Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[NH2:11])[CH2:3][CH2:2]1.[CH2:12](C(CC)(CC)C([O-])([O-])[O-])[CH3:13]>C(OCC)(=O)C>[CH:1]1([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:11]=[C:12]2[CH3:13])[CH2:3][CH2:2]1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: Nc1ccccc1NC1CC1
Solvent: CCOC(C)=O
Product: Cc1nc2ccccc2n1C1CC1
Yield: 94.4 %

Procedure:
A solution of 1.71 g (0.0115 mole) of N-cyclopropyl-1,2-phenylenediamine and 2.12 ml (0.0115 mole) of triethylorthoacetate in 50 ml of ethyl acetate was heated to reflux for 2 hours. The solvent was removed and the residue partitioned between chloroform and water. The organic phase was separated, dried over sodium sulfate and concentrated to give 1.87 g of a brown oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[C:19](O)=[O:20].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:13]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1ncccn1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ncccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.7 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H) in CH2Cl2 (10 mL) was treated with pyrimidine-2-carboxylic acid (129 mg, 1.04 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) and triethylamine (440 mg, 4.35 mmol). The reaction was stirred at room temperature for 48 hour, and then water (10 mL) was added. The reaction was stirred for 1 hour. The solid which separated was filtered and washed with CH2Cl2 (10 mL). The filtered cake was dried to yield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2-carboxamide (110 mg, 38% yield). 1H NMR (400 MHz, (CD3)2SO) δ 12.21 (br s, 1H), 10.47 (s, 1H), 9.06 (d, 2H), 8.40 (d, 1H), 7.87 (d, 1H), 7.77 (t, 1H); LCMS (APCI+) m/z 335.9, 337.9 (M+H)+, Retention time=2.70 minutes (Method 2).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:40][C:41]1([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:43][CH2:42]1>C1COCC1>[N:3]1[CH:4]=[C:5]([C:7]([NH:40][C:41]2([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:43][CH2:42]2)=[O:9])[CH:6]=[N:1][CH:2]=1
Reactant: O=C(O)c1cncnc1
Reactant: CCOC(=O)C1(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(NC(=O)c2cncnc2)CC1
Reaction time: 8 h

Procedure:
A solution of 6.80 g (54.8 mmol) of pyrimidine-5-carboxylic acid, 18.82 mL (135 mmol) of triethylamine and 19.27 g (60 mmol) of TBTU in 200 mL THF was stirred for 30 minutes at ambient temperature. Then 9.11 g (55 mmol) of ethyl 1-amino-cyclopropanecarboxylate hydrochloride were added and the mixture was stirred further overnight. Then the mixture was evaporated down, the residue was stirred with 200 mL water and the crude product was extracted with ethyl acetate. The intermediate product was purified by column chromatography (silica gel, dichloromethane+0-4% methanol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.N1C=CN=[CH:14]1.Cl[Si:19]([CH:22]([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O>[Si:19]([O:10][CH2:9][C:5]1[C:4]([O:11][CH3:12])=[CH:3][C:2]([NH2:1])=[C:7]([Cl:8])[CH:6]=1)([C:22]([CH3:24])([CH3:14])[CH3:23])([CH3:21])[CH3:20]
Reactant: c1c[nH]cn1
Reactant: COc1cc(N)c(Cl)cc1CO
Reactant: CC(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (4-amino-5-chloro-2-methoxyphenyl)methanol (intermediate 38; 1.5 g, 0.008 mol) in dimethylformamide (35 mL) was added imidazole (1.7 g, 0.02 mol). The mixture was cooled to 0° C. and chloro(isopropyl)dimethylsilane (2.5 g, 0.01 mol) was added dropwise. The reaction was stirred overnight at room temperature. The solvent was removed and the crude was partitioned between water and hexane, the organic layer was washed with water, sodium bicarbonate 4% and brine, dried, filtered and evaporated to dryness. The crude obtained was purified by column chromatography with silica gel, eluting with hexane/ethyl acetate (from 8/1 to 4/1). The title compound was obtained as a yellow solid (58%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([OH:13])[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH3:19])=[O:17])=[N:4]1)[CH3:2].[C:20](=[O:23])([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>CC(C)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([O:23][CH3:20])=[CH:9][CH:8]=3)=[C:10]([O:13][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([O:18][CH3:19])=[O:17])=[N:4]1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CCl)cc1
Reactant: CCn1nc(C(=O)OC)c(=O)c2cc(O)c(O)cc21
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1nc(C(=O)OC)c(=O)c2cc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Yield: 137.9 %

