Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.CN(C=O)C.[C:26]([CH:28]=[CH:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)#[N:27].C1CCN2C(=NCCC2)CC1>CCOC(C)=O>[C:26]([CH2:28][CH:29]([CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)[N:15]1[CH:14]=[C:13]([C:11]2[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:12]=2)[CH:17]=[N:16]1)#[N:27]
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C=CC#N)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CCN(C(=O)OC(C)(C)C)CC4)c3)n2)cn1
Temperature: 45 °C
Yield: 61.9 %

Procedure:
To 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation K; 50 mg, 0.19 mmol) was added DMF (950 μL, 0.19 mmol), tert-butyl 4-(2-cyanovinyl)piperidine-1-carboxylate (Table 1, compound 1; 67 mg, 0.28 mmol) and DBU (185 μL, 1.3 mmol). The reaction mixture was heated to 45° C. for 8 hours, then diluted in EtOAc and washed with water and brine. The organic layer was dried with MgSO4, filtered and concentrated down to a yellow oil. Purification of the resulting crude material by reverse phase HPLC using a 0-100% acetonitrile/water gradient afforded tert-butyl 4-(2-cyano-1-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)piperidine-1-carboxylate (59 mg, 62% yield). MS (apci) m/z=502.2 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH2:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:20][C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24].O1CCOCC1.C1(C)C=CC=CC=1>O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][C:21]1[N:10]=[C:8]([C:7]2[CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[O:9][CH:20]=1
Reactant: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Reactant: COC(=O)CC(=O)CCl
Solvent: C1COCCO1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1coc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 46.3 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzamide (5.0 g, 20.0 mmol), methyl 4-chloroacetoacetate (3.01 g, 20.0 mmol), dioxane (30 mL), and toluene (300 mL) was refluxed for 5 days, with continuous water removal (Dean Stark trap). The volatiles were removed in vacuo and the residue waspurified by flash chromatography on silica gel (eluting solvent: hexane/EtOAc 3/1) to give a brown viscous oil (3.2 g). Crystallization of the brown oil from ethyl ether (after cooling to 0° C.) gave a white solid (2.6 g, 38% yield), m.p. 126°-128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5])=[O:24])(=[O:20])[CH3:19]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cccc(N)c1C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(NC(=O)COC(C)=O)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-methoxybenzonitrile (3.7 g) in methylene chloride (50 ml) is added pyridine (2.4 ml), and thereto is added dropwise acetoxyacetyl chloride (2.7 ml) which is cooled in an ice bath. The mixture is stirred at room temperature for 1 hour, and thereafter, the solvent is distilled off under reduced pressure. The resulting crude crystals are washed with water and ether and then are recrystallized from ethanol to give the title compound (5.4 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH:13]([NH2:17])[CH2:12][CH:11]1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:4].[O:30]([CH2:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:16])[CH2:14][CH:13]([NH:17][C:38](=[O:39])[CH2:37][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:12][CH:11]1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CC(N)CC1C1CCCCC1
Reactant: O=C(Cl)COc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CC(NC(=O)COc2ccccc2)CC1C1CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
To a solution of 3-(4-amino-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylic acid methyl ester (30 mg, 0.073 mmol, 1.0 equiv) in DCM (1.0 mL) at 0° C. was added phenoxyacetyl chloride (0.02 ml, 0.145 mmol, 2.0 equiv) and TEA (0.02 mL). The resulting mixture was then stirred at 0° C. for 20 minutes after which the solvent was removed under vacuum. The residue was purified by silica gel column chromatography (EtOAc/hepatane 10%˜80%) to give product (20 mg). MS: 547 [M+H+].)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[CH3:12].[CH3:13][C:14]1[C:18]([CH3:19])=[C:17]([CH3:20])[NH:16][N:15]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:15]2[C:14]([CH3:13])=[C:18]([CH3:19])[C:17]([CH3:20])=[N:16]2)=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: Cc1n[nH]c(C)c1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1ccc(-n2nc(C)c(C)c2C)cc1C
Yield: 52.6 %

Procedure:
A mixture of 4-methoxy-3-methyl-phenylboronic acid 10 g, 3,4,5-trimethyl-1H-pyrazole (described in Reference Preparation example 49) 7.3 g, copper(II) acetate 18.4 g, pyridine 10.0 g, molecular sieves 4 A 20.0 g and acetonitrile 300 ml was stirred with heating under reflux for thirty hours. The reaction mixture was filtered through Celite and was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(4-methoxy-3-methyl-phenyl)-3,4,5-trimethyl-1H-pyrazole 7.3 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[O:30][C:31]=1[CH3:32])[CH2:7][O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[CH3:2].[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)[O:30][C:31]=1[CH3:32])[CH2:7][O:8][C:9]1[C:13](/[CH:14]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:12][N:11]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1)[CH3:2]
Reactant: CCOc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(COc2nn(-c3ccccc3)cc2/C=C/P(=O)(OCC)OCC)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 15 h
Yield: 60.9 %

