Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC>C1(C)C=CC=CC=1.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:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccn2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 120 °C
Yield: 81.6 %

Procedure:
To a solution of 2.0 g of 10,11-dihydro-10-(4-iodobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 4.39 g of 2-[(tri-n-butyl)stannyl]pyridine in 30 ml of toluene under nitrogen is added 0.2 g of tetrakis(triphenylphosphine)palladium and the mixture heated to 120° C. for 16 hours. The toluene is evaporated in vacuo and the oily residue diluted with 50 ml of chloroform and washed with water, dried(Na2SO4), filtered through diatomaceous earth and evaporated in vacuo to give a residue which is columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 1.44 g of the desired product as a solid, m.p. 170°-172° C.; M+H=366.1; M+Na=388.1.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=1[NH:22][C:23](=[O:31])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([NH:39][C:19]([C:17]1[S:18][C:14]([CH3:13])=[C:15]([NH:22][C:23](=[O:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:16]=1)=[O:21])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1sc(C(=O)O)cc1NC(=O)Cc1ccccc1
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)NCc2ccccc2)cc1NC(=O)Cc1ccccc1
Yield: 92.3 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.26 g, 1.7 mmol), 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid from Step 1 (0.29 g, 1.1 mmol), and benzyl amine (0.11 g, 1.1 mmol). Acidification of the aqueous workup mixture with dilute hydrochloric acid prior to filtration afforded 0.37 g of 5-methyl-4-phenylacetylamino-thiophene-2-carboxylic acid benzylamide. A sample of the crude product was stirred in 2 M aqueous KHCO3 for several hours, filtered off, rinsed with water, dried, and recrystallized from acetonitrile to give product with a mp 167-170° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[Li]CCCC.[Li]>O1CCCC1.C(OCC)(=O)C>[CH2:24]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[N:32]1[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(=O)CCCC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4-acetylbutyric acid 1-7 (25.0 g, 192 mmol), triethylamine (29.5 ml, 211 mmol) in tetrahydrofuran (500 mL) at −78° C. was added pivaloyl chloride (26.0 ml, 211 mmol). After 20 min, the mixture was warmed to 0° C. for 1.0 h and then recooled to −78° C. To a stirred solution of (S)-(−)-4-benzyl-2-oxazolidinone (37.4 g, 211 mmol) in tetrahydrofuran (500 ml) at −78° C. was added nBuLi (84.5 ml, 211 mmol, 2.5M in hexanes) dropwise over 10 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 10 minutes, the reaction was warmed to 0° C. for 1.0 h. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The reaction mixture was filtered and concentrated at reduced pressure to give 1-8 as a solid which was triturated with ethyl ether and filtered to give a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:13].[C:14]([C:16]1[N:20]([CH3:21])[C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([C:16]1[N:20]([CH3:21])[C:19]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:13])=[CH:18][CH:17]=1)#[N:15]
Reactant: CNS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)c(F)c1
Reaction time: 16 h
Yield: 30.6 %

