Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17](I)[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])[C:8](=[O:11])[O:9][CH3:10].[C:40]([Cu])#[N:41].O>CN(C=O)C>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:40]#[N:41])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])[C:8](=[O:11])[O:9][CH3:10]
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(I)ccc1-c1cc(C(C)C)ccc1OC
Reactant: N#C[Cu]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C#N)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl [3,5-bis(trifluoromethyl)benzyl][(4-iodo-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]carbamate from Example 10 (0.03 g, 0.045 mmol) and CuCN (0.008 g, 0.09 mmol) in DMF (1 ml) was stirred at 100° C. overnight. Water (10 ml) was added and the mixture was extracted with EtOAc (3×15 ml). The combined EtOAc layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after preparative thin layer chromatography using 2:8 EtOAc/hexane as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.72 (s, 1H), 7.74 (m, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.49 (m, 1H), 7.38 (m, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.28 (m, 1H), 6.94 (d, J=2.5 Hz, 1H), 6.91 (m, 1H), 4.26-4.49 (m, 4H), 3.81 (m, 3H), 3.70 (s, 3H), 2.92 (m, 1H), 1.22 (s, 6H). LC-MS (M+1) 565.3 (4.42 min).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:48]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:50])[CH3:49]>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([N:54]6[CH2:55][CH2:56][N:51]([C:48](=[O:50])[CH3:49])[CH2:52][CH2:53]6)=[N:7][CH:6]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: CC(=O)N1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(Cl)nc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(N4CCN(C(C)=O)CC4)nc3)cn2)cc1
Yield: 52.6 %

Procedure:
Using {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.307 mmol) obtained in Step A in Example 1-D-48 and N-acetylpiperazine (59 mg, 0.461 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Example 1-D-48, amination was carried out, to obtain a crude product of 1-{4-[5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-piperazin-1-yl}-ethanone as a yellow solid (120 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-109) as a yellow powder (46 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]([CH3:29])[C:20]1=[O:30]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]([CH3:29])[C:20]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CN1Cc2ccccc2C(N)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(C)Cc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 174-175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14](Br)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:21][NH:22][CH3:23]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][CH3:19])[N:15]=[C:14]([N:22]([CH3:23])[CH3:21])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Br)n1
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(N(C)C)n1
Yield: 8 %

Procedure:
2.5 g (0.007 mol) of 4-amino-N-(2-bromo-6-methylamino-pyridin-4-yl)-benzenesulfonamide were stirred with 80 ml of dimethylamine in an autoclave at 160° C. for 7 hours. The residual dimethylamine was left to evaporate and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1, then 2:1 and finally 3:1. The polar fractions were chromatographed twice on silica gel with ethyl acetate/hexane 2:3 and 1:1 as the eluent. There was obtained 0.175 g (8%) of 4-amino-N-(2-dimethylamino-6-methylamino-pyridin-4-yl)-benzenesulfonamide as beige crystals: MS (ISP): me/e=322 (C14H20N5O2S+).
Reaction SMILES: [N:1]1([C:10]2[S:14][C:13]([C:15]([O:17]C)=O)=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[NH3:32]>CO>[N:1]1([C:10]2[S:14][C:13]([C:15]([NH2:32])=[O:17])=[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[CH:11]=2)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)(F)F
Temperature: 125 °C
Reaction time: 4 h

Procedure:
A mixture of 26.8 mg of methyl 5-(1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethoxy)benzyl]oxy}thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol is stirred in a microwave vial at 125° C. for 4 h in the microwave cavity. The reaction mixture is concentrated to dryness, the resulting residue is dissolved in ethyl acetate and purified by flash chromatography [Silica gel, eluent: ethyl acetate/methanol, elution gradient of 100/0 (v/v) to 95/5 (v/v)] to yield the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-])(=[O:3])[CH3:2].S(OC)(OC)(=O)=O.[C-:20]#[N:21].[K+]>CS(C)=O>[C:1]([NH:4][CH2:5][C:6]1[N:7]=[C:8]([C:20]#[N:21])[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)NCc1cccc[n+]1[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CS(C)=O
Product: CC(=O)NCc1cccc(C#N)n1
Reaction time: 3 h
Yield: 15.2 %

