Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH3:12])[CH:5]=1.[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18].B(F)(F)F.P(=O)([O-])[O-]>C(Cl)Cl>[CH3:14][O:13][CH:3]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH3:12])[CH:5]=1)[P:15]([O:19][CH2:20][CH3:21])(=[O:22])[O:16][CH2:17][CH3:18]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(C(OC)OC)ccc1Cl
Agent: FB(F)F
Agent: O=[PH]([O-])[O-]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(OC)c1ccc(Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of dimethyl acetal 3 (4.3 g, 20 mmol), sieve-dried CH2Cl2 (20 ml) and triethyl phosphite (4.1 ml, 24 mmol) was stirred under argon at -78° C. Boron trifluoride ethereats (2.95 ml, 24 mmol) was added dropwise at -78° C., the solution was stirred 5 min and stored overnight at -20° C. The next day the reaction was warmed to room temperature and stirred 5 hours to complete phosphonate formation. With vigorous stirring, the reaction was quenched with solid NaHCO3 followed by 40 ml saturated NaHCO3 solution. After gas evolution ceased, 40 ml CH2Cl2 and 20 ml H2O were added, the biphasic mixture was partitioned and the CH2Cl2 phase was recovered, dried over Na2SO4 and evaporated. After pumping in vacuo, the oil was purified on a silica gel plug, eluting with CH2Cl2 to yield phosphonate 4 as a light yellow oil (6.01 g., 99%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:24])([F:23])[CH2:21]I>CN(C=O)C>[I:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:21][C:20]([F:24])([F:23])[F:19])[CH:7]=[N:6][C:5]=2[N:4]([CH3:12])[CH:3]=1
Reactant: FC(F)(F)CI
Reactant: Cn1cc(I)c2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cc(I)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 90 °C
Yield: 77 %

Procedure:
To a stirred suspension of 5-iodo-7-methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (13.7 g, 49.8 mmol) in anhydrous DMF (137 ml) was added potassium carbonate (13.8 g, 100 mmol) and 1,1,1-trifluoro-2-iodoethane (7.36 ml, 74.7 mmol). The resulting mixture was heated at 90° C. for 24 h. The reaction mixture was partitioned between brine/water (1:1, 1.41) and ethyl acetate (350 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3×350 ml). The combined organic phase was washed with brine/water (1:1, 4×350 ml), dried and concentrated. The residue was purified by flash chromatography (0-45% ethyl acetate/cyclohexane) to give the title compound (13.7 g, 77%). LCMS RT=1.05 min, M+H+=358.0.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](=[O:23])[CH:7]=[C:8]1[C:19]2=[C:20]3[C:15](=[CH:16][CH:17]=[CH:18]2)[CH:14]=[CH:13][C:12]([O:21][CH3:22])=[C:11]3[CH2:10][CH2:9]1)[CH3:4]>CO.Cl[Pd]Cl>[CH2:3]([O:5][C:6](=[O:23])[CH2:7][CH:8]1[C:19]2=[C:20]3[C:15](=[CH:16][CH:17]=[CH:18]2)[CH:14]=[CH:13][C:12]([O:21][CH3:22])=[C:11]3[CH2:10][CH2:9]1)[CH3:4]
Reactant: CCOC(=O)C=C1CCc2c(OC)ccc3cccc1c23
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC1CCc2c(OC)ccc3cccc1c23
Reaction time: 0.25 h

Procedure:
55 mg of PdCl2 in 5 ml of methanol are treated with 25 mg of sodium borohydride. After 15 minutes' stirring, the compound obtained in Step F (1 g, 3.54.10-3 mol), diluted with methanol (15 ml), is added. The mixture is purged with argon and placed under hydrogen. The reaction is monitored by GPC analysis. After 1 hour 30 minutes' hydrogenation, the reaction mixture is filtered over Celite, rinsed and then evaporated under reduced pressure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([CH:13]3[CH2:15][CH2:14]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:17]1[N:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:19][CH:18]=1>>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][CH:24]([O:23][C:20]2[CH:21]=[N:22][C:17]([N:1]3[C:9]4[C:4](=[CH:5][C:6]([NH:10][C:11]([CH:13]5[CH2:14][CH2:15]5)=[O:12])=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[CH:18][CH:19]=2)[CH2:29][CH2:28]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: O=C(Nc1ccc2[nH]ccc2c1)C1CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(NC(=O)C5CC5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using N-(1H-indol-5-yl)cyclopropanecarboxamide (intermediate-02) and tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24]([O:26]CC)=[O:25])([CH3:23])[CH3:22])[CH:18]=2)[NH:13][C:12]=1[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O.C(OC(=O)C)C.CCCCCC>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24]([OH:26])=[O:25])([CH3:23])[CH3:22])[CH:18]=2)[NH:13][C:12]=1[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: Cc1[nH]c2ccc(OC(C)(C)C(=O)O)cc2c1C(=O)OCc1ccccc1
Reaction time: 24 h
Yield: 82.5 %

