Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]1[N:12]([CH3:25])[N:13]=[C:14]2[C:23]=1[C:22]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=1[N:16]=[C:15]2[NH2:24].[CH:26]([N:29]=[C:30]=[O:31])([CH3:28])[CH3:27]>ClCCl.C(Cl)(Cl)Cl>[NH2:24][C:15]1[C:14]2=[N:13][N:12]([CH3:25])[C:11]([CH2:10][CH2:9][NH:8][C:30]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:31])=[C:23]2[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=1
Reactant: Cn1nc2c(N)nc3c(c2c1CCN)CCCC3
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)NCCc1c2c3c(nc(N)c2nn1C)CCCC3
Temperature: 4 °C

Procedure:
Triethylamine (2.84 mL, 20.4 mmol) was added to a suspension of 1-(2-aminoethyl)-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 50) (1.0 g, 4.08 mmol) in dichloromethane (50 mL) and cooled to 4° C. Isopropyl isocyanate (0.44 mL, 4.48 mmol) was added dropwise to the reaction mixture and maintained at ambient temperature for 16 hours. The reaction mixture was diluted with chloroform (50 mL) and the precipitate was collected by filtration, washed with water, and dried under reduced pressure to afford N-[2-(4-amino-2-methyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-N′-isopropylurea as tan needles, mp 237-238° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][C:3]=1[F:26].[CH3:27][N:28]([CH3:40])[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)=[O:30]>>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[C:31]([CH:32]=[CH:33][CH:34]=4)[C:29]([N:28]([CH3:40])[CH3:27])=[O:30])=[C:3]([F:26])[CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CN1CCN(c2cc(N3CCc4cc(F)c(Br)cc4C3)nc(N)n2)CC1
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Product: CN1CCN(c2cc(N3CCc4cc(F)c(-c5cccc(C(=O)N(C)C)c5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 127 starting from 4-(7-bromo-6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and {3-[(dimethylamino)carbonyl]phenyl}boronic acid (Frontier, Cat. No. D4088). LCMS (M+H)+: m/z=490.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1>CCCCC.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: OC1(c2ccc(Br)cc2)COC1
Reaction time: 1 h
Yield: 63.2 %

Procedure:
1-Bromo-4-iodobenzene (0.65 g, 2.3 mmol, Lancaster) was stirred in pentane (7 mL) and then n-BuLi (1.6 M in hexane, 1.4 mL, 2.3 mmol) was added dropwise at rt. The mixture was and the stirred for 1 h. A white precipitate formed and the precipitate was allowed to settled. The pentane was removed by pipette. The mixture was diluted with pentane (7 mL) back up to the original volume. The mixture was then added to a solution of 3-oxetanone (0.315 g, 4.37 mmol) in THF (7 mL) that was cooled in an ice bath. The mixture was then allowed to come to rt and stirred for about 2 h. The mixture was quenched by the addition of saturated NH4Cl (10 mL) and allowed to stir overnight. EtOAc (15 mL) was added and the layers separated. The aqueous layer was then extracted with EtOAc (5 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. The solid was purified by flash column chromatography (40 g Silicycle™ column) eluting with 20-50% EtOAc/heptane. The solid was recrystallized by dissolving in a mixture of heptane and DCM and concentrating under reduced pressure until a precipitate had formed. The solid was collected by filtration and washed with heptane (10 mL) to provide 3-(4-bromophenyl)oxetan-3-ol (0.333 g, 63%): 1H NMR (400 MHz, DMSO) δ 7.65-7.43 (m, 4H), 6.42 (s, 1H), 4.68 (dd, J=50.6, 6.8, 4H).
Reaction SMILES: [O:1]=[P:2]12[O:13]P3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][P-](F)(F)(F)(F)F.[CH2:22]([N+:26]1[CH:30]=[CH:29][N:28]([CH3:31])[CH:27]=1)[CH2:23][CH2:24][CH3:25].C(=O)(OC)OC.[FH:38]>>[P:2]([F:15])([F:38])([O-:13])=[O:1].[CH2:22]([N+:26]1[CH:30]=[CH:29][N:28]([CH3:31])[CH:27]=1)[CH2:23][CH2:24][CH3:25]
Reactant: F
Reactant: F[P-](F)(F)(F)(F)F
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: CCCC[n+]1ccn(C)c1
Solvent: COC(=O)OC
Product: O=P([O-])(F)F
Temperature: 110 °C

