Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([O-:3])=[O:2].Cl[CH2:12][CH:13]([OH:15])[CH3:14].[OH-].[Na+]>O>[OH:15][CH:13]([CH3:14])[CH2:12][S:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(O)CCl
Reactant: O=[N+]([O-])c1ccccc1S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)CSc1ccccc1[N+](=O)[O-]
Yield: 94.8 %

Procedure:
In accordance with Reaction I of Example 1, 15.5 g. (0.1 mole) of 2-nitrothiophenol, 11.34 g. (0.12 mole) of 1-chloro-2-propanol, 4.0 g. (0.1 mole) of sodium hydroxide and 150 ml. of water were used for the reaction and an oily product was extracted with benzene after the reaction and benzene was distilled off after a dehydration to obtain 20.2 g. of blackish brawn liquid 2-(β-hydroxypropylthio)nitrobenzene (yield of 94.8%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:4]([N:6]1[CH2:10][C@H:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)[CH2:8][C@H:7]1[C:19]([NH:21][C@H:22]([CH:28]([OH:35])[C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30])[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)=[O:20])=[O:5].C(N(CC)CC)C.[C:47]([N:51]=[C:52]=[O:53])([CH3:50])([CH3:49])[CH3:48]>ClCCl>[C:47]([NH:51][C:52](=[O:53])[NH:2][C@@H:3]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:4]([N:6]1[CH2:10][C@H:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)[CH2:8][C@H:7]1[C:19]([NH:21][C@H:22]([CH:28]([OH:35])[C:29]([NH:31][CH:32]1[CH2:33][CH2:34]1)=[O:30])[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)=[O:20])=[O:5])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)(C)[C@H](N)C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N[C@H](C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-(5-chloro-pyridin-2-yloxy)-N-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)pyrrolidine-2-carboxamide HCl salt (45 mg, 0.077 mmol) in dichloromethane (3.0 mL) was added triethylamine (0.02 mL, 0.154 mmol). After 5 minutes at room temperature, tert-butylisocyanate (0.01 mL, 0.077 mmol) was added and the reaction mixture was stirred at room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, and brine. The dichloromethane layer was then evaporated to dryness under reduced pressure to give (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(5-chloropyridin-2-yloxy)-N-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)pyrrolidine-2-carboxamide.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>C(Cl)Cl>[Br:36][CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc2c(c1)CC(CO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(CBr)O2
Yield: 82.5 %

Procedure:
To a solution of 5.0 g (22.5 mmole) ethyl 2-hydroxymethyl-2,3-dihydrobenzofuran-5-carboxylate in 80 ml methylene chloride under nitrogen was added in one portion 6.5 (24.7 mmole) triphenylphosphine and the resulting solution was stirred for ten minutes. To this was added, in portions over twenty minutes, 4.39 g (24.7 mmole) N-bromosuccinimide and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with methylene chloride, extracted with water, brine and dried (MgSO4). Evaporation in vacuo afforded an oil which was triturated with ethyl ether and filtered to remove insoluble triphenylphosphine oxide. Evaporation of the filtrate yielded 8.4 g of crude product which was charged to a column containing 200 g silica gel and eluted with methylene chloride to provide 5.29 g of purified product, TLC Rf 0.85. Mass spectrum (m/e) 286 (M+). 1H-NMR(CDCl3) ppm(delta): 3.2 (CH2Br), 3.6 (benzyl CH2).
Reaction SMILES: [Cl:1][C:2]([Cl:9])=[CH:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].O>C(Cl)Cl.C1(C)C=CC=CC=1.CCCCCCC.C(OC(=O)C)C>[Cl:1][C:2]([Cl:9])=[CH:3][C:4]1[S:5][C:6]([C:10](=[O:12])[CH3:11])=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: ClC(Cl)=Cc1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(C=C(Cl)Cl)s1
Temperature: 10 °C

