Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[Br-].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Zn+])=[CH:20][CH:19]=1)#[N:17]>O1CCCC1.ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][C:2]2[O:6][C:5]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(-c2ccc(Br)o2)nc1
Reactant: N#Cc1ccc(C[Zn+])cc1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1ccc(Cc2ccc(-c3ccc(C#N)cn3)o2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
Continuing with Scheme 7, a solution of 2 (996 mg, 4 mmol) in tetrahydrofuran (25 mL) was added palladium tetrakis(triphenyl-phosphine) (228 mg) and p-cyanobenzyl zinc bromide (12 mL, 0.5 M in THF, 6 mmol). The reaction mixture was stirred 24 h at room temperature. The mixture was diluted with dichloromethane, washed with saturated NH4Cl and the organic layer was dried over anhydrous Na2SO4. After filtration and on concentration the residue was purified by chromatography (SiO2), hexanes (100–40%)/EtOAc (0–60%), to afford 35 in 48% yield, mp 204–206° C. 1H nmr (DMSO-d6); δ 4.23 (s, 2H), 6.46 (d, J=3.3 Hz, 1H), 7.27 (d, J=3.3 Hz, 1H), 7.51 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 8.25 (dd, J=8.4 Hz, 1.8 Hz, 1H), 8.92 (d, J=1.8 Hz, 1H). 13C nmr; δ 156.3, 152.6, 150.9, 150.6, 143.2, 140.5, 132.4, 129.6, 118.6, 117.5, 117.1, 113.5, 110.3, 109.5, 106.0, 33.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([OH:33])=[C:29]([CH:32]=1)[C:30]#[N:31].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:33][C:28]4[CH:27]=[CH:26][C:25]([Cl:24])=[CH:32][C:29]=4[C:30]#[N:31])=[C:17]3[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: N#Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(Cl)cc4C#N)ncnc32)CC1
Temperature: 160 °C
Yield: 23.5 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.178 mmol), 5-chloro-2-hydroxybenzonitrile (Maybridge, Tintagel, Cornwall, UK; 28 mg, 0.178 mmol), and potassium carbonate (54 mg, 0.392 mmol) in dimethylformamide (1 mL) was heated in the microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture and the resulting precipitate was filtered through a silica gel plug, eluting with methanol. The solvent was removed and the residue was purified by HPLC to give 4-[4-(4-chloro-2-cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (19 mg, 24%) as a white solid. Mass spectrum MH+=455. 1H NMR (300 MHz, DMSO-d6) δ 1.41 (s, 9H), 1.96-2.04 (m, 4H), 2.96-3.08 (m, 2H), 4.02-4.12 (m, 2H), 4.96-5.06 (m, 1H), 7.69 (d, 1H, J=8.7 Hz), 7.94 (dd, 1H, J=2.6, 8.9 Hz), 8.25 (d, 1H, J=2.4 Hz), 8.50 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])#[N:2].N.[H][H]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]([O:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CCCC(CCC#N)Oc1cccnc1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOC(=O)CCCC(CCCN)Oc1cccnc1

Procedure:
A solution of crude ethyl 7-cyano-5-[3-pyridyloxy)-heptanoate (1.74 g) in 50 mL of methanol saturated with ammonia is subjected to hydrogenation for 5 hours at 3 atmospheres pressure of hydrogen using Raney Nickel (1.0 ml aqueous suspension) as the catalyst. The catalyst is filtered off and washed with methanol. The filtrate is evaporated and the residue filtered through a plug of silica gel using ether as eluent to remove remaining triphenylphosphine oxide. The compound is eluted from the silica gel using methanol:triethylamine (95:5). The solvent is evaporated to yield ethyl 8-amino-5-(3-pyridyloxy)-octanoate; 1H NMR (CDCl3): delta 8.28 (br,1H), 8.19 (br,1H), 4.39 (m,1H), 4.08 (q,2H).
Reaction SMILES: [H-].[Na+].C([O:10][C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1)C1C=CC=CC=1.FC(F)(F)S([O:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[CH2:28][O:29][CH2:30][CH3:31])(=O)=O.[O-]S(C(F)(F)F)(=O)=O>COCCOC>[CH2:30]([O:29][CH2:28][C:27]([F:32])([F:33])[C:26]([F:34])([F:35])[C:25]([F:36])([F:37])[CH2:24][O:23][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][CH:13]=1)[CH3:31]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOCC(F)(F)C(F)(F)C(F)(F)COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.2 %

