Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:34][C:35]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:36]=1[CH2:37]Cl>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:37][C:36]3[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:35]=3[Cl:34])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Reactant: FC(F)(F)c1ccc(CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(OCc2ccc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
To 20 ml of N,N-dimethylformamide are added 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (0.70 g) and potassium carbonate (0.31 g) and 2-chloro-4-trifluoromethylbenzyl chloride (0.50 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 5 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.80 g of desired compound (melting point: 156.0°-159.0° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:22])[C:20]=1[OH:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=[O:6].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:22])[C:20]=1[O:21][CH2:24][CH:25]1[CH2:27][CH2:26]1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)=[O:6]
Reactant: BrCC1CC1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(O)c(Cl)c2)cc1
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OCC3CC3)c(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 103.5 %

Procedure:
Methyl 4-(3,5-dichloro-4-(cyclopropylmethoxy)benzamido)benzoate (6) (120 mg, 100%) was prepared from methyl 4-(3,5-dichloro-4-hydroxybenzamido)benzoate (5) (100 mg, 294 μmol) and (bromomethyl)cyclopropane (57 μL, 588 μmol) using a procedure essentially the same as in Step (i) for AAA-001 except the mixture was stirred at 50° C. for 18 h: m/z 392 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 7.99 (4H, d), 7.85 (2H, d), 3.99 (2H, d), 3.90 (3H, s), 1.49-1.29 (1H, m), 0.65-0.60 (2H, m), 0.37-0.34 (2H, m).
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13]2[C:8](=[C:9]([C:16]([F:19])([F:18])[F:17])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:20])[CH3:4].[F:21][C:22]1[N:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[F:21][C:22]1[N:27]=[CH:26][C:25]([O:1][CH2:2][C@H:3]([N:5]2[C:13]3[C:8](=[C:9]([C:16]([F:19])([F:17])[F:18])[C:10]([C:14]#[N:15])=[CH:11][CH:12]=3)[CH:7]=[C:6]2[CH3:20])[CH3:4])=[CH:24][CH:23]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)CO
Reactant: Oc1ccc(F)nc1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1[C@H](C)COc1ccc(F)nc1

Procedure:
Synthesized as described in Example 139C using 1-[(1R)-2-hydroxy-1-methylethyl]-2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 329) and 6-fluoro-3-pyridinol: MS (ES) m/z 378 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9][OH:10])=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Cl:13]NC(=O)CCC(N)=O>CN(C)C=O>[OH:10][N:9]=[C:8]([Cl:13])[C:7]1[CH:11]=[CH:12][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: CCCc1ccc(C=NO)cc1
Reactant: NC(=O)CCC(=O)NCl
Solvent: CN(C)C=O
Product: CCCc1ccc(C(Cl)=NO)cc1
Reaction time: 0.17 h

