Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].Cl.[Br:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:31][CH2:30][NH:29][CH2:28][C@H:27]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:23]=[CH:24][CH:25]=1>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:6]([N:29]2[CH2:30][CH2:31][C@H:26]([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Br:19])[CH:21]=3)[C@H:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:28]2)=[O:7])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Brc1cccc([C@H]2CCNC[C@H]2c2ccccc2)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=556.0 (M+), was prepared in accordance with the general method of example 1 from 3,5-bis(trifluoromethyl)benzoyl chloride and rac-cis-4-(3-bromo-phenyl)-3-phenyl-piperidine hydrochloride.
Reaction SMILES: I[CH3:2].[F:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:7][NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10]>>[F:3][C:4]1[CH:5]=[C:6]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:7][NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:2])=[CH:18][C:17]2=[O:23])=[N:13][C:12]=1[CH3:24])=[O:10]
Reactant: CI
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccc(F)c(F)c1
Product: COc1ccn(-c2nc(C)c(C(=O)NCc3ccc(F)c(F)c3)s2)c(=O)c1
Yield: 66 %

Procedure:
Following the procedure as described in Example 9, making variation only as required to use iodomethane in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-(3,4-difluorobenzyl)-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 66% yield: mp 183-185° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.65 (d, J=8.1 Hz, 1H), 7.18-7.05 (m, 3H), 6.20-6.15 (m, 2H), 5.97 (d, J=2.5 Hz, 1H), 4.53 (d, J=5.8 Hz, 2H), 3.82 (m, 3H), 2.68 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 168.4, 162.3, 162.1, 153.6, 152.7, 135.0, 131.4, 123.7, 121.8, 117.6, 117.4, 116.9, 116.7, 104.0, 96.2, 56.0, 43.0, 17.3; MS (ES+) m/z 392.2 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[C:16](=[CH:18][CH:19]=[C:20]([OH:36])[C:21]=1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[OH:17].C(O)C.[OH-].[Na+:42].O>>[Na+:42].[C:20]1([C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O-:35])=[O:34])=[C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([O-:37])=[O:2])[C:16](=[CH:18][CH:19]=1)[OH:17])[OH:36].[Na+:42]
Reactant: COC(=O)CCCCCCCCCCCc1c(O)ccc(O)c1CCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C([O-])CCCCCCCCCCCc1c(O)ccc(O)c1CCCCCCCCCCCC(=O)[O-]

Procedure:
Hydroquinone bislauric acid methyl ester prepared in Example 1 (2.8 g) was stirred in sodium hydroxide ethanol/water solution at room temperature for 12 hours. At first, the solution was cloudy. By the end of the reaction, the solution was clear. The crude product was extracted with n-butanol twice. After the solvent was rotevaporated, the remaining material was washed with ethanol. The white solid material was collected by filtration. NMR results showed that the material is the desired product. ##STR23##
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[C:17]=3[CH3:24])=[C:7]([C:12]([NH2:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:25][CH3:26].BrC[CH2:29][CH2:30][CH2:31][Cl:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:32][CH2:31][CH2:30][CH2:29][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[C:17]=3[CH3:24])=[C:7]([C:12]([NH2:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:25][CH3:26]
Reactant: ClCCCCBr
Reactant: COc1cc2c(Nc3cccc(CO)c3C)c(C(N)=O)cnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3cccc(CO)c3C)c(C(N)=O)cnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.4 %

Procedure:
7-Hydroxy-4-[3-(hydroxymethyl)-2-methylanilino]-6-methoxy-3-quinolinecarboxamide (0.90 mg, 2.54 mmol) was dissolved in DMF (10 ml), 1-bromo-4-chlorobutane (0.28 ml, 2.79 mmol) and Cs2CO3 (1.7 g, 5.2 mmol) were added and the mixture was stirred at ambient temperature for three days. The mixture was poured out on water and extracted with methylenechloride. The residue was chromatographed on silica using ethylacetate/methanol (1:0–>5:1) as eluent, affording 550 mg (50% yield) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][N:13](COCC[Si](C)(C)C)[C:9]=2[C:8]([C:22]#[N:23])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[C:27]([F:44])[C:26]=2[O:45][CH3:46])[N:6]=1.C(=O)(O)[O-:53].[Na+]>O.S(=O)(=O)(O)O>[Cl:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[C:10]2[N:11]=[CH:12][NH:13][C:9]=2[C:8]([C:22]([NH2:23])=[O:53])=[C:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]3)=[C:27]([F:44])[C:26]=2[O:45][CH3:46])[N:6]=1
Reactant: COc1c(Nc2nc(Cc3c(Cl)cccc3Cl)c3ncn(COCC[Si](C)(C)C)c3c2C#N)ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1c(Nc2nc(Cc3c(Cl)cccc3Cl)c3nc[nH]c3c2C(N)=O)ccc(N2CCNCC2)c1F
Temperature: 90 °C

