Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH3:52][C:53]1(C)C(C)(C)OB(C=C)O1>CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([CH:52]=[CH2:53])=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCO
Product: C=Cc1ccc([C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCC)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)c(-n2ccc(C)n2)c1
Temperature: 80 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.388 mmol, see Example 1u) in EtOH:H2O (15 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (90 mg, 0.58 mmol), KHCO3 (389 mg, 3.88 mmol), and PdCl2(PPh3)2 (41 mg, 0.058 mmol). The reaction mixture was heated to 80° C. for 1 h, then cooled to RT. The reaction was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification with a 40 g Isco RediSep silica cartridge (EtOAc:heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(2-(3-methyl-1H-pyrazol-1-yl)-4-vinylphenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[CH3:15].[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17]>C1CCCCC1>[CH:16]([NH:20][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([CH3:15])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9])([CH2:18][CH3:19])[CH3:17]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCC(C)N
Solvent: C1CCCCC1
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 10.04 g. (0.04 mole) of 2,4-dichloro-3,5-dinitrotoluene, 5.85 g. (0.08 mole) of sec-butylamine and 200 ml. of cyclohexane is stirred at reflux for six hours. The mixture is filtered and the filtrate is evaporated at reduced pressure. The filtrate is partitioned between ether and dilute hydrochloric acid. The organic phase is washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. Crystallization of the residue from ethanol gives 7.71 g. of orange crystals, m.p. 40°-46° C. Two recrystallizations from ethanol give the analytical sample, m.p. 45°-47° C. Analysis Calcd. for C11H14ClN3O4 : C, 45.92; H, 4.90; Cl, 12.32; N, 14.61. Found: C, 45.96; H, 4.97; Cl, 12.36; N, 14.78.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=[O:20].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[C:4]([NH2:5])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1Cl
Reaction time: 12 h
Yield: 99 %

Procedure:
A solution of 2-chloro-4-(4-formylphenoxy)benzonitrile (1.0 equiv) in DMSO (0.2 M solution) was treated with K2CO3 (0.5 equiv) and 33% H2O2. After 12 h, the reaction mixture was poured into H2O and extracted with ethyl acetate. The combined organic layers were washed twice with water and brine. After drying the extracts over magnesium sulfate and evaporation under vacuum, the crude product was purified by silica gel chromatography using the appropriate eluent (typically mixtures of hexanes/ethyl acetate) to afford the title compound as a solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:13])[C:3]=1[F:14].Cl.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[CH:18]([CH2:24][C:25](O)=[O:26])[CH2:17]2.C(N=C=NC(C)C)(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[N:16]12[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23]1)[CH:18]([CH2:24][C:25]([O:1][C:2]1[C:3]([F:14])=[C:4]([F:13])[C:5]([C:6]([OH:8])=[O:7])=[C:9]([F:12])[C:10]=1[F:11])=[O:26])[CH2:17]2
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: O=C(O)c1c(F)c(F)c(O)c(F)c1F
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Oc1c(F)c(F)c(C(=O)O)c(F)c1F
Reaction time: 8 h
Yield: 235.9 %