Procedure:
To 4-propylbenzaldehyde oxime (1.4 g, 8.58 mmol) in dimethylformamide (3 mL) was added N-chlorosuccinamide (1.145 g, 8.58 mmol) in batches over a period of 10 min. at room temperature. The reaction mixture was stirred at that temperature for an additional 10 min., and partitioned between ethyl acetate (20 mL) and brine (2×20 mL). The ethyl acetate layer was dried over sodium sulfate and purified by silica gel column chromatography using hexane and ethyl acetate. Fractions corresponding to the desired product were collected and concentrated to yield the title compound, which was immediately used for the subsequent step. LCMS M+1=198.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][N:6]([C:28]1[S:29][CH:30]=[CH:31][N:32]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])=[N:15][CH:14]=[C:13]2[F:27])(=[O:9])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:46][C:47]#[N:48]>CN(C=O)C.C(OCC)(=O)C>[C:47]([CH2:46][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:16]1[C:17]2[C:12](=[CH:11][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:3]=3[O:2][CH3:1])[C:28]3[S:29][CH:30]=[CH:31][N:32]=3)(=[O:8])=[O:9])=[CH:19][CH:18]=2)[C:13]([F:27])=[CH:14][N:15]=1)#[N:48]
Reactant: N#CCBr
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4O)ncc(F)c3c2)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4OCC#N)ncc(F)c3c2)c(OC)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
N-(2,4-dimethoxybenzyl)-4-fluoro-1-(2-hydroxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (0.078 g, 0.141 mmol) was dissolved in DMF (0.7 mL) and cesium carbonate (0.148 g, 0.456 mmol) was added, followed by bromoacetonitrile (10.58 μl, 0.152 mmol). The reaction was heated to 60° C. and stirred overnight. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford 1-(2-(cyanomethoxy)phenyl)-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide. (ESI) 591.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:4][CH2:3]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:6][CH2:7]1
Reactant: Nc1nnc(Br)s1
Reactant: CN1CCN(Cc2cccc(OCCCN)c2)CC1
Product: CN1CCN(Cc2cccc(OCCCNc3nnc(N)s3)c2)CC1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(4-methyl-1-piperazinyl) methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][C:22]([Br:29])=[CH:23][CH:24]=3)[C:19](=[O:30])[C:18]=2[CH:17]=1>C(OCC)C>[C:4]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:19]1([OH:30])[C:18]2[CH:17]=[C:16]([Br:15])[CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][C:22]([Br:29])=[CH:23][CH:24]=2
Reactant: O=C1c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: Brc1ccccc1-c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC1(c2ccccc2-c2ccccc2)c2cc(Br)ccc2-c2ccc(Br)cc21
Reaction time: 3 h

Procedure:
A Grignard reagent prepared from 0.72 g (30 mmol) of magnesium turnings and 5.1 ml (30 mmol) of 2-bromobiphenyl in 15 ml of diethyl ether is added dropwise over the course of 2 hours while stirring (in an ultrasonic bath) to a boiling suspension of 10.0 g (29.6 mmol) of 2,7-dibromo-9-fluorenone in 1 00 ml of dry diethyl ether. After addition is complete, the mixture is boiled for a further 3 hours. After cooling overnight, the precipitate formed is filtered off with suction and washed with cold ether. The magnesium complex filtered off is hydrolyzed in a solution of 15 g of ammonium chloride in 250 ml of ice water. After 1 hour, the 9-(2-biphenylyl)-2,7-dibromo-9-fluorenol formed is filtered off with suction, washed with water and sucked dry. For the ring closure reaction, the dried fluorenol is boiled in 100 ml of glacial acetic acid, after addition of 3 drops of concentrated hydrochloric acid, for 6 hours. The mixture is allowed to crystallize overnight, the product formed is filtered off with suction and washed with glacial acetic acid and water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12])[CH2:6]O.P(Br)(Br)[Br:17].O>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12])[CH2:6][Br:17]
Reactant: COc1cc(CO)cc(OC)c1C(C)C
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: COc1cc(CBr)cc(OC)c1C(C)C
Yield: 175.2 %

Procedure:
To 3,5-Dimethoxy-4-i-propylbenzyl alcohol (12.57 g, 59.8 mmol) in dry ether (100 mL) at 0° C. was added PBr3 (3.0 mL, 31.2 mmol) dropwise under nitrogen. The reaction was monitored by TLC. After the reaction was completed (˜4 h), water (180 mL) was added. The organic layer was separated and the aqueous layer was extracted with ether (3×50 mL). The extract was washed with water (20 mL), sat. Na2CO3 (20 mL), water (20 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation of the solution yielded pure bromide (14.93 g, 91.4%) as a white solid. 1HNMR (CDCl3, ppm): δ 1.29 (d, J=7.1 Hz, 6H), 3.64 (hept, J=7.1 Hz, 1H), 3.84 (s, 6H), 4.50 (s, 2H), 6.60 (s, 2H).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([C:10]([C:12]3[N:13]=[CH:14][N:15](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:16]=3)=O)=[CH:7][CH:8]=[CH:9][C:2]=12.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:15]1[CH:16]=[C:12]([CH2:10][C:6]2[C:3]3=[N:4][S:5][N:1]=[C:2]3[CH:9]=[CH:8][CH:7]=2)[N:13]=[CH:14]1
Reactant: O=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2nsnc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(Cc2c[nH]cn2)c2nsnc2c1

