Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].N1C=CC=CC=1.Cl[C:18]([C:20]1[C:32]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[C:33]([C:36]#[N:37])[C:34]#[N:35])[C:24]=2[CH:23]=[CH:22][CH:21]=1)=[O:19]>ClCCl>[C:36]([C:33]([C:34]#[N:35])=[C:25]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:18]([O:4][CH2:3][CH2:2][N:1]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])=[O:19])[C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)#[N:37]
Reactant: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)Cl)cccc21
Reactant: OCCN(CCO)CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC(C#N)=C1c2ccccc2-c2c(C(=O)OCCN(CCO)CCO)cccc21

Procedure:
A solution of 100.0 grams of triethanolamine and 58 milliliters of dry pyridine in 350 milliliters of dry dichloromethane was stirred at room temperature under a nitrogen atmosphere. A solution of 8.0 grams of (4-chloroformyl-9-fluorenylidene)malononitrile in 400 milliliters of dry dichloromethane was added over a period of 1 hour. After addition, the reaction mixture was further stirred for another hour. The reaction mixture was washed several times with water to remove the excess amines and the corresponding hydrochloride salts, dried with anhydrous magnesium sulfate and filtered. Evaporation of the filtrate gave 5 grams of crude product. Purification by recrystallization from isopropanol afforded 4.5 grams of pure (1c), mp., 155.5°-156.5° C.
Reaction SMILES: [NH2:1][CH:2]([C:8]1([S:21][CH2:22][CH2:23][OH:24])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1([S:21][CH2:22][CH2:23][OH:24])[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[NH:1][S:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][CH2:25][C:26]#[C:27][CH3:28])=[CH:35][CH:34]=1)(=[O:38])=[O:37])[CH3:7]
Reactant: CCOC(=O)C(N)C1(SCCO)CCN(Cc2ccccc2)CC1
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OCC)C2(SCCO)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of ethyl amino{1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}acetate (2.1 g, 5 mmol) and 4-but-2-ynyloxy benzenesulfonyl chloride (1.24 g, 5.1 mmol) in dichloromethane (200 ml) at 0° C., N,N-diisopropylethylamine (3.0 g, 23.6 mmol) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 4 h and quenched with water. The reaction mixture was washed with water, dried over anhydrous MgSO4, filtered and concentrated. It was purified by silica gel column chromatography eluting with 80% ethyl acetate:hexane to give ethyl{1-benzyl-4-[(2-hydroxyethyl)sulfanyl]-4-piperidinyl}({[4-(2-butynyloxy)phenyl]sulfonyl}amino)acetate as a brown oil; Yield: 1.0 g (85%); Electrospray Mass Spec: 561 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[CH:6][C:5]=1[F:11]
Reactant: Cc1cccc(CCl)n1
Reactant: COC(=O)c1ccc(O)cc1F
Agent: Cl
Product: COC(=O)c1ccc(OCc2cccc(C)n2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except KI (1.3 eq.) is also added from 2-Fluoro-4-hydroxy-benzoic acid methyl ester [197507-22-5] and 2-(chloromethyl)-6-methyl-pyridine hydrochloride [CAS 3099-29-4]. MS (ES+) 276.2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[C:3]([C:13]([OH:15])=[O:14])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=C=O
Agent: [K+]
Product: Cc1ccc2ccc(C(=O)O)c(O)c2n1
Temperature: 170 °C
Yield: 29.1 %

