Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16].CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C1(C)C=CC=CC=1.I[C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([O:51][CH3:52])[CH:45]=1>COCCOCCOC>[CH3:52][O:51][C:46]1[CH:45]=[C:44]([CH:49]=[C:48]([CH3:50])[CH:47]=1)[O:1][CH2:2][C@@H:3]1[C@:12]2([CH3:13])[C@H:7]([C:8]([CH3:15])([CH3:14])[CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5][C@@:4]1([CH3:17])[OH:16]
Reactant: COc1cc(C)cc(I)c1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](CO)[C@](C)(O)CC[C@@H]12
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Solvent: COCCOCCOC
Solvent: Cc1ccccc1
Product: COc1cc(C)cc(OC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
(1S,2R,4aS,8aS)-1-(hydroxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (3) (prepared according to Kuchkova et al., Synthesis, 1045-1048, 1997) (0.24 g, 1.0 mmol), Cu(I)I (0.019 g, 0.10 mmol)) and 3,4,7,8-tetramethyl-[1,10]phenanthroline (0.047 g, 0.20 mmol)) were added to an oven dried sealed tube, sealed with a rubber septum, and flushed with a stream of nitrogen for 15 min. Anhydrous toluene (5 mL), anhydrous diglyme (1 mL) and 1-iodo-3-methoxy-5-methylbenzene (2) (0.273 g, 1.10 mmol) were added via a syringe with vigorous stirring under a stream of nitrogen at room temperature. The rubber septum was replaced with the Teflon cap and the sealed tube was heated at 120° C. in an oil bath for 18 h. The reaction was allowed to cool to room temperature, and then quenched with ethyl acetate. The resulting suspension was filtered through a celite pad. The filtrate and the washings were concentrated to dryness. The crude product was purified by flash chromatography (Hexanes/EtOAc, 9:1) to yield (1S,2R,4aS,8aS)-1-(3-methoxy-5-methylphenoxymethyl)-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (4) (0.33 g, 92% yield) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:20])=[O:19]>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH2:10][NH:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CNN(c2cc(Cl)c(C(C(=O)O)c3ccc(Cl)cc3)c(Cl)c2)C(=O)N1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a stirred and refluxed solution of 1.5 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin2(3H)-yl)benzeneacetic acid in 100 parts of acetic acid were added 3 parts of zinc. Stirring was continued for 30 minutes at reflux temperature. The zinc salts were filtered off and the filtrate was evaporated. The residue was washed with water whereupon the solid product was filtered off and dissolved in a mixture of trichlorometmhane and methanol (90:10 by volume). The solution was dried, filtered and evaporated. The residue was washed with ethyl acetate and 2,2'-oxybispropane and dried, yielding 0.98 parts (67.2%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-3,5-dioxo-1,2,4-triazin-2(1H)-yl)benzeneacetic acid; mp. 194.2° C. (compound 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:32]=[CH:31][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:33]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl[C:53](=[O:60])[CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:32]=[CH:31][C:25]([O:26][CH2:27][CH2:28][CH2:29][NH:30][C:53](=[O:60])[CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:33]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Product: COC(=O)CCC(=O)NCCCOc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1

Procedure:
41 mg of 3-(4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}phenoxy)propylamine obtained in Example 16 and 12 μL methyl 4-chloro-4-oxobutyrate were reacted in the same manner as in Example 17, to give 24 mg of the title compound as a colorless amorphous.
Reaction SMILES: [OH:1][CH:2]([C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:3]([O:5][CH3:6])=[O:4].I[CH3:17]>C(OCC)C.[Ag-]=O>[CH3:17][O:1][CH:2]([C:7]([CH3:15])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)C(C)(C)c1ccccc1
Reactant: CI
Agent: O=[Ag-]
Solvent: CCOCC
Product: COC(=O)C(OC)C(C)(C)c1ccccc1
Temperature: 40 °C
Reaction time: 26 h

