Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.[O:36]1[CH2:40][CH:39](O)[CH:38]([OH:42])[CH2:37]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:30][CH2:31][C:32]2([O:42][C@H:38]3[CH2:37][O:36][CH2:40][C@H:39]3[O:35]2)[CH2:33][CH2:34]1
Reactant: OC1COCC1O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)O[C@H]2COC[C@H]2O3)c2ncnn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
A mixture of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.75 g), tetrahydrofuran-3,4-diol (0.48 g), p-toluenesulfonic acid monohydrate (0.028 g) and toluene (25 mL) was subjected to an azeotropic dehydration reaction by stirring at 110° C. for 16 hr in a reaction vessel equipped with a Dean-stark trap. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.77 g, 90%).
Reaction SMILES: C1OC2C(=CSC=2)[O:3]C1CO.[CH:12]1([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.BrC1C=CC(C2C=CC(OC(CCC)C(O)=O)=CC=2)=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:21]1([NH:20][C:19]([NH:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: OCC1COc2cscc2O1
Agent: CCCC(Oc1ccc(-c2ccc(Br)cc2)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.26 g of a mixture of 80% of EDT-methanol and 20% of hydroxy-PDT (corresponding to 18.9 mmol; 15.1 mmol based on the main component EDT-methanol), 3.14 g (15.2 mmol) of N,N′-dicyclohexylcarbodiimide and 0.3 g (2.45 mmol) of 4-(dimethylamino)pyridine are dissolved in 100 ml of CH2Cl2 and cooled in an ice bath. 5.25 g (15.0 mmol) of [(4′-bromo-1,1′-biphenyl-4-yl)oxy]-valeric acid are added a spatula at a time to the ice-cooled solution while stirring. After 1 hour, the reaction is continued at room temperature. After a further 65 hours, the colourless precipitate formed (N,N′-dicyclohexylurea) is filtered off. The clear, colourless solution is washed in succession with 3×250 ml of 1 N HCl, 3×150 ml of saturated NaHCO3 solution and 1×150 ml and 2×100 ml of saturated NaCl solution. The organic phase is dried over MgSO4, the desiccant is filtered off and the solvent is removed on a rotary evaporator. This gives 7.98 g of crude product.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O>[N:27]1([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reactant: C1COCCN1
Solvent: O
Product: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12

Procedure:
wherein R3 is C, N—CH3 or a direct C—C bond. The yield is modest (around 60% w/w yield). The patent discloses the reaction of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17β-ol with morpholine in the presence of water to yield 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol. The step is conducted for a reaction time of three days after which the solvents are removed by evaporation and the final product is crystallized from acetone followed by further recrystallization from methanol.
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[O:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[O:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@H](C)c1cc(-c2cccc(Cl)c2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)c1cc(-c2cccc(Cl)c2)on1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
The title compound of Example 16.1 (56 g, 211 mmol) and lithium hydroxide monohydrate (10.6 g, 253 mmol) were mixed with THF/Water (7/5, 1.2 L) and stirred at RT over night. Reducing the volume of the mixture in vacuo to about half, followed by dilution with brine, extraction with ether and then drying over MgSO4 and in vacuo concentration gave crude product. The crude product was purified by flash column chromatography on silica using heptane/EtOAc (7:3) to give the title compound (40 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]#N)[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C@:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16].[S-2].[Na+].[Na+].[CH3:25][N:26]([CH3:36])[C:27]([C:29]1[CH:34]=[CH:33]C(I)=[CH:31][CH:30]=1)=[O:28]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9][C:10]2[CH:33]=[CH:34][C:29]([C:27](=[O:28])[N:26]([CH3:36])[CH3:25])=[CH:30][CH:31]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:21])[C@:14]([OH:20])([CH3:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CN(C)C(=O)c1ccc(I)cc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(SC#N)c(Cl)c1Cl)C(F)(F)F
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)cc1
Temperature: 50 °C

