Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20].[H-].[Na+].[C:24]([C:28]1[CH:32]=[C:31]([C:33](O)=[O:34])[O:30][N:29]=1)([CH3:27])([CH3:26])[CH3:25].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:17])[F:16])[N:5]=[C:4]([NH:18][C:33]([C:31]2[O:30][N:29]=[C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:32]=2)=[O:34])[C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(C(=O)O)on1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2[N+](=O)[O-])on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (100 mg, 0.315 mmol, prepared as described in Example 1, Step B above) in THF (10 mL) was treated with NaH (37.8 mg, 0.944 mmol, 60% dispersion in oil), and the mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (69.2 mg, 0.409 mmol, prepared as described in Example I above) in DCM (10 mL) was treated with oxalyl chloride (35.7 μL, 0.409 mmol) and DMF (2 drops), and the resulting mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, and the residue was taken up in anhydrous THF (6 mL). The above-prepared acid chloride solution was added to the sodium anilide solution above, and the resulting mixture was stirred at room temperature for 15 min. The resulting mixture was then quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (30 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 25-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H16N4O4ClF3: 469.1 (M+H). Measured: 469.1.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:27][CH:28]([CH3:32])[CH2:29][NH:30][NH2:31]>CO>[CH3:27][CH:28]([CH3:32])[CH2:29][N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:31]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Reactant: CC(C)CNN
Solvent: CO
Product: CC(C)Cn1nccc1-c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Yield: 14.9 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2-methylpropylhydrazine (300 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (48 mg, 15% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 0.83 (6H, d, J=6.8 Hz), 2.17-2.25 (1H, m), 3.25-3.27 (4H, m), 3.89-3.92 (4H, m), 4.34 (2H, d, J=7.6 Hz), 6.72 (1H, d, J=8.0 Hz), 7.00-7.04 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.45-7.49 (2H, m), 7.59 (1H, d, J=2.0 Hz), 8.15 (1H, d, J=7.6 Hz); LCMS (mobile phase: from 90% water and 10% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=3.396 min; MS Calcd.:379, MS Found: 380 [M+H]+.
Reaction SMILES: C1(O[C:8](=[O:25])[NH:9][CH:10]2[CH2:15][CH2:14][C:13]([N:22]([CH3:24])[CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)C=CC=CC=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[CH:37]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]1>O1CCOCC1>[CH3:24][N:22]([CH3:23])[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11][CH:10]([NH:9][C:8]([N:39]2[CH2:40][CH2:41][CH2:42][CH:37]([C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([O:27][CH3:26])[CH:29]=4)[NH:33][CH:32]=3)[CH2:38]2)=[O:25])[CH2:15][CH2:14]1
Reactant: COc1ccc2[nH]cc(C3CCCNC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(NC(=O)Oc2ccccc2)CC1
Solvent: C1COCCO1
Product: COc1ccc2[nH]cc(C3CCCN(C(=O)NC4CCC(c5ccccc5)(N(C)C)CC4)C3)c2c1

Procedure:
The polar diastereoisomer of (4-dimethylamino-4-phenylcyclohexyl)-carbamic acid phenyl ester (330 mg, 0.98 mmole) was added to a solution of 5-methoxy-3-piperidine-3-yl-1H-indole (225 mg, 0.98 mmole) in dioxane (10 ml). The reaction mixture was then boiled under reflux for 32 hours. The reaction mixture was worked up by distilling off dioxane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×15 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The polar diastereoisomer of 3-(5-methoxy-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexyl)-amide was purified by column chromatography with methanol. It was obtained in a yield of 220 mg (47%) as a colourless solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20].[Cl-].[Na+]>C1COCC1>[CH2:19]([O:21][CH2:22][C:23]([N:9]1[CH:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:24])[CH3:20]
Reactant: CCOCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 24 h
Yield: 56.1 %

Procedure:
36.7 g (207 mmol) of (S)-4-benzyloxazolidin-2-one in 800 ml of THF are introduced into a round-bottomed flask and under a nitrogen stream. The reaction medium is cooled to −78° C. and 83 ml (207 mmol) of n-butyllithium (2.5 M/hexane) are added dropwise. 30 minutes later, 25.4 g (207 mmol) of ethoxyacetyl chloride are added at −78° C. The reaction medium is stirred for 24 hours and then poured into a saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated off. 30.6 g (56%) of the expected product are obtained in the form of an orange-colored oil after purification by chromatography on a silica column eluted with a heptane and ethyl acetate (60/40) mixture.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16].C1(N=C=NC2CCCCC2)CCCCC1>C1(=O)OC(=O)CC1.C1(C)C=CC=CC=1>[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:11]1(=[O:16])[NH:10][C:14](=[O:15])[CH2:13][CH2:12]1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CCC(=O)O
Agent: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: O=C1CCC(=O)N1

