Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][O:11][CH3:12])=[O:9])=[CH:4][C:3]=1[NH:13][C:14]1[C:19]2=[C:20]([CH:26]([CH3:28])[CH3:27])[C:21]([C:23]([OH:25])=O)=[CH:22][N:18]2[N:17]=[CH:16][N:15]=1.Cl.[CH2:30]([NH2:32])[CH3:31].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O>[CH2:30]([NH:32][C:23]([C:21]1[C:20]([CH:26]([CH3:27])[CH3:28])=[C:19]2[N:18]([CH:22]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:13][C:3]1[CH:4]=[C:5]([C:8]([NH:10][O:11][CH3:12])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1])=[O:25])[CH3:31]
Reactant: CCN
Reactant: CONC(=O)c1ccc(F)c(Nc2ncnn3cc(C(=O)O)c(C(C)C)c23)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCNC(=O)c1cn2ncnc(Nc3cc(C(=O)NOC)ccc3F)c2c1C(C)C
Yield: 51 %

Procedure:
A mixture of Example 13 (20 mg, 0.052 mmol), ethylamine hydrochloride (6 mg, 0.08 mmol), BOP reagent (34 mg, 0.08 mmol), and N-methyl morpholine (0.012 mL, 0.1 mmol) in dimethyl formamide (0.5 mL) was stirred at RT for 18 h. The mixture was purified by reverse phase HPLC. The appropriate fractions were concentrated and the residue was converted to the HCl salt to obtain the desired product as a white solid (11 mg, 50%). LC/MS; (M+H)+=415.2
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]3)=[N:9][C:10]=2[C:11]2[CH:24]=[CH:23][C:14]([C:15]([NH:17][C:18]3[CH:22]=[CH:21][O:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:31](O)(=[O:35])[C:32]#[C:33][CH3:34]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[C:31](=[O:35])[C:32]#[C:33][CH3:34])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[CH:22]=[CH:21][O:20][N:19]=3)=[O:16])=[CH:23][CH:24]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC#CC(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCCN3)nc(-c3ccc(C(=O)Nc4ccon4)cc3)c12
Product: CC#CC(=O)N1CCCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccon3)cc2)c2c(N)nccn12
Yield: 6.6 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(isoxazol-3-yl)benzamide (intermediate 35) and 2-butynoic acid, to afford the title compound (2 mg, 6.6%). Data: UPLC(C) Rt: 2.23 min; m/z 470.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[NH2:19][C@H:20]([C:23]([NH2:25])=[O:24])[CH2:21][OH:22]>>[C:23]([C@@H:20]([NH:19][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[CH2:21][OH:22])(=[O:24])[NH2:25]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NC(=O)[C@@H](N)CO
Product: NC(=O)[C@H](CO)NC(=O)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(1-(S)-Carbamoyl-2-hydroxy-ethyl)-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.30 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of L-serinamide. LC/MS [5.09 min; 445 (M+1)]
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:14]=[N:13][CH:12]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[N:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:14]=[N:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-n2ncnn2)cc1
Reaction time: 2 h

Procedure:
2-(4-Nitrophenyl)-2H-tetrazole (200 mg, 1.05 mmol) was suspended in ethanol (1 mL). Ethyl acetate (1 mL) was added to improved solubility. The solution was degassed and purged with nitrogen 3 times before palladium on carbon (10% w/w, 223 mg, 0.2 mmol) was added. The mixture was degassed and purged with hydrogen 3 times and stirred under a hydrogen balloon for 2 hours. The reaction was diluted with acetone and passed through a plug of silica gel, which was washed thoroughly with acetone. The filtrated was concentrated to give the crude product which was used as isolated.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[CH3:20][S:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH2:35]Cl)=[N:33][N:34]=[C:30]3[CH2:29][N:28]=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:26]=2[CH:43]=1>CN(C)C=O>[CH3:20][S:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH2:35][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:33][N:34]=[C:30]3[CH2:29][N:28]=[C:27]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:26]=2[CH:43]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CON3C(=O)c4ccccc4C3=O)n1-2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylformamide is treated with 8-methylthio-6-phenyl-1-(chloromethyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine to give 8-methylthio-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]-benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21](O)=[O:22].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: COc1cccc(-c2ccc3c(C(=O)O)c(OC)ccc3c2)c1
Reactant: Nc1ccccc1
Product: COc1cccc(-c2ccc3c(C(=O)Nc4ccccc4)c(OC)ccc3c2)c1
Yield: 85 %

