(NC(=O)[C@H](N)Cc2c[nH]cn2)ccc1C(=O)N1CCCC1

Procedure:
350.0 mg (0.81 mmol) (R)-2-amino-3-(1-benzyl-1H-imidazol-4-yl)-N-[3-methyl-4-(pyrrolidin-1-yl-carbonyl)-phenyl]-propionamide are dissolved in 10.0 ml acetic acid and combined with 150.0 mg Pd(OH)2. The mixture is hydrogenated in a Parr apparatus at ambient temperature at 3 bar hydrogen pressure for eight hours. Then the catalyst is filtered off and the filtrate is evaporated down i. vac.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[C:5](/[N:7]=[C:8]1/[N:9]([C@@H:30]2[CH2:35][CH2:34][C@H:33]([C:36](O)=[O:37])[CH2:32][CH2:31]2)[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:21][CH2:20]3)[N:13]=[CH:12][C:11]=2[NH:29]/1)=[O:6].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[F:55][C:56]1([F:60])[CH2:59][NH:58][CH2:57]1>CN(C=O)C.C(Cl)Cl>[F:55][C:56]1([F:60])[CH2:59][N:58]([C:36]([C@@H:33]2[CH2:34][CH2:35][C@H:30]([N:9]3[C:10]4[CH:15]=[C:14]([O:16][CH2:17][CH2:18][N:19]5[CH2:20][CH2:21][CH:22]([C:25]([OH:28])([CH3:26])[CH3:27])[CH2:23][CH2:24]5)[N:13]=[CH:12][C:11]=4[NH:29]/[C:8]/3=[N:7]\[C:5](=[O:6])[C:4]3[CH:39]=[CH:40][CH:41]=[C:2]([F:1])[CH:3]=3)[CH2:31][CH2:32]2)=[O:37])[CH2:57]1
Reactant: CC(C)(O)C1CCN(CCOc2cc3c(cn2)[nH]/c(=N\C(=O)c2cccc(F)c2)n3[C@H]2CC[C@@H](C(=O)O)CC2)CC1
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCN(CCOc2cc3c(cn2)[nH]/c(=N\C(=O)c2cccc(F)c2)n3[C@H]2CC[C@@H](C(=O)N3CC(F)(F)C3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of cis-4-((E)-2-(3-fluorobenzoylimino)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)cyclohexanecarboxylic acid (0.05 g, 0.088 mmol) in DMF (1 mL) was added CDI (0.029 g, 0.176 mmol), and the resulting mixture was stirred at RT for 1 hour. To this mixture was added 3,3-difluoroazetidine hydrochloride (0.057 g, 0.440 mmol), and the mixture was stirred at RT for 1 hour. The mixture was diluted with DCM (10 mL) and washed with aqueous NH4Cl (5 mL) and brine (5 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (5-75% ACN/H2O; 0.1% TFA) to afford (E)-N-(1-(cis-4-(3,3-difluoroazetidine-1-carbonyl)cyclohexyl)-6-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)ethoxy)-1H-imidazo[4,5-c]pyridin-2(3H)-ylidene)-3-fluorobenzamide (35 mg, 61.8% yield). MS m/z=643.2 [M+H]. Calc'd for C33H41F3N6O4: 642.3.
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[N:4]([CH2:15][CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>CN(C=O)C>[CH2:15]([N:4]1[C:3](=[O:17])[C:2]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:22][CH2:23][O:18][CH2:19][CH2:20]3)=[CH:30][CH:29]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])[CH3:16]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 29 %

