Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][CH:11]([C:17](=[O:23])[NH:18][CH2:19][CH2:20][CH:21]=O)[CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C@@H:26]([C@H:34]([C@@H:36]1[C@@H:40]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:39]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C@H:38]([N:57]2[CH:62]=[CH:61][C:60](=[O:63])[N:59]([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=3)[C:58]2=[O:73])[O:37]1)[OH:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C(O)(=O)C>[Si:42]([O:41][C@H:40]1[C@@H:39]([O:49][Si:50]([C:53]([CH3:55])([CH3:56])[CH3:54])([CH3:51])[CH3:52])[C@H:38]([N:57]2[CH:62]=[CH:61][C:60](=[O:63])[N:59]([CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH3:72])=[CH:67][CH:66]=3)[C:58]2=[O:73])[O:37][CH:36]1[C@H:34]([OH:35])[C@@H:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:25][CH2:21][CH2:20][CH2:19][NH:18][C:17](=[O:23])[C@H:11]([C@@H:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[NH:10][C:9](=[O:24])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43]
Reactant: CC(C)C(O)C(NC(=O)OCc1ccccc1)C(=O)NCCC=O
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@@H](O)C(C)C)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reaction time: 2.5 h
Yield: 59.5 %

Procedure:
A solution of [2-hydroxy-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (175 mg, 0.519 mmol, obtained from Reference Example 14) and tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (300 mg, 0.416 mmol, obtained from Reference Example 6) in anhydrous tetrahydrofuran was stirred at room temperature under a nitrogen atmosphere for 15 minutes. Acetic acid (3 drops) and sodium triacetoxyborohydride (176 mg, 0.831 mmol) were added and the resulting solution was stirred under nitrogen for an additional 2.5 hours. The reaction mixture was basified to pH 9 with aqueous sodium carbonate solution, and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (flash column, silica gel, 2.5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(1S)-1-hydroxy-2-methylpropyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (258 mg, 60%) as a white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH2:8][Br:9])[CH:7]=1.[Br:12]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1.O>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[C:6]([CH:8]([Br:12])[Br:9])[CH:7]=1
Reactant: COc1ncc(CBr)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: O
Product: COc1ncc(C(Br)Br)cc1Br
Temperature: 80 °C
Reaction time: 4 h

Procedure:
3-Bromo-5-bromomethyl-2-methoxy-pyridine (6.03 g, 21.5 mmol), N-bromosuccinimide (4.09 g, 23.0 mmol), and azobisisobutyronitrile (one scoop) were combined in benzene (40 mL) and stirred at 80° C. for 4 hours. After cooling, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give 3-Bromo-5-dibromomethyl-2-methoxy-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[CH:7]=1.[NH2:41][C@@H:42]([C:45]([OH:47])=[O:46])[CH2:43][OH:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:37])([CH3:38])[CH2:9][C:10]([OH:36])([C:32]([F:34])([F:35])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:26]([NH:41][C@@H:42]([C:45]([OH:47])=[O:46])[CH2:43][OH:44])=[O:27])[CH:29]=[CH:30][CH:31]=2)[CH:7]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@H](CO)C(=O)O)c1)C(F)(F)F

Procedure:
Prepared similarly to Intermediate 4 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and D-serine.
Reaction SMILES: [CH:1]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1([CH3:22])[NH:20][C:19](=O)[CH2:18][CH2:17]1.P(Cl)(Cl)(Cl)=O>>[CH3:15][C:16]1([CH3:22])[N:20]=[C:19]([N:13]2[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[O:6][C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:18][CH2:17]1
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1(C)CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)CCC(N2c3ccccc3Oc3ccccc32)=N1

Procedure:
Reaction of phenoxazine, 5,5-dimethyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)-PHENOXAZINE, m.p. 148°-150°C. Conversion of the free base to the hydrochloride salt affords 10-(5,5-DIMETHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 239°-242.5°C. (corr.), in a 48% overall yield.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][C:9](=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1N=C(c2ccccc2)C(c2ccccc2)=N1
Reactant: CCOC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)[nH]c1=O

Procedure:
4,5-Diphenylimidazol-2-one was treated with ethyl 8-bromooctanoate and potassium carbonate in butanone to give after work-up the title compound, m.p. 78°-79° C., Found:C, 73.7;H, 7.4;N, 6.7%;C25H30N2O3 requires: C, 73.9;H, 7.4;N, 6.9%
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[NH:22])[CH:13]=2)[NH:8][C:7]1=[O:24])C.[OH-].[Na+].FC(F)(F)C(O)=O>C(O)C>[NH:20]([CH2:19][CH2:18][CH2:17][O:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:24])[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[CH2:15]2)[C:21]([NH2:23])=[NH:22]
Reactant: CCOC(=O)CC1Cc2cc(OCCCNC(=N)N)ccc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)NCCCOc1ccc2c(c1)CC(CC(=O)O)C(=O)N2
Temperature: 25 °C
Yield: 74.1 %

Procedure:
A solution of [6-(3-Guanidino-propoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid ethyl ester (0.76 g, 1.6 mmol) in ethanol (7 mL) was treated with 0.5 N aqueous NaOH and heated at reflux for 3 h. The resulting precipitate was cooled to room temperature, treated with trifluoroacetic acid (1.5 mL) and the solution thus formed concentrated in vacuo to yield a clear, colorless oil. Purification by reverse phase HPLC gave the title compound (0.38 g, 55% yield) as a fluffy white solid.
Reaction SMILES: [CH2:1]1[N:6]([C:7]2[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][O:3][CH2:2]1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.[H-].[Na+]>CN(C)C=O>[N:6]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[O:13][C:15]2[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH:20]=2)[CH2:1][CH2:2][O:3][CH2:4][CH2:5]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCOCC2)ccc1[N+](=O)[O-]
Yield: 83.6 %

Procedure:
By using 0.72 g of 2-(4-morpholino)phenol, 1.15 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.17 g of sodium hydride (55% by weight) and 10 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 1.44 g of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[CH3:29][NH:30][O:31][CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:32][O:31][N:30]([CH3:29])[C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (CAS 102185-35-3, 500 mg, 2.16 mmol) in DCM (5 mL) was added EDCI (CAS 25952-53-8, 497 mg, 2.59 mmol) and stirred for 10 min at rt. A solution of N,O-dimethylhydroxylamine hydrochloride (CAS 6638-79-5, 253 mg, 2.59 mmol) and DIPEA (0.429 mL, 2.59 mmol) in DCM (5 mL) was added and the reaction mixture was left to stir at rt over a weekend. The mixture was diluted with DCM (30 mL) and extracted with saturated aq NaHCO3 (50 mL). The organic phase was washed with water before being dried over MgSO4 and filtered. The solvent was removed in vacuo to give tert-butyl 1-(methoxy(methyl)amino)-3,3-dimethyl-1-oxobutan-2-ylcarbamate (466 mg, 79%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@:4]([C:7]1[C:12]([F:13])=[C:11]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:10]=[C:9]([Br:21])[N:8]=1)([OH:6])[CH3:5].C([O-])(O)=O.[Na+].[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>C1COCC1.O>[Br:21][C:9]1[N:8]=[C:7]([C@@:4]([OH:6])([CH3:5])[CH2:3][NH:2][S:36]([C:33]2[CH:32]=[CH:31][C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=2)(=[O:37])=[O:38])[C:12]([F:13])=[C:11]([Si:14]([CH2:17][CH3:18])([CH2:19][CH3:20])[CH2:15][CH3:16])[CH:10]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@](C)(O)CN)c1F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc([C@](C)(O)CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1F
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of crude (R)-1-amino-2-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-propan-2-ol hydrochloride (43.5 g, 109 mmol) in 335 ml THF was added a solution of NaHCO3 (21.02 g, 250 mmol) in 500 ml water. The mixture was cooled to 0-5° C. and a solution of 4-nitrobenzenesulfonyl chloride (26.5 g, 120 mmol) in 100 ml THF was added in a dropwise. The resulting emulsion was stirred overnight while allowing the temperature to reach rt. The mixture was extracted with TBME. The organic layer was dried with MgSO4.H2O, filtered and evaporated to give an orange resin which was purified on a silica gel column by eluting with Hexanes/10-20% EtOAc to yield 37.56 g of the title compound as a yellow resin. TLC (Hex/EtOAc 3/1) Rf=0.34; HPLC: RtH11=1.678 min; ESIMS: 548, 550 [(M+H)+, 1Br]; 1H-NMR (400 MHz, DMSO-d6): 8.40 (d, 2H), 8.06 (t, 1H), 7.97 (d, 2H), 7.45 (d, 1H), 5.42 (s, 1H), 3.23 (d, 2H), 1.44 (s, 3H) 0.97-0.81 (m, 15H); Chiral HPLC (Chiralpak AD-H 1213, UV 210 nm): 90% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccc(F)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-fluorophenol: ESMS m/e: 509.1 (M+H)+.
Reaction SMILES: Br[CH:2]([C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([F:23])=[CH:15][CH:14]=1)=[O:12])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C([O-])=[O:25].[Na+].CO>C(OCC)(=O)C>[F:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([C:11](=[O:12])[CH:2]([OH:25])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C[O-]
Reactant: CCOC(=O)CCCC(Br)C(=O)c1ccc(F)c2ccccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCCC(O)C(=O)c1ccc(F)c2ccccc12

Procedure:
A mixture of ethyl 5-bromo-6-(4-fluoro-1-naphthyl)-6-oxohexanoate (34.3 g), sodium formate (34.0 g) and methanol (150 ml) was stirred with heating under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 6-(4-fluoro-1-naphthyl)-5-hydroxy-6-oxohexanoate was obtained as a yellow oil (19.0 g, 65%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2].[Cl-].CS(C)=O.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C=O)cc(C(=O)OCC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Treat a solution 5-hydroxymethyl-N-methyl-N-propyl-isophthalamic acid ethyl ester (5.79 g, 20.7 mmol) in dichloromethane (50 mL) at −78° C. with oxalyly chloride (1.99 mL, 22.8 mmol), DMSO (3.5 mL, 49.5 mmol), and triethylamine (8.6 mL, 62.1mmol). Stir at −78° C. for 30 min, warm to room temperature and stir for 1 h. Quench with ice and extract with dichloromethane (100 mL). Wash with saturated aqueous NaHCO3, saturated aqueous sodium chloride, dry (magnesium sulfate) concentrate and purify (silica gel chromatography, eluting with 40:60 to 50:50 ethyl acetate:hexanes) to give the title compound (4.53 g, 78%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:11][CH:10](O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.S(=O)(=O)(O)O.N>ClC1C=CC=CC=1.CCO>[CH2:1]([N:8]1[CH2:9][CH:10]2[O:16][CH:14]([CH2:13][N:12]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:18])=[O:19])[CH2:11]2)[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)N1CC(O)CN(Cc2ccccc2)CC(O)C1
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Clc1ccccc1
Solvent: CCO
Product: O=S(=O)(c1ccccc1)N1CC2CN(Cc3ccccc3)CC(C1)O2
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 9 %

Procedure:
The chlorobenzene solution from step (ii) above was treated at 50° C. with water (6 mL) and then concentrated sulfuric acid (60 mL) was added over 10 min. whilst maintaining the temperature at between 50 and 60° C. The mixture was then heated to 110° C. for 1 hour. The mixture was allowed to cool to 50° C. and EtOH (60 mL) was added in one portion, causing the internal temperature to rise to 67° C. The mixture was basified by the addition of aqueous ammonia (17.5%, 300 mL) with external cooling to keep the internal temperature between 60 and 70° C. Chlorobenzene (600 mL) was added and the mixture was stirred rapidly for 10 minutes. The mixture was allowed to settle and the layers were separated. The upper (chlorobenzene) layer was subjected to reduced pressure (50 mbar) distillation to remove 380 mL of solvent. The mixture was allowed to cool to 50° C. and 480 mL of ethanol was added. The mixture was cooled to 7° C. and the resulting solid was filtered and washed with ethanol (2×50 mL) before drying to constant weight under reduced pressure at 40° C. The product was obtained as an off white solid, 10.25 g (9.0% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13]O)[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12.N1C=CC=CC=1.S(Cl)([Cl:23])=O.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][CH2:13][Cl:23])[CH:6]=[C:7]2[O:11][CH2:10][O:9][C:8]=12
Reactant: COc1cc(CCO)cc2c1OCO2
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(CCCl)cc2c1OCO2
Temperature: 60 °C
Yield: 94.3 %

Procedure:
3.92 g (20 mmol) of 2-(3-methyoxy-4,5-methylenedioxyphenyl)ethyl alcohol (3) and 1.94 ml (24 mmol) of pyridine were dissolved in 40 ml of toluene, and to this mixture was added portionwise 1.74 ml (24 mmol) of thionyl chloride in 5 ml of toluene under cooling with water. The mixture was heated to 60° C. for 2 hours, then cooled and washed with 30 ml of water, 20 ml of water, 30 ml of a saturated sodium hydrocarbonate aqueous solution and 30 ml of a saturated saline solution successively in this order. This reaction mixture was then dried over anhydrous sodium sulfate and decolored by active carbon. The solvent was distilled off to obtain 4.05 g of 2-(3-methoxy-4,5-methylenedioxyphenyl)ethyl chloride (5) as a crystal with a yield of 94%, which was recrystallized from n-hexane. Melting point: 67°-68° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:32][C:33]([O:37][C:38]([F:41])([F:40])[F:39])=[C:34]([F:36])[F:35].C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:34]([F:36])([F:35])[CH:33]([F:32])[O:37][C:38]([F:41])([F:40])[F:39])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: FC(F)=C(F)OC(F)(F)F
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F

Procedure:
3.0 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 40 mL of dimethylformamide, 25 g of triethylamine was added, and stirring was carried out at 50° C. for 3 hours while trifluoromethyl trifluorovinyl ether was blown. To this solution, ethyl acetate was added, the solution was washed with a saturated aqueous solution of citric acid, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 1.71 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH2:14][NH2:15]>CCO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:14][NH2:15])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NN
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Solvent: CCO
Product: NNC(=O)c1ccc2[nH]ccc2c1
Yield: 77.4 %

Procedure:
To a solution of methyl 1H-indole-5-carboxylate (0.9 g, 5.142 mmol) in EtOH (10 mL) was added NH2NH2 (1.8 mL, 38.11 mmol). The reaction was heated at reflux for 12 h. The solvent was removed in vacuo to give a yellow solid, which was recrystallized with 60% EtOAc in n-hexane (10 mL) to afford 1H-indole-5-carbohydrazide (0.7 g, 3.98 mmol, 77.8%). MS (ESI, pos. ion) m/z: 176 (M+1).
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]1[O:28][C:19]([CH3:27])([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:18][CH2:17]1.[CH2:29](I)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>O1CCCC1.CS(C)=O>[CH3:27][C:19]1([CH2:20][CH:21]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[O:18][CH2:17][CH2:16][O:28]1
Reactant: CCCCCCCCCCCCCCCCCCI
Reactant: CCOC(=O)CCC1(C)OCCO1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCC(CC1(C)OCCO1)C(=O)OCC
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
To a solution of about 34.35 g of isopropylcyclohexylamine in about 150 ml of tetrahydrofuran at about -20° C. was added about 156.89 ml of an about 1.55M n-butyllithium, at a rate so that the final temperature reached about 10° C. The solution was then cooled to about -70° C. and about 25 g of ethyl levulinate ethylene ketal was added dropwise. After about 15 minutes, the solution was warmed to about -30° C. and maintained at that temperature while it was added rapidly, dropwise to a stirred solution of about 80.44 g of octadecyl iodide in about 150 ml of dimethyl sulfoxide and about 50 ml of tetrahydrofuran at room temperature. This mixture was stirred overnight, the volatile solvents were removed and water was added. The resulting solid was collected by filtration and extracted with ether giving a solution and a solid. This solution and original filtrate were combined and extracted with ether. This ether extract was dried and the solvent removed giving an oil. This oil was subjected to HPLC, eluting with hexane:ether (about 9:1). The product band was collected and the solvent removed, giving about 30.76 g of the desired title compound as a solid, mp 33°-34° C.