Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:14])[CH3:13]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc(C(=O)O)c1C

Procedure:
WO 95/09843 describes a multistage process for the preparation of 3-acetoxy-2-methylbenzoic acid. This process starts from 3-methoxybenzoyl chloride. The 3-methoxybenzoyl chloride is reacted with aniline to give 3-methoxy-N-phenylbenzamide. In a second step, the 3-methoxy-N-phenylbenzamide is reacted with 2 equivalents of n-butyllithium and then alkylated using methyl iodide. 3-Methoxy-2-methyl-N-phenylbenzamide is formed here, which is then reacted with aqueous hydrochloric acid and aqueous hydrogen bromide in boiling acetic acid with hydrolysis of the amide group and cleavage of the methoxy group to give 3-hydroxy-2-methylbenzoic acid. The 3-hydroxy-2-methylbenzoic acid must be acylated with acetic anhydride in order to obtain the 3-acetoxy-2-methyl-benzoic acid. The individual reaction steps are described in greater detail in WO 95/09843 under Preparation 9 A, B and C and Example 81.
Reaction SMILES: [OH-].[Na+:2].[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([OH:8])=[O:7])[CH3:4]>O>[CH2:3]([CH:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([O-:8])=[O:7])[CH3:4].[Na+:2]
Reactant: CCCCC(CC)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCC(CC)C(=O)[O-]

Procedure:
A solution of 120 g (3.0 moles) of sodium hydroxide was dissolved in 500 ml of distilled water. 2-Ethylhexanoic acid (475 g, 3.3 moles) was added with stirring to form sodium 2-ethylhexanoate. In a separate container, 200 g (0.5 mole) of chromium nitrate nonahydrate was dissolved in 500 ml of distilled water. The chromium nitrate solution was slowly added to the sodium 2-ethylhexanoate solution with good stirring. When the addition was complete, 500 ml of hexane were added and stirring was continued for 10 minutes. The layers were separated and the hexane layer containing the aquated chromium III tri-2-ethylhexanoate was washed with dilute sodium hydroxide solution, water, dilute sodium carbonate solution and finally with distilled water. The hexane solution was then dried over anhydrous magnesium sulfate. Most of the hexane was removed under reduced pressure and the resulting concentrate was slowly added to 500 ml of acetone. The resulting blue granular solid was filtered and air dried to yield 130 g (54%) of aquated chromium tri-2-ethylhexanoate. Molecular weight determination indicated that the compound is polymeric in nature, probably due to the oxygen bridging of chromium atoms.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[C:5]([S:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH:4]=1)#N.C(O)=[O:24]>[Ni]>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[S:14][C:5]1[CH:4]=[C:3]([CH:1]=[O:24])[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: O=CO
Reactant: CS(=O)(=O)Nc1ccc(C#N)cc1Sc1ccc(F)cc1F
Agent: [Ni]
Product: CS(=O)(=O)Nc1ccc(C=O)cc1Sc1ccc(F)cc1F

Procedure:
A mixture of 4'-cyano-2'-(2,4-difluorophenylthio)methanesulfonanilide (4.8 g) and Raney's Nickel (4.8 g) in 75% formic acid (130 ml) was stirred and refluxed for 2 hours. The mixture was filtered and the filtrate was concentrated to dryness. The residue was dissolved in chloroform, washed with an aqueous solution of sodium bicarbonate, dried and evaporated. The oily residue (5 g) was purified by column chromatography on silica gel (100 g) eluting with a mixture of toluene and ethyl acetate (5:1) to give crystals of 2'-(2,4-difluorophenylthio)-4'-formylmethanesulfonanilide (3.0 g).
Reaction SMILES: Cl.Cl.[N:3]1([NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:11])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Br[CH2:25][C:26]#[N:27].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:26]([CH2:25][N:6]1[CH2:5][CH2:4][N:3]([NH:9][C:10]([C:12]2[CH:17]=[N:16][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][CH:13]=2)=[O:11])[CH2:8][CH2:7]1)#[N:27]
Reactant: N#CCBr
Reactant: O=C(NN1CCNCC1)c1cnc(-c2ccccc2)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCN1CCN(NC(=O)c2cnc(-c3ccccc3)nc2)CC1
Yield: 40.6 %

