Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.[N:39]1[CH:44]=[CH:43][C:42]([CH2:45]Cl)=[CH:41][CH:40]=1.O>O1CCCC1.CN(C)C=O>[C:14]([O:13][C:11]([NH:10][C:9]([N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([CH2:45][C:42]4[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=4)[CH2:32][CH2:31]3)=[CH:23][CH:24]=2)[CH2:19]1)=[N:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(Cc4ccncc4)CC3)cc2C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 78.4 %

Procedure:
To a solution of N,N′-di-tert-butoxycarbonyl-7-(piperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxamidine (100 mg) in a mixture of tetrahydrofuran (1 ml) and dimethylformamide (1 ml) were added 9.1N sodium hydroxide (0.068 ml) and 4-picolyl chloride hydrochloride (51 mg), and the mixture was stirred at 50° C. for 5 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by preparative thin layer chromatography (chloroform:methanol=20:1) and dried under reduced pressure to give the title compound (93 mg).
Reaction SMILES: [F:1][CH2:2][C:3]([O:5]CC)=O.[CH:8](OCC)=O.C[O-].[Na+].[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][C:18]([NH2:20])=[O:19].Cl>CO.O>[OH:19][C:18]1[N:20]=[C:3]([OH:5])[C:2]([F:1])=[CH:8][C:17]=1[C:16]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CC(N)=O
Reactant: CCOC(=O)CF
Reactant: CCOC=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(F)c(O)nc1O
Reaction time: 3.5 h
Yield: 61 %

Procedure:
To a solution of ethyl fluoroacetate (34 g) and ethyl formate (28 g) at 0° C. is added sodium methoxide (26 g). After 3.5 hours at 20° C., a solution of methyl malonamate (40 g) in methanol (350 mL) is added and the mixture heated at reflux for 0.5 hour. To the hot mixture is added a solution of 37% hydrochloric acid (48 mL) in water (352 mL). The reaction mixture is heated at reflux for 10 minutes. After standing at 0° C. for 18 hours, the mixture is filtered and the collected solid is washed with 3 to 400 mL of water and then vacuum dried to give methyl 2,6-dihydroxy-5-fluoronicotinate, (36.6 g, 61%): mp 208°-213° C.; HPLC 95.4%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:35]1[C:43]2[CH:42]=[CH:41][NH:40][C:39](=O)[C:38]=2[CH:37]=[CH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCOCC1>[CH2:28]([N:35]1[C:43]2[CH:42]=[CH:41][N:40]=[C:39]([Br:1])[C:38]=2[CH:37]=[CH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]ccc2c1ccn2Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Brc1nccc2c1ccn2Cc1ccccc1
Reaction time: 1 h

Procedure:
35 g of N-bromosuccinimide are added to a solution of 52 g of triphenylphosphine in 1.5 l of dioxane. After stirring the mixture for 1 hour, 9 g of 1-benzyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one in 200 ml of dioxane are added and the mixture is heated at reflux for 15 hours. After removal of the dioxane under reduced pressure, 100 ml of triethylamine are added to the residue and the whole is then concentrated in vacuo. Chromatography on silica gel (cyclohexane/ethyl acetate: 50/50) enables the expected product to be isolated.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16]([CH:18]1[C:23](=[O:24])[CH2:22][CH2:21][NH:20][CH2:19]1)=[O:17].C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C.O>[CH3:14][O:15][C:16]([CH:18]1[C:23](=[O:24])[CH2:22][CH2:21][N:20]([C:11]([CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)=[O:12])[CH2:19]1)=[O:17]
Reactant: O=C(Cl)C1COc2ccccc2O1
Reactant: COC(=O)C1CNCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CN(C(=O)C2COc3ccccc3O2)CCC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 2,3-dihydrobenzo[1,4]dioxine-2-carbonyl chloride (2.0 g, 10.0 mmol) and 4-oxopiperidine-3-carboxylic acid methyl ester (2.14 g, 11.0 mmol) in DMF (5 ml) was added triethylamine (1.54 ml). The reaction mixture was stirred at RT for 5 h. The reaction mixture was taken up in water, made alkaline with aq NaOH and extracted with DCM to give 1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-4-oxopiperidine-3-carboxylic acid methyl ester. A mixture of this product (0.2 g, 0.62 mmol), K2CO3 (0.17 g, 1.23 mmol) and methyl iodide (0.08 ml, 1.25 mmol) in acetone (20 ml) was irradiated in the microwave reactor at 56° C. for 90 min. Water was added and the reaction mixture extracted with EtOAc (3×5 ml). The combined organic phases were dried over Na2SO4, filtered and the filtrate was evaporated to give 1-(2,3-dihydrobenzo[1,4]dioxine-2-carbonyl)-3-methyl-4-oxopiperidine-3-carboxylic acid methyl ester, which was finally reduced with LiAlH4 in THF to afford the title compound.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.O>ClCCCl.CO>[Cl:25][C:19]1[CH:18]=[C:17]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:22]=[C:21]([Cl:23])[C:20]=1[Cl:24]
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCN(Cc2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: O
Solvent: ClCCCl
Solvent: CO
Product: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCNC1
Yield: 92.6 %

