Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([O:9][C:10](=[O:40])[CH:11]([N:15]([CH2:27][CH2:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[CH2:33][CH2:32]1)=[O:30])[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[ClH:1].[OH:39][CH2:38][CH2:37][N:34]1[CH2:35][CH2:36][N:31]([C:29](=[O:30])[CH2:28][CH2:27][N:15]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]([CH:12]([CH3:14])[CH3:13])[C:10]([OH:40])=[O:9])[CH2:32][CH2:33]1
Reactant: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)OCc2ccccc2)C(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(CCC(=O)N2CCN(CCO)CC2)C(C(=O)O)C(C)C)cc1
Yield: 126.5 %

Procedure:
To a solution of 2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxopropyl}(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester hydrochloride (1.49 grams, 2.49 mmol) in ethanol (80 mL) was added 10% palladium on activated carbon (0.11 grams). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 16 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving 2-[{3-[4-(2-hydroxyethyl)piperazin-1-yl]-3-oxo-propyl}(4-methoxybenzenesulfonyl)amino]-3-methylbutyric acid hydrochloride as a white solid (1.6 grams, 92%).
Reaction SMILES: C([O:3][C:4]1[CH2:5][C@@H:6]([CH2:11][C@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=O)[CH2:14][CH2:13]2)[CH2:7][C:8](=[O:10])[CH:9]=1)C.C1(CN2CCCC2=[O:37])C=CC=CC=1.Cl>O1CCCC1>[O:37]=[C:13]1[CH2:14][CH2:15][N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:12]1[CH2:11][CH:6]1[CH2:5][C:4](=[O:3])[CH2:9][C:8](=[O:10])[CH2:7]1
Reactant: CCOC1=CC(=O)C[C@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Reactant: O=C1CCCN1Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CC(=O)CC(C[C@H]2C(=O)CCN2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone and (5S,1S)-5-[(3ethoxy-5-oxo-3-cyclohexen-1-yl)methyl[-1-(phenylmethyl)-2-pyrrolidinone (150 mg, 0.46 mmol) in 10 mL of tetrahydrofuran was treated with 2 mL of 2N HCl and stirred at room temperature for 2 h, then refluxed for 1 h. The solvent was removed on a rotary evaporator and the residue was extracted with methylene chloride. The combined extracts were dried over Na2SO4 and evaporated to give 130 mg of (S)-5-[[oxo-1-(phenylmethyl)-2-pyrrolidinyl]methyl]-1,3-cyclohexanedione, mp 159°-161° C. (ethyl acetate), which was identical in all respects to that obtained in the synthesis from (E)-4-[2(S)-5-oxo-1-(phenylmethyl)-2-pyrrolidinyl]-2-butenoic acid, ethyl ester.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([O:12][CH2:13][CH2:14]O)[CH:11]=1.O1CCCC1.[OH-].[K+]>C(O)(C)(C)C>[Cl:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([O:12][CH:13]=[CH2:14])[CH:11]=1
Reactant: OCCOc1cncc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: C=COc1cncc(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (58.6 g, 493 mmol) was added to a mixture of 3-chloro5-(2-hydroxyethoxy)pyridine (14.5 g, 82.1 mmol) and tetrahydrofuran (100 ml). The mixture was stirred for 1 h at 50° C. The mixture was evaporated. Potassium hydroxide (9.0 g, 164 mmol) and tert-butanol (100 ml) were added and the mixture was stirred for 3 days at 100° C. The solvent was evaporated. Water (150 ml) was added and the mixture was extracted twice with diethyl ether (100 ml). Yield 6.77 g, 53%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:8]=[C:9]([NH:11][C:12]([O:14][CH2:15][C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][C:19]=3[CH:20]=2)=[O:13])[CH:10]=1)=[O:4].[Li+].[OH-]>C1COCC1>[C:25]1([C:22]2[CH:23]=[CH:24][C:18]3[O:17][C:16]([CH2:15][O:14][C:12]([NH:11][C:9]4[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:8]=4)=[O:13])=[CH:20][C:19]=3[CH:21]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1cc(NC(=O)OCc2cc3cc(-c4ccccc4)ccc3o2)cc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cc(C(=O)O)cc(-c2ccccc2)c1)OCc1cc2cc(-c3ccccc3)ccc2o1
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of 5-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-biphenyl-3-carboxylic acid methyl ester (0.125 g, 0.2618 mmol) in THF (2 mL) was added at room temperature 1.0 M LiOH and the mixture was stirred for 3 h. The solvent was evaporated, water was added, followed by 2N HCl to adjust the pH to 1-2, and the product was extracted, washed with water, then brine, and dried over magnesium sulfate and concentrated to dryness. Purification by crystallization gave 0.040 g of 5-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-biphenyl-3-carboxylic acid 401 as a white solid, mp: 235.7-238.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C([O:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][CH2:36]Cl)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH:7]=[C:6]2[CH:18]1[CH2:23][CH2:22][N:21]([CH2:36][CH2:35][O:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([OH:38])=[O:26])[CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2Cc1ccsc1
Reactant: CCOC(=O)c1ccccc1OCCCl
Product: COc1ccc2c(c1)c(C1CCN(CCOc3ccccc3C(=O)O)CC1)cn2Cc1ccsc1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 3.3 g (10 mmol) of 5-methoxy-3-piperidin-4-yl-1-thiophen-3-ylmethyl-1H-indole and 2.6 g (12 mmol) of 2-(2-chloro-ethoxy)-benzoic acid ethyl ester. After standard work-up and recrystallisation with ethanol, 1.8 g (37% of yield) of the expected acid were obtained.
