Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][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)[CH:8]=[CH:9][C:10]=1C=O)=[O:4].[BH4-].[Na+].[CH3:21][OH:22]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:14]=[CH:15][C:16]([CH2:21][OH:22])=[CH:17][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccccc2)ccc1C=O
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)c1cccc(-c2ccc(CO)cc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 1.56 g (6.5 mmol.) 4-formyl-biphenyl-3-carboxylic acid methyl ester in 30 mL methanol at 0° C. was added 307 mg (8.1 mmol.) sodium borohydride. The mixture was stirred at 0° C. for 1 hour, then quenched with saturated ammonium chloride solution. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined, washed successively with water, brine then dried (MgSO4) and concentrated in vacuo to yield an oil. Chromatography on Silica Gel eluting with ethyl acetate/hexanes (1:5) afforded 1.5 g 4′-hydroxymethyl-biphenyl-3-carboxylic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:56])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:55])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:54])=[CH:11]/[CH2:12][CH2:13]/[C:14](/[CH3:53])=[CH:15]/[CH2:16][CH2:17]/[C:18](/[CH3:52])=[CH:19]/[CH2:20][CH2:21]/[C:22](/[CH3:51])=[CH:23]/[CH2:24][CH2:25]/[C:26](/[CH3:50])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:49])=[CH:31]/[CH2:32][CH2:33]/[C:34](/[CH3:48])=[CH:35]/[CH2:36][CH2:37]/[C:38](/[CH3:47])=[CH:39]/[CH2:40][CH2:41]/[C:42](/[CH3:46])=[CH:43]/[CH2:44][OH:45].[C:57]([O-])(=[O:59])[CH3:58].[Na+]>C(OC(=O)C)(=O)C.O>[C:57]([O:45][CH2:44][CH:43]=[C:42]([CH3:46])[CH2:41][CH2:40][CH:39]=[C:38]([CH3:47])[CH2:37][CH2:36][CH:35]=[C:34]([CH3:48])[CH2:33][CH2:32][CH:31]=[C:30]([CH3:49])[CH2:29][CH2:28][CH:27]=[C:26]([CH3:50])[CH2:25][CH2:24][CH:23]=[C:22]([CH3:51])[CH2:21][CH2:20][CH:19]=[C:18]([CH3:52])[CH2:17][CH2:16][CH:15]=[C:14]([CH3:53])[CH2:13][CH2:12][CH:11]=[C:10]([CH3:54])[CH2:9][CH2:8][CH:7]=[C:6]([CH3:55])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:56])[CH3:1])(=[O:59])[CH3:58]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CO
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3.5 Grams of undecaprenol were dissolved in 15 ml of acetic acid anhydride and the solution was added with 2.0 g of anydrous sodium acetate at room temperature. The mixture was stirred at 100° C. for one hour to complete the reaction. Upon cooling, the reaction product was poured in water to hydrolyze excessive acetic acid anhydride. After extraction with n-hexane, the extract was washed with water and concentrated. The concentrate was purified by chromatography with 50 g of silica gel in n-hexane/benzene solvent mixture as elution solvent to obtain the final product as a white solid (m.p. 36.0°-37.0° C.). Yield 3.5 g
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[SH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1>C(#N)C>[CH:16]1([N:7]2[CH2:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([S:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: O=C(O)c1ccc(S)cc1
Solvent: CC#N
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Sc3ccc(C(=O)O)cc3)ncc21
Yield: 26.8 %

