Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:10])[C:8]=1[F:9])[NH2:5].Cl[CH2:12][CH2:13][OH:14]>C(O)C.[OH-].[Na+]>[OH:14][CH2:13][CH2:12][NH:5][C:4]1[CH:6]=[C:7]([CH3:10])[C:8]([F:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(N)cc(C)c1F
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(NCCO)cc(C)c1F
Yield: 86.5 %

Procedure:
In a mixed solution of 100 ml of ethanol and 60 ml of a 2N-NaOH solution were dissolved 12.3 g of the 3,5-dimethyl-4-fluoroaniline and 81 g of 2-chloroethanol, and the resulting solution was subjected to reaction with refluxing for 3 hours. After completion of the reaction, the ethanol was distilled off and the residue was extracted with ethyl acetate, after which the extract was washed with water, dried and then concentrated to obtain 14 g of crude N-(2-hydroxyethyl)-3,5-dimethyl-4-fluoroaniline. Subsequently, this crude compound was dissolved in 100 ml of isopropanol, followed by adding thereto 15 g of iodoethane and 20 g of potassium carbonate, and the reaction was carried out with refluxing for 5 hours. After completion of the reaction, the solvent was distilled off and the residue was extracted with ethyl acetate, and the extract was washed with water, dried and then concentrated to obtain 16 g of a crude product of the desired compound. The crude product was purified by a column chromatography (packing; Wakogel C-300, a registered trade name, mfd. by Wako Pure Chemical Industries, Ltd., eluent: ethyl acetate : n-hexane =1 : 2) to obtain 9.5 g of oily N-ethyl-N-(2-hydroxyethyl)-3,5-dimethyl-4-fluoroaniline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:45])([F:44])[F:33])=[CH:37][CH:38]=3)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Br)cc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Br)cc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 642 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C@@H:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:6].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30](/[CH:33]=[CH:34]/[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([C:43](O)=[O:44])[CH2:38]2)=[O:36])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C@@H:5]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:6][C:43]([C@@H:39]1[CH2:40][CH2:41][CH2:42][N:37]([C:35](=[O:36])/[CH:34]=[CH:33]/[CH:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:26])[CH2:28][CH2:29]2)[CH2:38]1)=[O:44]
Reactant: COC(=O)C[C@H](N)CCc1ccc(OC)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/C(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H](CCc1ccc(OC)c(OC)c1)NC(=O)[C@@H]1CCCN(C(=O)/C=C/C2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a mixture of 3(R)-(3,4-dimethoxyphenethyl)-β-alanine methyl ester (0.87 g), (R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidinecarboxylic acid (1.19 g) and 1-hydroxybenztriazole (0.44 g) in dimethylformamide (9 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.59 ml) at 0° C. The reaction mixture was stirred overnight at room temperature, and then poured into water. The whole was extracted with ethyl acetate, washed with aqueous saturated NaHCO3, water, and brine, dried over MgSO4, and evaporated in vacuo, subsequently. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: n-hexane=(5:1) to give N-[(R)-1-[3-(1-tert-butoxycarbonyl-4-piperidyl)-(E)-acryloyl]-3-piperidylcarbonyl]-3(R)-(3,4-dimethoxyphenethyl)-β-alanine methyl ester as a colorless oil (1.83 g).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:31][CH2:32][CH3:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([OH:29])=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:30])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[Br:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]O)=[CH:49][CH:48]=1>CS(C)=O.CN(C)C1C=CN=CC=1>[Br:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][O:28][C:27]([CH2:26][C:8]2([NH:15][C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:17])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:31][CH2:32][CH3:33])[C:7]2=[O:30])=[O:29])=[CH:49][CH:48]=1
Reactant: OCc1ccc(Br)cc1
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Product: CCOC(CN1C(=O)C(CC(=O)OCc2ccc(Br)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Reaction time: 18 h
Yield: 47.5 %