Procedure:
(R)-N[2,3-Dichloro-4-thiocyanatophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 39) (0.5 g) as a solution in DMF was treated with a solution of sodium sulphide (403 mg) in water (2 ml) and the mixture was heated at 50° C. for 1 hour. The reaction mixture was then treated with a solution of N,N-dimethylcarbamoyl-4-iodobenzene (0.455 g) in DMF (5 ml), followed by cuprous oxide (0.121 g). The reaction mixture was heated at 150° C. for 4.5 hours under an argon atmosphere. The reaction mixture was quenched with water (100 ml), and DCM was added (100 ml) and the mixture was filtered through diatomaceous earth. The aqueous layer was separated and washed with DCM (3×50 ml). The organic extracts were combined and dried. The volatile material was removed by evaporation, and the product was purified by chromatography using a Mega Bond Elut column (20 g silica) eluting with 0-5% MeOH/DCM to yield the title compound as a white solid. (0.53 g) 80%. NMR: 1.60 (s, 3H), 2.95 (d, 6H), 7.30 (d, 1H); 7.30-7.50 (m, 4H), 7.85 (s, 1H), 7.90 (d, 1H), 9.90 (s, 1H); m/z: 479.
Reaction SMILES: [O:1]=[S:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([N:18]3[CH2:23][CH2:22][N:21]4[CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=[C:20]4[CH2:19]3)=[N:6][C:5]=2[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C)C=O>[N:39]1([C:27]([C:25]2[N:26]=[C:20]3[CH2:19][N:18]([C:7]4[N:8]=[C:9]([NH:11][CH:12]5[CH2:13][CH2:14][O:15][CH2:16][CH2:17]5)[C:10]5[S:2](=[O:1])[CH2:3][CH2:4][C:5]=5[N:6]=4)[CH2:23][CH2:22][N:21]3[CH:24]=2)=[O:28])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1
Reactant: O=C(O)c1cn2c(n1)CN(c1nc3c(c(NC4CCOCC4)n1)S(=O)CC3)CC2
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cn2c(n1)CN(c1nc3c(c(NC4CCOCC4)n1)S(=O)CC3)CC2)N1CCOCC1
Temperature: 25 °C

Procedure:
50 mg of 7-[5-oxo-4-(tetrahydropyran-4-ylamino)-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-2-yl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (see 13.1) are placed in 2 ml dimethylformamide, then 66 μl diisopropylethylamine and 54.2 mg O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) are added. After 15 min a suspension of 11.4 mg morpholine in 300 μl dimethylformamide is added. The reaction mixture is stirred at ambient temperature until there is no further reaction, and the product is purified directly by preparative HPLC (method B). 40 mg of Example 48 are obtained as a solid. Analytical HPLC-MS (method D): RT=0.79 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:44]=[CH:43][C:10]([O:11][CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:42])[C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1.[OH-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([O:11][CH:12]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][NH:28][C:29](=[O:42])[C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[C:13]([OH:15])=[O:14])=[CH:43][CH:44]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Oc1ccc(-c2ccccn2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Oc2ccc(-c3ccccn3)cc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 81.9 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-(4-pyridine-2-ylphenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (500 mg), which is the product of Example 134, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (390 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:33])([CH2:27][N:28]1[CH:32]=[N:31][N:30]=[N:29]1)[C:10]([F:26])([F:25])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20](OC)=[N:21][CH:22]=2)=[CH:13][N:12]=1.P(Cl)(Cl)([Cl:36])=O>CN(C=O)C>[Cl:36][C:20]1[N:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:26])([F:25])[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:33])[CH2:27][N:28]3[CH:32]=[N:31][N:30]=[N:29]3)=[N:12][CH:13]=2)=[CH:22][N:21]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ncc(-c2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cn1
Solvent: CN(C)C=O
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(-c2cnc(Cl)nc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(2-methoxypyrimidin-5-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (37; 80 mg, 0.17 mmol) was added phosphorus oxychloride (POCl3; 1.0 mL) followed by DMF (cat) at RT under inert atmosphere. The reaction mixture was gradually heated to 80° C. and stirred for 2 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with ice-cold water (30 mL), made basic (pH ˜8) using satd NaHCO3 solution and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 38% EtOAc/hexane) afford 57 (25 mg, 0.05 mmol, 31%) as a semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.84 (s, 2H), 8.74 (s, 1H), 8.71 (s, 1H), 8.01 (dd, J=8.0, 2.5 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.05 (br s, OH), 6.82-6.77 (m, 1H), 6.73-6.69 (m, 1H), 5.52 (d, J=14.5 Hz, 1H), 5.23 (d, J=14.5 Hz, 1H). MS (ESI): m/z 466 (M+H)+. HPLC: 93%.
Reaction SMILES: [CH3:1][CH:2]([CH2:21][CH3:22])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:7]([NH2:20])[N:6]=1.C1C(=O)N([Br:30])C(=O)C1.C(Cl)Cl>C(Cl)(Cl)Cl>[Br:30][C:10]1[N:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:20])[N:6]=[C:5]([O:4][CH2:3][CH:2]([CH3:1])[CH2:21][CH3:22])[N:13]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC(C)COc1nc(N)c2ncn(C3CCCCO3)c2n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC(C)COc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
A solution of 2-[(2-methylbutyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (245 mg) in dry chloroform (2.9 mL) was cooled to 0° C. and NBS (150 mg) was added to give a green/brown solution. The reaction mixture was stirred at room temperature for 6 h. The mixture was taken up into DCM (20 mL) and was washed with water (20 mL). The organics were separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give the title compound as green solid (292 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].[Br:32][C:33]1[C:34]([NH2:40])=[N:35][CH:36]=[C:37](I)[CH:38]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:32][C:33]1[C:34]([NH2:40])=[N:35][CH:36]=[C:37]([C:15]2[CH:14]=[CH:13][C:4]([O:5][CH2:6][CH2:7][N:8]3[CH2:9][CH2:10][CH2:11][CH2:12]3)=[C:3]([O:2][CH3:1])[CH:16]=2)[CH:38]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCCN1CCCC1
Reactant: Nc1ncc(I)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cnc(N)c(Br)c2)ccc1OCCN1CCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
1-{2-[2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl}pyrrolidine (5.81 g), tetrakis(triphenylphosphine)palladium (0.97 g) and potassium carbonate (6.94 g) were added to a solution of 3-bromo-5-iodopyridin-2-amine (5.00 g) in dioxane (40 ml) and water (4 ml) at room temperature. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was returned to room temperature and a saturated aqueous sodium bicarbonate solution was added, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=50:1->20:1->10:1 (v/v)] to give 4.03 g of the title compound as an oily substance.
Reaction SMILES: Br.C([O:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:15])=[CH:12][C:11]=1[O:28][CH3:29])C1C=CC=CC=1>C(O)(=O)C>[OH:9][C:10]1[CH:27]=[CH:26][C:13]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=2)=[O:15])=[CH:12][C:11]=1[O:28][CH3:29]
Reactant: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)ccc1O
Reaction time: 1.5 h

