Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6](S(C2C=CC=CC=2)(=O)=O)[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[Cl:18][C:19]1[C:24](B(O)O)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])O.[Na+].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.O>[Cl:18][C:19]1[C:24]([C:2]2[NH:6][CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=Cc1cc(Br)n(S(=O)(=O)c2ccccc2)c1
Reactant: OB(O)c1cccnc1Cl
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: O
Solvent: COCCOC
Product: O=Cc1c[nH]c(-c2cccnc2Cl)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 32.9 %

Procedure:
5-Bromo-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (2.67 g), (2-chloropyridin-3-yl)boronic acid (2.00 g), sodium hydrogen carbonate (2.15 g) and tetrakis(triphenylphosphine)palladium (738 mg) were added to a deaerated mixture of 1,2-dimethoxyethane (40 mL) and water (10 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 5 hr. The reaction mixture was allowed to cool, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→1:1). The obtained pale-yellow oil was dissolved in methanol (15 mL) and tetrahydrofuran (15 mL), 8 mol/L aqueous sodium hydroxide solution (15 mL) was added dropwise at room temperature and the mixture was stirred for 30 min. The reaction mixture was diluted with saturated brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the residue and insoluble crystals were collected by filtration to give the title compound as brown crystals (yield 578 mg, 33%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>[N+](C)([O-])=O>[CH3:1][C:2]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Product: Cc1ccc([N+](=O)[O-])c(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2,6-Dimethylbenzoic acid (15 g) dissolved in 350 ml of nitromethane was cooled in an ice bath and treated with 18.9 ml of 70% nitric acid and then 14 ml of concentrated sulfuric acid. The bath was removed and the mixture was stirred at room temperature for 22 hr. The mixture was poured into ethyl acetate, washed several times with water, dried, evaporated, and 17.2 g of 2,6-dimethyl-3-nitrobenzoic acid, mp 115.9-116.5° C., was obtained. ##STR123##
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:29]=[CH:30][C:31]=1[F:32].[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:28]3[CH:29]=[CH:30][C:31]([F:32])=[C:26]([F:25])[CH:27]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(F)c(F)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3,4-Difluorophenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz, not F-decoupled) 7.25 (q, 1H), 7.04 (m, 1H), 6.74 (d, 1H), 5.37 (s, 2H), 3.57 (m, 4H), 3.24 (m, 2H), 3.12 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=423.1, found 423.0.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-:3])=[O:2].[Cl:15][C:16]1[N:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18](Cl)[C:17]=1[Cl:25]>CN(C=O)C>[Cl:22][C:20]1[C:19]([Cl:23])=[C:18]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:11]([F:12])([F:13])[F:14])[C:17]([Cl:25])=[C:16]([Cl:15])[N:21]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: Clc1nc(Cl)c(Cl)c(Cl)c1Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Nc2c(Cl)c(Cl)nc(Cl)c2Cl)c(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
Sodium hydride (4.8 grams of 57% oil dispersion) was washed with pentane and 30 ml. of DMF was added under nitrogen. The slurry was stirred and cooled to 0° C. To this was added a solution of 4-nitro-2-trifluoromethylaniline (11.0 grams, 0.053 mole) in 20 ml. of DMF; the addition was carried out slowly, keeping the temperature of the reaction mixture below 10° C. The reaction mixture was stirred for one hour, slowly reaching room temperature. The reaction mixture was then cooled to 0° C., pentachloropyridine (10 grams; 0.059 mole) added, and the reaction mixture stirred for 72 hours, slowly reaching room temperature. A yellow solid crystallized. It was separated and recrystallized from ethanol. Elemental analysis showed:
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.C(Cl)(=O)C.[Br:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:7][N:5]([CH2:4][C:22]1[NH:23][C:24]2[C:20]([CH:21]=1)=[CH:19][C:18]([O:17][C:16]1[CH:27]=[CH:28][C:13]([Br:12])=[CH:14][CH:15]=1)=[CH:26][CH:25]=2)[CH3:6]
Reactant: CN(C)CN(C)C
Reactant: Brc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CN(C)Cc1cc2cc(Oc3ccc(Br)cc3)ccc2[nH]1

