Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl.ClC[CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:42][CH2:43][N:38]3[CH2:37][CH2:41][CH2:40][CH2:39]3)=[C:22]([CH3:27])[CH:21]=2)[CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(c2ccc(O)c(C)c2)C2CCCc3ccccc32)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(c2ccc(OCCN3CCCC3)c(C)c2)C2CCCc3ccccc32)cc1

Procedure:
A mixture of (4-methoxyphenyl)(3-methyl-4-hydroxyphenyl)-1,2,3,4-tetrahydronaphth-1-yl-methane (345 mg, 0.001 mol), anhydrous K2CO3 (2.0 gm, 0.014 mol), and 1-(2-chloroethyl)piperidine hydrochloride (400 mg, 0.002 ml) and dry acetone (25.0 ml) was refluxed for 10 hrs, K2CO3 was filtered off, acetone was distilled off, and the residue was diluted with water. The reaction mixture was extracted with ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil which was filtered through basic alumina column with benzene as the eluent and concentrated to give title compound of formula I. Yield 324 mg (72%).
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C:10](=[O:15])[CH2:9]1)C1C=CC=CC=1.[ClH:16].[H][H]>CO.[Pd]>[ClH:16].[CH3:14][C@@H:12]1[CH2:13][NH:8][CH2:9][C@@H:10]([OH:15])[CH2:11]1
Reactant: [H][H]
Reactant: C[C@H]1CC(=O)CN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C[C@@H]1CNC[C@@H](O)C1

Procedure:
To a solution of (S)-1-benzyl-5-methyl-piperidin-3-one (0.9 g, 4 mmol) was dissolved in methanol, 25% aq, hydrochloric acid solution added until the pH was acidic, followed by palladium (10% on activated charcoal, 0.2 g). The mixture was stirred under 1 atmosphere of hydrogen (balloon) for 6 h. The reaction was then filtered through Hyflo and concentrated to afford the title product as a white powder (0.66 g, quant). MS (ISP)=116.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=2)=[C:4]([F:17])[CH:3]=1.C([Li])CCC.[B:23](OC)([O:26]C)[O:24]C.Cl>CCCCCC.C1COCC1.C(OCC)C>[F:17][C:4]1([B:23]([OH:26])[OH:24])[CH2:3][CH:2]=[CH:7][CH:6]=[C:5]1[C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[C:10]([F:16])[CH:9]=1
Reactant: Fc1cc(Br)ccc1-c1cc(F)c(F)c(F)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)C1(F)CC=CC=C1c1cc(F)c(F)c(F)c1
Temperature: -74 °C
Reaction time: 2 h

Procedure:
4-Bromo-2,3′,4′,5′-tetrafluoro-1,1′-biphenyl (T-39) (12.0 g) and diethyl ether (220 ml) were put into a reaction vessel under a nitrogen atmosphere and cooled to −74° C. 1.57M of n-butyl lithium in n-hexane solution (31.5 ml) was added dropwise thereto in the temperature range of −74° C. to −68° C. and stirred another 120 minutes. Then, trimethyl borate (6.70 ml) in THF (20 ml) solution was added dropwise in the temperature range of −75° C. to −68° C. and the stirring was continued for another 180 minutes while the reaction mixture was allowed to come to 25° C. Then, the reaction mixture was cooled to −30° C. and 6N-hydrochloric acid (40 ml) was slowly added dropwise thereto, and the mixture was stirred for another 180 minutes. After the reaction thus obtained had been allowed to come to 25° C., it was poured into ice-water (200 ml) and mixed. Organic and aqueous layers were separated by adding ethyl acetate 200 ml). The aqueous layer was extracted with toluene. The organic layers combined were washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure and 2,3′,4′,5′-tetrafluoro-1,1′-biphenylboronic acid (T-40) (8.91 g) was obtained. The yield based on the compound (T-39) was 85%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]([CH2:14][CH2:15]O)[CH2:11][CH:12]=[CH2:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:30]([NH2:33])[CH:31]=[CH2:32].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([CH2:11][CH:12]=[CH2:13])[CH2:14][CH2:15][N:33]2[CH2:30][CH:31]=[CH2:32])=[CH:4][CH:3]=1
Reactant: C=CCN
Reactant: C=CCN(CCO)C[C@H](O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN1CCN(CC=C)[C@H](c2ccc(Cl)cc2)C1
Temperature: 5 °C
Reaction time: 12 h
Yield: 102.5 %

