Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([CH:20]=[N:21]O)[CH:3]=1.O=P(Cl)(Cl)[Cl:25].N1C=CC=CC=1C>>[Cl:25][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: ON=Cc1cc(O)nc(SCc2ccc3ccccc3c2)n1
Solvent: Cc1ccccn1
Product: N#Cc1cc(Cl)nc(SCc2ccc3ccccc3c2)n1

Procedure:
6-hydroxy-2-(2-naphthylmethyl)thio-4-pyrimidine carboxaldehyde oxime (720 mg, 2.31 mmol), POCl3 (3 ml), and 2-picoline (0.5 ml) are heated to reflux for 2 hrs. The reaction mixture is poured onto ice/water, extracted thrice with ethyl acetate, dried with MgSO4, and concentrated in vacuo. The product is purified by chromatography (SiO2, ethyl acetate/hexane, 5/95): 524 mg (1.67 mmol, 73%), mp 120-121° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17]([C:19]1([OH:27])[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1)#[CH:18].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][C:19]3([OH:27])[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
A stirred mixture of 4-bromo-4'-ethoxybiphenyl (1.1 g), 3-ethynyl-3-hydroxyquinuclidine (600 mg), bis(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg) and dry triethylamine (5.0 ml) in dry dimethylformamide (20 ml) was stirred at 90° C. under an atmosphere of argon for 4 hours. The dimethylformamide and triethylamine were removed by evaporation and the residue was treated with saturated sodium carbomate solution (20 ml). The solid obtained was collected by filtration and crystallised from dimethylformamide to give 3-[2-(4'-ethoxybiphenyl-4-yl)ethynyl]quinuclidin-3-ol (300 mg) as a soild, m.p. 255-256° C.; microanalysis, found C, 79.1; H, 7.3; N, 3.9%; C23H25NO2 requires C, 79.5; H, 7.3; N, 4.03%; NMR (DMSO-d6): 1.2-.1.4(3H, t), 1.52-1.71(1H, m), 1.8-2.0(3H, m), 2.6-2.98(5H, m), 3.05-3.2(1H, m), 4.0-4.16(2H, q), 5.51-5.62(1H, br), 6.95-7.05(2H, d), 7.4-7.5(2H, d) an 7.57-7.68(4H, m); m/z 348 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][N:12](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:6]=[C:5]([CH2:31][OH:32])[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C>[OH:32][CH2:31][C:5]1[CH:6]=[C:7]([O:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:3]([CH2:2][OH:1])[N:4]=1
Reactant: COC(=O)CCN(CCOc1cc(CO)nc(CO)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)CCNCCOc1cc(CO)nc(CO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
To a solution of 155 mg of methyl 3-[[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-(2-nitro-benzenesulfonyl)-amino]-propanoate in 6 ml of acetonitrile, under argon, was added 325 mg of caesium carbonate and 67 μl of thiophenol. The mixture was stirred for 4 hours at room temperature and then filtered through a sinter of porosity 4. The cake was washed with EtOAc and the filtrate was concentrated under reduced pressure and purified on a Mega BE-SCX, 2GM 12ML cartridge (Varian), using washing with MeOH and detachment of the expected product with a 2N solution of ammonia in MeOH. The fractions containing the desired product were combined and concentrated under reduced pressure. 82 mg of methyl 3-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethylamino]-propanoate were obtained. LC/MS (B): tr=0.33 min; [M+H]+: m/z 285.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1I)[CH:2]=[CH2:3].Cl>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][S:11]([C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[NH:4][CH:1]=[C:2]2[CH3:3])(=[O:13])=[O:12]
Reactant: C=CCNc1ccc(S(C)(=O)=O)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(S(C)(=O)=O)cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
A solution of allyl-(2-iodo-4-methanesulfonyl-phenyl)-amine (1.43 g, 4.1 mmol) in DMF (20 mL) is treated with n-Bu4NCl (1.47 g, 5.32 mmol), Pd(OAc)2 (56.6 mg, 0.2 mmol), and stirred at 100° C. for 1 h. HCl (5.3 mL, 3 M) is added, and the mixture is cooled to rt, filtered through a pad of Celite, and extracted with EtOAc (3×50 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 60% EtOAc in heptane to afford 5-methanesulfonyl-3-methyl-1H-indole (370 mg, 43%).
Reaction SMILES: Br[C:2]1[CH:41]=[CH:40][C:5]([O:6][C:7]2[CH:8]=[C:9]([S:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[C:10]([NH:13][C:14]3[S:18][N:17]=[C:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[N:15]=3)=[N:11][CH:12]=2)=[CH:4][CH:3]=1.C[Li].C([Li])CCC.CN(C)[CH:51]=[O:52].[NH4+].[Cl-]>C1COCC1>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[S:32][C:9]1[C:10]([NH:13][C:14]2[S:18][N:17]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:15]=2)=[N:11][CH:12]=[C:7]([O:6][C:5]2[CH:40]=[CH:41][C:2]([CH:51]=[O:52])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Oc4ccc(Br)cc4)cc3Sc3ccccc3Cl)n2)CC1
Agent: [Cl-]
Agent: [Li]C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Oc4ccc(C=O)cc4)cc3Sc3ccccc3Cl)n2)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 39.5 %

