Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])OCC([O-])=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][CH:13]=1)[N:18]=[C:14]([C:2]([F:1])([F:8])[F:9])[CH:13]=[C:12]2[OH:11]
Reactant: O=C([O-])COC(F)(F)F
Reactant: COc1ccc(N)cc1
Product: COc1ccc2nc(C(F)(F)F)cc(O)c2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 117.5 %

Procedure:
A solution of trifluoro-3-oxa-butyrate (14.95 g, 81 mmol) and PPA (72 ml) was heated at 100° C. and then treated with p-anisidine (10 g, 81 mmol) portion wise. The reaction mixture was further heated to 150° C. and stirred for 2 h at 150° C. After cooling to RT, the reaction mixture was poured into a beaker containing ice water. After stirring for 20 min, the mixture was filtered, and the resulting solid was washed with water (˜3 L). The resulting pinkish-purple solid was dried under vacuum to provide 6-methoxy-2-(trifluoromethyl)quinolin -4-ol (11.58 g, 47.6 mmol, 58.6% yield), which was used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[NH2:7])[CH3:2].C([O:16][CH:17]=[C:18]([C:24](OCC)=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>>[CH2:12]([O:11][C:10]1[CH:9]=[C:8]2[C:6](=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])[NH:7][CH:24]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2=[O:16])[CH3:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCOc1ccc(N)cc1OCC
Product: CCOC(=O)c1c[nH]c2cc(OCC)c(OCC)cc2c1=O
Yield: 69 %

Procedure:
3,4-Diethoxyaniline (3.7 g) and diethyl ethoxymethylenemalonate (5.3 g) were reacted in the same manner as in Experimental Example 1 to obtain 6,7-diethoxy-3-ethoxycarbonyl-4(1H)-quinolone (4.3 g). The compound (3 g) was subjected to hydrolysis and decarboxylation in the same manner as in Experimental Example 2 to obtain 6,7-diethoxy-4(1H)-quinolone (compound 10, 1.9 g).
Reaction SMILES: [CH2:1]1[O:4][C@H:2]1[CH3:3].[SH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1>>[OH:4][C@@H:2]([CH3:3])[CH2:1][S:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=1
Reactant: C[C@H]1CO1
Reactant: COC(=O)c1ccc(S)cc1
Product: COC(=O)c1ccc(SC[C@H](C)O)cc1

Procedure:
150 mg of (S)-propylene oxide was reacted with methyl 4-mercaptobenzoate via Procedure S to afford (S)-methyl 4-(2-hydroxypropylthio)benzoate. 650 mg of (S)-methyl 4-(2-hydroxypropylthio)benzoate was reacted via Procedure R to give (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate. 350 mg of (S)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (S)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (Q1) 431.3 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[C:5]2=[N:6][CH:7]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[C:5]2=[N:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(I)c21
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ncccc4F)c4ncc(F)cc34)nc(NCC(F)(F)F)c21
Temperature: 150 °C

Procedure:
150 mg (0.155 mmol, approx. 55% purity) of the compound obtained in example 21A was dissolved in 1-methyl-2-pyrrolidone (2.7 ml) in a reaction vessel suitable for a microwave and 0.675 ml 2,2,2-trifluoroethylamine was added. Then it was sealed with a corresponding septum and heated in the microwave at 150° C. for 21 h. After cooling, the reaction mixture was purified by preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 31 mg of the title compound was obtained (39% of theor.).
Reaction SMILES: C(=O)([O-])[O-].[CH:5]1[C:10](N=C=S)=[CH:9][C:8]2[C:14]([O:16][C:17]3([C:27]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=4[O:25][C:19]4[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:18]3=4)[C:7]=2[CH:6]=1)=[O:15]>O.CS(C)=O>[CH:5]1[CH:10]=[CH:9][C:8]([C:14]([OH:16])=[O:15])=[C:7]([C:17]2[C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[O:25][C:26]3[C:27]=2[CH:28]=[CH:29][C:30]([CH:31]=3)=[O:32])[CH:6]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12

