Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15](C(O)(CCC2(C)OCC(C)(C)CO2)CO)[CH:16]=[CH:17][CH:18]=1.[CH3:34][C:35]([CH3:37])=[O:36]>>[C:35]([CH2:37][CH2:34][C:35]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH:14]=2)[CH2:37][O:12][C:13]([CH3:14])([CH3:18])[O:36]1)(=[O:36])[CH3:34]
Reactant: CC1(C)COC(C)(CCC(O)(CO)c2cccc(OCc3ccc4ccccc4c3)c2)OC1
Reactant: CC(C)=O
Product: CC(=O)CCC1(c2cccc(OCc3ccc4ccccc4c3)c2)COC(C)(C)O1
Yield: 45 %

Procedure:
Using the procedure described in Example 1, 2-[3-(naphth-2-ylmethoxy)phenyl]-4-(2,5,5-trimethyl-1,3-dioxan-2-yl)butane-1,2-diol (0.77 g) was reacted with acetone to give 4-(2-acetylethyl)-2,2-dimethyl -4-[3-(naphth-2-ylmethoxy)phenyl]-1,3-dioxolane (0.32 g, 45%), as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:20]#[N:21])([CH3:19])[CH3:18])[CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[SH:23][CH2:24][C:25](O)=[O:26]>>[C:20]([C:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:25](=[O:26])[CH2:24][SH:23])[CH:3]=1)=[O:22])([CH3:19])[CH3:18])#[N:21]
Reactant: O=C(O)CS
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)CS
Yield: 79.9 %

Procedure:
A solution of N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 5 (500 mg, 1.704 mmol) in mercaptoacetic acid (3 mL, 43.2 mmol) was stirred at 100° C. for 2 h. Quenched with water and extracted with EtOAc. Organic layer was washed with NaHCO3 solution, brine, dried and evaporated. Purification by chromatography (0-4% methanol in CH2Cl2) gave pure 3-(2-cyanopropan-2-yl)-N-(3-(2-mercaptoacetamido)-4-methylphenyl)benzamide 16 (500 mg, 80%). 1H-NMR (400 MHz, CDCl3) 1.78 (s, 6H), 2.31 (s, 3H), 3.45 (d, J=9.4 Hz, 2H), 7.21 (d, J=8.2 Hz, 1H), 7.52 (t, J=8.2 Hz, 1H), 7.70-7.79 (m, 3H), 7.92-8.08 (m, 3H), 8.67 (br s, 1H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C@@H:5]1([N:14]2[C:18]3[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=3[N:16]=[C:15]2Cl)[O:11][C@@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]1[OH:7]>>[CH:1]1([NH:4][C:15]2[N:14]([C@@H:5]3[O:11][C@@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]3[OH:7])[C:18]3[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=3[N:16]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: OC[C@@H]1O[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Product: OC[C@@H]1O[C@@H](n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O

Procedure:
The procedure is the same as that described for compound 7a, except that cyclopropylamine was used instead of isopropylamine, and compound 4a (300 mg, 0.80 mmoles) was used. Yield 299 mg (65%) as a white solid. Mp: 184-186° C. 1H NMR (DMSO-d6): δ7.47 (s, 1H), 7.36 (s, 1H), 7.05 (bs, 1H, D2O exchangeable), 5.72 (m, 1H), 5.24 (m, 1H, D2O exchangeable), 5.17 (m, 1H, D2O exchangeable), 4.65 (bs, 2H, D2O exchangeable), 4.53 (m, 1H), 4.42 (m, 1H), 4.15 (m, 1H), 3.66 and 3.57 (m, 2H), 0.86 (m, 2H), 0.57 (m, 1H), 0.50 (m, 1H). Anal. (C15H17O4N3Cl2) C, H, N.
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:2]3[N:18]=[C:5]4[C:6]([C:10]5[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: N#Cc1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3nc4c(-c5ccc(C#N)cc5)cccn4n3)cc2)CC1

