Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:19][CH2:18][CH:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:11]1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C1COCC1>[CH3:17][O:16][C:14]([CH:13]1[CH2:18][CH2:19][N:10]([S:29]([C:26]2[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=2)(=[O:30])=[O:31])[CH2:11][CH2:12]1)=[O:15]
Reactant: COC(=O)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (9.4 ml, 54.1 mmol) was added in one portion to a stirred solution of methyl isonipecotate (6.78 g, 47.4 mmol) in THF (100 ml) at room temperature. To this mixture was added 4-nitrobenzenesulfonyl chloride (10.0 g, 45.1 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After this time, the resulting solid precipitate was collected by filtration and washed with cold THF (50 ml) before being dried under to give the title compound (14.8 g, 100% yield) as a white solid. δH (500 MHz, DMSO) 8.45 (2H, d), 8.02 (2H, d), 3.66-3.54 (5H, m), 2.52 (2H, obscured), 2.45-2.36 (1H, m), 1.96-1.88 (2H, m), 1.64-1.52 (2H, m). Tr=1.88 min m/z (ES+) (M+H+) 329.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9](C)[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:23].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:23]
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c-2ccc(F)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ncn2c1CNC(=O)c1c-2ccc(F)c1Cl

Procedure:
14.55 g (43 mmol) of ethyl 7-chloro-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate was heated to boiling under reflux for 15 minutes with 1.90 g (45.7 mmol) of sodium hydroxide in 80 ml of ethanol and 30 ml of water. The reaction mixture was then cooled and treated with 10.4 ml of 4N hydrochloric acid. By suction filtering the suspension obtained and drying the product there was obtained 7-chloro-8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid of decomposition point 260°.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH3:27])[CH:34]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-methoxyphenyl-boronic acid, 5-(3-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside is obtained in the form of a white powder (yield=77%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:22])[CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:35]([N:36]=[C:37]=[O:38])=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:26][CH:25]=1>CN1C(=O)CCC1>[C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13](=[O:22])[CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:37](=[O:38])[NH:36][C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:27]3[CH:26]=[CH:25][CH:24]=[CH:29][CH:28]=3)[CH2:19][CH2:20]2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)CN2CCC(O)CC2)C1
Reactant: O=C=Nc1ccccc1-c1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)CN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)C1
Temperature: 70 °C

Procedure:
{(R)-1-[2-(4-Hydroxy-piperidin-1-yl)-acetyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Intermediate Z1) (520 mg, 1.6 mmol) and 2-biphenylisocyanate (930 mg, 2.65 mmol) are dissolved in NMP (2 ml) and heated to 70° C. overnight. Purification is carried out by reverse phase column chromatography (Isolute™ C18, 0-100% MeOH in water—0.1% TFA). The fractions containing the product are concentrated in vacuo to remove the acetonitrile and the aqueous is treated with saturated sodium bicarbonate solution. The product is extracted with DCM and the combined organic portions are concentrated in vacuo to afford the title product. [MH+ 523.24].
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C([O-])(=O)C.[K+].C(N(CC)CC)C.[CH3:20][C@@H:21]([CH2:25][CH2:26][CH:27]=[C:28](C)[CH3:29])[CH2:22]C=O>O>[C:5]([O:4][CH:1]=[CH:2][C@@H:28]([CH3:29])[CH2:27][CH2:26][CH:25]=[C:21]([CH3:22])[CH3:20])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCC[C@H](C)CC=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)OC=C[C@@H](C)CCC=C(C)C
Temperature: 120 °C

Procedure:
A 50 mL round-bottom-flask equipped with a condenser was charged with acetic anhydride (6.1 mL, 64.8 mmol), potassium acetate (0.51 g, 5.18 mmol) and triethylamine (4.5 mL, 32.4 mmol). To the stirred mixture was (S)-3,7-dimethyloct-6-en al (5.0 g, 32.4 mmol) slowly. The reaction mixture was heated to 120° C. for 7.5 hours. After cooling to room temperature, the reaction mixture was poured into water (25 mL) and then extracted with toluene (10 mL). The organic layer was washed with saturated aqueous sodium carbonate (25 mL×2) and brine (25 mL). The material was transferred to a 50 ml round-bottom-flask and the separate funnel was washed with toluene (1 mL). The solution of the title compound in toluene (11 ml) (15.7 g) was used directly for the next step. Mass spectrum (ESI+ve) m/z 187 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1.CO>ClCCl>[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccno2)C(C)C)co1
Yield: 80 %

