Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:16][SH:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7].[N+]([O-])(O)=O.[C:22](C1C(C)=NNC=1C)(=[NH:24])[NH2:23].C(N(CC)CC)C>CN(C)C=O>[NH:1]([CH2:2][CH2:3][CH2:4][CH:5]([CH2:16][SH:17])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])[C:22]([NH2:24])=[NH:23]
Reactant: NCCCC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reactant: Cc1n[nH]c(C)c1C(=N)N
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Solvent: CCN(CC)CC
Product: N=C(N)NCCCC(CS)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(5-amino-2-mercaptomethylpentanoyl)-L-proline (2.3 g), guanyl-3,5-dimethylpyrazole nitrate (2.41 g) and triethylamine (3.36 ml) in dimethylformamide (20 ml) is stored at room temperature under a blanket of argon for sixteen hours. The solvents are removed in vacuo, the residue is dissolved in 0.1 N hydrochloric acid (10 ml) and zinc dust (500 mg) is added. The suspension is stirred at room temperature for two hours. After filtering, the filtrate is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle. The column is washed with water until no more acid is eluted and 1-(5-guanidino-2-mercaptomethylpentanoyl)-L-proline is then eluted with a pyridine-acetate buffer at pH 6.5.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]([C:23]1[CH:27]=[C:26]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:57][CH2:56][CH2:55][CH2:54][C@@H:53]5[CH3:58])=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:25]([C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([O:65][CH2:66][CH2:67][O:68][CH:69]3CCCC[O:70]3)[CH:60]=2)[N:24]=1)([CH3:22])[CH3:21])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+:86]1[CH:91]=CC=C[CH:87]=1>CO>[CH:69]([OH:70])=[O:68].[CH3:87][N:86]([CH3:91])[CH2:67][CH2:66][O:65][C:61]1[CH:60]=[C:59]([N:25]2[C:26]([NH:28][C:29]([NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@H:35]([O:42][C:43]4[CH:44]=[CH:45][C:46]5[N:47]([C:49]([N:52]6[CH2:57][CH2:56][CH2:55][CH2:54][C@@H:53]6[CH3:58])=[N:50][N:51]=5)[CH:48]=4)[CH2:34][CH2:33]3)=[O:30])=[CH:27][C:23]([C:20]([CH3:22])([CH3:21])[CH2:19][OH:18])=[N:24]2)[CH:64]=[CH:63][CH:62]=1
Reactant: c1cc[nH+]cc1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)CO)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 45 °C
Reaction time: 19 h
Yield: 91.2 %

Procedure:
A solution of Intermediate 153g (317 mg, 0.31 mmol) in MeOH (3.1 mL) was treated with pyridinium para-toluenesulfonate (235 mg, 0.93 mmol) and the mixture was stirred at 45° C. for 19 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and a saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with water, a saturated aqueous sodium bicarbonate solution, and brine, dried (Na2SO4) and concentrated in vacuo to a cream coloured foam. The foam was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as a colourless glass (217 mg, 75%). LCMS (Method 3): Rt 5.06 min, ink 933.7 [MH+].
