Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1.CO>ClCCl>[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccno2)C(C)C)co1
Yield: 80 %

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine provided, after silica gel chromatography using a gradient of 1-4% methanol in dichloromethane, 225 mg (80%) of the desired compound. 1H NMR (DMSO-d6) δ 0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.35-1.54 (m, 2H), 1.80-1.95 (m, 1H), 2.55-2.73 (m, 4H), 2.83 (s, 3H), 2.94-3.09 (m, 1H), 3.53-3.63 (m, 1H), 3.73-3.86 (m, 1H), 3.92 (t, J=8.4 Hz, 1H), 4.08-4.34 (m, 3H), 4.65 (d, J=6 Hz, 1H), 5.04 (s, 2H), 5.91 (d, J=9 Hz, 1H), 6.29 (d, J=2.4 Hz, 1H), 7.01 (d, J=9 Hz, 1H), 7.06-7.27 (m, 10H), 7.69 (d, J=9 Hz, 1H), 7.77 (s, 1H), 8.52 (d, J=2.4 Hz, 1H). Mass spectrum: (M+H)+ =689; (M+NH4)+ =706. Anal. Calcd for C37H48N6O7 : C, 64.52; H, 7.02; N, 12.20. Found: C, 64.52; H, 7.14; N, 12.06.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:22])[NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])[C:15]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:22]
Reactant: CN(C)CCNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNC(=O)c1cc(Cl)c(F)c(CN)c1

Procedure:
was prepared according to Scheme C3 (step B) from [3-chloro-5-(2-dimethylamino-ethylcarbamoyl)-2-fluoro-benzyl]-carbamic acid tert-butyl ester (120 mg, 0.3 mmol) and TFA (1 mL) in CH2Cl2. MS (LC-MS): 274.0 [M]+; tR (HPLC conditions c): 2.17 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1F>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[O:8][CH:6]1[CH2:7][N:2]([CH3:1])[CH2:3][C:4]2[O:11][CH:10]=[CH:9][C:5]1=2
Reactant: CN1Cc2occc2C(O)C1
Reactant: Fc1cccc(Cl)c1Cl
Product: CN1Cc2occc2C(Oc2cccc(Cl)c2Cl)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,3-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH2:1](OC(=O)C)C.Cl.C(OCC)(=O)C.[CH:14]([C:16]1[CH:48]=[CH:47][C:19]([O:20][CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:33]([CH3:34])=[CH:32][C:31]([O:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])OC(C)(C)C)=[CH:30][C:29]=3[CH3:46])[CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)=[O:15].C(Cl)(=O)C>C(N(CC)CC)C.ClCCl>[CH:14]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[C:29]([CH3:46])=[CH:30][C:31]([O:35][CH2:36][CH2:37][NH:38][C:39](=[O:45])[CH3:1])=[CH:32][C:33]=3[CH3:34])[CH:25]=[CH:26][CH:27]=2)=[CH:47][CH:48]=1)=[O:15]
Reactant: Cc1cc(OCCNC(=O)OC(C)(C)C)cc(C)c1-c1cccc(COc2ccc(C=O)cc2)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)NCCOc1cc(C)c(-c2cccc(COc3ccc(C=O)cc3)c2)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 4 M hydrogen chloride ethyl acetate solution was dropwise added under ice-cooling to an ethyl acetate solution of tert-butyl [2-({3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)ethyl]carbamate, followed by stirring at 0° C. for 2 hours. Dichloromethane, acetyl chloride and triethylamine were added to the resulting compound, followed by stirring at room temperature for 12 hours to obtain N-[2-({3′-[(4-formylphenoxy)methyl]-2,6-dimethylbiphenyl-4-yl}oxy)ethyl]acetamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[C:24](=[O:28])[CH2:23][CH2:22]2.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: O=C1CCc2cc(-c3ccc(OCc4ccccc4)cc3)ccc21
Yield: 36.1 %

