Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([NH:5][C@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=O)=O.[OH:16][C@@H:17]1[CH2:21][N:20](C(OC(C)(C)C)=O)[C@H:19]([C:29]2[NH:30][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][CH:44]=[C:45]([C:50]6[N:51]=[C:52]([C@@H:55]7[CH2:59][CH2:58][CH2:57][N:56]7[C:60](=[O:70])[C@@H:61]([NH:65][C:66]([O:68][CH3:69])=[O:67])[CH:62]([CH3:64])[CH3:63])[NH:53][CH:54]=6)[CH:46]=5)[CH:41]=4)=[CH:36][CH:35]=3)=[CH:32][N:33]=2)[CH2:18]1.O[C@@H:72]1CN(C(=O)[C@@H](NC(OC)=O)C(C)C)[C@H](C2NC=C(C3C=CC(C4C=C5C(=CC=4)C=C(C4NC([C@@H]6CCCN6C(OC(C)(C)C)=O)=NC=4)C=C5)=CC=3)N=2)C1>>[CH3:69][O:68][C:66](=[O:67])[NH:65][CH:61]([C:60]([N:56]1[CH2:57][CH2:58][CH2:59][CH:55]1[C:52]1[NH:53][CH:54]=[C:50]([C:45]2[CH:44]=[CH:43][C:42]3[C:47](=[CH:48][CH:49]=[C:40]([C:37]4[CH:38]=[CH:39][C:34]([C:31]5[NH:30][C:29]([CH:19]6[CH2:18][C:17](=[O:16])[CH2:21][N:20]6[C:7](=[O:9])[CH:6]([N:5]([CH3:3])[CH3:72])[C:10]6[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=6)=[N:33][CH:32]=5)=[CH:35][CH:36]=4)[CH:41]=3)[CH:46]=2)[N:51]=1)=[O:70])[CH:62]([CH3:64])[CH3:63]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](O)C[C@H]1c1nc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)c[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6C[C@H](O)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(=O)CN6C(=O)C(c6ccccc6)N(C)C)[nH]5)cc4)ccc3c2)c[nH]1)C(C)C

Procedure:
[1-(2-{4-[6-(4-{2-[1-(2-Dimethylamino-2-phenyl-acetyl)-4-oxo-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester was prepared following Example BN substituting (R)-2-(dimethylamino)-2-phenylacetic acid for (R)-2-(methoxycarbonylamino)-2-phenylacetic acid and (2S,4S)-tert-butyl 4-hydroxy-2-(5-(4-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate for (S)-tert-butyl 2-(5-(6-(4-(2-((2S,4S)-4-hydroxy-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate. C47H50N8O5 calculated 806.4 observed [M+1]+ 807.3; rt=1.53 min.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[NH2:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][C:13]([OH:15])=[O:14]>>[NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[C:16]([OH:18])(=[O:17])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].[NH3:10]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: NC(CC(=O)O)C(=O)O
Product: N
Product: O=C(O)/C=C\C(=O)O

Procedure:
We have found that this object is achieved by a process for preparing D,L-aspartic acid by heating aqueous solutions of ammonium salts of aspartic acid at elevated temperatures under pressure, acidifying the reaction solution to liberate D,L-aspartic acid and isolating the D,L-aspartic acid, when maleic acid and ammonia are reacted in a molar ratio of from 1:2.1 to 1:50 in aqueous solution at from 60° C. to 250° C. under pressures of at least 1 bar, the pressure being controlled during the reaction in such a way that the reaction mixture is almost entirely in the liquid phase.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[OH:7][CH:4]1[CH2:5][CH2:6][N:2]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:3]1
Reactant: OC1CCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(O)C1
Temperature: 5 °C

Procedure:
Into a 500 mL 3-necked round bottom flask was placed a solution of pyrrolidin-3-ol hydrochloride (20.2 g, 163.43 mmol) in H2O (60 mL) while cooling to 5° C. Adjustment of the pH to 7 was accomplished by the NaOH (10%). This was followed by the addition of a solution of benzyl chloroformate (36.8 g, 216.47 mmol), which was added dropwise with stirring, while cooling to a temperature of 5° C. The resulting solution was allowed to react, with stirring, for 2 hours at 5° C. Then the resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The resulting solution was extracted three times with 100 mL of ethyl acetate and the organic layers combined and dried over MgSO4 and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 30 g (crude) of benzyl 3-hydroxypyrrolidine-1-carboxylate as brown oil.