Procedure:
A mixture of 2-acetylaminomethylpyridine N-oxide (1.00 g) and dimethyl sulfate (0.63 ml) was stirred for three hours. Dimethyl sulfoxide (6 ml) and potassium cyanide (392 mg) were added to the mixture and the solution was stirred for two hours at ambient temperature. Additional potassium cyanide (392 mg) was added to the mixture and which was further stirred for two hours. After the solvent was removed by concentration, the residue was mixed with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (15 g) by eluting with a mixture of ethyl acetate and methanol (20:1) to give 6-acetylaminomethyl-2-pyridinecarbonitrile (0.16 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[OH-].[Na+]>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(CN2CCN(c3ccnc4[nH]ccc34)CC2)cc1
Yield: 81.3 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.50 g, 16.4 mmol) and N-benzyl piperazine (3.18 g, 18.0 mmol) were melted at 175° C. for 3 hours in a sealed tube, resulting in the formation of a crystalline solid mass. A solution of 0.1 M aqueous NaOH (10 mL) was added and the solid was broken up to give a suspension. Filtration gave 4-(4-benzyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine as a white solid (3.90 g). LCMS (APCI+) m/z 293 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:73]([SH:80])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:73]([S:80][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.98 g, 34.47 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (8.86 g, 68.94 mmol). Then Pd2(dba)3 (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and BnSH (4.48 g, 36.19 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere and then allowed to warm to ambient temperature. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (white solid, 12.44 g, 86.0% yield). 1H NMR (400 MHz, CDCl3): δ 9.19 (s, 1H), 7.79 (dd, 1H), 7.41 (dd, 1H), 7.24 (m, 5H), 7.18 (m, 1H), 7.00 (m, 1H), 6.87 (m, 1H), 4.08 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)cc4)CC3)nn2-c2ccccc2)cc1

Procedure:
77 mg (65%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (70 mg, 0.225 mmol), 1-(4-chlorophenyl)piperazine (61 mg, 0.225 mmol), DIPEA (0.059 mL, 0.338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>C(O)C>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: COCCN
Solvent: CCO
Product: COCCNc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1
Reaction time: 3 h

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 3.0 ml of ethanol were added 25.6 mg (0.337 mmol) of 2-methoxyethylamine, and then the reaction mixture was stirred at 60 for 3 h. Another 51.2 mg (0.674 mmol) of 2-methoxyethylamine were added, and the mixture was stirred at 60° C. for a further 12 h. This was followed by stirring in the microwave at 80° C. for a further 24 h and then at 120° C. for 45 min. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 15.3 mg (12% of theory)
Reaction SMILES: [Cl-:1].[CH2:2]([N+:9]12[CH2:16][C:13]([OH:17])([CH2:14][CH2:15]1)[CH2:12][CH2:11][CH2:10]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:21][CH3:22]>CN(C=O)C>[Cl-:1].[CH2:2]([N+:9]12[CH2:16][C:13]([O:17][CH2:21][CH3:22])([CH2:14][CH2:15]1)[CH2:12][CH2:11][CH2:10]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OC12CCC[N+](Cc3ccccc3)(CC1)C2
Reactant: CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC12CCC[N+](Cc3ccccc3)(CC1)C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 1-benzyl-5-hydroxy-1-azoniabicyclo[3.2.1]octane chloride (D7a, 3.05 g, 0.012 mole) in dry DMF (100 ml) under nitrogen was treated with sodium hydride (600mg of 80% oil dispersion, 0.020 mole) and stirred at room temperature for 40 min. The mixture was then treated with bromoethane (4.7 ml, 0.063 mole) and stirred at room temperature for 16h. The excess sodium hydride was destroyed by addition of ethanol (5 ml) and the mixture acidified with glacial acetic acid (5 ml) and then concentrated in vacuo to give an orange semi-solid containing the title compound (D8). This was used in the next step without any purification.
Reaction SMILES: [OH:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][CH:2]1[C:7]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])=[CH:6][CH2:5][N:4]([CH3:20])[CH2:3]1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1
Product: COc1cc(OC)c(C2=CCN(C)CC2OC(C)=O)c(OC)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2.79 g (10 mmol) of 3(R,S)-hydroxy-1-methyl4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine (VII) were dissolved in 15 ml of acetic anhydride and stirred at 100° C. for 4 h. The solution was then evaporated in vacuo in a rotary evaporator and the residue was dissolved in 10 ml of water, adjusted to pH >12 with sodium hydroxide solution and extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were washed with 10 ml of saturated sodium chloride solution, then dried over sodium sulfate and evaporated in vacuo on a rotary evaporator.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]([NH2:7])=[CH:5][CH:6]=1.[CH2:10]=[CH:11][C:12](=[CH2:14])[CH3:13]>CCCCC>[CH3:14][C:12]([CH3:13])=[CH:11][CH2:10][C:5]1[CH:6]=[C:1]([CH3:9])[C:2]([NH2:8])=[CH:3][C:4]=1[NH2:7]
Reactant: Cc1ccc(N)cc1N
Reactant: C=CC(=C)C
Solvent: CCCCC
Product: CC(C)=CCc1cc(C)c(N)cc1N