Procedure:
A solution of 2-Chloro-9-cyclopentyl-8,9-dihydro-5,7,7-trimethyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (100 mg, 0.324 mmol) and 4-mercaptobenzoic acid (50 mg, 0.324 mmol) in acetonitrile (5 mL) was heated under reflux for 4 hours. Additional 4-mercaptobenzoic acid (50 mg, 0.324 mmol) was added and the reaction mixture was heated under reflux for 16 hours. After cooling, the crude reaction mixture was filtered through Celite and washed with acetonitrile. The crude product was purified by column chromatography (0%-10% MeOH:CH2Cl2) and triturated with MeOH to give the title compound (37 mg, 27% yield) as a white solid. NMR DMSO D6 1.03 (6H, s), 1.20-1.38 (6H, m), 1.42-1.53 (2H, m), 3.17 (3H, s), 3.27 (2H, s), 4.47 (1H, dt), 7.72 (2H, dd), 7.99 (2H, dd), 8.02 (1H, s); MS (ES+) 427, (ES−) 425.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][NH:7][N:8]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]=1[CH2:10][O:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:4].C[O:30][C:31](=[O:62])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38]C(C2C(COC3C=CC=CC=3)=NN(C3C(Cl)=CC=CC=3Cl)N=2)=O)[CH:33]=1>>[C:12]12([O:11][CH2:10][C:9]3[N:8]([CH:22]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[NH:7][NH:6][C:5]=3[C:3]([NH:38][C:34]3[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=3)[C:31]([OH:62])=[O:30])=[O:4])[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]3)[CH2:19]1)[CH2:21]2
Reactant: COC(=O)c1cccc(NC(=O)c2nn(-c3c(Cl)cccc3Cl)nc2COc2ccccc2)c1
Reactant: COC(=O)C1=C(COC23CC4CC(CC(C4)C2)C3)N(C2CCCCCC2)NN1
Product: O=C(Nc1cccc(C(=O)O)c1)C1=C(COC23CC4CC(CC(C4)C2)C3)N(C2CCCCCC2)NN1

Procedure:
5-(Adamantan-1-yloxymethyl)-1-cycloheptyl-3H-[1,2,3]triazole-4-carboxylic acid methyl ester was converted to the corresponding acid (as in Example 28, step c) which was then coupled to methyl 3-aminobenzoate (as in Example 28, step d). Hydrolysis of the methyl ester (as in Example 28, step e) resulted in the preparation of 3-{[5-(adamantan-1-yloxymethyl)-1-cycloheptyl-3H-[1,2,3]triazole-4-carbonyl]-amino}-benzoic acid. 1H NMR (d6-DMSO) 12.91 (1H, s), 10.62 (1H, s), 8.51 (1H, m), 7.98-7.95 (1H, m), 7.68 (1H, d, J=9 Hz), 7.47-7.42 (1H, m), 4.98 (2H, s), 4.71-4.66 (1H, m), 2.48-2.07 (7H, m), 1.80-1.54 (20H, m). The material was further analysed as its N-methyl D-glucamine salt.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([OH:14])(=O)=[O:12].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+:21].[OH-].[Na+].C>S1(CCCC1)(=O)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:21])(=[O:14])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: Nc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.3 %

Procedure:
2-Amino-5-nitrobenzenesulfonic acid (200.00 g, 0.917 mol) was suspended in warm sulfolane (250 mL) and the suspension was heated to 80° C. Phosphorous oxychloride (126 mL, 1.375 mol) was added and resulting mixture was heated to 110-120° C. and stirred for 4 h. The resulting solution was cooled to 60° C. and added dropwise into concentrated aqueous ammonium hydroxide solution (800 mL, 11.9 mol) at <10° C. The flask was rinsed with warm sulfolane (50 mL) and the wash was added into the above reaction mixture. The resulting suspension was stirred at 25° C. for 1 h, heated to 95° C. and stirred for 1 hour. The mixture was cooled to 80° C. and the pH was adjusted to 6-8 with 3.0 M aqueous hydrochloric acid solution (−600 mL) and allowed to cool to 25° C. The dark green suspension was filtered, and the wet filter cake was washed with water (300 mL) and dried at 60° C. overnight to give the crude product (140 g) as a green-yellow solid. The crude product was dissolved in 0.5 M aqueous sodium hydroxide solution (1.4 L, 0.7 mol). Charcoal (14 g) was added and the mixture was heated to reflux and stirred for 15 min. The mixture was filtered through Celite and washed with 0.5 M aqueous sodium hydroxide solution (100 mL). The pH of the filtrate was adjusted to 6-8 with concentrated aqueous hydrochloric acid solution (˜60 mL) and the yellow suspension was allowed to cool to 25° C. The mixture was filtered and the wet filter cake was washed with water (200 mL) and dried at 60° C. overnight to afford the desired product, 2-amino-5-nitrobenzenesulfonamide (130 g, 0.599 mol, 65%) as a bright yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:33]4[CH2:34][CH2:35][N:30]([C:27](=[O:29])[CH3:28])[CH2:31][CH2:32]4)=[O:26])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Product: CC(=O)N1CCN(C(=O)c2cc(C(=O)NCCc3ccc(-c4ccc(Cl)c(Cl)c4)o3)[nH]n2)CC1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 1-acetylpiperazine. The crude product was triturated in CH2Cl2 at room temperature to afford the product. 1H NMR (400 MHz, CDCl3): 2.15 (3H, s), 3.01 (2H, t), 3.58 (2H, m), 3.72 (2H, m), 3.78 (2H, q), 3.84 (4H, m), 6.21 (1H, d), 6.59 (1H, d), 7.04 (1H, s), about 7.28 (1H, broad s), 7.41 (2H, m), 7.74 (1H, s), 11.35 (1H, broad s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:10]2([CH3:21])[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[O:13][C:12]([NH2:20])=[N:11]2)[C:5]([O:8]C)=[N:6][CH:7]=1.Cl.O1CCOCC1>O>[NH2:1][C:2]1[CH:3]=[C:4]([C@:10]2([CH3:21])[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[O:13][C:12]([NH2:20])=[N:11]2)[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1ncc(N)cc1[C@]1(C)C[C@@H](C(F)(F)F)OC(N)=N1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@@]1(c2cc(N)c[nH]c2=O)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 100 °C

Procedure:
(4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (14b, 0.650 g, 2.224 mmol, as described in Example 146, method U, Step 2), hydrogen chloride, 4.0 N solution in 1,4-dioxane (1.0 mL, 28.8 mmol) and water 0.5 mL were combined in a microwave tube. The vials was sealed and heated at 100° C. for 3 h. The mixture was concentrated to dryness and carried to the next step without purification. MS m/z=291.0 [M+H]+. Calculated for C11H13F3N4O2: 290.2
Reaction SMILES: [F:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:14]([CH3:17])([O-:16])=[O:15].CN(C)C(N(C)C)=N>CCOC(C)=O.O>[F:1][C:2]1[C:7]([CH:8]([CH2:17][N+:14]([O-:16])=[O:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)/C=C/c1cccnc1F
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CC(C[N+](=O)[O-])c1cccnc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To (E)-methyl 3-(2-fluoropyridin-3-yl)acrylate (0.945 g, 5.22 mmol) was added nitromethane (10.0 mL, 186 mmol) and 1,1,3,3-tetramethylguanidine (0.120 mL, 0.956 mmol). The reaction mixture was stirred at room temperature for 30 min, heated to 50° C. for 1 h, and diluted with EtOAc and water. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 60% EtOAc in hexanes) gave methyl 3-(2-fluoropyridin-3-yl)-4-nitrobutanoate (0.996 g, 4.11 mmol, 79% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 243.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][CH3:6])[CH3:2].[Br-:10]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH:5]([Br:10])[CH3:6])[CH3:2]
Reactant: [Br-]
Reactant: CCOC(CC)OCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(OCC)C(C)Br
Temperature: 25 °C