Procedure:
To a solution of methyl 2-hydroxy-3-methyl-3-phenylbutanoate (0.50 g, 2.4 mmol, from Reference Example 37) in diethyl ether (11 mL) is added silver (I) oxide (4.3 g) and iodomethane (8.7 mL). The reaction mixture is stirred in a 40° C. oil bath under nitrogen atmosphere for 26 hours. The reaction mixture is combined with that from a previous run conducted under the same conditions and filtered through a plug of diatomaceous earth. The filtrate is concentrated under reduced pressure and then purified by flash chromatograhy (silica gel, hexanes/ethyl acetate) to furnish 0.52 g of a clear, colorless liquid (68% combined yield). MS (ES+): (M+H)=222.9
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[CH:18]=[C:19]2[C:27]([C:28]3[CH:33]=[C:32]([CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:31]=[CH:30][C:29]=3[O:39][C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[F:47])=[CH:26][N:25]([CH3:48])[C:20]2=[C:21]([O:23][CH3:24])[N:22]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[O:39][C:29]1[CH:30]=[CH:31][C:32]([CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][C:28]=1[C:27]1[C:19]2[C:20](=[C:21]([O:23][CH3:24])[N:22]=[C:17]([CH:1]=[CH2:2])[CH:18]=2)[N:25]([CH3:48])[CH:26]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COc1nc(Br)cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1cc2c(-c3cc(CS(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c2c(OC)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
Tributyl(vinyl)tin (0.053 g, 0.167 mmol), the product from Example 91E (0.075 g, 0.140 mmol) and Pd(PPh3)2Cl2 (9.80 mg, 0.014 mmol) were combined in dioxane (1.163 mL) and sparged with argon for 15 minutes. The mixture was stirred for 2 hours at 100° C., cooled and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), treated with 3-mercaptopropyl functionalized silica gel, filtered, and concentrated. Purification by chromatography (silica gel, 0-40% ethyl acetate in heptanes) afforded the title compound (0.041 g, 61%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1F)=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:19][NH:20][CH2:21][CH2:22][NH2:23]>N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:23][CH2:22][CH2:21][N:20]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CNCCN
Reactant: CCOP(=O)(CC(=O)c1ccccc1F)OCC
Solvent: c1ccncc1
Product: CCOP(=O)(C=C1NCCN(C)c2ccccc21)OCC
Temperature: 95 °C
Yield: 26.6 %

Procedure:
A mixture of 10.45 g (38.1 mmol) of [2-(2-fluorophenyl)-2-oxoethyl]phosphonic acid diethyl ester and 14.1 g (190 mmol) N-methylethylenediamine in 100 ml of pyridine was heated at 95° C. for 18 hours. The solvent was evaporated and the residue was partitioned between 200 ml of water and 2×100 ml of dichloromethane. The combined organic portions were dried (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography eluting with 5% methanol/dichloromethane to give 3.14 g (26%) of (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester as a light brown oil; MS: m/e 311.0 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.Cl.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:18][C:5](=[O:9])[CH2:6][CH2:7][CH:8]2[CH2:1][CH2:2][C:3](=[O:10])[NH:4]2)=[CH:15][CH:14]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: O=C1CCC2CCC(=O)N12
Agent: Cl
Product: O=C1CCC(CCC(=O)OCc2ccc(Cl)cc2)N1
Temperature: 100 °C

Procedure:
Five grams of dihydro-1H-pyrrolizine-3,5(2H,6H) -dione (III) are dissolved in 31 g of p-chlorobenzyl alcohol and 0.2 ml of concentrated hydrochloric acid is added. The solution is heated at 100° C. for 65 hours. The mixture is cooled and chromatographed over silica gel in dichloromethane. The starting p-chlorobenzyl alcohol is eluted with dichloromethane and the product is eluted with 2.5% methanol in dichloromethane. The eluate containing the product is concentrated at reduce pressure and the residual oil solidifies upon standing. The solid is recrystallized from toluene diethyl ether to yield 5-oxo-2-pyrrolidinepropanoic acid p-chlorobenzyl ester with a melting point of 63°-64° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:20]([O:22][CH3:23])=[O:21].Cl>[OH-].[Na+]>[CH3:23][O:22][C:20]([NH:1][C@H:2]1[CH2:3][C:4]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:10]1=[O:12])=[O:21]
Reactant: COC(=O)Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)N[C@H]1Cc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of L-phenylalanine (16.5 g., 0.1 m) in 1N NaOH (100 ml) to which solid Na2CO3 (5.3 g, 0.05 m) had been added was added to the methyl chloroformate (7.8 ml, 0.1 m). Stirring was continued for 1/2 hr. with cooling and 1/2 hr. without. The mixture was carefully acidified with concentrated HCl to pH 2-3. After extraction with CH2Cl2 and drying (Na2SO4), evaporation of the solvent left
Reaction SMILES: [Sn].[C:2]([O-:5])(=[O:4])[CH3:3].[Sn+2:6].[C:7]([O-:10])(=[O:9])[CH3:8].[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[C:2]([O-:5])(=[O:4])[CH3:3].[Sn+4:6].[C:7]([O-:10])(=[O:9])[CH3:8].[C:11]([O-:14])(=[O:13])[CH3:12].[C:2]([O-:5])(=[O:4])[CH3:3]
Reactant: [Sn+2]
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Sn]
Product: [Sn+4]