Procedure:
To a suspension of methyl 1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydrocinnoline-3-carboxylate (11 g, 35.8 mmol), potassium carbonate (16.33 g, 118 mmol) and potassium iodide (1.189 g, 7.16 mmol) in acetone (200 mL) at room temperature, was added 1-(chloromethyl)-4-methoxybenzene (16.82 g, 107 mmol). The mixture was then heated to reflux overnight. After cooling to room temperature, the mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and brine. The organic phase was separated, and the aqueous phase was extracted with dichloromethane several times. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by automatic silica gel column chromatography (Combiflash RF) eluting with methanol/dichloromethane (0-20%) to afford methyl 1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydrocinnoline-3-carboxylate (15 g, 24.68 mmol, 68.9% yield) as a light yellow solid. LCMS: (M+H)+: 505.1.
Reaction SMILES: C([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O>C(Cl)Cl>[NH2:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 0.17 h

Procedure:
While maintaining the nitrogen atmosphere, the product of Step (K) above is admixed with 3 fold molar excess of carbobenzoxy-L-phenylalanine [Boc-L-phenylalanine, Peninsula, supra.] dissolved in methylene chloride. The resulting mixture is shaken and after about 10 minutes, 3 fold molar excess of N,N-dicyclohexylcarbodiimide in 15 ml. of methylene chloride is added with stirring. The resulting mixture is shaken at room temperature for 4.5 to 5 hours. At the end of this period, the reaction mixture is filtered and the residue washed and dried.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[N:3]=1.[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH2:38])[CH2:34][CH2:33]1.CCOC(C)=O>O>[ClH:1].[ClH:1].[NH2:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:4]([NH:16][CH2:17][CH2:18][NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[N:3]=2)[CH2:34][CH2:33]1
Reactant: COc1ccc(S(=O)(=O)NCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)NCCNc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Product: Cl

Procedure:
The operation is carried out as in Stage 2 of Example 10 starting from 126 mg of the product obtained in Stage 1 above and 319 mg of trans-1,4-diaminocyclohexane and the reaction medium is heated to approximately 140° C. for approximately 3 hours, left to return to 80° C., 5 ml of AcOEt is added, 5 ml of warm water is added, the reaction medium is left to return to ambient temperature, followed by extracting with 2×5 ml of ethyl acetate, washing with 5 ml of saturated sodium chloride, then drying. After purification by chromatography on silica eluting with methylene chloride/methanol/ammonium hydroxide in a proportion of 85/15/1.5, 5 ml of 1.4N hydrochloric acid/ethanol is added, the reaction medium is left to crystallize, followed by filtering, rinsing with 5 ml of ether and drying under vacuum. In this way 95 mg of expected product is obtained in the form of a beige solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].[C:21]1([C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N+]=[N-])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.CCOCC>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][CH:18]=[O:19])[C:15](=[O:20])[N:10]2[C:11]=1[C:12]([O:14][CH:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Yield: 40 %

Procedure:
A solution of (6R,7R)-3-acetoxymethyl-7-formamidoceph-3-em-4-carboxylic acid (6.20g, 20 mmole) in dry tetrahydrofuran (150 ml) was stirred with a solution of diphenyldiazomethane (20 mmole; prepared in ether solution, then evaporated) in dry tetrahydrofuran (20 ml) at +20° to +25° for 16 hrs. The solvent was evaporated and the solution of the residue in methylene chloride (150 ml) was washed successively with 2N-hydrochloric acid 3%-aqueous sodium bicarbonate solution. The solution was dried and evaporated leaving a foam which was chromatographed on kieselgel G (250g) in benzeneethyl acetate (9:1, then 1:1). The appropriate fractions were combined, evaporated, and triturated with ethyl acetate to give the title compound as a crystalline solid (3.789g, 8.1 mmole, 40%), m.p. 158.6 to 160.4(cap.); [α]D +32.8; λmax 261 nm (ε7,750); νmax 3410 (NH), 1788 (azetidin-2-one), 1732 (OCOCH3), 1705 (CO2R) and 1698 and 1502 cm-1 (CONH); τ 1.80 (1H,d,J9Hz, NH), 2.70(10H,m, [C6H5 ]CH), 3.03(1H,s, [C6H5 ]2CH), 4.10 (1H, dd,J9 and 4.5Hz, C7 -H), 4.90 and 5.23 (2H, ABq, J14Hz, CH 2 OCOCH3), 5.04 (1H, d, J5Hz, C6 -H), 6.38 and 6.72 (2H, ABq, J18Hz, C2 -H2), 8.00 (3H,s, OCOCH3). (Found: C, 62.1; H, 4.8; N, 5.8; S, 6.9. C24H22N2O6S(466.5) requires C, 61.8; H, 4.8; N, 6.0; S, 6.9%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([CH:24]([CH3:26])[CH3:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([O:29][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:28])[CH2:23][CH2:22][C@@H:21]([CH:24]([CH3:26])[CH3:25])[C@@H:12]32)[C:3]1([CH3:32])[CH3:33]
Reactant: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Yield: 91.9 %