Procedure:
13.22 g of propion-aldehyde-diethyl-acetal are dissolved in 15 ml of carbon tetrachloride; at -10° C. 20 ml of the carbon tetrachloride solution of 17.58 g of bromide are dropped to it under stirring. After its warming to room temperature it is distilled in vacuo.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CC1
Temperature: 100 °C
Yield: 78 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 55 mg, 0.186 mmol) and cyclopropanamine (25.7 μl, 0.371 mmol, Aldrich), heating at 100° C. for 30 min. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2-(3-(cyclopropylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70-0.75 (m, 2H) 0.96 (dd, J=6.65, 1.96 Hz, 2H) 2.56 (s, 3H) 2.86-2.96 (m, 3H) 3.44 (td, J=6.80, 2.25 Hz, 2H) 6.98 (br. s., 1H) 7.16 (d, J=2.15 Hz, 1H) 7.37 (t, J=7.82 Hz, 1H) 7.58 (d, J=1.17 Hz, 2H) 7.99 (dd, J=7.63, 1.17 Hz, 1H) 12.83 (br. s., 1H). MS (ESI, pos. ion) m/z: 334.2 (M+1).
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:14](Cl)(=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18].C([Li])CCC>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: C=CCCC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve (R)-4-Benzyl-2-oxazolidinone (5.906 g, 33.33 mmoles) and 4-Pentenoyl chloride (4.54 g, 38.33 mmoles) in THF (50 mL). Cool the mixture in a dry ice acetone bath, and add n-Butyl Lithium (36.66 mmoles; 14.66 mL; 10.12 g) dropwise at −78° C. Stir the mixture at −78° C. for 30 min and then warm to ambient temperature. Quench the solution with 60 ml of sat. ammonium chloride, and then extract with 60 ml MTBE. Separate the organics and dry over magnesium sulfate. Filter the drying agent and concentrate under vacuum to an oil (6.96 g). LCMS=100% 260 amu (M+1).
Reaction SMILES: O=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].O.[NH2:13][NH2:14]>CO>[CH:2](=[N:13][NH2:14])[C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Reactant: NN
Solvent: CO
Solvent: O
Product: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=NN

Procedure:
A solution of 4.0 g of 6-deoxy-L-galactose in 10 ml of methanol and 10 ml of hydrazine hydrate was stirred overnight, then evaporated to dryness, giving 4.4 g of 6-deoxy-L-galactose hydrazone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:12]=[C:11]([CH3:13])[O:10][C:5]=2[N:6]=[C:7]([NH2:9])[N:8]=1.[C:14]([C:18]1[S:19][CH:20]=[CH:21][C:22]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])([O:16][CH3:17])=[O:15]>C(#N)C>[CH3:1][O:2][C:3]1[C:4]2[CH:12]=[C:11]([CH3:13])[O:10][C:5]=2[N:6]=[C:7]([NH:9][C:27]([NH:26][S:23]([C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:14]([O:16][CH3:17])=[O:15])(=[O:24])=[O:25])=[O:28])[N:8]=1
Reactant: COc1nc(N)nc2oc(C)cc12
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Solvent: CC#N
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(OC)c2cc(C)oc2n1

Procedure:
A 0.2 g sample of 4-methoxy-6-methylfuro[2,3-d]pyrimidin-2-amine of Example 8 was stirred in 10 ml of anhydrous acetonitrile while 2.0 ml of a 1M solution of 2-carbomethoxy-3-thiophenesulfonylisocyanate in acetonitrile was added at once. The mixture immediately became homogenous then the solid product crystallized out at ambient temperature and was collected after 1 hour. The yield of product was 0.3 g, m.p. 194°-196°. An NMR (60 MHz) spectrum (CDCl3 /DMSO-d6) exhibited absorptions at 2.5, 4.2, 6.4, 7.3, 7.9, 3.9 (methyl ester), 7.5 and 12.5 (broad NH's) ppm and the infrared spectrum (nujol) exhibited bands at 3100 (NH), 1730 (ester), 1700 (urea) cm-1 indicating the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](Br)=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)n(-c2ccc([N+](=O)[O-])cc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C)nn2-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 94.2 %

Procedure:
To a solution of 1-(4′-nitrophenyl)-5-bromo-3-methylpyrazole (100 mg, 0.35 mmol) in THF (5 mL) was added Pd(PPh3)4 (20 mg, 0.017 mmol) and 4-methoxyphenylboronic acid (60 mg, 0.39 mmol), followed by 2 M Na2CO3 (0.35 mL, 0.70 mmol). The mixture was heated to reflux for 4 hr, and was then quenched with water and extracted with EtOAc. The extract was dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/acetate, 15:1) to give the title compound (102 mg, 94%). mp: 155-158° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][OH:33]>>[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][O:33][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1
Reactant: OCc1ccccc1F
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccccc2F)n1
Yield: 61 %

