Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=O.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][C@H:27]([NH:29][CH2:30][C:31]([F:35])([CH3:34])[CH2:32][OH:33])[CH3:28])=[CH:18]1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:10])[C:7]=1[C@@H:8]1[C:18]2[NH:17][C:25]3[C:20]([C:19]=2[CH2:26][C@@H:27]([CH3:28])[N:29]1[CH2:30][C:31]([F:35])([CH3:34])[CH2:32][OH:33])=[CH:21][CH:22]=[CH:23][CH:24]=3
Reactant: C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(F)CO
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc(F)c([C@@H]2c3[nH]c4ccccc4c3C[C@@H](C)N2CC(C)(F)CO)c(F)c1
Temperature: 90 °C
Yield: 10.3 %

Procedure:
(E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (565 mg, 2.50 mmol) was added to a suspension of 3-(((R)-1-(1H-indol-3-yl)propan-2-yl)amino)-2-fluoro-2-methylpropan-1-ol (661 mg, 2.50 mmol) in toluene (11.3 ml)/acetic acid (1.25 ml). The reaction was heated to 90° C. for 5 h. After cooling, the volatiles were removed under vacuum, then the residue was passed through an SCX-2 column, eluting with methanol to remove unreacted aldehyde. The column was then eluted with NH3/MeOH to liberate the products. The basic filtrate was evaporated then the crude product was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (Isomer 1-122 mg, 10.3%) as a yellow solid and (E)-methyl 3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (Isomer 2-129 mg, 11% as a yellow/orange solid. Isomer 1-1H NMR (400 MHz, CDCl3, 27° C.) 1.10 (3H, d), 1.14 (3H, d), 2.54 (1H, dd), 2.62-2.73 (1H, m), 3.06-3.3 (2H, m), 3.40 (1H, dd), 3.56 (1H, t), 3.80 (3H, s), 3.87-4.08 (1H, m), 4.27 (1H, s), 5.16 (1H, s), 6.37 (1H, d), 7.01 (2H, d), 7.07-7.15 (2H, m), 7.14-7.24 (1H, m), 7.42-7.56 (2H min), 7.71 (1H, s). m/z (ES+), [M+H]+=473. Isomer 2—1H NMR (400 MHz, CDCl3, 27° C.) 1.15 (3H, d), 1.20 (3H, d), 2.65 (1H, dd), 2.79 (1H, t), 2.93-3.09 (2H, m) 3.57 (1H, dt), 3.70 (1H, dd), 3.78 (3H, s), 4.2-4.67 (1H, n), 5.42 (1H, s), 6.32 (1H, d), 6.94 (2H, d), 7.06-7.15 (2H, m), 7.19-7.27 (2H, n, 7.42 (1H, s), 7.51 (11H, dd), 8.02 (1H, s). m/z (ES+), [M+H]+=473.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[CH:32]1([CH:38]=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:32]1([CH2:38][NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=2[C:12]2[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]3[C:24]4[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=4[CH:22]=[CH:21][CH:20]=3)[CH:13]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCC4CCCCC4)ncn3)cccc2s1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.17 g, 0.3 mmol) in 1,2-dichloroethane (10 mL) was added cyclohexanecarboxaldehyde (0.1 g, 0.9 mmol, Aldrich) and the mixture was stirred at 40° C. for 2 h. Sodium triacetoxyborohydride (0.40 g, 1.9 mmol, Aldrich) was added and the reaction mixture was stirred for 18 h at room temperature. After the addition of water (2 mL), the reaction mixture was evaporated in vacuum. The residue was diluted with H2O (10 mL) and extracted with EtOAc (2×20 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Purification of the residue by silica gel chromatography (6:1, hexanes: EtOAc) afforded the title compound as an yellow solid. Mp: 232–234° C. MS(ESI, pos. ion) m/z: 542 (M+1).
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH2:23]=[O:24].Cl>O.CO>[OH:24][CH2:23][C:19]1[CH:20]=[CH:21][C:16]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:17][C:18]=1[OH:22]
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Reactant: C=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCCc1ccc(CO)c(O)c1
Yield: 19.4 %

