Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](O)=[O:10])[CH:4]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.O>[F:12][C:2]([F:1])([F:13])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[CH:4]=1
Reactant: O=C(O)c1cc(C(F)(F)F)ccn1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: OCc1cc(C(F)(F)F)ccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
To a solution of 4-trifluoromethyl-pyridine-2-carboxylic acid (500 mg, 2.62 mmol) in THF (20 mL) at 0° C. was added triethylamine (0.40 mL, 2.88 mmol) followed by ethyl chloroformate (0.28 mL, 2.88 mmol). A thick white precipitate formed. The reaction mixture was stirred at 0° C. for 15 min then a solution of sodium borohydride (297 mg, 7.85 mmol) in water (5 mL) was slowly added via pipet. Vigorous gas evolution was observed and all solids dissolved. The reaction was stirred at 0° C. for 10 min then warmed to room temperature and stirred for 1 h. The reaction was diluted with water and extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by chromatography with 20% to 50% EtOAc/hexanes to afford 296 mg (64%) of (4-trifluoromethyl-pyridin-2-yl)-methanol as a colorless oil that freezes just below room temperature. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.76 (d, J=4.9 Hz, 1H), 7.55 (s, 1H), 7.45 (d, J=4.9 Hz, 1H), 4.87 (s, 2H).
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]#[CH:3].[CH2:6]=[C:7]=[CH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>CCOCC>[OH:14][CH:9]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][C:7]#[C:6][CH:1]=[C:2]=[CH2:3]
Reactant: C=C=CC(=O)CCCC
Reactant: C#CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=C=CC#CCC(O)CCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 125 mmol. of propargyl-magnesium bromide in 85 ml. of ether at -20° C. is added a solution of 11.7 g. (95 mmol.) of 1,2-octadien-4-one in 30 ml. of ether during 30 minutes. After the addition, the solution is stirred at 25° C. overnight, cooled to 0° C., and treated dropwise with 18 ml. of saturated ammonium chloride solution. The mixture is filtered, and the filtrate is washed with brine, dried over magnesium sulfate, and concentrated. The product is distilled from anhydrous potassium carbonate to provide the title compound as a colorless liquid, b.p. 84°-87° C. (8 mm.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CI.CN(C=O)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[N:5]=[C:4]([N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[CH3:19])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1nc(N)nc(Nc2cccc(F)c2F)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(c1nc(N)nc(C#N)n1)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To 2-amino-4 cyano-6-(2,3-difluorophenylamino)-[1,3,5]triazine (Intermediate 54, 332 mg, 1.34 mmol) were added potassium carbonate (203 mg, 1.46 mmol), methyl iodide (83 μL, 1.34 mmol) and anhydrous DMF (3 mL). The mixture was stirred at room temperature for 1 h and then diluted with 1M aq. citric acid (10 mL). The resulting mixture was extracted with ethyl acetate (2×10 mL) and the combined extracts washed with water (4×10 mL), saturated brine (10 mL) and dried further over anhydrous sodium sulfate. Evaporation of the solvent gave a gum which was loaded onto a silica column and eluted with heptane-30% ethyl acetate to give the desired compound (320 mg, 91%). Method B HPLC-MS: MH+ requires m/z=262. Found: m/z=262, Rt=1.76 min (98%).
Reaction SMILES: NS(C1C=CC(C(NC[C@@H](C(O)=O)NC(=O)C2C=CC(C(NCC3C=CC=C(O)C=3)=O)=CC=2Cl)=O)=CC=1)(=O)=O.[Cl:40][C:41]1[CH:66]=[C:65]([C:67]([NH:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[C:73]([OH:77])[CH:72]=2)=[O:68])[CH:64]=[CH:63][C:42]=1[C:43]([NH:45][C@H:46]([C:60]([OH:62])=[O:61])[CH2:47][NH:48][C:49](=[O:59])[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([N:56](C)C)[CH:51]=1)=[O:44]>>[NH2:56][C:52]1[CH:51]=[C:50]([CH:55]=[CH:54][CH:53]=1)[C:49]([NH:48][CH2:47][C@@H:46]([C:60]([OH:62])=[O:61])[NH:45][C:43](=[O:44])[C:42]1[CH:63]=[CH:64][C:65]([C:67]([NH:69][CH2:70][C:71]2[CH:76]=[CH:75][CH:74]=[C:73]([OH:77])[CH:72]=2)=[O:68])=[CH:66][C:41]=1[Cl:40])=[O:59]
Reactant: CN(C)c1cccc(C(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)c1
Agent: NS(=O)(=O)c1ccc(C(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)cc1
Product: Nc1cccc(C(=O)NC[C@H](NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)O)c1

