Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:13]([NH:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=3)[N:12]=2)[CH2:6][CH2:5]1.O1CCCC1.[N:39]([Sn](CCCC)(CCCC)CCCC)=[N+:40]=[N-:41]>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[NH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[C:13]([NH:25][C:26]3[CH:33]=[CH:32][C:29]([C:30]4[NH:41][N:40]=[N:39][N:31]=4)=[CH:28][CH:27]=3)[N:12]=2)[CH2:8][CH2:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(-c4nnn[nH]4)cc3)c3ncn(C4CCCC4)c3n2)CC1
Temperature: 120 °C

Procedure:
296 mg of the product obtained in Example 83 in 3 ml of toluene and 0.26 ml of azido tributyltin are mixed together at ambient temperature then the reaction medium is heated at a temperature of approximately 120° C. for 22 hours then left to return to ambient temperature. 7 ml of tetrahydrofuran is added to the suspension obtained, gaseous hydrochloric acid is bubbled through for 1 minute then nitrogen is bubbled through for 10 minutes, the product obtained is separated, followed by rinsing with ether and drying under reduced pressure at 50° C. In this way 374 mg of expected product is obtained.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44]1([S:50](Cl)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:44]1([S:50]([NH:8][C@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NS(=O)(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and phenylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19](=[O:23])[CH:20](O)[CH3:21])[CH3:17].N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:23])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C)OS(=O)(=O)C(F)(F)F
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a stirred solution of trifluoromethanesulfonic anhydride (30 mL, 170 mmol) in anhydrous dichloromethane (50 mL) was added drop-wise a solution of 2-hydroxypropanoic acid ethyl ester (20 g, 170 mmol) and pyridine (14 mL) in dichloromethane (50 mL) at 0° C. (Ice bath) over a period of 1 h under nitrogen. The ice bath was then removed and the reaction mixture was stirred for additional 2 h. The inorganic salt was then filtered off and the organic solution was washed with water, dried over sodium sulfate, and evaporated to give desired product as pink colored oil (37.4 g, 88%) which was used as such for the next step. 1HNMR (300 MHz, CDCl3): δ 1.38 (t, J=4.8 Hz, 3H), 1.77 (d, J=4.8 Hz, 3H), 4.32-4.37 (m, 2H) and 5.28 (q, J=6.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)C>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CC(=O)O
Product: C[C@@H]1N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 g (0.3 mol) of (S)-5-(o-chlorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 700 ml of dry acetone. The solution is treated with 79 ml of ground potassium carbonate and with 31.4 ml of methyl iodide and the mixture is stirred at room temperature for 4 hours. The mixture is treated with 30 ml of glacial acetic acid and evaporated. The residue is treated with an ice/water mixture and extracted several times with methylene chloride. The organic phase is washed with water, dried over sodium sulphate, concentrated and treated with methanol. After filtering off the separated crystals, there is obtained (S)-5-(o-chlorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 159°; [α]25D =+381.2° (1 percent solution in methylene chloride).
Reaction SMILES: [Cl:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1.[CH3:41][N:42]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)[CH3:43].F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl>C(#N)C.CS(C)=O>[Cl:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:42]([CH3:43])[CH3:41])=[O:15])=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(C)C(=O)c1ccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-benzoic acid (0.023 g, 0.041 mmol) in acetonitrile (3 ml) was treated with BOP reagent (0.02 g, 0.04 mmol) followed by triethylamine (0.013 mL, 0.09 mmol). To the mixture was added (CH3)2NH2.HCl (4 mg, 0.045 mmol), and the reaction was stirred at ambient temperature overnight. The reaction mixture was then concentrated in-vacuo to afford an oil. The crude product was then dissolved in DMSO and purified via reverse-phase HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:H2O, UV detection at 254 nm) to afford the title compound, 186 mg (77%); MS (ESI) m/e 596 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25]C)[CH:21]=3)[C:16]=2[O:27][C:28]2[CH:42]=[CH:41][C:31]([O:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:30][CH:29]=2)[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])(=[O:4])=[O:3].[ClH:43].B(Br)(Br)Br.CO>C(OCC)(=O)C.C(OCC)C>[ClH:43].[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[C:16]([O:27][C:28]3[CH:42]=[CH:41][C:31]([O:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:30][CH:29]=3)=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([OH:25])[CH:19]=[CH:18]3)[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])(=[O:3])=[O:4]
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(C)(=O)=O)c(S(C)(=O)=O)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1S(C)(=O)=O
Temperature: 0 °C
Yield: 45 %

