Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([S:3]([CH3:6])(=[O:5])=[O:4])=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:37]1[CH:38]=[CH:39][C:40]2[C:41]3[N:50]([CH2:51][CH:52]4[CH2:57][CH2:56][O:55][CH2:54][CH2:53]4)[C:49]([CH2:58][CH3:59])=[N:48][C:42]=3[C:43]([NH2:47])=[N:44][C:45]=2[CH:46]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O.C(#N)C>[CH2:58]([C:49]1[N:50]([CH2:51][CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[C:41]2[C:40]3[CH:39]=[CH:38][C:37]([CH:2]=[CH:1][S:3]([CH3:6])(=[O:5])=[O:4])=[CH:46][C:45]=3[N:44]=[C:43]([NH2:47])[C:42]=2[N:48]=1)[CH3:59]
Reactant: CCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCOCC1
Reactant: C=CS(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(C=CS(C)(=O)=O)ccc3c2n1CC1CCOCC1
Temperature: 120 °C
Yield: 59.4 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (7 mg, 0.03 mmol), acetonitrile (15 mL), N,N-dimethylformamide (15 mL), methyl vinyl sulfone (150 mg, 1.41 mmol), triethylamine (0.53 mL, 3.8 mmol), tri-o-tolylphosphine (23 mg, 0.08 mmol) and 7-bromo-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (500 g, 1.28 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 16 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The resulting solid was partitioned between chloroform (100 mL) and 1% aqueous sodium carbonate (100 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (2×50 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-15% CMA over 1200 mL followed by 15-20% CMA over 1100 mL). Recrystallization from methanol provided 315 mg of 2-ethyl-7-[2-(methylsulfonyl)ethenyl]-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH:66]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:64]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][CH:66]([C:69]([NH2:71])=[O:70])[CH2:65][CH2:64]1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: NC(=O)C1CCNCC1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(C(N)=O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and piperidine-4-carboxylic acid amide in DMSO at ambient temperature.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[N:13](CCC#N)[CH:14]=[CH:15][CH:16]=3)[N:5]2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([C:12]3[NH:13][CH:14]=[CH:15][CH:16]=3)[N:5]2[N:4]=1
Reactant: CSc1ncc2ccc(-c3cccn3CCC#N)n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc2ccc(-c3ccc[nH]3)n2n1

Procedure:
3-[2-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-pyrrol-1-yl]-propionitrile: The above bis-TFA salt (92 mg) was taken up in DCM and washed with dilute, aqueous, NaOH. The organic layer was dried by passing through a plug of Na2SO4 and solvent evaporated to yield 2-methylsulfanyl-7-(1H-pyrrol-2-yl)-pyrrolo[2,1-f][1,2,4]triazine (46 mg, 0.20 mmol) which was taken up in acetonitrile (1.0 mL) and treated with 2-propenenitrile (19 uL, 0.29 mmol) and Triton B (5 μL). The mixture was stirred at RT for 1 h. The reaction was taken up in EtOAc and washed with water and brine. The organic layer was dried by passing through a plug of Na2S0. Solvent was removed by rotary evaporation and the resulting residue was triturated with ether (2×2 mL) to yield 44 mg (78%) of product. HPLC RT: 2.93 min; LC/MS: 284 (M+H); 1H NMR (DMSO-d6): 8.99 (s, 1H), 7.13 (m, 1H), 7.09 (s, 2H), 6.66 (dd, J=3.8, 1.7, 1H), 6.27 (dd, J=3.8, 2.9, 1H), 4.30 (t, J=6.6, 2H), 2.86 (t, 2H, J=6.6), —SMe singlet presumably under DMSO peak.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:12]=[CH:11][C:10]=2[N+:21]([O-:23])=[O:22])[CH:4]=1)#[CH:2].[CH2:24]([N:31]=[N+:32]=[N-:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C(O)(C)(C)C>[O-]S([O-])(=O)=O.[Cu+2].O>[CH2:24]([N:31]1[CH:2]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[C:5]([C:9]3[CH:14]=[C:13]([N:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)[CH:12]=[CH:11][C:10]=3[N+:21]([O-:23])=[O:22])[CH:4]=2)[N:33]=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(-c2cn(Cc3ccccc3)nn2)ccn1

