Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:30]=[CH:31][CH:32]=1)[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH2:12]1)([O-:3])=[O:2].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][N:8]([CH2:7][C:6]1[CH:30]=[CH:31][CH:32]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:9][CH2:10][N:11]1[CH:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:29])[CH:17]=2)[CH2:12]1)[CH3:39]
Reactant: O=[N+]([O-])c1cccc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)CN(CCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1)Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
106 mg of N-(3-nitrobenzyl)-2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 123-b), 40 mg of ethyl bromoacetate, and 33 mg of potassium carbonate were dissolved in 1 mL of acetonitrile, followed by stirring at room temperature for 3 hours. After completion of the reaction, water was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using PLC (chloroform:methanol=20:1) to obtain 97 mg (yield 76%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:28][C:29]1[N:34]=[C:33]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2c(c1)CCN(c1ccnc(Cl)n1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Yield: 79.3 %

Procedure:
A mixture of 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol), 2,4-dichloropyrimidine (0.298 g, 2.0 mmol), and sodium bicarbonate (0.2 g, 2.4 mmol) in ethanol (10 mL) was heated at 80° C. for 3 hours. It was quenched with water and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (SiO2, 30-6-% ethyl acetate/hexane) to provide the title compound (0.749 g, 79% yield): 1H NMR (CDCl3) 7.95 (d, 1H), 7.32-7.41 (m, 4H), 6.94 (d, 2H), 6.83 (d, 2H), 6.69 (m, 3H), 6.37 (m, 1H), 5.9 (d, 1H), 5.03 (s, 2H), 4.97 (m, 1H), 3.80 (s, 3H), 3.25-3.62 (m, 2H), 3.13 (m, 1H), 2.86 (m, 3H); ES-MS (m/z) 472 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:17])=[O:16])(C)(C)C.[ClH:28]>C(Cl)Cl.C(OCC)(=O)C>[ClH:28].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])(=[O:16])=[O:17]
Reactant: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NCCCCCCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred solution of [6-(2-Nitrobenzenesulfonylamino)-hexyl]-carbamic acid t-butyl ester (2.0 g, 4.9 mmol) in 25 mL of methylene chloride at room temperature was added 3 mL of saturated HCl solution in ethyl acetate and stirred for 4 h. The precipitated solid was filtered to yield the titled compound as white solid (1.58 g, 95%); mp 161-162 ° C.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:21]1CCN2C(=NCCC2)CC1.C=O>C1COCC1.C(OCC)(=O)C>[CH2:17]([C:11](=[CH2:21])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:18]([CH3:19])[CH3:20]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)C(CC(C)C)P(=O)(OCC)OCC
Agent: C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(CC(C)C)C(=O)OCC
Yield: 62.8 %

Procedure:
333 mg of lithium chloride was suspended in 14 ml of dry THF. Then, 2.0 g of ethyl 2-diethylphosphono-4-methylpentanoate was added thereto under stirring. Then, 1.41 g of DBU was added thereto in the form of a dry THF solution. Then, a suspension of 348 mg of paraformaldehyde in dry THF was added thereto. The mixture was stirred at room temperature overnight. The reaction solution was subjected to filtration, and the collected substance was washed with a small amount of benzene. The filtrate and the washing solution were put together and concentrated under reduced pressure. The syrup thereby obtained was dissolved in 60 ml of ethyl acetate. The ethyl acetate layer was washed with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, solvent was distilled off to obtain 700 mg of ethyl 2-isobutyl-2-propenoate as colorless oily substance.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[NH+]1C=CC=CC=1>CCOCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:13][C:12]1=[S:17]
Reactant: O=Cc1ccccc1
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Agent: CC(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: O=C1C(=Cc2ccccc2)SC(=S)N1N=c1sc2ccccc2s1
Temperature: 120 °C

Procedure:
A mixture of 2.0g of 3-[(1,3-benzodithiol-2-ylidene)amino]- 2-thioxo-4-thiazolidinone (see example 37), benzaldehyde (20 ml, excess) and pyridinium acetate (5 ml) is prepared and heated at 120° C for 3 days under nitrogen with stirring. The mixture is then cooled, diluted with ether and filtered. The residue is washed with water and recrystallized from dimethylformamide to yield 2.2 g of the title compound, melting point 288°-289° C.
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].Br[C:31]1[CH:36]=[C:35]([C:37](F)(F)F)[CH:34]=[CH:33][C:32]=1Cl>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:34]3[CH:33]=[CH:32][CH:31]=[CH:36][C:35]=3[CH3:37])[CH2:25][C:24]2=[O:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2s1
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Agent: Cl
Product: Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4s3)CCCCC2)C(=O)C1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(benzothiophen-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-chloro-5-trifluoromethylbenzene was used instead of 1-bromotoluene in Step 1 thereof, 123 mg of the titled compound was prepared.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].[OH-].[Li+].C(O)C.Cl>O>[O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)CCCn1c2c(c(=O)[nH]c1=O)CCCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCn1c2c(c(=O)[nH]c1=O)CCCC2
Yield: 79.1 %

