Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:23][C:24]1[N:25]=[CH:26][NH:27][CH:28]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:4].[C:29]([CH2:35][C@@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:37](O)=[O:38])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].C(N1CCOCC1)C.C(Cl)CCl>CN(C)C=O>[CH:17]1([CH2:16][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:37](=[O:38])[C@@H:36]([CH2:35][C:29](=[O:34])[C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:23][C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[C@@H:7]([OH:15])[CH:8]([OH:14])[CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCC(CC)C(O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC(CC)C(O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
A mixture of 880 mg (2.23 mmol) of (S)-α-amino-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]imidazole-4-propionamide, 608 mg (2.45 mmol) of (R)-α-(pivaloylmethyl)hydrocinnamic acid (see EPA 0 184 550), 0.35 ml (2.76 mmol) of 4-ethylmorpholine, 662 mg (4.9 mmol) of HBT and 529 mg (2.76 mmol) of EDC in 20 ml of dimethylformamide is stirred at room temperature overnight. Thereafter, the reaction mixture is evaporated to dryness in a high vacuum, the residue is poured into a mixture of ice and 2N sodium bicarbonate solution and extracted three times with ethyl acetate. The extracts are washed in succession with saturated ammonium chloride solution, 2N sodium bicarbonate solution and saturated sodium chloride solution and combined. After drying the organic solution over magnesium sulphate the solvent is evaporated under reduced pressure and the residue (1.01 g), for purification, is chromatographed on 70 g of silica gel using a 20:1:0.1 mixture of methylene chloride, methanol and ammonia as the eluting agent. Crystallization of the thus-obtained crude product from methylene chloride/methanol/ether yields 900 mg of (S)-N-[(1S,2R,3RS)-1-(cyclohexylmethyl)-4-ethyl-2,3-dihydroxyhexyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide, melting point 160°, MS: 624 (M)+.
Reaction SMILES: [O:1]([CH2:8][C:9]([O:11][CH:12]1[C:23]2[C:24](=[O:25])[C:19]([O:26][Si](C(C)(C)C)(C)C)([CH2:20][CH2:21][CH:22]=2)[C:18]#[C:17][CH:16]=[CH:15][C:14]#[C:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(#N)C.C(Cl)(Cl)Cl>[O:1]([CH2:8][C:9]([O:11][CH:12]1[C:23]2[C:24](=[O:25])[C:19]([OH:26])([CH2:20][CH2:21][CH:22]=2)[C:18]#[C:17][CH:16]=[CH:15][C:14]#[C:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC12C#CC=CC#CC(OC(=O)COc3ccccc3)C(=CCC1)C2=O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C(COc1ccccc1)OC1C#CC=CC#CC2(O)CCC=C1C2=O
Reaction time: 72 h

Procedure:
To a solution of compound 11a in 26 mL of acetonitrile was added 4 mL of 48% HF. The solution was stirred for 72 h. The solution was diluted with chloroform and washed with water. The organic fraction was dried over MgSO4 and concentrated and the residue chromatographed over silica gel (5:1 hexane/ethyl acetate) to give 8-[(phenoxymethyl)carbonyloxy]-1-hydroxy-bicyclo[7.3.1]trideca-4,9-diene-2,6-diyn-13-one (11b) (116 mg).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[CH:7]=[C:8]([N:18]2[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]2=[O:28])[CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH:16]2[CH:14]([O:15]2)[CH2:13]1>CC(C)=O.O>[N:1]([CH:16]1[CH:14]([OH:15])[CH2:13][N:12]([C:11]2[CH:10]=[CH:9][C:8]([N:18]3[CH2:22][C@H:21]([CH2:23][NH:24][C:25](=[O:27])[CH3:26])[O:20][C:19]3=[O:28])=[CH:7][C:6]=2[F:5])[CH2:17]1)=[N+:2]=[N-:3]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC4OC4C3)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC(O)C(N=[N+]=[N-])C3)c(F)c2)C(=O)O1
Temperature: 55 °C

Procedure:
Sodium azide (42 mg, 0.64 mmol) was added to a solution of N-({(5S)-3-[3-fluoro-4-(6-oxa-3-azabicyclo[3.1.0]hex-3-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (36 mg, 0.107 mmol, prepared using the general procedure described for Example 40) in 2:1 acetone-H2O (1.0 mL) and the solution heated at 55° C. for 16 hours. The solution was cooled, concentrated to remove acetone, diluted with water and extracted with chloroform. Combined organic extracts were dried (MgSO4), filtered and concentrated to provide the title compound. This material was used directly in the next reaction. MS (m/z): [M+H]+=379
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[C:17](=[O:31])[CH:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.BrC1C=NC(N2CCC(OC3C=CN([C:52]4[CH:57]=[CH:56][C:55](S(C)(=O)=O)=[CH:54][CH:53]=4)C(=O)C=3)CC2)=NC=1.C1(B(O)O)CC1>C1COCC1>[CH3:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH:19]=[CH:20][C:15]([O:14][CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)=[CH:7][N:6]=4)[CH2:9][CH2:10]3)=[CH:16][C:17]2=[O:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ccc(Br)cn4)CC3)cc2=O)cc1
Reactant: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ncc(Br)cn4)CC3)cc2=O)cc1
Agent: OB(O)C1CC1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-n2ccc(OC3CCN(c4ccc(-c5ccccc5)cn4)CC3)cc2=O)cc1
Temperature: 120 °C

Procedure:
Example 116 was prepared according to procedures described in Example 105 substituting 4-(1-(5-bromopyridin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one for 4-(1-(5-bromopyrimidin-2-yl)piperidin-4-yloxy)-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one, substituting phenylboronic acid (Aldrich) for cyclopropylboronic acid and substituting DMF for THF. The reaction was heated under microwave conditions at 120° C. for 10 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.37 (d, J=2.45 Hz, 1H), 7.95 (d, J=8.31 Hz, 2H), 7.77 (dd, J=9.05, 2.20 Hz, 1H), 7.51-7.63 (m, 5H), 7.34 (t, J=7.58 Hz, 2H), 7.21 (t, J=7.82 Hz, 1H), 6.90 (d, J=8.80 Hz, 1H), 5.98-6.04 (m, 2H), 4.65-4.73 (m, 1H), 3.92-4.00 (m, 2H), 3.26-3.34 (m, 2H), 3.20 (s, 3H), 1.92-2.00 (m, 2H), 1.51-1.61 (m, 2H). MS (ESI) 502 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:12]=2[O:16][CH2:17][CH2:18][CH3:19])[N:7]1[C:26](=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl>[C:26]([N:7]1[C:8]2[C:13](=[C:12]([O:16][CH2:17][CH2:18][CH3:19])[C:11]([CH:20]3[CH2:25][CH2:24][N:23]([C:1](=[O:3])[CH3:2])[CH2:22][CH2:21]3)=[CH:10][CH:9]=2)[CH2:14][CH2:15][C@@H:6]1[CH3:5])(=[O:28])[CH3:27]
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOc1c(C2CCN(C(C)=O)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Acetyl chloride (6 μL, 0.08 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (26.1 mg, 0.07 mmol) and triethylamine (0.03 mL, 0.21 mmol) in dichloromethane (1.0 mL), and the reaction stirred at room temperature overnight. The reaction solution was purified directly via column chromatography on silica gel (Biotage 10 g column, gradient elution with 10-20% methanol in ethyl acetate) to afford (S)-1-(4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidin-1-yl)ethan-1-one (19 mg, 71%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.05 (m, 6H), 1.17-1.29 (m, 1H), 1.38-1.47 (m, 1H), 1.54-1.59 (m, 1H), 1.65-1.81 (m, 5H), 2.01 (s, 6H), 2.16-2.35 (m, 2H), 2.48-2.59 (m, 1H), 2.71-2.78 (m, 1H), 3.01-3.03 (m, 2H), 3.55-3.76 (m, 2H), 3.90 (br d, J=14.66 Hz, 1H), 4.52 (br d, J=13.20 Hz, 1H), 7.04 (br s, 2H). MS (ESI, pos. ion) m/z 373 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C[CH2:18][O:17][CH2:16]C1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:13][CH2:18][O:17][CH2:16][CH2:12]2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: C1COCCN1
Reactant: CN(C)c1ccc(N)c(C(N)=O)c1
Product: NC(=O)c1cc(N2CCOCC2)ccc1N

Procedure:
According to the preparation of compound 25, morpholine was used to afford 29 (0.8 g) as brown powder; MS m/z 221 (M+).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[NH2:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([OH:42])=O)=[CH:34][CH:33]=1>>[NH2:31][C:32]1[N:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[C:40]([N:2]([CH3:1])[CH2:3][C:4]2[S:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5]=2[CH3:13])=[O:42])=[CH:34][CH:33]=1
Reactant: CNCc1sc2ccccc2c1C
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)sc2ccccc12
Yield: 73 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (2.2 g, 73%) was prepared as a yellow solid: 1H NMR (300 MHz, DMSO-d6) 8.21 (s, 1H), 2.81-2.75 (m, 1H), 2.71-2.59 (m, 3H), 7.41-7.25 (m, 2H), 6.85-6.65 (m, 1H), 6.50-6.41 (m, 1H), 5.01-4.81 (m, 2H), 4.78-4.61 (m, 2H), 3.12 (s, 3H), 2.41 (s, 3H); MS (ESI) m/e 338 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:29][C:20]1[C:19]2[N:18]=[C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 4-fluorophenylisocyanate (0.137 g, 1.0 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol. The resulting pale yellow precipitate (identified as the bis-adduct) was isolated by filtration. The filtrate was concentrated under vacuum to provide an off-white solid. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.22 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(4-fluorophenyl)urea as a white solid, m.p. 145-150° C. Mass spec M+1=469.2. Analysis: C27H25FN6O: %C, 69.21; %H, 5.37; %N, 17.94; Found: %C, 66.70; %H, 5.33; %N, 17.03.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[CH3:19][O:20][CH2:21][C@H:22]([NH2:25])[CH2:23][CH3:24]>CCO>[Cl:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:25][C@@H:22]([CH2:21][O:20][CH3:19])[CH2:23][CH3:24])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(Cl)ccnc1Cl
Reactant: CC[C@@H](N)COC
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@H](COC)Nc1nccc(Cl)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 155.4 %

Procedure:
2,4-Dichloro-3-nitropyridine (1.0 g, 5,18 mmol) was dissolved in EtOH (20 mL), followed by the addition of Et3N (1.05 g, 10.4 mmol) and (R)-1-methoxymethyl-propylamine (0.72 g, 5.18 mmol) and the reaction was heated at 60° C. for 3 h. The reaction was concentrated in vacuo to yield 2.09 g of (R)-(4-chloro-3-nitro-pyridin-2-yl)-(1-methoxymethyl-propyl)-amine as a crude viscous oil: MS (AP) m/z 259.69 [(M+H)+, 97].
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C@H:29]([C:32]([O:34][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:33])[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)O)C1
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
DBU (0.764 mL) was added to a mixture of benzyl bromide (0.61 mL), (S)-1-tert-butoxycarbonyl-pyrrolidine-3-carboxylic acid (1 g) in anhydrous toluene (10 mL) and the mixture was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-35% to give benzyl (S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylate (0.859 g)
Reaction SMILES: [Na:1].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].[Br:44]Br>C(=S)=S>[Br:44][C:37]1[C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[C:33]([C:40]([OH:42])=[O:41])[C:34]([OH:39])=[C:35]([CH3:38])[CH:36]=1.[Na:1]
Reactant: BrBr
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: [Na]
Solvent: S=C=S
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(Br)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