Procedure:
A solution of benzo[1,2,5]thiadiazol-4-yl-(1-trityl-1H-imidazol-4-yl)-methanone (Intermediate L3) (500 mg, 1.12 mmol) in methylene chloride (2 mL) was treated with triethylsilane (8 mL), and trifluoroacetic acid (8 mL) at rt for 48 h. This mixture was evaporated under vacuum and quenched with a ˜7M NH3-MeOH solution. The solvent was exchanged with CH2Cl2. The solution was concentrated onto silica gel and purified by chromatography, eluting with 3% NH3-MeOH:CH2Cl2 to give 4-(1H-imidazol-4-ylmethyl)-benzo[1,2,5]thiadiazole (Intermediate L4). 4-(1H-imidazol-4-ylmethyl)-benzo[1,2,5]thiadiazole (Intermediate L4) was subjected to the appropriate process steps in Method A to produce 4-benzo[1,2,5]thiadiazol-4-ylmethyl-1,3-dihydro-imidazole-2-thione (Compound 16).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][CH2:27][CH2:26][C:25]3=[O:29])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>>[OH:33]/[N:32]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:28][CH2:27][CH2:26][C:25]2=[O:29])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(N3CCCC3=O)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(N3CCCC3=O)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from 1-{4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-pyrrolidin-2-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=414.3 ([M+H]+).
Reaction SMILES: [NH3:1].O.Cl[C:4]1[C:5]([CH3:11])=[N:6][CH:7]=[C:8]([CH3:10])[N:9]=1>>[CH3:11][C:5]1[C:4]([NH2:1])=[N:9][C:8]([CH3:10])=[CH:7][N:6]=1
Reactant: N
Reactant: Cc1cnc(C)c(Cl)n1
Solvent: O
Product: Cc1cnc(C)c(N)n1
Temperature: 165 °C
Reaction time: 16 h

Procedure:
Ammonia in water (3 mL, 48.5 mmol) was added to 3-chloro-2,5-dimethylpyrazine (0.121 mL, 1 mmol) and the mixture heated by microwaves to 165° C. for 7 hours. Following LCMS analysis, the reaction was then reheated to 165° C. for a further 16 hours, by microwaves. After cooling, the solvent was removed under a stream of nitrogen and the crude redissolved in dichloromethane (20 mL). Water (25 mL) was added and the mixture basified to pH14 using sodium hydroxide solution (18 N). The organic layer was removed and the aqueous layer extracted with dichloromethane (5×25 mL). The organic phases were combined and dried using a hydrophobic frit, then evaporated in vacuo to give the title product (109 mg). This was used directly in the next step with no further purification. LCMS (2 min, high pH) Rt 0.47 min, m/z (ES+) 124 (M+H).
Reaction SMILES: C([O:8][CH:9]([CH2:36]OC1C=CC(F)=CC=1)[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC2C=CC=CC=2)=[O:24])[C:15](=[O:33])[CH2:14][S:13]1(=O)=O)C1C=CC=CC=1.[CH2:45](OCC#C[C@@H](OC(=O)C)CCCCC)[C:46]1C=CC=[CH:48][CH:47]=1>>[OH:8][C@@H:9]([CH2:36][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:10][CH2:11][CH:12]1[N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:15](=[O:33])[CH2:14][S:13]1
Reactant: CCCCC[C@@H](C#CCOCc1ccccc1)OC(C)=O
Reactant: O=C(CCCCCCN1C(=O)CS(=O)(=O)C1CCC(COc1ccc(F)cc1)OCc1ccccc1)OCc1ccccc1
Product: CCCCC[C@H](O)CCC1SCC(=O)N1CCCCCCC(=O)O

