Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[C:11]([Br:13])[C:10]([NH:14][C:15]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[CH2:19][C@H:18]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:16])=[CH:9][C:8]=1[O:31][CH3:32])(C)(C)C.FC(F)(F)C(O)=O.P([O-])([O-])([O-])=O>ClCCl>[Br:13][C:11]1[C:10]([NH:14][C:15]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[CH2:19][C@H:18]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[O:16])=[CH:9][C:8]([O:31][CH3:32])=[C:7]([CH:12]=1)[C:6]([OH:33])=[O:5]
Reactant: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C(=O)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NC(=O)N2C=CC(=O)C[C@H]2c2ccc(F)cc2)c(Br)cc1C(=O)O
Yield: 71.2 %

Procedure:
(S)-5-Bromo-4-{[2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carbonyl]-amino}-2-methoxy-benzoic acid tert-butyl ester (170 mg) was stirred in 10 ml dichloromethane with 0.1 ml trifluoroacetic acid for 5 hours. Phosphate buffer (pH 7) was added, the layers separated, and the dichloromethane removed in vacuo. The residue was dissolved in acetone and recrystallized by slow addition of water. The crystals were filtered and dried to give 108 mg of (S)-5-bromo-4-{[2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carbonyl]-amino}-2-methoxy-benzoic acid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[C:18]([NH2:20])=[O:19].Cl>O>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:17]1[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=1
Reactant: NC(=O)C(N)c1ccc(Cl)cc1Cl
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 7.9 g of sodium carbonate and 31 ml of water was added dropwise 5.1 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 39 ml of water and then 3.1 g of 2-amino-2-(2,4-dichlorophenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 5.4 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 1.54 g (yield, 35%) of the desired compound, 3-(2,4-dichlorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1007; m.p., 192.8° C.). The continued elution with the above solvent system gave 0.53 g of the configurational isomer, 3-(2,4-dichlorophenyl)-5-trifluoromethyl-2-oxo-1,2-dihydropyrazine (m.p., 131.7° C.).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH3:7][Si:8](Cl)([CH3:10])[CH3:9]>C[Si](N[Si](C)(C)C)(C)C>[Si:8]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][Si:8]([CH3:10])([CH3:9])[CH3:7])([CH3:10])([CH3:9])[CH3:7]
Reactant: OCCCCO
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)OCCCCO[Si](C)(C)C
Temperature: 50 °C

Procedure:
1,4-Butanediol (54 g, 0.60 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.3 mL trimethylsilyl chloride. A portion of HMDS (ca. 20 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (120 mL, 0.66 mol total) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50° C. Heating was continued at 100° C. (3 h), and 150° C. (1.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 127.8 g of colorless oil, bp 97-99° C./15 mm. 1H NMR (CDCl3): 3.75-3.50 (m, 4 H), 1.75-1.50 (m, 4 H), 0.16 (s, 18 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15]O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:23])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2ccccc2CO)cc(OC)c1OC
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2ccccc2CCl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(3,4,5-Trimethoxyphenyl)benzyl alcohol (630 mg) was dissolved in chloroform (10 mL), and to the solution thionyl chloride (0.153 mL) was added at 0° C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then recrystallized from chloroform-hexane to obtain the title compound.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)[S:9][CH:10]=1.C(O)(=O)C.O1CCCC1>O>[CH:2]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)[S:9][CH:10]=1)=[O:1]
Reactant: CC(=O)Nc1nc(C=Cc2cc(C3OCCO3)cs2)cs1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C=Cc2cc(C=O)cs2)cs1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 92.8 %

Procedure:
To N-(4-{2-[4-(1,3-dioxolan-2-yl)thiophen-2-yl]vinyl}-1,3-thiazol-2-yl)acetamide (1.418 g, 4.398 mmol) were added acetic acid (16.8 ml), tetrahydrofuran (5.6 ml) and water (5.6 ml), and the mixture was stirred at 55° C. for 2.5 hr. The reaction mixture was concentrated, and diisopropyl ether was added. The precipitated solid was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give N-{4-[2-(4-formylthiophen-2-yl)vinyl]-1,3-thiazol-2-yl}acetamide (1.136 g, 4.081 mmol, yield 92.8%) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:41]1>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>[CH3:19][C:17]1[CH:18]=[C:10]([CH2:9][CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:41])[N:7]=2)[CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(Br)n2)cc2cn[nH]c12
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1cccc(C(Cc2cc(C)c3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)n1
Temperature: 110 °C
Yield: 94 %

Procedure:
A microwave tube was charged with (±)-N-(1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide (11 mg, 0.0187 mmol, 1.0 equiv), Pd(PPh3)4 (2 mg, 0.1 equiv) and anhydrous tetrahydrofuran (0.5 mL) under nitrogen. ZnMeCl (2.0 M in tetrahydrofuran, 0.12 mL, 0.24 mmol) was added via syringe resulting in gas evolution. The vial was sealed and heated by microwave at 110° C. for 4 h. Tetrahydrofuran was removed in vacuo and the residue was partitioned between ethyl acetate and concentrated ammonium hydroxide solution. The organic layer was separated and washed with brine, dried and concentrated. Flash column chromatography (10% methanol/methylene chloride) afforded the desired product (9.2 mg, 94%) as a white powder. MS (ESI) [M+H]+=524. 1H-NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.33 (br., 1H), 7.22-6.80 (m, 7H), 6.65 (d, J=8.0 Hz, 1H), 6.59 (br., 1H), 6.20 (br., 1H), 5.20-5.08 (m, 1H), 4.62-4.48 (m, 1H), 4.22 (s, 2H), 4.20-4.03 (m, 2H), 3.40-3.28 (m, 1H), 3.10-2.97 (m, 1H), 2.97-2.78 (m, 2H), 2.54 (s, 3H), 2.45 (s, 3H), 1.95-1.50 (m, 5H). HPLC tR=1.11 min.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]1[C:15]([O:21][CH3:22])=[C:14]3[NH:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=O)=[CH:28][C:29]=4[C:13]3=[CH:12][C:11]2=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:22][O:21][C:15]1[C:14]2[NH:23][C:24]3[C:29](=[CH:28][C:27]([CH2:30][NH:32][CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])=[CH:26][CH:25]=3)[C:13]=2[CH:12]=[C:11]2[C:10]3[CH:9]=[C:8]([CH2:6][NH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:38])[CH:20]=[CH:19][C:18]=3[NH:17][C:16]=12
Reactant: COc1c2[nH]c3ccc(C(=O)NCCN(C)C)cc3c2cc2c1[nH]c1ccc(C(=O)NCCN(C)C)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c2[nH]c3ccc(CNCCN(C)C)cc3c2cc2c1[nH]c1ccc(CNCCN(C)C)cc12
Yield: 7.6 %

Procedure:
To a solution of N2,N10-bis(2-(dimethylamino)ethyl)-6-methoxy-5,7-dihydroindolo[2,3-b]carbazole-2,10-dicarboxamide (0.49 g, 0.97 mmol) in THF (100 mL) at 0° C. was added LiAlH4 (0.784 g, 20.66 mmol) under Ar and heated to reflux. The reaction mixture was quenched by dropwise addition of water (2 mL). The solution was filtered, concentrated, and purified by flash chromatography to provide the title product (35.8 mg). 1H-NMR (DMSO-d6, 400 MHz) δ ppm 10.94 (s, 2H), 8.74 (s, 1H), 8.05 (s, 2H), 7.36-7.22 (m, 4H), 4.12-4.05 (m, 2H), 3.84 (s, 3H), 3.16 (d, J=4.4 Hz, 4H), 2.62 (t, J=6.4 Hz, 4H), 2.34 (t, J=6.4 Hz, 4H), 2.10 (s, 12H); MS (ESI) m/z 485.4 (M−H)−
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[N:32][C:33]#[N:34])SC)=[CH:24][CH:23]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1>>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([C@@H:14]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[N:32][C:33]#[N:34])[NH:42][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[CH:38][CH:39]=3)=[CH:24][CH:23]=2)[CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12]
Reactant: CSC(=NC#N)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1
Reactant: NCc1ccc(F)cc1
Product: N#CN=C(NCc1ccc(F)cc1)Nc1ccc([C@@H](Cc2ccncc2)c2ccc(OC(F)F)c(OC(F)F)c2)cc1