Procedure:
Under a dry argon atmosphere, a stirred solution of 3.0 g (0.017 mole) of 2-(2,2-dichloroethenyl)thiophene and 1.33 g (0.017 mole) of acetyl chloride in 10 ml of methylene chloride was cooled to -20° C. During a five minute period 2.24 g (0.017 mole) of anhydrous aluminum chloride was added. The reaction mixture was warmed to 10° C., then poured into 250 ml of cold water. The resultant mixture was extracted with two 100 ml portions of diethyl ether. The combined extracts were washed with 30 ml of a dilute sodium carbonate solution, dried with anhydrous sodium sulfate and filtered. The solvent was evaporated to give a brown solid. The solid was dissolved in a small amount of toluene and subjected to column chromatography on 100 g of silica gel using n-heptane followed by a solution of 10% ethylacetate in n-heptane as eluant. A white solid was obtained and recrystallized from n-heptane to give 2.5 g of crude product. A sample of the crude product was sublimed at 90° C./7 pa to yield 5-(2,2-dichloroethenyl)-2-thienylethanone; mp 81°-85° C. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[N:6]=1.[C:13]([CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](=O)[CH3:28])=[CH:22][CH:21]=1)[CH3:19])([O:15][CH3:16])=[O:14]>>[C:13]([CH:17]=[C:18]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)[CH2:8]2)[CH3:28])=[CH:22][CH:21]=1)[CH3:19])([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C=C(C)c1ccc(CC(C)=O)cc1
Reactant: Cc1nc(C2CNCCO2)cs1
Product: COC(=O)C=C(C)c1ccc(CC(C)N2CCOC(c3csc(C)n3)C2)cc1

Procedure:
Prepared analogously to Example 13 by reaction of 2-(2-methyl-thiazol-4-yl)morpholine with 1-[4-(2-carbomethoxy-1-methyl-ethenyl)phenyl]propan-2-one followed by purification of the base on a silica gel column using chloroform/methanol/ammonia=9:1:0.1 as eluant.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH3:22])[C@H:11]([C:19]([OH:21])=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([O:26][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[NH2:29])C.[OH-].[Na+]>C(O)C>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([S:7]([N:10]([CH3:22])[C@H:11]([C:19]([NH:29][CH:28]([C:27]([OH:37])=[O:26])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(C)[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(C)[C@@H](Cc2ccccc2)C(=O)NC(Cc2ccccc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)-N-methylphenylalanine was coupled to L-phenylalanine ethyl ester using the procedure described in Method 3 (400 mg, 62%). The title compound was prepared via hydrolysis of the ethyl ester using NaOH in ethanol. Proton and carbon NMR analyis indicated a mixture of diastereomers.
Reaction SMILES: [CH2:1]([N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([OH:23])=O)[CH2:16][C:17]([OH:19])=[O:18])[CH2:2][N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=O>C(Cl)Cl>[CH2:20]1[N:15]([CH2:14][CH2:13][N:12]([CH2:24][C:25]([OH:27])=[O:26])[CH2:1][CH2:2][N:3]2[CH2:8][C:9](=[O:10])[O:11][C:5](=[O:7])[CH2:4]2)[CH2:16][C:17](=[O:19])[O:18][C:21]1=[O:23]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)O
Solvent: ClCCl
Product: O=C(O)CN(CCN1CC(=O)OC(=O)C1)CCN1CC(=O)OC(=O)C1

