Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:15])=[O:6])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]([NH2:27])=[O:26]>CN(C=O)C>[CH3:3][C:2]([CH3:16])([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:25]([NH2:27])=[O:26])=[CH:10][C:9]=1[CH3:15])=[O:6])[CH3:1]
Reactant: Cc1cc(O)ccc1NC(=O)OC(C)(C)C
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(OCC(N)=O)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
To a 200 mL round bottomed flask with a stirring bar, and an argon inlet was added 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenol (5.00 g, 22.39 mmot), Cs2CO3 (14.59 g, 44.78 mmol), DMF (50 mL), and bromoacetamide (3.24 g, 23.51 mmol). This mixture was stirred vigorously at ambient temperature for 24 h. The mixture was filtered through a frit and the DMF was removed under high vacuum. The residue was dissolved in EtOAc (300 mL) and washed wit H2O (2×) and brine (1×). Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a solid. This material was triturated with EtOAc, the solid was collected by filtration and dried in vacuo to give 4.91 g (78%) of 4-(1,1-dimethyl-ethoxycarbonyl)amino-3-methylphenoxyacetamide as a white, crystalline solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1/[CH:17]=[CH:18]/[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20].O>CS(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH:17]1[CH2:4][CH:18]1[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20]
Reactant: C[S+](C)(C)=O
Reactant: CON(C)C(=O)/C=C/c1cc(F)ccc1Br
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CON(C)C(=O)C1CC1c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 122 mg, 3.05 mmol, Aldrich) was added to a suspension of trimethylsulfoxonium iodide (671 mg, 3.05 mmol, Aldrich) in DMSO (6 mL). The mixture was stirred at 25° C. for 30 min, and (E)-3-(2-bromo-5-fluorophenyl)-N-methoxy-N-methylacrylamide was added as a solution in DMSO (3 mL). The mixture was stirred at 25° C. for 12 h, then transferred to a separatory funnel with H2O (40 mL), and the title compound was extracted using 75% ether/hexane (3×40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by flash column chromatography (33% EtOAc/hexane) afforded the title compound as a colorless oil. MS m/z: 302 and 304 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:69])[C:58]2[CH:63]=[C:62]([F:64])[CH:61]=[CH:60][C:59]=2[C:65]([F:68])([F:67])[F:66])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.O>[F:64][C:62]1[CH:61]=[CH:60][C:59]([C:65]([F:67])([F:66])[F:68])=[C:58]([CH:63]=1)[C:57]([N:54]1[CH2:55][CH2:56][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:22]([C:19]2[CH:18]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[F:10])[O:21][N:20]=2)=[O:24])[CH2:52][CH2:53]1)=[O:69]
Reactant: NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1
Reactant: O=C(O)c1cc(-c2ccccc2F)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2F)on1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 32.7 %

Procedure:
DIPEA (219 mg, 0.29 mL, 1.68 mmol) was added to a stirred solution of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid (100 mg, 0.48 mmol) in DMF (2 mL). HOBT (68.5 mg, 0.5 mmol) and EDCI (97.2 mg, 0.5 mmol) were then added at room temperature. After 2 minutes, 2-amino-1-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (100 mg, 0.48 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid precipitated. The obtained solid was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in hexane as eluent) to afford 82 mg (32.5% yield) of 5-(2-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.05%. 1H NMR (DMSO-d6): δ 8.8 (t, 1H), 7.9 (m, 2H), 7.4 (m, 5H), 7.2 (d, 1H), 7.2 (d, 1H), 4.2 (m, 2H), 3.9 (m, 1H), 3.5 (m, 3H), 3.4 (m, 1H), 3.1 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:10].Cl.[CH2:12]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[CH3:13].C(=O)([O-])O.[Na+]>>[CH2:12]([O:14][C:15]([C:16]1[NH:17][C:2]2[C:3]([F:10])=[CH:4][N:5]=[CH:6][C:7]=2[C:8]=1[NH2:9])=[O:18])[CH3:13]
Reactant: N#Cc1cncc(F)c1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1[nH]c2c(F)cncc2c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.8 %

Procedure:
A mixture of 4-chloro-5-fluoro-nicotinonitrile (3.5 g, 22.4 mmol), glycine ethyl ester hydrochloride (9.4 g, 67.1 mmol) and sodium hydrogencarbonate (11.3 g, 134.2 mmol) in IMS (60 mL) was stirred at reflux for 18 hours. The reaction was then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated and washed with water and brine, dried over sodium sulphate, filtered and concentrated to give a solid which was triturated in diethyl ether. The mixture was aged at room temperature for 18 hours and the precipitate was filtered off and dried under vacuum at 60° C. to give the title compound as a beige solid (2.29 g, 46%). LCMS (method B): RT=1.50 min, M+H+=224.
Reaction SMILES: CC(C)[O-:3].[Al+3:5].CC(C)[O-:8].CC(C)[O-:12]>O>[O-2:3].[O-2:8].[O-2:12].[Al+3:5].[Al+3:5].[OH-:3].[Al+3:5].[OH-:3].[OH-:3]
Reactant: CC(C)[O-]
Agent: [Al+3]
Solvent: O
Product: [O-2]
Product: [OH-]

Procedure:
The resulting supernatant (solids content, 0.17 mass %), 94.4 g (fine α-alumina particles, 0.16 g), 25 g of aluminum hydroxide obtained by hydrolyzing aluminum isopropoxide, and 105.6 g of purified water at room temperature (about 25° C.), were mixed with one another and introduced into a sand grinder and stirred at 2000 rpm for 30 minutes, followed by evaporating water under reduced pressure in a rotary evaporator on a water bath at 60° C., to give a dried mixture in a powdery form.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH3:5].[CH3:6][CH2:7]N(C(C)C)C(C)C.Cl[C:16](=[N:22][OH:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(Cl)Cl>[O:23]1[C:7]2([CH2:5][CH2:4][O:3][CH2:2][CH2:1]2)[CH2:6][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:22]1
Reactant: CCOC(=O)C(Cl)=NO
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1=NOC2(CCOCC2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 25 %

Procedure:
The ether solution was transferred to a 100 mL round-bottom flask equipped with a magnetic stir bar, and DIPEA (1.1 eq., 0.96 mL, 5.5 mmol) was added via syringe. Ethyl 2-chloro-2-(hydroxyimino)acetate (1 eq., 758 mg, 5.00 mmol) was dissolved in DCM (50 mL) and placed in a dropping funnel. The DCM solution was added dropwise to the vigorously stirred ether reaction mixture over a period of 2 h. The resulting solution was stirred at RT for 3 days. The solvent was removed under reduced pressure, and the residue was purified by column chromatography using a 24-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 2:3, v/v over 30 min, yielding 264 mg (25%) of the desired ester. 1H-NMR (400 MHz, CDCl3) δ: 4.35 (q, J=7.2 Hz, 2H), 3.89 (ddd, J=11.7, 8.6, 3.4 Hz, 2H), 3.63-3.76 (m, 2H), 2.99 (s, 2H), 1.87-1.98 (m, 2H), 1.74-1.87 (m, 2H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[CH3:27][C:28](=[CH2:37])[C:29]([O:31][CH2:32][CH2:33][N:34]=[C:35]=[O:36])=[O:30].O>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][C:35](=[O:36])[NH:34][CH2:33][CH2:32][O:31][C:29](=[O:30])[C:28]([CH3:37])=[CH2:27])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Solvent: O
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCNC(=O)Nc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 494 (0.055 g, 0.15 mmol) was dissolved in dry pyridine (0.3 mL) and isocyanatoethyl methylacrylate (0.031 mL, 0.22 mmol) was added. The solution was stirred at room temperature for 1 h. H2O was added and the water phase was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 2:1 as the eluent. This afforded the title compound as oil. 13C NMR (CDCl3) δ 196.5, 167.5, 159.2 (dd), 155.8, 155.6 (dd), 148.2, 139.7, 136.3, 135.9, 135.1, 133.9, 132.4, 132.0, 128.6, 126.1, 124.5 (dd), 124.2 (dd), 123.3, 121.2, 116.3, 112.7, 111.6 (dd), 104.9 (dd), 63.9, 39.3, 19.6, 18.2
Reaction SMILES: [OH-:1].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([CH:11](Cl)Cl)(O)[CH3:9].[OH2:14]>C1C=CC=CC=1>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]([CH3:9])[C:11]([OH:14])=[O:1]
Reactant: CC(O)(c1cccs1)C(Cl)Cl
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C(=O)O)c1cccs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
In 40 ml of benzene, 3.93 g of sodium hydroxide (98 mmol) was crushed finely. Under vigorous agitation, 2.09 g of 1-(2-thienyl)-1-dichloromethylethanol (9.9 mmol) was added thereto and agitated for 24 hours at room temperature and then 20 ml of water was added thereto under ice cooling. After washing the diethylether, the aqueous alkaline solution was neutralized (about pH 2) with 6 N hydrochloric acid and extracted with diethylether. The ether layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and then the ether was distilled off. Thus, 1.22 g of α-(2-thienyl)propionic acid was obtained (yield 79%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:33][CH:34]1[CH2:37][CH:36]([OH:38])[CH2:35]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[OH:38][C@@H:36]1[CH2:37][C@H:34]([NH:33][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=2)=[O:22])[CH2:35]1.[OH:38][C@H:36]1[CH2:37][C@H:34]([NH:33][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[CH:19]=2)=[O:22])[CH2:35]1
Reactant: NC1CC(O)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2C[C@@H](O)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2C[C@H](O)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (250 mg, 0.57 mmol), 3-aminocyclobutanol hydrochloride (98 mg, 0.79 mmol) and DMF (2.8 mL). N,N-diisopropylethylamine (266 mg, 0.36 mL, 2.06 mmol) was added followed by HATU (237 mg, 0.62 mmol). The yellow solution was stirred at room temperature overnight (a precipitate was formed). The reaction mixture was diluted with water and petroleum ether. The suspension was filtered. The solid was washed with water and a little petroleum ether. The resulting off-white powder was dried under high vacuum. The mixture of cis- and trans-product (265 mg off-white powder) was submitted for further separation by SFC chromatography (KROMASIL OD 3×25 cm, 25% MeOH/CO2+0.1% Triethylamine) to afford 139 mg (48%) 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclobutyl)-amide as an off-white solid and 102 mg (35%) 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (trans-3-hydroxy-cyclobutyl)-amide as an off-white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>O1CCCC1.O>[CH3:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])=[O:20])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: N[C@@H](CO)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)N[C@@H](CO)C(=O)O)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
L-Serine (100 g, 0.952 mol) (Wako Pure Chemical Industries, Ltd.), potassium carbonate (131.5 g, 0.952 mol) (Wako Pure Chemical Industries, Ltd.), and water 1 L were placed into a recovery flask (egg plant flask), followed by stirring vigorously. p-Methylbenzoyl chloride prepared in Step 1 was dissolved in tetrahydrofuran (Wako Pure Chemical Industries, Ltd.), which was added dropwise to this solution for 30 minutes. During this process, pH was maintained in the vicinity of 8 while additionally adding potassium carbonate. After the completion of the dropwise addition, the agitation was performed for 1 hour. The reaction solution was added to water 1 L which was prepared in a distinct vessel, and then pH was adjusted to not more than 3 with hydrochloric acid, followed by being cooled to 4° C. Precipitated crystals were filtrated, followed by being recrystallized with a mixed solvent of ethanol (Wako Pure Chemical Industries, Ltd.)/water=6/4. An objective substance was obtained in an amount of 106.0 g (yield: 64.7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH3:14].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:22](=[O:24])[CH3:23])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH3:14]
Reactant: CC(=O)Cl
Reactant: Cc1cc(=O)oc2cc(O)c(Br)cc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc2oc(=O)cc(C)c2cc1Br
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.7 %

