Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)Cl)C=CC=CC=1.C[Si]([C:45]1[NH:46][CH:47]=[CH:48][N:49]=1)(C)C>C(#N)C>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:46]2[CH:47]=[CH:48][N:49]=[CH:45]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)c1ncc[nH]1
Reactant: ClC(c1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: c1ccc(-c2ccc(C(c3ccccc3)n3ccnc3)cc2)cc1
Yield: 52.1 %

Procedure:
167 g (0.6 mol) of biphenyl-4-yl-phenyl-chloromethane [alternatively named as diphenyl-phenyl-chloromethane or as α-(biphenyl-4-yl)benzyl chloride] and 92 g (0.66 mol) of trimethylsilylimidazole, dissolved in 500 ml of acetonitrile, are heated under reflux for 15 hours. After distilling off the solvent, the crystalline residue is purified by recrystallization from ethyl acetate. 97 g (52% of theory) of (biphenyl-4-yl)-imidazol-1-yl-phenylmethane of melting point 142° C. are obtained.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].[CH:22]1([O:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][N:31]=[C:30]([CH:36]=[O:37])[CH:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.[Cl-].[NH4+]>[CH:22]1([O:27][C:28]2[C:33]([O:34][CH3:35])=[CH:32][N:31]=[C:30]([CH:36]([OH:37])[CH2:20][C:19]3[C:18]([Cl:21])=[CH:17][N:16]=[CH:15][C:14]=3[Cl:13])[CH:29]=2)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1cnc(C=O)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cnc(C(O)Cc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
n-Butyllithium (3.21 mL of 2.5 M solution) is added to a solution of diisopropylamine (1.15 mL) in dry tetrahydrofuran (25 mL) with the temperature being maintained below −60° C. After 30 min a solution of 3,5-dichloro-4-methylpyridine (1.21 g) in tetrahydrofuran (7 mL) is added dropwise and the mixture stirred for a further 30 min. A solution of 4-cyclopentyloxy-5-methoxypyridine-2-carboxaldehyde (1.65 g) in tetrahydrofuran (7 mL) is added and the mixture stirred for 4 hours whilst being allowed to warm to room temperature. After a further 18 hours at room temperature the mixture is diluted with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate. The extracts are washed with water, dried (MgSO4) and evaporated to give a yellow oil. The oil is triturated with n-pentane to give (±)-1-(4-cyclopentyloxy-5-methoxypyridin-2-yl)-2-(3,5-dichloropyridin-4-yl)ethanol (1.4 g) as an off-white solid, m.p. 110-112° C. [1Hnmr in D6-DMSO shifts relative to Me4Si: 1.55-1.78, 6H, m; 1.95, 2H, m; 3.27, 2H, m; 3.79, 3H, s; 4.89, 2H, m; 5.64, 1H, d; 7.07, 1H, s; 7.98, 1H s; 8.54, 2H, s.].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C([O:22][B:23](OC(C)C)[O:24]C(C)C)(C)C>C1COCC1>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([B:23]([OH:24])[OH:22])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Biphenylboronic acid was prepared differently than described in the literature (see Yabroff, D. L.; Branch, G. E.; Bettman, B. J. Am. Chem. Soc. 1934, 56, 1850-1857). To a solution of 4-bromobiphenyl (2.00 g, 8.58 mmol) in THF (20 mL) at -78° C. was added n-butyllithium (4.0 mL of 2.5 M in hexanes) in a slow stream via syringe. After 15 minutes, triisopropylborate (3.0 mL, 13 mmol) was added in a slow stream via syringe. After 10 minutes, the resultant homogeneous solution was allowed to warm to ambient temperature over 45 minutes and partitioned between EtOAc (50 mL) and 10% aqueous HCI (50 mL). The aqueous layer was separated and extracted with more EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a crude product which was triturated with hexanes to yield 1.53 g (90%) of 4-biphenylboronic acid as a white solid. 1H NMR (DMSO-d6): δ 8.05 (s, 2H), 7.83 (d, 2H, J=8.5 Hz), 7.65 (d, 2H, J=7.0 Hz), 7.60 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.4 Hz), 7.33 (t, 1H, J=7.2 Hz). Anal. C12H11BO2 : C, 72.78; H, 560. Found: C, 72.51; H, 5.62.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][CH2:23]Cl.C(O)(=O)C>CN(C)C=O>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:21][O:22][CH3:23])[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COCCl