Procedure:
A 200g (1.64 mol) portion of 2,4-toluenediamine, 167g (2.45 mol) of isoprene, 200g (2.78 mol) pentane, and 20g of catalyst comprised of 13% alumina and 87% silica were reacted at 200° C. in a similar fashion as indicated in Example 5. Isolation of catalyst free sample was accomplished by hot filtration. Selective removal of all residual low boiling hydrocarbons by vacuum distillation afforded the following product mixture:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([CH2:11][Br:19])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc2ccsc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc(Br)cc2ccsc12
Temperature: 0 °C
Yield: 51.1 %

Procedure:
The thiophene (10.16 g, 1.0 equiv), NBS (8.76 g, 1.1 equiv), and benzoyl peroxide (0.54 g, 0.05 equiv) were dissolved in CCl4, heated to reflux under UV irradiation for 2 hr and then cooled to 0° C. and filtered. The filtrate was evaporated. Repeated trituration with hexane gave 5-bromo-7-bromomethyl-benzo[b]thiophene (7.0 g). Concentration of the hexane gave an oil which was purified by column chromatography (SiO2, hexane) to give additional product (total yield 9.96 g, 86%).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:13](#[N:16])[CH:14]=[CH2:15]>>[C:13]([C:14]1[CH2:15][O:12][C:3]2[C:4]([CH:5]=1)=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=2[F:1])#[N:16]
Reactant: COc1ccc(F)c(O)c1C=O
Reactant: C=CC#N
Product: COc1ccc(F)c2c1C=C(C#N)CO2
Yield: 13.6 %

Procedure:
Crude 3-fluoro-hydroxy-6-methoxybenzaldehyde (8.0 g) from above, acrylonitrile (13 mL; 193 mmol) and 1,4.diazadicyclo [2,2,2]octane (0.66 g; 5.9 mmol) were refluxed in a three-necked round-bottom flask (50 mL) under nitrogen for 4 h. Rotary-evaporation of the volatiles left a thick, red oil which was flash-chromatographed on a silica column eluted with methylene chloride/n-hexane (4:5). Concentration of relevant fractions gave an impure product (91% GC) which was crystallized form EtOAc to give 1.31 g of the title compound as colourless bars. Mp. 133°-135° C.
Reaction SMILES: [CH:1]1([C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH:3]=[CH:2]1>C1CCCCC1.[Pt]>[C:7]([O:9][CH3:10])(=[O:8])[C:4]1[CH:5]=[CH:6][C:1]([C:11]([O:13][CH3:14])=[O:12])=[CH:2][CH:3]=1
Reactant: COC(=O)C1C=CC(C(=O)OC)CC1
Agent: [Pt]
Solvent: C1CCCCC1
Product: COC(=O)c1ccc(C(=O)OC)cc1
Temperature: 150 °C