Procedure:
2 g of the polymeric support resin from Example 8A (loading about 1.36 mmol/g, 2.72 mmol) are suspended in 20 ml of DMF and shaken with 1.23 g (5.98 mmol) of 1-azabicyclo[2.2.2]oct-3-ylacetic acid hydrochloride and 130 mg (1.09 mmol) of DMAP for 10 min. Then 1.06 ml (6.80 mmol) of N,N′-diisopropylcarbodiimide are added, and the mixture is shaken overnight. The resin is filtered off with suction, washed twice each with 20 ml each of DMF, THF and DCM and dried under high vacuum. 2.318 g of the polymer-bound title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N:29]12[CH2:37][C:33]([CH2:38][NH2:39])([CH2:34][CH2:35][CH2:36]1)[CH2:32][CH2:31][CH2:30]2>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:39][CH2:38][C:33]23[CH2:37][N:29]([CH2:30][CH2:31][CH2:32]2)[CH2:36][CH2:35][CH2:34]3)=[O:8])=[C:4]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:3]=1
Reactant: NCC12CCCN(CCC1)C2
Reactant: COCCOc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCOc1cc(N)c(Cl)cc1C(=O)NCC12CCCN(CCC1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution of 4-amino-5-chloro-2-(2-methoxyethoxy)benzoic acid (2.09 g, 8.5 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.46 g, 9.0 mmol), stirred for one hour, degassed under a stream of nitrogen over 10 minutes, and cooled (0° C.). A solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (1.36 g, 8.8 mmol) in tetrahydrofuran (5 mL) was added dropwise, and stirring was continued at room temperature for 18 hours. The solution was concentrated in vacuo and the residue was taken up in methylene chloride (100 mL) and washed with saturated sodium carbonate (50 mL). The organic solution was dried (Na2SO4), concentrated in vacuo, and passed through a short column of alumina (eluted with 5% methanol/methylene chloride). The filtrate was concentrated in vacuo and, at this point, appeared to be contaminated with some highly insoluble impurity. The residue was taken up in tetrahydrofuran and filtered, and the filtrate was concentrated in vacuo, triturated from cold ether, and recrystallized from acetonitrile (2 crops) to afford 1.59 g (49%) of colorless crystals; mp 154.0°-155.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[Br:13]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.S(=O)(=O)(O)O>[Br:13][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
A solution of 3-nitrobenzoic acid (16.7 g, 100 mmol) in trifluoroacetic acid (50 mL) and sulfuric acid (20 mL) at 50° C. N-Bromosuccinimide (26.7 g, 150 mmol) was added in three portions over 3 hours. The mixture was stirred for 16 hours and then cooled to room temperature. The mixture was poured into ice water (200 mL) and extracted three times with ethyl acetate. The combined organic layers were combined, dried over sodium sulfate and concentrated under vacuum. The residue was recrystallized from dichloromethane to provide a white solid (17.7 g, 72%). 1H NMR (300 MHz, DMSO-d6) δ13.8 (bs, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.37 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:16]=[O:17])[C@@H:12]([CH3:15])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Si]([C:22]([F:25])([F:24])[F:23])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@H:11]([CH:16]([OH:17])[C:22]([F:25])([F:24])[F:23])[C@@H:12]([CH3:15])[CH2:13][CH3:14])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC[C@H](C)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 5-chlorothiophene-2-sulfonyl isoleucinal (770 mg, 2.6 mmol, see Example 118, parts 1&2) in THF (5 mL) was added TMS-CF3 (5 mL, 0.5M in THF). The resulting mixture was treated with TBAF (250 μL, 1M in THF). The cold bath was removed and the reaction was stirred at 25° C. overnight. The reaction was quenched with HCl (25 mL, 2M) and the resulting solution was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL) then dried over MgSO4. The residue was submitted to RP-HPLC (see example 155 for procedure) to give 74 mg of the desired product (m/z=364.0 (M−H), rt=1.23 min).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])(=[O:5])[CH3:4].O>CCOCC>[Br:1][CH2:4][C:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])=[O:5]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: BrBr
Solvent: O
Solvent: CCOCC
Product: N#Cc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Br2 (1 mmol) was dropwise added to a solution of 3-acetylbenzonitrile (1 mmol) in Et2O (15 ml) at 0° C., and then the mixture was stirred at r.t. for 4 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na2SO4, and was concentrated to give an oil, i.e., 3-(2-bromoacetyl)benzonitrile, which was directly used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23](=[O:26])[NH:24][CH3:25])[CH2:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]([CH:16]=O)=[C:10]([CH:15]=1)[C:11](OC)=[O:12].[NH2:27][C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23](=[O:26])[NH:24][CH3:25])[CH2:5][C:6]1[CH:15]=[C:10]2[C:9]([CH2:16][N:27]([C@@H:28]3[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]3)[C:11]2=[O:12])=[C:8]([CH3:18])[C:7]=1[CH3:19]
Reactant: CNC(=O)c1ccc(Cc2cc(C(=O)OC)c(C=O)c(C)c2C)cc1F
Reactant: N[C@H]1COCC[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(Cc2cc3c(c(C)c2C)CN([C@H]2COCC[C@@H]2O)C3=O)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.2 %

Procedure:
To a solution of methyl 5-(3-fluoro-4-(methylcarbamoyl)benzyl)-2-formyl-3,4-dimethylbenzoate (0.09 g) in THF (2.00 mL) were added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.03 g) and anhydrous magnesium sulfate (0.06 g), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated, and the residue was diluted with methanol (2.00 mL)-THF (2.00 mL). Sodium triacetoxyborohydride (0.11 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (0.04 g).
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[NH2:19][C:20]1[C:24]([Br:25])=[CH:23][NH:22][N:21]=1>>[Br:25][C:24]1[CH:23]=[N:22][N:21]2[C:3]([CH:2]([F:18])[F:1])=[CH:4][C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)=[N:19][C:20]=12
Reactant: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1n[nH]cc1Br
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(Br)cnn12
Yield: 92.9 %

