Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[CH:6][N:7]=1.[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.O.CN(C=O)C>[CH3:11][C:10]1[C:4]2[C:5](=[CH:6][N:7]=[C:2]([C:23]3[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=3)[CH:3]=2)[NH:8][N:9]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cnc(Br)cc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1n[nH]c2cnc(-c3cnn(C)c3)cc12
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
In a microwave vial was charged with tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (53 mg, 0.17 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70.6 mg, 0.34 mmol), potassium acetate (205.5 mg, 2.09 mmol), cesium carbonate (166.0 mg, 0.51 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed with dichloromethane (1:1) (13.9 mg, 0.017 mmol). DMF (2.6 mL) and water (0.5 mL) were added. Nitrogen was passed through the mixture for 15 minutes and the vial was capped. The reaction mixture was subjected to microwave irradiation at 125° C. for 20 min. The reaction mixture was filtered through a pad of Celite® and diluted with water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 50-100% ethyl acetate in heptanes, followed by 0-30% methanol in ethyl acetate) to give 127 as a foam (26.0 mg, 71.8%). 1H NMR (400 MHz, DMSO) δ 13.08 (broad s, 1H), 8.90 (s, 1H), 8.19 (s, 1H), 7.98 (s, 1H), 7.94 (s, 1H), 3.88 (s, 3H), 2.53 (s, 3H). LC/MS: m/z 214.1 [M+1]
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH:12]=[CH2:13])[C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])C=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[N:4]1([C:5](=[O:10])[C:6]([F:7])([F:8])[F:9])[CH2:1][CH:13]=[CH:12][CH2:11]1
Reactant: C=CCN(CC=C)C(=O)C(F)(F)F
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: O=C(N1CC=CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To a stirred solution of 319 (26.9 mmol) in freshly distilled CH2Cl2 (250 mL), under nitrogen (1 atm) was added Grubb's Catalyst {RuCl2(CHC6H5)[P(C6H11)2], 0.5 mol %}. After 1.5 h stirring at room temperature, TLC indicated complete conversion of the starting material to a more polar product. The reaction was quenched by bubbling air through the solution. The solution was concentrated and subjected to chromatography purification (5–20% EtOAc in hexanes) to yield 1-(2,5-dihydro-pyrrol-1-yl)-2,2,2-trifluoro-ethanone (320) (22.0 mmol, 82% yield).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br.Br[C:16]1[CH:21]=[CH:20][N:19]=[N:18][CH:17]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27](B(O)O)[CH:28]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([O:32][CH3:33])=[C:25]([C:16]2[CH:21]=[CH:20][N:19]=[N:18][CH:17]=2)[CH:24]=1
Reactant: Brc1ccnnc1
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: [Pd]
Agent: Br
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1-c1ccnnc1
Temperature: 110 °C
Yield: 56.6 %

Procedure:
To an argon purged flask containing toluene (187 mL), ethanol (20.6 mL) and a 2M aqueous solution of sodium carbonate (132.3 mL) was added 4-bromopyridazine hydrobromide (Preparation 5, 15 g, 64 mmol), 5-chloro-2-methoxybenzeneboronic acid (13.4 g, 72 mmol) and tetrakis(triphenylphosphine) palladium (0) (3.2 g, 2.8 mmol). The flask was purged with argon again, then the reaction mixture heated to 110° C. for 4 hours. The mixture was filtered through Celite™ and the filtrate concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was dissolved in ethyl acetate and extracted with a 2M aqueous solution of hydrogen chloride (×3). The aqueous layer was basified with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was then washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound (8 g, 58%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].[B-](F)(F)(F)[CH:13]=[CH2:14].[K+]>C(O)C>[CH3:11][C:3]1[C:2]([CH:13]=[CH2:14])=[CH:7][CH:6]=[CH:5][C:4]=1[N+:8]([O-:10])=[O:9]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CCO
Product: C=Cc1cccc([N+](=O)[O-])c1C

Procedure:
1-Bromo-2-methyl-3-nitrobenzene (5.00 g, 23.1 mmol), potassium trifluoro(vinyl)borate (5.00 g, 37.3 mmol)), TEA (6.45 mL, 46.3 mmol) and PdCl2(dppf)-CH2Cl2Adduct (0.945 g, 1.157 mmol) were added to ethanol (75 mL). The mixture was degassed and then reflux for 3 hrs. The reaction was poured into brine and extracted with ETOAc. The organic layer was separated, dried over Na2SO4, filtered then concentrated. The residue was purified by chromatography on a 330 g ISCO Redi-Sep column using ethyl acetate/hexane solvent system to yield 2-methyl-1-nitro-3-vinylbenzene.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([NH:14][C:15]2[C:16]([NH2:21])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31](=[O:32])[NH:21][C:16]1[C:15]([NH:14][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:34])([CH3:23])([CH3:24])[CH3:25]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ncccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ncccc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 119.4 %