Procedure:
3-(4-aminosulfonylbenzoyl)amino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine; N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(3-dimethylaminobenzoyl)amino-L-alanine;
Reaction SMILES: O[CH2:2][C@H:3]1[N:8]([CH2:9][CH:10]([OH:21])[C:11]2[CH:20]=[CH:19][C:14]3[C:15](=[O:18])[O:16][CH2:17][C:13]=3[CH:12]=2)[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:4]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[O:18]=[C:15]1[C:14]2[CH:19]=[CH:20][C:11]([CH:10]3[O:21][CH2:2][C@@H:3]4[CH2:4][N:5]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:6][CH2:7][N:8]4[CH2:9]3)=[CH:12][C:13]=2[CH2:17][O:16]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc3c(c2)COC3=O)[C@H](CO)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCN2CC(c3ccc4c(c3)COC4=O)OC[C@@H]2C1
Temperature: 100 °C

Procedure:
tert-Butyl(3S)-3-(hydroxymethyl)-4-[2-hydroxy-2-(1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (3.3 g, 8.4 mmol) and cyanomethylene tri-n-butylphosphorane (3.65 g, 15.1 mmol) were dissolved in 30 mL of benzene, the solution was degassed, and then heated to 100° C. for 3 h. LC-MS showed the product peak (M+1=389). The reaction mixture was cooled and evaporated to dryness. The residue was purified by MPLC through a 330 g Redi-sep column and eluted with a 15% acetone/85% hexane mixture to yield a cis-trans mixture of the title compound.
Reaction SMILES: CC(C)(S([NH:6][C:7]1([C:11]2[S:15][C:14]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[CH:26]=[CH:27][N:28]=[C:22]4[CH:21]=3)=[O:17])=[CH:13][CH:12]=2)[CH2:10][O:9][CH2:8]1)=O)C.Cl.O1CCOCC1>CO>[NH2:6][C:7]1([C:11]2[S:15][C:14]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[CH:26]=[CH:27][N:28]=[C:22]4[CH:21]=3)=[O:17])=[CH:13][CH:12]=2)[CH2:10][O:9][CH2:8]1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(C(=O)NCc3ccn4ccnc4c3)s2)COC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1(c2ccc(C(=O)NCc3ccn4ccnc4c3)s2)COC1
Reaction time: 2 h

Procedure:
5-(3-(1,1-Dimethylethylsulfinamido)oxetan-3-yl)-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide (432 mg, 1 mmol) in 10 ml methanol was treated with 4N aqueous HCl in dioxane (0.75 ml, 3 mmol) and the mixture was stirred for 2 hours. Concentration provided the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(CC)=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
210.0 g (1.10 mol) of 4-bromo-2-fluorophenol are dissolved in 1.1 l of ethyl methyl ketone, and 175.0 g (1.27 mol) of potassium carbonate and 150.0 ml (1.26 mol) of benzyl bromide are added. The mixture is refluxed for 5 h and stirred at room temperature for 16 h. The batch is filtered, and the filtrate is concentrated to dryness. The crude product is crystallised from heptane at reduced temperature.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[CH3:20][N:21]([CH:23]=O)[CH3:22].C(OC(OCC)N(C)C)C.C(Cl)Cl.CO>CO>[Br:1][C:2]1[N:18]=[C:17]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)=[C:4]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])[N:3]=1
Reactant: CN(C)C=O
Reactant: Nc1nc(Br)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: CCOC(OCC)N(C)C
Solvent: ClCCl
Solvent: CO
Product: CN(C)C=Nc1nc(Br)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
The compound was produced analogously to example 8 except that the following amounts were used: 2-bromo-2′-deoxyadenosine (330 mg, 1.0 mmol), DMF (3 ml), dimethylformamide-diethylacetal (0.85 ml, 5 mmol). Colourless amorphous solid (306 mg, 80%). TLC (CH2Cl2/MeOH, 9:1): Rf 0.33. UV (MeOH): 318 (28600), 238 (13000). 1H-NMR ((D6(DMSO): 2.32, 2.67 (2m, H—C(2′)); 3.14, 3.23 (2s, CH3—N); 3.56 (m, H—C(5′)); 3.86 (m, H—C(4′)); 4.39 (m, H—C(3′)); 4.95 (t, J=5.5 Hz, HO—C(5′)); 5.33 (d, J=4.3 Hz, HO—C(3′)); 6.31 (“t”, J=6.3 Hz, H—C(1′)); 8.44 (s, H—C(8)); 8.85 (s, H—C(N═)). Anal. calc. for C13H17BrN6O3 (385.22): C, 40.53; H, 4.45; N, 21.82; found: C, 40.66; H, 4.50; N, 21.79.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[C:12]([CH3:14])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:15])[C:4]=1[NH:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=O.[NH3:29]>>[F:26][C:24]([F:25])([F:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[N:29]=[CH:1][C:3]2[C:4](=[C:5]([CH3:15])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:12]([CH3:14])[CH:13]=2)[N:16]=1
Reactant: N
Reactant: CCOC(=O)c1c(C)cc(C=O)c(NC(=O)c2ccccc2C(F)(F)F)c1C
Product: CCOC(=O)c1c(C)cc2cnc(-c3ccccc3C(F)(F)F)nc2c1C
Yield: 15 %

Procedure:
Instead of the compound of formula (II) used in Example 1, ethyl 4-formyl-2,6-dimethyl-3-(o-trifluoromethylbenzoylamino)benzoate was used and reacted with ammonia in the same way as in Example 1. The reaction product was chromatographed on a silica gel column. The solvent was evaporated, and the residue was recrystallized from ethanol to give 2-(o-trifluoromethylphenyl)-7-ethoxycarbonyl-6,8-dimethylquinazoline having a melting point of 68° to 69° C. in a yield of 15%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Br[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C[C@H](C)N1
Yield: 59.7 %

Procedure:
2,6-cis-Dimethylpiperazine (40.3 mmol, 4.6 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (40.3 mmol, 13.58 g) and potassium carbonate (81 mmol, 11.13 g) were combined and stirred overnight at room temperature in acetonitrile (25 mL). The reaction mixture was diluted with ethyl acetate and filtered through dicalite. The filtrate was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 90/10/1 dichloromethane/methanol/ammonia) to afford the title compound (8.91 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[CH:8]=[CH:9][C:10](=O)[CH2:11][CH3:12]>C(O)(=O)C>[CH2:11]([C:10]1[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=[CH:8][CH:9]=1)[CH3:12]
Reactant: CCC(=O)C=CCl
Reactant: Nc1nc[nH]n1
Solvent: CC(=O)O
Product: CCc1ccnc2ncnn12

Procedure:
A mixture of 3-amino-1,2,4-triazole (11.74 g) and 1-chloro-1-penten-3-one (16.5 g) in acetic acid (225 ml) was heated under reflux for 45 minutes. The reaction mixture was cooled, poured onto ice and extracted with dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure to give 7-ethyl-1,2,4-triazolo[1,5-a]pyrimidine. Yield 11.72 g.
Reaction SMILES: C(O[C:4](=[O:14])[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:6]O)C.[NH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1)[NH2:16]>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[C:4](=[O:14])[N:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][N:18]=3)[NH:16][CH:6]=2)[CH:9]=1
Reactant: NNc1ccc(C(F)(F)F)cn1
Reactant: CCOC(=O)C(=CO)c1cccnc1
Product: O=c1c(-c2cccnc2)c[nH]n1-c1ccc(C(F)(F)F)cn1

Procedure:
The compound is prepared analogously to Example 2 from 580 mg (3.00 mmol) of the compound from Example 2A and 558 mg (3.00 mmol) 2-hydrazino-5-(trifluoromethyl)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])[O-].[Na+].[Na+].CO.CCOCC>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[O:14][C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:5]=1
Reactant: COC(=O)CNC(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cnc(-c2cccnc2)o1

