Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH3:36])[C:23]([CH3:35])=[C:24]([C:33]#[N:34])[C:25]=1[C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)=[O:20])[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([O:18][C:19]([C:21]1[N:22]([CH3:36])[C:23]([CH3:35])=[C:24]([C:33]#[N:34])[C:25]=1[C:26]1[CH:31]=[CH:30][C:29]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])=[CH:28][CH:27]=1)=[O:20])[CH3:17]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1c(-c2ccc(O)cc2)c(C#N)c(C)n1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(C)n1C
Temperature: 0 °C

Procedure:
Add trifluoromethanesulfonic anhydride (1.2 Eq.) to 4-cyano-3-(4-hydroxy-phenyl)-1,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-238) and pyridine (1.5 Eq) in methylene chloride dropwise with stirring at 0° C. Stir the reaction mixture for 2 hours and then allow the reaction to warm to room temperature. Wash the organic layer with 1.0 N HCl, water, dry over potassium carbonate, filter, and concentrate under reduced vacuum. Purify the residue by silica gel chromatography (Chromatotron™) eluting with methylene chloride to provide the title compound as a yellow solid. Mass spectrum (m/e): 417.1 (M*+1): (Bruker 300) 1H NMR (CDCl3) δ 7.29-7.32 (2H, d), 7.27-7.29 (2H, d), 4.01-4.11 (2H, dd), 3.85-3.89 (3H, s), 2.43-2.47 (3H, s), 0.90-1.00 (3H, t).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[O:69][N:68]=[CH:67][C:66]=1[C:70](O)=[O:71]>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:66]5[CH:67]=[N:68][O:69][C:65]=5[CH3:64])=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: Cc1oncc1C(=O)O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2cnoc2C)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.8 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 5-methyl-4-isoxazolecarboxylic acid (0.127 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-4-yl)carbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.138 g). 1H NMR Spectrum: (DMSO d6 373K) 1.83 (m, 2H), 2.08 (m, 2H), 2.40 (s, 3H), 3.52 (m, 2H), 3.80 (m, 2H), 3.97 (s, 3H), 4.79 (m, 1H), 7.24 (m, 1H), 7.24 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.89 (s, 1H), 8.39 (s, 1H), 8.59 (s, 1H), 9.27 (br s, 1H); Mass Spectrum: (M+H)+ 512.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:15])[C:8]([C:12]([OH:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.O.C([O-])(O)=O.[Na+].[CH3:22][CH2:23]O>S(=O)(=O)(O)O>[CH2:22]([O:13][C:12]([C:8]1[C:7]([OH:15])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[CH:9]=1)=[O:14])[CH3:23]
Reactant: O=C(O)c1cc2cc(Br)ccc2cc1O
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2cc(Br)ccc2cc1O
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 81 g (0.3 mol) of 7-bromo-3-hydroxy-2-naphthoic acid in 600 ml dried EtOH and 60 ml conc. sulfuric acid was heated at reflux for 16 hours. The mixture was cooled to room temperature and treated with water (4000 ml) and neutralised with NaHCO3. The solid was separated by filtration and dried in a drying chamber afforded 75.3 g (85%) of the titled compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][N:29]([C:35]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:17]([C:25]([F:27])([F:26])[F:28])[CH:16]=2)=[O:13])=[O:36])[CH2:30][CH2:31]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc2ccccc2cc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1c(OC(=O)N2CCOCC2)ccc2ccccc12
Yield: 98 %

Procedure:
Using 3-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-2-naphthamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:34]=[CH:33][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:31]=4[NH:30][C:29](=[O:32])[CH2:28]5)[CH:17]=3)=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[NH:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH:40]=O>C(O)C.N1CCCCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[C:31]=4[NH:30][C:29](=[O:32])[C:28]5=[CH:40][C:36]4[NH:35][CH:39]=[CH:38][CH:37]=4)[CH:17]=3)=[O:14])=[CH:33][CH:34]=2)[CH2:6][CH2:7]1
Reactant: O=Cc1ccc[nH]1
Reactant: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4cccc5c4NC(=O)C5)c3)cc2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4cccc5c4NC(=O)C5=Cc4ccc[nH]4)c3)cc2)CC1

