Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:23]=1[S:32]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[N:10]=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Cc2cc3ccccc3cn2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(3,5-dichloro-4-isoquinolin-3-ylmethyl-phenyl)-4-trifluoromethyl-benzenesulfonamide was synthesized (65%) from 3,5-dichloro-4-isoquinolin-3-ylmethyl-phenylamine (236), 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (br s, 1H), 9.19 (s, 1H), 8.35 (d, J=8.2 Hz, 1H), 8.19 (d, J=1.1 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.99 (dd, J=8.3, 1.2 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.71 (td, J=7.5, 1.0 Hz, 1H), 7.60 (td, J=7.5, 0.8 Hz, 1H), 7.22 (s, 2H), 4.42 (s, 2H). MS (EI): m/z 543 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O.C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Yield: 144 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (0.3 g, 1.67 mmol) in N,N-dimethylformamide (4.0 mL) was added sodium hydride (60% in oil, 0.073 g, 1.83 mmol) with stirring under ice-cooling, and the mixture was stirred at the same temperature for 15 min. 3-Bromobenzyl bromide (0.44 g, 1.75 mmol) was added to the mixture with stirring under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution and saturated brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.84 g, yield 72%) as a colorless powder. 1H NMR (CDCl3) δ: 2.60 (2H, t, J=7.8 Hz), 2.90 (2H, t, J=7.8 Hz), 3.67 (3H, s), 5.01 (2H, s), 6.88 (2H, d, J=8.4 Hz), 7.12 (2H, d, J=8.4 Hz), 7.25 (1H, m), 7.35 (1H, d, J=7.5 Hz), 7.45 (1H, d, J=7.5 Hz), 7.59 (1H, s).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([Cl:52])[CH:48]=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([Cl:53])=[CH:47][CH:48]=[C:49]([Cl:52])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1ccc(Cl)c(CBr)c1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(Cl)ccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,3,4-trichlorobenzene and isolated as light red solid. MS (m/e): 475.2 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:16])=O)[C:2]1=2.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].Cl>C(Cl)Cl.O.CN(C)C=O>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][CH2:11][O:12][CH2:13][C:14]([N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])=[O:16])[C:2]1=2
Reactant: O=C(O)COCCc1cccc2ccsc12
Reactant: CCNCC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)COCCc1cccc2ccsc12
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
In 10 mL of methylene chloride is dissolved 1.20 g of 2-(2-benzo[b]thiophen-7-ylethoxy)-acetic acid. The solution is cooled to 5° C., 0.49 mL of oxalyl chloride and 0.1 mL of N,N-dimethylformamide are added thereto, and the resulting mixture is stirred at ambient temperature for 1.5 hours. The mixture is then cooled to 5° C., 2.6 mL of diethylamine is added, and the resulting mixture is stirred at ambient temperature for 2 hours. Water is added to the reaction mixture, pH is adjusted to 1.0 with 2 mol/L hydrochloric acid, and organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 1.36 g of 2-(2-benzo[b]thiophen-7-ylethoxy)-N,N-diethylacetamide is obtained as an oily product.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH:22]1[CH2:26][CH2:25][CH:24]([C:27]2[C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23]1>>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]3[C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=[CH:29][N:28]=3)[CH2:23]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: NCc1cccnc1C1CCNC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: NCc1cccnc1C1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 81 %

Procedure:
Starting from 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.60 g, 2.0 mmol) and 2-(3-pyrrolidinyl)-3-pyridinemethanamine, a procedure analogous to that given in Example 1 provided the title compound (0.74 g, 81%) as a yellow solid, mp 226°-228° C.
Reaction SMILES: IC1C=C([N+]([O-])=O)C=C2C=1CCCN2C(=O)C(F)(F)F.[Cl:21][C:22]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][CH2:26][N:27]2C(=O)C(F)(F)F>CN(C=O)C.[Cu]Cl>[Cl:21][C:22]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][CH2:26][NH:27]2
Reactant: O=C(N1CCCc2c(Cl)cc([N+](=O)[O-])cc21)C(F)(F)F
Agent: Cl[Cu]
Agent: O=C(N1CCCc2c(I)cc([N+](=O)[O-])cc21)C(F)(F)F
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)c2c(c1)NCCC2
Reaction time: 7 h