Procedure:
A solution of 2-phenyl-pyrimidine-5-carboxylic acid piperazin-1-ylamide dihydrochloride (0.29 mmol), bromoacetonitrile (0.29 mmol) and Na2CO3 (1.46 mmol) in wet THF (8 mL) is stirred at rt overnight. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 1-2% methanol in DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid (4-cyanomethyl-piperazin-1-yl)-amide (38 mg, 40%) as a solid. MS: 323 (M+H); 1H NMR (300 MHz, CDCl3): δ 2.60-3.30 (m, 8H), 3.55 (s, 2H), 6.63 (br, 0.5 N—H), 7.14 (br, 0.5 N—H), 7.52 (s, 3H), 8.53 (d, 2H), 9.06-9.38 (m, 2H).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].C([O-])(=[O:8])C=C.[Na+]>>[C:1]([NH2:4])(=[O:8])[CH:2]=[CH2:3].[C:1](#[N:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)[O-]
Agent: [Na+]
Solvent: C=CC#N
Product: C=CC(N)=O

Procedure:
Three jacketed glass columns, each column being charged with 40 parts of the above-prepared fixed cells, were connected in series. A mixed solution of 4 parts of acrylonitrile and 96 parts of a 0.1% aqueous solution of sodium acrylate (neutralized with Na2CO3 to pH 8.0) was introduced into the first column (hereinafter referred to as "Column No. 1") from the top thereof, and passed therethrough at a temperature of 5° C. and SV (Space Velocity)=0.8 hr-1. 96 parts of the reaction solution flowing out of Column No. 1 was mixed with 4 parts of acrylonitrile, introduced into the second column (hereinafter referred to as "Column No. 2") from the top thereof, and passed therethrough at SV=0.8 hr-1. The effluent from the bottom of Column No. 2 in the amount of 96.5 parts was mixed with 3.5 parts of acrylonitrile, introduced into the third column (hereinafter referred to as "Column No. 3") from the top thereof, and passed therethrough at a temperature of 5° C. and SV=0.8 hr-1. The reaction in each column proceeds smoothly without causing the trouble resulting from the swelling of the fixed cells. As an effluent from the bottom of Column No. 3, a 15.4% aqueous solution of acrylamide containing no acrylonitrile was obtained. This aqueous solution was vacuum-concentrated at 45° C. by use of a flash evaporator while bubbling air therethrough, to thereby obtain a concentrated solution having an acrylamide concentration of 28%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH2:13]>C(#N)C>[CH:5]1[C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=[C:9]2[C:4]=1[C:3]1[C:2]([NH:1]2)=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]([OH:13])=[O:13])=[CH:5][C:4]=3[C:3]2=[C:2]2[NH:1][C:9]3[CH:8]=[CH:7][C:6]([C:10]([OH:12])=[O:11])=[CH:5][C:4]=3[C:3]=12
Reactant: O
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Solvent: CC#N
Product: O=C(O)c1ccc2[nH]c3c4[nH]c5ccc(C(=O)O)cc5c4c4c5cc(C(=O)O)ccc5[nH]c4c3c2c1
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
10 ml of acetonitrile were placed in a 200 ml three-mouth flask followed by dissolving 1.42 g of indole-5-carboxylic acid. On the other hand, preparation of the oxidizing agent solution was carried out by dissolving 16.2 g of anhydrous ferric chloride and 5.4 g of water in 40 ml of acetonitrile and stirring for 10 minutes. Next, after dropping in the prepared oxidizing agent solution into the aqueous indole-5-carboxylic acid solution over the course of 30 minutes, the solution was stirred for 10 hours at 60° C. The reaction solution changed from a pale yellow color to a light green color while generating a small amount of heat, and its pH was 1 or less. Following completion of the reaction, the reaction solution was aspiration filtered with a Kiriyama funnel, washed with acetonitrile and then methanol and dried to obtain 1.12 g of light green 6,11-dihydro-5H-diindolo[2,3-a:2′,3′-c]carbazole-2,9,14-tricarboxylic acid (indole-5-carboxylic acid trimer) (yield: 79%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:20]1([C:23]#[CH:24])[CH2:22][CH2:21]1.O>CN(C=O)C.[Cu]I>[CH:20]1([C:23]#[C:24][C:2]2[CH:3]=[CH:4][C:5]3[C:6](=[O:12])[CH2:7][CH2:8][O:9][C:10]=3[CH:11]=2)[CH2:22][CH2:21]1
Reactant: O=C1CCOc2cc(Br)ccc21
Reactant: C#CC1CC1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCOc2cc(C#CC3CC3)ccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of 7-bromochroman-4-one (2.0 g, 8.8 mmol) in DMF (10 mL) was added CuI (380 mg, 1.7 mmol), Pd(PPh3)Cl2 (540 mg, 0.8 mmol) and triethylamine (5 mL) under nitrogen at rt. The suspension was warmed to 100° C. and then cyclopropylacetylene (1.1 g, 17.6 mmol) was added dropwise. The mixture was stirred at 100° C. under nitrogen for 2 h. The reaction mixture was cooled to rt, poured into water, and extracted with EtOAc. Organics were separated and washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography to give 1.65 g (88%) of the title compound as a tan solid. 1H NMR (300 MHz, CDCl3): δ 0.83-0.93 (4H, m), 1.44-1.49 (1H, m), 2.79 (2H, t, J=6.6 Hz), 4.52 (2H, t, J=6.6 Hz), 6.96-7.00 (2H, m), 7.79 (1H, d, J=7.8 Hz). [M+H] calc'd for C14H12O, 213; found 213.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](I)[CH:14]=3)=[O:12])=[CH:9][N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][C:33]#[CH:34])([CH3:28])([CH3:27])[CH3:26].C(NC(C)C)(C)C>C1COCC1.[Cu](I)I.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>[C:25]([O:29][C:30](=[O:35])[NH:31][CH2:32][C:33]#[C:34][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)=[O:12])[CH:14]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(c1cccc(I)c1)c1cn(C2CCCC2)c2ncnc(Cl)c12
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCC#Cc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(Cl)c23)c1
Yield: 85.8 %