Procedure:
From the compound of Example 10 (400 mg, 0.79 mmol) and 4-fluorobenzylamine (1 ml, excess) as a white solid (300 mg). 1Hnmr (300 MHz, CDCl3) δ 3.29 (2H, d, J 8.0 Hz), 4.23 (1H, t, J 7.99 Hz), 4.43 (2H, d, J 5.67 Hz), 5.10 (1H, br), 6.44 (1H, t, J 73.57 Hz), 6.48 (1H, t, J 73.34 Hz), 6.90 (2H, d, J 5.89 Hz), 7.02-7.06 (2H, c), 7.10 (1H, br), 7.13-7.26 (8H, c) and 8.39 (2H, d, J 5.97 Hz). m/z (ESI, 60V) 582 (MH+, 100), 562 (21), 540 (39), 489 (15), 447 (12).
Reaction SMILES: [S:1]1[C:5]2[C:6]([CH2:10][C:11]([OH:13])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:14][C:15]1[C:16]([C:21]2[NH:25][N:24]=[CH:23][N:22]=2)=[C:17]([NH2:20])[S:18][CH:19]=1>>[S:1]1[C:5]2[C:6]([CH2:10][C:11]([NH:20][C:17]3[S:18][CH:19]=[C:15]([Br:14])[C:16]=3[C:21]3[NH:25][N:24]=[CH:23][N:22]=3)=[O:13])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1cccc2ncsc12
Product: O=C(Cc1cccc2ncsc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(benzo[d]thiazol-7-yl)acetic acid (25.5 mg, 0.13 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (22.3 mg, 0.093 mmol) according to protocol A. The crude product was purified by prep HPLC. LCMS Retention time (min)=4.075, method [7], MS(ESI) 421.9 (M+H). 1H NMR (CDCl3) δ 12.39 (s, 1H), 9.02 (s, 1H), 8.22, (d, J=6.6 Hz, 1H), 7.65-7.61 (m, 1H), 7.54 (s, 1H), 7.55-7.49 (m, 1H), 6.90 (s, 1H), 4.19 (s, 2H).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)[CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11]Cl)[CH2:7][CH2:8]Cl.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:1][CH:2]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]2)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:11][N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCc2cc(C(O)CCCN(CCCl)CCCl)ccc2N1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C1CCc2cc(C(O)CCCN3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
2.5 Grams of 6-{1-hydroxy-4-[bis-chloroethyl-amino]butyl}-3,4-dihydrocarbostyril, 1.5 g of aniline and 2.2 g of potassium carbonate were mixed in 150 ml of ethanol and the mixture was refluxed by heating for 24 hours. The reaction mixture was concentrated under a reduced pressure and the residue thus obtained was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was separated and purified by a preparative thin layer chromatography and recrystallized from isopropanol to obtain 0.2 g of 6-[1-hydroxy-4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydrocarbostyril in colorless needle-like crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][N:14]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:13](=[O:21])[C@H:12]([NH:22][C:23]([N:25]2[CH2:30][CH2:29][CH:28]([N:31]3[C:39]4[C:34](=[N:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:10]1.[K].[P:42]([O:60][CH2:61]Cl)([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>>[P:42]([O:60][CH2:61][N:33]1[C:34]2=[N:35][CH:36]=[CH:37][CH:38]=[C:39]2[N:31]([CH:28]2[CH2:29][CH2:30][N:25]([C:23]([NH:22][C@@H:12]3[CH2:11][CH2:10][C@@H:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[F:1])[CH2:15][N:14]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:13]3=[O:21])=[O:24])[CH2:26][CH2:27]2)[C:32]1=[O:40])([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:43]
Reactant: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: O=P(OCCl)(OCc1ccccc1)OCc1ccccc1
Agent: [K]
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)n(COP(=O)(OCc3ccccc3)OCc3ccccc3)c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyri din-1-yl)piperidine-1-carboxamide, potassium salt, [Burgey et al. U.S. Pat. No. 6,953,790 B2] (1.00 g, 1.65 mmol) in anhydrous, degassed DMF (200 mL) at ambient temperature was added dibenzyl chloromethyl phosphate [Mäntylä et al. Tetrahedron Lett. 2002, 43, 3793] (0.54 g, 1.65 mmol). The resulting mixture was stirred at ambient temperature for 4 h, filtered, and purified by preparative HPLC on a C18 reversed phase column, eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 0:100:0.1. The product-containing fractions were poured into saturated aqueous NaHCO3 and extracted with EtOAc (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=857.7 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[C:14]([O:18][C:19]([N:21]1[CH2:28][CH:27]2[CH:23]([CH2:24][N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:35][NH2:36])[CH2:26]2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH:23]2[CH:27]([CH2:26][N:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:35][NH:36][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[NH:7][N:6]=[C:5]4[Cl:13])[CH2:24]2)[CH2:28]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ccccc3CN)CC2C1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccccc3CNc3ccc4c(=O)[nH]nc(Cl)c4c3)CC2C1
Temperature: 90 °C
Yield: 21 %

Procedure:
A mixture of 6-bromo-4-chloro-2H-phthalazin-1-one (136 mg, 0.52 mmol), 5-(2-aminomethyl-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (150 mg, 0.48 mmol), Pd2(dba)3 (22 mg, 0.024 mmol), BINAP (49 mg, 0.078 mmol) and NaOt-Bu (147 mg, 1.56 mmol) in DMA (10 mL) was purged with nitrogen for 10 min. The mixture was heated at 90° C. for 2 h. The mixture was allowed to cool and diluted with ethyl acetate (30 mL) and washed with ammonium chloride (25 mL). The organic layer was dried and concentrated. Chromatography on silica yielded the title compound (50 mg, 19%) m/z (M+H)=496.12.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][CH2:40][C:41]([OH:43])=[O:42]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][CH2:40][C:41]([OH:43])=[O:42])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Reactant: NCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCC(=O)O
Yield: 58.8 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (400 mg) prepared by the method described in Preparation 2 and glycine (300 mg), N-(3-hexadecanoyloxyoctadecanoyl)glycine (260 mg) was obtained as powders according to a similar manner to that of Preparation B-1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=3)[C:10]([CH2:24][CH3:25])=[C:9]([CH3:26])[N:8]=2)=[CH:4][CH:3]=1.C[N:28]([C:30](ON1N=NC2C=CC=NC1=2)=[N+:31](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:31][C:30]#[N:28])=[O:22])=[CH:16][CH:15]=3)[C:10]([CH2:24][CH3:25])=[C:9]([CH3:26])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(CC(=O)NC#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A 8-mL vial was charged with 2-[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetic acid (30 mg, 0.077 mmol, 1 eq.), cyamide (30 mg, 0.71 mmol, 9 eq.), HATU (44 mg, 0.16 mmol, 1.5 eq.), diisopropylethylamine (35 mg, 0.27 mmol, 3.5 eq.) and DMF (0.5 ml). The resulting mixture was stirred at rt overnight until the starting acid was consumed. The mixture was added to NaHCO3 aq. (5 ml) and extracted with ethyl acetate (5 ml×3). The organic layers were combined and dried over Na2SO4. Removal of solvent gave a residue, which was purified by chromatography on silica gel using 0.5˜3% of MeOH in DCM as eluent to give the title compound as a white solid (16 mg, 50% yield). MW=411.91. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (brs, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.55 (d, J=4.0 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H), 7.15 (d, J=4.0 Hz, 1H), 5.77 (s, 2H), 2.74 (q, J=7.6 Hz, 2H), 2.40 (s, 3H), 1.20 (t, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[S:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([CH3:25])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCC(=O)NCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NCCCCCCOS(C)(=O)=O
Yield: 107.2 %

Procedure:
To a solution of 2.00 g (7.37 mmol) of N-(6-hydroxyhexyl)caprylamide and 1.23 ml of triethylamine in 50 ml of methylene chloride was added 0.68 ml (8;84 mmol) of methanesulfonyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 2.54 g of the desired compound (98.6%, colorless powder), mp: 62.0°-63.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:11][C@H:10]([NH:12][OH:13])[CH2:9]2)=[CH:4][CH:3]=1.[N:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]=[O:16].CCO>C1COCC1>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][NH:14][C:15]([N:12]([C@H:10]1[CH2:11][C@@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9]1)[OH:13])=[O:16])[CH3:22]
Reactant: CCOC(=O)CN=C=O
Reactant: ON[C@H]1C[C@@H](c2ccc(F)cc2)C1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CNC(=O)N(O)[C@H]1C[C@@H](c2ccc(F)cc2)C1
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a stirred solution of cis-3-(4-fluorophenyl)cyclobutylhydroxylamine (0.9 g, 5 mmol) in THF (20 ml) was added ethyl isocyanatoacetate (0.71 g, 5.5 mmol). After stirring for 10 minutes, EtOH was added. Volatiles were removed in vacuo and the resulting residue was recrystallized from ethyl acetate/n-hexane to afford 1.10 g (71% yield) of the title compound as colorless needles, m.p. 130-132° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[F:34].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=3)[C:11]([NH:13][C:14]([CH3:20])([CH3:19])[C:15]([F:16])([F:18])[F:17])=[O:12])[CH2:2][CH2:3]2)=[O:30])=[CH:27][C:26]=1[F:34]
Reactant: CC(C)(NC(=O)c1cccc(CN2CCNCC2)c1)C(F)(F)F
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1)C(F)(F)F
Reaction time: 0.08 h
Yield: 70.6 %

Procedure:
3-(Piperazin-1-ylmethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (1.518 mmol, 0.5 g), 4-amino-3-fluorobenzoic acid (1.518 mmol, 0.235 g) and triethylamine (3.80 mmol, 0.529 mL, 0.384 g) were dissolved in dichloromethane (15.18 mL) and stirred for 5 minutes. 1-Propanephosphonic acid cyclic anhydride (3.04 mmol, 1,799 mL, 1.932 g, 50% solution in ethyl acetate) was added dropwise and the reaction mixture was allowed to stir for 1 hour. Dichloromethane was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated to yield the title compound (500 mg). MS (ESI) m/z 467.4 [M+H]+