Procedure:
5-(1-Ethoxycarbonyl-1-methyl-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (6.88 g, 16.5 mmol, 1.0 eq) was dissolved in THF (16 mL), followed by LiOH (0.395 g, 16.5 mmol, 1.0 eq) in H2O (16 mL). The reaction mixture was refluxed for 24 hours. Another equivalent of LiOH was added, and reflux was continued for another 24 hours. The reaction was then judged complete by TLC in hexane ethyl acetate 1:1. 5.0 g of the product was obtained, 84% yield (crude).
Reaction SMILES: [CH3:1][N:2]1CCOCC1.ClC(OCC(C)C)=O.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)[C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:1][NH:2][C:25](=[O:26])[C@@H:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][S:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
A solution of N-methylmorpholine (0.217 ml) and isobutyl chloroformate (0.256 ml) in tetrahydrofuran (5 ml) is added to a solution of (2R)-2-(tert-butoxycarbonylamino)-3-(4-methylbenzylthio)propionic acid (reference compound No. 3-1, 700 mg) in tetrahydrofuran (15 ml) under a nitrogen atmosphere and freezing medium (ice-sodium chloride) cooling, and the mixture is stirred for 15 minutes. Then, a 40% aqueous N-methylamlne solution (0.756 ml) is added thereto under a freezing medium (ice-sodium chloride) cooling, and the mixture is further stirred for two hours. A 5% aqueous sodium hydrogencarbonate solution is added to the system of reaction, and the whole is extracted with ethyl acetate. The organic layer is washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give the titled compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:29]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:29]=3)=[CH:23][CH:24]=2)[N:7]=1)[CH3:4]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Reactant: ClCc1cccc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4ccccc4)n3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 2-chloromethyl-6-phenylpyridine (306 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (689 mg, yield: 95%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CS(C)=O.[C:29]([C:33]1[O:34][C:35]2[C:36](=[C:38]([C:50]#[N:51])[C:39]([CH3:49])=[C:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:41]=2F)[N:37]=1)([CH3:32])([CH3:31])[CH3:30]>C(OCC)(=O)C>[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:41]2[C:40]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[C:39]([CH3:49])[C:38]([C:50]#[N:51])=[C:36]3[C:35]=2[O:34][C:33]([C:29]([CH3:32])([CH3:30])[CH3:31])=[N:37]3)[CH2:20]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)C)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(N2CCC[C@H](NC(=O)OCc3ccccc3)C2)c2oc(C(C)(C)C)nc2c1C#N
Temperature: 90 °C
Reaction time: 11 h
Yield: 75.3 %

Procedure:
Triethylamine (83 μl, 598 μmol) and (3S)-3-benzyloxycarbonylaminopiperidine (70 mg, 298 μmol) were added to a dimethyl sulfoxide (3.8 ml) solution of 2-tert-butyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-72) (77 mg, 249 μmol), followed by stirring at 90° C. for 11 hours. After cooling, the reaction liquid was diluted with ethyl acetate, this was washed with saturated brine and 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1→4:1, v/v) to obtain the entitled compound (98 mg, 75%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)([O-:10])=[O:9].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(O)CCC>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCCCO
Product: O=C1NC(=O)C(=Cc2ccc([N+](=O)[O-])cc2)N1
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A mixture of 100 grams (1.0 mole) of hydantoin, 151 grams (1.0 mole) of 4-nitrobenzaldehyde, 77 grams (1.0 mole) of ammonium acetate, 120 grams (2.0 moles) of acetic acid, and 200 ml of n-butanol were held for 3 hours at reflux temperature. After the cooling, there were obtained 219 grams of 5-(4'-nitrobenzylidene)-hydantoin, corresponding to 94% of the theory based on hydantoin. The product had a melting point of 253°-254° C. and homogeneous by thin layer chromatography.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[NH:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=2[C:13]([OH:15])=O.[N:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=2)[NH2:27])[CH:21]=[N:20][CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[N:18]1[CH:23]=[C:22]([C:24]2[CH:25]=[C:26]([NH:27][C:13]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[NH:4][C:3]([C:2]([F:1])([F:17])[F:16])=[C:11]4[CH3:12])=[O:15])[CH:28]=[CH:29][CH:30]=2)[CH:21]=[N:20][CH:19]=1
Reactant: Cc1c(C(F)(F)F)[nH]c2c(C(=O)O)cccc12
Reactant: Nc1cccc(-c2cncnc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1c(C(F)(F)F)[nH]c2c(C(=O)Nc3cccc(-c4cncnc4)c3)cccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
To a suspension of 2-trifluoromethyl-3-methylindole-7-carboxylic acid (122 mg) and 3-(pyrimidin-5-yl)aniline (86 mg) in dichloromethane (3 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg) and 4-dimethylaminopyridine (30 mg). The mixture was stirred at ambient temperature for 18 hours and diluted with dichloromethane. The solution was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-[3-(pyrimidin-5-yl)-phenyl]-3-methyl-2-trifluoromethyl-1H-indole-7-carboxamide (106 mg, 53.5%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:38])([F:37])[C:12]([CH2:32][NH:33][CH2:34][CH2:35][CH3:36])([OH:31])[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>>[CH2:34]([N:33]([CH2:32][C:12]([CH2:13][NH:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)([OH:31])[C:11]([F:10])([F:37])[F:38])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:35][CH3:36]
Reactant: O=C(O)c1ccccc1
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: C[O:2][C:3](=[O:20])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]/[OH:6].CO.[OH-].[Na+].Cl>O>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:3]([OH:20])=[O:2]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)/C(=N/O)c1ccccc1Oc1ccccc1
Yield: 72.9 %