Procedure:
A solution of 5-iodo-7-nitro-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D53P) (1.69 g, 6.73 mmol) in DMF (25 ml) was treated with copper (I) chloride (1.66 g, 16.8 mmol) at 130C. for 7 h. On cooling the solution was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc and washed with 5M HCl, then dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography to give a (1:1) mixture of the title compound and 5-chloro-7-nitro-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (591 mg). This mixture was treated with potassium carbonate in methanol to yield the title compound (450 mg) as a brown solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.49 (d, 1H), 7.19 (d, 1H), 4.31 (br.s, 1H), 3.33 (m, 2H), 2.82 (t, 2H), 1.98 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[O:22]1[C:24]2([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[OH:22][C:24]1([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[O:5][CH2:6][CH2:7][N:8]2[C:9](=[O:18])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCCC2(CCC1)CO2
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cccc(OCC2(O)CCCCCCC2)c1
Temperature: 120 °C

Procedure:
The suspension of phenol 24 (1.0 g, 3.5 mmol), 1-oxa-spiro[2.7]decane (0.5 g, 3.2 mmol) and Cs2CO3 (1.14 g, 3.5 mmol) in DMSO (4 mL) was heated at 120° C. for 16 h. After completion of reaction, the mixture was quenched by the addition of 1N HCl and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography (0 to 10% 7N NH3/methanol —CH2Cl2) afforded 2-(2-(3-(1-hydroxy-cyclooctylmethoxy)-phenoxy)-ethyl)-isoindole-1,3-dione as yellow oil. Yield (0.53 g, 35%): 1H NMR (400 MHz, CDCl3) δ 7.92-7.98 (m, 1H), 7.40-7.51 (m, 3H), 7.08-7.14 (m, 1H), 6.45-6.54 (m, 3H), 4.03 (s, 2H), 3.68-3.76 (m, 2H), 1.35-1.92 (m, 16H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C.[Pt]=O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: Cc1cccc(C=O)n1
Reactant: C1CCNC1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1cccc(CN2CCCC2)n1
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A mixture of 6-methylpyridine-2-carboxaldehyde (1.2 g), pyrrolidine (0.78 g) and platinum oxide (0.15 g) in ethanol (50 ml) was hydrogenated at atmospheric pressure for 30 min. The catalyst was filtered off and the filtrate was evaporated. The residue (1.6 g) was purified by chromatography on alumina (60 g, Type UGI), eluting with ether-hexane (1:1) to give the title compound as a colourless mobile oil (1.15 g).
Reaction SMILES: [CH2:1](O)CCCCO.C(O)C(O)CCCC.N1CCCC1=O.CCCCC([CH2:29][CH2:30][CH:31]([O:36]S([O-])(=O)=O)[CH2:32][CH:33]([CH3:35])[CH3:34])CC.[Na+]>O>[CH3:35][CH:33]([CH2:32][C:31]([OH:36])([C:30]#[CH:29])[CH3:1])[CH3:34]
Reactant: OCCCCCO
Reactant: CCCCC(CC)CCC(CC(C)C)OS(=O)(=O)[O-]
Agent: CCCCC(O)CO
Agent: O=C1CCCN1
Agent: [Na+]
Solvent: O
Product: C#CC(C)(O)CC(C)C
Yield: 188.1 %

Procedure:
Ink I-1 containing inventive Dye 1 was prepared by dissolving 0.57 g dye, 1 g 1,5-pentanediol, 0.2 g 1,2-hexanediol, 0.6 g 2-pyrrolidinone, 0.04 g Tergitol 15-S-9 and 0.03 g Surfynol 465® (Air Products Co.) in enough water to give a total weight of 10 g. Ink I-2 was made in the same way except 0.52 g of inventive Dye 2 was used.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][C:18](O)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.B>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCC(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@H]1COCCCO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 120.3 %

