Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]([CH2:25][CH3:26])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.I.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](SC)=[NH:34]>CCO>[CH2:25]([N:17]([CH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:33]([C:29]4[S:28][CH:32]=[CH:31][CH:30]=4)=[NH:34])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH3:26]
Reactant: CSC(=N)c1cccs1
Reactant: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(N)cc23)C1
Agent: I
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)C1CCCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
To a solution of tert-butyl 3-(5-amino-1H-indol-3-yl)cyclohexyl(ethyl)carbamate (0.62 g, 1.73 mmol) in dry EtOH (25 mL) was added methyl thiophene-2-carbimidothioate hydroiodide (1.00 g, 3.47 mmol) and the reaction left to stir at room temperature for 48 hours. The solvent then was evaporated and the mixture dissolved in dichloromethane (20 mL) and washed with 2N NaOH (10 mL). The organic layer was extracted and evaporated. The crude was purified on column chromatography (2 M NH3 in MeOH:CH2Cl2, 2:98 to 5:95) to give the title compound as a yellow solid (0.80 g, quantitative). 1H-NMR (DMSO-d6) δ 1.04 (t, 3H, J=6.9 Hz), 1.36 (s, 9H), 1.44-1.68 (m, 5H), 1.84-2.04 (m, 3H), 3.05-3.20 (m, 2H), 3.42-3.53 (m, 1H), 4.19-4.26 (m, 1H), 6.21 (s, 2H), 6.64 (dd, 1H, J=1.8, 8.4 Hz), 6.92 (s, 1H), 7.09 (dd, 1H, J=3.6, 5.1 Hz), 7.26 (s, 1H), 7.29 (s, 1H), 7.58 (d, 1H, J=5.1 Hz), 7.70 (d, 1H, J=3.9 Hz), 10.67 (s, 1H). ESI-MS (m/z, %) 467 (MH+, 100)
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:31]([O:33][C:34](Cl)=[O:35])[CH3:32]>ClCCl>[C:1]1([C:7]2[NH:8][C:9](=[O:24])[N:10]([S:12]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:34]([O:33][CH2:31][CH3:32])=[O:35])[CH2:19][CH2:18]4)(=[O:14])=[O:13])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)cn1S(=O)(=O)c1ccc2c(c1)CCN2
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1CCc2cc(S(=O)(=O)n3cc(-c4ccccc4)[nH]c3=O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
4-Phenyl-1-(indoline-5-sulfonyl)-2-imidazolone (150 mg, 0.44 mmol) prepared in Preparation 3 was dissolved in 10 ml of dichloromethane and then pyridine (39 μl, 0.484 mmol) and ethylchloroformate (46 μl, 0.484 mmol) were added thereto one after another. After the reaction mixture was stirred for one hour at room temperature, it was diluted with dichloromethane and washed twice with brine. The organic layer thus obtained was dried over anhydrous magnesium sulfate, concentrated to an oily state under reduced pressure, and then purified by silica gel column chromatography (eluent:dichloromethane/methanol=15/1, v/v) to afford 173 mg of the title compound as a white solid.