Procedure:
Under these reaction conditions, DTPA ethyl ester comes off the column first, followed by the cyclic product (HETA) and the LiLo ethyl ester (FIG. 8). These three products have different Rf values in TLC, as shown in FIG. 9. The TLC Rf values of In(111) labeled LiLo, HETA and DTPA chelates are provided for comparison (FIG. 10). The formation of the cyclic product was confirmed by spectral analyses using IR, NMR and FAB MS. The FAB mass spectral data are provided in FIG. 11. Also, when the reaction volume was 500 mL (methylene chloride), the DTPA anhydride coupling to the diamine resulted exclusively in the formation of the cyclic product HETA. The nitro derivative of HETA was converted to isothiocyanate derivative of HETA as follows: 500 mg of nitro-HETA was taken in 50 ml of absolute ethanol and reduced to amine derivative using catalytic amounts of PD/C(10%) under hydrogen atmosphere. The solution was filtered and 1 ml of thiophosgene was added dropwise. The solution was stirred for 2 hours and rotoevaporated to obtain the isothiocyanate derivative of HETA. This product was further purified by silica gel column chromatography using 4% methanol in methylene chloride as the solvent (Yield 350 mg). The isothiocyanate derivative of HETA thus obtained was coupled to the human monoclonal antibody 16.88. The resultant 16.88-HETA conjugate was labeled with In(111), and incubated with excess DTPA to assess stability. Stability of the radioimmunoconjugate was followed over a period of 7 days. The results are shown in FIG. 13. 16.88-HETA. In(111) was much more stable than 16.88-DTPA.In(111).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42](O)=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH:18]([N:31]1[C:39]2[C:34](=[CH:35][C:36](/[C:40](/[CH3:45])=[CH:41]/[C:42]([NH:1][C:2]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:43])=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1
Reactant: CCOC(=O)CCCOc1cc(C)ccc1N
Product: C/C(=C\C(=O)Nc1ccc(C)cc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccccc2)c2ccccc2)c1

Procedure:
406 mg of compound 50 was obtained in a similar manner to those described in the Examples 1 and 2 using 712 mg of ethyl 4-(2-amino-5-methylphenoxy)butyrate and 551 mg of 3-(1-benzhydrylindol-5-yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[NH2:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:13])[CH2:8]2
Reactant: NCc1cccnc1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1NCc1cccnc1

Procedure:
Phenyl-5-[(pyridin-3-ylmethyl)-amino]-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 3-(aminomethyl)pyridine. Mass spectrum (ES) MH+=428.
Reaction SMILES: COC1C=CC(O)=CC=1.[OH-].[K+].ClC1C=CC(I)=CC=1.[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=2)=[CH:23][CH:22]=1.Br>C(O)C.[Cu].C(O)(=O)C.CC1C=CC(C)=CC=1>[Cl:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [Cu]
Agent: Br
Agent: COc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Solvent: Cc1ccc(C)cc1
Product: Oc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 49 %

Procedure:
A 1 liter 3-necked flask is equipped with a mechanical stirrer, a Dean-Stark trap carrying a reflux condenser, and a heating mantle, and is charged with 4-methoxyphenol (35.9 grams, 0.29 mol), 85 percent KOH (19.1 grams, 0.29 mol ,and p-xylene (350 ml). The mixture is heated at reflux for 1 hour, removing the water of reaction azeotropically. Then it is cooled, and 1-chloro-4-iodobenzene (69 grams, 0.29 mol), copper powder (2.9 grams, 46 mmol), and cuprous chloride (2.9 grams, 29 mmol) are added, and the mixture is heated at reflux for 20 hours. Workup consists of diluting the cooled mixture with Et2O (200 ml), filtration through a medium-fritted funnel, and concentration of the filtrate to leave a deep dark oily residue. This crude material, consisting primarily of 4-(4-chlorophenoxy)anisole, is treated with glacial acetic acid (275 ml) and 48 percent HBr (105 ml), then the mixture is heated at reflux for 24 hours. Workup consists of partitioning the mixture between H2O (1.2 l) and CH2CL2 (0.5 l), washing the organic phase with H2O (0.5 l), and concentration to leave a deep dark oily residue. This residue is taken up in ethanol (0.5 l) and treated with activated carbon (Norit; ca. 50 grams). Filtration through celite, and concentration of the filtrate gave the crude title compound as a thick, red oil. Further purification of the product is achieved by chromatography on a column packed with flash-grade silica gel (6"×2" i.d.), eluting with CH2CL2, to give after concentration a pinkish solid, which is subsequently recrystallized from hexane-EtOAc to give 31.4 grams (49 percent yield) of pure 4-(4-chlorophenoxy)phenol as off-white prisms, m.p. 85° C. to 86° C.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].C(N(CC)C(C)C)(C)C.[Cl:26][C:27]1[N:28]([CH2:35][C@:36]([OH:40])([CH3:39])[CH2:37][OH:38])[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:10][CH:11]=1)[C:3](=[O:4])[O:38][CH2:37][C@@:36]([OH:40])([CH3:39])[CH2:35][N:28]1[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[N:31]=[C:27]1[Cl:26]
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: CN(C(=O)Cl)c1ccc(OC(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CN(C(=O)OC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl)c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 66 %