Procedure:
Diphosphorus pentoxide (reagent, produced by Wako Pure Chemical Industries, Ltd.) (2.8 g) was weighed into a 250 ml-volume PFA vessel, and 5.7 g of 1-butyl-3-methylimidazolium hexafluorophosphate (reagent, produced by Wako Pure Chemical Industries, Ltd.) was added. Subsequently, 14.0 g of a dimethyl carbonate solution of 10% hydrogen fluoride was added, and the mixture was refluxed at 110° C. for 1 hour while flowing nitrogen. Thereafter, the reaction solution was heated at 130° C. for 17 hours, thereby distilling off the excess solvent and reaction by-products, and then cooled to room temperature to obtain 1-butyl-3-methylimidazolium difluorophosphate. Anion analysis was performed in the same manner as in Example 1-1, as a result, the purity of the obtained 1-butyl-3-methylimidazolium difluorophosphate was 92% in terms of the relative area.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15](Cl)=[O:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:18]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[N:23]([C:15]([CH:12]3[CH2:13][CH2:14][N:9]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:10][CH2:11]3)=[O:16])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: O=C(C1CCN(Cc2ccccc2)CC1)N1c2ccccc2CCc2ccccc21
Reaction time: 14 h
Yield: 36.4 %

Procedure:
A mixture of 1-benzyl-4-piperidinecarbonylchloride hydrochloride (25.0 g, 91 mmol), 10,11-dihydro-5H-dibenzo[b,f]azepine (17.6 g, 90 mmol), N,N-dimethylaniline (25 ml) and toluene (150 ml) was heated at reflux temperature under stirring for 14 h. The mixture was decanted and to the remaining solid 10% ammonia (100 ml) and chloroform (150 ml) were added. The phases were separated and the combined toluene and chloroform phases were dried (K2CO3) and evaporated in vacuo. The residue was purified by chromatography on silica gel (300 g) using benzene and ethyl acetate as eluents. The crude base was crystallised from cyclohexane, yielding 13.0 g (36%) of 4-((10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)carbonyl)-1-benzylpiperidine.
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([OH:21])=[O:20])=[C:14]([CH2:17]Cl)[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(OCC)(=O)C>O1CCCC1>[C:1]([NH:9][CH:10]1[C:22](=[O:23])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N+:25]3([CH3:24])[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:15][S:16][C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1
Reactant: O=C(O)C1=C(CCl)CS[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)C(NC(=O)c4ccccc4)[C@H]3SC2)CCCC1
Reaction time: 2 h