Procedure:
To E-α-hydroxyimino-2-phenoxyphenylacetic acid methyl ester (9.99 g, 0.0368 mole) were added methanol (36.8 ml), sodium hydroxide (3.23 g, 0.081 mole) and water (36.8 ml) and the mixture was heated under reflux for one hour. After heating, conc. hydrochloric acid (1 ml) was added to the mixture under ice cooling and the precipitated crystals were filtered off and recrystallized (methanol/ethyl acetate/n-hexane) to obtain E-α-hydroxyimino-2-phenoxyphenylacetic acid (6.90 g, yield: 72.9%) as colorless crystals (decomposition: 180° C.).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:12]([CH2:14][CH2:15][C:16](OCC)=[O:17])[CH:13]=1.N.[H][H]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([O:21][CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:12]([CH2:14][CH2:15][CH2:16][OH:17])[CH:13]=1
Reactant: CCOC(=O)CCc1cc(Cl)ccc1OCCc1ccccc1
Reactant: [H][H]
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCCc1cc(Cl)ccc1OCCc1ccccc1
Reaction time: 1 h
Yield: 35.2 %

Procedure:
1.84 g of aluminum lithium hydride was added to a solution of 10.76 g of the crude ethyl 3-[5-chloro-2-(2-phenylethoxy)phenyl]propionate in 100 ml of tetrahydrofuran under ice-cooling and the mixture was stirred at the same temperature for 1 hour. Then 25% aqueous ammonia was added thereto until no hydrogen gas evolved any more. After filtering with the use of Celite and anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (developing solvent; ethyl acetate:n-hexane =1:9) to give 3.31 g of 3-[5-chloro-2-(2-phenylethoxy)phenyl]propanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[CH:4][N:3]=1.[H-].[Na+].C1N=CN([C:17](N2C=NC=C2)=[O:18])C=1.O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[O:9][C:17](=[O:18])[NH:8][C:6]=2[N:7]=1
Reactant: Nc1ncc(O)c(N)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc2oc(=O)[nH]c2n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2,4-Diamino-pyrimidin-5-ol (500 mg, 3.97 mmol) [prepared according to the method of Hull. J. Chem. Soc. 1956, 2033-2035] was suspended in DMF (10 mL). To this was added consecutively NaH (86.7 mg, 3.77 mmol) and CDI (707 mg, 4.36 mmol), and the reaction mixture was heated with vigorous stirring at 60° C. for 3 h. The mixture was cooled to ambient temperature, and then quenched with water (25 mL). The solvent and water were removed via rotary evaporation, and the residue was then triturated in water (5 mL). The solid was then collected by filtration and dried, affording 230 mg (38%): 1H NMR (400 MHz, d6-DMSO) δ 11.90 (br s, 1H), 7.72 (br s, 1H), 6.72 (s, 2H); Analysis calc'd for C5H4N4O2.0.2 H2O: C, 38.56; H, 2.85; N, 35.98. Found: C, 39.01; H, 2.71; N, 35.58; [M+H]+ m/z 153.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:19])[C:10]=1[C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(C)C.CO>O>[CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:19])[C:10]=1[CH:20]([CH3:21])[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: Cc1nc2ccccc2c(NCc2ccccc2)c1C(C)O
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution prepared from 1-(4-benzylamino-2-methyl-3-quinolinyl)-ethanone (4 g), sodium borohydride (1 g), 75 ml of isopropanol and 25 ml of methanol was stirred one hour at 45°, cooled, stirred with 500 ml of water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate, filtered and evaporated to 4 g of solid. This material was purified by flash chromatography (silica, 10% methanol in dichloromethane) to give 3.6 g of solid, mp 176°-177°.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].C(S)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Solvent: Cc1ccccc1
Solvent: CCCCS
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of cis chrysanthemic acid (1.0 g) in toluene (9 g) was added butanethiol (107 mg). Irradiation with a high pressure mercury lamp (100 W) was made for one hour. After the reaction was over, similar after-treatment as in Example 1 was applied to obtain chrysanthemic acid (0.9 g). A part of the product was converted to ethyl ester in a usual manner. Gas chromatography assay of the product gave the following isomer ratio: cis, 5.2%; and trans, 94.8%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=O.C(N(CC)CC)C.C1C(SSC2C=CC([N+]([O-])=O)=C(C(O)=O)C=2)=CC(C(O)=O)=C([N+]([O-])=O)C=1.CN(C=O)C>O1CCCC1>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCCCCCCCCCCC(=O)O
Agent: O=C(O)c1cc(SSc2ccc([N+](=O)[O-])c(C(=O)O)c2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCN
Reaction time: 16 h

