Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][OH:8].N1C=CC=CC=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)(Cl)Cl>[C:17]([O:8][CH2:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[Cl:10])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCc1cc(Br)ccc1Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCc1cc(Br)ccc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-2-chlorobenzylalcohol (1.0 g) and pyridine (0.44 mL) in chloroform (40 mL) was added benzoyl chloride (0.58 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N HCl under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed successively with water, an aqueous saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was triturated with diisopropylether to give 5-bromo-2-chlorobenzyl benzoate (753 mg) as a colorless powder.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([Cl:30])=[C:11]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.N>ClCCl>[NH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:10]=1[Cl:30])[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N)c(Cl)c(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
(I11B): To the stirred solution of tert-butyl 4-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)piperazine-1-carboxylate (2.0 g, 4.58 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (8.89 mL, 115 mmol) slowly drop wise at room temperature, stirred it for 3 hours at room temperature. On completion of the reaction, the reaction mixture was diluted with methylene chloride (300 mL), cooled it to 0° C., basified with ammonia solution and extracted twice, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude material was washed with diethyl ether several times and dried under vacuum to get 3-amino-4-chloro-5-(piperazin-1-yl)benzonitrile (1.0 g) as a brown color solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:13][N:14](C(OCC3C=CC=CC=3)=O)[CH2:15][CH2:16][N:8]3[C:9]=2[C:4]=1[CH:5]1[CH2:29][CH2:28][CH2:27][CH:6]1[CH2:7]3.FC(F)(F)S(O)(=O)=O.C1(OC)C=CC=CC=1.[OH-].[Na+].C(Cl)[Cl:51]>O>[ClH:51].[F:30][C:2]([F:1])([F:31])[C:3]1[CH:12]=[CH:11][C:10]2[CH2:13][NH:14][CH2:15][CH2:16][N:8]3[C:9]=2[C:4]=1[CH:5]1[CH2:29][CH2:28][CH2:27][CH:6]1[CH2:7]3
Reactant: O=C(OCc1ccccc1)N1CCN2CC3CCCC3c3c(C(F)(F)F)ccc(c32)C1
Reactant: ClCCl
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: O
Product: Cl
Product: FC(F)(F)c1ccc2c3c1C1CCCC1CN3CCNC2
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution containing the compound of example 29 (0.345 g, 0.80 mmol) dissolved in methylene chloride (1.2 mL) were added trifluoromethane sulfonic acid (0.496 mL, 5.6 mmol) and anisole (0.261 mL, 2.4 mmol) at room temperature. After 1 hour, the reaction was completed and the reaction mixture was basified to a pH of 12 with 1N NaOH. Water and methylene chloride were added and the reaction mixture was stirred for 45 minutes. The contents of the flask were transferred to a separatory funnel, and the aqueous layer was extracted with methylene chloride (4×). The combined organic layers were dried with magnesium sulfate, filtered and concentrated to give yellow oil. Further purification (10% ammonia in 2M solution of ethanol/Ethyl acetate) yielded 0.190 g of the free amine product (80%). The free amine was then taken and converted into the hydrochloride salt. After the compound was dissolved in diethyl ether, HCl in a 2M solution in diethyl ether (0.32 mL, 0.64 mmol) was added. After the mixture stirred for 30 minutes, the resulting yellow precipitate was filtered off to give 0.1932 g of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[Br:19])[CH:12]=[C:11]([C:20]([O:22]CC)=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O[Li].O.Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[Br:19])[CH:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)c2c(Br)cccc2c1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c2c(Br)cccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
Ester 8 (2.29 g, 5.94 mmol) was dissolved in a 3:1:1 mixture of THF:CH3OH:H2O (0.1 M). LiOH—H2O was added and the reaction mixture was stirred at 25° C. for 24 h. Upon completion, the reaction mixture was acidified to pH 1 with the addition of 10% aqueous HCl. A precipitate formed during the acidification and it was collected by vacuum filtration. The remaining aqueous layer was then extracted with ethyl acetate (3×). The organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The filtered and extracted products were combined to give 9 (2.09 g, 100%) as a pale yellow solid. 1H NMR (DMSO-d6, 500 MHz) δ 8.23 (s, 1H), 8.10 (d, J=6.0 Hz, 1H), 7.91 (d, J=6.5 Hz, 1H), 7.61 (d, J=7.0 Hz, 2H), 7.55 (s, 1H), 7.43-7.39 (m, 3H), 7.33 (t, J=7.0 Hz, 1H), 5.35 (s, 2H). 13C NMR (DMSO-d6, 125 MHz) δ 166.7, 153.8, 136.2, 135.9, 135.0, 129.8, 128.8, 128.2, 127.8, 127.7, 127.5, 124.7, 123.8, 115.5, 107.0, 70.4. IR (film) νmax 3368, 2969, 1680 cm−1. ESI-TOF HRMS m/z 357.0125 (M+H+, C18H13BrO3 requires 357.0121).
Reaction SMILES: CO[CH:3]([O:14]C)[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([N+:11]([O-])=O)[CH:5]=1.[C:16]1([NH:22][C:23](=O)[CH3:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:24][C:23]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:14])=[CH:5][C:6]=2[N:11]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: COC(OC)c1ccc(I)c([N+](=O)[O-])c1
Product: Cc1nc2cc(C=O)ccc2n1-c1ccccc1
Yield: 25.4 %

Procedure:
The title compound was prepared with the analogous procedure described in example 3 using 4-Dimethoxymethyl-1-iodo-2-nitrobenzene (155 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) as starting materials to yield the title compound as pale yellow oil (30 mg, 25% yield). 1H NMR (DMSO) δ 2.50 (s, 3 H), 7.31 (d, J=8.3 Hz, 1 H), 7.61-7.68 (m, 5 H), 7.82 (d, J=8.3 Hz, 1 H), 8.25 (s, 1 H), 10.10 (s, 1 H); 13C NMR δ 13.6, 111.4, 120.1, 124.2, 127.0, 129.8, 130.2, 132.3, 139.1, 154.7, 158.3, 192.4. HRMS (FAB): cal. for C15H13N2O [M+H+]: 237.1028; found: 237.1024.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[F:14][CH:15]([F:24])[O:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-:26].[K+].[K+]>>[F:14][CH:15]([F:24])[O:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[O:23][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]([OH:13])=[O:26]
Reactant: O=C([O-])[O-]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: Oc1cccc(OC(F)F)c1
Agent: [K+]
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1Oc1cccc(OC(F)F)c1

Procedure:
The title compound was prepared using 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde and 3-difluoromethoxyphenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[CH:12]=2)[NH:7][C:6]=1[Si](C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:16])=[O:17])[CH:12]=2)[NH:7][CH:6]=1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)c(CCCO)c2c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCO)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a solution of 0.0551 g (0.155 mmol, 1.0 equiv.) of 3-(3-hydroxypropyl)-2-trimethylsilyl-N-methyl-1H-indole-5-methanesulfonamide in 2 mL of methylene chloride at 0° C. was added 0.01 mL (0.155 mmol, 1.0 equiv.) of trifluoroacetic acid. After 15 minutes the reaction was allowed to warm to room temperature. After a total of thirty minutes the reaction was poured into 15 mL of ethyl acetate and washed with 5 mL of saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 0.0413 g (95%) of 3-(3-hydroxypropyl)-N-methyl-1H-indole-5-methanesulfonamide, homogeneous by 1H NMR and TLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[C:11]([Cl:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
To a solution of 4-benzyloxy-2-chlorobenzoic acid (788 mg) in tetrahydrofuran (7.9 ml) was dropwise added a boran-dimethyl sulfide complex (10.0 M, 0.6 ml) at room temperature under a nitrogen atmosphere, and the mixture was refluxed under heating for 2.5 hr. The reaction mixture was allowed to cool to room temperature and 1N hydrochloric acid (1.5 ml) was dropwise added carefully, which was followed by stirring for 30 min. Water was added to the reaction mixture and the resulting product was extracted three times with ethyl acetate. The organic layers were combined, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the objective compound (778 mg) as a white powder.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28](O)=[O:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.C(Cl)(=O)C(Cl)=O.[C:46]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])(=[O:49])[NH:47][NH2:48]>C(Cl)Cl.CN(C=O)C>[C:51]([O:50][C:46]([NH:47][NH:48][C:28]([C:24]1[CH:23]=[C:22]([O:21][C:17]2[CH:16]=[C:15]3[C:20](=[CH:19][CH:18]=2)[N:12]([C:10](=[O:11])[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:32])([F:1])[F:31])[CH:4]=2)[CH:13]=[CH:14]3)[CH:27]=[CH:26][N:25]=1)=[O:29])=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1