Reaction SMILES: C([S:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])[C@H:23]([CH2:39][O:40][NH:41][C:42](=[O:44])[CH3:43])[CH2:22]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>CO.O.[N+]([O-])([O-])=O.[Ag+]>[SH:20][C@@H:21]1[CH2:25][N:24]([C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)=[O:27])[C@H:23]([CH2:39][O:40][NH:41][C:42](=[O:44])[CH3:43])[CH2:22]1
Reactant: CC(=O)NOC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CC(=O)NOC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.42 h
Yield: 72.5 %

Procedure:
To a solution of (2S,4S)-4-tritylthio-2-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (7a: 452 mg) in methanol (9 ml) under ice cooling are dropwise added pyridine (149 μl) and then a solution of silver nitrate (289 mg) in a mixture of water (1.5 ml) and methanol (15 ml), and the mixture is stirred for 25 minutes. Separating silver salt is collected by filtration, washed with methanol, ether, and petroleum ether, and dried. To a suspension of this crude silver salt in a mixture of dichloromethane (3.5 ml) and methanol (3.5 ml) is introduced hydrogen sulfide gas for 5 minutes. The resulting silver sulfide is filtered off and washed with a mixture of methanol and dichloromethane. The filtrate is concentrated in vacuo. The residue is purified by silica gel chromatography to give (2S,4S)-4-mercapto-2-acetylaminooxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (8a: 198 mg) as a pale yellow foam. Yield: 73%.
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17](Br)[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1.O>C1COCC1>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([F:43])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1F)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 2 h
Yield: 49.5 %

Procedure:
To a cooled (−60° C.) solution of 800 mg 19d in 10 mL THF was added 2.04 mmol n-butyllithium. After stirring at −60° C. for 30 min 877 mg N-fluorobenzenesulfonimide was added. The mixture was allowed to reach room temperature and was stirred for another 2 h. Water was added and the mixture was extracted with 2×ethyl acetate. The combined organic phases were dried and concentrated. The crude product by column chromatography over silica to afford an oil, which was crystallized from heptane/diisopropyl ethyl ether to give compound 340 mg of 27a as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[CH:35][C:20]([O:21][S:22]([C:25]3[S:29][CH:28]=[C:27]([C:30]([OH:32])=[O:31])[C:26]=3[O:33]C)(=[O:24])=[O:23])=[C:19]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.B(Br)(Br)Br.C(Cl)Cl.C(=O)=O.CC(C)=O>C(Cl)Cl>[Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[CH:35][C:20]([O:21][S:22]([C:25]3[S:29][CH:28]=[C:27]([C:30]([OH:32])=[O:31])[C:26]=3[OH:33])(=[O:24])=[O:23])=[C:19]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COc1c(C(=O)O)csc1S(=O)(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1sc2c(Br)c3ccccc3c(-c3ccc(OS(=O)(=O)c4scc(C(=O)O)c4O)c(C4CCCC4)c3)c2c1C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