Procedure:
To (R)-1-(4-chlorophenyl)-2-[(2-hydroxyethyl)(2-propenyl)amino]-1-ethanol (724 mg, 2.5 mmol) produced in Example 13, tetrahydrofuran (2.51 g) and triethylamine (868 mg, 3.5 equivalents) were added. The mixture was cooled to 5° C. Methanesulfonyl chloride (899 mg, 3.2 equivalents) was added dropwise thereto, and then allylamine (839 mg, 6.0 equivalents) was added dropwise thereto. The temperature of the mixture was raised to 25° C., and then the mixture was stirred for 12 hours. To the mixture, 10 wt % aqueous solution of sodium carbonate (4.15 g) was added. After the organic layer and aqueous layer were separated, the aqueous layer was extracted with toluene (5 mL). The organic layers were combined, and washed twice with distilled water (5 mL). The obtained organic layer was concentrated and dried under vacuum, to obtain 709 mg of the title compound as pale yellow oil (yield: 92%, chemical purity: 81.7 area %).
Reaction SMILES: Cl[CH2:2][C:3]1[NH:15][C:14](=[O:16])[CH:13]2[CH:5]([C:6]3[CH2:7][CH2:8][C:9]4[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=4[C:11]=3[S:12]2)[N:4]=1.C(N(C(C)C)CC)(C)C.[NH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[OH:37][C:33]1[CH:32]=[C:31]([NH:30][CH2:2][C:3]2[NH:15][C:14](=[O:16])[CH:13]3[CH:5]([C:6]4[CH2:7][CH2:8][C:9]5[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=5[C:11]=4[S:12]3)[N:4]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C1NC(CCl)=NC2C3=C(SC12)c1ccccc1CC3
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1NC(CNc2cccc(O)c2)=NC2C3=C(SC12)c1ccccc1CC3
Yield: 31.4 %

Procedure:
A solution of EXAMPLE 12E (18 mg), diisopropylethylamine and 3-aminophenol (10 mg) in N,N-dimethylformamide (0.5 mL) were heated at 70° C. for 2 hours. The mixture was cooled and purified by HPLC on a C18 column using 0-70% acetonitrile/0.1% trifluoroacetic acid in water to provide 7 mg of the title compound as the trifluoroacetate salt. 1H NMR (DMSO-d6) δ 12.29 (s, 1H), 9.01 (s, 1H), 8.17 (bs, 1H), 7.53 (m, 1H), 7.31-7.38 (m, 3H), 6.86 (t, J=7.9 Hz, 1H), 6.11 (m, 1H), 6.06 (t, J=2.1 Hz, 1H), 6.03 (dd, J=7.9, 2.1 Hz, 1H), 4.22 (s, 2H), 3.01 (m, 2H), 2.94-2.96 (m, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:17]1)(=[O:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:56][CH2:57][CH2:58][NH:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][N+:61]=1[O-:66]>C1COCC1>[C:13]([N:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:56][CH2:57][CH2:58][NH:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][N+:61]=3[O-:66])=[CH:27][CH:28]=2)[CH2:17]1)(=[O:15])[CH3:14]
Reactant: CCOC(=O)CC1(Cc2ccc(O)cc2)CCCN(C(C)=O)C1
Reactant: [O-][n+]1ccccc1NCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1(Cc2ccc(OCCCNc3cccc[n+]3[O-])cc2)CCCN(C(C)=O)C1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
Diethyl azodicarboxylate (267 mg, 1.53 mmol) was added to a solution of the product from STEP 8 (348 mg, 1.09 mmol) and triphenylphosphine (437 mg, 1.66 mmol) in 3.9 ml THF at 0° C. and stirred for 15 min. 2-(3-Hydroxypropylamino)pyridine N-oxide (418 mg, 2.48 mmol) was added. The reaction was warmed to 40° C. After 15 min, the reaction was cooled to room temperature and stirred for 18 h. The reaction was concentrated and the residue was purified by chromatography (on silica gel, dichloromethane/2-propanol/acetic acid=95/5/0.5) to give a product mixture in 406 mg. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2[N:14]=[C:15](S(C)(=O)=O)[N:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].[NH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>CN1CCCC1=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2[N:14]=[C:15]([NH:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23]
Reactant: NC1CCOCC1
Reactant: CS(=O)(=O)c1ncc2cc(C(=O)c3ccc(F)cc3)n(-c3c(F)cccc3F)c2n1
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(F)cc1)c1cc2cnc(NC3CCOCC3)nc2n1-c1c(F)cccc1F
Temperature: 90 °C