Procedure:
4-{4-[8-(4-Cyano-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(4-cyano-phenyl)-[1,2,4]-triazolo[1,5-a]pyridine (0.164 g, 0.644 mmol) and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.214 g, 0.773 mmol) in a manner analogous to Example 311a and 311b to give product (0.181 g, 57%). MP=96-100° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.70 (s, 1H), 8.85 (d, 1H), 8.40 (d, 2H), 8.00 (m, 3H), 7.62 (d, 2H), 7.15 (m, 3H), 4.05 (m, 2H), 2.80 (br m, 2H), 2.60 (m, 1H), 1.75 (m, 2H), 1.45 (m, 2H), 1.41 (s, 9H). MS=495 (MH)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[F:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>CO.C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:1][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]4[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with 1-(4-fluorophenyl)piperazine (90 mg, 0.50 mmol) as described in General Procedure X to afford Iaa (69.0 mg, 55.6%) as an ivory colored solid, tlc Rf=0.4 (10% MeOH/CH2Cl2-0.20% Et3N), m/z obs=461 (M+1).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH3:29][N:30]1[C:34](=[O:35])[N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:32]([C:44]2[CH:49]=[CH:48][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:45]=2)=[N:31]1>>[CH3:29][N:30]1[C:34](=[O:35])[N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:32]([C:44]2[CH:49]=[CH:48][C:47]([C:2]3[N:7]4[CH:8]=[C:9]([CH2:11][CH2:12][C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:46][CH:45]=2)=[N:31]1
Reactant: Brc1cnc(N2CCOCC2)c2nc(CCc3ccc4ccccc4n3)cn12
Reactant: Cn1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n(COCC[Si](C)(C)C)c1=O
Product: Cn1nc(-c2ccc(-c3cnc(N4CCOCC4)c4nc(CCc5ccc6ccccc6n5)cn34)cc2)n(COCC[Si](C)(C)C)c1=O
Yield: 45.7 %

Procedure:
Compound 3a (350 mg, 0.760 mmol) was subjected to Suzuki coupling conditions with 1-methyl-3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-[[2-(trimethylsilyl)ethoxy]methyl]-4,5-dihydro-1H-1,2,4-triazol-5-one (983 mg, 2.28 mmol) using the reaction conditions described in Example 1, Step G to obtain compound 10e as a yellow solid (230 mg, 43% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C36H42N8O3S: 633.3 (M+H). Found 633.5.
Reaction SMILES: N[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31].N([O-])=O.[Na+].CC#N.O.[ClH:42]>O.Cl[Cu]>[Cl:42][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]([CH:18]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][C:3]=1[O:28][CH2:29][C:30]([F:33])([F:32])[F:31]
Reactant: CCOC(=O)C(CC1CC1)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(CC1CC1)c1cc(OCC(F)(F)F)c(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
Ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.85 g, 1.78 mmol) was dissolved in a mixture of MeCN/H2O/HCl 15 mL/15 mL/2 mL at 0° C. A solution of NaNO2 (0.185 g, 2.68 mmol) in water (2 mL) was added drop wise at 0° C., and the reaction mixture was stirred for 40 min, at the same temperature. A solution of CuCl (1.8 g, 17.8 mmol) in water (10 mL) was added drop wise at 0° C. The reaction mixture was heated to 90° C. for 2 h. The reaction mixture was extracted with EtOAc (3×50 mL), and the combined organic layers were washed with water (50 mL) followed by brine (50 mL). The solution was dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-chloro-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-3-cyclopropylpropanoate (0.528 g) as a yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].Br[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>CO.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>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][N:34]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:30])[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
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: [K+]
Solvent: COCCOC
Solvent: CO
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)(C)C)C[C@H](C)N3C(C)=O)nc1

Procedure:
In a separate vial, Tert-butyl ((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (for a preparation see Intermediate 61) (2.2 g, 5.11 mmol), methyl 6-bromonicotinate (1.325 g, 6.13 mmol), Pd(PPh3)4 (0.591 g, 0.511 mmol) and potassium carbonate (2.120 g, 15.34 mmol) were combined in methanol (10 mL) and DME (3 mL) and heated under microwave irradiation to 100° C. for 70 mins. The two reaction mixtures were combined and partitioned between water (150 mL) and DCM (3×150 mL). The aqueous layer was acidified to pH 3 via the addition of aq. HCl and extracted with DCM (3×100 mL). The combined organic layers were dried by passing through a hydrophobic frit, and concentrated in vacuo to give crude methyl 6-((2S,4R)-1-acetyl-4-((tert-butoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (2.2 g) which was used directly in the next step without further purification. LCMS: (Formate, 2 min), Rt=1.06 min, MH+440.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][O:10]C(=O)C)=[C:6]([CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[C:16]2[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:5]=[CH:4][N:3]=1.O.[NH2:28][NH2:29]>CCO>[F:26][C:25]1[C:20]([C:16]2[N:15]([CH2:14][C:6]3[C:7]([CH2:8][CH2:9][OH:10])=[C:2]([NH:28][NH2:29])[N:3]=[CH:4][N:5]=3)[CH:19]=[CH:18][N:17]=2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncnc(Cn2ccnc2-c2ncccc2F)c1CCO
Temperature: 70 °C

