Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:12])[N:9](S(C3C=CC=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1.[OH-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([CH3:12])[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: COc1cnc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cnc2[nH]c(C)cc2c1
Yield: 90.7 %

Procedure:
A solution of 5-methoxy-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (950 mg, 3.14 mmol) and 40% aqueous sodium hydroxide (106 ml) in methanol (160 ml) was heated at reflux for 30 minutes. After cooling, the mixture was poured onto cooled water and extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1/1). The fractions containing the expected product were combined and evaporated to give 5-methoxy-2-methyl-1H-pyrrolo[2,3-b]pyridine (462 mg, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH2:29][OH:30])[N:23]=[C:22]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[N:36]1[C:40](=[O:41])[CH2:39][CH2:38][C:37]1=[O:42]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]([O:28][N:36]3[C:40](=[O:41])[CH2:39][CH2:38][C:37]3=[O:42])=[O:27])=[C:24]([CH2:29][OH:30])[N:23]=[C:22]2[CH2:31][CH2:32][CH2:33][CH3:34])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCc1nc(CO)c(C(=O)O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
206 mg of N,N-dicyclohexylcarbodiimide were added to a suspension of 464 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylic acid (prepared as described in Example 4) and 140 mg of N-hydroxysuccinimide in 10 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 16 hours. At the end of this time, the material which had precipitated was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 1:15 by volume mixture of methanol and methylene chloride as the eluent, to afford 0.52 g of the title compound as crystals, melting at 107°-109° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20]OC)[CH2:11][CH2:10][N:9]([S:12]([CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[F:27][C:28]([F:38])([F:37])[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>CCCCCCC>[CH3:18][CH:16]([CH3:17])[CH2:15][S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:34]([C:33]3[CH:35]=[CH:36][C:30]([O:29][C:28]([F:27])([F:37])[F:38])=[CH:31][CH:32]=3)[CH2:20][CH2:19]2)[CH2:11][CH2:10]1)(=[O:13])=[O:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)CC(C)C)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Yield: 77.2 %

Procedure:
This material was prepared in analogy to example 1 step D) 4-(2-methoxy-ethyl)-1-(2-methyl-propane-1-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (0.134 g), dimethylaluminium chloride in heptane (1.0 molar, 1.2 ml) and 4-(trifluoromethoxy)-aniline (0.106 g) to give the desired 8-(2-methyl-propane-1-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.134 g) as an off-white solid. MS (ESI): 435.15 (MH+).
Reaction SMILES: [ClH:1].C(O)C.[C:5](/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:17])=[CH:11][CH:10]=1)#[N:6].[CH2:30](N)[CH2:31][NH2:32].C(=O)([O-])O.[Na+]>C(O)C>[ClH:1].[NH:6]1[CH2:30][CH2:31][N:32]=[C:5]1/[CH:7]=[CH:8]/[C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: NCCN
Reactant: N#C/C=C/c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1ccc(/C=C/C2=NCCN2)cc1)c1ccc(-c2ccccc2)cc1
Reaction time: 16 h

Procedure:
10.1 N Hydrogen chloride-ethanol solution (30 ml) was added to an ethanol suspension of N-[4-[(E)-2-cyanoethenyl]phenyl][1,1′-biphenyl]-4-carboxamide (250 mg, 0.771 mmol) obtained in Reference Example under room temperature, which was stirred for 16 hours. After the solvent was distilled out under reduced pressure, ethanol was again added to the residue, and then ethylenediamine (0.155 ml, 2.31 mmol) was added at room temperature, which was stirred for 16 hours. Sodium hydrogencarbonate solution was added to the reaction mixture, and the precipitated crude product was washed with water and chloroform. This product was dissolved in methanol. 1 N Hydrochloric acid (4 ml) was added to the solution, and the solvent was distilled out under reduced pressure. Small amount of water was added to the resulting residue, to give the titled compound (124 mg) as a colorless powder.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][C@H:17]([C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[N:22]1([C:20]([C@H:17]2[CH2:18][CH2:19][NH:15][CH2:16]2)=[O:21])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@H]1CCNC1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Pyrrolidine (51 μL, 1.03 mmol) was added to a solution of (S)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (200 mg, 0.93 mmol), HATU (391 mg, 1.03 mmol) and DIPEA (410 μL, 2.35 mmol) in DMF and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of (S)-3-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a pale brown oil (110 mg, 70%). 1H NMR (CDCl3, 400 MHz) δ 4.01 (m, 3H); 3.52-3.41 (m, 3H); 3.25-3.11 (m, 2H); 3.10-2.97 (m, 2H); 2.89 (dt, J=11.4, 7.5 Hz, 1H); 2.11-1.99 (m, 1H); 2.01-1.91 (m, 2H) and 1.93-1.82 (m, 2H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][S:2]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:19][CH:18]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of methyl 4-(chlorosulfonyl)benzoate (Example 5-10c) (4 g, 17.09 mmol) in dichloromethane (40 mL) at 0° C. in an ice bath, was added (4-methoxyphenyl)methanamine (2.56 mL, 19.65 mmol) and triethylamine (2.38 mL, 17.1 mmol). The ice bath was then removed and the mixture was allowed to warm to ambient temperature with stirring for an additional 2 hours. Upon completion (monitored by TLC 40% ethyl acetate/hexanes), the solvent was removed in vacuo. The residue was re-dissolved in ethyl acetate (200 mL), washed with 1N HCl (aq, 20 mL), water (20 mL) and brine (20 mL) then dried over magnesium sulfate. The solution was concentrated and the product purified by re-crystallization with hot ethyl acetate/hexanes to afford pure methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (4.3 g, 74.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.67 (s, 3H), 3.78 (s, 3H), 3.93 (s, 2H), 6.78 (m, 2H), 7.09 (m, 2H), 7.87 (m, 2H), 8.08 (m, 2H), 8.25 (br, s, 1H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].[O-]S([O-])(=O)=O.[Mg+2].S(=O)(=O)(O)O>ClCCl>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reaction time: 336 h
Yield: 39.5 %

Procedure:
This compound was prepared from 4-(bromomethyl)benzoic acid (2.15 g; 10.0 mmol), t-butyl alcohol (4.8 mL; 50 mmol), anhydrous MgSO4 (4.8 g; 40 mmol), and concentrated sulphuric acid in dichloromethane (40 mL) as described in Example 6a. After 14 days, the mixture was worked up as described in Example 6a. 1.07 g (39%) product was obtained (white solid). The product was used in 7b without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.[CH3:15][C:16]1[C:20]([S:21](Cl)(=[O:23])=[O:22])=[C:19]([CH3:25])[O:18][N:17]=1.C1OCCOCCOCCOCCOCCOC1>C(#N)C.O>[Cl:7][C:8]1[CH:14]=[CH:13][C:11]([NH:12][S:21]([C:20]2[C:16]([CH3:15])=[N:17][O:18][C:19]=2[CH3:25])(=[O:23])=[O:22])=[CH:10][CH:9]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1noc(C)c1S(=O)(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a suspension of potassium carbonate (0.18 g (1.28 mmol)) in acetonitrile (5.0 ml), 4-chloroaniline (0.33 g (2.56 mmol)), 3,5-dimethyl-4-isoxazolesulfonyl chloride (0.50 g (2.56 mmol)), 18-crown-6 (0.20 g (0.77 mmol)), were added with stirring at room temperature and the resulting mixture was stirred for 16 hours at the same temperature. Then, water (15.0 ml) was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with chloroform as eluent, to give 0.68 g (92%) of N-(4-chlorophenyl)-3,5-dimethyl-4-isoxazolesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:7])=[O:6].Cl.[N:17]([O-])=O.[Na+]>O>[CH2:12]([N:11]1[C:10]2[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=2[N:1]=[N:17]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNc1ccc(C(=O)O)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCn1nnc2cc(C(=O)O)ccc21
Yield: 72.6 %

Procedure:
To a stirred and cooled mixture of 43.7 parts of 3-amino-4-(butylamino)benzoic acid and 200 parts of a hydrochloric acid solution 6N was added dropwise a solution of 22 parts of sodium nitrite in a small amount of water. Upon complete addition, the reaction mixture was stirred for 4 hours at 10°-20° C. The product was filtered off, washed with 30 parts of water and crystallized from a mixture of 2-propanone and ethyl acetate. The product was filtered off and dried, yielding 33.3 parts (72.6%) of 1-butyl-1H-benzotriazole-5-carboxylic acid; mp. 192.5° C. (int. 9).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:9])[C:3]=1[N+:15]([O-:17])=[O:16].C(N(C(C)C)CC)(C)C.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:38][CH:37]=[N:36][N:35]=2)=[CH:30][C:29]=1[NH2:39]>CCCCO>[CH3:12][C:11]([CH3:14])([CH3:13])[CH2:10][N:8]([CH3:9])[C:4]1[C:3]([N+:15]([O-:17])=[O:16])=[C:2]([NH:39][C:29]2[CH:30]=[C:31]([C:34]3[NH:38][CH:37]=[N:36][N:35]=3)[CH:32]=[CH:33][C:28]=2[CH3:27])[N:7]=[CH:6][N:5]=1
Reactant: Cc1ccc(-c2nnc[nH]2)cc1N
Reactant: CN(CC(C)(C)C)c1ncnc(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc(-c2nnc[nH]2)cc1Nc1ncnc(N(C)CC(C)(C)C)c1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 30.5 %

Procedure:
A solution of (6-Chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-methyl-amine (185 mg, 0.72 mmol), diisopropylethylamine (0.13 mL, 0.72 mmol) and 2-Methyl-5-(4H-[1,2,4]triazol-3-yl)-phenylamine (126 mg, 0.72 mmol) in 3 mL of n-BuOH was heated with stirring at 80° C. for 18 h. The solvent was then evaporated in vacuo and the crude product was purified by flash chromatography to afford 87 mg of the product (30%). MS (m/z) calcd for C19H24N8O2 (MH+), 397.2, found, 397.3.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([CH2:9][C:10](OCC)=[O:11])#N.Cl[C:16]([Cl:24])([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(C=C)=O>C(OCC)(=O)C>[Cl:24][C:16]([C:22]#[N:23])([CH2:7][CH2:9][CH:10]=[O:11])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C(Cl)(Cl)C#N
Agent: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cl)(C#N)CCC=O
Temperature: 5 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a suspension of finely ground K2CO3 (4.26 g, 30 mmol) in 100 mL of ethyl acetate were added sequentially 5.65 g of ethyl cyanoacetate (50 mmol) and 9.1 g of ethyl dichlorocyanoacetate (50 mmol) at 0° C. Acrolein (6.72 g, 120 mmol) was added within a period of 1 h using a syringe pump. The resulting mixture was stirred at 5° C. for 3 hours, filtered through Celite with the aid of CH2Cl2, concentrated (25° C., 25 mm Hg), and distilled to give 15.6 of the title compound (77%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[CH:57]=[C:56]([C:61]1[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=1)[CH:55]=[CH:54]2>CN(C)C=O>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][CH:60]=1)[CH:57]=[C:56]([C:61]1[CH:62]=[C:63]([NH:67][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:64]=[CH:65][CH:66]=1)[CH:55]=[CH:54]2
Reactant: COc1ccc2cc(-c3cccc(N)c3)ccc2c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2cc(-c3cccc(NC(=O)c4cc5cccc(O)c5oc4=O)c3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
Diisopropylethylamine (DIEA, 0.0115 mL, 0.067 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.012 g, 0.06 mmol) and O-(7-Azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluronium hexafluorophosphate (HATU, 0.025 g, 0.067 mmol) in 0.5 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-methoxy-naphthalen-2-yl)-phenylamine (0.015 g, 0.06 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in dimethylsulfoxide (DMSO). The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% acetonitrile (ACN)/H2O with 0.05% trifluoroacetic acid (TFA) at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected. Solvent was removed under vacuum and the resulting solid was left overnight in vacuo to give 0.010 g of product in 38% yield: LCMS (ESI) m/z 438 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][OH:13])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1.[H-].[Na+].[CH3:20]I>C1COCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][CH3:20])=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH:15]([CH3:17])[CH3:16])[N:3]=1
Reactant: CC(C)n1nc(Br)c2ccc(CO)cc2c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc2c(Br)nn(C(C)C)c(=O)c2c1
Reaction time: 20 h
Yield: 69.5 %

Procedure:
4-Bromo-7-hydroxymethyl-2-isopropyl-2H-phthalazin-1-one (0.11 g, 0.37 mmol) was dissolved in THF (2 ml). To this was added NaH (60%, 0.019 g, 0.44 mmol) as a THF suspension (2 ml). To this was added methyl iodide (0.063 g, 0.48 mmol) and the reaction mixture was stirred for 20 hours. The reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography (elution: 80% heptane, 20% EtOAc) to give the title compound (0.08 g, 69% yield) as a white solid.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:18]/[C:19](O)=[O:20]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:19](=[O:20])/[CH:18]=[CH:17]/[C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccco1
Agent: Cl
Product: O=C(/C=C/c1ccco1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-furyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 247 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[C:20](OC)(OC)(OC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)NC1CCC(=O)NC1=O
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C1CCC(n2cnc3ccc(Br)cc3c2=O)C(=O)N1
Yield: 10 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-bromo-benzamide (1.0 g, 3 mmol) and trimethyl orthoacetate (1.6 mL) and p-toluene sulfonic acid (250 mg) in acetonotrile (10 mL) was heated to reflux for 7 days. The suspension was filtered and washed with ethyl acetate (10 mL), methanol (5 mL) and ethyl acetate (10 mL) to give 3-(6-bromo-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as an off-white solid (108 mg, 10% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 5.17 min (98.7%); mp: 273-275° C.; 1H NMR (DMSO-d6) δ 2.14-2.27 (m, 1H, CHH), 2.56-2.69 (m, 2H, 2CHH), 2.64 (s, 3H, CH3), 2.72-2.90 (m, 1H, CHH), 5.29 (dd, J=6, 11 Hz, 1H, NCH), 7.58 (d, J=9 Hz, 1H, Ar), 7.98 (dd, J=2, 9 Hz, 1H, Ar), 8.12 (d, J=2 Hz, 1H, Ar), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.72, 23.42, 30.50, 56.64, 118.80, 121.77, 127.94, 128.95, 137.51, 145.76, 155.74, 159.32, 167.24, 172.49; LCMS: MH=350, 352; Anal Calcd for C14H12N3O3Br: C, 48.02; H, 3.45; N, 12.00. Found: C, 48.02; H, 3.18; N, 11.76.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([Br:10])[S:8][CH:9]=1)(=[O:3])[CH3:2].S(C1C=CC(C)=CC=1)(O[CH3:15])(=O)=O.[H-].[Na+]>C(#N)C>[Br:10][C:7]1[S:8][CH:9]=[C:5]([N:4]([CH3:15])[C:1](=[O:3])[CH3:2])[N:6]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CC(=O)Nc1csc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N(C)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32 %