Procedure:
Prepared from 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (example C.2 step 1) (21.40 g, 80 mmol) and commercially available 3-amino-4-bromopyrazole (13.29 g, 80 mmol) as described in example C.1, step 2a to give 3-bromo-7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (29.14 g, 92%) as a yellow solid. MS (ISP) 392.0 [(M+H)+], 394.0 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>>[NH:11]([S:8]([C:6]1[CH:5]=[CH:4][C:3]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19]2)=[C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:7]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)Nc3ccccc3)cc2N)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(S(=O)(=O)Nc3ccccc3)cc2NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of tert-butyl 4-[2-amino-4-(anilinosulfonyl)phenyl]-1,4-diazepane-1-carboxylate (176 mg, 0.39 mmol), methylsulfonyl chloride (0.040 mL, 0.47 mmol) and pyridine (0.285 mL, 3.51 mmol) in CH2CL2 (5 mL) was stirred at room temperature overnight. The reaction mixture was quenched with NaHCO3 aq (3×30 mL). The organic phase was separated, dried (MgSO4) and filtered. The volatiles were evaporated followed by purification of the oily residue by chromatography (SiO2, hexane/EtOAc 4:1) to give 110 mg of tert-butyl 4-{4-(anilinosulfonyl)-2-[(methylsulfonyl)amino]phenyl}-1,4-diazepane-1-carboxylate (yield 58%).
Reaction SMILES: O=[N:2][NH2:3].Cl.C(N(CC)CC)C.[C:12]1([CH3:19])[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>>[CH:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[N:3][N:2]=1
Reactant: NN=O
Reactant: Cc1ccccc1C
Agent: Cl
Solvent: CCN(CC)CC
Product: c1ccc2cnncc2c1
Temperature: 25 °C
Yield: 63 %

Procedure:
1,1′-Carbonyldiimidazole (2.0 g, 12.6 mmol) was added to a stirred solution of 5-methylisoxazole-3-carboxylic acid in DMF (50 ml). The solution was stirred for 0.5 h before adding the preceding hydrazine (2.63 g, 11.7 mmol). After 1 h at room temperature, the solution was poured into water and the resultant precipitate was filtered, washed with water (30 ml) and hexane (100 ml), and dried in vacuo to give the ketohydrazine (3.1 g, 79%); MS (ES+) m/e 334 [MH]+. A solution of the ketohydrazine (1.0 g, 3.0 mmol) and triethylamine hydrochloride (0.2 g, 1.45 mmol), in xylene (30 ml), was heated at reflux for 4 h. The solution was cooled to room temperature and the solvent removed in vacuo. The residue was chromatographed through silica gel, eluting with ethyl acetate, to give the title-phthalazine (0.60 g, 63%), mp 186-188° C.; 1H NMR (250 MHz, CDCl3) δ1.22-1.54 (4H, m, 2 of CH2), 1.94-2.06 (4H, m, 2 of CH2), 2.58 (3H, s, Me), 3.60 (1H, s, CH), 4.08 (1H, s, CH), 6.90 (1H, s, Ar—H); MS (ES+) m/e 316 [MH]+.
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22](O)=[O:23])[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:61]1[C:65]([CH2:66][CH2:67][NH2:68])=[N:64][N:63]=[N:62]1.CCN(CC)CC>CN(C=O)C>[C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22](=[O:23])[NH:68][CH2:67][CH2:66][C:65]5[N:61]=[N:62][NH:63][N:64]=5)[CH2:20][CH2:21]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: NCCc1nnn[nH]1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NCCc4nn[nH]n4)CC3)n21
Temperature: 0 °C
Yield: 80.7 %

Procedure:
1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid (50 mg, 0.09 mmol) and HATU (57 mg, 0.15 mmol), were combined with a heterogeneous solution of 2-(1H-tetrazol-5-yl)-ethylamine formiate (45 mg, 0.26 mmol) in anhydrous DMF (1 mL) and cooled to 0° C. Et3N (0.043 mL, 0.3 mmol) was added to the reaction. After 18 h the reaction slowly warmed to room temperature. The crude reaction solution was filtered and purified via reverse HPLC to yield 45 mg of the title compound as a white solid, m/z 619.5 [M+1]+).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O=S(Cl)Cl.[CH:14](O)([CH3:16])[CH3:15]>>[CH:14]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1])([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)C[C@H](N)C(=O)OC(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture of L-Leucine (1 g, 1 eq.), SOCl2 (1.7 ml, 3 eq.) in isopropanol (15 ml) was stirred under microwave irradiation at 100° C. for 1 hour. Solvent was then evaporated, the residue filtered and Et2O was added to give L-Leucine isopropyl ester as a yellow oil in 71% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm): 0.88 (dd, J=6.41 Hz and J=2.14 Hz, 6H), 1.22 (t, J=6.03 Hz, 6H), 1.60-1.75 (m, 3H), 3.82 (t, J=7.10 Hz, 1H), 4.97 (m, 1H), 8.61 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]C1C=CC(C(Cl)=O)=CC=1>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([CH3:25])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Product: Cc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Yield: 6.3 %

