Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:18]/[CH2:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:31][C:32]([O:34]CC)=[O:33])=[N:21]1.C(O)C.C>O>[F:6][C:7]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:17]=[CH:18]/[CH2:19][N:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:31][C:32]([OH:34])=[O:33])=[N:21]1
Reactant: CCOC(=O)Cc1nn(C/C=C/c2cccc(C(F)(F)F)c2F)c(=O)c2ccccc12
Agent: C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1nn(C/C=C/c2cccc(C(F)(F)F)c2F)c(=O)c2ccccc12
Reaction time: 2 h

Procedure:
A solution of 183.6 g (2.185 mol) of sodium bicarbonate in 4.2 1 of water is rapidly added to a suspension of 474.4 g (1.092 mol) of ethyl (E) -3-[3-[2-fluoro-3-(trifluoromethyl)phenyl]-2-propenyl]-3,4-dihydro-4-oxo-1-phthalazineacetate in 4.2 1 of ethanol and heating is carried out for 2 h at reflux. A solution of 36.7 g (0.436 mol) of sodium bicarbonate in 800 ml of water is added and heating is carried out for 4 h 30 at reflux. 50 g of Norit are added and heating is carried out for a further 1 h at reflux. The mixture is filtered while hot through Hyflo and the ethanol is evaporated under vacuum. The residual aqueous phase is diluted with water to a volume of 10 l, cooled and acidified to pH=2 with 6N HCl (approximately 300 ml). The precipitate obtained is filtered, washed with water and dried under vacuum at 60° C. and then recrystallized from a hexane/ethyl acetate mixture to give a solid melting at 170°-172° C. Weight obtained: 382 g (Yd. 86%)
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:31]([CH2:33][NH2:34])[OH:32]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C@@:7]([CH3:17])([C:14]([NH:34][CH2:33][CH2:31][OH:32])=[O:16])[CH2:6][CH2:5]2
Reactant: NCCO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)NCCO)O2
Yield: 81.6 %

Procedure:
Following the amide coupling procedure described in protocol A, 1.846 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (7.37 mmol), 1.315 g CDI (8.11 mmol) and 991 mg ethanolamine (16.22 mmol) produced 1.765 g of (R)-6-hydroxy-N-(2-hydroxyethyl)-2,5,7,8-tetramethylchroman-2-carboxamide as a waxy white solid.
Reaction SMILES: Cl.[CH2:2]([C:6]1([N:26]([CH3:28])[CH3:27])[CH2:11][CH2:10][CH:9]([CH:12]([O:20]C(OCC)C)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]>O1CCCC1.C(Cl)Cl>[CH2:2]([C:6]1([N:26]([CH3:27])[CH3:28])[CH2:11][CH2:10][CH:9]([CH:12]([OH:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC1(N(C)C)CCC(C(Cc2ccccc2)OC(C)OCC)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCC1(N(C)C)CCC(C(O)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 M hydrochloric acid (20 ml) was added to a solution of {1-butyl-4-[1-(1-ethoxy-ethoxy)-2-phenylethyl]cyclohexyl}dimethylamine (1.09 g, 2.90 mmol) in anhydrous tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 3 d. The tetrahydrofuran was removed i. vac. and the acid aqueous solution was extracted with diethyl ether (3×10 ml) and thereafter rendered alkaline with 4 M sodium hydroxide solution. The alkaline phase was extracted with methylene chloride (4×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (646 mg) was purified by flash chromatography with methylene chloride/methanol (9:1→8:2→0:1). The product obtained in this way was in the form of the hydrochloride. It was taken up in methylene chloride and the suspension was washed with saturated potassium carbonate solution. The organic phase was dried with sodium sulfate and concentrated i. vac.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].O[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>>[CH3:37][N:34]1[CH2:35][CH2:36][N:31]([CH2:30][CH2:29][CH2:28][O:20][C:17]2[CH:18]=[CH:19][C:14]3[C:13]4[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=4[CH2:7][CH2:6][C@H:5]([NH:4][C:2](=[O:3])[CH3:1])[C:15]=3[CH:16]=2)[CH2:32][CH2:33]1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: CN1CCN(CCCO)CC1
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OCCCN3CCN(C)CC3)cc1[C@@H](NC(C)=O)CC2
Yield: 22 %

Procedure:
Using an analogous procedure to that described for Example 7, N-acetyl-colchicinol was reacted with 4-(3-hydroxypropyl)-1-methylpiperazine to give N-[(5S)-3-(3-(4-methylpiperazin-1-yl)propoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH2:15][OH:16])[N:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([CH:15]=[O:16])[N:14]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2nc(CO)cs2)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(Nc2nc(C=O)cs2)cc1