Procedure:
(2 1) 150 g of 3-pentadecylphenol and 17.7 g of paraformaldehyde were dispersed in 300 ml of water and 150 ml of methanol, and the dispersion was stirred at 50° C. for 12 hours. The reaction mixture was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. 300 ml of hexane were added to the residue to precipitate a crystal. The crystal was recovered by filtration and dried to obtain 32 g of 2-hydroxymethyl-5-pentadecylphenol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]2[CH2:15][NH:14]/[C:13](=[N:16]\[C:17]([C:19]3[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=3)=[O:18])/[NH:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:35]1[O:37][C@H:36]1[CH2:38][OH:39]>C(O)C.CO>[OH:37][C@@H:36]([CH2:38][OH:39])[CH2:35][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C@H:11]2[CH2:15][NH:14]/[C:13](=[N:16]/[C:17]([C:19]3[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=3)=[O:18])/[NH:12]2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CO1
Reactant: Nc1nc(N)c(C(=O)/N=C2\NC[C@H](CCCc3ccc(O)cc3)N2)nc1Cl
Solvent: CCO
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C(=O)/N=C2/NC[C@H](CCCc3ccc(OC[C@@H](O)CO)cc3)N2)nc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [(S)-4-[3-(4-hydroxy-phenyl)-propyl]-imidazolidin-(2E)-ylidene]-amide (Example 18) (37.5 mg, 0.09 mmol) in Ethanol (2 ml) is added triethylamine (63 l, 0.45 mmol) and (S)-glycidol (6.07 l, 0.09 mmol). The resulting mixture is heated at reflux for 18 hours and then allowed to cool to room temperature. The reaction mixture is diluted with MeOH (1 ml) and purified on a Waters 3000 prep HPLC system, (Microsorb C18, Water (0.1% TFA): MeCN) to afford the title compound; [M+H]+ 464.
Reaction SMILES: [OH-].[Na+].O.[NH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1.C(Cl)(=O)OCC.[C:21](=S)=[S:22]>>[N:4]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1)=[C:21]=[S:22]
Reactant: S=C=S
Reactant: CCOC(=O)N1CCC(N)C1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)N1CCC(N=C=S)C1
Reaction time: 3 h
Yield: 100 %

Procedure:
(a-4) A mixture of 8.6 parts of sodium hydroxide and 120 parts of water was stirred at a temperature below 10° C. and there were added successively 17 parts of carbon disulfide and 35 parts of ethyl 3-amino-1-pyrrolidinecarboxylate. Stirring was continued for 3 hours. Then there were added dropwise 23.5 parts of ethyl carbonochloridate. Upon completion, stirring was continued for 2 hours at 60° C. The reaction mixture was extracted with methylbenzene. The extract was dried, filtered and evaporated, yielding 55 parts (100%) of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate as a residue (interm. 6).
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([N:10]([CH3:31])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([O:24]C2C=CC=CC=2)=O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[CH3:40]N(C)C=O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:33]=[CH:32][C:7]([C:8]([N:10]([CH3:31])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[O:24])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1OCCCNC(=O)Oc1ccccc1
Reactant: C1CNCCN1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)NCCCOc2ccccc2N(C)C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 4-nitro-N-methyl-N-[2-(3-phenoxycarbonylaminoprop-1-yloxy)phenyl]benzamide (383 mg) and piperazine (256 mg) in N,N-dimethylformamide (8 ml) was stirred at 80° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and then the organic solution was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of solvents afforded 4-nitro-N-methyl-N-[2-{3-(4-methyl-1-piperazinyl)carbonylaminoprop-1-yloxy}phenyl]benzamide (357 mg) as a slightly yellow oil.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[N:41]([C:47]1[C:48]([CH2:61][OH:62])=[C:49]([C:53]3[CH:54]=[C:55]([C:58]([OH:60])=O)[NH:56][CH:57]=3)[CH:50]=[CH:51][CH:52]=1)[N:40]=[CH:39]2)([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42](=[O:46])[N:41]([C:47]1[C:48]([CH2:61][OH:62])=[C:49]([C:53]3[CH:54]=[C:55]([C:58]([NH2:2])=[O:60])[NH:56][CH:57]=3)[CH:50]=[CH:51][CH:52]=1)[N:40]=[CH:39]2)([CH3:33])([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4c[nH]c(C(=O)O)c4)c3CO)ncc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc2c(=O)n(-c3cccc(-c4c[nH]c(C(N)=O)c4)c3CO)ncc2c1
Yield: 26.1 %

Procedure:
HATU (104 mg, 0.27 mmol) and triethyl amine (1 mL) were added to a solution of 4-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrole-2-carboxylic acid (95 mg, 0.23 mmol) in dry THF (15 mL). Ammonia gas was bubbled through the solution for 5 h. The mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=2:1) to give 4-[3-(6-tert-butyl-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrole-2-carboxylic acid amide (25 mg, yield 26%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.43 (s, 1H), 8.28 (d, J=8.5 Hz, 1H), 7.98-7.92 (m, 2H), 7.52-7.39 (m, 2H), 7.26-7.19 (m, 2H), 7.03 (d, J=1.6 Hz, 1H), 4.38 (s, 2H), 1.38 (s, 9H). LC-MS calcd for C24H24N4O3 (m/e) 416.18, obsd 417 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:61]1[CH:66]=[CH:65][CH:64]=[C:63]([CH2:67][NH2:68])[CH:62]=1>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:68][CH2:67][C:63]3[CH:62]=[N:61][CH:66]=[CH:65][CH:64]=3)=[O:13])=[CH:14][CH:15]=2)=[N:4][C:3]=1[CH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[CH:22][CH:21]=1)(=[O:18])=[O:19]
Reactant: NCc1cccnc1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(CN2CCOCC2)cc1
Yield: 68.4 %