Procedure:
A solution of 50 mg of 4-ethynyl-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridine, 20 μL of benzyl azide, 16.3 μL of 1 M aqueous sodium ascorbate solution, 5.4 μL of 0.3 M CuSO4 solution, 326 μL of tert-butanol, and 326 μL of water was stirred for 2 days and then the solvent was evaporated at reduced pressure. The residue was dissolved in dichloromethane. The solution was washed with water and dried. The solvent was evaporated at reduced pressure and the residue was chromatographed on silica gel eluting with a 0% to 4% gradient of methanol in dichloromethane. The process yielded 22 mg of product.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[C:18]([NH:20][C:21]([CH3:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:43]([O-])=[O:44])C=1.[CH2:46]([NH2:51])[C:47]([CH3:50])([CH3:49])[CH3:48]>ClCCl>[CH2:46]([NH:51][C:43](=[O:44])[NH:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[C:18]([NH:20][C:21]([CH3:27])([CH3:26])[C:22]([F:24])([F:25])[F:23])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)[C:47]([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3)CC2)c1)C(F)(F)F
Reactant: CC(C)(C)CN
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C(F)(F)F)c3)CC2)cc1
Yield: 69 %

Procedure:
3((4-(4-Aminobenzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (0.129 mmol, 58 mg) and 4-nitrophenylchloroformate (0.142 mmol, 29 mg) were stirred together in dichloromethane (1 mL) for 16 hours. After this time neopentylamine (0.259 mmol, 32 μL) was added. The volatiles were removed under vacuum and this residue was purified by silica chromatography to yield the title compound (50 mg). MS (ESI) m/z 562.5 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>O1CCCC1.C(=S)=S>[C:16]([NH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[CH:5][C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1)(=[O:18])[CH3:17]
Reactant: Nc1ccc2cc3ccccc3cc2c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: S=C=S
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2cc3ccccc3cc2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
2-Acetamidoanthracene was prepared in 97% yield by stirring a solution of 1 equivalent of 2-aminoanthracene and 1.5 equivalents of acetic anhydride in dry tetrahydrofuran for 3 hours at room temperature. This product (2.9 g) was dissolved in 35 ml of carbon disulfide and 4 ml of oxalyl chloride was added. The stirred mixture was cooled to 0° C. and treated with 2.5 g of anhydrous aluminum chloride. Another 35 ml of carbon disulfide and 2.5 g of aluminum chloride were added after 2 hours. The mixture was stirred 2 hours at 0° C. and overnight at room temperature and then treated with dilute HCl. The brown precipitate that formed was washed with water and then digested well with 5% NaOH solution. After collection, the insoluble solids were washed with water and dried in air to give 1.25 g (35%) of a mixture of 2-,6-, and 7-acetamido-1,9-oxalylanthracenes.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[O-].[Na+].CO.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]Cl.O>CO>[C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
To a solution of N-Boc-tyrosine (281 mg, 1.0 mmol) in methanol (0.5 mL) were added 28% sodium methoxide-methanol solution (0.8 mL, 4.0 mmol) and 2-picolyl chloride hydrochloride (230 mg, 1.4 mmol), and the mixture was stirred at 25° C. for 24 hr. Then, water (3 mL) was added make the system homogeneous, which system was then analyzed by HPLC. As a result, the objective N-Boc-(O-2-picolyl)tyrosine (346 mg, conversion yield 93%) was confirmed.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][NH:29][S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:32])=[O:31])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:33]1([S:30]([NH:29][CH2:28][C:26]2[N:27]=[C:23]([N:21]3[CH2:22][CH:19]([OH:18])[CH2:20]3)[S:24][CH:25]=2)(=[O:32])=[O:31])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=S(=O)(NCc1csc(N2CC(O)C2)n1)c1ccccc1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]azetidine (2.79 g, 4.95 mmol) (obtained as described in Reference Example 65(1)) in anhydrous tetrahydrofuran (140 ml) was added a solution of 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (5.94 ml, 5.94 mmol) in an ice bath and the mixture was stirred in an ice bath for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]-3-hydroxyazetidine (1.06 g, yield 66%) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][N:13]2[CH2:14][CH2:15][CH:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:11][CH2:12]2)[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
A mixture of 4-(3-indolyl)piperidine (7.88 g), N-(2-bromoethyl)phthalimide (10.0 g) and sodium hydrogen carbonate (3.64 g) in dry N,N-dimethylformamide (93 ml) was heated at 68°-74° C. for 4 hours. After cooling, the reaction mixture was poured into ice-water (1,000 ml). The resulting precipitate was collected by filtration and washed with methanol to give 1-(2-phthalimidoethyl)-4-(3-indolyl)piperidine (5.53 g).
Reaction SMILES: [OH:1][C:2]([P:14](=[O:17])([OH:16])[OH:15])([P:10](=[O:13])([OH:12])[OH:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.I[CH3:19]>[OH-].[Na+].O.C(O)C>[OH-:1].[OH:1][C:2]([P:14]([OH:15])([OH:16])=[O:17])([P:10]([OH:11])([OH:12])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[CH3:19]
Reactant: CI
Reactant: O=P(O)(O)C(O)(Cc1ccccn1)P(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[n+]1ccccc1CC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 80 °C
Yield: 165.4 %