Procedure:
A solution of 14.4 g (54.1 mmol) of ethyl 3-(2,4-dioxo-3,4,5,6,7,8-hexahydro-1(2H)-quinazolinyl)-propanecarboxylate and 6.47 g (270.4 mmol) of lithium hydroxide in 200 ml of a mixture of ethanol and water (4:1) are heated under reflux for one hour. The cooled solution is then mixed with 1 M hydrochloric acid until a pH of 1 is reached, and then concentrated to dryness. The resulting residue is dissolved in about 20 ml of water. On addition of ether, the product is obtained as a precipitate which is filtered off with suction and dried under reduced pressure. This gives 10.2 g (42.8 mmol, 79% yield) of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and acetophenone, 3-(4-chlorophenyl)-1-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:47][CH3:48])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl.C([N:52]=C=NCCCN(C)C)C.CN(C)C=O>O>[C:40]([C:39]1[CH:38]=[CH:37][C:36]([C:32]2[O:33][C:34]([CH3:35])=[C:30]([CH2:29][O:28][C:27]3[CH:45]=[CH:46][C:24]([CH2:23][O:22][C:12]4[C:11](/[CH:10]=[CH:9]/[P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[CH:15][N:14]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:13]=4)=[CH:25][C:26]=3[O:47][CH3:48])[N:31]=2)=[CH:44][CH:43]=1)(=[O:42])[NH2:52]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(OC)c1)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(N)=O)cc3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.5 %

Procedure:
A mixture of 4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid (0.18 g), 1-hydroxybenzotriazole ammonia complex (0.06 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.08 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-(3-{[4-({2-[4-(carbamoyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenylphosphonate as colorless crystals (0.15 g, yield 83%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-148° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:38])[N:14]([CH:21]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:15]2=[O:20].[Cl:39][CH2:40][C:41](Cl)=[O:42]>>[Cl:39][CH2:40][C:41]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:38])[N:14]([CH:21]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:15]2=[O:20])=[O:42]
Reactant: O=C(Cl)CCl
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CN)c3C2=O)ccc1OC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CNC(=O)CCl)c3C2=O)ccc1OC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Triethylamine (0.52 g, 5.11 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione hydrochloride(1.0 g, 2.13 mmol). The clear solution was cooled in an ice bath to 5° C. Chloroacetyl chloride (0.30 g, 2.56 mmol) was added keeping the temperature between 5-9° C. The mixture was stirred at 5° C. for 30 min and then warmed to room temperature for 2 hours. The mixture was washed with water (2×30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride:ethyl acetate 7:3) to give 2-chloro-N-({2-[1-(3ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide (1.0 g, 92%): 1H NMR (CDCl3) δ 7.84-7.65 (m, 4H), 7.14-7.12 (m, 2H), 6.86 (d, J=8.9 Hz, 1H), 5.94-5.88 (dd, J=4.6, 10.3 Hz, 1H), 4.79 (d, J=6.5 Hz, 2H), 4.614.51 (dd, J=10.4, 14.4 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.02 (s, 2H), 3.85 (s, 3H), 3.80-3.72 (dd, J=4.6, 14.4 Hz, 1H), 2.86 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[N:13]([CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl.O>C(O)C>[ClH:25].[NH:23]([N:24]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][C:14]2[N:13]([CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C:10]1=2)[C:20]([NH2:22])=[NH:21]
Reactant: CCCn1ccc2c1CC(c1ccccc1)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCn1ccc2c1CC(c1ccccc1)CC2=NNC(=N)N
Yield: 91.6 %

Procedure:
A mixture of 6-phenyl-1-propyl-4,5,6,7-tetrahydroindol-4-one (0.80 g), aminoguanidine hydrochloride (0.46 g), concentrated hydrochloric acid (0.19 ml), water (0.19 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water and washed with diethylether. To the mixture was added 1N sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added a solution of 4N hydrochloric acid in ethyl acetate (2 ml). The solvent was evaporated, and the residue was recrystallized from ethanol to give 4-guanidinoimino-6-phenyl-1-propyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 9) (1.0 g) as colorless crystals of E/Z compounds.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Sn](CCCC)(CCCC)CCCC)[CH:8]=[N:9][CH:10]=1)=[O:4].Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH3:40].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:40][N:36]1[CH2:37][CH2:38][CH2:39][C@@H:35]1[CH2:34][C:28]1[C:27]2[C:31](=[CH:32][CH:33]=[C:25]([C:7]3[CH:8]=[N:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[CH:26]=2)[NH:30][CH:29]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C(=O)OC)c1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)c1cncc(-c2ccc3[nH]cc(C[C@H]4CCCN4C)c3c2)c1

