Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:32][N:33]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([NH:33][CH3:32])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OC)nc1Cl
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)NC)s3)C[C@H]2OC)nc1Cl
Yield: 83.3 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid obtained in Example (11b) (40 mg, 0.09 mmol), methylamine hydrochloride (8 mg, 0.11 mmol), WSC hydrochloride (61 mg, 0.32 mmol), HOBT (22 mg, 0.16 mmol), diisopropylethylamine (0.020 mL, 0.12 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 32 mg of the title compound as a white solid (77%).
Reaction SMILES: [CH2:1]([N:4]1[C@H:18]2[C@@H:8]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19]=3[C:16]([CH2:17]2)=[C:15]([CH2:20][OH:21])[NH:14]4)[CH2:7][C@H:6]([NH:22][C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:5]1)[CH:2]=[CH2:3].[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:21][CH2:20][C:15]1[NH:14][C:13]2[C:19]3[C:16]=1[CH2:17][C@@H:18]1[C@@H:8]([C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:7][C@H:6]([NH:22][C:23](=[O:29])[N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:5][N:4]1[CH2:1][CH:2]=[CH2:3])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4[nH]c(CO)c(c34)C[C@H]21
Solvent: c1ccncc1
Product: C=CCN1C[C@@H](NC(=O)N(CC)CC)C[C@@H]2c3cccc4[nH]c(COC(C)=O)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
213.6 mg (0.54 mmol) of 3-(6-allyl-2-hydroxymethyl-8α-ergolinyl)-1,1-diethylurea is dissolved in 5 ml of pyridine and mixed with 10 ml (0.11 mol) of acetic anhydride. After stirring for 2 hours at room temperature, the reaction mixture is added to ice, stirred for 1 hour and worked up in the way indicated above.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH2:14]2)=[CH:3][CH:2]=1.C(Cl)(Cl)[Cl:28]>Cl.O1CCOCC1>[ClH:28].[ClH:28].[ClH:28].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([NH2:19])[CH2:17][CH2:18]2)=[CH:3][CH:2]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(CCc2ccnc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(CCc2ccnc3ccccc23)CC1
Reaction time: 2 h
Yield: 100 %

Procedure:
1,1-dimethylethyl {1-[2-(4-quinolinyl)ethyl]-4-piperidinyl}carbamate (9a) (278 mg) was dissolved in chloroform and diluted with 4N HCl in dioxane solution. After stirring two hours, the reaction mixture was evaporated to dryness to afford the product as a solid (180 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10]([C:15]1[C:16]([CH2:23][CH2:24][O:25][Si](C(C)(C)C)(C)C)=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1)=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CCOC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH:9]1[C:10]([C:15]1[C:16]([CH2:23][CH2:24][OH:25])=[CH:17][C:18]([O:21][CH3:22])=[N:19][CH:20]=1)=[CH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CCO[Si](C)(C)C(C)(C)C)c(C2=CC3CCC2N3C(=O)OC(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(CCO)c(C2=CC3CCC2N3C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
To a stirred solution of 7-tert-butoxycarbonyl-2-{4-[2-(tert-butyldimethylsilanyloxy)ethyl]-2-methoxy-5-pyridinyl}-7-azabicyclo[2.2.1]hept-2-ene (360 mg, 0.78 mmol) in anhydrous THF (8 mL) was added 1.56 mL (1.56 mmol) of 1 M tetrabutylammonium fluoride in THF. The reaction solution was stirred at room temperature for 6 h, and then poured into a mixture of water (10 mL) and EtOAc (60 mL). The organic layer was separated and washed with brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography with hexane/EtOAc (2:1) to afford 7-tert-butoxycarbonyl-2-[4-(2-hydroxyethyl)-2-methoxy-5-pyridinyl]-7-azabicyclo[2.2.1]hept-2-ene as a syrup (270 mg, 100%). 1H NMR (CDCl3) δ 7.82 (s, 1H), 6.66 (s, 1H), 6.20 (s, 1H), 4.91 (s, 1H), 4.78 (s, 1H), 3.91 (s, 3H), 3.77 (br s, 2H), 3.20-2.85 (m, 2H), 2.40 (br s, 1H), 2.10-1.89 (m, 2H), 1.44 (s, 9H), 1.36-1.16 (m, 2H); 13C NMR (CDCl3) δ 164.05, 156.36, 149.36, 145.98, 144.61, 132.12, 123.75, 111.27, 80.38, 62.92, 62.28, 61.45, 53.33, 36.88, 28.16, 25.83, 23.46. MS m/z (%): 346 (M+, 1), 318 (8), 262 (100), 218 (12), 199 (21). Anal. Calcd for (C19H26N2O4. 1/3H2O) C, 64.75; H, 7.63; N, 7.95. Found: C, 64.55; H, 7.29; N, 7.64.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1/[CH:21]=[CH:22]/[S:23](Cl)(=[O:25])=[O:24]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:23](/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])(=[O:25])=[O:24])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Reactant: COc1ccccc1/C=C/S(=O)(=O)Cl
Product: COc1ccccc1/C=C/S(=O)(=O)Nc1cc(Cl)ccc1S(N)(=O)=O

Procedure:
The title compound was synthesized as described for Example 226 a) starting from 2-amino-4-chlorobenzenesulfonamide and (E)-2-(2-methoxyphenyl)ethenesulfonyl chloride.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[C:13]([F:20])[CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>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>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=2)=[C:13]([F:20])[CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: O=Cc1cnccc1Br
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: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cnccc1-c1ccc(Cl)cc1F
Temperature: 85 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
To a mixture of 4-bromonicotinaldehyde (3.00 g, 16.13 mmol), (4-chloro-2-fluorophenyl)boronic acid (2.81 g, 16.13 mmol), cesium carbonate (10.51 g, 32.3 mmol) and Pd(PPh3)4 (0.932 g, 0.806 mmol) was added THF (50 mL) and water (8 mL). Nitrogen gas was bubbled through the stirred suspension for 5 min. The reaction mixture was stirred under nitrogen atmosphere at 85° C. for 6 h. The reaction mixture was then cooled to room temperature and filtered through celite. The filtrate was diluted with ethyl acetate (30 mL) and washed with water (1×25 mL) and brine (1×25 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (ethyl acetate/hexanes) to yield 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (1.5 g, 6.37 mmol, 39% yield for two steps). 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 9.18 (s, 1H), 8.86 (d, J=5.1 Hz, 1H), 7.30 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:31])=[C:25]([C:27]([O:29]C)=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:31])=[C:25]([C:27]([OH:29])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
A solution of methyl 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazole-4-carboxylate (Preparation 71) (1.00 g, 2.26 mmol) in 1,4-dioxane (10 ml) was treated with an aqueous sodium hydroxide solution (1N, 1.5 ml) and stirred at room temperature for 4 hours. Further aqueous sodium hydroxide (1N, 3.0 ml) was added and the mixture was stirred for 20 hours. The solvent was removed under reduced pressure and the residue was dissolved in water and washed with ethyl acetate. The layers were separated and the aqueous layer was acidified with solid citric acid then extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a white foam (0.83 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[NH:42][C:41](=[O:43])[O:40][N:39]=2)=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:38]4[NH:42][C:41](=[O:43])[O:40][N:39]=4)=[CH:36][CH:37]=3)=[O:23])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc(-c5noc(=O)[nH]5)cc4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
To a mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (40 mg, 0.1 mmol) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(4H)-one hydrochloride (22 mg, 0.1 mmol) in 3 mL of DCM was added EDCI (58 mg, 0.3 mmol) followed by N-methylimidazole (25 mg, 0.3 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl)benzamide (15 mg, 26%) as white solid. 1H NMR (300 MHz, DMSO): δ 10.82 (s, 1H), 10.22 (s, 1H), 9.43 (s, 1H), 8.98 (s, 1H), 8.64 (d, 1H, J=8.1 Hz), 8.12-8.02 (m, 3H), 7.87-7.54 (m, 5H), 7.01 (d, 1H, J=9.0 Hz), 3.82 (s, 3H), 3.76 (s, 3H). LC-MS: 568 [M+H]+, tR=1.54 min. HPLC: 97.16% at 214 nm, 96.94% at 254 nm, tR=2.86 min.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([N:16](CC1C=CC=CC=1)[CH3:17])[CH2:11]2)(=[O:4])[CH3:3].[H][H]>CO.[Pd]>[ClH:1].[C:2]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH:10]([NH:16][CH3:17])[CH2:11]2)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1cccc2c1CCC(N(C)Cc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC1CCc2c(cccc2NC(C)=O)C1