Procedure:
To a solution of (1S,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethylicosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (3 g, 6.54 mmol) and potassium carbonate (1.808 g, 13.08 mmol) in DMF (60 mL) was added (bromomethyl)benzene (0.816 mL, 6.87 mmol). The reaction mixture was heated up to 60° C. for 3 h. LCMS indicated the starting material was consumed. The reaction mixture was quenched with 60 ml water, a white precipitate was observed. The white solid was collected through filtration and washed with distilled water. The solid was dried in the air to provide the title compound as white solid (3.3 g, 92%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.42-7.28 (m, 5H), 5.27-5.01 (m, 2H), 3.18 (dt, J=11.22, 5.53 Hz, 1H), 2.40-2.09 (m, 3H), 1.91-1.73 (m, 2H), 1.72-0.78 (m, 21H), 0.95 (s, 3H), 0.91 (s, 3H), 0.84 (d, J=7.02 Hz, 3H), 0.80 (s, 3H), 0.75 (s, 3H), 0.73 (s, 3H), 0.73 (d, J=6.71 Hz, 3H).
Reaction SMILES: O=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16](O)=[O:17])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[NH4+:27]>>[C:20]1([NH:19][C:16]([C:11]2[C:10]3[O:9][C:8]4[C:7](=[CH:15][CH:2]=[CH:3][CH:4]=4)[C:2](=[C:3]4[CH2:7][CH:6]5[NH:27][CH:5]([CH2:6][CH2:5]5)[CH2:4]4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:17])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3oc12
Reactant: Nc1ccccc1
Agent: [OH-]
Product: O=C(Nc1ccccc1)c1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2

Procedure:
Using an adaptation of the method described in Procedures 25 and 33, substituting 3-(4-carboxyxanthen-9-ylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 2m for 9-oxo-9H-xanthene-4-carboxylic acid 5j and aniline for ammonium hydroxide in Procedure 25, the title compound 12 was obtained.
Reaction SMILES: [CH:1]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3](I)[CH:2]=1.[OH-:16].[Na+].[O-:18][O-].[Na+].[Na+]>[Cu].O>[CH:2]1[C:3]([OH:16])=[CH:4][CH:5]=[C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:18])=[CH:10][CH:9]=2)[CH:1]=1
Reactant: [O-][O-]
Reactant: Ic1ccc(Oc2ccc(I)cc2)cc1
Reactant: [OH-]
Agent: [Cu]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(Oc2ccc(O)cc2)cc1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
In a 0.5-liter three-neck flask equipped with stirrer, thermometer, and ball condenser, 84.4 g (0.2 mole) of 4,4'-diiododiphenyl ether, 93.0 g (2.32 moles) of NaOH, 2.1 g of powdered copper, 1.7 g of cuprous chloride, 3.3 g of sodium peroxide, and 33 ml of water were heated over 4 hours to 190° C. After cooling to 140° C., another 37 ml of water were added and the batch was stirred for another 3 hours at 150° C. After cooling to room temperature, the batch was mixed with 200 ml of water and filtered. 200 g of ice were added to the filtrate, which was acidified with concentrated hydrochloric acid. The precipitated 4,4'-dihydroxydiphenyl ether was drawn off by suction and recrystallized from 0.8 liter of water. Yield: 33.5 g (83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+:21].[OH-].[Na+].C>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:21])(=[O:14])=[O:12]
Reactant: [NH4+]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
2-Amino-5-nitrobenzenesulfonic acid (200.00 g, 0.917 mol) was suspended in warm sulfolane (250 mL) and the suspension was heated to 80° C. Phosphorous oxychloride (126 mL, 1.375 mol) was added and resulting mixture was heated to 110-120° C. and stirred for 4 h. The resulting solution was cooled to 60° C. and added dropwise into concentrated aqueous ammonium hydroxide solution (800 mL, 11.9 mol) at <10° C. The flask was rinsed with warm sulfolane (50 mL) and the wash was added into the above reaction mixture. The resulting suspension was stirred at 25° C. for 1 h, heated to 95° C. and stirred for 1 hour. The mixture was cooled to 80° C. and the pH was adjusted to 6-8 with 3.0 M aqueous hydrochloric acid solution (˜600 mL) and allowed to cool to 25° C. The dark green suspension was filtered, and the wet filter cake was washed with water (300 mL) and dried at 60° C. overnight to give the crude product (140 g) as a green-yellow solid. The crude product was dissolved in 0.5 M aqueous sodium hydroxide solution (1.4 L, 0.7 mol). Charcoal (14 g) was added and the mixture was heated to reflux and stirred for 15 min. The mixture was filtered through Celite and washed with 0.5 M aqueous sodium hydroxide solution (100 mL). The pH of the filtrate was adjusted to 6-8 with concentrated aqueous hydrochloric acid solution (˜60 mL) and the yellow suspension was allowed to cool to 25° C. The mixture was filtered and the wet filter cake was washed with water (200 mL) and dried at 60° C. overnight to afford the desired product, 2-amino-5-nitrobenzenesulfonamide (130 g, 0.599 mol, 65%) as a bright yellow powder.
Reaction SMILES: [C:1]1([C:7](=[O:23])[CH:8]=[CH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([OH:20])=[C:12]([O:21]C)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.Cl>ClCCl>[C:1]1([C:7](=[O:23])[CH:8]=[CH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([OH:20])=[C:12]([OH:21])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C=CC(=O)c2ccccc2)cc(C(F)(F)F)c1O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C(C=Cc1cc(O)c(O)c(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution containing 0.32 g of the above product obtained in Example 85 in 10 ml of dichloromethane 3 ml of 1 molar BBr3 --CH2Cl2 was added. The mixture was stirred for 20 min at room temperature, acidified with 10 ml 2 N hydrochloric acid and extracted with dichloromethane. The solvent was evaporated in reduced pressure and the residue crystallized from acetone-dichloromethane. Yield 0.07 g (23%), m.p. 196°-201° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:21])[CH2:13][CH:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Se](=O)=O.C(O)CCCC>CCOCC>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[O:21])[CH:13]=[C:14]([C:16]3[NH:20][N:19]=[N:18][N:17]=3)[O:15][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)CCOc1cccc2c1C(=O)CC(c1nnn[nH]1)O2
Agent: O=[Se]=O
Solvent: CCCCCO
Solvent: CCOCC
Product: CC(C)CCOc1cccc2oc(-c3nnn[nH]3)cc(=O)c12