Procedure:
tert-Butyl 4-(5-(5-(4-bromophenoxy)-3-(2-chlorophenylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (500 mg, 0.741 mmol) was dissolved in THF (7 mL) and cooled to −78° C. Methyllithium (556 μL, 0.889 mmol) was added and the reaction was stirred for 5 minutes. Butyllithium (356 μL, 0.889 mmol) was added and the reaction was stirred for 5 minutes. N,N-dimethylformamide (115 μL, 1.48 mmol) was added and the reaction was slowly warmed to ambient temperature. The reaction was poured into NH4Cl, extracted with EtOAc, concentrated and purified on silica gel (5 to 10% EtOAc in hexanes) to afford tert-butyl 4-(5-(3-(2-chlorophenylthio)-5-(4-formylphenoxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (183 mg, 0.293 mmol, 39.6% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[NH:3][C:4]([NH:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2
Reactant: NCc1ccccc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: Clc1nc2ncnc-2c(NCc2ccccc2)[nH]1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
189 mg of 2,6-dichloropurine, 4 ml of butanol and 0.12 ml (1.1 mol) of benzylarnine are mixed at room temperature and the medium is heated at a temperature of 75° C. for 5 hours and then it is left at room temperature overnight.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:21][NH:22][C:23]([C:25]1([NH:28][C:29]2[C:34]([Cl:35])=[CH:33][N:32]=[C:31](Cl)[N:30]=2)[CH2:27][CH2:26]1)=[O:24].CNC(C1(NC2C(Cl)=CN=C(NC3C(OC)=CC4CCN(CCOC)CCC=4C=3)N=2)CC1)=O>>[CH3:21][NH:22][C:23]([C:25]1([NH:28][C:29]2[C:34]([Cl:35])=[CH:33][N:32]=[C:31]([NH:1][C:2]3[C:18]([O:19][CH3:20])=[CH:17][C:5]4[CH2:6][CH2:7][N:8]([CH2:11][C:12](=[O:13])[N:14]([CH3:16])[CH3:15])[CH2:9][CH2:10][C:4]=4[CH:3]=3)[N:30]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: CNC(=O)C1(Nc2nc(Cl)ncc2Cl)CC1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Agent: CNC(=O)C1(Nc2nc(Nc3cc4c(cc3OC)CCN(CCOC)CC4)ncc2Cl)CC1
Product: CNC(=O)C1(Nc2nc(Nc3cc4c(cc3OC)CCN(CC(=O)N(C)C)CC4)ncc2Cl)CC1

Procedure:
Following a procedure similar to Example 258c, 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and 1-(2,5-dichloro-pyrimidin-4-ylamino)-cyclopropane carboxylic acid methylamide were converted to 1-{5-chloro-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclopropane carboxylic acid methylamide as a white solid (28 mg, 19%). MP: 118-125° C.; 1H-NMR (CDCl3) 8.21 (s, 1H), 7.97 (s, 1H), 7.63 (br s, 1H), 6.63 (s, 1H), 6.38 (br s, 1H), 5.62 (s, 1H), 3.87 (s, 3H), 3.27 (s, 2H), 3.16 (s, 3H), 2.97 (s, 3H), 2.91 (m, 2H), 2.85 (m, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.69 (m, 4H), 1.75 (m, 2H), 1.09 (br s, 2H); LC/MS (ESI+): 502.30 (M+H).
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:24]1[N:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[N:25]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:31][C:26]1[CH:27]=[C:28]([CH3:30])[N:29]=[C:24]([N:3]2[CH2:4][CH2:5][C@H:6]3[C@H:1]([N:8]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[O:21][N:20]=[C:19]([CH3:22])[N:18]=4)=[O:10])[CH2:7]3)[CH2:2]2)[N:25]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: Cc1noc(-c2ccccc2C(=O)N2C[C@H]3CCNC[C@H]32)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(C)nc(N2CC[C@@H]3CN(C(=O)c4ccccc4-c4nc(C)no4)[C@@H]3C2)n1
Temperature: 200 °C
Yield: 59.6 %

