Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:11][C:12]([F:27])([F:26])[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:14]1[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:20])[F:21])=[CH:18][C:13]=1[C:12]([F:11])([F:26])[F:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CN(N)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CN(Nc1ccc(C(F)(F)F)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 26.5 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2,4-bis(trifluoromethyl)phenylboronic acid (Ryscor; 1.75 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 10% ethyl acetate/hexanes, to give N′-(2,4-bis-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (646 mg, 36%) as a solid.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH:17][C:3]2[CH:2]=[C:1]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]=[C:1]([CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:13]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(N)n[nH]1
Reactant: N#CC=Cc1ccccc1
Product: Cc1cc(Nc2cc(N3CCCCC3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 67 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and piperidine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH2:16]I)[C@@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@H:13]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:12]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC>CCO.CCOC(C)=O.[Pd]>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14]([CH2:18][O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:13]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C@@H:12]1[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1[C@H](COCc2ccccc2)[C@@H](CI)N(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H]1[C@H](COCc2ccccc2)[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.5 %

Procedure:
A mixture of (2S*,3S*,4S*,5S*)-1-benzyloxycarbonyl-4-benzyloxymethyl-3-[N-(t-butoxycarbonyl)amino]-5-iodomethyl-2-phenylpyrrolidine (9.85 g, 15.0 mml), Et3N (5.23 ml, d0.726, 37.5 mmol), and 10% Pd-C (1.83 g) in EtOH-AcOEt (2:1, 210 ml) was stirred under a slightly positive pressure of H2 (baloon) at room temperature for 5 hours, during which the white solids of Et3NH+I- precipitated. The catalysts and white precipitates were filtered off by the aid of a Celite pad, and washed with AcOEt followed by CH2Cl2 throughly. The combined filtrate and washings were concentrated in vacuo. The residue was diluted with PhMe-AcOEt (1:1, 200 ml), washed with sat. Na2SO3 aq. solution (×3), H2O (×2), and sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give the title compound (7.60 g, 95%) as slightly yellow solids. This was employed in the next step without further purification. A portion of it (0.15 g) was recrystallized from AcOEt-n-hexane to give an analytical sample of the title compound (0.11 g, 65%) as white fine needles (mp 143-144 C.): IRmax (nujol): 3380(s), 1710(s), 1688(s), 1520(s), 1500(w), 770(m), 738(s), 715(s), 698(s) cm-1 ; 1H-NMR δ: 7.50-7.17(m, 1H), 7.12-6.93(m,1H), 5.25(d, J=8.4 Hz, 1H), 5.04(br.s, 2H), 4.49(br.s, 2H), 4.26(ddd, J=11.3, 9.0, 9.0 Hz, 1H), 4.16-4.00(m, 1H), 3.95-3.77(m, 1H), 3.55(br.d, J=4.8 Hz, 2H), 1.97-1.80(m, 1H), 1.63(br.d, J=4.4 Hz, 3H), 1.40(br.s, 9H) ppm.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:12]=[C:11](N(C2C=CC(OC)=CC=2)C)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Cl:23]CC1NC(=O)C2C(=CC=CC=2)N=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:23][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([CH2:2][Cl:1])[N:12]=1
Reactant: COc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: O=c1[nH]c(CCl)nc2ccccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: ClCc1nc(Cl)c2ccccc2n1

Procedure:
(2-Chloromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A mixture of 2-chloromethyl-quinazolin-4(3H)-one (256 mg, 1.32 mmol), phosphoryl chloride (1.23 ml, 13.2 mmol) and N,N-dimethylaniline (0.34 ml, 2.64 mmol) in chloroform (10 ml) was heated under reflux for 4 h. The reaction mixture was poured onto ice and extracted by ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel with acetate and hexane (1:1) as eluent, yielding 180 mg of 4-chloro-2-chloromethyl-quinazoline. The intermediate (170 mg, 0.80 mmol) and (4-methoxy-phenyl)-methylamine (131.7 mg, 0.96 mmol) in isopropyl alcohol (5 ml) with concentrated HCl (0.05 ml) was stirred at room temperature overnight. The precipitation was formed and collected by filtration, then washed and dried to give 231 mg (92%) of the title compound. 1H NMR (CDCl3): 7.82 (d, J=8.7 Hz, 1H), 7.59-7.53 (m, 1H), 7.15-7.12 (m, 2H), 7.03-7.00 (m, 2H), 6.95-6.91 (m, 2H), 4.73 (s, 2H), 3.85 (s, 3H), 3.62 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl[CH2:11][C:12](Cl)=[O:13].[CH2:15]([N:17]=[C:18]=[S:19])[CH3:16]>>[CH2:15](/[N:17]=[C:18]1\[S:19][CH2:11][C:12](=[O:13])[N:4]\1[C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:2]=1[CH3:1])[CH3:16]