Procedure:
A solution of 4-(4-methyl-piperazin-1-ylmethyl)-N-[3-(2-oxo-2,3-dihydro-1H-indol-7-ylamino)-phenyl]-benzamide (23 mg, 0.05 mmol) is heated with 1H-pyrrole-2-carbaldehyde (5 mg, 0.05 mmol) in ethanol (2 ml) in the presence of 2 drops of piperidine for 12 hours. It is then concentrated and purified by HPLC to give the desired compound: 1H NMR (DMSO-d6) δ 2.40-2.48 (m, 2H), 2.79 (s, 3H), 2.96-3.08 (m, 4H), 3.36-3.46 (m, 2H), 3.75 (s, 2H), 6.37 (s, 1H), 6.71 (d, 1H, J=7.8 Hz), 6.85 (s, 1H), 6.97 (t, 1H, J=7.8 Hz), 7.11 (d, 1H, J=7.2 Hz), 7.19 (t, 1H, J=7.8 Hz), 7.24 (d, 1H, J=7.8 Hz), 7.30 (t, 1H, J=7.8 Hz), 7.36 (s, 1H), 7.47 (d, 2H, J=7.8 Hz), 7.53 (s, 1H), 7.75 (s, 1H), 7.93 (d, 2H, J=7.8 Hz), 10.13 (s, 1H), 10.60 (s, 1H), 13.36 (s, 1H); LC-MS: 533.2 (MH+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][C:13]([NH:16]C(=O)OCC2C=CC=CC=2)=[N:14][CH:15]=1>CO.C1COCC1.[C].[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=1
Reactant: O=C(Nc1cnc(CCOC2CCCCO2)cn1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cnc(CCOC2CCCCO2)cn1
Reaction time: 2 h
Yield: 117.4 %

Procedure:
To a solution of benzyl {5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazin-2-yl}carbamate (416 mg) in methanol (20 mL) and THF (10 mL) was added 10% palladium carbon (100 mg), followed by stirring for 2 hours under a hydrogen atmosphere. It was filtered through Celite and concentrated to obtain 5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]pyrazin-2-amine (305 mg) as a pale yellow oily substance.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:34]=[CH:33][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:32])[C:15]([CH2:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:35](Cl)([CH3:38])(=[O:37])=[O:36].N1C=CC=CC=1>CC(C)=O>[CH:26]1([CH2:25][C:15]2([CH3:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]([OH:23])=[C:13]([C:8]3[NH:7][C:6]4[CH:33]=[CH:34][C:3]([NH:2][S:35]([CH3:38])(=[O:37])=[O:36])=[CH:4][C:5]=4[S:10](=[O:12])(=[O:11])[N:9]=3)[C:14]2=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC1(CC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 76.4 %

