Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCBr)NC1CC1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 90.7 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (458.6 mg, 1.60 mmol) and N-cyclopropyl-6-bromohexanesulfonamide (500 mg, 1.76 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (711.3 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 90.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:7]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(COc3ccccc3Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ccccc1OCc1cccc(OCC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.7 %

Procedure:
A solution of 215 mg of 1-[(2-chlorophenoxy)methyl]-3-[[N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]benzene, as prepared in the preceding step, in methylene chloride (2 mL) was treated with 1.5 mL of 4 N HCl in dioxane. The reaction mixture was stirred at ambient temperature for 1 h, and then concentrated to provide 183 mg of the title compound as a colorless powder after repeated concentrations from diethyl ether/hexane/methanol. 1H-NMR (300 MHz, DMSO-d6) δ 8.51 (br s, 2 H), 7.45 (dd, 1 H, J=1.3, 7.9 Hz), 7.27-7.35 (m, 2 H), 7.21 (d, 1 H), 6.90-7.05 (m, 4 H), 5.18 (s, 2 H), 3.87 (d, 2 H), 2.90 (t, 2 H, J=10 Hz), 2.05 (m, 1 H), 1.91 (d, 2 H, J=13.8 Hz), and 1.5-1.54 (m, 2 H). Mass spectrum (MALDI-TOF; α-cyano-4-hydroxycinnamic acid matrix) calcd. for C19H22ClNO2 : 332.1 (M+H). Found: 332.0.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([CH2:20][C:21]([F:24])([F:23])[F:22])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:1](=[O:3])[CH3:2])=[C:15]([CH2:20][C:21]([F:22])([F:23])[F:24])[CH:14]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccc(Br)cc1CC(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(Br)cc1CC(F)(F)F
Reaction time: 0.75 h
Yield: 78.7 %

Procedure:
Acetyl chloride (0.91 mL, 12.8 mmol) followed by triethylamine (1.8 mL, 12.8 mmol) were added to a stirred solution of 4-bromo-2-(2,2,2-trifluoroethyl)phenol (2.55 g, 10.7 mmol) dissolved in CH2Cl3 (20 mL). The reaction was stirred for 45 mins and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine dried over Na2SO4 and concentrated. Purification by flash column chromatography (0% to 20% EtOAc in hexanes) gave the product as a clear oil (2.50 g). LCMS: apci 297 MH+
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].[Cl:20][CH2:21][CH2:22][CH2:23]Br.CC(C)=O>O>[Cl:20][CH2:21][CH2:22][CH2:23][O:11][C:7]1[C:6]([O:12][CH3:13])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[C:9]([OH:10])[CH:8]=1
Reactant: COc1cc(C(C)=O)c(O)cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)c(O)cc1OCCCCl
Yield: 70.3 %

Procedure:
A mixture of 2,4-dihydroxy-5-methoxyacetophenone (1.4 g, 7.7 mmol), K2CO3 (1.4 g, 10.0 mmol), 3-chlorobromopropane (1.6 g, 10.0 mmol) and acetone (25 mL) was stirred and refluxed under N2 for 16 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with ethyl acetate. The extract was washed (H2O, brine) dried (MgSO4) and concentrated to yield 1.4 g of an off-white solid. Recrystallization twice from ethanol afforded 0.4 g of the alkylated phenol as a solid, m.p. 99°-101° C.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[O:19][C:18](=[O:20])[C:17]2[N:21]=[C:14]([S:15][CH:16]=2)[S:13][CH2:12][CH2:11][N:10]2[C@H:6]([CH2:7][O:8][C:9]2=[O:22])[CH:5]=[CH:4][CH2:3]1.[OH:30][C@@H](C(C)(C)CCCC)/C=C/[C@H]1COC(=O)N1CCSC1SC=C(C(OCC)=O)N=1.O1CCCC1>CO>[O:22]=[C:9]1[N:10]([CH2:11][CH2:12][S:13][C:14]2[S:15][CH:16]=[C:17]([C:18]([OH:19])=[O:20])[N:21]=2)[C@@H:6](/[CH:5]=[CH:4]/[CH2:3][C@:2]([OH:30])([CH3:1])[CH2:23][CH2:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH2:7][O:8]1
Reactant: C[C@]1(CCCC(F)(F)F)CC=C[C@H]2COC(=O)N2CCSc2nc(cs2)C(=O)O1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@](O)(C/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1)CCCC(F)(F)F