Procedure:
To a solution of acid 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carboxylic acid, Example 28-A, (0.100 g, 0.226 mmol) in DCM (5 mL) is added Et3N (0.09 mL), DMF (2 drops) and oxalyl chloride (0.17 mL, 0.340 mmol, 2.0 M DCM). After 0.5 h tert-butyl carbazate is added (0.045 g, 0.340 mmol). After 1.5 h the solution is diluted with DCM (10 mL) and then washed with pH 7 buffer (15 mL). The organic layer is then dried (Na2SO4), filtered, and concentrated. The residue is separated via FCC (30-60% EtOAc/heptane) to give N′-{4-[1-(3-Trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyridine-2-carbonyl}-hydrazinecarboxylic acid tert-butyl ester. MS (ESI) m/z 484.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH2:23][OH:24])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].[H-].[Na+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Br.Cl>CN(C)C=O.C(OCC)(=O)C>[OH:10][C:4]1[CH:5]2[CH2:9][CH:8]([CH2:7][CH2:6]2)[C:2](=[O:1])[C:3]=1[C:11]([C:13]1[C:14]([CH2:23][O:24][CH2:27][CH:29]2[CH2:30][O:31]2)=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1)=[O:12]
Reactant: O=C(C1=C(O)C2CCC(C2)C1=O)c1ccc(C(F)(F)F)nc1CO
Reactant: BrCC1CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(C1=C(O)C2CCC(C2)C1=O)c1ccc(C(F)(F)F)nc1COCC1CO1
Reaction time: 18 h

Procedure:
1.5 g of 4-hydroxy-3-(2-hydroxymethyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one are dissolved in 15 ml of dimethylformamide and, at room temperature, treated with 0.4 g of sodium hydride (80% suspension in oil, 0.013 mol), a little at a time. After 15 minutes at a temperature of 22° C., 3 ml (0.036 mol) of epibromohydrin are added dropwise, and the reaction mixture is stirred at this temperature for another 18 hours. Ethyl acetate is then added, and the mixture is acidified to pH 3 using 10% hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the crude product is purified chromatographically (mobile phase: toluene/ethyl alcohol/dioxane/triethylamine/water 100:40:20:20:5 parts by volume). This gives the title compound (triethylamine salt) in the form of a yellowish resin, which is released similarly to example H4. Trituration with hexane gives 600 mg of pure 4-hydroxy-3-(2-oxiranylmethoxy-methyl-6-trifluoromethylpyridin-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one of melting point 54-56° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17][C:18](OC)=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH2:24]>>[C:1]([C:5]1[CH:6]=[C:7]([C:16](=[O:22])[CH2:17][C:18]([NH:24][CH3:23])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: COC(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CNC(=O)CC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 2 h