Procedure:
A solution of 0.3 parts of 5-[2,3-dihydro-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole and 0.44 parts of selenium dioxide in 20 parts of amyl alcohol was heated under gentle reflux for 8 hours. After cooling, ether was added to the reaction mixture, the resulting precipitate was filtered off and the filtrate was evaporated to give a solid which was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 40°-60°C) giving 5-[5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole as colourless prisms, m.p. 165°-166°C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](Cl)(C)C.[Cl:25][CH:26]([O:30][C:31](Cl)=[O:32])[CH2:27][CH2:28][CH3:29]>ClCCl>[Cl:25][CH:26]([O:30][C:31]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:32])[CH2:27][CH2:28][CH3:29]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CCCC(Cl)OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
To a suspension of gabapentin (8.55 g, 50 mmol) in dichloromethane at 0° C. was added triethylamine (21 mL, 150 mmol) and TMSCl (6.4 mL, 50 mmol). The resulting suspension was stirred at 0° C. for 20 minutes and then a solution of chloroformate (132) (8.55 g, 50 mmol) in dichloromethane was added. The reaction was stirred for another hour at room temperature, then quenched with citric acid and extracted with dichloromethane. The combined organic phase was washed with water and brine and dried over Na2SO4. Filtration and evaporation gave 9.5 g of crude product (133), which was used directly in the subsequent step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][OH:20])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O[C:22]1[CH:54]=[CH:53][C:25]([CH2:26][CH:27]2[S:31][C:30](=[O:32])[N:29]([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)[C:28]2=[O:52])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[N:16][O:17][CH2:18][CH2:19][O:20][C:22]3[CH:54]=[CH:53][C:25]([CH2:26][CH:27]4[S:31][C:30](=[O:32])[N:29]([C:33]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]4=[O:52])=[CH:24][CH:23]=3)[CH3:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=NOCCO)c1ccc(-c2ccc(C)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccc(C)cc2)cc1
Yield: 86.5 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 539 mg of 2-[1-(4'-methylbiphenyl-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 26), 931 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 366 mg of diethyl azodicarboxylate, 1.24 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=1[O:35][CH3:36].[C:37]1([P:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br-:1].[CH3:36][O:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([CH3:34])[C:28]=1[CH2:27][P+:43]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cccc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 61.5 %

Procedure:
After 4.34 g of N-bromosuccinimide and 0.54 g of benzoyl peroxide were added to a solution of 3.03 g of 2,3-dimethylanisole in 70 ml of carbon tetrachloride, the mixture was heated under reflux for 30 minutes. After cooling, insoluble solid in the reaction mixture were filtered off and the filtrate was concentrated under reduced pressure to give an oil. The obtained oil was dissolved in 50 ml of benzene, and 5.82 g of triphenylphosphine was added to the solution. The mixture was heated under reflux for 11 hours. After cooling, the precipitated crystals were collected by filtration and recrystallized from methylene chloride-benzene to give 6.51 g of (2-methoxy-6-methylbenzyl)(triphenyl)phosphonium bromide as colorless crystals.