Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][Mg]Cl)=[CH:5][CH:4]=1.[CH3:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][C:21]([C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]([NH:13][CH3:12])=[O:23])=[O:22])=[CH:5][CH:4]=1
Reactant: CN1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1ccccc1C(=O)Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
At 0° C., (4-methoxybenzyl)magnesium chloride (0.25 M in THF)(37 ml, 9.3 mmol) was added to 2-methylisoindoline-1,3-dione (1.00 g, 6.2 mmol) in THF (3.0 mL)(Reference: Synthetic Comm. 2004, 34(7), 1301-1308). The mixture was stirred at 0° C. for 5 minutes, then quenched with 10 mL of water. The reaction was warmed to RT and concentrated to yield 2-(2-(4-methoxyphenyl)acetyl)-N-methylbenzamide as a white solid (crude). The material was carried on to next step without further purification. MS m/z=284 [M+1]+. Calc'd for C17H17NO3: 283.33.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH3:22][O:23][C:24](=[O:32])[C@H:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[NH2:26].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:31][O:30][C:28](=[O:29])[CH2:27][CH:25]([NH:26][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[C:24]([O:23][CH3:22])=[O:32]
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1(Cl)[CH2:11][C:10]1([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C=CC(O)=CC=1)[OH:21].CCCCCC>C1C=CC=CC=1.O>[Cl:8][C:9]1[CH2:11][CH:2]([C:1]([OH:6])=[O:7])[CH:3]([C:4]([OH:21])=[O:5])[CH2:18][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Oc1ccc(O)cc1
Reactant: CC1(c2ccccc2)CC1(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCCC
Product: O=C(O)C1CC(Cl)=C(c2ccccc2)CC1C(=O)O
Temperature: 197 °C
Reaction time: 6 h

Procedure:
Into a test tube fitted with a cold finger condenser and a nitrogen bypass was put maleic anhydride (1.93 g., 19.7 mmole) and 1,1-dichloro-2-methyl-2-phenylcyclopropane (4.06 g., 20.2 mmole) along with 17.6 mg. hydroquinone. The tube containing the mixture was partially immersed in an oil bath whose temperature was slowly increased. Initial gas evolution was noted at 160°C. (bath). Steady gas evolution occurred at 178°C. with a final heating to 197°C. to insure complete reaction. Total heating time was 6 hours. The product was dissolved in benzene (5 ml.) and the solution was poured into 50 ml. n-hexane. The resultant oil soon crystallized giving 4.65 g (90 percent, m.p. 82°-90°C.) crude product which behaved as a mixture of anhydride and acid. Solution in water gave pure 1-chloro-2-phenylcyclohexene-4,5-dicarboxylic acid (m.p. 187°-189°C.).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]=1[NH2:8].C(Cl)(Cl)Cl.[CH3:20][CH2:21]OCC>C(O)(=O)C>[CH3:13][C:10]([CH3:11])([CH3:12])[CH2:9][N:6]1[C:7]2[N:8]=[C:20]([CH3:21])[NH:1][C:2]=2[C:3](=[O:15])[NH:4][C:5]1=[O:14]
Reactant: CCOCC
Reactant: CC(C)(C)Cn1c(N)c(N)c(=O)[nH]c1=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2CC(C)(C)C

Procedure:
10.4 g of 5,6-diamino-1-(2,2-dimethylpropyl)-2,4-(1H,3H)-pyrimidine dione (XXVIII) was refluxed in 75 ml of acetic acid for 1 hour. 50 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 11.4 g. The amide was refluxed in 50 ml of 1N NaOH for 1 hour and then neutralized with 5N HCl. Yield 7.2 g (XXXIV). NMR (see Table I).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=[C:3]1[C:18]([O:20]CC)=O.[CH3:23][NH2:24]>>[CH3:23][NH:24][C:18]([C:3]1[C:2](=[O:1])[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:5][CH:4]=1)=[O:20]
