Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1>>[O:12]=[C:4]1[NH:5][C:6]2[C:11](/[C:3]/1=[CH:2]/[NH:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1Nc2ccccc2C1=CO
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Product: CS(=O)(=O)Nc1ccc(N/C=C2\C(=O)Nc3ccccc32)cc1

Procedure:
The title compound was prepared analogous to Example 5 from 3-(hydroxymethylene)-1,3-dihydro-2H-indol-2-one (0.164 g, 1.02 mmol) and N-(4-aminophenyl)-methanesulfonamide [53250-82-1, 0.186 g, 1.0 mmol] to provide a yellow solid (0.249 g). 1H NMR (DMSO) 10.67 (d, 1H); 10.45 (s, 1H); 9.56 (s, 1H); 8.50 (d, 1H); 7.52 (d, 1H); 7.35 (d, 2H); 7.18 (d, 2H); 6.95 (m, 1H); 6.89 (m, 1H); 6.80 (m, 1H); 2.92 (s, 3H). MP>250. APCI (−ve) 328. Analytical Calculated for C16H15N3O3S: C, 58.35; H, 4.59; N, 12.76; S, 9.73. Found: C, 58.40; H, 4.63; N, 12.75; S, 9.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:19])[C:16]([OH:18])=[O:17])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH2:20]([O:22][CH2:23][CH2:24]O)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:19])[C:16]([O:18][CH2:21][CH2:20][O:22][CH2:23][CH3:24])=[O:17])[S:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CCOCCO
Reactant: COc1ccc(-c2csc(NC(=O)C(=O)O)n2)cc1
Product: CCOCCOC(=O)C(=O)Nc1nc(-c2ccc(OC)cc2)cs1

Procedure:
Using a method similar to Example 12, 6.95 g of N-[4-(4-methoxyphenyl)-thiazol-2-yl]-oxamic acid and 5.6 g of ethylene glycol monoethyl ether give, after crystallization of the crude product from ethanol/active charcoal, 4 g of the compound of the formula I, with R1 =4--OCH3 --C6H4 and R2 =CH2CH2 --OC2H5, of melting point 130°-133° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl[CH2:18][CH2:19][N:20]1[CH:25]=[C:24]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:39].O>CCO>[C:27]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]2[CH:23]=[CH:22][C:21](=[O:39])[N:20]([CH2:19][CH2:18][NH:1][C:2]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:3]=3[CH:4]=[CH:5][N:6]4[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:25]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cn1ccc2c(N)cccc21
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCCl
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cn1ccc2c(NCCn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Temperature: 50 °C
Reaction time: 24 h
Yield: 41.2 %

Procedure:
To a stirring solution of ethyl (4-amino-1H-indol-1-yl)acetate (94 mg) in EtOH (7 mL) was added 1-(2-chloroethyl)-5-(diphenylmethyl)-2(1H)-pyridinone (70 mg) at ambient temperature. The reaction mixture was warmed to 50° C. After 24 hours, to the mixture was added water and the resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:EtOAc=5:1) to give ethyl [4-({2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}amino)-1H-indol-1-yl]acetate (45 mg).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[C:6]([Cl:20])[N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:6]1[N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[C:4]([C:1]([NH2:2])=[O:3])[C:5]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3cccc(C#N)c3)c(C(N)=O)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(-c2c(C(N)=O)c3n(c2Cl)CCNC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 2.90 g (7.23 mmol) of tert-butyl 8-carbamoyl-6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 7 ml of dichloromethane are added slowly 7 ml (72 mmol) of trifluoroacetic acid. After stirring for 1 hour at room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the aqueous phase is basified by addition of aqueous ammonia. The white solid formed is separated out by filtration, rinsed with water and triturated in acetonitrile to give 1.7 g of 6-chloro-7-(3-cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide in the form of a white powder after separating out by filtration and drying under reduced pressure.
Reaction SMILES: [CH2:1]([CH:8]1[NH:12][C:11](=[O:13])[NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CN(C=O)C>[CH2:1]([CH:8]1[NH:12][C:11](=[O:13])[N:10]([CH2:29][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=C1NC(=O)C(Cc2ccccc2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(Cc2ccccc2)C(=O)N1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.8 %

Procedure:
A solution of the product from step (a) (4.0 g) in DMF (10 ml) was added under N2 to a stirred suspension of anhy. K2CO3 (3.0 g) in DMF (10 ml), followed by the addition of a solution of p-nitrophenethyl bromide (4.9 g, Aldrich) in DMF (5 ml). After additions were complete, the mixture was stirred at room temperature for 17 hours, then at 40° C. for 48 hours. The mixture was poured into ice-water, stirred for 2 hours, and the resulting precipitate filtered off, washed with water, and triturated with ethanol to give the desired product as a pale yellow solid (3.7 g).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[CH2:2]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>CCOCC>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[O:1][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH:3]=2)=[CH:14][CH:13]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1COc2ccccc21
Solvent: CCOCC
Product: Fc1ccc(-c2cc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To an ice-cold solution of 3-coumaranone (10 mmol, 1.34 g) in ether (20 mL) was added 4-fluoro-phenyl magnesium bromide (2 M in ether, 20 mmol, 10 mL) and the reaction stirred for 3.5 hours. The reaction was quenched with H2O (10 mL), the pH was adjusted to 7 with sufficient 10% HCl and extracted with ether (3×10 mL). The ether extract was collected, dried, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography (eluent:hexanes) to obtain 4-fluorophenyl-benzofuran.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1oc(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c1OCc1ccccc1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Product: Cn1c(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Yield: 74.36 %

Procedure:
3-Benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-07) (2.3 g, 74.36%) was synthesized as a yellow solid from 3-benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-4-oxo-4H-pyran-2-carboxylic acid (12-07) (3.0 g, 6.68 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C([O-])=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.Cl.[CH3:32]O>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][N:1]([CH3:32])[CH:5]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: O=C([O-])N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: CO
Agent: Cl
Product: Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 51.8 %

Procedure:
A solution of 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (440 mg, 0.93 mmol) in a solution of HCl/MeOH (2M, 10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude was purified by reverse phase preparative HPLC to afford 224 as a yellow solid (180 mg, 51.8%). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.095-9.098 (d, J=1.5 Hz, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.14 (s, 1H), 7.87 (s, 1H), 7.64-7.69 (t, J=13.5 Hz, 1H), 7.13-7.16 (d, J=12.5 Hz, 1H), 6.55-6.58 (d, J=14.5 Hz, 1H), 3.90-3.91 (d, J=8 Hz, 3H), 3.78-3.87 (m, 6H), 3.01-3.05 (t, J=13 Hz, 2H), 1.87-1.91 (m, 2H); MS (ESI) m/z: 375 [M+H]+.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:34]1(=[O:39])[CH2:38][CH2:37][CH2:36][CH2:35]1.[Cl-].[NH4+]>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:34]2([OH:39])[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Reactant: O=C1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2ccc(Cc3ccccc3OCc3ccccc3)cc2)CCCC1
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 294 mL) was added dropwise to a solution of 1-benzyloxy-2-(4-bromobenzyl)benzene (1.5 g, 4.25 mmol) in THF (16.5 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this mixture, a solution of cyclopentanone (357 mg, 4.25 mmol) in THF (4 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for 50 minutes and at 0° C. for one hour, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (1.14 g, 75%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:5]=[C:4]([S:16][CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:5]=[C:4]([S:16][CH3:17])[N:3]=1
Reactant: CCC(CC)Nc1nc(SC)nc(Cl)c1C=O
Reactant: OB(O)c1ccccc1Cl
Product: CCC(CC)Nc1nc(SC)nc(-c2ccccc2Cl)c1C=O

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-chlorophenylboronic acid to give the title compound 4-(2-chloro-phenyl)-6-(1-ethyl-propylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 0.91 (m, 6H), 1.42-1.60 (m, 4H), 2.45 (s, 3H), 4.21 (m, 1H), 7.32 (m, 4H), 8.96 (br s, 1H), 9.44 (s, 1H). LC MS (m/e)=350 (MH+).
Reaction SMILES: C1([O:6][C:7](=[O:39])[C@@H:8]([NH:15][C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:37])[NH:35][OH:36])[CH:21]=2)=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)CCCC1.[OH-].[Na+]>C1COCC1>[OH:36][NH:35][C:34]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][C:27]([NH:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][NH:18][C:16](=[O:17])[NH:15][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]([OH:39])=[O:6])=[O:38])=[O:37]
Reactant: O=C(CCCCCCC(=O)Nc1cccc(CNC(=O)N[C@H](C(=O)OC2CCCC2)c2ccccc2)c1)NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(CCCCCCC(=O)Nc1cccc(CNC(=O)N[C@H](C(=O)O)c2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound (79) (75 mg) was dissolved in THF (1 ml) and 2M NaOH (aq, 1 ml) added. The reaction was stirred at room temperature for 2 h. THF was removed under a stream of N2 and the aqueous layer (˜1 ml) was purified by preparative HPLC to yield compound (80). LCMS purity 99%, m/z 471 [M++H]+, 1H NMR (400 MHz, MeOD), δ: 1.20-1.35 (4H, m, 2×CH2), 1.45-1.65 (4H, m, 2×CH2), 2.00 (2H, t, CH2), 2.25 (2H, t, CH2), 4.20 (2H, s CH2NH), 5.25 (1H, s CHPh), 6.90 (1H, d, Ar), 7.10 (1H, t, Ar), 7.15-7.40 (7H, m, Ar).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:4].[Li+].[OH-]>CO>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[N:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]=2)[CH:12]=1
Reactant: COC(=O)c1cnc(-c2cccnc2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc(-c2cccnc2)nc1
Yield: 29.9 %

Procedure:
A solution of 2-pyridin-3-yl-pyrimidine-5-carboxylic acid methyl ester (0.73 g, 3.32 mmol) and 1M aqueous LiOH (3.32 mL) in MeOH (5 mL) is stirred at room temperature overnight. The MeOH is removed in vacuo, and the aqueous solution is treated with 3 N HCl to adjust the pH ˜2-3. The solid is filtered off and washed with water and dried in vacuum to yield 2-pyridin-3-yl-pyrimidine-5-carboxylic acid (0.2 g, 30%) as a solid. MS: 202 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([N:33]([CH2:47][C:48]([NH:50][NH2:51])=[O:49])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([F:46])([F:45])[F:44])(=[O:36])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C(=O)C.C(OCC)(=O)C>[CH2:26]([N:33]([CH2:47][C:48]([NH:50][NH:51][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=1)=[O:49])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]([F:44])([F:45])[F:46])(=[O:36])=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: NNC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccccc1C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(C(=O)NNC(=O)CN(Cc2ccccc2)S(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
To a stirred solution of 3-methylsulfonylbenzoic acid (60 mg) in N,N-dimethylacetamide (1.3 mL) was added 1,1′-carbonyl-diimidazole (52 mg). The mixture was stirred at 50° C. for 20 min. After cooling to r.t., N-benzyl-N-hydrazinocarbonylmethyl-2-trifluoromethyl-benzenesulfonamide (100 mg) was added and the mixture was stirred at 100° C. overnight. After cooling to r.t. the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, dichloromethane to dichloromethane/methanol 95:5) to give N-benzyl-N-{2-[N′-(3-methanesulfonyl-benzoyl)-hydrazino]-2-oxo-ethyl}-2-trifluoromethyl-benzenesulfonamide (111 mg) as a colorless oil. MS: 570.3 ([M+H]+)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:40][C:41]12[CH2:48][CH:45]([NH:46][CH2:47]1)[CH2:44][C:43]([CH3:50])([CH3:49])[CH2:42]2.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:46]1[CH2:47][C:41]3([CH3:40])[CH2:48][CH:45]1[CH2:44][C:43]([CH3:50])([CH3:49])[CH2:42]3)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CC1(C)CC2CC(C)(CN2)C1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc2[nH]1
Reaction time: 0.5 h
Yield: 57.1 %

Procedure:
To a solution of 1H-Indole-2,5-dicarboxylic acid 2-ethyl ester (890 mg, 3.8 mmol) in dry DMF (10 mL) at room temperature under an inert atmosphere of nitrogen was added HOBt (570 mg, 4.2 mmol) and EDAC (951 mg, 4.9 mmol), and the resulting solution was stirred for 30 min. 1,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane hydrochloride (796 mg, 4.2 mmol) was added to the solution followed by DIPEA (1.98 mL, 11.4 mmol), and the reaction mixture was stirred for 16 h at room temperature. The reaction was quenched by the addition of water (20 mL) followed by extraction with DCM (3×50 mL). The combined organic phases were dried (MgSO4), filtered, and evaporated in vacuo. The resulting solid was purified by silica gel chromatography using a mixture of ethyl acetate and heptane (1:2) as eluent. Pure fractions were collected, the solvent evaporated in vacuo and dried in vacuo at 50° C. affording 800 mg (57%) of the title compound as a solid. MS-ESI m/z 369; 1H NMR (300 MHz, CDCl3) δ 0.94 (d, 3H), 1.04 (d, 3H), 1.14-1.19 (m, 4H), 1.24-1.29 (m, 2H), 1.39-1.45 (m, 4H), 1.58-1.63 (m, 1H), 1.76-1.79 (m, 1H), 3.25-3.30 (m, 1H), 3.35 (d) and 3.65 (d, 1H), 4.06-4.09 (m) and 4.64-4.67 (m, 1H), 4.42 (q, 2H), 7.27 (s, 1H), 7.39-7.46 (m, 2H), 7.82 (d, 1H), 9.05 (s, 1H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([Cl:11])=[N:6][C:5]=2[N:12]=1.Cl.[OH-:14].[Na+]>>[Cl:11][C:7]1[N:8]=[C:9]([Cl:10])[C:4]2[S:3][C:2](=[O:14])[NH:12][C:5]=2[N:6]=1
Reactant: [OH-]
Reactant: Clc1nc(Cl)c2sc(Cl)nc2n1
Agent: Cl
Agent: [Na+]
Product: O=c1[nH]c2nc(Cl)nc(Cl)c2s1
Temperature: 60 °C
Yield: 50 %

Procedure:
A suspension of the trichloro compound (22: 3.0 g, 12 mmol) in 1N NaOH (35 mL) was heated at 60° C. for 1 h. The solution was treated with decolorizing carbon and then acidified with 10% aqueous HCl. The resulting precipitate was collected and reprecipitated from dilute base with glacial acetic acid to provide 24 as orange needles (1.38g, 50%): mp. 191°-192° C.: UV λmax (pH 1) 254 nm (ε 5,300), 290 (11,400): UV λmax (pH 7,11) 226 nm (ε 28,900), 300 (14,100). Anal. Calcd. for C5HCl2N3OS: C, 27.04: H, 0.45: C1, 31.93: N, 18.93. Found: C, 26.78: H, 0.61: C1, 32.15: N, 18.66. Single crystal X-ray analysis of 24 showed the structure assignment to be correct.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:10]/[C:9]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:8]=1)=[O:11]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1cccc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
1-[5-(Trifluoromethyl)phenyl]ethanone (0.20 mL, 0.0013 mol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.17 mL, 0.0013 mol) were combined in a sealed tube and heated in a microwave to 120° C. for 15 minutes, the reaction was allowed to cool and was concentrated to remove the residual DMF acetal, to give (2E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one, 0.32 gm, as a red oil, LC/MS (M+H)+: 244.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[NH:6][CH:5]=1.Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20].O>CN(C)C=O>[Br:3][C:4]1[C:12]2[C:11]([Cl:13])=[N:10][CH:9]=[N:8][C:7]=2[N:6]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:5]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.205 g, 5.13 mmol) was suspended in 5 mL dimethylformamide. The mixture was stirred for 10 min and then cooled at 0° C. with an ice bath. 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1 g, 4.30 mmol) dissolved in 5 mL dimethylformamide was added dropwise and the mixture was stirred for 30 min. At the same temperature [2-(chloromethoxy)ethyl](trimethyl)silane (0.9 g, 5.4 mmol) dissolved in 5 mL dimethylformamide was added dropwise and stirred for 30 min at 0° C. The mixture was poured into water and extracted twice with ethyl acetate. The organics were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 1.18 g (76% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][C@@H:28]3[CH2:29][CH2:30][O:26][CH2:27]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: N[C@@H]1CCOC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@@H]3CCOC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (3R)-tetrahydrofuran-3-amine. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (t, J=4.4 Hz, 2 H), 7.83 (s, 1 H), 7.65 (t, J=3.7 Hz, 1 H), 7.47 (t, J=3.8 Hz, 1 H), 7.31 (d, J=2.1 Hz, 1 H), 7.24 (d, J=2.1 Hz, 1 H), 6.56 (d, J=1.5 Hz, 1 H), 6.01 (s, 1 H), 5.08 (s, 2 H), 4.40 (brs, 2 H), 4.02 (t, J=3.6 Hz, 1 H), 3.88 (m, J=7.2 Hz, 1 H), 3.80 (m, J=5.4 Hz, 1 H), 3.64 (d, J=4.5 Hz, 3 H), 2.30 (t, J=3.7 Hz, 4 H).
Reaction SMILES: [F:1][C:2]([F:19])([C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=[O:17])[NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].S(Cl)(Cl)=O.[CH3:24]O>>[F:19][C:2]([F:1])([C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([O:18][CH3:24])=[O:17])[NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: CO
Reactant: O=C(O)c1[nH]nc(C(F)(F)C(F)(F)F)c1C(F)(F)F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1[nH]nc(C(F)(F)C(F)(F)F)c1C(F)(F)F

Procedure:
0.8 g (2.6 mmol) of 3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazol-5-carboxylic acid are dissolved in 15.0 ml of methanol and then slowly admixed dropwise with 0.58 ml (7.9 mmol) of thionyl chloride. The reaction solution is then heated under reflux for 16 hours. After cooling, the solvent is removed under reduced pressure on a rotary evaporator and the residue is taken up in ethyl acetate. The organic phase is carefully admixed with saturated sodium hydrogencarbonate solution. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. This gives 0.75 g of methyl 3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (96%) as a colourless oil.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([CH2:17][NH2:18])[OH:16]>C(#N)C>[CH2:7]1[C:3]2([CH2:6][CH2:5][CH2:4]2)[CH2:2][N:18]1[CH2:17][CH2:15][OH:16]
Reactant: NCCO
Reactant: BrCC1(CBr)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CC2(CCC2)C1

Procedure:
To a three neck 3 L round bottom flask was added 1,1-bis(bromomethyl)cyclobutane (100 g, 0.43 mol), potassium carbonate (285 g, 2.06 mol), acetonitrile (1000 mL) and ethanolamine (37.8 g, 0.62 mol). The reaction mixture was heated to reflux for 2 days. The reaction mixture was concentrated to half volume and water was added (300 mL). The aqueous layer was extracted with dichloromethane (2×500 mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound.