Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[O:20])=[C:8]([C:11]3[N:12]4[CH:18]=[N:17][CH:16]=[C:13]4[S:14][CH:15]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[I:34][CH3:35]>ClCCl>[I-:34].[OH:1][C@@H:2]([C@H:4]1[C:32](=[O:33])[N:6]2[C:7]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)=[O:20])=[C:8]([C:11]3[N+:12]4[C:13](=[CH:16][N:17]([CH3:35])[CH:18]=4)[S:14][CH:15]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4cncn34)[C@H](C)[C@H]12
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3csc4cn(C)c[n+]34)[C@H](C)[C@H]12
Product: [I-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of 102 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-3-yl)-1-methyl-1-carbapen-2-em-3-carboxylate 1.5 ml of dry dichloromethane was added 2.7 ml of iodomethane, and the mixture was stirred under the atmosphere of argon in the darkness at room temperature for 3 days. Unreacted reagent was removed under reduced pressure to give 122 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(6-methylimidazo[5,1-b]thiazolium-3-yl)-1-carbapen-2-em-3-carboxylate iodide.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][C:11]=1[CH3:12].[C:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])[CH3:14]>C(OCC)C>[CH3:6][C:7]1[N:8]=[C:9]([C:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)([OH:15])[CH3:14])[S:10][C:11]=1[CH3:12]
Reactant: CC(=O)c1cccs1
Reactant: Cc1ncsc1C
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1nc(C(C)(O)c2cccs2)sc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 9.7 ml) was added dropwise to a stirred solution of 4,5-dimethylthiazole (2.5 g) in dry diethyl ether (30 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylthiophene (3.1 g) in diethyl ether (20 ml) was added dropwise. After a further 1 hour the mixture was allowed to warm to room temperature and was then worked up in the normal fashion to yield the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[N:11]([C:22](=[O:23])[CH2:21][Cl:20])[CH2:10][CH2:9][NH:8][C:7]1=[O:12]
Reactant: O=C1NCCNC1c1cccs1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1NCCN(C(=O)CCl)C1c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
18.2 g (0.1 mol) of 3-(2-thienyl)-piperazin-2-one, prepared in accordance with Example 16, are dissolved in 150 ml of chloroform and 11.1 g (0.11 mol) of triethylamine and 12.4 g (0.11 mol) of chloroacetyl chloride are added. The mixture is stirred for 4 hours at room temperature, the reaction solution is concentrated in vacuo and the residue is stirred with water and ethyl acetate. The ethyl acetate solution is separated off, dried and evaporated in vacuo.
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[O:21]([C:18]1[CH:19]=[CH:20][C:15]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[N:12][C:13]=3[NH2:14])[NH:5][N:6]=2)=[CH:16][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)n1nc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: Nc1ncnc2[nH]nc(-c3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.5 h

Procedure:
1-tert-butyl-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (19 mg, 54.1 mmol) was dissolved in a solution of formic acid (1 mL) and conc. HCl (0.1 mL) and heated to reflux. The reaction was allowed to proceed 30 min., then concentrated in vacuo and the products purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 304.1, found 304.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: COCCN(C)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COCCN(C)CCOc1ccc(CCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1F
Yield: 35.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.3 mg) was obtained.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:14]([NH:16][C@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH3:13])=O)C1C=CC=CC=1.[ClH:26].O>CO.[Pd]>[ClH:26].[NH2:11][C@@H:12]([C:14]([NH:16][C@H:17]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])[CH3:13]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)N

Procedure:
A solution of 7 g. of Nα -benzyloxycarbonyl-D-alanyl-L-leucine, methyl ester in 100 ml. of methanol and 22 ml. of 0.95 l N hydrogen chloride in methanol is stirred with 500 mg. of 20% palladium on carbon catalyst under hydrogen at one inch water pressure until thin layer chromatography of a sample shows complete conversion (three to six hours). The solution is filtered to remove the catalyst and is evaporated to a foam. Solution in chloroform, 50 ml., and precipitation by ethyl ether affords an oil which is collected and dried at 45° C. and 1 mm. pressure. The oil is used in the next step without further purification.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24].[C:25]([O:44][CH2:45][C@@H:46]1[C@@H:53]2[C:49](=[N:50][O:51][CH2:52]2)[CH2:48][O:47]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[Cl:16][C:17]1[C:22]([F:23])=[C:21]([C@:49]23[CH2:48][O:47][C@H:46]([CH2:45][O:44][C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C@H:53]2[CH2:52][O:51][NH:50]3)[CH:20]=[CH:19][C:18]=1[F:24]