Reaction SMILES: [N:1]1([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>ClCCl>[C:15]([N:4]1[CH2:3][CH2:2][N:1]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:5]1)(=[O:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NN1CCNCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1CCN(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(1-piperazinyl)-tert-butoxycarboxamide (15 g) in dichloromethane (200 ml) was added acetic anhydride (7.74 ml) and pyridine (6.63 ml). The mixture was stirred at ambient temperature for 1 hour. The solution was washed with saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was collected, dried over magnesium sulfate, and concentrated. The residue was triturated with n-hexane to give N-(4-acetyl-1-piperazinyl)-tert-butoxycarboxamide (16.4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[N:13]=2)[CH:5]=[N:6][CH:7]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:20][C:16]1[N:15]=[C:14]([C:12]2[N:13]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:3]=3)[C:9]3[CH:23]=[CH:22][NH:21][C:10]=3[N:11]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cccc(-c2nc(-c3cncc(Br)c3)c3cc[nH]c3n2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: Cc1cccc(-c2nc(-c3cncc(C#C[Si](C)(C)C)c3)c3cc[nH]c3n2)n1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a suspension of of 4-(5-bromo-pyridin-3-yl)-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Example 16) (1 eq, 0.451 mmol, 250 mg) in TEA/DMF (1:1, 6 ml) are added copper (I) iodide (0.1 eq, 0.045 mmol, 8.8 mg), PdCl2(PPh3)2 (0.1 eq, 0.045 mmol, 32.3 mg), and trimethylsilylacetylene (Sigma-Aldrich, St. Louis, USA) (1.5 eq, 0.68 mmol, 0.098 ml). The resulting mixture is stirred at 90° C. for 1 h. The solvents are removed in vacuo, then sat. aqueous NaHCO3 solution is added, and the mixture is extracted with EtOAc. The organic layer is washed with sat. aqueous NaCl solution, dried with MgSO4, and concentrated under reduced pressure. The crude product is purified by reversed phase HPLC and recrystallized in EtOAc giving the title compound; [M+H]+=384.
Reaction SMILES: C[N:2]([CH3:7])[CH2:3][CH2:4][CH2:5]N.[C:8]([N:16]1[C:20]2[N:21]=[CH:22][C:23]3[C:24](OC4C=CC=CC=4)=[N:25][C:26]4[N:27]([N:29]=[CH:30][N:31]=4)[C:28]=3[C:19]=2[CH:18]=[N:17]1)(=O)[C:9]1C=CC=CC=1.N1(N2N3C4C5C=NNC=5N=CC=4C=NC3=NC2)CCCC1>>[CH2:8]([N:16]1[C:20]2[N:21]=[CH:22][C:23]3[C:24]([N:2]4[CH2:3][CH2:4][CH2:5][CH2:7]4)=[N:25][C:26]4[N:27]([N:29]=[CH:30][N:31]=4)[C:28]=3[C:19]=2[CH:18]=[N:17]1)[CH3:9]
Reactant: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12
Reactant: CN(C)CCCN
Agent: C1=NC2=NCN(N3CCCC3)N2c2c1cnc1[nH]ncc21
Product: CCn1ncc2c1ncc1c(N3CCCC3)nc3ncnn3c12

Procedure:
By substituting pyrrolidine for 3-(dimethylamino)propylamine in the procedure of Example 1 (c), 8-ethyl-5-(1-pyrrolidinyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[1,5-a]pyrimidine is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: N#Cc1ccccc1N1CCNCC1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 88 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 88%). 1H NMR (200 MHz, CDCl3): δ 3.31 (s, 4H), 3.84 (s, 4H), 4.15 (s, 3H), 7.03-7.10 (m, 2H), 7.25-7.61 (m, 5H), 7.82 (dd, J=8.7 and 5.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([S:13][CH3:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([S:13][CH3:14])[N:10]([CH2:22][C:23]([N:25]3[CH2:26][CH2:27][N:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:29][CH2:30]3)=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CSc1cc(-c2ccc(F)cc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CSc1cc(-c2ccc(F)cc2)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 3-(4-Fluoro-phenyl)-5-methylsulfanyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.7-7.76 (m, 2H), 6.96-7.1 (m, 4H), 6.88-6.92 (m, 2H), 6.64 (s, 1H), 5.3 (s, 2H), 3.7-3.84 (m, 4H), 3.04-3.2 (m, 4H), 2.5 (s, 3H). 13C NMR (400 MHz, CDCl3): 164.8, 152, 140, 127.4, 119, 118.4, 118.2, 116.2, 116, 108, 52.8, 52, 51.8, 45.4, 42.2, 20.