Procedure:
1.40 g (0.0041 mol) of 5-acetylamino-2-(N-benzyl-N-methylamino)-tetraline-hydrochloride (Example 4.1.26) are hydrogenated in 50 ml of methanol in the presence of 0.4 g of 10% palladium/charcoal at 60° C. under a pressure of 4 bar until the uptake of hydrogen has ceased. After the catalyst has been removed by suction filtering, the residue is concentrated by rotary evaporation, finally at 80° C. under a complete water-jet vacuum. The residue is crystallised from 15 ml of methanol and 15 ml of diethylether. After suction filtering, washing with methanol/ether and drying at 80° C. the title compound is obtained in a yield of 0.85 g (81.5% of theory) and with a melting point of 253° C., which does not change after recrystallisation from methanol/ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:30].[NH2:31][CH2:32][CH2:33][CH2:34][CH2:35][P+:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C)C=O.C(Cl)Cl>[Br-:30].[CH3:15][C:11]([CH3:16])([CH2:10][CH2:9][N:8]([CH3:17])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:12](=[O:14])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35][P+:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CCC(C)(C)C(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCC(C)(C)C(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
4-[(tert-butoxycarbonyl)(methyl)amino]-2,2-dimethylbutanoic acid (Organic and Molecular Chemistry, 2011, 9, 1846-1854, 117 mg, 0.48 mmol) was dissolved in N,N-dimethylformamide (1.2 mL) and treated with N,N-carbonyldiimidazole (104 mg, 0.64 mmol). The mixture was stirred at room temperature for 30 minutes. (4-Aminobutyl)(triphenyl)phosphonium bromide (277 mg, 0.67 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction mixture was then diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (210 mg, 69%) as a white foam. Sample was used crude in next step.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[F:16][C:17]([F:29])([F:28])[C:18]1[N:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:24]([C:21]2[CH:22]=[N:23][C:18]([C:17]([F:29])([F:16])[F:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(C(F)(F)F)c2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 12.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (100 mg, 0.47 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (138 mg, 0.56 mmol), pyridine (0.08 ml, 0.94 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (25 mg, 13%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [C@H:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C1(C(O)=O)C2(CCCCC2)C1.[NH2:23][CH2:24][C@H:25]([OH:27])[CH3:26].Cl.NCC(N)=O>>[OH:27][C@H:25]([CH3:26])[CH2:24][NH:23][C:9]([C@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11]
Reactant: O=C(O)[C@@H]1CC12CCCCC2
Reactant: C[C@@H](O)CN
Agent: Cl
Agent: NCC(N)=O
Agent: O=C(O)C1CC12CCCCC2
Product: C[C@@H](O)CNC(=O)[C@@H]1CC12CCCCC2

Procedure:
The title compound was prepared as described in Example 3 substituting the product from Example 9 for the product from Example 1B and substituting (R)-1-amino-2-propanol, purchased from Aldrich, for 2-aminoacetamide hydrochloride. 1H NMR (400 MHz, CD3OD) δ 3.80 (m, 1H), 3.16 (m, 2H), 1.20-1.70 (m, 11H), 1.13 (d, 3H), 1.02 (dd, 1H), 0.69 (dd, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 173.9, 67.5, 48.0, 38.7, 30.2, 30.0, 28.9, 27.5, 26.9, 26.8, 21.1, 19.4; MS (CI) m/z 212 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH:2]([CH3:4])C.[C:20](=O)(SC)OC(OC(=O)CCC)C>>[C:1]([O:6][CH:7]([O:9][C:10]([O:12][CH:13]1[CH2:18][C:17](=[O:19])[NH:16][C:14]1=[O:15])=[O:11])[CH3:8])(=[O:5])[CH2:2][CH2:4][CH3:20]
Reactant: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Reactant: CCCC(=O)OC(C)OC(=O)SC
Product: CCCC(=O)OC(C)OC(=O)OC1CC(=O)NC1=O

Procedure:
Following the procedures for synthesizing [(1-isobutanoyloxyethoxy)carbonyloxy]succinimide (17) and replacing compound (2) with compound (4) affords [(1-butanoyloxyethoxy)carbonyloxy]succinimide (18).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:10]1[S:14][C:13]([NH2:15])=[N:12][N:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9]>C(OCC)(=O)C>[CH2:5]([C:10]1[S:14][C:13]([N:15]=[C:1]=[O:2])=[N:12][N:11]=1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C(Cl)Cl
Reactant: CCCCCc1nnc(N)s1
Solvent: CCOC(C)=O
Product: CCCCCc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-pentyl-2-amino-1,3,4-thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-pentyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: CP(C)C.O1CCCC1.[N:10]([CH2:13][CH2:14][O:15][C:16]([C@:18]1([F:38])[C@@H:23]2[C@H:19]1[CH2:20][C@@H:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C@@:22]2([NH2:27])[C:24]([OH:26])=[O:25])=[O:17])=[N+]=[N-]>O1CCCC1.O>[NH2:10][CH2:13][CH2:14][O:15][C:16]([C@:18]1([F:38])[C@@H:23]2[C@H:19]1[CH2:20][C@@H:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[C@@:22]2([NH2:27])[C:24]([OH:26])=[O:25])=[O:17]
Reactant: [N-]=[N+]=NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Product: NCCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)O)[C@@H]21
Reaction time: 13 h
Yield: 35.4 %

