Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:21]>O>[Cl:21][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1ccc2onc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2onc(Cl)c2c1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
3-Hydroxy-5-methyl-1,2-benzisoxazole (15.0 g, 100.6 mmol; preparation: Australian Journal of Chemistry (1977), 30(8), 1847-50) were suspended in triethylamine (15.4 ml, 110.6 mmol), and phosphorus oxytrichloride (37.0 g, 22.5 ml, 241.4 mmol) was added dropwise with cooling to this mixture at room temperature. Since stirring of the reaction mixture became almost impossible after about half the amount of phosphorus oxytrichloride had been added dropwise, the temperature was raised to 50° C. After dropwise addition of the total amount of phosphorus oxytrichloride, the reaction mixture was heated at 130° C. for 5 h, after which the reaction was complete according to TLC. After cooling, the mixture was slowly added dropwise to water (200 ml) while cooling, the aqueous phase was extracted 3 times with MtB ether, the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. This resulted in 14.6 g of 3-chloro-5-methyl-1,2-benzisoxazole (yield: 87%) as viscous oil which solidified overnight. MS (MSD) m/z 168 [M+H+].
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1>>[CH3:7][N:6]1[C:2]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Product: Cn1ncc([N+](=O)[O-])c1O[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 93 %

Procedure:
Following the procedure for Example 230, reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate gave (R)-tert-butyl 3-(1-methyl-4-nitro-1H-pyrazol-5-yloxy)piperidine-1-carboxylate as a pale yellow oil (0.34 g, 93%). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.15-4.85 (m, 1H), 3.84-3.72 (m, 2H), 3.69 (s, 3H), 3.41 (d, J=14.2 Hz, 1H), 3.30-3.13 (m, 1H), 2.11-2.02 (m, 1H), 1.94-1.82 (m, 2H), 1.63-1.52 (m, 1H), 1.42 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[C@@H:13]([CH2:21]O)[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(OP(OC2C=CC=CC=2)([N:51]=[N+:52]=[N-:53])=O)=CC=1>C1COCC1>[N:51]([CH2:21][C@@H:13]1[C@H:14]2[O:18][C:17]([CH3:19])([CH3:20])[O:16][C@H:15]2[C@H:11]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[CH:10]=[CH:9]2)[CH2:12]1)=[N+:52]=[N-:53]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](CN=[N+]=[N-])C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol (2.68 g, 8.28 mmol) was dissolved in THF (32 mL), treated with PPh3 (3.05 g, 11.6 mmol), and the reaction vessel was cooled in an ice-brine bath. Diisopropyl azodicarboxylate[DIAD] (2.3 mL, 12 mmol) was added dropwise via syringe and the mixture was stirred for 10 min. A solution of diphenylphosphonic azide [DPPA] (2.50 mL, 11.6 mmol) in THF (7.8 mL) was added dropwise via syringe to afford a off-white mixture, which was stirred for 21 h, allowing the ice bath to warm to RT; HPLC/LC MS indicated complete consumption of starting material and formation of product. At 22.5 h the reaction mixture was concentrated in vacuo and purified by column chromatography (4×22 cm silica; 0-25% EtOAc/Hex) to afford the title compound (2.27 g, 78%) as a clear, colorless oil: MS (ESI+) for C15H17ClN6O2 m/z 349.2 (M+H)+; MS (ESI−) for C15H17ClN6O2 m/z 393.2 (M+HCO2)−; HPLC purity >95% (ret. time, 4.169 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:14]([CH3:26])[C:13](=[O:27])[C:12](C(O)C)=[C:11]3[NH:31]C(=O)C)=[CH:4][CH:3]=1.O1CCOCC1.Cl>CCOC(C)=O>[NH2:31][C:11]1[C:10]2[C:15](=[N:16][C:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)[N:14]([CH3:26])[C:13](=[O:27])[CH:12]=1
Reactant: CC(=O)Nc1c(C(C)O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1c(=O)cc(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc21

Procedure:
The product of Example 3 (21 mg) was combined with 2.8 mL of 1,4-dioxane and 1 mL 1M aqueous HCl. After 15 hours at room temperature the reaction was diluted with EtOAc and washed with water followed by saturated aqueous NaHCO3 solution before drying (Na2SO4). The concentrated residue was purified by preparative TLC (silica gel) eluted with EtOAc affording the title compound. HPLC/MS: 430.0 (M+1), 432.0 (M+3); Rt=3.77 min.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9](Cl)=[CH:10][C:11]=2[CH3:15])[N:6]=1)(=O)C.[CH3:17][O-:18].[Na+]>CO>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[N:8][C:9]([O:18][CH3:17])=[CH:10][C:11]=2[CH3:15])[N:6]=1
Reactant: C[O-]
Reactant: CC(=O)Nc1ccc2c(C)cc(Cl)nc2n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2ccc(N)nc2n1

