Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>CCO>[CH2:22]([S:12][C:10]1[O:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Sc1nnc(-c2ccccc2)o1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1ccc(CSc2nnc(-c3ccccc3)o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 92.3 %

Procedure:
5-Phenyl-[1,3,4]oxadiazole-2-thiol (Aldrich, 3.1 g, 17.4 mmol) was added to EtOH (30 mL) and cooled to 0° C. while stirring. Diisopropylethylamine (3.1 mL, 17.4 mmol) was then added and the mixture became a clear solution. Benzyl bromide (2.08 mL, 17.4 mmol) was added and the resulting mixture was allowed to warm to room temperature while stirring. After 45 min, a thick white precipitate formed. The mixture was stirred an additional 1 hr followed by the addition of 1M NaOH (3 mL). The mixture was filtered, washed with 1M NaOH (2×20 mL), 3% citric acid (2×20 mL), H2O (2×20 mL) and the precipitate was dried under vacuum to afford 4.31 g (92%) 2-benzylsulfanyl-5-phenyl-[1,3,4]oxadiazole as a white solid. 1H NMR (CDCl3, 300 MHz) δ 4.57 (s, 2H), 7.37 (m, 3H), 7.48 (m, 5H), 7.99 (m, 2H); MS (DCl/NH3) m/z 269 (M+H)+.
Reaction SMILES: C([C:5]1[C:13]([CH2:14][NH:15][C:16](=[O:24])[CH:17]([CH3:23])[CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:12]([NH2:25])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.[C:26]([OH:32])([C:28]([F:31])([F:30])[F:29])=[O:27]>C(Cl)Cl>[F:29][C:28]([F:31])([F:30])[C:26]([OH:32])=[O:27].[NH2:25][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:13]=1[CH2:14][NH:15][C:16](=[O:24])[CH:17]([CH3:23])[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C(=O)NCc1c(N)ccc(C(=O)O)c1C(C)(C)C)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)NCc1cc(C(=O)O)ccc1N)C1CCCC1
Reaction time: 12 h

Procedure:
To a stirred solution of t-butyl-4-amino-3-[(2-cyclopentyl-N-methylacetylamino)methyl]benzoic acid (0.75 g, 2.16 mmole) in CH2Cl2 (20 mL) at RT was added TFA (20 mL). After 12 hr, the reaction contents were evaporated, washed with hexanes and dried under high vacuum overnight affording the title compound (0.63 g, 2.16 mmol) as an orange oil. This product was used without further purification: MS (ES) m/e 292 (M+H-TFA)+.
Reaction SMILES: [C:1]1([P:7]2(=O)[CH2:11][CH2:10][CH2:9][C:8]2=[CH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([SiH3])C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([P:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[CH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C1CCCP1(=O)c1ccccc1
Agent: [SiH3]c1ccccc1
Solvent: Cc1ccccc1
Product: C=C1CCCP1c1ccccc1
Temperature: 60 °C
Yield: 105 %

Procedure:
In a 250 ml round bottom 2-neck flask charged with a magnetic stirring bar and 60 ml freshly distilled toluene, 8.5 g 1-phenyl-2-methylenephospholane-1-oxide (0.04 mol) was dissolved and 11 g of PhSiH3 was added. The flask was flushed with argon and the reaction mixture heated to 60° C. for 2 days. Then the solvent was evaporated and the residue purified by flash chromatography (hexane followed by hexane/EtOAc 15:1) to yield 7.4 g (95%) of 1-phenyl-2-methylenephospholane as a colorless oil, 1H NMR (200 MHz) δ: 1.55-2.10 (m, 4H), 2.20-2.65 (m, 2H), 5.51 (dd, 1H, J=1.6, J=11.0), 5.76 (dd, 1H, J=1.5, J=28.7), 7.05-7.50 (m, 5H), 31 P NMR (200 MHz) δ: −12.6.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:30])[CH2:26]/C=C/C)[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[CH2:3][CH2:2]1.[C:31](O)(=O)C>>[CH3:31][C:7]1[N:6]=[C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:30])[CH3:26])[CH2:22][CH2:23]3)[CH2:14][CH2:15]2)[C:4]2[CH2:3][CH2:2][O:1][C:9]=2[CH:8]=1
Reactant: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CC(=O)O
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nc(C)cc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (96 mg, 83%), MS (ISP) m/z=387.4 [(M+H)+], mp 217.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate E) (136 mg, 0.3 mmol) and acetic acid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][SH:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[N:13]1([CH2:18][CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:17]=[CH:16][N:15]=[N:14]1.[H-].[Na+].O>CN(C=O)C.ClCCl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][CH2:19][CH2:18][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Reactant: C=CCOc1ccc(CS)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CSCCn2ccnn2)cc1
Temperature: -30 °C
Reaction time: 12 h
Yield: 78.7 %