Procedure:
Dissolve the product of Example 35 in ethyl acetate (10 mL) and diethyl ether (5 mL). Add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (5.0 mL) and blanket with nitrogen. Cool the solution to 0° C. with an external ice bath. Add BBr3 (0.1 mL, 1.1 mmol) and stir for 1 hour. Quench with water (1.0 mL) and dilute with dichloromethane (10 mL). Separate the layers, wash the organic layer with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). Dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a column eluting the 6-(3,4-bis-methanesulfonyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol with a step gradient of methanol/dichloromethane (O to 5%). Dissolve the free base in diethyl ether (5.0 mL), ethyl acetate (6.0 mL) and methanol (1.0 mL) and add 2M HCl in diethyl ether (0.1 mL, 0.2 mmol). Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2 mm of Hg) at 65° C. for 48 hours to give 61 mg of the title compound (45%): mass spectrum (ion spray): m/z: 594.9 (M+H—HCl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:18][O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[F:24][C:23]([F:26])([F:25])[S:20]([O-:22])(=[O:21])=[O:19].[CH3:1][O:2][C:3]([C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N+:12]2[CH3:18])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cccnc2c1[N+](=O)[O-]
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2ccc[n+](C)c2c1[N+](=O)[O-]
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of the 7-(methoxycarbonyl)-8-nitroquinoline (3.00 g, 12.9 mmol) in toluene (52 mL) at rt under N2 was added MeOTf (7.31 mL, 64.6 mmol). The solution was warmed to 75° C. and stirred for 16 h. The resulting mixture was concentrated and the residue was triturated with ethyl acetate to afford 7-(methoxycarbonyl)-1-methyl-8-nitroquinolinium trifluoromethanesulfonate as a white solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:21][O:22][CH3:23])[CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:21][O:22][CH3:23])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCn1cc(Br)sc1=Nc1cccc(CN2CCNCC2)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COCn1cc(Br)sc1=Nc1cccc(CN2CCN(C(=O)c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
77 mg (0.217 mmol) of 1-(6-(5-bromo-3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridin-2-ylmethyl)-piperazine was dissolved in 10 ml of chloroform, 0.363 ml (2.60 mmol) of triethylamine was added thereto, 0.126 ml (1.09 mmol) of benzoyl chloride was gradually dropped thereinto and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography to give 81 mg (0.161 mmol) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:24][CH2:23]2)[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46](O)=[O:47])=O)(C)(C)C>>[NH2:32][C:33]1[S:37][C:36]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=2[F:45])=[N:35][C:34]=1[C:46]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH:22]2[CH2:23][CH2:24]2)[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:47]
Reactant: Nc1cnn(C2CC2)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cc(F)ccc2F)nc1C(=O)O
Product: Nc1sc(-c2cc(F)ccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CC[C@H](N)[C@@H](F)CC1

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-cyclopropyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonyl-amino)-2-(2,5-difluorophenyl)thiazole-4-carboxylic acid gave 276 as the monoformate salt as an off-white solid (170 mg, 40% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.54 (s, 1H), 8.06 (ddd, J=9.4, 5.8, 3.2 Hz, 1H), 7.39 (s, 1H), 7.28 (td, J=9.9, 4.4 Hz, 1H), 7.19-7.11 (m, 1H), 4.86 (dtd, J=49.0, 9.3, 3.6 Hz, 1H), 3.62-3.49 (m, 2H), 3.50-3.38 (m, 4H), 2.45-2.31 (m, 1H), 2.26-2.06 (m, 2H), 1.99-1.86 (m, 1H), 1.21-1.12 (m, 2H), 1.15-1.05 (m, 2H). LCMS (ES+) m/z 492 (M+1)
Reaction SMILES: C(N(CC)CC)C.[H][H].[C@@H:10]1([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:13]([CH2:14][OH:15])[CH2:12][CH2:11]1.C[OH:28]>[C].[Pd]>[C@@H:10]1([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:13]([CH2:14][OH:15])[CH2:12][C@H:11]1[OH:28]
Reactant: Nc1ncnc2c1ncn2[C@H]1CC[C@@H](CO)O1
Reactant: CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)C[C@H]1O
Temperature: 25 °C

