Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][N:44]=1)[C:40]#[N:41]>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[C:39]([CH:42]=[CH:43][N:44]=3)[C:40]#[N:41])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N#Cc1ccnc(Br)c1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cc(C#N)ccn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromoisonicotinonitrile following a procedure analogous to that described in Example 583. LC-MS Method 2 tR=1.419 min, m/z=478.1; 1H NMR (CD3OD) 0.93 (s, 3H), 1.26 (s, 3H), 1.57 (d, 3H), 2.17 (s, 2H), 2.25 (m, 1H), 2.41-2.58 (m, 2H), 3.06 (m, 1H), 5.58 (m, 1H), 7.08 (d, 2H), 7.25-7.40 (m, 5H), 7.59 (d, 1H), 7.80 (d, 2H), 8.10 (s, 1H), 8.29 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1OS(C(F)(F)F)(=O)=O.[CH3:23][C:24]1[C:25](B(O)O)=[CH:26][S:27][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1[C:25]1[C:24]([CH3:23])=[CH:28][S:27][CH:26]=1
Reactant: CCOC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Reactant: Cc1cscc1B(O)O
Product: CCOC(=O)Cc1ccc(-c2cscc2C)c(OC)c1
Yield: 72 %

Procedure:
Prepared in a similar manner to example 1 from ethyl 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetate (example 27d) and 4-methylthiophen-3-ylboronic acid. Yield: 72%. 1H NMR (400 MHz, dMSO): δ 1.19-1.22 (m, 3H), 2.00 (s, 3H), 3.62 (s, 2H), 3.69-3.73 (m, 3H), 4.08-4.13 (m, 2H), 6.86-6.88 (d, 1H), 6.98-6.99 (d, 1H), 7.08-7.10 (d, 1H), 7.16-7.17 (t, 1H), 7.26-7.27 (d,1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:33]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:34])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)N3CCOCC3)ccc2C)cc1

Procedure:
A stirred solution of 5′-amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (520 mg) in dry THF (25 ml) containing triethylamine (0.57 ml) was treated with 4-morpholine-carbonyl chloride (0.26 ml). After 18 h. the mixture was partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol 1:1 gave the title compound as a yellow oil (416 mg).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:40]=[CH:39][C:35]3[O:36][CH2:37][O:38][C:34]=3[CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)Cl>[O:36]1[C:35]2[CH:39]=[CH:40][C:32]([C:30]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([NH:18][C:13](=[O:14])[C:12]4[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=4)[CH:31]=3)=[CH:33][C:34]=2[O:38][CH2:37]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc3c(c2)OCO3)cc1NC(=O)c1ccc(F)cc1
Reaction time: 5 h

Procedure:
0.054 mL of triethylamine and 0.034 mL of 4-fluorobenzoyl chloride were added to 3.5 mL of methylene chloride solution containing 60 mg of tert-butyl 2-amino-4-(benzo[1,3]dioxol-5-yl)benzoate at room temperature sequentially and stirred at the same temperature for 5 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(4-fluorobenzamido)benzoate.
Reaction SMILES: NCC1C[CH2:7][N:6]([C:9]2[C:14]([F:15])=[CH:13][N:12]=[C:11]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[N:10]=2)[CH2:5][CH2:4]1.[C:32]([N:39]1CCNCC1)(OC(C)(C)C)=O>>[F:15][C:14]1[C:9]([N:6]2[CH2:5][CH2:4][NH:39][CH2:32][CH2:7]2)=[N:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][N:26]([C:29](=[O:31])[CH3:30])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)=[N:12][CH:13]=1
Reactant: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCC(CN)CC4)n3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(=O)N1CCN(c2ccc(Nc3ncc(F)c(N4CCNCC4)n3)cc2)CC1