Reaction SMILES: [F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:16]=2[F:29])=[C:11]([F:30])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].C([O-])([O-])=O.[Cs+].[Cs+].BrCC(O[CH:42]([CH3:44])[CH3:43])=O.O>CN(C=O)C>[F:1][C:2]1[C:12]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:16]=2[F:29])=[C:11]([F:30])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH:42]([CH3:44])[CH3:43])=[O:7]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(CNc2c(F)ccc(OCC(=O)O)c2F)c(F)c(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c(F)c(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A mixture of 2-[2,4-difluoro-3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]phenoxy]acetic acid (I(g)) (300 mg, 0.83 mmol, 1.0 eq) and Cs2CO3 (407 mg, 1.25 mmol, 1.5 eq) in DMF (5 mL) was stirred at room temperature for 1 h, then isopropyl bromoacetate (171 mg, 0.91 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 1 h. The resulting mixture was poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (310 mg, 81%).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([C:36]#[CH:37])[CH:33]=[CH:34][CH:35]=1>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([C:37]#[C:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=2)[CH:12]=3)[N:19]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: COc1cccc(C#Cc2ccc3c(=NO)cc(-c4cc5ccccc5cn4)oc3c2)c1

Procedure:
2-isoquinolin-3-yl-7-(3-methoxyphenyl)ethynyl-chromen-4-one oxime was prepared in 22% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 3-methoxyphenylacetylene. The title compound was isolated as an orange solid and as a 93/7 mixture of Z/E oxime isomers.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[I-].[Na+].[OH-].[Na+].Cl[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(CC)(C)C.C1(C)C=CC=CC=1>[C:13]1([CH2:12][CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1c[nH]nn1
Reactant: ClCCc1ccccc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)(C)O
Solvent: Cc1ccccc1
Product: c1ccc(CCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
1,2,3-Triazole (1634 mg, 23.7 mmol), sodium iodide (2364 mg, 15.8 mmol), sodium hydroxide (946 mg, 23.7 mmol) were added to t-amyl alcohol (6.2 ml), and the mixture was refluxed under stirring for 1 hour. 1-Chloro-2-phenylethane (2217 mg, 15.8 mmol) was dissolved in t-amyl alcohol (6.2 ml) and added dropwise under reflux over 1 hour. The mixture was refluxed under stirring for 3.5 hours. The mixture was cooled to room temperature and toluene (50 ml) was added. The mixture was washed with water (50×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1→1/3) to give 1-(2-phenylethyl)-1H-1,2,3-triazole as a colorless oil (2.0 g, yield 73%). 2-(2-Phenylethyl)-2H-1,2,3-triazole (315 mg) was obtained as a colorless oil (yield 12%). 1-(4-phenylethyl)-1H-1,2,3-triazole