Procedure:
Br-AcO-AR, 307 mg (0.741 mmoles), and 0.18 ml of triethylamine were dissolved in 30 ml of methanol and 620 mg of 2% palladium carbon was added to the solution. While stirring the mixture at room temperature, hydrogen gas was passed in a flow rate of 40 ml/min. After the palladium carbon was filtered, the filtrate was washed with ethanol and the solvent was distilled off under reduced pressure. The residue was dissolved in 8 ml of methanol and 0.4 ml of 28% sodium methoxide (methanolic solution) was added to the solution. The mixture was stirred at room temperature for 30 minutes. The reaction solution was quantitatively determined by HPLC, where 77.8 mg (0.33 mmoles) of 2',3'-dideoxyadenosine and 32.4 mg (0.30 mmoles) of 3'-deoxyadenosine were produced in yields of 45% and 17%, respectively. 300 MHz nuclear magnetic resonance spectra of the purified and isolated 2',3'-dideoxyadenosine and 3'-deoxyadenosine supported the structures of the products.
Reaction SMILES: [Na+].[CH2:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O-:17])(=O)=[O:15])=[CH:10][CH:9]=1)[CH:3]=[C:4]=[CH:5][CH3:6].P(Cl)(Cl)([Cl:20])=O.O>C(#N)C.S1(CCCC1)(=O)=O>[CH2:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([Cl:20])(=[O:17])=[O:15])=[CH:10][CH:9]=1)[CH:3]=[C:4]=[CH:5][CH3:6]
Reactant: CC=C=CCOc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Solvent: O
Product: CC=C=CCOc1ccc(S(=O)(=O)Cl)cc1
Temperature: 62.5 °C
Reaction time: 0.25 h
Yield: 64.7 %

Procedure:
To a suspension of product from Example 9 (740 mg, 2.48 mmol) in acetonitrile (2 ml) and sulfolane (2 ml) was added phosphoryl chloride (0.9 ml, 9.93 mmol) and the resulting mixture was heated at 60-65° C. for 2 hours. The mixture was cooled in ice and cold water was added, dropwise, while stirring was continued for an additional 15 minutes. The reaction mixture was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. The crude residue was purified by flash chomatography to give 415 mg (65%) of the product.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:25]3[CH2:26][CH2:27][N:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Solvent: O
Solvent: C1CCOC1
Product: O=C(N1CCN(c2ccccc2)CC1)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of 2.9 g (0.01 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 15 ml of tetrahydrofuran was treated while stirring with 1.6 g (0.01 mole) of 1-phenylpiperazine added all at once, a solid formed instantaneously and after stirring for 2 hr, the reaction mixture was diluted with 200 ml of water, the solid did not dissolve. The solid was removed by filtration and when triturated with chloroform, all but about 1 g of solid dissolved. The chloroform solution was dried over magnesium sulfate then concentrated in vacuo. The oily residue crystallized when triturated with ligroin. Recrystallization from benzene/ligroin yielded 2.0 g (48.1%) of fine white crystals, m.p. 160°-161° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3]([CH:9]=O)=[CH:2]2.[ClH:11].[NH2:12][OH:13]>CO.C(O)(C)C>[ClH:11].[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3]([CH:9]=[N:12][OH:13])=[CH:2]2
Reactant: NO
Reactant: O=CC1=CN2CCC1CC2
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: ON=CC1=CN2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
1-Azabicyclo[2.2.2]oct-2-ene-3-carboxaldehyde (1 g, 7.29 mmol) was dissolved in 50 ml of methanol. Hydroxylamine hydrochloride was added to the solution and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo to afford a white crystalline residue. The crystalline residue was suspended in 50 ml of isopropanol and refluxed for 15 minutes A crystalline material separated to afford the desired oxime (1.08 g, 75%), mp 227°-229° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[C:16]([CH2:20][C:21](Cl)=[O:22])([CH3:19])([CH3:18])[CH3:17].[F:24][C:25]([F:37])([F:36])[CH:26]([CH3:35])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:20][C:21]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:34]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH:26]([CH3:35])[C:25]([F:24])([F:36])[F:37])=[CH:29][CH:30]=3)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)=[O:22]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CC(Oc1ccc(N2CCC3(CCN(C(=O)CC(C)(C)C)CC3)C2=O)cc1)C(F)(F)F

Procedure:
White crystalline solid. MS (ESI): 441.3 (MH+). This example was prepared in analogy to example 7 step A) to B) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), tert-butyl acetyl chloride and 4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine.
Reaction SMILES: [C:1]([C:3]1[C:20](F)=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][C:6]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])#[N:2].O.[NH2:23][NH2:24].C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:20](=[CH:19][CH:18]=[CH:17][C:4]=2[O:5][C:6]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])[NH:24][N:23]=1
Reactant: NN
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(F)c1C#N
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(F)cc1Oc1cccc2[nH]nc(N)c12

Procedure:
A mixture of EXAMPLE 428A (14.8 g), hydrazine monohydrate (2.74 mL) and N-ethyl-N-isopropylpropan-2-amine (18 mL) in dioxane (150 mL) was heated at 90° C. overnight. The solvent was removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting from 80%-100% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [Si]([N:8]1[CH:11]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:10]([NH:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:37])(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:13]([O:12][CH:11]1[NH:8][C:9](=[O:37])[CH:10]1[NH:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N1[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)COC1NC(=O)C1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of (3RS,4RS)-1-(tert-butyldimethylsilyl)-4-(isobutoxy)-3-(triphenylmethylamino)azetidin-2-one (160 mg, 0.3 mmol) in tetrahydrofuran (4 mL) was cooled in an ice bath and treated with acetic acid (25 mg, 0.4 mmol) followed by dropwise addition of 1M tetrabutylammonium fluoride (0.6 mL, 0.6 mmol). The mixture was stirred for 20 min and passed through silica gel (10 g) eluted with ethyl acetate. The eluate was concentrated and the residue was chromatographed on silica gel eluted with 20% ethyl acetate:hexane to give the title compound. MS(ES) m/e 423 [M+Na]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[CH:25])[CH3:21]>CCCCCCC.CCOC(C)=O>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[C:25][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH3:21]
Reactant: C#CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C#N)cc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCN(CC)CC#Cc1ccc(C#N)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-cyano-phenyl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 6:4; yield (95.4 mg, 90%); 1H NMR δ (CDCl3): 7.58 (d, J=8.65 Hz, 2H), 7.49 (d, J=8.63 Hz, 2H), 3.64 (s, 2H), 2.61 (q, J=7.16 Hz, 4H), 1.11 (t, J=7.15 Hz, 6H); LCMS m/z: 212.
Reaction SMILES: CC1N=C([C:7]2C=CC=[CH:12][C:8]=2[C:9](O)=O)ON=1.CC1C=CC([C:21]([OH:23])=[O:22])=C(N2N=CC=N2)N=1.Cl.[F:32][C:33]([F:50])([F:49])[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([O:40][CH2:41][CH:42]2[CH2:47][CH:46]3[NH:48][CH:43]2[CH2:44][CH2:45]3)[N:35]=1>>[F:50][C:33]([F:49])([F:32])[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([O:40][CH2:41][CH:42]2[CH2:47][CH:46]3[N:48]([C:21]([O:23][C:8]([CH3:7])([CH3:9])[CH3:12])=[O:22])[CH:43]2[CH2:44][CH2:45]3)[N:35]=1
Reactant: FC(F)(F)c1ccnc(OCC2CC3CCC2N3)n1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: Cc1ccc(C(=O)O)c(-n2nccn2)n1
Agent: Cl
Product: CC(C)(C)OC(=O)N1C2CCC1C(COc1nccc(C(F)(F)F)n1)C2

Procedure:
Prepared analogous to example 127 substituting 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid with 6-methyl-2-(2H-1,2,3-triazol-2-yl)nicotinic acid with the title compound of step B. MS (ESI) mass calcd. for C21H20F3N7O2, 459.2; m/z found 460.2 [M+H]+. 1H NMR (MeOD): 8.89-8.82 (m, 1H), 8.02-7.82 (m, 3H), 7.48-7.14 (m, 2H), 4.75-4.71 (m, 1H), 4.44-4.07 (m, 2H), 3.91-3.84 (m, 1H), 2.64-2.56 (m, 3H), 2.48-2.30 (m, 1H), 2.02-1.43 (m, 6H).