Procedure:
In THF (100 ml) was dissolved 3-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethoxy)propionic acid (2.48 g, 8.51 mmol). At room temperature, a 10.0M borane-dimethyl sulfide solution (2.79 ml, 27.9 mmol) was added and the mixture was stirred at room temperature for 3.5 hours and then, at 60° C. for 30 minutes. After cooling to room temperature, the reaction mixture was poured in ice water (100 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/methanol (20/1) eluate fractions, the title compound (2.84 g, 100%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:29][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[CH:11][C:12]=3[C:13]3(OCCC[O:14]3)[C:5]2=[N:4][CH2:3]1.CS(O)(=O)=O.[Na+].[Cl-]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:30])[CH2:29][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([NH:19][S:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)(=[O:21])=[O:22])=[CH:11][C:12]=3[C:13](=[O:14])[C:5]2=[N:4][CH2:3]1
Reactant: CC1(C)CN=C2N(C1)c1ccc(NS(=O)(=O)c3ccccc3)cc1C21OCCCO1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CN=C2C(=O)c3cc(NS(=O)(=O)c4ccccc4)ccc3N2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of N-(3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)benzenesulfonamide (0.064 g, 0.14 mmol, 1 eq) in CH2Cl2 (4 mL) was added methanesulfonic acid (2 mL). The reaction was stirred at rt overnight and then poured into brine. It was basified to pH 10, saturated with solid NaCl, and extracted with EtOAc. The combined organics were dried over sodium sulfate and concentrated. The crude residue purified by column chromatography using acetone/hexanes (40/60) as an eluent to give the title compound as a yellow foam (0.032 g, 58% ). NMR (400 Mz, DMSO-d6): consistent. MS: (ES−) m/z 368 [M−H].
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][NH:13][CH3:14])[CH3:2].C(N(C(C)C)C(C)C)C.Cl.[O:25]=[C:26]1[NH:32][C:31]2[N:33]=[CH:34][C:35]([CH:37]=[CH:38][C:39]([OH:41])=O)=[CH:36][C:30]=2[CH2:29][NH:28][CH2:27]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH2:12][N:13]([CH3:14])[C:39](=[O:41])/[CH:38]=[CH:37]/[C:35]1[CH:34]=[N:33][C:31]2[NH:32][C:26](=[O:25])[CH2:27][NH:28][CH2:29][C:30]=2[CH:36]=1)[CH3:2]
Reactant: CCc1c(CNC)oc2ccccc12
Reactant: O=C(O)C=Cc1cnc2c(c1)CNCC(=O)N2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
A solution of (3-ethyl-benzofuran-2-ylmethyl)methylamine (185 mg, 0.979 mmol) and (i-Pr)2EtN (0.427 mL, 2.44 mmol) in DMF (25 mL) was treated successively with 3-(2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride (250 mg, 0.816 mmol), HOBt (115 mg, 0.856 mmol), and EDC (316 mg, 2.44 mmol). After stirring overnight at room temperature, the mixture was diluted with water and then extracted with EtOAc (3×). The combined organics were washed with brine and dried, filtered and concentrated in vacuo. Purification by column chromatography (silica gel, CH2Cl2/CH3OH, 40:2 to 35:2) gave the title compound (125 mg, 37%) as a yellow solid: ESI MS m/z 405 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH:27]1([C:32]([Cl:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.CS(C)=O>N1C=CC=CC=1>[ClH:34].[CH:27]1([C:32]([NH:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]4[CH:24]5[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]5)[CH2:20]4)=[O:18])=[CH:14][CH:15]=3)=[CH:6][CH:5]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1)C1CCCC1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 38.5 μl (0.32 mmol) of cyclopentanecarbonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is mixed with 3 ml of DMSO and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 22 mg (38.2% of theory) of the title compound are obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd]>[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[NH2:18])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc(N)c1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of 1-(2-t-butyldimethylsilyloxyethoxy)-3-nitrobenzene (7.918 g, 27 mmol) in ethanol (150 ml) was added 10% palladium catalyst on charcoal (2 g) and the reaction mixture was hydrogenated at atmospheric pressure for 2 hours. It was then filtered through kieselguhr and evaporated under reduced pressure to yield the product as a yellow oil (6.707 g, 94%)
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].C(OCCC)CC>C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].[S:2]([O-:5])(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCCOCCC
Solvent: CCO
Product: CS(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
Methanesulfonic acid (1.3 ml, dissolved in 11 ml of absolute ethanol) is slowly added to a solution of Donepezil (3.79 g) in absolute ethanol (38 ml) with stirring at room temperature, and 50 ml of dipropyl ether is added. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 180.3° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH2:41]>C1COCC1.CCOC(C)=O>[CH3:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][NH:41][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[N:9]=[C:8]([C:6]3[CH:5]=[C:4]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][CH:25]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:13]=[CH:12][CH:11]=2)[CH:15]=1)(=[O:21])=[O:22]
Reactant: COCCOCCN
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCCNS(=O)(=O)c1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1
Yield: 68.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 2-(2-methoxy-ethoxy)-ethylamine [CAS-no. 31576-51-9] (0.244 mg, 2.04 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.160 g, 68%) as a light yellow oil. MS (ISP) 572.2 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2[CH:33]=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1CCCCC1>CO>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=2/[CH:33]=[C:6]2\[C:7](=[O:11])[NH:8][C:9]3[C:5]\2=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2C=O)CC1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 100 °C
Yield: 116.1 %

Procedure:
To a mixture of 6-chlorooxindole (4.58 g, 20 mmol) and 4-(4-bromo-2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (10 g, 26 mmol) in methanol (50 mL) was added piperidine (2.56 mL, 26 mmol) dropwise. The mixture was then heated at 100° C. for 3 h. After cooled to 4° C., the mixture was filtered and the precipitate was collected, dried to give the title compound as a bright yellow solid (12.4 g, 90%).
Reaction SMILES: [C:1](#[N:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:4]#[N:5]>N1C2C(=CC=CC=2)C=CC=1>[CH:7]1[CH:8]=[CH:9][C:2]2[C:3](=[C:4]3[N:5]=[C:4]4[N:10]=[C:1]([C:2]5[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=54)[N:10]=[C:1]4[NH:5][C:4]([C:3]5[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=54)=[N:10][C:1]4=[N:5][C:4]([C:3]5[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=54)=[N:10][C:1]=2[NH:5]3)[CH:6]=1
Reactant: N#Cc1ccccc1C#N
Solvent: c1ccc2ncccc2c1
Product: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Temperature: 25 °C

Procedure:
78.2 mmoles of phthalonitrile and 15.8 mmoles of a trihalogenometal are added to 100 ml of quinoline purified by distillation twice. The mixture is heated under reflux for 0.5 to 3 hours and cooled to room temperature, and the reaction product is filtered. The solid product is washed with successive, toluene, acetone and methanol, and then with methanol by using a Soxhlet's extractor. The washed product is dried in vacuo at 60° C., to obtain a monohalogenometal phthalocyanine.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[S:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[C:17]#[N:18].[CH3:19][O-].[Na+].CI>CO>[NH2:1][C:2]1[C:3]([C:17]#[N:18])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:19])[N:7]=1
Reactant: C[O-]
Reactant: N#Cc1c(N)[nH]c(=S)c(C#N)c1-c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1nc(N)c(C#N)c(-c2ccccc2)c1C#N
Temperature: 0 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
To a stirred solution of 0.19 g (0.75 mmol) 6-amino-4-phenyl-2-thioxo-1,2-dihydro-pyridine-3,5-dicarbonitrile in 25 ml methanol were added 0.14 ml (0.76 mmol) sodium methylate solutiuon (5.4M in methanol) and 0.09 ml (1.5 mmol) methyl iodide and stirring continued for 16 hours at room temperature. The reaction mixture was then cooled to 0° C. and the resulting crystals collected by filtration and washed with ether/methanol (3/1) to afford 0.1 g (50%) 2-amino-6-methylsulfanyl-4-phenyl-pyridine-3,5-dicarbonitrile as a white crystalline solid. EI-MS m/e (%): 266 (M+, 40), 265 ([M—H]+, 100).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7]>[OH-].[Na+]>[Br:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(OCc2cccc(Br)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(OCc2cccc(Br)c2)c1C(=O)O

Procedure:
A solution of 3-(3-bromo-benzyloxy)-phthalic acid dimethyl ester (1.9 g, 5.8 mmol) in reagent alcohol (100 mL) and 3 N sodium hydroxide (60 mL) was refluxed for two hours. The solution was evaporated and the residue was dissolved in water (100 mL) and washed with methylene chloride (3×100 mL) then acidified to pH around 4. The resulting mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts was washed with water (2×100 mL), dried and concentrated to give 3-(3-bromo-benzyloxy)-phthalic acid as an off-white solid (2.5 g, 109% crude yield). The product was used in the next step without further purification.