Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([O:22][CH3:23])=[C:14]([Cl:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Reactant: O=C1CCC(=O)N1Cl
Product: COc1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 5, intermediate from (4R,9aR)-6-methoxy-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-chlorosuccinimide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1F.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1F
Product: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
4-Amino-2,3-difluoro-5-nitro-benzoic acid methyl ester 4 (23.48 g, 101.1 mmol), the product of Example 1, Step C, is suspended in xylenes (125 mL) and aniline (92 mL, 1011 mmol) is added. The reaction mixture is stirred at 125° C. for 16 hours under N2. The reaction mixture is cooled to room temperature and solids precipitate out of solution. The solids are collected by filtration and are washed with xylenes and then diethyl ether. Recovered 22.22 g (72.78 mmol) of yellow solid which is pure desired product. The filtrate is concentrated under reduced pressure, redissolved in methylene chloride and flushed through a plug of silica gel eluting with methylene chloride. The desired fractions are concentrated under reduced pressure to give a brown solid which is triturated with diethyl ether to give 5.47 g (17.91 mmol) of yellow solid which is pure desired product. Combined product yield is 27.69 g (90%). MS APCI (−) m/z 304 (M−1) detected.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[C:22]1=[O:37].[N:38]1([C:43]2[CH:44]=[CH:45][C:46](/[CH:51]=[CH:52]/[C:53](O)=[O:54])=[N:47][C:48]=2[O:49][CH3:50])[CH:42]=[CH:41][N:40]=[CH:39]1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(Cl)CCl>[N:38]1([C:43]2[CH:44]=[CH:45][C:46](/[CH:51]=[CH:52]/[C:53]([NH:20][N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:34])([F:35])[F:36])[C:22]3=[O:37])=[O:54])=[N:47][C:48]=2[O:49][CH3:50])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: COc1nc(/C=C/C(=O)O)ccc1-n1ccnc1
Reactant: NN1CCCC(c2ccccc2C(F)(F)F)C1=O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1nc(/C=C/C(=O)NN2CCCC(c3ccccc3C(F)(F)F)C2=O)ccc1-n1ccnc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 130.3 %

Procedure:
IPEA (742 μL), EDC (206 mg) and HOBT (146 mg) were added to a mixture of 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (185 mg), (E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylic acid (340 mg) and DMF (5 mL), and the reaction solution was stirred at room temperature for 14 hours. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate→ethyl acetate:methanol=9:1) to obtain the title compound (453 mg). The property value of the compound is as follows.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([Cl:31])=[O:30])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[ClH:31].[CH2:21]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:30])=[CH:32][CH:33]=1)[CH2:22][CH2:23][CH3:24]
Reactant: NCCCSc1ccncc1
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 72.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 0.93 ml (4.96 mmol) of 4-n-butylbenzoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minute. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.10 g of the desired compound (free base) (80.7%, colorless wax), mp: 46.0°-47.0° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:61](O)=[O:62])[CH2:56][CH2:57][C:58](=[O:60])[NH2:59])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>>[C:44]([NH:54][C@H:55]([C:61]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:62])[CH2:56][CH2:57][C:58](=[O:60])[NH2:59])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-glutamine.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[Cl:14])(=[O:3])[CH3:2].NC1C(C)=CC(CN)=CC=1Cl.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([NH:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[Cl:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C)cc(C#N)cc1Cl
Agent: Cc1cc(CN)cc(Cl)c1N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)cc(CN)cc1Cl

Procedure:
Step G (2): 4-acetamido-3-chloro-5-methylbenzonitrile was reduced to 4-amino-3-chloro-5-methylbenzylamine by heating it at reflux with 2.2 eq. of LAH in THF for 2 hrs. 1H NMR (500 MHz, CD3OD) δ 7.31 (s, 1 H), 7.17 (s, 1 H), 3.73 (s, 2 H), 2.23 (s, 3 H), 2.15 (s, 3 H).
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:25]=[C:26]([CH:38]=[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:40]=1)[CH2:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH:30]=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[BH4-].[Na+].Cl>C1COCC1.CCO>[CH2:42]([O:41][C:39]1[CH:38]=[C:26]([CH:25]=[C:24]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:40]=1)[CH2:27][C:28]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:29]=1[CH2:30][OH:31])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1cc(Cc2cc(OC)ccc2C=O)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCOc1cc(Cc2cc(OC)ccc2CO)cc(OCCCCCCCCCCCCCCCCCCCCCC)c1
Reaction time: 3.5 h
Yield: 94 %

