Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-:16].[Cs+].[Cs+].[F:21][C:22]([F:28])([F:27])[CH:23]([CH3:26])[CH2:24]O.C(O)=O>CC(N(C)C)=O>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:16][C:23]([CH3:26])([CH3:24])[C:22]([F:28])([F:27])[F:21])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Reactant: CC(CO)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=CO
Solvent: CC(=O)N(C)C
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F

Procedure:
To 2-Fluoro-5-methanesulfonyl-benzoic acid (247569-56-8) (600 mg) in dimethylacetamide (10 mL) was added cesium carbonate at 170° C. 2-trifluoromethyl-propanol (0.94 mL) was first added to the reaction mixture followed by additionally 0.47 mL every 24 hours. After a total of 72 hours, the reaction mixture was acidified by addition of formic acid, concentrated in vacuo and purified by preparative HPLC to yield the title compound as a light brown solid (897 mg). MS (m/e): 325.3. (M−H, 100%)
Reaction SMILES: C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[F:14][C:15]([F:31])([F:30])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH:26]=[C:25]([C:27]([NH2:29])=O)[N:24]=[CH:23]1.CCN(CC)CC>C(Cl)Cl>[F:30][C:15]([F:14])([F:31])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH:26]=[C:25]([C:27]#[N:29])[N:24]=[CH:23]1
Reactant: NC(=O)c1cn(-c2ccccc2C(F)(F)F)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cn(-c2ccccc2C(F)(F)F)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
TFAA (2.5 mL, 17.7 mmol) was added at 0° C. to a stirred mixture of 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carboxamide (3.97 g, 8.177 mmol), Et3N (5 mL, 35.87 mmol), and dry DCM (100mL), the resulting mixture was stirred at 0° C. for 2 h. The solvent was removed in vacuo, the residue was purified by flash chromatography (SiO2, 80% EtOAc/hexanes) to give 1-(3′-methylsulfonyl)biphenyl-4-yl)-2-(2-(trifluoromethyl)phenyl-1H-imidazole-4-carbonitrile as a pale-yellow to white solid (3.13 g, 82%). MS (ESI) 468 [M+H]+.
Reaction SMILES: O1[CH2:19][CH:2]1[CH:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2.S(O[CH2:25][CH2:26][NH2:27])(O)(=O)=O.[OH-:28].[Na+]>O.C(O)C>[NH:27]1[CH2:26][CH2:25][O:28][CH:2]([CH:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[CH2:8][CH2:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]2=3)[CH2:19]1
Reactant: [OH-]
Reactant: C(=C1c2ccccc2CCc2ccccc21)C1CO1
Reactant: NCCOS(=O)(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C(=C1c2ccccc2CCc2ccccc21)C1CNCCO1

Procedure:
A mixture of 5-(2,3-epoxypropylidene)-10,11-dihydro-5H--dibenzo[a,d]cycloheptene (0.65 g), 2-aminoethyl hydrogensulfate (2.5 g) and sodium hydroxide (1.6 g) in water (8 ml) was stirred in ethanol (11 ml) under reflux for 15 hours. The reaction mixture was concentrated and extracted with chloroform. The chloroform extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-(morpholin-2-yl)methylidene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 221°-224° C. (oxalate).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1.S(Cl)([Cl:24])=O>>[I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([Cl:24])=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1
Reactant: O=C(O)c1ccc(-c2c(I)cc(I)cc2I)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2c(I)cc(I)cc2I)cc1[N+](=O)[O-]

Procedure:
4-iodotoluene is reacted with picryl chloride in the presence of copper bronze at 215° C. to yield 2′,4′,6′-trinitro-4-methylbiphenyl (1). C 7 ⁢ H 7 ⁢ I + C 6 ⁢ H 2 ⁢ Cl ⁢ N 3 ⁢   ⁢ O 6 ⁢ → Δ Cu ⁢ C 13 ⁢ H 9 ⁢ I 3 ⁢ N 3 ⁢   ⁢ O 6 2′,4′,6′-trinitro-4-methylbiphenyl (1) is reacted with stannous chloride and hydrochloric acid to yield 2′,4′,6′-triamino-4-methylbiphenyl (2). C 13 ⁢ H 9 ⁢ N 3 ⁢   ⁢ O 6 ⁢ → H ⁢   ⁢ Cl Sn ⁢   ⁢ Cl 2 ⁢ C 13 ⁢ H 15 ⁢ N 3 2′,4′,6′-triamino-4-methylbiphenyl (2) is reacted with sodium nitrite and hydrochloric acid to convert the amino groups to diazonium groups. The diazonium groups react with potassium iodide to yield 2′,4′,6′-triiodo-4-methylbiphenyl (3). C 13 ⁢ H 15 ⁢ N 3 ⁢ → H ⁢   ⁢ Cl Na ⁢   ⁢ N ⁢   ⁢ O 2 ⁢ → K ⁢   ⁢ I ⁢   ⁢ C 13 ⁢ H 9 ⁢ I 3 Aromatic nitration of 2′,4′,6′-triiodo-4-methylbiphenyl (3) is performed with nitric acid and sulfuric acid to yield a mixture of 2′,4′,6′-triiodo-2-nitro-4-methylbiphenyl (4) and 2′,4′,6′-triiodo-3-nitro-4-methylbiphenyl (5). The products are separated using column chromatography. C 13 ⁢ H 9 ⁢ I 3 ⁢ → H 2 ⁢   ⁢ S ⁢   ⁢ O 4 H ⁢   ⁢ N ⁢   ⁢ O 3 ⁢ C 13 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 2 The methyl group of 2′,4′,6′-triiodo-3-nitro-4-methylbiphenyl (5) is oxidized by potassium permanganate to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6). C 13 ⁢ H 8 ⁢ I 3 ⁢ N ⁢   ⁢ O 2 ⁢ → K ⁢   ⁢ Mn ⁢   ⁢ O 4 ⁢ C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) is reacted with thionyl chloride to yield 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7). C 13 ⁢ H 6 ⁢ I 3 ⁢ N ⁢   ⁢ O 4 ⁢ → S ⁢   ⁢ O ⁢   ⁢ Cl 2 ⁢ C 13 ⁢ H 5 ⁢ Cl ⁢ I 3 ⁢ N ⁢   ⁢ O 3 The hydroxyl groups of D-Glucosamine (8) are protected by reaction with acetic anhydride in the presence of pyridine to yield 1,3,4,6-tetra-O-acetyl-D-glucosamine (9). C 6 ⁢ H 13 ⁢ N ⁢   ⁢ O 5 ⁢ → C 5 ⁢   ⁢ H 5 ⁢ N C 4 ⁢   ⁢ H 6 ⁢   ⁢ O 3 ⁢ C 14 ⁢ H 21 ⁢ N ⁢   ⁢ O 9 1,3,4,6-tetra-O-acetyl-D-glucosamine (9) is reacted with 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carbonyl chloride (7) to yield 2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10). C14H21NO9+C13H5ClI3NO3→C27H25I3N2O12 2-nitro-4-(2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (10) is treated with stannous chloride in the presence of hydrochloric acid to yield 2-amino-4-(2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (11). C 27 ⁢ H 25 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 12 ⁢ → Sn ⁢   ⁢ Cl 2 ,   ⁢ H ⁢   ⁢ Cl ⁢ C 19 ⁢ H 19 ⁢ I 3 ⁢ N 2 ⁢   ⁢ O 6
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:41])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36]([O:38]CC)=O)[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH2:42]([Mg]Br)[CH3:43].Cl.O1CC[CH2:49][CH2:48]1>>[CH2:48]([C:36]([OH:38])([CH2:42][CH3:43])[CH2:35][O:34][C@H:31]1[CH2:30][CH2:29][C@H:28]([N:18]2[C:17](=[O:41])[C:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:33][CH2:32]1)[CH3:49]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reactant: C1CCOC1
Reactant: CC[Mg]Br
Agent: Cl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)(CC)CC)CC2)c2ncnn12
Reaction time: 16 h

Procedure:
Ethyl [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (0.5 g) was dissolved in tetrahydrofuran (10 mL), and ethylmagnesium bromide (3.0 M diethyl ether solution, 0.75 mL) was added at 0° C. After stirring at the same temperature for 16 hr, 1 N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 49%).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][CH3:3].C(N(CC)CC)C.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>C(Cl)Cl>[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)([O:4][CH2:1][CH2:2][CH3:3])(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 12 h
Yield: 94.7 %

Procedure:
A 100 L glass, jacketed reactor was charged with 1-propanol (2.098 kg; 34.9 mol), triethylamine (4.585 kg; 45.3 mol; 1.3 equivalents) and DCM (20.1 L). The mixture was cooled to a temperature of about 5° C. to 15° C. and cautiously charged with a solution of p-toluenesulfonyl chloride (6 kg; 31.47 mol; 0.9 equivalents) in DCM (10.5 L) over 30 minutes. Once the addition was complete, the mixture was warmed to a temperature of about 18° C. to 22° C. and stirred for 12 hours. The reaction mixture was assayed by 1H NMR (in CDCl3) and deemed complete. HCl (6 N; 2.98 L) was cautiously charged while maintaining the temperature below 25° C. The aqueous phase was removed, and the organic phase was washed 2× with water (21 L. each wash), dried with MgSO4, and filtered over Celite®. The filtered solids were then washed with DCM (4 L) and concentrated to a residue. The residue was dissolved in heptane and concentrated again to afford a final propyl tosylate product (6.385 kg, 95% yield).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]([NH2:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].C(OC(=O)[NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1)(C)(C)C.C(N(CC)CC)C.C1C[O:42][CH2:41]C1>>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C@@H:9]([NH:15][C:41]([NH:30][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([NH2:22])=[CH:28][CH:27]=1)=[O:42])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN)cc1
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@H](N)CCCCNC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCNC(C)=O)NC(=O)NCc1ccc(N)cc1
Temperature: -10 °C

Procedure:
(R)-ethyl 6-acetamido-2-aminohexanoate 186 (1 equivalent, 120 mg, 0.55 mmol) was dissolved in anhydrous THF (4 mL) and trisphosgene (0.33 equivalent, 55 mg, 0.18 mmol) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, then refluxed for 2 h. tert-butyl-N-[4-(aminomethyl)phenyl]carbamate (1 equivalent, 123 mg, 0.55 mmol) and triethylamine (2 equivalent, 154 μl, 1.1 mmol) were added successively and the resulting solution was stirring at room temperature overnight. The reaction mixture was concentrated, washed by 30 ml of NaHCO3 and extracted by 3×30 ml EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (CH2Cl2/MeOH) to afford the urea protected (21 mg, 8%) Rf=0.18 (CH2Cl2/MeOH 95/5). 1H NMR (200 MHz, CDCl3) δ 7.30 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.5 Hz, 2H), 6.68 (s, 1H), 6.10-5.90 (m, 1H), 5.43 (d, J=7.7 Hz, 1H), 5.30 (t, J=5.7 Hz, 1H), 4.51-4.35 (m, 1H), 4.35-4.25 (m, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.26-3.08 (m, 2H), 1.91 (s, 3H), 1.85-1.15 (m, 6H), 1.50 (s, 9H), 1.25 (t, J=7.1 Hz, 3H). Finally, the urea was dissolved in 2 ml of DCM and 2 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture was concentrated and purified on reverse phase (H2O/MeCN) to afford the urea deprotected (7 mg, 44%) as a colorless oil Rf=0.42 (CH2Cl2/MeOH 90110). 1H NMR (200 MHz, CDCl3): δ 7.06 (d, J=8.4 Hz, 2H), 6.62 (d, J=8.4 Hz, 2H), 6.15-5.92 (m, 1H), 5.36 (d, J=8.1 Hz, 1H), 5.16 (t, J=5.8, 1H), 4.55-4.35 (m, 1H), 4.22 (d, J=5.6 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.28-3.10 (m, 2H), 1.92 (s, 3H), 1.90-1.27 (m, 6H), 1.25 (t, J=7.1 Hz, 3H). HPLC method A tr=6.75 nm (91.30%). ESI-MS m/z: 365.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[N:7]([C:8]2[CH:17]=[N:16][C:15]3[C:10](=[C:11]([C:18]4[NH:26][C:25]5[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=5[CH:19]=4)[CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:35])[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:17]=[N:16][C:15]2[C:10]([N:9]=1)=[C:11]([C:18]1[NH:26][C:25]3[CH2:24][CH2:23][NH:22][C:21](=[O:27])[C:20]=3[CH:19]=1)[CH:12]=[CH:13][CH:14]=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCCN1c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Yield: 19 %

Procedure:
A solution of tert-butyl 3,3-dimethyl-4-(8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)piperazine-1-carboxylate (27 mg, 0.057 mmol) and TFA (4.36 μl, 0.057 mmol) in DCM (567 μl) was stirred at RT for 20 min. Purification by silica gel (100% DCM to 8% [2 M NH3 in MeOH]/DCM) provided 2-(3-(2,2-dimethylpiperazin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (19% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H) 2.32-2.35 (m, 1H) 2.66-2.71 (m, 2H) 2.86 (t, J=6.94 Hz, 2H) 2.95-2.99 (m, 1H) 3.44 (td, J=6.75, 2.35 Hz, 2H) 3.60 (t, J=4.9 Hz, 2H) 6.96 (s, 1H) 7.09 (d, J=2.15 Hz, 1H) 7.52 (t, J=7.63 Hz, 1H) 7.73 (d, J=7.04 Hz, 1H) 7.92 (d, J=7.43 Hz, 1H) 8.81 (s, 1H) 11.71 (s, 1H). MS (ESI, pos. ion) m/z: 377.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1.CC1C=CC(S([CH2:35][N+:36]#[C-])(=O)=O)=CC=1.CC([O-])(C)C.[K+].CC(O)(C)C>COCCOC.O>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:35]#[N:36])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CC(C)(C)O
Product: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
To a solution of bis(3-(trifluoromethoxy)phenyl)methanone (9.94 g, 28.4 mmol), prepared as described in Procedure 13, in DME (200 mL) was added TosMIC (7.49 g, 38.3 mmol). The reaction mixture was cooled in an ice-bath and a 1.0 M solution of t-BuOK in t-BuOH (77 mL, 77 mmol) in DME (77 mL) was added via cannula as a slow stream. Upon completion of addition, the ice-bath was removed and the reaction mixture was stirred at rt for 16 h. After this time, additional TosMIC (3.75 g, 19.2 mmol) was added at rt and the reaction mixture was stirred for an additional hour. At the conclusion of this period, the reaction was poured into H2O (150 mL) and extracted with hexane (3×200 mL). The organic portions were combined and dried over Na2SO4, filtered and concentrated under reduced pressure to yield a residue. The residue was purified on a silica gel ISCO cartridge with elution at 0 to 15% EtOAc/hexane to give 2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile (6.7 g, 67% yield) as a clear yellow oil. LCMS: RT=3.90 min [M−H] 360.2 (2 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H(CDCl3) ppm 5.18 (s, 1 H), 7.18 (s, 2 H), 7.24 (d, J=9.67 Hz, 2 H), 7.30 (d, J=7.91 Hz, 2 H), 7.46 (t, J=7.91 Hz, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)[CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Reactant: Fc1cccc(CBr)c1
Product: N#Cc1ccc(N(Cc2cccc(F)c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl)amino]pyrimidine and 3-fluorobenzyl bromide
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1.[CH3:20][N:21]([C@@H:29]([CH3:45])[C:30](=[O:44])[NH:31][C@H:32]1[CH2:38][O:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[NH:34][C:33]1=[O:43])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[Cl:46][C:47]1[N:48]([C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[C:60]#[N:61])[C:49]2[C:54]([C:55]=1[CH2:56]O)=[CH:53][CH:52]=[CH:51][CH:50]=2.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.CO>[Cl:46][C:47]1[N:48]([C:58]2[CH:65]=[CH:64][CH:63]=[CH:62][C:59]=2[C:60]#[N:61])[C:49]2[C:54]([C:55]=1[CH2:56][N:34]1[C:33](=[O:43])[C@@H:32]([NH:31][C:30](=[O:44])[C@@H:29]([N:21]([CH3:20])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH3:45])[CH2:38][O:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]1=3)=[CH:53][CH:52]=[CH:51][CH:50]=2
Reactant: N#Cc1ccccc1-n1c(Cl)c(CO)c2ccccc21
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@@H](C(=O)N[C@H]1COc2ccccc2N(Cc2c(Cl)n(-c3ccccc3C#N)c3ccccc23)C1=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 50 %

Procedure:
Diethyl azodicarboxylate solution 40 wt. % in toluene (DEAD 40% w/w, 360 mg, 377 μl, 828 μmol, Eq: 2) was added to a solution of tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)propan-2-yl)carbamate (226 mg, 621 μmol, Eq: 1.5), 2-(2-chloro-3-(hydroxymethyl)-1H-indol-1-yl)benzonitrile (117 mg, 414 1=01, Eq: 1.00) and Ph3P (217 mg, 828 μmol, Eq: 2) in THF (5 mL) and the mixture was stirred at RT for 2.5 d. The mixture was diluted with MeOH (10 mL), concentrated and the residue purified by preparative TLC to give tert-butyl (S)-1-((S)-5-((2-chloro-1-(2-cyanophenyl)-1H-indol-3-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (130 mg, 50%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]=1.C([N:19]([CH2:22][CH3:23])[CH2:20]C)C.Cl.N1CCC1>CC#N>[N:19]1([C:2]2[O:6][N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=3)[N:3]=2)[CH2:20][CH2:23][CH2:22]1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(-c2noc(Cl)n2)cc1[N+](=O)[O-]
Agent: C1CNC1
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(-c2noc(N3CCC3)n2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (107) (3.6 g, 15.02 mmol, 1.00 equiv) in CH3CN (40 mL) was added triethylamine (3.03 g, 29.94 mmol) and azetidine hydrochloride (1.68 g, 17.96 mmol). The resulting solution was stirred for 1 hour at room temperature, concentrated under vacuum and purified by prep-HPLC to afford 5-(azetidin-1-yl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (108) as a white solid. MS m/z 261.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4]2[CH2:5][C:6]3[C:10]([C@H:3]12)=[C:9]([CH3:11])[S:8][C:7]=3[C:12](=[O:14])[CH3:13].[CH:16](=O)[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>C(O)C.Cl.C(O)(C)C.C(OCC)C>[O:14]=[C:12]([C:7]1[S:8][C:9]([CH3:11])=[C:10]2[C:6]=1[CH2:5][C@H:4]1[C:2]([CH3:15])([CH3:1])[C@H:3]12)[CH:13]=[CH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1
Reactant: CC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reactant: O=Cc1ccc(C=O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CCO
Product: Cc1sc(C(=O)C=Cc2ccc(C=O)cc2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reaction time: 24 h
Yield: 36.7 %

Procedure:
A solution of (1aS,5aR)-1-(1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-ethanone (600 mg, 2.72 mmol) and terephthalaldehyde (913 mg, 6.81 mmol) in ethanol (10 mL) and approx. 6 N HCl in isopropanol (6 mL) is stirred at rt for 16 h. Further 6 N HCl in isopropanol (5 mL) is added and stirring of the dark solution is continued at rt for 24 h. The reaction mixture is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 solution followed by water. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propenyl]-benzaldehyde (336 mg) as a yellow powder; LC-MS: tR=1.14 min, [M+1]+=337.29; 1H NMR (CDCl3): δ 10.04 (s, 1H), 7.94-7.89 (m, 2H), 7.80-7.71 (m, 3H), 7.30 (d, J=15.8 Hz, 1H), 3.14 (dd, J=5.9, 18.8 Hz, 1H), 2.95 (d, J=18.8 Hz, 1H), 2.44 (s, 3H), 2.00-1.91 (m, 2H), 1.15 (s, 3H), 0.75 (s, 3H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.B(Cl)(Cl)Cl>CO.C(Cl)Cl>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]3[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:13]=3[C:12]=2[C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: ClB(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Yield: 89.6 %

Procedure:
A 250 mL, 3 neck, round bottomed flask fitted with a mechanical agitator and connected to a sodium hydroxide scrubber is purged with nitrogen and charged with 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene (5.3 g, 19.6 mmol), p-anisoyl chloride (3.68 g, 21.56 mmol), and 100 mL of methylene chloride. To this slurry at 20° C. is added boron trichloride (3.4 mL, 39.8 mmol) which had been condensed in a graduated cylinder. The reaction mixture is quenched after 40 minutes by the slow addition of 50 mL of methanol over approximately 5 minutes followed by addition of 50 mL of water over 5 minutes. The organic phase is washed with 50 mL brine, dried over sodium sulfate, filtered, and concentrated affording a dark orange oil. Addition of 10 mL of methanol followed by sonication for 5 minutes resulted in crystallization of 7.1 g of crude product as a yellow solid. The crude material is recrystallized from 3:1 hexanes/toluene affording 5.9 g of product as pale yellow crystals. (75%).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:10])=[N:6][O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].Br[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1>>[CH3:10][C:5]1[C:4]([C:1]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)([OH:3])[CH3:2])=[C:8]([CH3:9])[O:7][N:6]=1
Reactant: CC(=O)c1c(C)noc1C
Reactant: Brc1ccsc1
Product: Cc1noc(C)c1C(C)(O)c1ccsc1

Procedure:
The title compound was prepared following the general method of Example 4 but starting with 4-acetyl-3,5-dimethylisoxazole and 3-bromothiophene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O-:17])=[O:16])=[C:13]([CH2:18]Br)[NH:12][C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:10]1.[CH:25]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:26]2.[C:40](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C:14]([C:15]([O:17][CH3:40])=[O:16])=[C:13]([CH2:18][N:32]2[CH:29]3[CH2:30][CH2:31][CH:25]2[CH2:26][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]3)[NH:12][C:11]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[N:10]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2
Reactant: O=C([O-])C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(CN2C3CCC2CN(C(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.8 %

Procedure:
To a solution of methyl (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate (compound C, 80 mg, 0.13 mmol) in dimethylformamide (3.0 mL) was added compound tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (28 mg, 0.13 mmol) and potassium carbonate (40 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-water, extracted with EA (20 mL) three times. The combined organic phase was concentrated to give a crude tert-butyl 8-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (80 mg).