Reactant: CN
Reactant: CCCOc1ccccc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Product: CCCOc1ccccc1-c1ncc(C(=O)NC)c(=O)[nH]1

Procedure:
Ethyl 1,6-dihydro-6-oxo-2-(2-propoxyphenyl)pyrimidine-5-carboxylate (1 g, U.S. Pat. No. 4,031,093) was treated with methylamine (33% in industrial methylated spirit, 50 ml) in a pressure vessel (379 kPa) at 120° C. for six hours and then allowed to cool. Solvent was removed under reduced pressure to afford a white solid which was triturated with ether, 0.88 g, m.p. 190°-191° C. This solid together with another sample prepared similarly (0.32 g) was recrystallised from ethanol to afford the title compound, 0.98 g, m.p. 192°-193° C.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][NH:11][C@@H:10]1[C@@H:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=1[CH3:26])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:36](Cl)(Cl)=[O:37]>C(Cl)Cl.C1(C)C=CC=CC=1>[O:8]([C@@H:9]1[C@@H:10]2[N:11]([C:36](=[O:37])[N:16]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([Cl:25])[C:18]=3[CH3:26])[C@H:14]2[CH3:15])[CH2:12][CH2:13]1)[Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(N[C@@H](C)[C@H]2NCC[C@@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude 61I (˜1.81 mmol) in CH2Cl2 (10 mL) was added i-Pr2NEt (2 mL) followed by 20% phosgene in toluene (2.5 mL) dropwise. The reaction was stirred at rt overnight. Reaction was extracted with EtOAc (50 mL) which was washed twice with 1N HCl and then saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Purification by flash chromatography (silica gel, 0 to 10% EtOAc in hexane) provided the title compound (369 mg): MS (ES) m/z 420.23 [M+H]+
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[BH4-].[Na+]>C1COCC1.C(O)C.O>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:11][CH:10]=1
Reactant: NCC(=O)O
Reactant: O=Cc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To water (40 ml) was added glycine (246 mmol, 18.5 g) and aqueous sodium hydroxide (10M; 100 mmol, 10 ml). 4-Bromobenzaldehyde (130 mmol, 24 g) was added to afford a suspension. Ethanol (40 ml) and THF (90 ml) were added, followed by sodium borohydride (174 mmol, 6.6 g) and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and washed with ether (×3) and the aqueous layer acidified to pH ˜6.5 at which point precipitation occurred. The solid was filtered and washed with water and diethyl ether before co-evaporation with toluene to give 2-(4-bromobenzylamino)acetic acid (7H2) 11.3 g; 1H NMR (400 MHz, DMSOd6) δ 7.56 (d, 2H) 7.38 (d, 2H) 3.85 (s, 2H) 3.10 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20].C(Cl)Cl>CN1CCCC1=O.CO>[NH2:20][CH2:19][CH2:18][NH:21][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Reactant: NCCN
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCn1cc(C(=O)O)c(=O)c2ccc(NCCN)cc21
Temperature: 130 °C
Yield: 44.6 %

Procedure:
To a solution of 7-chloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1,7 g) in 1-methyl-2-pyrrolidinone (20 mL) was added ethylenediamine (2.1 g). The mixture was heated at 130° C. for 10 h. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH, filtered to give the title compound (830 mg).