Procedure:
A mixture of Intermediate 12 (50 mg, 0.17 mmol), 2-chloro-4,6-dimethylpyrimidine (24 mg, 0.17 mmol) and DIPEA (0.87 mL, 0.5 mmol) in ACN (1 mL) was heated in the microwave at 200° C. for 90 min. The mixture was concentrated in vacuo and was purified on a Prep Agilent system with a XBridge C18 OBD 50×100 mm column eluting with 5 to 99% 0.05% NH4OH in H2O/ACN over 17 min to afford the desired product as a colorless foam (41 mg, 60%). MS (ESI) mass calculated for C22H24N6O2, 404.20; m/z found, 405.2. 1H NMR (500 MHz, CDCl3): 8.12-8.03 (m, 1H), 7.59-7.49 (m, 2H), 7.41-7.36 (m, 1H), 6.31-6.26 (m, 1H), 4.41-4.23 (m, 3H), 4.11-4.05 (m, 1H), 4.05-3.78 (m, 2H), 3.68-3.64 (m, 0H), 3.05-2.83 (m, 2H), 2.46-2.40 (m, 3H), 2.34-2.24 (m, 6H), 2.15-2.04 (m, 1H), 2.00-1.86 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14](SC#N)[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=3)[C:6]=2[CH:22]=1.[Si:23]([O:40][C@H:41]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[C@H:44]([NH2:52])[CH2:43][CH2:42]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.CS(C)=O>C1COCC1>[Si:23]([O:40][C@H:41]1[C:50]2[C:45](=[CH:46][C:47]([F:51])=[CH:48][CH:49]=2)[C@H:44]([NH:52][C:14]2[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=[C:10]([N:7]3[C:6]4[CH:22]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[N:15]=2)[CH2:43][CH2:42]1)([C:36]([CH3:39])([CH3:37])[CH3:38])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N)c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Reactant: N#CSc1nc(-n2cnc3ccc(F)cc32)ncc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](Nc2nc(-n3cnc4ccc(F)cc43)ncc2[N+](=O)[O-])c2cc(F)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.4 %

Procedure:
6-Fluoro-1-(5-nitro-4-thiocyanatopyrimidin-2-yl)-1H-benzo[d]imidazole (498 mg, 1.57 mmol, 1.1 equiv) was added to a solution of (1R,4R)-4-(tert-butyldiphenylsilyloxy)-7-fluoro-1,2,3,4-tetrahydronaphthalen-1-amine (600 mg, 1.43 mmol, 1 equiv) in THF (20 mL) containing DIEA (1.5 mL), followed by adding 2 mL of DMSO. The resulted red solution was stirred at RT for 16 h. THF was evaporated off The residue was dissolved in EtOAc, washed with water and brine, dried (Na2SO4). The organic layer was evaporated to dryness. The residue was purified on ISCO (12 g column, MeOH—CH2Cl2 0-5%) to give a yellow solid product (633 mg, 65%). MS (ESI): 677.3.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26][CH3:27])(=[O:4])[CH2:2][CH3:3].C([O-])(O)=[O:29].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26]([CH3:27])=[O:29])(=[O:4])[CH2:2][CH3:3]
Reactant: O=C([O-])O
Reactant: CCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1C
Temperature: 4 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
3-Propanoyl-4-(2-methylphenylamino)-8-(2-methylthioethoxy)quinoline (0.10 g, 0.26 mmol) was dissolved in methylene chloride (5 ml). NaHCO3 (45 mg) in H2 0 (5 ml) was added. The mixture was cooled to 4° C. A solution of 71% m-CPBA (0.062 g, 0.25 mmol) in methylene chloride (5 ml) was added dropwise. After stirring for 1 h at 2°-4° C., the organic layer was washed with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated. Chromatography (SiO2 ; CH2Cl2 :EtOH 90:10) gave 50 mg (48%) of the desired product.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:7]=1[NH2:8])([O-:5])=[O:4].F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CC(N(C)C)=O>[N+:3]([C:6]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[CH:9][C:7]=1[NH:8][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)([O-:5])=[O:4]
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.9 %

