Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]([F:25])([F:24])[C:11]([NH:13][C:14]1[N:15]=[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]2[CH:23]=1)=[O:12]>C(#N)C>[Br:1][C:23]1[N:17]2[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]2=[N:15][C:14]=1[NH:13][C:11](=[O:12])[C:10]([F:24])([F:9])[F:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(Nc1cn2cc(F)ccc2n1)C(F)(F)F
Solvent: CC#N
Product: O=C(Nc1nc2ccc(F)cn2c1Br)C(F)(F)F
Temperature: 25 °C

Procedure:
N-Bromosuccinimide (2.96 g, 0.0166 mol) was added to a solution of 2,2,2-Trifluoro-N-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-acetamide (compound c, 3.74 g, 0.0151 mol) in acetonitrile (70 mL) and stirred at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. Reaction mixture was concentrated under reduced pressure, crude product taken up in ethyl acetate, washed with water, organic layer collected, dried over Na2SO4, concentrated in vacuo and crude product purified by column chromatography (50% ethyl acetate/hexanes) to give product as an off white solid. Rf 0.47, 50% ethyl acetate/hexanes; MS m/z 327 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CCO.Cl.[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[C:39]([N:42]([CH3:44])[CH3:43])[CH:40]=2)[N:35]=[CH:34][CH:33]=1>O>[ClH:31].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:32]4[C:41]5[C:36](=[CH:37][CH:38]=[C:39]([N:42]([CH3:44])[CH3:43])[CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccc(N(C)C)cc45)cc3)cc2)nc(N)n1

Procedure:
To a solution of amide E5 (228 mg, 0.62 mmol) in 1:2 EtOH:H2O (20 mL) were sequentially added c.HCl (0.17 mL, 5.61 mmol) and 4-chloro-6-dimethylaminoquinoline (03) (140 mg, 0.68 mmol), and the resulting mixture was refluxed for ˜12 h. MS and TLC analysis (eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:AcOH) after this time showed some starting material still present in the reaction mixture, thus more 03 (140 mg, 0.68 mmol) was added. After a further few hours refluxing, TLC showed the reaction was complete, and thus solvent was removed under reduced pressure. The residue was crystallized from MeOH:EtOAc to afford Cpd. P as an (extremely fine) amorphous yellow solid (170 mg, 51%). 1H NMR [(CD3)2SO] δ2.28 [s, 3H], 3.15 [s, 6H, ArN(CH3)2], 6.21 [br s, 1 H, ArH], 6.89 [d, J=6.71 Hz, 1 H, ArH], 7.65 [m, 5 H, ArH], 7.82 [m, 4 H, ArH & ArNH2], 7.96 [d, J=9.39 Hz, 1 H, ArH], 8.18 [d, J=8.57 Hz, 2 H, ArH], 8.35 [t, J=12.38, 6.19 Hz, 1 H, ArH], 10.44 [br s, 1 H, ArH], 10.65 [br s, 1 H, ArNHAr], 10.71 [s, 1 H, ArNHAr], 12.75 [br s, 1 H, ArC(O)NH], 14.56 [d, J=4.10 Hz, 1 H, quinolinyl N+H]. LCMS (APCI+): 506 (100%). HPLC: 97.6%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[Br:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg+2].[Cl-].[Cl-].[CH2:20]=[O:21].[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([Br:16])=[CH:11][C:12]([OH:15])=[C:13]([CH:14]=1)[CH:20]=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)c(Br)c1
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: CC#N
Product: O=Cc1cc(OCc2ccccc2)c(Br)cc1O
Temperature: 72 °C

Procedure:
To a chilled solution of phenol (Step 1) (4.7 g, 16.8 mmole) in ACN was added MgCl2 (1.92 g, 20 mmole) portion-wise while maintaining the temperature below 10° C., followed by paraformaldehyde (2.52 g, 84 mmole) and TEA (9.5 mL, 67 mmole) producing a 15° C. exotherm. The mixture was heated to 72° C. for 2 hrs. The reaction was cooled to room temperature and poured into saturated aqueous ammonium chloride (500 mL), extracted with ethyl acetate (2×150 mL). The combined organic phases were washed with aqueous NaHCO3 solution (2×150 mL), aqueous 1N HCl solution (2×150 mL), and brine (2×150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was subjected to flash chromatography (Silica, 5% ethyl acetate/hexane). ESLRMS m/z 306.9 (M+H).
Reaction SMILES: Cl[Si:2]([CH3:17])([CH3:16])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:5]=[C:4]1[CH3:15].CCN(CC)CC.C[SiH]([N:28](C1C2C(=C(C)C=C(C)C=2)C(C)=C1C)[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)C>CCCCCC>[CH:29]1([NH:28][Si:2]([CH3:17])([CH3:16])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[CH:5]=[C:4]2[CH3:15])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC1=Cc2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Reactant: CC1=C(C)C(N(C2CCCCC2)[SiH](C)C)c2cc(C)cc(C)c21
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-s-indacen-1-yl) silane (5.67 g, 0.0216 moles) was stirred in hexane (50 mL) as NEt3 (2.18 g, 0.0216 moles) and cyclohexylamine (2.13 g, 0.0216 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (6.62 g, 94.3 percent).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[N:9]1[S:10][N:11]=[C:12]2[CH:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[CH:14][C:13]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(N(CC)CC)C>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[C:18]([C:16]1[CH:15]=[CH:14][C:13]2=[N:9][S:10][N:11]=[C:12]2[CH:17]=1)=[O:19]
Reactant: O=C(O)c1ccc2nsnc2c1
Reactant: CNC1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C(=O)c1ccc2nsnc2c1)C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-Methyltetrahydro-2H-pyran-4-amine (0.4 g, 3.4 mmol), [2,1,3]-benzothiadiazole-5-carboxylic acid (0.23 g, 1.4 mmol), DMAP (0.2 g: 1.6 mmol), HOBT (0.2 g, 1.5 mmol), triethylamine (1.0 ml) and EDCI (1 g, 6.4 mmol) were dissolved in DMF (30 ml). The mixture was stirred at room temperature for 18 h and then concentrated under vacuum. Chloroform (100 ml) was added and the mixture washed with water (100 ml) and H2SO4 (→pH 2) and NaHCO3 solution (100 ml). The aqueous was extracted with chloroform (100 ml) and the combined organics were dried (MgSO4), concentrated under vacuum, and the crude product was purified on a silica gel column eluting with chloroform/THF (90:10), to give the product as an oil which crystallized on standing. Mp=106-108° C., 1H NMR (300 MHz, CDCl3, rotamers) δ 8.06 (d, J=9.0 Hz, 1H); 8.01 (s, 1H); 7.60 (d, J=9.0 Hz, 1H); 4.92-4.75 and 4.15-3.10 (m, 5H); 3.10-2.80 (m, 3H) and 2.05-1.50 ppm (s, 4H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].Cl>C1COCC1.C(OCC)(=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][CH:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=1)[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: ClCCCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(CCCCl)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of p-tolylacetic acid (1 g) in THF (30 mL) was stirred at −78° C. for 30 minutes. n-Butyl lithium (2.66 M solution in hexane, 5.01 mL) was added to the solution, and the reaction solution was stirred at −78° C. for three hours. Thereafter, the reaction solution was stirred at 0° C. for 30 minutes, 1-bromo-3-chloropropane (0.725 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 24 hours. Thereafter, ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.53 g of the title compound. The property values corresponded to the reported values (CAS #2856-76-0).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.C1(C)C=CC(S([CH2:21][N+:22]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC.C(O)C>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@H:4]3[C:21]#[N:22])[CH2:2]1)[CH2:8]2
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1C2CC3CC1CN(C3)C2
Temperature: -78 °C
Reaction time: 5 h

Procedure:
Azaadamantan-4-one (3.76 g, 24.9 mmol; see Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080-1082.) and p-toluenesulfonylmethyl isocyanide (TOSMIC, 6.38 g, 32.3 mmol) were dissolved in a mixture of 1,2-dimethoxyethane (87 mL) and ethanol (3.2 mL) and chilled to −78° C. To the reaction mixture was added potassium tert-butoxide (6.70 g, 59.7 mmol) over a period of 1 minute. The cooling bath was removed and the reaction mixture was stirred at 25° C. for 5 hours and then heated at 40° C. for 0.5 hour. The reaction mixture was cooled and filtered through a glass frit. The filtrate was concentrated, and the residue was purified by silica gel chromatography (10% concentrated NH4OH in acetonitrile, Rf=0.25) to afford the title compound. An aliquot of the solid was then dissolved in 10:1 ether/methanol and treated with fumaric acid (10 mg/mL solution in 10:1 ether/methanol). The precipitate was filtered and dried under vacuum to afford the title compound as a fumarate for characterization: 1H NMR (500 MHz, methanol-d4) δ 2.07-2.14 (m, 2H), 2.22-2.32 (m, 3H), 2.47 (s, 2H), 3.49-3.56 (m, 5 H), 3.59-3.66 (m, 2 H), 6.70 ppm (s, 2.8 H; C4H4O4); MS (DCI/NH3) m/z 163 (M+H)+; Anal. Calcd. for C10H14N2.1.45C4H4O4: C, 57.41; H, 6.04; N, 8.48. Found: C, 57.26; H, 6.04; N, 8.87.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([S:11]([NH:14][C:15](=[O:25])[C:16]1[CH:21]=[C:20]([F:22])[C:19](F)=[CH:18][C:17]=1[F:24])(=[O:13])=[O:12])([CH2:9][CH3:10])[CH3:8].[Cl:26][C:27]1[CH:28]=[C:29]([OH:35])[CH:30]=[N:31][C:32]=1[O:33][CH3:34]>CS(C)=O.O>[CH:7]([S:11]([NH:14][C:15](=[O:25])[C:16]1[CH:21]=[C:20]([F:22])[C:19]([O:35][C:29]2[CH:30]=[N:31][C:32]([O:33][CH3:34])=[C:27]([Cl:26])[CH:28]=2)=[CH:18][C:17]=1[F:24])(=[O:13])=[O:12])([CH2:9][CH3:10])[CH3:8]
Reactant: CCC(C)S(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Reactant: COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)S(=O)(=O)NC(=O)c1cc(F)c(Oc2cnc(OC)c(Cl)c2)cc1F
Temperature: 90 °C
Yield: 52.1 %

Procedure:
Potassium carbonate (0.140 g, 1.01 mmol) was added to a stirred solution of N-(sec-butylsulfonyl)-2,4,5-trifluorobenzamide (Preparation 68, 0.090 g, 0.30 mmol) in DMSO (1 mL). After 10 minutes a solution of 5-chloro-6-methoxypyridin-3-ol (Preparation 77, 0.088 g, 0.51 mmol) in DMSO (2 mL) was added at room temperature. The mixture was heated at 90° C. for 72 hours. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3×25 mL). The combined organics were washed with water (25 mL), dried over magnesium sulfate, filtered, evaporated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0 to 66% EtOAc in heptane to yield the title compound (0.068 g):
Reaction SMILES: [C:1](Cl)(=[O:14])[O:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[NH:16]1[CH2:21][CH:20]=[CH:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C1COCC1.O>[N:16]1([C:1]([O:2][CH2:3][C:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=2)=[O:14])[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17]1
Reactant: O=C(Cl)OCc1ccc2ccccc2c1
Reactant: C1=CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccc2ccccc2c1)N1CC=CCC1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
Naphthalen-2-ylmethyl carbonochloridate (11.00 g, 49.85 mmol) was dissolved in THF (25 mL) and this was added dropwise to a cooled (0° C.) solution of 1,2,3,6-tetrahydropyridine (3.79 ml, 41.5 mmol) and NaHCO3 (4.18 g, 49.8 mmol) in water (88 mL). A precipitate formed in the reaction immediately, therefore after the addition, additional THF (63 mL) was added to solubilize the reaction mixture. The solution was removed from the bath and warmed to ambient temperature for 16 hours. The reaction was concentrated in vacuo then methylene chloride was added. The mixture was separated, the aqueous layer was washed with methylene chloride, and the combined organics were dried over Na2SO4 and concentrated in vacuo to provide the desired product as an oil (11 g).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([Si:9]([CH2:13][CH3:14])([CH2:11][CH3:12])Cl)[CH3:8].[OH:15][C@@H:16]([C@@H:18]1[C@@H:21]([C@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[NH:20][C:19]1=[O:33])[CH3:17]>C(Cl)Cl>[CH2:7]([Si:9]([CH2:13][CH3:14])([CH2:11][CH3:12])[O:15][C@@H:16]([C@@H:18]1[C@@H:21]([C@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[NH:20][C:19]1=[O:33])[CH3:17])[CH3:8]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@H]1CCc2ccccc2C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@H]1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.06 ml of pyridine and 0.1 ml of triethylchlorosilane were added successively at 0° C. to 100 mg (0.39 mmol) of the hydroxyethyl compound from step 1 in 3 ml of anhydrous methylene chloride and then stirred at room temperature for 3 h. The reaction mixture was diluted with 10 ml of methylene chloride and washed successively with dilute hydrochloric acid, saturated NaHCO3 solution and water. After drying over sodium sulfate and concentration in vacuo, the residue was chromatographed on silica gel (eluent: toluene/ethyl acetate=1:2). Yield: 122 mg (85%). -1H-NMR (200 MHz, CDCl3): δ=0.50-0.70 (2×m, 6H and 9H, SiCH3CH3); 1.28 (d, 3H, CH--CH3); 1.95-2.38 (m, 2H, CH--CH2 --CH2); 2.76 (dt, 1H, CH--CH2 --CH2) 3.02-3.16 (m, 3H, CH--CH2 --CH2 and H-3); 4.23 (mc, 1H, CH--CH3); 4.43 (dd, 1H, H-4); 5.8 (bs, 1H, NH); 7.22-7.38 and 7.45-7.57 (2×m, 3 H, aromatic H); 8.02 (dd, 1H, aromatic H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[NH:13][C:14]2[CH:20]=[C:19]([C:21](Cl)=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[NH:34][C:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:3]3[C:4]([C:8]([F:10])([F:11])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:13][C:14]=2[CH:20]=1)=[O:22]
Reactant: O=C(Cl)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Reactant: Nc1ccc2ccccc2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Temperature: 60 °C

Procedure:
To a stirred suspension of 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carbonyl chloride (394 mg, 1.0 mmol) and quinolin-2-ylamine (144 mg, 1.0 mmol) in THF (6 mL) was added DIPEA (0.53 ml, 3.0 mmol). The solution was heated at 60° C. for 2 days and the reaction was quenched with water and aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (1:4) as eluent to give 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carboxylic acid quinolin-2-ylamide as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (d, 1H), 8.37 (d, 1H), 8.08 (d, 1H), 7.94 (m, 4H), 7.83 (m, 1H), 7.74 (m, 1H), 7.54 (m, 1H). MS (m/z) 467.1 (M+1); Retention time: 1.45 min (Method 10).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[N+:11]([O-])=O.Cl>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][C:3]=1[NH2:11]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Product: N#CSc1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
of 1-amino-2-nitro-4-thiocyanatobenzene is mixed with 6ml. of concentrated hydrochloric acid and the mixture cooled to about -40° C. A solution of 12 g. stannous chloride in 6 ml. concentrated hydrochloric acid is added dropwise and the mixture allowed to warm slowly to room temperature. After 15-20 minutes at 15°-20° C, the product is filtered off and washed with 12 ml. 6N hydrochloric acid. Treatment with 25 ml. of saturated potassium bicarbonate solution and extraction with chloroform gives the free base. Recrystallization from benzene yields 1,2-diamino-4-thiocyanatobenzene.
Reaction SMILES: CO[C:3](=[O:18])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]2[C:14]=1[N:13]([CH3:15])[CH:12]=[CH:11]2)=O.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][C:29]([NH2:31])=[O:30])=[CH:20]1.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]2[C:29](=[O:30])[NH:31][C:3](=[O:18])[C:4]=2[C:6]2[CH:7]=[CH:8][C:9]([O:16][CH3:17])=[C:10]3[C:14]=2[N:13]([CH3:15])[CH:12]=[CH:11]3)=[CH:20]1
Reactant: COC(=O)C(=O)c1ccc(OC)c2ccn(C)c12
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2c1ccn2C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a mixture of (1-methyl-4-methoxyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (0.27 g, 1.10 mmol) and 2-(1H-indol-3-yl-acetamide (0.17 g, 1 mmol) in DMF (5 mL) was added a solution of potassium tert-butoxide in THF (1.0 M, 4.0 mL, 4.0 mmol) at room temperature. The reaction mixture was heated at 60° C. for 4 hrs, cooled to room temperature, and quenched with hydrochloric acid (1.0 N). After stirring at room temperature for 30 min, the mixture was extracted with ethyl acetate and the extract was washed with water, saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate), filtered and evaporated. Flash column chromatography on silica gel eluting with chloroform and acetone gave 3-(1H-indol-3-yl)-4-(4-methoxy-1-methyl-1H-indol-7-yl)-pyrrole-2,5-dione (270 mg, 72.7%). 1H NMR (d6-DMSO, 400 MHz) 3.65 (s, 3H), 3.84 (s, 3H), 6.46˜6.55 (m, 4H), 6.78 (d, J=7.6 Hz, 1H), 6.95 (t, J=7.2 Hz, 1H), 7.13 (d, J=3.2 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.86 (d, J=3.2 Hz, 1H), 11.05 (s, 1H), 11.79 (s, 1H); MS (ES, m/z): C22H17FN3O3: 372.19(M++1), 370.29 (M+−1).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.[C:12]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Cu]Br>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([C:4]1[CH:9]=[N:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[C:12]([O:20][CH2:21][CH3:22])=[O:19])[CH3:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(Br)cn1
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)c1ccc(OC)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 36.2 mmoL, 1.45 g) was added into a solution of 5-bromo-2-methoxy-pyridine (16.5 mmoL, 2.13 mL), copper(I) bromide (32.9 mmoL, 4.72 g) and diethyl malonate (32.9 mmoL, 5.0 mL) in 1,4-dioxlane (20 mL) slowly at room temperature. After the addition, the resulting mixture was heated to 100° C. and stirred overnight. The mixture was then passed through a pad of Celite to remove brown solid. The filtrate was then concentrated in vacuo to afford a brown oil, which was then purified by column chromatography using hexanes:ethyl acetate (4:1˜2:1 ratio) as eluent to afford the title compound as a slight yellow oil.
Reaction SMILES: I[CH:2]1[C:11](=[O:12])[N:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][C@@H:9]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.[P:21]([O:28]CC)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]2[CH2:8][CH2:7][CH2:6][C@H:5]3[N:10]2[C:11](=[O:12])[CH:2]([P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH2:3][CH2:4]3)=[CH:14][CH:15]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc([C@H]2CCC[C@H]3CCC(I)C(=O)N32)cc1
Product: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccc(OC)cc3)N2C1=O
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of (6R*,9aS*)-3-iodo-6-(4-methoxyphenyl)octahydroquinolizin-4-one (34 mg) with triethyl phosphite (1 mL) was stirred at 120° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 35 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][CH:14]=2)[CH:7]=1.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:20][C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:9]3[CH2:10][CH2:11][CH2:12][C:8]=3[C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:22][CH2:28][C:27]3[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=3)[N:18]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(O)c1cccc(C2=C(c3cc(Cl)ccc3O)CCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(OCc1ccc(Cl)cc1)c1cccc(C2=C(c3cc(Cl)ccc3OCc3ccc(Cl)cc3)CCC2)n1

Procedure:
6-{2-[5-Chloro-2-(hydroxy)-phenyl]-cyclopent-1-enyl}-pyridine-2-carboxylic acid (97 mg, 0.30 mmol) was refluxed in 2-butanone (4 mL) with 4-chlorobenzyl bromide (140 mg, 0.70 mmol) and potassium carbonate (1.0 g) under nitrogen for five hours. The reaction mixture was then filtered through highflo, evaporated down to an oil and chromatographed on a Water's sep-pak (10 g) with ether/iso-hexane (15/85) to give (160 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH:13]([CH3:15])[CH3:14])[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.[Si:25](OS(C(F)(F)F)(=O)=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH:13]([CH3:14])[CH3:15])[NH:5][C:6]([O:8][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[O:7]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)O[Si](C)(C)C(C)(C)C)C(C)C
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.0 ml) of N-t-butoxycarbonyl-L-valine methyl ester (115.5 mg, 0.5 mmol) and 2,6-lutidine (0.116 ml, 1.0 mmol) was added dropwise t-butyldimethylsilyltrifluoromethane sulfonate (0.172 ml, 0.75 mmol) at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 153.2 mg.