Procedure:
This HA-HZ was dissolved in distilled water (Milli Q water), and an equal amount of 100 mM carbonate buffer (Ph 9.0) was then added thereto to a final concentration of 1 mg/ml. Thereafter, FITC dissolved in DMSO that was 1/10 the volume of the HA-HZ solution was added to the mixture at an additive ratio of FITC/HA unit=3.0 mol/mol, and the obtained mixture was then reacted in the dark at room temperature for 1 hour. Thereafter, 25 ml of the reaction solution was poured in PD-10 columns (10 columns) that had previously been equilibrated with a 50 mM carbonate buffer (pH 9.0), so as to remove unreacted FITC. Succinic anhydride dissolved in DMSO (3.5 ml) was added to the thus roughly purified solution at an additive ratio of succinic anhydride/HZ=250 mol/mol, and the same above reaction was carried out. The reaction mixture was dialyzed against large excess amount of distilled water (Milli Q water) for purification, followed by freeze-drying, so as to obtain fluorescein-labeled HA-HZ-SUC, which was formed by labeling HA-HZ with FITC.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[N:4]1([C:7]2[N:12]([CH3:13])[C:11](=[O:14])[N:10]([CH3:15])[C:9](=[O:16])[CH:8]=2)[CH2:6][CH2:5]1>>[CH3:13][N:12]1[C:7]([NH:4][CH2:6][CH2:5][NH:3][CH2:1][CH3:2])=[CH:8][C:9](=[O:16])[N:10]([CH3:15])[C:11]1=[O:14]
Reactant: CCN
Reactant: Cn1c(N2CC2)cc(=O)n(C)c1=O
Product: CCNCCNc1cc(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 7.6 g of a 70% aqueous ethylamine solution was added 0.91 g of the previously obtained Compound 12, followed by stirring at room temperature for 3 hours. After completion of the stirring treatment, the reaction solution was concentrated under reduced pressure, and 80 ml of ethanol were added to the resultant residue. Then, the ethanol solution was further concentrated under reduced pressure. Ether was added to the resultant residue, and crystallization was then effected. Afterward, a mixed solution of ether and hexane in a ratio of 1:1 (volume ratio) was added thereto. The crystals were then collected by filtration to obtain 1.07 g of N-(1,3-dimethyl-2,4-dioxopyrimidine-6-yl)-N'-ethylethylene-diamine (Compound 13).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1>>[CH3:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:11][C:10]2[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[N:8]([C:20]([N:17]3[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]3)=[O:21])[N:9]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Reactant: CC1CCN(C(=O)Cl)CC1
Product: Cc1cc(Cl)nc2c1c(OC(=O)N1CCC(C)CC1)nn2C(=O)N1CCC(C)CC1

Procedure:
In analogy to example 1, 1.2 g (6.54 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 1.29 g (7.98 mmol) of 4-methylpiperidine-1-carbonyl chloride. Yield: 238 mg (8%), M+H+: 434.27.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[K+].F[C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:26])(=[O:25])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3>CN(C)C=O>[F:1][C:2]([F:7])([F:6])[CH:3]([CH3:4])[O:5][C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:25])(=[O:26])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: O=S1(=O)c2ccccc2Oc2cc(F)ccc21
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
(rac)-1,1,1-Trifluoro-2-propanol (Oakwood) (0.45 g, 0.004 mole) was added to a stirred, ice-bath cooled mixture of potassium hydride (approximate 50% dispersion in mineral oil) (Aldrich) (0.32 g, 0.004 mole) and N,N-dimethylformamide (50 mL). The ice-bath was removed, and the reaction was stirred at ambient temperature for 1 hour. 3-Fluorophenoxathiin 10,10-dioxide (Example 47) (1.00 g, 0.004 mole) was added, and the mixture was heated at reflux under nitrogen for 2 hours. The reaction was cooled, and the volatiles were removed by spin evaporation in vacuo. The residue was purified by column chromatography on Silica Gel 60 using ethyl acetate-hexanes:3-7. The appropriate column fractions were combined, and the volatiles were removed by spin evaporation in vacuo to give 1.21 g (87% yield) of (rac)-3-(2,2,2-trifluoro-1-methylethoxy)phenoxathiin 10,10-dioxide. Recrystallization from ethanol gave 1.03 g (74yield) of the analytical sample, m.p. 97-98.5° C.
Reaction SMILES: [F:1][C:2]([F:5])(O)[CH3:3].[CH3:6][C:7]1([CH3:25])[C@@H:9](/[CH:10]=[CH:11]\[C:12](=[O:14])[OH:13])[C@H:8]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)(Cl)Cl>[CH3:6][C:7]1([CH3:25])[C@@H:9](/[CH:10]=[CH:11]\[C:12](=[O:13])[O:14][CH2:3][CH:2]([F:5])[F:1])[C@H:8]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: CC(O)(F)F
Reactant: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)O
Solvent: ClC(Cl)Cl
Product: CC1(C)[C@H](C(=O)OCc2ccccc2)[C@@H]1/C=C\C(=O)OCC(F)F