Procedure:
1.58 g (6.14 mmol) (4-allyloxy-phenyl)-methanethiol and 1.64 g (6.14 mmol) toluene-4-sulfonic acid 2-[1,2,3]triazol-1-yl-ethyl ester were dissolved in 15 ml DMF and cooled to −30° C. 294 mg (12.3 mmol) 95% Sodium hydride were added, the mixture allowed to warm to r.t. and stirred for 12 h. 10 ml Water were added and the residue dissolved in dichloromethane. The organic phase was dried over Na2SO4, solvents removed and the remaining material purified by chromatography on silica gel (ethyl acetate/n-heptane 1:1) to yield 1.33 g (79%) yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>C(O)(C)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:15]=[C:13]([CH2:12][Cl:11])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: O=C(CCl)CCl
Solvent: CC(C)O
Product: ClCc1coc(-c2ccc(Br)cc2)n1
Temperature: 25 °C

Procedure:
4-bromo-benzamide (4.03 g, 20.11 mmol), and 1,3-dichloro-acetone (3.83 g, 30.17 mmol) are placed in a 250 mL flask and dissolved in 150 mL of isopropyl alcohol. The mixture is heated to reflux for 5 hours and cooled to ambient temperature. The reaction is concentrated to dryness. The resulting solid is triturated with diethyl ether and filtered to remove unreacted 4-bromo-benzamide. The filtrate is concentrated to the title compound as an oily solid (3.1 g) and is used without further purification. MS (m/e) 273.9 (M+1)
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][N+:5]1[CH:13]=[C:12]2[N:7](C(=O)[NH:9][CH2:10][CH2:11]2)[CH:6]=1.[ClH:15]>>[ClH:15].[ClH:15].[F:2][CH2:3][CH2:4][N:5]1[CH:13]=[C:12]([CH2:11][CH2:10][NH2:9])[N:7]=[CH:6]1
Reactant: O=C1NCCc2c[n+](CCF)cn21
Agent: Cl
Agent: [Br-]
Product: NCCc1cn(CCF)cn1

Procedure:
A solution of 2-(2-Fluoro-ethyl)-5-oxo-5,6,7,8-tetrahydro-imidazo[1,5-c]pyrimidin-2-ium bromide (0.64 g, 2.42 mmol) in aqueous 6 M HCl, was heated at 130° C. for 60 hours and the solvent evaporated to yield the titled product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([NH:30][CH2:31][CH2:32][OH:33])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1.[Cl-].[NH4+]>CC(N(C)C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:19]([NH:30][CH2:31][CH2:32][O:33][C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:18]=[CH:17][N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncccn1
Reactant: COc1cccc(Oc2c(NCCO)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(Oc2c(NCCOc3ncccn3)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of Compound B (116 mg) obtained in Example 19-(1) in dimethylacetamide (2 ml) is added sodium hydride (60% dispersion-type, 33 mg), and thereto is added 2-chloropyrimidine (40 mg). The reaction solution is stirred at room temperature overnight, and the mixture is treated with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol=20:1), and crystallized from chloroform/diisopropyl ether to give 4-tert-butyl-N-[5-(3-methoxyphenoxy)-6-{2-(pyrimidin-2-yloxy)ethylamino}pyrimidin-4-yl]benzenesulfonamide (125 mg) as crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Reaction time: 0.75 h
Yield: 64.9 %