At -78° C., to a stirred suspension of 5-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxysulfonyl]-4-methoxy-thiophene-3-carboxylic acid (0.286 g, 0.426 mmol) in CH2Cl2 (2.86 mL) was added 1M BBr3 /CH2Cl2 (1.32 mL, 1.32 mmol). After the addition was complete the dry ice/acetone bath was replaced with an ice water bath and the reaction was stirred for 1 h. The reaction was quenched with crushed ice, diluted with H2O (40 mL) and extracted with EtOAc. The combined organic extracts were combined with product from an identical experiment and concentrated. Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil, eluting with 35% EtOAc/hexane gave 0.273 g (95%) of the title compound as a pale yellow solid, mp >230° C.; 1H NMR (DMSO-d6) δ 1.31-1.40 (m, 2 H), 1.47 (s, 3 H), 1.50-1.67 (m, 5 H), 1.80-1.83 (m, 1 H), 2.42 (s, 3 H), 3.32 (quintet, 1 H), 7.22 (dd, 1 H), 7.31-7.37 (m, 3 H), 7.48 (t, 1 H), 7.64 (t, 1 H), 8.19 (d, 1 H), 8.64 (s, 1 H). IR (KBr) 3400, 2950, 1650, 1375 and 1150 cm-1. mass spectrum (-ACPI), n/z 665 (M-H). Anal. Calcd. for C30H25BrO6S3.0.5H2O: C, 54.05; H, 3.93 N, 0.00. Found: C, 54.09; H, 3.98 N, 0.05.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][C@H:12]([CH2:16][OH:17])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[C:18](O)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[OH:17][CH2:16][CH:12]1[O:13][CH2:14][CH2:15][N:10]([C:6]2[CH:5]=[C:4]([C@@H:2]([NH:1][C:18](=[O:27])[CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:3])[CH:9]=[CH:8][CH:7]=2)[CH2:11]1
Reactant: CC(N)c1cccc(N2CCO[C@H](CO)C2)c1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)C=Cc1ccccc1)c1cccc(N2CCOC(CO)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mixture of (S)-{4-[3-(1-amino-ethyl)-phenyl]-morpholin-2-yl}-methanol (27 mg, 0.09 mmol), cinnamic acid, Preparation 27 (12.8 mg, 0.09 mmol), EDC (34 mg, 0.18 mmol), DMAP (11 mg, 0.09 mmol), triethylamine (0.05 ml, 0.36 mmol) in dichloromethane (0.6 ml) was stirred at room temperature overnight. The reaction mixture was purified by filtering through 2 g silica-gel syringe with 60:40:1 acetone:hexanes:methanol. The filtrate was concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:45][CH2:46][N:47]1[CH2:51][CH2:50][CH2:49][C@H:48]1[C:52](O)=[O:53])[C:3](=[O:44])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:43])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:42])[NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34][CH2:33]3)[CH:27]=[CH:26][N:25]=2)[CH:5]=1.[CH3:55][NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:55][N:56]([CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[C:52]([C@@H:48]1[CH2:49][CH2:50][CH2:51][N:47]1[CH2:46][CH2:45][N:2]([CH3:1])[C:3](=[O:44])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[O:43])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:42])[NH:31][C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34][CH2:33]3)[CH:27]=[CH:26][N:25]=2)[CH:5]=1)=[O:53]
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Reactant: CN(CCN1CCC[C@H]1C(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To a mixture of (S)-1-(2-(N-methyl-3-((4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzamido)ethyl)pyrrolidine-2-carboxylic acid (0.035 mmol, 25.7 mg), tert-butyl 5,8,11-trioxa-2-azatetradecan-14-oate 135c (0.042 mmol, 12.4 mg) and DIEA (0.212 mmol, 27 mg) in DMF (0.15 mL) was added HATU (0.042 mmol, 16 mg). The mixture was stirred at 60° C. for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried and concentrated. 23% of the residue was purified by prep. HPLC to give a yellow solid (4 mg, 37%). MS (ES, m/z): 1002.36 [M+H]+.