Procedure:
Using the procedure of Example 53, difluoro-ethanol and the product of Step B of Example 57 were reacted to obtain benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-(2,2-difluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+52° (c=0.2% in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:17][C:16]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(Br)s1
Reactant: COc1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)s1
Yield: 62.6 %

Procedure:
Following General Procedure B, 4-methoxyphenylboronic acid (2.7 g, 18 mmol) was reacted with methyl 5-bromothiophene-2-carboxylate (2.0 g, 9.0 mmol) to afford the desired product (1.4 g, 61%): 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=3.9 Hz, 1H), 7.53 (td, J=9.7, 2.5 Hz, 2H), 7.14 (d, J=3.9 Hz, 1H), 6.89 (td, J=9.7, 2.5 Hz, 2H), 3.87 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3]1.N1C=CN=C1.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.O>[Si:26]([O:1][CH:2]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:3]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NC1CC(O)CNC1=O
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CC(O[Si](C)(C)C(C)(C)C)CNC1=O
Reaction time: 15 h
Yield: 85.8 %

Procedure:
To a stirred solution of compound 1C (0.355 g, 1.54 mmol) in 5 mL of DMF at room temperature was added imidazole (401 mg, 5.89 mmol) and then t-butyldimethyl chlorosilane (401 mg, 2.31 mmol). After 15 h, the reaction mixture is diluted with 25 mL water and extracted four times with 20 mL portions of ether. The combined organic extracts were washed three times with water, once with saturated NaCl. The organic layer was dried over MgSO4, and then filtered and evaporated under reduced pressure. Purification by silica gel chromatography (2:1 EtOAc/CH2Cl2) provided the title compound (455 mg, 86%) as a white solid. MS [M+H]+: found 345.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)[CH3:10]>>[CH2:9]([C:11]1[CH:16]=[C:15]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: Nc1ccc(Br)cc1
Reactant: CCc1cccc(B(O)O)c1
Product: CCc1cccc(-c2ccc(N)cc2)c1
Yield: 97.5 %

Procedure:
The title compound (300 mg) was prepared from 4-bromoaniline (270 mg, 1.56 mmol) and 3-ethylphenylboronic acid (300 mg, 2.04 mmol) as a colourless liquid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH3:12])[N:5]=[C:4]([NH:13][C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[N:3]=1.[Na].[CH3:20][OH:21]>>[C:17]([C:14]([NH:13][C:4]1[N:3]=[C:2]([O:21][CH3:20])[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH3:12])[N:5]=1)([CH3:16])[CH3:15])#[N:18]
Reactant: CO
Reactant: CCNc1nc(NC(C)(C)C#N)nc(Cl)c1C#N
Agent: [Na]
Product: CCNc1nc(NC(C)(C)C#N)nc(OC)c1C#N
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2.7 grams of 4-chloro-2-(1-cyano-1-methylethylamino)-6-ethylamino-5-pyrimidinecarbonitrile in 50 ml of methanol was added a solution of 0.3 gram of sodium in 10 ml of methanol. The reaction mixture was heated under reflux for 3 hours. An additional small quantity of sodium in methanol was then added to the reaction mixture, and heating under reflux was continued for 1.5 hours. The excess methanol was removed from the reaction mixture by evaporation under reduced pressure. The residue was extracted with a mixture of diethyl ether and water. The diethyl ether layer was separated, washed with water, then dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure to a residue. The residue was washed with methylcyclohexane, and the insoluble solid was collected by filtration. The solid was recrystallized from benzene to give 1.7 grams of 2-(1-cyano-1-methylethylamino)-6-ethylamino-4-methoxy-5-pyrimidinecarbonitrile; mp, 130°-132°.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Cl:16])=[CH:5][C:6]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)O.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[Br:1][C:2]1[S:3][C:4]([Cl:16])=[CH:5][C:6]=1[CH2:7][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1
Reactant: OC(c1cccc(Cl)c1)c1cc(Cl)sc1Br
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(Cc2cc(Cl)sc2Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-bromo-5-chloro-3-thienyl)(3-chlorophenyl)methanol from Example 1, Step 4 (2.50 g, 7.40 mmol) in dichloromethane at r.t. was added trifluoroacetic acid (5.70 mL, 74.0 mmol) (a red solution formed) followed by triethylsilane (5.91 mL, 37.0 mmol) (red solution turned into yellow) and the mixture was stirred at r.t. for 30 min. and concentrated. The residue was co-evaporated with toluene and then pumped under high vacuum. The crude was purified by flash chromatography (100% hexanes) to give the desired product as a colorless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[N+:34]([O-:36])=[O:35])CCC>>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[C:7]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=3[N+:34]([O-:36])=[O:35])[CH2:16][CH2:15]2)=[CH:10][CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1[N+](=O)[O-]
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1[N+](=O)[O-])=C2
Yield: 73.2 %