Reaction SMILES: [CH:1]1([N:7]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:8](=[O:27])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[NH:23][C:24](=[O:26])[CH2:25][N:17]2[CH2:16]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:36][CH2:37][CH2:38][CH3:39]>CN(C)C=O>[CH:1]1([N:7]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:8](=[O:27])[CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]2[N:23]([CH2:36][CH2:37][CH2:38][CH3:39])[C:24](=[O:26])[CH2:25][N:17]2[CH2:16]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CN(C(=O)CCCOc1ccc2c(c1)CN1CC(=O)NC1=N2)C1CCCCC1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)CN2Cc3cc(OCCCC(=O)N(CC(=O)OC)C4CCCCC4)ccc3N=C21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-(N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramidyl)acetate in dry dimethylformamide was added sodium hydride (1.05 equivalents). The mixture was stirred at 60° C. for 30 minutes to give a homogeneous solution. 1-Bromobutane (1.1 equivalents) was added via a syringe after which the mixture was evaporated. The residue was dissolved in ethyl acetate and washed with saturated brine, dried and filtered. Evaporation of the solvent afforded methyl 2-(N-cyclohexyl-4-(1-butyl-2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutyramidyl)acetate.
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:55][O:56][C:57]1[N:62]=[CH:61][C:60](B(O)O)=[CH:59][CH:58]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:7][CH:8]=2)[C:3](=[O:28])[C:2]=1[C:60]1[CH:61]=[N:62][C:57]([O:56][CH3:55])=[CH:58][CH:59]=1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCOCC3)cc21
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3ccc(F)cc3F)c3ccc(OCCN4CCOCC4)cc3C2=O)cn1
Yield: 81 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-{2-(morpholin-4-yl)ethoxy}-1H-inden-1-one obtained in Step 1 of Example 124 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one and 6-methoxy-3-pyridinylboronic acid instead of 3-pyridinylboronic acid to obtain the title compound (81%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.O[N:71]=[C:72]([NH2:76])[CH2:73][CH2:74][CH3:75]>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[O:27][N:76]=[C:72]([CH2:73][CH2:74][CH3:75])[N:71]=4)=[CH:22][N:21]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCCC(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CCCc1noc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.60 g), 4-methylmorpholine (0.28 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g), 1-hydroxybenzotriazole monohydrate (0.17 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 min, N′-hydroxybutanimidamide (0.14 g) was added, and the mixture was further stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Xylene (50 mL) was added to the residue, and the mixture was heated under reflux for 24 hrs. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give 5-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-3-propyl-1,2,4-oxadiazole as colorless crystals (0.12 g, yield 18%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 192-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=1.N[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.C[N:36]1C(=O)CCC1>CO>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][C:5]1[C:12](=[O:13])[N:8]2[CH2:9][CH2:10][CH2:11][N:7]2[C:6]=1[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:36][CH:33]2[CH2:32][CH2:31][O:30][CH2:29][CH2:34]2)[N:15]=1
Reactant: CN1CCCC1=O
Reactant: NC1CCCCO1
Reactant: CS(=O)(=O)c1nccc(-c2c(Cc3ccccc3Cl)c(=O)n3n2CCC3)n1
Solvent: CO
Product: O=c1c(Cc2ccccc2Cl)c(-c2ccnc(NC3CCOCC3)n2)n2n1CCC2
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
To a solution of 2-(2-chloro-benzyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-6,7-dihydro-5H-pyrazolo[1,2-a]pyrazol-1-one, 8, (0.10, 0.26 mmol) in NMP (2 mL) is added amino tetrahydropyran (0.09 mL, 0.78 mmol). After stirring 1.5 hours at 90° C., the reaction mixture is diluted with methanol (to 5 mL) and is purified by reversed phase liquid chromatography (CH3CN/water/1% TFA) to afford 44 mg (40%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.30 (d, J=5.1 Hz, 1H), 7.39-7.12 (m, 4H), 6.57 (d, J=5.1 Hz, 1H), 4.10-3.94 (m, 9H), 3.60-3.48 (m, 2H), 2.80-2.68 (m, 2H), 2.95-1.95 (m, 2H), 1.65-1.50 (m, 2H); ESI− MS: m/z (rel intensity) 426.0 (100, M+−H).