Procedure:
According to general procedure B, 4-bromo-3-fluoro-N-methylbenzenesulfonamide (158 mg, 0.59 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (106 mg, 0.70 mmol), potassium fluoride (113 mg, 1.95 mmol), and tris(dibenzylideneacetone)dipalladium (15 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (89 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluoro-N-methylbenzenesulfonamide (53 mg, 31%) was provided after purification. HRMS: calcd for C13H12FN3O2S, 293.06342; found (EI, M+.), 293.0627. HPLC purity 99.5% at 210-370 nm, 8.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[NH:23]C(=O)OC(C)(C)C)=[CH:12][C:11]=1[NH:31][C:32]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=[C:34]([CH3:44])[N:33]=1)#[N:9]>C(Cl)Cl>[NH2:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:13]1[CH:12]=[C:11]([NH:31][C:32]2[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:35]=[C:34]([CH3:44])[N:33]=2)[C:10]([C:8]#[N:9])=[N:15][CH:14]=1
Reactant: Cc1cc(-c2ccccc2)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cnc2C#N)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccccc2)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)cnc2C#N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (1.0 ml, 13 mmol) was added to a solution of tert-butyl (1S,2R)-2-(6-cyano-5-(6-methyl-4-phenylpyridin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate (24 mg, 0.048 mmol) in DCM (2 ml). The reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure to afford 5-((1R,2S)-2-aminocyclohexylamino)-3-(6-methyl-4-phenylpyridin-2-ylamino)picolinonitrile. The material was used in the next step without further purification. MS ESI calc'd. for C24H27N6 [M+H]+ 399. found 399.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[CH:19][CH:18]=1)[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][CH2:59][CH2:60][CH2:61][CH2:62][O:63][C:64]1[CH:73]=[CH:72][CH:71]=[C:70]([OH:74])[C:65]=1[C:66]([O:68][CH3:69])=[O:67].C(N(CC)C(C)C)(C)C>C(#N)C.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]2)=[CH:19][CH:18]=1)[C:13]([NH:58][CH2:59][CH2:60][CH2:61][CH2:62][O:63][C:64]1[CH:73]=[CH:72][CH:71]=[C:70]([OH:74])[C:65]=1[C:66]([O:68][CH3:69])=[O:67])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2)S(=O)(=O)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A solution of (2S)-2-[(benzyloxy)carbonyl]amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoic acid (10 mg, 23.1 μmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (10.7 mg, 24.3 μmol) and N,N-dimethylformamide (1 mL) was stirred at 0° C. After stirring for 15 min, methyl 2-(4-aminobutoxy)-6-hydroxybenzoate (6.09 mg, 25.4 μmol) and N,N-diisopropylethylamine (12.1 μL) were added to the reaction. The resulting mixture was stirred at 25° C. for 3 h. The reaction solution was diluted with acetonitrile and purified by preparative LCMS to yield the desired product (4.7 mg, 31%). MF=C32H35N3O10S; LCMS found for C32H36N3O10S (M+H)+: m/z=654.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:15]([C:18]1[S:22][C:21]([N:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=3)[C:24]2=[O:38])=[N:20][C:19]=1[CH3:39])(=[O:17])[CH3:16]>>[C:15]([C:18]1[S:22][C:21]([N:23]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[O:34])=[CH:31][CH:30]=3)[C:24]2=[O:38])=[N:20][C:19]=1[CH3:39])(=[O:17])[CH3:16]
Reactant: C1CCNCC1
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)nc1C
Solvent: NCc1ccccc1
Product: CC(=O)c1sc(N2CCN(Cc3ccc(C(=O)N4CCCCC4)cc3)C2=O)nc1C
Yield: 54 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with piperidine to react with 4-((3-(5-acetyl-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 54% yield: 1H NMR (300 MHz, CDCl3) δ 7.45-7.22 (m, 4H), 4.50 (s, 2H), 4.15-4.01 (m, 2H), 3.69-3.32 (m, 6H), 2.60 (s, 3H), 2.40 (s, 3H), 1.71-1.20 (m, 6H); MS (ES+) m/z 427.1 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:10]([F:22])=[C:11]([CH2:18][C:19](=O)[CH3:20])[C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=1)C1C=CC=CC=1.FC1C(O)=CC=C([N+]([O-])=O)C=1CC(=O)C>>[F:22][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]2[C:11]=1[CH:18]=[C:19]([CH3:20])[NH:15]2
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Product: Cc1cc2c(F)c(O)ccc2[nH]1

Procedure:
1-(3-Benzyloxy-2-fluoro-6-nitro-phenyl)-propan-2-one can also be converted to 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one by the following two alternate methods.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:13][CH2:14][CH:15]([OH:25])[C:16]2[N:17]=[C:18]([NH:21]C(=O)C)[S:19][CH:20]=2)[CH3:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[ClH:26]>>[ClH:26].[ClH:26].[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:13][CH2:14][CH:15]([OH:25])[C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)[CH3:12])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: CC(=O)Nc1nc(C(O)CNC(C)Cc2ccc(C(=O)O)cc2)cs1
Agent: Cl
Product: CC(Cc1ccc(C(=O)O)cc1)NCC(O)c1csc(N)n1

Procedure:
Prepared analogously to Example 9 by reaction of N-[2-(4-carboxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-acetylamino-thiazol-4-yl)ethanamine and 1N hydrochloric acid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]O>>[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CN(C)CCO
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Product: CN(C)CCOc1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccccc3)nc12

Procedure:
This was similarly prepared from 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide and 2-(dimethylamino)ethanol. MS (ESI) m/z 375.1 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.25-8.33 (1H, m), 8.16 (1H, s), 8.08-8.13 (2H, m), 7.53 (2H, t, J=7.78 Hz), 7.44 (1H, t, J=7.32 Hz), 7.20 (1H, d, J=2.14 Hz), 6.98 (1H, dd, J=8.85, 2.14 Hz), 4.30 (2H, t, J=5.34 Hz), 3.01 (2H, t, J=5.34 Hz), 2.52 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:31])[N:24]([CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:32][Mg]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:31])[N:24]([CH2:26][CH2:27][C:28]([OH:30])([CH3:32])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[Mg]Br
Reactant: CC(=O)CCn1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)nc1C
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1CCC(C)(C)O