Procedure:
2-(3′,5′-Di(docosyloxy)benzyl)-4-methoxybenzaldehyde (450 mg, 0.50 mmol) was dissolved in THF-EtOH (4 ml+0.5 ml), sodium borohydride (34 mg, 0.90 mmol) was added, and the mixture was stirred for 3.5 hr. 1N Hydrochloric acid was added dropwise to the reaction mixture to quench the reaction, and the mixture was extracted with chloroform (15 ml), washed once with 1N hydrochloric acid (10 ml), and 3 times with water (5 ml). The solvent was evaporated, and the obtained residue was precipitated with methanol (5 ml) to give 2-(3′,5′-di(docosyloxy)benzyl)-4-methoxybenzyl alcohol (424 mg, 0.47 mmol, 94%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:19]([F:22])([F:21])[F:20])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]>CCO>[Br:1][C:2]1[C:3]([C:19]([F:22])([F:20])[F:21])=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Br)c(C(F)(F)F)nn1C
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(Br)c(C(F)(F)F)nn1C
Yield: 85 %

Procedure:
To a stirred solution of 4-bromo-5-(2-methoxy-5-nitro-phenyl)-1-methyl-3-trifluoromethyl-1H-pyrazole (0.08 g, 0.20 mmol) in EtOH (0.7 mL) was added SnCl22H2O (0.18 g, 0.80 mmol, 4.0 eq.) and the mixture was stirred at reflux for 2 hours followed by the removal of EtOH under vacuum. The resulting solid was dissolved in EtOAc and 1N NaOH was added until the pH was adjusted to 6. The mixture was stirred overnight and filtered through celite. The aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and evaporated to give 3-(4-bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.06 g, 0.06 g, 0.17 mmol, 99% yield after two steps) as a white solid: LCMS m/z (%)=350 (M+H79Br, 95), 352 (M+H81Br, 100). 1H NMR (400 MHz, CDCl3) δ: 6.78 (dd, J=14.0, 6.0 Hz, 1H), 6.76 (dd, J=8.0, 4.0 Hz, 1H), 6.54 (d, J=4.0 Hz, 1H), 3.67 (s, 3H), 3.66 (s, 3H) 3.36 (broad s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH:3]([OH:32])[CH2:4][N:5](C(OCC1C=CC=CC=1)=O)[C@H:6]([C:11]([NH:13][C@H:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9].C(OC(N[C@@H](CC(C)C)C(O)CN(C(OCC1C=CC=CC=1)=O)[C@H](C(OCC[Si](C)(C)C)=O)CC(C)C)=O)(C)(C)C.[ClH:78].[H][H].O>CO.[Pd].C(Cl)(Cl)Cl>[ClH:78].[ClH:78].[NH2:1][C@@H:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH:3]([OH:32])[CH2:4][NH:5][C@H:6]([C:11]([NH:13][C@H:14]([C:18]([O:20][CH3:21])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)N(CC(O)[C@@H](N)CC(C)C)C(=O)OCc1ccccc1)C(C)C
Reactant: [H][H]
Agent: [Pd]
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)CN(C(=O)OCc1ccccc1)[C@@H](CC(C)C)C(=O)OCC[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NCC(O)[C@@H](N)CC(C)C)C(C)C
Reaction time: 3 h

Procedure:
A solution of 109 mg of (3S)-N-[N-(3-amino-2-hydroxy-5-methylhexyl)-N-[(phenylmethoxy)-carbonyl]-L-leucyl]-L-valine, methyl ester (Isomer B, prepared from N-[(3S)-3-[[(t-butyloxy)carbonyl]-amino]-2-hydroxy-5-methylhexyl]-N-[(phenylmethoxy)carbonyl]-L-leucine, 2-(trimethylsilyl)ethyl ester, Isomer B using a procedure analogous to that described in Example 8 for preparing the corresponding Isomer A) in 3 ml of methanol was treated with 0.63 ml of 1N hydrochloric acid and 75 mg of 10% palladium on charcoal and subjected to a steady stream of hydrogen at 1 atmosphere pressure. After 3 hours, a silica gel TLC run in 9:1, chloroform: methanol, checked with UV and PMA, indicated complete disappearance of the starting compound. The reaction was worked up by filtering through a Celite pad, concentrating the filtrate in vacuo, and recrystallizing the residue from methanol/ether at room temperature, then storing in the freezer overnight to afford 73 mg of partially purified product, melting at 232°-234° C. Chromatography was performed on a 35 ml column of HP-20 resin, eluting with a gradient from 175 ml of 96:3:1 to 2:2:96, water: 1N hydrochloric acid: methanol. The fractions were checked by silica gel TLC run in 5:1:1:1, butanol: pyridine:acetic acid:water and sprayed with ninhydrin. Pooling of product containing fractions followed by lyophilization yielded 17 mg of the title compound as a hydrate with 1.0 mole of water, melting point 125°-140° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[CH3:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:13][C:14]1[N:19]=[CH:18][C:17]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: Cc1ccc(B(O)O)cn1
Product: Cc1ccc(-c2ccc3ncc(C=O)n3c2)cn1
Yield: 40 %