Procedure:
A mixture of the product of Example 43B (50 mg, 0.068 mmol) and 4 drops of water in sulfuric acid (1 mL) was heated at 90° C. for 40 minutes. The mixture was poured onto ice water, neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to provide the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 8.37 (s, 1H), 7.63(dd, J=2.1 Hz, J=9.3 Hz, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 7.41 (m, 1H), 6.32 (t, J=9 Hz, 1H), 4.81 (s, 2H), 3.94 (s, 3H), 3.40 (m, 4H), 3.26 (m, 4H). MS: 544 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:32]([OH:34])[CH3:33]>>[CH2:32]([O:34][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1)[CH3:33]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1

Procedure:
A portion of 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (5 g) was refluxed in ethanol in presence of K2CO3 (3.2 g) for about 8-10 h. TLC was monitored. After the completion of the reaction, the reaction mass was filtered through vacuum and the filtrate was evaporated to yield the title compound. (Wt. 4.6 g Y: 90%).
Reaction SMILES: [CH:1]([CH:3]([CH2:8][CH2:9][O:10][CH3:11])[CH2:4][CH2:5][O:6][CH3:7])=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl>[CH3:7][O:6][CH2:5][CH2:4][CH:3]([CH2:8][CH2:9][O:10][CH3:11])[CH:1]=[CH:17][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCC(C=O)CCOC
Solvent: ClCCl
Product: CCOC(=O)C=CC(CCOC)CCOC
Yield: 82.7 %

Procedure:
A solution of 23 (1.10 g, 6.88 mmol) and (carbethoxymethylene)triphenylphosphorane (2.63 g, 7.56 mmol, 1.1 equiv) was refluxed in CH2Cl2 (8.2 mL) for 24 h. The solvent was removed at reduced pressure. The oily residue was chromatographed [silica, hexanes/diethyl ether (1:1)] to yield a pale yellow oil (1.31 g, 88%): 1H NMR δ 1.50-1.62 (m, 2H), 1.69-1.85 (m, 2H), 2.45-2.51 (m, 1H), 3.23-3.33 (m, 10H), 5.79 (d, J=16.1 Hz, 1H), 6.71 (dd, J=9.5 Hz, J2=16.1 Hz, 1H); 13C NMR δ 14.46, 34.42, 36.40, 58.79, 60.48, 70.42, 122.03, 152.01, 166.73; FAB-MS obsd 231.1596, calcd 231.1598 [(M+H)+, M=C12H22O4].
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][C:21]=2F)[N:18]([C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][OH:25])[CH:17]=[C:16]([C:30]([O:32]CC)=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=2)[CH:7]=1)[CH3:2].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[OH-].[Li+].CS(O)(=O)=O>C1COCC1.O>[CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][C:21]=2[N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)[N:18]([C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][OH:25])[CH:17]=[C:16]([C:30]([OH:32])=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[N:40]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)OCC)cn([C@H](CO)C(C)(C)C)c3nc2F)cn1
Reactant: CN1CCNCC1
Agent: CS(=O)(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)O)cn([C@H](CO)C(C)(C)C)c3nc2N2CCN(C)CC2)cn1
Temperature: 50 °C
Reaction time: 10 h
Yield: 22 %

