Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([OH:34])=O)[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].[H-].[Na+]>O1CCCC1.CN(C)C=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:34])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NS(C)(=O)=O)c3ccccn3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g (4.5 mmol) of 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-hydroxycarbonylethyl)-amide and 0.73 g (4.7 mmol) of carbonyldiimidazole were dissolved in 80 ml of tetrahydrofuran and 5 ml of dimethylformamide and stirred for 30 minutes at ambient temperature and for 2 hours at 90° C. In parallel 0.55 g (5.8 mmol) of methansulphonic acid amide and 0.28 g (5.8 mmol) of sodium hydride were suspended in 15 ml of dimethylformamide and stirred for 2 hours at ambient temperature. Then this suspension was added at ambient temperature to the tetrahydrofuran solution. After 12 hours at ambient temperature 50 ml of water were added and the pH value was adjusted to 6.8. The solution Was extracted 4× with methylene chloride, the combined organic phases were dried over sodium sulphate and evaporated down. The crude product was chromatographed on silica gel (methylene chloride/ethanol (40:1)). The desired fractions were combined and evaporated down. Yield: 1.05 g (44% of theory),
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CC([O-])(C)C.[K+].CCOC(C)=O>COCCOC>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([CH2:12][CH3:13])[CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCc1cc(Br)c2ncccc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 53.2 %

Procedure:
A mixture of 8-bromo-6-ethylquinoline (1.3 g, 5.51 mmol, 1.04 equiv) and 1-(tert-butoxycarbonyl)homopiperazine (1.06 g, 1.0 equiv) in 5.5 mL of DME was degassed with compressed nitrogen gas for 5 minutes. To the mixture was added t-BuOK (0.83 g, 1.4 equiv). After degassing for another 2 minutes, allylchloro[1,3-(2,6-di-isopropylphenyl)imidazol-2-ylidene]palladium (II) (61 mg, 0.02 equiv) was added and the resulting mixture was heated at 60° C. overnight and cooled down to room temperature. EtOAc (˜70 mL) was added and the mixture was filtered through celite. The filtrate was washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 20% EtOAc in hexane to afford the title compound (1.0 g). MS (ES) m/z 356.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH:15]([CH2:20][CH3:21])[C:16]([O:18][CH3:19])=[O:17].[H-].[Na+].[C:24](#N)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][N:11]([CH:15]([CH2:20][CH3:21])[C:16]([O:18][CH2:19][CH3:24])=[O:17])[C:10](=[O:13])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(c2cccc(Cl)c2)CN1
Reactant: CC#N
Reactant: CCC(Br)C(=O)OC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(CC)N1CC(c2cccc(Cl)c2)CC1=O
Temperature: 50 °C