Procedure:
A solution of 4-chloro-2-ethyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.217 g, 0.80 mmol) and 4-morpholinoaniline (0.285 g, 1.60 mmol) in DMF (2.0 mL) was heated at 110° C. for 15 mins in a microwave reactor. The mixture was purified by preparative HPLC (C8 50×250, 0.1M NH4OAc/MeCN, gradient) which gave impure product. Repurification was done by preparative HPLC (C8 50×250, 0.1M NMR OAc/MeCN, 50% MeCN isocratic) to give the title compound (0.096 g, 29%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.22-7.16 (m 1H), 7.12-7.09 (m, 4H), 6.62-6.57 (m 2H), 6.52-6.48 (m, 2H), 3.84 (q, 2H), 3.81-3.78 (m, 4H), 2.99-2.95 (m, 4H), 1.47 (t 3H); 13C NMR (500 MHz, CDCl3): δ 159.4, 149.2, 131.5, 129.5, 128.9, 128.4, 128.1, 125.1, 123.6, 115.6, 109.8, 66.9, 49.7, 35.6, 14.0; Mass Spectrum: M−H+ 414.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](=[O:23])[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[C:9]=2[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:4].[OH-].[Na+].Cl>CO.O>[CH3:16][O:15][C:10]1[C:9]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]2[C:13]([CH:14]=[C:5]([C:3]([OH:4])=[O:2])[C:6](=[O:23])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CCCCCOc1c(OC)ccc2cc(C(=O)OC)c(=O)[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCOc1c(OC)ccc2cc(C(=O)O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester (240 mg) obtained in Example 1-1 was dissolved in methanol (7 ml) and water (3 ml), to which sodium hydroxide (120 ml) was added, and the solution was stirred at room temperature for 1.5 hours. While the reaction vessel was cooled with ice, the solution was acidified with the addition of concentrated hydrochloric acid, and extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered to remove the desiccating agent, and concentrated under reduced pressure to give the title compound (228 ml) (Table 6).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH:4]=[CH:3]1.P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.CN([CH:25]=[O:26])C>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([CH:25]=[O:26])=[CH:3]1
Reactant: CN(C)C=O
Reactant: Cc1cc(C)c2ccn(C)c2c1
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Product: Cc1cc(C)c2c(C=O)cn(C)c2c1
Temperature: 25 °C

Procedure:
A solution of 1,4,6-trimethyl-1H-indole (800 mg, 5 mmol) in DMF (0.9 mL) was cooled to 5° C. under nitrogen. The pyrophosphoryl chloride (1.4 mL, 10 mmol) was then slowly introduced. Upon complete addition the cooling bath was removed and the reaction was allowed to warm to ambient temperature. After a total of 45 minutes the reaction was cooled to 5° C. and slowly quenched with 2N NaOH. The pH was adjusted to 8. The solid that precipitate out from the solution was collected by filtration and was washed with water. The remaining white solid was dried in the oven and was confirmed to be the title compound (875 mg, 93%).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>O>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:10][CH2:9][C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NCC(=O)c1ccco1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCC(=O)c1ccco1)c1ccc(Cl)cc1
Yield: 98.1 %

Procedure:
To a mixture of 10 g of (2-furylcarbonyl)methylamine hydrochloride, 12.5 g of sodium bicarbonate, 200 ml of ethyl acetate and 100 ml of water are dropwise added 12.0 g of 4-chlorobenzoyl chloride at a temperature below 10° C. under stirring. The mixture is stirred at room temperature for 3 hours. Then, the ethyl acetate layer is collected, washed with water and dried. Said ethyl acetate layer is evaporated under reduced pressure to remove solvent. 16.0 g of N-(4-chlorobenzoyl)-(2-furylcabonyl)methylamine are thereby obtained. Yield: 98.2%
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([Br:18])=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:18][C:8]1[C:7]([CH:21]=[CH2:22])=[C:16]([CH3:17])[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc2ncccc2c(Br)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2ncccc2c1Br
Temperature: 80 °C
Yield: 78 %

Procedure:
A mixture of 5-bromo-7-methylquinolin-6-yl trifluoromethanesulfonate (230 mg, 0.62 mmol), tributyl(vinyl)stannane (200 μL, 0.68 mmol), lithium chloride (78 mg, 1.86 mmol) and PdCl2(PPh3)2 (43 mg) in DMF (10 mL) was heated at 80° C. for 16 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc) to provide 5-bromo-7-methyl-6-vinylquinoline (120 mg). LCMS-ESI+ (m/z): 248.2, 250.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:31])([F:30])[CH:23]([F:29])[O:24][C:25]([F:28])([F:27])[F:26])[CH:3]=1.[Cl:32]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][C:22]([F:30])([F:31])[CH:23]([F:29])[O:24][C:25]([F:26])([F:27])[F:28])[C:3]=1[Cl:32]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2N)cc1SCC(F)(F)F
Solvent: CC#N
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Reaction time: 0.17 h