Procedure:
The compound was prepared by reaction of 2-methoxy-6-(3-methoxyphenyl)-1-naphthoic acid (300 mg, 0.97 mmol, 1 eq) with aniline (1 eq) according to method D. Purification by column chromatography with hexane/ethyl acetate 2/1 as the eluent yielded the desired compound in a yield of 85%, 316 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([CH2:28][CH2:29][C:30]([OH:32])=O)[CH:3]=1.[NH2:33][C:34]1[C:39]([NH2:40])=[CH:38][C:37]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[CH:36][N:35]=1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[NH2:33][C:34]1[C:39]([NH:40][C:30](=[O:32])[CH2:29][CH2:28][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:5]=2)=[CH:38][C:37]([C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)=[CH:36][N:35]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1N
Reactant: Cc1cc(CCC(=O)O)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: Cc1cc(CCC(=O)Nc2cc(-c3ccc(Cl)cc3)cnc2N)nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 40 °C
Yield: 91.4 %

Procedure:
300 mg of 3-[4-methyl-6-(trityl-amino)-pyridin-2-yl]propionic acid (compound C4) and 156 mg of 2,3-diamino-5-(4-chlorophenyl)-pyridine (compound F4) are dissolved in 13 ml of pyridine and sequentially treated with 280 mg of O-[(ethoxycarbonyl)canomethylene-amino]-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate and 153 μl of diisopropylethyl amine. The reaction mixture is warmed to 40° C. for 120 h. Purification of the crude product by chromatography on silica gel (eluent: dichloromethane/methanol 8:1) afforded 405 mg of the title compound as an oil. ESI-MS: 624.1/626.1 (MH+, 100%/38%). TLC: Rf=0.32 (dichloromethane/methanol 8:1).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1.[ClH:26]>O>[Cl:26][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][C:16]=3[CH:25]=2)=[CH:8][CH:7]=1
Reactant: Cl
Reactant: CCOC(=O)c1cc2cc(-c3ccc(N)cc3)ccc2o1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2cc(-c3ccc(Cl)cc3)ccc2o1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of 6.9 g of sodium nitrite in 40 ml of water was added drop-by-drop to a stirred mixture of 30 g of 12C and 160 ml of 6 N hydrochloric acid, the rate of addition being adjusted to maintain the temperature of the reaction mixture at 0°-5° C. The mixture was stirred for 1 hour at 0°-5° C., then added with vigorous stirring, to 50 ml of 20% aqueous cuprous chloride heated to 70° C. The resulting mixture was heated to 70° C., then allowed to cool. The solid was collected, washed with water, dried (P2O5, reduced pressure) and dissolved in tetrahydrofuran. The solution was suspended on 75 g of silica gel and dry column chromatographed, using chloroform as eluent. The product was removed from the combined appropriate fractions with tetrahydrofuran. The solvent was evaporated ad the residue was dried (drying pistol, P2O5, refluxing acetone) to give ethyl 5-(4-chlorophenyl)benzofuran-2-carboxylate (12 D), mp 108°-110° C.
Reaction SMILES: [CH2:1]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:21])[CH:19]=O.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1COCC1.CO>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:18]([CH3:21])[CH3:19]
Reactant: CC(C)C=O
Reactant: c1ccc(CNOCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CN(Cc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of II (1 eq.), 2-methylpropanal (1 eq.) and BH3(pyridine) (1 eq.) in THF:MeOH (1:3) was added PPTS (1 eq.). The reaction mixture was stirred at rt for 12 h and afforded, after aqueous workup and purification by column chromatography, III as a colorless oil.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([NH2:18])=[CH:8][N:7]=1)([CH3:5])([CH3:4])[CH3:3].[N:19]([C:22]1[CH:23]=[C:24]([CH:32]=[CH:33][CH:34]=1)[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:20]=[O:21]>>[C:2]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]([NH:18][C:20]([NH:19][C:22]2[CH:34]=[CH:33][CH:32]=[C:24]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=2)=[O:21])=[CH:8][N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=C=Nc1cccc(Oc2ccccc2)c1
Reactant: CC(C)(C)c1ncc(N)c(-c2ccccc2)n1
Agent: Cl
Product: CC(C)(C)c1ncc(NC(=O)Nc2cccc(Oc3ccccc3)c2)c(-c2ccccc2)n1
Yield: 25.3 %

