Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=1)[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.O[N:38]1[C:42]2[CH:43]=CC=C[C:41]=2N=N1.C(N)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:10])[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[N:18]=1)[CH2:12][C:13]([NH:38][CH:42]([CH3:43])[CH3:41])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)CN(Cc1cccc(Br)n1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
N-[(Benzyloxy)carbonyl]-N-[(6-bromopyridin-2-yl)methyl]glycine (0.16 g, 0.42 mmol) was dissolved in DMF (2.1 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.081 g, 0.42 mmol) and 1-hydroxybenzotriazole hydrate (0.066 g, 0.43 mmol) were added. Isopropyl amine (0.025 g, 0.42 mmol) was added and the reaction was stirred overnight. The reaction was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by reverse phase HPLC (10-100% acetonitrile/water+0.05% TFA modifier) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:9](=[O:10])[N:8]([CH2:11][C@@H:12](O)[C:13]([F:16])([F:15])[F:14])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:6]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:9](=[O:10])[N:8](/[CH:11]=[CH:12]/[C:13]([F:16])([F:15])[F:14])[C:7]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:6]1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@@H](O)C(F)(F)F)c1=O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O
Reaction time: 12 h

Procedure:
At RT, 280 mg (0.74 mmol) of the compound of Example 7A were initially charged together with 108 mg (0.89 mmol) of 4-dimethylaminopyridine in 5.3 ml of pyridine, 0.31 ml of trifluoromethanesulphonic anhydride (1.84 mmol) was added in portions and the mixture was stirred for 12 h. The pyridine was removed on a rotary evaporator. The residue was taken up in acetonitrile and 1N hydrochloric acid and purified by preparative HLPC [Method 9]. This gave 230 mg (86% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][C:17]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC>[F:14][C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:22]3[C:17]([CH3:16])=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Reactant: Cc1ncccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ncccc1-c1nc2c(C)c(F)ccc2cc1C=O
Temperature: 90 °C
Yield: 90.5 %

Procedure:
A mixture of 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (8.0 g, 35.77 mmol), 2-methylpyridin-3-ylboronic acid pinacol ester (9.58 g, 39.35 mmol), tetrakis-(triphenylphosphine)palladium(0) (207 mg, 18 mmol) and Na2CO3 (5.69 g, 53.66 mmol) in water (50 mL) and DME (100 mL) was degassed and flushed three times with nitrogen gas, then heated at 90° C. for 24 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with DCM (150 mL) and washed with water (150 mL). The aqueous phase was extracted with DCM (2×100 mL) and the combined organic fractions were washed with brine (150 mL), then dried (phase separator) and evaporated in vacuo. The crude material was triturated in hexane (50 mL), then the solid was filtered off and dried under vacuum to give the title compound (9.07 g, 90%) as a pale yellow solid. δH (DMSO-d6) 9.94 (s, 1H), 9.09 (1H, s), 8.61 (dd, J 4.9, 1.7 Hz, 1H), 8.26 (dd, J 8.9, 6.4 Hz, 1H), 7.78 (dd, J 7.7, 1.7 Hz, 1H), 7.69 (t, J 9.2 Hz, 1H), 7.40 (dd, J 7.7, 4.9 Hz, 1H), 2.61 (d, J 2.4 Hz, 3H), 2.34 (s, 3H). LCMS (ES+) 281 (M+H)+, RT 2.26 minutes.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])O[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][NH2:25]>CO>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][OH:17])[N:25]([CH3:24])[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1cc(CO)occ1OC(c1ccccc1)c1ccccc1
Reactant: CN
Solvent: CO
Product: Cn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Reaction time: 4 h

Procedure:
To a solution of 3.035 g of 3-diphenylmethoxy-6-hydroxymethyl-4-pyrone in 20 ml of methanol is added 50 ml of 40% aqueous methylamine solution, and the mixture is stirred for 4 hours. The reaction mixture is condensed under reduced pressure to a volume of 15 ml, and the resulting crystal is collected by filtration, washed with a small amounts of water and ethyl acetate in this sequence, and dried under reduced pressure to give 2.04 g of the title compound.
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27]OC3C=CC=CC=3)[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(N[C@H]2CC[C@H]([CH2:49][O:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)CC2)CCCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:21]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([CH2:49][O:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=3)[CH2:5][CH2:6]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:22][CH2:23][CH2:24][CH2:27][CH2:25][CH2:26]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)[C@H]2CC[C@H](COc3ccccc3)CC2)s1
Reactant: COc1ccc(OC[C@H]2CC[C@H](NC3CCCCCC3)CC2)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(OC[C@H]2CC[C@H](N(C(=O)Nc3ncc(SCC(=O)O)s3)C3CCCCCC3)CC2)cc1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-phenoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cycloheptyl-[trans-4-(4-methoxy-phenoxymethyl)-cyclohexyl]-amine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[S:11][CH:10]=[N:9][C:8]=3[CH:12]=2)[CH2:3][CH2:2]1.I[C:14]1[C:15]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]2)=[N:16][C:17]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[N:18][C:19]=1[O:20][CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu](I)I>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]3[S:11][C:10]([C:14]4[C:15]([NH:28][C@@H:29]5[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]5)=[N:16][C:17]([N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)=[N:18][C:19]=4[O:20][CH3:21])=[N:9][C:8]=3[CH:12]=2)[CH2:3][CH2:2]1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
Reactant: c1nc2cc(C3CC3)ccc2s1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(C3CC3)ccc2s1

Procedure:
Following the same procedure as in step 3 of Example 337 using 5-cyclopropyl-1,3-benzothiazole (61.4 mg, 0.35 mmol, 1.80 equiv), tert-butyl (3R)-3-[[5-iodo-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (100 mg, 0.19 mmol, 1.00 equiv), cesium carbonate (0.37 g, 6.00 equiv, 1.14 mmol), Pd(PPh3)4 (40.4 mg, 0.035 mmol, 0.18 equiv) and copper iodide (6.7 mg, 0.035 mmol, 0.18 equiv) in DMF (6.0 mL). The crude product was purified by flash chromatography on silica gel, eluting with petroleum ether/ethyl acetate (20:1-5:1) to provide the title compound as a white solid. MS m/z [M+H]+ (ESI): 567.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[C:22]([N+:24]([O-])=O)[C:21]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:20][C:19]=3[O:34][CH3:35])[N:11]=2)=[CH:2]1.[NH4+].[Cl-].O.C(Cl)Cl>C(O)C.[Fe].CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:23]=[C:22]([NH2:24])[C:21]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:20][C:19]=3[O:34][CH3:35])[N:11]=2)=[CH:2]1
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C)c(-c2c[nH]c3ccccc23)n1
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
A mixture of 4-(1H-indol-3-yl)-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-5-methylpyrimidin-2-amine (Intermediate 13, 157 mg, 0.33 mmol), iron (111 mg, 1.99 mmol) and NH4Cl (12.41 mg, 0.23 mmol) was heated in ethanol (6 mL) and water (2 mL) at reflux for 2 h. The mixture was then cooled and concentrated in vacuo to give a thick slurry. CH2Cl2 (100 mL) and CH3OH (10 mL) were then added and the mixture was stirred for 0.25 h, then filtered. The filter cake was washed with CH2Cl2 (50 mL) and CH3OH (5 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-5% methanolic ammonia in CH2Cl2 gave the title compound (113 mg, 77%) as a pale yellow dry film; m/z: ES+ MH+ 444.53.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=3[NH:13][C:12]2=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=3[N:13]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:12]2=[O:23])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2c(=O)[nH]c3c([N+](=O)[O-])cccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(=O)n(S(=O)(=O)c2ccc(C)cc2)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-[(4-methylphenyl)sulfonyl]-4-nitro-1,3-dihydro-2H-benzimidazol-2-one from Step B (500 mg, 1.50 mmol) in DMF (50 mL) was added potassium carbonate (207 mg, 1.50 mmol) and the resulting mixture was stirred at ambient temperature for 10 min. Methyl bromoacetate (252 mg, 1.65 mmol) was added dropwise and the reaction mixture was stirred for 1 h, then poured into H2O (50 mL). The resulting precipitate was isolated by filtration, washed with 1420, and dried in vacuo to give the title compound. MS: m/z=406 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([CH:30]2[CH2:32][CH2:31]2)[OH:29])=[CH:6][CH:5]=1.[CH3:33]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:25])([F:27])[F:26])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH:28]([CH:30]2[CH2:32][CH2:31]2)[O:29][CH3:33])=[CH:6][CH:5]=1
Reactant: CI
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F)C1CC1
Reaction time: 0.08 h
Yield: 77.2 %

Procedure:
Sodium hydride (60% in oil, 52.4 mg, 1.31 mmol) was added to a stirred solution of {9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}(cyclopropyl)methanol (500 mg, 1.09 mmol) in N,N-dimethylformamide (4.0 mL) at room temperature. After stirring 5 min, methyl iodide (232 mg, 1.64 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (396 mg, 0.842 mmol, 77%).
Reaction SMILES: CC1C=C(N[C:10]2[N:15]=[C:14]([N:16]3[CH:20]=[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:18]([CH3:26])=[N:17]3)[CH:13]=[CH:12][N:11]=2)C=C(C)C=1.C(=O)([O-])[O-].[K+].[K+].ClC1C=CN=[C:36]([S:40]C)N=1>C(#N)C.C(OCC)(=O)C>[CH3:26][C:18]1[C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:20][N:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([S:40][CH3:36])[N:15]=2)[N:17]=1
Reactant: CSc1nccc(Cl)n1
Reactant: CCOC(=O)c1cn(-c2ccnc(Nc3cc(C)cc(C)c3)n2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccnc(SC)n2)nc1C
Temperature: 80 °C
Yield: 707.8 %

Procedure:
To a solution of ethyl 3-methyl-1H-pyrazole-4-carboxylate 2 (5.0 g, 32 4 mmol) in anhydrous acetonitrile (60 mL) were added potassium carbonate (8.96 g, 64.9 mmol) and 4-chloro-2-(methylthio)pyrimidine 11 (5.47 g, 34.1 mmol) at room temperature (rt). The resulting suspension was heated at 80° C. for 8 hours with monitoring a reaction with LC-MS or thin layer chromatography (TLC). It was diluted with ethyl acetate and washed with brine. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacou. The resulting residue was recrystallized with methanol to give 7.88 g (83%) of ethyl 3-methyl-1-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate 12; MS (ESI) m/z 279 [M+H]+. The resulting pyrazole-4-carboxylate 12 (7.44 g, 26 7 mmol) was dissolved in 30 mL of DCM and then cooled to 0° C. To this was added 3-chloroperbenzoic acid (mCPBA, 13.2 g, 58.8 mmol) at the same temperature. The reaction was warmed to room temperature, stirred for 2 hours and then quenched by addition of saturated NaHCO3 solution. The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacou. The resulting residue was recrystallized with iso-propylether to give 7.88 g (83%) of ethyl 3-methyl-1-(2-(methylsulfonyl)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate 13 as a colorless solid (6.92 g, 83%); m/z 311 [M+H]+. The obtained sulfoxide 13 (3.0 g, 9.7 mmol) was mixed with acetic acid (0.42 mL, 9.7 mmol) and 3,5-dimethylaniline (1.4 mL, 9.7 mmol) in 10 mL of n-butanol. After being heated at reflux for 2 hours, the mixture was concentrated in vacou. The resulting residue was extracted with DCM, washed with a saturated NaHCO3 solution. The collected organic layer was dried over anhydrous sodium sulfate, concentrated in vacou and then recrystallized with ethyl acetate to afford 0.86 g (26%) of Compound No. 2 as a pale yellow solid; m/z 352 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]([NH2:16])([CH3:15])[CH3:14].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl.C(=O)([O-])O.[Na+]>[C:13]([NH:16][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[F:1])([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)N
Reactant: Cc1cccc(C(=O)O)c1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)NC(C)(C)C)c1F
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a stirred solution of 2-fluoro-3-methylbenzoic acid (8.76 mmol, 1.35 g), 2-methylpropan-2-amine (9.43 mmol, 1 mL, 0.690 g) and triethylamine (28.7 mmol, 4 mL, 2.90 g) in dichloromethane (20 mL) was added 1-propanephosphonic acid cyclic anhydride (13.50 mmol, 8 mL, 8.59 g, 50% solution in ethyl acetate). The reaction was stirred for 2 hours and diluted with dichloromethane and aqueous sodium hydrogen carbonate. The organic layer was separated, dried and concentrated under reduced pressure to yield the title compound (1 g).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[C:27]([NH2:28])=[CH:26][NH:25][N:24]=2)=[O:22])=[CH:16][CH:15]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[C:27]([NH:28][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:2]=3[F:1])=[CH:26][NH:25][N:24]=2)=[O:22])=[CH:18][CH:19]=1
Reactant: COc1cccc(C(=O)O)c1F
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: O
Product: COc1cccc(C(=O)Nc2c[nH]nc2C(=O)Nc2ccc(F)cc2)c1F
Yield: 62.3 %

Procedure:
2-Fluoro-3-methoxybenzoic acid (0.047 g, 0.28 mmol), 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (Example 2B) (0.055 g, 0.25 mmol), EDC (0.58 g, 0.30 mmol) and HOBt (0.041 g, 0.30 mmol) were stirred at room temperature in DMSO (1.25 ml) for 5 hours. The reaction mixture was poured into water (30 ml) and the resultant solid was collected by filtration and dried in a vacuum oven to give the title compound as a grey solid (0.058 g, 63%). (LC/MS: Rt 3.99, [MH]+ 372.98).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]=2[CH:20]=1)#[N:2].[C:21](=[O:38])([O:36][CH3:37])[O:22][C:23]1[CH:28]=[C:27]([NH2:29])[C:26]([Br:30])=[CH:25][C:24]=1[CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.N1C=CC=CC=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CC1CCCO1.C(OCC)(=O)C>[Br:30][C:26]1[CH:25]=[C:24]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:23]([O:22][C:21]([O:36][CH3:37])=[O:38])=[CH:28][C:27]=1[NH:29][C:12]([CH:10]1[O:11][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=2[N:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9]1)=[O:14]
Reactant: COC(=O)Oc1cc(N)c(Br)cc1C1CCCC1
Reactant: CCOC(=O)N1CC(C(=O)O)Oc2ccc(C#N)cc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2Br)Oc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 6-cyano-4-ethoxycarbonyl-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid (552 mg, 2.0 mmol) and (5-amino-4-bromo-2-cyclopentyl-phenyl) methyl carbonate (691 mg, 2.20 mmol) in 2-methyltetrahydrofuran (7 mL) at room temperature was added pyridine (404 μL, 5.0 mmol) followed by the addition of T3P (3181 mg, 2.98 mL of 50% w/w solution, 5.0 mmol). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate then quenched with a saturated aqueous solution of NaHCO3 (4 mL) and stirred for 15 min. The layers were separated, and the aqueous layer was extracted once more with ethyl acetate. The combined organic extracts were filtered to give a white solid. The remaining filtrate was dried over Na2SO4, filtered and concentrated in vacuo to obtain a creamy solid. The combined solids were triturated with hexane (5×5 mL) and washed with ethyl acetate (1 mL) and dichloromethane (1 mL) to provide ethyl 2-(2-bromo-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate as a white solid (403 mg, 99% yield). LC/MS m/z 573.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6](O)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:47])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39]S(C)(=O)=O)[C:22]=1[CH2:44][CH2:45][CH3:46])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:47])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:44][CH2:45][CH3:46])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 69.4 %

Procedure:
A mixture of 1.16 g (0.006 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.93 g (0.006 mole) of [4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester and 1.65 g (0.012 mole) of anhydrous potassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrous dimethylformamide was stirred at reflux for 21 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 40% ethyl acetate-hexane to give 2.45 g (70% yield) of [4-acetyl-3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH:10]([F:12])[F:11])([NH2:9])[CH2:5][CH2:6][CH2:7][NH2:8].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.C[O-].[Na+]>CO>[NH2:9][C:4]1([CH:10]([F:12])[F:11])[CH2:5][CH2:6][CH2:7][NH:8][C:3]1=[O:2]
Reactant: COC(=O)C(N)(CCCN)C(F)F
Agent: C[O-]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: NC1(C(F)F)CCCNC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl-2-difluoromethyl-2,5-diaminopentanoate-dihydrochloride (2.7 g) in dry methanol (30 ml) is added under nitrogen 2 equivalents of sodium methylate in methanol (0.46 g of sodium in 20 ml of methanol). The reaction mixture is stirred for 3 hours at room temperature then the solvent is evaporated under reduced pressure. The residue is extracted with ether to yield crude 3-amino-3-difluoromethyl-2-piperidone which is purified either by crystallization from CHCl3 /pentane: (m.p.: 149° C.) or by distillation (b.p. 135° C./0.05 mmHg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH3:35])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].[O:36]=[C:37]1[CH2:41][CH2:40][C:39](=[O:42])[N:38]1[CH:43](CC([O-])=O)[C:44]([O-:46])=O>>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH3:35])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:37](=[O:36])[CH2:41][CH2:40][C:39]([NH:38][CH2:43][CH2:44][O:46][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]3[C:32]4[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=4)[CH2:26][N:25]([CH3:35])[CH2:24]3)[CH:18]=2)(=[O:16])=[O:15])=[O:42])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: O=C([O-])CC(C(=O)[O-])N1C(=O)CCC1=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)CCC(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Reaction time: 0.32 h

Procedure:
Compound 181 was prepared from compound 28 and (2,5-dioxopyrrolidin-1-yl)succinate following the procedure outlined in example 175. The crude product (200 mg) was purified by Flash-Prep-HPLC with the following conditions: Column, C18 silica gel; mobile phase, CH3CN/H2O/CF3COOH=0.05/100/0.05 increasing to CH3CN/H2O/CF3COOH=90/100/0.05 within 19 min; Detector, UV 254 nm. This resulted in 201 mg (78%) of a TFA salt of N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)succinamide as a white solid. 1H-NMR (300 MHz, DMSO+DCl, ppm): δ 7.76 (d, J=7.5 Hz, 2H), 7.68 (s, 2H), 7.63˜7.52 (m, 6H), 6.64 (s, 1H), 4.88˜4.82 (m, 2H), 4.62-4.42 (m, 4H), 3.76˜3.60 (m, 4H), 3.43˜3.30 (m, 25H), 3.14˜3.10 (m, 4H), 2.97 (s, 6H), 2.86˜2.82 (m, 4H), 2.27 (s, 4H). MS (m/z): 589 [M/2+1]+.