Procedure:
To a solution of 7-benzoylamino-3-chloromethyl-3-cephem-4-carboxylic acid (14 g) in tetrahydrofuran (280 ml) was added dropwise 1-methylpyrrolidine (16.9 g) over a period of 10 minutes at 10° C. After the mixture was stirred for two hours at 25°~28° C., ethyl acetate (280 ml) was added thereto. The precipitate was collected by filtration, washed with ethyl acetate and diisopropyl ether, dried over phosphorus pentoxide to give 7-benzoylamino-3-(1-methyl-1-pyrrolidinio)methyl-3-cephem-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[I:32][C:33]1[C:34](=[O:52])[N:35]([C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:45])[C:36](=[O:43])[N:37]([CH2:39][CH2:40][CH:41]=O)[CH:38]=1>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][N:10]([CH2:41][CH2:40][CH2:39][N:37]2[CH:38]=[C:33]([I:32])[C:34](=[O:52])[N:35]([C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:45])[C:36]2=[O:43])[CH2:9]3)=[CH:6][CH:7]=1
Reactant: O=CCCn1cc(I)c(=O)n(C(=O)c2ccccc2)c1=O
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2CC3CC3(c3ccc(Cl)cc3)C2)c1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-(4-chlorophenyl)-3-azabicyclo[3.1.0]hexane (racemate, reference procedure for preparation reported in WO2005/080382, 136 mg, 0.703 mmol), acetic acid (0.060 mL, 1.055 mmol), and sodium triacetoxyborohydride (164 mg, 0.774 mmol) were added at 0° C. to a solution of 3-[5-iodo-2,4-dioxo-3-(phenylcarbonyl)-3,4-dihydro-1(2H)-pyrimidinyl]propanal (P38, 280 mg, 0.703 mmol) in 1,2-Dichloroethane (DCE) (8.7 ml). The mixture was stirred at 0° C. for further 4 hours. Water was added and the reaction mixture was concentrated removing the solvent under vacuum. The residue was re-dissolved in ethyl acetate and the organic layer washed with aqueous saturated NaHCO3 solution. The aqueous solution was extracted with ethyl acetate (3×20 ml). The organic layers were collected, dried over Na2SO4, filtrated and evaporated. The crude was purified by chromatography (SPE Si 10 g) with toluene/acetone 8/2. The title compound was recovered as a light yellow oil (190 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:36]5[NH:40][C:39](=[O:41])[O:38][N:37]=5)=[CH:26][CH:25]=4)=[C:19]([CH2:42][CH2:43][CH3:44])[N:18]=[C:17]3[CH3:45])=[CH:12][CH:11]=2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:45][C:17]1[N:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH:5]3[CH2:6][CH2:7][CH2:8][C:2](=[O:1])[CH2:3][CH2:4]3)=[CH:15][CH:14]=2)[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)=[C:19]([CH2:42][CH2:43][CH3:44])[N:18]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCCC(O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(C)n(-c2ccc(OC3CCCC(=O)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 51.2 %

Procedure:
To a solution of 3-{4-[(4-hydroxycycloheptyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.10 g) in methylene chloride (2 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.11 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.051 g, 53%).
Reaction SMILES: [CH:1]([O-])([O-])OC.[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[NH:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17])(=[O:8])[CH3:7].N1C2C(=CC=CC=2)C=CC=1>CO>[C:6]([NH:9][C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][CH:22]=1)[NH:13][C:14](=[O:19])/[CH:15]=[C:16](\[O:18][CH3:1])/[CH3:17])(=[O:8])[CH3:7]
Reactant: CC(=O)CC(=O)Nc1cccc(NC(C)=O)c1
Reactant: COC([O-])[O-]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CO/C(C)=C\C(=O)Nc1cccc(NC(C)=O)c1
Temperature: 140 °C
Yield: 58.5 %

Procedure:
11.7 g of methyl orthoformate were added to a solution of 23.4 g of m-acetamido-acetylacetanilide in 250 ml of anhydrous methanol and the mixture was refluxed for 3 hours and cooled. 0.6 ml of quinoline were added thereto and the methanol was distilled off under reduced pressure. Toluene was added to the residue and the mixture was heated at 140° C. for one hour while distilling a methanol-toluene azeotrope. The mixture was then concentrated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with ethyl acetate yielded 14.5 g of m-acetamido-3-methoxy-crotonanilide melting at 167° C. Crystallization from acetone did not change the melting point.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][C:22]([F:26])([F:25])[CH2:23][SH:24].Cl>CN(C)C=O>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([S:24][CH2:23][C:22]([F:26])([F:25])[F:21])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: FC(F)(F)CS
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(SCC(F)(F)F)c(C(=O)O)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 4.58 mmol 2-fluoro-5-methanesulfonyl-benzoic acid (Example B4(b)) in 6 ml N,N-dimethylformamide were added 13.8 mol cesium carbonate and 9.16 mmol 2,2,2-trifluoro-ethanethiol and the mixture was stirred at 90° C. for 30 min. The reaction mixture was then cooled to room temperature and acidified to pH1 by addition of hydrochloric acid before being extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford the title compound as a red-brown solid which was used in the next step without further purification (yield 99%). MS (m/e): 312.9 ([M−H]−, 100%).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[CH:16]=[CH: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.[CH:24]([C:26]1[CH:37]=[C:36]([CH3:38])[C:29]([O:30][CH2:31][C:32]([O:34]C)=[O:33])=[C:28]([CH3:39])[CH:27]=1)=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=2)[C:16]([CH2:24][C:26]2[CH:37]=[C:36]([CH3:38])[C:29]([O:30][CH2:31][C:32]([OH:34])=[O:33])=[C:28]([CH3:39])[CH:27]=2)=[CH:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc2ccn(C(c3ccccc3)c3ccccc3)c2c1
Reactant: COC(=O)COc1c(C)cc(C=O)cc1C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cc2cn(C(c3ccccc3)c3ccccc3)c3cc(Cl)ccc23)cc(C)c1OCC(=O)O
Temperature: 0 °C
Yield: 89 %