Procedure:
A solution of 3-acetoxymethyl-7β-(2-thienylacetamido) ceph-3-em-4-carboxylic acid (146.5 g.) in pyridine (600 ml.) was treated with acetic anhydride (45 ml.) and the mixture stirred vigorously at 22° for 45 minutes. The material which crystallised out was isolated by filtration washed with pyridine and ethyl acetate, and dried in vacuo to give the pyridinium salt of the title compound (95.15 g., 54.5%). This pyridinium salt was stirred with water (350 ml.) and ethyl acetate (700 ml.) and 2N-hydrochloric acid (ca 120 ml.) added until all the solid had dissolved. The organic phase was separated, washed with water, dried and evaporated in vacuo to give the title compound (77 g.) as a white solid, m.p. 151°-152.5°, [α]D + 480° 5% sodium carbonate), λmax. 235 nm. (ε 15,200), νmax. 3293 (NH), 1746 (β-lactam), 1722 and 2600 (CO2H), 1722 and 1208 (CH2OCOCH3) and 1660 and 1528 cm.-1 (CONH), τ (D2O - sodium bicarbonate) 2.7 and 3.0 (thienyl, 1-proton t and 2-proton d), 3.62 (C(2) --H, broad s), 4.58 (C(7) --H, d, J 4.5 Hz), 4.69 (C(6) --H, d, J 4.5 Hz), 5.18 (C(4) --H, broad s), 6.15 (CH2CONH, s) and 7.9 (--OCOCH3, s) (CH2OAc obscured by H2O band). (Found: C, 48.3; H, 4.1; N, 7.0; S, 16.2. Calc. for C16H16N2O6S2 : C, 48.4; H, 4.05; N, 7.05; S, 16.15%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][N:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:25]2[CH:37]=[CH:38][N:39]([S:40]([C:43]3[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=3)(=[O:42])=[O:41])[C:24]=2[C:23]1=[O:50]>>[CH3:12][N:7]1[C:6]2[C:13]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([C:26]3[C:25]4[CH:37]=[CH:38][N:39]([S:40]([C:43]5[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=5)(=[O:42])=[O:41])[C:24]=4[C:23](=[O:50])[N:22]([CH3:21])[CH:27]=3)[CH:3]=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: CN1C(=O)COc2ccc(Br)c(Oc3ccccc3)c21
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c(c4Oc4ccccc4)N(C)C(=O)CO5)cn(C)c(=O)c32)cc1

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 6-bromo-4-methyl-5-phenoxy-2H-1,4-benzoxazin-3(4H)-one and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C30H26N3O6S (M+H)+: m/z=556.2. found: 556.0.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
16 g of carbazole was dissolved in 80 ml of N,N′-dimethylformamide. To this was added 18 g of N-bromosuccinimide and allowed the reaction to stir at room temperature overnight. The reaction mixture was poured into water and the precipitated white solid was filtered, washed with methanol and dried under vacuum to obtain 20 g of 3-bromocarbazole. It was further converted to its acetyl derivative by refluxing with acetic anhydride (3 vol) with traces of conc. sulfuric acid. Aqueous workup yielded an off-white solid, which was then washed with n-hexane and dried under vacuum to obtain 23 g 9-acetyl-3-bromocarbazole, quantitatively.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][C:18]([O:20]CC)=[O:19])[N:16]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:4])([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].[OH-].[Na+].Cl>C(O)C.O.C(O)(=O)C>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[S:13][CH:14]=[C:15]([CH2:17][C:18]([OH:20])=[O:19])[N:16]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)Cc1csc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(Nc2nc(CC(=O)O)cs2)cc(C(C)(C)C)c1O
Yield: 67.3 %