Procedure:
A solution of Example 41H (1.17 g, 2.33 mmol), mesyl chloride (0.720 mL, 9.31 mmol), and pyridine (1.51 mL, 18.61 mmol) in acetone (30 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.968 g, 42%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.84 (m, 7H) 1.34 (m, 4H) 1.53 (m, 3H) 2.20 (m, 2H) 3.07 (m, 3H) 7.57 (m, 3H) 7.76 (m, 3H) 8.17 (m, 1H) 10.28 (m, 1H) 13.83 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][N:14]1[CH2:19][CH2:18][C:17]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)([CH3:20])[CH2:16][CH2:15]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:17]3([CH3:20])[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)=[CH:22][CH:23]=2)[N:10]=1
Reactant: CN1CCC(C)(c2ccc(N)cc2)CC1
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(C)(c2ccc(Nc3nc(Cl)c(F)cc3C(N)=O)cc2)CC1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 2,6-dichloro-5-fluoronicotinamide (287 mg, 1.372 mmol) and 4-(1,4-dimethylpiperidin-4-yl)aniline (267 mg, 1.307 mmol) in THF (10 mL) was added lithium bis(trimethylsilyl)amide (4.57 mL, 4.57 mmol) at room temperature. After 30 min, the reaction was quenched by the addition of satd. NH4Cl. The mixture was extracted with methylene chloride twice, the combined organic layers were washed with water and brine, and then concentrated. The residue was purified by MPLC (ISCO, 6-10% ammonia/methanol/methylene chloride, 40 g silica gel column) to give 229 mg of product as yellow solid.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=[C:14]([C:19](=[O:21])[CH:20]=2)[C:15]([O:17]C)=[O:16])=[CH:7][CH:6]=1)C(C)=O.C(O)(=O)C>CO.[OH-].[Na+]>[NH2:1][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=[C:14]([C:19](=[O:21])[CH:20]=2)[C:15]([OH:17])=[O:16])=[CH:7][CH:6]=1
Reactant: COC(=O)c1cn(-c2cccnc2)c(-c2ccc(NC(C)=O)cc2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2cccnc2)cc1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
In 3 ml of methanol and 5 ml of 10% by weight aqueous sodium hydroxide solution was dissolved 0.5 g of methyl 6-(4-acetaminophenyl)-1-(3-pyridyl)-4-oxo-1,4-dihydronicotinate, and they were reacted at 60° C. for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals were collected by filtration, washed with 10 ml of water, and then dried to obtain 0.34 g of 6-(4-aminophenyl)-1-(3-pyridyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 207°-208° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[C:20](=[O:21])[N:12]2[CH:13]([C:18]#[N:19])[C:14]([CH3:17])([CH3:16])[S:15][C@H:11]12.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([C:28]([NH:9][CH:10]2[C:20](=[O:21])[N:12]3[CH:13]([C:18]#[N:19])[C:14]([CH3:16])([CH3:17])[S:15][C@H:11]23)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C#N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1C#N
Reaction time: 0.33 h

Procedure:
Triethylamine (44.5g., 0.44 mole) is added to a slurry of 6-amino-2,2-dimethyl-3-cyanopenam hydrochloride (46.6g., 0.2 mole) in methylene chloride (1500 ml.) at room temperature and the resulting mixture stirred for 20 minutes. Triphenylmethyl chloride (66.9 g., 0.24 mole) is added in one portion to the mixture which is stirred at room temperature for 3.5 hours. The methylene chloride layer is separated and washed with water (5 × 100 ml.). It is then dried (Na3SO4) and concentrated in vacuo to orange-red viscous oil. Methanol (50 ml.) is added and the mixture stirred for a half hour to give a yellow-white solid. The solid is filtered, resuspended in fresh methanol, and the suspension stirred for a half hour. The solid is recovered by filtration and dried in a vacuum oven at room temperature. Yield of crude = 47 gms. M.p. 116-119° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([C@H:13]([NH2:15])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>CCOC(C)=O>[C:7]1([C@H:13]([NH:15][CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)CBr
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CN[C@H](C)c1ccccc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Methyl 2-bromoacetate (621 g, 4.1 mol) was added dropwise to a mixture of (1R)-1-phenylethanamine (410 g, 3.4 mol) and triethylamine (377 g, 3.7 mol) in EtOAc (4.5 L) at r.t. The mixture was then stirred at 50-60° C. overnight then cooled to r.t. The mixture was then washed with water (800 mL) and brine (100 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound (587 g, 90%) as yellow oil; 1H NMR: (CDCl3) 1.29 (3H, d), 3.13-3.24 (2H, m), 3.60 (3H, s), 3.68-3.71 (1H, m), 7.13-7.26 (5H, m).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][OH:19])=[NH:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:28]([O-])([O-])OCC>O1CCOCC1>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:17]=[CH:28][O:19][N:18]=3)[CH2:14][CH2:15]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC([O-])[O-]
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=N)NO)CC1
Solvent: C1COCCO1
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(c2ncon2)CC1
Temperature: 100 °C
Yield: 69 %