Procedure:
A mixture of 163 (1.72 g, 4.6 mmol) and hydrazine monohydrate (0.95 g, 19 mmol) in EtOH (20 mL) is heated at 70° C. overnight. The solvent is removed in vacuo and the residue is triturated with ethyl acetate and ethyl ether. Filtration gives the product (164) as a white solid.
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.[CH3:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]1C>C(O)CCC>[CH3:12][C:13]1[N:14]([C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CC1Cc2ccccc2N1C
Solvent: CCCCO
Product: Cc1cc2ccccc2n1-c1nc(Cl)nc2[nH]cnc12
Temperature: 100 °C

Procedure:
The same procedure as in stage 1 of Example 1 is carried out, mixing 378 mg of 2,6-dichloropurine, 10 ml of butanol and 0.32 of dimethylindoline. The mixture is heated at 100° C. for approximately 5 hours and allowed to return to ambient temperature. Partial drying and washing with isopropanol are carried out. The product is dried and 423 mg of expected product are thus obtained.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:16])[NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:18]1C=NC=CC=1>>[C:1]1([O:7][C:8](=[O:16])[NH:9][CH2:10][C:11]2[CH:18]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccnc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Product: O=C(NCc1ccccn1)Oc1ccccc1

Procedure:
The title compound is prepared analogously to pyridin-3-yl-carbamic acid phenyl ester, by substituting C-pyridin-2-yl-methylamine for 3-aminopyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:40])[C@@H:12]([NH:21][C:22](=[O:39])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].C(N(CC)CC)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:40])[C@@H:12]([NH:21][C:22](=[O:39])[C@@H:23]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:48](=[O:50])[CH3:49])=[CH:34][CH:33]=2)[NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(N)cc2)[C@@H](C)c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(NC(C)=O)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution of 2-{(2S,3S)-2-[(R)-2-(4-amino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (100 mg, 0.177 mmol) in dichloromethane (10 mL) was added triethylamine (50 μL, 0.354 mmol) followed by acetic anhydride (22 μL 0.212 mmol). The reaction mixture was then stirred overnight at room temperature. The solvent was removed in vacuo and the residue was purified by chromatography over silica gel gradient eluted from 10% to 75% ethyl acetate in hexanes to afforded 2-{(2S,3S)-2-[(R)-2-(4-acetylamino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyryl-amino}-thiazole-4-carboxylic acid methyl ester which was used immediately in the following step of the synthesis (107 mg, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[CH3:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccnnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1ccnnc1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
To a degassed mixture containing 4-bromopyridazine (0.10 g, 0.63 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.18 g, 0.69 mmol), sodium carbonate (0.27 g, 2.52 mmol), dioxane (5.2 mL) and water (1.01 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) in one portion under a nitrogen atmosphere. The mixture was heated with fast stirring at 95° C. for 4 h, cooled to room temperature and filtered. The filtered solution was acidified to below pH 4 with 1N HCl (5.0 mL). The resultant precipitate was recovered by filtration, washed with water (3×3.0 mL) and air dried. The resultant tan solid was suspended in n-pentane (4 mL), stirred for 20 min, recovered by filtration and air dried to afford 4-methyl-3-(pyridazin-4-yl)benzoic acid as a tan solid which was used without further purification. LCMS: retention time: 1.325 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Sunfire, 5 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 215 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[C:13]2[O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]3[C:12]=2[CH:11]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([C:8]1[C:13]2[O:14][CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH:16]3[C:12]=2[CH:11]=[C:10]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3c(Cc4ccccc4)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-c2cc(Cc3ccccc3)c3c(c2)C2CNCCC2O3)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 6-benzyl-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.137 g, 0.270 mmol) was dissolved in CH2Cl2 (5 mL). Trifluoracetic acid (0.44 mL, 5.670 mmol) was added and the reaction mixture was stirred at rt under N2 for 4 h. The reaction mixture was cooled to 0° C. and 25% aqueous NaOH (15 mL) was added. The reaction mixture was partitioned between CH2Cl2 and water. The water layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography (1% NH4OH, 5.95% CH3OH, 93.05% CH2Cl2), and Example 250 was obtained in 86% yield. MS (ESI+) for C24H21Cl2NO m/z 410.0 (M+H)+.
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.[CH2:12]([NH2:15])[CH2:13][CH3:14]>C(O)CCC>[CH2:12]([NH:15][C:4]1[NH:3][C:2]([Cl:1])=[N:10][C:9]2[C:5]=1[N:6]=[CH:7][N:8]=2)[CH2:13][CH3:14]
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCCN
Solvent: CCCCO
Product: CCCNc1[nH]c(Cl)nc2ncnc1-2
Temperature: 75 °C

Procedure:
189 mg of 2,6-dichloropurine, 4 ml of butanol and 0.09 ml (1.1 mol) of propylamine are mixed at room temperature and the medium is heated at a temperature of 75° C. for 2 hours 30 minutes.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[O:23][CH3:24])=O)(C)(C)C.[N+:25]([O-])([OH:27])=[O:26].C(Cl)(Cl)Cl>O>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:23][CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:21]([N+:25]([O-:27])=[O:26])[CH:22]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)c(OC)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OC)c(OCCCN)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
The ester 198 (4.0 g, 11.8 mmol) was added in small portions to a stirred solution of 70% HNO3 (2 mL acid/g of substrate) at room temperature and the reaction mixture was allowed to stir overnight. After 16 hours TLC (CHCl3) revealed the complete loss of starting material. The reaction mixture was cooled in an ice bath, and 15 g of iced water was added, precipitating the product. The precipitate was collected by vacuum filtration and washed with small amount of iced water. The filtrate was cooled and a second crop of precipitate was collected by vacuum filtration and washed with iced water. The combined precipitate was dried in vacuo to provide compound 199 as a yellow solid, which was not purified further, but used directly in the subsequent reaction (2.3 g, 70%). mp=101-103° C.; 1H-NMR (CDCl3/DMSO-d6, 270 MHz): δ2.31 (m, 2H, H2′), 3.20 (br, 2H, H3′), 3.95 (s, 3H, OCH3ether), 3.98 (s, 3H, OCH3ester), 4.24 (t, 2H, J=5.95 Hz, H1′), 7.11 (s, 1H, H6), 7.49 (s, 1H, H3), 8.21 (s, 3H, NH); 13C-NMR (CDCl3, 68.7 MHz): δ26.5 (C2′), 37.0 (C3′), 53.0 (OCH3ester), 56.0 (OCH3ether), 66.7 (C1′), 108.3 (C3), 111.0 (C6), 121.6 (Carom), 140.9 (C2), 149.3 (Carom), 152.6 (Carom), 166.8 (C═O); MS (E/I) m/z (relative intensity): 284 (M+., 90), 237 (70), 227 (93), 196 (47), 181 (38), 137 (100), 122 (81), 93 (52), 79 (44); HRMS (E/I) exact mass calcd for C12H17N2O6: m/e 284.1008, obsd m/e 284.1018; IR (Nujolò) n: (cm−1) 3472, 2937, 2911, 2855, 1733, 1532, 1516, 1462, 1377, 1292, 1224, 1143, 1052, 884, 812, 792, 773, 756, 724, 646.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:13](=[O:14])[CH2:12][Cl:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(N)cc(Br)c1
Reactant: O=C(Cl)CCl
Product: COc1cc(Br)cc(NC(=O)CCl)c1

Procedure:
In a manner similar to Preparation 3, react 3-bromo-5-methoxybenzeneamine with chloroacetyl chloride to obtain the title compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18](O)=O)=[CH:12]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]([NH:52][C:53]1[C:58]([NH2:59])=[CH:57][CH:56]=[C:55]([N:60]2[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]2)[N:54]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C=O)C>[CH2:45]([N:52]1[C:53]2=[N:54][C:55]([N:60]3[CH2:61][CH2:62][N:63]([CH3:66])[CH2:64][CH2:65]3)=[CH:56][CH:57]=[C:58]2[N:59]=[C:18]1[C:13]1[CH:14]=[CH:15][C:16](=[O:17])[N:11]([CH3:10])[CH:12]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CN1CCN(c2ccc(N)c(NCc3ccccc3)n2)CC1
Reactant: Cn1cc(C(=O)O)ccc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc3nc(-c4ccc(=O)n(C)c4)n(Cc4ccccc4)c3n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
DIPEA (51 mg; 0.392 mmol) is added to a suspension of 1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid D-7 (20 mg; 0.131 mmol) and HATU (70 mg; 0.183 mg) in DMF. The mixture is stirred at RT for 5 min. N2-Benzyl-6-(4-methyl-piperazin-1-yl)-pyridine-2,3-diamine E-3.1 is then added and the reaction mixture stirred at RT for 1 h. The reaction mixture is extracted with DCM and NaHCO3 solution. The organic layer is dried over Na2SO4 and concentrated in vacuum. To the formed amide is added 1 ml glacial acetic acid, the reaction is stirred at 120° C. for 2 days. The crude reaction mixture is purified by using reversed phase chromatography (Method: prep. HPLC1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-])=O)[CH:8]=[CH:7][CH:6]=2>[Pd].CO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH2:12])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1cc2c([N+](=O)[O-])cccc2cn1
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(N)cccc2cn1
Yield: 76.1 %

Procedure:
A solution of (D1) (1 g, 5.3 mM) and 10% palladium on charcoal (0.15 g) in methanol (40 ml) was hydrogenated at atmospheric pressure for 1 h. The catalyst was filtered off and the filtrate concentrated under reduced pressure to afford the product as a grey solid (0.64 g).