Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10](/[CH:13]=[C:14](/[C:17]([O:19]C)=[O:18])\[CH2:15][CH3:16])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[S:9][C:10](/[CH:13]=[C:14](\[CH2:15][CH3:16])/[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC/C(=C\c1ccc(C(=O)OC(C)(C)C)s1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
5-[(1E)-2-(methoxycarbonyl)-but-1-en-1-yl]thiophene-2-carboxylic acid tert-butyl ester (34.6 g, 120 mol) was dissolved in tetrahydrofuran (150 mL), and methanol (60 mL), 1 N lithium hydroxide solution (144 mL, 144 mmol) was added, and the mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure. 0.5 N-Hydrochloric acid solution and ethyl acetate were added to the obtained residue, the organic layer was extracted, and the aqueous layer was extracted three times with ethyl acetate. The organic layers were collected, washed with brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent of the filtrate was evaporated under reduced pressure to give the title compound (32.2 g, 114 mmol, 95%).
Reaction SMILES: [CH3:1][C@H:2]1[C:20](=[O:21])[O:19][C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:16](=[O:17])[O:15][C@H:14]([C@@H:26](/[CH:28]=[CH:29]/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][C@H:7]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([Cl:43])[CH:42]=2)[C:5](=[O:6])[NH:4][CH2:3]1.ClN1C(=[O:52])CCC1=O>COCCOC.O>[CH3:1][CH:2]1[C:20](=[O:21])[O:19][CH:18]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:16](=[O:17])[O:15][CH:14]([CH:26]([CH:28]2[O:52][CH:29]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:27])[CH2:13][CH:12]=[CH:11][C:9](=[O:10])[NH:8][CH:7]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:44][CH3:45])=[C:41]([Cl:43])[CH:42]=2)[C:5](=[O:6])[NH:4][CH2:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)/C=C/c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Agent: COc1ccc(CC2NC(=O)/C=C/CC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)/C=C/c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)[C@H](C)CNC2=O)cc1Cl
Solvent: COCCOC
Solvent: O
Product: COc1ccc(CC2NC(=O)C=CCC(C(C)C3OC3c3ccccc3)OC(=O)C(CC(C)C)OC(=O)C(C)CNC2=O)cc1Cl

Procedure:
Likewise, cryptophycin 3 (about 40 mg, 0.063 mmol) is put into 2:1 DME/H2O (about 6 mL) and N-chlorosuccinimide (0.075 mmol) is added and is heated at about 60-70 C for about 24 hours. A further quantity of NCS (8 mg) is added and continue heating for about another 24 hours. The solvent is removed and the residue subject to HPLC (35% H2O/CH3CN 6 mL/min) to give the desired cryptophycin compounds. The resulting mixture is further purified by HPLC using methanol/water (about 4:1) to obtain the desired purified cryptophycin compounds.
Reaction SMILES: C(S[CH2:6][C@@:7]1([CH3:14])[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])(C)(C)C.C(O)(=O)C.O.OO.ClCl.[S:24]([Cl:28])(Cl)(=[O:26])=[O:25].C1(C)C=CC=CC=1.CCCC(C)C>>[CH3:6][C@@:7]1([CH2:14][S:24]([Cl:28])(=[O:26])=[O:25])[C:8](=[O:13])[NH:9][C:10](=[O:12])[NH:11]1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)SC[C@@]1(C)NC(=O)NC1=O
Agent: ClCl
Agent: OO
Solvent: CCCC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Temperature: 35 °C
Yield: 87 %