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COCN1C(=O)N([C@H](C)c2ccccc2)[C@H]2COC(=O)[C@H]21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
4.0 g (93 mmol) sodium hydride (55 percent in oil) was added in 10 portions in 2 hours at -10° C. under argon to a solution of 19 g (77 mmol) of (3as,6aR)[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d]-imidazol-2,4-(3H,3aH)-dione and 9.42 g (120 mmol) of chloromethyl methyl ether in 200 ml of dried N,N-dimethylformamide. The reaction mixture was stirred at 5° C. for 2 hours and then at room temperature for another 2 hours. Then 2 ml of acetic acid was added. Then the mixture was evaporated to dryness. Then the residue was taken up in 50 ml of water and 100 ml of dichloromethane, the phases were separated and the aqueous phase was extracted 2 times with 100 ml of dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. After chromatographing the oily residue over silica gel with 500 ml of dichloromethane/ethyl acetate and concentration of the fractions 4.0 g (18 percent) of the title product was obtained as white powder. Concerning the product:
Reaction SMILES: Cl[C:2]1C(CN)=CC=C(Cl)N=1.[CH2:11]([N:13]([CH2:18][C:19]1[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:14]([NH:16][CH3:17])=[S:15])[CH3:12].CNC(N(CC)CC1C=NC=CC=1)=S>>[CH3:2][S:15][C:14](=[N:16][CH3:17])[N:13]([CH2:11][CH3:12])[CH2:18][C:19]1[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=1
Reactant: NCc1ccc(Cl)nc1Cl
Reactant: CCN(Cc1ccc(F)nc1)C(=S)NC
Agent: CCN(Cc1cccnc1)C(=S)NC
Product: CCN(Cc1ccc(F)nc1)C(=NC)SC

Procedure:
The reaction procedure of Example 13 (2) was repeated except that N-ethyl-N-(6-fluoro-3-pyridylmethyl)-N'-methylthiourea was used in lieu of N-methyl-N'-ethyl-N'-(3-pyridylmethyl)thiourea to give S-methyl-N-ethyl-N-(6-fluoro-3-pyridylmethyl)-N'-methylisothiourea as a pale brown oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)(=[O:4])=[O:3].[H-].[Na+].CS(O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>ClCCl.CO>[C:35]([O:34][C:32](=[O:33])[NH:31][CH:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:10]2[C:9]3[CH:15]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12][C:11]2=[O:14])[CH2:26][CH2:27]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)NC(=O)CO2
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(S(C)(=O)=O)cc32)CC1
Yield: 66 %

Procedure:
6-(Methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 101) (280 mg, 1.23 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (1.62 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 66% yield as a yellow gum.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[C:6]12([OH:18])[CH2:15][C:10]3([OH:16])[CH2:11][CH:12]([CH2:14][C:8]([OH:17])([CH2:9]3)[CH2:7]1)[CH2:13]2>CN(C=O)C>[CH3:1][O:2][C:3]([O:18][C:6]12[CH2:15][C:10]3([O:16][C:3]([O:2][CH3:1])=[O:4])[CH2:11][CH:12]([CH2:14][C:8]([O:17][C:3]([O:2][CH3:1])=[O:4])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:4]
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)OC12CC3CC(OC(=O)OC)(C1)CC(OC(=O)OC)(C3)C2
Temperature: 25 °C
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3,5-adamantanetriol obtained by the method of Example 32 and 36 mmole of pyridine were dissolved in 10 mL of DMF. To the mixture, 33 mmole of methoxycarbonyl chloride was added dropwise with stirring at room temperature. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3,5-adamantanetriol was 99% and 1,3,5-tris(methoxycarbonyloxy)adamantane (yield 95%) was formed.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O-])([O-])=[O:6].[K+].[K+].[Cl:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:13]=1[OH:22].Cl>O>[Cl:11][C:12]1[C:17]([C:18]([F:20])([F:21])[F:19])=[C:16]([CH:15]=[CH:14][C:13]=1[OH:22])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1ccc(O)c(Cl)c1C(F)(F)F
Yield: 11.7 %

Procedure:
Chloroform (6.7 g, 2.0 eq.) was added dropwise to a stirred mixture of Ca(OH)2 (8.95 g, 120 mmol.), K2CO3 (13.5 g, 98 mmol.), 2-chloro-3-(trifluoromethyl)phenol (50. g, 22 mmol.), and H2O (50 mL) at 60°-70° over 2 hours. The reaction mixture was cooled, and acidified with conc. HCl. The product was extracted into EtOAc and dried over Na2SO4. Solvent was evaporated, the crude product was separated and purified through a silica column, eluting with hexane and EtOAc (3:2) to give 580 mg (10%) of the title compound.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[N:15](S(C2C=CC(C)=CC=2)(=O)=O)[CH:14]=1.[OH-].[K+]>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:6]=1[C:13]1[C:21]2[C:16](=[N:17][CH:18]=[C:19]([C:22]3[CH:23]=[C:24]([C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])[CH:25]=[CH:26][CH:27]=3)[CH:20]=2)[NH:15][CH:14]=1
Reactant: COc1cccc(OC)c1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1-c1c[nH]c2ncc(-c3cccc(C(=O)N4CCOCC4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
Methanol (1 mL) was added to crude (3-(3-(2,6-dimethoxyphenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone from step 1 and potassium hydroxide (50% w/v, 0.038 mL, 0.34 mmol) was added to the resulting solution. The mixture was stirred for 30 minutes at room temperature before being diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography afforded (3-(3-(2,6-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (7) (31% yield from (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone) as light yellow solids. 1H NMR (500 MHz, CD3OD) δ 3.65 (m, br, 8H), 3.75 (s, 6H), 6.77 (d, J=8.5 Hz, 2H), 7.31 (t, J=8.5 Hz, 1H), 7.39 (m, 1H), 7.46 (s, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.67 (m, 1H), 7.74 (m, 1H), 7.91 (d, J=2.0 Hz, 1H), 8.45 (d, J=2.0 Hz, 1H). MS: m/z 444.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][S:18][C:17]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:16]1=2)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].B.O1CCCC1>O1CCCC1.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:15]1[CH2:20][CH2:19][S:18][C:17]2[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:16]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(=O)N1CCSc2ccc([N+](=O)[O-])cc21
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a stirred solution of tert-butyl 2-hydroxyethyl(2-(6-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-oxoethyl)carbamate (620 mg, 1.560 mmol) in tetrahydrofuran (5 mL) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran; 4.68 mL, 4.68 mmol), dropwise to avoid excessive bubbling. The mixture was then stirred at room temperature for 2 hours. The mixture was then quenched via the slow, dropwise addition of MeOH. The quenched reaction was then diluted with ethyl acetate and washed with saturated sodium carbonate (3×). The organic phase was dried, filtered, and concentrated giving a red oil (595 mg, 99%). 1H NMR (DMSO-d6) δ 7.59-7.44 (m, 1H), 7.38-7.32 (m, 1H), 7.22-7.13 (m, 1H), 4.74 (t, J=5.1 Hz, 1H), 3.69-3.62 (m, 2H), 3.61-3.39 (m, 6H), 3.29-3.17 (m, 2H), 3.15-3.04 (m, 2H), 1.31, 1.24 (2s, 9H); ESI-MS (m/z, %): 406 (M+Na, 55), 328 (40), 284 (100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1/[CH:13]=[C:14]1\[CH2:15][N:16]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:18][CH:19]\1O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([OH:43])(=[S:42])[CH3:41].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.O>C1(C)C=CC=CC=1>[C:40]([S:42][CH:19]1[CH2:18][CH2:17][N:16]([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:15]/[C:14]/1=[CH:13]\[C:9]1[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:12]=[CH:11][N:10]=1)(=[O:43])[CH3:41]
Reactant: CC(O)=S
Reactant: CC(C)(C)OC(=O)n1ccnc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1nccn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
To a solution of (E)-3-{[1-(t-butoxycarbonyl)-1H-imidazol-2-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (2.45 g) in toluene (100 ml) were added successively thioacetic acid (0.60 ml) and N,N-dimethylformamide dineopentyl acetal (2.36 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane and dichloromethane (1:5:1) as the eluent to afford the title compound (0.72 g, yield: 26%) as a colourless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[C:4]([CH3:24])[N:3]=1.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C.Cl.[CH3:43][O:44][C:45](=[O:48])[CH2:46][NH2:47]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([NH:47][CH2:46][C:45]([O:44][CH3:43])=[O:48])=[O:21])=[CH:22][CH:23]=3)[CH2:13][CH2:14]2)=[C:4]([CH3:24])[N:3]=1
