Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.C(N(CC)CC)C.Cl.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37]Cl)=[CH:33][CH:32]=1.[Na]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)[C:8]=2[N:9]=1
Reactant: ClCc1ccncc1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(Cc3ccncc3)c2n1
Temperature: 70 °C

Procedure:
To a suspension of NaH (60% in mineral oil, 32 mg) in 6 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.65 mmol) and the mixture heated to 70° C. In a second flask containing triethyl amine (220 μL, 1.59 mmol) in 4 mL of dimethylformamide was added 4-picolyl chloride hydrochloride (137 mg, 0.84 mmol). This dark red mixture was added to the above solution of the sodium salt of 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one. The mixture was heated to 70° C., then cooled to room temperature. The mixture was poured into 20 mL of ice water, and the resulting precipitate was removed by filtration and washed with water. This solid was washed with 10% methanol in ethyl acetate to provide 96 mg of crude product. The filtrate was concentrated to provide an additional 77 mg of crude product. An analytical sample was obtained by purification by flash chromatography, eluting with a gradient of ethyl acetate to 10% methanol in ethyl acetate to provide 2-amino-6-(2,6-dichlorophenyl)-8-pyridin-4-ylmethyl-8H-pyrido[2,3-d]pyrimidin-7-one; mp 268°-270° C. dec.
Reaction SMILES: [NH:1]1[C:5]([NH:6][CH:7]=[C:8]([C:12]([O-:14])=O)[C:9]([O-:11])=[O:10])=[CH:4][CH:3]=[N:2]1.CN(C=O)C.[CH3:20][CH2:21]O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[O:14]=[C:12]1[N:1]2[N:2]=[CH:3][CH:4]=[C:5]2[NH:6][CH:7]=[C:8]1[C:9]([O:11][CH2:20][CH3:21])=[O:10]
Reactant: CCO
Reactant: O=C([O-])C(=CNc1ccn[nH]1)C(=O)[O-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2ccnn2c1=O
Temperature: 25 °C

Procedure:
A solution of the 2-((1H-pyrazol-5-ylamino)methylene)malonate (4.0 g, 15.8 mmol) in Dowtherm (15 mL) was heated to 250° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, DMF/EtOH (10 mL, 1/1, v/v) was added to the mixture and formed precipitate was filtered, which was washed with EtOH and dried under vacuum to give ethyl 7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate; 1.9 g (58%). 1H NMR (300 MHz, DMSO) δ 13.01 (brs, 1H), 8.58 (s, 1H), 7.91 (d, J=2.1 Hz, 1H), 6.30 (d, J=1.8 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH:34][P:35]([OH:38])([OH:37])=[O:36])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3].[OH-].[Ca+2:40].[OH-]>O>[Ca:40].[CH2:1]([O:4][N:5]=[C:6]([C:29]1[N:33]=[C:32]([NH:34][P:35]([OH:37])([OH:38])=[O:36])[S:31][N:30]=1)[C:7]([NH:9][CH:10]1[C:27](=[O:28])[N:12]2[C:13]([C:24]([O-:26])=[O:25])=[C:14]([CH2:17][N+:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][S:16][C@H:11]12)=[O:8])[CH:2]=[CH2:3]
Reactant: [Ca+2]
Agent: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1nsc(NP(=O)(O)O)n1
Agent: [OH-]
Solvent: O
Product: [Ca]

Procedure:
A suspension of 7-[2-allyloxyimino-2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (5.81 g) in water (150 ml) was adjusted to pH 6.0 with calcium hydroxide (760 mg). After a small amount of insoluble material was filtered off, the filtrate was lyophilized to give calcium salt of 7-[2-allyloxyimino-2-(5-phosphonoamino-1,2,4-thiadiazol-3-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer) (6.2 g), mp.>230° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C(S([C:32]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]2=[O:42])(=O)=O)=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:32]4([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[C:33](=[O:42])[C:34]5[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:40]4=[O:41])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1ccccc1S(=O)(=O)C1(c2ccccc2)C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)C1(c1ccccc1)N1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.2 g, 10 mmol), K2CO3 (1.6 g, 11.6 mmol) and 2-toluenesulfonyl-2-phenyl-1,3-indandione (4.2 g, 10 mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator. The residue was purified twice using a flash chromatography column (SiO2, 45 g and 40 g; eluted with DCM). The product thus purified was recrystallized from ethanol (30 ml) and isopropyl ether, yield: 2.8 g, m.p. 149°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C@H:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.CC#N.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@H:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][C:11]([OH:13])=[O:12])=[CH:26][CH:27]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OCc1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCCCCCCCC[C@H](CC(=O)O)OCc1ccc(OC)cc1
Reaction time: 8 h
Yield: 88.9 %

Procedure:
Ester 32 (4.01 g, 10.4 mmol) was dissolved in THF/MeOH/CH3CN mixture (v/v/v, 1/1/1, 90 mL). Lithium hydroxide monohydrate (874 mg, 20.8 mmol) as a solution in water (30 mL) was added, and the mixture stirred overnight. The solvent amount was reduced in vacuo to about 30 mL. To the remaining aqueous solution was added hydrochloric acid (1 M) to bring the pH down to 3. The aqueous layer was extracted with diethyl ether (3×40 mL). The combined organic extracts were dried over sodium sulfate. The drying agent was removed by filtration and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 50% ethyl acetate/hexanes over 60 min, 85 mL/min) to give the product 34 (3.37 g, 89%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=6.1 Hz, 2H), 6.82 (d, J=6.1 Hz, 2H), 4.46 (s, 2H), 3.81 (m, 1H), 3.75 (s, 3H), 2.65-2.49 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.20 (m, 18H), 0.85 (t, J=5.8 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([CH2:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[BH4-].[Na+].O>C(O)(=O)C.CO>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:22])[C:8]([CH2:20][CH3:21])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(N)cc2)c(C#N)c(CC)n1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(NCc3ccccc3)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Add 3-(4-amino-phenyl)-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.297 g, 1.0 mmol, prepared in example E-153), benzaldehyde (0.106 g, 1.0 mmol), and one drop of acetic acid in methanol with stirring at room temperature. After 4 hours, add sodium borohydride (0.075 g, 2.0 mmol) portionwise and continue stirring at room temperature. After 18 hours, pour the reaction mixture into water and extract with EtOAc. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound. Mass spectrum (m/e): 388.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][C:14]([O:20][CH2:21][CH:22]4[CH2:24][O:23]4)=[CH:15][CH:16]=3)[O:11][CH:10]=2)=[CH:5][CH:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30][NH2:31].C(N(C(C)C)CC)(C)C>C(O)C>[OH:23][CH:22]([CH2:24][NH:31][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([C:26]([F:35])([F:36])[F:25])[CH:28]=1)[CH2:21][O:20][C:14]1[CH:13]=[C:12]2[C:17]([C:18](=[O:19])[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][O:11]2)=[CH:16][CH:15]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2coc3cc(OCC(O)CNCc4cccc(C(F)(F)F)c4)ccc3c2=O)cc1

Procedure:
3-(4-Methoxyphenyl)-7-(oxiran-2-ylmethoxy)chromen-4-one (0.24 g, 0.74 mmol), 3-(trifluoromethyl)benzylamine (0.11 ml, 0.74 mmol) and diisopropylethylamine (0.26 g, 1.47 mmol) was stirred in ethanol (15 ml) at 78° C. overnight. The solvent was removed under reduced pressure, and the residue chromatographed on silica gel, eluting with 5% methanol/dichloromethane, followed by recrystallization from ethyl acetate/hexane to provide 7-[2-hydroxy-3-({[3-(trifluoromethyl)phenyl]methyl}amino)propoxy]-3-(4-methoxyphenyl)chromen-4-one.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[NH:11][C:10]1=[O:19])(=O)=O.[C:20]1([N:26]2[C:30]3([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:29](=[O:36])[NH:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]2[N:9]([CH2:8][CH2:7][CH2:6][N:33]3[CH2:32][CH2:31][C:30]4([N:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:27][NH:28][C:29]4=[O:36])[CH2:35][CH2:34]3)[C:10](=[O:19])[NH:11][C:12]=2[CH:17]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: CS(=O)(=O)OCCCn1c(=O)[nH]c2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCN(c2ccccc2)C12CCN(CCCn1c(=O)[nH]c3cc(Cl)ccc31)CC2
Yield: 25 %

Procedure:
A mixture of 4.9 parts of 5-chloro-1,3-dihydro-2-oxo-2H-benzimidazole-1-propanol methanesulfonate, 3.7 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one, 3.4 parts of sodium carbonate and 90 parts of N,N-dimethylformamide is stirred and heated for 1 hour at 50°-60° C. The N,N-dimethylformamide is distilled off and the residue is taken up in water. The product is extracted with 4-methyl-2-pentanone. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue solidifies on triturating in 4-methyl-2-pentanone. The product is filtered off and crystallized twice: first from 2-propanol and then from a mixture of N,N-dimethylformamide and water, yielding 1.8 parts (25%) of 8-[3-(5-chloro-1,3-dihydro-2-oxo-2H-benzimidazol-1-yl)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one; mp. 233.7° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:17])OCC(Cl)(Cl)Cl.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:29]=[C:28]([NH2:30])[NH:27][N:26]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:30][C:28]1[NH:27][N:26]=[C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[F:18])[CH:29]=1)=[O:17]
Reactant: O=C(Nc1cccc(Cl)c1Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cc(-c2ccccc2F)n[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2ccccc2F)n[nH]1)Nc1cccc(Cl)c1Cl
Yield: 92.1 %

Procedure:
A solution of 2,2,2-trichloroethyl 2,3-dichlorophenylcarbamate (0.286 g, 0.847 mmol; general method D), 3-(2-fluorophenyl)-1H-pyrazol-5-amine (0.150 g, 0.847 mmol) and I-PR2NET (0.219 g, 1.69 mmol) in DMF (1 mL) was stirred at 90° C. overnight. Water was added (30 mL) and the mixture was extracted with EtOAc (3×30 mL), dried (MgSO4), filtered and concentrated to yield crude 1-(2,3-dichlorophenyl)-3-(3-(2-fluorophenyl)-1H-pyrazol-5-yl)urea as an off-white solid (285 mg, 92% yield). 1H-NMR (DMSO-d6): δ 9.86 (s, 1H), 8.25 (d, 1H, J=7.2 Hz), 7.81 (t, 1H, J=7.2 Hz), 7.45-7.27 (m, 5H), 6.65 (s, br, 1H). 5.67 (s, 1H), one urea proton not visible. LC-MS (EI) m/z: 365.0 367.0 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].[CH:27]#[CH:28].[ClH:29]>>[ClH:29].[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:27][CH3:28])([OH:14])[C:10]([CH3:15])([CH3:16])[CH:9]1[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#C
Reactant: COc1ccc(CC2N(Cc3ccccc3)CCC(=O)C2(C)C)cc1
Agent: Cl
Agent: [Li]
Product: CCC1(O)CCN(Cc2ccccc2)C(Cc2ccc(OC)cc2)C1(C)C
Yield: 55 %

Procedure:
In a manner similar to the method described in example 47, 5 g of 1-benzyl-3,3-dimethyl-2-(p-methoxybenzyl)-4-piperidone is reacted with acetylene lithium (prepared from 1 g of lithium in 75 ml of liquid ammonia). The crude product from this reaction is reduced catalytically as described before, leading to the above-mentioned compound which is secured as the hydrochloride. Yield 55%. Melting point 171° - 172° C with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([Br:15])=[C:10]([CH:16]([CH3:18])[CH3:17])[N:9]=2)[CH:7]=1.[CH2:23]([N:25]=[C:26]=[S:27])[CH3:24].C(N(CC)CC)C>C(O)C>[CH:16]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([NH:25][CH2:23][CH3:24])=[S:27])[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])[NH:13][C:12](=[O:14])[C:11]=1[Br:15])([CH3:18])[CH3:17]
Reactant: CCN=C=S
Reactant: CCCOc1ccc(N)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCOc1ccc(NC(=S)NCC)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Yield: 681.7 %

Procedure:
The compound (4.0 g, 10 mmol) of example 34 was suspended in ethanol (10 ml), and added with ethyl isothiocyanate (0.9 g, 1.1 mmol) and triethylamine (1 mL). After refluxed for 3 h, the reaction mixture was concentrated to dryness. The resultant solid was washed with distilled water and recrystallized from ethyl acetate-petroleum ether to give the title compound (3.4 g, yield: 74%). 1H NMR (DMSO-d6) δ: 12.38 (1H, br), 9.41 (1H, br), 7.74 (1H, d), 7.54 (1H, dd), 7.15 (1H, d), 4.04 (2H, t), 3.46 (2H, m), 3.37 (1H, m), 1.75 (2H, m), 1.18 (6H, d), 1.11 (3H, t), 0.97 (3H, t).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2cccnc2c1Br
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc2cccnc2c1Br
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of 8-bromo-7-hydroxyquinoline (65 g, 0.29 mol), potassium carbonate (120 g, 0.87 mol), and methyl iodide (82 g, 0.58 mol) in acetone (500 mL) was heated to reflux for 4 hrs. The mixture was then cooled to rt and filtered. The filtrate was concentrated, dissolved in ethyl acetate (1 L), washed with water (300 mL×2) and saline (200 mL), dried over Na2SO4 and concentrated. The residue was recrystallized in ethyl acetate and hexane (1:1) to give 8-bromo-7-methoxyquinoline (40 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:4][CH:5]=[CH:6][N:7]=1.NN.CCO>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:8]([NH2:9])[C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: NC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Yield: 79.5 %

Procedure:
A solution of 2-[(3-chloropyrazin-2-yl)-(4-phenoxyphenyl)-methyl]-isoindole-1,3-dione (1.04 g, 0.0023 mol) and anhydrous hydrazine (0.247 mL, 0.0078 mol) in DCM (8.8 mL)/EtOH (6 mL) was stirred at rt overnight. The white precipitate (phthalic hydrazide) was filtered and washed with DCM. The filtrate was collected and concentrated in vacuo and purified by flash column chromatography using 10%-30% EtOAc in hexanes to afford 570 mg of the title compound as an orange oily solid. 1H NMR (400 MHz, CDCl3): δ 2.38 (br. s., 2H), 5.54 (s, 1H), 6.89-7.01 (m, 4H), 7.09 (t, J=7.45 Hz, 1H), 7.27-7.36 (m, 4H), 8.26 (d, J=2.27 Hz, 1H), 8.53 (d, J=2.53 Hz, 1H). MS (ES+): m/z 294.72 (90) [MH+]. HPLC: tR=2.15 min (Open Lynx, polar—5 min).
Reaction SMILES: CCN(C(C)C)C(C)C.C(Cl)CCl.[Br:14][C:15]1[C:16]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:17]([Cl:21])[S:18][C:19]=1[Cl:20].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([C:39]([NH:25][S:22]([C:16]2[C:15]([Br:14])=[C:19]([Cl:20])[S:18][C:17]=2[Cl:21])(=[O:23])=[O:24])=[O:40])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: NS(=O)(=O)c1c(Cl)sc(Cl)c1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NS(=O)(=O)c2c(Cl)sc(Cl)c2Br)CC1
Reaction time: 16 h

Procedure:
60 mg of DMAP, 130 mg of DIEA and 192 mg of EDC are added to a solution of 155 mg of 4-bromo-2,5-dichloro-thiophene-3-sulfonamide and 230 mg of 1-(tert.butyloxycarbonyl)-piperidine-4-carboxylic acid in 8 ml of DMF. The mixture obtained is stirred for ca. 16 h at ca. 30°, solvent is evaporated and the evaporation residue is treated with EtAc. The mixture obtained is washed with aqueous 1 N HCl, aqueous saturated NaHCO3 and brine, and dried. Solvent from the organic phase obtained is evaporated and the evaporation residue is subjected to chromatography. 4-(4-Bromo-2,5-dichloro-thiophene-3-sulfonylaminocarbonyl)-piperidine-1-carboxylic acid tert.-butyl ester is obtained and lyophilized from 1,4-dioxane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:3]3[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: COc1cccc(F)c1O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Product: COc1cccc(F)c1OCCOc1nccnc1N1CCNCC1

Procedure:
The title compound was prepared starting from 2-fluoro-6-methoxyphenol (178 mg, 1.25 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.17 mmol; prepared in Example 52, Step 2) to give 230 mg (66%) of a yellow oil. HRMS m/z calcd for C17H21FN4O3 (M)+ 348.1598, found 348.1602.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8](Br)[CH:7]=1)[CH3:2].[CH2:15]([O:22][C:23](=[O:47])[N:24]([CH2:45][CH3:46])[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:7]=[C:8]([C:27]2[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:26]=2[CH2:25][N:24]([C:23]([O:22][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:47])[CH2:45][CH3:46])[C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCOC(=O)Cc1ccc(O)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)OCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester and ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[O:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[Cl:16]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1cc(C(=O)O)oc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxylic acid (116 mg, 0.44 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (171 mg, 0.44 mmol)[prepared according to Preparation 6] and n,n-diisopropylethylamine (0.39 ml, 2.22 mmol) in dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (228 mg, 0.49 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-furancarboxamide (116 mg, 0.19 mmol, 42% yield) as a yellow oil: LCMS (ES) m/e 591, 593 (M, M+2)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.CCN(CC)CC>C(Cl)Cl.C(Cl)Cl.CS(C)=O>[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: OCc1ccc(-c2ccncc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2ccncc2)cc1
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride in CH2Cl2 (15 mL, 1M) was added, dropwise, DMSO (3 mL). The resulting solution was stirred for 5 min then a solution of 4-[pyridin-4-yl]-benzyl alcohol (2.80 g, 15 mmol) (reference example 19a) in CH2Cl2/DMSO (27 mL, 3:1 CH2Cl2/DMSO) was added dropwise. The resulting mixture was stirred 5 min then Et3N added (15 mL, 108 mmol) in one portion. The cold bath was removed and stirring continued for 15 min. The reaction mixture was then diluted with ethyl acetate, washed with water and then brine, dried over MgSO4 and concentrated. The crude, orange solid product was used without further purification.