Procedure:
(5S)-5-[(Tert-butylthio)methyl]-5-methylimidazolidine-2,4-dione (WO 03/106689) (1.00 eq, 56.9 mmol, 12.3 g) was charged to a 250 mL jacketed vessel followed by acetic acid (1.72 mol, 98.4 mL, 103 g) and water (683 mmol, 12.3 mL, 12.3 g). The resulting mixture was stirred at 300 rpm and heated to 35° C. to dissolve all solids. The mixture was cooled to 10° C. and a solution of hydrogen peroxide, 11.68M, 35% w/w in water (56.9 mmol, 4.87 mL, 5.53 g) was charged as one portion, resulting in an exotherm to 17° C. Analysis of the reaction mixture by hplc 48 min after the addition of peroxide revealed conversion to a diastereoisomeric mixture of sulfoxides along with 4.6 area % of starting material remaining. The mixture was cooled to 6° C., stirred at 400 rpm and chlorine gas (159 mmol, 3.57 L at STP, 2.80 eq) was added over 28 min (constant jacket temperature of 6° C.) until the reaction mixture turned green and a sharp decrease in temperature of the reaction mixture was noted. HPLC analysis of the mixture at this point revealed complete conversion of the sulfoxide intermediates to the required sulfonyl chloride. The mixture was heated to 15° C., discharged from the vessel and concentrated to about 30% of the original volume under reduced pressure. Toluene (577 mmol, 61.5 mL, 53.2 g) was then charged to give a 3 phase mixture, which was re-evaporated. Further toluene (798 mmol, 85.0 mL, 73.5 g) was added and the mixture re-evaporated. Iso-hexane (464 mmol, 61.5 mL, 40.0 g) was then added to the sticky residue to give a suspension that was collected by filtration, washed with iso-hexane (371 mmol, 49.2 mL, 32.0 g) and sucked dry on the filter. The damp product (16.27 g) was dried in a vacuum oven at 40° C. to give [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride as a white crystalline solid (0.868 eq, 49.4 mmol, 11.2 g) in 87% yield.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[Na+].[Cl-].[OH:28][NH3+:29]>C(O)C.O>[OH:28][N:29]=[C:1]([C:4]1[O:8][C:7]([N:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:5]=1)[CH3:2]
Reactant: [NH3+]O
Reactant: CCOC(=O)CN(CC(=O)OCC)c1ncc(C(C)=O)o1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CN(CC(=O)OCC)c1ncc(C(C)=NO)o1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
To a solution of diethyl 2,2′-((5-acetyloxazol-2-yl)azanediyl)diacetate (300 mg, 1.01 mmoles) in ethanol (6 mL), a solution of sodium acetate (165 mg, 2.01 mmoles) and hydroxylammonium chloride (139 mg gm, 2.01 mmoles) in water (2 ml) was added and the reaction mixture was refluxed for 1 h. The reaction mixture was cooled to room temperature and solvent was evapourated in vacuum. The residue was diluted with ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 252 mg (80%) of title product as thick liquid.
Reaction SMILES: C([C@H:4]1[CH2:7][C@H:6]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][C:17]=3[F:30])=[C:11]([CH2:31][CH2:32][CH3:33])[N:10]3[N:34]=[C:35]([CH3:37])[N:36]=[C:9]23)[CH2:5]1)(=O)C.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:43].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:30][C:17]1[CH:18]=[C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:21][C:16]=1[CH2:15][C:12]1[C:13](=[O:14])[N:8]([C@H:6]2[CH2:5][C@H:4]([OH:43])[CH2:7]2)[C:9]2[N:10]([N:34]=[C:35]([CH3:37])[N:36]=2)[C:11]=1[CH2:31][CH2:32][CH3:33]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](C(C)=O)C2)c2nc(C)nn12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: ClC(Cl)Cl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@H](O)C2)c2nc(C)nn12
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a mixture of 4′-{[4-(trans-3-acetylcyclobutyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (1.38 g), 30% aqueous hydrogen peroxide solution (13.85 mL) and chloroform (20 mL) was added trifluoroacetic acid anhydride (7.66 mL), and the mixture was stirred at 60° C. for 15 hr. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (3 mL)-methanol (3 mL) was added 2 N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was acidified with 1 N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel chromatography [eluent: hexane/ethyl acetate=60/40→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (0.90 g, 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH2:13]([OH:16])[CH2:14][CH3:15].CCN(CC)CC.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C1COCC1.O>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:12])[O:16][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCO
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCOC(=O)Nc1cccc(N)c1