Procedure:
As depicted in above Scheme 4, 6-arm PEG (1) synthesized in the Scheme 1 is reacted with succinic reagents, e.g., succinic anhydride and toluene as solvent to synthesize 6-arm PEG-succinic acid (6-arm PEG-SA) (6). The 6-arm PEG SA (6) is reacted with N-hydroxy succinimide (NHS) and N, N′-dicyclohexylcarbodiimide (DCC) to produce 6-arm PEG-succinimide succinate (6-arm PEG-SS) (7).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH2:16][CH3:17]>>[CH2:16]([C:17]1[N:4]2[CH:5]=[CH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:3]2=[N:1][N:2]=1)[CH3:15]
Reactant: CCOC(CC)(OCC)OCC
Reactant: NNc1nccc(-c2ccccc2)n1
Product: CCc1nnc2nc(-c3ccccc3)ccn12

Procedure:
A mixture of 1.55 g. of 2-hydrazino-4-phenylpyrimidine and 25 ml. of triethyl orthopropionate is refluxed for 6 hours. On cooling the desired compound is obtained by filtration, m.p. 246°-247° C.
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][C:12](=[O:14])[NH:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[NH:1]([C:8]1[C:9](=[O:10])[N:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:12](=[O:14])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(Nc2ccccc2)C(=O)N1
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: O=C1C=C(Nc2ccccc2)C(=O)N1c1ccccc1
Yield: 45.4 %

Procedure:
A mixture of 1.98 g (7.5 mmol) of the anilinosuccinimide prepared in Example 1 above and 1.96 g (22.5 mmol) of MnO2 in 45 mL of toluene is refluxed for six hours. The mixture is filtered, while hot, and the resulting solid is heated in another 50 mL of boiling toluene and filtered again while hot. Cooling the combined toluene filtrates gives 450 mg of the title product as yellow-orange needles. Concentration of the toluene solution gives another 360 mg; m.p. 228°-233° C. (lit (7) m.p. 230°-230.5° C.).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12]1([CH2:18][C:19](O)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:12]1([CH2:18][C:19]([CH:8]2[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]2=[O:7])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C(O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)Cc2ccccc2)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5.00 g, 32.05 mmol), phenylacetic acid (6.53 g, 48.03 mmol), 4-dimethylaminopyridine (1.95 g, 16.01 mmol) in dry CH2Cl2 (30 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (7.26 g, 35.22 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (150 ml) and the combined solution was washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallized from MeOH giving 5-phenylacetyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 8 (6.10 g, 69%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1)=O.[Li+].[BH4-]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([C:11]#[N:12])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(C#N)c(-c2ccccc2)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1-c1ccccc1
Temperature: 70 °C

Procedure:
6-Cyano-biphenyl-3-carboxylic acid methyl ester from step 2 (1.4 g, 5.9 mmol) was dissolved in THF (24 ml). LiBH4 in THF (2M, 5.9 ml, 11.8 mmol) was added. The reaction mixture was heated to 70° C. for 3 hours. The reaction mixture was quenched carefully with 3N HCl and then extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product. FAB MS: 210 m/z (M+ +H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[NH:9][CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([O:39][CH3:40])[C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[N:9]([C:31]([C:30]3[CH:34]=[C:35]([O:39][CH3:40])[C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=3)=[O:32])[CH2:10]2)=[CH:5][C:4]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)NC2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1O[Si](C(C)C)(C(C)C)C(C)C)CC(C)(C)N(C(=O)c1cc(OC)c(OC)c(OC)c1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.8 %