Procedure:
In this example, the spacer unit is 11-amino-undecanoic acid. The spacer (411 mg, 2.04 mmol, 4 eq) is suspended in a dry organic solvent, for example tetrahydrofuran (THF). Depending on its solubility and the stability of the Raman marker unit, the suspension temperature can be varied between −78° C. and reflux. First, an auxiliary base (2.1 ml triethylamine) is added. Then, the activated marker unit in a suitable organic solvent, for example DTNB-NHS (300 mg, 0.51 mmol in 10 ml THF and 5 ml DMF), is added dropwise. Depending on the reactivity, the reaction mixture is stirred 10 to 48 h, in this case 16 h. The solvent is removed by vacuum, the remaining solid is washed with NaHSO4 solution and a suitable organic solvent. Further purification can be achieved by column chromatography, preferably on reversed phase silica (yield: 260 mg, 0.34 mmol, 67%).
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])C.[OH-].[K+]>C(O)C.O>[OH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1/[CH:6]=[CH:5]/[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C=Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)/C=C/c1ccccc1O
Yield: 51.9 %

Procedure:
To a solution of 100.0 g 3-(2-hydroxy-phenyl)-acrylic acid ethyl ester in 500 ml of ethanol, a solution of 50.9 g potassium hydroxide in 500 ml of water was dropped in at room temperature. After stirring at reflux for 28 hours, the reaction mixture was concentrated. The residue was diluted with 500 ml HCl 2N and extracted with ether. The organic phase was washed with 2N HCl and water, dried and evaporated to dryness. The resulting solid was recrystallized to yield 44.3 g of colourless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15](=[CH:26][N:27](C)C)[C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)=O)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:37]C1C=C(C(=CN(C)C)C(C2C=CC(F)=CC=2)=O)C=CN=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:37][NH:27][CH:26]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)C=C(C(=O)c1ccc(F)c(F)c1)c1ccnc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cc(-c2c[nH]nc2-c2ccc(F)c(F)c2)ccn1
Yield: 87 %

Procedure:
The reaction was carried out in the same manner as in Example 2-2) except for using 9.28 g (23.0 mmol) of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-1-(3,4-difluorophenyl)-3-dimethylamino-2-propen-1-one obtained in Example 24-2) in place of 2-(2-t-butoxycarbonylaminopyridin-4-yl)-3-dimethylamino-1-(4-fluorophenyl)-2-propen-1-one to obtain 7.41 g of the title compound as a white powder. (Yield: 87%)
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([OH:24])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:33][CH2:34][CH3:35].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:33][CH2:34][CH3:35])=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(O)cc12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)(C)C)c(=O)c2ccc(OCCC)cc12
Yield: 87.8 %

Procedure:
A solution of tert-butyl(4-butoxy-6-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.52 g, 1.2 mmol), 1-bromopropane (0.16 ml, 1.2 mmol) and potassium carbonate (0.16 g, 1.2 mmol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl(4-butoxy-2-neopentyl-1-oxo-6-propoxy-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.50 g, 89.3%) as an amorphous.