Procedure:
To a solution of 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid (490 mg, 1.07 mmol, 1.00 equiv), EDCI (250 mg, 1.31 mmol, 1.22 equiv), HOBt (180 mg, 1.33 mmol, 1.24 equiv), triethylamine (330 mg, 3.27 mmol, 3.04 equiv) and pyridin-3-ylmethanamine (330 mg, 3.06 mmol, 2.84 equiv) in N,N-dimethylformamide (20 mL) was stirred overnight at room temperature. The product was precipitated by the addition of 60 mL ice/water. The solid was collected by filtration and washed with water (1×20 mL) and dried in an oven under reduced pressure to give 0.40 g (68%) of 4-(5-methyl-4-((4-(morpholinomethyl)phenylsulfonyl)methyl)oxazol-2-yl)-N-(pyridin-3-ylmethyl)benzamide as a white solid. LC-MS: (ES, m/z): 547 [M+H]+. 1HNMR (400 MHz, DMSO-d6, ppm) δ 9.22 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 7.98 (d, J=7.6Hz, 2H), 7.86 (d, J=7.6Hz, 2H), 7.74-7.72 (m, 3H), 7.53 (d, J=7.6Hz, 2H), 7.36 (s, 1H), 4.67 (s, 2H), 4.51 (d, J=4.0Hz, 2H), 3.55 (s, 6H), 2.32 (s, 4H), 2.15 (s, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:70]([C:73]([CH3:76])([CH3:75])[CH3:74])([CH3:72])[CH3:71])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,-27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in dry methylene chloride (3 ml) was added an excess of 2,6-lutidine (45 ml) and the mixture was stirred at room temperature. After 10 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (64 ml) was added by syringe. After 15 minutes the reaction mixture was diluted with ethyl acetate, extracted from saturated bicarbonate, washed with brine and the organic phase dried over magnesium sulfate. Removal of solvent in vacuo and flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (235 mg). (1H NMR consistent with the desired structure).
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][CH2:12][C:13]([C:16](F)=[O:17])([F:15])[F:14])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].S(=O)(=O)(O)[OH:20]>>[C:1]([C:5]([C:8]([O:11][CH2:12][C:13]([C:16]([OH:17])=[O:20])([F:14])[F:15])([F:9])[F:10])([F:6])[F:7])([F:2])([F:3])[F:4]
Reactant: O=C(F)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(O)O
Product: O=C(O)C(F)(F)COC(F)(F)C(F)(F)C(F)(F)F

Procedure:
The crude product CF3CF2CF2OCH2CF2COF was rectified under nitrogen at ordinary pressure using a 10-stage Oldershaw rectification column to give 2020 g of CF3CF2CF2OCH2CF2COF. Its boiling point was 78° C. A 30-g portion of the CF3CF2CF2OCH2CF2COF obtained was hydrolyzed by gradually pouring the same into 30 g of dilute sulfuric acid with stirring. The product was washed several times with dilute sulfuric acid and then distilled under reduced pressure to give 20.5 g of pure CF3CF2CF2OCH2CF2COOH. The thus-obtained CF3CF2CF2OCH2CF2COOH had a boiling point of 84° C. at a pressure of about 2.7×103 Pa. A 5.9-g portion of the CF3CF2CF2OCH2CF2COOH obtained was dissolved completely in 29.8 g of pure water. The pH of the solution was 1.28. The pH was adjusted to 7 by adding an aqueous solution of sodium hydroxide dropwise. The resulting aqueous solution contained 19.8% by mass of CF3CF2CF2OCH2CF2COONa. The aqueous solution was dried under vacuum at 80° C., and the melting point of the CF3CF2CF2OCH2CF2COONa obtained (solid salt) was measured by DSC and found to be 191.8° C. A 0.2% (by mass) aqueous solution of this CF3CF2CF2OCH2CF2COONa had a surface tension of 68.5 mN/m. The surface tension of a 2.0% (by mass) aqueous solution thereof was 48.0 mN/m.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[S:19](Cl)(=[O:21])=[O:20]>>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[S:19]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:20])=[O:21]
Reactant: Cc1noc(N)c1Br
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Product: COc1ccc(OC)c(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 58 %