Procedure:
A solution of 4-benzyloxyphenyl boronic acid (0.15 g, 0.66 mmol), 5-bromo-1-indanone (0.10 g, 0.44 mmol), palladium acetate (2.0 mg, 0.009 mmol), tricyclohexylphosphine (7.0 mg, 0.018 mmol) and potassium fluoride (0.077 g, 1.32 mmol) in dioxane (2.5 mL) was stirred at 75° C. for 3 h. The reaction mixture was filtered through celite. Silica gel chromatography eluting with 25% ethyl acetate/hexane gave 0.05 g of desired product: 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J=8.0 Hz, 1H), 7.68 (s, 1H), 7.62 (t, 3H), 7.51 (d, J=7.3 Hz, 2H), 7.46 (t, J=7.5 Hz, 2H), 7.38–7.42 (m, 1H), 7.13 (d, J=8.7 Hz, 2H), 5.18 (s, 2H), 3.23 (t, J=5.8 Hz, 2H), 2.78 (t, J=6.0 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@@:19]([OH:40])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:20]([N:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27](F)=[CH:28][CH:29]=2)[N:24]=[CH:23]1)[CH3:21].O>CN1C(=O)CCC1.CCOC(C)=O>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@@:19]([OH:40])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:20]([N:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])=[CH:28][CH:29]=2)[N:24]=[CH:23]1)[CH3:21]
Reactant: OCC(F)(F)C(F)F
Reactant: C[C@@H](n1cnc2cc(F)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](n1cnc2cc(OCC(F)(F)C(F)F)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 120 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of 2,2,3,3-tetrafluoropropanol (381 mg, 2.9 mmol) in anhydrous NMP (10 mL) was treated with NaH (55% in hexane, 126 mg, 2.9 mmol) for 10 min at room temperature. Once H2 ceased to evolve, (1R,2R)-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4triazol-1-yl)propyl]-7-fluoroquinazolin-4(3H)-one (400 mg, 0.96 mmol, obtained in example 12) was added and the mixture was stirred at 120° C. overnight. Once the reaction was completed, water and EtOAc were added. The aqueous phase was separated and reextracted with further EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography to give the title compound as an amorphous white solid (200 mg, 48%): 1H NMR (300 MHz, CDCl3) δ (TMS) 8.56 (s, 1H, N=CH--N), 8.29 (d, J=9.5, 1H, arom), 7.76 (s, 1H, triazole), 7.74 (s, 1H, triazole), 7.48 (dt, Jd =6.5, Jt =8.8, 1H, arom), 7.15 (m, 2H, arom), 6.9-6.7 (m, 2H, arom), 6.08 (tt, J=4.5, J=53, 1H, CHF2), 5.92 (dq, Jd =2, Jq =7.3, 1H, MeCH), 5.51 (d, J=1.5, 1H, OH), 5.16 (d, J=14.3, 1H, CH(H)), 4.49 (tt, J=1.5, J=12, 2H, CH2), 4.01 (d, J=14.3, 1H, CH(H)), 1.29 (d, J=7.3, 3H, CHMe); GC/MS 304 (N-ethylheterocycle group, C13H12F4N2O2), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =-16.7° (c 1, CHCl3). Analysis calculated for C23 H19F6N5O3 : C 52.38; H 3.63; N 13.28. Found: C 51.84; H 3.68; N 12.29.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH3:11])=[CH:6][CH:5]=1.B(Br)(Br)Br>ClCCl>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH3:11])=[CH:6][CH:5]=1
Reactant: COc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Cc1nc(N(C)c2ccc(O)cc2)c2ccccc2n1
Temperature: 10 °C