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:3].[B-](F)(F)(F)F.CNC.[N+:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[O:35][CH:36]1[CH2:41][CH2:40][CH:39]([C:42]([OH:44])=O)[CH2:38][CH2:37]1)([O-:28])=[O:27].CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][N:2]([CH3:3])[C:42]([CH:39]1[CH2:38][CH2:37][CH:36]([O:35][C:34]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]=2[N+:26]([O-:28])=[O:27])[CH2:41][CH2:40]1)=[O:44]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)C1CCC(Oc2ccncc2[N+](=O)[O-])CC1
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CCC(Oc2ccncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TBTU (630.0 mg, 1.962 mmol) and dimethylamine (1.784 mL of 2 M, 3.568 mmol) were added to a solution of 4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxylic acid (475 mg, 1.784 mmol) and DIPEA (253.6 mg, 341.8 μL, 1.962 mmol) in THF (9.500 mL) and the resulting solution was stirred at RT overnight. The reaction mixture was partitioned between EtOAc and water, and the combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with 0-100% EtOAc/petroleum ether using the ISCO column companion system (12 g column) Clean fractions were combined and concentrated in vacuo to yield N,N-dimethyl-4-[(3-nitro-4-pyridyl)oxy]cyclohexanecarboxamide as a pale yellow oil. (180 mg, 34%). MS (ES+) 294.3.
Reaction SMILES: C(OC(N[C@H:9]([C:25]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([F:51])[C:33]=1[CH2:34][CH2:35][C@H:36]1[O:41][CH2:40][C@@H:39]([CH2:42][OH:43])[N:38](C(OC(C)(C)C)=O)[CH2:37]1)=[O:26])[CH:10]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O)(C)(C)C.[C:52](N1C=CN=C1)(N1C=CN=C1)=[O:53].[Cl:64][C:65]1[N:70]=[C:69]([CH2:71][NH2:72])[CH:68]=[CH:67][CH:66]=1>N1C=CC=CC=1>[Cl:64][C:65]1[N:70]=[C:69]([CH2:71][NH:72][C:52](=[O:53])[O:43][CH2:42][C@@H:39]2[CH2:40][O:41][C@H:36]([CH2:35][CH2:34][C:33]3[C:32]([F:51])=[CH:31][N:30]=[CH:29][C:28]=3[NH:27][C:25](=[O:26])[CH2:9][CH:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:37][NH:38]2)[CH:68]=[CH:67][CH:66]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cncc(F)c1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NCc1cccc(Cl)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Product: O=C(CC(c1ccc(F)cc1)c1ccc(F)cc1)Nc1cncc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCc2cccc(Cl)n2)CO1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-Butyl (2R,5R)-2-[2-(3-{[N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]amino}-5-fluoropyridin-4-yl)ethyl]-5-(hydroxymethyl)morpholine-4-carboxylate (Example 149, Step 7) (677 mg, 0.95 mmol) and carbonyldiimidazole (154 mg, 0.95 mmol) was added dry pyridine (22.5 mL). The resulting solution was heated at 60° C. and stirred for 2 h. This solution was then distributed in 0.5 mL (0.021 mmol) aliquots to 45 2-dram sample vials, each containing a diverse amine (0.042 mmol); among them (6-chloropyridin-2-yl)methanamine. The resulting mixtures were stirred at 60° C. for 3 h. Solvent was removed under stream of N2 gas. The residues were diluted with 4 N HCl/diethyl ether (1 mL) and stirred at room temperature for 16 h. Solvent was removed under stream of N2 gas, and the residues were diluted with DMSO and purified by mass-guided reversed-phase HPLC (10-90% CH3CN:0.1% NH4OH/H2O). HRMS (ES) 683.2353 (M+H). found, 683.2355 required.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O:14]=[C:15]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:19]2=[C:25]([C:28]([NH2:30])=O)[N:26]=[CH:27][N:18]2[C:17]2[CH:31]=[CH:32][S:33][C:16]1=2>O1CCOCC1.N1C=CC=CC=1>[O:14]=[C:15]1[N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[C:19]2=[C:25]([C:28]#[N:30])[N:26]=[CH:27][N:18]2[C:17]2[CH:31]=[CH:32][S:33][C:16]1=2
