Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][CH2:11][CH:12]=O.C(N(CC)CC)C.Cl.[CH3:22][O:23][NH2:24]>CO>[CH3:22][O:23][N:24]=[CH:12][CH2:11][CH2:10][C:3]1[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=CCCc1c(Cl)cc(Cl)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=CCCc1c(Cl)cc(Cl)cc1Cl
Temperature: 60 °C
Yield: 104.2 %

Procedure:
To a solution of 3-(2,4,6-trichloro-phenyl)-propionaldehyde (0.45 g, 1.8 mmol) in methanol (5 ml), triethylamine (0.4 ml, 2.8 mmol) followed by O-methylhydroxylamine-hydrochloride (0.24 g, 2.8 mmol) was added and the mixture was heated at 60° C. for 2 hours. When the TLC confirmed the completion of the reaction, the reaction mass was allowed to attain ambient temperature and quenched with water and methanol was removed with a rotavapor. The resulting aqueous solution was extracted with ethyl acetate (3×30 ml). The combined ethyl acetate layers were washed with water and dried over sodium sulfate before complete evaporation of the solvents to give the crude mass. The resulting crude mass was purified over column chromatography (silica gel 60-120 mesh, 1% ethyl acetate in hexane) to afford 3-(2,4,6-trichloro-phenyl)-propionaldehyde O-methyl-oxime (0.5 g, 80%)
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])C.CCOCC>C(O)C>[C:24]1([CH2:23][N:20]2[CH2:19][CH2:18][N:17]([C:15]([NH:14][C:8]3([C:6]([OH:7])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:16])[CH2:22][CH2:21]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1(NC(=O)N2CCN(Cc3ccccc3)CC2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=C(NC1(C(=O)O)CCCCC1)N1CCN(Cc2ccccc2)CC1
Yield: 42 %

Procedure:
600 ml of 1N aqueous sodium hydroxide solution was added to a solution of 7.62 g (20 mmol) of 1-[[(4-phenylmethyl-1-piperazinyl)carbonyl]amino]cyclohexanecarboxylic acid ethyl ester in 300 ml of ethanol, and the mixture was heated under reflux for 2 hours. After ether was added to the reaction solution to wash it, the aqueous layer was neutralized by concentrated hydrochloric acid and extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.90 g (42%) of the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]3[C:9]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:27](C)=O.[Na+]>C(Cl)Cl.[OH-].[Na+]>[CH3:27][N:12]1[CH2:11][CH2:10][C:9]2[C:15](=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)[CH2:14][CH2:13]1
Reactant: c1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1CCc2nn(-c3ccccc3)c(-c3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.5 %

Procedure:
To a solution of 33.5 mg of 2,3-diphenyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 176, Step D) in 5 mL of CH2Cl2 were added 0.15 g of paraformaldehyde and 0.15 g of NaBH(OAc)3. The mixture was stirred at RT for 12 h and was diluted with 20 mL of 1 M NaOH. After stirring for 3 h, the mixture was extracted with CH2Cl2 (2×10 mL) and the combined organic layers were concentrated. Chromatography on SiO2 (0 to 5% 2 M NH3 in MeOH/CH2Cl2) gave 22.3 mg of the title compound as a white solid. MS (ESI): exact mass calculated for C20H21N3, 303.17; found, m/z 304.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.35-7.30 (m, 3H), 7.27-7.21 (m, 2H), 7.20-7.16 (m, 3H), 7.15-7.12 (m, 2H), 3.06-3.02 (m, 2H), 2.83-2.79 (m, 2H), 2.72-2.67 (m, 4H), 2.50 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH3:27])[CH:23]=1)[CH2:15][CH3:16]>C(N(CC)CC)C>[CH2:14]([O:17][C:18]1[CH:19]=[C:20]([N:28]2[CH2:29][CH2:30][N:31]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:32][CH2:33]2)[CH:21]=[C:22]([O:24][CH2:25][CH2:26][CH3:27])[CH:23]=1)[CH2:15][CH3:16]
Reactant: CCCOc1cc(OCCC)cc(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCOc1cc(OCCC)cc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 1-(3,5-dipropoxyphenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(3,5-dipropoxyphenyl) 4-(p-nitrobenzyl)piperazine.
Reaction SMILES: C1(C[O:8][CH2:9][CH:10]([O:20][C:21](=[O:77])[CH2:22][CH2:23][C:24]2([CH2:53][CH2:54][C:55]([O:57][CH:58]([CH2:68][O:69]CC3C=CC=CC=3)[CH2:59][O:60]CC3C=CC=CC=3)=[O:56])[CH2:29][C:28](=[O:30])[C:27]3[CH:31]=[CH:32][C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]4[C:52]5[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=5[CH:46]=[CH:45][CH:44]=4)=[C:34]([CH2:35][CH2:36][CH3:37])[C:26]=3[O:25]2)[CH2:11][O:12]CC2C=CC=CC=2)C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[OH:60][CH2:59][CH:58]([O:57][C:55](=[O:56])[CH2:54][CH2:53][C:24]1([CH2:23][CH2:22][C:21]([O:20][CH:10]([CH2:11][OH:12])[CH2:9][OH:8])=[O:77])[CH2:29][C:28](=[O:30])[C:27]2[CH:31]=[CH:32][C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][C:43]3[C:52]4[CH2:51][CH2:50][CH2:49][CH2:48][C:47]=4[CH:46]=[CH:45][CH:44]=3)=[C:34]([CH2:35][CH2:36][CH3:37])[C:26]=2[O:25]1)[CH2:68][OH:69]
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OC(COCc1ccccc1)COCc1ccccc1)(CCC(=O)OC(COCc1ccccc1)COCc1ccccc1)CC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)OC(CO)CO)(CCC(=O)OC(CO)CO)CC2=O
Yield: 74 %