Procedure:
A mixture of 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-N-hydroxy-piperidine-1-carboxamidine (50 mg, 0.13 mmol), dioxane (2 ml) and ethyl orthoformate (2 ml) were heated for 17 hours at 100° C. The volatiles were removed in vacuo, and the residue was purified using radial chromatography on silica gel (20:1:1 CH2Cl2:MeOH:NH4OH) to provide COMPOUND 335 as a yellow oil (34.2 mg, 69%). 1H NMR (CHCl3) δ 1.70-1.82 (m, 5H), 1.96-2.00 (m, 2H), 2.10 (s, 6H), 2.68-2.86 (m, 3H), 3.83 (s, 4H), 4.08-4.13 (m, 2H), 7.09 (dd, 2H, J=5.7, 8.4 Hz), 7.37 (d, 2H, J=8.4 Hz), 8.29 (s, 1H), 8.34 (d, 2H, J=5.7 Hz); 13C NMR (CHCl3) δ 18.4, 26.7, 46.9, 55.0, 57.6, 122.8, 133.8, 138.4, 146.3, 157.6, 164.3, 169.9; ES-MS m/z 401 (M+Na). Anal. Calcd. for C21H26N6.0.2H2O.0.4CH2Cl2: C, 61.78; H, 6.59; N, 20.20. Found: C, 61.77; H, 6.59; N, 19.93.
Reaction SMILES: O[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1cc(C)c(Cc2nc(C)nc(O)c2C)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(Cc2nc(C)nc(Cl)c2C)c(C)c1
Yield: 97 %

Procedure:
A mixture of 4-hydroxy-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine (1.2 g, 4.68 mmol) and POCl3 (25 ml) was heated at reflux for 1 hour. The mixture was cooled and evaporated to dryness. The residue was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to dryness to give 1.24 g (97%) of golden crystals, mp 82-84° C.
Reaction SMILES: Br[CH2:2][C@H:3]([CH3:21])[C@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[CH2:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:29][NH:30][CH3:31].O>CN(C)C=O>[CH2:5]([C@@H:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C@@H:3]([CH3:21])[CH2:2][N:30]([CH3:31])[CH3:29])[CH3:6]
Reactant: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CBr
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](c1cccc(OCc2ccccc2)c1)[C@@H](C)CN(C)C
Yield: 89 %