Procedure:
A solution of (4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(3-iodo-phenyl)-methanone (500 mg, 1.1 mmol), Prop-2-ynyl-carbamic acid tert-butyl ester (341 mg, 2.2 mmol), Copper Iodide (21 mg, 0.11 mmol), PdCl2(PPh3)2 (77 mg, 0.11 mmol), and diisopropylamine (111 mg, 1.1 mmol) in THF (25 mL) was stirred at room temperature under N2. After 24 h the reaction was quenched with saturated aqueous NH4Cl and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash column chromatography (hexanes/ethyl acetate 7:3) afforded the title compound as a yellow solid (452 mg, 86%). %). MS: 479.2/481.2 (MH+); HPLC Rf: 7.26 min. (HPLC method 4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>C(#N)C>[CH3:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OC)cc1
Yield: 91530.9 %

Procedure:
To a solution of ethyl 2-(4-hydroxyphenyl)acetate (15 g, 0.09 mmol) in acetonitrile (100 mL) were added anhydrous K2CO3 (27.23 g, 0.19 mol) followed by Me2SO4 (14.94 g, 0.11 mol) at RT. The reaction mixture was then refluxed for 5 h, filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (300 mL). The organic layer was then washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-methoxyphenyl)acetate (16 g, 84%) as a solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)CCC.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>CN(C)C=O>[CH2:7]([O:3][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([C:13]#[N:14])=[CH:16][CH:17]=1)[CH2:6][CH2:5][CH3:4]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCO
Product: CCCCOCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
To a mixture of sodium hydride (270 mg, 11 mmol, 66% in oil) and tetrahydrofuran (20 mL) was added n-butanol (1.1 mL, 12 mmol) at 0° C., which was stirred for 45 minutes at room temperature. The reaction mixture was cooled to 0° C., and a mixture of 4-cyanobenzyl bromide (1.5 g, 7.4 mmol) and tetrahydrofuran (10 mL) was added dropwise at that temperature. The reaction mixture was stirred for 3 hours at room temperature, and N,N-dimethylformamide (10 mL) was added to the reaction mixture and stirred for further 4.5 hours at the same temperature. The reaction mixture was partitioned into water and diethyl ether. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:6) to obtain the title compound (1.2 g, 84%).
Reaction SMILES: [O:1]=[C:2]1[CH:7](C(OCC)=O)[C:6](=[O:13])[CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:4][NH:3]1>C(#N)C.O>[C:14]1([CH:5]2[CH2:4][NH:3][C:2](=[O:1])[CH2:7][C:6]2=[O:13])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1C(=O)NCC(c2ccccc2)C1=O
Solvent: O
Solvent: CC#N
Product: O=C1CC(=O)C(c2ccccc2)CN1
Yield: 62.2 %

Procedure:
Sodium (380 mg, 16.52 mmol) was dissolved in anhydrous ethanol (13 mL) and the resulting solution was treated dropwise with 3-(2-ethoxycarbonyl-acetylamino)-2-phenyl-propionic acid ethyl ester (4.23 g, 13.76 mmol) dissolved in anhydrous toluene (35 mL). The reaction was kept at 80° C. for 1.5 hours. After cooling, the mixture was extracted with water. The aqueous extracts were acidified with 2 N HCl, extracted with ethyl acetate and the organic layers were collected, dried over Na2SO4 and evaporated to dryness to obtain ethyl 2,4-dioxo-5-phenylpiperidine-3-carboxylate (1.73 g, Y=48%) which was used for the next step without further purification. Ethyl 2,4-dioxo-5-phenylpiperidine-3-carboxylate (1.73 g, 6.63 mmol) was dissolved in acetonitrile containing 1% of water (30 mL) and the resulting solution was refluxed for 2 hours. After evaporating to dryness, the crude material was chromatographed on silica gel, eluting with methylene chloride/methanol 92/8, to give the title compound (780 mg, Y=62%) as a solid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:21]3[S:20][CH2:19][CH:18]2O)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.CS([O-])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(O)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reaction time: 2.5 h
Yield: 81.53 %

Procedure:
To a solution of 3-hydroxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (2) in dimethylformamide (9.5 parts, dried over Molecular Sieves) cooling at -50° C. under nitrogen are added triethylamine (4 equivalents) and then methanesulfonyl chloride (2 equivalents) over 3 minutes at -52° to -45° C. After 2.5 hours at -55° to -45° C., the produced methanesulfonate (3) solution is stirred for 50 minutes at -15° to -12° C. diluted with ethyl acetate, washed with water, 5% hydrochloric acid, and water, dried over sodium sulfate, and concentrated. The residue is crystallized from methanol to give 7beta-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester (6). (Yield: 81.53%). mp. 166° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19]1(=O)[O:24][C:22](=[O:23])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:18]1[C:22](=[O:23])[C:21]2[C:20](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-chlorophenyl)thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 9, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [Br:1][CH2:2][C:3](C1NCCS1)=[O:4].[CH:10]1([CH:13](Cl)[C:14]([NH2:16])=O)[CH2:12]C1>>[Br:1][CH2:2][C:3]([N:16]1[CH2:12][CH2:10][CH2:13][CH2:14]1)=[O:4]
Reactant: NC(=O)C(Cl)C1CC1
Reactant: O=C(CBr)C1NCCS1
Product: O=C(CBr)N1CCCC1

Procedure:
In a manner similar to that described above, bromoacetylthiazolidine, cyclopropylchloroacetamide were prepared. ##STR10##
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[F:35])/[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Br:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)(C)O
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (6 g, 28 mmol) prepared in Example 1 and E/Z-6-bromo-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one (6 g, 17 mmol) prepared in Example 90 in dichloromethane (200 mL) were added triethylamine (15 mL, 114 mmol) and AgF (2.8 g, 22 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (30 mL), and DBU (34 g, 138 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (10-40% EtOAc in hexanes) to give as rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a light yellow solid (1.4 g, 15%)
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH2:11](Br)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:3]([O:2][P:1]([CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: BrCCc1ccccc1
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCc1ccccc1)OCC
Temperature: -15 °C
Yield: 51.6 %

Procedure:
Diethyl phosphite (27.64 g, 200 m mole) was dissolved in DMF (200 ml), and to the solution at nitrogen atmosphere while stirring and -15° C., sodium hydride (60% in oil, 9.6 g, 220 m mole) was added. The mixture was stirred for 1 hour at not more than 0° C. To the solution phenethyl bromide (37.0 g, 200 m mole) was dropwise added and further the mixture was stirred overnight at room temperature. DMF was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, and dried with anhydrous sodium sulfate. The solvent was evaporated and the thus obtained oily product was distilled under reduced pressure to obtain diethylphenethylphosphonate (25.0 g, yield: 51.6%) of boiling point 136.5~137.5° C./3 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:29]1[CH:30]=[N:31][CH:32]=[N:33][CH:34]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)CCN>O1CCOCC1.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:20][C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Brc1cncnc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Agent: I[Cu]I
Agent: CN(C)CCN
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cncnc1
Yield: 54.8 %

Procedure:
In a test tube for wicrowave reactor, a solution of 0.20 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl benzoic acid amide synthesized in Step 1 of Synthetic Example 19, 0.10 g of 5-bromopyrimidine, 4.8 mg of copper iodide, 0.21 g of potassium phosphate and 4.4 mg of N,N-dimethyl ethylene diamine in 1 mL of 1,4-dioxane was placed, and reacted by use of a microwave focused chemical synthesizer (Discover manufactured by CEM Corporation) at 120 W and 120° C. for 20 minutes. After the completion of the reaction, insoluble material was removed through silica gel column, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.13 g of the aimed product as white crystal.