Procedure:
The titled product of Example 46 (0.258 g, 0.246 mmol) was dissolved in 25 ml of tetrahydrofuran, and then hydrogenated at room temperature using hydrogen at atmospheric pressure and 10% palladium on carbon (Pd/C) as catalyst. The insolubles were removed by filtration, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel column. Elution with 5% methanol/ethyl acetate afforded 125 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(O)(=O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Cl
Reactant: Nc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1Nc1ccccc1

Procedure:
0.6 g (2.46 mmol) of 4,6-dichloro-3-nitro-quinoline (step c)) and 0.247 ml (2.71 mmol) of aniline in 4 ml of acetic acid are stirred at room temperature for 4 h (tlc-control). A precipitate is formed. The reaction mixture is poured into 150 ml of water. The solid is filtered off and washed with water and hexane. The filtrate is dissolved in ca. 50 ml of diethylether, filtered from insoluble material, and the solvent is evaporated. The residue (title compound, yellow crystals) is dried at 60° C. overnight. mp: 174-175° C.; ES-MS: m/e0=300.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[N:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCOCC4)cc3c2)nc1)N1CCOCC1

Procedure:
The product from Example 44E and morpholine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 8.70 (m, 1H), 8.24 (d, J=1.8 Hz, 1H), 7.95 (m, 3H), 7.58 (d, J=8.7 Hz, 1H), 6.82 (s, 1H), 3.3-4.1 (m, 16H), 3.37 (t, J=7.5 Hz, 4H); MS (DCI) m/z 422 (M+H)+;
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[N:9][C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O-:24][CH2:25][CH3:26].[Na+]>C(O)C>[CH2:25]([O:24][C:2]1[C:11]2[CH:10]=[N:9][C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:26]
Reactant: CCOC(=O)c1cnc2nc(N3CCN(C)CC3)ncc2c1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnc2nc(N3CCN(C)CC3)ncc2c1OCC
Yield: 90.7 %

Procedure:
A mixture containing 3.0 g of ethyl 5-chloro-2-(4-methyl-1-piperazinyl)pyrido[2,3-d]pyrimidine-6-carboxylate, 0.7 g of sodium ethoxide, and 50 ml of absolute ethanol was heated to reflux for 2 hours. The ethanol was removed by distillation in vacuo, the residue was extracted with chloroform and the extract washed with water, and dried over anhydrous magnesium sulfate. After the solvent was distilled off the residue was crystallized from n-hexane to give 2.8 g of the product as pale yellow needles, m.p. 105° - 108°C.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12](=[O:31])[C:13]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].O>CS(C)=O>[CH3:30][C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:13]3([C:12]([O:11][CH2:9][CH3:10])=[O:31])[CH2:4][CH:14]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:21]=2)[N:26]=1
Reactant: CCOC(=O)C=C(C(=O)OCC)c1ccc2nc(C)ccc2c1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1(C(=O)OCC)c1ccc2nc(C)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
Sodium hydride (0.52 g) was added in small portions to a stirred suspension of trimethylsulfoxonium iodide (2.81 g) in DMSO (28 mL) at room temperature. After 0.5 h, the clear reaction mixture was cooled to 0° C. and a solution of diethyl-2-(2-methyl-6-quinolinyl)-2-butenedioate (2.0 g) in DMSO (14 mL) was quickly added and the stirring continued for 0.5 h after which time water (30 mL) was added. The mixture was extracted twice with ether (30 mL), the organic phase was washed with saturated ammonium chloride, dried over sodium sulphate and evaporated under reduced pressure to give 2 g of the title product which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:17])[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([Cl:18])[CH:3]=1.Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Cl.[I-].[K+]>C(O)C>[Cl:18][C:4]1[CH:3]=[C:2]([N:1]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][C:10](=[O:17])[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: Cc1cc(N)cc(Cl)c1NC(=O)CC1CCCC1
Reactant: ClCCOCCCl
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(N2CCOCC2)cc(Cl)c1NC(=O)CC1CCCC1
Temperature: 170 °C
Yield: 41 %

Procedure:
N-(4-Amino-2-chloro-6-methyl-phenyl)-2-cyclopentyl-acetamide (830 mg), bis-(2-chloroethyl)ether (3.35 mL) and potassium iodide (470 mg) were mixed in absolute ethanol (33 mL) and heated to 170° C. for 1 hour in a sealed microwave process vial. The crude mixture was concentrated in vacuo and purified by flash chromatography to furnish 390 mg (41%) of the title compound as a white solid. LC-MS (m/z) 337 (MH+); tR=2.61, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.22 (m; 2H), 1.51 (m, 2H), 1.61 (m, 2H), 1.77 (m, 2H), 2.11 (s, 3H), 2.25 (m, 1H), 2.26 (m, 2H), 3.10 (m, 4H), 3.71 (m, 4H), 6.80 (d, 1H), 6.84 (d, 1H), 9.18 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH3:35])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][CH3:35])[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: CCN(c1ccc(I)cc1)c1ncccn1
Product: CCN(c1ccc(/C=C/CC(NC(=O)c2c(Cl)cccc2Cl)C(=O)OC)cc1)c1ncccn1
Yield: 72.9 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (214 mg) was reacted with N-(4-iodophenyl)-N-ethylpyrimidin-2-amine (254 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(ethyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (258 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=4/1→hexane/ethyl acetate=2/1 hexane/ethyl acetate=1/2) was used for purification.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CC)CC)C.[OH:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=O>CO>[NH2:4][C:3]1[O:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: O=C(CO)c1ccc(F)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: N#Cc1c(-c2ccc(F)cc2)coc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of malononitrile (0.31 g, 4.65 mmol) and triethylamine (0.65 ml, 4.65 mmol) in methanol (5 ml) was added drop-wise to a stirred suspension of 2-hydroxy-4′-fluoroacetophenone (0.65 g, 4.22 mmol) in methanol (16 ml) under a nitrogen atmosphere at ambient temperature. When the addition was complete, the mixture was stirred for 18 hr at ambient temperature. The solvent was then removed in vacuo, water (50 ml) was then added to the residue and the mixture was extracted with dichloromethane (3×50 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude 2-amino-4-(4′-fluorophenyl)-3-furonitrile which was partially purified by flash chromatography (silica) eluting with dichloromethane and ethyl acetate (1:1). This gave a 3.5:1 mixture of the product and 2-hydroxy-4′-fluoroacetophenone (0.60 g), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:30](I)[CH2:31][CH2:32][CH3:33]>O>[CH2:30]([N:1]([CH2:4][CH2:5][CH2:10][CH3:9])[C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1C
Reaction time: 0.5 h
Yield: 122.4 %