Procedure:
N-Methyl-N-(4-trifluoromethoxyphenyl)-carbamoyl chloride (1.33 g, 5.23 mmol), N,N-diisopropylethylamine (1.2 ml, 6.97 mmol) and 4-dimethylaminopyridine (85 mg, 0.70 mmol) were added to a suspension of (R)-2-chloro-1-(2,3-dihydroxy-2-methyl)propyl-4-nitroimidazole prepared in Example 10 (0.82 g, 3.48 mmol) in toluene (10 ml) followed by stirring at 100° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, and the solution was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl N-methyl-N-(4-trifluoromethoxyphenyl)carbamate (1.04 g, yield 65%) as a light yellow amorphous form.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([O:8]C)=[O:7])[C:4]=1[C:13]([O:15]C)=[O:14].[OH-].[K+].CO>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1cccc(OC)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(C(=O)O)c1C(=O)O
Yield: 83.9 %

Procedure:
A suspension of dimethyl 3-methoxyphthalate (69.45 g, 0.31 mol) [prepared as per J. Chem. Soc., Perkin Trans. 1, 1989, 391] in water (300 ml) was treated with potassium hydroxide (43.7 g, 0.78 mol) and the mixture was stirred and held at reflux for 4 hours. Upon cooling to room temperature the methanol liberated during the course of the reaction was removed in vacuo, the mixture acidified to pH 2 or below by the addition of 5M hydrochloric acid and evaporated gently in vacuo to induce crystallization. The solid material was filtered off, washed with a little ice cooled water, sucked dry under reduced pressure and dried in a vacuum oven at 50° C. overnight to afford 3-methoxyphthalic acid (51.0 g, 84%) as a colourless solid. 1H NMR (DMSO-d6) 13.05 (2H, br s), 7.48 (2H, m), 7.33 (1H, m), 3.82 (3H, s). MS: [M+H]+ 197.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[CH:9][C:8]([Cl:10])=[CH:7][CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C1c2cc(Cl)ccc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.2 %

Procedure:
A mixture of 2-bromomethyl-5-chloro-benzoic acid methyl ester (0.200 g, 0.76 mmol), benzylamine (0.135 mL, 1.25 mmol), and K2CO3 (0.276 g, 3.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-6-chloro-2,3-dihydro-isoindol-1-one (0.118 g, 60%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.23 (s, 2H), 4.68 (s, 2H), 7.29 (m, 7H), 7.76 (d, 1H). GC-MS: m/z 257 (M)+, 180 (M−77)+.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([CH2:7][C:8](=[O:9])[CH2:6][CH2:1][CH2:2][CH3:3])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCC(=O)Cc1ccccc1
Reaction time: 15 h

Procedure:
100 ml of n-tetrabutyl tin, then 120 mg of [benzyl (chloro) bis(triphenyl phosphine)]palladium were added to a solution of 40 ml of phenyl acetyl chloride in 500 ml of tetrahydrofuran. The mixture was stirred for 15 hours at reflux, filtered on clarcel and evaporated to dryness. The residue was distilled at 65° C. to 68° C. under 0.5 mm of mercury and the main fraction was chromatographed on silica (eluant: hexane--ethyl acetate (9-1)) to obtain 27.5 g of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[N:14]([C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=1[OH:26])=O>C(O)C.CCOCC>[CH3:1][N:2]1[C:10]2=[N:9][CH:8]=[CH:7][CH:6]=[C:5]2[C:4]([CH3:11])([CH3:12])[C:3]21[CH:13]=[N:14][C:16]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[CH:18][C:17]=1[O:26]2
Reactant: COc1cc(O)c(N=O)c(OC)c1
Reactant: C=C1N(C)c2ncccc2C1(C)C
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(OC)c2c(c1)OC1(C=N2)N(C)c2ncccc2C1(C)C

