Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[C:35]([CH3:40])[CH:34]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([F:32])=[CH:34][C:35]=3[CH3:40])=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH2:24]4)[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Reactant: Cc1cc(F)ccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 92.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.08 g, 0.18 mmol) obtained in Example 120, step 2 and 4-fluoro-2-methylaniline (0.034 g, 0.27 mmol), the title compound (0.088 g, 91%) was obtained.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:13][CH2:12]2)[CH3:10])=[N:5][CH:6]=[CH:7][N:8]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C.Cl.C(OCC)(=O)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]([CH:14]1[CH2:13][CH2:12][N:11]([CH:9]([C:4]2[C:3](=[O:2])[NH:8][CH:7]=[CH:6][N:5]=2)[CH3:10])[CH2:16][CH2:15]1)=[O:26]
Reactant: COc1nccnc1C(C)N1CCC(C(=O)Cc2ccccc2F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(c1ncc[nH]c1=O)N1CCC(C(=O)Cc2ccccc2F)CC1
Yield: 53.8 %

Procedure:
After dissolving 118 mg of 1-[1-[1-(3-methoxy-2-pyrazinyl)ethyl]piperidin-4-yl]-2-(2-fluorophenyl)ethanone in 2 ml of ethanol, 6 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was heated to reflux for 9 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: ethyl acetate/methanol), diethyl ether was added and the precipitate was filtered out to obtain the title compound (61 mg, 38% yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37](Cl)=[O:38]>ClCCl>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7](=[N:14][O:15][CH2:16][C:17]1[N:22]=[C:21]([NH:23][C:37](=[O:38])[O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])[CH:20]=[CH:19][N:18]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cn1ccnc1C(=NOCc1nccc(N)n1)c1ccccc1
Reactant: CCCCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCOC(=O)Nc1ccnc(CON=C(c2ccccc2)c2nccn2C)n1
Yield: 12 %

Procedure:
A solution of 2-[({[(1-methyl-1H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-amine (200 mg, 0.64 mmol), triethylamine (0.18 mL, 1.29 mmol), chloroformic acid n-amyl ester (0.19 mL, 1.29 mmol) in dichloromethane (10 mL) was stirred 4 h20 at room temperature. After dilution with water (50 mL), the layers were separated and the aqueous layer further extracted with dichloromethane (30 mL). The combined organic layers were dried over MgSO4 and the solvents removed in vacuo. Purification on silica gel afforded pentyl {2-[({[(1-methyl-1H-imidazol-2-yl)(phenyl)methylene]amino}oxy)methyl]pyrimidin-4-yl}carbamate as an oil [34 mg, yield 12%; HPLC/MS: m/z=423 (M+H); log P(HCOOH)=2.28].
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([N+:19]([O-:21])=[O:20])=[C:2]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c([N+](=O)[O-])cc2c1=O
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c([N+](=O)[O-])cc2c1=O
Temperature: 120 °C
Yield: 54 %

Procedure:
A mixture of 9.3 g (0.03 mole) of 7-chloro-1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-3-quinolinecarboxylic acid and 12.9 g (0.15 mole) of piperazine in 60 ml of dimethylsulphoxide is warmed at 120° C. for 15 minutes. After a short time, a precipitate separates out of the hot solution. The mixture is concentrated under a high vacuum, the residue is stirred with 30 ml of water and the mixture is heated again at 95° C. for 30 minutes. The mixture is adjusted to pH 8 with 2N hydrochloric acid and the precipitate is filtered off with suction and washed with water and methanol. 5.8 g (54% of theory) of 1-cyclopropyl-1,4-dihydro-6-nitro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid of decomposition point 296° to 298° C. are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33]([CH3:44])(=[N:35][C:36]([CH:38]3[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]3)=[O:37])=[O:34])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH2:45](I)[CH3:46]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[S:33]([CH3:44])(=[N:35][C:36]([CH:38]3[CH2:43][CH2:42][N:41]([CH2:45][CH3:46])[CH2:40][CH2:39]3)=[O:37])=[O:34])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=NC(=O)C1CCNCC1)c1ccccc1-c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CCI
Product: CCN1CCC(C(=O)N=S(C)(=O)c2ccccc2-c2ccc(C(=O)Nc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Yield: 77 %