Procedure:
In 10 ml of dimethyl sulfoxide was dissolved 0.336 g of (+)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one. To the solution were added successively 0.108 g of 4-dimethylaminopyridine, 0.170 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.166 g of 4-bromobenzyl alcohol. The resulting mixture was stirred for 18 hours, followed by concentration. The concentrate was diluted with ethyl ether, washed successively with dilute hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.219 g (48%) of the title compound as a white powder.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.C(OC([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=O)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN2CCNCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with 1-tert-butoxycarbonyl piperazine in N,N-dimethylacetamide at room temperature followed by treatment with trifluoroacetic acid at room temperature to yield trans-N-methyl-N-[4-(4-piperazin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 504 (MH+).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46]Br)=[CH:40][CH:39]=1>CN(C=O)C>[CH3:35][O:36][C:37](=[O:48])[C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH2:46][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:24])[CH3:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:40][CH:39]=1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-pyrrolidin-2-one (3.20 g, 9.21 mmol) in DMF (30 mL) at 0° C. was added NaHMDS (1M in THF, 11.5 mL, 11.5 mmol). After 1 h, 4-(3-bromo-propyl)-benzoic acid methyl ester (2.84 g, 11.0 mmol) was added and the reaction mixture was stirred at 70° C. for 18 h. The DMF was removed in vacuo and the residue was dissolved in EtOAc. The organic solution was washed with water, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography (30% EtOAc in hexanes) to yield 3.39 g of 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester. 1H NMR (CDCl3) (selected peaks) δ 7.92 (m, 2H), 7.25-7.09 (m, 7H), 3.86 (s, 3H), 3.80 (m, 1H), 3.61 (m, 1H), 3.46 (m, 1H), 2.90 (m, 1H), 2.78-2.57 (m, 4H), 2.38-2.18 (m, 2H), 0.83 (s, 9H); MS 524.1 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C@@H:24]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:25]Br)=[C:17]2[C:22]=1[NH:21][C:20](=[O:23])[CH:19]=[CH:18]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>CN(C=O)C>[N:1]([CH2:25][C@@H:24]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:22]2[C:17]=1[CH:18]=[CH:19][C:20](=[O:23])[NH:21]2)[O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 80 °C
Yield: 148.3 %

Procedure:
NaN3 (266 mg, 4.1 mmol) was added to a stirred solution of (R)-8-(benzyloxy)-5-[2-bromo-1-[(tert-butyldimethylsilyl)oxy]ethyl]quinolin-2(1H)-one (1 g, 2.05 mmol) in DMF (20 mL) at rt and warmed to 80° C. for 3 h. The resulting solution was poured into H2O (80 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (2×100 mL), brine (100 mL), dried over Na2SO4 (s), and concentrated to give the title compound (1.37 g) as a yellow solid. The compound was used with no further purification. ES/MS calcd. for C24H31N4O3Si+ 451.2. found m/z=451.3 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:10]([CH2:11][OH:12])[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][F:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:7]2)[C@H:3]1[OH:24].[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[Si:29]([O:12][CH2:11][C@H:10]1[O:9][C@H:8]2[C@H:4]([N:5]=[C:6]([N:13]([CH2:21][CH2:22][F:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[S:7]2)[C@@H:3]([OH:24])[C@@H:2]1[OH:1])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCF)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.6 %

Procedure:
To a solution of tert-butyl (3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(2-fluoroethyl)carbamate (16 g, 43.7 mmol) in dichloromethane (100 mL) was added tert-butylchlorodimethylsilane (7.6 g, 50.7 mmol), 4-dimethylaminopyridine (530 mg, 4.34 mmol) and triethylamine (6.6 g, 65 mmol). After stirred for 6 h at room temperature, the resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column, eluting with 20% petroleum in ethyl acetate to give compound 69 as pale yellow oil (10 g, 48%). (ES, m/z) [M+H]+ 481.0; 1H NMR (300 MHz, CDCl3) δ 6.17-6.19 (d, J=6.3 Hz, 1H), 4.42-4.74 (m, 3H), 3.52-4.26 (m, 7H), 1.56 (s, 9H), 0.92 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
500 mg of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 0.76 ml of triethylamine were dissolved in 10 ml of dry acetonitrile, and the resulting solution was cooled with ice. To the solution was added 710 mg of 2-methylbenzoyl chloride, and the mixture was allowed to stand at room temperature for 90 minutes. The same procuedre as in Example 1 gave 260 mg (yield: 38.4%) of 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)uridine as crystals having a melting point of 108° to 109° C. This was identical with the crystals obtained in Examples 1 by the mixed examination.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([CH3:23])([CH3:22])[CH2:12][C@:13]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:14][C:15]#[CH:16])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N1C=CN=C1.[Si:29](Cl)([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31]>CN(C=O)C>[CH3:22][C:11]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([CH3:23])[CH2:12][C@:13]([O:21][Si:29]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:30][CH3:31])([C:17]([F:19])([F:20])[F:18])[CH2:14][C:15]#[CH:16]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1C(=O)O)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CC[C@@](CC(C)(C)c1ccc(F)cc1C(=O)O)(O[Si](CC)(CC)CC)C(F)(F)F
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To a solution of 10.6 g (0.032 mol) of 5-fluoro-2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzoic acid and 17.8 g (0.026 mol) of imidazole in 70 mL of DMF was added 75.6 mL (0.45 mol) of TESCl. The reaction mixture was stirred at 100° C. for 3 days. Volatiles were removed in vacuo, the reaction mixture was cooled to 10° C. with an ice bath, and 1 L of 1 N HCl was added. The ice bath was removed and the mixture was stirred at room temperature for 2 hours. Ethyl acetate was added and the mixture was washed with 1 N HCl, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. 200 mL of 1 N HCl is added and stirred for 1 hour. Ethyl acetate was added and the mixture was washed with 1 N HCl, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-((S)-1,1-dimethyl-3-triethylsilanyloxy-3-trifluoromethylhex-5-ynyl)-5-fluorobenzoic acid.
Reaction SMILES: [C:1]([C:6]1[C:7](Cl)=[C:8]2[S:14][CH:13]=[C:12]([O:15][CH3:16])[C:9]2=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([CH3:26])[CH:20]=1>C1(OC)C=CC=CC=1>[C:1]([C:6]1[C:7]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([OH:18])=[CH:20][C:21]=2[CH3:26])=[C:8]2[S:14][CH:13]=[C:12]([O:15][CH3:16])[C:9]2=[N:10][CH:11]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(O)ccc1N
Reactant: CCCC(=O)c1cnc2c(OC)csc2c1Cl
Solvent: COc1ccccc1
Product: CCCC(=O)c1cnc2c(OC)csc2c1Nc1ccc(O)cc1C

Procedure:
6-Butyryl-7-chloro-3-methoxythieno[3,2-b]pyridine (1.5 g, 0.0056 mol) and 4-hydroxy-2-methylaniline (1.37 g, 0.011 mol) in anisole (30 ml) were heated under reflux in a nitrogen atmosphere for 36 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between chloroform and sodium bicarbonate solution. The insoluble material was filtered off. The chloroform layer was washed with sodium bicarbonate solution (2×100 ml), dried over magnesium sulphate, filtered and evaporated to give a brown solid. The product was purified by flash chromatography using chloroform as eluant. The solid obtained was recrystallised from ethanol to give the title compound, 0.81 g, m.p. 255°-257°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[CH2:22]([O:21][CH2:20][C:13]1[N:14]([CH2:15][C:16]([CH3:19])([OH:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH:1][C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:11]=2[N:12]=1)[CH3:23]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3ccccc3c2n1CC(C)(C)O
Yield: 83.6 %