Procedure:
70 ml. of 33 percent hydrobromic acid in acetic acid are added within 15 minutes at 10° to 20 g of 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzophenone (dissolved in 150 ml of methylene chloride). After stirring at 20° for 1.5 hours, the reaction mixture is poured into 600 ml. of ice-water: the methylene chloride phase is separated and the aqueous phase is extracted twice more with 100 ml. of methylene chloride. The combined methylene chloride phases are washed with 600 ml of water, dried over sodium sulfate and evaporated. The residue is chromatographed on 150 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane, there is obtained 4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone of melting point 97°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:22][CH2:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:45]=2)[C:40]1=[O:52])(=O)C>>[C:48]([C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:52])[N:39]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:12]=[N:13][N:14]([CH:16]5[CH2:18][CH2:17]5)[CH:15]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:24]=1[CH2:23][OH:22])[CH2:47]2)([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Reactant: Cn1cc(Br)nc(Nc2cnn(C3CC3)c2)c1=O
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)nc(Nc2cnn(C3CC3)c2)c1=O
Yield: 35.1 %

Procedure:
Using the same general procedure as Example 105, reaction of 109c (310 mg, 1.00 mmol) and 103f (536 mg, 1.20 mmol) afforded a 35% yield (184 mg) of 109 as an off-white solid: mp 218-219° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.20 (s, 1H), 7.73 (m, 3H), 7.61 (m, 2H), 7.51 (t, 1H, J=7.9 Hz), 7.43 (m, 1H), 7.31 (s, 1H), 4.95 (s, 2H), 4.90 (t, 1H, J=5.0 Hz), 4.48 (d, 2H, J=5.0 Hz), 3.64 (m, 1H), 3.52 (s, 3H), 1.37 (s, 9H), 0.93 (m, 4H); MS (ESI+) m/z 525.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)=[CH:4][CH:3]=1.[C:28](=[O:35])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH2:29].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:29][C:28](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: CC1(C)C=C(c2ccc(F)cc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C=C2c1ccc(F)cc1