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[C:37]([O:41][C:42]([NH:44][C@@H:45]([CH:49]([CH3:51])[CH3:50])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:46](=[O:47])[C@@H:45]([NH:44][C:42]([O:41][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:43])[CH:49]([CH3:51])[CH3:50])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(OC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
The solution of 300 mg (0.59 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one in 3 ml of pyridine was admixed with 14 mg of 4-dimethylaminopyridine, 383 mg of (S)-2-tert-butoxycarbonylamino-3-methylbutanoic acid and 130 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the mixture was stirred at 23° C. for 16 hours. The mixture was poured into water and extracted repeatedly with dichloromethane, and the combined organic extracts were washed with water and saturated sodium chloride solution and dried over sodium sulphate. The residue obtained after filtration and solvent removal was purified by chromatography. 314 mg (75%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>>[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:25]
Reactant: O=C(Cl)c1cccs1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4cccs4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.068 mMol) 2-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7. MS(m/e): 353(M+1)
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH2:16]Br.CN(C=O)C.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.[K].CCOCC>O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][C:3]=1[CH2:16][N:27]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 18 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
A 12 L flask was charged with (4-bromo-3-bromomethyl-phenoxy)-tert-butyl-dimethyl-silane (568 g 1.49 mol), DMF (3.1 L), and potassium phthalimide (316 g 1.71 mol). An exotherm to 34° C. occurred. After 40 min, the reaction mixture was cooled to 18° C. Ether (6.2 L) and DI water (4.9 L) were added, and the layers were separated. The organic layer was washed with saturated NaCl solution (2 L), dried (Na2SO4), filtered, and concentrated. The residue was recrystallized from heptane (1.5 L) to give the title compound (454 g, 68%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]1[O:23][C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14]1>CCOCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][C:16]2([O:23][CH2:13][CH2:14][O:15]2)[CH2:17][CH2:18]1
Reactant: Brc1ccccn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCOCC
Product: OC1(c2ccccn2)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 2-bromopyridine (14 g, 88.6 mmol) in anhydrous ether (300 mL) cooled at −78° C. was slowly added a solution of 2.5 M butyl lithium (36 mL). After the addition, stirring was continued at −78° C. for 1 hour. To it was slowly added a solution of 1,4-cyclohexanedione mono-ethylene ketal (15 g, 96 mmol) in anhydrous ether (300 mL). When the addition was complete, the mixture was allowed to warm to 0° C. and stirring was continued for 1 hour. The reaction was quenched by the addition of an aqueous solution (100 mL) of ammonium chloride (4.5 g). The organic phase was separated and the aqueous phase was extracted with methylene chloride 4 times. The combined organic phases were dried over MgSO4 and concentrated. Crystallization from EtOAc provided 7 g of the desired product. The mother liquid was purified on silica gel eluting with 10% MeOH/EtOAc to give 3 g of the desired product. MS calculated (M+H)+ 236. found 236.0.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:20])OC2C=CC(Cl)=CC=2)[O:7][N:6]=1)([CH3:4])[CH3:3].[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[C:37]([F:43])=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39]>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH3:34])[N:29]=[CH:28][N:27]=[C:26]2[O:35][C:36]1[C:37]([F:43])=[C:38]([NH:39][C:11]([NH:10][C:8]2[O:7][N:6]=[C:5]([C:2]([F:1])([CH3:3])[CH3:4])[CH:9]=2)=[O:20])[CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccc(Cl)cc2)on1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.8 %

Procedure:
A mixture of 4-chlorophenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate (prepared as described in Example 257A) (213 mg, 0.714 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared as described in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea (147 mg, 64%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) 810.55 (brs, 1H), 8.89 (brs, 1H), 8.58 (s, 1H), 8.03 (m, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.20 (s, 1H), 4.00 (s, 6H), 1.69 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 486 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:42])[C@@H:15]([CH2:32][CH2:33][CH2:34][NH:35][C:36]([NH2:41])=[N:37][N+]([O-])=O)[NH:16][C:17]([C:19]2[CH:30]=[C:29]([CH3:31])[C:22]3[NH:23][C:24]([CH2:26][CH2:27][CH3:28])=[N:25][C:21]=3[CH:20]=2)=[O:18])=[CH:8][CH:7]=1)=[O:3].[C:43]([OH:46])(=[O:45])[CH3:44]>[Pd]>[NH2:1][C:2]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14](=[O:42])[C@@H:15]([CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:41])[NH:16][C:17]([C:19]2[CH:30]=[C:29]([CH3:31])[C:22]3[NH:23][C:24]([CH2:26][CH2:27][CH3:28])=[N:25][C:21]=3[CH:20]=2)=[O:18])=[CH:8][CH:7]=1)=[O:3].[CH3:19][C:17]([CH2:44][C:43]([OH:46])=[O:45])=[O:18]
Reactant: CC(=O)O
Reactant: CCCc1nc2cc(C(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc3ccc(CNC(N)=O)cc3)cc(C)c2[nH]1
Agent: [Pd]
Product: CC(=O)CC(=O)O
Product: CCCc1nc2cc(C(=O)N[C@H](CCCNC(=N)N)C(=O)NCc3ccc(CNC(N)=O)cc3)cc(C)c2[nH]1
Yield: 54 %

Procedure:
Prepared analogously to Example 4c) from (R)-N-[[4-(aminocarbonylaminomethyl)phenyl]methyl]-N5 -[amino(nitroimino)methyl]-N2 -[(7-methyl-2-propyl-1H-benzimidazol-5-yl)carbonyl]-ornithinamide by catalytic hydrogenation in the presence of palladium black and 80% aqueous acetic acid in a yield of 54% of theory.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1.[C:12]([Cu])#[N:13]>>[C:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][N:3]=1)#[N:13]
Reactant: N#C[Cu]
Reactant: Cc1cnc(Br)c([N+](=O)[O-])c1
Product: Cc1cnc(C#N)c([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 79.3 %

Procedure:
A round bottom flask was charged with 2-bromo-5-methyl-3-nitropyridine (60.53 g, 278.9 mmol) and CuCN (27.52 g, 307.3 mmol) The flask was evacuated, and back-filled with nitrogen. DMF (150 mL) was added via cannula. The solution was heated to 70° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into EtOAc (500 mL) and water (250 mL). Both phases were filtered through a 1 cm bed of celite. The layers were separated, and the organic phase washed with water (2×100 mL) then with a solution of 1:1 sat. aq. NH4Cl/NH4OH (2×100 mL). The combined aqueous layers were extracted with EtOAc (2×200 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (36.10 g, 79% yield).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH:34]4[CH2:37][O:36][CH2:35]4)[CH2:30][CH2:29]3)=[CH:24][N:23]=2)[C:15]2[N:16]([N:18]=[CH:19][N:20]=2)[CH:17]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][N:31]([CH:34]4[CH2:37][O:36][CH2:35]4)[CH2:32][CH2:33]3)=[CH:24][N:23]=2)[C:15]2[N:16]([N:18]=[CH:19][N:20]=2)[CH:17]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c3ncnn3c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: O=C1c2cc3c(n2CCN1c1nccc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4ncnn4c2)c1CO)CCCC3
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
A mixture of 122a (200 mg, 0.29 mmol) and lithium hydroxide (42 mg, 1.0 mmol) in i-propanol/THF (1:1, 3.5 mL) and water (1 mL) was stirred at 40° C. for 0.5 h. The mixture was evaporated under reduced pressure and the residue was diluted with water (5 mL). It was extracted with ethyl acetate (2×5 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 122 (70 mg, 38%) as pale yellow solid. MS-ESI: [M+H]+ 647.3. 1H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.69 (s, 1H), 8.61 (s, 1H), 8.57-8.55 (m, 2H), 7.93 (d, J=2.5 Hz, 1H), 7.48-7.43 (m, 2H), 7.37-7.35 (m, 1H), 6.59 (s, 1H), 5.05 (t, J=5.0 Hz, 1H), 4.57-4.55 (m, 2H), 4.61-4.59 (m, 2H), 4.40-4.39 (m, 2H), 4.26-4.12 (m, 3H), 3.92-3.89 (m, 1H), 3.43 (t, J=6.0 Hz, 1H), 3.11-3.09 (m, 4H), 2.63-2.57 (m, 2H), 2.50-2.47 (m, 2H), 2.40-2.39 (m, 4H), 1.79-1.77 (m, 2H), 1.70-1.68 (m, 2H).