Procedure:
To a suspension of 2-acetamido-5-methyl-7-chloro-1,8-naphthyridine (23.5 g., 0.10 mole) in 250 ml. of methanol is added sodium methoxide (16.2 g., 0.30 mole). The resulting solution is stirred at reflux under nitrogen atmosphere for 18 hours. The methanol is removed in vacuo and the residue is taken up in chloroform (250 ml.) and water (100 ml.). The chloroform layer is separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is recrystallized from ethanol to yield 2-amino-5-methyl-7-methoxy-1,8-naphthyridine melting at 233°-236° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16][CH3:17])=[C:11]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[C:11]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(OCc2ccccc2)cc1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: O
Solvent: CS(C)=O
Product: CCC(=O)c1ccc(OCc2ccccc2)cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 7 %

Procedure:
1-{4-(Benzyloxy)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml) to prepare a solution. A sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (15 mg, yield 7%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].[N:27]([CH2:30][CH:31]=[CH2:32])=C=S>CC#N>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:27][CH2:30][CH:31]=[CH2:32])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: C=CCN=C=S
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC#N
Product: C=CCNC(=S)N[C@H]1[C@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanato-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.50 g, 1.31 mmol) in CH3CN, was added neat 3-isothiocyanatoprop-1-ene (0.155 g, 1.2 mmol), dropwise. The reaction was stirred at room temperature until complete by TLC (3 h). The reaction was washed with a minimal amount of saturated aqueous NaHCO3 (15 mL). The aqueous layer was then extracted three times with DCM, and the organic layers were combined, dried with MgSO4, filtered and concentrated. The concentrated mixture was purified via flash column chromatography in a solvent system of 1:1 EtOAc and hexanes, providing (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-allylthioureido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate (0.410 g, 81% yield) 1H NMR (500 MHz, CDCl3) δ 1.98 (s, 3H), 2.00 (s, 3H), 2.03 (s, 3H), 2.05 (s, 3H), 3.81-3.83 (m, 1H), 4.02-4.08 (m, 3H), 4.21 (dd, 1H, J=4.6, 12.5 Hz), 5.06-5.15 (m, 3H), 5.20-5.30 (m, 2H), 5.72 (d, 1H, J=8.6 Hz), 5.75-5.8 (s, 1H), 6.42-6.52 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[NH2:9][C:10]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]2[C:11]=1[CH2:12][O:13][C:14]2=[O:20].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[F:19][C:17]1[CH:16]=[C:15]2[C:11]([CH2:12][O:13][C:14]2=[O:20])=[C:10](/[N:9]=[CH:7]/[C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH:18]=1
Reactant: Cn1ccnc1C=O
Reactant: Nc1cc(F)cc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cn1ccnc1/C=N/c1cc(F)cc2c1COC2=O
Yield: 68.7 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-carbaldehyde (659 mg, 6.0 mmol), 4-amino-6-fluoroisobenzofuran-1(3H)-one (1.0 g, 6.0 mmol), and anhydrous magnesium sulfate (7.2 g, 60.0 mmol) in acetonitrile (100 mL) was heated to reflux for 2 days. The solution was filtered and the solvents were removed in vacuum. The crude product was re-crystallized from isopropanol to afford the title compound (1.068 g, yield 68%) LC-MS (ESI) m/z: 260 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.04 (s, 3H), 5.49 (s, 2H), 7.24 (s, 1H), 7.54-7.58 (m, 2H), 7.73-7.76 (m, 1H), 8.70 (s, 1H).
Reaction SMILES: [C:1]1([S:7][CH2:8][C@H:9]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:17][C:16]=2[S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:32]([O:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][O:55][Si:56]([C:69]([CH3:72])([CH3:71])[CH3:70])([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Si:32]([O:49][CH2:50][CH2:51][N:52]([CH2:53][CH2:54][O:55][Si:56]([C:69]([CH3:72])([CH3:71])[CH3:70])([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:11](=[O:12])[CH2:10][C@@H:9]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:17][C:16]=1[S:25]([C:28]([F:29])([F:31])[F:30])(=[O:27])=[O:26])[CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:45]([CH3:46])([CH3:47])[CH3:48])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Reactant: CC(C)(C)[Si](OCCNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](OCCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F)(c1ccccc1)c1ccccc1
Yield: 83.1 %