Procedure:
A solution of 19.0 g (0.100 mol) of 77 in 300 ml of dry chloroform was refluxed under vigorous stirring with 40 g of P2O5 for 24 h. The mixture was filtered after cooling. The filtrate was evaporated in vacuo leaving a red oil. The precipitate was dissolved in water at 0°-5° C. and the aqueous solution made basic with sodium carbonate. Extraction with 3×200 ml of dichloromethane, drying of the combined organic phases over magnesium sulphate, and removal of the solvent in vacuo gave a red oil which was combined with the above mentioned oil obtained from the chloroform phase. The oil was applied to a silica gel column (eluent; methanol/ether=1/19) giving a colorless oil, 78. Yield: 5.9 g (0.034 mol, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15]Br.FC(F)(F)C1C=CC(C2(C#N)CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: BrCCCCBr
Agent: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CC1(c2cccc(Cl)c2)CCCC1

Procedure:
1-(3-Chlorophenyl)cyclopentanecarbonitrile (494) was synthesized from 2-(3-chlorophenyl)acetonitrile (493) and 1,4-dibromobutane following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237).
Reaction SMILES: [C:1]([CH:12]1C(=O)O[C:15](C)([CH3:19])[O:14][C:13]1=[O:21])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)C>[O:11]=[C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][C:13]([O:14][CH2:15][CH3:19])=[O:21]
Reactant: CCCCCCCCCC(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CCCCCCCCCC(=O)CC(=O)OCC
Yield: 98 %

Procedure:
The resulting 5-decanoyl-2,2-dimethyl-1,3-dioxane-4,6-dione was allowed to reflux in ethanol for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=3/7) to obtain the ethyl 3-oxododecanoate shown by the formula below.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[S:15][C:14]([N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:13][N:12]=3)=[CH:10][C:4]=2[O:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=1)[CH2:17][NH:16][C:14]1[S:15][C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[O:3][C:4]=3[CH:10]=2)=[N:12][N:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc3[nH]c(=O)oc3c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CNc1nnc(-c2ccc3[nH]c(=O)oc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Yield: 52.7 %

Procedure:
tert-Butyl (S)-1-(5-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (130 mg, 205 μmol) in 10 mL DCM was treated with 10 mL TFA for 60 minutes. After removing the solvent, the remaining residue was dissolved in 100 mL EtOAc. The resulting solution was washed with a mixture of aqueous saturated sodium bicarbonate plus 5% 5N NaOH, then twice with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate. Removal of the solvent gave the title compound 6-(5-((S)-2-amino-3-(4(trifluoromethyl)phenyl)propylamino)-1,3,4-thiadiazol-2-yl)benzo[d]oxazol-2(3H)-one as an off-white amorphous solid (47 mgs, 53%). LCMS (API-ES) m/z (%): 436.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 2.78 (dd, J=13.60, 7.53 Hz, 1H) 2.99 (dd, J=13.60, 5.58 Hz, 1H) 3.35-3.40 (m, 1H) 3.40-3.47 (m, 1H) 3.48-3.55 (m, 1H) 7.13 (d, J=8.22 Hz, 1H) 7.48 (d, J=8.02 Hz, 2H) 7.53 (dd, J=8.12, 1.47 Hz, 1H) 7.62 (d, J=7.24 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:15][C:14]3[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][CH2:10][CH2:9][C:8]=3[C:7]=2[CH:20]=1.C1OCCOCCOCCOCCOCCOC1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:15][C:14]3[C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][CH:10]=[CH:9][C:8]=3[C:7]=2[CH:20]=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCSc1ccccc1-3
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2[nH]c3c(c2c1)C=CSc1ccccc1-3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
9-Methoxy-6,7-dihydro-12H-5-thia-12-aza-dibenzo[a,e]azulene (57 mg, 0.203 mmoL) in DMF (2 mL) was treated with KO2 (58 mg, 0.811 mmoL) and 18-Crown-6 (54 mg, 0.203) and the reaction mixture was stirred at room temperature for 6 hours. Water was added to quench the reaction. The mixture was then partitioned between EtOAc and saturated NH4Cl. The aqueous phase was extracted two times with EtOAc. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, 1:1 hexanes:EtOAc as eluent) to yield the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:39]1[CH:40]=[CH:41][C:42]2[O:46][C:45](=[O:47])[N:44]([CH3:48])[C:43]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2](=[O:37])[C@@H:3]([NH:20][C:21]([C:23]1([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1)=[O:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:39]2[CH:40]=[CH:41][C:42]3[O:46][C:45](=[O:47])[N:44]([CH3:48])[C:43]=3[CH:49]=2)=[CH:9][CH:10]=1
Reactant: Cn1c(=O)oc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1c(=O)oc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Temperature: 75 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
(S)-tert-Butyl 4-(1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 16, step (i), 224 mg) in acetonitrile (10 mL) under nitrogen was treated with 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (99 mg) followed by an aqueous solution of potassium carbonate (2M, 0.433 mL) and 1,1 bis(bi-tert-butylphosphino)ferrocene palladium dichloride (6 mg). The reaction mixture was stirred at 75° C. for 18 h and then evaporated to an oil, dissolved in dichloromethane and absorbed onto silica. Purification by chromatography on silica eluting with 50% ethyl acetate in isohexane and then 100% ethyl acetate afforded the sub-titled compound (150 mg).
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[C@H:29]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:28]([S:36]([O-:39])(=[O:38])=[O:37])[C:27]1=[O:40])=O)(C)(C)C.C(Cl)Cl>C(O)=O>[NH2:25][C@H:26]1[C@H:29]([CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)[N:28]([S:36]([OH:39])(=[O:37])=[O:38])[C:27]1=[O:40]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(S(=O)(=O)[O-])[C@H]1C1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=CO
Solvent: ClCCl
Product: N[C@@H]1C(=O)N(S(=O)(=O)O)[C@H]1C1CCCCC1

Procedure:
(trans)-3-(t-Butoxycarbonylamino)-4-cyclohexyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (3.8 g) is stirred in 20 ml of formic acid for 3 hours, followed by the addition of 20 ml of methylene chloride. The precipitated title compound (1.0 g) is filtered off, melting point 217°-219° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C.C(Cl)Cl>[CH2:22]([O:21][C:19]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17])=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)Oc1c(C)n(C)ccc1=O
Reaction time: 0.25 h

Procedure:
With stirring, 11.2 ml of triethylamine are added at room temperature to a suspension of 5.56 g of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone in 100 ml of acetonitrile and 100 ml of methylene chloride, followed by the addition of 7.64 ml of ethyl chloroformate. Within 15 minutes a complete solution forms and, after a further 45 minutes, the volatile constituents are removed by evaporation under reduced pressure. The residue is dried under a high vacuum and the unreacted starting material is crystallised from ethyl acetate. 3-Ethoxycarbonyloxy-1,2-dimethyl-4(1H)-pyridinone is obtained from the mother liquor in the form of a yellow foam with a melting point of 113°-115° C.; thin-layer chromatogram: Rf=0.05 (7:3 mixture of methylene chloride and acetone), 0.10 (9:1 mixture of methylene chloride and isopropanol, 0.20 (9:1 mixture of methylene chloride and methanol), and 0.35 (4:1 mixture of methylene chloride and methanol).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O-])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:38]([NH+:40](CC)[CH2:41]C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:14][C:13]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([C:35](=[O:36])[N:40]([CH3:41])[CH3:38])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:12]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)[O-])n1-c1ccc(OC)cc1
Reactant: CC[NH+](CC)CC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)N(C)C)n1-c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
To a solution of triethylammonium 3,4-bis(benzyloxy)-5-(ethoxycarbonyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (5) (10.84 g, 17.99 mmol) in DMF (150 mL), at 0° C. was added HATU (10.26 g, 27.0 mmol), dimethylamine hydrochloride (2.93 g, 36.0 mmol) and DIPEA (18.8 ml, 108 mmol). The reaction mixture was stirred at RT for 16 h and partitioned between EtOAc (500 mL) and 1M HCl (aq.) (250 mL). The organic phase was washed successively with 1M HCl (aq.) (250 mL), sat. NaHCO3 (aq.) (2×250 mL), and brine (2×250 mL), dried (MgSO4), filtered and concentrated in vacuo to afford ethyl 3,4-bis(benzyloxy)-5-(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (6) (7.62 g, 79%) as a light yellow oil, that solidified on standing: m/z 529 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 7.51-7.21 (m, 10H), 7.14-7.03 (m, 2H), 6.94-6.84 (m, 2H), 5.12 (s, 2H), 4.96 (s, 2H), 4.00 (q, J=7.1 Hz, 2H), 3.77 (s, 3H), 2.70 (s, 6H), 1.00 (t, J=7.1 Hz, 6H).