Reaction SMILES: [Cl-:1].[OH:2][CH2:3][CH2:4][N+:5]1[CH:9]=[CH:8][N:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]2[N:19]3[N:20]=[CH:21][C:22]([N+:23]([O-])=O)=[C:18]3[N:17]=[C:16]([CH3:26])[CH:15]=2)[CH:6]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[Cl-:1].[NH2:23][C:22]1[CH:21]=[N:20][N:19]2[C:14]([NH:13][CH2:12][CH2:11][CH2:10][N:7]3[CH:8]=[CH:9][N+:5]([CH2:4][CH2:3][OH:2])=[CH:6]3)=[CH:15][C:16]([CH3:26])=[N:17][C:18]=12
Reactant: [H][H]
Reactant: Cc1cc(NCCCn2cc[n+](CCO)c2)n2ncc([N+](=O)[O-])c2n1
Agent: [Pd]
Agent: [Cl-]
Solvent: CCO
Product: Cc1cc(NCCCn2cc[n+](CCO)c2)n2ncc(N)c2n1
Product: Cl
Yield: 3 %

Procedure:
3.5 g of 1-(2-hydroxyethyl)-3-[3-(5-methyl-3-nitropyrazolo[1,5-a]pyrimidin-7-ylamino)propyl]-3H-imidazol-1-ium chloride in 150 cc of ethanol and then 0.39 g of 5% palladium on carbon (containing 50% water) were introduced into a 250 cc hydrogenator. Between 11 and 12 bars' pressure of hydrogen were introduced into the reactor and the reaction medium was brought to 60° C. After 4 hours of reaction, the catalyst was filtered over Celite and a stream of gaseous hydrochloric acid was passed through the filtrate. The reaction medium was poured into 100 cc of diisopropyl ether. After stirring, the precipitate was filtered off. It was washed with diisopropyl ether and dried under vacuum over phosphoric anhydride. This gave 3.3 g of a highly hygroscopic product. A 3% aqueous solution of this product was formed, and was lyophilized. The resulting solid was taken up at reflux in 30 cc of absolute ethanol. This gives 2.25 g of 3-[3-(3-amino-5-methylpyrazolo[1,5-a]pyrimdin-7-ylamino)propyl]-1-(2-hydroxyethyl)-3H-imidazol-1-ium chloride in the form of the dihydrochloride, after drying under vacuum over phosphoric anhydride, with a yield of 85%, whose analysis calculated for C15H22N7OCl, 2HCl (MW=424.76 g) was as follows:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:14][C:13]1[CH:15]=[CH:16][C:10]([S:7]([O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: C#CCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Yield: 74 %

Procedure:
This compound was synthesized as a colorless oil from pent-4-yn-1-ol (145.0 mg, 132 mmol), TsCl (426.3 mg, 2.24 mmol), Et3N (349.4 mg, 3.44 mmol), and DMAP (210.1 mg, 1.72 mmol) in 74% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.77 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 4.24-3.97 (m, 2H), 2.42 (s, 3H), 2.23 (td, J=6.9, 2.6 Hz, 2H), 1.99-1.67 (m, 3H); 13C NMR (100 MHz, CDCl3, δH) 145.06, 133.09, 130.09, 128.12, 82.33, 69.68, 68.98, 27.91, 21.85, 14.90. ESI-MS: 239.1 (M+H+), 261.1 (M+Na4).