Procedure:
To 1-benzhydryl-6-chloro-1H-indole (1.0 eq) and methyl 2-(4-formyl-2,6-dimethylphenoxy)acetate (0.6 eq) in CH2Cl2 (0.1M) at 0° C. was added neat triethysilane (3 eq) followed by triflouroacetic acid (3 eq). After 10 minutes at 0° C. the reaction was warmed to room temperature and stirred until the initially formed spot by TLC yields a new spot. The reaction was then quenched by the addition of saturated sodium bicarbonate, diluted with CH2Cl2 and washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and purified by column chromatography to yield 89% of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[N:36]1[CH:41]=[CH:40][C:39]([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:38][CH:37]=1>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:46][CH2:47][C:42]([C:39]4[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=4)([C:48]([NH2:50])=[O:49])[CH2:43][CH2:44]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccncc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccncc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (7.5 mmol) and 4-(pyridin-4-yl)-piperidine-4-carboxylic acid amide hydrochloride (5 mmol). Chromatograph on silica gel eluting with 10% methanol/dichloromethane to give the title compound: Rf =0.28 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:12](Cl)=[N:13][CH:14]=[C:15]([Cl:17])[CH:16]=2)=[O:10])=[N:6][CH:7]=1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(O)C>[ClH:1].[ClH:1].[ClH:1].[ClH:1].[Cl:17][C:15]1[CH:16]=[C:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:10])[C:12]([NH:32][CH2:31][CH:28]2[CH2:27][CH2:26][N:25]([C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[CH2:30][CH2:29]2)=[N:13][CH:14]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cnc1Cl
Reactant: NCC1CCN(c2ccncc2)CC1
Solvent: CCO
Product: Cl
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cnc1NCC1CCN(c2ccncc2)CC1
Yield: 30.9 %

Procedure:
A suspension of N-(5-chloropyridin-2-yl)-2,5-dichloropyridine-3-carboxamide (0.807 g, 2.68 mmol) and 1-(4-pyridinyl)piperidine-4-methylamine (510 mg) in ethyl alcohol (5 mL) was heated in a sealed tube for 24 hours. Filtered the solids and purified by RPHPLC. The pure product containing fractions were combined and lyophilized to give 0.1 g of an off-white solid.
Reaction SMILES: [CH:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][CH2:16][CH2:17][CH:18]1[O:22][CH2:21][CH2:20][O:19]1>>[Br-:15].[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[CH2:17][CH2:16][N+:12]1[CH:11]=[CH:10][C:9]([CH:1]=[CH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1
Reactant: C(=Cc1ccncc1)c1ccccc1
Reactant: BrCCC1OCCO1
Product: C(=Cc1cc[n+](CCC2OCCO2)cc1)c1ccccc1
Product: [Br-]