Reactant: Fc1cccc(F)c1Cl
Reactant: c1ccc(C(OC[C@H]2OCC3=NOC[C@@H]32)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc([C@]23CO[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]2CON3)c(F)c1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
A stirred solution of 2,2,6,6-tetramethylpiperidine (1.31 mL, 7.78 mmol) in dry THF (20 mL) under nitrogen was cooled in an acetone/dry ice cooling bath. n-Butyl lithium (2.5 M in hexanes, 3.11 mL, 7.78 mmol) was added to this solution such that the internal temperature remained below −75° C. The pale yellow solution was stirred at this temperature for 15 minutes before the addition of a solution of 2-chloro-1,3-difluoro-benzene (0.86 mL, 7.78 mmol) in dry THF (2 mL). The solution was stirred for an additional 30 minutes at −78° C. before the addition of a solution of (3aR,4S)-4-((trityloxy)methyl)-3,3a,4,6-tetrahydrofuro[3,4-c]isoxazole (1.5 g, 3.89 mmol) in dry THF (12 mL). The reaction was stirred at −78° C. After 60 min, the reaction was quenched with saturated aqueous ammonium chloride and then removed from the cooling bath. The mixture was partitioned between EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with brine (1×), then dried over (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 5% to 20% to 30% EtOAc in n-hexane) to give the title compound (712 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 3.23-3.35 (m, 2 H) 3.47 (dd, J=9.84, 6.42 Hz, 1 H) 3.86 (dd, J=8.31, 3.79 Hz, 1 H) 3.91 (dd, J=10.33, 1.90 Hz, 1 H) 4.08-4.20 (m, 2 H) 4.22-4.33 (m, 1 H) 6.92-7.00 (m, 1 H) 7.20-7.36 (m, 9 H) 7.41-7.48 (m, 6 H) 7.57-7.67 (m, 1 H).
Reaction SMILES: C(=[N:8][N:9]([CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH:10]([CH3:12])[CH3:11])C1C=CC=CC=1.Cl>C(O)C>[NH2:18][C:17]1[C:14]([C:15]#[N:16])=[CH:13][N:9]([CH:10]([CH3:11])[CH3:12])[N:8]=1
Reactant: CC(C)N(C=C(C#N)C#N)N=Cc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)n1cc(C#N)c(N)n1

Procedure:
A mixture of Intermediate 2-((2-benzylidene-1-isopropylhydrazinyl)-methylene)malononitrile (9.42 g, 40 mmol), concentrated hydrochloric acid (5 ml), and ethanol (50 ml) was heated at reflux for 20 min. The reaction mixture was concentrated and ether (50 ml) was added. The mixture was sonicated, then the upper ether layer was discarded. To the residue was added 20 ml of 5N aqueous sodium hydroxide solution and the mixture was extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (1:1 hexanes/ethyl acetate eluant) to afford 3-amino-1-isopropyl-1H-pyrazole-4-carbonitrile as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 5.51 (s, 2H), 4.22 (m, 1H), 1.31 (d, J=7 Hz, 6H); MS m/z 151.2 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:19][C:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([OH:30])[C:23]([C:31]2[CH:35]=[CH:34][O:33][C:32]=2[CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=1>C1COCC1>[NH2:19][C:20]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([OH:30])[C:23]([C:31]2[CH:35]=[CH:34][O:33][C:32]=2[CH2:36][CH2:37][OH:38])=[CH:22][CH:21]=1
Reactant: COC(=O)c1c(N)ccc(-c2ccoc2CCO[Si](C)(C)C(C)(C)C)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1c(N)ccc(-c2ccoc2CCO)c1O
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Tetrabutylammonium fluoride (1M solution in THF, 25 mL) was added to a solution of methyl 6-amino-3-{2-[2-(tert-butyldimethylsilanyloxy)-ethyl]-furan-3-yl}-2-hydroxybenzoate (Intermediate 29, 1.34 g) in THF (75 mL) and the mixture was stirred for 1 hour. The mixture was evaporated to dryness and water and ethyl acetate were added. The organic layer was separated, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-50% to give methyl 6-amino-2-hydroxy-3-[2-(2-hydroxyethyl)-furan-3-yl]-benzoate (0.88 g) as a yellow gum.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=1[CH2:7][CH2:6]2)=C.C[N+]1([O-])CC[O:24]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.[Os](=O)(=O)(=O)=O.O>[CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[C:12]1[O:11][N:10]=[C:9]([C:16]([O:18][CH3:19])=[O:17])[C:8]=1[CH2:7][CH2:6]2)=[O:24]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c(C(=O)OC)noc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1noc2c1CCc1cc(C=O)ccc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of methyl 7-vinyl-4,5-dihydronaphtho[2,1-d]isoxazole-3-carboxylate (Preparation 45B, 65 mg, 0.255 mmol) in THF (4 mL) were sequentially added N-methylmorpholine-N-oxide in water (0.084 mL, 0.407 mmol) and osmium tetroxide in water (0.062 mL, 10.19 μmol) at room temperature. The solution was stirred vigorously at room temperature overnight. Sodium periodate (109 mg, 0.509 mmol) in water (1 mL) was added and the mixture was stirred at room temperature under nitrogen for two hours. Water (2 mL) was then added and the mixture was concentrated to remove THF. The resulting solid was filtered, washed with water (2×2 mL), and dried to give 72 mg of product as a yellow solid. The compound had an HPLC ret. time=0.88/2.0 min. (condition E).