Procedure:
The title compound was prepared by following the procedure as described for Intermediate 1 using 6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde and 6-methylpyridin-3-ylboronic acid. Yield: 40%; 1H NMR (DMSO-d6; 300 MHz): δ 10.0 (s, 1H), 9.74 (s, 1H), 8.79 (d, 1H, J=1.8 Hz), 8.38 (s, 1H), 7.93-7.78 (m, 4H), 7.33 (d, 1H, J=8.1 Hz), 2.66 (s, 3H); MS: m/z 238(M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][N:22]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:25]\[C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:28][CH:27]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(C(F)(F)F)nc1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 5 ml was added 6-(trifluoromethyl) nicotinaldehyde 69 (70.8 mg, 0.404 mmol). PTSA (154 mg, 0.808 mmol) was added, and the reaction mixture stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound (E)-6-methoxy-5-morpholino-2-((6-(trifluoromethyl)pyridin-3-yl)methylene)-2,3-dihydro-1H-inden-1-one 70. The crude 70 was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 32% ethyl acetate in hexane to afford yellow coloured solid 70.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][OH:24])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]([C:8](=[N:23][O:24][CH:33]([CH3:35])[CH3:34])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:19])([F:21])[F:20])=[N:6][CH:7]=1
Reactant: O=C(NCC(=NO)c1ncc(Br)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 13 h
Yield: 63.8 %

Procedure:
To a suspension of 1.80 g of the N-[2-(5-bromo-3-chloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide prepared in Step 3 in Synthetic Example 20 and 0.86 g of potassium carbonate in 10 ml of N,N-dimethylformamide, 1.30 g of 2-iodopropane was added, and the mixture was stirred at room temperature for 13 hours. After completion of the reaction, the reaction mixture was mixed with 100 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:4 to 2:2) as the eluent to obtain 1.26 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:13])[CH2:11][NH2:12].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1.O>C1C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:12][CH2:11][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[OH:13])[CH3:23])=[CH:17][CH:16]=1
Reactant: CC(=O)Cc1ccc(C)cc1
Reactant: NCC(O)c1cc2ccccc2o1
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(CC(C)NCC(O)c2cc3ccccc3o2)cc1

Procedure:
A mixture of 2-(2-benzofuranyl)-2-hydroxy ethanamine (1.0 g) and 4-methylphenylacetone (0.76 g) in benzene (50 ml) was heated under reflux using a Dean and Stark head until the required amount of water had been collected. The solvent was evaporated, replaced with ethanol (50 ml) and the solution hydrogenated at atmospheric pressure over platinum oxide until the theoretical amount of hydrogen had been taken up. The reaction mixture was filtered through diatomaceous earth, the filtrate evaporated and the residue chromatographed on Kieselgel 60. Elution with 2% methanolchloroform gave N-[2-(4-methylphenyl)-1-methylethyl]-2-(2-benzofuranyl)-2-hydroxy ethanamine, as an 80:20 mixture of diastereoisomers, m.p. 92-98 (cyclohexane).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:3])[NH2:2].[Si](Cl)(C)(C)C>ClCCCl>[OH:3][C:1]1[C:4]2[C:5](=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=2)[N:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:2]=1
Reactant: CCOC(=O)C(=O)Nc1c(C)cccc1C(N)=O
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1nc(O)c2cccc(C)c2n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a solution of ethyl 2-(2-carbamoyl-6-methylphenylamino)-2-oxoacetate (490 mg, 1.96 mmol) and TEA (10.4 mL, 75 mmol) in DCE (20 mL) was added TMS-Cl (3.6 mL, 29 mmol) and the solution was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between DCM (100 mL) and saturated aq NaHCO3. The separated aqueous phase was extracted with DCM (2×100 mL) and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 10-40% EtOAc/hexanes to afford ethyl 4-hydroxy-8-methylquinazoline-2-carboxylate as a solid (330 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=7.2 Hz, 3H), 2.58 (s, 3H), 4.39 (q, J=7.2 Hz, 2H), 7.46-7.64 (m, 1H), 7.64 (m, 1H), 8.02 (m, 1H), 12.62 (br s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:11]=[C:12]2[C:18]3=[CH:19][C:20]4[N:21]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:22]5[C:27]([C:28]=4[CH:29]=[C:17]3[N:16]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:13]2=[CH:14][CH:15]=1)=[CH:26][C:25](Br)=[CH:24][CH:23]=5.C([O-])([O-])=O.[Na+].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:18]3=[CH:19][C:20]4[N:21]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:22]5[C:27]([C:28]=4[CH:29]=[C:17]3[N:16]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:13]2=[CH:14][CH:15]=1)=[CH:26][C:25]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[CH:24][CH:23]=5
Reactant: OB(O)c1cccs1
Reactant: CCCCCCCCCCCCn1c2ccc(Br)cc2c2cc3c(cc21)c1cc(Br)ccc1n3CCCCCCCCCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCn1c2ccc(-c3cccs3)cc2c2cc3c(cc21)c1cc(-c2cccs2)ccc1n3CCCCCCCCCCCC