Procedure:
In a Parr pressure reactor, dimethyl cyclohex-2-ene-1,4-dicarboxylate (2.42 g, 12.2 mmol) is dissolved in cyclohexane (120 ml, 0.10 M) and a catalytic amount of platinum on carbon (476 mg, 5 percent Pt/C, 1 mole percent platinum) powder is added. The reactor is pressurized with air (240 psi (1.65 MPa) at 23° C. after saturation of the solution) and its contents are heated at a 150° C. set-point temperature for 3 days under rapid stirring (160 rpm). After opening the cooled Parr reactor, a suspension of black platinum on carbon (Pt/C) in a near colorless solution is present. All solvent is removed from a sample of the suspension, and the entire residue is dissolved in CDCl3 for 1H NMR analysis. Integration of the respective resonances shows the presence of about 23 percent unreacted dimethyl cyclohex-2-ene-1,4-dicarboxylate starting material, of about 59 percent dimethyl terephthalate oxidation product, and of about 18 percent dimethyl cyclohexane-1,4-dicarboxylate disproportionation by-product. Column chromatography (Si35, SF40-150 g, AnaLogix column with 10 percent ethyl acetate/hexane isocratic eluent) provides pure dimethyl terephthalate.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:13](C1CCC(=O)CC1)([CH3:16])([CH3:15])[CH3:14].N1CCOCC1>C1CCCCC1>[C:13]([CH:4]1[CH2:5][CH2:6][C:1]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:2][CH2:3]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: CC(C)(C)C1CCC(=O)CC1
Solvent: C1COCCN1
Solvent: C1CCCCC1
Product: CC(C)(C)C1CC=C(N2CCOCC2)CC1

Procedure:
Compound III′ (white solid) is obtained quantitatively according to Example 1, from 4-tert-butylcyclohexanone (77.12 g, 0.50 mol), morpholine (54.01 g, 0.62 mol) and cyclohexane (60 mL).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10]2)=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[CH:2].C(O)(=O)C1C=CC=CC=1.[CH2:31]([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][C:38](I)=[CH:37][CH:36]=1)[CH3:32]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:38]3[CH:39]=[CH:40][C:35]([C:34]([O:33][CH2:31][CH3:32])=[O:42])=[CH:36][CH:37]=3)=[CH:4][C:5]=2[CH2:20][CH3:21])[CH2:11][CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 90.0 mg, 0.33 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 100.0 mg (72%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([Mg]Br)[CH3:29].O>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[C:9]([CH:10]([OH:11])[CH2:28][CH3:29])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nccc(Oc3ccc(C(C)(C)C)cc3C=O)c2cc1OC
Reactant: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1cc(C(C)(C)C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(Tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{5-(tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].C(N(CC)CC)C.Cl[P:16]([O:22][CH2:23][CH2:24][C:25]#[N:26])[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:25]([CH2:24][CH2:23][O:22][P:16]([C:4]1[NH:3][C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=1)[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)#[N:26]
Reactant: N#CCCOP(Cl)N1CCCC1
Reactant: Clc1nc[nH]c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCOP(c1nc(Cl)c(Cl)[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a stirred solution of 4,5-dichloroimidazole (1.59 g, 11.63 mmol) and triethylamine (1.95 mL, 1.41 g, 13.96 mmol) in CH2Cl2 (30 mL) was added dropwise Chloro(2-Cyanoethoxy) pyrrolidinophosphine (2.40 g, 11.63 mmol) in CH2Cl2 (10 mL) at room temperature. The mixture was stirred for 4 h at room temperature. The reaction mixture was filtered to remove the resulting salt, and the solvent was removed under reduced pressure to give the crude product as a pale yellow oil (2.93 g, 82%). 31P NMR (CDCl3) δ 123.2.