Procedure:
Using general method A, 2-t-butyl-4-phenylpyrimidin-5-amine hydrochloride (100 mg, 0.379 mmol, available from Example 279) and 1-(3-isocyanatophenoxy)benzene (88 mg, 0.417 mmol) were combined to yield 1-(2-t-butyl-4-phenylpyrimidin-5-yl)-3-(3-phenoxyphenyl)urea (42 mg, 25% yield). 1H NMR (DMSO-d6): δ 1.38 (s, 9H), 6.61-6.63 (m, 1H), 7.01-7.56 (m, 1H), 7.73-7.75 (m, 2H), 8.10 (s, 1H), 9.02 (s, 1H), 9.19 (s, 1H). LC-MS (EI) m/z: 439.3 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[NH:6])(=[O:3])[CH3:2].Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=1)=O>CN(C=O)C>[F:20][CH:19]([F:21])[O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[NH:7][CH:9]=2)=[CH:13][CH:14]=1
Reactant: O=C(CBr)c1ccc(OC(F)F)cc1
Reactant: CC(=O)NC(=N)N
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(-c2ccc(OC(F)F)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.8 %

Procedure:
Acetyl guanidine (2.6 g, 25.7 mmol, 3.0 eq) was dissolved in DMF anhydrous (40 mL) and 2-Bromo-1-(4-difluoromethoxy-phenyl)-ethanone (2.3 g, 8.5 mmol, 1.0 eq) was added; the mixture was stirred under nitrogen at room temperature for 4 days. DMF was dried; the residue was washed with water, filtered and dried. The crude was crystallized from methanol to give 1.2 g of the title compound (yield: 53%).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:13]3[N:17]4[CH:18]=[C:19]([C@@H:22]([N:27]5[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]5)[C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][C:16]4=[N:15][N:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:40][N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][C:43]([CH3:55])=[N:42]1>>[CH3:40][N:41]1[C:45]([C:2]2[C:11]([CH3:12])=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:13]4[N:17]5[CH:18]=[C:19]([C@@H:22]([N:27]6[CH2:31][CH2:30][C@H:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28]6)[C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:21][C:16]5=[N:15][N:14]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:44][C:43]([CH3:55])=[N:42]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C)n1
Reactant: Cc1c(Br)ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Product: Cc1cc(-c2ccc3ccc(-c4nnc5ccc([C@@H](N6CC[C@H](NC(=O)OC(C)(C)C)C6)C(F)(F)F)cn45)nc3c2C)n(C)n1

Procedure:
Prepared as described in Example 191, using tert-butyl (S)-1-((R)-1-(3-(7-bromo-8-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate in place of 7-bromo-2,8-dimethylquinoline and substituting 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Step A. LCMS APCI (+) m/z 621 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:20]1=O>>[F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]2[S:16][C:19]3[CH2:24][CH2:23][CH2:22][CH:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[C:20]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: COc1ccccc1C1CCCC(Br)C1=O
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Product: COc1ccccc1C1CCCc2sc(Nc3ccc(-n4cnc(C)c4)c(F)c3)nc21

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (45 mg, 0.18 mmol) and crude 2-bromo-6-(2-methoxy-phenyl)-cyclohexanone (153 mg, 0.50 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-yellow solid (14 mg, 18%). MS ISP (m/e): 435.4 [(M+H)+]. mp 227-230° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([N:12]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)[CH3:13])=[O:11])[C:5]([CH3:24])=[CH:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[CH:21]1([CH2:20][N:17]2[CH2:18][CH2:19][CH:14]([N:12]([CH3:13])[C:10](=[O:11])[CH2:9][NH:8][C:6]3[C:5]([CH3:24])=[CH:4][N:3]=[C:2]([NH:32][CH2:31][C:30]4[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[N:7]=3)[CH2:15][CH2:16]2)[CH2:23][CH2:22]1
Reactant: Cc1cnc(Cl)nc1NCC(=O)N(C)C1CCN(CC2CC2)CC1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1ccc(CNc2ncc(C)c(NCC(=O)N(C)C3CCN(CC4CC4)CC3)n2)cc1
Yield: 36 %