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino 2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine provided, after silica gel chromatography using a gradient of 1-4% methanol in dichloromethane, 225 mg (80%) of the desired compound. 1H NMR (DMSO-d6)δ0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.35-1.54 (m, 2H), 1.80-1.95 (m, 1H), 2.55-2.73 (m, 4H), 2.83 (s, 3H), 2.94-3.09 (m, 1H), 3.53-3.63 (m, 1H), 3.73-3.86 (m, 1H), 3.92 (t, J=8.4 Hz, 1H), 4.08-4.34 (m, 3H), 4.65 (d, J=6 Hz, 1H), 5.04 (s, 2H), 5.91 (d, J=9 Hz, 1H), 6.29 (d, J=2.4 Hz, 1H), 7.01 (d, J=9 Hz, 1H), 7.06-7.27 (m, 10H), 7.69 (d, J=9 Hz, 1H), 7.77 (s, 1H), 8.52 (d, J=2.4 Hz, 1H). Mass spectrum: (M+H)+ =689; (M+NH4)+ =706. Anal. Calcd for C37H48N6O7 : C, 64.52; H, 7.02; N, 12.20. Found: C., 64.52;H, 7.14; N, 12.06.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.Cl[CH2:12][C:13]([O-:15])=[O:14].[Na+].Cl>CO.O>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:12][C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(SCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.5 %

Procedure:
Into a 500 ml three-necked flask were charged 60 ml of water, 120 ml of methanol and 75 g of sodium hydroxide. 75 g of 4-aminothiphenol and 85 g of sodium chloroacetate were then slowly added to the mixture over an ice bath. Thereafter, the reaction mixture was allowed to cool to room temperature where it was then stirred for 6 hours. After reaction, concentrated hydrochloric acid was added dropwise to the reaction mixture over an ice bath until the pH value of the solution reached 1. As a result, precipitation of a solid matter was observed. The precipitate was filtered off, thoroughly washed with water, and then dried to obtain 95 g of 4-aminophenylsulfanylacetic acid (white powder).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[C:15]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C(=O)C>[C:15]1([S:21]([C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:28][CH:29]=2)(=[O:22])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (3.96 g 25 mmol) in N,N-dimethylacetamide (36 mL) was rapidly added thionyl chloride (3.10 g, 26 mmol) and the mixture (a precipitate formed after a few minutes) stirred at -15° C. to -5° C. for 1 hour. 4-(Phenylsulfonyl)benzenamine (3.97 g, 17 mmol) was then added in one portion and the mixture allowed to stir at room temperature overnight. The solution was poured into water, the resulting solid was filtered off, washed with 3N HCl, then water and dried at 65° C. for 2 hours. The solid was dissolved in 300 mL of refluxing methylene chloride and stirred and heated as hexane was added to replace the methylene chloride as it boiled off. When 250 mL of hexane had been added (precipitate formed at about 180 mL addition) the mixture was concentrated to 250 mL and refrigerated. The yield of light tan solid was 5.92 g (93%), mp 164°-166° C. 1H-NMR (250 MHz, d6 -DMSO): 1.59 (s, 3H, CH3), 7.57-7.72 (m, 4H, OH, aromatic), 7.92-8.04 (m, 6H, aromatic), 10.43(s, 1H, NH). Analysis for C14H14F3NO4S: Calculated: C, 51.47; H, 3.78; N, 3.75 Found: C, 51.22; H, 3.83; N, 3.72
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[N:5]2.[F:13][C:14]1[CH:23]=[C:22]2[C:17]([N:18]=[CH:19][C:20](=O)[NH:21]2)=[CH:16][CH:15]=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:7]1[CH:6]=[N:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=1.[Cl:27][C:20]1[CH:19]=[N:18][C:17]2[C:22](=[CH:23][C:14]([F:13])=[CH:15][CH:16]=2)[N:21]=1
Reactant: O=c1cnc2ccc(F)cc2[nH]1
Reactant: O=c1cnc2cc(F)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccc2nc(Cl)cnc2c1
Product: Fc1ccc2ncc(Cl)nc2c1
Yield: 44 %
Yield: 38 %

Procedure:
A solution of 6-fluoroquinoxalin-2(1H)-one & 7-fluoroquinoxalin-2(1H)-one (3 g, 18.28 mmol) in POCl3 (20 ml) was refluxed for 3 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The combine organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to afford regioisomers as a mixture. The above mixture was separated by SFC purification to afford 2-chloro-6-fluoroquinoxaline (0.75 g, 44%) and 2-chloro-7-fluoroquinoxaline (0.65 g, 38%) as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:13]=1[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][NH:24][O:25][CH3:26].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[Si:46](Cl)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47].N1C=CN=C1>CN(C)C=O.O>[Si:46]([O:21][C:18]1[CH:19]=[CH:20][C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([C:14]([N:24]([O:25][CH3:26])[CH3:23])=[O:16])[CH:17]=1)([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47]
Reactant: O=C(Nc1ccc(O)cc1C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a solution of 2-{[(benzyloxy)carbonyl]amino}-5-hydroxybenzoic acid (92 g, 0.32 mol) and N,O-dimethylhydroxyamine hydrochloride (38 g, 0.38 mol) in N,N-dimethylformamide (500 ml) was added triethylamine (53 ml, 0.40 mol), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (73 g, 0.38 mol), and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (500 ml), and tert-butyl(dimethyl)silyl chloride (48 g, 0.32 mol) and imidazole (21 g, 0.32 mol) were added. The mixture was stirred at room temperature for 6 hrs., poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give benzyl (4-{[tert-butyl(dimethyl)silyl]oxy}-2-{[methoxy(methyl)amino]carbonyl}phenyl)carbamate (91 g, yield 64%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]1[S:27][CH:28]=[CH:29][CH:30]=1)CCC>>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[O:9][C:10]3[C:2]([C:26]4[S:27][CH:28]=[CH:29][CH:30]=4)=[CH:3][C:4]([OH:19])=[CH:5][C:6]=3[N:7]=2)=[CH:16][CH:15]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Product: Oc1ccc(-c2nc3cc(O)cc(-c4cccs4)c3o2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 53, Step a, from 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole and 2-(tributylstannyl)thiophene. The product was obtained as a white solid (95% yield), m.p. 95-100° C.); MS m/e 338 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1.Br.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=O.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:10][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=S)c1ccc(F)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nc(-c3ccccn3)cs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Fluorobenzenecarbothio-amide (250 mg, 1.61 mmol) and 2-bromo-1-pyridin-2-ylethanone hydrobromide (450 mg, 1.61 mmol) were dissolved in DMF (2 mL), and triethylamine (0.23 mL, 1.61 mmol) was added. The reaction was stirred at room temperature for 90 min, and then heated at 50° C. for 30 min. The mixture was diluted with EtOAc. The organic layer was washed with brine, and dried over Na2SO4. The drying agent was filtered off, and the filtrate was concentrated to afford the title compound. LC-MS 257.1 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:19]([O:21][C:22](=[O:36])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=1[CH2:25][N:24]([CH2:2][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][O:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:36]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1onc(-c2ccccc2)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2ccccc2)noc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
Ethyl 4-(bromomethyl)-3-phenylisoxazole-5-carboxylate (28.1 g, 90.6 mmol) was dissolved in 200 mL of DMF. N-(2,4-dimethoxybenzyl)glycine ethyl ester (22.9 g, 90.6 mmol) and potassium carbonate (9.2 g, 66.4 mmol) were added, and the mixture was stirred at room temperature for 16 h. EtOAc (200 mL) and water (100 mL) were added and the aqueous layer was extracted with additional EtOAc. The combined organic layer was washed with water and brine, and dried over MgSO4. After solvent was removed in vacuo, the crude product was purified by flash chromatography (0-40% EtOAc/hexanes) to give 29.6 g of the title compound. MS: (+) m/z 483.73 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH3:12][O:13][CH2:14][CH:15]1[CH2:20][NH:19][CH2:18][CH2:17][NH:16]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH:15]1[NH:16][CH2:17][CH2:18][N:19]([C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=2)[CH2:20]1
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: COCC1CNCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CN(c2ncc(C(=O)OC)cn2)CCN1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.7 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (300 mg, 1.74 mmol) in DCM (4.70 mL) was added to a stirred solution of 2-(methoxymethyl)piperazine (226 mg, 1.74 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.752 mL, 4.35 mmol) in DCM (4.00 mL) at 25° C. under nitrogen. The resulting solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and diluted with MeOH. The resulting mixture was filtered. The filtrate was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford methyl 2-(3-(methoxymethyl)piperazin-1-yl)pyrimidine-5-carboxylate (346 mg, 75%) as a yellow solid. This was used directly with no further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]([I:12])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.N1C2C=CC=C(O)C=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH:17]([N:30]1[CH2:35][CH2:34][N:33]([C:9](=[O:11])[CH2:8][C:6]2[C:5]([I:12])=[CH:4][C:3]([C:13]([O:15][CH3:16])=[O:14])=[C:2]([F:1])[CH:7]=2)[CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(I)c(CC(=O)O)cc1F
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(I)c(CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.8 %

Procedure:
A mixture of 2-(5-fluoro-2-iodo-4-(methoxycarbonyl)phenyl)acetic acid (100 mg, 0.30 mmol), 1-benzhydrylpiperazine (82 mg, 0.33 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (86 mg, 0.45 mmol), 1H-benzo[d][1,2,3]triazol-4-ol (61 mg, 0.45 mmol) and triethylamine (91 mg, 0.90 mmol) in DCM (5.0 mL) was stirred at room temperature for 16 h. The mixture was diluted with DCM (20 mL), washed with HCl (2M, 10 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Combiflash (60%-70% CH3CN in 0.1% HCOOH) to afford methyl 4-(2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl)-2-fluoro-5-iodobenzoate (70 mg, 41%) as a white solid. LCMS (ESI): m/z: 572.8 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CN(C1C=CN=CC=1)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 61.2 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), 3-methoxybenzenesulfonyl chloride (260 mg, 1.3 mmol) and DMAP (cat.) gave the title compound (250 mg, 56%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:16]([NH:23][C:24](=[O:44])[CH2:25][NH:26][C:27](=[O:43])[C:28]2[CH:33]=[C:32]([NH:34][C:35]3[NH:36][CH2:37][CH:38]([OH:41])[CH2:39][N:40]=3)[CH:31]=[C:30]([OH:42])[CH:29]=2)[CH2:17][C:18]([O:20]CC)=[O:19])[CH:5]=[C:6]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.O.[OH-].[Li+].ClCCl>C(#N)C.O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:16]([NH:23][C:24](=[O:44])[CH2:25][NH:26][C:27](=[O:43])[C:28]2[CH:33]=[C:32]([NH:34][C:35]3[NH:40][CH2:39][CH:38]([OH:41])[CH2:37][N:36]=3)[CH:31]=[C:30]([OH:42])[CH:29]=2)[CH2:17][C:18]([OH:20])=[O:19])[CH:5]=[C:6]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C2(C#N)CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: N#CC1(c2cc(Cl)cc([C@H](CC(=O)O)NC(=O)CNC(=O)c3cc(O)cc(NC4=NCC(O)CN4)c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3S)-ethyl 3-(3-chloro-5-(4-cyanotetrahydro-2H-pyran-4-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate (from step 2 above) (0.842 mmol, crude residue) in a mixture of acetonitrile/water (1:1) (6 mL) was added lithium hydroxide monohydrate (180.0 mg, 4.289 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo to afford a yellow-orange viscous residue. The residue was dissolved in water (25 mL) and stirred with dichloromethane (50 mL). The aqueous layer was separated and acidified with TFA (1 mL in 3 mL ACN) and evaporated in vacuo to afford a pale orange viscous residue. The crude residue was purified by reverse-phase preparative HPLC on a Biotage 40+M (100 g) C18HS column and a gradient 10-60% acetonitrile in water containing 0.05% TFA to give the desired product, after lyophilization, as a colorless lyophilized powder (305 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 599 (35ClM+H) and m/z 601 (37ClM+H); Calcd for C28H31ClN6O7:599.03.