Procedure:
8-Hydroxyquinaldine (5.0 g) and potassium carbonate (13.02 g) are mixed together in a stainless steel bomb and heated to 170° C. under 800 p.s.i. CO2 for 6 days. The reaction is then cooled and the resulting solid is partitioned between EtOAc and water. The organic layer is extracted with water (3×). The combined aqueous layers are washed with EtOAc (3×). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, dried and recrystallized from i-PrOH to yield 1.86 g of the title compound as a gold solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24](Cl)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[N:33]1([CH2:39][CH2:40][OH:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.[H-].[Na+].O>CN(C=O)C>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([C:9]2[CH:30]=[CH:29][C:12]3[NH:13][C:14]([NH:16][C:17]([C:19]4[N:20]=[C:21]5[CH:26]=[CH:25][C:24]([O:41][CH2:40][CH2:39][N:33]6[CH2:38][CH2:37][O:36][CH2:35][CH2:34]6)=[N:23][N:22]5[CH:28]=4)=[O:18])=[N:15][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cc(-c3cccc(C(F)(F)F)c3)ccc2[nH]1)c1cn2nc(OCCN3CCOCC3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (100 mg) and 2-morpholin-4-yl-ethanol (250 μL) in dry DMF (1 mL) was added NaH (100 mg, 60% dispersion in mineral oil) and the mixture was stirred at room temperature for 1 h. To this was added water (20 mL) and the reaction mixture stirred for 10 minutes. The precipitated solid was filtered and purified by column chromatography (12 g pre-packed silica gel column cartridge) using DCM and 2N ammonia in methanol to afford 6-(2-morpholin-4-yl-ethoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (42 mg). LCMS (m/z): 552.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH2:19]Cl)C>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:16][O:18][CH3:19]
Reactant: Oc1ccc(Br)cc1Br
Reactant: CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1ccc(Br)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
A flask was charged with 2,4-dibromophenol (50.4 g, 200 mmol), potassium carbonate (69.1 g, 500 mmol) and acetone (500 mL). The suspension was stirred at RT for 30 minutes and then treated dropwise with chloromethyl ethyl ether (19 mL, 213 mmol). After 3 h at RT the mixture was filtered and the filtrate was partitioned between EtOAc and water. The organic phase was separated, washed with water, aqueous saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford 54.2 g 2,4-dibromo-1-(methoxymethoxy)benzene, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C([Li])CCC.[CH3:17][N:18]([CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])[CH3:19].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH3:19][N:18]([CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1([CH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:7])=[O:5])=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:31])[CH3:17]
Reactant: CN(C)CC1CCc2ccccc2C1=O
Reactant: CNC(=O)c1ccccc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1CC1(O)c2ccccc2CCC1CN(C)C
Temperature: 5 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere there is added at room temperature 40.0 g (0.28 mole) of o-methyl-N-methyl benzamide and 250 ml. of anhydrous tetrahydrofuran. The reaction flask is immersed in an ice bath and cooled to an internal temperature of 5°C. Stirring is initiated and 380 ml. of 1.6 m. n-butyllithium (0.616 mole) in hexane is added dropwise in ca. 1 hour maintaining the temperature below 8°C. The resulting red dilithio salt is stirred at 5°C. for 1 additional hour and the reaction flask is then immersed in a dry-ice acetone bath and cooled to an internal temperature of -60°C. To the cold reaction mixture a solution of 56.8 g. (0.28 mole) of 2-(dimethylaminomethyl)-3,4-dihydro-1-(2H)-naphthalenone in 140 ml. of anhydrous tetrahydrofuran is added dropwise in ca. 45 min. maintaining the temperature between -60°C and -50° C. The resulting reaction mixture is stirred at -60°C. for 1 hour, allowed to warm to 0°C in ca 1 hour, and then treated with 200 ml. of saturated aqueous ammonium chloride while maintaining the temperature below 10°C. The resulting two layers are separated and the tetrahydrofuran layer is dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel with benzene; ethylacetate (1:1) to provide α-(2-dimethylaminomethyl-1,2,3,4-tetrahydro-1-hydroxy-1-naphthyl)-N-methyl-o-toluamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]1([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1>>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C:20]2([NH:19][C:15]([C@H:9]3[CH2:10][C:11](=[O:14])[CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C[C@@H]1C(=O)O
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(=O)CCN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 86.2 %

Procedure:
The title compound (D63) (295 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (R)-1-(tert-butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (200 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (206 mg). Reaction time: 18 hrs
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+:16].[Cs+].CC(C)=O>O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Cs+:16]
Reactant: O=C(O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])c1cc(O)ccc1O
Yield: 200 %

Procedure:
1 mol of 2,5-dihydroxybenzoic acid and 0.5 mol of cesium carbonate were added to 200 ml of acetone and 200 ml of water and dissolved therein by stirring. After completely dissolving, the resultant solution was concentrated to dryness to give 1 mol of cesium 2,5-dihydroxybenzoate. 85.8 g (0.3 mol) of cesium 2,5-dihydroxybenzoate, 57.9 g (0.3 mol) of bromooctane and 300 ml of DMF were introduced into a reactor and reacted under a nitrogen gas stream at 100° C. for 3 hours. The reaction solution was concentrated, washed with water and dried to give 78 g (0.29 mol) of 2,5-dihydroxybenzenecarboxylic octane.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C1COCC1>[N:14]1([C:2]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:9](=[O:10])[O:8][CH2:7]3)=[O:3])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OCc2cc(C(=O)N3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution-of 5-chlorocarbonylphthalid (39 g, 0.2 mole) in THF (400 ml) is added to a solution of morpholine (22 g, 0.25 mole) and triethylamine (26 g, 0.25 mole) in THF (200 ml) at 0° C. The mixture is stirred for 1 hour and is allowed to warm to room temperature. The reaction mixture is then poured into ice water (500 ml). THF is evaporated off in vacuo and the pH of the solution is adjusted to pH=2. The solution is cooled to 5° C. and the precipitated crystals are filtred off and washed with water (100 ml).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].Br[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COc1cccc(CCBr)c1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3cccc(OC)c3)CC1)O2
Yield: 83.1 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 1-(2-bromo-ethyl)-3-methoxy-benzene (0.16 ml, 1.5 mmol) as described in Example 56, Step A, giving (E)-3-{1′-[2-(3-methoxy-phenyl)-ethyl]-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (181 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][N:4]1[CH:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1nc[nH]n1
Reactant: ClCc1cccc(Cl)c1
Product: Nc1ncn(Cc2cccc(Cl)c2)n1