Procedure:
The title compound was prepared using the method of the previous Example starting from (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide and methylmagnesium bromide. The crude product was purified by flash chromatography on silica gel by using CH2Cl2-MeOH as a gradient eluent (100:1-98:2). The final purification was made by preparative HPLC to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.30 (6H, s), 1.65 (1H, broad s), 1.88 (2H, m), 2.42 (3H, s), 4.02 (2H, m), 4.30 (1H, distorted dd), 4.38 (1H, distorted dd), 4.55 (1H, m), 6.60 (1H, d), 7.47 (1H, s), 7.50 (1H, d), 7.62 (1H, d), 7.65 (1H, d), 7.84 (1H, dd), 7.99 (1H, d).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6]CC)=[O:5].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25])([O-:20])=[O:19].[OH-].[Na+]>C(O)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[NH:25][C:24]([C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=3)=[N:2][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1nc(-c2cccc([N+](=O)[O-])c2)[nH]c1-c1ccc(Cl)cc1

Procedure:
Ethyl 5-(4-chlorophenyl)-2-(3-nitrophenyl)imidazole-4-carboxylate obtained by reacting and treating ethyl 2-hydroxyimino-3-(4-chlorophenyl)-3-oxopropionate and 3-nitrobenzylamine in the same manner as in Starting Material Synthetic Example 1 is dissolved in ethyl alcohol and 1 M aqueous sodium hydroxide solution is added. The mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-chlorophenyl)-2-(3-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH2:8]2.C([O-])=O.[NH4+]>CO.[Pd]>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[CH:2]1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:4]2
Reactant: COC(=O)C=C1C2CC3CC(C2)CC1C3
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)CC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate 71 (6.4 g, 31.07 mmol) in methanol (100 mL) was added ammonium formiate (7.8 g, 124.33 mmol), then under argon was added palladium on charcoal (0.6 g, 10%). The reaction mixture was stirred at room temperature for 3 hours. The catalyst was filtered through Celite® and the solvent removed under reduced pressure. The crude was treated with water and ethyl acetate, and the organic layer was extracted and the solvent was removed under reduced pressure. The title compound was obtained as an colourless iol (6.2 g, 95%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([NH2:12])[C:5]=2[CH:4]=1.[CH3:19][O:20][CH2:21][CH2:22][C@H:23]1[CH2:28]N[CH2:26][CH2:25][NH:24]1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[N:10]=[C:11]([N:12]3[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:22][CH2:21][O:20][CH3:19])[CH2:28]3)[C:5]=2[CH:4]=1
Reactant: COCC[C@H]1CNCCN1
Reactant: NC1=Nc2ccccc2Nc2ccc(Cl)cc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3ccc(Cl)cc32)CCN1
Temperature: 110 °C
Reaction time: 46 h
Yield: 45 %

Procedure:
Combine 2-chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (0.840 g, 3.0 mmol), (S)-2-(2-methoxy-ethyl)-piperazine (0.865 g, 6.0 mmol), N,N-diisopropylethylamine (0.53 mL, 3.0 mmol), DMSO (1.25 ml), and toluene (5.0 ml) and stir and heat the mixture at 110° C. After 46 hours, cool the mixture to ambient temperature and dilute with ethyl acetate. Wash the organic layer with 0.1N NaOH and brine, dry (sodium sulfate) and concentrate the organic layer to 0.985 g of the crude product. Silica gel chromatography, eluting with dichloromethane/methanol (90:10) gives 0.501 g of the title compound as a yellow foam: mass spectrum (ion spray): m/z=371 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1>[Pd].CO>[NH2:8][C:7]1[C:2]([OH:1])=[CH:3][C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH3:14])=[N:5][CH:6]=1
Reactant: C[C@@H](COc1cc(O)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H](COc1cc(O)c(N)cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.5 %