Procedure:
By the same procedure as the reaction of Example 8 using the compound 64-2 (More polar) instead of the compound 7 and using a mixture of tetrahydrofuran and methanol instead of methanol, the title compound having the following physical data was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:31][CH2:32][CH3:33])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([O:23]C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)[C:6]=2[C:5]([CH3:34])=[C:4]([CH3:35])[N:3]=1.Cl.O1CCOCC1>ClCCl>[NH2:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:31][CH2:32][CH3:33])[N:10]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][OH:23])[C:6]=2[C:5]([CH3:34])=[C:4]([CH3:35])[N:3]=1
Reactant: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCN(OC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCCCNO
Reaction time: 2 h

Procedure:
The preparation of tert-butyl 4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl[(tert-butoxycarbonyl)oxy]carbamate is described in Parts A-F of Example 14. A mixture of 4M hydrochloric acid in dioxane (2.25 mL, 9.0 mmol, 20 eq) was added to a solution of tert-butyl 4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl[(tert-butoxycarbonyl)oxy]carbamate (0.22 g, 0.45 mmol, 1 eq) in dichloromethane (5 mL) and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting white solid was concentrated from chloroform and dried under vacuum to provide N-[4-(4-amino-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]hydroxylamine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:23]=[CH:22][C:8]2[N:9]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=4)[N:12]=[C:10]3[S:11][C:7]=2[CH:6]=1.[C:24]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]3[N:12]=[C:10]4[N:9]([CH:14]=3)[C:8]3[CH:22]=[CH:23][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:6][C:7]=3[S:11]4)=[CH:16][CH:17]=2)=[O:35])[CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCCl)ccc23)cc1
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCCl)ccc34)cc2)no1

Procedure:
A mixture of 7-(2-chloro-ethoxy)-2-(4-amino-phenyl)-benzo[d]imidazo[2,1-b]thiazole (1 equivalent) and phenyl 5-tert-butylisoxazol-3-ylcarbamate, prepared as described in WO 2006/082404 A1 (1 equivalent) in anhydrous THF is stirred at selected temperatures between rt and 50° C. until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between water and either dichloromethane or a mixture of dichloromethane and isopropanol. The separated aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane, and the combined organic layers are dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-chloro-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)COc1nc(-c2ccc(F)cc2)cs1
Reactant: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1nc(-c2ccc(F)cc2)cs1)Nc1ccccc1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 50.7 mg (0.54 mmol) of aniline. Yield: 7.6 mg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1=[O:23]>CN(C)C=O.C(Cl)(Cl)Cl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:20]2[CH2:21][CH2:22][NH:17][C:18](=[O:23])[CH2:19]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1CN(c2ccc([N+](=O)[O-])cc2)CCN1
Temperature: 140 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 1.275 g (9.04 mmol) of 4-fluoronitrobenzene in 30 mL of N,N-dimethylformamide were added 1.87 g (13.56 mmol) of potassium carbonate and 905 mg (9.04 mmol) of piperazine-2-one, and the mixture was stirred for 1 hour at 130° C. and for 1 hour at 140° C. The reaction mixture was cooled to room temperature and diluted with chloroform, then, insoluble substances were removed off by filtration. The filtrate was condensed under reduced pressure and the resulting solid was washed with ethanol to give 859 mg (43%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:18]1([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][C:28](B4OC(C)(C)C(C)(C)C4)=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:28]3[CH:27]=[C:26]4[C:31]([CH:32]=[CH:33][C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:25]4)=[CH:30][CH:29]=3)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([CH2:16][OH:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](CO)C1
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](CO)C1

Procedure:
Following the general procedure for the Suzuki coupling, trans-[3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutyl]-methanol (139.2 mg, 0.4045 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (141 mg, 0.426 mmol), Na2CO3 (107 mg, 1.01 mmol) and Pd(PPh3)4 (30 mg, 0.026 mmol) in DMF (10 mL)/water (2 mL). The crude material was purified by column chromatography on silica gel [Jones Flashmaster, 10 g/70 mL cartridge, eluting with CH2Cl2 (1-7)→2% MeOH in CH2Cl2 (8-22)→5% MeOH in CH2Cl2 (23-41)→7% MeOH in CH2Cl2 (42-51)], yielding the title compound. 1H NMR (CDCl3, 400 MHz) δ 2.42-2.60 (m, 3H), 2.60-2.73 (m, 3H), 3.88 (d, J=6.4 Hz, 2H), 5.19 (brs, 2H), 5.44-5.53 (mc, 1H), 7.39 (s, 1H), 7.46-7.52 (m, 1H), 7.52-7.58 (m, 2H), 7.71 (dd, J=1.7, 8.3 Hz, 1H), 7.92 (d, J=8.5 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 8.17-8.22 (m, 2H), 8.27 (d, J=8.5 Hz, 1H), 8.29-8.32 (m, 1H), 8.36 (s, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135) δ 30.62 (+), 32.16 (2C, −), 46.70 (+), 65.12 (−), 101.04 (Cquart), 116.13 (Cquart), 118.88 (+), 120.64 (+), 125.82 (Cquart), 127.27 (+), 127.45 (2C, +), 128.17 (+), 128.21 (+), 128.71 (2C, +), 129.40 (+), 136.23 (Cquart), 136.49 (+), 139.23 (Cquart), 148.28 (Cquart), 150.47 (Cquart), 151.57 (+), 157.09 (Cquart) 157.97 (Cquart). MS (ES+): m/z 422.1 (51) [MH+], 338.2 (39) [MH+-cyclobutene-CH2OH]. HPLC: tR=2.4 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:22])[C:14]3[CH:15]=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:22])[C:14]3[CH:15]=[C:16]([NH:21][C:13](=[O:12])[CH2:14][C:10]([CH3:22])([CH3:11])[CH3:7])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(N)cc2c(c1C)OCC2(C)c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OCC2(C)c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 3-(4-isopropylphenyl)-3,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 35, the title compound was synthesized in the same manner as in Example 1. Yield: 59%. Melting point: 132-133° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].O.[C:13]([OH:17])(=[O:16])[CH:14]=[O:15]>CC(C)=O>[OH:15][CH:14]([C:13]([OH:17])=[O:16])[NH:7][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1
Reactant: O=CC(=O)O
Reactant: Cc1cc(C)cc(C(N)=O)c1
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)cc(C(=O)NC(O)C(=O)O)c1

Procedure:
A mixture of 3,5-dimethylbenzamide (22.6 g, 0.15 mol) and glyoxylic acid monohydrate (15.3 g, 0.17 mol) in acetone (120 ml) is heated under nitrogen atmosphere at reflux for 6 h. The solvent is evaporated in vacuo to give 2-hydroxy-N-(3,5-dimethylbenzoyl)glycine. To a solution of 2-hydroxy-N-(3,5-dimethylbenzoyl)glycine in methanol (350 ml) is added concentrated sulfuric acid (4.6 ml) at room temperature. The mixture is stirred for 2 days and then concentrated in vacuo. The residue is diluted with ethyl acetate, washed with two portions of saturated sodium bicarbonate solution and with two portions of brine. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give 2-methoxy-N-(3,5-dimethyl benzoyl)glycine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[C:33]([NH:32][C:28]1[CH:27]=[C:26]([CH:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][NH:16][C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:9][CH2:10][CH2:11][CH2:12]3)=[O:15])[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=1)(=[O:35])[CH3:34]
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCC3)CC2)c1