Reactant: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 80.7 %

Procedure:
4.44 ml (31.9 mmol) of trifluoroacetic anhydride were added dropwise at 5°-8° to a suspension of 8.98 g (31.1 mmol) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxamide in 50 ml of dioxan and 5.4 ml of pyridine. The beige solution obtained was stirred at 50° for 2.5 hours and subsequently poured into 220 ml of ice-water. The resulting precipitate was filtered off. After drying at 70°/10 Torr there were obtained 6.78 g (80%) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carbonitrile as a white powder of m.p. 249°-251°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20](CC([O-])=O)=[CH:19][C:18]=2[CH3:27])=[CH:4][CH:3]=1.Cl.C[OH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:28]3[CH:32]=[CH:31][N:30]=[C:29]3[CH3:33])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:36])=[CH:19][C:18]=2[CH3:27])=[CH:4][CH:3]=1
Reactant: Cc1cc(CC(=O)[O-])ccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Reactant: CO
Agent: Cl
Product: Cc1cc(O)ccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of [4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]-3-methylphenyl]acetate (4.30 g), 37% hydrochloride (3 ml), and methanol (150 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, which was poured into a 10% aqueous solution of sodium hydrogen carbonate. The precipitated crystals were filtered, washed with pure water and air-dried to give crystals of 4-[3-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]propyloxy]-3-methylphenol (3.90 g, 99%). Recrystallization from tetrahydrofuran-hexane gave colorless prisms (2.56 g, 65%). Melting point 175-176° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]([F:42])([F:41])[C:7]([C:37]([F:40])([F:39])[F:38])([C:33]([F:36])([F:35])[F:34])[O:8][CH2:9][C:10]1([CH2:18][O:19][C:20]([C:29]([F:32])([F:31])[F:30])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])[CH2:15]OS(=O)(=O)[O:12][CH2:11]1>CC(C)=O>[N:1]([CH2:15][C:10]([CH2:9][O:8][C:7]([C:6]([F:5])([F:41])[F:42])([C:37]([F:38])([F:39])[F:40])[C:33]([F:34])([F:35])[F:36])([CH2:18][O:19][C:20]([C:21]([F:22])([F:24])[F:23])([C:25]([F:28])([F:27])[F:26])[C:29]([F:32])([F:31])[F:30])[CH2:11][OH:12])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S1(=O)OCC(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)CO1
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(CO)(COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)COC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.8 %

Procedure:
Sodium azide (4.4 g, 66.9 mmol) was added to a stirred solution of compound 10 (21.2 g, 33.4 mmol) in dimethylformaldehyde (120 mL). The reaction mixture was stirred at 60° C. for 4 hours. The solvent was removed under vacuo and the residue was dissolved in tetrahydrofuran (120 mL). Sulfuric acid (0.87 mL) and water (0.32 mL) were added to the stirred tetrahydrofuran solution and the resulting mixture was stirred at room temperature for an additional hour. After removal the solvent, the residue was redissolved in dichloromethane (200 mL) and extracted with perfluorohexane (100 mL 4 times). The combined extraction was washed with dichloromethane (10 mL) and concentrated under vacuo to give the pure azide 11 as a clear oil (19.3 g, 97%). 1H NMR (400 MHz, CDCl3) δ 3.47 (s, 2H), 3.63 (s, 2H), 4.02 (s, 4H); 19F NMR (376 MHz, CDCl3) δ −73.21 (s); 13C NMR (100.7 MHz, CDCl3) δ 45.8, 49.8, 60.2, 66.8, 79.6 (m), 120.2 (q, J=293.3 Hz); MS (CI) m/z 598 (M++1, 72), 570 (100); HRMS (CI) Calcd for C13H10F18N3O3: 598.0435, Found: 598.0418.