Reaction SMILES: C(S)C.[H-].[Na+].[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[CH:17]=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>CN(C=O)C>[CH2:29]([O:28][C:16]1[CH:17]=[C:18]([OH:20])[CH:19]=[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:15]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(COc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Solvent: O
Product: Oc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
Ethanethiol (10 g, 216 mmol) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 2.4 g, 100 mmol) in dry DMF (120 mL) at 0° C. After 1 h, 1,3,5-tribenzyloxybezene (24 g, 60 mmol) was added in 10 batches and the mixture was heated to 150° C. for 1.5 h. After the reaction was cooled, water (500 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (benzene) to give 3,5-dibenzyloxyphenol as white solid (11%) after recrystallization from carbon tetrachloride and product #d as white solid (56%) after recrystallization from EtOAc and hexane. Compound #d was identified by mp 107-109° C.; 1H NMR (CDCl3, 400 MHz) δ 7.36-7.23 (m, 15H), 6.25 (d, J=2.2 Hz, 1H), 6.07 (d, J=2.2 Hz, 1H), 4.96 (s, 2H), 4.92 (s, 2H), 3.99 (s, 2H); 13C NMR (CDCl3, 400 MHz) δ 158.4, 157.9, 154.9, 140.7, 136.7, 136.6, 128.4, 128.2, 128.1, 127.8, 127.5, 127.3, 127.0, 125.6, 108.5, 94.7, 93.3, 70.2, 69.9, 28.3; HRMS (ESI) calcd for C27H24O3Na (M+Na) 419.1623, found 419.1645.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3].[OH:16][C@H:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([C:26]3[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=3)[C:20]=2[C@H:19]([CH3:34])[CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([NH:15][C:31]([C:29]1[S:30][C:26]([C:25]2[C:20]3[C@H:19]([CH3:34])[CH2:18][C@@H:17]([OH:16])[C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:27][CH:28]=1)=[O:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)O)s3)c21
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)N[C@H](CN=[N+]=[N-])Cc4ccc(Cl)cc4Cl)s3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
(S)-1-Azido-3-(2,4-dichlorophenyl)propan-2-amine (20 mg, 0.0724 mmol) was added to a solution of 5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylic acid (35 mg, 0.145 mmol) in DCM (0.5 mL) DMF (125 μL) was added to solubilize the starting material completely. DIPEA (126 μL, 0.724 mmol) was added, followed by the addition of HBTU (30 mg, 0.079 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS of the reaction mixture showed no more starting material. The solvent was removed, and the resulting residue was purified by reversed phase HPLC to yield N—((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide product as a solid (4 mg, 10%). m/z 504 (MH+).
Reaction SMILES: [N:1]1([C:6]2[C:7]3[N:8]([C:16]([C:19]([O:21]CC)=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.C1COCC1.[OH-].[Na+].Cl>O.C(O)C>[N:1]1([C:6]2[C:7]3[N:8]([C:16]([C:19]([OH:21])=[O:20])=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCOC(=O)c1cnc2c(-n3cncn3)cc(C(F)(F)F)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2c(-n3cncn3)cc(C(F)(F)F)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a mixture of ethyl 8-(1H-1,2,4-triazol-1-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (320 mg), THF (4 mL) and ethanol (4 mL) was added 2N aqueous sodium hydroxide solution (0.98 mL), and the mixture was stirred at room temperature 3 hr. The reaction mixture was acidified with 1N hydrochloric acid, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from THF/hexane to give the title compound (270 mg).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][NH:12][CH2:13][CH2:14][NH:15][CH3:16].[O-]S([O-])(=O)=O.[Mg+2]>C(O)C>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]1[N:15]([CH3:16])[CH2:14][CH2:13][N:12]1[CH3:11]
Reactant: CNCCNC
Reactant: COc1ccccc1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: COc1ccccc1C1N(C)CCN1C
Reaction time: 0.33 h
Yield: 88 %

Procedure:
A solution of o-anisaldehyde (9.0 g, 66 mmol) and N,N′-dimethylethylenediamine (7.9 mL, 73 mmol) in ethanol (180 mL) was stirred at r.t. for overnight. MgSO4 (30 g) was added and the mixture was stirred for 20 min. The reaction mixture was filtered and washed with ether. The solvent was removed in vacuo to afford 2-(2-methoxyphenyl)-1,3-dimethylimidazolidine as a light yellow solid, 12 g, yield 88%. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 2.21 (s, 6H) 2.57-2.72 (m, 2H) 3.34 (d, J=2.75 Hz, 2H) 3.82 (s, 3H) 4.13 (s, 1H) 6.88 (d, J=8.24 Hz, 1H) 7.00 (t, J=7.48 Hz, 1H) 7.25-7.30 (m, 1H) 7.67 (d, J=7.63 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[S:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14].O.[OH-].[Li+]>C1COCC1.CO.O>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([S:11][C:12](=[O:16])[N:13]([CH3:14])[CH3:15])[CH:6]=1
Reactant: COC(=O)c1ccc(Br)cc1SC(=O)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)C(=O)Sc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.5 %

Procedure:
