Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:7]2[S:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[CH3:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ccccc3c2C)C2CCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (228 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (198 mg, 92%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(OCC)(=O)C>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: CC1(C)OC(c2ccc(O)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ccc(C2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenol (10.0 g, 45.5 mmol) and Cs2CO3 (23.5 g, 68.25 mmol) in DMF (60 mL) was added ethyl α-bromoacetate (11.6 g, 68.25 mmol). The mixture was stirred at room temperature for 24 hours, then diluted with-ethyl acetate, washed with water, dried over Na2SO4. After filtration and evaporation, the residue was dried under high vacuum to provide [4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenoxy]-acetic acid ethyl ester (12.52 g, 90% yield) as an oil.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[NH2:33].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]4[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=4)=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:21]=[CH:20][C:19]=1[NH2:33]
Reactant: Ic1cnc2cc(-c3ccncc3)ccn12
Reactant: CC1(C)OB(c2ccc(N)c(Cl)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1Cl
Yield: 46 %

Procedure:
Combine 3-iodo-7-pyridin-4-yl-imidazo[1,2-a]pyridine (2.18 g, 6.8 mmol), 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (crude material from previous step, excess), potassium carbonate (2.8 g, 3 equiv.), dioxane (30 mL), and water (15 mL). De-gas thoroughly with nitrogen then add dichloro-bis(triphenylphosphine) palladium (II) (0.143 g, 3 mol %). Heat reaction at 80° C. overnight. Concentrate to dryness then slurry in DCM and filter via Celite®, washing with DCM. Concentrate filtrate then purify by silica plug (Hexanes→1:1 Hexanes:Ethyl Acetate→2.5% Methanol:DCM→5% Methanol:DCM) to give an orange-yellow solid (1.42 g, 46%). MS (ES), m/z 321.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].C(N(CC)CC)C.[C:38]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40][CH2:39]1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:38](=[O:45])[CH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:28][CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(N)cc1
Reactant: O=C1CCCC(=O)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(NC(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.6 %

Procedure:
To a solution of 2-(4-aminobenzyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (139 mg) in tetrahydrofuran (5 ml) were added triethylamine (0.084 ml), glutaric anhydride (51 mg), and the mixture was stirred at room temperature for 24 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and isopropyl ether was added to the obtained residue and the mixture was crystallized. The obtained crystals were collected by filtration and dried under reduced pressure at 50° C. to give the title compound (131 mg, 76%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.FC(F)(F)S(O)(=O)=O.O>ClCCCl>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([F:21])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCCl
Product: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(F)c21
Temperature: 75 °C
Reaction time: 60 h
Yield: 22.8 %

Procedure:
A solution of (S)-N-trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was treated with Selectfluor (3.9 g, 11 mmol), trifluoromethanesulfonic acid (8 mL, 90 mmol) and stirred 60 hours at 75° C. The product mixture was poured into water (200 mL), extracted with EtOAc (200 mL), the organic phase washed with saturated aqueous NaHCO3 (2×100 mL), brine (100 mL), dried with Na2SO4 and concentrated. The crude product was purified by flash chromatography (6% EtOAc in hexane, silica) resulting in 0.6 g of a white solid. MS calculated for C13H12ClF4NO+H: 310, observed: 310.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=O)=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:30])[C@H:16]([C:20]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][C:46]([CH3:48])([CH3:49])[CH3:47])=[O:44])=[O:26])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)NC(C)(C)C)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
2 g (3.35 mmol) Z-Val-Val-MeVal-Pro-OH and 0.692 g (3.35 mmol) H-Pro-NHC(CH3)3 were dissolved in 34 ml of dry dichloromethane. After cooling to 0° C., 1.35 ml (12.1 mmol) N-methylmorpholine, 0.114 g (0.84 mmol) HOBt and 0.645 g (3.35 mmol) EDCI were added and the reaction mixture stirred overnight at room temperature. 80 ml dichloromethane were added and the organic phase thoroughly washed with saturated aqueous NaHCO3 solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution (1×). The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 1.8 g of the product which was used in the next reaction without further purification.
Reaction SMILES: F[C:2]1[C:3]([CH:16]=[O:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[NH:18]1[CH:22]=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:12][C:9]1([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]2[CH:4]=[C:3]([CH:16]=[O:17])[C:2]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:11][C:10]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(F)cc21
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(-n3cccn3)c(C=O)cc21
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of 0.200 g (0.845 mmol) of 3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthaldehyde, 0.058 g (0.854 mmol) of pyrazole, and 0.130 g (0.939 mmol) of potassium carbonate in 2 mL dimethylsulfoxide was heated to 95° C. for 18 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The product was purified on flash chromatography on silica gel (5% ethyl acetate/hexane) to afford 0.101 g (42%) of 5,5,8,8-tetramethyl-3-pyrazol-1-yl-5,6,7,8-tetrahydro-2-naphthaldehyde. (mp=95.7-97.6).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:15]2)[C:11]([NH2:23])=[CH:10][C:9]=1[NH:24][C:25]1[N:30]=[C:29]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)[CH:28]=[CH:27][N:26]=1>C(Cl)Cl.CO>[CH3:6][O:7][C:8]1[C:9]([NH:24][C:25]2[N:30]=[C:29]([C:31]3[CH:32]=[N:33][N:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=34)[CH:28]=[CH:27][N:26]=2)=[CH:10][C:11]([NH:23][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([N:14]2[CH2:15][C:16]3([N:21]([CH3:22])[CH2:20][CH2:19][CH2:18]3)[CH2:17]2)[CH:13]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
A solution of acryloyl chloride (0.766 mL, 0.77 mmol, 1.0 M in CH2Cl2) was added dropwise over 10 minutes to 4-methoxy-6-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 162, 333 mg, 0.73 mmol) in CH2Cl2 (6 mL), which was cooled in an ice/CH3OH bath. The mixture was then stirred for 0.5 h, then diluted with 10% CH3OH in CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-10% methanolic ammonia in CH2Cl2 gave the title compound (193 mg, 52%) as an beige solid after trituration with diethyl ether; 1H NMR: 1.69 (2H, dt), 2.03-2.08 (2H, m), 2.38 (3H, s), 2.63 (2H, t), 3.65 (2H, d), 3.83 (3H, s), 3.94 (2H, d), 5.68 (1H, dd), 6.19 (1H, dd), 6.25 (1H, s), 6.47 (1H, dd), 7.06 (1H, td), 7.19 (1H, d), 7.44 (1H, dd), 7.67 (1H, s), 7.98 (1H, s), 8.29 (1H, d), 8.47 (1H, d), 8.75 (1H, s), 8.78 (1H, d), 9.25 (1H, s); m/z: ES+ MH+ 511.34.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([OH:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[C:17]=1[F:26]>CCOC(C)=O>[CH2:7]([O:14][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH3:25])[C:17]=1[F:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1F
Reactant: OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Temperature: 180 °C

Procedure:
To a suspension of potassium carbonate (19.2 g, 138 mmol) and benzyl alcohol (22 mL) is added 1,2-difluoro-3-methyl-4-nitrobenzene (12 g, 69 mmol, ref. WO2007121416) and the mixture is heated to 180° C. for 2 h. The reaction mixture is then diluted with EtOAc and washed with water. The organic layer is concentrated and the residue is separated with FCC (EtOAc/heptane from 0 to 20%) to give 1-benzyloxy-2-fluoro-3-methyl-4-nitrobenzene. 1H NMR (400 MHz, MeOD) δ ppm 7.87 (dd, J=9.35, 2.02 Hz, 1 H), 7.44-7.47 (m, 2 H), 7.32-7.41 (m, 3 H), 7.17 (t, J=8.72 Hz, 1 H), 5.26 (s, 2 H), 2.49 (d, J=2.78 Hz, 3 H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24](O)=[O:25])=[CH:22][N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1.Cl.C([N:49]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:45])=[C:9]([CH2:11][O:12][C:13]2[CH:42]=[CH:41][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]([NH2:49])=[O:25])=[CH:22][N:21]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:43][CH3:44])[N:10]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(COc2nn(Cc3ccc(Oc4ccccc4)cc3)cc2C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(Cc3ccc(Oc4ccccc4)cc3)cc2C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A mixture of 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (0.80 g), 1H-1,2,3-benzotriazol-1-ol ammonia complex (0.22 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.28 g), and N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carbamide (0.75 g, yield 94%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from acetone-hexane. Melting point: 105–106° C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([C:12]([O-:14])=[O:13])[C:5]=2[N:4]=1.O.[OH-].[Li+]>C1COCC1.O>[CH3:1][N:2]([CH3:18])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:5]=2[N:4]=1
Reactant: CN(C)c1nc2c(C(=O)[O-])cc([N+](=O)[O-])cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1nc2c(C(=O)O)cc([N+](=O)[O-])cc2[nH]1
Yield: 91.6 %

Procedure:
2-(dimethylamino)-6-nitro-1H-benzimidazole-4-carboxylate (1.5 g) and lithium hydroxide hydrate (2.4 g) in THF—H2O (1:1, 100 mL) was stirred at 50° C. for 2 hours. THF was removed under reduced pressure, and 1N hydrochloric acid was added to the residue with stirring under ice-cooling to adjust the pH to 5. The precipitate was collected by filtration and dried under reduced pressure to obtain the titled compound (1.38 g) as yellow solid.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1>[Cu].C(O)CC(C)C>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Cu]
Solvent: CC(C)CCO
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc(Nc2ccccc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 42.8 %

Procedure:
A mixture of 4-chloro-3-nitrobenzoic acid (5.70 gm, 23 mmol), aniline (3.17 mL, 35 mmol), N-methylmorpholine (3.24 mL, 25 mmol), copper powder (0.1 gm, 1.57 mmol) and isoamyl alcohol (200 mL) was heated to reflux with stirring for 6 days. The mixture was then cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue taken up in ethyl acetate. The organic phase was washed with 3N HCl (2×1 L). The resulting organic phase was then extracted with saturated aqueous sodium carbonate solution. The aqueous phase was then washed with diethyl ether, followed by ethyl acetate. The aqueous phase was cautiously acidified to pH=1 with 6N HCl, and the resulting precipitate was filtered and dried to afford 2.54 gm of the title compound which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:31]=[CH:32][CH:33]=1)[CH2:16][CH2:17][NH:18][C:19]1[C:20](=[O:30])[N:21]([CH2:26][C:27]([OH:29])=O)[C:22]([CH3:25])=[CH:23][N:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[C:41]([CH2:44][NH2:45])[CH:42]=2)[NH:37][CH:36]=1.C1C=CC2N(O)N=NC=2C=1.Cl.CN1CCOCC1>CN(C)C=O>[CH3:25][C:22]1[N:21]([CH2:26][C:27]([NH:45][CH2:44][C:41]2[CH:42]=[C:43]3[C:38](=[CH:39][CH:40]=2)[NH:37][CH:36]=[C:35]3[CH3:34])=[O:29])[C:20](=[O:30])[C:19]([NH:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([CH:33]=[CH:32][CH:31]=2)[CH2:12][O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:24][CH:23]=1
Reactant: Cc1c[nH]c2ccc(CN)cc12
Reactant: Cc1cnc(NCCc2cccc(COCCNC(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1c[nH]c2ccc(CNC(=O)Cn3c(C)cnc(NCCc4cccc(COCCNC(=O)OC(C)(C)C)c4)c3=O)cc12
Yield: 96.1 %

Procedure:
A mixture of 2-[3-{[3-({2-[(tert-butoxycarbonyl)amino]ethoxy}methyl)phenethyl]amino}-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 107) (174 mg, 0.38 mmol), (3-methyl-1H-indol-5-yl)methylamine (preparation 36) (67 mg, 0.42 mmol), HOBT (77 mg, 0.57 mmol), WSCDl.HCl (91 mg, 0.47 mmol) and N-methylmorpholine (124 ml, 1.13 mmol) in N,N-dimethylformamide (5 ml), was stirred at room temperature for 20 hrs. The reaction mixture was partitioned between ethyl acetate and water and the phases separated. The organic layer was dried over MgSO4 and evaporated under reduced pressure to give the title compound as a white solid, (220 mg, 96%).
Reaction SMILES: [C:1](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:3])[CH3:2].[CH3:14][C:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][C:16]1=[O:22].C(N(CC)CC)C.CC(C)(O)C#N.C([O-])(=O)C>C(#N)C>[C:1]([CH:17]1[C:16](=[O:22])[C:15]([CH3:23])([CH3:14])[CH2:20][CH2:19][C:18]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: CC(C)(O)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)C1C(=O)CCC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50-mL single neck round bottom flask was charged with 4-nitrophenyl acetate (2.03 g, 11.2 mmol), 4,4-dimethyl-1,3-cyclohexanedione (2.10 g, 15 mmol) and acetonitrile (15 mL). Then triethylamine (2.5 g, 25 mmol) and acetone cyanohydrin (0.14 mL, 1.5 mmol) were added and the mixture was stirred for 2 hours at ambient temperature. NMR analysis of an aliquot showed that 43% of the starting acetate was still unreacted. The mixture was then refluxed for 2 hours after which time NMR analysis of an aliquot showed no starting acetate remaining.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[CH:74]=[CH:73][N:72]([C:75]([O:77][C:78]([CH3:81])([CH3:80])[CH3:79])=[O:76])[C:71]1=[O:82]>CN(C=O)C>[C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([NH:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[CH:74]=[CH:73][N:72]([C:75]([O:77][C:78]([CH3:79])([CH3:81])[CH3:80])=[O:76])[C:71]1=[O:82])=[O:14])([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1ccn(C[C@H]2NC(=O)[C@H]2N)c1=O
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ccn(C(=O)OC(C)(C)C)c2=O)cs1
Yield: 87.7 %

Procedure:
Prepared in analogous manner to example 4 step 4, using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (117 mg, 0.276 mmol), HATU (105 mg, 0.276 mmol), DIPEA (36 mg, 0.28 mmol), tert-butyl 3-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-2-oxo-2,3-dihydro-1H-imidazole-1-carboxylate (65 mg, 0.23 mmol) and DMF (5 mL). The crude residue was purified via silica gel chromatography (MeOH-DCM, 3%), affording the title compound (140 mg, 88%). LCMS: m/z=694.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([Br:12])[C:9](=[O:13])[NH:8][C:7]=1[C:14]([F:17])([F:16])[F:15])=[O:5])[CH3:2].[CH2:18](O)[C:19]([F:22])([F:21])[F:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.CCCCCCC>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[C:10]([Br:12])[C:9]([O:13][CH2:18][C:19]([F:22])([F:21])[F:20])=[N:8][C:7]=1[C:14]([F:17])([F:15])[F:16])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1cc(Br)c(=O)[nH]c1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Temperature: 50 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
5-Bromo-1,6-dihydro-6-oxo-2-(trifluoromethyl)-3-pyridinecarboxylic acid ethyl ester (111 g, 0.35 mol) was dissolved in tetrahydrofuran (1600 mL). To the solution were added trifluoroethanol (38 mL, 0.53 mol), triphenylphosphine (117 g, 0.42 mol) and diisopropyl azodicarboxylate (89.4 mL, 0.42 mol) at 0° C. The mixture was stirred for 30 min at 0° C., for 1 h at room temperature and for 18 h at 50° C. The mixture was cooled, poured into n-heptane (3.8 L) and extracted with 80% methanol (2×3.8 L). The methanol phase was extracted with another 3.8 L of n-heptane, the n-heptane phases were combined and dried with MgSO4. The solvent was removed in vacuo to give the title compound (121.5 g) as yellowish oil.