Reaction SMILES: Cl.[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][OH:14].C(N(CC)CC)C.[CH3:22][O:23][C:24]([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:25].OS([O-])(=O)=O.[K+]>C1COCC1.O>[OH:14][N:13]([C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[OH:2])[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:24]([O:23][CH3:22])=[O:25]
Reactant: COC(=O)CCCC(=O)O
Reactant: ONc1ccc2ccccc2c1O
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCCC(=O)N(O)c1ccc2ccccc2c1O
Temperature: 0 °C
Yield: 56 %

Procedure:
Into a solution of 2 g (9.5 mmol) of 1-hydroxy-2-naphthylhydroxylamine hydrochloride in THF (10 ml) and water (2 ml) was added 2 ml (14.2 mmol) of triethylamine, the mixture was cooled to 0° C., and 395 mg (2.4 mmol) of acid chloride of 4-methoxycarbonylbutanoic acid was added followed by stirring at room temperature. Aqueous KHSO4 was then added and the mixture extracted with CH2Cl2. The organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under a reduced pressure, and the residue subjected to silica gel column chromatography to give 405 mg (56%) of a hydroxyamic acid derivative.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[C:24]([CH3:25])=[CH:23][S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccccn3)nc(NCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH2:17])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29](O)=[O:30].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH:17][C:29]([C:28]3[N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[CH:26]=[N:25][C:24]=3[Cl:23])=[O:30])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: NCc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of ({3-[(5-bromo-4-fluoro-2-nitrophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (690 mg, 1.454 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (403 mg, 1.454 mmol) and HOBT (267 mg, 1.745 mmol) in DMF (4 ml) was added EDC (335 mg, 1.745 mmol) and the reaction mixture was stirred at RT for 45 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material (942 mg) was used directly in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (t, 1H), 8.32 (d, 1H), 7.98 (s, 1H), 7.45-7.56 (m, 1H), 7.41 (t, 1H), 7.31 (d, 1H), 5.49 (s, 2H), 4.48 (d, 2H), 3.38 (t, 2H), 0.74 (t, 2H), −0.09 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[N:18][N:19]=3)[N:16]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:33]([NH2:35])[CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>O1CCCC1.C(Cl)Cl>[CH2:33]([NH:35][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[N:15]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[N:18][N:19]=3)[N:16]=2)=[CH:10][C:2]=1[F:1])[CH3:34]
Reactant: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1F
Reactant: CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoic acid (10 mg, 0.02 mmol), 2.0 M of ethylamine in tetrahydrofuran (23 μL), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12 mg, 0.028 mmol), and N,N-diisopropylethylamine (10.0 μL, 0.059 mmol) in methylene chloride (0.5 mL) was stirred at RT for 2 h. The solvent was evaporated. The residue was dissolved in methanol, and purified by RP-HPLC (pH=10) to afford the desired product. Analytical LCMS: (M+H)+=454.0. 1H-NMR (400 MHz, CD3OD): 1.12 (t, 3H), 1.84 (m, 2H), 2.02 (m, 2H), 3.42 (q, 2H), 7.80 (m, 2H), 7.90 (d, 2H), 7.98 (m, 1H), 8.18 (m, 2H), 8.32 (d, 1H), 9.00 (d, 1H), 9.10 (d, 1H), 9.32 (s, 1H).
Reaction SMILES: C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl[C:40]1[N:45]=[C:44]([NH:46][CH2:47][CH2:48][CH3:49])[C:43]([C:50]#[C:51][CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:68])[C@@H:57]([N:59]([CH3:67])[C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])[CH3:58])=[CH:42][N:41]=1.[CH3:69][C:70]1[CH:75]=[C:74]([NH2:76])[CH:73]=[CH:72][N:71]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[CH3:67][N:59]([C@@H:57]([CH3:58])[C:56]([NH:55][CH2:54][CH2:53][CH2:52][C:51]#[C:50][C:43]1[C:44]([NH:46][CH2:47][CH2:48][CH3:49])=[N:45][C:40]([NH:76][C:74]2[CH:73]=[CH:72][N:71]=[C:70]([CH3:69])[CH:75]=2)=[N:41][CH:42]=1)=[O:68])[C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63]
Reactant: CCCNc1nc(Cl)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Reactant: Cc1cc(N)ccn1
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCNc1nc(Nc2ccnc(C)c2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 38.5 %

Procedure:
To a solution of tris(dibenzylideneacetone)dipalladium(0) (1.0 mg) in 1,4-dioxane (0.86 mL), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (1.5 mg) was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at 100° C. for 5 minutes. The reaction mixture was cooled to room temperature, and then (S)-tert-butyl (1-((5-(2-chloro-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (V1, 12.5 mg), 2-methyl-4-aminopyridine (4.0 mg) and cesium carbonate (19 mg) were added, and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, and then ethyl acetate was added to the reaction mixture. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 80 to 0% hexane in ethyl acetate) to obtain (S)-tert-butyl methyl(1-((5-(2-((2-methylpyridin-4-yl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)carbamate (V2, 5.6 mg) as yellow oil.
Reaction SMILES: Br.[CH3:2][C:3]1[N:4]=[C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)[O:6][CH:7]=1.CCOCC>CC(O)=O>[CH3:2][C:3]1[N:4]=[C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[O:6][CH:7]=1
Reactant: Cc1coc([C@H]2CCCN2C(=O)OCc2ccccc2)n1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1coc([C@H]2CCCN2)n1
Reaction time: 1 h

Procedure:
HBr in AcOH (60 mL) was added to (R)-benzyl 2-(4-methyloxazol-2-yl)pyrrolidine-1-carboxylate (neat) at room temperature. After 1 h, ether (20 mL) was added slowly with vigorous string. Stirring was continued for 10 min and allowed to settle for 5-10 min. The supernatant was decanted. This process was repeated 3-4 times until the supernatant was colourless. The semi-solid was dissolved in water (50 mL) and brought to pH ˜8 with 1N LiOH and extracted with 5% MeoH/95% CHCl3