Procedure:
Ruf, U.S. Pat. No. 5,068,373, Entitled Method for the Preparation of Anhydrous Tin—(IV)—Carboxylates, issued Nov. 26, 1991, relates to a method of reacting metallic tin or tin (II) acetate with an excess of acetic anhydride to produce tin (IV) acetate. The tin (IV) acetate is separated from the reaction mixture and used as separated or, if desired, is subsequently converted to tin (IV) carboxylate having four or more carbon atoms by reaction with the appropriate carboxylic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH2:10][CH2:9]1.C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>ClCCl>[CH3:53][S:54]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]([N:18]2[CH2:22][CH:21]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:19]2[C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[C:39]=2[F:45])=[O:17])[CH2:10][CH2:9]1)(=[O:56])=[O:55]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC1CN(C(=O)NCC2CCNCC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)NCC2CCN(S(C)(=O)=O)CC2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (piperidin-4-ylmethyl)-amide trifluoroacetic acid prepared in Example 44 (35 mg, 0.05 mmol) was reacted with triethylamine and methanesulfonyl chloride (6.5 mg, 0.06 mmol) in dichloromethane to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid (1-methanesulfonyl-piperidin-4-ylmethyl)-amide as a white solid (Yield, 13 mg, 39%).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCCC(=O)CC(=O)OC
Reactant: [H][H]
Agent: [Ru]
Solvent: ClCCl
Solvent: CO
Product: CCCCC[C@@H](O)CC(=O)OC
Yield: 94.9 %

Procedure:
Into a 100-ml autoclave (made of Hastelloy) were introduced 20 g of methyl 3-oxooctanoate (manufactured by Inoue Perfumery Mfg. Co., Ltd., Japan) and 40 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 150 mg of Ru2Cl4 ((+)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 1.2 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 65° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 6 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 19.2 g of methyl (R)-3-hydroxyoctanoate. Yield, 95%.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:18]1([C@H:17]([NH:24][C@H:2]([CH3:15])[CH2:3][C:4]2[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1cccc(CC(C)=O)c1
Reactant: C[C@@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Cc1cccc(C[C@@H](C)N[C@H](C)c2ccccc2)c1
Yield: 41 %

Procedure:
A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 90) (45.3 g, 236 mmol), (R)-α-methyl benzylamine (27.6 ml, 214 mmol), sodium triacetoxyborohydride (68.1 g, 321 mmol) and acetic acid (14.7 ml, 257 mmol) in dichloromethane (1500 ml) was stirred at room temperature for 18 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (600 ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with further dichloromethane (2×100 ml). The combined organic extracts were washed with brine (100 ml), dried (sodium sulfate), filtered through celite and reduced in vacuo. The oil was dissolved in methanol (200 ml), treated with 1M hydrogen chloride in methanol (300 ml) and reduced in vacuo to give a 4:1 mixture of diastereomers (R,R major) as an off-white, hydrochloride salt. Two successive crystallisations (diisopropylether/methanol) gave the title compound (27.3 g) as a colourless crystalline solid.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([F:18])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[F:18][C:16]1([CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15][NH:14][CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC1(F)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1(F)CNC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.5 %

Procedure:
tert-Butyl (1-benzhydryl-3-fluoroazetidin-3-yl)methylcarbamate (0.6 g, 1.35 mmol) was dissolved in ethanol and Pd(OH)2 (0.38 gm, 2.7 mmol) was added. The reaction mixture was stirred at rt for 14 h under H2 atmosphere. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 0.2 g of tert-butyl (3-fluoroazetidin-3-yl)methylcarbamate (66% yield).
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.Cl[Si:12]([CH3:15])([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C(OCC)C>[CH3:13][Si:12]([CH3:15])([CH3:14])[C:7]1[S:6][CH:10]=[CH:9][N:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: c1cscn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: C[Si](C)(C)c1nccs1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Mix n-butyl lithium (20.4 mL, 51.0 mmol, 2.5 M in hexane) with diethyl ether (50 mL) in a three-necked flask, equipped with a dropping funnel and thermometer. Cool to −78° C. and add dropwise a solution of thiazole (4.25 g, 50.0 mmol) in diethyl ether (50 mL). After the addition is complete, stir the reaction mixture at −78° C. for 30 min, followed by addition of chlorotrimethylsilane (5.4 g, 50.0 mmol). Stir at −78° C. for an hour and then warm to room temperature. Quench the reaction by adding saturated sodium bicarbonate. Extract the aqueous layer with diethyl ether. Wash the combined organic portions with brine and dry over sodium sulfate. Filter and concentrate under reduced pressure to give a residue. Purify by distillation to give 8.33 g (52-56° C./15 mm Hg) of title compound. 1H NMR (400 MHz, CDCl3) 8.13 (d, 1H, J=2.6 Hz), 7.54 (d, 1H, J=2.6 Hz), 0.43 (s, 9H).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[C:31](=[O:32])[CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[NH:28][C:27]2=[O:37])=[CH:22][C:10]=1[C:11]([O:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12].[CH2:38](Br)[CH:39]=[CH2:40]>O>[Cl:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[C:31](=[O:32])[CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[N:28]([CH2:40][CH:39]=[CH2:38])[C:27]2=[O:37])=[CH:22][C:10]=1[C:11]([O:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12]
Reactant: C=CCBr
Reactant: CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C(=O)OC(C)(C)C(=O)OCC)c2)c1=O