Procedure:
2,6-Di-tert-butyl-4-[(4-ethoxycarbonylmethyl-2-thiazolyl)amino]phenol (produced in Example 17) (0.80 g) was dissolved in 30 ml of ethanol, a solution of 2 g of sodium hydrosulfite in 20 ml of water was added and then 15 ml of 2 N aqueous sodium hydroxide was added, and the resultant mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled in an ice bath and, after addition of 15 ml of 2 N hydrochloric acid and further addition of 3 ml of acetic acid, extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The colorless crystals thus obtained were washed with diethyl ether to give 0.50 g of the desired compound.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].[N:5]([C@@H:8]1[CH2:13][O:12][C@H:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[OH:27])=[N+:6]=[N-:7]>CO>[N:5]([C@H:8]1[CH2:13][O:12][C@@H:11]([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C@@H:9]1[OH:27])=[N+:6]=[N-:7]
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](C(c2ccccc2)c2ccccc2)C[C@H]1O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=N[C@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1O

Procedure:
(1R,4R,7S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 8c (0.04 g, 0.15 mmol) was treated with NaN3 (0.05 g, 0.75 mmol) and NH4Cl (0.018 g, 0.33 mmol) (Procedure F) yielded (2R,4S,5S)-5-Azido-2-benzhydryl-tetrahydro-pyran-4-ol 30b, 0.04 g (95%, [α]D=(+)108, c=1, MeOH).
Reaction SMILES: [Na].[F:2][C:3]([F:21])([S:17]([OH:20])(=[O:19])=[O:18])[C:4]([O:6][CH:7]1[CH:14]2[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2)=[O:5].[Br-].[SH+:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.O>C(#N)C>[CH:8]12[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:15]3)[CH:7]1[O:6][C:4]([C:3]([F:21])([F:2])[S:17]([O-:20])(=[O:18])=[O:19])=[O:5])[CH2:16]2.[SH+:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(OC1C2CC3CC(C2)CC1C3)C(F)(F)S(=O)(=O)O
Agent: C1CC[SH+]C1
Agent: [Br-]
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: O=C(OC1C2CC3CC(C2)CC1C3)C(F)(F)S(=O)(=O)[O-]
Reaction time: 15 h

Procedure:
1.08 Parts of sodium salt of 2-adamantyl difluorosulfoacetate obtained in Example 5 (2) was dissolved in 10.8 parts of acetonitrile. To the solution, 0.93 parts of 1-oxo-2-phenylethyl)tetrahydrothiophenium bromide and 9.3 parts of ion-exchanged water were added. The added mixture was stirred for 15 hours. After the stirring, the resulting mixture was concentrated, and then the concentrate was extracted with 50 parts of chloroform twice. The organic layers were combined and then washed with ion-exchanged water. The washed organic layer was concentrated. The concentrate was washed with 30 parts of tert-butyl methyl ether and the solid deposited was collected by filtration to obtain 1.25 part of 12-oxo-2-phenylethyl)tetrahydrothiophenium (2-adamantyloxycarbonyl)difluoromethanesulfonate in the form of white solid, which is called as acid generator B6.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:36])=[O:35])=[CH:30][CH:29]=2)=[N:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(Oc2nc(-c3cccnc3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1cnc(-c2cccnc2)nc1Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of Compound 16e (0.4 g; 0.77 mmol) in EtOH (10 mL) was added 0.5N NaOH (2.3 mL; 1.15 mmol). The reaction was stirred at room temperature for 3 h. Additional 0.5N NaOH (6 mL; 3 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 h. The solution was adjusted to pH 2 with 1N HCl. The white solid was collected by filtration to afford Compound 16f. MS: m/z 492.3 (M+H)+.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:20][CH:21]([CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:22][OH:23])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:23][CH2:22][CH:21]([O:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CCCCCCCCOCC(CO)OCCCCCCCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCCCOCC(COS(=O)(=O)c1ccc(C)cc1)OCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
p-Toluenesulfonyl chloride (1.2 g) was added to a stirred solution of 2,3-di-n-octyloxy-1-propanol (930 mg) in dried pyridine (10 ml) at 2° C. over 7 minutes. The reaction mixture was stirred at 0° to 5° C. for 2 hours and at room temperature overnight. The resultant solution was poured into ice water (50 ml) and extracted with ethyl acetate (40 ml). The extract was washed with dil. hydrochloric acid (20 ml) and a saturated aqueous solution of sodium chloride (20 ml) in turn, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give oil (920 mg) of 2,3-di-n-octyloxy-1-propyl p-toluenesulfonate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O>>[CH2:23]([O:22][C:16](=[O:21])[CH:17]=[C:18]([NH:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1)[CH3:20])[CH3:24]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ccc(OCc2ccccc2)cc1
Product: CCOC(=O)C=C(C)Nc1ccc(OCc2ccccc2)cc1
Yield: 49.9 %