Procedure:
To a stirred suspension of sodium hydride (2.40 g, 60 mmol) in dimethylacetamide (60 ml) at room temperature under a nitrogen atmosphere was added a solution of 2-nitro-4-trifluoromethylaniline (10.31 g, 50 mmol) in dimethylacetamide (20 ml) during 30 min. After stirring the mixture at room temperature for 15 min., a solution of 2-fluoropyridine (5.83 g, 60 mmol) in dimethylacetamide (20 ml) was added during 5 min. The resulting mixture was heated to reflux for about 8 h. Volatiles were removed by evaporation under reduced pressure. The residue was dissolved into ethyl acetate (200 ml) and washed with water (3×100 ml). The organic layer was dried (magnesium sulfate) and concentrated to dryness. Column chromatography (silica gel, 250 g; n-hexane/ethyl acetate (17/3)) yielded 3.38 g (23%) of the titled compound as yellow solids.
Reaction SMILES: [ClH:1].[C:2]([C:6]1[N:7]([CH2:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:8]=[C:9]([C:11]2[CH:12]=[C:13]([C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)[CH:14]=[CH:15][CH:16]=2)[N:10]=1)([CH3:5])([CH3:4])[CH3:3].C([SiH](CC)CC)C.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[ClH:1].[CH2:17]([C:13]1[CH:12]=[C:11]([C:9]2[N:10]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[N:7]([CH2:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:8]=2)[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)c1nc(-c2cccc(C(=O)c3ccccc3)c2)cn1CC1CCOCC1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(-c2cccc(Cc3ccccc3)c2)cn1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
Under an argon atmosphere, a free base of Compound 48 (57 mg, 0.14 mmol) obtained in Example 48 was dissolved in trifluoroacetic acid (1 mL), and triethylsilane (91 μL, 0.57 mmol) was added thereto, and then, the mixture was stirred overnight at room temperature. Under ice-cooling, an aqueous sodium hydrogen carbonate solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give a free base of the title compound (35 mg, 0.09 mmol, yield: 64%). Then, the obtained free base was treated with 4 mol/L hydrogen chloride-ethyl acetate to give the title compound 51 (30 mg, 0.07 mmol, yield: 78%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][C:15]=2[O:28][CH3:29])=[CH:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)=[O:4].[OH-].[Na+].CO.Cl>O>[C:11]([C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][C:15]=2[O:28][CH3:29])=[CH:7][CH:8]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)c1cc(C(C)=O)ccc1-c1ccc(OCc2ccccc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(OCc2ccccc2)ccc1-c1ccc(C(C)=O)cc1C(=O)O
Temperature: 25 °C
Yield: 74 %

Procedure:
To 4-Acetyl-4′-benzyloxy-2′-methoxybiphenyl-2-carboxylic acid methyl ester 7b (4.06 g, 9.7 mmol) and NaOH (0.773 g, 19.4 mmol) was added methanol (60 mL) and water (60 mL). The reaction was refluxed under Ar for 7 h then cooled to room temperature. After placing in an ice bath, 1 M HCl was added to give a yellow precipitate that was filtered, washed with water and recrystallized from THF/hexanes to give 2.7 g (69%) of 8b as yellow crystals. 1H-NMR (400 MHz, CDCl3) dH 2.68 (4H, s, COCH3), 3.62 (3H, s, OCH3), 5.16 (2H, s, CH2Ph), 6.77 (1H, s, ArH), 7.18 (1H, s, ArH), 7.33-7.52 (5H, m, CH2Ph), 3.90 (3H, s, OCH3), 5.22 (2H, S, CH2Ph), 6.58 (1H, s, ArH), 6.90 (1H, s, ArH), 7.34-7.50 (6H, m, ArH+Ch2Ph), 8.17 (1H, d, ArH), 8.50 (1H, s, ArH),
Reaction SMILES: N1C(C)=CC=CC=1C.P(Cl)(Cl)(Cl)=O.[CH:14]([NH:16][C@@H:17]1[C@@H:20]([CH2:21][CH:22]=[CH2:23])[N:19]([C:24](=[C:29]([CH3:31])[CH3:30])[C:25]([O:27][CH3:28])=[O:26])[C:18]1=[O:32])=O.C(OCC)(=O)C>ClCCl.[Cl-].[Na+].O>[N+:16]([C@@H:17]1[C@@H:20]([CH2:21][CH:22]=[CH2:23])[N:19]([C:24](=[C:29]([CH3:31])[CH3:30])[C:25]([O:27][CH3:28])=[O:26])[C:18]1=[O:32])#[C-:14]
Reactant: C=CC[C@@H]1[C@@H](NC=O)C(=O)N1C(C(=O)OC)=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+][C@H]1C(=O)N(C(C(=O)OC)=C(C)C)[C@@H]1CC=C
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
2,6-Lutidine (3.82 ml) and phosphorus oxychloride (1.37 ml) were added to a solution of methyl 2-[(3R,4R)-3-formamido-2-oxo-4-allylazetidin-1yl]-3-methylbut-2-enoate (970 mg) in dichloromethane (10 ml) at 0° C., and the mixture was stirred for three hours at 0° C. Then, the reaction mixture was poured into a mixture of ethyl acetate (100 ml) and brine (50 ml). The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The oily residue was chromategraphed on silica gel (15 g) eluting with a mixture of hexane and ethyl acetate (10:1-3:1) to give methyl 2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (766 mg) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:25]([NH2:29])[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.O.CN(C)C=O>[CH2:25]([NH:29][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=2)[CH2:13][CH2:12]1)=[O:16])[CH2:26][CH2:27][CH3:28]
Reactant: O=C(O)C1CCN(C(=O)c2ccc(F)cc2)CC1
Reactant: CCCCN
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCNC(=O)C1CCN(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-Fluorobenzoyl)piperidine-4-carboxylic acid (8.79 g, 35.0 mmol) is dissolved in methylene chloride (75 mL) at 0° C., and dimethylformamide (0.20 mL) and oxalyl chloride (4.9 g, 39 mmol) are added. The mixture is stirred at room temperature for 2 hr. In a second flask, butylamine (2.6 g, 35 mmol) and potassium carbonate (9.67 g, 75.4 mmol) are dissolved in water (100 mL) and methylene chloride (200 mL) at 0° C. The first mixture is added to the second dropwise over 45 min, and the mixture is stirred at 0° C. for 2 hr. The organic phase is separated, washed twice with saturated sodium bicarbonate, twice with 1N HCl, dried over magnesium sulfate, and evaporated. Recrystallization from ethyl acetate-hexane affords the title compound.
Reaction SMILES: [N+:1]([C:4]1([CH3:13])[CH2:10][N:9]([CH3:11])NCC(C)[CH2:5]1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1([CH3:13])[CH2:10][N:9]([CH3:11])[CH2:4][CH2:10][N:9]([CH3:11])[CH2:5]1
Reactant: [H][H]
Reactant: CC1CNN(C)CC(C)([N+](=O)[O-])C1
Agent: [Ni]
Solvent: CCO
Product: CN1CCN(C)CC(C)(N)C1
Yield: 144.4 %