Procedure:
Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane (0.186 g, 0.25 mL, 1.83 mmol) in CH2Cl2 (10 mL) with acetyl chloride (0.143 g, 0.13 mL, 1.83 mmol) followed by a solution of 5-(4-bromophenoxy)indole (0.394 g, 1.37 mmol) in CH2Cl2 (5 mL), gave after work-up 2-(N,N-dimethylaminomethyl)-5-(4-bromophenoxy)indole as a brown gum. This was treated with finely ground potassium cyanide (0.34 g, 5.21 mmol) and methyl iodide (0.77 g, 0.34 mL, 5.44 mmol) in DMF (30 mL) for 16 hr, and after appropriate work-up, 3-cyanomethyl-5-(4-bromophenoxy)indole was obtained as a brown gum 0.29 g, (ca 65%; carried through to next stage without further purification).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[OH:26])[CH3:2].[CH2:27]([C@@H:29]1[O:31][CH2:30]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][N:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:25])[C:4]=1[O:26][CH2:27][C@@H:29]1[CH2:30][O:31]1)[CH3:2]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1O
Reactant: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OC[C@@H]1CO1
Reaction time: 24 h
Yield: 63.8 %

Procedure:
To a solution of the compound of Example 32 (315 mg, 896 μmol) in isopropanol (10 mL) and 3 N aq. NaOH (2 mL), (R)-epichlorohydrine (249 mg, 2.69 mmol) is added. The mixture is stirred at rt for 18 h before another portion of (R)-epichlorohydrine (249 mg, 2.69 mmol) is added. Stirring is continued at rt for 24 h. The mixture is diluted with EA and washed with water. The org. extract is concentrated and the crude product is purified on prep. TLC plates using heptane:EA 7:3 to give 2-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-5-isobutyl-4-methyl-pyridine (233 mg) as a colourless oil; LC-MS: tR=1.18 min, [M+H]+=408.09.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[ClH:7].Cl.[CH:9]1[CH:18]=[CH:17][C:16]2[CH2:19][CH2:20][CH2:21][N:14]3[C:15]=2[C:10]=1[C@H:11]1[CH2:24][NH:23][CH2:22][C@H:12]1[CH2:13]3>>[ClH:7].[ClH:7].[CH3:5][C:4]([CH3:6])=[CH:3][CH2:2][N:23]1[CH2:24][C@H:11]2[C@H:12]([CH2:13][N:14]3[CH2:21][CH2:20][CH2:19][C:16]4[CH:17]=[CH:18][CH:9]=[C:10]2[C:15]3=4)[CH2:22]1
Reactant: c1cc2c3c(c1)[C@H]1CNC[C@H]1CN3CCC2
Reactant: CC(C)=CCBr
Agent: Cl
Product: CC(C)=CCN1C[C@H]2CN3CCCc4cccc(c43)[C@H]2C1

Procedure:
Using 4-bromo-2-methyl-2-butene and following the procedures described in EXAMPLE 104, (±)-cis-5,6,8,8a,9,10,11,11a-octahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline free base from EXAMPLE 11 was converted into the title compound of EXAMPLE 106 as an off-white powder. 1H NMR (dmso-D6) δ: 11.05 (broad s, 1H), 6.86 (t, 1H, J=6.2 Hz), 6.81 (t, 1H, J=7.0 Hz), 6.59 (q, 1H, J=7.3 Hz), 5.33-5.27 (m, 1H), 3.90-3.60 (m, 4H), 3.50-3.25 (m, 2H), 3.10-2.95 (m, 3H), 2.90-2.75 (m, 3H), 2.72-2.65 (m, 2H), 1.95-1.85 (m, 2H), 1.72 (s, 3H), 1.64 (s, 3H). LRMS (ES)+: 283.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.C(N(CC)CC)C>COCCOC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[NH:31][N:30]=[N:29][N:26]=3)=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:27][CH:28]=1
Reactant: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(-c2nnn[nH]2)cc1
Reaction time: 48 h
Yield: 45.5 %

