Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][N:10]=1>C(OCC)(=O)C>[CH3:14][S:11]([C:8]1[S:7][C:6]([N:5]=[C:1]=[O:2])=[N:10][CH:9]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1cnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cnc(N=C=O)s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-5-methylsulfonylthiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about one hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 5-methylsulfonylthiazol-2-yl isocyanate dimer.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1.[OH-].[Na+]>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:10]([NH2:11])=[C:9]([N:8]=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([NH2:13])=[N:35]2)=[CH:30][CH:29]=1
Reactant: N#CC(C#N)=NNc1ccccc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Nc1ccccc1
Solvent: N#CCC#N
Product: Nc1nn(-c2ccc(F)cc2)c(N)c1N=Nc1ccccc1
Reaction time: 4 h

Procedure:
1-(4-fluorophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and 4-fluorophenylhydrazine hydrochloride (81 mg, 0.5 mmol) with the addition of 0.5 mL of 5% sodium hydroxide solution. After reacting for 4 hrs, very little solid had formed; however, analysis of the reaction solution by TLC indicated that no starting material remained. The resulting solid was removed by filtration and the solvent was evaporated from the filtrate to yield 29 mg (20%) of the compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][CH:3]=1.[CH3:20][N:21]=[C:22]=[O:23]>C1C=CC=CC=1>[CH3:20][NH:21][C:22]([N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]([CH3:1])=[CH:3][N:4]=1)=[O:23]
Reactant: CN=C=O
Reactant: Cc1cnc(Nc2ccccc2)n1-c1ccccc1
Solvent: c1ccccc1
Product: CNC(=O)N(c1ccccc1)c1ncc(C)n1-c1ccccc1
Yield: 59.4 %

Procedure:
A mixture of 6.25 g (0.025 mol) of 5-methyl-1-phenyl-2-phenylamino imidazole (derivative No. 1), 1.44 g of methyl isocyanate (0.025 mol) and 20 ml of benzene are refluxed for 6 hours. After the solvent has been evaporated in vacuo, the residue is taken up in ether, filtered, and recrystallized from a mixture of isopropanol/isopropyl ether. 4.55 g of greyish-beige crystals are obtained in a yield of 59.5%, melting point 147° C measured by Koefler's block.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:24])([CH3:23])[C:19]([NH:21][CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1>>[CH3:22][NH:21][C:19](=[O:20])[C:18]([CH3:24])([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[N:3][C:2]([C:35]4[CH:34]=[N:33][C:32]([CH3:31])=[CH:37][CH:36]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)[CH3:23]
Reactant: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)C(C)(C)N1CCN(Cc2cc3nc(-c4ccc(C)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N-methyl-isobutyramide (Example 88) was reacted with 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine via General Procedure A. Purification on silica yielded 177. NMR (400 MHz CDCl3): 1.27 (6H, s, CH3), 2.58 (8H, b, CH2), 2.65 (3H, s, CH3), 2.82 (3H, d (J=4.97), CH3), 3.86 (2H, s, CH2), 3.90-3.92 (4H, m, CH2), 4.06-4.09 (4H, m, CH2), 7.21 (1H, b, NH), 7.26 (1H, d (J=8.23), ar), 7.33 (1H, s, ar), 8.58 (1H, dd (J=8.07, 2.17), ar), 9.53 (1H, d (J=1.80), ar). MH+510.24
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][N:5]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:4](=[O:16])[C:3]=1[C:17]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([N+:27]([O-])=O)=[CH:26][C:20]=2[S:19](=[O:31])(=[O:30])[N:18]=1.NN>CO.C1COCC1.[Ni]>[NH2:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:17]([C:3]3[C:4](=[O:16])[N:5]([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[N:6]=[C:7]([CH:8]([CH3:10])[CH3:9])[C:2]=3[OH:1])=[N:18][S:19](=[O:30])(=[O:31])[C:20]=2[CH:26]=1
Reactant: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc([N+](=O)[O-])ccc3N2)c1=O
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a solution of 5i (0.100 g, 0.22 mmol) in MeOH (5 mL) and THF (5 mL) was added Raney-Nickel (0.6 mL, 50% slurry in H2O) followed by anhydrous NH2NH2 (0.3 mL, 9.56 mmol). The reaction mixture was stirred 15 min at ambient temperature, filtered using a syringe filter with 0.2 μm PTFE membrane, and concentrated in vacuo. The crude mixture was purified by flash column chromatography using silica gel eluted with 0-3% MeOH/CH2Cl2 to give 5j (0.072 g, 77%) as a red solid. 1H NMR (400 MHz, D6-DMSO) δ 7.0 (br s, 1 H), 6.93 (s, 1 H), 6.79 (d, J=2.8 Hz, 1 H), 6.76 (d, J=2.4 Hz), 5.33 (br s, 2 H), 3.86 (t, J=6.8 Hz, 2 H), 3.22 (m, 1 H), 1.52 (m, 3 H), 1.08 (d, J=7.2 Hz, 6 H), 0.90 (d, J=6.4 Hz, 6 H). MS(ESI+) m/e 420 [M+H]+.
Reaction SMILES: [C:1]([C@@H:4]([C@H:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5])([OH:3])=[O:2].[NH2:11][C@@H]1C[C@H](C(OC)=O)C=C1.[Cl-].[NH4+:22].N.CO>C(O)C>[NH4+:11].[NH4+:22].[C:8]([O-:10])(=[O:9])[CH:6]([CH:4]([C:1]([O-:3])=[O:2])[OH:5])[OH:7]
Reactant: COC(=O)[C@@H]1C=C[C@H](N)C1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 2 h

Procedure:
To a mixture of (1S,4R)-Methyl 4-aminocyclopent-2-ene-1-carboxylate L-tartrate (10 g, 34.3 mmol) and ammonium chloride (1.85 g, 34.3 mmol) in ethanol (79 g) was added a 2M solution of ammonia in methanol (17.2 mL, 34.4 mmol). The mixture was stirred for 2 h, resulting in precipitation of the tartaric acid di-ammonium salt. The solid was removed by filtration and the filtrate was concentrated to about 10 mL. The concentrated filtrate was diluted with methyl isobutyl ketone (MIK), resulting in precipitation of (1S,4R) Methyl-4-aminocyclopent-2-ene-1-carboxylate hydrochloride. The solid was collected by filtration and dried in a vacuum oven (100 mbar) at 50° C. for 24 h.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@H:32]2[CH2:34][O:33]2)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C@H:32]([OH:33])[CH2:34][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:28][CH:27]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(C)(C)c1ccc(OC[C@H]2CO2)cc1
Product: CC(C)(C)c1ccc(OC[C@H](O)CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)cc1

Procedure:
Compound 185 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=150-152° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89 (d, J=7.2 Hz, 1H), 7.79 (m, 2H), 7.56 (m, 1H), 7.28 (d, J=8 Hz, 2H), 6.85 (d, J=8 Hz, 2H), 4.84 (s, 1H), 3.94 (m, 2H), 3.85 (m, 1H), 3.07 (s, 2H), 2.80 (m, 2H), 2.45 (m, 4H), 1.99 (m, 2H), 1.82 (m, 2H); LCMS: 508 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=35.55 min.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]([OH:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.C(OCC)(=O)C>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[OH:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)c1ccc(O)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
15.3 g of chromium trioxide is added dropwise to a solution of 15 g of ethyl 4-hydroxymandelate in 240 ml of acetic acid. The mixture is stirred at room temperature for 2 hours, poured into 1 l of ethyl acetate and extracted with saturated aqueous Na2CO3 solution. The aqueous phases are extracted with methylene chloride. The organic phases are washed with saturated aqueous Na2CO3 solution, followed by washing with water. The organic phases are dried over sodium sulfate. Filtration, evaporation of the solvent and distillation (ball-tube still distillation, boiling point 205° C. (0.076 bar)) give 4.04 g (27 wt %) ethyl 4-hydroxybenzoylformate as a yellow solid.
Reaction SMILES: [NH2:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=2)[CH:4]=[C:3]1[C:23](OCC)=[O:24].[BH4-].[Na+]>C(O)C>[NH2:1][N:2]1[C:3]([CH2:23][OH:24])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:10]=2)=[C:6]1[C:7]#[N:8]
Reactant: CCOC(=O)c1cc(-c2cccc(OCc3ccccc3)c2)c(C#N)n1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1c(-c2cccc(OCc3ccccc3)c2)cc(CO)n1N
Temperature: 80 °C
Yield: 99.8 %

Procedure:
To a solution of ethyl 1-amino-4-[3-(benzyloxy)phenyl]-5-cyano-1H-pyrrole-2-carboxylate (1.00 g, 2.77 mmol) in ethanol (24 mL) was added sodium borohydride (523 mg, 13.8 mmol). The mixture was heated (80° C.) for 17 h and then cooled to rt. The reaction was quenched with the addition of water (25 mL) and the mixture was extracted with ethyl acetate (2×25 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated to dryness to obtain 883 mg (100%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.48-7.42 (m, 2 H), 7.41-7.28 (m, 4 H), 7.25-7.19 (m, 2 H), 6.97-6.93 (m, 1 H), 6.41 (s, 1 H), 6.07 (s, 2 H), 5.23 (t, 1 H), 5.13 (s, 2 H), 4.49 (d, 2 H).
Reaction SMILES: [OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[CH2:15][CH:16]([OH:27])[CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:34]1(=[O:40])[O:39][C:37](=[O:38])[CH2:36][CH2:35]1>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH2:13][N:14]([CH2:28][CH2:29][S:30]([OH:33])(=[O:31])=[O:32])[CH2:15][CH:16]([OH:27])[CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38]
Reactant: CCCCCCCCNCC(O)CN(CCS(=O)(=O)O)CC(O)CNCCCCCCCC
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1C
Product: CCCCCCCCN(CC(O)CN(CCS(=O)(=O)O)CC(O)CN(CCCCCCCC)C(=O)CCC(=O)O)C(=O)CCC(=O)O
Yield: 80.5 %