Procedure:
A mixture of tert-butyl ((2S)-1-((4-hydroxy-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (3.84 g) and 10% palladium/carbon (containing water (50%), 0.40 g) and methanol (50 mL) was stirred at room temperature for 15 hr under a hydrogen atmosphere. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure to give the title compound (3.35 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[C:4]([F:11])[CH:3]=1.Br[C:13]1[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[N:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:15][CH:14]=2)=[C:4]([F:11])[CH:3]=1
Reactant: OB(O)c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(Br)cc3F)nc2)CC1
Yield: 41.5 %

Procedure:
1,1-Dimethylethyl 4-({[6-(4-bromo-2-fluorophenyl)-3-pyridinyl]oxy}methyl)-1-piperidinecarboxylate (0.23 g, ˜90% purity, 42%) was prepared as a white solid from (4-bromo-2-fluorophenyl)boronic acid (0.30 g, 1.36 mmol), 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (0.44 g, 1.19 mmol), 2M Na2CO3 (2 mL), and PdCl2(PPh3)2 (85 mg, 0.12 mmol) in DME (4 mL) in a manner similar to Example 21, Step 3. The material was purified by chromatography on a silica gel column eluted with 20% EtOAc/hexanes. 1H NMR (400 MHz, CDCl3): δ 8.38 (d, 1H, J=2.7 Hz), 7.90-7.85 (m, 1H), 7.72 (d, 1H, J=8.8 Hz), 7.45-7.30 (m, 2H), 7.30-7.25 (m, 1H), 4.25-4.10 (m, 2H), 3.99 (d, 2H, J=6.4 Hz), 2.95-2.80 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.25 (m, 2H); LRMS (ESI), m/z 465/467 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O.C1(C)C=CC=CC=1.BrC1C=CC(C2N(C3C=CC(Cl)=CC=3)C(=O)C3C=NN(C4C=CC=C(SC)C=4)C=3N=2)=CC=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([Cl:20])=[N:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: CSc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: ClC(=Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 170 °C

Procedure:
4-Bromo-N-(4-chloro-phenyl)-benzimidoyl chloride is prepared by heating 4-bromo-N-(4-chloro-phenyl)-benzamide (13.39 g, 43.2 mmol) and thionyl chloride (100 mL) for 1 h. The clear solution is concentrated and the residue obtained is coevaporated with toluene (100 mL). A solution of 5-amino-1-(3-nitro-phenyl)-1H-imidazole-4-carboxylic acid ethyl ester (1, 4.00 g, 14.4 mmol) in dry chloroform (50 mL) is then added and the resulting mixture is concentrated to afford a dry residue. It is heated to 170° C. with out solvent for 6 h. The crude product obtained is purified by column chromatography to afford the product as greenish black solid as product (6).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=1.[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](N)[C:16]=1[CH3:22].N(OC(C)(C)C)=O>C1(C)C=CC=CC=1>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[C:16]=1[CH3:22]
Reactant: c1cnccn1
Reactant: Cc1c(N)cccc1COC1CCCCO1
Agent: CC(C)(C)ON=O
Solvent: Cc1ccccc1
Product: Cc1c(COC2CCCCO2)cccc1-c1cnccn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 1.4 %

Procedure:
A stirred solution of 50.0 g (0.624 mol) of pyrazine and 13.8 g (0.624 mol) of 3-amino-2-methylbenzenemethanol tetrahydropyranyl ether was warmed to 84° C.±6° C. and 9.6 g (0.094 mol) of t-butyl nitrite was added dropwise during 10 minutes. Upon complete addition, the reaction mixture was stirred at 85° C.±6° C. for 0.75 hours, then allowed to cool slowly to ambient temperature. The reaction mixture was dissolved in 100 mL of toluene, and subjected to column chromatography on silica gel, eluting with toluene-methylene chloride (3:1), methylene chloride, and finally ethyl acetate-methylene chloride (4:1). All the fractions were combined and subjected to a second column chromatography on silica gel, eluting with ethyl acetate-methylene chloride (1:19), ethyl acetate-methylene chloride (1:9), and ethyl acetate. The appropriate fractions were combined and concentrated under reduced pressure to give a residual oil. The oil was subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 2.4 g of 2-methyl-3-(pyrazinyl)-benzenemethanol tetrahydropyranyl ether, b.p. 163° C.±3° C./0.04 mm.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:12][C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: CCOC(=O)c1cccc(Nc2nc(Cl)nc3[nH]cnc23)c1
Yield: 86.6 %

Procedure:
The procedure is carried out as in Example 1, starting with 189 mg of 2,6-dichloropurine, 5 ml of butanol and 206 mg of ethyl 3-aminobenzoate. 275 mg of the expected product are thus obtained.