Procedure:
In a 2 l three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 54.4 g (278 mmoles, 1 eq) of 4-(3-chlorophenyl)-2-pyrrolidinone 379 are dissolved in 1.4 l acetonitrile. 64 ml (100.7 g, 556 mmoles, 2 eq) of methyl 2-bromobutanoate are added and the temperature raised to 50° C. 22.24 g (556 mmoles, 2 eq) of sodium hydride are added by portions, the temperature raising to 65° C. The mixture is stirred one more hour at 50° C. The mixture is concentrated to dryness, the residue suspended in ethyl acetate, washed with water, the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness. The residue is purified by PrepLC (1 kg SiO2, pet. ether/EtOAc, 70:30) to give 56.7 g of pure 380, 69%. 1H NMR (250 MHz, (CD3)2SO): 0.80-1.00 (m, 3H), 1.60-1.90 (2H, m), 2.35-2.55 (m, 1H: partially overlapped with solvent), 2.60-2.90 (m, 1H: partially overlapped with solvent), 3.70 (s, 3H), 3.50-3.80 (m, 3H), 4.50 (m, 1H), 7.20-7.50 (m, 4H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5].C=O.N1CCC[CH2:15]1.C(O)(=O)CC>C(O)(C)C>[CH3:1][C@@H:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11])[C:3](=[CH2:15])[CH:4]=[O:5]
Reactant: CC(C)=CCC[C@H](C)CC=O
Reactant: C1CCNC1
Agent: C=O
Solvent: CCC(=O)O
Solvent: CC(C)O
Product: C=C(C=O)[C@@H](C)CCC=C(C)C
Temperature: 45 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (S)-3,7-dimethyloct-6-enal (3.0 g, 19.45 mmol) in isopropyl alcohol (20 mL) at room temperature. was added 37% aqueous formaldehyde (14.46 mL, 194.5 mmol), pyrrolidine (1.61 mL, 19.45 mmol) and propionic acid (1.45 mL, 19.45 mmol). The mixture was warmed to 45° C. and stirred for 2 hours. The reaction was then cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate (100 mL). The mixture was extracted with dichloromethane and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:petroleum ether/ethyl acetate=160:1->110:1) to afford the title compound as a colorless oil (3.2 g, Yield: 98%). Rf=0.7 (10:1) petroleum ether/:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 6.22 (s, 1H), 5.98 (s, 1H), 5.09-5.05 (m, 1H), 2.73-2.67 (m, 1H), 1.94-1.90 (m, 2H), 1.67 (s, 3H), 1.57 (s, 3H), 1.54-1.48 (m, 1H), 1.42-1.37 (m, 1H), 1.06 (d, J=6.8 Hz, 3H) ppm.
Reaction SMILES: Cl.CN([CH2:5][C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)C.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:17]=1[NH2:18].COC1C=CC=C(OC)C=1C(O)=O>C(O)CO>[NH2:18][C:17]1[C:19]([O:23][CH3:24])=[CH:20][C:21]([CH2:5][C:6]2[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)=[CH:22][C:16]=1[O:15][CH3:14]
Reactant: COc1cccc(OC)c1N
Reactant: CN(C)Cc1c[nH]c(=O)[nH]c1=O
Agent: COc1cccc(OC)c1C(=O)O
Agent: Cl
Solvent: OCCO
Product: COc1cc(Cc2c[nH]c(=O)[nH]c2=O)cc(OC)c1N
Yield: 28.8 %

Procedure:
A mixture of 10.04 g (49 mmol) of 5-[(dimethylamino)methyl]uracil hydrochloride (B. Roth, J. Z. Strelitz, and B. S. Rauckman, J. Med. Chem. 23, 379 (1980) and 7.48 g (49 mmol) of 2,6-dimethoxyaniline (m.p. 73°-74.5°; prepared from 2,6-dimethoxybenzoic acid by the procedure in Org. Reactions 3, 330 (1946)) in 50 mL of ethylene glycol under nitrogen was heated at 145° for 5 hours. The mixture was cooled and the precipitated solid was collected, suspended in 300 mL of boiling ethanol and collected to give 3.91 g (29%) of the title compound; m.p. 243°-245° (dec.).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH:18](N)[CH2:17][CH2:16]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS[C:24](=[N:36][C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C([N:49](CC)CC)C>CN(C)C=O>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH:15]3[CH2:16][CH2:17][CH:18]([N:25]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[C:24]([NH:36][C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])=[NH:49])[CH2:19][CH2:20]3)[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: NC1CCC(CCN2CCN(c3ccccc3)CC2)CC1
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(NC(=O)OCc1ccccc1)N(C(=O)OCc1ccccc1)C1CCC(CCN2CCN(c3ccccc3)CC2)CC1
Yield: 63.3 %

