Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])=[CH:21][CH:20]=1>>[F:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:31]([C:26]3[N:27]=[C:28]([CH3:30])[S:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=3)=[O:32])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2oc(CC3CCCCN3)cc12
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3c(F)cccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (60 mg) was prepared from (RS)-2-(4-fluoro-benzofuran-2-ylmethyl)-piperidine, D76 (157 mg) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (160 mg) according to a procedure similar to that described for Example 4.
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[C:16]([NH:19][NH:20][C:21]([C@@H:23]1[CH2:29][CH2:28][C@@H:27]2[CH2:30][N:24]1[C:25](=[O:39])[N:26]2[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:22])(=O)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:32]([O:31][N:26]1[C:25](=[O:39])[N:24]2[CH2:30][C@H:27]1[CH2:28][CH2:29][C@H:23]2[C:21]1[O:22][C:16]([CH3:17])=[N:19][N:20]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
(CF3SO2)2O (0.50 mL) was slowly added to a solution of (2S,5R)—N′-acetyl-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.5 g) and pyridine (0.5 mL) in dry DCM (10 mL) at −10° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched carefully with sat. NaHCO3. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 10:1 to 1:1 petroleum ether/EtOAc) to afford (2S,5R)-6-(benzyloxy)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (0.3 g, 63%) as a slight yellow solid. ESI-MS (EI+, m/z): 315.0 [M+H]+.
Reaction SMILES: C([O:8][C:9]([C@@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:12][C@H:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14]([O:16][CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:15])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:19]([O:18][CH2:17][O:16][C:14]([C@@H:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:12][C@H:11]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:9]([OH:10])=[O:8])=[O:15])(=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21]
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)O

Procedure:
A solution of 2.5 g of pivaloyloxymethyl 4-(benzyloxycarbonyl)-2,4-(R*,R*)-dibenzylbutyrate in 75 ml of ethanol is hydrogenated at atmospheric pressure in the presence of 0.2 g of 5% palladium on carbon. The reaction is filtered and evaporated to give 4-(pivaloyloxymethoxycarbonyl)-2,4-(R*,R*)-dibenzylbutyric acid.
Reaction SMILES: CN(C)S([N:6]1[C:10]2[CH:11]=[N:12][N:13]([CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14](=[O:15])[C:9]=2[N:8]=[C:7]1Cl)(=O)=O.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:18]([O:17][CH2:16][N:13]1[C:14](=[O:15])[C:9]2[NH:8][C:7]([N:30]3[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]3)=[N:6][C:10]=2[CH:11]=[N:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)S(=O)(=O)n1c(Cl)nc2c(=O)n(COCc3ccccc3)ncc21
Product: CC(C)(C)OC(=O)N1CCN(c2nc3cnn(COCc4ccccc4)c(=O)c3[nH]2)CC1
Temperature: 150 °C
Yield: 75.8 %

Procedure:
A mixture consisting of 2.31 g of 5-benzyloxymethyl-2-chloro-4-oxo-4,5-dihydroimidazo[4,5-d]pyridazine-1-sulfonic acid dimethylamide and 4.49 g of t-butyl piperazine-1-carboxylate was heated at 150° C. under nitrogen atmosphere for 2.5 hours. The residue was purified by silica gel column chromatography. Thus, 1.94 g of the title compound was obtained from the fraction eluted with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:35]/[O:36][C:37]2([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:39][CH2:38]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29]OS(C)(=O)=O)[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-:64].[SH:65][CH:66]1[CH2:73][N:69]2[CH:70]=[N:71][CH:72]=[N+:68]2[CH2:67]1>CN(C=O)C>[Cl-:64].[CH:43]([O:42][C:40]([C:37]1([O:36]/[N:35]=[C:14](/[C:12]2[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[S:10][CH:11]=2)\[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][S:65][CH:66]3[CH2:73][N:69]4[CH:70]=[N:71][CH:72]=[N+:68]4[CH2:67]3)[CH:26]=[N:25]2)=[O:16])[CH2:39][CH2:38]1)=[O:41])([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: SC1Cn2cnc[n+]2C1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(COS(C)(=O)=O)n2)cs1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CSC3Cn4cnc[n+]4C3)n2)cs1
Yield: 33.1 %

Procedure:
Prepared in an anlogous manner to example 138, step 1 using benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-(((methylsulfonyl)oxy)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (54 mg, 0.068 mmol), sodium iodide (17.2 mg, 0.115 mmol), cesium carbonate (24.5 mg, 0.075 mmol), 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-4-ium chloride (13.4 mg, 0.075 mmol) and DMF (600 μL). The slurry was concentrated in vacuo, and the crude residue was purified via reverse phase prep HPLC (Xselect CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (19.7 mg, 34%) as white solid. LCMS: Rt=0.91 min, m/z=840.4 (M+) Method 2m_acidic.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][CH:6]=1)[CH3:2]>CCCCCC.[O-2].[O-2].[Mn+4]>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:17])[CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[CH:7][CH:6]=1)[CH3:20]
Reactant: CCOC(OCC)c1ccc(C(O)CC(C)(C)C)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCCCCC
Product: CCOC(OCC)c1ccc(C(=O)CC(C)(C)C)cc1
Yield: 92.4 %

Procedure:
Dissolve 1-[4-(diethoxymethyl)-phenyl]-3,3-dimethylbutan-1-ol (3.8 g, 13.57 mmol) in hexane (50 mL). Add manganese dioxide (3.5 g, 40.71 mmol) and stir the mixture at 60° C. overnight. Filter the solid and concentrate the filtrate in vacuo to give the desired intermediate as a colorless oil (3.49 g, 93%).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]#[CH:59])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[C:51]([C:58]#[CH:59])[CH:52]=[CH:53][CH:54]=4)[O:49][C:48]=3[C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C#Cc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: N
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1cccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc12
Yield: 100 %

Procedure:
Following the procedure of 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-ethynyl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was subjected to flash chromatography (SiO2, gradient 0 to 20% methanolic ammonia in DCM) to afford the title compound as a white solid (8 mg, 100%). 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=7.8, 1.6 Hz, 1H), 7.97 (dd, J=7.6, 1.8 Hz, 1H), 7.48 (t, J=7.4 Hz, 1H), 7.42-7.28 (m, 7H), 7.14 (d, J=8.4 Hz, 2H), 4.65 (s, 1H), 4.01 (bs, 2H), 2.42-2.33 (m, 2H), 2.17-2.07 (m, 2H), 2.03-1.91 (m, 1H), 1.71-1.58 (m, 1H). LCMS (Method E): RT=3.64 min, [M+H]+=392.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([S:22]([NH:21][C:18]2[CH:19]=[CH:20][C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:9]=3[CH:17]=2)(=[O:23])=[O:24])=[CH:30][CH:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CCOC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1

Procedure:
According to Step 5, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid ethyl ester (1.24 g, 2.5 mmol) from Example 1d) with 1M sodium hydroxide solution in ethanol/water (2:1, 49 mL), the desired compound is obtained at quantitative yield (1.18 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH:28]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(OCC)(=O)C.O>ClCCl>[CH2:40]([C:37]1[CH:36]=[CH:35][C:34]([CH:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=2)=[O:6])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:39][CH:38]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CCCCCC(Br)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(N)c2)c2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCC(Nc1cccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)c1)c1ccc(CC(C)C)cc1
Yield: 54.4 %

Procedure:
A mixture of ethyl 4-[3-(3-aminobenzoyl)indol-1-yl]-butyrate (176 mg), 1-(1-bromohexyl)-4-isobutylbenzene (233 mg) and diisopropytethylamine (194 mg) in dichloromethane (5 ml) was refluxed for 20 hours. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated and washed-with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane-and ethyl acetate (3:1) to give ethyl 4-[3-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl]-indol-1-yl]butyrate (155 mg) as an oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](O)=[O:36])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl.[CH2:52]([NH2:54])[CH3:53].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:52]([NH:54][C:35](=[O:36])[C@@H:34]1[CH2:38][CH2:39][CH2:40][N:33]1[C:31](=[O:32])[C@H:23]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:22][C:20](=[O:21])[CH2:19][NH:18][C:16](=[O:17])[C@@H:14]([CH3:15])[NH:13][C:11](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[NH2:1])[CH3:53]
Reactant: CCN
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reaction time: 24 h

Procedure:
0.7 g. (1 mmoles) of Z-Tyr-D-Ala-Gly-Phe-Pro-OH (3rd step of Example 5) are dissolved in 2 ml. of dimethyl formamide, then 0.1 g. (1.24 mmoles) of ethylamine hydrochloride, 0.17 ml. (1.24 mmoles) of triethylamine and 0.21 g. (1 mmole) of dicyclohexyl-carbodiimide are added. The reaction mixture is allowed to stand for one day, filtered and diluted with 30 ml. of ethyl acetate. The solution is washed with 0.5N sulphuric acid, water, 5% solution of sodium hydrogen carbonate and water, then dried and evaporated. The residue on evaporation (Rf2 0.80-0.85) is dissolved in 30 ml. of methanol and hydrogenated in the presence of palladium as catalyst. At the end of the reaction the catalyst is filtered off, the solution evaporated, rubbed with ether, filtered, washed with ether and dried. Yield: 0.43 g. (75%) of the named pentapeptide; Rf4 0.34-0.44.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([O:3][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(COC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 72.4 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and 4-methoxybenzyl chloride (16.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-(4-methoxybenzyl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (29.8 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[OH-].[Na+].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>CO.O>[CH3:11][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[C:8](=[O:9])[CH:10]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc(C)cc1C
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)C=Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
2,4-Dimethylacetophenone (44ak, 1.48 g, 10.0 mmol) and sodium hydroxide (0.54 g, 13.5 mmol) were combined in methanol (30 ml) and stirred for 30 min at room temperature. A solution of benzaldehyde (1b, 1.02 ml, 10.0 mmol) and methanol (30 ml) was added dropwise and the mixture stirred for 18 hr at room temperature. Water (25 ml) was added and the mixture neutralized with hydrochloric acid (1 N). The mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was distilled bulb to bulb to give 1.98 g (84%) of a yellow oil: [expected mp 68° C.]; 1H NMR δ 2.37 (s, 3H), 2.44 (s, 3H), 7.05 (m, 2H), 7.16 (d, 1H, J=16.1 Hz), 7.38 (m, 3H), 7.49 (d, 1H, J=15.9 Hz), 7.54 (m, 3H); 13C NMR: δ 20.4, 21.4, 126.0, 126.6, 128.2, 128.5, 128.8, 130.4, 132.2, 134.7, 136.1, 137.4, 140.8, 145.0, 195.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@@H:8]([CH3:12])[C:9]([NH2:11])=O)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]([C:9]#[N:11])[CH3:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](C#N)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
To a stirred solution of tert-butyl[(1S)-2-amino-1-methyl-2-oxoethyl]carbamate (Step 1, 0.7 g, 0.004 mol) in N,N-dimethylformamide (5 mL) was added 343 mg of cyanuric chloride (0.00186 mol) at once. The reaction mixture was stirred for 4 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with EtOAc in hexane (30-50%) to yield the desired product (400 mg, 63%). 1H-NMR (300 MHz, DMSO-d6): 7.74 (d, J=7.0 Hz, 1H), 4.48 (m, 1H), 1.40 (s, 9H), 1.35 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:17]([Mg]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:7]1([CH:6]([NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[O:2][CH3:1])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1ccccc1/N=C/c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1NC(Cc1ccccc1)c1ccccc1
Temperature: -80 °C
Yield: 96.1 %

Procedure:
To a solution of 4.22 g (20.0 mmol) of 9 in 50 mL of THF, 48.0 mL (26.0 mmol) of 0.55 M BnMgCl in THF was added with vigorous stirring at −80° C. This mixture was slowly warmed to room temperature, and then 2 mL of water was added. The resulting mixture was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether=40:1, vol.) to give 5.83 g (96%) of B3.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:6]=2[C:5]=1[C:15]([O:17]C)=O)=[C:2]=[S:3].[CH3:19][C:20]1[N:24]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:23]=[N:22][CH:21]=1>>[CH3:19][C:20]1[N:24]([CH2:25][CH2:26][CH2:27][N:28]2[C:15](=[O:17])[C:5]3[C:6]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:23]=[N:22][CH:21]=1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCCCC2
Reactant: Cc1cncn1CCCN
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc3c(c2c1=O)CCCCCC3

Procedure:
The compound was synthesized starting from methyl 4,5,6,7,8,9-hexahydro-2-isothiocyanatocycloocta[b]thiophene-3-carboxylate (0.10 g, 0.36 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.049 g, 0.36 mmol) as described above.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[N+:12]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:20]=[C:19]([C:2]2[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:18]=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCCc1ccc(N)c(Br)c1
Product: CCCc1ccc(N)c(-c2cccc([N+](=O)[O-])c2)c1

Procedure:
2-bromo-4-propylaniline and 3-nitrobenzene boronic acid can be combined to form 2-(3-nitrophenyl)-4-propylaniline,
Reaction SMILES: [Na].[CH3:2][C:3]1[N:7]2[C:8](=[S:12])[NH:9][N:10]=[CH:11][C:6]2=[CH:5][N:4]=1.[CH3:13]I>CO>[CH3:2][C:3]1[N:7]2[C:8]([S:12][CH3:13])=[N:9][N:10]=[CH:11][C:6]2=[CH:5][N:4]=1
Reactant: CI
Reactant: Cc1ncc2cn[nH]c(=S)n12
Agent: [Na]
Solvent: CO
Product: CSc1nncc2cnc(C)n12
Temperature: 25 °C

Procedure:
To a solution of 0.23 gm. of sodium in 10 ml. of methanol is added 1.66 gm. of 6-methyl-imidazo[1,5-d]-as-triazine-4(3H)-thione with warming to produce a solution. The mixture is cooled to room temperature and 0.75 ml. of methyl iodide is added. Cooling overnight gives a solid which is recrystallized from a mixture of 20 ml. of acetone and 6 ml. of ethanol and treated with charcoal. This solid is recrystallized from 20 ml. of ethanol, giving the desired product, m.p. 182.5°-184° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27](Cl)=[O:28])=[CH:21][CH:20]=1>CN(C)C1C=CN=CC=1.ClCCl>[N:1]1([C:27]([O:26][CH2:25][C:22]2[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C1CCCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl piperidine-2-carboxylate (15 g, 95 mmol), triethylamine (27 ml, 191 mmol) and 4-dimethylaminopyridine (0.58 g, 4.8 mmol) in dichloromethane (100 ml) at 0° C. is added a solution of benzyl chloridocarbonate (17 g, 100 mmol) dropwise. The reaction is allowed to warm slowly to room temperature. It is stirred at room temperature overnight (16 h), then allowed to stand for 2 days. The crude product is extracted with dichloromethane, washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine. The organic phase is dried with anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography over silica gel 60 (300 g) with cyclohexane/ethyl acetate as eluent to afford a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH:20]=1>CCOC(C)=O.CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]1
Reactant: CC(C)C(=O)Nc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C(=O)Nc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)c(F)cc1F
Yield: 84.6 %

Procedure:
A solution of tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (2.40 g, 6.31 mmol) and 10% Pd/C (500 mg) in EtOAc (40.0 mL) and MeOH (10.0 mL) was hydrogenated (200 psi) at room temperature overnight. The reaction mixture was filtered through celite and washed with ethanol (3×10 mL). The combined extracts were concentrated in vacuo to afford 2.04 g (5.34 mmol, 85%) of tert-butyl 4-[2,4-difluoro-5-(isobutyrylamino)phenyl]-1-piperidinecarboxylate: ESMS m/e: 383.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH2:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:12]1[N:11]([CH3:21])[N:10]=[CH:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:32][C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)[N:7]=1
Reactant: Cn1ncc(-c2ccnc(Cl)n2)c1-c1ccc(Cl)cc1Cl
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2nccc(-c3cnn(C)c3-c3ccc(Cl)cc3Cl)n2)cc1OC

Procedure:
The title compound is prepared as described in Example 1 but using 2-chloro[5-(2,4-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidine and 3,4-dimethoxy-phenylamine.