Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1.[CH2:32]([N:34](CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.Cl.CN>C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:5]2[CH2:11][C:10]([F:13])([F:12])[C:9](=[O:14])[N:8]([CH3:15])[C:7]3[CH:16]=[N:17][C:18]([NH:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([NH:34][CH3:32])=[O:27])=[CH:23][C:22]=4[O:30][CH3:31])=[N:19][C:6]2=3)[CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCC1)CC(F)(F)C(=O)N2C
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCC2)CC(F)(F)C(=O)N3C)c(OC)c1
Reaction time: 0.25 h
Yield: 50.6 %

Procedure:
A mixture of 0.100 g (0.23 mmole) of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-1), 0.092 g (0.92 mmole) of triethylamine, 0.148 g (0.39 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.023 g (0.35 mmole) of methylamine hydrochloride was added. The mixture was stirred for 3 hours, then taken up in 100 mL of ethyl acetate and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (gradient 100:0:0-92:8:0.3) to give 0.052 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-3).
Reaction SMILES: [O:1]=[C:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[Cl:19][CH:3]([C:2](=[O:1])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)Cc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)Cc1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Ethyl 3-oxo-4-phenylbutyrate (4.8 g, 23 mmol) and methylene chloride (48 ml) were mixed, and sulfuryl chloride (3.1 g, 1 equivalent) was gradually added thereto dropwise. After the addition, the mixture was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added, and extraction was carried out with ethyl acetate (20 ml). The solvent was evaporated away under reduced pressure and drying was carried out in vacuum to obtain the title compound as a yellow oil (4.8 g, yield: 86%).
Reaction SMILES: COC(C1C=C(C)SC=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=O.NN>C(O)C>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH3:20])[C:12]([NH2:11])=[O:23]
Reactant: COC(=O)c1cc(C)sc1NC(=O)c1ccc(OC)c(OC)c1
Agent: NN
Solvent: CCO
Product: COc1ccc(C(N)=O)cc1OC
Reaction time: 12 h
Yield: 92.5 %

Procedure:
Subsequently, 2-(3,4-dimethoxy-benzoylamino)-5-methyl-thiophene-3-carboxylic acid methyl ester (16 mg) synthesized by the above process was dissolved in ethanol (5 ml). Hydrazine (1 ml) was then added to the solution at room temperature, and the mixture was stirred at that temperature for 12 hr. After the completion of the reaction, the reaction system was concentrated under the reduced pressure, and the residue was purified by column chromatography eluted with a chloroform-methanol system to give N-(3-hydrazinocarbonyl)-5-methylthiophen-2-yl)-3,4-dimethoxy-benzamide (8.0 mg, yield 50%).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:7]([F:35])=[C:8]([CH:12]2[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])([C:17]#[N:18])[CH:15]([CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])[NH:14][CH:13]2[C:32](O)=[O:33])[CH:9]=[CH:10][CH:11]=1.[NH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[NH:41][C:40]2=[O:47]>C(N(CC)CC)C>[O:46]=[C:42]1[C:43]2[C:39](=[CH:38][C:37]([NH:36][C:32]([CH:13]3[CH:12]([C:8]4[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=4[F:35])[C:16]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[F:26])([C:17]#[N:18])[CH:15]([CH2:27][C:28]([CH3:31])([CH3:29])[CH3:30])[NH:14]3)=[O:33])=[CH:45][CH:44]=2)[C:40](=[O:47])[NH:41]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc3c(c2)C(=O)NC3=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of thionyl chloride (2 mL), rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (110 mg, 0.24 mmol) was added and the mixture was stirred at rt for 2 hrs. The excess thionyl chloride was removed and the residue was dissolved in methylene chloride (5 mL) and 5-amino-isoindole-1,3-dione (Aldrich, 0.30 mmol) was added followed by the addition of triethylamine (0.2 mL). The mixture was stirred overnight. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 40-80% EtOAc/hexanes) to give a pale yellow solid. 10 mg.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)[CH:19]=[N:18][CH:17]=4)=[CH:14][N:13](S(C4C=CC=CC=4)(=O)=O)[C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]5)[CH:19]=[N:18][CH:17]=4)=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3c(c2)c(-c2cncc(N4CCN(C(=O)OC(C)(C)C)CC4)n2)cn3S(=O)(=O)c2ccccc2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2cnc3[nH]cc(-c4cncc(N5CCN(C(=O)OC(C)(C)C)CC5)n4)c3c2)cn1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 4-{6-[5-(1-methyl-1H-pyrazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}piperazine-1-carboxylate (0.077 g, 0.13 mmol) in MeOH (1.3 ml) was added potassium carbonate (0.053 g, 0.34 mmol). The reaction mixture was stirred at 50° C. for 1 hour, then at room temperature for 16 hours. The reaction mixture was diluted with MeOH (10 mL) and DCM (10 mL), silica gel was added, and concentrated to a crude residue. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient, followed by MeOH/DCM gradient) to afford tert-butyl 4-{6-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl]pyrazin-2-yl}piperazine-1-carboxylate as a white solid. LRMS calculated for C24H28N8O2 [M+H]+, 461.2; found 461.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5](O)=[S:6].Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:31][CH2:30]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][CH:29]([NH:28][C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:30][CH2:31]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[S:6]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(C)cc1C(O)=S
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=S)c4cc(C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-methylthiobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:4][CH:3]=1.[CH:14]1([CH2:17][NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:16]C1>CN(C=O)C>[CH:17]1([NH:18][C:19]([C:20]2[CH:21]=[C:22]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[N:9]=4)=[CH:4][CH:3]=3)[C:23]([CH3:26])=[CH:24][CH:25]=2)=[O:36])[CH2:14][CH2:16]1
Reactant: Cc1noc(-c2ccc(I)cc2)n1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)n1

Procedure:
Example 24 was prepared using 5-(4-iodophenyl)-3-methyl-[1,2,4]oxadiazole (Intermediate 12) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 17) using DMF as the solvent.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[CH2:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)=[CH:28][C:23]=2[CH2:22][CH2:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1ccc2c(c1)CCO2
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc5c(c4)CCO5)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2,3-dihydro-1-benzofuran-5-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(2,3-dihydro-1-benzofuran-5-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][C:18]([NH2:25])([C:20]1[N:24]=[CH:23][O:22][N:21]=1)[CH3:19]>>[CH3:17][C:18]([NH:25][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:20]1[N:24]=[CH:23][O:22][N:21]=1)[CH3:19]
Reactant: CC(C)(N)c1ncon1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1cccc(-c2cccc(Cl)c2)n1)c1ncon1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-methyl-1-[1,2,4]oxadiazol-3-yl-ethylamine (CAN 1153757-41-5) as starting materials, MS (EI): m/e=343.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1CCNCC1
Product: Ic1ccc(N2CCCCC2)nc1

Procedure:
Prepared from 2-chloro-5-iodopyridine and piperidine by the method of Example 9 (d).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:26]=[C:25](F)[CH:24]=[C:23](F)[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3].[C:31]([NH:34][C@:35]1([CH:48]([CH2:50][CH3:51])[CH3:49])[CH2:39][CH2:38][N:37]([C@@H:40]([CH2:44][CH:45]=[CH2:46])[C:41](O)=[O:42])[C:36]1=[O:47])(=[O:33])[CH3:32].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:31]([NH:34][C@:35]1([CH:48]([CH2:50][CH3:51])[CH3:49])[CH2:39][CH2:38][N:37]([C@@H:40]([CH2:44][CH:45]=[CH2:46])[C:41]([NH:29][C@H:19]([C@H:18]([OH:30])[CH2:17][NH:16][C@@H:7]2[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=3)[C@H:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH2:6]2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:42])[C:36]1=[O:47])(=[O:33])[CH3:32]
Reactant: C=CC[C@@H](C(=O)O)N1CC[C@](NC(C)=O)(C(C)CC)C1=O
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c2cc(OC)ccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC=C)N2CC[C@](NC(C)=O)(C(C)CC)C2=O)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
Step N (1): (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol (20 mg, 0.05 mmol) from step E (2), (S)-2-((S)-3-acetamido-3-sec-butyl-2-oxopyrrolidin-1-yl)pent-4-enoic acid (14 mg, 0.048 mmol) from step L (7), EDC (10 mg, 0.05 mmol), HOBt (7 mg, 0.05 mmol), DIEA (40 μL, 0.24 mmol) were mixed in 2 mL of DMF. The mixture was stirred at RT for 24 h. Purified with reverse phase Prep-HPLC to give 14.1 mg of (S)-2-((S)-3-acetamido-3-sec-butyl-2-oxopyrrolidin-1-yl)-N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-hydroxy-1-phenylbutan-2-yl)pent-4-enamide as a light brown viscous residue (TFA salt): LC-MS (M+H)+=661.37, 1H NMR (300 MHz, CDCl3) δ ppm 0.82 (t, J=5.86 Hz, 2H) 0.89-1.69 (m, 5H) 1.86-2.04 (m, 4H) 2.35-2.90 (m, 5H) 3.05-4.17 (m, 19H) 4.57 (d, J=6.59 Hz, 1H) 4.75 (d, J=4.76 Hz, 1H) 4.87-4.98 (m, 1H) 5.12-5.34 (m, 1H) 5.38-5.57 (m, 1H) 5.78-5.94 (m, 1H) 6.01 (s, 1H) 6.84-6.95 (m, 1H) 7.02-7.36 (m, 8H) 7.70 (d, J=9.15 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:26])=O)(=[O:17])=[O:16])=[O:13])[N:4]=1.[CH3:27][Li].O.Cl>O1CCCC1.CCOCC>[C:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:15]([NH:14][C:12]([NH:11][C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=1)=[O:13])(=[O:17])=[O:16])(=[O:26])[CH3:27]
Reactant: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(C)=O)n1
Reaction time: 4 h

Procedure:
A mixture containing 0.85 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-carboxybenzenesulfonamide in 50 ml of anhydrous tetrahydrofuran was treated with 40 ml of a 1.4 molar solution of methyl lithium (low halide, Aldrich) in ether at 25° under a nitrogen atmosphere. The mixture was stirred for 4 hours at 25° and was then poured into 500 ml of water containing 10 ml of concentrated hydrochloric acid. The precipitated oil was extracted into methylene chloride and the oil on evaporation of solvent was purified by preparative thin layer chromatography on silica gel (Analtec, 2000 micrron, 20×20 plates) by elution with ethyl acetate/hexane in a one to one ratio. The isolated product was recrystallized from a 1-chlorobutane and hexane mixture to give 0.1 g, m.p. 126°-8°. The infrared absorption showed a broadened carbonyl peak at 1710 cm-1, and the absence of the 3500 and 3400cm-1 peaks of the starting material. The nuclear magnetic resonance spectrum showed peaks at 2.6 ppm, s, 3H, ##STR58## 4.0 ppm, s, 6H, CH3O of pyrimidine; 5.7 ppm, s, 1H, pyrimidine proton at position 5; and 7.3-7.7 ppm and 8.0 ppm, m, 4H, aromatic, which are consistent with the desired structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:32])[C:5]([O:30][CH3:31])=[C:6]([CH:29]=1)[CH2:7][O:8][CH2:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1.[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)#[N:34]>O1CCCC1.[Pd].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>[CH3:31][O:30][C:5]1[C:6]([CH2:7][O:8][CH2:9][C:10]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:29][C:2]([C:38]2[CH:39]=[CH:40][C:35]([C:33]#[N:34])=[CH:36][CH:37]=2)=[CH:3][C:4]=1[CH3:32]
Reactant: COc1c(C)cc(Br)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2ccc(C#N)cc2)cc1COCC1(c2ccccc2)CCNCC1
Temperature: 120 °C

Procedure:
tert-Butyl 4-((5-bromo-2-methoxy-3-methylbenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (65 mg, 0.13 mmol), 4-cyanophenylboronic acid (76.4 mg, 0.52 mmol), and tetrakis(triphenylphosphine) palladium(0) (20 mg, 0.01 mmol) were combined in dry tetrahydrofuran (2 mL) in a microwave tube and sealed. After flushing with nitrogen, 0.46 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 28 mg (51%). 1H-NMR (CDCl3, 500 MHz) δ 7.69 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H), 7.53 (s, 1H), 7.37 (s, 1H), 7.36 (s, 1H), 7.27-7.30 (m, 3H), 7.17-7.20 (m, 2H), 4.46 (s, 2H), 3.61 (s, 3H), 3.50 (s, 2H), 2.89-2.92 (m, 2H), 2.72-2.76 (m, 2H), 2.31 (s, 3H), 2.16-2.19 (m, 2H), 1.88-1.93 (m, 2H). 13C-NMR (CDCl3, 126 MHz) δ 157.1, 145.4, 144.4, 134.7, 132.5, 132.4, 131.7, 129.2, 128.3, 127.6, 127.4, 126.1, 125.8, 119.1, 110.6, 80.2, 68.2, 60.9, 42.7, 41.9, 33.6, 16.2. Mass spec.: 427.42 (MH)+. Accurate mass spec.: m/z 427.2378 [MH]+, Δ=1.8 ppm.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[CH:11]2.[CH3:18][C:19](N(C)C)=[O:20]>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[CH:12]=[C:11]2[C:19](=[O:20])[CH3:18]
Reactant: CC(=O)N(C)C
Reactant: COc1ccc2c(ccn2C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)c(C(C)=O)cn2C
Reaction time: 0.08 h