Procedure:
A solution of trans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cylohexylamine (0.43 g, 1.5 mmol), S-methyl-N,N'-dicarbobenzyloxy isothiourea (Nowak K. and Kania L., Rocz. Chem., 1969;43(11):1953-1960) (0.59 g, 1.65 mmol) and triethylamine (0.18 g, 1.8 mmol) in dimethylformamide (DMF) (50 mL) was stirred at room temperature 3 days. An additional amount of the starting amine (0.075 g, 0.26 mmol) was added, and the reaction mixture was allowed to stand one more day and then evaporated to dryness. The residue was recrystallized from Et2O-hexane to yield trans-N-{4-[2-(4-phenyl-piperazin-1-yl)-ethyl]-cyclohexyl-N, N'-dicarbobenzyloxyguanidine 0.568 g (63%) white solid; mp 136-137° C.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH2:20])=[CH:14][CH:13]=1>CCCCCC>[Br:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][CH:1]=[O:3])=[CH:14][CH:13]=1
Reactant: COc1nc(Br)ccc1N
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: COc1nc(Br)ccc1NC=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To formic acid (12 mL) was added acetic anhydride (12 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min. 6-Bromo-2-methoxypyridin-3-amine (8.8 g) was gradually added to the reaction mixture at 0° C. over 10 min, and the mixture was stirred at 0° C. for 30 min. IPE (50 mL) and hexane (50 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The obtained solid was collected by filtration to give the title compound (8.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.C1C=CC2N(O)N=[N:40]C=2C=1.C(Cl)CCl.N.O>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH2:40])=[O:13])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=C(O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A mixture of 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (156 mg, 0.29 mmol), HOBT (59 mg, 0.44 mmol), EDC (84 mg, 0.44 mmol), and NH3—H2O (28-30% NH3 basis, 2×4 ml, excess) in DMF (3 ml) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (40-100% EtOAc in hexane) to yield the title compound (69 mg, 45%).
Reaction SMILES: NC[C:3]1[S:4][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19](F)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:6]([CH3:8])[N:7]=1.[CH3:26][O:27][CH2:28][CH2:29][OH:30].C[C:32]#[N:33]>>[CH3:26][O:27][CH2:28][CH2:29][O:30][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:11]2[N:10]=[C:9]([C:5]3[S:4][C:3]([NH:33][CH3:32])=[N:7][C:6]=3[CH3:8])[CH:14]=[CH:13][N:12]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24]
Reactant: COCCO
Reactant: CC#N
Reactant: Cc1nc(CN)sc1-c1ccnc(Nc2ccc(F)c([N+](=O)[O-])c2)n1
Product: CNc1nc(C)c(-c2ccnc(Nc3ccc(OCCOC)c([N+](=O)[O-])c3)n2)s1

Procedure:
By alkylation of [4-(2-aminomethyl-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-fluoro-3-nitrophenyl)-amine with 2-methoxy-ethanol. Yellow solid. Anal. RP-HPLC: tR=12.8 min (10-70% MeCN, purity >90%). 1H-NMR (DMSO-D6) δ: 2.41 (s, 3H, CH3), 2.86 (d, 3H, J=4.5 Hz, CH3), 3.24 (s, 3H, CH3), 3.66 (m, 2H, CH2), 4.23 (m, 2H, CH2), 6.93 (d, 1H, J=6.0 Hz, pyrimidinyl-H), 7.32 (d, 1H, J=5.0 Hz, Ph-H), 7.79 (m, 1H, Ph-H), 8.08 (d, 1H, J=5.0 Hz, Ph-H), 8.35 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 8.54 (m, 1H, NH), 9.68 (s, 1H, NH). MS (ESI+) m/z 417.08 [M+H]+ (C18H20N6O4S requires 416.46).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].F[B-](F)(F)F.[CH2:13]([O+](CC)CC)C.N.Cl.C[O:23][C:24](=[O:29])[C@H:25]([CH2:27]O)N.ClC(Cl)C>ClCCl>[C:2]([C:1]1[O:6][CH2:13][CH:27]([CH2:25][C:24]([OH:23])=[O:29])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(N)=O
Reactant: CC[O+](CC)CC
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Agent: F[B-](F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CC(C)(C)C1=NC(CC(=O)O)CO1