Procedure:
0.35 g of sodium hydride (50% dispersion in white oil) is added to 40 ml of dimethylformamide while stirring. 2.9 g of ethyl 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methyl-propionate [sic] are added portionwise as the solid. After completion of the addition the mixture is stirred at room temperature for a further hour. 1.2 g of allyl bromide are now added in one portion. The reaction mixture is stirred at room temperature for 18 hours and thereafter introduced into 100 ml of water at 0° C. The mixture is extracted twice with 150 ml of ethyl acetate each time. The organic phases are washed once with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel with ethyl acetate/n-hexane (1:4). There is obtained ethyl 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-(2-propenyl)-4 -trifluoromethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methyl-propionate as an oil;
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([CH:15]=[O:16])[C:12]([CH2:17][CH3:18])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:15]([C:13]2[C:12]([CH2:17][CH3:18])=[N:11][N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH:14]=2)[OH:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCOc1cccc(-n2cc(C=O)c(CC)n2)c1
Solvent: C1CCOC1
Product: CCOc1cccc(-n2cc(C(O)C3CCCCC3)c(CC)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution (20 mL) of 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde (1.7 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise under ice-cooling cyclohexylmagnesium bromide (12.0 mL, 1M tetrahydrofuran solution). After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (2.2 g, 96%) as a pale-yellow oil.
Reaction SMILES: C([O:7][CH2:8][C:9]([F:15])([F:14])[S:10]([O-:13])(=[O:12])=[O:11])(=O)C(C)(C)C.[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>CO.O>[F:14][C:9]([F:15])([S:10]([O-:13])(=[O:12])=[O:11])[CH2:8][OH:7].[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)C(=O)OCC(F)(F)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])C(F)(F)CO
Reaction time: 8 h

Procedure:
Triphenylsulfonium 2-(pivaloyloxy)-1,1-difluoroethanesulfonate, 243.5 g (0.48 mole), was dissolved in 760 g of methanol and ice cooled. An aqueous solution of 40 g sodium hydroxide in 120 g water was added dropwise to the solution at a temperature below 5° C. It was aged at room temperature for 8 hours. At a temperature below 10° C., dilute hydrochloric acid (99.8 g of 12N hydrochloric acid in 200 g of water) was added to quench the reaction. The methanol was distilled off in vacuum, after which 1,000 g of dichloromethane was added to the residue. The organic layer was washed with 30 g of a saturated sodium chloride solution three times. The organic layer was concentrated, after which 1 L of diisopropyl ether was added to the residue for crystallization. The crystals were filtered and dried, obtaining the target compound. 187 g (purity 78%, net yield 78%).
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.CN(CCN(C)C)C.C([Li])CCC.[CH2:25]([O:27][C:28](=[O:36])[C:29](=[CH:32]OCC)[C:30]#[N:31])[CH3:26]>C1(C)C=CC=CC=1.O>[CH2:25]([O:27][C:28](=[O:36])/[C:29](/[C:30]#[N:31])=[CH:32]/[C:10]1[C:4]2[O:3][C:2]([F:1])([F:11])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)[CH3:26]
Reactant: FC1(F)Oc2ccccc2O1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)/C(C#N)=C/c1cccc2c1OC(F)(F)O2

Procedure:
40.0 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 29.5 g (254 mmol) of TMEDA and 35 ml of toluene are metallated analogously to Example 2c) at from -15° to -10° C. with 106.2 g (307 mmol) of n-butyllithium solution (18.5% in toluene). 52.1 g (308 mmol) of ethoxymethylenecyanoacetic acid ethyl ester in 115 ml of toluene are added to the reaction mixture at from -15° to -10° C. over a period of 2 hours. The resulting suspension is poured, after 20 minutes at +10° C., into 350 ml of water, the aqueous phase is separated off and the organic phase is concentrated by evaporation in a vacuum rotary evaporator to yield the desired product.