Procedure:
To a mixture of 3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.44 g), tetraethyl methylenediphosphonate (0.31 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.34 g, yield 55%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][N:16](CCC4C=CN=C(OC)C=4)[CH2:15][CH2:14]3)[S:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:30]1SN=C(C2C=CN=C(Cl)C=2)N=1.Br[CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:30][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH2:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:17][CH2:18]3)[S:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(CCN2CCN(c3nc(-c4ccnc(Cl)c4)ns3)CC2)ccn1
Reactant: Clc1cc(-c2nsc(Cl)n2)ccn1
Reactant: BrCCc1ccccc1
Product: Cc1cc(-c2nsc(N3CCN(CCc4ccccc4)CC3)n2)ccn1

Procedure:
In analogy to the procedure described for the synthesis of 3-(2-chloropyridin-4-yl)-5-(4-(2-(2-methoxypyridin-4-yl)ethyl)piperazin-1-yl)-1,2,4-thiadiazole (Example 168), the tile compound was prepared from 5-chloro-3-(2-chloropyridin-4-yl)-1,2,4-thiadiazole and (2-bromo ethyl)benzene.
Reaction SMILES: N#N.[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13](=[O:18])C(Cl)(Cl)Cl)=[CH:10][CH:9]=[CH:8][C:7]=2[O:19][CH3:20].[OH-:21].[K+].Cl.[CH3:24]O>>[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]([O:18][CH3:24])=[O:21])=[CH:10][CH:9]=[CH:8][C:7]=2[O:19][CH3:20]
Reactant: CO
Reactant: [OH-]
Reactant: COc1cccc2c(C(=O)C(Cl)(Cl)Cl)c(C)[nH]c12
Agent: Cl
Agent: N#N
Agent: [K+]
Product: COC(=O)c1c(C)[nH]c2c(OC)cccc12
Temperature: 25 °C
Yield: 96 %

Procedure:
To a 1 L round-bottomed flask equipped with a magnetic stirrer and a N2 bubbler were added 2-methyl-3-trichloroacetyl-7-methoxyindole (22.8 g, 74.37 mmol) and MeOH (150 mL). The mixture was stirred at RT to give a slurry. KOH (42.5 wt %, 2 mL) was added and the reaction stirred for 5 min. HCl (0.1N, 500 mL) was added dropwise. The slurry was stirred at RT for 1 h and filtered. The cake was washed with DI water (3×30 mL) and suction dried for 18 h to give 2-methyl-3-methoxycarbonyl-7-methoxyindole (15.57 g, 96% yield). 1H NMR (CDCl3) δ2.71 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 6.63 (d, J=7.9 Hz, 1H), 7.12 (dd, J=7.9, 8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 8.84 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:23][NH2:24]>O>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:20])[NH:23][N:24]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CCC(=O)c1ccc(CCCn2ccnc2)cc1
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccc(CCCn3ccnc3)cc2)=NN1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
2 g of 4-{4-[3-(1-imidazolyl)-propyl]-phenyl}-4-oxo-butyric acid are suspended in 10 ml of water, 0.68 g of hydrazine hydrate are added and the mixture is then stirred at 90° C. for 2 hours. After the mixture has been cooled, it is extracted with chloroform and the chloroform solution is washed with water, dried over Na2SO4 and concentrated to dryness.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:24]1[C:25]([NH2:32])=[N:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>COCCOC.O.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>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH2:32])[C:24]=1[C:17]1[CH:18]=[CH:19][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1ccnc(N)c1I
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: COCCOC
Solvent: O
Product: COc1ccnc(N)c1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A mixture of sodium carbonate (122 mg), tetrakis(triphenylphosphine)palladium(0) (33.2 mg), 4-phenoxyphenylboronic acid (160 mg) and 3-iodo-4-methoxypyridin-2-amine (144 mg) in DME (10 mL) and water (3 mL) was stirred at 80° C. overnight. The mixture was added with silica gel, concentrated in vacuo, and purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (124 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:18]=[C:11]3[N:12]=[C:13]([CH3:17])[CH:14]=[C:15]([OH:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:19]Br>C(Cl)Cl>[BrH:19].[Br:19][C:14]1[C:13]([CH3:17])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:18]=2)[C:15]=1[OH:16]
Reactant: Cc1cc(O)n2nc(-c3cccc(Cl)c3)cc2n1
Reactant: BrBr
Solvent: ClCCl
Product: Br
Product: Cc1nc2cc(-c3cccc(Cl)c3)nn2c(O)c1Br
Reaction time: 1 h
Yield: 193.4 %