Procedure:
To a solution of (4-methoxy-phenyl)-(2-methyl-quinazolin-4-yl)-methyl-amine hydrochloride salt (106 mg, 0.336 mmol) in dichloromethane (10 mL) at −78° C. was added slowly boron tribromide (1M in CH2Cl2, 0.75 mL) under argon. The cold bath was removed and the reaction mixture was allowed to warm up slowly to 10° C. in 1.5 h. The reaction mixture was quenched with water (10 mL), basified with 2N NaOH to pH=10, and extracted with EtOAc (2×25 mL). The EtOAc extracts were dried and evaporated to give a light brown residue. The crude was purified by column chromatography (SiO2, EtOAc:hexanes/15-50%) to give the product as a white solid, which was further purified by recrystallization from MeOH: 1H NMR (acetone-d6) 8.74 (s, 1H), 7.75 (m, 1H), 7.67 (m, 1H), 7.20-7.18 (m, 3H), 7.12 (m, 1H), 7.04-6.99 (m, 2H), 3.64 (s, 3H), 2.79 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][SH:5].C1(CCS)C=CC=CC=1.Cl[C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])=[O:30])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1>>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][S:5][C:17]1[N:22]=[N:21][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:38])([F:40])[F:39])=[O:30])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: CC(C)CCS
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(Cl)nn2)CC1
Agent: SCCc1ccccc1
Product: CC(C)CCSc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure set forth above in Example 6, only making variations using 3-methylbutane-1-thiol to replace 2-phenylethanethiol to react with [4-(6-chloropyridazin-3-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (24.3 mg, 26.4% yield). 1H NMR (400 MHz, CDCl3) δ 8.04, 7.98, 6.99, 3.79, 3.56, 3.45-3.47, 3.40, 1.85-1.87, 1.52, 0.72-0.80, 0.46-0.48, 0.09-0.10.
Reaction SMILES: [CH2:1](N(CC)CCN)C.C(N([CH2:14][CH2:15][NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]1[C:21]([N+:26]([O-:28])=[O:27])=[N:22][N:23]([CH3:25])[CH:24]=1)CC)C>>[CH:15]1([NH:16][C:17](=[O:29])[CH:18]=[CH:19][C:20]2[C:21]([N+:26]([O-:28])=[O:27])=[N:22][N:23]([CH3:25])[CH:24]=2)[CH2:14][CH2:1]1
Reactant: CCN(CC)CCNC(=O)C=Cc1cn(C)nc1[N+](=O)[O-]
Reactant: CCN(CC)CCN
Product: Cn1cc(C=CC(=O)NC2CC2)c([N+](=O)[O-])n1

Procedure:
N,N-diethylethylenediamine, 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid N-diethylaminoethylamide; m.p. 109°-110° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH3:15][CH:16]1[N:21](C(OCC2C=CC=CC=2)=O)[CH:20]([CH:32]2[CH2:34][O:33]2)[CH2:19][CH2:18][CH2:17]1>C(O)(C)(C)C.O>[CH3:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH:20]([CH:32]([OH:33])[CH2:34][O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:21]1
Reactant: CC1CCCC(C2CO2)N1C(=O)OCc1ccccc1
Reactant: Oc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC1CCCC(C(O)COc2ccc(F)cc2)N1

Procedure:
A solution of a p-fluorophenol in t-butanol is treated with one equivalent of potassium t-butoxide, followed by the compound of Example 35A. The reaction mixture is then refluxed until all epoxide has reacted. The reaction is cooled, diluted with water, and extracted with ethyl acetate. The organic extracts are dried and concentrated. The carbobenzyloxy protecting group is removed by standard hydrogenolysis and the final product purified by chromatography.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].O>CN(C)C=O>[CH2:30]([O:29][C:27]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=2)[CH2:6][CH2:7]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](N)CC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](NC(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2.0 g (0.0008 mol) of trans-ethyl 4-(4-aminocyclohexyl)benzoate, 1.25 ml of triethylamine and 1.26 ml (0.0084 mol) of benzyl chloroformate at 95% in 40 ml of dimethylformamide is stirred at room temperature for 3 hours. The mixture is poured into water, extracted with ethyl acetate and dried, and the solvent is evaporated off. The residue is purified by chromatography on a silica gel column, eluting with an 8/2 cyclohexane/ethyl acetate mixture. The compound of the title is obtained.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=[N:15]O)=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O.O.C(=O)([O-])O.[Na+]>ClCCCl>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:15])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(-c2n[nH]cc2C=NO)o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: O
Product: N#Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Yield: 96 %