Procedure:
2.8 g of 60% sodium hydride in mineral oil was added to 100 ml of dry 1,2-dimethoxyethane. The mixture was stirred, and 10 g (0.0499 moles) of 4-benzyloxyphenol was added. The resulting solution was stirred for 30 minutes more, then was cooled down to room temperature using an ice bath. 19 g (0.0511 moles) of 5-ethoxy-2,2,3,3,4,4-hexafluoropentyl trifluoromethanesulfonate (prepared essentially as in Example 3) was then added slowly. When the triflate addition was complete, the ice bath was removed, and the product-containing mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure, and 200 ml of water, followed by 150 ml of diethyl ether, were added sequentially with stirring. Once all of the solids had dissolved, two homogeneous liquid layers formed. The layers were separated, and the aqueous layer was extracted twice with 150 ml aliquots of diethyl ether. The resulting ether layers were then combined, were washed once with 125 ml of 1 N aqueous sodium hydroxide and twice with 150 ml aliquots of deionized water, were dried using anhydrous magnesium sulfate, and were stripped to dryness using a rotary evaporator. The resulting solid was dissolved in ethanol and was hydrogenated for 18 hours at 60 psi (3100 torr) in the presence of a 10%-palladium-on-carbon catalyst. When the hydrogenation was complete, the catalyst solid was removed by filtration, and the solvent from the filtrate was removed using a rotary evaporator. The resulting material was purified using chromatography on silica gel (2.5% methanol in chloroform) to yield 2.85 g of 4-(5-ethoxy-2,2,3,3,4,4-hexafluoropentoxy)phenol.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12](Br)=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5](Br)[CH:4]=2.F[C:20]1(F)[C:33](F)(F)[C:32]2C=C(Br)C=CC=2C2[C:21]1=[CH:22][C:23](Br)=CC=2>>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([CH2:4][CH2:3][CH2:2][CH2:15][CH2:14][CH3:9])=[CH:13][C:14]=3[C:15]=1[F:16])=[CH:7][CH:6]=[C:5]([CH2:32][CH2:33][CH2:20][CH2:21][CH2:22][CH3:23])[CH:4]=2
Reactant: FC1(F)c2cc(Br)ccc2-c2ccc(Br)cc2C1(F)F
Reactant: Fc1c(F)c2cc(Br)ccc2c2ccc(Br)cc12
Product: CCCCCCc1ccc2c(c1)c(F)c(F)c1cc(CCCCCC)ccc12

Procedure:
In analogy to Examples 1 and 2, 9,10-difluoro-2,7-dibromophenanthrene and 9,9,10,10-tetrafluoro-2,7-dibromo-9,10-dihydrophenanthrene can be reacted with other Grignard reagents to give symmetrically substituted compounds of the formula (Ia1) and (Ia2).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[NH:6]1[CH2:10][CH2:9][CH:8](OS(C2C=CC(C)=CC=2)(=O)=O)[C:7]1=[O:22]>CC(C)=O>[C:1]([O:4][CH:8]1[CH2:9][CH2:10][NH:6][C:7]1=[O:22])(=[S:3])[CH3:2]
Reactant: CC([O-])=S
Reactant: Cc1ccc(S(=O)(=O)OC2CCNC2=O)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=S)OC1CCNC1=O
Yield: 23 %