Procedure:
Example 72 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.38–7.25 (m, 5H), 7.03–6.97 (m, 3H), 6.49 (br s, 1H), 3.29 (dd, 2H, J=5.6, 12.0 Hz), 2.98–2.94 (m, 2H), 2.55–2.49 (m, 3H), 2.33 (t, 2H, J=6.8 Hz), 2.20 (s, 3H), 2.01–1.95 (m, 4H), 1.86–1.62 (m, 10H); ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=O)[CH2:6][C:4](=[O:5])[CH2:3]1.[H][H]>C(O)CO>[CH3:1][C:2]1([CH3:10])[CH2:9][CH2:7][CH2:6][C:4](=[O:5])[CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: OCCO
Product: CC1(C)CCCC(=O)C1
Yield: 4 %

Procedure:
Sasson et al. achieved reduction of dimedone via transfer hydrogenation in ethylene glycol as hydrogen donor in the presence of the homogenous catalyst RuCl2 (PPh3)3. Among a number of different reduction products 3,3-dimethylcyclohexan-1-one was obtained only in 4% yield which is an unacceptable low selectivity.
Reaction SMILES: [F:1][C:2]1([F:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([CH2:16][OH:17])=[CH:14][N:13]=[CH:12]2)[C:3]1([CH3:19])[CH3:18].[H-].[Na+].I[CH2:24][CH3:25]>CN(C=O)C.C([O-])(O)=O.[Na+].C(OCC)(=O)C>[F:20][C:2]1([F:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[C:15]([CH2:16][O:17][CH2:24][CH3:25])=[CH:14][N:13]=[CH:12]2)[C:3]1([CH3:18])[CH3:19]
Reactant: CC1(C)C(n2cncc2CO)c2ccccc2C1(F)F
Reactant: CCI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCc1cncn1C1c2ccccc2C(F)(F)C1(C)C
Reaction time: 2 h

Procedure:
To a solution of [3-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-3H-imidazol-4-yl]-methanol, (160 mg, 0.575 mmol) in DMF (5 mL) is added a 60% dispersion of NaH in oil (46 mg, 1.15 mmol). The reaction is permitted to stir for 30 minutes at room temperature, at which time iodoethane (0.05 mL, 0.63 mmol) is added. The reaction is permitted to stir for 2 hours at which time it is diluted with saturated aqueous NaHCO3 and ethyl acetate. The layers are separated and the organic layer is dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:6) to furnish 1-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-5-ethoxymethyl-1H-imidazole; HRMS: (ESI) m/z 307.1634 [(M+H)+: Calcd for C17H21N2OF2: 307.1622]; 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=2.5 Hz, 3 H), 1.28 (t, J=7.1 Hz, 3 H), 1.33 (d, J=3.3 Hz, 3 H), 3.51-3.68 (m, 2 H), 4.54-4.70 (m, 2 H), 5.58 (br. s., 1 H), 7.19 (s, 1 H), 7.23-7.26 (m, 1 H), 7.34 (s, 1 H), 7.55-7.63 (m, 2 H), 7.69-7.76 (m, 1 H).
Reaction SMILES: [O:1]([C:8]1[C:13]([NH2:14])=[C:12]([C:15]#[C:16][CH3:17])[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>O1CCCC1>[CH3:17][C:16]1[NH:14][C:13]2[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][CH:10]=[N:11][C:12]=2[CH:15]=1
Reactant: CC#Cc1ncnc(Oc2ccccc2)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
4-Phenoxy-6-prop-1-yn-1-ylpyrimidin-5-amine (776.0 mg) was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. To this solution was added dropwise a 1.0 M solution (4 mL) of potassium tert-butoxide in tetrahydrofuran, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33→20:80) to give the title compound (578.6 mg) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>C(O)C>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Sc1ccccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCSc1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.9 %