Procedure:
A reactor was charged with 27 g (0.05 mole) of 11,15-dihydroxy-13-sulfoethyl-9,13,17-triazapentacosane and 100 g of xylene, to which 12 g (0.12 mole) of succinic anhydride were then added with stirring to conduct a reaction at 50° C. for 6 hours. After xylene was distilled off under reduced pressure, 300 ml of water were added, and 10% sodium hydroxide was further added to keep the pH of the reaction mixture at 7. Thereafter, the reaction mixture was subjected to electrodialysis and lyophilized, thereby obtaining 28 g (isolation yield: 76%) of 6,10-dihydroxy-4,12-dioctyl-3,13-dioxo-8-sulfoethyl-4,8,12-triaza-1,15-pentadecanedicarboxylic acid as white crystals.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccccn3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3ccccn3)C2=O)sc1C(=O)O
Yield: 97 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(pyridin-2-ylmethyl) imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 97% yield: MS (ES+) m/z 319.1 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[C:4](=[O:34])[CH2:3]1.Br[CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[N:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[C:49]([O:48][C:46]([N:39]1[C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]([CH2:36][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:38]1)=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a stirring solution of 597.8 mg (1.3 mmol) 2-(2,4-Dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 48, in 15 mL DMF at 0° C. is added 3.13 mL (1.57 mmol, 1.2 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The reaction is allowed to warm to RT over 20 min, then is cooled back to 0° C., and 445.4 mg (1.43 mmol, 1.1 equiv) of 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole is added in one portion. The reaction is allowed to warm to RT., and after 20 min is concentrated in vacuo. The residue is taken up in water-ethyl acetate, and is poured into a separatory funnel containing water and ethyl acetate. The layers were separated, and the aqueous layer is extracted with ethyl acetate. The combined organics were dried (Na2SO4) filtered and concentrated in vacuo to afford an amber oil, which is purified by silica gel flash column chromatography to afford 561 mg of the title compound as a viscous, glassy oil: 1H NMR (CDCl3, 400 MHz) δ8.52 (d, br, 2H, J=18.8), 8.01 (d, 1H, J=8.4), 7.78 (m, 2H), 7.46 (t, 1H, J=20), 7.36-7.23 (m, 6H), 7.13 (m, 2H), 6.93 (m, 2H), 4.95 (m, 1H), 4.41 (d, br, 1H), 4.34 (dd, 1H, J=5.2, 8.4), 3.83 (s, 3H), 3.83 (dd, 1H), 3.55 (dd, 1H, J=5.1, 16.6), 1.64 (s, 9H), 1.03 (dd, 6H, J=2.0, 6.5); low resolution MS (FAB)m/e 689 (MH+).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[C:9](=[O:15])[NH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH:25]([O:28][CH3:29])[O:26][CH3:27]>CN(C)C=O>[CH3:27][O:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23][N:12]1[CH:13]=[C:8]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[C:9](=[O:15])[NH:10][C:11]1=[O:14]
Reactant: Cc1nc(C)c(-c2c[nH]c(=O)[nH]c2=O)s1
Reactant: COC(CCBr)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2sc(C)nc2C)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
To a suspension of 5-(2,4-dimethyl-1,3-thiazol-5-yl)-2,4(1H,3H)-pyrimidinedione (Prep34, 250 mg, 1.120 mmol) in N,N-Dimethylformamide (DMF) (4 mL), Potassium carbonate (124 mg, 0.896 mmol) was added and the mixture was stirred at rt for 1 hour. Afterwards 3-bromo-1,1-bis(methyloxy)propane (0.170 mL, 1.120 mmol) was added dropwise and the reaction mixture was stirred at rt overnight. The day after the reaction was quenched with water and extracted with AcOEt. Organic phase was dried over Na2SO4 and concentrated under vacuum providing a crude as a clear oil. The latter was purified by flash chromatography (eluent:DCM/MeOH/NH3 97:3:0.1) affording the title compound (155 mg, 0.429 mmol) as a white solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([N:19]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][N:28]=1)[C:24]#[N:25])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([N:19]([C:21]1[CH:22]=[C:23]([C:24]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:25]=2)[CH:26]=[CH:27][N:28]=1)[CH3:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CN(Cc1ccccc1)c1cc(C#N)ccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)c1cc(-c2nc(=O)c3ccccc3s2)ccn1
Yield: 30.5 %

Procedure:
Methyl thiosalicylate (0.70 g, 4.2 mmol) and 2-[N-benzyl-N-methylamino]isonicotinonitrile (0.46 g, 2.1 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.68 ml, 4.9 mmol) was added thereto. The reaction mixture was refluxed for 8 hrs, subjected to silica gel (50 g) column chromatography, eluted with hexane-ethyl-acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.23 g, 15%).
Reaction SMILES: [CH3:1][Si:2]([CH3:30])([CH3:29])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=O)OC(C)(C)C)[CH2:17]3)[C:10]=2[CH:9]=[CH:8]1.ClC1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][N:33]=1.CCN(C(C)C)C(C)C>Cl.O>[CH3:29][Si:2]([CH3:30])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]4[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][N:33]=4)[CH2:17]3)[C:10]=2[CH:9]=[CH:8]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(N3CC[C@@H](Nc4ccc(C#N)cn4)C3)ncnc21
Temperature: 120 °C
Reaction time: 14 h