A mixture of 4-bromo-2-dimethylcarbamoylsulfanyl-benzoic acid methyl ester (2.04 g, 6.42 mmol) and lithium hydroxide hydrate (404 mg, 9.62 mmol) in (1/1/1) THF/MeOH/H2O (21 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated to remove most organic solvents. The residue was diluted with water (100 mL) and extracted with EtOAc (20 mL), which is discarded. The aqueous layer was acidified to pH 3-4 using 1 N HCl and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to provide 4-bromo-2-dimethylcarbamoylsulfanyl-benzoic acid (1.67 g). 1H NMR (200 MHz, CDCl3): δ ppm)=7.76 (m, 2H), 7.61 (dd, J=8.2, 2.0 Hz, 1H), 3.15 (br s, 3H), 3.06 (br s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:22])[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[C:9]([CH:19]([CH3:21])[CH3:20])[S:8][C:6]=2[N:7]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[N:26]=[CH:25]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:23][N:24]1[CH:28]=[C:27]([S:29]([NH:22][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]3[S:8][C:9]([CH:19]([CH3:20])[CH3:21])=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=4)[C:5]=23)(=[O:31])=[O:30])[N:26]=[CH:25]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(N)c23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2c(C(C)C)sc3nc(C)cc(NS(=O)(=O)c4cn(C)cn4)c23)c1

Procedure:
Following general method outlined in Example 1, starting from 6-methyl-2-(1-methylethyl)-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (60 mg, 0.192 mmol) (Description 21) and 1-methyl-1H-imidazole-4-sulfonyl chloride (69.4 mg, 0.384 mmol), the title compound (37 mg) was isolated as a TFA salt. LCMS (B) m/z: 457 [M+1]+, Rt 2.85 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([CH:19]1[NH:23][C:22](=[O:24])[CH:21]([CH3:25])[NH:20]1)([CH3:18])[CH3:17]>ClCCl.CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:20]1[CH:21]([CH3:25])[C:22](=[O:24])[NH:23][CH:19]1[CH:16]([CH3:18])[CH3:17])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC1NC(C(C)C)NC1=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)C1NC(=O)C(C)N1C(=O)CNC(=O)OCc1ccccc1

Procedure:
The same procedure of the example 2, starting from N-benzyloxycarbonylglycine and 2-isopropyl-5-methyl-4-imidazolidinone afforded 1-(2-benzyloxycarbonylaminoacetyl)-2-isopropyl-5-methyl-4-imidazolidinone as a diastereoisomeric mixture Rf=0.52 and 0.57 (dichloromethane/methanol 9:1, silica gel plates) then the oily title compound as a diastereoisomeric mixture, Rf=0.24 and 0.27 (dichloromethane/methanol 7:3, silica gel plates). Mass spectrum (E.I., 70 e V, 1.5 mA), m/z=156 (M.+ --C3H7).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>O1CCOCC1.O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:8]([CH3:11])=[CH:9][CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: COC(=O)c1ccc(C)c(-c2ccc(C#N)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4′-cyano-6-methyl-biphenyl-3-carboxylic acid methyl ester 2 (2.56 g, 10.3 mmol) in 1,4-dioxane-H2O (1:1 mixture, 20 ml) is added NaOH (1.22 g, 30.2 mmol)). The reaction is stirred at ambient temperature for 24 hours. To this mixture is added aqueous HCl (1 N, 36 ml) and it is then extracted with ethyl acetate (40 ml×3). The organic layers are combined, dried over anhydrous Na2SO4. The solver is removed. The solid obtained is washed with small amount of acetonitrile and air dried to give 4′-cyano-6-methyl-biphenyl-3-carboxylic acid 3: 1H NMR (DMSO-d6) δ 7.94 (d, 2H, J=8.0 Hz), 7.84 (dd, 1H, J1=8.4 Hz, J2=1.2 Hz), 7.75 (d, 1H, J=1.2 Hz), 7.61 (d, 2H, J=8.0 Hz), 7.48 (d, 1H, J=8.4 Hz), 2.29 (s, 3H); LC-MS m/z 238.1 (M+1).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH2:23][CH2:24][CH3:25]>>[C:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:17]([NH:20][C@H:21]([CH2:26][OH:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])[CH2:13][CH:14]([CH3:15])[CH3:16])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCC[C@H](N)CO
Product: CCCC[C@@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Yield: 58 %

Procedure:
N-[(phenylmethoxy)carbonyl]-L-leucine was used instead of 1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid, and L-norleucinol was used instead of L-valinol in the process according to Reference Example 178 to obtain 421 mg (58%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19].CCN(C(C)C)C(C)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC#N.O>[CH2:12]([N:4]1[C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[CH2:11][CH:2]([NH:1][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[C:3]1=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1Cc2cnccc2N(Cc2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cnccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a suspension of 1G (140 mg, 0.55 mmol) in CH3CN (4 mL) at RT was added DIPEA (153 μL, 0.88 mmol), followed by benzenesulfonyl chloride (84 μL, 0.66 mmol). After addition, the reaction was stirred at RT for 30 min. The reaction was diluted with H2O and extracted with EtOAc (20 mL×3). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel (12 g) column chromatography eluting with a gradient of EtOAc (20-100%) in hexane to give the title compound as a white solid (182 mg, 84%). LC/MS (method A): retention time=2.10 min, (M+H)+=394. 1H-NMR (DMSO6, 400 MHz): δ 8.25-8.36 (m, 3H), 7.85-7.90 (m, 2H), 7.52-7.70 (m, 3H), 7.15-7.30 (m, 5H), 6.93 (d, J=4 Hz, 1H), 5.04 (dd, J1=28.6 Hz, J2=16.3 Hz 2H), 4.35-4.46 (m, 1H), 2.90-3.15 (m, 2H).
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.[OH:12][C@@H:13]([C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[C:20]([F:23])[C:21]=1[F:22])[CH2:14][OH:15]>N1C=CC=CC=1>[F:23][C:20]1[CH:19]=[C:18]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:17]=[C:16]([C@H:13]([OH:12])[CH2:14][O:15][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:21]=1[F:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CO)c1
Solvent: c1ccncc1
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Temperature: -15 °C
Reaction time: 4.5 h
Yield: 81 %

Procedure:
p-Toluenesulfonyl chloride (12.4 g, 64.8 mmol) in pyridine (35 mL) was added dropwise over 7 min to a cooled (−10 to −20° C.) solution of ethyl 3-{3-[(1S)-1,2-dihydroxyethyl]-4,5-difluorophenyl}propanoate (17.7 g, 64.8 mmol) in pyridine (70 mL) under N2. The reaction was stirred at −10 to −20° C. for ˜4.5 h. The reaction was quenched with ice H2O and stirred overnight. The reaction mixture was diluted with H2O and extracted three times with ethyl ether. The combined organic layers were washed with 1N HCl, aq. CuSO4, and brine. The organic layer was dried over MgSO4, filtered, and concentrated. Purification by column chromatography (0-80% ethyl acetate:hexane) afforded the desired product (22.5 g, 81%) along with some recovered starting material (2.13 g).
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[C:9]([C:17]1[CH:43]=[CH:42][C:20]([O:21][CH2:22][CH:23]([OH:41])[CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:28]([OH:40])[CH:27]=2)=[CH:19][C:18]=1[OH:44])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:45](O)(=[O:48])[CH:46]=[CH2:47]>C1(C)C=CC=CC=1.C1(C=CC(O)=CC=1)O.COC1C=CC(O)=CC=1>[C:45]([O:41][CH:23]([CH2:22][O:21][C:20]1[CH:42]=[CH:43][C:17]([C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:18]([OH:44])[CH:19]=1)[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[O:39])[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:28]([OH:40])[CH:27]=1)(=[O:48])[CH:46]=[CH2:47]
Reactant: O=C(c1ccccc1)c1ccc(OCC(O)COc2ccc(C(=O)c3ccccc3)c(O)c2)cc1O
Reactant: C=CC(=O)O
Agent: COc1ccc(O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OC(COc1ccc(C(=O)c2ccccc2)c(O)c1)COc1ccc(C(=O)c2ccccc2)c(O)c1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
3 g of trifluoromethanesulfonic acid, 0.1 g of hydroquinone and 0.1 g of hydroquinone monomethyl ether were added to a solution of 48.5 g (0.1 mole) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-2-propanol and 43.6 g (0.6 mole) of acrylic acid in 600 ml of toluene, and the solution was heated for 3 hours at a temperature of 105° to 110° C. After cooling to room temperature, the reaction mixture was washed with 1.5 liters of water. The toluene was then distilled off from the reaction mixture under a pressure of 20 mbar. The oily residue remaining was dissolved in hot ethanol. Cooling this solution to room temperature gave 40 g (75 percent of theory) of 1,3-bis-(4-benzoyl-3-hydroxyphenoxy)-prop-2-yl acrylate in the form of colorless crystals having a melting point of 98° to 100° C. and a purity of 99 percent (HPLC). The UV spectrum gave two absorption maxima at wave lengths of 287 nm (extinction 0.520; extinction coefficient 28,100) and 324 nm (extinction 0.335; extinction coefficient 18,100).
Reaction SMILES: O=[C:2]1CCCC[N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:25]I.C(O)(=O)[CH2:28][C:29]([CH2:34][C:35](O)=O)([C:31]([OH:33])=O)O>C1COCC1.CCOCC>[CH3:25][C:29]1([CH3:28])[CH2:34][CH2:35][CH2:2][N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:31]1=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: CI
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(C)(C)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To the title compound of Step (A) (1.08 g, 5.42 mmol) in 10.8 ml THF at -78° C., lithium bis(trimethylsilyl)amide (1M in THF, 13.6 ml, 13.6 mmol) was added dropwise in 10 min. The mixture was stirred at -78° C. for 30 minutes and methyl iodide (4.62 g, 32.52 mmol) was added. The reaction mixture was slowly warmed to room temperature and stirred at room temperature for two days. To the reaction mixture, 30 ml Et2O and 15 ml 5% aqueous citric acid were added. The organic liquid was separated and washed with 10 ml 5% citric acid, H2O, brine and dried and concentrated. The residue was chromatographed on silica gel using 19:1 hexane/EtOAc to give the title compound of this step (440 mg, 38%) as a light yellow oil.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH:12]1[CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C.[N+]([NH:29][C:30](N)=[O:31])([O-])=O>CC(C)=O.O>[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH:12]1[CH2:15][N:14]([C:30]([NH2:29])=[O:31])[CH2:13]1
Reactant: Fc1cccc(OC2CNC2)c1
Reactant: NC(=O)N[N+](=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: NC(=O)N1CC(Oc2cccc(F)c2)C1
Reaction time: 1 h
Yield: 43.6 %

Procedure:
A stirred slurry of 3 g (0.012 mole) of 3-(3-fluorophenoxy)azetidine oxalate [1:1] in 20 ml of acetone was treated with 3 ml of triethylamine and stirred for 1 hr. The resulting solution was treated with 2.5 g (0.024 mole) of nitrourea and 2 ml of water then stirred for 16 hr. The reaction mixture was diluted with water and the product crystallized. Recrystallization from methanol-water yielded 1.1 g (43.6%) of a white crystalline solid, m.p. 169°-170° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]1[CH2:4][CH2:5][OH:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:6][CH2:5][CH2:4][CH:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1([CH3:11])[CH3:1])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)C=CC=CC1CCO
Solvent: c1ccncc1
Product: CC(=O)OCCC1C=CC=CC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 2,2-dimethylphenethyl alcohol (118.0 g, 0.786 mol) in pyridine (700 mL). Add, by dropwise addition, acetic anhydride (222 mL, 240.7 g, 2.358 mol) and stir overnight at room temperature. Evaporate the solvent in vacuo and purify by distillation to give the title compound as a clear colorless oil; bp 75° C.@0.4 mmHg.
Reaction SMILES: Cl.[C:2]1([C:8]2[N:13]=[N:12][C:11]([CH2:14][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:24]=1>C(Cl)Cl>[C:2]1([C:8]2[N:13]=[N:12][C:11]([CH2:14][NH:15][S:29]([C:25]3[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])=[CH:10][CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCc1ccc(-c2ccccc2)nn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCc1ccc(-c2ccccc2)nn1)c1cccnc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
To a solution of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride (121 mg) (containing 0.458 mmol of a pure content) obtained in Reference Example 2-(c) in methylene chloride (1 ml) were added triethylamine (0.26 ml, 1.8 mmol) and 3-pyridylsulfonyl chloride (see The Journal of Organic Chemistry, 54, 389 (1989)) (83.2 mg, 0.468 mmol), followed by stirring at room temperature for 17 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; ethyl acetate:acetonitrile=1:0→0:1 (V/V), then chloroform), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (130 mg) as a slightly brown solid. (Yield: 87%)