Procedure:
To a solution of [7-(2,6-difluoro-phenyl)-2-methanesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(4-fluoro-phenyl)-methanone, 4, (0.50 g, 1.28 mmol) in 1-methyl-2-pyrrolidinone (4 mL) is added 4-aminotetrahydropyran (0.18 g, 1.80 mmol). The reaction mixture is heated to 90° C. for 19 hours after which the reaction is cooled to room temperature and concentrated in vacuo. The crude residue is purified over silica (40% EtOAc/hexanes) to afford 444 mg of the desired product as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.74 (s, 1H), 7.93 (dd, J=9.0, 5.4 Hz, 2H), 7.48-7.39 (m, 1H), 7.20 (t, J=9.0 Hz, 2H), 7.12-7.06 (m, 3H), 4.10-3.95 (m, 3H), 3.49 (t, J=7.6 Hz, 2H), 2.40 (t, J=7.6 Hz, 2H), 2.06-2.01 (m, 2H); HRMS calcd for C24H19F3N4O2 (M+H)+ 453.1539; found 453.1551.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][C@H:44]5[CH2:45][CH2:46][CH2:47][NH:48][CH2:43]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CCCNC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-1-Boc-3-aminopiperidine. The final compound was purified by reverse phase HPLC and basified to give the free base. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.95 (m., 14 H) 2.40 (t, J=7.38 Hz, 2 H) 2.80 (br. s., 1 H) 2.96 (br. s., 1 H) 3.33 (s, 3 H) 3.81 (br. s., 1 H) 3.94 (s, 3 H) 4.06 (t, J=13.64 Hz, 2 H) 4.45 (m, 1 H) 7.34-7.55 (m, 2 H) 7.90 (s, 1 H) 8.03 (d, J=7.58 Hz, 1 H) 8.21 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H). [M+H] calculated for C27H35F2N7O3, 544; found 544.
Reaction SMILES: [Na+].[C:2]([C:5]1[CH:33]=[CH:32][C:8]([O:9][CH2:10][CH:11]([OH:31])[CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]3[C:18](=[O:25])[CH:19]=[C:20]([C:22]([O-:24])=[O:23])[O:21][C:16]=3[C:15]=2[CH2:28][CH2:29][CH3:30])=[C:7]([CH2:34][CH2:35][CH3:36])[C:6]=1[OH:37])(=[O:4])[CH3:3].[I-:38].[I-].[I-].[K+].[K+].[K+].S(=O)(O)[O-].[Na+].II.Cl>[OH-].[NH4+]>[C:2]([C:5]1[CH:33]=[C:32]([I:38])[C:8]([O:9][CH2:10][CH:11]([OH:31])[CH2:12][O:13][C:14]2[CH:27]=[CH:26][C:17]3[C:18](=[O:25])[CH:19]=[C:20]([C:22]([OH:24])=[O:23])[O:21][C:16]=3[C:15]=2[CH2:28][CH2:29][CH3:30])=[C:7]([CH2:34][CH2:35][CH3:36])[C:6]=1[OH:37])(=[O:4])[CH3:3]
Reactant: [I-]
Reactant: CCCc1c(OCC(O)COc2ccc3c(=O)cc(C(=O)[O-])oc3c2CCC)ccc(C(C)=O)c1O
Agent: Cl
Agent: II
Agent: O=S([O-])O
Product: CCCc1c(O)c(C(C)=O)cc(I)c1OCC(O)COc1ccc2c(=O)cc(C(=O)O)oc2c1CCC
Reaction time: 0.25 h