Procedure:
Product of Example 26 was ethylated using standard N-alkylating procedure with ethyl iodide to give titled compound in 77% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=O)[CH:4]=1.Cl.N1C=CC=CC=1.[K+].[C:19]([O:25][CH3:26])(=[O:24])[CH2:20]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH:9]=[CH:20][C:19]([O:25][CH3:26])=[O:24])[CH:4]=1
Reactant: COc1ccnc(C=O)c1
Reactant: COC(=O)CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC(=O)C=Cc1cc(OC)ccn1
Temperature: 120 °C

Procedure:
A mixture of 45 g of 4-methoxypyridine-2-carbaldehyde (Ashimori et al., Chem. Pharm. Bull. 38, 2446–2458 (1990)), 75.80 g of pyridine hydrochloride, 102.45 g of monomethyl malonate potassium salt and 4.1 ml of piperidine in 700 ml of pyridine are slowly heated, with stirring, to 120° C. When the evolution of gas starts, the heating source is temporarily removed to stop the reaction from becoming too violent. Once the reaction has subsided, the mixture is stirred at 120° C. for a further 2.5 h, and the pyridine is then distilled off under reduced pressure. The residue is partitioned between ethyl acetate/water and the organic phase is washed with water and dried. The residue obtained after concentration is chromatographed on a silica gel column using ethyl acetate/petroleum ether 2:1. This initially gives 43.2 g of the title compound as a yellow oil which crystallizes on standing and then shows a m.p. of 80–82° C. The mass spectrum shows the molecular peak MH+ at 194 Da.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([Cl:20])[C:11]=1[C:21]1[NH:22][CH:23]=[CH:24][N:25]=1.O>CN(C)C=O>[Br:1][C:24]1[N:25]=[C:21]([C:11]2[C:12]([Cl:20])=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[Cl:9])[NH:22][CH:23]=1
Reactant: FC(F)(F)c1cc(Cl)c(-c2ncc[nH]2)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cc(Cl)c(-c2nc(Br)c[nH]2)c(Cl)c1
Reaction time: 7 h
Yield: 13.1 %

Procedure:
A solution of N-bromosuccinimide (0.63 g, 0.0036 mol) in dimethylformamide (dried over 4Å molecular sieve, 18 ml was added dropwise with stirring to a solution of 2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole (1.0 g, 0.0036 mol) in dimethylformamide (dried over 4Å molecular sieve, 18 ml) and stirred for 7 hours. The mixture was poured into water (180 ml) and extracted with dichloromethane (5×30 ml). The combined extracts were washed with water (3×50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluted with a mixture of ethyl acetate and petroleum spirit (bp 60°-80° C.) (3:5) to give 4-bromo-2-(2,6-dichloro-4-trifluoromethylphenyl)-imidazole (0.17 g), m.p. 224°-225° C., as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:3]=1[C:4]([O:6]C1C=CC=CC=1)=O.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=1.CO>C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:27]([C:25]1[N:26]=[C:22]([NH:21][C:4](=[O:6])[C:3]2[CH:13]=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:2]=2[OH:1])[S:23][CH:24]=1)=[O:28]
Reactant: COc1cc(O)c(C(=O)Oc2ccccc2)cc1OC
Reactant: COC(=O)c1csc(N)n1
Solvent: CO
Solvent: Cc1ccccc1C
Product: COC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2O)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
In 250 mg of xylene were suspended 250 mg of phenyl 2-hydroxy-4,5-dimethoxybenzoate (3a) and 144 mg of methyl 2-amino-1,3-thiazole-4-carboxylate (4a) in a stream of argon, which was then heated to reflux (at 140° C.) for 7 hours. The reaction was not completed. After cooling, methanol was added, followed by stirring for one hour. The precipitated crystal was collected by filtration and dried under reduced pressure at 60° C. to provide 170 mg of the same compound (5a) as that of Example 4 at a yield of 55%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.BrC1C=CC(OC)=CC=1.[Mg].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Brc1ccccn1
Agent: COc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)cc1