Procedure:
The reaction described in Preparation 44 was repeated, but using 3 g of 2-p-anisidinothiazol-4-yl-methanol, 6.1 g of pyridine sulfur trioxide complex, 5.3 ml of triethylamine and 90 ml of dimethyl sulfoxide, giving the title compound as pale brown crystals.
Reaction SMILES: [CH:1]([N:4]([CH:36]([CH3:38])[CH3:37])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2[CH:21]=[C:20]([O:22]C)[CH:19]=[CH:18][C:17]=2[C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:34]C)[CH:30]=3)[CH:25]=2)=O)=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(N(C(C)C)CCOC1C=CC(CC2C=C(OC)C=CC=2C2C=CC3C(=CC=C(OC)C=3)C=2)=CC=1)(C)C>>[CH:36]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=2[C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]=[C:29]([OH:34])[CH:28]=[CH:27]3)=[CH:10][CH:9]=1)([CH3:37])[CH3:38]
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(C(=O)c2ccc(OCCN(C(C)C)C(C)C)cc2)c1
Agent: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(Cc2ccc(OCCN(C(C)C)C(C)C)cc2)c1
Product: CC(C)N(CCOc1ccc(Cc2cc(O)ccc2-c2ccc3cc(O)ccc3c2)cc1)C(C)C

Procedure:
Synthesized from [4-(2-diisopropylaminoethoxy)phenyl][5-methoxy-2-(6-methoxynaphthalen-2-yl)phenyl]methanone according to an analogous synthetic method to Example 337 described below, diisopropyl{2-{4-[5-methoxy-2-(6-methoxynaphthalen-2-yl)benzyl]phenoxy}ethyl}amine (398 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (80 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[CH:14]=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH2:19][CH2:18][C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]1=2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:14]=[C:15]2[C:16]3[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=3[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=3)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: BrC=C1c2ccccc2CCc2ccccc21
Reactant: COc1cc(B(O)O)ccc1Cl
Product: COc1cc(C=C2c3ccccc3CCc3ccccc32)ccc1Cl
Yield: 29.6 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 4-chloro-5-methoxyphenylboronic acid (160 mg, 0.78 mmol) and 5-bromomethylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (222 mg, 0.85 mmol) provides 80 mg of title compound in 23% yield as a colorless oil. HPLC shows 92% purity.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:16]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[Cl:24].C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[C:32]([NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][C:7]=1[Cl:24])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN)c2CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCSc1c(Cl)ccc2c1CCNCC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 11.4 %

Procedure:
To a solution of 6-(3-aminopropylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (46.7 mg, 0.126 mmol) in dry DCM (0.5 mL) at ambient temperature under nitrogen, add triethylamine (19.3 μL, 0.139 mmol) and benzoyl chloride (16.1 μL, 0.139 mmol). Stir at ambient temperature for 2.5 h. Add aqueous saturated ammonium chloride and water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Dissolve the residue in DCM (0.16 mL), add trifluoroacetic acid (44.6 μL, 0.58 mmol) and stir for 18 h at ambient temperature. Concentrate in vacuo and purify by preparative HPLC [Column: YMC ODS-AQ 120 Å 20×250 mm [S10-20 μm]; eluent: 95:5 to 5:95 A/B; solvent A: water, 0.1% TFA, 1% isopropanol; solvent B: acetonitrile, 0.05% TFA, 1% isopropanol; flow rate 20 mL/min] to give the title compound (7.0 mg, 12%). MS (APCI+) m/z 375 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[C:35]([N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:34]=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-4-(piperidin-1-yl)benzamido)-4-phenylbenzoate (0.13 g) in methanol (1.5 mL) and ethyl acetate (3.0 mL), 10% palladium-carbon (0.063 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.084 g of tert-butyl 2-(2-hydroxy-4-(piperidin-1-yl)benzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [Sn].[CH2:2]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=O)=[CH:6][CH:5]=1)[CH3:3].Cl>C(O)(=O)C>[CH2:2]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Agent: Cl
Agent: [Sn]
Solvent: CC(=O)O
Product: CCc1ccc(Cc2ccccc2C(=O)O)cc1

Procedure:
(b.2) (Alternative reduction procedure) Tin powder (15 g) is added to a solution of 2-(4-ethylbenzoyl)benzoic acid (3 g) in acetic acid (50 ml). Concentrated hydrochloric acid (5 ml) is added and the mixture is refluxed for 3 hours, then decanted from the undissolved tin, cooled, and diluted with water to afford a precipitate of 2-(4-ethylbenzyl)benzoic acid.
Reaction SMILES: [OH:1][CH:2]1[CH2:15][CH:14]([OH:16])[C@H:13]([S:17][CH2:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:26][Mg]I.[Mg].CI>C(OCC)C>[OH:1][CH:2]1[CH2:15][CH:14]([OH:16])[C@H:13]([S:17][CH2:18][C:19]([OH:25])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:3]1[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCCCCC(=O)CS[C@H]1C(O)CC(O)[C@@H]1CC=CCCCC(=O)O
Reactant: C[Mg]I
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: CCCCCC(C)(O)CS[C@H]1C(O)CC(O)[C@@H]1CC=CCCCC(=O)O

Procedure:
Add dropwise 0.37 g. 9,11-dihydroxy-15-oxo-13-thia-5-prostenoic acid, dissolved in 10 ml. dry diethyl ether, to a methyl magnesium iodide solution, prepared from 0.024 g. magnesium shavings and 0.14 g. methyl iodide in 15 ml. dry diethyl ether, stir the reaction for one hour, pour into 50 ml. saturated aqueous NH4Cl solution, extract with diethyl ether, dry the organic phase over Na2SO4 and distill off the solvent to obtain, as the residue, 9,11,15-trihydroxy-15-methyl-13-thia-5-prostenoic acid.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[CH2:54][O:53][CH2:52][C@H:51]2[OH:55])=[N:45][C:46]=1[CH2:47][CH3:48]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[C@@H:51]([O:55][CH2:2][CH3:3])[CH2:52][O:53][CH2:54]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1COC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow oil. IR (liq.) 2973, 2936, 2874, 1606, 1566, 1481, 1441, 1396, 1287, 1230, 1203, 1181, 1124, 1078, 1046 cm−1; OAMS supporting ions at: ESI+ 406.2; MS (EI) nm/z 405 (M+); HRMS (FAB) calcd for C21H28CLN3O3+H1 406.1897, found 406.1889.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([CH3:22])[O:15][C@@H:7](SC2C=CC=CC=2)[C@@H:6]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2].[Br:31]Br>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([CH3:22])[O:15][C@@H:7]([Br:31])[C@@H:6]1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](Sc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](C)O[C@@H](Br)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution containing 1.00 g (2.32 mmol) of 8 in 25 mL of anhydrous CH2Cl2 at 0° C. under argon was added 0.50 g (0.16 mL, 3.14 mmol) of Br2. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and washed with 100 mL of 3% aq NaHSO3. The organic layer was separated, dried (MgSO4) and concentrated under diminished pressure. The residue was then purified by flash chromatography on a silica gel column (26×4 cm).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:37]=[CH:36][CH:35]=[CH:34][C:8]=2[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:19]([NH2:33])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.Cl[C:48](=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50]>ClCCl.O>[CH2:52]([O:51][C:49](=[O:50])[C:48]([NH:33][C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][C:9]3[C:8]4[CH:34]=[CH:35][CH:36]=[CH:37][C:7]=4[O:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:16][CH:15]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:54])[CH3:53]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(N)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCc1oc2ccccc2c1Cc1ccc(-c2ccc(OCCCc3ccccc3)c(NC(=O)C(=O)OCC)c2)cc1
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A solution of 4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-ylamine (129 mg, 0.264 mmol) and diisopropylethylamine (0.115 mL, 2.5 equiv., 0.66 mmol) in dichloromethane (5 mL) was treated with a solution of ethyl chlorooxoacetate (44 mg, 1.2 equiv., 0.317 mmol) in dichloromethane (1 mL). After stirring for 2 h, the solution was diluted with water and extracted with dichloromethane (2×15 mL). The combined organic layers were washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by prep thin layer chromatography (25% ethyl acetate in heptane) afforded N-[4′-(2-butyl-benzofuran-3-ylmethyl)-4-(3-phenyl-propoxy)-biphenyl-3-yl]-oxalamic acid ethyl ester (120 mg, 77%).
Reaction SMILES: [CH:1]([C:4]1[S:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:12]([OH:14])=O)([CH3:3])[CH3:2].[CH3:25][C:26]1[N:31]=[N:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1>>[CH:1]([C:4]1[S:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:17]=1)[C:12]([NH:33][CH2:32][C:29]1[N:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=1)=[O:14])([CH3:2])[CH3:3]
Reactant: Cc1ccc(CN)nn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ncsc3C(C)C)c2)nc1
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nn3)cc(-c3ncsc3C(C)C)c2)nc1

Procedure:
3-(5-Isopropyl-thiazol-4-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid was reacted with C-(6-methyl-pyridazin-3-yl)-methylamine using the procedure of Example 2 to give 3-(5-isopropyl-thiazol-4-yl)-N-(6-methyl-pyridazin-3-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=444.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH:13]=O.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][N:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=CCn1c(=O)ccc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3cccnc32)CC1
Reaction time: 0.17 h
Yield: 48.4 %

Procedure:
To a solution of 0.29 g of (2-oxo-1,8-naphthyridin-1(2H)-yl)acetaldehyde in 10 mL of methylene chloride, 0.30 g of tert-butyl (piperidin-4-yl)carbamate and 87 μL of acetic acid were added, the mixture was stirred for 10 minutes, and to the reaction mixture, 0.48 g of sodium triacetoxyborohydride was then added and the mixture was stirred at room temperature for 4 hours. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=100:1 to obtain 0.27 g of tert-butyl (1-(2-(2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[S:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:2](=[O:8])[C:3](=[O:5])[N:22]([CH:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]2=[S:21])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(NC(=S)Nc1ccc(C(C)(C)C)cc1)C(C)(C)C
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(C(C)(C)C)cc2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
Ethyl chlorooxoacetate (0.46 mL, 4.10 mmol) was added to a stirring solution of the above thiourea (0.80 g, 2.74 mmol) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.61 g (64%) of 1-(4-tert-butyl-phenyl)-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidine-4,5-dione as a yellow solid: mp 208.9–209.5° C.; 1H NMR (DMSO-d6): δ 7.52 (d, 2H), 7.40 (d, 2H), 4.85 (q, 1H), 1.48 (d, 3H), 1.30 (s, 9H), 1.00 (s, 9H); IR (KBr): 3505, 2930, 1780 cm1; MS (m/z) 346 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]([CH2:12]Cl)=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[S:8][C:10]([CH3:12])=[CH:11][C:4]=2[CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: C=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc2cc(Br)ccc2s1
Temperature: 55 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
A mixture of 4-bromothiophenol (5.0 g, 26.4 mmol), 2,3-dichloro-1-propene (2.6 g, 23.8 mmol) and potassium carbonate (4.4 g, 31.7 mmol) in acetone (20 ml) was stirred at 55° C. for 6 hours. After cooling to room temperature, acetone was removed under vacuum and the residue was taken into water and extracted with ethyl acetate twice. The combined organic layers were washed with 1 M sodium hydroxide, water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Diethylaniline (30 ml) was added to the residue and the resulting mixture was stirred at 185° C. for 15 hours. Ethyl acetate was added to the cooled mixture and diethylaniline was removed by washing with 1 M HCl four times. The organic layer was dried over sodium carbonate to give 5-bromo-2-methylbenzothiophene (5.3 g, 88%, 95.1% AUC GC): 1H NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.26 (dd, J=8.7, 1.8 Hz, 1H), 6.83 (s, 1H), 2.51 (s, 3H).
Reaction SMILES: [CH3:1][OH:2].N1C=CC=CC=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20](=[N:21][S:22]Cl)[C:19](=[O:24])[N:18]([CH3:25])[C:17]1=[O:26]>C(Cl)Cl>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20](=[N:21][S:22][O:2][CH3:1])[C:19](=[O:24])[N:18]([CH3:25])[C:17]1=[O:26]
Reactant: CN1C(=O)C(=NSCl)N(c2ccccc2F)C1=O
Reactant: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COSN=C1C(=O)N(C)C(=O)N1c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.2 g (0.1 mole) methanol and 7.9 g (0.1 mole) pyridine in 20 ml of methylene chloride was added dropwise to a solution of about 0.1 mole of 1-(2-fluorophenyl)-3-methyl-5-chlorothioimino-2,4-imidazolidinedione in 100 ml of methylene chloride at 0°C. The resulting reaction mixture was stirred for about 30 minutes at 0°C., washed with water, washed with sodium bicarbonate, dried over magnesium sulfate, and evaporated under reduced pressure to give a yellow solid residue. The solid was washed with isopropyl alcohol to give the product as a pale yellow solid, m.p. 124°-127° C. Elemental analysis showed:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[N+:6]([O-:8])[CH:7]=1.[CH2:9]([SH:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[C:10]1([CH2:9][S:16][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N+:6]=2[O-:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: SCc1ccccc1
Reactant: [O-][n+]1cccc(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1cc(Cl)ccc1SCc1ccccc1

Procedure:
As described in U.S. Pat. No. 4,394,155, Example 1, 2-(phenylmethylthio)-5-chloropyridine N-oxide is prepared from 5-chloropyridine N-oxide and benzylmercaptan. To a well stirred solution of 2.5 g (9.01 mol) of the thio compound in 25 mL chloroform is added 4 g (0.02 mol) of MCPBA in 50 mL chloroform.