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.Br[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29]1([C:55]3[C:46](=[CH:47][C:48]4[O:53][CH2:52][CH2:51][O:50][C:49]=4[CH:54]=3)[O:45][CH2:44]1)[C:30](=[O:43])[N:31]2[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.BrC1C=CC=C2C=1C1(C3C(=CC4OCCOC=4C=3)OC1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][N:2]([CH3:12])[C:3]1[N:4]=[CH:5][C:6]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[C:29]2([C:55]4=[CH:54][C:49]5[O:50][CH2:51][CH2:52][O:53][C:48]=5[CH:47]=[C:46]4[O:45][CH2:44]2)[C:30](=[O:43])[N:31]3[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:7][CH:8]=1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: OB(O)c1cnc2ccccc2c1
Product: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3Cc2ccccn2)cn1

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 2-(dimethylamino)pyridine-5-boronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-(6-(dimethylamino)pyridin-3-yl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (44%) as a colorless solid: mp 187-188° C. (methanol/dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.61-8.56 (m, 1H), 7.80-7.77 (m, 1H), 7.70-7.62 (m, 1H), 7.32-7.17 (m, 3H), 6.91-6.81 (m, 2H), 6.66 (dd, J=8.8, 2.5 Hz, 1H), 6.40 (s, 1H), 6.27 (s, 1H), 6.21 (d, J=8.8 Hz, 1H), 5.25 (d, J=15.8 Hz, 1H), 4.93 (d, J=15.8 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.46 (d, J=9.0 Hz, 1H), 4.30-4.08 (m, 4H), 3.05 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 178.2, 158.5, 155.6, 155.4, 149.5, 147.4, 144.7, 142.7, 138.0, 137.6, 137.2, 137.1, 129.5, 128.8, 125.9, 122.8, 122.7, 122.0, 121.7, 111.2, 108.6, 104.3, 99.4, 64.6, 64.0, 58.4, 46.2, 38.1; MS (ES+) m/z 507.0 (M+1).
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[C:16]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[C@H:17]([CH3:19])O.N1C(C)=CC=CC=1C.[CH2:37]([O:40][NH2:41])[CH:38]=[CH2:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:22]([O:21][C:16](=[O:20])[C@@H:17]([CH3:19])[NH:41][O:40][CH2:37][CH:38]=[CH2:39])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C=CCON
Reactant: C[C@H](O)C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CCON[C@H](C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
A solution of triflic anhydride (10.86 g, 38.5 mmol) in dry CH2Cl2 (20 mL) was added dropwise to a solution of benzyl (S)-lactate (1a) (6.31 g, 35 mmol) in dry CH2Cl2 (100 mL) with cooling (−68˜−72° C.) and stirring. After 5˜7 min, a solution of 2,6-lutidine (4.31 g, 40.3 mmol) in dry CH2Cl2 (15 mL) was added dropwise at the same temperature and the reaction mixture was stirred for 30 min at −68˜−72° C. A solution of O-allylhydroxylamine (4.55 g, 77 mmol) in dry CH2Cl2 (15 mL) was added dropwise to the prepared solution of the alkylating reagent with cooling (−68˜−72° C.) and stirring. The reaction mixture was stirred for 15 min at ca. −72° C. and then was allowed to warm up to RT. After stirring for 15 h at RT, the reaction mixture was thoroughly shaken with sat. aqueous NaHCO3 (200 mL) and dried over MgSO4. After removal of the solvent, the residue was purified by dry flash chromatography (Silica Gel 60H for TLC, 10% EtOAc-hexanes) to afford 8.20 g (99.6%) of the product 2a as a pale yellowish oil. 1H NMR (100 MHz) in CDCl3+1 drop of D2O (J, Hz): δ 1.28 (3H, d, 3J=7.1, MeCH), 3.82 (1H, q, 3J=7.1, MeCH), 4.22 (2H, dt, 3J=5.7, 4J=1.2, OCH2CH═CH2), 5.16-5.37 (2H, m, CH═CH2), 5.23 (2H, CH2Ph), 5.76-6.15 (1H, m, 3J=5.7, 3Jcis=9.9, 3Jtrans=17.1, CH═CH2), 7.38 (5H, Ph). 13C (100 MHz) in CDCl3: δ 14.81, 59.09, 66.63, 75.22, 117.53, 128.06, 128.24, 128.56, 134.37, 135.84, 174.01. IR (film), cm−1: 3264, 1740, 1456, 1208, 1170. Anal. Calcd for C13H17NO3: C, 66.4; H, 7.3; N, 5.95. Found: C, 66.3; H, 7.4; N, 6.15%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23]([N:25]([CH2:28]C)CC)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].CN>ClCCl.CCCCCC.O1CCCC1>[CH3:23][NH:25][C:28](=[O:32])[O:14][CH2:13][CH2:12][CH:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[F:22]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCO)c1cc(F)ccc1F