Procedure:
A solution of 4-acetamido-2-bromothiazole (prepared as described in Example 1) and methyl tosylate (4.65g, 25mM) in dry acetonitrile (125 ml.) was treated with a 60% dispersion of sodium hydride in oil (1g, 25mM) and the mixture stirred 72 hours at ambient temperature. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was chromatographed on silica (Woelm grade 1, 150g) using 2% methanol in chloroform as eluant. Evaporation of the appropriate fractions followed by recrystallisation from hexane gave the title compound (1.9g, 32%) mp 84° C. Found: C, 30.55; H, 2.95; N, 11.8%. C6H7N2BrOS requires C, 30.7; H, 3.0; N,.11.9%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:18]=1[OH:30].C1(C)C=CC=CC=1>C(N(C(C)C)C(C)C)C>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:18]=1[O:30][CH2:11][CH:9]([OH:10])[CH2:8][O:7][C:6]1[CH:12]=[CH:13][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=1
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: FC(F)(F)c1ccc(OCC2CO2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: OC(COc1ccc(C(F)(F)F)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl

Procedure:
8 g of 2-(4-trifluoromethyl-phenoxymethyl)-oxirane and 3.8 g of 2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenol are stirred in 80 ml of N-ethyl-diisopropylamine and 50 ml of toluene for 14 days at 100° C. The reaction mixture is concentrated, and the residue is taken up in ethyl acetate and washed with hydrochloric acid and water. After concentration of the organic phase and purification over silica gel, 1-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-3-(4-trifluoromethyl-phenoxy)-propan-2-ol is obtained. 1H-NMR (CDCl3) 300 MHz: 2.81 (d, 1H), 4.15-4.48 (m, 5H), 4.59 (d, 2H), 6.11 (t, 1H), 6.86 (s, 2H), 7.01 (d, 2H), 7.58 (d, 2H)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[C:9]([OH:11])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[N:18]=1.[NH2:19][NH2:20].O1CCOCC1>C(OCC)(=O)C>[NH:19]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:18]=1)=[N:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:9]([OH:11])[N:10]=2)[NH2:20]
Reactant: Oc1nc2ccc(Cl)nc2nc1-c1ccccc1
Reactant: NN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NNc1ccc2nc(O)c(-c3ccccc3)nc2n1
Temperature: 100 °C

Procedure:
To a flask was added 6-chloro-3-phenylpyrido[2,3-b]pyrazin-2-ol (8-2, 3.41 g, 13.23 mmol), anhydrous hydrazine (5.0 mL, 159 mmol), and finally 1.4 Dioxane (60 mL). The stirred reaction mixture was then heated to 100° C. in a hot oil bath under an atmosphere of nitrogen with an air cooled reflux condenser attached. Upon completion of the reaction the mixture was cooled to room temperature, suspended in ethyl acetate and washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 8-3 as an orange/tan foam. HRMS (M+H)+: observed=254.1041, calculated=254.1037.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[O:29][C:26]([CH2:30][C:31]([O:33]C)=[O:32])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[O:29][C:26]([CH2:30][C:31]([OH:33])=[O:32])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cc4)cc3)(CC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1nnc(Nc2ccc(-c3ccc(C45CCC(CC(=O)O)(CC4)O5)cc3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of methyl 2-(4-(4′-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptan-1-yl)acetate (110 mg, 0.24 mmol) in THF (4 mL) and Methanol (1 mL) was added 1N NaOH (0.72 mL, 0.72 mmol) and the reaction was let stir at rt for 2 hr. The resulting yellow reaction mixture was partially concentrated by rotary evaporation in vacuo (rt water bath). The yellow solution was diluted with MeOH, filtered and purified on preparative HPLC (10-50% MeCN:5 mM NH4OH) to afford 52 mg (49%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.36 (s, 9H), 1.63-1.82 (m, 4H), 1.90-2.02 (m, 2H), 2.08-2.21 (m, 2H), 2.79 (s, 2H), 7.42 (d, J=8.3 Hz, 2H), 7.56-7.70 (m, 6H), 10.51 (br. s., 1H). ESI-MS m/z: 448.1 [M+H]+, retention time 1.08 min (condition E). HR/MS [M+H]+: found 448.2236. calc. 448.2218. RT: 2.27 (Condition L).