Procedure:
That is, as shown in the Reaction Scheme below, (4-methoxyphenyl)magnesium bromide was synthesized from 22.4 g (120 mmol) of 4-bromoanisole by a conventional method by using 3.4 g of magnesium (Mg) in dry tetrahydrofuran (THF) under argon stream and added slowly into a solution of 15.8 g (100 mmol) of 2-bromopyridine and 1.8 g of (1,2-bis(diphenylphosphino)-ethane)dichloronickel (II) (Ni(dppe)Cl2) in dry THF and the mixture was refluxed for 1 hour. After adding 250 ml of an aqueous solution of 5% hydrochloric acid to the reaction mixture, the reaction mixture was washed with chloroform. The water layer was neutralized with an aqueous solution of sodium hydrogen carbonate and the objective compound was extracted with chloroform and the organic layer was distilled off under reduced pressure. The distillate immediately solidified at room temperature to obtain 15.1 g (81.5 mmol) of 2-(4-methoxy-phenyl)pyridine (4-MeO-PPy) as white solid. Identification was performed by elementary analysis of C, H and N and 1H-NMR.
Reaction SMILES: C([CH:7]([NH2:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])CCCCC.[CH:15]([OH:17])=O>>[CH2:7]([N:14]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:15]=[O:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=CO
Reactant: CCCCCCC(N)CCCCCC
Product: CCCCCCCN(C=O)CCCCCC

Procedure:
20.0 g (100 mmol) of 1-hexylheptylamine are heated under reflux with 20.0 g (400 mmol) of 92 percent formic acid for 1 hour. The excess formic acid is distilled off over a 10 cm Vigreux column and the reaction product which remains is subjected to fractional distillation in vacuo. Yield 18.1 g (79%)--boiling point 165° C. (1 mm Hg)-nD 20=1.4577. The reaction product contains a small content of bisformamide which can be removed by distillation only with difficulty but does not interfere in the further reactions.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH:27]C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:26][O:25][CH2:24]3)=[O:22])[CH3:19])=[C:14]([F:45])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4].N1CCCCC1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6]([C:12]2[CH:17]=[CH:16][C:15]([C@H:18]([NH:20][C:21]([C:23]3([NH2:27])[CH2:24][O:25][CH2:26]3)=[O:22])[CH3:19])=[C:14]([F:45])[CH:13]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[O:4]
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)COC2)c(F)c1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-4′-((R)-1-{[3-(9H-fluoren-9-ylmethoxycarbonylamino)-oxetane-3-carbonyl]-amino}-ethyl)-3′-fluoro-biphenyl-2-carboxylic acid methyl ester (100 mg, 159 μmol, step C) in dry DMF (1.8 ml) was added piperidine (0.2 ml) and the solution was stirred at room temperature for 2 h. The brown solution was concentrated to dryness under high vacuum. The remaining residue was purified by chromatography (silica gel; DCM/MeOH 98:2) and the title compound was obtained as white solid (60 mg, 92%). MS: 407.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].[H-].[Na+].Br[CH2:16][CH:17]=[CH:18][CH3:19].O>C1(C)C=CC=CC=1>[CH2:16]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:11][CH3:12])[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:17]=[CH:18][CH3:19]
Reactant: CCOC(=O)NCC(OC)OC
Reactant: CC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC=CCN(CC(OC)OC)C(=O)OCC
Reaction time: 1 h

Procedure:
89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise to 17.5 g (0.58 mol) of NaH (80% strength in paraffin oil) in 500 ml of absolute toluene at 80° C. The mixture is then stirred for one hour and 80 g (0.59 mol) of 1-bromo-2-butene are subsequently added dropwise at 80° C. The mixture is stirred at 80° C. overnight and cooled, the salts are dissolved with water and the aqueous phase is separated off and extracted with toluene. The toluene solutions are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:19]#N)[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1.C(O)=[O:26]>[Ni].[NH4+]>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([CH:19]=[O:26])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1
Reactant: O=CO
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccc(C#N)cc32)CC1
Agent: [Ni]
Agent: [NH4+]
Product: CN1CCC(=C2c3ccccc3C=Cc3ccc(C=O)cc32)CC1