Procedure:
This compound is prepared essentially by the method as described in Example 5, Step E, except that the benzyl 7-{2-(3-benzyloxy-4-[4-fluorophenoxy]butyl)-1,1,4-trioxo-3-thiazolidinyl}heptanoate is replaced by 1-benzyloxy-4(S)-acetyloxy-2-nonyne and no chromatographic purification is needed. The title compound is obtained as a mobile oil which is used immediately in Step A-6 below.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS(O)(=O)=O.C(Cl)(Cl)Cl>C(OCC)C>[C:17]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:9]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[OH:8])=[O:10])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: O=C(c1ccccc1-c1ccccc1)C(O)c1ccccc1
Yield: 62 %

Procedure:
168.18 g (1.0 mole) of benzil in 2 liters of ethyl ether was placed in a 5 liter, three necked round bottomed flask, fitted with a reflux condenser, mechanical stirrer, addition funnel and nitrogen bypass. All of the glassware was flame-dried before use while being flushed with nitrogen. A3 molar solution in ethyl ether of phenyl magnesium bromide (181.23 g. 1.0 mole) was then placed in the addition funnel and added dropwise to the flask over a period of 1.5 hours. The solution was then refluxed overnight. Hydrolysis of the Grignard complex was then accomplished using a 10% solution of H2SO4 with the concurrent addition of 1.5 liters of CHCl3. After complete hydrolysis, the organic layer was separated and washed with one liter of water. The organic layer was dried with magnesium sulfate, concentrated and recrystallized with hexane to give phenylbenzoin (m.p. 87-88 lit 88° C.) of 99% purity in yield of 62%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])#[N:2].[OH-:15].[Na+].OO>CS(C)=O.C(O)C>[NH2:2][C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[O:13][CH3:14])=[O:15]
Reactant: [OH-]
Reactant: COc1c(C#N)ccc(C(=O)O)c1C
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Product: COc1c(C(N)=O)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
To a solution of 4-cyano-2-methyl-3-(methyloxy)benzoic acid (80 mg, 0.42 mmol) in DMSO:ethanol (1:4, 1 mL) was added 1N aqueous sodium hydroxide (1 mL), and hydrogen peroxide (30% wt. in water, 1 mL). The mixture was stirred at room temperature for 72 hours, then partitioned between 1N aqueous sodium hydroxide and ethyl acetate and the organic layer discarded. The pH of the aqueous portion was adjusted to 7 using 1N aqueous hydrochloric acid. The aqueous portion was extracted several times using ethyl acetate, and the combined organic portion was washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded 55 mg, 0.26 mmol (63%) of 4-(aminocarbonyl)-2-methyl-3-(methyloxy)benzoic acid. 1H NMR (400 MHz, d6-DMSO): 7.77 (br s, 1H), 7.60 (br s, 1H), 7.54 (d, 1H), 7.41 (d, 1H), 3.72 (s, 3H), 2.41 (s, 3H). MS (EI) for C10H9NO3: 190 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:8]3)=[CH:22][CH:23]=2)=[O:37])=[CH:34][CH:33]=1
Reactant: CCOC(=O)Cc1nn(Cc2ccc(N)cc2)c2ccccc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc12
Yield: 53.5 %

Procedure:
The crude ethyl 2-[1-(4-aminobenzyl)-1H-indazol-3-yl]acetate (about 0.663 mmol) obtained in the last step and triethylamine (1.0 mL) were dissolved in dichloromethane (15 mL). In an ice bath, a dichloromethane solution (10 mL) of 4-chlorobenzoyl chloride (117 mg, 0.669 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was reacted at room temperature for 16 hours. An aqueous solution of sodium bicarbonate was added to quench. It was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was rotate evaporated. The resulting residue was chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a white solid 159 mg, at a total yield over two steps of reactions of 53.5%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Sn](CCCC)(CCCC)[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1)CCC.[F-].[K+]>C1(C)C(C)=CC=CC=1>[S:22]1[CH:23]=[CH:24][C:20]([C:2]2[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=2)[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reactant: CCOC(=O)COc1cccc(Br)c1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCOC(=O)COc1cccc(-c2ccsc2)c1
Yield: 64.6 %