Procedure:
To a stirred slurry of 2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (8.83 g, 34 mmol) in CH2Cl2 (150 mL) was added added dropwise a solution of bromine (1.804 ml, 35.0 mmol) in CH2Cl2 (50 mL) over 15 min. After 1 h, the reaction mixture was concentrated to give 6-bromo-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol, hydrobromide (14.2 g) as brown solid. LCMS of this solid showed presence of unreacted material and two new products, the expecteded monobrominated and dibrominated products. So, this solid resuspended in MeOH/CH2Cl2 (1:1, 100 mL) and a solution of briomine in CH2Cl2 (1.4 mL) was added over 5 min. After 1 h, the reaction mixture was concentrated and the resulting tan solid was used in the next step without purification. To the above crude product was added N,N-diethylaniline (16.23 ml, 102 mmol) and POCl3 (47.5 ml, 510 mmol) and the mixture was stirred at 120° C. for 16 h. Then, cooled, concentrated and the dark residue taken up in EtOAc (250 mL) and stirred with ice-water for 30 min. Aqueous layer separated and organic layer washed with water (2×50 mL). The combine aqueous layers extracted with EtOAc (100 mL) and the combine organic layers washed with brine (50 mL), dried (Na2SO4/C), filtered and concentrated to give dark paste. Purification by flash column chromatography on silica gel column using 5-10% EtOAc/Hex/5% CH2Cl2 (2.5% increment/lit) provided 6-bromo-7-chloro-2-(3-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine (2.003 g, 5.61 mmol, 16.50% yield) as pale yellow solid. 1H NMR (500 MHz, CDCl3) δ: 8.00 (s, 1H), 7.89-7.83 (m, 1H), 7.43-7.36 (m, 2H), 6.94 (s, 1H), 2.78 (s, 3H). LCMS (M+H) calcd for C13H9BrCl2N3: 355.94. found: 358.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27](Br)[CH:26]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].IC.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C2(c3ccc(O)c(Br)c3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc(C2(c3ccc(O)cc3)N=C(NC(=O)OC(C)(C)C)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.8 %

Procedure:
To a solution of [3,3-bis-(4-hydroxy-phenyl)-3H-isoindol-1-yl]-carbamic acid tert-butyl ester (Scheme #2, C) (5.0 g, 12.0 mmol) and cesium carbonate (3.9 mL, 12.0 mmol) in N,N-dimethyl formamide (100 mL) was added iodomethane (0.7 mL, 11.4 mmol) in N,N-dimethyl formamide (3 mL) and the mixture stirred at ambient temperature for 18 hours. The N,N-dimethyl formamide was removed under reduced pressure to yield an amber syrup. To this was added ethyl acetate (250 mL) and the mixture stirred vigorously for 0.5 h. The insolubles were filtered and the filtrate concentrated under reduced pressure to yield a tan solid. The crude compound was purified using flash chromatography (silica; 90:10 dichloromethane:ethyl acetate) to give the title compound as a white solid (2.11 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ 7.83 (d, J=7.5 Hz, 1 H), 7.64 (t, J=7.3 Hz, 1 H), 7.55-7.49 (m, 2 H), 7.16 (d, J=8.8 Hz, 2 H), 7.04 (d, J=8.6 Hz, 2 H), 6.89 (d, J=8.8 Hz, 2 H), 6.71 (d, J=8.7 Hz, 2 H), 3.71 (d, J=8.3 Hz, 3 H), 1.46 (s, 9 H); MS (APCI+) m/z 430 [M+1]+; tR=2.20 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([NH:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C:17]#[N:16])=[CH:19][CH:20]=1)=[O:13]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COc1ccc(C(OC)C(=O)O)c(Cl)c1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(Cl)c1

Procedure:
(RS)-(2-Chloro-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-2-(2-chloro-4-methoxy-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow oil. MS 345.2 ([M+H]+)
Reaction SMILES: [CH:1]1([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[ClH:13]>C(O)(=O)C>[Cl:13][CH2:3][CH2:2][CH:1]=[CH:4][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: OC(c1ccc(F)cc1)C1CC1
Reactant: Cl
Solvent: CC(=O)O
Product: Fc1ccc(C=CCCCl)cc1