Procedure:
20 μL of a 1M trimethylphosphine/tetrahydrofuran solution was added to 6 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-azidoethyl)ester dissolved in a mixture of 0.15 mL of tetrahydrofuran and 0.02 mL of water at room temperature, and the mixture was stirred for 13 hours. After the solvent was distilled under reduced pressure, the residue was purified by reverse phase column chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.), eluent:water to a 50% aqueous solution of acetonitrile), and the obtained solids were further washed with tetrahydrofuran, thereby yielding 2 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-aminoethyl)ester.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](OCC2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C@H:30]([NH2:33])[CH2:31][OH:32])=[CH:21]1>ClC1C=CC=CC=1>[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][C@H:30]2[CH2:31][O:32][C:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:33]2)=[CH:21]1
Reactant: O=C(CCc1ccccc1)OCc1ccccc1
Reactant: Cn1cc(C[C@H](N)CO)c2ccccc21
Solvent: Clc1ccccc1
Product: Cn1cc(C[C@H]2COC(CCc3ccccc3)=N2)c2ccccc21
Yield: 76 %

Procedure:
Under an argon atmosphere, a mixture of benzyl 3-phenylpropionate (1.5 mmol), (S)-2-(N-methylindol-3-ylmethyl)-2-aminoethanol (1.5 mmol), Zn4(OCOCF3)6O (0.15 mmol) and chlorobenzene (2.5 mL) was heated under reflux for 18 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography to give (S)-4-(N-methylindol-3-ylmethyl)-2-(2-phenylethyl)-1,3-oxazoline in 76% yield. The compound was identified by comparison with physical property data of the known compound.
Reaction SMILES: [Cl:1][C:2]1[C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=[C:17]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[NH2:47][CH2:48][CH2:49][N:50]1[C:54](=[O:55])[C:53]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:52]2[C:51]1=[O:60].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:20]([C:21](=[O:23])[NH:47][CH2:48][CH2:49][N:50]2[C:54](=[O:55])[C:53]3=[CH:56][CH:57]=[CH:58][CH:59]=[C:52]3[C:51]2=[O:60])=[CH:19][CH:18]=[C:17]([Cl:24])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)O)c3Cl)c2n1
Reactant: NCCN1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)NCCN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
To a suspension of 8-(2,6-dichloro-3-carboxybenzyloxy)-2-methylquinoline (800 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (508 mg) and 1-hydroxybenzotriazole (388 mg) in N,N-dimethylformamide (8 ml) was added N-(2-aminoethyl)phthalimide hydrochloride (551 mg), and the mixture was stirred for 3 hours at ambient temperature. To the reaction mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with chloroform. The insoluble material was filtered off, and the filtrate was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate to give 8-[2,6-dichloro-3-[N-(2-phthalimidoethyl)carbamoyl]benzyloxy]-2-methylquinoline (1.04 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([Br:22])=[C:9]([NH2:11])[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(N)nc(-c2ccc(Cl)c(OC)c2F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Br
Yield: 77 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (778 mg, 2.5 mmol) and N-bromosuccinimide (489 mg, 2.75 mmol) were combined in chloroform (10 mL) and heated at reflux for 12 h. The cooled reaction mixture was concentrated and the product was purified by flash chromatography on silica gel to yield the title compound (752 mg, 77% yield): mp 173-175° C.: 1H NMR (CDCl3) δ 7.66 (dd, 1H), 7.24 (dd, 1H), 5.73 (br s, 2H), 4.03 (s, 3H), 4.01 (d, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[C:17]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:16][C:7]2=[N:8][C:9]=1[N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])[CH:2]=[CH2:3].CC1(C)O[O:32]1>CC(C)=O>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:17]2[O:16][C:7]3=[N:8][C:9]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])=[C:4]([CH2:1][CH:2]4[CH2:3][O:32]4)[CH:5]=[C:6]3[C:18]=2[C:19]([NH:21][CH3:22])=[O:20])=[CH:24][CH:25]=1
Reactant: CC1(C)OO1
Reactant: C=CCc1cc2c(C(=O)NC)c(-c3ccc(F)cc3)oc2nc1N(C)S(C)(=O)=O
Solvent: CC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CC3CO3)cc12

Procedure:
5-allyl-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridine-3-carboxamide was stirred with a solution of dimethyldioxirane in acetone until LCMS indicated complete conversion to product. The solution was evaporated to dryness to afford the title compound. MS (ESI) m/z 434.1 (M+1). NMR (400 MHz, CD3CN) δ 8.23 (s, 1H), 8.04-8.00 (m, 2H), 7.33-7.29 (m, 2H), 6.83 (br s, 1H), 3.28 (s, 3H), 3.26-3.24 (m, 2H), 3.16 (s, 3H), 3.05-2.99 (m, 1H), 2.92-2.90 (d, 3H), 2.82-2.79 (m, 1H), 2.63-2.61 (m, 1H)