Procedure:
Prepared in analogy to example 3a) starting with 3-amino-1,2,4-triazole and 3-chloro benzyl chloride. The title compound was obtained as a colorless solid (Yield=9%). MS ISP (m/e): 211.0 & 209.0 (43 & 100) [M+].
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:11])([CH2:9][OH:10])[C:5](OC)=[O:6]>CO>[F:3][C:4]([F:11])([CH2:9][OH:10])[C:5]([NH:2][CH3:1])=[O:6]
Reactant: COC(=O)C(F)(F)CO
Reactant: CN
Solvent: CO
Product: CNC(=O)C(F)(F)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methylamine in methanol (33% wt, 10 mL) was added methyl 2,2-difluoro-3-hydroxypropanoate (1.0 g, 7.1 mmol) and the mixture stirred at room temperature overnight. After evaporation the residue was recrystallized from diethyl ether/hexanes to afford 2,2-difluoro-3-hydroxy-N-methylpropanamide.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([Br:11])=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C(OCC)(=O)C.CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[C:5]([Br:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)c(C(=O)O)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N)ccc1Br
Reaction time: 72 h

Procedure:
To a solution of 6-amino-3-bromopicolinic acid (30 g) in ethyl acetate (300 mL) and methanol (300 mL) was added TMS-diazomethane (70 mL, 2M in hexanes) and the reaction mixture was stirred for 3 days. The mixture was concentrated, taken up in ether (500 mL) and washed with aqueous Na2CO3 solution (twice), then washed with brine, dried over sodium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.Cl[CH2:14][C:15]1[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=1>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[N:9]([CH2:14][C:15]3[O:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: FC(F)(F)c1ccc(CCl)o1
Product: O=C1CNc2ncc(I)cc2N1Cc1ccc(C(F)(F)F)o1
Yield: 87 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (659 mg) was reacted with 2-(chloromethyl)-5-(trifluoromethyl)furan as in General Procedure 1 to give the title compound as a beige solid (87% yield). M.p. 189-191° C., LCMS: m/z=424.20 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 4.21 (s, 2H), 4.95 (bs, 1H), 5.05 (s, 2H), 6.39 (s, 1H), 6.75 (s, 1H), 7.50 (s, 1H), 7.96 (s, 1H).
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)#[CH:25]>>[C:35]([O:34][C:32]([N:29]1[CH2:30][CH2:31][CH:26]([C:24]2[N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:2]=[N:3][CH:25]=2)[CH2:27][CH2:28]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2cnnn2C2CCc3c(CC(=O)O)c4ccccc4n3C2)CC1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and tert-butyl 4-ethynylpiperidine-1-carboxylate. MS (+ESI) m/z: 480.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12].Br[C:16]1[C:17]([NH2:23])=[N:18][CH:19]=[C:20]([Br:22])[N:21]=1>>[Br:22][C:20]1[N:21]=[C:16]([O:14][CH:10]([C:3]2[C:4]([F:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH:11]([CH3:12])[CH3:13])[C:17]([NH2:23])=[N:18][CH:19]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC(C)C(O)c1c(F)ccc(F)c1Cl
Product: CC(C)C(Oc1nc(Br)cnc1N)c1c(F)ccc(F)c1Cl

Procedure:
5-bromo-3-[1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propoxy]-pyrazin-2-ylamine was prepared following procedure 2 from 1-(2-chloro-3,6-difluoro-phenyl)-2-methyl-propan-1-ol and 3,5-dibromo-pyrazin-2-ylamine.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:37]=[CH:36][C:35]2[C:34](=[O:38])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:39])[C:26]=2[CH:25]=1>>[CH:25]1[C:26]2[C:27](=[O:39])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34](=[O:38])[C:35]=2[CH:36]=[CH:37][C:24]=1[CH2:23][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccc3c(c2)C(=O)c2ccccc2C3=O)c1
Yield: 38 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-chloromethyl anthraquinone were reacted by the same way with the example 1 to obtain the titled compound (193 mg, yield: 38.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:5]([C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O)=O.[NH2:20][CH2:21][CH2:22][SH:23].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:19][C:17]1[CH:16]=[C:4]([C:5]23[S:23][CH2:22][CH2:21][N:20]2[C:9](=[O:11])[C:8]2[C:7]3=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[C:2]([CH3:1])[CH:18]=1
Reactant: NCCS
Reactant: Cc1cc(C)cc(C(=O)c2ccccc2C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cc(C)cc(C23SCCN2C(=O)c2ccccc23)c1
Yield: 53 %