Procedure:
The title product (1.06 g, yield: 83%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 24 utilizing (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 600 mg, 1.2 mmol) and bis(2-(tert-butyldiphenylsilyloxy)ethyl)amine (INTERMEDIATE 29, 0.700 g, 1.20 mmol) as starting materials. The title product was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].C(N(CC)CC)C>ClCCl>[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:28]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccco3)CC1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a solution of spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione (0.1 g, 0.33 mmol) in dichloromethane (3.0 mL) was added 2-furoyl chloride (0.050 g, 0.40 mmol) followed by triethylamine (0.114 mL, 0.79 mmol). The reaction mixture was stirred for 1 h at room temperature. The organic layer was separated, washed with water (2.0 mL), dried with sodium sulfate and concentrated under vacuum. The crude product was crystallized from EtOAc and hexanes to give the desired product as a purple solid (0.08 g, 61%). M.p.=165° C.; 400 MHz 1H NMR (DMSO-d6) δ 7.89-7.85 (m, 3H), 7.78 (t, 1H), 7.57 (t, 1H), 7.02 (d, J=3.6 Hz, 1H), 6.63 (d, J=3.6 Hz, 1H), 4.24 (d, 2H), 3.13 (s, 2H), 2.15 (brs, 2H), 2.08 (brs, 2H), 1.95 (m, 2H); LCMS: 396 [M+H].
Reaction SMILES: [C:1](=[O:27])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.Cl.Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[CH:42][CH:41]=1>CN(C=O)C>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([N:46]2[CH2:51][CH2:50][N:49]([C:1]([O:2][CH2:3][CH:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[O:27])[CH2:48][CH2:47]2)=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCC1CCNCC1)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.8 %

Procedure:
(1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (Intermediate 2; 10.0 g, 26.3 mmol), was dissolved in DMF (50 mL). DIPEA (16.0 mL, 92.0 mmol) and 4-(4-chlorophenyl)piperazine dihydrochloride (7.09 g, 26.3 mmol) were added and the reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was then concentrated in vacuo. The resulting residue was dissolved in EtOAc (300 mL) and washed with a 1 M aq Na2CO3 solution (6×200 mL), 10% citric acid solution (50 mL), brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in a mixture of DCM (100 mL) and TFA (20 mL), stirred for 4 hours and then concentrated in vacuo. The residue was dissolved in 1 M aq Na2CO3 solution (220 mL), and extracted with DCM (3×200 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was recrystallised from EtOAc to give (1-piperidin-4-yl)methyl 4-(4-chlorophenyl)piperazine-1-carboxylate (4.07 g, 45.7%) as a cream solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]2[CH2:14][C:15]3[C:16]([O:24][CH3:25])=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[C:20]=3[O:21][C:11]=2[C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:23][O:22][C:19]1[C:20]2[O:21][C:11]3[C:10](=[O:26])[N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:27])=[O:2])[CH2:13][C:12]=3[CH2:14][C:15]=2[C:16]([O:24][CH3:25])=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC2=C(Oc3c(OC)ccc(OC)c3C2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(OC)c2c1CC1=C(O2)C(=O)N([C@@H](CC(C)C)C(=O)O)C1
Yield: 244.9 %

Procedure:
A solution of (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid methyl ester (1.4 g, 1.39 mmol) and lithium hydroxide monohydrate (0.18 g, 4.26 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (30 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-(5,8-dimethoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid (1.23 g, 89.5%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].O.[NH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1.C(=O)([O-])[O-].[Ca+2]>ClC(Cl)Cl>[N:6]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1)=[C:1]=[S:2]
Reactant: CCOC(=O)N1CCC(N)C1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)N1CCC(N=C=S)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
a-1) To a stirred mixture of 25 parts of carbonothioic dichloride, 65 parts of water and 210 parts of trichloromethane were added dropwise 9.3 parts of ethyl 3-aminopyrrolidinecarboxylate. Upon completion, the reaction mixture was stirred for 15 minutes at room temperature. 10.7 Parts of calcium carbonate were added portionwise during a period of 10 minutes and stirring was continued overnight at room temperature. The reaction mixture was filtered and the separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was distilled at 6.65 Pa, yielding 7.5 parts (69.3%) of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate; bp. 101° C. (interm 6).
Reaction SMILES: [CH:1]1[C:9]2[C:10]3[C@@H:15]([CH2:16][C:7]4[C:8]=2[C:4]([NH:5][CH:6]=4)=[CH:3][CH:2]=1)[NH:14][CH2:13][C@H:12]([C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH:11]=3.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=[C:25]=[O:26].[N-]=C=O>O1CCCC1>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:24][C:25]([N:14]1[C@H:15]2[C:10]([C:9]3[CH:1]=[CH:2][CH:3]=[C:4]4[C:8]=3[C:7](=[CH:6][NH:5]4)[CH2:16]2)=[CH:11][C@@H:12]([C:17]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:18])[CH2:13]1)=[O:26]
Reactant: O=C([C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2NC1)N1CCCC1
Reactant: COc1ccccc1N=C=O
Agent: [N-]=C=O
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)N1C[C@H](C(=O)N2CCCC2)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C