Procedure:
To a stirred solution of 1-benzyl-3-(3,4,5-trichloro-phenyl)-3-trifluoromethyl-pyrrolidine (Preparation 38, 4 g, 9.828 mmol) in 1,2-dichloroethane (40 mL) was added 1-chloroethyl chloroformate (1.91 mL, 17.69 mmol) and the resulting reaction mixture was refluxed for 3 hours. After complete consumption of starting material, reaction mixture was concentrated under reduced pressure to afford yellow oily residue, which was dissolved in MeOH (40 mL) and the mixture was refluxed at 2 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford yellow oil, to which water (50 mL) was added and extracted with hexane (3×50 mL). Aqueous layer was basified using saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford brown thick oil (5.5 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired compound was eluted in 4% methanol in dichloromethane to afford product as yellow thick oil (2.9 g, impure). Impure compound was as such for next reaction. (m/z): 317.9 (M+H).
Reaction SMILES: [N+]([O-])([O-])=[O:2].[NH4+].[Ce].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[S:16][C:17]2[C:18](=[C:20](N)[C:21]([O:26][CH3:27])=[CH:22][C:23]=2[O:24]C)[N:19]=1>O.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[S:16][C:17]2[C:23](=[O:24])[CH:22]=[C:21]([O:26][CH3:27])[C:20](=[O:2])[C:18]=2[N:19]=1
Reactant: COc1cc(OC)c2sc(-c3c(F)cccc3F)nc2c1N
Reactant: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC1=CC(=O)c2sc(-c3c(F)cccc3F)nc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of 1.22 g of cerium ammonium nitrate (2.23 mmol, 2.1 equivalents) in 8 ml of water is added to 343 mg (1.06 mmol) of 2-(2,6-difluorophenyl)-5,7-dimethoxy-1,3-benzothiazol-4-amine in solution in 25 ml of ethyl acetate. The reaction mixture is maintained under vigorous stirring at ambient temperature for 1 hour 30 minutes then the organic phase is separated and washed with 3 times 20 ml of water, then dried over magnesium sulphate, filtered and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane: 3/7) and 280 mg (yield=86%) of 2-(2,6-difluorophenyl)-5-methoxy-1,3-benzothiazole-4,7-dione is obtained in the form of yellow powder.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([OH:22])=[O:21])[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(N=C=NC2CCCCC2)CCCCC1.[F:38][C:39]1[C:44](O)=[C:43]([F:46])[C:42]([F:47])=[C:41]([F:48])[C:40]=1[F:49]>C(OCC)(=O)C>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([O:22][C:44]1[C:43]([F:46])=[C:42]([F:47])[C:41]([F:48])=[C:40]([F:49])[C:39]=1[F:38])=[O:21])[CH:14]=[CH:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCOc1ccc2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 110.3 %

Procedure:
To a suspension of 6-octyloxy-2-naphthoic acid (3.15 g, 10.5 mmol) and dicyclohexylcarbodiimide in ethyl acetate (25 ml) at 0° C. was added pentafluorophenol (2.12 g, 11.5 mmol). The mixture was stirred at 25° C. for a period of 18 h. The precipitate was removed by filtration. The filtrate was washed with water (2×150 ml) and brine and dried with magnesium sulfate. Removal of the ethyl acetate in vacuo gave 5.4 g of pentafluorphenyl 6-octyloxy-2-naphthoate as a solid: 1 H NMR (400 MHz, CD3OD) δ0.88 (t, 3H, J =6.9 Hz), 4.10 (t, 2H, J=6.6 Hz), 7.16 (d, 1H), 7.21 (d, 1H), 7.80 (d, 1H), 7.87 (d, 1H), 8.08 (dd, 1H), 8.69 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[C:4]([Cl:9])[N:3]=1.[H-].[Na+].[H][H].[CH3:14][N:15]([CH3:30])[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[S:26](Cl)(=[O:28])=[O:27].Cl>C(COC)OC.O>[CH3:14][N:15]([CH3:30])[C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[S:26]([NH:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[C:4]([Cl:9])[N:3]=1)(=[O:28])=[O:27]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: [H][H]
Reactant: Nc1cnc(Br)c(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(C)c1cccc2c(S(=O)(=O)Nc3cnc(Br)c(Cl)n3)cccc12
Reaction time: 24 h
Yield: 52.1 %

Procedure:
2 -Amino-5-bromo-6-chloropyrazine (0.417 g) was added to a stirred suspension of sodium hydride (oil-free; 0.24 g) in dry dimethoxyethane (20 ml). When evolution of hydrogen ceased, 5-dimethylamino-1-naphthalenesulphonyl chloride (0.594 g) was added. The mixture was stirred for 24 hours and then water (25 ml) and 2M hydrochloric acid (2 ml) were added. The mixture was extracted with ethyl acetate (2×25 ml) and the extracts were dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by elution with ethyl acetate/hexane (1:3 v/v) through a silica gel Mega Bond Elut column to give 5-dimethylamino-N-(5-bromo-6-chloro-2-pyrazinyl)-1-naphthalenesulphonamide (0.46 g), m.p. 180-182° C. (after trituration with ether); mass spectrum (+ve FAB, methanol/NBA): 442 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[N:11]([O-])=O.[Na+].O.O.[Cl:17][Sn]Cl>Cl>[ClH:17].[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2[nH]ncc2c1
Reaction time: 1 h

Procedure:
To a solution of 1H-indazol-5-ylamine (20 g, 153 mmol) in cone. HCl (50 mL) was added an aqueous solution (50 mL) of NaNO2 (19 g, 158 mmol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (90 g, 306 mmol) in cone. HCl (70 mL), pre-cooled to 0° C., was then added. The reaction solution was stirred for 2 h at RT. The precipitate was filtered and washed with ether to yield (1H-indazol-5-yl)-hydrazine hydrochloride as a yellow solid, which was used for the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.CN(C=O)C.CS(O[CH2:23][C:24]1([CH3:35])[O:28][C:27]2=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]2[CH2:25]1)(=O)=O>O>[CH3:23][C:24]1([CH2:35][S:3][C:4]2[O:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[O:28][C:27]2=[N:29][C:30]([N+:32]([O-:34])=[O:33])=[CH:31][N:26]2[CH2:25]1
Reactant: CC1(COS(C)(=O)=O)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Sc1nc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(CSc2nc3ccccc3o2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
Sodium hydride (50 mg, 1.25 mmol) was added to a mixture of 2-mercaptobenzoxazole (200 mg, 1.3 mmol) and DMF (3 ml) followed by stirring at room temperature for 1 hour. To the reaction mixture, 2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl methanesulfonate prepared in Example 41 (330 mg, 1.2 mmol) was added, and the resulting mixture was stirred at 60-70° C. for 5 hours. The reaction mixture was allowed to return to room temperature. Water was added to the solution, and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with 5% sodium hydroxyde solution and water three times, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography(n-hexane/ethyl acetate=1/1) to afford 2-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethylthio)benzoxazole (37 mg, yield 9%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[S:16][C:15]([C:17]([OH:19])=O)=[CH:14][CH:13]=1.C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH2:43]>O1CCCC1.O>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[NH:43][C:17]([C:15]1[S:16][C:12]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[N:8]=[CH:7][N:6]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: O=C(O)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Reactant: Nc1ccc(F)cc1F
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1F)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Reaction time: 1 h
Yield: 42.8 %

Procedure:
300 mg of 5-(6-bromoquinazolin-4-yl)thiophen-2-carboxylic acid (compound in Production Example 382) was dissolved in 4 mL tetrahydrofuran, then 0.37 mL triethylamine and 0.14 mL isobutyl chlorocarbonate were added thereto under ice-cooling, and the mixture was stirred for 1 hour under nitrogen atmosphere. This mixture was added to a solution of 1.15 g 2,4-difluorophenylamine in 10 mL tetrahydrofuran and stirred at room temperature for 1 hour. Further, the reaction mixture was stirred at 70° C. for 3 hours, then water was added thereto, the reaction mixture was extracted with ethyl acetate, and the solvent was evaporated. The residue was washed with ether to give 171 mg of the title compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][C@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@:11]1([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)[C:19]1[CH2:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].CCN(CC)CC.[NH2:45][CH2:46][CH2:47][OH:48].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[NH2:1][C@H:2]([C:7]([O:9][C@H:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C@:11]1([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](=[O:34])[NH:45][CH2:46][CH2:47][OH:48])=[CH:31][CH:30]=1)[C:19]1[CH2:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Reactant: NCCO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(=O)O[C@H]1c2ccccc2C[C@]1(Cc1ccc(C(=O)NCCO)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
To a solution of 4-{[(1′R,2′R)-1′-(L-leucyloxy)-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}benzoic acid (24, 130 mg, 0.26 mmol), Et3N (78 mg, 0.78 mmol) and 2-amino ethanol (24 mg, 0.39 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The separated organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 70 mg (54%) of the title compound as an off white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][NH:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1>>[CH3:9][C:4]1[N:5]=[C:6]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[CH:7]=[C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)[N:3]=1
Reactant: CNc1cccc(O)c1
Reactant: Cc1nc(Cl)cc(Cl)n1
Product: Cc1nc(N(C)c2cccc(O)c2)cc(N(C)c2cccc(O)c2)n1
Yield: 45 %

Procedure:
This compound was obtained (yield 45%) based on the method described in Production Example 2B using 4,6-dichloro-2-methylpyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-methylaminophenol instead of the 3-aminophenol.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH:12]1([N:22]=[C:23]=[O:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:2][O:3][NH:4][C:23]([NH:22][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[O:24]
Reactant: O=C=NC1CCCc2ccccc21
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)NC1CCCc2ccccc21
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 76.6 %

Procedure:
To an ice cold, stirred mixture of 6.7 grams (0.080 mole) of methoxyamine hydrochloride in 80 ml. of methylene chloride is added a solution of 8.1 grams (0.080 mole) of triethylamine in 20 ml. of methylene chloride. The mixture is stirred at 15° C. for 15 minutes, and is then allowed to warm to 15° to 25° C. while a solution of 6.94 grams (0.04 mole) of 1,2,3,4-tetrahydro-1-naphthyl isocyanate in 25 ml. of methylene chloride is added dropwise. The mixture is stirred for 30 minutes at room temperature and then filtered. The filtrate is washed with water, dried sodium sulfate, and the solvent evaporated at reduced pressure to give a solid. Recrystallization of the solid from acetone/hexane gives 6.75 grams of the product, melting point 122° to 125° C. Recrystallization of the product from acetone/hexane gives the analytical sample, melting point 123.5° to 125° C. Analysis Calculated for C12H16N2O2 : C, 65.43; H, 7.32; N, 12.72. C, Found: C, 65.32; H, 7.33; N, 12.64.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][N:9]1[CH2:12][CH2:11][C:10]1=[O:13].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>O1CCCC1>[CH2:16]([O:15][C:14]([CH:11]1[CH2:12][N:9]([CH3:8])[C:10]1=[O:13])=[O:18])[CH3:17]
Reactant: CCOC(=O)OCC
Reactant: CN1CCC1=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1CN(C)C1=O
Reaction time: 0.42 h

