Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][NH2:13])=[S:11])=[CH:5][CH:4]=1.Cl.[C:15](=N)(N)[CH3:16].C([O-])(=O)C.[Na+].C(O)CCC>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:15]([CH3:16])=[N:13][N:12]=[C:10]2[SH:11])=[CH:5][CH:4]=1
Reactant: CC(=N)N
Reactant: COc1ccc(NC(=S)NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: COc1ccc(-n2c(C)nnc2S)cc1
Yield: 83 %

Procedure:
A mixture of 13.5 parts of N-(4-methoxyphenyl)hydrazinecarbothioamide, 15 parts of ethanimidamide hydrochloride, 15 parts of sodium acetate and 120 parts of 1-butanol is stirred and refluxed for 1 hour. The reaction mixture is cooled, 100 parts of water are added, followed by the addition of 140 parts of petroleumether. The precipitated product is filtered off and dried, yielding 12.5 parts (83%) of 4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazole-3-thiol; mp. 214.2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:21])[C:5]2[NH:6][C:7](=[O:20])[C:8]3[CH:19]=[CH:18][CH:17]=[N:16][C:9]=3[N:10]([CH:13]3[CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1>[C:22]([N:6]1[C:7](=[O:20])[C:8]2[CH:19]=[CH:18][CH:17]=[N:16][C:9]=2[N:10]([CH:13]2[CH2:15][CH2:14]2)[C:11]2[N:12]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:21])[C:5]1=2)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Cl)nc2c1NC(=O)c1cccnc1N2C1CC1
Agent: CN(C)c1ccncc1
Product: CC(=O)N1C(=O)c2cccnc2N(C2CC2)c2nc(Cl)cc(C)c21
Temperature: 130 °C

Procedure:
A mixture of 2-chloro-11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and acetic anhydride with 4-dimethylaminopyridine was heated at 130° C. until a clear solution was obtained. The solvent was evaporated and the residue was chromatographed over silica gel with ethyl acetate/hexane to give 0.85 g of the title compound, which crystallized from isopropyl ether/ethyl acetate, m.p. 204°-206° C.
Reaction SMILES: [C:1]([S:5]([N:7]=[C:8]([C:10]1[CH:11]=[C:12]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH:13]=[C:14]2[C:19]=1[O:18][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:16][C:15]2=[O:26])[CH3:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[B-]C#N.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO>[CH3:4][C:1]([CH3:2])([S@:5]([NH:7][CH:8]([C:10]1[CH:11]=[C:12]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])[CH:13]=[C:14]2[C:19]=1[O:18][C:17]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[CH:16][C:15]2=[O:26])[CH3:9])=[O:6])[CH3:3]
Reactant: CC(=NS(=O)C(C)(C)C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: O=C([O-])[O-]
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(N[S@](=O)C(C)(C)C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: -15 °C
Reaction time: 5 h
Yield: 5.53 %

Procedure:
The 8-(1-(tert-butylsulfinylimino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide was diluted in DCM (35 mL) and MeOH (35 mL), acetic acid (4.6 mL, 80.4 mmol) and sodium cyanotrihydroborate (1.9 g, 30.2 mmol) was added at −15° C. The resulting mixture was stirred at −15° C. for 5 hrs then allowed to warm to 0° C. A sat. sol. of Na2CO3 was added at 0° C. until pH˜8-9 and extracted with DCM (×2). The organic phase was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel (column SiO2, 15-40 μm-150 g Merck) eluting with 5 to 15% EtOH in DCM. The fractions containing impure product were concentrated down and repurified using the same system. The fractions containing pure 8-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide were combined and the solvent was evaporated to dryness to afford 2.48 g, (5.52 mmol, 54.9%) as a white foam. The fractions containing a mixture of diastereoisomers were combined, concentrated and purified by preparative HPLC on a Waters X-Bridge system. The fractions containing the desired compound were evaporated to dryness to afford a further crop of 8-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (0.25 g, 0.556 mmol, 5.53%) as a white foam. These 2 batches (2.48 g) and (0.25 g) were combined to give 8-(1-((R)-1,1-dimethylethylsulfinamido)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (2.73 g, 60%, diastereomeric excess >95%). Mass Spectrum: M+H+ 450.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4](=[CH2:6])[CH3:5].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(OCC)(=O)C>[CH2:8]([O:7][CH2:3][C:4]([CH3:6])=[CH2:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: C=C(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
Under nitrogen stream, 50 % sodium hydride (5.28 g; 0.11 mole) was added to dry tetrahydrofuran (50 ml), and a solution of methallyl alcohol (7.2 g;0.1 mole) in dry tetrahydrofuran (20 ml) was portionwise added thereto with ice-cooling, followed by stirring for 30 minutes. A solution of benzyl bromide (17.1 g; 0.1 mole) in dry tetrahydrofuran (20 ml) was added thereto to quench the reaction. The reaction mixture was diluted with ethyl acetate and washed successively with lN hydrochloric acid, water and an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 1-benzyloxy-2-methyl-2-propene.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[BH4-].[Na+]>>[I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)/C=C/I
Agent: [BH4-]
Agent: [Na+]
Product: CCCCCC(O)/C=C/I