Procedure:
A solution of Compound 106 (93 mg), 4-methoxybenzylamine (345 μL) and diisopropylethylamine (45.5 μL) in n-butanol (1.5 mL) was stirred overnight under reflux. Subsequently, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1 to 4:1) to give 43 mg (36% yield) of the desired product as a white amorphous.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:19]=[CH:18][C:9]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1)=[O:5].[Li][CH3:22].[Cl-].[NH4+]>C1COCC1>[C:4]([C:6]1[CH:19]=[CH:18][C:9]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:22]
Reactant: [Li]C
Reactant: CCOC(=O)c1cc2ccc(C(=O)N(C)OC)cc2s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(C)=O)cc2s1
Temperature: 25 °C

Procedure:
To a solution of ethyl 6-{[methoxy(methyl)amino]carbonyl}-1-benzothiophene-2-carboxylate (0.07 g, 0.22 mmol) in THF (3 mL) at −78° C. was added MeLi (0.15 mL, 1.6 M in Et2O, 0.24 mmol). The reaction was stirred for 1 h at −78° C. before saturated ammonium chloride solution was added to quench the reaction. At which time the reaction mixture was allowed to warm to room temperature and then extracted with a mixture of hexane:ethyl acetate solution (3:1) (3×). The combined organic layers was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was chromatographed to provide the ketone. 1H NMR (CDCl3, 600 MHz) δ 8.46 (s, 1H), 8.07 (s, 1H), 7.98 (dd, J=8.2, 1.2 Hz, 1H), 7.92 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 2.69 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). MS: cal'd (MH+) 249, exp (MH+) 249.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([NH:23][C@@H:24]([C:27]([OH:29])=[O:28])[CH2:25][OH:26])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl>[C:1]1([CH:7]([O:29][C:27](=[O:28])[C@@H:24]([CH2:25][OH:26])[NH:23][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CO)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of approximately 214 g of diphenyldiazomethane in 1 l of methylene chloride is added dropwise at 22°, while cooling, to a solution of 236.7 g of the resulting crude (2R)-BOC-serine in 700 ml of methylene chloride and the mixture is stirred for 11/2 hours at 20°. The mixture is concentrated by evaporation in vacuo, the residue is taken up in ethyl acetate and washed at 0° with a phosphate buffer of a pH of 2.0 then of a pH of 7.0. The dried organic phase yields a crystalline residue on concentration by evaporation which is digested in hexane and, after filtering, (2R)-N-BOC-serine diphenylmethyl ester is obtained; m.p. 116°-117° (corrected).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C>C(O)C.[OH-].[Pd+2].[OH-].[C]>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: O=[N+]([O-])c1nc(Cl)[nH]c1I
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Reaction time: 5 h
Yield: 83.5 %