Procedure:
The title compound (0.2 g) was prepared from 4-oxo-azepane-1-carboxylic acid tert-butyl ester (Example 59, Step B; 10 mmol) as in Example 59, Steps C through E, using 4-methyl-benzoyl chloride (11 mmol) in place of 4-chloro-benzoyl chloride. MS (ESI): exact mass calculated for C21H23N3, 317.19; found, m/z 318.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.34-7.33 (m, 2H), 7.29-7.26 (m, 2H), 7.24-7.21 (m, 3H), 7.10-7.09 (m, 2H), 5.40 (s, 2H), 3.33-3.27 (m, 4H), 3.11-3.09 (m, 2H), 3.00-2.98 (m, 2H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:17][C:3]1=2.[H-].[Na+].O.C(O)(=O)C.[CH3:30][C:31]1([CH3:38])[O:35][CH:34](CO)[CH2:33][O:32]1>>[CH3:30][C:31]1([CH3:38])[O:35][CH2:34][CH:33]([CH2:22][O:21][C:19](=[O:20])[CH2:18][C:15]2[CH:16]=[CH:17][C:3]3[N:2]([CH3:1])[CH2:8][C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[C:5](=[O:13])[C:4]=3[CH:14]=2)[O:32]1
Reactant: CC1(C)OCC(CO)O1
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)OCC3COC(C)(C)O3)ccc21

Procedure:
Methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-2-acetate (1.5 g) was dissolved in Solketal (20 ml), and 50% oily sodium hydride (0.2 g) was added. The mixture was maintained at 80°-100° C. under reduced pressure using an aspirator. The reaction mixture was poured into water (150 ml) and acetic acid (0.5 ml), and the system was extracted with dichloromethane. The extract was dried over MgSO4, and then, the solvent was distilled off. The residual oily matter was subjected to liquid column chromatography using 100 g of Wakogel C-200 to afford the desired compound as a yellow oily material (0.950 g) eluted with a mixed liquid of benzene-dichloromethane (1:1).
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=2[O:31][CH2:32][CH:33]2[CH2:35][O:34]2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1>CO.O1CCCC1>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:39]=[CH:38][CH:37]=[CH:36][C:30]=2[O:31][CH2:32][CH:33]([OH:34])[CH2:35][N:12]2[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: OC1CCNCC1
Reactant: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CCCCc2ccccc2OCC(O)CN2CCC(O)CC2)cc(OC)c1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
561 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 688 mg of 4-hydroxypiperidine hydrochloride in methanol, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the solvent was removed by distillation under reduced pressure, the residue was mixed with tetrahydrofuran, and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, to give a colorless oil, which was dissolved in 20 ml of tetrahydrofuran. 1.02 g of 2-{2-[4-(3,5-dimethoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in Example 11(a)] were added to the resulting solution, and the mixture was stirred at 60° C. for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.26 g (yield 95%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[C:15](=[S:23])[NH:14][C:13](=[O:24])[CH:12]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15](=[S:23])[NH:14][C:13](=[O:24])[CH:12]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(OC)cc2OC)cc(=O)[nH]c1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2cc(=O)[nH]c(=S)n2CC(=O)O)c(OC)c1
Temperature: 35 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of ethyl 2-(6-(2,4-dimethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate (6.8 g, 20.3 mmol) in methanol (34 mL) was added 6N aqueous NaOH (16.9 mL), and the solution was stirred at 35° C. for 3 hours. The mixture was concentrated under reduced pressure, and water (100 mL) was added. The aqueous layer was washed with ethyl acetate (2×200 mL), and acidified with concentrated HCl to pH ˜2. The resultant acidic aqueous solution was extracted with EtOAc (3×200 mL), and the combined organic layers were dried with sodium sulfate, and concentrated under reduced pressure to give the title compound 6.53 g (99%) as a white solid.