Procedure:
Treatment of 63 g. (0.25 mole) of 1-iodo-trans-1-octen-3one (Example 724) with sodium borohydride in the manner described in Example 726 gave 58 g. of yellow oil. The oil is purified by adsorption chromatography on a magnesia silica gel column using benzene as eluent to give a light yellow oil.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C@H:27]([OH:34])[CH2:28]OS(C)(=O)=O)=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]>C(#N)C>[ClH:4].[Cl:4][C:5]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C@H:27]([OH:34])[CH2:28][NH:3][CH2:1][CH3:2])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: CCN
Reactant: CS(=O)(=O)OC[C@@H](O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Solvent: CC#N
Product: CCNC[C@@H](O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: Cl
Temperature: 50 °C

Procedure:
Aqueous ethylamine (70%) (2 mL) was added to a solution of 2-chloro-5-[(3S)-3-hydroxy-4-[(methylsulfonyl)oxy]butyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide (Example 1c) (0.2 g) in acetonitrile (5 mL) and heated at 50° C. for 2.5 hours. On cooling the reaction mixture was concentrated and purified by solid phase extraction on Waters' SCX resin, eluting with ammonia in methanol (7M). Further purification by reverse phase HPLC (gradient 25–95% acetonitrile in 0.2% aqueous trifluoroacetic acid (TFA) on Symmetry™ column). The residue was dissolved in methanol (5 mL) and hydrochloric acid in 1,4-dioxane (4M, 1 mL) was added, evaporation and recrystallisation from acetonitrile, gave the titled compound (0.13 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:19])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:20]([O-])=O.[Na+].[CH2:24]1[C:32]2[C:27](=[CH:28][C:29]([N:33]3[C:37](=[O:38])[CH2:36][C:35]([CH3:39])=[N:34]3)=[CH:30][CH:31]=2)[CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>Cl.C(O)C>[OH:19][C:4]1[C:3]([NH:2][N:20]=[C:36]2[C:37](=[O:38])[N:33]([C:29]3[CH:28]=[C:27]4[C:32](=[CH:31][CH:30]=3)[CH2:24][CH2:25][CH2:26]4)[N:34]=[C:35]2[CH3:39])=[CH:8][C:7]([CH3:9])=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=1
Reactant: O=N[O-]
Reactant: Cc1cc(N)c(O)c(-c2cccc(C(=O)O)c2)c1
Reactant: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=NN(c2ccc3c(c2)CCC3)C(=O)C1=NNc1cc(C)cc(-c2cccc(C(=O)O)c2)c1O
Temperature: 0 °C
Yield: 15 %

Procedure:
3′-Amino-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid hydrochloride 11f (346 mg, 1.07 mmol) was dissolved in hydrochloric acid (5 mL, 2 mol/L) upon cooling by an ice-water, followed by addition of 2 mL of aqueous sodium nitrite (81 mg, 1.17 mmol). After the mixture was reacted for 30 minutes, 2-indan-5-yl-5-methyl-2,4-dihydro-pyrazol-3-one 1i (229 mg, 1.07 mmol) was added. The mixture was adjusted to pH 8 with saturated aqueous sodium bicarbonate, followed by addition of 5 mL of ethanol. The mixture was reacted overnight at room temperature. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with ethanol. The filtrate was poured into a mixture of ice and water. The resulting mixture was adjusted to pH 4 with concentrated hydrochloric acid to form precipitates. The mixture was filtered and the filter cake was washed three times with ethyl acetate, and then dried to obtain the title compound 2′-hydroxy-3′-[N′-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene)-hydrazino]-5′-methyl-biphenyl-3-carboxylic acid 29 (75 mg, yield 15%) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1N.C(Cl)Cl.[Br:14][CH2:15][C:16](Br)=[O:17].C([N:21](CC)CC)C>>[Br:14][CH:15]([C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=1[Cl:10])[C:16]([NH2:21])=[O:17]
Reactant: O=C(Br)CBr
Reactant: CCN(CC)CC
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Product: NC(=O)C(Br)c1c(Cl)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 18 h