Procedure:
A 500-mL flask was charged with methyl 3-(3,5-ditert-butyl-4-hydroxy-phenyl)-3-oxo-propanoate (24.3 g, 79.3 mmol) and a 40% methylamine solution (55 g). The solution was stirred for 2 h. The conversion of the starting material (Rf 0.91) to the title compound (Rf 0.4) was monitored by TLC using 1:1 ethyl acetate-hexane as solvent and UV detection of the substances. The solution was diluted with 2-propanol (100 mL) and evaporated. The solid residue was taken up in boiling 2-propanol (ca. 100 mL) and evaporated again. The residue was again taken up in boiling toluene (ca. 75 mL) and the hot solution was concentrated to afford a crystalline suspension. This suspension was re-dissolved by heating and the hot solution was diluted with cyclohexane (80 mL) to cause immediate crystallization. The suspension was homogenized by reheating, allowed to cool to room temperature, then refrigerated overnight and filtered. The filter cake washed with cyclohexane and hexane, dried to constant weight at 65° C. and 20 torr to afford 22.77 g of the title compound. This material was recrystallized by dissolving in boiling toluene (ca. 120 mL) followed by the addition of cyclohexane (100 mL). The suspension was allowed to cool to room temperature, then refrigerated and filtered. The filter cake was washed with cyclohexane then hexane and dried to constant weight at 65° C. and 20 ton to afford 22.03 g of the title compound (91%). TLC (1:1 ethyl acetate-hexane) Rf 0.48; 1H-NMR (300 MHz, DMSO-d6) δ 1.37 (9H, s), 2.57 (3H, d, J=4.6 Hz), 3.73 (2H s), 7.73 (2H, s), 7.85 (1H, s), 8.08 (1H, br s).
Reaction SMILES: OCCNCCO.[OH:8][CH:9]([CH2:17][OH:18])[CH2:10][NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15].BrCC(OC)=O.Br[CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28]>>[OH:16][CH:13]([CH2:14][OH:15])[CH2:12][N:11]([CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([OH:29])=[O:28])[CH2:10][CH:9]([OH:8])[CH2:17][OH:18]
Reactant: COC(=O)C(Br)C(C)C
Reactant: OCC(O)CNCC(O)CO
Agent: COC(=O)CBr
Solvent: OCCNCCO
Product: CC(C)C(C(=O)O)N(CC(O)CO)CC(O)CO

Procedure:
By conducting the procedure described in Example 1, except that the bis-(2-hydroxyethyl)amine is replaced by an equimolar quantity of bis-(2,3-dihydroxypropyl)amine and the methyl bromoacetate is replaced by an equimolar quantity of methyl 2-bromoisovalerate, there is obtained 2-[N,N-bis-(2,3-dihydroxypropyl)amino]isovaleric acid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:8][CH:9]=1)=[O:4].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:6]2[CH:7]=[CH:8][CH:9]=[C:5]2[C:3](=[O:4])[CH2:2][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[C:12]([F:18])[CH:13]=1
Reactant: O=C(CCl)c1cccn1Cc1ccc(Cl)cc1F
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(c2ccccc2)CC1)c1cccn1Cc1ccc(Cl)cc1F

Procedure:
A mixture of 2-chloroacetyl-1-(4-chloro-2-fluorobenzyl)pyrrole, N-phenylpiperazine and triethylamine in methanol is treated by the procedure described in Example 1b to produce 1-(4-chloro-2-fluorobenzyl)-2-[α-(4-phenylpiperazino)acetyl]pyrrole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:31])[NH:6][C:7]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([NH:22][C:23]([CH2:25][O:26]C(=O)C)=[O:24])=[C:17]([CH3:30])[CH:16]=1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+].Cl>CO.ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:31])[NH:6][C:7]([C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([NH:22][C:23](=[O:24])[CH2:25][OH:26])=[C:17]([CH3:30])[CH:16]=1)=[N:8]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(NC(=O)COC(C)=O)c(C)c3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(NC(=O)CO)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48.9 %