Procedure:
6-Nitro-1,4,6-trimethyldiazacycloheptane (13.1 g, 70 mmol) was was dissolved in absolute ethanol (20 ml) and 2 spatulas of Raney nickel added. The mixture was hydrogenated at approx. 1.1 atmospheres hydrogen pressure until no more hydrogen was taken up. It was filtered over a small pad of Celite and the filtrate evaporated and distilled to give the free amine as a colourless oil (7.95 g, 72%) b.p.>70° C./0.1 mm. IR (film) 3348 (s), 2945 (s), 2813 (s), 1670 (m), 1538 (m), 1462 (s), 1376 (m), 1284 (m), 1093 (s) cm−1. 1H NMR (CDCl3) δ 1.00 s(3H), 2.32 s(6H), 2.28 and 2.44 and 2.63, 3 m (10H including N—H). 13C NMR (CDCl3) δ 26.37, 48.91, 52.54, 60.35, 71.17. MS (FAB+) 158.1 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]#[N:5].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(N(CC)CC)C>[CH3:16][S:17]([O:1][N:2]=[C:3]([C:6](=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]#[N:5])(=[O:19])=[O:18]
Reactant: N#CC(=NO)C(=O)C=Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(C#N)C(=O)C=Cc1ccccc1

Procedure:
2-Hydroxyimino-3-oxo-5-phenyl-pent-4-enenitrile (4.0 g; 0.02 mol) is treated with methanesulfonyl chloride and triethylamine as described in example 3.4. The crude brown product is recrystallized from 40 ml of ethanol. 2-Methylsulfonyloxyimino-3-oxo-5-phenyl-pent-4-enenitrile (2.2 g; %) is obtained as a light ochre solid (mp 163-165° C.).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][C:11]#[CH:12])=[O:7])([CH3:4])[CH3:3].[CH2:16]([N:23]=[N+:24]=[N-:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.CC(O)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:16]([N:23]1[CH:12]=[C:11]([CH2:10][C@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:13]([OH:15])=[O:14])[N:25]=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nn1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 430 mg Boc-L-propargylglycine, 269 mg benzyl azide, 36 mg copper(II)acetate and 80 mg sodium ascorbate in 15 ml water/t-BuOH (1:1) was stirred for 12 h at RT. The reaction mixture was diluted with ethyl acetate, washed with brine (2×) and the aqueous phase reextracted with ethyl acetate. The crude product obtained after evaporation of the solvent was pure enough for the subsequent transformation. Yield: 855 mg.