Procedure:
A solution of (R)-tert-butyl 1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ylcarbamate (700 mg, 1.61 mmol) in HCl (in MeOH, 6 N, 5 mL) was stirred at ambient temperature for 3 hours. The volatiles were removed under reduced pressure. The residue was dissolved in DMSO (3 mL). 6-chloronicotinonitrile (323 mg, 2.41 mmol), KI (10 mg, 0.06 mmol) and DIPEA (311 mg, 2.41 mmol) were then added. The reaction mixture was stirred at 120° C. for 14 h, cooled to ambient temperature, diluted with H2O (20 mL), and extracted with EtOAc (3×40 mL). The combined extracts were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound. MS (m/z): 436 (M+H)+.
Reaction SMILES: FC(F)(F)C([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:19][C:20]2[C:25]([F:26])=[C:24]([F:27])[C:23]([C:28]([F:31])([F:30])[F:29])=[C:22]([F:32])[C:21]=2[F:33])C(=O)C(F)(F)F)=[CH:8][C:7]=1[C:34](=[O:36])[NH2:35])=O>CO.O>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:19][C:20]2[C:21]([F:33])=[C:22]([F:32])[C:23]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:27])[C:25]=2[F:26])=[CH:8][C:7]=1[C:34]([NH2:35])=[O:36]
Reactant: NC(=O)c1cc(N(Cc2c(F)c(F)c(C(F)(F)F)c(F)c2F)C(=O)C(F)(F)F)ccc1OC(=O)C(F)(F)F
Solvent: CO
Solvent: O
Product: NC(=O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1O
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a solution of 2-carbamoyl-4-[2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl-(2,2,2-trifluoroacetyl)amino]phenyl trifluoroacetate (300 mg, 0.52 mmole) in methanol (8 ml) and water (3 ml) was added c-HCl (2.0 ml) at 40° C. under a nitrogen atmosphere. After the reaction mixture was stirred for 24 hr, the organic solvent was removed in vacuo. The residue was extracted with ethyl acetate (20 ml×3). The organic layer was washed with water and then dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was recrystallized from methylene chloride/hexane (1:10) to give 120 mg (60% yield) of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzamide as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl[C:16]1[C:17]2[C:22]([N:23]=[C:24]3[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]3)=[CH:21][CH:20]=[CH:19][CH:18]=2>Cl.CO>[CH:18]1[C:17]2[C:22](=[N:23][C:24]3[C:29]([C:16]=2[NH:12][C:11]2[CH:13]=[CH:14][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][CH:19]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Clc1c2ccccc2nc2ccccc12
Agent: Cl
Solvent: CO
Product: CN1CCN(c2ccc(Nc3c4ccccc4nc4ccccc34)cc2)CC1
Reaction time: 0.5 h
Yield: 12 %

Procedure:
0.191 g (1.0 mmol) of 4-(4-methylpiperazin-1-yl)aniline, 2.5 ml of methanol and a few drops of concentrated hydrochloric acid were mixed and heated under reflux. The 9-chloroacridine (1-1,5 equivalents) and 2.5 ml methanol were mixed separately and added to the reaction mixture in small portions. After 30 min of stirring, two drops of concentrated hydrochloric acid were added, and heating was continued for 2 h. The reaction mixture was then evaporated to dryness and purified by chromatography (silica gel column; gradient from 100% methylene chloride to 90% methylene chloride and 10% methanol; when 4-(4-methylpiperazin-1-yl)aniline eluted from the column, the eluent was changed to methylene chloride:methanol:triethylamine 94:5:1). A final amount of 0.126 g (34%, overall yield 12%) of the title compound in pure form was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][C:11]1[N:15]=[C:14]([CH3:16])[NH:13][N:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:12]2[C:11]([CH3:10])=[N:15][C:14]([CH3:16])=[N:13]2)[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: Cc1n[nH]c(C)n1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(Cl)cc(-n2nc(C)nc2C)n1
Temperature: 25 °C
Reaction time: 66 h
Yield: 68.8 %

Procedure:
4,6-dichloro-2-methylpyrimidine (2-1) (137.8 g, 845 mmol), 3,5-dimethyl-1H-1,2,4-triazole (2-2) (82 g, 845 mmol), and Cs2CO3 (275 g, 845 mmol) were suspended in DMF (1 L) and the resulting mixture was stirred at room temperature for 66 h. The mixture was then poured into water (2 L) and stirred for 1 hour. The precipitate was filtered, washed with water (2×) and dried under vacuum to afford Intermediate 2 as an off-white solid (130 g, 69%). MS: m/z=224.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: Cn1cccc1CCN
Product: Cn1cccc1CCNS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrol and 2,4,5-trichlorobenzenesulphonylchloride analogously to Example A.