Procedure:
4-Benzyloxyaniline (10 g) and ethyl acetoacetate (6.9 g) were heated at 120° C. for 3 hours. The residue was purified by chromatography on silica eluting with a mixture of dichloromethane, and pentane. The desired fractions were concentrated and the sample evaporated to give the sub-title compound (7.8 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][C:14]1([CH3:28])[CH2:23][C@H:22]2[C@H:17]([CH2:18][CH2:19][CH2:20][NH:21]2)[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]1=2>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:21]3[C@@H:22]4[C@@H:17]([C:16]5[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=5[C:14]([CH3:28])([CH3:13])[CH2:23]4)[CH2:18][CH2:19][CH2:20]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CC1(C)C[C@@H]2NCCC[C@@H]2c2ccccc21
Product: CC1(C)C[C@H]2[C@H](CCCN2C(=O)c2ccc3[nH]cnc3c2)c2ccccc21
Yield: 58 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-6,6-dimethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 58% of theory; LC (method 1): tR=2.84 min; Mass spectrum (ESI+): m/z=360 [M+H]+.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([CH3:13])=[C:11](I)[CH:10]=[CH:9][N:8]=1.[O:15]=[C:16]([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18].O.C1COCC1>CCCCCC.C1COCC1>[F:6][C:7]1[C:12]([CH3:13])=[C:11]([C:16]([OH:15])([CH2:21][CH3:22])[C:17]([O:19][CH3:20])=[O:18])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(I)ccnc1F
Reactant: CCC(=O)C(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)(C(=O)OC)c1ccnc(F)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
6.9 ml (11 mmol) of 1.6M butyllithium in hexane are added dropwise to a solution, stirred at −78° C. of 2.6 g (11 mmol) of 2-fluoro-4-iodo-3-methylpyridine (described in J.O.C., 1993, 58, pp.7832) in 100 ml of THF. The reaction mixture is then stirred for 10 minutes at −78° C. before the addition of a solution of 1.5 g (12.9 mmol) of methyl 2-oxo-butyrate in 20 ml of THF. The reaction mixture is stirred for 10 minutes at −78° C., and then hydrolysed with a mixture of water/THF. The aqueous phase is decanted and then extracted 3 times with 50 ml of methyl acetate each time. The combined organic phases are dried, concentrated and purified by chromatography over silica (eluant:dichloromethane/acetone 95/5) to yield the expected product.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([N:13]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=2[C:42]2[CH:47]=[C:46]([CH:48]([CH3:50])[CH3:49])[CH:45]=[CH:44][C:43]=2[O:51][CH3:52])[C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:16][N:15]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>O1CCOCC1.[Cl-].[Na+].O>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([N:13]([CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:33]=2[C:42]2[CH:47]=[C:46]([CH:48]([CH3:50])[CH3:49])[CH:45]=[CH:44][C:43]=2[O:51][CH3:52])[C:14]2[N:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][N:19]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.9 %

Procedure:
To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (197 mg) is added a 4N-hydrochloric acid in dioxane (2.5 ml) and the mixture is stirred at room temperature for 3 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 4-{2-[(3,5-bis-trifluoromethyl-phenyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (104 mg). MS (m/z): 716 [M+H]+