Procedure:
A mixture of 1.70 g of 1-methyl-4-(3-cyano-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine (prepared as described in U.S. Pat. No. 3,988,342 (1976)), 1.70 g of Raney nickel-ammonium alloy, and 25 ml of 75% aqueous formic acid was stirred under reflux for 1.5 hours. The cooled mixture was filtered and the filtrate was made basic by the additional of solid sodium bicarbonate. Extraction of the neutralized mixture with chloroform and evaporation of the solvent gave 1.30 g of 1-methyl-4-(3-formyl-5H-dibenzo[a,d]cycloheptene-5-ylidene)piperidine.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[C:8]2=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:35]([CH2:38][C:39]([O:41]CC)=[O:40])=[C:36]=[S:37]>C(Cl)(Cl)Cl>[C:39]([CH2:38][NH:35][C:36]([C:11]1[C:12](=[O:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8](=[O:25])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:10]=1[OH:14])=[S:37])([OH:41])=[O:40]
Reactant: CCOC(=O)CCCCCN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Reactant: CCOC(=O)CN=C=S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCn1c(O)c(C(=S)NCC(=O)O)c(=O)n(C2CCCCC2)c1=O
Reaction time: 168 h
Yield: 60.2 %

Procedure:
A mixture of ethyl 6-(3-cyclohexyl-2,4,6-trioxotetrahydro-1(2H)-pyrimidinyl)hexanoate (330 mg, 0.94 mmoles), diisopropylethylamine (324 uL, 1.87 mmoles) and ethyl isothiocyanatoacetate (139 uL, 1.12 mmoles) in chloroform (20 mL) was stirred for 7 days. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The residue was purified by flash chromatography (hexane—20% ethyl acetate in hexane) to give the title compound as a clear oil (250 mg, 60%). The diester was dissolved in ethanol (3 mL) and treated with 1 molar sodium hydroxide (2 mL). The mixture was stirred overnight, taken up in ethyl acetate and washed with 1 molar hydrochloric acid (×2), dried and evaporated. Crystallization from acetic acid afforded the title compound (160 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.13 (br s, 1 H), 12.50 (s, 1 H), 12.03 (br s, 1 H), 4.71 (m, 1 H), 4.35 (d, J=5.05 Hz, 2 H), 3.84 (t, J=7.20 Hz, 2 H), 2.10-2.38 (m, 4 H), 1.80 (d, J=12.63 Hz, 2 H), 1.42-1.71 (m, 7 H), 1.21-1.42 (m, 4 H), 1.01-1.22 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:35][S:36]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH2:9]2)=[CH:4][CH:3]=1)(=[O:38])=[O:37]
Reactant: Nc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2
Yield: 49 %

Procedure:
7-Amino-2-(4-phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline (3 g, 8.6 mmol) was dissolved in dichloromethane (100 ml), and 2,6-lutidine (1.2 ml, 10.32 mmol) was added. To this methylsulfonyl chloride (0.73 ml, 9.46 mmol) was added dropwise. A further portion of 2,6-lutidine (0.6 ml, 5.16 mmol) and methylsulfonyl chloride (0.37 ml, 4.78 mmol) were later added. The mixture was partitioned between sodium bicarbonate solution (100 ml) and dichloromethane (3×50 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo. Chromatography of the residue on alumina with ethyl acetate +0-1% methanol gradient elution gave the title compound as an oil (1.8 g, 49%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]([NH2:32])[CH:26]=1>C(OCC)(=O)C>[NH2:32][C:27]1[CH:26]=[C:25]([Cl:24])[CH:30]=[CH:29][C:28]=1[S:31][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)/C(=C/c1ccccc1)NC(=O)OCc1ccccc1
Reactant: Nc1cc(Cl)ccc1S
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccc(Cl)cc1N)c1ccccc1
Yield: 28 %