Procedure:
A mixture of 2,6-dimethyl-phenylamine (0.62 mL, 5.0 mmol), DMSO (100 mL), conc. Aqueous HCl (36.5-38%, 5.0 mL), and dried CuCl2 was stirred at 90° C. under nitrogen for 5 h. The reaction was quenched with water. The pH of the mixture was adjusted to ˜8 using a 10% sodium hydroxide solution. The mixture was extracted with ether (3×100 mL). The solution was dried over Na2SO4 and concentrated to dryness. The resulting brown oil was dissolved in dichloromethane (anhydrous, 20 mL) and N-ethyldiisopropylamine (DIPEA, 1.0 mL, 5.8 mmol) was added. The mixture was cooled to 0° C., acetoxyacetyl chloride (0.8 mL, 7.4 mmol) was added slowly. The mixture was stirred at room temperature under nitrogen for 17 h. The mixture was concentrated to dryness and purified by column chromatography. Acetic acid (4-formyl-2,6-dimethyl-phenylcarbamoyl)-methyl ester was obtained as yellow/beige solid (96 mg). A mixture of acetic acid (4-formyl-2,6-dimethyl-phenylcarbamoyl)-methyl ester (96 mg, 0.38 mmol), 2-amino-4,6-dimethoxy-benzamide (74 mg, 0.38 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (96 mg, 0.53 mmol) and dimethylacetamide (3 mL) was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off and washed with water. The filtrate was extracted with dichloromethane, dried over Na2SO4, purified by column chromatography, using (1) 5% methanol/dichloromethane, and (2) 10% methanol/dichloromethane as eluents. Acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methyl ester was obtained as a beige solid (70 mg, 43%). Acetic acid [4-(5,7-dimethoxy-4-oxo-3,4-dihydro-quinazolin-2-yl)-2,6-dimethyl-phenylcarbamoyl]-methyl ester (70 mg, 0.16 mmol) was dissolved in methanol/dichloromethane (10 mL) and a solution of potassium carbonate (442 mg, 20 mmol) in water was added. The solution was stirred at room temperature for 17 h. 2 N HCl was added to adjust the reaction mixture pH to ˜8. The mixture was then concentrated under reduced pressure. The resulting precipitate was filtered off, washed with water, air-dried, then washed with ether and dried, leaving N-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-2-hydroxyacetamide (30 mg, 49%) as a light brown solid. Selected data: MS (ES) m/z: 384.1; MP 190-192° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])[C:4]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:14]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:46]>>[NH2:46][C:6]1[C:5]2[N:14]=[C:2]([CH3:1])[N:3]([CH2:15][CH2:16][C:17]([NH:19][CH2:20][CH2:21][CH3:22])=[O:18])[C:4]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: [NH4+]
Reactant: CCCNC(=O)CCn1c(C)nc2cnc3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCCNC(=O)CCn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
3-(2-Methyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide (610 g, 20.2 mmol) was treated with mCPBA (8.15 g, 35.4 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (7.52 g, 39.5 mmol) according to a modification of the method described in Part D of Example 8. The reaction was not washed with 10% aqueous sodium hydroxide prior to the addition of ammonium hydroxide. The crude product was twice triturated with ethyl acetate and isolated by filtration. The solid was then purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol). The product was then triturated sequentially with 10% aqueous sodium hydroxide and acetone (2×). The solid was then purified again by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 95:5 to 90:10). The resulting solid was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight to provide 0.477 g of 3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-N-propylpropanamide as an off-white powder, mp 188-189° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6]([N+:21]([O-])=O)=[CH:7][C:8]([CH3:20])=[C:9]([C:11]2[CH2:16][CH2:15][CH:14]([N:17]([CH3:19])[CH3:18])[CH2:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2]>CO.[Pd]>[CH3:19][N:17]([CH3:18])[CH:14]1[CH2:13][CH2:12][CH:11]([C:9]2[C:8]([CH3:20])=[CH:7][C:6]([NH2:21])=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1C1=CCC(N(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)c(OC(C)C)cc1C1CCC(N(C)C)CC1
Reaction time: 6 h

Procedure:
To a solution of 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-N,N-dimethylcyclohex-3-enamine (0.1 mmol) in 10 mL of MeOH, is added Pd/C (5 mg) under argon. The suspension is stirred under 1 atm. H2 for 6 hours. After filtering, solvent is removed and 4-(4-(dimethylamino)cyclohexyl)-2-isopropoxy-5-methylaniline is obtained. MS (ES+): 291.24 (M+1)+.
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:37]([CH:39]1[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]1)#[N:38]>>[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:33][N:34]([CH:42]3[CH2:43][CH2:44][CH:39]([C:37]#[N:38])[CH2:40][CH2:41]3)[CH2:35]2)=[N:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: N#CC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CN(C3CCC(C#N)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt (as prepared in Example 81, Step D) and 4-cyano-cyclohexanone using the procedure described in Step E of Example 1.