Procedure:
A mixture of 855 mg. (7.5 mmoles) potassium thioacetate and 1.27 g (5 mmoles) crude 2-pyrrolidon-3-yl-p-toluenesulfonate in 40 ml. acetone was refluxed under nitrogen for ca. 20 hr. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was partitioned between 50 ml. ethyl acetate and 50 ml. water and the ethyl acetate layer was washed with 40 ml. water and 40 ml. saturated aqueous sodium chloride solution. The ethyl acetate solution was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was chromatographed on silica gel, eluting with ethyl acetate, to yield 180 mg. (23% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29]Br)[CH:22]=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CCO>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][N:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCBr)c2)c1N
Reactant: CN1CCNCC1
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(OCCN3CCN(C)CC3)c2)c1N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To the suspension of 3-{5-amino-4-[3-(2-bromoethoxy)-benzoyl]-pyrazol-1-yl}-N-cyclopropyl-4-methyl-benzamide (24 mg, 0.05 mmol) in EtOH (1 ml) was added 1-methylpiperazine (100 mg, 1 mmol) and the mixture was stirred at 80° C. overnight. The solvent was removed, residue was dissolved in EtOAc, washed by water, dried over Na2SO4. Solvent was removed, desired product was obtained as a colorless oil (18 mg, 72%). HPLC (4 minute gradient) tR 1.33 min; MS m/z 503.29 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccc(Br)c1
Reactant: Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1
Solvent: O
Solvent: CCCO
Product: O=C(Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 46.7 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.1 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-(4-fluorophenyl)-1,8-naphthyridine (1.7 g). The product obtained by precipitation in water (2 g) is dissolved in boiling propanol (200 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with propanol (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Fluorophenyl)-1,8-naphthyridin-2-yl]-3-bromobenzamide (1.4 g), m.p. 210° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1)[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(Cl)CCl>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])=[CH:25][CH:24]=1)(=[O:27])=[O:28])=[O:6]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(S(=O)(=O)NC(=O)c2ccc(Cl)cc2Cl)cc1
Reaction time: 16 h

Procedure:
To a stirring solution of 2,4-dichlorobenzoic acid (1.25 eq) in dry dichloromethane (10 mL/mmol), 4-(tert-butyl-dimethylsiloxy)phenylsulfonamide (1.0 eq) is added in one portion followed by EDC (1.25–1.5 eq) and finally, NN-dimethyl-4-aminopyridine (1.2 equiv). The mixture is vigorously stirred under nitrogen for 16 hr, concentrated under reduced pressure, and the residue partitioned between ethyl acetate and water. The organic layer is washed with 1N hydrochloric acid (4 times, 20 mL/mmol), then the combined aqueous phases extracted with ethyl acetate (twice, 20 mL/mmol). The combined organic layers are finally washed with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography or crystallization if necessary or desired. ESI-MS m/e 458.0 (M+−H; 460.0 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[C:12]([C:18](O)=[O:19])[NH:13]3)=[CH:5][CH:4]=1.Cl.Cl.Cl.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C@@H:32]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)[CH3:33])[CH2:27][CH2:26]1>>[OH:40][CH:37]1[CH2:36][CH2:35][N:34]([C@@H:32]([CH3:33])[CH2:31][N:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:18]([C:12]3[NH:13][C:14]4[C:10]([CH:11]=3)=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH:17]=[CH:16][CH:15]=4)=[O:19])[CH2:30][CH2:29]2)[CH2:39][CH2:38]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: COc1ccc(-c2cccc3[nH]c(C(=O)O)cc23)cc1
Agent: Cl
Product: COc1ccc(-c2cccc3[nH]c(C(=O)NC4CCN(C[C@H](C)N5CCC(O)CC5)CC4)cc23)cc1