Procedure:
Heat Then g. of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehydeoxime together with 3.4 g of phosphorus oxychloride in 20 ml of 1,2-dichloroethane for 1 hour under reflux. To the resulting product add ice together with 50 ml of water. The adjust the pH to from 3 to 4 with sodium hydrogen carbonate and remove the formed crystals by vacuum filtration. Wash the crystals with water to obtain a 96% yield of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carbonitrile [m.p. 237.5° to 239° C (from ethanol)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:12][C:13]2[CH:18]=[N:17][CH:16]=[C:15]([Cl:19])[N:14]=2)[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>ClCCl>[Cl:19][C:15]1[N:14]=[C:13]([NH:12][CH:8]([C:4]2[CH:3]=[C:2]([NH:1][C:27](=[O:29])[CH3:28])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10][CH3:11])[CH:18]=[N:17][CH:16]=1
Reactant: CCCC(Nc1cncc(Cl)n1)c1cccc(N)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(Nc1cncc(Cl)n1)c1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
To a stirred solution of N-[1-(3-aminophenyl)butyl]-6-chloropyrazin-2-amine (0.10 g, 0.36 mmol) and triethylamine (100 μl, 0.72 mmol) in dichloromethane (3 mL) cooled to 0° C. was added acetyl chloride (31 μL, 0.43 mmol). The resulting mixture was stirred at room temperature for 18 h. then diluted with dichloromethane (10 mL) and washed with H2O (10 mL) and brine (10 mL). The organic phase was collected, dried and concentrated and the residue purified by flash chromatography eluting with ethyl acetate-hexane (1:1) to give pure product (94 mg, 82%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[CH2:14][C:13]1=[O:21]>>[O:10]1[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:14]3[C:15]4[C:20](=[N:19][CH:18]=[CH:17][CH:16]=4)[NH:12][C:13]3=[O:21])=[CH:11][C:7]=2[CH2:8][CH2:9]1
Reactant: O=C1Cc2cccnc2N1
Reactant: O=Cc1ccc2c(c1)CCO2
Product: O=C1Nc2ncccc2C1=Cc1ccc2c(c1)CCO2

Procedure:
2,3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 7-aza-2-oxindole to give 0.2 g of 3-(2,3-dihydrobenzofuran-5-ylmethylene)-1,3-dihydropyrrolo[2,3-b]pyridin-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([CH2:14][CH2:15][NH:16][CH2:17][C@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH:45]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][N:16]([CH2:17][CH:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)[CH2:15][CH2:14][CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1CSc2ccc(N3C[C@@H](CNCCC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Product: CC(C)(C)[Si](C)(C)OCCN(CCC1Cn2c(=O)ccc3ccc(F)c1c32)CC1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 76 %

Procedure:
Starting from the compound of Example 10 and tert-butyldimethylsilyloxy-acetaldehyde and using procedure E, the title compound was obtained as a colourless solid (100 mg; 76% yield).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[F:25]C1N=C(F)N=C(F)N=1>C(Cl)Cl>[CH:1]1([CH2:6][C@@H:7]([C:8]([F:25])=[O:9])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (Tetrahedron, 2001, 57(36), 7675-7683) (4.0 g, 15.60 mmol) in DCM was added pyridine (1.38 ml, 17.2 mmol) and a solution of 2,4,6-trifluoro-1,3,5-triazine (2.3 g, 17.2 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 2 h. The solution was then washed with citric acid (20 mL×2) and brine (20 mL), then concentrated to provide the crude product, 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-fluoro-4-oxobutanoate, as a yellow oil (3.8 g, 57% yield), which was used directly in the next step. MS: 257 ([M−H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[H-].[Na+].[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24](Cl)=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17].O>CN1C(=O)CCC1>[CH2:16]([O:18][C:19]([C:21]1[S:25][C:24]([N:9]2[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[CH:10][C:6]=3[N:7]=[CH:8]2)=[N:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:20])[CH3:17]
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Reaction time: 0.33 h
Yield: 83.6 %