Procedure:
Dissolve 10.9 gm of 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid sodium salt in 250 ml of 28% ammonium hydroxide solution. Cool the mixture in an ice-water bath. Add 285 ml of a 0.2 m aqueous potassium triiodide solution dropwise. Stir in the cold for 15 minutes. Add sodium bisulfite until iodine color is discharged. Acidify the mixture slowly with 20% aqueous hydrochloric acid. Separate the solids by filtration, wash with water and dry. Dissolve the solids in methanol and esterify with diazomethane in ether. Chromatograph on silica gel, eluting with 15% ethyl acetate in toluene (mp 137°-141° C.). Crystallize from toluene (mp 150°-153° C.). Reflux 2.1 gm of ester product in a mixture of 2.1 gm of sodium bicarbonate, 200 ml of denatured alcohol and 20 ml of water for 1 hour. Strip the mixture to dryness and triturate the residue in ethyl acetate. Separate the solids, dissolve in water and acidify with 10% aqueous hydrochloric acid. Separate the solids by filtration. (mp 179°-182° C.)
Reaction SMILES: [C:1]([C:5]1[O:10][C:9](=O)[CH:8]=[C:7]([OH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+:13].[OH-]>C1(C)C=CC=CC=1>[C:1]([C:5]1[NH:13][C:9](=[O:10])[CH:8]=[C:7]([OH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(O)cc(=O)o1
Reactant: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(O)cc(=O)[nH]1
Yield: 80 %

Procedure:
A mixture of 6-(tert-butyl)-4-hydroxy-2H-pyran-2-one (38 g, 168 mmol) and aq. NH4OH (150 mL, 30%) in dry toluene (200 mL) was heated at reflux for 1 h. The resulting mixture was concentrated and purified by CC (PE/EA=5/1) to give compound 17a (22.5 g, 80%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][CH:14]=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1.CC(O)=O.[BH3-]C#N.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]([CH2:13][CH2:14][NH:25][C:22]1[CH:21]=[CH:20][C:19]([C:18]([O:17][CH3:16])=[O:26])=[CH:24][CH:23]=1)[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NCCN(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 334.5 %

Procedure:
A stirred solution of N-benzyloxycarbonyl-N-methylaminoacetaldehyde (1.77 g, 1.1 mmol) in toluene (3 mL) was added methyl-4-aminobenzoate (1.29 g, 8.5 mmol), and the mixture was stirred for 1 hr at room temp. The reaction mixture was evaporated under a reduced pressure and the residue was dissolved into MeCN (15 mL). To the solution was added AcOH (2.44 mL, 43 mmol) and NaBH3CN (2.67 g, 43 mmol), and the resulting mixture was stirred for 15 hr at room temp. The reaction was quenched by the addition of sat. NaHCO3. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with n-hexane: EtOAc (7:3, v/v) as eluent to give 1.26 g (43%) methyl 4-[2-(N-benzyloxy carbonyl-N-methylamino)ethylamino]benzoate as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ2.96 (s, 3H), 3.32 (br m, 2H), 3.50-3.60 (m, 2H), 3.82 (s, 3H), 5.15 (each d, 2H, J=14.6 Hz), 6.35 and 6.58 (m, total 2H), 7.36 (s, 5H), 7.76 and 7.84 (m, total 2H); MS (FAB) m/z 342 (M++1).
Reaction SMILES: C[O:2][C:3]1[C:4]2[N:5]([C:15]([CH2:18][CH3:19])=[N:16][N:17]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.Cl>C(O)(=O)C>[CH2:18]([C:15]1[N:5]2[C:6]3[C:11]([N:12]=[C:3]([OH:2])[C:4]2=[N:17][N:16]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=3)[CH3:19]
Reactant: CCc1nnc2c(OC)nc3cc(OC)ccc3n12
Agent: Cl
Solvent: CC(=O)O
Product: CCc1nnc2c(O)nc3cc(OC)ccc3n12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture consisting of 3.3 g. (0.013 mole) of 4,7-dimethoxy-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, 33 ml. of 1N hydrochloric acid and 99 ml. of glacial acetic acid was refluxed for a period of two hours. Upon completion of this step, the reaction mixture was cooled to room temperature and poured over ice/water. The resulting mixture was then stirred for a period of 20 minutes and extracted with ethyl acetate. The latter extract next washed with saturated brine and dried over anhydrous magnisium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was finally obtained a yellowish solid product which was washed with water and air-dried to constant weight to ultimately afford 1.87 g. (67%) of pure 1-ethyl-4-hydroxy-7-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >250° C.
Reaction SMILES: [CH3:1][C:2]([CH3:38])([P:35](=[O:37])=[O:36])[N:3]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH2:24][CH2:25][NH:26][C:27]2[C:32](Cl)=[CH:31][N:30]=N[C:28]=2Cl)[CH:17]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH3:15])(=[O:6])=[O:5].[CH3:39]C(C)(P(=O)=O)N(C1C=C(C)C=C(OCCNC2C(Cl)=C(Cl)N=NC=2)C=1)S(C1C=CC=CC=1OCC)(=O)=O>>[CH3:1][C:2]([CH3:38])([P:35](=[O:37])=[O:36])[N:3]([C:16]1[CH:17]=[C:18]([O:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:39][CH:28]=2)[CH:19]=[C:20]([CH3:22])[CH:21]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][CH3:15])(=[O:6])=[O:5]
Reactant: CCOc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2c(Cl)cnnc2Cl)c1)C(C)(C)P(=O)=O
Reactant: CCOc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2cnnc(Cl)c2Cl)c1)C(C)(C)P(=O)=O
Product: CCOc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2ccncc2)c1)C(C)(C)P(=O)=O