Reactant: Cc1cccc(N)c1C
Reactant: O=C(Cl)CCl
Reactant: CCN=C=S
Product: CC/N=C1\SCC(=O)N1c1cccc(C)c1C

Procedure:
2-[(Z)-Ethylimino]-3-(2,3-dimethylphenyl)-thiazolidin-4-one is prepared following Method B and starting from 2,3-dimethylaniline, chloroacetyl chloride and ethylisothiocyanate. LC-MS: tR=0.66 min, [M+1]+=249, 1H NMR (CDCl3): δ 7.24-7.19 (m, 2H), 7.00-6.96 (m, 1H), 4.01 (s, 2H), 3.45-3.27 (m, 2H), 2.34 (s, 3H), 2.05 (s, 3H), 1.16 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]([CH3:20])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:23].[C:28](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:22][CH3:28])[C:10](=[O:21])[N:11]([CH3:20])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:23]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c2c(c(OC)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (7.25 g, 18 mmol) in anhydrous DMF (75 mL) was added cesium carbonate (5.98 g, 18 mmol) and iodomethane (2.86 mL, 46 mmol). The reaction was stirred at room temperature overnight, and LCMS showed 70% completion. The reaction was heated to 50° C. for 7 hours and then allowed to stir at room temperature again overnight. LCMS indicated completion. The reaction was concentrated to dryness, and the resulting residue was dissolved in chloroform. The solution was extracted twice with saturated Na2SO3 solution, dried over sodium sulfate, filtered, and evaporated to afford a dark brown oil.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])[C:9]=1[CH3:26].CCN(CC)CC.C([O-])(O)=O.[Na+].[C:39]1([CH3:64])[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH2:49][O:50][C:51](=[O:63])[C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[C:54]([S:59](Cl)(=[O:61])=[O:60])[CH:53]=2)(=[O:47])=[O:46])=[CH:41][CH:40]=1>C(Cl)Cl.O>[C:39]1([CH3:64])[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH2:49][O:50][C:51](=[O:63])[C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[C:54]([S:59]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:10]3[C:9]([CH3:26])=[C:8]([O:7][CH2:6][CH2:5][CH2:4][O:3][CH3:2])[CH:13]=[CH:12][N:11]=3)=[O:16])(=[O:61])=[O:60])[CH:53]=2)(=[O:47])=[O:46])=[CH:41][CH:40]=1
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)c2ccc(C)c(S(=O)(=O)Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cc(C(=O)OCCS(=O)(=O)c3ccc(C)cc3)ccc2C)c1C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of 2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-1H-benzimidazole sodium salt (RABEPRAZOLE sodium salt, 1.0 g, 2.62 mmol), 5 mL of Et3N, and about 1 g of NaHCO3 in CH2Cl2 (15 mL) was added the sulfonyl chloride (Intermediate 49, 1.30 g, 3.15 mmol, 1.2 eq) in CH2Cl2 (5 mL) at room temperature, and then the mixture was stirred for 0.5 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried, and concentrated. The residual oil was purified by column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to yield 1.6 g (80%) of 3-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 53) as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([O:11]CC)=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16].[C:17](Cl)(=[O:21])/[CH:18]=[CH:19]/[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:15]([C:17](=[O:21])[CH:18]=[CH:19][CH3:20])=[CH:14][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:16]
Reactant: CCOC(=O)C1Cc2ccc(Cl)c(Cl)c2O1