Reaction SMILES: [OH:1][CH:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:3].[CH3:10]O>>[CH3:10][O:1][CH:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:3]
Reactant: CC(O)N1CCCC1=O
Reactant: CO
Product: COC(C)N1CCCC1=O
Temperature: 20 °C

Procedure:
To 70 g of N-(α-hydroxyethyl)pyrrolidone (0.54 mol), 70 g of methanol (2.2 mol) was added and the mixture was stirred at 20° C. to make a solution. 2 g of dried Diaion PK 208H (cross-linked polystyrenesulfonic acid resin, made by Mitsubishi Chemical Industries Co.) was added to the solution and after 30 minutes of reaction, the reaction mixture was analyzed with a liquid chromatography. The reaction ratio of N-(α-hydroxyethyl)pyrrolidone was 98.6 mol % and the selectivity in forming N-(α-methoxyethyl)pyrrolidone based on N-(α-hydroxyethyl)pyrrolidone was 99.6 mol %.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@@H:23]([O:26][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (0.92 g, 2.0 mmol) in 10 ml of CH2Cl2 is added at 0° C. methanesulfonyl chloride (0.31 mL, 4.0 mmol) followed by triethylamine (0.56 ml, 4.0 mmol). The reaction mixture is stirred at room temperature for 24 h and treated with water. The aqueous layer is extracted 2 times with CH2Cl2. The organic layer is dried with sodium sulfate, filtered and concentrated under reduced pressure to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(cis-4-methanesulfonyloxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: S([Cl:5])(O)(=O)=O.O.[N:7]([CH2:14][CH2:15][OH:16])([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10]>>[ClH:5].[N:7]([CH2:14][CH2:15][OH:16])([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10]
Reactant: O=S(=O)(O)Cl
Solvent: OCCN(CCO)CCO
Solvent: O
Product: Cl
Reaction time: 1 h

Procedure:
A suspension of 3.7 g of the sulfochloride of the formula (7) in 15 g of triethanolamine and 3 g of water is stirred at 150° for one hour. The excess solvent is substantially removed in vacuo at 120°-150° C., and 50 ml of isopropanol are added to the viscous residue. The precipitated product is filtered off with suction, washed repeatedly with isopropanol and taken up in approx. 40 ml of water. The cloudy solution is clarified by filtration with 0.2 g of active charcoal through a pressure filter. This gives an aqueous solution of the bistriethanolamine salt of the formula ##STR16## which still contains triethanolamine hydrochloride.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[CH3:23]CN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:46][C:47]([CH3:52])([CH3:51])[C:48]([O-:50])=[O:49]>C(Cl)Cl.O>[CH3:51][C:47]([NH:46][C:20](=[O:22])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:14][CH:15]=1)([CH3:52])[C:48]([O:50][CH3:23])=[O:49]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(N)C(=O)[O-]
Reactant: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
To a stirred solution of 2-(4-(quinolin-2-ylmethoxy)phenyl)acetic acid (5.0 g, 0.017 mol) in DCM (50 mL) were added DIPEA (6.6 g, 0.05 mol), HOBT (3.4 g, 0.02 mol) and EDC (4.9 g, 0.02 mol) at RT under an inert atmosphere. After 10 minutes, 2-amino-2-methylpropanoate (3.9 g, 0.02 mol) was added to the reaction mixture and stirring was continued for 4 h. The reaction mixture was diluted with water and extracted with DCM (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4. Evaporation of organic solvents in vacuo afforded methyl 2-methyl-2-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetamido)propanoate (5.0 g, 74%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].Cl.Cl.[NH2:18][CH:19]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([N:35](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:35][N:2]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][CH2:9][CH2:10][C:11]([NH:18][CH:19]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:13])=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(CNCCC(=O)O)cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CC(N)c1cccnc1
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
Product: CCOC(=O)CC(NC(=O)CCNCc1ccc(C=NN)cc1)c1cccnc1
Reaction time: 8 h
Yield: 68.1 %

Procedure:
3-[4-cyanobenzyl]aminopropanoic acid (0.41 g; 2 mmoles), ethyl βamino-β-(3-pyridyl)-propanoate dihydrochloride (0.46 g; 1.7 mmoles), N,N-diisopropylethylamine (0.52 g; 4 mmoles) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.88 g; 2 mmoles) were stirred in N,N-dimethylformamide (25 ml) at room temperature for 1 hr. The reaction mixture was taken down to dryness and the residue was purified by HPLC. The lyophilized product was redissolved in ethanol (30 ml). The solution was saturated with HCl gas and allowed to stir overnight. The mixture was taken down to dryness and the residue was redissolved in ethanol (20 ml). To this solution, ammoniumchloride (1 g) and ammonium hydroxide (10 ml) were added. The reaction mixture was stirred at room temperature for 4 hrs and the solvent was removed under reduced pressure. The residue was purified by HPLC using acetonitrile/water/trifluoroacetic acid system. The desired fractions were collected and lyophilized to give 460 mg of white material (57% yield). FAB-MS: MH+ =398.2.