Procedure:
Phosphoryl chloride (1.05 ml) was added dropwise to ice-cooled dimethylacetamide (10 ml) and the solution was stirred, in ice, for 5 min. A solution of 5-methoxy-1-methyl-1H-indole (1.4 g) in dimethylacetamide (5 ml) was added dropwise, and the resulting solution was stirred at 85° for 2 h, then cooled, and partitioned between sodium carbonate (2N; 100 ml) and ethyl acetate (2×100 ml). The combined organic extracts were washed with water (2×100 ml), dried and evaporated in vacuo. The residue was purified by FCC eluting with ethyl acetate to give a solid which was crystallised from a mixture of ethyl acetate and hexane to give the title compound (0.6 g), m.p. 167°-168°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=2)=[C:6]([N+:25]([O-])=O)[CH:5]=1.[NH4+].[Cl-]>CCO.O(C(C)C)C(C)C.[Fe]>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[CH:15][CH:16]=2)=[C:6]([NH2:25])[CH:5]=1
Reactant: COC(=O)c1ccc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: COC(=O)c1ccc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A suspension of 4-(4-tert-butoxycarbonylamino-phenoxy)-3-nitro-benzoic acid methyl ester (18.0 g, 46 mmol), Fe powder (13.5 g, 232 mmol) and NH4Cl (12.4 g, 232 mmol) in aqueous EtOH [prepared from EtOH (180 mL) and H2O (180 mL)] was gradually heated to reflux and refluxed for 1.5 hours. The reaction mixture was filtrated through celite pad and the filtrate was evaporated. The aqueous residue was portioned between AcOEt and 5% NaHCO3 and then filtered through celite pad. The organic layer was separated, washed H2O and brine, dried over MgSO4 and evaporated to give pale brown oil, which was diluted with i-Pr2O (100 mL) and stirred at room temperature for 1 hour. The resulting crystal was collected by filtration, washed with i-Pr2O, and dried at 40° C. overnight under reduced pressure to give the title compound as colorless crystal (10.5 g, 63%).
Reaction SMILES: [CH:1]1([C:10](Cl)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:13]1[CH2:18][CH:17]=[C:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.[NH4+].[OH-]>ClCCl.C1COCC1>[CH:1]1([C:10]([N:13]2[CH2:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:17][CH2:18]2)=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCc2ccccc21
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(C1CCc2ccccc21)N1CC=C(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
1-Indanecarboxylic acid chloride (4.5 g), prepared as described in International Patent Application No. WO 9533721-A1 in dichloromethane (25 ml) was added drop-wise at 0-5° C. to a mixture of 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (5 g) (see general method for preparation in Guillaume et al. Eur. J. Med. Chem. 1987, 22, 33-43) and triethylamine (3.8 ml) in THF (50 ml). The resulting mixture was stirred overnight at room temperature. The mixture was poured into diluted aqueous NH4OH (500 ml) and extracted several times with dichloromethane (4×100 ml). The combined organic phases were worked up according to the general procedure above. Column chromatography (eluted with ethyl acetate/heptane 70/30) of the crude product afforded pure title compound 4a as a visceous oil (4.7 g) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:19]=2)=[CH:12][C:11]=1[CH3:45])([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>O1CCCC1.CO>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][CH:25]=3)[N:19]=2)=[CH:12][C:11]=1[CH3:45])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(Cc2ccc(C(F)(F)F)cc2)c2cccc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CN(Cc2ccc(C(F)(F)F)cc2)c2cccc(-c3ccc(C(F)(F)F)cc3)n2)ccc1OC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.5 %

Procedure:
To a solution of ethyl 2-methyl-2-{2-methyl-4-[([4-(trifluoromethyl)benzyl]{6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}amino)methyl]phenoxy}propanoate (0.07 g, 0.11 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 2M aq. NaOH (1 mL). The resulting solution was stirred at room temperature for 20 h then concentrated in vacuo. The residue was acidified with 2M HCl aq. and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated to afford the title compound as a colourless oil (60 mg).