Procedure:
5.087 g (16.54 mmol) of the product of step 2 is dissolved in 80 ml tetrahydrofurane and 1.79 ml (16.5 mmol) 1-isocyanato-2-methoxy-benzene is added and stirred at room temperature. In order to trap excess isocyanate 0.3 equivalent 3-amino-1,2-propanediol is added and stirred for 2.5 hours. Then the reaction mixture is washed with saturated sodium hydrogen carbonate solution and brine, dried with Na2SO4 and partially evaporated. Crystallization give (6aR,9R)-9-(Pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydro-4H-indolo[4,3-fg]quinoline-7-carboxylic acid (2-methoxy-phenyl)-amide. MS/ES: 457 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:6]([NH2:8])[N:7]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:8][C:6]1[N:7]=[C:2]([NH2:1])[N:3]=[N:4][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[Cl:16])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(N)nnc1-c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
A solution of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine (2 gm, 8 mM) and acetic anhydride (10 mls) in acetic acid (20 mls) was stirred and heated to reflux for 2 hours. The solution was then cooled and evaporated down in vacuo. The residue was treated with aqueous 0.880 ammonia (100 mls) and the resultant mixture was stirred for 2 hours. The solid was separated by filtration, dried then recrystallized from isopropanol to give 5-acetamido-3-amino-6-(2,3-dichlorophenyl)-1,2,4-triazine. Yield 1.0 gms (42%), m.p. 250°-252° (uncorrected).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH3:26])[CH:23]=3)[S:18][C:11]=12)[NH2:5].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:35](=[O:40])[CH2:36][C:37](O)=[O:38].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:37](=[O:38])[CH2:36][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])=[O:40])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH3:26])[CH:23]=3)[S:18][C:11]=12
Reactant: O=C(O)CC(=O)Nc1ccccc1F
Reactant: CCCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5F)cc4F)c3s2)c1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a solution of the amino compound 133 (400 mg, 1.08 mmol) in DMF (20 mL), 3-(2-fluorophenylamino)-3-oxopropanoic acid (29) (427 mg, 2.17 mmol), EDC (352 mg, 2.60 mmol) was added HOBT (499 mg, 2.60 mmol). The reaction mixture was allowed to stir for 1 hr. The solution was extracted with EtOAc and the extract was washed with water, aqueous ammonium chloride and brine then dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5) to afford title compound 130 (215 mg, 36% yield) as a yellow solid. 1H NMR (DMSO-d6). δ (ppm): 10.56 (s, 1H), 10.06 (s, 1H), 8.43 (d, J=5.6 Hz, 1H), 8.10-7.96 (m, 1H), 7.94 (d, J=1.2 Hz, 1H), 7.87 (dd, J=1.6 and 12.8 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H), 7.68 (s, 1H), 7.49 (t, J=8.8 Hz, 1H), 7.42 (dd, J=2.0 and 8.8 Hz, 1H), 7.32-7.25 (m, 1H), 7.22-7.14 (m, 2H), 6.58 (d, J=5.6 Hz, 1H), 3.98 (t, J=7.2 Hz, 2H), 3.62 (s, 2H), 1.78 (sex, J=7.2 Hz, 2H), 0.87 (t, J=7.2 Hz, 3H). MS (m/z): 548.1 (M+H).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]([C:7]1([C:10]2[S:11][C:12]([C:15]3[CH:20]=[C:19]([NH:21][C:22]4[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=4)[CH:18]=[C:17]([CH3:32])[CH:16]=3)=[CH:13][N:14]=2)[CH2:9][CH2:8]1)=O)=[O:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:32][C:17]1[CH:18]=[C:19]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:20]=[C:15]([C:12]2[S:11][C:10]([C:7]3([C:5]4[O:2][CH:1]=[N:3][N:4]=4)[CH2:8][CH2:9]3)=[N:14][CH:13]=2)[CH:16]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(=O)NNC=O)CC3)s2)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(c4nnco4)CC3)s2)c1
Temperature: 100 °C
Yield: 22 %

Procedure:
The product from Step 1 (85 mg, 0.184 mmol) was taken up in THF (2 mL) in a microwave vial, and Burgess reagent (88 mg, 0.368 mmol) was added. The reaction was heated in the microwave at 100° C. for 30 min. The yellow reaction mixture was concentrated to dryness, and the resulting residue was purified by flash chromatography (25-100% ethyl acetate in hexanes) to afford N-(3-methyl-5-{2-[1-(1,3,4-oxadiazol-2-yl)cyclopropyl]-1,3-thiazol-5-yl}phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (18 mg, 22%) as a colorless solid. MS ESI: [M+H]+ m/z 445.0. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.23 (s, 1H), 8.81 (d, 4.9, 1H), 7.97 (s, 1H), 7.96 (s, 1H), 7.46 (s, 1H), 7.26 (d, J=4.9, 1H), 7.15 (s, 1H), 2.29 (s, 3H), 1.94-1.82 (m, 4H). rhSYK activity=+++