Procedure:
Triethylamine (1.5 mL, 11.0 mmol) was added to a mixture of N3-phenylpyridine-2,3-diamine (510 mg, 2.75 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.94 g, 4.96 mmol), HOAt (670 mg, 4.96 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.95 g, 4.96 mmol) in anhydrous DCM (30 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 10 min then slowly warmed to RT. Stirring at RT was continued for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light brown foam (1.17 g, quantitative). LCMS (Method C): RT 3.04 min [M+H]+ 357.3.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH:12]([C:14]([O:16]CC)=[O:15])[CH3:13].CO.[OH-].[Na+]>C1COCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH:12]([C:14]([OH:16])=[O:15])[CH3:13])=[C:4]([CH:9]=1)[C:3]([OH:19])=[O:2]
Reactant: CCOC(=O)C(C)Oc1ccc(Br)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(Oc1ccc(Br)cc1C(=O)O)C(=O)O
Temperature: 85 °C
Yield: 87.9 %

Procedure:
A solution of 5-bromo-2-(1-ethoxycarbonyl-ethoxy)-benzoic acid methyl ester (41.1 g, 124 mmol) in a mixture of THF (250 mL), MeOH (250 mL) and a 5 M aqueous NaOH solution (300 mL) is heated under reflux (85° C.) for 16 h. After cooling to room temperature the resulting suspension is concentrated by rotary evaporation. The residue is dissolved in water and acidified with an aqueous concentrated HCl solution under cooling with ice. The aqueous phase is extracted twice with EtOAc and the combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a beige solid (31.5 g, 109 mmol, 88%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=13.04 (bs, 2H), 7.72 (d, J=2.7 Hz, 1H), 7.63 (dd, J=8.9, 2.7 Hz, 1H), 6.92 (d, J=8.9 Hz, 1H), 4.90 (q, J=6.6 Hz, 1H), 1.49 (d, J=6.6 Hz, 3H). MS (ES+): 289 (M(C10H979BrO5)+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:31])=[N:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[C:19]([CH2:29][CH3:30])=[N:20][N:21]4[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[N:23][C:22]=34)=[CH:13][CH:12]=2)[CH:10]=1)=O)C.CC(C[AlH]CC(C)C)C.C1COCC1>ClCCl>[CH2:29]([C:19]1[C:18]([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([N:9]3[CH:10]=[C:6]([CH2:4][OH:3])[C:7]([CH3:31])=[N:8]3)=[CH:12][CH:13]=2)=[C:22]2[N:23]=[C:24]([CH3:28])[CH:25]=[C:26]([CH3:27])[N:21]2[N:20]=1)[CH3:30]
Reactant: CCOC(=O)c1cn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(-n2cc(CO)c(C)n2)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
1-[4-(2-Ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-ylmethyl)-phenyl]-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (17) (618 mg, 1.53 mmol) was dissolved in 10 ml of dichloromethane and cooled at −70° C. A 1M solution of DIBAH in THF (3.1 ml, 3.1 mmol) was added and the reaction mixture was stirred for 2 h at −70° C. The mixture was quenched with water and diluted with dichloromethane. The mixture was filtrated and extracted with dichloromethane. Organic layer was washed with water and brine, dried over Na2 SO4 and concentrated to afford a yellow foam. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1O[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:4](=[O:23])[CH:3]=1.[CH2:24]([NH2:31])[C:25]1C=C[CH:28]=[CH:27][CH:26]=1>C(O)C>[CH3:1][C:2]1[N:31]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:4](=[O:23])[CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(=O)c(C(=O)Nc2ccccc2)c(-c2ccccc2)o1
Solvent: CCO
Product: CCCCCn1c(C)cc(=O)c(C(=O)Nc2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
1 g (3.23 mmol) of 6-methyl-4-oxo-N,2-diphenyl-4-H-pyran-3-carboxamide and 590 mg (6.78 mmol) of benzylamine were dissolved in 10 ml of ethanol, and the resulted mixture was stirred over night at room temperature. Ethanol was removed under vacuo. The crystal residue was recrystallized from ethylacetate to afford 700 mg of the title compound having mp. 164°-165.5° C.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1.Cl([O-])(=O)(=O)=O.[Na+]>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C/C=C/C=O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 92.5 %