Procedure:
The product of Example 44 (2.7 g, 8 mmol) was dissolved in N,N-dimethylformamide, potassium carbonate (2.7 g, 20 mmol) and dimethylamine hydrochloride (0.7 g, 8 mmol) were added therein, and it was reacted at room temperature for 12 hours. After the reaction solution was poured into water, the aqueous phase was extracted with dichloromethane twice, then the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated through silica gel column chromatography to give target 2.1 g, yield: 89%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22](O)=[O:23])[CH:4]=[N:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:16][N:15]1[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][C:5]=1[C:22]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23])=[O:21]
Reactant: C1CCNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)NCCc1nc2ccccc2n1C
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 1-methyl-5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethylcarbamoyl)-1H-pyrazole-4-carboxylic acid (25 mg, 76.4 μmol) and pyrrolidine (6.52 mg, 7.58 μL, 91.6 μmol) according to the method described in example 37, step 3 as light red solid (15 mg, 39.4 μmol, 51.6%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:30]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH2:31]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[C:30]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:35]=[CH:34][C:33]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:32][CH:31]=1
Reactant: OC1(c2ccccc2)C=CC=CC1
Reactant: OCCCN1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(OCCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
A mixture of 1-(3-hydroxypropyl)pyrrolidine (400 mg), triphenylphosphine (812 mg) in toluene (18 mL) is stirred for five minutes at room temperature, 1-hydroxybiphenyl (493 mg) is then added. The mixture is cooled and diisopropyl azodicarboxylate (609 μL) is added. The mixture is stirred for 48 hours room temperature, concentrated under reduced pressure and diluted with ethyl acetate. The organic layer is washed with water and extracted with an aqueous 1N hydrochloric solution. The aqueous phase is washed with ethyl acetate, then made alkaline with an aqueous 5N sodium hydroxide solution and extracted twice with ethyl acetate. These extracts are pooled, dried over magnesium sulphate, concentrated under reduced pressure, diluted with diethyl oxide and mixed with a solution of oxalic acid (169 mg) dissolved in acetone. The precipitate is filtered, washed with diethyl oxide and dried to give 480 mg of 1-{3-[(biphenyl-4-yl)oxy]propyl}pyrrolidine, oxalate as a white solid melting at 201° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>O1CCOCC1>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N+:15]([O-:27])=[CH:14][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Solvent: C1COCCO1
Product: O=S(=O)(c1ccccc1)n1ccc2c[n+]([O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
A 100 mL round-bottomed flask was charged with a solution of 1-benzenesulfonyl-1H-pyrrolo[3,2-c]pyridine (0.6 g, 2.3 mmol) in dioxane (20 mL). To the resultant solution was added mCPBA (0.6 g, 3.45 mmol) and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo then the residue was dissolved in DCM (50 mL), and washed successively with aqueous sodium sulfite solution, aqueous sodium bicarbonate solution and brine. The organic layer was isolated then dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (0.6 g, 95%). 1H NMR (DMSO, 300 MHz): δ 8.61 (dd, J=1.8, 0.7 Hz, 1 H); 8.13 (dd, J=7.2, 1.8 Hz, 1 H); 8.09-8.04 (m, 2 H); 8.01 (d, J=3.7 Hz, 1 H); 7.92 (d, J=7.2 Hz, 1 H); 7.80-7.73 (m, 1 H); 7.69-7.61 (m, 2 H); 6.83 (dd, J=3.7, 0.8 Hz, 1 H).
Reaction SMILES: [OH-].[Na+].[C:3]([OH:7])(=[S:6])[CH2:4][CH3:5].[C:8]([NH:11][C:12](=[O:15])[CH2:13]Cl)(=[O:10])[CH3:9]>O>[C:8]([NH:11][C:12](=[O:15])[CH2:13][S:6][C:3](=[O:7])[CH2:4][CH3:5])(=[O:10])[CH3:9]
Reactant: CC(=O)NC(=O)CCl
Reactant: CCC(O)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(=O)SCC(=O)NC(C)=O
Reaction time: 0.08 h

Procedure:
To a solution of 4.0 g. (0.1 mole) of sodium hydroxide in 50 ml. of water, cooled in ice and having nitrogen bubbled therethrough, was added 9.5 g. (0.1 mole) of thiopropionic acid. The reaction mixture was stirred for 5 minutes, after which there was added 13.7 g. of N-acetyl-chloroacetamide in 50 ml. of water. The reaction mixture was heated on a steam bath for 10 minutes, then cooled, filtered, and air dried. The product was washed with ether/hexane (3:1) three tims with 150 ml. each washing, and then air dried. The product was recrystallized from water to yield 8.0 g. of white crystals.
Reaction SMILES: C([O:8][C:9](=[O:42])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:21]=1)[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1C=CC=CC=1.[OH-].[Na+].O.Cl>CO>[C:15]([O:14][C:12]([NH:11][C@H:10]([C:9]([OH:42])=[O:8])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:21]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.9 %

Procedure:
30.0 g of the crystals obtained in Example 4 was dissolved in 600 ml of methanol, and after the addition of 65 ml of 10% sodium hydroxide, the mixture was stirred at a room temperature for 20 hours, and 1000 ml of water was added. The reaction mixture was adjusted to pH 4 with concentrated hydrochloric acid, and extracted twice with 800 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under a reduced pressure to crystallize the title compound, which was then filtered and washed with hexane to obtain 25.2 g of colorless crystals.