Reactant: COC(=O)CN
Reactant: Cc1nc(N)nc(N)c1N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1ccc(N2CCN(c3c(C)nc(N)nc3N)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.2 %

Procedure:
A mixture of 3.9 g (0.012 mole) of 4-[4-(2,4-diamino-6-methyl-5-pyrimidinyl)-1-piperazinyl]benzoic acid, 6.5 g (0.039 mole) of diethyl phosphorocyanidate and 6.6 ml (0.047 mole) of triethyl amine in 500 ml of N,N-dimethylformamide (dried over 4H molecular sieves overnight) was stirred at room temperature for five hours. A mixture of 1.8 g (0.014 mole) of glycine methyl ester, hydrochloride, 2 ml (0.014 mole) of triethylamine and 10 ml of N,N-dimethylformamide was added to the suspension and the mixture was stirred at room temperature for another two hours. The solvent was removed under high vacuum (0.1 mm, dry ice-2-propanol trap) at 48° C. The solid residue was dissolved in 200 ml of ice water and neutralized with saturated sodium carbonate solution to pH 8. The solid was collected and washed with 100 ml of water. Recrystallization from acetonitrile gave 2.6 g of the product as a pale yellow solid, mp 255° C. (with decomposition).
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([OH:15])=O.[NH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH2:34][C:33]1=[O:42]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[N:35]1([C:13]([C:16]2[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=2)[CH2:19][N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:15])[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:32][C:33](=[O:42])[CH2:34]1
Reactant: O=C1CNc2ccccc2N1
Reactant: CN(Cc1cccc(C(=O)O)c1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(Cc1cccc(C(=O)N2CC(=O)Nc3ccccc32)c1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 27.2 %

Procedure:
WSC.HCl (640 mg, 3.4 mmol) and 4-(dimethylamino)pyridine (330 mg, 2.7 mmol) were added to a solution of tert-butyl N-(3-carboxybenzyl)-N-methylcarbamate (700 mg, 2.6 mmol) and 1,2,3,4-tetrahydroquinoxalin-2-one (440 mg, 2.9 mmol) in dichloromethane (20 ml). The mixture was stirred for 18 h, reduced in vacuo and taken up in ethyl acetate. This solution was washed with 0.3N potassium hydrogen sulphate and saturated sodium hydrogen carbonate solutions, dried and reduced. Chromatography (50% EtOAc/50% 60-80 pet.ether) afforded tert-butyl N-(3-(1,2,3,4-tetrahydroquinoxalin-3-on-1-carbonyl) benzyl)-N-methylcarbamate (280 mg, 27%) as an orange oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1)[CH3:2].C([O-])(=O)C.[K+].[I:15]Cl>C(O)(=O)C>[NH2:9][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]([I:15])=[CH:7][N:6]=1
Reactant: CCc1ccnc(N)c1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCc1cc(N)ncc1I
Temperature: 80 °C
Yield: 73.8 %

Procedure:
4-ethyl-2-aminopyridine (10.0 g, 81.9 mmol) and potassium acetate (8.00 g, 81.9 mmol) were dissolved in 100 mL of acetic acid and heated to 80° C. with continuous stirring. In a separate flask, iodomonochloride (13.2 g, 81.9 mmol) was dissolved in 30 mL of acetic acid and added to the above reaction mixture drop wise. Once the addition was completed, the reaction mixture was heated for an additional 4 h. Progress of the reaction was monitored by gas chromatography and HPLC. When the reaction was completed, the reaction mixture was cooled to room temperature and quenched with an aqueous solution of saturated sodium bisulfite (10 mL). Acetic acid was removed under vacuum and the residue was dissolved in ethyl acetate and neutralized with saturated NaHCO3. The organic layer was separated from the aqueous layer and the solvent was removed under vacuum. The crude was purified by silica gel column chromatography eluting with 25% ethyl acetate/hexanes. 15 g of desired product was obtained (74% yield).