Procedure:
Into tetrahydrofuran (20 ml) containing diisopropylamine (1.82 ml) is added 15% n-butyllithium-hexane (7.5 ml), and the mixture is stirred for 25 minutes. To this solution are added 1-methyl-2-azetidinone dropwise at -70° C. and after 20 minutes, diethyl carbonate (1.33 ml). After 2.5 hours stirring, reaction mixture is quenched with 10% hydrochloric acid (15 ml) and extracted with ethyl acetate. The solvent is evaporated to give 1-methyl-2-oxoazetidine-3-carboxylic acid ethyl ester (476 mg). Colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1.[OH-].[Na+].O>CS(C)=O>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=[C:3]1[CH2:2][O:12][C:13]1[CH:14]=[C:15]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=1
Reactant: CCCCCC(O)c1cccc(O)c1
Reactant: BrCc1cc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(O)c1cccc(OCc2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.5 %

Procedure:
2-Bromomethylbenzofuran (5 g, 0.024 mol) and 1-(3-hydroxyphenyl)-1-hexanol (4.7 g,0.024 mol) were dissolved in DMSO (75 ml). To this clear, homogeneous solution was added an aqueous solution of sodium hydroxide (12.5 ml, 2N solution; 0.025 mol NaOH). Immediately after the sodium hydroxide solution was added, the reaction mixture became warm (45°-50° C.). This clear, homogeneous solution was stirred at room temperature for 6 hours, and then poured into water (300 ml). The organics were extracted thoroughly with ethyl acetate (3×50 ml), and the combined organic extract was washed with water, 1N sodium hydroxide solution (to remove excess phenol), water, 0.1N hydrochloric acid solution, water and finally brine. After drying over anhydrous magnesium sulfate, all volatiles were removed from the ethyl acetate extract to leave a clear liquid (7.2 g) which was chromatographed on silica gel using 10% ethyl acetate in hexanes as eluent to obtain the pure compound as a clear, colorless liquid (4.4 g, 56%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:13][C:14]([OH:21])([C:17]([F:20])([F:19])[F:18])[CH2:15][OH:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CS(C)=O>[CH2:1]([C:3]1([CH2:13][C:14]([OH:21])([C:17]([F:19])([F:18])[F:20])[CH:15]=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CC(O)(CO)C(F)(F)F)CCCc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1(CC(O)(C=O)C(F)(F)F)CCCc2ccccc21
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To a solution of 2-[(1-ethyl-1,2,3,4-tetrahydro-1-naphthalenyl)methyl]-3,3,3-trifluoro-1,2-propanediol (Intermediate 16) (2.03 g, 6.71 mmol) in anhydrous dichloromethane (50 ml), anhydrous dimethylsulphoxide (50 ml) and triethylamine (5.9 ml, 42 mmol) stirred under nitrogen in an ice-water bath at 9° C., was added pyridine-sulphur trioxide complex (5.37 g, 33 mmol) portionwise over 20 min. The solution was then allowed to warm to room temperature and stirred for 65 h. The reaction mixture was added to aqueous ammonium chloride solution (350 ml) and extracted into dichloromethane (×2). The combined organic layers were washed successively with water (2×200 ml) and saturated brine (2×200 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo. The brown oil obtained was applied to a 50 g silica SPE cartridge eluting with 0 to 100% dichloromethane in heptane gradient to give the title compound as a mixture of diastereomers (380 mg, 19%).