Procedure:
0.9 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 30 mL of acetonitrile, and 0.27 g of N-chlorosuccinimide was added under cooling with ice. After stirring for 10 minutes under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 5-amino-4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole. Then, the obtained pyrazole derivative was dissolved in 30 mL of tetrahydrofuran, and 0.3 mL of t-butyl nitrite was added under cooling with ice. After stirring at room temperature for 12 hours, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:10) to obtain 0.75 of 4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].ClC1C=C(Cl)C=C(Cl)C=1[O:19][C:20](=O)[CH:21]([CH3:34])[C:22](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:23].C(OC(=O)C)C>C1(C)C(C)=CC=CC=1>[OH:23][C:22]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[S:6][CH2:7][CH2:8][N:9]2[C:20](=[O:19])[C:21]=1[CH3:34]
Reactant: CC(C(=O)Oc1c(Cl)cc(Cl)cc1Cl)C(=O)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: O=[N+]([O-])C=C1NCCS1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCS2
Reaction time: 8 h
Yield: 46.4 %

Procedure:
2-Nitromethylene-thiazolidine (7.3 g, 50 mmol) and 2-methyl-malonic acid bis-(2,4,6-trichloro-phenyl) ester (23.8 g, 50 mmol) in xylene (80 mL) was taken in a reaction flask and the flask was heated to reflux for 3 hours. The reaction mixture was monitored by TLC (100% ethylacetate). The reaction mixture was cooled, concentrated and partitioned between DCM and water. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. The crude product was kept at 0° C. for overnight. The solid formed was collected and washed with hexane and ether to afford 5.3 g of the product (46% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1.Cl[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14]1
Reactant: ClCc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccn3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 57 (c)] with 2-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-[3-(pyridin-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate as a colourless resin; MS: 583 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1.Cl.[CH2:40]([NH2:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:40]([NH:42][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1)[CH3:41]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCNCCCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 64.6 %

Procedure:
In a manner similar to that of Example 1b, by reaction of 600 mg (1 mmol) of ethyl 4′-(5-bromopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 850 mg (10.4 mmol) of ethylamine hydrochloride and 1.44 g (10.4 mmol) of potassium carbonate in 50 ml of ethanol. 350 mg of ethyl 4′-(5-ethylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a colorless oil (yield=62%).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH:15]=[C:16](Cl)[CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C1(C)C=CC=CC=1>O>[NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)=Cc1cc(C)nc(Nc2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Yield: 37.4 %

Procedure:
Into a 100 ml reaction flask equipped with a stirrer, a thermometer and a condenser, 5.2 g (0.02 mol) of 2-anilino-4-methyl-6-(2-chloropropen-1-yl)pyrimidine, 1.3 g (0.024 mol) of finely pulverized KOH and 50 ml of toluene were charged, and the mixture was reacted for 10 hours under reflux. The reaction mixture was cooled, water was added, and the mixture was subjected to liquid separation. The toluene layer was washed with water. The toluene layer was concentrated and subjected to column chromatography to obtain 1.67 g of 2-anilino-4-methyl-6-(1-propynyl)pyrimidine having a melting point of from 125° to 126° C. The yield was 37.4%.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[N:13]=2)[CH:9]=[N:8]1.C(Cl)[Cl:28].Cl.O1CCOCC1>>[ClH:28].[NH:7]1[CH:11]=[C:10]([C:12]2[N:17]3[CH:18]=[CH:19][N:20]=[C:16]3[CH:15]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[N:13]=2)[CH:9]=[N:8]1
Reactant: COC(=O)c1cc2nccn2c(-c2cnn(COCC[Si](C)(C)C)c2)n1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc2nccn2c(-c2cn[nH]c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.4 %

Procedure:
In a 100 mL flask, methyl 5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate (0.477 g, 1.28 mmol) (Example 45; Step C) was dissolved in DCM (12.8 mL, 1.28 mmol). To this was added 4N HCl in dioxane (4.79 mL, 19.2 mmol). After stirring at ambient temperature for 4 hours, the reaction mixture was concentrated down to remove solvents. The resultant solid was diluted in DCM, sonicated and filtered to afford 0.363 g (100% yield) of the HCl salt as a light yellow solid. MS (apci) m/z=244.3 (M+H).