Procedure:
2-Chloro-5-iodo-4-nitroimidazole (273 mg) was dissolved in ethanol (5 ml), then triethylamine (420 μl) and 20% palladium hydroxide-carbon (27 mg) were added, the reaction mixture was subjected to hydrogenation at a room temperature under normal pressure for 5 hours, there was obtained 2-chloro-4-nitroimidazole (123 mg, yield: 83.4%) as colorless solid product.
Reaction SMILES: [Br:1][C:2]1[C:10]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:9][C:8]2[C:4](=[C:5]([C:23]([NH:25][CH3:26])=[O:24])[N:6]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:7]=2)[CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:10]([N:11]([CH3:27])[S:12]([CH3:15])(=[O:13])=[O:14])=[CH:9][C:8]2[C:4](=[C:5]([C:23]([NH:25][CH3:26])=[O:24])[N:6]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[N:7]=2)[CH:3]=1
Reactant: CNC(=O)c1c2cc(Br)c(NS(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c2cc(Br)c(N(C)S(C)(=O)=O)cc2nn1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a suspension of 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)-2H-indazole-3-carboxamide (0.5 g, 1.1 mmol) and K2CO3 (0.5 g, 3.4 mmol) in DMF (10 mL) was added dropwise CH3I (0.8 g, 5.6 mmol) at 0° C. under N2, and then the mixture was stirred at 80° C. for 2 hours. After concentration under vacuum, the residue was suspended in H2O and extracted with DCM. The combined organic layer was washed with H2O, brine, dried over Na2SO4, filtrated and concentrated to give 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-2H-indazole-3-carboxamide (0.48 g, yield: 93%). 1H-NMR (CDCl3, 400 MHz) δ 8.21 (s, 1H), 8.01 (s, 1H), 7.56˜7.60 (m, 2H), 7.21˜7.27 (m, 2H), 6.97 (s, 1H), 3.228 (s, 3H), 3.07 (d, J=4.8 Hz, 3H), 2.77 (s, 3H). MS (M+H)+: 455/457.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21].C(O)CO>[Cu]I.C(O)CCC>[CH2:9]([NH:16][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccccc1Br
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: OCCO
Product: O=C(O)c1ccccc1NCc1ccccc1
Temperature: 100 °C
Yield: 52.8 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μL, 1.20 mmol), 2-iodobenzoic acid (248 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). After heated for a specified duration, the reaction was allowed to reach room temperature. Water and diluted HCl (10%) was added until ˜pH 3. Diethyl ether (2 mL) was added and the organic layer was analyzed by tlc. The reaction mixture was further extracted by diethyl ether (4×10 mL) and the combined organic phase was washed with brine and dried over Na2SO4. The solvent was rotary evaporated and the yellowish-brown residue was purified by column chromatography using a solvent mixture (diethyl ether/ethyl acetate=1/1, Rf=0.3) to afford 2-(N-benzyl)aminobenzoic acid (161 mg, 71% isolated yield) as light yellow solid. For aryl bromide substrate: copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μl, 1.20 mmol), 2-bromobenzoic acid (201 mg, 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 1-butanol (1.0 mL) was used and heated to 100° C. The above workup procedures was followed and obtained 2-(N-benzyl)aminobenzoic acid (120 mg, 53% isolated yield) as light yellow solid. For aryl chloride substrate: copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (636 mg, 3.00 mmol), benzylamine (131 μl, 1.20 mmol), 2-chlorobenzoic acid (157 mg, 1.00 mmol), ethylene glycol (111 μl, 2.00 mmol) and 1-butanol (1.0 mL) was used and heated to 100° C. The above workup procedures was followed and obtained 2-(N-benzyl)aminobenzoic acid (109 mg, 48% isolated yield) as light yellow solid. The spectral data (1H NMR) matched with the literature references and indicated >95% purity. See Chang, M. R.; Takeuchi, Y.; Hashigaki, K.; Yamato, M. Heterocycles 1992, 33, 147–152. Moore, J. A.; Sutherland, G. J.; Sowerby, R.; Kelly, E. G.; Palermo, S.; Webster, W. J. Org. Chem. 1969, 34, 887–892.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:20]2[CH:27]=[C:26]([F:28])[C:24](N)=[N:23][C:21]2=[O:22])[C@H:6]1[F:29])(=[O:3])[CH3:2].C(O)(=[O:32])C>>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:20]2[CH:27]=[C:26]([F:28])[C:24](=[O:32])[NH:23][C:21]2=[O:22])[C@H:6]1[F:29])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(F)c(N)nc2=O)O[C@@H]1COC(=O)c1ccccc1
Reactant: CC(=O)O
Product: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(F)c(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1

Procedure:
A mixture of 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluorocytosine (650 mg) in 80% acetic acid (50 ml) is heated under reflux for 48 hours. After removal of the solvent in vacuo the residue is chromatographed over a column of silica gel G60 (22×2 cm) using CHCl3 :MeOH (30:1 v/v as the eluent. Each fraction is checked by tlc and the appropriate fractions are collected and evaporated in vacuo, and the residue is crystallized from ethanol to give pure 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluorouracil, 300 mg, m.p. 177°-179°.