Procedure:
A suspension of methyl 3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (220 mg, 0.55 mmol), sodium azide (43 mg, 0.66 mmol), and triethylamine hydrochloride (91 mg, 0.66 mmol) in anhydrous ethylene glycol dimethyl ether (3 mL) was fluxed for 48 h. Reaction mixture was concentrated, resuspended in water (10 mL) and extracted with ethyl acetate (2×20 mL). The organic layer was washed with 0.5 N HCl solution and brine, dried over MgSO4. After filtration, the filtrate was concentrated to give methyl 3-[(4-methoxyphenethyl)-(4-(tetrazol-5yl)benzenesulfonyl)-amino]-propionate (112 mg, 0.25 mmol).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.S(Cl)([Cl:32])=O>ClCCl.CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([Cl:32])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1

Procedure:
To 0.05 mol of 4-(4-(2-quinolinylmethyloxy)styryl) benzoic acid in dichloromethane solution (500 ml), chilled in an ice bath, is added thionyl chloride (0.06 mol) and a few drops of dimethylformamide. Upon completion of the reaction, the clear solution is evaporated to give 4-(4-(2-quinolinylmethyloxy)styryl)benzoyl choride.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH2:30])[CH:29]=1)=[CH:17]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH:30][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=3)[CH:29]=1)=[CH:17]2
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
4-Hydroxy-3-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.47 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 7 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give an orange solid. Recrystallization from methanol gave the product (300 mg), mp 195-196° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>CN1C(=O)CCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:22]2[CH:23]=[CH:24][C:20]([CH3:19])=[N:21]2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: Cc1cc[nH]n1
Reactant: CSc1nc(N)nc(Br)c1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N)nc(-n2ccc(C)n2)c1C#N
Temperature: 70 °C
Yield: 11.2 %

Procedure:
To a stirred solution of 2.05 g (8.36 mmol) 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile in 15 ml NMP were added 3.00 g (9.20 mmol) cesium carbonate and 0.74 ml (9.20 mmol) 3-methyl-pyrazole and the mixture heated at 70° C. for 16 h. The reaction mixture was then poured into 400 ml ice-water and the resulting precipitate collected by filtration. Chromatography (ethyl acetate/hexane 1/1 then 2/1) afforded 230 mg (11%) 2-amino-4-(3-methyl-pyrazol-1-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 247 (M+H+, 100).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Cl:12])=[C:6]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][C:6]=1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: COC(=O)c1cc(OC)c(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.51 g (1.31 mmol) of 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-benzoic acid methyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([NH:1][CH2:2][C:3]([N:5]1[CH2:9][C:8](=[O:10])[NH:7][C:6]1([CH3:12])[CH3:11])=[O:4])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)NC(=O)CN1C(=O)CN
Product: CC(=O)NCC(=O)N1CC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 1-(2-aminoacetyl)-2.2-dimethyl-4-imidazolidinone (5 g) in acetic anhydride (20 ml) was stirred at room temperature for 1 hour. Evaporation under vacuum and crystallization of the residue from 2-propanol gave 4.63 g of the title compound, m.p. 214°-215° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)=[N:24][CH:23]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: Cc1cnc(-c2cccc(C=O)c2)s1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncc(C)s2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 3-(5-methylthiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 425.02 g/mol.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19].Br[CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]2>>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:21][CH2:22][O:23][C:24]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:25]=4[CH:26]=[CH:27][C:28]([CH3:34])=[N:29]5)[CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19]
Reactant: CN1C(=O)COc2c(CC3CCNCC3)cccc21
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Product: Cc1ccc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5C)CC3)cccc2n1

Procedure:
The title compound was prepared from 4-methyl-8-(piperidin-4-ylmethyl)4H-benzo[1,4]oxazin-3-one and 5-(2-bromoethoxy)-2-methylquinoline in a similar manner to Example 1.
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C(O)C>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][C:2]2([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][OH:22])[CH2:26][CH2:27]3)[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]2=[O:10])=[CH:15][CH:16]=1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(CCCC2(Br)C(=O)NC(=O)NC2=O)cc1
Solvent: CCO
Product: COc1ccc(CCCC2(N3CCN(CCO)CC3)C(=O)NC(=O)NC2=O)cc1
Yield: 3.7 %