Procedure:
To a solution of 453.1 mg (1.776 mmol) of compound 17 and 545 mL (3.9 mmol) of triethylamine in dry acetonitrile (5 mL) was added 255 mL (3.59 mmol) of acetyl chloride. The reaction mixture was stirred for 15 hours at room temperature, quenched with 1N HCl, diluted with chloroform and separated. The organic layer was washed with saturated aqueous NaHCO3 and saturated aqueous brine, dried (MgSO4) and evaporated to dryness to yield 404.9 mg (1.363 mmol, 76.7% yield) of the crude compound 18. This compound was used for the next reaction without a further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:19])=[O:18].[NH2:20][C:21]1[N:26]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[CH:24]=[C:23]([CH3:30])[N:22]=1>O1CCOCC1>[CH3:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([S:12]([NH:15][C:16]([NH:20][C:21]3[N:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[CH:24]=[C:23]([CH3:30])[N:22]=3)=[O:17])(=[O:14])=[O:13])[C:5]=2[O:4][S:3]1(=[O:19])=[O:18]
Reactant: CC1Cc2cccc(S(=O)(=O)N=C=O)c2OS1(=O)=O
Reactant: Cc1cc(C2CC2)nc(N)n1
Solvent: C1COCCO1
Product: Cc1cc(C2CC2)nc(NC(=O)NS(=O)(=O)c2cccc3c2OS(=O)(=O)C(C)C3)n1
Reaction time: 18 h

Procedure:
66.5 ml of a 10.78% solution of 3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl isocyanate in dioxane is added dropwise over 5 minutes at room temperature to a mixture of 3.72 g of 2-amino-4-cyclopropyl-6-methylpyrimidine in 100 ml of absolute dioxane. The mixture is stirred for a further 18 hours and then concentrated by evaporation. The residue is crystallised by trituration with a 1:2 mixture of ethyl acetate and petroleum, affording 11.2 g of N-(3,4-dihydro-3-methyl-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl)-N'-(4-cyclopropyl-6-methylpyrimidin-2-yl)urea with a melting point of 216°-217° C.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[CH2:2][C:3]([OH:5])=[O:4].[CH2:16]([OH:23])[C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19]>C(O)C.[Pd]>[NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:16]([OH:23])[C:17]([NH2:22])([CH2:20][OH:21])[CH2:18][OH:19]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: NC(CO)(CO)CO
Solvent: CCO
Product: NCC(=O)O