Procedure:
To a solution of 2-amino-5-mesityl-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (100 mg, 0.34 mmol) and N,N-dimethylformamide (2 ml) was added sodium hydride (60% in oil, 27 mg, 0.66 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of n-BuI (184 mg, 1.00 mmol) and N,N-dimethylformamide (1 ml) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 1 hour, the mixture was diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (4:1) to give 85 mg (62%) of the title compound as an oil.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH3:16])[C:5]1[N:30]([CH2:31][CH:32]([OH:34])[CH3:33])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: CC(O)CN
Reactant: COc1cc2c(cc1OC)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1OC)-c1c(ccn1CC(C)O)C2
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-5,6-dimethoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.56 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 0.91 g (40%) of (RS)-1-(1,4-dihydro-6,7-dimethoxy-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol was obtained as an oil.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.ClCCl.Cl.ClCCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:4]1(/[CH:3]=[CH:2]/[C:1]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:1](=[O:10])/[CH:2]=[CH:3]/[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:15][CH:14]=2)=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(/C=C/c1ccccc1)Nc1ccc(OC(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Cinnamoyl chloride (16.79 g, 100.8 mmoL) was added to a solution of 4-aminophenol (5.00 g, 45.8 mmol) and DMAP (0.56 g, 4.58 mmol) in pyridine (5mL). The reaction mixture was stirred at room temperature for 30 min whereupon a solid mass formed. Dichloromethane (50mL) was added and the resultant suspension was stirred at room temperature for 2 h. The reaction mixture was poured into 10% hydrochloric acid/dichloromethane and shaken. The precipitated white solid was removed by filtration, washed with dichloromethane, 10% hydrochloric acid and then dichloromethane again. The organic layer of the filtrate was separated and washed with 10% hydrochloric acid (×2) and brine, dried (Na2SO4) and evaporated to give the title compound (15.1 g, 89%). 1HNMR (300 MHz) (CDCl3) δ 6.55 (1H, d, J=16 Hz), 6.64 (1H, d, J=16 Hz), 7.18 (2H, d), 7.35-7.45 (6H, m), 7.58 (4H, m), 7.67 (2H, m), 7.78 (1H, d, J=16) and 7.88 (1H, d, J=16).
Reaction SMILES: [C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[C:14]2[C:13](=[O:24])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:26]([F:29])([F:28])[F:27])[OH:25])([O:3]CC)=[O:2].O.[OH-].[Li+].Cl>C(O)C.O>[C:1]([CH:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[N:23])[CH:17]=2)[C:14]2[C:13](=[O:24])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]1([C:26]([F:28])([F:29])[F:27])[OH:25])([OH:3])=[O:2]
Reactant: CCOC(=O)C1C(c2cccc(C#N)c2)C2=C(CCCC2=O)NC1(O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(C2C3=C(CCCC3=O)NC(O)(C(F)(F)F)C2C(=O)O)c1
Temperature: 90 °C
Yield: 84.6 %

Procedure:
A suspension of 3-carboethoxy-2-trifluoromethyl-2-hydroxy-4-(3-cyanophenyl)-4,6,7,8-tetrahydro-5(1H )-quinolone (3.39 g) in ethanol (20 ml) and water (20 ml) was treated with lithium hydroxide monohydrate (0.75 g). The mixture was heated at 90° C. for 1.5 hours, diluted with water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts were washed (water and brine), dried, filtered, and evaporated to yield a foam which was purified by chromatography (ethyl acetate and ethyl acetate/methanol, 3:1) to afford 3-carboxy-2-trifluoromethyl-2-hydroxy-4-(3-cyanophenyl)-4,6,7,8-tetrahydro-5(1H)-quinolone (2.67 g ) as a pale yellow foam; MS: m/z=381(m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](Br)[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[O:6].[OH:20][C:21]1C=C(C=CC=1)C=O>>[CH3:21][O:20][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:5]=[O:6]
Reactant: CCCCCCCCOc1c(Br)cc(C=O)cc1Br
Reactant: O=Cc1cccc(O)c1
Product: CCCCCCCCOc1ccc(C=O)cc1OC

Procedure:
The title compound was prepared using a procedure analogous to Aldehyde 3 substituting 3-methoxy-4-hydroxybenzaldehyde for 3-hydroxybenzaldehyde: ESI-MS 265.2 (M+H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[CH:24][N:25](COCC[Si](C)(C)C)[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:21][C:22]1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH3:19])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 56.9 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.053 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from boiling IPA, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-methylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.043 g, 0.103 mmol, 56.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.17 (br. s., 1H), 8.25 (m, 1H), 7.78 (s, 1H), 7.50 (m, 1H), 7.44 (s, 1H), 7.36 (t, J=8.03 Hz, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 4.54 (d, J=5.36 Hz, 2H), 2.33 (s, 3H). LC-MS (ES−) m/z 417.04, 419.01 [M−1]. LC-MS (ES+) m/z 418.79, 420.06 [M+H].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(I)ccc21

Procedure:
This compound was prepared from 5-iodo-1H-indole and benzenesulfonylchloride by the method outlined under 1.a).