Procedure:
To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-7-fluoro-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate Intermediate 76 (200 mg, 0.31 mmol, 1 equiv.) in THF (1.2 mL) was added 1-methylpiperazine (0.041 mL, 0.37 mmol, 1.2 equiv.). This reaction was stirred at 50° C. for 10 h. 2 M lithium hydroxide (0.307 mL) was added. The reaction was stirred at 50° C. for 2 h, cooled to room temperature, and diluted with water. 10% wt. sol. of methanesulfonic acid was added until pH 5-6 was reached. The precipitate was discarded. The solution was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the aqueous layer was concentrated. The compound was purified (HPLC) and concentrated to provide (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid as a solid (52.8 mg, 22%). Calcd for C32H37F3N8O5S [M+H]+: 703.2. H1NMR (d6-DMSO) δ 15.18 (s, 1H), 9.51 (s, 1H), 8.8 (d, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 8.2 (s, 1H), 7.6 (m, 1H), 5.71-5.68 (m, 1H), 5.09-5.02 (m, 1H), 4.09-4.0 (m, 2H), 3.29-3.27 (m, 2H), 3.21-3.19 (m, 2H), 3.15-3.04 (m, 2H), 2.18-2.14 (m, 2H), 2.05 (s, 3H), 1.95-1.91 (m, 2H), 1.12 (t, 3H), 0.95 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH:17]([N:20]([CH2:23][CH2:24][C:25]#[N:26])[S:21]Cl)([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH:17]([N:20]([CH2:23][CH2:24][C:25]#[N:26])[S:21][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:19])[CH3:18]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CC(C)N(CCC#N)SCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(CCC#N)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 0 °C

Procedure:
2.2 g (0.01 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate and 1.8 g (0.01 mole) of N-isopropyl-N-cyanoethylaminosulfenyl chloride were dissolved in 30 ml of methylene chloride, and the solution was cooled to 0° C. 1.2 g (0.012 mole) of triethylamine was dropwise added thereto with stirring, and allowed to react for 2 hours at the same temperature. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The methylene chloride layer was dried and concentrated under reduced pressure to obtain an oily product which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities.
Reaction SMILES: S(Br)([Br:3])=O.[C:5]12(O)[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1>C1C=CC=CC=1>[Br:3][C:5]12[CH2:14][CH:10]([CH2:11][CH2:12][CH2:13]1)[CH:9]1[CH2:15][CH:6]2[CH2:7][CH2:8]1
Reactant: OC12CCCC(C1)C1CCC2C1
Reactant: O=S(Br)Br
Solvent: c1ccccc1
Product: BrC12CCCC(C1)C1CCC2C1
Yield: 61.8 %

Procedure:
Six milliliters (78 millimoles) of thionyl bromide are added to 20 ml of a solution of 5.36 g (32 millimoles) of tricyclo [4.3.1.12,5 ] undecane-1-ol in dry benzene and the entirety is refluxed for 1.5 hours. The reaction mixture is concentrated under reduced pressure and there is further added 20 ml of dry benzene. Reduced pressure concentration is repeated to distill out the excess thionyl chloride completely. The residue is distilled under reduced pressure to collect a fraction boiling at 96°-8° C./2mmHg. Thus 4.53 g (yield 61.3%) of 1-bromotricyclo [4.3.1.12,5 ] undecane are obtained. After cooling, colorless crystals having a melting point of 57.7°-58.5° C. are obtained. The properties of this product are the same as those shown in Example 1.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24]Br>C(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:24][CH2:2][C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:3]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: Clc1ccc(CBr)cc1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(NC(=O)CCc1ccc(Cl)c(Cl)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl acetamidomalonate (48.2 g) was dissolved in ethanol (250 ml) containing sodium ethoxide (10.2 g) and stirred at room temperature for 0.5 hours before adding 3,4-dichlorobenzyl bromide and heating at reflux for 3.5 hours. After cooling, the title compound was collected by filtration and dried under reduced pressure(36.73 g).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)s1
Yield: 35.7 %