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-phenyl)-1H-indole-2-carboxylic acid, 128 (see example 141) and amine 50.
Reaction SMILES: [CH:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5](=[O:8])[CH2:6]Br)([CH3:3])[CH3:2].[C:17]1([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[C:5](=[O:8])[CH2:6][NH:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:3])[CH3:2]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1cccc(N(C(=O)CBr)C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-Isopropyl-N-(3-methoxy-phenyl) bromoacetamide, prepared as in Part B, (12.0 g 41.9 mmol), N-phenyl phenylenediamine (7.7 g, 41.9 mmol) and potassium carbonate (5.79 g) in DMF (100 mL) is stirred at RT for 20 h. The reaction mixture is filtered through celite and the filtrate diluted with ethyl acetate (150 mL) and washed with water (2×100 mL), 2N hydrochloric acid (2×100 mL), 1N aqueous sodium hydrogen carbonate (100 mL), dried (K2CO3 /MgSO4), and concentrated in vacuo. Purification by silica gel flash column chromatography using 20% ethyl acetate in hexane as eluent gave 8.2 g of N-Isopropyl-N-(3-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide as a light brown foam: 1H NMR (300 MHz, CDCl3) δ7.43 (t, 1H, J=8.0), 7.3-7.1 (m, 3H), 7.02 (m, 2H), 6.9-6.6 (m, 7H), 6.36 (d, 1H, J=7.8), 5.3 (s, br, 1H), 4.95 (m, 1H, J=6.8), 3.88 (s, 3H), 3.53 (s, 2H), 1.06 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[C:9]([N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13]O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CS([Cl:37])(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[NH:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[C:9]([N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][CH2:13][Cl:37])=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCCl)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of (R)-tert-butyl(1-(benzyl(2-hydroxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2.80 g, 8.0 mmol) in CH2Cl2 (20 mL) were added Et3N (1.60 g, 16 mmol) and MsCl (1.40 g, 12.0 mmol) dropwise at −10° C. under N2. The mixture was stirred at rt overnight. The mixture was quenched with water (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4, filtered, concentrated to afford (R)-tert-butyl(1-(benzyl(2-chloroethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (3.0 g, 100% yield) as a yellow solid, which was used for the next step without further purification. LC-MS m/z 369.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.37-7.28 (m, 3H), 7.22-7.20 (m, 2H), 5.27-5.18 (m, 1H), 4.93-4.86 (m, 1H), 4.64-4.39 (m, 2H), 3.85-3.66 (m, 2H), 3.61-3.39 (m, 2H), 2.03-1.97 (m, 1H), 1.45 (s, 9H), 0.98 (d, J=6.8 Hz, 3H), 0.93 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1>>[Cl:16][C:13]1[CH:12]=[C:3]2[C:2](=[CH:15][CH:14]=1)[N:1]=[C:24]([C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[CH:25]=[C:4]2[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CC(=O)c1ccc(F)cc1
Product: Fc1ccc(-c2cc(-c3ccccc3)c3cc(Cl)ccc3n2)cc1
Temperature: 165 °C

Procedure:
A three-necked, 2 L round-bottomed flask equipped with a thermometer, a mechanical stirrer and a distillation unit fitted with a nitrogen inlet valve was charged with 2-amino-5-chlorobenzophenone (695.0 g, 3.00 mol), and 4'-fluoroacetophenone (456.0 g, 3.30 mol), p-tosic acid (47.62 g, 0.25 mol). The reaction mixture was heated under nitrogen at 165° C. (44 h). The yellow 4'-acetophenone that co-distilled with the water was separated and reintroduced to the reaction mixture throughout the heating period. The mixture was further heated to 190° C. (2 h). The mixture was cooled to 120° C. and was poured into 95% ethanol (10 L) while vigorously stirring with a mechanical stirring rod set up. The mixture was filtered and the precipitate was washed with ethanol (1 L). The solid was dried in a vacuum oven at 80° C. (16 h). Yield 969 g, 97%; mp 141.0°-142.1° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7]CO)=[N+:2]=[N-:3].S(Cl)(C)(=O)=O.[CH3:15][S:16]([O:19][CH2:20]CN=[N+]=[N-])(=[O:18])=[O:17]>>[CH3:15][S:16]([O:19][CH2:20][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:5][CH2:6][CH3:7])(=[O:18])=[O:17]
Reactant: [N-]=[N+]=NCCCCCO
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Product: CCCC(COS(C)(=O)=O)N=[N+]=[N-]