Procedure:
Synthesized from 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (2.3 g) and tributyl(4-methoxy-2-nitrophenyl)tin (3.9 g) according to an analogous synthetic method to Preparation Example 77, the title compound (1.7 g) was obtained.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=O)[C:6]([Cl:8])=[O:7].[N:11]1([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])C=[CH:14][CH:13]=[CH:12]1>ClCCCl>[Cl:8][C:6]([C:5]1[N:11]([N:16]2[C:20](=[O:21])[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH:12]=[CH:13][CH:14]=1)=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(Cl)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of anhydrous aluminium chloride (3.1 g; 4.7×5 mM) in 20 ml of 1,2-dichloroethane was cooled with ice to 0°-5° C., and oxalyl chloride (3 g; 4.7×5 mM) was added dropwise to the suspension. After stirred at 0°-5° C. for 20 minutes, a suspension of N-(1H-pyrrol-1-yl)phthalimide (IX-I; 1.0 g; 4.7 mM) in 1,2-dichloroethane was added thereto. Thereafter, the mixture was stirred for 50 minutes with slowly raising the temperature to room temperature. The reaction mixture was poured into ice water and insoluble materials was removed by filteration. To the filtrate was added ethyl acetate with thoroughly stirring to separate an organic phase. The organic phase was dried with sodium sulfate, and the solvent was then removed by distillation to obtain the compound (IX-61)
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)(=O)C.CO>O>[O:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][OH:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)OCc1cccc(Oc2ccccc2)c1
Solvent: O
Solvent: CO
Product: OCc1cccc(Oc2ccccc2)c1
Reaction time: 9 h
Yield: 90 %

Procedure:
2.42 g. (0.01 mole) of 3-phenoxybenzyl acetate, 10 cm3. of methanol, 10 cm3. of water and 0.2 g. of acid ion exchange resin (Nafion H) are refluxed with stirring for nine hours. After cooling the reaction mixture is filtered off and evaporated. The residue is dissolved in 30 cm3. of methylene chloride, washed with 10 cm3. of 1N sodium hydroxide solution and 10 cm3. of water then evaporated. 1.8 g. of 3-phenoxybenzyl alcohol are obtained. nD20 : 1.593, yield 90%.
Reaction SMILES: [N:1]1([C:7]([NH:9][C:10]2[CH:31]=[CH:30][C:13]([O:14][CH2:15][C:16]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:17]=3[O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:12][C:11]=2[F:32])=[S:8])[CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.Cl[C:34](OC(Cl)(Cl)Cl)=[O:35].C(N(CC)CC)C>O1CCOCC1>[N:1]12[CH:7]([N:9]=[C:10]3[CH:31]=[CH:30][C:13]([O:14][CH2:15][C:16]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:17]=4[O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:12][CH:11]3[F:32])[S:8][C:34](=[O:35])[N:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(NC(=S)N2CCCCN2)c(F)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Oc1cc(C)ccc1COC1=CC(F)C(=NC2SC(=O)N3CCCCN23)C=C1
Yield: 31.4 %

Procedure:
By the method of Example 1, Step D, of U.S. Pat. No. 4,906,281, 1.50 g (0.00325 mole) of methyl 2-[2-[4-(perhydropyridazin-1-ylthiocarbonylamino)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate and 0.36 g (0.09017 mole) of trichloromethyl chloroformate were reacted in the presence of 0.36 g (0.0035 mole) of triethylamine in 35 mL of dioxane, yielding 0.50 g of methyl 2-[2-[4-(8-thia-1,6-diazabicyclo[4.3.0]nonane-7-on-9-ylimino)-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as a syrup. The NMR and IR spectra were consistent with the proposed structure. NMR: 1.60 (d, 3H, JHH =8.0 Hz); 1.78-1.96 (m, 4H); 2.30 (s, 3H); 3.64-3.80 (m, 4H); 3.70 (s, 3H); 4.80 (q, 1H, JHH =8.0 Hz); 5.10 (dd, 2H); 6.58-7.30 (m, 6H) .
Reaction SMILES: N([O-])=O.[Na+].[C:5]([C:7]1[CH:8]=[C:9]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)=[CH:18][C:17](N)=[N:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])#[N:6].[ClH:29].C(O)(=O)C>O>[Cl:29][C:17]1[CH:18]=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=2)[N:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([C:5]#[N:6])[CH:8]=2)[N:16]=1
Reactant: Cl
Reactant: COc1ccc(-n2nc(N)cc2-c2ccc(SC)cc2)cc1C#N
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-n2nc(Cl)cc2-c2ccc(SC)cc2)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (0.36 g) in water (0.5 ml) was added to an ice cooled mixture of 1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazol-3-amine (1.08 g), concentrated hydrochloric acid (15 ml) and acetic acid (35 ml). The mixture was stirred at 0° C. for 30 minutes and added portionwise to a mixture of cuprous chloride (1.37 g) and concentrated hydrochloric acid (10 ml) at ambient temperature. The mixture was refluxed for 1 hour, poured into water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluting with toluene to give 3-chloro-1-(3-cyano-4-methoxyphenyl)-5-[4-(methylthio)phenyl]pyrazole (0.29 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][N:8]([CH:9]([CH3:11])[CH3:10])[C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])=[CH:5][CH:4]=1
Reactant: CC(C)NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C(Cl)Cl
Product: CC(C)N(Cc1ccc(C(F)(F)F)cc1)C(=O)C(Cl)Cl
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of 21.7 g of N-(4-trifluoromethylbenzyl)-N-isopropylamine is added while stirring in a 4 neck-flask with 20 ml of 20% sodium-hydroxide solution. The reaction-mixture is then cooled while stirring in an alcohol/CO2 -bath to a temperature of from -10° to -5° whereupon 14.7 g of dichloroacetyl chloride is added slowly, dropwise thereto. After about 1/2 hour, when everything is added, the cooling-bath is removed and the reaction mixture is stirred for 2 hours until it reaches room temperature. It is then poured into ice/water and the organic material is extracted with toluene. The toluene-phases are collected, washed first with diluted sodium hydroxide, then with diluted hydrochloric acid and eventually twice with water, dried over sodium sulfate and concentrated in a rotatory evaporator. A clear oil is thus obtained, which becomes solid after a while. The solid mass is then triturated with hexane and filtered to yield 21.7 g of cristalline N-(4-trifluoromethylbenzyl)-N-isopropyl-dichloroacetamide, melting at 92° to 93°.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:40]([O:43][CH2:44][CH2:45]Br)(=[O:42])[CH3:41]>CN(C=O)C>[C:40]([O:43][CH2:44][CH2:45][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:33])=[CH:17][C:18]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)(=[O:42])[CH3:41]
Reactant: COC(=O)C1(NC(=O)c2ccc(O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of step 1 of example 254 (70 mg, 0.157 mmol) was dissolved in DMF (1 ml). Potassium carbonate (108 mg, 0.786 mmol) was added and subsequently 2-bromoethyl acetate (39 mg, 0.235 mmol). The mixture was stirred at room temperature for 2 h and then partitioned between EA and water. The aqueous phase was extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient).