Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].C[CH2:37][N:38]([CH:42]([CH3:44])C)[CH:39]([CH3:41])C.[C:45]1([S:55](Cl)(=[O:57])=[O:56])[CH:50]=[CH:49][CH:48]=[C:47]([S:51](Cl)(=[O:53])=[O:52])[CH:46]=1>C(Cl)Cl>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH3:35])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:55]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([S:51]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:44]4[C:32]5[C:41](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=5)[CH2:39][N:38]([CH3:37])[CH2:42]4)[CH:18]=3)(=[O:16])=[O:15])(=[O:53])=[O:52])[CH:46]=2)(=[O:57])=[O:56])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(S(=O)(=O)NCCOCCOCCOCCNS(=O)(=O)c4cccc(C5CN(C)Cc6c(Cl)cc(Cl)cc65)c4)c3)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a solution of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 28, 50 mg, 0.0917 mmol) and DIEA (35.5 mg, 0.275 mmol) in dry DCM (0.183 mL) under N2 was added benzene-1,3-disulfonyl dichloride (12.7 mg, 0.0459 mmol) in DCM (0.183 mL). The reaction mixture was stirred at room temperature for 60 minutes at which point LCMS indicated complete conversion. The solvent was removed and the resulting residue brought up in 4 mL ACN/H2O solution (1:1). Filtration and purification by preparative HPLC gave the title compound (16.6 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 8.28 (s, 1H), 8.06 (d, 1H), 7.85 (d, 2H), 7.75 (d, 2H), 7.70 (s, 1H), 7.63 (t, 2H), 7.53 (m, 3H), 6.82 (s, 1H), 4.52 (d, 1H), 3.85 (d, 1H), 3.61-3.46 (m, 28H), 3.13 (s, 6H), 3.09-3.03 (m, 7H). MS (m/z): 1294.99 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[C:9]([CH3:21])=[C:8]([F:22])[CH:7]=2)[CH2:3][CH2:2]1.Br[C:25]1[C:26](=[O:43])[N:27]([CH3:42])[C:28]2[N:33]([C:34]3[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])[N:32]=[CH:31][C:29]=2[N:30]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:7]=[C:8]([F:22])[C:9]([CH3:21])=[C:10]([C:25]3[C:26](=[O:43])[N:27]([CH3:42])[C:28]4[N:33]([C:34]5[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=5[F:41])[N:32]=[CH:31][C:29]=4[N:30]=3)[CH:11]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c(Br)nc2cnn(-c3c(F)cccc3F)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1nc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 125 °C

Procedure:
A mixture of N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (520 mg, 1.63 mmol), 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[4,3-b]pyrazin-6(7H)-one (505 mg, 1.48 mmol) in 3.5 mL of dioxane and 1.5 mL of 2 N Na2CO3 was heated in a microwave at 125° C. for 25 min. It was diluted with EtOAc and washed with 1 N NaOH. The EtOAc layer was separated, dried and concentrated. Purification of the crude material on an ISCO 40 g column (with 30-75% EtOAc in Hexanes) provided N-cyclopropyl-3-(1-(2,6-difluorophenyl)-7-methyl-6-oxo-6,7-dihydro-1H-pyrazolo[4,3-b]pyrazin-5-yl)-5-fluoro-4-methylb enzamide as an off white amorphous solid. MS (ES+): 454.1 (M+H)+.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([NH:13][CH2:14][CH3:15])[CH3:12].[CH2:16]=O>O1CCOCC1.O>[C:4]1([CH:3]([OH:10])[C:2]#[C:1][CH2:16][N:13]([CH2:14][CH3:15])[CH2:11][CH3:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=O
Reactant: CCNCC
