Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:20][N:19]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 5-(trifluoromethyl)picolinic acid (200 mg, 1.04 mmol) and BOP-Cl (330 mg, 1.30 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)picolinamide (195 mg, 55% yield) as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)CCC.[F-].[K+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C.O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a mixture of 3-bromobenzaldehyde (930 mg, 5.0 mmol) and toluene (10 mL) were added tri-n-butyl (2-pyridyl) tin (2.1 g, 5.6 mmol) and bis(triphenylphosphine)palladium (II) chloride (350 mg, 0.50 mmol), and the reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature, and saturated aqueous potassium fluoride solution (1 mL) was added at that temperature and stirred for 30 minutes at room temperature. Water and ethyl acetate were added to the reaction mixture, which was then filtered through a Celite pad. The organic layer of the filtrate was separated and washed with saturated aqueous sodium chloride. The solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (530 mg, 58%).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[CH:8]=[C:9]([NH:24][C:25]([C:27]2[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:10]=[CH:11][C:12]=1[C:13]([O:22][CH3:23])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:4]([CH3:6])[CH3:5].[CH2:34]([O:36][CH2:37]Cl)[CH3:35].Cl>C1COCC1>[CH2:34]([O:36][CH2:37][N:24]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:22][CH3:23])([C:18]([F:20])([F:21])[F:19])[C:14]([F:17])([F:16])[F:15])=[C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=1)[C:25]([C:27]1[C:32]([CH3:33])=[N:31][CH:30]=[CH:29][N:28]=1)=[O:26])[CH3:35]
Reactant: CCOCCl
Reactant: COC(c1ccc(NC(=O)c2nccnc2C)cc1CC(C)C)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCN(C(=O)c1nccnc1C)c1ccc(C(OC)(C(F)(F)F)C(F)(F)F)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
Sodium hydride (32 mg, 60% by weight, 0.8 mmol) was suspended in THF (10 ml) and a THF (5 ml) solution of N-{3-isobutyl-4-[1-methoxy-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pheny}-3-methylpyrazine-2-carboxamide (300 mg, 0.67 mmol) was added dropwise thereto. The reaction solution was stirred at room temperature for 30 minutes, and was added with a THF (2 ml) solution of chloromethyl ethyl ether (76 mg, 0.8 mmol) and stirred for 5 hours. The reaction solution was poured into a diluted HCl solution, followed by extracting with ethyl acetate, and washing with water. The solution was dried over magnesium sulfate, and concentrated under reduced pressure, and then the residue was purified by using silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 0.24 g of the desired compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[C:42](=[O:45])([O-])[O-].[K+].[K+].O>C(COC)OC>[OH:45][C:42]1[C:14]([CH3:13])=[CH:15][C:7]([C:7]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]4[C:23]([CH:24]=3)=[CH:22][C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=4)=[C:12]3[C:8]=2[CH2:9][NH:10][C:11]3=[O:39])=[CH:8][C:12]=1[CH3:11]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(-c3cc4cc(CN5CCCCC5)ccc4n3C(=O)OC(C)(C)C)c3c2CNC3=O)cc(C)c1O
Yield: 102.4 %

Procedure:
In a similar manner to Step 1 of Example 152, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in dimethoxyethane (9.6 mL), and the solution was treated with 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)phenol (42.0 mg, 0.168 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (5.5 mg, 0.0067 mmol), potassium carbonate (58.0 mg, 0.421 mmol) and water (0.030 mL), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-(4-hydroxy-3,5-dimethylphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (39.1 mg, yield 82%).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>C(O)C>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C=O)cc1OCCCCCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCOc1ccc(CO)cc1OCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 3,4-dihexoxybenzaldehyde (15.3 g., 0.05 M), sodium borohydride (1.85 g., 0.05 M) and ethanol (350 ml.) is stirred at room temperature for one hour and then concentrated in vacuo. The residue is dissolved in chloroform (500 ml.), the solution washed with water (4× 100 ml.), dried (Na2SO4) and evaporated under reduced pressure to give 3,4-dihexoxybenzyl alcohol (15.0 g.) as a pale yellow oil.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[S:3][C:2]=1[SH:10].[H-].[Na+].CN(C)C=O.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[N:32]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:23][CH2:22]1>O>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][N:32]2[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=[C:28]2[NH:27][CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][S:10][C:2]3[S:3][C:4]4[C:9]([N:1]=3)=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:26][CH2:25]2)=[CH:35][CH:36]=1
Reactant: Sc1nc2cccnc2s1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2c(NC3CCN(CCSc4nc5cccnc5s4)CC3)nc3ccccc32)cc1
Reaction time: 1 h
Yield: 6.4 %