Procedure:
4-Amino-2-(ethoxymethyl)-α,α-dimethyl-1H-Imidazo[4,5-c]quinoline-1-ethanol (CAN 144875-48-9, 1.6 g, 5.09 mmol) was combined with acetonitrile (60 mL) to give a white suspension. Then triethylamine (1.77 mL, 12.7 mmol) and trityl chloride (1.7 g, 6.11 mmol) were added under Argon with stirring. The reaction mixture was irradiated in a microwave reactor at 100° C. for 30 minutes. Upon stirring the mixture the product precipitated and was isolated by filtration at 0° C., washed with cold acetonitrile and dried to yield the title compound (2.37 g, 83%) as white solid; MS (ESI): 557.5(MH+).
Reaction SMILES: [CH2:1]([O:19][C:20]1[O:24][C:23]([C:25]([OH:27])=O)=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18].[CH2:28](OC1OC(C(O)=O)=CC=1)[CH2:29]CCCCCCCCCCCC.C([Mg]Br)C.C[Mg]Br>>[CH2:1]([O:19][C:20]1[O:24][C:23]([C:25]([CH2:28][CH3:29])=[O:27])=[CH:22][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH3:18]
Reactant: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)O)o1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: CC[Mg]Br
Agent: C[Mg]Br
Product: CCC=CCC=CCC=CCCCCCCCCOc1ccc(C(=O)CC)o1

Procedure:
When in the procedure of Example 1 (B) an appropriate amount of 5-(9,12,15-octadecatrien-1-yloxy)-2-furoic acid is substituted for 5-(tetradecyloxy)-2-furoic acid, and an appropriate amount of ethyl magnesium bromide is substituted for methyl magnesium bromide, ethyl 5-(9,12,15-octadecatrien-1-yloxy)-2-furyl ketone is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])[CH:6]=[CH:5]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2cc(Br)ccc2n1

Procedure:
(6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine was prepared from 6-bromo-2-chloroquinoline and 2-methoxybenzylamine as described in example 2 step A.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](O)=[O:17])=[CH:13][CH:14]=3)[C:9]([CH3:19])=[C:8]2[CH3:20])=[CH:4][C:3]=1[O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].Cl.[CH:31]([C:34]1[CH:35]=[C:36]([C@@H:40]([NH2:42])[CH3:41])[CH:37]=[CH:38][CH:39]=1)([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16](=[O:17])[NH:42][C@H:40]([C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([CH:31]([CH3:33])[CH3:32])[CH:35]=4)[CH3:41])=[CH:13][CH:14]=3)[C:9]([CH3:19])=[C:8]2[CH3:20])=[CH:4][C:3]=1[O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl
Reaction time: 15 h

Procedure:
The (S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (55 mg, 0.13 mmol), the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride (37 mg, 0.19 mmol) and HATU (61 mg, 0.16 mmol) were dissolved in DMF (3 mL) and DIEA (0.1 mL). It was stirred for 15 h. The solution was filtered and purified by preparative HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:22]3[C:21](=[O:33])[NH:20][C:19](=[O:34])[N:18]([CH3:35])[C:17]=3[C:16]=2[C:36]([O:38][CH3:39])=[O:37])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:41][C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:43].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:23]([CH2:24][C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[Cl:32])[C:22]3[C:21](=[O:33])[N:20]([CH2:41][C:42](=[O:43])[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:19](=[O:34])[N:18]([CH3:35])[C:17]=3[C:16]=2[C:36]([O:38][CH3:39])=[O:37])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c2c(=O)[nH]c(=O)n(C)c12
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c2c(=O)n(CC(=O)c3ccccc3)c(=O)n(C)c12
Yield: 84.3 %

Procedure:
A solution of methyl 6-{(3R)-3-[(tertbutoxycarbonyl)amino]piperidin-1-yl}-5-(2-chloro-5-fluorobenzyl)-1-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (50 mg), α-bromoacetophenone (27 mg) and potassium carbonate (25 mg) in N,N-dimethylformamide was stirred at 25° C. for 14 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a preparative thin-layer chromatography (hexane/ethyl acetate=2/1) to obtain the title compound (51 mg) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=[O:36].C(OCC)(OCC)OCC.O1CCC[C@H]1CN>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([CH2:1][C@@H:2]4[CH2:3][CH2:4][CH2:5][O:36]4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: NC[C@@H]1CCCO1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1C[C@@H]1CCCO1
Yield: 67.1 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), (S)-(tetrahydrofuran-2-yl)methanamine (0.102 ml, 0.99 mmol), and acetic acid (0.1 ml) were used to give 90.1 mg (0.29 mmol, 67.1% yield) of the title compound.