Reactant: C#CC(O)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CC#CC(O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylpropargyl alcohol (119.12 g) in dioxane (650 ml), a solution of diethylamine (99.2 g) in water (300 ml), a solution of 37% formalin (148.9 g) in dioxane (200 ml) and a solution of cupric sulfate (pentahydrate) (8.11 g) in water (180 ml) were added with stirring at room temperature. The resulting mixture was stirred at about 70° C. for 2 hours and then filtered off, and the filtrate was evaporated under reduced pressure. The residual oily material was dissolved in benzene (450 ml) and extracted with three 300 ml portions of 5% aqueous solution of hydrochloric acid, and the extracts were combined together and washed with benzene (300 ml). The washed extract was neutralized with an aqueous solution of sodium hydroxide and extracted with three 400 ml portions of chloroform, and the extracts were washed with water (500 ml) and dried over sodium sulfate. The chloroform-extracts were evaporated and then distilled to afford N-(4-phenyl-4-hydroxy-2-butynyl)-N,N-diethylamine, b.p., 134°-137° C./0.12 mmHg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=[S:21].[NH4+].[OH-].O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([NH:19][C:20]([NH2:22])=[S:21])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCCOc1cc(Oc2ccccc2)cnc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOc1cc(Oc2ccccc2)cnc1NC(N)=S
Reaction time: 19 h
Yield: 81 %

Procedure:
3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-ylamine (0.3 mmol) is dissolved in THF (4 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 19 hours. 32% NH4OH (21 eq.) is added and stirred 3 hours at room temperature. Water (50 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-ethoxy)-5-phenoxy-pyridine-2-yl]-thiourea is obtained as brown oil in a yield of 81%; HPLC (method C): 1.85 min; LC-MS (method A): 1.68 min, 320.15 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3C=CC4OCCOC=4C=3OC2)C1=O.Cl.[F:46][CH:47]([F:56])[C:48]1[C:49]([CH2:54]O)=[N:50][CH:51]=[CH:52][CH:53]=1.Cl.FC(F)(F)C1C(CO)=NC=CC=1>>[F:46][CH:47]([F:56])[C:48]1[C:49]([CH2:54][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C@@:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])=[N:50][CH:51]=[CH:52][CH:53]=1
Reactant: OCc1ncccc1C(F)F
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Agent: Cl
Agent: O=C1Nc2ccccc2C12COc1c2ccc2c1OCCO2
Agent: OCc1ncccc1C(F)(F)F
Product: O=C1N(Cc2ncccc2C(F)F)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 11.78 and making non-critical variations using (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-f][1,4]benzodioxine-7,3′-indol]-2′(1′H)-one, and 3-(difluoromethyl)pyridin-2-yl methanol hydrochloride to replace (3-(trifluoromethyl)pyridin-2-yl)methanol hydrochloride, (8S)-1′-{[3-(difluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (50%) as a colorless solid: mp 181-182° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.56 (d, J=4.9 Hz, 1H), 8.08 (d, J=7.7 Hz, 1H), 7.52-7.50 (m, 1H), 7.52-7.42 (m, 1H), 7.25-7.15 (m, 2H), 7.01 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.42 (s, 1H), 5.18 (ABq, 2H), 4.72 (ABq, 2H), 4.19-4.12 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 155.0, 152.9 (t, JC-F=4.3 Hz), 151.4, 144.6, 143.2, 138.2, 135.0 (t, JC-F=7.0 Hz), 132.5, 129.1, 128.0 (t, JC-F=22.6 Hz), 123.9, 123.5, 123.3, 122.0, 113.8 (t, JC-F=236.6 Hz), 112.3, 109.7, 99.1, 79.7, 64.7, 64.1, 57.8, 42.3; MS (ES+) m/z 436.9 (M+1).
Reaction SMILES: C([O:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6])(=O)C>O1CCCC1.CO.O>[OH:4][C@H:5]([C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)[CH3:6]
Reactant: CC(=O)O[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 3 h
Yield: 224 %

Procedure:
—Potassium hydroxide (22.5 g) was added to a solution of (20S)-20-(acetyloxy)pregn-4-en-3-one (17.9 g) in tetrahydrofuran (418 ml), methanol (380 ml) and water (125 ml). The mixture was stirred for 3 h at room temperature and then poured into water (2 l). The product was extracted into ethyl acetate; the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Column chromatography afforded (20S)-20-hydroxypregn-4-en-3-one (compound 7a; 35.4 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH:29]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][CH:32]=1)=O>>[C:38]([CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:29][CH2:2][CH2:1][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[C@@H:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:32][CH:33]=1)([OH:40])=[O:39]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Product: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Yield: 92.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (296 mg) and (4-formylphenyl)acetic acid (630 mg) according to an analogous synthetic method to Example 212,the title compound (379 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[N:6][CH:7]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]3[CH:18]=[CH:19][C:20]([S:23]([NH:26][C:27](=[O:29])[CH3:28])(=[O:25])=[O:24])=[CH:21][CH:22]=3)[CH:10]=[C:11]([C:13]([F:14])([F:16])[F:15])[N:12]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cncc(C)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
A mixture of 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide (0.5 g, 1.3 mmol), acetic anhydride (0.40 g, 3.9 mmol), DMAP (0.09 g, 0.7 mmol) and triethylamine (0.16 g, 1.6 mmol) was stirred at room temperature for 16 hours. The reaction mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the residue was recrystallized from ethyl acetate and hexane to afford 0.4 g (72%) of N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide as a colorless solid: mp (DSC) 268-270 _C. Anal. Calc'd. for C18H15F3N4O3S: C, 50.94; H, 3.56; N, 13.20; S, 7.56. Found: C, 50.68; H, 3.47; N, 12.53; S, 7.43.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]#[CH:19]>C1COCC1>[CH3:13][C:12]([O:14][CH2:19][C:18]#[CH:17])([CH3:15])[CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#CCBr
Reactant: CC(C)(O)COCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOC(C)(C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a mixture of NaH (5.0 g) in THF (50 mL) at 0° C. was added 1-(benzyloxy)-2-methylpropan-2-ol (9.36 g, 51.9 mmol) dropwise. After being stirred at room temperature for 0.5 h, 3-bromoprop-1-yne (12.4 g, 104 mmol) was added slowly at 0° C. The mixture was then stirred at reflux overnight. The reaction was quenched by addition of sat. NH4Cl. The resulting mixture was extracted with ethyl acetate (30 mL×3). The organic layer was combined, dried over with Na2SO4, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (20/1) to afford the title compound (9.72 g, 86%) as pale yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.34-7.35 (m, 5H), 4.56 (s, 2H), 4.18 (d, J=2.0 Hz, 2H), 3.38 (s, 2H), 2.34 (t, J=2.0 Hz, 1H), 1.25 (s, 6H).
Reaction SMILES: Cl.Cl.OC1CCN(CCN2CCC(N[C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][CH2:32][C:33]([CH3:36])(C)C)[CH:26]=[CH:25][CH:24]=4)=[O:20])CC2)CC1.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([NH2:50])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:39])[CH3:38].[CH:51]1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[C:27]([O:30][CH2:31][CH:32]2[CH2:33][CH2:36][CH2:51]2)[CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:46][CH2:45]1)=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)(C)CCOc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCC(O)CC4)CC3)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cc3c(OCC4CCC4)cccc3[nH]2)CC1
Temperature: 25 °C

Procedure:
To a solution of 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid (82) from example 34 (2.2 g, 8.97 mmol) in 20 ml of DCM is added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.98 g, 9.87 mmol), HOBT (1.37 g, 8.97 mmol), triethylamine (2.5 ml, 17.94 mmol) and EDC (1.72 g, 8.97 mmol). The mixture is stirred at room temperature over night. It is then washed with 2N—NaOH and brine, dried over anhydrous sodium sulphate and evaporated to give a yellow powder. The crude material is purified by chromatography on silicagel using hexane and EtOAc (from 0% to 20%).