Procedure:
[1-Hydroxy-2-(2-pyridinyl)ethylidene]bis[phosphonic acid] (3.53 mmol, 1.0 g) is dissolved in 8.8 ml of 1N sodium hydroxide solution and 8.8 ml of distilled water. To this is added iodomethane (17.67 mmol, 1.1 ml) in 18 ml of ethanol. This reaction mixture is heated at 80° C. until complete. The solvent is concentrated in vacuo and the residue is recrystallized from ethanol and water to yield 0.92 g of 2-(2-hydroxy-2,2-diphosphonoethyl)-1-methyl pyridinium hydroxide, inner salt, monosodium salt.
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH:23]=O.C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[NH:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][N:13]1[C:14]2[C:9](=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: c1ccc(Oc2cccc3c2CCCN3)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2cccc3c2CCCN3Cc2ncc[nH]2)cc1

Procedure:
Prepared analogously to Example 1, from 5-phenoxy-1,2,3,4-tetrahydro-quinoline, imidazole-2-carboxaldehyde, zinc chloride and sodium cyanoborohydride in methanol. MS (ISP): 306.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:52])[C@H:4]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH:5][C:6](=[O:47])[C@@H:7]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1)[NH:8][C:9](=[O:36])[C@H:10]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:11][C:12](=[O:27])[C@H:13]([CH2:25][OH:26])[NH:14]C(OCC1C=CC=CC=1)=O.[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:52])[C@H:4]([CH2:48][CH:49]([CH3:50])[CH3:51])[NH:5][C:6](=[O:47])[C@@H:7]([CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1)[NH:8][C:9](=[O:36])[C@H:10]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)[NH:11][C:12](=[O:27])[C@H:13]([CH2:25][OH:26])[NH2:14]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](N)CO

Procedure:
Nα -Benzyloxycarbonyl-L-seryl-L-tyrosyl-D-tryptophyl-L-leucine methyl ester, 9.0 g., is dissolved in 850 ml. of boiling methanol. The solution is shaken with hydrogen and 1200 mg. of 20% palladium-on-carbon at room temperature and atmospheric pressure. The reaction is complete in thirty to forty minutes as shown by thin layer chromatography. The reaction mixture is filtered, the solvent evaporated from the filtrate and the residue dried under reduced pressure, 7.1 g., and is used without purification.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)[NH2:2].CN(C)[CH:14]=[C:15]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:16](OCC)=[O:17].Cl.CCN(C(C)C)C(C)C>CC(O)C>[OH:17][C:16]1[N:1]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=2)[N:2]=[CH:14][C:15]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[CH:22]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccnc(OC)c1
Reactant: NNc1ccc(C(=O)O)cn1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Temperature: 25 °C