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:12])[NH:5][C:4]=2[CH:3]=1.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:13][CH2:14][CH2:15][C:16]([C:3]1[C:4]2[NH:5][C:6](=[O:12])[CH2:7][CH2:8][CH2:9][C:10]=2[S:11][C:2]=1[CH3:1])=[O:17]
Reactant: Cc1cc2c(s1)CCCC(=O)N2
Reactant: O=C(Cl)CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1sc2c(c1C(=O)CCCl)NC(=O)CCC2
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a mixture of 5 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-5-one and 4.5 g of 3-chloropropionyl chloride in 50 ml of dichloroethane was added 9.2 g of aluminum chloride and the mixture was stirred for 3 hours. The mixture was poured into ice-cold water and extracted with chloroform. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 5.6 g of 3-(3-chloropropionyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-5-one as white crystals, m.p. 86°-87° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][C:6](=[O:43])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:41]C)([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].C(N)(C)(C)C>>[CH3:44][Si:2]([CH3:1])([CH3:45])[CH2:3][CH2:4][O:5][C:6](=[O:43])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(OC)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Solvent: CC(C)(C)N
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Temperature: 60 °C
Yield: 41.5 %

Procedure:
A mixture of 2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (184 mg, 0.270 mmol) in tert-butylamine (2.8 mL, 27 mmol) was heated at 60° C. for 24 hours. The solution was allowed to cool to room temperature and concentrated. The residue was purified by silica gel column chromatography using MeOH/CH2Cl2 (0-30%) to provide 75 mg of the product as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 9H), 0.04 (s, 9H), 0.89 (appt t, 2H, J=9 Hz), 1.23 (appt t, 2H, J=9 Hz), 1.77 (s, 3H), 2.01-2.31 (m, 4H), 2.17 (s, 3H), 2.36 (d, 1H, J=22 Hz), 2.38 (d, 1H, J=22 Hz), 2.52 (septet, 1H, J=9 Hz), 3.39 (d, 2H, J=7 Hz), 3.51 (d, 3H, J=11 Hz), 4.01-4.08 (m, 2H), 4.30 (dd, 2H, J=8, 9 Hz), 5.11 (s, 2H), 5.19 (br t, 1H, J=6 Hz), 5.33-5.56 (m, 2H), 8.49 (br s, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 22.1 ppm; MS (m/z) 667.4 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:22][C:23](=[O:36])[C@@H:24]([NH:26][C:27](=[O:35])[CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH3:25])[C:18]([O:20]C)=[O:19])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].O>O.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C@H:17]([NH:22][C:23](=[O:36])[C@@H:24]([NH:26][C:27](=[O:35])[CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH3:25])[C:18]([OH:20])=[O:19])[CH:12]=[CH:13][C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(C)c(OCc2ccccc2)c1)NC(=O)[C@H](C)NC(=O)CN1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C[C@H](NC(=O)[C@H](C)NC(=O)CN2CCOCC2)C(=O)O)cc1OCc1ccccc1

Procedure:
(S)-Methyl 3-(3-(benzyloxy)-4-methylphenyl)-2-((S)-2-(2-morpholinoacetamido) propanamido)propanoate (1.2 g, 2.4 mmol) was treated with a solution of lithium hydroxide-H2O (300 mg, 7.2 mmol) in water/THF (10 mL/10 mL) for 30 min. The THF was removed and the aqueous phase was acidified to pH=3-4 with 1 N HCl and then concentrated to dryness to afford (S)-3-(3-(benzyloxy)-4-methylphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propanoic acid, which was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[NH2:28])[N:16]=[CH:15]2.[C:29](O)(=[O:32])[C:30]#[CH:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([NH:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:28][C:29](=[O:32])[C:30]#[CH:31])[N:16]=[CH:15]2
Reactant: C#CC(=O)O
Reactant: CCOc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4N)ncc3c2)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3c(F)ccc(OCC)c3Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 77.3 %