Reaction SMILES: [F:1][C:2]([F:17])([C:13]([F:16])([F:15])[F:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6].[C:18]1([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C:19]([OH:28])=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2.C(N(CC)CC)C.[OH-:46].[Na+]>ClCCl.O>[S:5]([C:4]([C:3]([C:2]([C:13]([F:16])([F:15])[F:14])([F:17])[F:1])([F:12])[F:11])([F:10])[F:9])([OH:28])(=[O:7])=[O:6].[S:5]([C:4]([C:3]([C:2]([C:13]([F:14])([F:15])[F:16])([F:1])[F:17])([F:12])[F:11])([F:10])[F:9])([OH:7])(=[O:6])=[O:46].[C:18]1([C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=2)[C:19]([OH:28])=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]2
Reactant: [OH-]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Oc1ccc2ccccc2c1-c1cccc2ccccc12
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 4 h

Procedure:
111.6 g of nonafluoro-n-butanesulfonyl fluoride (370 mmol) were added at room temperature to a solution of 45.6 g of racemic binaphthol (160 mmol) and 47.6 g of triethylamine (470 mmol; 65.5 ml) in 350 ml of dichloromethane. After a few minutes, the denser sulfonyl phase had disappeared, without the mixture warming appreciably. After stirring for 4 hours, the mixture was shaken once with 80 ml of aqueous sodium hydroxide solution (5% by weight) and once with 80 ml of water, and the organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The product crystallized out on cooling and was purified further by washing with a small amount of cold methanol and subsequent filtration with suction. This gave 123 g of binaphthol dinonaflate (90.0%) as colourless crystals having a melting point of 104.1° C.; HPLC purity>99% (RP-18; methanol/water 80:20; 254 nm)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]3([OH:20])[CH2:19][CH2:18]3)[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]3([OH:20])[CH2:19][CH2:18]3)[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC2(O)CC2)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC4(O)CC4)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 459 Step 1. LC-MS Method 2 tR=0.996, m/z=461.1; 1H NMR (CDCl3) 0.35 (m, 1H), 0.17 (m, 3H), 0.51 (m, 1H), 0.61 (m, 1H), 1.48 (d, 3H), 2.11 (s, 2H), 2.28 (m, 1H), 2.42 (m, 2H), 2.56 (s, 3H), 2.71 (s, 1H), 2.95 (m, 1H), 5.63 (m, 1H), 6.91 (m, 2H), 6.98 (m, 2H), 7.19 (m, 1H), 7.26-7.38 (m, 5H), 8.49 (d, 1H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH:7]=[CH2:8])[C:3](=[O:5])[CH3:4].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].OCC(CO)O.[Cl-].N>O1CCCC1>[CH3:4][C:3]([OH:5])([CH:2]([CH3:1])[CH2:6][CH:7]=[CH2:8])[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CBr
Reactant: C=CCC(C)C(C)=O
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: OCC(O)CO
Product: C=CCC(C)C(C)(O)CC(=O)OC
Temperature: 25 °C

Procedure:
3-Methyl-5-hexen-2-one (J. Chem. Soc., Chem. Comm. 19, 1991, 1399) (17 g, 106 mmol) and methyl bromoacetate (24.4 g, 159 mmol) were dissolved in tetrahydrofuran (100 mL), and the solution was added dropwise to a tetrahydrofuran (50 mL) (zinc (10.4 g, 159 mmol) and trimethyl borate (30 mL)) solution under reflux. After reflux for 3 hours, the mixture was cooled to room temperature, and glycerin (30 mL) and a saturated aqueous solution of ammonia chloride (100 mL) were added thereto, followed by two extractions with ethyl acetate. The ethyl acetate layer was washed with saturated saline, then dried, and then concentrated. The residue was purified by silica gel column chromatography (200 g) to obtain the compound of interest as an oil substance (11.7 g, 60%).