Procedure:
To a solution of 225 (300 mg, 0.83 mmol) in DCM (5 ml) was added TEA (0.23 ml, 1.65 mmol) and 3,4,5-trimethoxybenzoyl chloride (228 ml, 0.99 mmol). The reaction mixture was stirred at rt for 12 h. Water (10 ml) was added and the aqueous layer was extracted with DCM (3×30 ml). The combined organic phases were washed with sat. aq. NaHCO3 (10 ml) and brine (10 ml), dried (MgSO4) and concentrated in vacuo. Purification (flashmaster: 20 g, gradient elution 100% hex to 100% EtOAc over 25 min) afforded the title compound (240 mg, 52%) as a colourless oil. 1H NMR (270 MHz; CDCl3) 1.04 (18H, d, J=6.7 Hz, 6×CH3CH), 1.14-1.24 (3H, m, 3×CH), 1.55 (6H, s, 2×CH3), 2.74 (2H, s, CH2), 3.80 (3H, s, OCH3), 3.85 (6H, s, 2×OCH3), 3.86 (3H, s, OCH3), 4.19 (2H, s, CH2), 6.53 (1H, s, CH), 6.56 (2H, s, 2×CH), 6.71 (1H, s, CH). LC/MS (ES+) tr=0.2.23 min, m/z 580.24 (M++Na). HRMS (ES+) calcd for C31H47NO6Si (M++H) 558.3245, found 558.3237.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([OH:33])[N:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:42][C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:25][C:26]([C:28]2[CH:32]=[C:31]([O:33][CH2:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[N:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:29]=2)=[O:27])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7.00 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 45 ml DMF were added 2.1 ml benzyl bromoacetate and 8.2 g cesium carbonate. After stirring at RT for 12 h the reaction mixture was diluted with ethyl acetate and extracted with aqueous LiCl (4% w/w) and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was not further purified. Yield: 7.02 g yellowish oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:24])/[CH:15]=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH2:29][C:30]([CH2:32][Si](C)(C)C)=[CH2:31])(=O)C.P(OC(C)C)(OC(C)C)OC(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]1[CH2:32][C:30](=[CH2:29])[CH2:31][C@H:16]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(/C=C/c1ccc(Cl)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C=C(COC(C)=O)C[Si](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)OP(OC(C)C)OC(C)C
Solvent: C1CCOC1
Product: C=C1C[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Temperature: 25 °C
Yield: 39.1 %

Procedure:
An oven-dried 250 mL round bottom flask equipped with a magnetic stir bar and a septum, was charged with 4.705 g (13.7 mmol) of the product of Step A, 0.185 g (0.82 mmol) of palladium acetate, and 27 mL anhydrous tetrahydrofuran. The reaction mixture was freed of air by alternate cycles of degassing in vacuo and flushing with nitrogen using an external manifold attached through tubing to a needle inserted through the septum of the flask. To the brick red suspension was then added 3.80 mL (3.334 g, 17.9 mmol) 2-[(trimethylsilyl)methyl]-2-propen-1-yl acetate followed by 1.02 mL (0.860 g, 4.13 mmol) of triisopropyl phosphite. The reaction mixture was heated to reflux and stirred under nitrogen for 3 h at which point TLC analysis (15% ethyl acetate-hexanes) revealed consumption of the starting material and production of two new products. The reaction mixture was cooled to room temperature, transferred to a separatory funnel and partitioned between water and diethyl ether. The organic layer was washed with water, brine, dried (MgSO4), filtered and evaporated in vacuo. The product mixture was purified on a Biotage Flash 40i chromatography apparatus (90 g Flash 40M silica gel cartridge) eluted with 10% ethyl acetate-hexanes which afforded a less polar and a more polar product. Evaporation of the fractions containing the more polar product and drying in vacuo afforded 2.12 g of the title compound.
Reaction SMILES: [C:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[S:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH2:27])(=[O:26])=[O:25])(=[O:16])=[O:15])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.CO.[H][H].C(OCC)(=O)C.CO>CCOC(C)=O>[CH:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:24]([NH2:27])(=[O:25])=[O:26])(=[O:15])=[O:16])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(C2=CCCC2)cc1
Reactant: [H][H]
Solvent: CO
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(C2CCCC2)cc1
Yield: 57.1 %

