Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[C:24](=[O:25])[NH:23][N:22]=[N:21]3)[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](=O)([O-])[O-].[K+].[K+].IC>C(Cl)Cl>[CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[C:24](=[O:25])[N:23]([CH3:44])[N:22]=[N:21]3)[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:27]=[C:28]([CH3:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nn[nH]c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nnn(C)c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a solution of 1-[3-{2-[benzyl-(4-pyridin-3-yl-butyl)-amino]ethyl}-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-1,4-dihydrotetrazol-5-one (25 mg in 1.5 mL dry N,N-dimethylformamide) at 0° C. was added 13 mg potassium carbonate followed by 0.033 mL of a 10% solution of iodomethane in methylene cloride, and the mixture stirred at low temperature. After 2 hours, the reaction was quenched by the addition of saturated aqueous ammonium chloride and the mixture extracted with ethyl acetate. The organic portion was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 95:5) gave the title compound (20 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[CH:15]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])([CH3:17])[CH3:16]>>[CH:15]([O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1)([CH3:17])[CH3:16]
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Reactant: CC(C)Oc1cccc(N)c1
Product: Cc1cc(Nc2cccc(OC(C)C)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 3-isopropoxyaniline (60.4 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid (88 mg, 69%). 1H NMR (CDCl3): 8.64 (d, J=4.2 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 7.7 (t, J=8.1 Hz, 1H), 7.24 (m, 1H), 7.15 (m, 1H), 6.96 (s, 1H), 6.76 (m, 2H), 6.60 (d, J=8.1 Hz, 1H), 6.18 (m, 1H), 4.45 (m, 1H), 2.37 (s, 3H), 1.25 (d, J=6.0 Hz, 6H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH:19]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:18]3[C:29]([CH3:36])=[C:30]([OH:35])[C:31]([CH3:34])=[C:32]([CH3:33])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH:19]([C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:18]3[C:29]([CH3:36])=[C:30]([O:35][CH2:43][C:42]4[CH:45]=[CH:46][C:39]([O:38][CH3:37])=[CH:40][CH:41]=4)[C:31]([CH3:34])=[C:32]([CH3:33])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(Cc3ccccc3)CC1)O2
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C2(CCN(Cc4ccccc4)CC2)O3)cc1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 81.4 mg, 1.81 mmol) was added to a solution of 1′-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (824.0 mg. 1.81 mmol) in N,N-dimethylformamide (15 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (319.9 mg, 2.04 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain the title compound (539 mg, yield 52%). This was amorphous.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[I:24]N1C(=O)CCC1=O>O>[I:24][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12](=[O:16])[C:13](=[O:15])[C:14]=2[CH:1]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1C(=O)c2ccccc2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1C(=O)c2cc(I)ccc2-c2ccccc21
Temperature: 35 °C
Reaction time: 36 h
Yield: 75.4 %

Procedure:
Into a 200 mL volume eggplant-shaped flask, 10.0 g of 9,10-phenanthrenequinone, 54.8 g of trifluoroacetic acid, and 21.6 g of N-iodosuccinimide were added at room temperature, heated to 35° C., and then stirred for 36 hours in an argon atmosphere. The reaction mixture was poured into icy water. The solid precipitate was collected by filtration and recrystallized with tetrahydrofuran, thereby to give 12.1 g of 2-iodo-phenantrene-9,10-dione (yield 75%) as an orange-colored solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH:6]1[S:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:7]1=[O:22].O>CN(C=O)C>[N:1]([CH:6]1[S:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:7]1=[O:22])=[N+:2]=[N-:3]
Reactant: O=C1C(Cl)SCN1c1cccc(OC(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1SCN(c2cccc(OC(F)(F)F)c2)C1=O
Yield: 70.4 %

Procedure:
Sodium azide (2.78 g) was added to a solution of 5-chloro-3-(3-trifluoromethoxyphenyl)thiazolidin-4-one (7.50 g) in DMF (50 ml). After 2 hours the mixture was poured into water, extracted with ethyl acetate (x3), dried (MgSO4) and concentrated in vacuo to give the sub-title compound (5.40 g), which was used directly in the next step.
Reaction SMILES: I[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].C([Sn](CCCC)(CCCC)[C:39]1[O:40][CH:41]=[CH:42][CH:43]=1)CCC.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[O:40]1[CH:41]=[CH:42][CH:43]=[C:39]1[C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:20]([O:22][CH3:23])=[O:21])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3I)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccco3)cc2)CC1

Procedure:
A mixture of intermediate (29) (0.0036 mol), tributyl-2-furanyl-stannane (0.029 mol), PdCl2(PPh3)2 (0.0007 mol) and Na2CO3 (0.0576 mol) in dioxane (30 ml) was stirred and refluxed for 1 hour. Water was addedd. The mixture was extracted with ethyl acetate. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:cyclohexane/ethyl acetate 80/20). The pure fractions were collected and the solvent was evaporated, yielding 4-[4-[[2-(2-furanyl)benzoyl]amino]phenyl]-α-phenyl-1-piperazineacetic acid, methyl ester (intermediate 30, mp. 90° C.).
Reaction SMILES: [CH3:1][C:2]1[O:8][C:7]([CH3:9])=[CH:6][C:4](=[O:5])[CH:3]=1.[H][H]>CO.[Pd]>[CH3:9][C@H:7]1[CH2:6][C:4](=[O:5])[CH2:3][C@@H:2]([CH3:1])[O:8]1
Reactant: Cc1cc(=O)cc(C)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CC(=O)C[C@H](C)O1
Yield: 88 %

Procedure:
10 g of 2,6-dimethyl-gamma-pyrone are dissolved in 200 ml of methanol and then 0.8 g of palladium-on-charcoal at 10% is added. The reaction mixture is stirred for 24 hours under 25 atmospheres of hydrogen. The medium is filtered and then the solvent is evaporated off. 8.81 g of cis-2,6-dimethyltetrahydro-pyran-4-one are recovered. Yield=88%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH2:37][CH2:38][CH2:39][Cl:40].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:4]([C:5]([C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=3)=[O:6])=[CH:3][C:2]=2[O:1][CH2:37][CH2:38][CH2:39][Cl:40])=[CH:30][CH:31]=1
Reactant: ClCCCBr
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(O)c2)c2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2ccc(OCc3ccc(C)cc3)c(OCCCCl)c2)c2ccccc21
Temperature: 60 °C
Reaction time: 6 h
Yield: 82.9 %

Procedure:
Ethyl 4-{3-[3-hydroxy-4-(4-methylphenylmethoxy) benzoyl]indol-1-yl}butanoate (2.77 g) obtained in Step 1 was dissolved in N,N-dimethylformamide (30 ml). 1-Bromo-3-chloropropane (1.39 g) and potassium carbonate (0.97 g) were added to the resultant solution and stirred for 6 hours at 60° C. The reaction mixture was poured into 2N HCl and extracted with ethyl acetate. The resultant extract was sequentially washed with saturated sodium bicarbonate solution and brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), obtaining 2.67 g of ethyl 4-{3-[4-(4-methylphenylmethoxy)-3-(3-chloropropoxy)benzoyl]indol-1-yl}butanoate as a light yellow oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9].P(Cl)(Cl)(Cl)=O.C[CH2:18][O:19]CC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][N:2]1[C:6]([CH:18]=[O:19])=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C)cn1C
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1cc(C)c(C=O)n1C
Temperature: 90 °C
Yield: 84 %

Procedure:
A solution of methyl 1,4-dimethylpyrrole-2-carboxylate (2.5 g, 0.016 m) in 20 ml of dried 1,2-dichloroethane was added over two minutes to a stirred mixture of phosphorous oxychloride (2.3 ml) and dried, N,N-dimethylformamide (1.94 ml) in 50 ml of dichloroethane, and the resultant mixture heated at 90° C. (bath temperature) for 45 minutes. The cooled reaction mixture was treated with excess ice-water and ether, 10% aqueous sodium carbonate (50 ml) added, the ether layer removed and the aqueous phase re-extracted two times with fresh ether, and the combined ether layers washed well with water and dried over anhydrous sodium sulfate. Concentration of the ether solution yielded 2.48 g (84%) of methyl 1,4-dimethyl-5-formylpyrrole-2-carboxylate as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]([C:10]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:11]([F:15])[C:12]=1[CH2:13][OH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>ClCCl>[Si:35]([O:14][CH2:13][C:12]1[C:11]([F:15])=[C:10]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:2]=1[F:1])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c1OC1CCCCO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(CO[Si](C)(C)C(C)(C)C)c(F)c1OC1CCCCO1
Yield: 96.7 %

Procedure:
213 mg (0.50 mmol) of the above ethyl 3,5-difluoro-4-hydroxymethyl-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate was dissolved in 5 mL of dichloromethane, 68 mg (1.0 mmol) of imidazole and 302 mg (2.00 mmol) of tert-butyldimethylsilyl chloride were added and the mixture was heated at reflux for 30 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 256 mg of ethyl 4-tert-butyldimethylsilyloxymethyl-3,5-difluoro-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate (yield: 98%).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].[Cl-].[Al+3].[Cl-].[Cl-].CO>ClCCCl>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([C:8]1[S:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCCl
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3OC)sc2c1
Yield: 96.6 %

Procedure:
By the procedure of Example 5, 5.0 g. (0.0208 mole) of 3-phenyl-6-methoxybenzothiophene were treated with 3.60 g. (0.021 mole) of o-methoxybenzoyl chloride and 2.80 g. (0.021 mole) of aluminum chloride in 100 ml. of 1,2-dichloroethane as solvent. The crystalline product, 2-(2-methoxybenzoyl)-3-phenyl-6-methoxybenzothiophene (7.52 g.; 97 percent) was obtained from methanol, m.p. 111°-112° C. The product was sufficiently pure to be employed in the next succeeding step; however, a portion of the product was further purified by recrystallization from methanol with the following analytical result.
Reaction SMILES: [Br-:1].[Mg+2].[Br-].S(O[CH2:9][CH2:10][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])[CH3:12])(=O)(=O)C.O>CCOCC>[CH2:9]([Br:1])[CH2:10][CH:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH2:18][CH2:19][CH2:20][CH:21]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH3:22])[CH3:17])[CH3:12]
Reactant: [Br-]
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOS(C)(=O)=O
Agent: [Mg+2]
Solvent: O
Solvent: CCOCC
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCBr
Reaction time: 8 h

Procedure:
Magnesium bromide etherate (17 g, 55 mmol) and a stir bar were added to a 500 mL round bottom flask. The flask was sealed and flushed with nitrogen and anhydrous diethyl ether (200 mL) added via cannula. A solution of phytanyl mesylate (23) (10.9 g, 28.9 mmol (FW=377)) in anhydrous ether (50 mL) was also added via canulla, and the suspension stirred overnight. The following morning a precipitate had formed on the side of the flask. Chilled water (200 mL) was added (ppte dissolved) and the mixture transferred to a 1000-mL separating funnel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2×150 mL) and all ether phases combined. The ether phase was washed with water (2×150 mL), brine (150 mL) and dried over anhydrous Mg2SO4. The solution was filtered, concentrated, and purified by flash chromatography. Final yield 9.5 g (26.3 mmol, 91.1%).
Reaction SMILES: O=[C:2]1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]([NH:15][CH2:16][C:17]1[CH:18]=[C:19]([NH:27][C:28]([CH:30]2[CH2:39][C:38]3[CH:37]=[C:36]([O:40][C:41]4[CH:46]=[CH:45][N:44]=[C:43]([C:47]([NH:49][CH3:50])=[O:48])[CH:42]=4)[CH:35]=[CH:34][C:33]=3[CH2:32][CH2:31]2)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)=[O:14].CN.O>CCO>[CH3:50][NH:49][C:47]([C:43]1[CH:42]=[C:41]([O:40][C:36]2[CH:35]=[CH:34][C:33]3[CH2:32][CH2:31][CH:30]([C:28]([NH:27][C:19]4[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=[C:17]([CH2:16][NH:15][C:13](=[O:14])[CH2:12][NH:3][CH3:2])[CH:18]=4)=[O:29])[CH2:39][C:38]=3[CH:37]=2)[CH:46]=[CH:45][N:44]=1)=[O:48]
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CNC(=O)CN4C(=O)c5ccccc5C4=O)cc(C(F)(F)F)c2)CC3)ccn1
Agent: CN
Solvent: CCO
Solvent: O
Product: CNCC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(C(=O)NC)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-{[7-({[3-({[(1,3dioxo-1,3-dihydro-2-H-isoindol-2-yl)acetyl]-amino}methyl)-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]-oxy}-N-methylpyridine-2-carboxamide (0.819 g, 1.19 mmol) in EtOH (20 mL) was added a 40% aqueous solution of methyl amine in water (5.00 mL, 44.8 mmol). The reaction mixture was allowed to stir at rt for 5 h and then concentrated. The residue was purified by column chromatography to give N-methyl-4-{[7-({[3-({[(methylamino)acetyl]amino}-methyl)-5-(trifluoromethyl)phenylamino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-pyridine-2-carboxamide I-345 (0.124 g, 19%) as a white solid. 1H NMR (400 MHz, d6-DMSO, HCI salt) δ: 10.65 (s, 1H), 9.19-9.09 (br s, 1H), 8.85-8.77 (m, 1H), 8.50 (d, 1H), 8.17-8.02 (m, 2H), 7.66 (s, 1H), 7.41-7.36 (m, 1H), 7.28-7.21 (m, 1H), 7.19-7.14 (m, 1H), 7.04-6.94 (m, 2H), 4.22 (t, 2H), 3.83-3.76 (m, 2H), 3.67 (t, 2H), 3.03-2.81 (m, 5H), 2.77 (d, 3H), 2.17-2.08 (m, 1H), and 1.89-1.75 (m, 1H). LCMS: (FA) ES+543.2, ES−541.2.
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.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([C:28]([O:30][CH3:31])=[O:29])[NH:19]1>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:19]2[CH:20]([C:28]([O:30][CH3:31])=[O:29])[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18]2)=[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: COC(=O)C1Cc2ccccc2CN1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2CN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Aldrich), the title compound was prepared as a solid (mp=37-40° C). The reaction was monitored by tlc (Rf=0.64 in 10% MeOH/DCM).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:4]1.CS(O[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)(=O)=O>CN(C)C=O>[CH3:11][O:10][C:8]([C:5]1[CH:6]=[CH:7][N:3]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[N:4]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: COC(=O)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 0 °C
Yield: 23.4 %

Procedure:
A suspension of 60% dispersion of sodium hydride in mineral oil (192 mg, 4.8 mmol) in 20 mL of N,N-dimethylformamide was cooled to 0° C., and methyl 3-pyrazolecarboxylate (605.37 mg, 4.8 mmol) was gradually added with stirring in nitrogen atmosphere. The reaction mixture was stirred at room temperature for 0.5 h and cooled again to 0° C. A solution of 1,1-dimethylethyl 4-[(methylsulfonyl)oxy]-1-piperidine-carboxylate (1.18 g, 4 mmol) (i.e. the product of Example 18, Step A) in 5 mL of N,N-dimethylformamide was gradually added to the reaction mixture. The resulting mixture was stirred for 5 days at 60° C. The reaction mixture was poured in ice water and extracted with ethyl acetate. The organic layer was dried (MgSO4), evaporated in vacuo, and purified by medium-pressure liquid chromatography on silica gel eluting with 0-10% methanol in ethyl acetate as eluant to give 290 mg of the title compound as a white solid.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C1CN([P+](O[N:37]2N=[N:44][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N.CCN(CC)CC>CN(C=O)C>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[NH2:44])=[O:17])=[CH:18][CH:19]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(Cn2cnc3ccccc32)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(Cn2cnc3ccccc32)cc1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A solution of 4-((1H-benzo[d]imidazol-1-yl)methyl)benzoic acid (0.1 mmol) in DMF (1 mL) was sequentially treated with PyBOP (0.12 mmol), 1,2-phenylenediamine (0.12 mmol) and Et3N (0.3 mmol). After stirring at 23° C. for 4 h, the reaction was filtered and the crude material was purified by HPLC to yield 4-((1H-benzo[d]imidazol-1-yl)methyl)-N-(2-aminophenyl)benzamide. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.88 (s, 2H), 5.60 (s, 2H), 6.54-6.61 (m, 1H), 6.76 (d, J=8.08 Hz, 1H), 6.93-6.98 (m, 1H), 7.13 (d, J=7.58 Hz, 1H), 7.18-7.23 (m, 2H), 7.43 (d, J=8.34 Hz, 2H), 7.48-7.54 (m, 1H), 7.65-7.70 (m, 1H), 7.93 (d, J=8.08 Hz, 2H), 8.46 (s, 1H), 9.60 (s, 1H). ESI-MS: m/z 343.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:17](=O)([O:23]C(C)(C)C)[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: COc1ccc(N)cn1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 5-amino-2-methoxypyridine (8.00 g, 64.4 mmol) and triethylamine (11.7 mL, 83.8 mmol) in dioxane (32 mL) at 0° C. was added a solution of di-tert-butyl carbonate in dioxane (20 mL). The reaction mixture was allowed to warm to RT, stirred for 16 h. After concentration in vacuo, the residue was dissolved in 65 mL of EtOAc and 32 mL of a saturated aqueous NaHCO3 solution and stirred at RT for 2 h. The layers were separated. The organic layer was washed with water and dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound.