Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][CH2:7]Cl)[CH3:4].[H-].[Na+].[CH2:11]([C:13]1[C:18]([OH:19])=[N:17][C:16]([CH3:20])=[C:15]2[S:21][CH:22]=[CH:23][C:14]=12)[CH3:12].O>CN(C=O)C>[CH2:11]([C:13]1[C:18]([O:19][CH2:7][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2])=[N:17][C:16]([CH3:20])=[C:15]2[S:21][CH:22]=[CH:23][C:14]=12)[CH3:12]
Reactant: CCc1c(O)nc(C)c2sccc12
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(OCCCN(C)C)nc(C)c2sccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.1 %

Procedure:
3-(N,N-Dimethylamino)propylchloride hydrochloride (5.51 g, 34.9 mmol) and sodium hydride (60% in oil, 1.55 g, 38.8 mmol, prewashed with pentane) in DMF (30 ml) were stirred at room temperature for one hour. This solution was then added to a mixture of 4-ethyl-7-methylthieno[2,3-c]pyridin-5-ol (2.9 g, 15.0 mmol) and sodium hydride (60% in oil, 0.60 g, 15.0 mmol, prewashed in pentane) in DMF (30 ml) which had been allowed to react for two hours. The combination was stirred at room temperature for three days, poured into H2O (500 ml), extracted with CH2Cl2 (3×200 ml) and dried over MgSO4. The solvent was removed in vacuo and the product was purified by flash chromatography on silica gel 60 (120 g) using 8% MeOH in CH2Cl2 as the eluant to give the product (2.3 g, 55% yield) as a yellow oil; IR (neat) 1440, 1580 and 2980 cm-1 ; mass spectrum m/z 279 (MH+); 1H NMR (CDCl3) δ 1.20 (t, J=7 Hz, 3H, CH2CH3), 1.68 to 2.90 (m, 6H, CH2CH2N, CH2CH3), 2.27 (s, 6H, N(CH3)2), 2.63 (s, 3H, 7-CH3), 4.43 (t, J=6 Hz, 1H, OCH2CH2), 7.27 and 7.53 each (d, J=6 Hz, 1H, thiophene-H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:21])=[C:4]([CH:6]=[C:7]([CH3:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[Cl:19])[NH2:5].[C@@H:22]12[C:31](=O)[O:30][C:28](=[O:29])[C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27]2.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:21])=[C:4]([N:5]2[C:28](=[O:29])[CH:23]3[CH:22]([CH2:27][CH2:26][CH2:25][CH2:24]3)[C:31]2=[O:30])[CH:6]=[C:7]([CH3:20])[C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[Cl:19]
Reactant: Cc1cc(N)c(C)c(Br)c1Oc1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: Cc1cc(N2C(=O)C3CCCCC3C2=O)c(C)c(Br)c1Oc1ccc([N+](=O)[O-])cc1Cl
Yield: 84.5 %

Procedure:
To a solution of 3-bromo-4-(2-chloro-4-nitrophenoxy)-2,5-dimethylaniline (4.7 grams, 12.65 mmol) prepared in Part C in toluene (40 milliliters) was added cis-1,2-cyclohexane dicarboxylic anhydride (20.48 grams, 132.83 mmol) and a spatula tipful of toluene sulfonic acid. The reaction mixture was heated at reflux overnight and allowed to cool; washed with 5% NaOH solution (5x), water (3x) and brine (1x); dried over Na2SO4 and concentrated under reduced pressure to afford the crude desired product as a thick brown oil (5.43 grams, 10.69 mmol, 84%) which crystallized on standing and had a melting point of 187° C.-190° C. H'-NMR (CDCl3) 8.40 (d, J=2 Hz, 1H), 8.02 (d,d; J=2, 9 Hz, 1H), 7.00 (br, 5, 1H), 6.55 (d, J=9 Hz, 1H), 3.10 (M, 2H), 2.21 (brS, 6H), 1.93 (M, 4H), 1.58 (m, 4H).
Reaction SMILES: [OH-].[Na+:2].[O:3]=[C:4]1[NH:9][C:8]2[N:10]=[CH:11][C:12](/[CH:14]=[CH:15]/[C:16](=[O:28])[N:17]3[CH2:20][CH:19]([O:21][CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH2:18]3)=[CH:13][C:7]=2[CH2:6][N:5]1[CH2:29][C:30]([O:32]CC)=[O:31].O>CO>[O:3]=[C:4]1[NH:9][C:8]2[N:10]=[CH:11][C:12](/[CH:14]=[CH:15]/[C:16](=[O:28])[N:17]3[CH2:20][CH:19]([O:21][CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH2:18]3)=[CH:13][C:7]=2[CH2:6][N:5]1[CH2:29][C:30]([O-:32])=[O:31].[Na+:2]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])CN1Cc2cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc2NC1=O

Procedure:
A solution of sodium hydroxide (1N, 438 μL, 0.44 mmol) was added to a suspension of (E)-ethyl 2-(2-oxo-6-(3-oxo-3-(3-(thiophen-2-ylmethoxy)azetidin-1-yl)prop-1-enyl)-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate (100 mg, 0.22 mmol) in methanol (5 mL) at room temperature. The reaction mixture was refluxed for 15 minutes then poured into cold water. The resulting precipitate was filtered and washed with diethyl ether. The title product was obtained as a white solid (53.5 mg, 54%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:6][CH2:5]2)=[N:8]1
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 78.6 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.2 g, 16 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 16 mmol), K2CO3 (2.2 g) and acetonitrile (100 ml) was stirred and refluxed for 6 hours. The reaction was poured into water and the resulting yellow solid that formed was collected to afford 5.3 g of product. The compound was recrystallized from acetonitrile and then from ethyl acetate to yield 3.0 g (45%) of a slightly yellow solid of 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyll-butoxy]-3-methoxyphenyl]ethanone, m.p.=133°-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])[CH2:6][CH2:5]2.BrC1C=C2C(=C([N+:30]([O-:32])=[O:31])C=1)N(C1(C=CC=CC1)C(N)=O)CC2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:30]([O-:32])=[O:31])[CH:10]=1)[N:7]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14])[CH2:6][CH2:5]2
Reactant: NC(=O)c1ccccc1N1CCc2cc(Br)ccc21
Reactant: NC(=O)C1(N2CCc3cc(Br)cc([N+](=O)[O-])c32)C=CC=CC1
Product: NC(=O)c1ccccc1N1CCc2cc(Br)cc([N+](=O)[O-])c21

Procedure:
It is predicted that if the 2-(5-bromo-indolin-1-yl)benzamide of Example 13a is treated in the manner of Example 1b that 1-(5-bromo-7-nitro-1-indolinyl)benzamide will be obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH2:1][Br:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2ccccc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(-c2ccccc2)c1