Procedure:
2,4,6-trichloroaniline, 49.1 gm, was added to 250 ml of methylene chloride. The system was cooled to 0° C. and 34.8 ml of triethylamine was then added. After addition of the triethylamine, 21.8 ml of bromoacetylbromide was added. The system was allowed to warm to room temperature and stirred there for 18 hours. The reaction was then stopped and the solvent was washed with saturated sodium bicarbonate solution. The methylene chloride layer was separated and partially stripped when a solid precipitated from solution. The solid was filtered and air dried to yield 41.4 gm of α-bromo-(2,4,6-trichlorophenyl) acetamide as a gray solid.
Reaction SMILES: [OH-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([O:39]C)=[O:38])=[CH:34][CH:35]=4)[N:30]([CH3:41])[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1.Cl>CO.O.ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([OH:39])=[O:38])=[CH:34][CH:35]=4)[N:30]([CH3:41])[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:17])=[O:18])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: COC(=O)c1ccc2c(C(C(=O)NS(=O)(=O)c3ccc(C)cc3OC)c3ccc4c(c3)OCO4)cn(C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2cc(C(=O)O)ccc12
Temperature: 45 °C
Yield: 92.4 %

Procedure:
Aqueous sodium hydroxide (9.0 liters of a 20% aqueous solution) was added to a stirred suspension of methyl 3-{1-(1,3-benzodioxol-5-yl)-2-[(2-methoxy4-methylphenyl)-sulfonylamino]-2-oxoethyl}-1-methyl-1H-indole-6-carboxylate (from step (b), 5.0 kg) in methanol (25 liters) and demineralised water (20 liters). The suspension was warmed to 45° C. for 1.5 h, cooled to room temperature and diluted with dichloromethane (25 liters). The pH of the aqueous phase was adjusted to 3 with the addition of concentrated hydrochloric acid (7.0 liters) and the phases separated. The organic phase was concentrated to low volume and filtration of the precipitated product gave the subtitle compound as a white crystalline solid (4.5 kg, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH:9]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:8][C:7]2=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[CH:5]=[C:6]2[C:14]=1[N:13]([CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=1)[C:12]1[CH2:11][CH2:10][CH:9]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:8][C:7]2=1
Reactant: CC(C)C(=O)NC1CCc2[nH]c3c(Cl)cc(C#N)cc3c2C1
Reactant: Fc1cccc(CBr)c1
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)cc(Cl)c3n2Cc2cccc(F)c2)C1
Yield: 10 %

Procedure:
Prepare the title compound by essentially following the procedure as described in Example 96 with N-(8-chloro-6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 18) and 3-fluorobenzyl bromide, to obtain the title compound as a white solid in 10% yield. MS (ES): 424 (M+1), 422 (M−1); HPLC (Method A): Rt=3.18 (92%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([C:38]([O:40][CH3:41])=[O:39])[S:36][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:34]=[C:35]([C:38]([O:40][CH3:41])=[O:39])[S:36][CH:37]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cs1
Yield: 97.8 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (138 mg), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (152 mg), tetrakis(triphenylphosphine)palladium(0) (44 mg) and 2M aqueous sodium carbonate solution (0.94 mL) in DME (10 mL) was stirred under nitrogen atmosphere at 100° C. for 2 hr stirred. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (132 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[N:7]=1
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3ccc(F)cc3F)c2n1
Reactant: NC(CO)CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
Reaction time: 2 h
Yield: 51.3 %

Procedure:
To a solution of 4-chloro-8-(2,4-difluorophenyl)-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (2.0 g, 5.6 mmol) in DCM (100 ml) was added a solution of serinol (650 mg, 7.1 mmol) in DMF (5 ml). The mixture was stirred for 2 h, washed with water (2×50 ml), dried (Na2SO4), and evaporated. Flash chromatography (EtOAc/Hexane, 3:1) provided the title compound as a white solid (1.1 g, 50%): LC-MS m/z 383 (M+H)+ retention 2.45 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[O:32][N:31]=[C:30]([CH2:33]OS(C)(=O)=O)[CH:29]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:33][C:30]2[CH:29]=[C:28]([CH3:27])[O:32][N:31]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: Cc1cc(COS(C)(=O)=O)no1
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)no1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with methanesulfonic acid 5-methyl-isoxazol-3-ylmethyl ester (described in WO 2004092172) gave the title compound. ES-MS m/e (%): 462.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([OH:15])C.[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[C:2]([NH2:1])(=[O:15])[CH2:6][C:7]([OH:9])=[O:8].[CH2:10]([O:9][C:7]([C:6]1[C:5]([CH3:12])=[CH:4][S:3][C:2]=1[NH:1][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:8])[CH3:11]
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: CCO
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)CC(=O)Nc1scc(C)c1C(=O)OCC
Product: NC(=O)CC(=O)O