Procedure:
To a solution of ethyl 2-bromothiazole-5-carboxylate (39 μl, 0.26 mmol) in toluene (2 mL) were added 4-(trifluoromethyl)phenylboronic acid (60 mg, 0.32 mmol), 2M Na2CO3(390 μl, 0.78 mmol), and catalytic amounts of Pd(PPh3)4 (61 mg, 0.05 mmol). The reaction mixture was refluxed for 6 hrs, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc/n-Hex=1:5) to give title compound (28 mg, 30%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](Cl)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C@@H:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22]([N:32]3[CH2:31][CH2:30][NH:29][C@H:28]([CH3:27])[CH2:33]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(Cl)nc1
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccccc4)c3)cn2)CCN1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-chloronicotinamide (0.18 mmol) was used in general procedure 3 with (R)-2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give (R)—N-(3-benzamido-4-chlorophenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 450.4 (M)+
Reaction SMILES: [N:1]1([C:10]2[O:11][C:12]([CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[N:1]1([C:10]2[O:11][C:12]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1oc(-n2cnc3ccccc32)nc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A mixture of methyl 3-{2-(1H-benzimidazol-1-yl)-4-[4-(trifluoromethyl)phenyl]-5-oxazolyl}propionate (1.00 g), 1N aqueous sodium hydroxide solution (10 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, dried and recrystallized from tetrahydrofuran-ethanol to give 3-{2-(1H-benzimidazol-1-yl)-4-[4-(trifluoromethyl)phenyl]-5-oxazolyl}propionic acid (1.00 g, yield 83%) as pale-yellow prism crystals. melting point: 224–226° C.
Reaction SMILES: [CH3:1][C:2]([NH2:12])([CH3:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>CC(O)C>[CH3:11][C:2]([NH:12][CH2:13][CH:14]([OH:15])[CH2:16][OH:17])([CH3:1])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCC1CO1
Reactant: CC(C)(N)CCc1ccccc1
Solvent: CC(C)O
Product: CC(C)(CCc1ccccc1)NCC(O)CO
Temperature: 75 °C

Procedure:
To 1,1-dimethyl-3-phenylpropylamine (3.6 g., 22 mmole) in 20 ml. 2-propanol at 50° C. in an oil bath was added glycidol (1.7 g., 23 mmole) in 10 ml. 2-propanol dropwise over 5-10 min. The mixture was heated at 75° C. for 2 hours. After evaporation of the solvent, vacuum distillation provided 3.9 g. (75%) of 3-(1,1-dimethyl-3-phenylpropylamino)-1,2-dihydroxypropane (bp 160°-180°/0.5 mm which crystallized upon standing (mp 74°-77° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].C(O)CO>O>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1cccc(F)c1
Solvent: O
Solvent: OCCO
Product: CCOC(=O)Cn1c(-c2cccc(F)c2)nc2cccnc21
Temperature: 195 °C
Yield: 91.2 %

Procedure:
A mixture of N-[3-[(3-fluorobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (20.44 g, 0.065 mole), and ethylene glycol (75 ml) was heated at 195° C. for 40 minutes. Water was added to the cooled reaction mixture and the solid was collected by filtration. The solid was suspended in water (2×100 ml) and collected by filtration to give 17.75 g of crude 2-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester. A portion of this solid (6.0 g, 0.02 mole) together with sodium hydroxide pellets (0.9 g, 0.0231 mole), and 50 ml of ethanol-water (1:1) was refluxed for 1 hour. The ethanol was evaporated. The residual aqueous mixture was cooled, diluted with water (50 ml) and extracted with diethyl ether (2×25 ml). The aqueous portion was acidified to a pH of 3 with concentrated hydrochloric acid. After precipitation was complete, the solid was collected by filtration. The filter cake was suspended in ethanol and filtered, giving 4.94 g (91%). Recrystallization of a 1.2-g sample from tetrahydrofuran gave 1.1 g of an off-white solid, mp 243°-245° C. with decomposition.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:17])[O:5][N:4]=1)[CH3:2].[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:17])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(C)c1-c1cc2ccccc2[nH]1
Reactant: CC(=O)Cl
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In the alternate procedure, 41.8 grams (0.163 moles) of silver triflouromethanesulfonate is added portionwise to a solution of 33.5 grams (0.148 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole in 450 milliliters of methylene chloride. The resulting suspension is then treated by dropwise addition with 12.8 grams (0.163 moles) of acetyl chloride in 50 milliliters of methylene chloride. The temperature rises to 35° C. during the addition. After the addition is complete, the mixture is stirred at room temperature for 4 hours and then filtered. The filtrate is washed with 150 milliliters of 2N sodium hydroxide, water and 2N sodium hydroxide, then dried over anhydrous magnesium sulfate and finally evaporated in vacuo to yield an oil. The oil is crystallized from ether to give 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-acetyl indole, m.p. 170°-173° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22]([OH:24])=O)[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@:21]([F:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:44])([F:36])[C:40]([F:43])([F:42])[F:41])=[O:24])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: C[C@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@](F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (R)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (63%). MS: m/e=608(M+H+).