Procedure:
Using a procedure similar to that described in Example 10, part b, except using methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-phenylacrylate (9a) (4.0 g, 12.9 mmol) as the olefin component, and 4-chloro-2-aminothiophenol (10 g, 62.7 mmol) as the thiol component (stirred for 6 days), the product was obtained as a crude oil. Flash column chromatography (5:1 hexanes:ethyl acetate) returned the title compound (1.7 g, 28%). Recrystallization from ethyl acetate-hexanes afforded the title compound (13a) (1.4 g) as a white solid (>98% erythro). MS APCI, m/z=471 (M+1). LC/MS: 2.90 min.
Reaction SMILES: C(CC[O:5][P:6]([O-])([O-:8])=[O:7])#N.[N:10]([C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:14]1)=[N+:11]=[N-:12].C1(N=C=NC2CCCCC2)CCCCC1.O>N1C=CC=CC=1.[OH-].[K+]>[P:6]([O:19][CH2:18][C@H:17]1[O:16][C@@H:15]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:14][C@@H:13]1[N:10]=[N+:11]=[N-:12])([OH:8])([OH:7])=[O:5]
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
A freshly prepared pyridinium salt of 2-cyanoethylphosphate (8.05 g, 23.64 mmol) was added to a solution of 3'-azido-2',3'-dideoxyuridine (2.50 g, 9.7 mmol) in dry pyridine (50 ml) and evaporated to dryness at 30° C. The concentrated residue was dissolved in pyridine (50 ml) and the solution again evaporated to dryness. The process was repeated twice and then the residue obtained was dissolved in dry pyridine (50 ml). Dicyclohexylcarbodiimide (8.08 g, 39.1 mmol) was added to the solution. The reaction mixture was stirred for 48 hours at room temperature. Water (10 ml) was added and the solution was then filtered to remove dicyclohexylurea. The clear solution was evaporated to dryness. The residue obtained was then dissolved in 1N KOH (250 ml) and heated for 15 minutes at 100° C. The cold solution was passed through a column of acidic Dowex 50 (H+), the effluent brought to pH 9 and passed through a column of Dowex (1×4 Cl-). A linear gradient elution of 0.015N HCl to 0.15N HCl resulted in 3'-azido-2',3'-dideoxyuridine-5'-monophosphate with a 73% yield.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:1]1([N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[C:17](=[O:20])[CH:18]=[CH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CC(=O)Cl
Reactant: Oc1cccc(CCNC2CCCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)N(CCc1cccc(O)c1)C1CCCCC1
Reaction time: 1 h

Procedure:
To a stirred solution of the oil isolated in Step E (313 mg, 1.4 mmol) in methylene chloride (10 mL) and saturated aqueous sodium bicarbonate solution (10 m) at 0° C. was added acryloyl chloride (115 μL, 1.4 mmol). The resulting mixture was stirred for 1 h and then was extracted with methylene chloride. The solution was concentrated, the resulting residue was dissolved in MeOH (3 mL) and aqueous LiOH solution (1N, 1 mL). The mixture was then stirred at room temperature for 30 minutes. The solution was acidified with 1N HCl and then extracted with methylene chloride. The solution was dried over sodium sulfate and concentrated to yield an oil.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>C1(C)C(C)=CC=CC=1>[Cl:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:16]1[NH:15][CH:19]=[CH:18][N:17]=1
Reactant: c1c[nH]cn1
Reactant: CN(C)Cc1c[nH]c2ccc(Cl)cc12
Solvent: Cc1ccccc1C
Product: Clc1ccc2[nH]cc(Cc3ncc[nH]3)c2c1
Yield: 84.5 %

Procedure:
A solution of 5-chlorogramine (3.73 g) and imidazole (1.22 g) in xylene (20 ml) was heated under reflux for 3 hours and the cooled. The solid was filtered off, washed with toluene followed by petrol and then crystallised from a mixture of isopropanol and petrol (b.p. 60°-80° C.) to give 5-chloro-3-(1-imidazolylmethyl)indole (3.50 g), m.p. 195°-197° C. Found: C, 62.48; H, 4.31; N, 18.09. C12H10ClN3 requires: C, 62.20; H, 4.35; N, 18.14%.