Procedure:
2,5-Dimethoxy-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5-dimethoxybenzenesulfonyl chloride according to the procedures described in Example 200. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 118-120°, yield 58%.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[Cs+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: [Cs+]
Agent: [OH-]
Solvent: Clc1ccccc1Cl
Solvent: CC(C)(C)O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a mixture of 12.8 g (86.4 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (78.3 mL) was added 15.3 g (86.4 mmol) of 95% cesium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 5.00 g (purity: 95.0%; 28.8 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (95.0 g) at 180° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 2 hours, the reaction mixture was cooled to room temperature, and 100 g of pure water was added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 50.0 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol was separated. This operation was repeated twice. Then, the resultant aqueous phase containing a cesium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was added dropwise to a 4% aqueous hydrochloric acid solution at 0° C. to deposit solids, followed by filtration. The resultant solids were washed with pure water and dried under a reduced pressure, and dissolved in an organic solvent and quantitatively determined by an HPLC internal standard analysis method, which showed that 7.92 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (purity: 76.1%; yield: 76%) and 166 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 2.1%) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH2:23]([Cl:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-:34].[Na+].[Na+].[ClH:39]>C(#N)C>[OH2:34].[ClH:32].[ClH:39].[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:23][CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH:10]2[CH2:15][CH2:14][N:13]([CH2:23][CH:24]=[CH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[ClH:32].[ClH:32]
Reactant: O=C([O-])[O-]
Reactant: ClCC=Cc1ccccc1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: Fc1ccc(NC(c2ccc(F)cc2)C2CCN(CC=Cc3ccccc3)CC2)cc1
Product: O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.41 g (11.3 mmol) of the N,α-bis(4-fluorophenyl)-4-piperidinemethanamine, 1.85 g (12.1 mmol) of cinnamyl chloride, and 2.00 g (19.0 mmol) of sodium carbonate in 300 mL of acetonitrile was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. An insoluble residue was removed by filtration. The CH2Cl2 solution was subjected to flash chromatography (silica gel, eluted with 3% CH3OH in CH2Cl2) to give an oil. This was converted to the HCl salt, and the salt was recrystallized from CH3OH/ether to give 1.83 g (32.7%) as a white crystalline solid, mp 239°-241° C.
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[O:9]1[C:10]2=[CH:11][CH:12]=[CH:17][C:16]2=[CH:15][CH:14]=[C:13]1[NH:6][C:5]1[CH:7]=[CH:8][CH:2]=[CH:3][CH:4]=1
Reactant: Nc1ccc(I)cc1
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: c1ccc(Nc2ccc3cccc-3o2)cc1
Temperature: 125 °C
Yield: 99.6 %

Procedure:
A mixture of 4-iodo-aniline (25.0 g, 114.1 mmol), 2-benzofuran-boronic acid (27.7 g, 171.2 mmol), PdCl2(O-tolylphosphine) (11.66 g, 14.8 mmol), and Na2CO3(60.49 g, 570.7 mmol) in DME/EtOH/H2O (4:2:1)(700 mL) was heated at 125° C. for 2 h. The reaction mixture was cooled to room temperature, filtered and washed. The solvent was removed under reduced pressure. The residue was partitioned (ethyl acetate/water) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel, eluting with dichloromethane to afford 4-benzofuran-2-yl-phenylamine (11) as a pale yellow solid (23.78 g, 99.5%): 1H NMR (300 MHz, CDCl3): δ 7.66 (d, J=9.0 Hz, 2H), 7.51-7.55 (m, 2H), 7.20-7.23 (m, 2H), 6.81 (s, 1H), 6.73 (d, J=9.0 Hz, 2H), 3.83 (bs, 2H) TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate/hexanes (2:1); Rf=0.45.
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[CH2:12]1[O:15][C@H:13]1[CH3:14]>O1CCCC1.CCOCC.[Cu]I>[CH3:12][C@H:13]([OH:15])[CH2:14][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: C[C@H]1CO1
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](O)Cc1ccc2c(c1)OCO2
Temperature: -50 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a suspension of magnesium turnings (17 g) in 50 mL tetrahydrofuran was added dropwise a solution of 5-bromo-1,3-benzodioxole (93.6 g). After complete addition, the mixture was diluted with 250 mL tetrahydrofuran and the resulting mixture was stirred overnight. 13 mL of the solution (0.78M) was transferred to a round bottom flask containing copper (I) iodide (0.12 g). The resulting mixture was cooled to -50 ° C. and a solution of (S)-(-)-propylene oxide in 3 mL tetrahydrofuran was slowly added then stirred 10 min. The mixture was diluted with ether. The isolated organic phase was washed with water and brine. The aqueous wash was extracted with ether (2×) and the combined organic solutions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50% ether in pentane) to give 1.66 g of the desired product (91%). Chiral HPLC analysis indicated that the optical purity of the material was 98.3%.