Procedure:
Into a three-necked 100 milliliter round bottom flask was charged a solution of 0.8 grams of the thus prepared 1,3,3-trimethyl-2-methylene-1,7-diazaindane in 20 milliliters of absolute ethanol. The solution was heated under a nitrogen pad to 60°-65° C. and 0.84 grams of 2-nitroso-3,5-dimethoxyphenol added to the flask. The reaction mixture was maintained at temperature and refluxing for a total reaction time of about 26 hours. The ethanol was removed on a rotary evaporator and the resulting reaction mixture taken up in ether and filtered. The ether solution sequentially was washed with 100 milliliters of a 10 percent sodium hydroxide solution, and 100 milliliters of a saturated sodium chloride solution and then dried over potassium carbonate. The ether was removed under vacuum. A silica gel column was used to isolate the final product, i.e., 1',3'-Dihydro-1',3',3'-trimethyl-5,7-dimethoxyspiro-[2H-1,4-benzoxazine-2,2'-[2H] pyrrolo[2,3-b]pyridine]. Identification of the product was confirmed by appropriate spectral analysis.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19]Cl)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][CH2:19][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(CCCl)cc1OC
Reactant: C1CNCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CCN2CCCNCC2)cc1OC
Yield: 77.1 %

Procedure:
32.27 g of homopiperazine, 13.2 g of 2-(3,4-dimethoxyphenyl)ethyl chloride and 71.3 g of potassium carbonate were added to 500 ml of acetonitrile. The obtained mixture was heated under reflux for 20 hours, cooled and filtered. The filtrate was concentrated under a reduced pressure to obtain a residue. This residue was extracted with ether thrice. The extracts were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent: chloroform/methanol/isopropylamine (100:10:1)) to obtain 13.40 g of the title compound as a yellow oil (yield: 77%).
Reaction SMILES: [N:1]1([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[N:1]1([C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C:23]3=[O:25])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCCNS(=O)(=O)c1ccc(N2CCCCCCC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCCN1S(=O)(=O)c1ccc(N2CCCCCCC2)cc1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
3.4 g of product obtained in stage A are heated to reflux for 1 hour with 3.4 g of sodium acetate in 68 cm3 of acetic anhydride. The mixture is cooled to room temperature and evaporated to dryness, the residue is taken up in 50 cm3 of water, filtered off and dried and 2.87 g of expected product are obtained. M.p. 150°-152° C. After crystallization in isopropanol, 1.9 g of pure product are obtained. M.p. 152°-153° C.
Reaction SMILES: OS(O)(=O)=O.[CH3:6][N:7]([CH2:17][CH:18](OC)OC)[C:8](=[O:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:6][N:7]1[C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:18]=[CH:17]1
Reactant: COC(CN(C)C(=O)Cc1ccccc1)OC
Agent: O=S(=O)(O)O
Product: CN1C=Cc2ccccc2CC1=O
Temperature: 110 °C
Yield: 100.1 %

Procedure:
To a 5 L Morton flask under a strong nitrogen atmosphere was added H2SO4, (1.42 L) and N-methyl-N-(2,2-dimethoxyethyl)phenylacetamide (712 g, 3 mol) was added dropwise to the reaction flask which caused an exotherm (22 to 78° C.). The resulting reaction was then heated to 110° C. for 3 h then cooled to room temperature and transferred to a 20 L Morton flask. At less than 10° C., the reaction mixture was quenched with aqueous sodium hydroxide (9.18 L, 5 N). Extractive workup with ethyl acetate (2×2.85 L), drying with sodium sulfate followed by concentrating to a solid, provided 520 g (73.5%) of 3-methyl-2,3-dihydro-1H-3-benzazepin-2-one as a solid. This material may be recrystallized from MTBE for added purity to give a solid, mp=81-82° C.; (M+H)+=174.2.