Procedure:
A mixture of 2.5 parts of thiazolo[5,4-b]pyridine-2-thiol, 1 part of a sodium hydride dispersion 50% and 45 parts of N,N-dimethylformamide was stirred for 1 hour. Then there was added a solution of 6.9 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-(4-fluorophenylmethyl)-1H-benzimidazol-2-amine in 45 parts of N,N-dimethylformamide. The whole was stirred overnight. Water was added dropwise. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.5 parts (6.4%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-(thiazolo[5,4-b]pyridin-2-ylthio)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 159.9° C. (compound 105).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1.[O:17]=[C:18]1[N:22]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[NH:19]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[N:1]1[CH:6]=[C:5]([C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:26]3[CH2:25][CH2:24][CH:23]([N:22]4[C:21]5[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=5[NH:19][C:18]4=[O:17])[CH2:28][CH2:27]3)[CH2:12][CH2:11]2)([CH3:9])[CH3:8])[CH:4]=[N:3][CH:2]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CC(C)(c1cncnc1)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(c1cncnc1)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.3 %

Procedure:
A mixture of 1-(2-(5-pyrimidinyl)-prop-2-yl)-4-oxopiperidine (117 mg), 4-(2-oxo-1-benzimidazolinyl)piperidine (128 mg), 1,2-dichloroethane (2.5 mL), glacial acetic acid (0.031 mL) and sodium triacetoxyborohydride (170 mg) was stirred at room temperature for 48 h. The reaction mixture was poured into dichloromethane (15 mL) and saturated aqueous Na2 CO3 (8 mL) and the layers separated. The aqueous layer was extracted with dichloromethane (2×15 mL) and the combined organic layers dried over Na2SO4 and concentrated under reduced pressure. Purification by column chromatography, eluting with a gradient of methylene chloride; 0-6% methanol; 1% NH4OH, followed by trituration with diethyl ether gave 104 mg of 1,3-dihydro-1-(1-{1-[2-(5-pyrimidinyl)-prop-2-yl]piperidin-4-yl}piperidin-4-yl)-2H-benzimidazol-2-one as a colorless solid: 1H NMR (400 MHz, CDCl3) 10.37 (br s, 1H), 9.10 (s, 1H), 8.88 (s, 2H), 7.30 (m, 1H), 7.12-7.01 (m, 3H), 4.37 (m, 1H), 3.11 (d, 2H), 2.86 (d, 2H), 2.53-2.30 (m, 5H), 2.18 (t, 2H), 1.85 (m, 4H), 1.57 (m, 2H), 1.40 (s, 6H). Treatment with citric acid in ethanol yielded the citrate salt, analysis calculated for C24H32N6O.0.1 H2O.1.5 C6H8O7 : C: 55.78, H: 6.27, N: 11.83 found C: 55.82, H: 6.56, N: 11.68.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]1([CH3:50])[CH:36]=[CH:35][C:34]([N:37]2[C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:43]3[C:38]2=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)([C:41]5[CH:40]=[CH:39][C:38]6[N:37]([C:34]7[CH:33]=[CH:32][C:31]([CH3:50])=[CH:36][CH:35]=7)[C:49]7[C:44]([C:43]=6[CH:42]=5)=[CH:45][CH:46]=[CH:47][CH:48]=7)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1(c2ccccc2)c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Reactant: Cc1ccc(-n2c3ccccc3c3ccccc32)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1ccc(-n2c3ccccc3c3cc(C4(c5ccccc5)c5ccccc5-c5nc6ccccc6c(-c6ccccc6)c54)ccc32)cc1
Yield: 83.4 %