Procedure:
Triethylamine [12.54 ml (90 mmol)] was added to a suspension of 6.67 g (60 mmol) of 2-mercaptopyridine and 15.24 g (60 mmol) of N-(2-bromoethyl)phthalimide in 200 ml of ethanol and stirred at room temperature for 24 hours. The mixture was heated under reflux for 2 hours. The solvent was distilled off, chloroform was added to the residue, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/n-hexane=1:2) to obtain 8.00 g of the desired compound (46.9%, colorless crystals).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([C@H:4]([N:7]([C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[NH2:8])[CH2:5][CH3:6])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:35]=[C:34]([B:36]2[O:40]C(C)(C)C(C)(C)[O:37]2)[CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>C(Cl)Cl.O>[CH3:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([CH3:16])[CH:13]=1)[C:9]([N:7]([C@H:4]([CH2:5][CH3:6])[C:2]([CH3:1])([CH3:3])[CH3:19])[NH:8][C:29]([C:28]1[CH:32]=[CH:33][C:34]([B:36]([OH:40])[OH:37])=[CH:35][C:27]=1[F:26])=[O:30])=[O:18]
Reactant: CC[C@@H](N(N)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Reactant: CC1(C)OB(c2ccc(C(=O)Cl)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC[C@@H](N(NC(=O)c1ccc(B(O)O)cc1F)C(=O)c1cc(C)cc(C)c1)C(C)(C)C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
In a 25 mL round bottom flask equipped with a magnetic stir bar were added (R)—N-(2,2-dimethylpentan-3-yl)-3,5-dimethylbenzohydrazide (1.317 g, 5.02 mmol) in 7 mL CH2Cl2 and a solution of potassium carbonate (1.388 g, 10.04 mmol) in distilled water (4 mL) were cooled in an ice bath at 0-4° C. and stirred for 10 min. The 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (1.714 g, 6.02 mmol) was added as a solution in 3.5 mL dichloromethane. The reaction was stirred at 0-4° C. for 30 min., the ice bath was removed and the mixture was stirred for 16 h at room temperature. The reaction was analyzed by LCMS and shows the reaction was complete. The organic layer was separated using a Biotage phase separator column and was transferred to a 40 g Redisep SiO2 column on the ISCO HPLC system. The compound was eluted with 0-100% EtOAc—hexanes and then with 10% MeOH—CH2Cl2. The desired fractions were combined and concentrated on a rotary evaporator to give the desired compound as an off-white foam (1.518 g, 59% yield). MS (ESI) calcd for C29H40BFN2O4 ([M+H]+) 511. found 511.
Reaction SMILES: Br[CH:2]1[C:6](=[O:7])[N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[Cl:16])[N:4]=[C:3]1[NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:19].[CH3:39][C:40]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][NH:42][N:41]=1>C(OCC)(=O)C>[Cl:16][C:9]1[CH:10]=[C:11]([Cl:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[C:6](=[O:7])[CH:2]([N:42]2[CH:43]=[C:44]([N+:45]([O-:47])=[O:46])[C:40]([CH3:39])=[N:41]2)[C:3]([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:19])=[N:4]1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1n1cc([N+](=O)[O-])c(C)n1

Procedure:
13 g of 4-bromo-1-(2,4,6-trichlorophenyl)-3-(3-octadecylureido)-2-pyrazolin-5-one and 10 g of 3-methyl-4-nitropyrazole were mixed at 90° C. for 2 hours. To the reaction mixture, 200 ml of ethyl acetate was added and the mixture was washed several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. The residual oil was dissolved in 50 ml of chloroform and purified with column chromatography using 500 g of silica gel (art 7734 manufactured by MERCK & Co.) wetted with chloroform as a bulking agent. Upon elution with a solvent mixture of chloroform and ethyl acetate (10:1), 10.9 g of an oily comprising the desired coupler was obtained.