Reaction SMILES: [F:1][C:2]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][S:5][C:6]1[N:11]=[C:10]([NH:12][S:13]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]2C)(=[O:15])=[O:14])[CH:9]=[C:8]([O:30][CH3:31])[N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:20]1[CH2:18][CH2:17][N:16]([S:13]([NH:12][C:10]2[CH:9]=[C:8]([O:30][CH3:31])[N:7]=[C:6]([S:5][CH2:4][C:3]3[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:2]=3[F:1])[N:11]=2)(=[O:15])=[O:14])[CH2:21]1
Reactant: COc1cc(NS(=O)(=O)N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)nc(SCc2cccc(F)c2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)N2CC[C@@H](N)C2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R)-4-[({2-[(2,3-difluorobenzyl)thio]-6-methoxypyrimidin-4-yl}amino)sulfonyl]-3-methylpiperazine-1-carboxylate (0.75 g) in DCM (10 ml) was added TFA (10 ml) slowly. The reaction then stirred at room temperature for 18 h. The reaction was reduced in vacuo and the residue purified by prep HPLC to give the title compound as a white solid. Yield: 0.27 g
Reaction SMILES: C(OC(=O)COC1C=CC(S)=CC=1C)C.[CH2:16]([O:18][C:19](=[O:34])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([S:29](Cl)(=O)=O)=[CH:24][C:23]=1[CH3:33])[CH3:17]>>[CH2:16]([O:18][C:19](=[O:34])[CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([SH:29])=[CH:24][C:23]=1[CH3:33])[CH3:17]
Reactant: CCOC(=O)COc1cc(C)c(S(=O)(=O)Cl)cc1C
Agent: CCOC(=O)COc1ccc(S)cc1C
Product: CCOC(=O)COc1cc(C)c(S)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.3, using compound 21.2 as the starting material. 1H NMR (300 MHz) (CDCl3) δ 7.11 (1H, s); 6.54 (1H, s); 4.59 (2H, s); 4.26 (2H, q, J=7.2 Hz); 3.10 (1H, s); 2.29 (3H, s); 2.21 (3H, s); 1.30 (3H, t, J=7.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][OH:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:10][C@H:9]1[CH2:24][O:25][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccc3ccccc3c2)C[C@H]1CO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](Oc3ccc4ccccc4c3)CN2C(=O)OC(C)(C)C)cc1
Yield: 93.4 %

Procedure:
To a stirred mixture of (2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinylmethanol (640 mg, 1.86 mmol), methyl 4-hydroxybenzoate (283 mg, 1.86 mmol) and PPh3 (488 mg, 1.86 mmol) in THF (18 ml) was added DIAD (0.37 ml, 1.86 mmol) at room temperature under an atmosphere of nitrogen. The mixture was stirred over night. After removal of the solvent, the resulting residue was chromatographed on silica gel [100 g, n-hexane/EtOAc(2/1)], to give methyl 4-[(2S,4S)-1-tert-butoxycarbonyl-4-(2-naphthyloxy)-2-pyrrolidinyl]methoxybenzoate (830 mg, 93%) as a colorless oil. 1H-NMR (CDCl3) δ1.50 (d, J=8.3 Hz, 9H), 2.34 (m, 1H), 2.53 (d, J=14.2 Hz, 1H), 3.72-3.85 (m, 1H), 3.86 and 3.87 (s, 3H, amide isomers), 4.17 (m, 1H), 4.26-4.52 (m, 2H), 5.06 (br, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 7.04 (br, 2H), 7.33 (t, J=7.3 Hz, 1H), 7.42 (t, J=7.3 Hz, 1H), 7.64-8.02 (m, 5H).