Procedure:
A mixture of (1R,2S)—N1-(6-(2-chloro-3-ethoxy-6-fluorophenyl)quinazolin-2-yl)cyclopentane-1,2-diamine (0.1 mmol), propiolic acid (0.007 mL, 0.12 mmol), HATU (57 mg, 0.15 mmol) and DIEA (0.052 mL, 0.3 mmol) in dichloromethane (1 mL) was stirred at room temperature for 40 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2-chloro-3-ethoxy-6-fluorophenyl)quinazolin-2-yl)amino)cyclopentyl)propiolamide (Compound 6) (35 mg, 76%). MS (ES+) C24H22ClFN4O2 requires: 452, found: 453 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Fc1cccc(F)c1Sc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3c(F)cccc3F)cc2)c1C
Yield: 21.4 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.1 g, 0.28 mmol) in dimethoxyethane (4 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,6-difluorobenzene (0.084 g) and 2.0 M aqueous sodium carbonate (1 mL, 2 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,6-difluoro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.027 g, 21%) as a solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.Cl.C(OC([NH:57][C@@H:58]([CH2:62][CH2:63][CH2:64][CH2:65][NH2:66])[C:59]([NH2:61])=[O:60])=O)C1C=CC=CC=1.Cl.NCC(N)=O>>[NH2:57][C@H:58]([C:59](=[O:60])[NH2:61])[CH2:62][CH2:63][CH2:64][CH2:65][NH:66][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:32][CH:33]=1)=[O:42]
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NCCCC[C@H](N)C(N)=O)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and (S)-2-benzyloxycarbonylamino-6-aminohexanamide hydrochloride instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: C[O-].[Na+].[N+:4]([C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1/[CH:9]=[CH:9]/[C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[N+:4]([O-:6])=[O:5])([O-:6])=[O:5]
Reactant: Cc1ccc(C=O)c([N+](=O)[O-])c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(/C=C/c2ccccc2[N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 1.4 g. of sodium methylate in 40 ml. of ethanol was added 6.8 g. of diethyl ortho-nitrobenzyl phosphonate. While stirring the solution at ambient temperature, a solution of 4.1 g. of 2-nitro-4-methylbenzaldehyde in 40 ml. of ethanol was dropwise added. After being stirred for 1.5 hours and allowed to stand overnight, the yellow crystals formed were filtered and washed with a small amount of ethanol to give 6.0 g. (85% yield) of trans-2,2'-dinitro-4-methylstilbene. This compound was then recrystallized from benzene to give a product melting at 170° to 171° C.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:22]=[C:21]([C:31]([OH:33])=O)[C:20]=2[CH2:34][C:35]#[N:36])=[CH:15][CH:14]=1.[CH:37]1[CH:38]=[CH:39][C:40]2N(O)N=[N:43][C:41]=2[CH:42]=1.[N:47]1(C2N=CC=CN=2)[CH2:52][CH2:51]N[CH2:49][CH2:48]1>ClCCl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:22]=[C:21]([C:31]([N:47]3[CH2:52][CH2:51][N:43]([C:41]4[CH:42]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:49][CH2:48]3)=[O:33])[C:20]=2[CH2:34][C:35]#[N:36])=[CH:17][CH:18]=1
Reactant: On1nnc2ccccc21
Reactant: N#CCc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: N#CCc1c(C(=O)N2CCN(c3ccccc3)CC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
EDAC (195 mg, 1.00 mmol) was added to a stirred solution of [B1] (250 mg, 0.7 mmol) and HOBT (133 mg, 0.8 mmol) in dichloromethane (40 ml) at room temperature under argon. After 15 minutes 2-(piperazinyl)pyrimidine (155 mg, 0.9 mmol) was added and stirring continued for 16 hours. The mixture was washed with saturated aqueous sodium bicarbonate solution (3×) then with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to give the crude, which was purified by preparative chromatography to give 9 mg of [C1].