Procedure:
By the procedure described in Ex 8., 4-styrylpyridine (3.62 g) and 2-(2-bromoethyl) 1,3-dioxolane (3.76 g) were reacted to obtain N-[2-(1,3-dioxolane-2-yl)ethyl]-4-styrylpyridinium bromide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br.[CH3:23][NH:24][CH:25]1[CH2:27][CH2:26]1.[ClH:28]>>[ClH:28].[ClH:28].[CH:25]1([N:24]([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CNC1CC1
Reactant: BrCCCCCCBr
Agent: Cl
Product: CN(CCCCCCOC1CCNCC1)C1CC1

Procedure:
In analogy to example 1.2a, 1.5 and 1.3, reaction of 4-Hydroxy-piperidine-1-carboxylic-acid tert-butyl ester and 1,6-dibromohexane, N-methylcyclopropylamine followed by treatment with 4N HCl yielded Cyclopropyl-methyl-[6-(piperidin-4-yloxy)-hexyl]-amine dihydrochloride, MS: 255 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].[C:9]1([CH2:15][C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCOCC>[OH-].[Na+]>[C:9]1([CH2:15][C:16]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C[C@@H](O)[C@H](NC(=O)Cc1ccccc1)C(=O)O
Reaction time: 16 h

Procedure:
L-Threonine (35.7 g) is dissolved in 1 N sodium hydroxide (1 liter) and chilled to -5° to -10° C. To the cold, mechanically stirred solution is added dropwise phenylacetyl chloride (46.3 g). The reaction mixture is stirred for about 16 hours as the temperature rises to 26° C. The mixture is washed with ether, acidified to pH 2 with hydrochloric acid, and extracted with ethyl acetate (two times). The combined extracts are dried over sodium sulfate and concentrated under reduced pressure until crystalline solids form. Ether is added to the mixture and the crystals are collected (34.8 g); melting point 161°-163° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:19]([S:22](Cl)(=[O:24])=[O:23])([CH3:21])[CH3:20]>C(Cl)Cl.N1C=CC=CC=1>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([NH:1][S:22]([CH:19]([CH3:21])[CH3:20])(=[O:24])=[O:23])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)C(C)C)c1
Reaction time: 72 h
Yield: 29.9 %

Procedure:
To a stirred solution of 1-(3-amino-4-benzyloxy-phenyl)-ethanone (EP 0 659 737) (30 g, 125.0 mmol) in CH2Cl2 (500 mL) and pyridine (250 mL) was added dropwise isopropylsufonyl chloride (28.6, 200 mmol) at room temperature. The reaction was stirred for 3 days under nitrogen atmosphere. The mixture was diluted with CH2Cl2 (700 mL) and washed with 1N hydrochloric acid, water, dried over Na2SO4, and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate/hexanes to give the title compound as a white solid (13 g, 30%); 1H NMR (300 MHz, CDCl3) δ 1.35(d, J=6.9 Hz, 6 H), 2.56(s, 3 H), 3.25–3.45(m, 1 H), 5.18(s, 2 H), 6.75(brs, 1 H), 7.02 (d, J=8.6 Hz, 1 H), 7.30–7.50(m, 5 H), 7.70(dd, J=8.6, 2.1 Hz, 1 H), 8.18 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 364.9 ((M+NH4)+, 100%; HRMS Calcd. for C18H22NO4S(MH+): 348.1264. Found: 348.1259.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1>C1COCC1.CCOC(C)=O>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][N:17]=[C:16]2[O:14][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[NH2:7]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
To a slurry of cesium carbonate (13.3 mmol) in THF was added 3-aminophenol (1.45 g, 13.3 mmol). After stirring 15 minutes at room temperature, 4-chloro-6,7-dimethoxyquinazoline (3.0 g, 13.3 mmol) was added and the reaction mixture heated at 50° C. overnight. The mixture was diluted with EtOAc and washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. to give 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (3.62 g, 12.2 mmol, 91%). 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.51 (s, 1H), 7.37 (s, 1H), 7.09 (t, 1H), 6.50 (d, 1H), 6.43 (s, 1H), 6.38 (d, 1H), 5.30 (br s, 2H), 3.99 (s, 3H), 3.97 (s, 3H); LC-MS (ESI) m/z 298 (M+H)+.