Procedure:
ALIQUAT™ 336 (0.6 g), 2-thiopheneboronic acid (0.921 g, 7.2 mmol), 2,8-dibromo-5,11-didodecylindolo[3,2-b]carbazole (2.252 g, 3 mmol), 2M Na2CO3 solution (7.5 mL, 15 mmol), Pd(PPh3)4 (72 mg, 0.06 mmol) and toluene (10 mL) were added into a 50 mL flask. The mixture was heated to gentle reflux and maintained for 48 h. The reaction mixture was cooled down, organic layer separated, dried, and filtered. The toluene solution was passed through a silica gel column and the solvent was removed. Recrystallization from toluene gave the title compound as a yellow solid. Yield: 1.476 g (61%).
Reaction SMILES: CN(C)CC[O:5][C:6]([O:10][Si](C)(C)C)=[C:7]([CH3:9])C.[CH2:16]([N+](CCCC)(CCCC)CCCC)CCC.C(OCCN(C)C)(=O)C(C)=C.[C:44]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])(=[O:48])[C:45]([CH3:47])=[CH2:46].C(O[Si](C)(C)C)(=O)C(C)=C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(=O)OC(C)CO1.C1COCC1>[C:44]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])(=[O:48])[C:45]([CH3:47])=[CH2:46].[CH3:16]/[CH:9]=[CH:7]/[C:6]([OH:5])=[O:10]
Reactant: CC(C)=C(OCCN(C)C)O[Si](C)(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C=C(C)C(=O)OCCCC
Agent: C=C(C)C(=O)OCCN(C)C
Agent: C=C(C)C(=O)O[Si](C)(C)C
Solvent: CC1COC(=O)O1
Solvent: C1CCOC1
Solvent: O
Product: C/C=C/C(=O)O

Procedure:
To a solution of 5.55 g (6.31 mL, 24 mmol) of 1-(2-dimethylaminoethoxy)-1-trimethylsiloxy-2-methyl-1-propene and 0.1 mL of tetrabutylammonium biacetate (0.04M in propylene carbonate) in 30 mL of THF was added a mixture of 7.6 g (8.1 mL, 48 mmol) of 2-dimethylaminoethyl methacrylate (purified by passage over a column of basic alumina under argon), and 23.9 g (26.7 mL, 168 mmol) of n-butyl methacrylate (purified by passage over a column of basic alumina under argon) from an addition funnel. The temperature of the reaction mixture rose from 27° C. to 61° C. during the course of the addition, and an ice bath was used to moderate the temperature rise. When, following the conclusion of the addition and removal of the cooling bath, the temperature was 32° C., the dropwise addition of 49.4 g (56.1 mL, 312 mmol) of trimethylsilyl methacrylate was begun. During the course of the addition the temperature of the reaction mixture rose to 56° C. while a total of 1.2 mL of tetrabutylammonium biacetate (0.04M in propylene carbonate) was added in 4 additions, and 20 mL of THF was added to reduce viscosity. Analysis of an aliquot of the solution by 1H NMR showed that there was no residual monomer present. After addition of 70 mL of tetrabutylammonium fluoride trihydrate (0.03M in methanol), the solution was refluxed for 12 hr. The solution was concentrated under reduced pressure with a rotary evaporator to give 80 g of a 40.58% solids solution of poly ω-2-β-dimethylaminoethyl isobutyrate(2-dimethylaminoethyl methacrylate [9 mol %]-co-n-butyl methacrylate [32 mol %]-b-methacrylic acid [59 mol %]).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.I[CH3:15]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:10]([CH3:15])[C:11](=[O:13])[CH3:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(=O)NC(C)c1ccc(Br)cc1
Product: CC(=O)N(C)C(C)c1ccc(Br)cc1

Procedure:
The title compound was prepared from N-[1-(4-bromophenyl)ethyl]acetamide and iodomethane in a manner similar to that described for description 24.