Procedure:
Following the procedure described in part E of Example 1 (R), (S)-α-[[2-[((1,1-dimethylethyl)dimethylsilyl)oxy]-2-[4-hydroxy-3-[(methylsulfonyl)amino]phenyl]ethyl]amino]-4-methoxybenzeneacetic acid was condensed with 3-aminophenylcarbamic acid, propyl ester to generate the title compound. The 3-aminophenylcarbamic acid, propyl ester was prepared by sequentially treating commercial 3-nitrophenyl isocyanate with PrOH containing Et3N at 80° C. for 12 hours followed by reduction with Na2S2O4 in THF/H2O at 100° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[N:35][CH:36]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[N:35][CH:34]=[N:33][CH:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cncnc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M96) (0.42 g, 0.80 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (230 mg, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2O.P(Br)(Br)[Br:15].O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:15][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]2
Reactant: COc1ccc2nccc(O)c2n1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nccc(Br)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
6-(Methyloxy)-1,5-naphthyridin-4-ol (21.5 g) (for a synthesis see WO2007016610 Preparation 2 (a)) was stirred in DMF (150 ml) at 0° C. under N2, and phosphorous tribromide (13.5 ml) was added slowly. The mixture was allowed to warm to room temperature and stirred for 90 minutes. H2O (375 ml) was added and the pH was adjusted to pH 7 by addition of solid Na2CO3. The solid was isolated by filtration with suction, dried on the sinter with suction for 2 h then dried under vacuum at 45° C. to give the desired compound (26.0 g, 90%). 1H-NMR (δ, ppm, DMSO-d6): 8.59 (d, 1H), 8.30 (d, 1H), 8.08 (d, 1H), 7.33 (d, 1H), 4.06 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([OH:13])=O)[CH:3]=1.S(Cl)(Cl)=O.N1C=CC=CC=1.[F:24][C:25]([F:34])([F:33])[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[CH:27]=1>ClCCl.CO.C1COCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([NH:32][C:28]2[CH:27]=[C:26]([C:25]([F:33])([F:24])[F:34])[CH:31]=[CH:30][N:29]=2)=[O:13])[CH:3]=1
Reactant: Nc1cc(C(=O)O)ncc1[N+](=O)[O-]
Reactant: Nc1cc(C(F)(F)F)ccn1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nc1cc(C(=O)Nc2cc(C(F)(F)F)ccn2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 4-amino-5-nitropicolinic acid (180 mg, 1.0 mmol) in 10 mL dichloromethane with 280 μL thionyl chloride was refluxed for 1 h, cooled to ambient temperature and concentrated to dryness i. vac. The residue was mixed with 10 mL THF and 10 mL dichloromethane and pyridine (100 μL, 1.3 mmol), and 4-trifluoromethyl-pyridin-2-amine (160 mg, 1.0 mmol) was added to the mixture. After stirring for 45 min the mixture was disturbed with methanol and concentrated i.vac. The residue was purified by chromatography on HPLC (C18 StableBond, eluent: H2O+0.15% HCOOH+10-100% acetonitrile)
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:24]([F:27])([F:26])[F:25])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[C:4]([C:24]([F:25])([F:27])[F:26])=[N:5][N:6]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(C=O)c2-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CO)c2-c2ccccc2)cc1
Reaction time: 2.5 h
Yield: 22.1 %

Procedure:
To a solution of the aldehyde prepared in Step 2 (165 mg, 0.41 mmol) in methanol (3.5 mL) at 0° C. was added sodium borohydride (16 mg, 0.41 mmol). The reaction solution was kept at 0° C. for 2.5 hours. The reaction was quenched with the addition of an aqueous 1M KHSO4 solution (3 mL). The mixture was extracted with dichloromethane and the organic solution dried and concentrated. The residue was chromatographed on silica (1:1 hexane:ethyl acetate) to give the desired product (36 mg, 46%) mp. 179-180° C.; 1H NMR d 7.91 (m, 2H), 7.53-7.40 (m, 5H), 6.75 (s, 2H), 4.53 (d, 2h, J=5.0 Hz), 4.30 (t, 1H, J=5.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[N+:26]([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[NH2:26]
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1[N+](=O)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1N
Temperature: 90 °C
Yield: 91.1 %

Procedure:
To a stirred solution of 500 mg (1.33 mmol) (4-methoxy-3-nitro-phenyl)-bis-(4-methyl-benzyl)-amine in 20 ml ethanol at room temperature were added 1.91 g (29.2 mmol) zinc powder and 147 mg (1.33 mmol) calcium chloride and the mixture was then heated at 90° C. for 16 hours. The mixture was then filtered and the filtrate diluted with ethyl acetate and washed with 0.5 N sodium hydroxide solution and then with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford 420 mg (91%) 4-methoxy-N1,N1-bis-(4-methyl-benzyl)-benzene-1,3-diamine as a dark brown oil. ES-MS m/e (%): 347 (M+H+, 100).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[C:18]1([CH2:24][CH:25]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C.N1CCCCC1.C(COC)OC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:13][C:12]1=[S:17]
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Reactant: O=CCc1ccccc1
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: C1CCNCC1
Product: O=C1C(=CCc2ccccc2)SC(=S)N1N=c1sc2ccccc2s1

Procedure:
A slurry of 2.98g of 3-[(1,3-benzodithiol-2-ylidene)amino] -2-thioxo-4-thiazolidinone (see example 37), phenylacetaldehyde (10 ml, excess) and acetic acid/piperidine (10 drops) in 600 ml of anhydrous glyme is heated at reflux for 4 days. The reaction mixture is filtered while hot, and the solid is collected and recrystallized from dimethylformamide to yield 1.78 g of the title compound, melting point 233°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:41]1(O)[CH2:45]C[CH2:43][CH2:42]1>O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH:16]2[CH2:43][CH2:42][CH2:41][CH2:45]2)=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: OC1CCCC1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccnc3OCC(=O)OC3CCCC3)c(Cl)cc2F)c1=O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.30 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6), 0.06 g of sodium carbonate, and 3.0 ml of cyclopentanol was stirred at 100° C. for 1.5 hours and then at 120° C. for 2 hours. The reaction mixture was cooled to room temperature and then poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of cyclopentyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-28).
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C:15]([C:35]#[N:36])([CH2:21][C:22]([O:24][CH:25]1[CH:30]([CH:31]([CH3:33])[CH3:32])[CH2:29][CH2:28][CH:27]([CH3:34])[CH2:26]1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].OO>O.CC(C)=O>[C:7]([O:11][C:12]([NH:14][C:15]([C:35](=[O:2])[NH2:36])([CH2:21][C:22]([O:24][CH:25]1[CH:30]([CH:31]([CH3:32])[CH3:33])[CH2:29][CH2:28][CH:27]([CH3:34])[CH2:26]1)=[O:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:13])([CH3:8])([CH3:10])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C#N)(CC(=O)OC1CC(C)CCC1C(C)C)NC(=O)OC(C)(C)C
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(CC(=O)OC1CC(C)CCC1C(C)C)(NC(=O)OC(C)(C)C)C(N)=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
Potassium carbonate (586 mg, 4.24 mmol), water (2.5 ml), ethyl 2-(tert-butoxycarbonylamino)-2-cyano-3-[(−)-menthyloxycarbonyl]propionate (1.00 g, 2.46 mmol) and acetone (5 ml) were mixed and 30% aqueous hydrogen peroxide solution (0.8 ml) was added dropwise under cooling with water. Then the mixture was heated at 10-30° C. of inner temperature and stirred for about 4 hours. The precipitated crystals were filtered and washed with sprayed water. It was dried in airflow at 60° C. overnight to give ethyl 2-(tert-butoxycarbonylamino)-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (802 mg, yield 73.3%). Optical purity was 10.7% d.e.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11](Cl)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH2:31])[CH:20]=1>C(N(CC)CC)C>[Cl:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]([NH:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[C:10]([CH3:17])=[C:9]([CH3:18])[N:8]=1
Reactant: NCCOCCCc1cccnc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCCc2cccnc2)c1C
Temperature: 45 °C

Procedure:
Anhydrous N,N-dimethylformamide (200 ml), anhydrous triethylamine (12.1 ml), and 2,4-dichloro-5,6-dimethyl-3-nitropyridine (16.05 g) were combined and 2-(3-pyridin-3-ylpropoxy)ethylamine (14.4 g) was then added with stirring. The pale yellow reaction mixture was heated to 45° C. under a nitrogen atmosphere for 1 hour. HPLC analysis indicated that the reaction was sufficiently complete to proceed. The reaction mixture was allowed to cool and the solvent was removed under reduced pressure. The resulting oil was dissolved in ethyl acetate and washed twice: once with a saturated aqueous solution of ammonium chloride and once with water. The organic layer was then extracted 3 times with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The product was passed through a silica gel column using 90/10 ethyl acetate/hexane as the eluant. The resulting oil was dried under vacuum at 60° C. for 2 hours. NMR analysis indicated sufficient purity for use of the product in the next step.
Reaction SMILES: [K].[CH3:2][CH:3]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][S:6]1(=[O:17])=[O:16])[CH3:4].[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>C(#N)C>[CH3:4][CH:3]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([C:20](=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18])[S:6]1(=[O:17])=[O:16])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Agent: [K]
Solvent: CC#N
Product: CC(C)N1C(=O)c2ccccc2N(C(=O)C(C)(C)C)S1(=O)=O

Procedure:
To 100 ml of acetonitrile was added 11.6 g of the potassium salt of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide. To the resultant stirred mixture was added dropwise 5.4 ml of trimethylacetyl chloride in 50 ml of acetonitrile over a 0.5 hour period. The resultant mixture was heated at 38°-40° C. for 22 hours, cooled, filtered and the solvent removed from the filtrate in vacuo. The residue was dissolved in 100 ml of ether and extracted with 100 ml of 5% potassium carbonate. The ether layer was washed once with 100 ml of water, dried with magnesium sulfate and filtered. The solvent was removed from the filtrate in vacuo and the solid residue, 8.3 g, extracted with 3-10 ml-portions of methanol. The resultant precipitate was air dried to afford 4.5 g of 3-(1-methylethyl)-1-(2,2-dimethyl-1-oxopropyl)-1H- -2,1,3-benzothiadiazin-4 (3H)-one-2,2-dioxide, m.p. 97.5°-99.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br[CH2:25][C:26]([C:28]1[CH:32]=[C:31]([CH3:33])[O:30][N:29]=1)=[O:27]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:25]=1[C:26]([C:28]1[CH:32]=[C:31]([CH3:33])[O:30][N:29]=1)=[O:27]
Reactant: Cc1cc(C(=O)CBr)no1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2cc(C)on2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 3-bromoacetyl-5-methylisoxazole (M. D. Amici et al., J. Org. Chem., 1989, 54, 2646).