Reactant: C/C=C/C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC=CC(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 6,7-dichloro-2,3-dihydro-2-benzofurancarboxylate (13.4 g, 0.05 mole) and crotonyl chloride (8.15 g, 0.09 mole) in CH2Cl2 (30 ml) cooled to 5° C. in an ice bath is added aluminum chloride (22.5 g, 0.17 mole) over a 10 minute period. The reaction mixture is stirred for 1 hour at 25° C. then for 20 minutes at reflux. The reaction mixture is poured into ice water, extracted into ether, washed with water and the ether evaporated in vacuo. The residue is treated with 10 N sodium hydroxide (100 ml) and the resultant sodium salt filtered and suspended in dilute hydrochloric acid which is extracted with ether (206 ml), washed with water, dried over magnesium sulfate, evaporated to 50 ml and treated with hexane to give 6,7-dichloro-2,3-dihydro-5-(1-oxo-2-butenyl)-2-benzofurancarboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)([CH3:4])(C)C.Br[CH2:17][CH2:18]Cl.[CH2:20]1COC[CH2:21]1>C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:12]([O:14][CH3:15])=[O:13])[CH2:18][CH2:17]2)=[CH:9][CH:10]=1)[CH2:4][CH2:20][CH3:21]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Reactant: ClCCBr
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCCCc1ccc(C2(C(=O)OC)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 g (19.4 mmol) of Methyl 4-tert-butylphenylacetate, 39 mg (1.0 m, 2 Eq.) of lithium bis(trimethylsilyl)amide, and 3 g (2 Eq.) of 1-bromo-2-chloroethane in 100 mL dry THF were reacted as described in Preparation 11, except that the reaction mixture was stirred for one hour at ambient temperature before work-up. This reaction yielded 4.21 g of a brown oil. This material was purified via silica gel chromatography eluting with a gradient solvent of hexane to hexane/EtOAc 19:1 to yield the title compound 1.57 g (35%) as a pale yellow solid m.p. 58°-60° C. Calculated for C15H20O2: Theory: C, 77.37; H, 8.81 Found: C, 77.54; H, 8.68.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.[CH:13]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.O>CN(C=O)C.C1C=CC=CC=1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:11]#[N:12])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: BrC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of NaH (1.1 g, 27.5 mmol) in DMF (15 mL) and benzene (30 mL) at 0° C. was treated dropwise with 4-bromophenylacetonitrile (5.0 g, 25.5 mmol), stirred for 45 minutes, treated portionwise with cyclohexyl bromide (3.15 mL, 25.5 mmol), warmed to room temperature, stirred for 90 minutes, treated with water, and extracted with diethyl ether. The extract was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5:1 hexanes/ethyl acetate to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH2:41][CH2:42][NH2:43])[CH:36]=[CH:37][C:38]=1[O:39][CH3:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:33]([O:32][CH3:31])[CH:34]=1)=[O:29]
Reactant: COc1ccc(CC2NCCc3c(OC)ccc(OC)c32)cc1OC
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(Br)CBr
Product: COc1ccc(CCNC(=O)CN2CCc3c(OC)ccc(OC)c3C2Cc2ccc(OC)c(OC)c2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 3,4-dimethoxyphenylethylamine
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:24]([OH:25])[C:23]([F:30])([F:29])[F:22])=[CH:9][N:10]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: c1csc(C2OCCO2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cnc(C2OCCO2)s1)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (2.00 g) in tetrahydrofuran (50 mL) was slowly added a 1.6M n-butyllithium hexane solution (8.7 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 30 min, and ethyl trifluoroacetate (5.4 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in methanol (30 mL), and sodium borohydride (0.27 g) was added by small portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (2.56 g, yield 79%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 256 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)[CH3:2].[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:16](=[O:19])[CH2:17][CH3:18])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCc1c[nH]c2cc(C(=O)OC)ccc12
Product: CCC(=O)c1[nH]c2cc(C(=O)OC)ccc2c1CC

Procedure:
Methyl 3-ethyl-2-propionylindole-6-carboxylate (65.7 mg) was prepared from methyl 3-ethylindole-6-carboxylate (184 mg) and propionyl chloride (0.17 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[N+:22]#[C-:23])/[C:11](/[N+:20]#[C-:21])=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[CH2:30]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[C:11]([N+:20]#[C-:21])[C:10]([N+:22]#[C-:23])=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:14][CH:15]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: [C-]#[N+]C(=C\c1ccc(O)cc1)/C(=C/c1ccc(OC)cc1)[N+]#[C-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: [C-]#[N+]C(=Cc1ccc(OC)cc1)C(=Cc1ccc(OCc2ccccc2)cc1)[N+]#[C-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
16 mg of xanthocillin X monomethyl ether was dissolved in 3 ml of DMF and 48 mg of potassium carbonate was added thereto. Further, 48 μl of benzyl bromide was added thereto and the mixture thus formed was stirred at room temperature for 20 hours. Then the reaction mixture was poured into 50 ml of water and extracted with 30 ml portions of ethyl acetate thrice. The extracts were combined, successively washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The sodium sulfate was filtered off and the solvent was distilled from the filtrate. Thus 20 mg of 1-(4'-benzyloxy- (5H, m) and 7.80 (4H, d).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([OH:27])=[N:18][C:19](SC)=[N:20][C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].O.[NH2:29][NH2:30]>COCCO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17]([OH:27])=[N:18][C:19]([NH:29][NH2:30])=[N:20][C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CCCc1nc(SC)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: NN
Solvent: COCCO
Solvent: O
Product: CCCc1nc(NN)nc(O)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
12.4 g of 5-[(2'-cyanobiphenyl-4-yl)methyl]-4-hydroxy-2-methylmercapto-6-propylpyrimidine, prepared above, are dissolved in 370 ml of 2-methoxyethanol. 33 ml of hydrazine hydrate are introduced and the mixture is then refluxed for 3 h. It is concentrated under vacuum and the concentrate is taken up in acetonitrile and triturated. The solid obtained is filtered off and washed with ether and isopropyl ether to give 9.9 g of 5-[(2'-cyanobiphenyl-4-yl)methyl]-2-hydrazino-4-hydroxy-6-propylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[C:4]([F:26])[CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:22])[F:23])[N:16]([CH3:27])[C:15]2=[O:25])=[C:4]([F:26])[CH:3]=1
Reactant: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CCS(=O)(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1.5 h
Yield: 118.3 %

Procedure:
1.00 g (2.41 mmol) of 3-(4-chloro-5-ethylsulfonylamino-2-fluorophenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was dissolved in 10 ml of acetone, and 0.17 g (1.20 mmol) of anhydrous potassium carbonate and 0.23 ml (2.41 mmol) of dimethyl sulfate were added thereto and the reaction was continued for 1.5 hours. After acetone was distilled off, the reaction product was dissolved in ethyl acetate, washed with water and saturated saline solution, and dried over anhydrous sodium sulfate. Thereafter the ethyl acetate was distilled off to obtain a crude product. The crude product was recrystallized from chloroformdiethyl ether, thereby obtaining 0.61 g of the objective product (yield: 59%) in the form of light yellow crystals.
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2)([O-:5])=[O:4]>CN(C)C=O.C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:13]1[CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(I)c2c(c1)CCN2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
A mixture of silver sulfate (100 g, 0.32 mol) and iodine (82 g, 0.32 mol) in N,N-dimethylformamide (700 mL) and ethanol (1400 mL) was treated with 5-nitro-2,3-dihydro-1H-indole I (48 g, 0.29 mol). The resulting mixture was stirred at 25° C. for 1.5 h, filtered and the filter pad washed with ethyl acetate. The filtrate was concentrated in vacuo to a volume of approximately 500 mL. This solution was treated with a 1.0 N aqueous sodium thiosulfate solution (100 mL) and a saturated aqueous sodium chloride solution (400 mL). The resulting precipitate was collected by filtration, washed with water and petroleum ether, and dried in vacuo to afford 7-iodo-5-nitro-2,3-dihydro-1H-indole II (83.9 g, 98.9%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.18 (d, J=2.20 Hz, 1H), 7.80 (d, J=1.46 Hz, 1H), 7.03 (broad s, 1H), 3.65 (t, J=8.97 Hz, 2H), 3.17 (t, J=8.60 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:33])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCCCSc1ccc(-c2ccc(C(=N)N)cc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCS(=O)c1ccc(-c2ccc(C(=N)N)cc2)cc1

Procedure:
Prepared from 4-amidino-4'-(4-methoxycarbonylbutylthio)biphenyl by oxidation with m-chloro-perbenzoic acid in methylene chloride at -20° C. for 15 hours.