Procedure:
Referring to the reaction formula above, 10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-ol (385 mg, 1.00 mmol) and 9-(p-tolyl)-9H-carbazole (291 mg, 1.20 mmol) are placed in a round bottom flask and then dissolved in 5 ml of dichloromethane. Subsequently, 286 of Eaton's reagent is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 100° C., the crude product is extracted with 8 ml of dichloromethane and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 521 mg of 10,11-diphenyl-11-(9-(p-tolyl)-9H-carbazol-3-yl)-11H-indeno[1,2-b]quinoline. The percentage yield is 83.4%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:23]=[O:24]>O1CCCC1>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([CH:23]=[O:24])[CH:10]=3)[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2cnn(C3CCCC3)c2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2cnn(C3CCCC3)c2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound 6-bromo-1-cyclopentyl-1H-indazole (1.19 g, 4.15 mmol) in dry tetrahydrofuran (10 ml) was stirred at −78° C. for 15 minutes followed by the addition of butyl lithium (0.532 g, 8.3 mmol). The reaction mixture was again stirred for 30 minutes at −78° C. followed by the dropwise addition of dimethylformamide (1.212 g, 16.6 mmol). The reaction mixture was stirred for 30 minutes at the same temperature followed by stirring it at room temperature for 1 hour. The reaction mixture was quenched with hydrochloric acid (1N) and extracted the compound with ethyl acetate and water. The organic layer was collected, washed with brine and dried over anhydrous sodium sulphate. The mixture was filtered and concentrated under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound. Yield: 465 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13]Cl.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].[I-].[K+].O>CN1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][N:31]1[CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:33][CH2:32]1
Reactant: ClCCCC(Oc1cc(Cl)ccc1Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN1CCCC1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCCC(Oc2cc(Cl)ccc2Cl)c2ccccc2)CC1
Reaction time: 4 h
Yield: 68.4 %

Procedure:
A solution of the product from Example 22 step (b) (0.20 g, 0.61 mmol), 1-tert-butoxycarbonylpiperazine (0.34 g, 1.83 mmol) and potassium iodide (0.051 mg, 0.31 mmol) in N-methylpyrrolidine was heated to 100° C. in a sealed vessel and stirred for 4 h. The reaction was cooled and poured into water (50 ml) and the mixture extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (3×30 ml), dried (magnesium sulphate) and evaporated to leave an oily residue (0.20 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]
Reactant: COc1cc2sc(C(=O)O)c(Cl)c2cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2sc(CO)c(Cl)c2cc1OC
Reaction time: 12 h

Procedure:
A suspension of 68 mmol of the compound obtained in Step B in 150 ml of tetrahydrofuran is added at 5° C. under an inert atmosphere to a solution of 0.1 mol of LiAlH4 in 60 ml of tetrahydrofuran. After 4 hours' reaction at room temperature, the reaction mixture is hydrolysed by the addition of water and then by an aqueous 2N sodium hydroxide solution. After 12 hours at room temperature, the reaction mixture is filtered over Celite. The organic phase is then concentrated under reduced pressure, taken up in dichloromethane and washed with water and then with a saturated NaCl solution. After the organic phase has been dried over calcium sulphate, the solution is concentrated under reduced pressure, enabling 15.7 g of the expected product to be obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:17]([Cl:27])=[N:18][C:19]([Cl:26])=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23])[OH:15]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:17]([Cl:27])=[N:18][C:19]([Cl:26])=[CH:20][C:21]=1[C:22]([F:25])([F:23])[F:24])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(C(F)(F)F)cc(Cl)nc2Cl)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(C(F)(F)F)cc(Cl)nc2Cl)c(OC)c1OC
Yield: 81.9 %

Procedure:
14 g of manganese dioxide was added to a solution having 5.4 g of (2,3,4-trimethoxy-6-methylphenyl)(2,6-dichloro-4-trifluoromethyl-3-pyridyl)methanol obtained in step (a) dissolved in 140 ml of toluene, followed by stirring under reflux by heating for 6 hours. The mixture was cooled and then subjected to filtration, and toluene was distilled off under reduced pressure to obtain 4.4 g (yield 81%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-2,6-dichloro-4-trifluoromethylpyridine (compound No. 3; m.p. 81-83° C.).
Reaction SMILES: Br[CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].C1C=CC2C(C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)C=2C=1.[OH-].[Na+].CO.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1.[OH-].[Na+]>CO.CN(C)C=O>[F:37][C:38]([F:46])([F:47])[C:39]1[CH:40]=[CH:41][C:42]([NH:43][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([CH3:8])[CH3:7])=[CH:44][CH:45]=1
Reactant: CC(C)C(Br)C(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1)C(=O)O
Reaction time: 18 h