Procedure:
(E)-2-(2-(4-Cyclopentenylphenyl)vinylsulfonamido)benzenesulfonamide (25.00 mg, 0.06 mmol) was dissolved in EtOAc (1.6 mL) and MeOH (1.6 mL) and hydrogenated under continuous flow hydrogenation conditions (full hydrogen, flow 1 ml/min, ethyl acetate/methanol 1:1 as eluent) at 50° C. using an H-Cube system. The solvent was removed in vacuo and the residue was purified by column chromatography on silica using heptane/ethyl acetate gradient mixtures as eluent (0-100% ethyl acetate) to give the product as a solid (14 mg, 55%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]1[O:17][N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>ClCCl.C(OCC)(=O)C>[OH:12][C:4]1[C:3]([C:13]2[O:17][N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=2)=[C:2]([O:1][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[C:11]2[C:6]([N:5]=1)=[N:7][CH:8]=[CH:9][N:10]=2
Reactant: CC(C)C(=O)Cl
Reactant: O=c1[nH]c2nccnc2c(O)c1-c1cc(C(F)(F)F)no1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(=O)Oc1c(-c2cc(C(F)(F)F)no2)c(O)nc2nccnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 8-hydroxy-7-(3-trifluoromethyl-isoxazol-5-yl)-5H-pyrido[2,3-b]pyrazin-6-one (Example 6.5) (0.037 g) and pyridine (0.1 ml) in dichloromethane (2 ml) was added dropwise isobutyryl chloride (0.05 ml). The reaction mixture was stirred at ambient temperature for 6 hours and stored at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed successively with water, aqueous sodium hydrogen carbonate (saturated) and brine. The organic phase was dried over magnesium sulfate and concentrated to give Compound No. B7 of Table B as a pale yellow solid (0.038 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:2]1=2.F[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:11][C:8]1[CH:9]=[CH:10][C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[CH:7]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc2c(c1)OCCO2
Temperature: 120 °C
Reaction time: 10 h
Yield: 67.2 %

Procedure:
5.9 g (39 mmol) of 2,3-dihydrobenzo[b]1,4-dioxin-6-amine and 5.0 g (35 mmol) of 2-fluoronitrobenzene were dissolved in N-methylpyrrolidone (70 mL) and 20.8 g (150 mmol) of potassium carbonate was added thereto. The solvent was heated with stirring for 10 hours at 120° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The extracted organic layer was washed with water, 10% hydrochloric acid, water, and a saturated aqueous solution of sodium chloride in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=1:4), to obtain 6.4 g (yield: 66%) of N-(2-nitrophenyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-amine as a red liquid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][CH:8]=[C:7]([C:10](OC)=[O:11])[CH:6]=1)[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:3][N:2]([CH2:4][C:5]1[S:9][CH:8]=[C:7]([CH2:10][OH:11])[CH:6]=1)[CH3:1]
Reactant: COC(=O)c1csc(CN(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CN(C)Cc1cc(CO)cs1
Yield: 93.1 %

Procedure:
A solution of methyl 5-(dimethylaminomethyl)-3-thiophenecarboxylate (1.5 g) in diethylether (50 ml) was treated with lithium aluminium hydride (0.21 g). After 1 hour water (2 ml) was added and the solution was filtered through diatomaceous earth. Evaporation of the filtrate gave an oily residue which distilled to give the title compound as an oil (1.2 g) b.p. (120°/0.1 mm).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=O)=O.[C-:28]#[N:29].[K+]>CN(C=O)C.O>[C:28]([CH2:6][CH2:7][CH2:8][C:9]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:29]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCOS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccc(OCc2ccccc2)c1CCCC#N
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of ethyl 2-(3-methanesulfonyloxypropyl)-3-benzyloxybenzoate (19.42 g, 31.7 mmol) and potassium cyanide (2.28 g, 35 mmol) in DMF (50 ml) was heated at 100° C. for 8 hr. The mixture was cooled, diluted with water (250 ml), and extracted three times with ethyl acetate. The ethyl acetate extracts were dried with brine, and concentrated in vacuo. The crude product was chromatographed on silica gel using methylene chloride as the eluent to give the product as an oil (5.25 g, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:12][CH:11]2[CH:9]([CH:10]2[NH:13]C(=O)OC(C)(C)C)[CH2:8]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:21])[C:6]=1[N:7]1[CH2:8][CH:9]2[CH:11]([CH:10]2[NH2:13])[CH2:12]1)=[O:44]
Reactant: Cn1ncc(N)c1N1CC2C(C1)C2NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC2C(N)C2C1
Yield: 32 %

Procedure:
Following the procedures as described in Example 113, tert-butyl 3-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 150 as a white solid (30 mg, 32%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.64-7.36 (m, 4H), 7.29 (t, J=8.7, 2H), 3.56 (s, 3H), 3.46-3.31 (m, 2H), 3.13 (t, J=15.2, 2H), 1.93 (s, 1H), 1.41 (s, 2H). ESIMS m/z=431.1 (M+1)