Procedure:
Ethyl 2-amino-4-methyl-thiophene-3-carboxylate, (27.0 mmol, 5.0 g), was heated in diethyl malonate (25 ml) at 180° C. for 3 hrs, and the formed ethanol was allowed to distil off. The oil bath temperature was lowered and diethyl malonate was distilled off at reduced pressure to give the intermediate malonic amide, 2-(2-ethoxycarbonyl-acetylamino)-4-methyl-thiophene-3-carboxylic acid ethyl ester, as an oil that slowly crystallized upon standing (7.7 g, 95%). The malonic amide was dissolved in N,N-dimethylacetamide, (DMA, 40 ml), and sodium hydride (NaH 80%, 2.0 equiv. 54 mmol, 1.62 g) was added. The mixture was heated at 60° C. for 1 h. After cooling and addition of water (300 ml), the product was precipitated by addition of concentrated hydrochloric acid (HCl) to pH 1.5. The precipitate was collected by filtration and recrystallized from methyl isobutyl ketone giving 6,7-dihydro-4-hydroxy-3-methyl-6-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester (3.8 g, 56%). The carboxylic acid ethyl ester, (11.9 mmol, 3.02 g), was dissolved in DMA (40 ml) and NaH (2.1 equiv., 25 mmol, 750 mg) was added. The mixture was heated to 40° C. for 10 min. Thereafter it was cooled to 10° C. and dimethyl sulphate (1.2 equiv., 14.3 mmol, 1.37 ml) was added. The mixture was stirred at ambient temperature for 1 h and then cooled on an ice bath. Water (200 ml) was added and the mixture was acidified with 5 M HCl to pH 1.5. The precipitate was collected and recrystallized from toluene/heptane giving the title compound (2.4 g, 75%).
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:51][CH2:52][CH2:53][OH:54]>O1CCCC1.C(#N)C>[OH:54][CH2:53][CH2:52][NH:51][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:16][CH2:15]1
Reactant: NCCO
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CC(=O)NCCO)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol (150 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (190 mg) in tetrahydrofuran (3 mL) and acetonitrile (3 mL) was added 2-aminoethanol (100 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (124 mg, yield 56%) as white crystals from a fraction eluted with ethyl acetate:hexane=50:50. melting point 214° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11][CH3:12])[C:3]=1[OH:13].CI.[C:16](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH2:10][O:11][CH3:12])[C:3]=1[O:13][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: COCc1ccc(OC)c(Br)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COCc1ccc(OC)c(Br)c1OC
Reaction time: 2.5 h
Yield: 51.2 %

Procedure:
24.1 g (0.098 mole) of 2-bromo-3-methoxy-6-methoxymethylphenol and 27.7 g of methyl iodide are dissolved in 200 ml of acetone in the presence of 14.82 g (0.107 mole) of potassium carbonate. This solution is heated at reflux temperature, with stirring, for 2.5 hours. It is then cooled, the mineral salts are filtered off and the filtrate is distilled to remove the acetone. The residue is taken up in water and extracted with dichloromethane. The organic phase is dried over anhydrous sodium sulfate and distilled under reduced pressure. 13.1 g of 1-bromo-2,6-dimethoxy-3-methoxymethylbenzene are obtained. Yield: 51% of theory; B.P.: 92°-115° C./0.005 mbar.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([N+:26]([O-:28])=[O:27])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:26]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24])[CH2:16][N:6]1[C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[O:3][C:2]1=[O:1])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc2oc(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc2oc(=O)n(Cc3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2 g (10.4 mmol) of methyl 2-oxo-2,3-dihydrobenzoxazole-5-carboxylate, 2.97 g (11.4 mmol) of 4-bromomethyl-1,2-dinitrobenzene (prepared in a corresponding manner to DE 3904797) and 5.7 g (41.4 mmol) of potassium carbonate are suspended in 50 ml of acetonitrile, and the mixture is stirred at 80° C. for 1 h. The reaction mixture is poured into 50 ml of water, extracted with 500 ml of MTBE, dried and evaporated to dryness. The residue is purified by column chromatography on silica gel; product: 1.5 g;
Reaction SMILES: Br.Br.[N:3]1([CH2:9][CH:10]2[C:19]3[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([Cl:39])=[O:38])=[CH:32][CH:31]=1>C(Cl)(Cl)Cl>[ClH:39].[N:3]1([CH2:9][C:10]2([C:37](=[O:38])[CH2:36][C:33]3[CH:32]=[CH:31][C:30]([C:29]([F:40])([F:28])[F:41])=[CH:35][CH:34]=3)[C:19]3[C:14](=[C:15]([OH:20])[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Reactant: Oc1cccc2c1CCNC2CN1CCCCC1
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(Cc1ccc(C(F)(F)F)cc1)C1(CN2CCCCC2)NCCc2c(O)cccc21

Procedure:
Prepared as Ex. No. 34, from 1.65 g (4.06 mmoles) of 1-(piperidin-1-yl)methyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, 2.6 ml (18.50 mmoles) of Et3N and 2.2 g (9.89 mmoles) of 4-trifluoromethylphenyl acetyl chloride in 30 ml of dry chloroform.