Procedure:
Reaction of 5-azidopentanol (1.1 g, 8.53 mmol) and mesyl chloride (0.98 mL, 12.79 mmol) within 3 h as described for synthesis of 156a gave compound 156d (1.54 g) as a crude colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]12([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=5)=[CH:24]4)=[CH:19][C:18]=3[O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.O>C1COCC1>[C:7]12([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:35]=[CH:34][C:30]([C:31]([N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)=[O:32])=[CH:29][CH:28]=5)=[CH:24]4)=[CH:19][C:18]=3[O:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[CH2:16][CH:11]3[CH2:10][CH:9]([CH2:15][CH:13]([CH2:12]3)[CH2:14]1)[CH2:8]2
Reactant: C1COCCN1
Reactant: COCCOCOc1cc2ccc(-c3ccc(C(=O)Cl)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1cc2ccc(-c3ccc(C(=O)N4CCOCC4)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.8 ml (20.6 mmol) of morpholine and 40 ml of THF were introduced into a round-bottomed flask. A solution of 3.5 g (6.9 mmol) of 4-[7-(1-adamantyl)-6-methoxyethoxymethoxy-2-naphthyl]benzoic acid chloride in THF was added dropwise and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated. The solid obtained was triturated in hexane, filtered and dried. 2.8 g (74%) of the expected amide were collected, which amide had a melting point of 86°-7° C.
Reaction SMILES: [C:1]([O:11]C)(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:13][NH2:14]>CO>[C:4]1([CH2:3][CH2:2][C:1]([NH:13][NH2:14])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)/C=C/c1ccccc1
Reactant: NN
Solvent: CO
Product: NNC(=O)CCc1ccccc1

Procedure:
Methyl trans-cinnamate (1.0 g) and hydrazine (1.2 mL) were heated in methanol (25 mL) at 60° C. for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate/methanol=95/5)to obtain a mixture of the entitled compound and an olefin-unreduced compound (2/1) (499 mg).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][C:17]=1[O:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][C:17]=1[O:24][CH2:25][CH:26]1[CH2:28][CH2:27]1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)c(OCC2CC2)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)c(OCC3CC3)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-3-(cyclopropylmethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.36-0.40 (2H, m), 0.62-0.67 (2H, m), 1.25-1.32 (1H, m), 3.88 (2H, d, J=6.8 Hz), 5.18 (2H, s), 5.72 (1H, d, J=1.6 Hz), 6.92 (1H, dd, J=4.0 Hz, 8.0 Hz), 7.01 (1H, d, J=1.6 Hz), 7.37 (1H, d, J=8.0 Hz), 7.40 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.56 (1H, d, J=2.0 Hz), 8.04 (1H, s), 8.68 (1H, d, J=5.2 Hz). [M+H] Calc'd for C20H17ClN4O2, 381; Found, 381.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[O:16][C:17]3[C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[CH3:2].C1N=[CH:35][N:34](C(N2C=NC=C2)=O)[CH:33]=1.CNC.C(O)C>CN(C=O)C>[CH3:33][N:34]([CH3:35])[C:24]([C:23]1[C:17]2[O:16][C:15]([NH:14][CH:11]3[CH2:10][CH2:9][N:8]([CH2:7][C:6]4[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=4)[CH2:13][CH2:12]3)=[N:19][C:18]=2[CH:20]=[CH:21][CH:22]=1)=[O:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1cc(CN2CCC(Nc3nc4cccc(C(=O)O)c4o3)CC2)ccc1OC
Agent: CNC
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOc1cc(CN2CCC(Nc3nc4cccc(C(=O)N(C)C)c4o3)CC2)ccc1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To the crude coupling product 2-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-benzo-oxazole-7-carboxylic acid (42.5 mg, 0.1 mmol, 1.0 equiv) dissolved in anhydrous DMF (1 mL) was added CDI (32.4 mg, 0.2 mmol, 2.0 equiv) and the reaction mixture stirred at 50° C. After 1 h, a solution of dimethylamine 5.6 M in ethanol (71 μL, 0.4 mmol, 4.0 equiv) was added and the reaction mixture stirred at 50° C. for another 24 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 9.0 mg (20%) of the title compound. MS (ESI): 452.0 [M+H]+.
Reaction SMILES: S([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]2[C:13]=1C(OCC)=O)(C)(=O)=O.[CH:19]([SH:22])([CH3:21])[CH3:20]>>[CH:19]([S:22][C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]2[CH:13]=1)([CH3:21])[CH3:20]
Reactant: CC(C)S
Reactant: CCOC(=O)c1c(S(C)(=O)=O)nc2ccccn12
Product: CC(C)Sc1cn2ccccc2n1

Procedure:
In a manner similar to the procedure in Reference Example 1, the oily title compound was prepared from ethyl 2-mesylimidazo[1,2-a]pyridine-3-carboxlate and isopropyl mercaptan. ##STR11##