To a solution of 1.53 g of the sodium salt of antibiotic X-537A in 30 ml carbon disulfide was added dropwise a solution of 0.14 ml bromine 10 ml carbon disulfide at -5° over 10 minutes. The solvent was removed under a stream of nitrogen at room temperature (approximately 2 hours). The residue was purified by dissolving it in ethyl acetate and the solution washed successively with aqueous sodium bisulfite and sodium carbonate. After drying (Na2SO4), the solution was evaporated under reduced pressure and the residue crystallized from ethyl acetate to give 5-bromo-3-methyl-6{-7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydro-pyranyl)-2-tetrahydrofuryl]heptyl} salicylic acid, sodium salt as colorless cubes, m.p. 185°, [α]D25 -7.36° (1% in methanol).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[CH:18]=[CH:19]3)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc3c(ccn3C)c2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) in toluene (8.1 mL) was added 1-methylindole-5-boronic acid pinacol ester (1.037 g, 4.03 mmol), potassium carbonate (1.67 g, 12.09 mmol) and palladium tetrakistriphenylphosphine (0.466 g, 0.403 mmol). The reaction was stirred at 100° C. and stirring continued for 16 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-5-yl)quinoline as a clear solid. Mass Spectrum (ESI) m/e=343.1 (M+1).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[CH2:6][NH:7][C:8]([C:10]1[C:11]([I:33])=[C:12]([C:14]([I:32])=[C:15]([C:18]([NH:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][O:24][C:25](=[O:27])[CH3:26])=[O:19])[C:16]=1[I:17])[NH2:13])=[O:9])(=[O:3])[CH3:2].[C:39](Cl)(Cl)=[O:40].[C:43]([O:46][CH2:47][C:48]1[C:49]([I:71])=[C:50]([C:52]([I:70])=[C:53]([C:56]([NH:58][CH2:59][CH:60]([O:66][C:67](=[O:69])[CH3:68])[CH2:61][O:62][C:63](=[O:65])[CH3:64])=[O:57])[C:54]=1[I:55])[NH2:51])(=[O:45])[CH3:44]>O1CCOCC1.C1(C)C=CC=CC=1.[Hg](OC(C(F)(F)F)=O)OC(C(F)(F)F)=O>[C:43]([O:46][CH2:47][C:48]1[C:49]([I:71])=[C:50]([NH:51][C:39]([NH:13][C:12]2[C:11]([I:33])=[C:10]([C:8]([NH:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:34][O:35][C:36](=[O:38])[CH3:37])=[O:9])[C:16]([I:17])=[C:15]([C:18]([NH:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][O:24][C:25](=[O:27])[CH3:26])=[O:19])[C:14]=2[I:32])=[O:40])[C:52]([I:70])=[C:53]([C:56]([NH:58][CH2:59][CH:60]([O:66][C:67](=[O:69])[CH3:68])[CH2:61][O:62][C:63](=[O:65])[CH3:64])=[O:57])[C:54]=1[I:55])(=[O:45])[CH3:44]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Reactant: O=C(Cl)Cl
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Agent: O=C(O[Hg]OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(=O)OCc1c(I)c(NC(=O)Nc2c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c2I)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Temperature: 60 °C
Reaction time: 16 h

Procedure:
3,5-Bis(2,3-diacetoxypropylaminocarbonyl)-2,4,6-triiodoaniline (260 mg, 0.30 mmol) was dissolved in dioxane (1.0 ml) and a solution of phosgene in toluene (1.93 M, 1.8 ml) was added. The flask was tightly sealed and then heated to 60° C. for 17 h. After cooling to room temperature, the solvent was distilled off at reduced pressure. Dioxane (3 ml) was added and distilled off again. This procedure was repeated twice. Dioxane (1 ml) was added followed by 3-acetoxymethyl-5-(2,3-diacetoxypropylaminocarbonyl)-2,4,6-triiodoaniline (0.245 g, 0.31 mmol), prepared according to Example 16a, and Hg(OCOCF3)2 (20 mg). The mixture was stirred for 16 h at room temperature, the solvent was evaporated and the residue was purified by preparative HPLC. Yield: 0.192 g (39%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:23]=[N:24][C:25]([S:28][CH2:29][C:30]([NH:32][CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]3)=[O:31])=[N:26][CH:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:23]=[N:24][C:25]([S:28][CH2:29][C:30]([NH:32][CH2:33][CH:34]3[CH2:39][CH2:38][CH2:37][N:36]([CH2:10][C:7]4[CH:8]=[C:9]5[C:4]([CH:3]=[CH:2][NH:1]5)=[CH:5][CH:6]=4)[CH2:35]3)=[O:31])=[N:26][CH:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(-c2cnc(SCC(=O)NCC3CCCNC3)nc2)cc1OC
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ccc(-c2cnc(SCC(=O)NCC3CCCN(Cc4ccc5cc[nH]c5c4)C3)nc2)cc1OC
Reaction time: 8 h
Yield: 64.3 %

Procedure:
1H-indole-6-carbaldehyde (238 mg, 1.64 mmol, 1.36 equiv) [Moyer, Mikel P.; Shiurba, John F.; Rapoport, Henry; J. Org. Chem.; 1986, 51, 5106-5110] was added to the solution of the 2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-N-piperidin-3-ylmethyl-acetamide 1h (TFA)n (1.20 mmol, obtained from step 6) and diisopropylethylamine (0.85 mL, 4.8 mmol, 4 equiv) in 50 mL dichloroethane. Sodium triacetoxyborohydride (0.47 g, 2.24 mmol, 1.8 equiv) was added to the solution and the resulting suspension was stirred vigorously overnight. Methanol (5 mL) was added to quench the reaction. The mixture was concentrated and the residue was diluted with ethyl acetate. The solution was poured into saturated NaHCO3 solution (40 mL) and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated. Chromatography on silica gel (10% methanol in chloroform) afforded 2-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylsulfanyl]-N-[1-(1H-indol-6-ylmethyl)-piperidin-3-ylmethyl]-acetamide (free base, 410 mg, 64%) as a light tan solid.
Reaction SMILES: [C:1]([N:3](C)[C:4](=[NH:12])OC1C=CC=CC=1)#[N:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1.N1C=CC=C[CH:30]=1>>[CH3:30][NH:12][C:4](=[N:3][C:1]#[N:2])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]([CH3:28])[CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1
Reactant: CN(C#N)C(=N)Oc1ccccc1
Reactant: c1ccncc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Product: CNC(=NC#N)Nc1ccc(C2=NNC(=O)CC2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-cyano-N1 -methyl-O-phenylisourea (0.175 g) in anhydrous pyridine (3 ml) was added 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (0.2 g). The mixture was stirred at room temperature for 3 hours, stirred under reflux for 4 hours and allowed to cool overnight. This mixture was evaporated under reduced pressure to give a solid which was triturated with diethyl ether to remove phenol. Thin layer chromatography indicated the presence of unreacted starting-material and the title compound.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][CH3:19])[C:14]=1[OH:15])[CH:10]=O)([CH3:6])[CH2:3][CH2:4][CH3:5].[C:22]([CH2:24]C(O)=O)#[N:23].N1CCCCC1.Cl>O.N1C=CC=CC=1>[CH3:1][C:2]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][CH3:19])[C:14]=1[OH:15])[CH:10]=[CH:24][C:22]#[N:23])([CH3:6])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)(C)c1cc(C=O)cc(C(C)(C)CCC)c1O
Reactant: N#CCC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: CCCC(C)(C)c1cc(C=CC#N)cc(C(C)(C)CCC)c1O

Procedure:
3,5-bis(1,1-dimethylbutyl)-4-hydroxycinnamonitrile was prepared by heating a mixture of 29 grams of 3,5-bis(1,1-dimethylbutyl)-4-hydroxybenzaldehyde, 25.5 grams of cyanoacetic acid, 75 milliliters of pyridine, and 3 milliliters of piperidine at 95° to 100° C. for 7 hours. The reaction mixture was poured into a solution of 50 milliliters of concentrated hydrochloric acid in 100 milliliters of water. The oil which precipitated was separated by extraction with petroleum ether and the extract was stripped under vacuum to a pot temperature of 50° C./13 mm. The residue, which weighed 32 grams, was a viscous liquid which crystallized slowly on standing.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:12][C:3]1[C:2]([CH3:1])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cc1c([N+](=O)[O-])ccc2cccnc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(N)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-methyl-7-nitroquinoline (1.8 g) in methanol (20 mL)is added Pd/C (10%, 0.45 g) and ammonium formate (2.77 g). The mixture is stirred at room temperature for 30 minutes, then filtered on Celite, with methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between H2O and CH2Cl2. The organic layer is dried over potassium carbonate, filtered and rotary evaporated to afford 7-amino-8-methylquinoline as a yellow solid.