Procedure:
3 g (29.6 mmol) of pivalic acid amide are stirred with 5.6 g (29.6 mmol) of triethyloxonium tetrafluoroborate in 50 ml of dichloromethane for 48 h. Ammonia is passed through the solution over a period of 3 h, the resulting residue is filtered off and the filtrate is concentrated in a rotary evaporator. 4.67 g (30 mmol) of L-serine methyl ester hydrochloride are added with 50 ml of dichloroethane, and the mixture is then heated at reflux for 8 h. Extraction with NaHCO3 solution and NH4Cl solution, drying over MgSO4 and purification by column chromatography (15×3 cm, pentane/diethyl ether 4:1) are carried out. Yield 1.34 g (24% of theory).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.[NH:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:14].Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:13]([C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH3:14])[CH3:20]
Reactant: O=C(O)CCCc1ccncc1
Reactant: CCOC(=O)CNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C)C(=O)CCCc1ccncc1
Reaction time: 8 h

Procedure:
4-(4-Pyridyl)butanoic acid 10-5 (100 mg, 1.8 mmol), H-Sar-OEt·HCl (300 mg, 2.0 mmol), BOP (965 mg, 2.2 mmol) and NMM (700 μL, 6.4 mmol) were combined in 9 mL DMF. After stirring overnight the mixture was diluted with EtOAc, washed with water (4×), sat. NaHCO3, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 80% to 100% EtOAc/hexane) provided 6-1 as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16]1[N:17]=[C:18]([NH2:21])[S:19][CH:20]=1.[Cl:22][C:23]1[C:28]([Cl:29])=[C:27]([Cl:30])[CH:26]=[CH:25][C:24]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:22][C:23]1[C:28]([Cl:29])=[C:27]([Cl:30])[CH:26]=[CH:25][C:24]=1[S:31]([NH:21][C:18]1[S:19][CH:20]=[C:16]([C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)=[CH:7][C:2]=2[Cl:1])[N:17]=1)(=[O:33])=[O:32]
Reactant: Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1Cl
Product: O=S(=O)(Nc1nc(-c2ccc(Oc3ccc(Cl)cc3)cc2Cl)cs1)c1ccc(Cl)c(Cl)c1Cl

Procedure:
The title compound was prepared from 4-[2-chloro-4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-amine (91 mg) and 2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (49.2 mg) with purity >90%: MS (pos) m/z 579.1, 581.1, 583.1; MS (neg) m/z 577.5, 579.5, 581.5.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(CC)CC.[CH3:32][C:33](OC(C)=O)=[O:34]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:12][CH2:13][NH:14][C:33](=[O:34])[CH3:32])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cnc(CN(CCCN)C2CCCc3cccnc32)c(C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCCN(Cc1ncc(C)cc1C)C1CCCc2cccnc21
Yield: 71.2 %

Procedure:
To a solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (78 mg, 0.23 mmol) in CH2Cl2 (2.5 mL) was added Et3N (100 μL, 0.72 mmol) followed by Ac2O (40 μL, 0.43 mmol). The resultant solution was stirred at room temperature for 45 minutes. The mixture was diluted with CH2Cl2 (20 mL), washed with brine (3×5 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 60 mg (71%) of the free base of the title compound as a white foam. Conversion of the foam to the HBr salt gave COMPOUND 362 as a white solid. 1H NMR (D2O) δ 1.42-1.47 (m, 2H), 1.71-1.80 (m, 4H), 1.99-2.17 (m, 2H), 2.32-2.39 (m, 2H), 2.41 (s, 3H), 2.45 (s, 3H), 2.62-2.72 (m, 1H), 2.92-2.97 (m, 4H), 4.11 (d, 1H, J=17.1 Hz), 4.33 (d, 1H, J=17.1 Hz), 4.45 (dd, 1H, J=10.5, 5.7 Hz), 7.84 (dd, 1H, J=8.1, 5.4 Hz), 8.19 (s, 1H), 8.32 (d, 1H, J=8.1 Hz), 8.42 (s, 1H), 8.57 (d, 1H, J=5.4 Hz); 13C NMR (D2O) δ 17.13, 17.56, 20.45, 20.65, 22.17, 27.85, 28.05, 37.58, 49.78, 52.00, 61.10, 125.88, 136.64, 137.42, 137.79, 139.39, 140.75, 148.15, 148.73, 149.28, 151.16, 174.37; ES-MS m/z 367 (M+H). Anal. Calcd. For C22H30N4O.2.9HBr.3.7H2O: C, 39.57; H, 6.08; N, 8.39; Br, 34.70. Found: C, 39.62; H, 5.85; N, 8.04; Br, 34.70.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH:10]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:37].[K+]>C1COCC1.O>[CH2:1]([O:8][C:9]([CH:10]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:37])=[O:26])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C=O)cc2)cc1)C(=O)OCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 94.4 %

Procedure:
Benzyl ester 3 (4.6 g, 9.7 mmol) was dissolved in THF (100 mL) and the solution stirred at 70° C. Potassium permanganate (7.7 g, 48.5 mmol) dissolved in water (125 mL) was added slowly through a dropping funnel over a period of 2 hours. After addition was complete, reaction mixture was stirred at 70° C. for 30 min and cooled to room temperature. The brown precipitate was filtered over a Celite® bed and the filtrate was concentrated under reduced pressure. The residual oil was taken up in EtOAc (100 mL) and acidified with 2.0 M HCl. The organic layer was separated and washed with water (1×100 mL) and brine (1×100 mL), dried, and concentrated under reduced pressure to yield the desired acid compound 4 (4.5 g, 94%). 1H NMR (DMSO-d6): 12.7 (br, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.4 Hz), 7.30-7.37 (m, 7H), 7.03 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 5.12 (s, 2H), 4.24-4.28 (m, 1H), 3.04 (dd, J=13.6 and 5.2 Hz, 1H), 2.91 (dd, J=13.6 and 9.6 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: O([C:8]([NH:10][C:11]1[S:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]=1)=[O:9])C1C=CC=CC=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C=O)C>[N:20]1([C:8]([NH:10][C:11]2[S:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: O=C(Nc1nc2cnccc2s1)Oc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1nc2cnccc2s1)N1CCCC1
Temperature: 70 °C
Yield: 98 %

Procedure:
A mixture of 2-phenoxycarbonylaminothiazolo[4,5-c]-pyridine (200 mg, 0.73 mmole) and pyrrolidine (0.3 ml) in DMF (2 ml) was heated at 70° C. for 30 minutes and evaporated in vacuo. The residue was triturated with ether to give 180 mg (98%) of the desired product. Mp. 218°~220° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[OH-].[NH4+]>B(F)(F)F.CO>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Agent: FB(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Temperature: 0 °C

Procedure:
N-(4-((3,6-Dichloro-2-pyridinyl)methoxy)phenyl)acetamide (30.27 grams; 0.097 mole) was mixed with a 170 ml. solution of boron trifluoride-methanol (1 gram per 10 ml.) and the resulting reaction mixture refluxed for a period of 4 1/2 hours. The reaction mixture was then diluted and cooled with ice water to a temperature of between about 0° to about 10° C. Concentrated ammonium hydroxide was added until the reaction mixture was basic. The reaction mixture was then extracted with portions of methylene chloride, the extracts combined and the solvent removed by evaporation. The residue thus obtained was extracted with five 500 ml. portions of hexane. The crystalline material which precipitated from the hexane mixture upon cooling was recovered by filtration. As a result of these operations, the desired 4-((3,6-dichloro-2-pyridinyl)methoxy)benzenamine compound was recovered as a light yellow crystalline solid having a melting point of 74°-75° C.