Procedure:
2.6 g of the resulting ether compound, 5.3 g of tri-n-butyl(3-thienyl)tin and 20 mg of tetrakis(triphenhylphosphine)paladium were dissolved in 10 ml of xylene, and the mixture was refluxed for 5.5 hours. A 25% aqueous solution of potassium fluoride was added to the solution, and then the precipitate was removed by filtration. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [hexane/ethyl acetate=20/1→15/1] to give 1.7 g of ethyl 3-(3-thienyl)phenoxyacetate as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5](N)=[C:4]([Cl:10])[CH:3]=1.Br.N([O-])=O.[Na+].[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CC(C)=O.O>[Br:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5](/[CH:18]=[CH:17]/[C:16]([O:20][CH3:21])=[O:19])=[C:4]([Cl:10])[CH:3]=1
Reactant: Nc1c(Cl)cc(Br)cc1Cl
Reactant: C=CC(=O)OC
Agent: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)/C=C/c1c(Cl)cc(Br)cc1Cl
Temperature: 0 °C

Procedure:
4-Bromo-2,6-dichloroaniline (5, 80 g) was dissolved in acetone (640 mL), and a 48% hydrogen bromide aqueous solution (120 mL) was added, followed by stirring at 0° C. A sodium nitrite (32 g) aqueous solution (160 mL) was added dropwise thereto, the mixture was stirred for 30 minutes, and methyl acrylate (200 mL), and water (200 mL) were added, followed by stirring for 1 hour. At room temperature, cuprous oxide (2 g) was added, followed by stirring for 2 hours. The reaction solution was extracted with ethyl acetate, and purified by column chromatography to obtain methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g). Methyl (E)-3-(4-bromo-2,6-dichlorophenyl)acrylate (48.5 g) was dissolved in dichloromethane, an ozone gas was introduced at −70° C., and ozone oxidization was performed. To the reaction solution was added dimethyl sulfide (40 mL), and this was extracted with ethyl acetate to obtain 4-bromo-2,6-dichlorobenzaldehyde (6, 37.2 g).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:6][CH:7]([N:9]([CH3:11])[CH3:10])[CH3:8])=[O:4].S(=O)(O)[O-:25].C(O)C(N)(CO)CO>>[CH3:10][N:9]([CH3:11])[CH:7]([CH3:8])[CH2:6][C:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][C:15]([OH:25])=[CH:16][CH:17]=1)[C:3](=[O:4])[CH2:2][CH3:1]
Reactant: CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Reactant: O=S([O-])O
Agent: NC(CO)(CO)CO
Product: CCC(=O)C(CC(C)N(C)C)(c1ccccc1)c1ccc(O)cc1
Reaction time: 0.03 h

Procedure:
The procedure of Example 5 is repeated using the methadone derivative 6-methylamino-4-phenyl-4-(4-hydroxyphenyl)heptan-3-one except for the following modifications. Instead of mixing the NaI125 reaction mixture on a Vortex mixer the mixture is shaken gently for 90 seconds and after addition of the bisulfite the mixture is shaken gently for 30 seconds. Finally 2.0 ml of 0.1 M Tris buffer pH 7.0 is used prior to the column chromatography step. The resulting above-captioned labeled antigen is obtained in Fractions #22-27 at a radioactive concentration of 10.5μCi/ml. EXAMPLE 7
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])[CH:6]=[CH:7][CH:8]=1.[OH:32][CH:33]([CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])[C:34](=[O:54])[CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][C:51](O)=[O:52])=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:51](=[O:52])[CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][C:34](=[O:54])[CH:33]([OH:32])[CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])=[CH:18][CH:17]=1
Reactant: O=C(O)COCCOCC(=O)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO
Reactant: NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCC(=O)NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO

Procedure:
31 is prepared similarly to 18 starting from 68 mg of 4-(3-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (15), 76 mg of [2-({2-[2-(3,4,5,6,7-pentahydroxy-2-oxoheptyloxy)ethoxy]ethylcarbamoyl}methoxy)-ethoxy]acetic acid (27), 62 μl of diisopropylcarbodiimide and 44 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 31: C43H55F2N3O14 (875.93) MS (ESI) 876 (M+H)