Procedure:
The title compound was prepared by hydrogenation of a solution of Z-Gly-Tris in ethanol at 40 pa. pressure in a Parr hydrogenator in the presence of palladium on carbon (10% ). The removal of the Z group was monitored by HPLC. The catalyst was removed by filtration and washed with ethanol. Evaporation of the solvent gave the title compound in 95% yield. The preparation of Z-Gly-Tris is described in Whittaker, R. G., Hayes, P. J., and Bender, V. J. (1993). Peptide Research 6; 125 and Australian Patent No. 649242.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](Cl)=[N:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-:32].[K+].[K+]>ClC(Cl)Cl>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:32].[C:24]1([NH:23][NH2:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C1CNCCN1
Reactant: Fc1ccccc1C(Cl)=NNc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: NNc1ccccc1
Product: O=C(c1ccccc1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a stirred mixture of 12.5 parts of piperazine, 3.6 parts of N,N-diethylethanamine and 75 parts of trichloromethane was added a solution of 9 parts of 2-fluoro-N-phenylbenzenecarbohydrazonoyl chloride in 75 parts of trichloromethane. The whole was stirred for 2 hours at room temperature. After the addition of 5 parts of potassium carbonate, the reaction mixture was stirred for 30 minutes at reflux temperature. The mixture was cooled, washed with 100 parts of water and the layers were separated. The organic layer was dried, filtered and evaporated, yielding 6 parts (55.8%) of 1-(2-fluorobenzoyl)-piperazine, 2-phenylhydrazine as a residue (int. 9).
Reaction SMILES: FC1C=CC=C(F)C=1C[NH2:5].C(N(CC)C(C)C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[F:39][C:40]1[CH:69]=[C:68](OC)[CH:67]=[C:66]([F:72])[C:41]=1[CH2:42][N:43]1[C:48]2[N:49]=[CH:50][CH:51]=[CH:52][C:47]=2[S:46](=[O:54])(=[O:53])[N:45]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])C=2)[C:44]1=[O:65]>CN(C=O)C>[F:39][C:40]1[CH:69]=[CH:68][CH:67]=[C:66]([F:72])[C:41]=1[CH2:42][N:43]1[C:48]2[N:49]=[CH:50][CH:51]=[CH:52][C:47]=2[S:46](=[O:53])(=[O:54])[N:45]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([O:63][CH3:64])[N:5]=2)[C:44]1=[O:65]
Reactant: NCc1c(F)cccc1F
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3cccnc32)c(F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2C(=O)N(Cc3c(F)cccc3F)c3ncccc3S2(=O)=O)nc1OC

Procedure:
The title compound (57 mg, 0.12 mmol) was prepared in two steps from (IntC3) (165 mg, 0.5 mmol), 2,6-difluorobenzylamine (70 uL, 0.6 mmol) and N,N-diisopropylethylamine (180 uL, 1.0 mmol); followed by 1,1′-carbonyldiimidazole (305 mg, 1.88 mmol), triethylamine (0.13 mL, 0.93 mmol) in DMF (1.5 mL) using the methods of (95).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[CH:6]=1)=O.O.[NH2:14][NH2:15]>C(O)C>[CH3:12][N:7]1[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([NH:14][NH2:15])=[O:2])=[CH:6]1
Reactant: COC(=O)c1ccc(=O)n(C)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cn1cc(C(=O)NN)ccc1=O
Temperature: 78 °C
Reaction time: 8 h

Procedure:
The title compound of Example 27 (775 mg, 4.64 mmol) was dissolved in ethanol (10 mL) and heated to 78° C. Hydrazine hydrate (1.12 mL, 23.2 mmol) was added and the reaction was stirred at 78° C. overnight. The reaction was then cooled to room temperature and the product (white solid) was filtered off (590 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1>ClCCl>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([NH:41][C:42]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:43])[CH:38]=[CH:39][CH:40]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COc1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (50 mg, 0.13 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (20 mg, 0.19 mmol) (Aldrich), followed by the addition of 3-methoxyphenyl isocyanate (24 mg, 0.16 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (3-methoxy-phenyl)-amide as a white solid. (Yield 45 mg, 64%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([S:8][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(Br)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Sc1cccc(Br)c1

Procedure:
10 g (52.9 mmol) of 3-bromothiophenol are placed in the presence of 9.4 ml (63.5 mmol) of ethyl bromoisobutyrate and 8 g (57.9 mmol) of K2CO3 in 100 ml of EtOH. This mixture is stirred at reflux for 4 h and then dry concentrated. The residue is taken up in water. After extraction in AcOEt and then drying on MgSO4, the organic phases are dry concentrated. The oil obtained is purified by flash chromatography on silica (petroleum ether:AcOEt 90:10) and 11a is isolated in the form of clear oil (16.8 g, quantitative yield). TLC silica gel 60 F 254 Merck, petroleum ether:AcOEt 90:10, Rf=0.72.