Procedure:
A of 5-Bromo-5-[3-(4-Methoxyphenyl)propyl]barbituric Acid (710 mg) and N-(2-hydroxyethyl)piperazine (281 mg) in 25 ml of ethanol is refluxed for 4 hours. The solvent is evaporated under reduced pressure and the residue is partitioned between 1 N hydrochloric acid and ethyl acetate. The aqueous phase is basified to pH=6-7 and extracted with ethyl acetate. The organic phase is concentrated to dryness and the residue is crystallized from ethyl acetate to give 30 mg of the product.
Reaction SMILES: [Na+].[N:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O-:13])=[O:12].[Na+].[CH3:15][C:16]1[O:20][C:19](=[O:21])[O:18][C:17]=1[CH2:22]Br>CC(C)=O>[N:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:15][C:16]2[O:20][C:19](=[O:21])[O:18][C:17]=2[CH3:22])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:22][C:17]1[O:18][C:19](=[O:21])[O:20][C:16]=1[CH3:15])=[O:12]
Reactant: Cc1oc(=O)oc1CBr
Reactant: O=C([O-])c1ccc(C(=O)[O-])nc1
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1oc(=O)oc1COC(=O)c1ccc(C(=O)OCc2oc(=O)oc2C)nc1

Procedure:
Analogously to Example 7, 6.3 g of pyridine-2,5-dicarboxylic acid sodium salt are reacted with 14.3 g of 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl bromide and the mixture is boiled under reflux in acetone for 2.5 hours. After chromatography over silica gel with ethyl acetate as the mobile phase, the product is recrystallized from hot ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=[CH:25]1)=O.CNC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([N:24]([CH3:25])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours with nitrogen bubbling through it. A solution of dimethylamine (2.26 g, 0.050 mole) in tetrahydrofuran (20 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The mixture was evaporated to an oil and partitioned between ethyl acetate (50 ml) and water (50 ml). The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined organic layers were washed once with water (50 ml), twice with 5% potassium hydroxide solution (50 ml portions), and once more with water (50 ml). Drying over magnesium sulfate, treatment with charcoal, filtration and evaporation of the solvents gave a residue which upon recrystallization from hot isopropyl ether and drying under high vacuum gave 3.20 g (59%) of title compound, mp 124°-126° C.
Reaction SMILES: O.[OH:2]OS([O-])=O.[K+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C@H:34]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]2)[C:19](=[O:33])[NH:20][C:21]2[S:22][C:23]([S:26][C:27](C)(C)[C:28]([OH:30])=[O:29])=[CH:24][N:25]=2)=[CH:12][CH:11]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C@H:34]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]2)[C:19](=[O:33])[NH:20][C:21]2[S:22][C:23]([S:26]([CH2:27][C:28]([OH:30])=[O:29])=[O:2])=[CH:24][N:25]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CCN(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CCN(C(=O)Nc2ncc(S(=O)CC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1
Temperature: 25 °C

Procedure:
To Montmorinonite (415 mg) was added H2O (98 μL) the mixture was stirred for 10 min before DCM (0.5 mL), oxone (428 mg, 0.70 mmol) and 2-{2-[3-[2-(4-methoxy-phenyl) -ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid (129 mg, 0.278 mmol) suspended in DCM (2.6 mL) was added in seqence. The mixture was stirred at rt for 1.5 hs. LCMS showed a 1:1 mixture of the sulfoxide and sulfone. The reaction mixture was filtered, washed with DCM and the filtrate was concentrated in vacuo. The mixture was purified by HPLC to give37 mg of {2-[3-[2-(4-methoxy-phenyl)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfinyl}-acetic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:11]=O)=O.C([O-])=O.[NH4+].C([NH2:19])=O>>[N:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:2])[NH:19][CH:11]=1
Reactant: NC=O
Reactant: COC(=O)c1sccc1NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2ccsc12
Temperature: 140 °C
Yield: 74 %

Procedure:
To a mixture of 3-formylaminothiophene-2-carboxylic acid methyl ester (20.5 g, 111 mmol) and ammonium formate (21 g, 333 mmol) was added formamide (29.8 g, 662 mmol). The slurry was heated to 140° C. for 10 hours. After cooling, the solid was filtered, washed with water and dried under vacuum to afford the product 3H-Thieno[3,2-d]pyrimidin-4-one (12.5 g, 74%). 1H NMR (DMSO, 400 Hz) δ 12.31 (br, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.16 (s, 1H), 7.41 (d, J=5.2 Hz, 1H). MS (ESI+) [M+H]+ 153