Procedure:
was produced in a 54% yield analogously to example 5. Oil. MS (m/e)=518. For this 2-ethoxy-benzenesulfonyl chloride is used in step 5c) instead of 2-methoxy-benzenesulfonyl chloride and one obtained N-(3-cyanomethoxy-5-methyl-phenyl)-2-ethoxy-benzenesulfonamide in a 70% yield (Fp. 142° C.) which was reacted analogously to example 5d) to form N-(dimethyloxophosphinyl-methyl)-N-(3-cyanomethoxy-5-methyl-phenyl)-2-ethoxy-benzene-sulfonamide (46% yield, Fp. 139°-141° C.) and this was reacted analogously to example 5e) to form N-(dimethyloxophosphinyl-methyl)-N-[3-(2-amino-ethoxy)-5-methyl-phenyl]-2-ethoxy-benzenesulfonamide (58% yield, oil, MS (m/e)=440) which was reacted analogously to example 5f) to form a mixture of N-(dimethyloxophosphinylmethyl)-N-{3-[2-(3,5-dichloropyridazin-4-ylamino)-ethoxy]-5-methyl-phenyl}-2-ethoxy-benzenesulfonamide and N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,4-dichloropyridazin-5-ylamino)-ethoxy]-5-methyl-phenyl}-2-ethoxy- benzenesulfonamide (55%, Fp. 114°-116° C.) from which the title compound was obtained analogously to example 5g) by catalytic hydrogenation.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[C:26]([CH3:35])=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([O:30]C)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.O1CCOCC1.[OH-].[Na+].Cl>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[C:26]([CH3:35])=[C:27]([CH:32]=[CH:33][CH:34]=4)[C:28]([OH:30])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)cccc1C(=O)O
Temperature: 70 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of methyl 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-2-methylbenzoate (100 mg) in MeOH-1,4-dioxane (1:2, 4.5 ml) was added iN NaOH solution (1.0 ml) and the mixture was stirred at 70° C. for 1 hour. After cooling, the mixture was acidified with iN HCl and extracted with EtOAc. The organic layer was washed with water and brine, dried over magnesium sulfate, evaporated in vacuo to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]-methyl}-2-methylbenzoic acid (97.0 mg) as a solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15]=3[CH:24]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[C:1]([C:8]1[CH:9]=[CH:10][C:5]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:15]=3[CH:24]=2)=[CH:6][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(-c3ccccc3)ccc2o1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)c1cc2cc(-c3ccc(C(C)=O)cc3)ccc2o1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
12.2 g of acetyl chloride was added to a mixture of 10.3 g of 1B, and 120 ml of carbon disulfide, then 21.8 g of anhydrous aluminum chloride was added in portions to the stirred mixture. The mixture then was stirred at room temperature for 2.5 hours, the temperature rising to 32° C. The mixture was poured into 1 liter of ice water, the mixture was stirred for 30 minutes, and the solution was extracted with ether. The extract was dried (MgSO4) and concentrated. The residue was washed with ether and dried. It was dissolved in 100 ml of chloroform, the solution was treated with a decolorizing agent, and 100 ml of hexane was added. The resulting solution was concentrated to about 100 ml and cooled to give ethyl 5-(4-acetylphenyl)benzofuran-2-carboxylate (6A), mp: 105°-107° C.