Procedure:
5-Methoxycarbonyl-3-pyridyltri-n-butylstannane (see Preparation and 5-bromo-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole (see Preparation 36) were reacted together in the presence of tri-o-tolylphosphine, triethylamine and palladium (II) acetate using a procedure similar to that described in Example 1. This yielded the title compound as an oil. The product, which was impure, was used without characterisation in the preparation of Example 49.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([OH:35])([CH3:34])[CH2:23][CH2:24][N:25]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[N:27]=[C:26]3Cl)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3([CH3:34])[O:35][C:26]4=[N:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][N:25]4[CH2:24][CH2:23]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)(CCn1cc([N+](=O)[O-])nc1Cl)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3(C)CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
4-{4-[4-(2-Chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylbutoxy]phenyl}piperazine-1-carboxylic acid tert-butyl ester (2.12 g) was dissolved in dimethylformamide (21 ml). 60% sodium hydride (0.24 g) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, the mixture was subjected to extraction with methylene chloride, and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=1:0→methylene chloride:ethyl acetate=1:1) to afford the title compound as a colorless powder (1.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>C(#N)C>[CH2:21]([O:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([Cl:11])[CH:4]=1)[CH:20]=[CH2:19]
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(Cl)c([N+](=O)[O-])cc1Cl
Yield: 93.5 %

Procedure:
The product of step (a) (59.3 g, 285 mmol), 550 ml acetonitrile, 43 g (314 mmol) of potassium carbonate and 27.2 ml (314 mmol) of allyl bromide were combined and heated to reflux, and then the reaction was evaporated under reduced pressure. The mixture was extracted with diethyl ether, washed with water, and separated. The organics were dried over magnesium sulfate and stripped to yield 66.1 g of 4-allyloxy-2,5-dichloronitrobenzene product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16]N1C(=O)CCC1=O.C(O)(=O)C>O>[Cl:16][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nccc(O)c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2ncc(Cl)c(O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A mixture of methyl 4-hydroxyquinoline-6-carboxylate (2.07 g), N-chlorosuccinimide (1.36 g), and acetic acid (56 mL) was stirred at room temperature for one day. The reaction mixture was diluted with water, and then, the precipitate was collected by filtration to obtain methyl 3-chloro-4-hydroxyquinoline-6-carboxylate (2.13 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:16][CH2:17][CH3:18])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: CCCN
Solvent: ClCCl
Product: CCCNS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 99.4 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and propylamine (0.32 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-propyl-2-(trifluoromethyl)benzenesulfonamide (0.53 g, 100%) was provided after purification. MS (ESI) m/z 346. HPLC purity 100.0% at 210-370 nm, 9.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:47]([C:49]1[N:50]=[C:51]([C:62]([O-])=[O:63])[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=1)#[N:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:15]1([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[N:2]([CH3:1])[CH3:21])[CH:13]=[CH:12][C:11]=2[NH:14][C:62]([C:51]2[N:52]([CH2:54][O:55][CH2:56][CH2:57][Si:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=[C:49]([C:47]#[N:48])[N:50]=2)=[O:63])[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Yield: 100.3 %

Procedure:
A solution of 365 mg (1.18 mmol) of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 827 mg (1.78 mmol) of PyBroP, 398 mg (1.30 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 618 μL, (3.55 mmol) of DIEA at RT for 16.5 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL) and the combined organic layers dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25-40% EtOAc-hexane afforded 660 mg (100%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C27H39N5O4SSi, 558.2 (M+H). found 557.9.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[Br:23]N1C(=O)CCC1=O>CC#N>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O
Solvent: CC#N
Product: COC(=O)c1nc(Br)c2cc(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 12.9 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (1 mmol, 293 mg), N-bromosuccinimide (1.2 mmol, 214 mg) and anhydrous MeCN (10 mL) was stirred at ambient temperature for 4 days before silica gel was added and the mixture was concentrated in vacuo. The residue was added on top of a chromatography column filled with silica gel. Elution with hexanes:ethyl acetate=75:25 gave the title compound as an off-white solid (48 mg); MS-(+)-ion: M+1, 79Br/81Br=372.4 and 374.4.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].N1C=CN=C1.[C:13]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:14].C(OCC)C>CN(C)C=O>[Si:17]([O:7][CH2:1][CH2:2][CH2:3][CH:4]([CH3:5])[OH:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(O)CCCO
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(O)CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
In N,N-dimethylformamide (200 ml) were dissolved 1,4-pentanediol (10.0 g, 96.0 mmol) and imidazole (6.6 g, 96.9 mmol). Under ice cooling, t-butyl chlorodiphenylsilane (25.2 ml, 96.4 mmol) was added dropwise. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 2 days. To the reaction mixture was added diethyl ether, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=5:1), whereby the title compound (32.0 g, 97%) was obtained as a colorless oil.