Procedure:
10 mmol 2-(3,5-dimethylbenzoyl)-benzoic acid were dissolved in 100 ml of xylene and, after addition of 20 mmol cysteamine, as well as a catalytic amount of p-toluenesulphonic acid, heated for 2 h under reflux on a water separator. The solvent was then removed in a vacuum and the residue recrystallised from ethanol. Yield 53%, m.p. 163° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21]>O1CCCC1>[OH:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20](=[O:22])(=[O:21])[NH:19][C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH:24]=1
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.2 g, 2.85 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCO3 solution (2.3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acryloyl chloride (16e) (0.21 g) in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was washed with diethyl ether and potroleum ether-ethyl acetate (3:1) affording the title compound (0.14 g, 68%). M.p. 164° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.49 (1H, d, J=16.0 Hz); 7.16-7.89 (12H, m); 7.98 (1H, br s); 10.52 (1H, s); 10.76 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 5% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 50:50; sample concentration 0.5 mg/ml; flow rate 0.8 ml/min; detector UV 220 nm). Anal. Calcd for C19H16N2O4S, %: C, 61.94; H, 4.38; N, 7.60. Found %: C, 61.44; H, 4.39; N, 7.48.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH3:36])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[CH2:32][CH:33](O)[CH3:34]>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][C:13]([O:15][CH:33]([CH3:34])[CH2:32][C:25]2[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=2[CH3:36])=[O:14])=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C(NCC(=O)O)=C(c2ccccc2)S1(=O)=O
Reactant: Cc1cc(C)c(CC(C)O)c(C)c1
Product: Cc1cc(C)c(CC(C)OC(=O)CNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c(C)c1

Procedure:
The title compound was prepared from [(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]acetic acid and 1-mesitylpropan-2-ol. Mass Spectrum: [M+H]+ 499.15, [M−H]− 497.98.
Reaction SMILES: CN1CC[O:5][CH2:4][CH2:3]1.[CH3:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([CH3:35])[CH:34]=1)[C:12]([C:14]1([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=2[CH3:30])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].C(Cl)(=O)C>>[C:4]([N:17]1[CH2:16][CH2:15][C:14]([NH:20][C:21](=[O:31])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=2[CH3:30])([C:12](=[O:13])[C:11]2[CH:10]=[C:9]([CH3:8])[CH:34]=[C:33]([CH3:35])[CH:32]=2)[CH2:19][CH2:18]1)(=[O:5])[CH3:3]
Reactant: COc1cccc(C(=O)NC2(C(=O)c3cc(C)cc(C)c3)CCNCC2)c1C
Reactant: CN1CCOCC1
Solvent: CC(=O)Cl
Product: COc1cccc(C(=O)NC2(C(=O)c3cc(C)cc(C)c3)CCN(C(C)=O)CC2)c1C
Reaction time: 48 h

Procedure:
A 25 mL vial was charged with a magnetic stir bar and morpholinomethylpolystyrene (PS-NMM, ˜300 mg, 1.92 mmol/g, 0.6 mmol). A solution of N-[4-(3,5-dimethyl-benzoyl)-piperidin-4-yl]-3-methoxy-2-methyl-benzamide (76 mg, 0.2 mmol in 2 mL CH2Cl2) was added, followed by acetyl chloride (16 μL, 0.22 mmol). The mixture was stirred for 2 days, filtered, and fractionated on a 2 g silica gel cartridge, eluting with a 0-100% ethyl acetate in hexanes gradient to provide N-[1-acetyl-4-(3,5-dimethyl-benzoyl)-piperidin-4-yl]-3-methoxy-2-methyl-benzamide. 1H NMR (500 MHz; CDCl3) δ (ppm): 7.6 (s, 2H), 7.15 (m, 2H), 6.87 (d, 2H), 6.7 (d, 1H), 4.17 (dt, 1H), 3.8 (s, 3H), 3.78 (m, 1H), 3.45 (t, 1H), 3.25 (t, 1H), 2.5 (m, 1H), 2.35 (m, 1H), 2.32 (s, 6H), 2.2 (m, 1H), 2.17 (m, 1H), 2.05 (s, 3H), 1.92 (s, 3H).