Procedure:
Two grams of α-bromoisovaleric acid (0.001 mole) dissolved in 10 ml of methanol is titrated to the phenolphthalein end point at 0° with 2 N sodium hydroxide/methanol. The alcohol is then removed and 10 ml of dimethylformamide and p-trifluoromethylaniline (3.54 g, 0.022 mole) added. The reaction mixture is heated at 100° for 2 hours and left at room temperature about 18 hours. The reaction mixture is poured into 50 ml of 0.1 N sodium hydroxide, washed with ether and the aqueous phase adjusted to pH 4 with conc. HCl and then extracted with chloroform (3X). The extracts are combined and washed with brine, dried, concentrated in a rotoevaporator and solvent removed under vacuum at about 50° to yield N-(p-trifluoromethylphenyl)valine.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH:16]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=1)[CH2:17][C:18]#[N:19]>C(O)(=O)C.C(Cl)Cl>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][CH3:30])[CH:21]=3)[CH2:17][C:18]#[N:19])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: CCOc1cc(C(N)CC#N)ccc1OC
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOc1cc(C(CC#N)N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)ccc1OC
Yield: 56 %

Procedure:
A stirred suspension of 3-nitrophthalic anhydride (0.24 g, 1.13 mmol) and 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanenitrile (0.25 g, 1.13 mmol) in 6 mL of acetic acid was heated to reflux under nitrogen for 12 hours. The acetic acid was removed in vacuo to afford an orange gum which was dissolved in methylene chloride (10 mL) and was washed with a saturated aqueous solution of sodium bicarbonate (2×10 mL). The organic layer was separated and the aqueous layer was extracted with methylene chloride (10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil. The crude product was purified by flash column chromatography (silica gel, 5% ethyl acetate/methylene chloride) and the resulting solid was dried in vacuio (60° C., <1 mm) to afford 0.25 g (56%) of 3-(3-nitrophthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanenitrile as a yellow solid: mp 155.5-157° C.; 1H NMR (CDCl3) δ8.20-8.09 (m, 2H), 8.02-7.86 (m, 1H), 7.15-7.02 (m, 2H), 6.88-6.76 (m, 1H), 5.64 (dd, J=6.3, 10.6 Hz, 1H), 4.09 (q, J=7 Hz, 2H), 3.85 (s, 3H), 3.84 (dd, J=10.6, 16.7 Hz, 1H), 3.26 (dd, J=6.3, 16.7 Hz, 1H), 1.46 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ165.3, 162.3, 150.1, 148.7, 144.9, 135.7, 133.5, 129.0, 128.1, 127.4, 123.2, 120.3, 116.6, 112.1, 111.5, 64.6, 55.9, 51.9, 20.9, 14.7; Anal. calcd for C20H17N3O6. Theoretical: C, 60.76; H, 4.33; N, 10.63. Found: C, 60.59; H, 4.22; N, 10.65.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:37]=[CH:36][C:29]2[N:30]([CH3:35])[C:31](=[O:34])[N:32]([CH3:33])[C:28]=2[CH:27]=1)=[O:25])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>CO>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][N:12]([CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([C:26]1[CH:37]=[CH:36][C:29]2[N:30]([CH3:35])[C:31](=[O:34])[N:32]([CH3:33])[C:28]=2[CH:27]=1)[OH:25])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17]
Reactant: Cn1c(=O)n(C)c2cc(C(=O)CCCCN(CCc3ccccc3Cl)C(=O)OC(C)(C)C)ccc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cn1c(=O)n(C)c2cc(C(O)CCCCN(CCc3ccccc3Cl)C(=O)OC(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
95 mg of Sodium tetrahydroborate was added to a solution of tert-butyl 2-(2-chlorophenyl)ethyl[5-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-5-oxopentyl]carbamate obtained in Reference Example 60 in methanol (10 ml) at room temperature. After stirring at room temperature for 2 hours, 20 ml of an aqueous saturated ammonium chloride solution was added. The liberated oil was extracted with chloroform (30 ml×2), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale yellow oil (1.25 g).
Reaction SMILES: C(OC([N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=O)(C)(C)C.Cl[C:25]1[N:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:26]=1[C:27]([OH:29])=[O:28].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:34][C:32]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:17]([CH2:16][NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH:18]=2)[N:33]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(N)c1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1cccc(Nc2nc(Cl)ccc2C(=O)O)c1
Yield: 25.3 %

Procedure:
A mixture of 3-(di-(t-butoxycarbonyl)aminomethyl)aniline (81 mg), 2,6-dichloronicotinic acid (90%, 53 mg), di-i-propylethylamine (64 mg) and 1,4-dioxane (1 ml) was heated under reflux for 3 days and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, methylene chloride:methanol=20:1) to give 24 mg of the titled compound (yield, 25%).