Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:11][CH2:10]1.[C-]#N.[Na+]>CS(C)=O.O>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:29]=[CH:28][CH:27]=[CH:26][C:20]=2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH2:13][CH2:14]1
Reactant: COc1ccccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN(C)C(=O)c1cccnc1NCCCN1CCN(c2ccccc2O)CC1
Yield: 25.7 %

Procedure:
A mixture of 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.54 g, 1.36 mmol), prepared as in Example 21, and sodium cyanide (0.33 g, 6.8 mmol) in 12 mL of DMSO was heated at reflux for 14 hours and then diluted with water and extracted twice with diethyl ether. The aqueous layer was extracted twice with methylene chloride and the combined methylene chloride layers were washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was purified on silica gel by column chromatography eluting with 8% methanol/methylene chloride to give 2-{3-[4-(2-hydroxyphenyl)-piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.134 g, 0.35 mmol) as an oil. The free base was recrystallized from a solution of fumaric acid in alcohol to give di(2-{3-[4-(2-hydroxyphenyl)-piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide) fumarate, m.p. 185°-186° C. Anal.: Calcd. for C21H30N5O2.(C4H4O4)0.5 : C, 62.57; H, 7.08; N, 15.86; Found: C, 62.44H, 7.08; N, 15.73%.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COc1cc2ncn(-c3nc(-c4cccc(C(F)(F)F)c4)c(C(=O)O)s3)c2cc1OC
Yield: 58.1 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-trifluoromethylphenylboronic acid (28.5 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid (26.1 mg, 58%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.90 (br.s. 1H); 8.82 (s, 1 H); 8.37-8.47 (m, 2 H); 7.87 (s, 1 H); 7.82 (d, 1 H); 7.72 (t, 1 H); 7.39 (s, 1 H); 3.87 (s, 3 H); 3.85 (s, 3 H). MS 450 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.[BH4-].[Na+].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>C(O)C.CCOCC>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: NCCCn1ccnc1
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCC(NCCCn1ccnc1)c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
In a similar manner to Example 1, a mixture of 4'-chloropropiophenone (8.4 g) and 1-(3-aminopropyl)imidazole (6.3 g) was heated at 120° C. for 9 hours. The cooled mixture was dissolved in absolute ethanol (100 ml), treated with sodium borohydride (3.9 g) and boiled under reflux for 16 hours. The oil obtained after work-up was dissolved in ether and treated with ethereal oxalic acid until the mixture was just acidic. The solid was filtered off and recrystallised from ethanol to give N-[1-(4-chlorophenyl)propyl]-3-(imidazol-1-yl)propylamine oxalate, m.p. 189°-190° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]([OH:13])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].N1C=CN=C1.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:10]([O:13][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC(O[Si](C)(C)C(C)(C)C)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
1 g of (3RS,4S)-4-(tert-butoxycarbonyl)amino-6-methylhepten-3-ol was dissolved in 2 ml of dry DMF, and 743 mg of tert-butyldimethylchlorosilane and 700 mg of imidazole were added thereto. The mixture was stirred at room temperature overnight. Then, 160 ml of ethyl acetate was added to the reaction solution. The mixture was washed with cooled 1N hydrochloric acid, with a saturated sodium hydrogencarbonate aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=30/1) to obtain 1.21 g of (3RS,4S)-4-(tert-butoxycarbonyl)amino-3-(tert-butyldimethylsilyl)oxy-6-methylheptene as colorless oily substance.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24].[OH-].[K+]>C1COCC1.O>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[C:5]([O:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCCCOc1cc(OCCCCCCCC)ccc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCOc1cc(OCCCCCCCC)ccc1C(=O)O
Reaction time: 6 h
Yield: 90.9 %

Procedure:
77.5 g (0.22 mol) of 4-Octyloxy-2-(pent-4-en-1-yloxy)benzoic acid methyl ester obtained in Step 2 is dissolved in 700 mL of THF. A solution of 66.6 (1.19 mol) of KOH in 200 mL of water is added. The mixture is heated to reflux and stirred for 6 h. The mixture is allowed to return to room temperature, then the solvents are distilled off and ice/water is added. After acidification with concentrated HCl, the mixture is extracted with several times with CH2Cl2. The resulting organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The product recrystallised from hexane gives a pure product as white crystals (66.9 g, 92%).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3Cl)CC2)c(OC)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:12].[Cl-]>C(Cl)Cl>[N+:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([Cl:12])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)CCCO[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cl)CCCO[N+](=O)[O-]
Temperature: 25 °C

Procedure:
In a three neck flask kept under argon and containing 90 ml of CH2Cl2, 4-nitrooxybutanoic acid (800 mg, 5.3 mmol) prepared as described above was charged. Then PCl5 was added in one portion (1.25 g, 6.0 mmol) and the resulting mixture was stirred at room temperature. The reaction was checked by IR spectroscopy. After ca. 2 hours stirrer was removed and the reaction mixture was distilled under vacuum. The crude chloride (900 mg, 5.4 mmol) was used in the further steps without purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)[C:11]2=[O:39])=[N:6][N:5]=1.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:40].[CH3:1][O:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:25])[N:12]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:11]2=[O:39])=[N:6][N:5]=1
Reactant: COCc1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COCc1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1

Procedure:
A solution of tert-butyl 4-[1-{[5-(methoxymethyl)-1,3,4-oxadiazol-2-yl]methyl}-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (872 mg; compound B8) in DCM (15 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (1.5 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([O:14]CC)=O)[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([Mg]Br)[CH:21]=[CH:22][C:23]=1[F:24].C1COCC1.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:21]2[CH:20]=[CH:19][C:18]([F:17])=[C:23]([F:24])[CH:22]=2)=[O:14])[N:3]=1
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)c(F)c1)c1nc(Cl)c2ccccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.8 %

Procedure:
A mixture of ethyl 4-chloroquinazoline-2-carboxylate (1 g, 4.2 mmol) in THF (50 mL) was filtered, and to the filtrate at −30° C. under Ar was added 0.5M (3,4-difluorophenyl)magnesium bromide/THF (10.4 mL, 5.2 mmol). The mixture was stirred at −30° C. for 1.5 h., at which time additional 0.5M (3,4-difluorophenyl)magnesium bromide/THF (3 mL) was added. After a further 1.5 h, additional 0.5M (3,4-difluorophenyl)magnesium bromide/THF (3 mL) was added. To the mixture was added saturated aq ammonium chloride and the mixture was allowed to warm to rt. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford (4-chloroquinazolin-2-yl)(3,4-difluorophenyl)methanone (330 mg, 26%), which was used directly in the next step.
Reaction SMILES: CC(N)C1C=CC=CC=1.C(OC([NH:20][CH2:21][C:22]([NH:24][C@H:25]([P:27](=[O:30])([OH:29])[OH:28])[CH3:26])=[O:23])=O)C1C=CC=CC=1>>[NH2:20][CH2:21][C:22]([NH:24][C@H:25]([P:27](=[O:28])([OH:30])[OH:29])[CH3:26])=[O:23]
Reactant: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)P(=O)(O)O
Agent: CC(N)c1ccccc1
Product: C[C@H](NC(=O)CN)P(=O)(O)O

Procedure:
In the manner analogous to that given in Example 1 (b), from the (+)-α-methylbenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-glycyl)amino] -ethylphosphonic acid there was obtained (1R)-1-glycylamino-ethylphosphonic acid of melting point 277°-280° C (decomposition); [α]D20 =- 69.6°(c = 1% in water).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH2:7]([S:9][C:10]1[C:11]2[N:12]([CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)[N:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[CH3:8]>O.CC(C)=O>[CH2:7]([S:9]([C:10]1[C:11]2[N:12]([CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)[N:13]=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])=[O:1])[CH3:8]
Reactant: O=S([O-])OO
Reactant: CCSc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)c1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.8 %

Procedure:
Oxone (4139 mg, 6.73 mmol) as a solution in water (volume: 40.0 mL) was added to a stirred suspension of 4-(ethylthio)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (910 mg, 3.06 mmol) in acetone (volume: 40 mL) at rt. The reaction mixture was stirred at rt for 3 hr. After the reaction mixture was diluted with water (5 ml), the acetone was removed by rotovap and the resulting suspension was filtered and the filter cake was washed with water. Drying afforded the title compound (890 mg, 2.84 mmol, 93% yield) as a yellow solid. The material was used as is in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (t, J=7.5 Hz, 3 H) 3.31-3.39 (m, 2 H) 7.31 (t, J=7.4 Hz, 1 H) 7.40-7.48 (m, 2 H) 7.74 (s, 1 H) 7.80 (d, J=7.3 Hz, 2 H) 7.98 (d, J=1.7 Hz, 1 H) 8.19-8.30 (m, 1 H) 8.49 (s, 1 H) 8.67 (d, J=1.8 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([OH:17])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23](=[O:26])[CH2:24]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:11]2([C:15](=[O:16])[N:14]([O:17][CH2:24][C:23]([O:22][CH3:21])=[O:26])[C:13](=[O:18])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(O)C2=O
Reactant: COC(=O)CBr
Product: COC(=O)CON1C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O

Procedure:
Employing 8-tert-butyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.56 g) and methylbromoacetate (190 μl), reaction was conducted in the same manner as in Example 40 to obtain an oily compound. This was separated by column chromatography (eluent; dichloromethane) to obtain 0.67 g of a coloress oily compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[N:9][NH2:10])=[N:4][CH:5]=[CH:6][N:7]=1.[CH:20](O)=O.C([O-])(O)=O.[Na+].[OH-].[Na+]>C(OCC)(OCC)OCC>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]1[CH:20]=[N:10][N:9]=[C:8]1[C:3]1[C:2]([NH2:1])=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: O=CO
Reactant: NN=C(Nc1cccc(F)c1F)c1nccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(OCC)OCC
Product: Nc1nccnc1-c1nncn1-c1cccc(F)c1F
Reaction time: 0.5 h
Yield: 92 %

Procedure:
3-Amino-N-(2,3-difluorophenyl)-N′-aminopyrazine-2-carboxamidine (500 mg, 1.89 mmol) was dissolved in CH(OEt)3 (20 mL) and HCOOH (5 mL) was added slowly at RT. The solution was kept at RT for 30 min and carefully neutralized with saturated NaHCO3 and 6N NaOH until a pH of 10 was achieved. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and evaporated to produce 3-(4-(2,3-Difluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine as yellow solid (480 mg, 92%). A small amount of the crude product was purified by HPLC for characterization and the remainder used directly in the next reaction without further purification. LC-MS m/e=274.8 (M+H). Using the same procedure, 3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyrazin-2-amine, 3-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, 3-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine, and 3-(4-(3-chloro-2-fluorophenyl)-4H-1,2,4-triazol-3-yl)pyridin-2-amine can be produced from 3-amino-N-(2,3-dichlorophenyl)-N′-aminopyrazine-2-carboxamidine, 3-amino-N-(3-chloro-2-fluorophenyl)-N′-aminopyrazine-2-carboxamidine, 2-amino-N-(2,3-difluorophenyl)-N′-aminopyridine-3-carboxamidine, 2-amino-N-(2,3-dichlorophenyl)-N′-aminopyridine-3-carboxamidine, and 2-amino-N-(3-chloro-2-fluorophenyl)-N′-aminopyridine-3-carboxamidine, respectively.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:5][OH:6].[F:19][CH2:20][C:21](OCC)=[O:22].[OH-].[Na+].Cl>FC(F)(F)CO.CO.O>[F:19][CH2:20][C:21]([NH:2][CH2:3][CH:4]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:5][OH:6])=[O:22]
Reactant: CCOC(=O)CF
Reactant: COc1ccc2cccc(C(CN)CO)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: OCC(F)(F)F
Solvent: O
Product: COc1ccc2cccc(C(CO)CNC(=O)CF)c2c1
Temperature: 40 °C

Procedure:
The compound obtained in Step B (5.6 mmol), in the form of the base, is dissolved in 40 ml of 2,2,2-trifluoroethanol; ethyl fluoroacetate (10.3 mmol) is added and the mixture is refluxed for 12 hours. When the reaction is complete, the mixture is poured into water and the aqueous phase is extracted twice with 60 ml of ether; the organic phase is washed with water, dried and evaporated. The oil obtained is dissolved in 30 ml of methanol and 10 ml of water; sodium hydroxide (8.25 mmol) is added and the mixture is heated at 40° C. for 30 minutes. The mixture is then poured into water; the aqueous phase is neutralised with 15 ml of hydrochloric acid solution (1 M) and is then extracted twice with 60 ml of ether. The organic phase is washed with water, dried and evaporated. The oil obtained is precipitated from a mixture of ether and petroleum ether (40/60); the precipitate formed is filtered off under suction and then recrystallised from toluene to yield the title compound in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[OH:16])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:5])=[O:4].Br[CH2:27][CH2:28][CH2:29][CH3:30]>>[F:25][C:2]([F:24])([F:1])[S:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[O:16][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:12][CH:11]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:10]2)(=[O:4])=[O:5]
Reactant: CCCCBr
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Product: CCCCOc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CC(N(CCC)CCC)C2

Procedure:
Using procedure 38, 2-(dipropylamino)-2,3-dihydro-6-hydroxy-1H-inden-5-yl trifluoromethanesulfonate (69, 0.38 g, 1 mmol) was treated with bromobutane (0.27 g, 2 mmol). Chromatographic purification yielded pure product 71 as a oil which was converted into the HCl salt and crystallized from EtOAc/hexane to give a white solid (mp 148-149° C.).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][N:4]=1.[NH:11]1[CH2:15][C:14](=[O:16])[NH:13][C:12]1=[O:17].N1CCCCC1>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7](/[CH:9]=[C:15]2/[C:14](=[O:16])[NH:13][C:12](=[O:17])[NH:11]/2)[CH:6]=[CH:5][N:4]=1
Reactant: O=C1CNC(=O)N1
Reactant: CSc1nccc(C=O)n1
Solvent: C1CCNCC1
Solvent: CCO
Product: CSc1nccc(/C=C2\NC(=O)NC2=O)n1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A 40 mL round bottomed vial was charged with 2-(methylthio)pyrimidine-4-carbaldehyde (4) (771 mg, 5 mmol), imidazolidine-2,4-dione (500 mg, 5 mmol, 1.0 equiv.), and piperidine (400 μL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80° C. and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol (1×20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)imidazolidine-2,4-dione (5a) as a yellow solid (565 mg, 1.18 mg theoretical, 48%). LC-MS m/z 237 (M+1). The same procedure can be used to prepare 5b or 5c by replacing imidazolidine-2,4-dione with 1-benzylimidazolidine-2,4-dione or 1-methylimidazolidine-2,4-dione respectively.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[OH-].[K+].[CH2:15](Br)[CH3:16]>CS(C)=O>[CH2:15]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[C:2]([CH3:1])=[CH:3]1)[CH3:16]
Reactant: CCBr
Reactant: COc1ccc2c(C)c[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1cc(C)c2ccc(OC)cc21
Yield: 72.2 %

Procedure:
The 1-ethyl-3-methyl-6-methoxyindol used is prepared as follows: 4.6 g of 3-methyl-6-methoxyindole [Chem. ber. 98, 1727 (1965)] are presented in 29 ml of dimethyl sulfoxide. 6.6 ml of 10n aqueous KOH are then added, and 3.25 g of ethyl bromide are added dropwise at 20° C. in the course of 30'. 1 hour later the reaction mixture is poured onto water and extracted with toluene. Chromatography over silica gel (hexane/ether 5:1) gives 3.9 g of 1-ethyl-3-methyl-6-methoxyindol in the form of an oil.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH2:3][OH:4].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][C:2]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH:3]=[O:4]
Reactant: Cc1ccc(CC(C)(CO)c2cccnc2)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: Cc1ccc(CC(C)(C=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of the product of STEP 3 (4.1 g, 16 mmol), N-methyl morpholine-N-oxide (2.9 g, 25 mmol), dry molecular sieves (8 g) and methylene chloride (35 ml) was stirred at room temperature for 15 min. Tetrapropylammoniumperruthenate (281 mg, 0.8 mmol) was added. The reaction was monitored by TLC, an additional N-methyl morpholine-N-oxide (0.73 g, 6.3 mmol), dry molecular sieves (2 g), and tetrapropylammoniumperruthenate (70.3 mg, 0.2 mmol) were added. After 2.5 h, the reaction mixture was filtered through a short column of Celite®. The filtrate was concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=4/1) to give a pale brown liquid in 1.66 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11]([NH:13][C:14]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[NH:16][N:15]=1)=[O:12])[CH2:5]2.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+]>CN1CCCC1=O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[NH:16][N:15]=[C:14]([NH:13][C:11]([CH:6]3[CH2:5][C:4]4[C:8](=[CH:9][CH:10]=[C:2]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:3]=4)[CH2:7]3)=[O:12])[CH:18]=2)=[CH:24][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: COc1ccc(-c2cc(NC(=O)C3Cc4ccc(Br)cc4C3)n[nH]2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2cc(NC(=O)C3Cc4ccc(-c5ccccc5)cc4C3)n[nH]2)cc1
Temperature: 85 °C

Procedure:
3-(5-Bromoindan-2-yl)carbonylamino-5-(4-methoxyphenyl)pyrazole (50 mg), tributylphenyltin (0.12 ml), a tris(dibenzylideneacetone)dipalladium chloroform complex (6 mg), tri-2-furylphosphine (11 mg) and lithium chloride (25 mg) were dissolved in N-methylpyrrolidone (1 ml) with heating, and the mixture was heated at 85° C. overnight. After allowing to cool, the reaction solution was concentrated under a reduced pressure. The residue was dissolved in ethyl acetate-hexane (1:1, 30 ml) and the solution was washed with saturated aqueous potassium fluoride solution and dried over anhydrous magnesium sulfate. The solvent was distilled away under a reduced pressure. The resultant residue was purified by preparative thin layer chromatography (chloroform: methanol=20:1) to obtain the title compound (4.4 mg).