Reaction SMILES: C1(C)C=CC=CC=1.S(Cl)([Cl:10])=O.[O:12]=[C:13]1[C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=[C:15]([C:22]([F:25])([F:24])[F:23])[N:14]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[O:12]=[C:13]1[C:18]([C:19]([Cl:10])=[O:20])=[CH:17][CH:16]=[C:15]([C:22]([F:25])([F:24])[F:23])[N:14]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C(F)(F)F)n(Cc2ccccc2)c1=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C(F)(F)F)n(Cc2ccccc2)c1=O

Procedure:
Toluene (20 mL), thionyl chloride (1.3 g, 10.7 mmol) and a catalytic amount of N,N′-dimethylformamide were added to 1,2-dihydro-2-oxo-1-phenylmethyl-6-(trifluoromethyl)pyri-dine-3-carboxylic acid (2.0 g, 7.2 mmol), and the mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 1,2-dihydro-2-oxo-1-phenylmethyl-6-(trifluoromethyl)pyridine-3-carbonyl chloride. The obtained acid chloride was dissolved in acetonitrile (30 mL), and 1,3-cyclohexanedione (0.9 g, 7.9 mmol) and sodium cyanide (0.8 g, 15.8 mmol) were added thereto. This mixture was stirred for a day at room temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After separating the inorganic substance by filtration, the solvent was distilled off under reduced pressure and thus obtained concentrated solution was purified by column chromatography, to obtain 1.5 g of a desired product (yield: 68%).
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([OH:15])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[P:17]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.FC(F)(F)C(O)=O>O1CCCC1>[CH:24]1([P:17]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:12]([OH:15])(=[O:14])=[O:13])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=S(=O)(O)c1ccccc1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=S(=O)(O)c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
n-Butyllithium (manufactured by Kanto Chemical Co., Inc., 1.65 M hexane solution, 5.1 ml, 8.4 mmol) was added to a tetrahydrofuran (THF) solution (20 ml) of benzenesulfonic acid (manufactured by Tokyo Chemical Industry Co., Ltd., 0.66 g, 4.2 mmol) at 0° C. under argon atmosphere and the mixture was stirred for 2.5 hours at room temperature. After cooling the reaction container to −78° C., chlorodicyclohexylphosphine (manufactured by Sigma-Aldrich, 0.89 mg, 3.8 mmol) was added thereto at −78° C. and stirred for 24 hours at room temperature. After ceasing the reaction with trifluoroacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd., 0.50 M THF solution, 8.4 ml, 4.2 mmol), the precipitate formed was collected by filtration and dried under reduced pressure to obtain 2-(dicyclohexylphosphino)benzenesulfonic acid (compound 1a). The yield was 0.66 g (85%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]([OH:12])=[O:11].Cl>C1COCC1.O>[N:1]1([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: O=C(O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1ccnc1
Reaction time: 8 h
Yield: 31.3 %

Procedure:
Imidazole (3.7 g, 54 mmol) was added to a suspension of sodium hydride (2.6 g of a 60% dispersion in oil, 60 mmol) in 50 ml dry THF. Bromoacetic acid (3.4 g, 24 mmol) was then added and the mixture stirred overnight. Water (1 ml) was then added and the solvent removed under reduced pressure. The residue was taken up in water (50 ml, pH>10), extracted with ether and the organic layer discarded. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted again with ether. The aqueous layer was evaporated to dryness. The oily residue was dissolved in absolute ethanol (EtOH) to precipitate NaCl, and recrystallized from acetone/methanol to give 1.22 g (7.5 mmol, 30%) pure product as the hydrochloride. 1H NMR: (DMSO-d6, 200 MHz) δ 9.20 (s, H2), 7.76 (d, J=1.5 Hz), 7.69 (d, J=1.5 Hz), 5.20 (s, CH2).0