Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].COC(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.7 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (3.5 g), 1-BOC-piperazine (2.76 g) and trimethylorthoformate (4.05 mL) was stirred in 1,2-dichloroethane (300 mL) for 1 hr at room temperature. To this was added sodium triacetoxyborohydride (3.92 g) and the reaction mixture was stirred for 24 hours at room temperature. The mixture was then quenched with brine, extracted with dichloromethane, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (3.4 g). Treatment with HCl in dichloromethane/methanol yielded 4-(2-chloro-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-4-yl)morpholine 30.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([NH:1][C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])(=[O:17])=[O:16]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: CS(=O)(=O)Cl
Product: COC(=O)c1ccc([C@H](C)NS(C)(=O)=O)cc1

Procedure:
Using methyl (S)-4-(1-aminoethyl)benzoate (0.61 g) and methanesulfonyl chloride (0.29 mL) and by the reaction and treatment in the same manner as in Preparation Example 71, the title compound (0.81 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][NH:41][CH2:42][CH2:43][CH2:44][CH2:45][OH:46])=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: NCCCCO
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(-c3ccc(CNCCCCO)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reaction time: 72 h

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 4-amino-1-butanol (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken for 3 days. Additional portions of 4-amino-1-butanol (0.1 mL) and sodium triacetoxyborohydride (0.089 g, 0.42 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 7 days. An additional portion of sodium triacetoxyborohydride (0.098 g, 0.46 mmol) was added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 12.5-14.8 min was collected, concentrated, and lyopholized to N1-{4-[4-amino-1-(4-{[(4-hydroxybutyl)amino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid. (0.030 g, 0.048 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, d, J=4.4 Hz), 8.35-8.40 (2H, m), 8.17 (2H, d, J=8.0 Hz), 8.00 (1H, t, J=7.4 Hz), 7.90 (1H, d, J=10.4 Hz), 7.75 (1H, d, J=7.2 Hz), 7.53-7.57 (2H, m), 7.45 (1H, s), 7.40 (1H, d, J=8.8 Hz), 3.96 (3H, s), 3.83 (2H, s), 3.39 (2H, t, J=6.2 Hz), 2.45-2.50 (2H, m), and 1.45-1.51 (4H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 9.93 min. MS: MH+624.3.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][CH:17]1[CH2:39][C:38]2[C:19](=[CH:20][C:21]3[N+:26]([O-:27])=[N:25][C:24]([CH2:28][CH2:29][CH2:30][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[N:23][C:22]=3[CH:37]=2)[CH2:18]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH3:16][CH:17]1[CH2:39][C:38]2[C:19](=[CH:20][C:21]3[N+:26]([O-:27])=[N:25][C:24]([CH2:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)=[N+:23]([O-:4])[C:22]=3[CH:37]=2)[CH2:18]1
Reactant: CC1Cc2cc3nc(CCCN4CCOCC4)n[n+]([O-])c3cc2C1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C1)[n+]([O-])c(CCCN1CCOCC1)n[n+]3[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
H2O2 (70%, 0.49 mL, ca. 9.7 mmol) was added dropwise to a stirred solution of TFAA (1.4 mL, 9.7 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 102 (320 mg, 1.0 mmol) and TFA (0.38 mL, 4.9 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×30 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1,4-dioxide 104 (148 mg, 44%) as a red solid: mp (MeOH/DCM) 119-121° C.; 1H NMR δ 8.27 (s, 1H, H-9), 8.23 (s, 1H, H-5), 3.45 (br t, J=4.5 Hz, 4H, 2×CH2O), 3.21-3.33 (m, 4H, 2×CH2), 2.68-2.81 (m, 3H, H-7, CH2), 2.48 (t, J=6.5 Hz, 2H, CH2N), 2.37 (br t, J=4.5 Hz, 4H, 2×CH2N), 2.06-2.13 (m, 2H, CH2), 1.20 (d, J=6.4 Hz, 3H, CH3); 13C NMR δ 155.2, 154.7, 150.2, 139.1, 133.8, 115.9, 113.9, 67.0 (2), 58.0, 53.5 (2), 41.4, 40.8, 35.0, 28.8, 21.8, 20.1. Anal. calcd for C18H24N4O3.¼CH3OH: C, 62.2; H, 7.2; N, 15.9. Found: C, 62.3; H, 7.0; N, 16.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:18]1([C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N+]=[N-])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CCc1nc(-c2ccc(Cl)cc2)co1)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