Procedure:
Reduction of cyclopropyl 4-fluorophenyl ketone by reaction with sodium borohydride gave cyclopropyl-4-fluorophenylcarbinol. Reaction of the cyclopropyl carbinol with hydrogen chloride in acetic acid effected opening of the cyclopropyl ring, chlorination and dehydration to afford 1-chloro-4-(4-fluorophenyl)-3-butene. The chlorobutene was reacted with dimethylamine in ethanol at 100° C. for forty-eight hours to provide N,N-dimethyl-4-(4-fluorophenyl)-3-butenylamine. A solution of 54.4 g. of the butenylamine in 343 ml. of ethanol containing 2.5 g. of Raney Nickel was hydrogenated to provide 47.71 g. of N,N-dimethyl-4-(4-fluorophenyl)butylamine. B.P. 115°-118° C. at 12 torr.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:34][CH:35]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(C2CCCCC2)cc1

Procedure:
The title compound, white solid (114 mg, 89%), MS (ISP) m/z=513.6 [(M+H)+], mp 230° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-cyclohexyl-benzoic acid.
Reaction SMILES: [Br:1][CH2:2][C:3]1([CH2:11][OH:12])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5][CH2:4]1.N1C=CN=C1.[Cl-].[C:19]([SiH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:22])([CH3:21])[CH3:20].[Cl-].[NH4+]>CN(C)C=O>[Br:1][CH2:2][C:3]1([CH2:11][O:12][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:4][O:5][C:6]([CH3:9])([CH3:10])[O:7][CH2:8]1
Reactant: CC1(C)OCC(CO)(CBr)CO1
Reactant: CC(C)(C)[SiH](c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC1(C)OCC(CBr)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.4 %

Procedure:
1.1 g (4.6 mmol equivalents) of 5-bromomethyl-2,2-dimethyl-5-hydroxymethyl-1,3-dioxane was dissolved in 23 mL of dimethylformamide, 626 mg (9.2 mmol equivalents) of imidazole and 1.43 mL (5.5 mmol equivalents) of t-butyldiphenylsilane chloride were added thereto, and the mixture was stirred at room temperature (25° C.) for 5 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added dropwise, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate, and subsequently concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=20/1) to give 1.70 g (3.56 mmol equivalents) of 5-bromomethyl-5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-1,3-dioxane.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=O)[C:8]([OH:19])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[ClH:17].[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=2)[C:8]([OH:19])=[C:7]([CH2:20][NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(Cl)c(F)c2)c1
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(Cl)c(F)c2)c1O
Product: Cl

Procedure:
5-(tert-Butyl)-3-((tert-butylamino)methyl)-4′-chloro-3′-fluoro-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 5-(tert-butyl)-4′-chloro-3′-fluoro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([CH3:10])[C:8]#[N:9].N>O>[CH3:10][C:7]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)([CH3:6])[C:8]([NH2:9])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C#N)N1CCOCC1
Agent: N
Solvent: O
Product: CC(C)(C(N)=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
272 ml of concentrated sulfuric acid are slowly added, with stirring, to 57.9 g of 2-methyl-2-morpholino-propionitrile (exothermic reaction). After the addition of 43 ml of water, the mixture is stirred for 2 hours at 100°-110° C. The reaction mixture is cooled to 50° C. and added dropwise at 0° C. to a solution of 846 ml of 20% ammonia in 242 ml of water. The mixture is then extracted repeatedly with dichloromethane. The organic phases are washed with saturated sodium chloride solution and with sodium sulfate. The crude title compound is obtained from the concentrated filtrate: 1H NMR (CDCl3), δ(ppm)=7.08 (1H, bs), 5.38 (1H, bs), 3.72(4H, m), 2.53 (4H, m), 1.22(6H, s)
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](N2CCCCC2)=[CH:7]1)[CH3:2].[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH2:33][CH2:34]Cl>>[CH3:21][O:22][C:23](=[O:36])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[O:32][CH2:33][CH2:34][N:11]1[CH2:12][CH2:13][CH:14]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:7]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)c1ccc(OC)cc1OCCCl
Reactant: CCOCCn1cc(N2CCCCC2)c2cccnc21
Product: CCOCCn1cc(C2CCN(CCOc3cc(OC)ccc3C(=O)OC)CC2)c2cccnc21
Yield: 87.6 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 3 g (10.9 mmol) of 1-(2-ethoxyethyl)-3-piperidin yl-1H-pyrrolo[2,3-b]pyridine and 4 g (16.5 mmol) of 2-(2-chloroethoxy)-4-methoxy-benzoic acid methyl ester. After standard work-up and purification, 2.3 g (44% yield) of 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidin-1-yl}-ethoxy)-4-methoxy-benzoic acid methyl ester were obtained.