Procedure:
As described for Example 157, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 2-fluorobenzyl alcohol instead of 3-chlorobenzyl alcohol, was converted to the title compound (75 mg, 61%) which was obtained as a light yellow foam. MS: m/e=485.5 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])[CH2:17][C:16]1([CH3:31])[CH3:30])=O)(C)(C)C>C(Cl)Cl>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:29])[C:22]=1[N:18]1[CH2:17][C:16]([CH3:30])([CH3:31])[NH:15][CH2:20][C:19]1=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2c(F)cccc2F)CC1(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CN(c2c(F)cccc2F)C(=O)CN1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
4.2 ml of trifluoroacetic acid (54.7 mmol) was added to a solution of 1.80 g of 4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (60c) (5.47 mmol) in methylene chloride (8.4 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 1.25 g of the title compound (yield: quant.).
Reaction SMILES: C([N:8]([CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1)CC1C=CC=CC=1)C1C=CC=CC=1.N#N.[H][H]>[Pd].CC(C)=O>[NH2:8][CH2:16][C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1
Reactant: [H][H]
Reactant: O=C1O[C@@H](CN(Cc2ccccc2)Cc2ccccc2)CN1c1ccc(N2CCOCC2)c(F)c1
Agent: [Pd]
Agent: N#N
Solvent: CC(C)=O
Product: NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1
Yield: 93.1 %

Procedure:
(S)-5-((dibenzylamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.95 g, 2 mmol) and 0.5 g of 10 wt % Pd—C were added to 20 mL acetone and the air was replaced with N2. The reaction stirred under 5 Mpa hydrogen at room temperature (25° C.) for 5 hours. Filtered and the solvent was evaporated to provide 0.55 g of white solid in 93% yield.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=O.Cl.CN(C)CCCN=C=NCC.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)=[N:31]1>ClCCl>[O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH:69][C:65]1[CH:66]=[CH:67][CH:68]=[C:63]([C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[C:35]([C:39]4[N:43]=[CH:42][N:41]([C:44]([C:45]5[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=5)([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=5)[N:40]=4)[CH:34]=3)[N:30]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[N:31]=2)[CH:64]=1)=[O:5]
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C(=O)c1ccccc1
Reaction time: 48 h

Procedure:
To a solution of 2-oxo-2-phenylacetic acid (0.074 g, 0.498 mmol) in 2.0 mL of dichloromethane, was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDCI) as a solid (0.098 g, 0.510 mmol). The solution was stirred at room temperature for 10 min before 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.150 g, 0.248 mmol), dissolved in 1 mL of dichloromethane was added. After 2 days at room temperature, the reaction was not complete. Another 2 equivalents of EDCI were added to the mixture, driving the reaction to completion within 12 hours. The reaction mixture was then partitioned between dichloromethane and water. The crude material that was obtained from evaporation of the extracts was not purified further. (Yield not calculated) ES-MS (m/z) 735 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[Br:13]Br>C(Cl)Cl>[Br:13][CH2:11][C:10]([C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:12]
Reactant: CC(=O)c1cc(F)c(F)cc1F
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)c1cc(F)c(F)cc1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A 1 L 3-neck round bottom flask was charged with 1-(2,4,5-trifluorophenyl)ethanone (49.7 g, 285 mmol) and DCM (350 mL). The flask was equipped with a 250 mL dropping funnel that contained a solution of bromine (14.6 mL, 283 mmol) in DCM (125 mL). This solution was added to the reaction flask over about 1 h at about 23° C. Once addition of the solution was complete, the reaction mixture was stirred for about 1 h at about 23° C. Ice water was added to the reaction flask and the layers were stirred for about 15 min. The layers were separated and the organic solution was then washed with water and brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a pale yellow solid (70.3 g, 97%): LC/MS (Table 1, Method b) Rt=2.20 min; MS m/z 251.0 (M+H)+.