To a solution of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.5 g) in dichloromethane (20 ml) was added diphenyldiazomethane (0.425 g). After stirring for 4 hours at room temperature, acetic acid (0.5 ml) was added to the mixture. The reaction mixture was washed with a saturated sodium hydrogen carbonate aqueous solution and water, and then dried over MgSO4. The solvent was distilled off and then the oily residue was subjected to a silica gel column chromatography. Crystals of diphenylmethyl 4-(4-chlorophenyl)-2-oxazolepropionate (0.759 g, 91%) were obtained from the fraction eluted with ether-hexane (1:3, V/V). Recrystallization from ether-hexane gave colorless prism crystals of mp 94°-95° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.I[CH2:14][CH3:15]>>[Cl:1][C:2]1[C:11]([O:12][CH2:14][CH3:15])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: CCI
Reactant: COC(=O)c1cnc(Cl)c(O)c1
Product: CCOc1cc(C(=O)OC)cnc1Cl
Yield: 43 %

Procedure:
The title compound is prepared in 43% yield (0.68 g, a white solid) from methyl 6-chloro-5-hydroxynicotinate (1.37 g, 7.28 mmol) and iodoethane instead of iodomethane by the similar manner in Step-2 of Amine-4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:8]2[O:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])[CH:7]=1.[O:17]1CC[CH2:19][CH2:18]1>C(OC(=O)C)(=O)C>[C:18]([N:10]1[C:9](=[O:14])[CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:15][CH3:16])[O:12][C:11]1=[O:13])(=[O:17])[CH3:19]
Reactant: C1CCOC1
Reactant: COc1ccc(Cl)cc1C1OC(=O)NC1=O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(Cl)cc1C1OC(=O)N(C(C)=O)C1=O
Reaction time: 16 h

Procedure:
5-(5-Chloro-2-methoxyphenyl)oxazolidine-2,4-dione (100 mg.) was dissolved in 2.5 ml. of tetrahydrofuran. Excess acetic anhydride (4 drops) was added, and the mixture allowed to stand at room temperature for 16 hours. Evaporation to dryness gave 3-acetyl-5-(5-chloro-2-methoxyphenyl)oxazolidine-2,4-dione [Rf 0.75 (1:1 ethyl acetate: chloroform; m.p. 160°-162° C⟧
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@@H:25]1[C@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@H:25]([CH3:24])[C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(F)cc(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: CCOC(=O)Cc1cc(F)cc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-5-fluoro-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [C:1]([NH:18][C@@H:19]([C:24]([OH:26])=O)[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:35]>ClCCl>[C:1]([NH:18][C@@H:19]([C:24]([F:35])=[O:26])[CH2:20][CH2:21][S:22][CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: CSCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
FMOC-D-Methionine (5.00 g, 13.46 mmol) (Bachem) was dissolved in dichloromethane (70 mL). Pyridine (1.09 mL, 13.46 mmol) (Aldrich) and cyanuric fluoride (1.82 g, 13.46 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred for 4 hours. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford FMOC-D-methionyl fluoride as a white powder. (Yield 3.7 g., 74%).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:39](=[O:40])[N:38]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[N:37]=[CH:36][CH:35]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[CH:30]=[C:29]([NH:31][C:32]([C:34]2[C:39](=[O:40])[N:38]([C:41]3[CH:42]=[CH:43][C:44]([F:47])=[CH:45][CH:46]=3)[N:37]=[CH:36][CH:35]=2)=[O:33])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([CH:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[S:13][C:6]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nccc(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)c3s2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Oc2ccnc3cc(C4CCNCC4)sc23)c(F)c1)c1ccnn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(7-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)thieno[3,2-b]pyridin-2-yl)piperidine-1-carboxylate (87.3 mg, 0.132 mmol) and CF3COOH (5 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (one hour). Then the solvent was removed and the residue was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (38.5 mg, 52%). LRMS (APCI pos): >99% purity, 254 nm, m/e 560 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 8.44 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 7.95 (dd, 1H), 7.61 (m, 2H), 7.38 (m, 1H), 7.21-7.28 (m, 4H), 6.46 (d, 1H), 3.23 (m, 2H), 3.06 (m, 1H), 2.79 (m, 2H), 2.11 (m, 2H), 1.77 (m, 2H),
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:19][O:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=O)[C@H:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:10])(C)(C)C>Cl.C(OCC)(=O)C>[CH2:12]([O:11][C@@H:9]([C@H:8]1[CH2:19][O:20][CH2:21][C@@H:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[NH:7]1)[CH3:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](COCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A solution of {(1R,2R)-2-benzyloxy-1-[2-(4-chlorophenyl)-2-oxoethoxymethyl]propyl}carbamic acid t-butyl ester (2.61 g) in a 4 N hydrochloric acid/ethyl acetate solution (40 mL) was stirred at room temperature for 1 hour. Solvent was removed by distillation under reduced pressure, and the resultant product was diluted with methanol (30 ml). While cooling with ice, to the stirring solution was added sodium cyanoborohydride (733 mg), and the resultant solution was stirred overnight at room temperature. Solvent was removed by distillation under reduced pressure. The resultant product was diluted with ethyl acetate. This solution was successively washed with saturated sodium bicarbonate water and brine, and the organic layer was then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 95/5→3/2), to thereby obtain the titled compound (1.435 g). The physical properties of this crude product were as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:12]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:11]2[CH:16]=[C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[N:14]=[C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:12]=2)=[CH:5][CH:4]=1
Reactant: Clc1cc(N2CCCC2)nc(N2CCCC2)n1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2cc(N3CCCC3)nc(N3CCCC3)n2)cc1
Reaction time: 18 h

Procedure:
A mixture of 2.44 g of p-anisidine is heated to 135° (oil bath). The molten mixture is treated with 4-chloro-2,6-di-1-pyrrolidinylpyrimidine V, J. Med. Chem., 33,1145 (1990), 500 mg! and the reaction is stirred at 135° for 18 hr. The reaction mixture is allowed to cool and is then partitioned between chloroform and water. The organic layer is separated, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product (1.93 g) is chromatographed on 180 g of mesh silica gel. The column is packed and eluted with dichloromethane/ethyl acetate (9/1). An initial fraction of 2000 ml is collected. The solvent system is then changed to ethyl acetate/dichloromethane (9/1) and 10 ml fractions are then collected. Based on their TLC homogeneity, fractions 5-25 are combined to give the title compound, which is recrystallized from ethanol/water and dried (18 hours, 0.01 mm, 40°), mp 162°-163°; IR (mineral oil) 3273, 2953, 2925, 2865, 2854, 1609, 1586, 1571, 1549, 1505, 1478, 1453, 1427, 1409, 1377, 1343, 1313, 1303, 1294, 1236, 1219, 1171, 1043, 821 and 788 cm-1 ; NMR (CDCl3, TMS) 7.30-7.20, 6.90-6.80, 6.19, 4.99, 4.03, 3.60-3.30 and 2.00-1.80δ; CMR (CDCl3, TMS) 161.9, 160.3, 155.6, 133.1, 123.9, 114.1, 72.6, 55.3, 46.1, 45.8, 25.4 and 25.1δ; MS M+ found=339, other ions 324, 311, 297, 283, 270, 242, 169, 148, 121, 70 and 55.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]([O:17]CC)=O)=[N:10]2)[CH:5]=[CH:4][N:3]=1.[NH2:20][NH2:21].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:14])=[N:12][C:11]([C:15]([NH:20][NH2:21])=[O:17])=[N:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(C)n(Cc2ccnc(Cl)c2)n1
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)NN)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazole-3-carboxylate (218 mg, 0.81 mmol) in MeOH (4.5 mL) was added NH2NH2.H2O (122 μL, 1.22 mmol) and TEA (511 μL, 3.6 mmol). The reaction was allowed to stir overnight at RT. The solvent was then removed under reduced pressure and the crude material was spun down from toluene (3×) to give 1-((2-chloropyridin-4-yl)methyl)-5-methyl-1H-1,2,4-triazole-3-carbohydrazide as a white solid, which was used directly for the next step without further purification. MS (ES+) C10H11ClN6O requires: 266 found: 267[M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:28]([O:32][C:33]([NH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15]([N:38]2[CH2:39][CH2:40][C@@H:36]([NH:35][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:37]2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=S(=O)(Cl)c1cccc(OCc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cccc(OCc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3-benzyloxyphenylsulfonyl chloride, as described above in Step C, (1.8 g, 7.2 mmol) in CH2Cl2 (50 mL) was added N,N-diisopropylethylamine (1.8 mL, 10.3 mmol) followed by (R)-3-(tert-butoxycarbonylamino)pyrrolidine (1.77 g, 9.5 mmol) and the reaction mixture was stirred at ambient temperature for 4 hours. The mixture was washed with 10% aqueous citric acid (75 mL), then water (50 mL), then saturated aqueous NaHCO3 (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—20% EtOAc to yield the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:28]([NH:30][C:31](=[N:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[N:45]=[C:46]([NH:49][C:50]([NH2:52])=[NH:51])[S:47][CH:48]=1)OC1C=CC=CC=1)#[N:29]>>[C:28]([NH:30][C:31]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:15][CH2:14][N:7]([CH2:6][C:5]1[CH:26]=[CH:27][C:2]([F:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:25])=[N:39][CH2:40][CH2:41][S:42][CH2:43][C:44]1[N:45]=[C:46]([NH:49][C:50]([NH2:52])=[NH:51])[S:47][CH:48]=1)#[N:29]
Reactant: CN(CCCCCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Product: CN(CCCCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.57 g (1.53 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,7-heptanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=654 ([M+H]+, 2), 91 (100); IR (KBr): 2163 cm-1 (C≡N). For further analysis, a portion of the compound is converted into the O,O'-ditoluoyltartaric acid salt in an ethanol/ether solvent mixture; m.p. 118° C. (ethanol/ether).
Reaction SMILES: [CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH2:29])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:39][O:40][C:41]1[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[C:42]=1[C:43](Cl)=[O:44]>ClCCl>[CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:43](=[O:44])[C:42]3[C:46]([O:50][CH3:51])=[CH:47][CH:48]=[CH:49][C:41]=3[O:40][CH3:39])=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(N)ccc3c2O)cc1
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(NC(=O)c4c(OC)cccc4OC)ccc3c2O)cc1
Reaction time: 14 h

Procedure:
7-Amino-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester (Example 6, 200 mg, 0.48 mmol) was dissolved in dichloromethane (3 mL) and diisopropylethylamine (160 μL, 114 mg, 0.96 mmol) under nitrogen. 2,6-dimethoxybenzoyl chloride (120 mg, 0.60 mmol) was added and the solution was allowed to stir for 14 h. The resulting suspension was filtered to provide the title -compound (100 mg, 0.17 mmol, 36%) as a red solid: NMR (DMSO-d6): δ 16.30 (s, 1H), 10.81 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=9 Hz, 1H), 7.92 (d, J=9 Hz, 1H), 7.82 (s, 1H), 7.73 (d, J=9 Hz, 2H), 7.21 (t, J=9 Hz, 1H), 7.07 (d, J=9 Hz, 2H), 6.67 (d, J=9 Hz, 2H), 4.72 (m, 1H), 3.87 (s, 3H), 3.82 (s, 6H), 1.32 (d, J=3 Hz, 6H); Analytical HPLC: 88% pure; MS (ES-NEG): [M−H] 578; Anal. Calc. for C29H29N3O8S: C, 60.09, H, 5.04, N, 7.25. Found: C, 57.26, H, 4.82, N, 7.09.