Procedure:
Combined 6-hydrazinylnicotinic acid (167 mg, 1.090 mmol), ethyl 3-(dimethylamino)-2-(2-methoxypyridin-4-yl)acrylate (300 mg, 1.199 mmol), 2-propanol (3632 μl), and hydrochloric acid (1.85% aqueous, 2.15 mL, 1.090 mmol). The reaction was stirred at room temperature. After 1 hour Hunig's base (949 μl, 5.45 mmol) was added to the suspension which became a yellow solution. The reaction was washed with EtOAc (2×15 mL) and the aqueous phase was concentrated in vacuo, yielding a yellow solid. The solid was triturated with 1N HCl (50 mL), collected by filtration, and washed with water. The solid was then slurried in methanol (2×60 mL) and diethyl ether (2×60 mL), the dried under vacuum to give the title compound. MS m/z [M+H]+ 313.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16](Cl)[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].OB1OB(O)OB(O)O1.[C:38](=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([O:5][C:6](=[O:28])[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([CH3:38])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OB1OB(O)OB(O)O1
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C#Cc2ccccc2)nc(NC(=O)C(C)NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butylN-[1-[[4-chloro-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate D3a (40 mg, 0.10 mmol), 2,4,6-trihydroxy-1,3,5,2,4,6-trioxatriborinane (36 μl, 0.26 mmol), Tetrakis(triphenylphosphine)palladium(0) (16.6 mg, 0.01 mmol), potassium carbonate (41.5 mg, 0.30 mmol), 1,2-dimethoxyethane (600 μl) and water (100 μl) is stirred for 2 day at 80° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 2 mg (5%). HPLC-MS: M+H=380; tR=2.18 min (*Method—2).
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C(N(CC)CC)C.[CH2:25]([O:27][C:28](=[O:42])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[CH:33][CH:32]=1)[CH3:26]>C1COCC1>[CH2:25]([O:27][C:28](=[O:42])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][NH:41][C:14]([NH2:17])=[N:13][C:11]([C:4]2[C:3]([NH2:2])=[N:8][C:7]([NH2:9])=[C:6]([Cl:10])[N:5]=2)=[O:12])=[CH:33][CH:32]=1)[CH3:26]
Reactant: CCOC(=O)COc1ccc(CCCCN)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(CCCCNC(N)=NC(=O)c2nc(Cl)c(N)nc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.74 g, 1.9 mmol) and triethylamine (0.5 mL) were sequentially added into a solution of 48 (0.62 g, 2.47 mmol) in THF (10 mL). The reaction mixture was stirred in the boiling solvent for 4 h and at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography (silica gel, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 49 (0.5 g, 57%) as a yellow solid. The purity of the product was confirmed by HPLC. m/z (APCI)=464 [C20H26ClN7O4+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH:21]=[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]1)[C:5]2=[O:29].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>O.CN(C)C=O>[C:23]1([C:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:6]3[C:5](=[O:29])[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH:3]=4)[NH:8][C:7]3=[O:12])[CH2:18][CH:19]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc2[nH]c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)c2c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc2[nH]c(=O)n(CCCCN3CC=C(c4ccccc4)CC3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A mixture of 6-amino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (390 mg), methanesulfonyl chloride (229 mg), potassium carbonate (276 mg) and dry N,N-dimethylformamide (10 ml) was stirred for 1 hour at room temperature. The mixture was poured into water, neutralized with 1N sodium hydroxide and extracted with ethyl acetate, and the extract was washed with brine. The organic layer was dried and evaporated. The crude residue was chromatographed on a silica gel (50 g), eluting with 10% methanol in dichloromethane to give 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-6-methylsulfonylamino-1,2,3,4-tetrahydroquinazoline-2,4-dione (292 mg). Recrystallization from ethyl acetate gave a crystal thereof (202 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=O)[CH2:9]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=2[C:10](=[N:24][NH:23][C:20]([NH2:22])=[NH:21])[CH2:9]1
Reactant: Cc1ccnc2c1C(=O)CC(c1sc(Cl)cc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1sc(Cl)cc1Cl)C2
Yield: 123.4 %

Procedure:
A mixture of 7-(3,5-dichlorothiophen-2-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.5 g), aminoguanidine hydrochloride (0.21 g), concentrated hydrochloric acid (0.4 ml), water (0.4 ml) and ethanol (15 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was washed with ethyl acetate. Under reduced pressure, the solvent was evaporated, and the residue was recrystallized from water. The resulting crystals were washed with ethanol to give 7-(3,5-dichlorothiophen-2-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 121) (0.40 g) as colorless crystals.
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][S:19][CH2:20][CH2:21][NH2:22]>>[N+:5]([CH:4]=[C:3]([NH:8][C:9]#[C:10][CH3:11])[NH:22][CH2:21][CH2:20][S:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)([O-:7])=[O:6]
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Reactant: NCCSCc1ccccn1
Product: CC#CNC(=C[N+](=O)[O-])NCCSCc1ccccn1

Procedure:
A solution of the product of Step A is treated with about an equimolar amount of 2-[(2-pyridyl)methylthio]ethylamine to produce, after workup, the title product.