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCCCCC
Product: CNC(=O)OCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.7 %

Procedure:
The 3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)-1-propanol (200 mg, 0.576 mmol) obtained in Example 207 was dissolved in dichloromethane (4 ml), followed by the addition, of triethylamine (84.2 μl, 0.605 mmol) and 4-nitrophenyl chloroformate (122 mg, 0.605 mmol). The resulting mixture was stirred at room temperature for 15 hours. After addition of methylamine (a 2.00M tetrahydrofuran solution, 2.0 ml, 4.00 mmol), the mixture was stirred at room temperature for 24 hours. Methylamine (a 2.00M tetrahydrofuran solution, 3.0 ml, 4.00 mmol) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane, washed successively with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=3:2 eluate was concentrated. The concentrate was purified further by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to yield the title compound (62.1 mg, 0.154 mmol, 27%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][C@@:9]3([CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[NH2:18])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH:31]=2)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][C@@:9]3([CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[NH:18][C:28]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[N:40]([CH3:41])[N:39]=[N:38][N:37]=4)[CH:31]=3)=[O:27])[CH2:8]2)=[CH:19][CH:20]=1
Reactant: N[C@@H]1CCCC[C@@]12CCCN(Cc1ccc(F)cc1)C2
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Solvent: C1CCOC1
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCCC[C@@]23CCCN(Cc2ccc(F)cc2)C3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A solution of (6S,7R)-2-(4-fluorobenzyl)-2-aza-spiro[5.5]undec-7-ylamine (90 mg, 0.32 mmol) in tetrahydrofuran (2 mL) was treated with [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (123 mg, 0.42 mmol), and the mixture was stirred at room temperature overnight. The solvent was removed under vacuum and the resulting solid was purified by chromatography on silica gel, eluting with 0.2:1.8:98 ammonium hydroxide/methanol/dichloromethane, to give the desired product (80 mg). 1H NMR (300 MHz, CDCl3) δ8.27 (bs, 1H), 7.94 (d, J=9 Hz, 1H), 7.82 (bs, 1H), 7.39 (t, J=8 Hz, 1H), 7.26-7.19 (m, 3H), 6.98-6.91 (m, 2H), 6.21 (bs, 1H), 4.17 (s, 3H), 3.98 (bs, 1H), 3.35 (m, 2H), 2.50-2.15 (m, 3H), 1.85 (m, 2H), 1.65-1.20 (m, 11H). Mass spec (ES+) m+/z 478.4 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:27])[CH:25]=[CH2:26])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH2:10][CH2:9]1
Reactant: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCC(N)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of [1-(4-Acryloylamino-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.57 g, 1.4 mmol) in DCM (10 ml) was added trifluoroacetic acid (10 ml) in one portion. The resulting mixture was then stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the reaction was concentrated under vacuum to afford the title compound (0.40 g, 93% yield) as an orange solid.