Procedure:
First, 8.22 g (115 mmol) of crotonaldehyde and 9.22 g (55.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvemnt and butanol (1.5 ml) were added, and 677 mg (5.55 mmol) of sodium perchlorate was added. Then the mixture was heated under reflux for 18 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.2 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 98%, yield of 91% based on benzenesulfonyl cyanide).
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:16]=1)[C:3](=[O:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[O:33]1[C:37](=[O:38])[CH2:36][CH2:35][C:34]1=[O:39].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.O>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]([N:2]([CH2:14][C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][CH2:35][C:34]([OH:39])=[O:33])[CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:1])=[O:13])=[O:12])([CH3:11])([CH3:9])[CH3:10]
Reactant: CN(Cc1cccc(-c2cnc(N3CCNCC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cccc(-c2cnc(N3CCN(C(=O)CCC(=O)O)CC3)nc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
tert-Butyl (2-{methyl[3-(2-piperazin-1-ylpyrimidin-5-yl)benzyl]amino}-2-oxoethyl)carbamate (200 mg) was dissolved in DMF (4 ml), and dihydrofuran-2,5-dione (50 mg) and K2CO3 (125 mg) were added thereto, followed by stirring at room temperature for 1 hour. Water and 1 M hydrochloric acid were added thereto, followed by extraction with EtOAc. The organic layer was dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 4-(4-{5-[3-({[N-(tert-butoxycarbonyl)glycyl](methyl)amino}methyl)phenyl]pyrimidin-2-yl}piperazin-1-yl)-4-oxobutanoic acid (168 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:38])=[CH:4][C:5]([N+:35]([O-:37])=[O:36])=[C:6]([O:8][C:9]2[C:10]([F:34])=[C:11]([CH2:16][NH:17][C:18]([C:20]3[N:24](COCC[Si](C)(C)C)[CH:23]=[N:22][C:21]=3[Cl:33])=[O:19])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:38])=[CH:4][C:5]([N+:35]([O-:37])=[O:36])=[C:6]([O:8][C:9]2[C:10]([F:34])=[C:11]([CH2:16][NH:17][C:18]([C:20]3[NH:24][CH:23]=[N:22][C:21]=3[Cl:33])=[O:19])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F)c1[nH]cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of N-({3-[(5-bromo-4-fluoro-2-nitrophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5carboxamide (55.0 mg, 0.084 mmol) in DCM (6 ml) was added TFA (3.00 ml) and the reaction mixture was stirred at RT for 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give N-({3-[(5-bromo-4-fluoro-2-nitrophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (33 mg, 0.063 mmol, 75% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.03 (d, 1H), 7.74 (s, 1H), 7.32-7.45 (m, 2H), 7.10 (d, 1H), 4.65 (s, 2 H). LC-MS (ES+) m/z 520.92, [M+H].
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:31])[NH:21][C:22]3[S:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][N:26]=3)=[CH:16][C:15]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:9][CH:8]=1.[OH-].[Na+].Cl>O1CCCC1.O>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:21][C:22]3[S:23][C:24]([C:27]([CH3:28])([CH3:29])[CH3:30])=[N:25][N:26]=3)=[O:31])=[CH:16][C:15]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:9][CH:8]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(C)(C)C)s4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4nnc(C(C)(C)C)s4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 60 °C

Procedure:
To a solution of the product of Example 181B in tetrahydrofuran and water (1:1) was added 1 M NaOH (5 equiv). The solution was heated at 60° C. for 40 minutes, cooled, adjusted to pH 6 with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum. The resultant residue was purified by silica gel chromatography eluting with 4% methanol in dichloromethane to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 1.41 (s, 9 H) 3.16-3.30 (m, 1 H) 5.64 (s, 1 H) 6.65 (d, J=8.46 Hz, 2 H) 6.85 (d, J=8.46 Hz, 1 H) 7.15 (d, J=8.46 Hz, 2 H) 7.65 (d, J=8.46 Hz, 1 H) 7.94 (dd, J=8.46, 1.84 Hz, 1 H) 8.10 (d, J=1.47 Hz, 1 H) 8.59 (s, 1 H) 8.89 (d, J=8.82 Hz, 1 H) 10.15 (s, 1 H) 12.85 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:39])[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:38])[C@@H:15]([NH:30]C(OC(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22]CC1C=CC=CC=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:40]>O1CCOCC1>[ClH:40].[CH2:1]([N:19]([CH2:18][CH2:17][CH2:16][C@H:15]([NH2:30])[C:14]([NH:13][CH2:12][CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:39])=[O:38])[C:20](=[O:21])[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](CCCN(Cc1ccccc1)C(=O)O)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 400 mg (0.73 mmol) of benzyl[2-({(2S)-5-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]pentanoyl}amino)ethyl]carbamate (Example 121A) and 1 ml of a 4M solution of hydrogen chloride in dioxane is stirred at RT for 2 h. The reaction solution is concentrated, coevaporated with dichloromethane several times and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][CH:17]([CH:25]([OH:52])[CH:26]([NH:34][C:35](=[O:51])[C@H:36]([CH:48]([CH3:50])[CH3:49])[NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N=C=N.CO>C(Cl)(Cl)Cl>[C:1]([NH:8][C@H:9]([C:13]([NH:16][CH:17]([CH:25]([OH:52])[CH:26]([NH:34][C:35](=[O:51])[C@H:36]([CH:48]([CH3:50])[CH3:49])[NH:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH:10]([CH3:11])[CH3:12])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Agent: N=C=N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C

Procedure:
Boc-valine was coupled to the resultant compound of Example 69 using the carbodiimide coupling procedure of Example 55 to provide, after silica gel chromatography using 3% methanol in chloroform, the desired compound (82%, Rf 0.7, 10% methanol in chloroform) as a white solid, m.p. 184°-184° C. Mass spectrum: (M+H)+ =703.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][C:11]([F:14])=[CH:12][N:13]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH:30]1[C:35]([OH:37])=[O:36]>>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][C:11]([F:14])=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([OH:37])=[O:36])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ncc(F)s2)=NC1c1ccc(Cl)cc1Cl
Yield: 60.8 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(5-fluorothiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.52 g, 1.06 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.21 g, 1.28 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellowish solid (0.35 g, 60%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Cl[C:2]1([CH2:10][C:11]#[C:12][CH2:13][CH3:14])[C:7](=[O:8])[CH2:6][CH2:5][CH2:4]C1=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:10]([C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH:4]=1)[C:11]#[C:12][CH2:13][CH3:14]
Reactant: CCC#CCC1(Cl)C(=O)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCC#CCC1=CCCC1=O
Yield: 73.9 %

Procedure:
2-chloro-2-(pent-2-ynyl)-cyclohexane-1,3-dione (80 g; 0.377 Mole) in dry xylene (800 ml) was allowed to reflux in the presence of anhydrous sodium carbonate (39.2 g; 0.38 Mole) until gas evolution ceased (12 h.). The reaction mixture was cooled, washed three times with water, and dried over magnesium sulfate, and the xylene was removed in vacuo. The resulting residue was distilled through a Vigreux column to afford 2-(pent-2-ynyl)-cyclopent-2-enone (41.3 g; 74 % yield), b.p. 67°-8°/0.01 Torr.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[NH2:14][OH:15].Cl>[OH-].[Na+]>[OH:15][NH:14][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([I:12])=[CH:11][C:2]=1[OH:1]
Reactant: NO
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NO)c1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
23.3 g (84 mmol) of methyl 2-hydroxy-4-iodobenzoate and 360 ml of sodium hydroxide solution (1 N) are introduced into a three-necked flask under a stream of nitrogen. 8 g (113 mmol) of hydroxylamine hydrochloride are added and the mixture is stirred at room temperature for two hours. The reaction medium is adjusted to pH 7-8 with concentrated hydrochloric acid and the solid is filtered off. The solid is dissolved in ethyl acetate and washed with water, and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue is triturated from heptane, filtered and dried. 17.6 g (71.5%) of the expected product are collected, with a melting point of 195-6° C.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: CNC(=O)C(C)Oc1ccc(O)cc1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)Oc1ccc(OCc2cccc(Cl)c2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 3-chloro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(3-chloro-benzyloxy)-phenoxy]-N-methyl-propionamide as a white solid; MS: m/e=320 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].Cl.Cl[CH2:14][CH2:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>ClC1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:19][CH2:18][N:16]([CH3:17])[CH2:15][CH2:14]1
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CN(CCCl)CCCl
Agent: Cl
Solvent: Clc1ccccc1
Product: CN1CCN(c2cc([N+](=O)[O-])ccc2Br)CC1
Yield: 26.5 %

Procedure:
A suspension of 2-bromo-5-nitrobenzenamine (26.0 g) and 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (23.0 g) in chlorobenzene (150 ml) was treated according to the method of Intermediate 56. Purification by FCC eluting with System A (300:8:1 gradient to 200:8:1) gave the title compound as a brown solid (9.498 g) m.p. 100°-103° C.