Procedure:
A mixture of the compound obtained in (3) described above (5.9 g), tert-butyl carbamate (2.06 g), cesium carbonate (9.6 g), tris(dibenzylideneacetone)dipalladium(0) (420 mg), biphenyl-2-yl-dibutylphosphate (840 mg) and 1,4-dioxane (30 mL) was heated under reflux under nitrogen atmosphere for 10 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue is purified by column chromatography on silica gel (Solvent; petroleum ether/ethyl acetate=100/1) to give the titled compound (2.8 g) as a yellow powder.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>O.CC(O)C>[CH:12]1([NH:19][C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NC1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(NC2CCCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 3.12 g (0.020 mol) of 4-fluoro-3-nitroaniline, 2.28 g (0.022 mol) of cycloheptylamine and 1.7 g (0.020 mol) of sodium hydrogen carbonate was refluxed for 3 hours in 5 ml of water and 5 ml of 2-propanol. After cooling to room temperature, the residues were filtered off and the filtrate was extracted with chloroform. The solvent was removed in vacuo and the residue was recrystallized from 20% hydrochloric acid. A green-brown solid melting at 153° C. was obtained.
Reaction SMILES: Br[C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].C(#N)C.C(=O)([O-])O.[Na+:18].[S:19](S([O-])=O)([O-:21])=[O:20].[Na+].[Na+]>O>[F:9][C:2]([F:10])([S:19]([O-:21])=[O:20])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].[Na+:18]
Reactant: OCCC(F)(F)C(F)(F)Br
Reactant: O=S([O-])S(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S([O-])C(F)(F)C(F)(F)CCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
A 2 litter reactor was charged with 151 g (0.67 mol) of 4-bromo-3,3,4,4-tetrafluorobutan-1-ol, 600 ml of acetonitrile, 600 ml of water, 112 g (1.33 mol/2.0 equivalent)) of sodium hydrogencarbonate, and 235 g (1.35 mol/2.0 equivalent) of sodium dithionite in a nitrogen stream. The mixture was stirred at room temperature for 12 hours. The reaction solution was extracted four times with 500 ml of acetonitrile. The solvent was evaporated from the resulting organic layer to obtain 120 g of the target sodium 1,1,2,2-tetrafluoro-4-hydroxybutane-1-sulfinate. The purity of the product was 80% and the yield was 77%.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]/[C:9]([OH:11])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>ClCCl>[OH:1][CH2:2]/[C:3](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]/[C:9]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:11]
Reactant: C1COCCN1
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/C(=O)O)CO
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/C(=O)N1CCOCC1)CO

Procedure:
Following the same manner as in Example 5, the reaction and after-treatment were conducted by using 400 mg of (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraenoic acid, 0.16 ml of triethylamine, 0.13 ml of ethyl chlorocarbonate and 0.20 ml of morpholine in 10 ml of dichloromethane to afford 210 mg of the end product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][N:11](C(C2C=CC=CC=2)C2C=CC=CC=2)[C@H:10]1[CH2:26][CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:12][NH:11][C@H:10]1[CH2:26][CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H]1[C@@H](NC(=O)OC(C)(C)C)CN1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Product: CC[C@@H]1NC[C@@H]1NC(=O)OC(C)(C)C
Yield: 78.5 %

Procedure:
The same operation as in Example (234e) was performed using cis(±)-3-(tert-butoxycarbonyl)amino-1-(diphenylmethyl)-2-ethylazetidine obtained in Example (235e) (154 mg, 0.42 mmol) and 10% Pd/C (30 mg), to obtain 66 mg of the title compound as a white solid (79%).
Reaction SMILES: FC(F)(F)C([O:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])=O.OO.[F:16][C:17]([F:41])([C:37]([F:40])([F:39])[F:38])[C:18]([F:36])([F:35])[C:19]([F:34])([F:33])[C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([I:26])([F:25])[F:24]>FC(F)(F)C(O)=O>[F:8][C:7]([F:10])([F:9])[C:6]([O:11][I:26]([O:5][C:6](=[O:11])[C:7]([F:8])([F:9])[F:10])[C:23]([F:25])([F:24])[C:22]([F:28])([F:27])[C:21]([F:30])([F:29])[C:20]([F:32])([F:31])[C:19]([F:33])([F:34])[C:18]([F:36])([F:35])[C:17]([F:41])([F:16])[C:37]([F:38])([F:39])[F:40])=[O:5]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: OO
Solvent: O=C(O)C(F)(F)F
Product: O=C(OI(OC(=O)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reaction time: 1.5 h
Yield: 66 %

Procedure:
1.3 ml (9.3 mmols) of trifluoroacetic anhydride was dissolved in 3.3 ml of trifluoroacetic acid, and 0.175 ml of a 30% hydrogen peroxide solution (H2O2, 1.71 mmol and H2O, 7.55 mmols) was added dropwise thereto while cooling in an ice bath. After completion of the addition, the mixture was stirred for 1.5 hour and 1.55 mmol of heptadecafluoro-n-octyl iodide was added and the mixture was allowed to react at 0° to 5° C. for 18 hours to obtain di(trifluoroacetoxy)iodoheptadecafluoro-n-octane in 66% yield.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH:17]=[CH:16][C:15]3[O:14][CH2:13][CH:12]([C:18](O)=[O:19])[CH2:11][C:10]=3[C:9]=2[CH:21]=1>>[CH3:1][NH:2][C:18]([CH:12]1[CH2:11][C:10]2[C:9]3[CH:21]=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][C:8]=3[CH:17]=[CH:16][C:15]=2[O:14][CH2:13]1)=[O:19]
Reactant: COc1ccc2ccc3c(c2c1)CC(C(=O)O)CO3
Reactant: CN
Product: CNC(=O)C1COc2ccc3ccc(OC)cc3c2C1

Procedure:
Methylamine, condensed with the acid obtained in Step B of Example 5, allows the title compound to be obtained.