Procedure:
5,6-Dimethoxybenzimidazole (470 mg, 2.64 mmol) was added to a suspension of NaH (60% in mineral oil, 112 mg, 2.8 mmol) in NMP (5 ml) at <5° C. The mixture was stirred for 20 min, then a solution of 2-chloro-4-phenylthiazole-5-carboxylic acid ethyl ester (589 mg, 2.2 mmol) in NMP (1.5 ml) was added over 2-3 min. The mixture was stirred 2.5 hrs at RT. Water (15 ml) was added and stirred for 20 min. Solid was collected by filtration to provide the product 2-(5,6-dimethoxy-benzoimidazol-1-yl)-4-phenylthiazole-5-carboxylic acid ethyl ester (753 mg. Yield 84%). 1H-NMR (300 MHz, CDCl3) 8.44(s, 1H); 7.87-7.90(m, 2H); 7.72(2, 1H); 7.44-7.49(m, 3H); 7.30(s, 1H); 4.32(q, J=Hz, 2H); 3.98(s, 3H); 3.97(s, 3H); 1.33(t, J=Hz, 3H). MS M/z 410(M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Br:20][C:21]1[S:25][C:24]([CH2:26]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>O1CCCC1.C(OCC)(=O)C>[Br:20][C:21]1[S:25][C:24]([CH2:26][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:23][CH:22]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1ccc(Br)s1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(Br)s4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 15.4 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (5-bromothiophen-2-yl)methanol (76 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (13 mg).
Reaction SMILES: C(O/[N:5]=[C:6](/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[OH:15])\[CH3:7])(=O)C>N1C=CC=CC=1>[CH3:7][C:6]1[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=2[O:15][N:5]=1
Reactant: CC(=O)O/N=C(\C)c1cccc(C)c1O
Solvent: c1ccncc1
Product: Cc1noc2c(C)cccc12
Temperature: 130 °C
Reaction time: 40 h
Yield: 79.7 %

Procedure:
(E)-1-(2-hydroxy-3-methylphenyl)ethanone O-acetyl oxime (Step 46.3) (6.0 g, 29.0 mmol) was dissolved in pyridine (60 mL) and the resulting mixture was heated up and stirred at 130° C. for 40 hr, cooled down to RT and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (hexane/EtOAc 0-50% EtOAc) to afford the title product (3.62 g, 23.12 mmol, 80% yield) as pale yellow oil. tR: 0.96 min (LC-MS 2); ESI-MS: 148 [M+H]+; Rf=0.56 (hexane/EtOAc 3:1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].O>C1COCC1>[C:15]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Sodium hydride (1.99 g, 50% in oil, 41.4 mmol, extracted with hexanes) was stirred in THF (50 ml) in a flame-dried flask at 0° C. under nitrogen. Indole-3-carboxaldehyde (5.00 g, 34.5 mmol) was added as a powder in small portions, and then the mixture was warmed to 40° C. for 30 min. The mixture was again cooled to 0° C., and benzyl chloroformate (4.92 ml, 34.5 mmol) was added. After warming to room temperature and stirring overnight, the mixture was poured into water (50 ml) and extracted with CH2Cl2 (50 ml). The organic layer was washed with water (50 ml), dried with MgSO4, filtered and evaporated to 9.2 g (95%) of a gold-brown oil. Crystallization from hot hexane gave 8.47 g (88%) of white crystalline product: mp 70°-71°