Procedure:
A mixture of 3-methylbiphenyl (5.23 g, 31.1 mmol), N-bromosuccinimide (5.56 g, 31.2 mmol), benzoyl peroxide (135 mg, 0.56 mmol), and carbon tetrachloride (150 ml) is refluxed for 17 h. The mixture is concentrated in vacuo and the residue is purified by flash column chromatography (hexane) to give 3-phenylbenzyl bromide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:20])[C:16]#[C:17][CH2:18][OH:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:18][C:17]#[C:16][CH2:15][OH:20])[N:3]=[CH:4][N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC#CCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 61.8 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 608 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 527 mg of 2-butyn-1,4-diol, to which 245 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 465 mg of 4-(2-fluorophenyl)-6-(4-hydroxy-2-butynyloxy)pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C:25]1([CH:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH:42]4[CH2:47][CH2:46][CH:45](O)[CH2:44][CH2:43]4)[CH:37]=3)[O:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:25]1([CH:31]2[CH2:40][CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH:42]4[CH2:47][CH2:46][CH:45]([O:5][C:4](=[O:6])[C:3]5[CH:7]=[CH:8][N:9]=[CH:10][C:2]=5[F:1])[CH2:44][CH2:43]4)[CH:37]=3)[O:32]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OC1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Reactant: O=C(O)c1ccncc1F
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OC1CCC(Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1)c1ccncc1F
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 158 mg of 3-fluoroisonicotinic acid (1.12 mmol) and 156 μl of triethylamine (1.12 mmol) in 16 ml of dichloromethane at 15° C. 138 μl of pivaloyl chloride (1.12 mmol) were added dropwise. The solution was stirred for 30 min. A solution of 110 mg of 4-(2-phenyl-chroman-6-yloxy)-cyclohexanol (0.34 mmol) in 4 ml of dichloromethane was added and 82 mg of 4-dimethylamino-pyridine (0.68 mmol) were added in one portion. Stirring at room temperature was continued for 16 h. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, and the aqueous layer extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and filtered, and the solvent removed by evaporation. The resulting oil was purified by reversed phase HPLC. 104 mg of the title compound were isolated as solid (69%).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]1[NH:35][N:34]=[C:33]([NH2:36])[CH:32]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:36][C:33]3[CH:32]=[C:31]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)[NH:35][N:34]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2cc(F)ccc2C1=CNc1cc(-c2ccco2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-furan-2-yl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.061 gms. 5-furan-2-yl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0263 gms.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=3)C3C=CC=CC=3C(=O)O2)=[CH:4][CH:3]=1.[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>>[C:5]1([C:8]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[O:29][C:28]=2[C:27]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:25]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: ClCC1CO1
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Product: c1ccc(-c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
(A-2) 159 g of 3,3-bis (4-hydroxyphenyl)-2-benzofuran-1-on, 426.6 g of epichlorohydrin, and 160 g of a 50% alkali aqueous solution are mixed in a 1 L flask and reacted together at 95° C. for 1 hour to form a bisphenylbenzofuran-type epoxy resin. 215 g of the bisphenylbenzofuran-type epoxy resin is mixed with 450 mg of triethylbenzylammoniumchloride, 100 mg of 2,6-diisobutylphenol, and 72 g of acrylic acid. The mixture is heated up to 90 to 120° C. and completely dissolved, while air is blown therein at a speed of 25 Ml. Then, the dissolved product is cooled down to room temperature to form a non-colored transparent solid bisphenylbenzofuran-type epoxy acrylate. 287 g of the synthesized bisphenylbenzofuran-type epoxy acrylate is dissolved in 2 kg of cellosolveacetate. The solution is mixed with 10 g of 1,2,3,6-tetrahydrophthacid anhydride, 108.5 g of benzophenonetetracarboxylic acid dianhydride, and 1 g of tetraethylammonium bromide. The mixture is slowly heated up to 110 to 115° C. for 2 hours to form a cardo-based binder resin with a weight average molecular weight of 30,000 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:13](=[O:26])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:33]([O:39][C@@H:40]1[C@@H:45]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@H:44]([O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:43]([CH2:60][O:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[O:42][C@@H:41]1Br)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].O>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[C:15]([CH:16]([CH3:18])[CH3:17])=[C:14]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]([O:26][C@@H:41]2[O:42][C@H:43]([CH2:60][O:61][C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[C@@H:44]([O:53][C:54](=[O:59])[C:55]([CH3:56])([CH3:57])[CH3:58])[C@H:45]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:40]2[O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:35])[CH3:36])=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(Cc2ccccc2)c(=O)[nH]n1C(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1c(Cc2ccccc2)c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 58.8 %

Procedure:
To a solution of 1-benzyloxycarbonyl-4-benzyl-5-isopropyl-1,2-dihydro-3H-pyrazol-3-one (0.16 g) in acetonitrile (5 mL) were added potassium carbonate (0.0757 g) and 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (0.278 g) successively under stirring at room temperature. In addition, the mixture was stirred at 50° C. for 4 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/6) to give 1-benzyloxycarbonyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (0.228 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[C:8]1([SiH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC(O)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][Si:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCC=C
Reactant: c1ccc([SiH](c2ccccc2)c2ccccc2)cc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: C=CCOCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.3 %

Procedure:
0.5 ml of a 0.1 N solution of chloroplatinic acid as the catalyst in 2-propanol was added to an excess amount [18.3 g (187 mmol)] of diallyl ether (F). 16 g (62.3 mmol) of triphenylsilane (A) was added thereto and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction according to the disappearance of an absorption due to SiH at 2100 cm-1 in the I.R. absorption spectrum, excess (F) was distilled off under reduced pressure. The residue was purified according to column chromatography to obtain 16.5 g (50.0 mmol) of 3-allyloxypropyltriphenylsilane (G-4) (yield: 80.3%).
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[CH:14][C:12](N)=[C:11]([I:16])[CH:10]=1.[ClH:17]>C(#N)C.[Cu](Cl)Cl>[Br:8][C:9]1[CH:15]=[CH:14][C:12]([Cl:17])=[C:11]([I:16])[CH:10]=1
Reactant: Cl
Reactant: Nc1ccc(Br)cc1I
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Clc1ccc(Br)cc1I
Temperature: 60 °C

Procedure:
tert-Butyl nitrite (3 ml, 25 mmol) is added to a suspension of copper(II) chloride (2.71 g, 20 mmol) in acetonitrile (60 ml) and the mixture is heated with stirring to 60° C. A solution of 4-bromo-2-iodoaniline (5 g, 17 mmol) in acetonitrile (15 ml) is added dropwise, and once the addition is complete the mixture is stirred at 60° C. for 2.5 hours. The mixture is cooled to room temperature, poured into 20% aqueous hydrochloric acid and extracted with diethyl ether. The organic extract is dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue is further purified by column chromatography on silica gel to give 4-bromo-1-chloro-2-iodobenzene (4.32 g) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:16][CH3:17].[OH-].[Na+]>C(Cl)Cl.CCN(C(C)C)C(C)C>[CH2:15]([S:18]([N:10]1[CH2:9][CH2:8][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)([C:13]#[N:14])[CH2:12][CH2:11]1)(=[O:20])=[O:19])[CH2:16][CH3:17]
Reactant: CCCS(=O)(=O)Cl
Reactant: N#CC1(c2ccccn2)CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(C#N)(c2ccccn2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Pyridin-2-ylpiperidine-4-carbonitrile (1-2) (3.55 g, 19 mmole) was dissolved in DCM-DIEA (v/v 5:1, 60 mL) at 0° C. To this solution was added n-PrSO2Cl (2.98, 21 mmole). The reaction mixture was then stirred for 1 h at 0° C. After this time, LCMS indicated that the reaction was completion. 2N NaOH (40 mL) was added and the reaction mixture was stirred 1 h at 0° C. The reaction mixture solution was then extracted with EtOAc (4×200 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, concentrated to afford the desired product 1-(propylsulfonyl)-4-pyridin-2-ylpiperidine4-carbonitrile (I-4A) as a yellow-brown solid. Analytical LCMS: single peak (214 nm), 2.642 min. This product was used in next step reaction without further purification.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH3:4].[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:13]([NH2:18])[CH:14]=[N:15]2)=[CH:10][CH:9]=1>N1C=CC=CC=1.[Au]>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:1]([CH2:2][CH2:3][CH3:4])=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: CCCC(=O)Cl
Reactant: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Agent: [Au]
Solvent: c1ccncc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)C
Temperature: 25 °C

Procedure:
Butyryl chloride (1.1 equivalent) was slowly added to a stirred solution of 7-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine (52.9 g, 0.18 mol.) in pyridine (700 mL) at room temperature. A pale yellow precipitate formed and then went into solution. The reaction mixture was heated at reflux for eight hours, and then allowed to slowly cool to room temperature over the weekend. The dark gold, turbid reaction mixture was concentrated under reduced pressure. The residue was dissolved in 1 N hydrochloric acid and then adjusted to pH 14 with the addition of 10% aqueous sodium hydroxide. A precipitate formed, was isolated by filtration, washed with water (3×100 mL), and dried overnight on the filter funnel to provide 7-bromo-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline as an off-white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5](OS(C(F)(F)F)(=O)=O)=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC.CN(C=O)C>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.O>[CH:1]1([C:4]2[C:5]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)c(C2CC2)cc1C(=O)OC
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccccn2)c(C2CC2)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A mixture of methyl 5-cyclopropyl-2-ethoxy-4-(((trifluoromethyl)sulfonyl)oxy)benzoate (2.5 g), 2-(tributylstannyl)pyridine (3.75 g), tetrakis(triphenylphosphine)palladium (0.784 g), and DMF (20 mL) was stirred overnight at 100° C. The reaction mixture was poured to water, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (480 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: Cc1ncc(C(CN)C2CCOCC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)C2CCOCC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=394.1, tR (minutes, Method F)=1.88
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([CH2:30][CH2:31][CH3:32])[CH:5]=1)=[S:3].Br[CH2:34][C:35](=O)[CH2:36][CH3:37]>CCO>[CH2:36]([C:35]1[N:1]=[C:2]([C:4]2[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]4)=[C:6]([CH2:30][CH2:31][CH3:32])[CH:5]=2)[S:3][CH:34]=1)[CH3:37]
Reactant: CCC(=O)CBr
Reactant: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Solvent: CCO
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 144) and 1-bromo-2-butanone (35.8 mg, 0.24 mmol) in EtOH (anhydrous, 8 mL) was heated at 70° C. for 6 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v) 1:2) gave 42 mg (42%) of the title compound as a clear oil. LC-MS: RT=4.85 min; (M+H)+ 508.2.