Procedure:
The titled compound was synthesized analogously as compound 1-(4-(4-(4-(4-(aminomethyl)piperidin-1-yl)-5-fluoropyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone, by using 1-Boc-piperazine. MS 400.3 (M+H); UV 203.8, 268.8 nm.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:5])=[C:2]=[O:3].[NH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[C:20]([NH:27]C(=O)C)[N:21]=[CH:22]2.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[NH2:27][C:20]1[N:21]=[CH:22][C:23]2[C:18]([CH:19]=1)=[C:17]([NH:16][C:2]([NH:1][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1)[CH3:5])=[O:3])[CH:26]=[CH:25][CH:24]=2
Reactant: CC(N=C=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)Nc1cc2c(N)cccc2cn1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)Nc1cccc2cnc(N)cc12)c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-(1-Isocyanatoethyl)-4-(trifluoromethyl)benzene (1.64 mmol) in toluene (8 mL) was treated with N-(5-amino-3-isoquinolinyl)acetamide (220 mg, 1.09 mmol) and DIEA (1.4 mL). The mixture was heated at 80° C. for 6 hours, cooled to room temperature, and the precipitate was collected by filtration. The solid was triturated with 97:3 CH2Cl2:CH3OH and stirred as a suspension in 48% aqueous HBr (8 mL) at 60° C. for 4 hours. After cooling to room temperature, the mixture was poured into concentrated NH4OH (20 mL) and filtered. The solid was washed with water and air-dried to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H), 8.64 (s, 1H), 7.91 (d, 1H), 7.58-7.74 (m, 4H), 7.22-7.36 (m, 3H), 7.14-7.18 (m, 2H), 6.97 (s, 1H), 4.94 (m, 1H), 1.44 (d, 3H, J=6.8 Hz); MS (ESI+) m/z 375 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C@@H:10]([NH:25]C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>ClCCl>[OH:40][C:34]([C:36]([F:39])([F:38])[F:37])=[O:35].[CH2:1]([O:8][C:9]([C@@H:10]1[CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)=[N:25]1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2=N[C@H](C(=O)OCc3ccccc3)CC2)cc1OC
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of (2S)2-tert-butoxycarbonylamino-5-(3,4-dimethoxy-phenyl)-5-oxo-pentanoic acid benzyl ester (10.46 g, 0.023 mol) in dichloromethane (150 ml) was cooled to 0° C. in an ice bath. TFA (40 ml) was slowly added to the stirring mixture and the reaction was allowed to warm to room temperature over two hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and the pH was adjusted to 7 with 1N NaOH. The organic extract was washed with brine (100 ml). The ethyl acetate extract was dried over anhydrous Na2SO4 and concentrated in vacuo to afford (2S)5-(3,4-dimethoxy-phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylic acid benzyl ester TFA salt (7.24 g, 0.021 mol, 91% yield). MS (LC-MS): Calculated for C20H21NO4 339.15. Found 340.16 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:26])[CH:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)OCC)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with ethyl bromoacetate according to the method of Example 1. The product was purified by chromatography on a 60-100 mesh Florisil and graded ethanol-chloroform mixtures.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].[CH2:7]([Si:11]([CH2:14][CH2:15][CH2:16][CH3:17])(Cl)[Cl:12])[CH2:8][CH2:9][CH3:10]>C1COCC1>[CH2:7]([Si:11]([CH2:14][CH2:15][CH2:16][CH3:17])([Cl:12])[CH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCC[Si](Cl)(Cl)CCCC
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Si](Cl)(CCCC)C1C=CC=C1
Temperature: -78 °C
Reaction time: 24 h

Procedure:
THF in a volume of 100 ml was added to 100 ml (200 mmol) of a 2M THF solution of sodium cyclopentadienide. The mixture was cooled to −78° C., and 100 ml of THF was added thereto. Further, 21.3 g (100 mmol) of dibutyldichlorosilane was gradually added dropwise. The mixture was stirred at room temperature for 24 hours and was concentrated under reduced pressure, and unreacted materials were distilled away. The residue was used in the next step without further purification.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][C:3]#[C:4][CH2:5][C:6]#[C:7][CH2:8][CH3:9].N1C2C(=CC=CC=2)C=CC=1>CO.[Pd]>[CH2:1]([OH:10])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH3:9]
Reactant: CCC#CCC#CCCO
Agent: [Pd]
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CC/C=C\C/C=C\CCO

Procedure:
(3Z,6Z)-nona-3,6-dienyl p-toluenesulfonate can be prepared from 2-Pentyn-1-ol by dissolving 2-Pentyn-1-ol (1.03 g, 12 mmol) in chloroform (10 ml) and adding pyridine (1.90 g, 24 mmol) followed by p-toluenesulfonyl chloride (3.43 g, 18 mmol) in small portions with constant stirring. After about 4 hrs, ether (30 ml) and water (7 ml) can be added and the organic layer can be washed successively with HCl (7 ml), 5% NaHCO3, water (7 ml) to produce pent-2-ynyl p-toluenesolfonate. Pent-2-ynyl p-toluenesolfonate (1.37 g, 5.78 mmol, 1.1 eq) can be added at low temperature under nitrogen to a well-stirred suspension in DMF (15 ml) of but-3-yn-1-ol (368 mg, 5.25 mmol), sodium carbonate (834 mg, 7.87 mmol), tetrabutylammonium chloride (1.46 g, 5.25 mmol) and copper(I) iodide (1.00 g, 5.25 mmol). The mixture can then be stirred at room temperature for about 48 hrs, and ether (30 ml) and 1M HCl (30 ml) can be added, the organic phase can be collected and washed with brine, and dried over sodium sulfate to produce nona-3,6-diyn-1-ol. Nona-3,6-diyn-1-ol (198 mg, 1.45 mmol) can be hydrogenated at atmospheric pressure, in the presence of a mixture of quinoline (44 mg) and palladium (5%) on calcium carbonate (100 mg), poisoned with lead in methanol (25 ml). After several hours, the methanol can be evaporated in vacuo, quinoline can be removed by silica gel column chromatography using ether-hexane (35:65) as the eluent to produce (3Z,6Z)-nona-3,6-dien-1-ol. (3Z,6Z)-Nona-3,6-dien-1-ol (167 mg, 1.19 mmol) can be dissolved in chloroform (5 ml) and the solution can be cooled in an ice bath. Pyridine (376 mg, 4.76 mmol) can be added, followed by p-toluenesulfonyl chloride (340 mg, 1.78 mmol) in small portions with constant stirring. The mixture can be stirred for about 24 hrs at low temperature, and ether (15 ml) and water (5 ml) can be added, the organic layer can be collected and washed successively with 1 N HCl (10 ml), 5% NaHCO3, water (10 ml), and brine (10 ml), and then dried over Na2SO4 to produce (3Z,6Z)-nona-3,6-dienyl p-toluenesulfonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:15]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:16][CH2:17][C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:17][C:18]#[N:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCCC(Br)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(CCC#N)c2ccccc2)CC1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A solution of 1-(tert-butyloxycarbonyl)piperazine (1.73 g, 9.3 mmol), 4-bromo-4-phenylbutyronitrile (2.5 g, 11 mmol) and K2CO3 (1.4 g, 10.2 mmol) in DMF (40 mL) was heated at 60° C. for 4 h. After this time the mixture was cooled to room temperature, filtered and the filtrate evaporated. The residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (2:1). The piperazine (2.69 g, 88%) was isolated as a pale yellow oil, which solidified on standing in the fridge. 1H NMR (250 MHz, CDCl3) δ1.41 (9H, s), 1.94-2.46 (8H, m), 3.32-3.60 (5H, m), 7.15-7.42 (5H, m). MS (ES+) (330, M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:36])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:36])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M69) (0.41 g, 0.80 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (172 mg, 54%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[CH:25][N:24]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:28]3[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1ncccc1C=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ncccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 12.2 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 2-Methoxy-pyridine-3-carbaldehyde (25.7 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 8.5 mg (12%) of the title compound. (300 MHz, DMSO-d6) 12.61 (s, 1H), 8.46 (d, J=7.5 Hz, 1H), 8.31 (s, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 7.21 (m, 3H), 6.38 (d, J=19 Hz, 2H), 5.17 (t, J=17 Hz, J=9 Hz, 1H), 4.05 (s, 3H), 2.89 (s, 1H), 2.80 (s, 1H), 2.61 (d, J=9 Hz, 1H), 2.24 (d, J=9 Hz, 1H), 1.39 (d, J=9 Hz, 1H). MS=411 (M+H), HPLC: 2.33 min. (G Method)
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[OH-:13].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:7]([S:8]([OH:13])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: [OH-]
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncc(Br)cc1S(=O)(=O)O
Temperature: 75 °C

Procedure:
2-Amino-5-bromopyridine-3-sulfonyl chloride (100 mg, 0.37 mmol) was taken into 1:1 aqueous dioxane (3 mL) and the mixture was basified to pH 14 by drop wise addition of 50% aqueous sodium hydroxide solution. The mixture was warmed to 75° C. for 0.5 h then cooled to room temperature and concentrated. The residue was taken into water (2 mL) and carefully acidified to pH 1-2 by concentrated aqueous hydrochloric acid addition and cooled to 0° C. After 1 h at 0° C. the crystalline solid obtained was collected by filtration and dried to give 2-amino-5-bromopyridine-3-sulfonic acid as a solid. 1H NMR (DMSO-d6): 8.24 (d, 1H), 8.06 (d, 1H). MS (EI) for C5H5N2SO3Br: 253, 255 (MH+, Br pattern).
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23].[CH3:24][N:25]([CH3:33])[CH:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1>>[Br:16][C:17]1[C:18]([F:23])=[C:19]([C:29]2([OH:32])[CH2:30][CH2:31][CH:26]([N:25]([CH3:33])[CH3:24])[CH2:27][CH2:28]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: Fc1ccccc1Br
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Product: CN(C)C1CCC(O)(c2cccc(Br)c2F)CC1

Procedure:
Add n-BuLi (20.2 mL, 1.6M in hexanes, 32.3 mmol) into a solution of 2,2,6,6-tetramethyl-piperidine (4.56 g, 32.6 mmol) in hexanes (30 mL) at −78° C. Add 1-bromo-2-fluoro-benzene (4.71 g, 26.9 mmol) and stir for 1 hr. Slowly add 4-dimethylamino-cyclohexanone (3.80 mL) in hexanes (30 mL) and stir for 1 hr. Remove the cooling bath and stir for two more hours. Partition the reaction mixture between saturated aqueous NaCl and ethyl acetate, dry the organic phase with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by chromatography on a silica gel column (DCM: 2M NH3 in MeOH, gradient) to give the title compound (2.04 g): MS (ES): m/z=318 (M+H)+ and 316 (M−H)−. 1HNMR (CDCl3): δ 7.43 (m, 2H), 6.98 (m, 1H), 2.45 (m, 2H), 2.21 (s, 6H), 2.13 (m, 1H), 1.92 (m, 2H), 1.64 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[Mg].C(O[C:14]1(OCC)[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19])C.[Cl-].[NH4+]>C(OCC)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][CH:14]1[CH2:18][CH2:17][CH2:16][N:15]1[CH3:19]
Reactant: CCOC1(OCC)CCCN1C
Reactant: Cc1cccc(CCl)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1cccc(CC2CCCN2C)c1

Procedure:
Prepare a Grignard solution from 103 g of 3-methylbenzyl chloride and 8 g of magnesium in 400 ml of diethyl ether. With stirring and boiling under reflux, add a solution of 126.9 g of 2,2-diethoxy-1-methylpyrrolidine dropwise to the Grignard solution. Keep the thus-prepared mixture at the boil for a further 1 hour before adding 130 ml of saturated ammonium chloride solution dropwise thereto. Then filter off the magnesium salts and dry the filtrate over sodium sulfate. Free the residue (31 g) from ether and then hydrogenate it with Raney nickel/hydrogen. Distil the hydrogenated product twice under a vacuum to obtain 16.2 g (13% of theory) of the title compound (b.p. 56° to 0.001 mm of Hg).
Reaction SMILES: [CH2:1]([S:4][CH:5]1[N:8]([CH2:9][C:10]([OH:12])=[O:11])[C:7](=[O:13])[CH:6]1[CH2:14][CH3:15])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CC(N(C)C)=O>[CH2:1]([S:4][CH:5]1[N:8]([CH2:9][C:10]([O:12][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=2)=[O:11])[C:7](=[O:13])[CH:6]1[CH2:14][CH3:15])[CH:2]=[CH2:3]
Reactant: C=CCSC1C(CC)C(=O)N1CC(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCSC1C(CC)C(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.33 h

Procedure:
A mixture of 2.5 g of 2-(4-allylthio-3-ethylazetidin-2-on-1-yl)acetic acid, 8 ml of dimethylacetamide and 636 mg of anhydrous sodium carbonate was stirred under argon for 20 minutes, and then 2.59 g of 4-nitrobenzyl bromide were added. After 30 minutes further stirring, the mixture was partitioned between ethyl acetate and water. The organic layer was separated and was washed with saturated sodium bicarbonate, with water, with brine, was dried over MgSO4, and was evaporated in vacuo to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures, afforded the title compound as a pale yellow oil. (3.0 g)
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:6]=[C:5]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1)#[N:2].[OH-].[Na+]>Cl.CC(O)=O>[C:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[N:6]=[C:5]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reaction time: 8 h
Yield: 99.5 %

Procedure:
5-Cyano-3-(3-pyridyl)-1-(4′-nitrophenyl)pyrazole (4.3 g, 15 mmol) was added to stirred slurry of SnCl2H2O (20 g, 90 mmol) in HCl/HOAc (35 mL/35 mL). A thick suspension formed and was stirred overnight. The reaction mixture was carefully basified with 50% NaOH to pH 13. The resulting solids were filtered, washed with water and dried to give the title compound (3.9 g, 99%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])[CH:8]=[N:9][CH:10]=1.[BH4-].[Na+]>CO>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:7]1[C:6]([CH2:5][CH2:4][CH2:3][OH:2])=[CH:10][N:9]=[CH:8]1
Reactant: COC(=O)CCc1cncn1Cc1ccccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCCc1cncn1Cc1ccccc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[3-(2-bromobenzyl)-3H-imidazol-4-yl]propionic acid methyl ester (1.89 g, 5.85 mmol) in MeOH at 0° C. is added NaBH4 and the resulting mixture is stirred at 0° C. for 1 h and warmed up to ambient temperature. The mixture is stirred at ambient temperature for 3 h and is quenched with saturated aqueous NH4Cl, and is adjusted pH to 7 with saturated aqueous Na2CO3. Then the reaction mixture is concentrated and extracted by CH2Cl2. The organic layer is washed with half saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated to yield a white solid. MS (ESI) m/z 295 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11][N:10]=1>C1C=CC=CC=1>[Cl:1][CH2:2][C:3]([NH:5][C:6]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11]1)=[O:7])=[O:4]
Reactant: O=C=NC(=O)CCl
Reactant: CCOc1nc(O)ns1
Solvent: c1ccccc1
Product: CCOc1nc(=O)n(C(=O)NC(=O)CCl)s1
Temperature: 20 °C
Reaction time: 17 h
Yield: 58 %

Procedure:
31.5 g of α-chloroacetyl isocyanate were added dropwise to a solution of 18.98 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 200 ml of benzene and after stirring the mixture for 17 hours at 20° C, it was vacuum filtered. The recovered crystals were dried to obtain 20 g of 2-(N-α-chloroacetylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 132° C.