Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:13]=2)[N:6]=1
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Product: CCCCCCCCCCCCCC(=O)NCCn1cc(CCCCCc2cn(C(=O)OC(C)(C)C)c(N)n2)nn1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.111 g, 0.401 mmol) was reacted with N-(2-azidoethyl)tetradecanamide (0.130 g, 0.401 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-tetradecanamidoethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.26 (s, 1H), δ 6.85 (s, 1H), δ 6.42 (s, 1H), δ 6.05 (s, 1H), δ 4.38 (s, 2H), δ 3.66 (s, 2H), δ 2.60 (s, 2H), δ 2.11 (s, 2H), δ 2.08 (t, 2H), δ 1.41 (m, 13H), δ 1.32 (s, 2H), δ 1.17 (s, 18H), δ 0.77 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 202.9, 174.3, 149.6, 148.3, 121.9, 100.1, 84.8, 49.5, 42.3, 39.5, 36.7, 32.1, 29.9, 29.8, 29.7, 29.6, 29.5, 29.5, 29.3, 28.9, 28.1, 25.9, 25.6, 22.9, 14.3 ppm; HRMS (ESI) calcd for C31H55N7O3 (M+) 573.4366, found 573.4365, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)tetradecanamide hydrochloride (0.118 g, 87% yield). 1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), δ 6.53 (s, 1H), δ 4.71 (s, 2H), δ 3.75 (s, 2H), δ 2.89 (s, 2H), δ 2.54 (t, 2H), δ 2.17 (t, 2H), δ 1.80 (s, 2H), δ 1.69 (s, 2H), δ 1.54 (s, 2H), δ 1.48 (s, 2H), δ 1.28 (s, 20H), 0.88 (t, 3H) ppm; 13C NMR (100 MHz, CD3OD) δ 175.6, 161.8, 147.2, 127.6, 127.4, 108.5, 52.3, 38.8, 36.6, 35.8, 31.9, 30.6, 29.7, 29.6, 29.5, 29.4, 29.2, 28.0, 27.9, 27.7, 25.8, 24.1, 23.6, 23.4, 22.6, 13.4 ppm; HRMS (ESI) calcd for C26H47N7O (M+) 473.3842, found 473.3834.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.[CH2:11]([CH:18]([C:24](=O)[CH3:25])[C:19](OCC)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:19]([OH:20])[C:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:24]([CH3:25])[N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: N=C(N)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl 2-benzyl-3-oxobutanoate(0.379 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature, and the reaction mixture was stirred for about 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:29])[F:30])=[CH:27][CH:26]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OC(F)(F)F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-trifluoromethoxyphenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [CH3:1][C:2]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]=[C:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1)[CH3:3].[OH-].[Na+]>O1CCCC1.CO>[CH3:3][C:2]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[CH2:20][CH:19]=[C:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)[CH3:1]
Reactant: COC(=O)c1ccc(C(C)(C)Oc2ccc3c(c2)C(c2ccccc2)=CC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc2c(c1)C(c1ccccc1)=CC2)c1ccc(C(=O)O)cc1
Yield: 85.5 %

Procedure:
Methyl 4-(1,1-dimethyl-3-phenyl-1H-inden-5-yloxymethyl)benzoate (300 mg, 0.78 mmol) and 3.9 mL of 2N NaOH in 5 mL of tetrahydrofuran and 5 mL of methanol were stirred at room temperature for 16 hours. The mixture was concentrated and acidified with 1N HCl (10 mL), extracted with ethyl acetate (20 mL×3). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was crystallized from ether-hexane to give 247 mg (85% yield) of the title compound as white crystals; 1H-NMR (DMSO-d6) δ1.31 (s, 6H), 5.20 (s, 2H), 6.57 (s, 1H), 6.89 (dd, J=1.1, 8.2 Hz, 1H), 7.02 (d, J=1.1 Hz, 1H), 7.36-7.57 (m, 8H), 7.95 (d, J=8.3 Hz, 2H), 12.94 (bs, 1H) ; MS m/e 371 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[Br:31][CH2:32][CH2:33]Br>CN(C)C=O>[Br:31][CH2:32][CH2:33][N:19]1[C:18]([O:22][CH3:23])=[N:17][C:16]2[C:20]1=[N:21][C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])=[N:14][C:15]=2[NH2:24]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCBr)c2n1

Procedure:
The compound obtained in Example 2-1 step (v) (2 g), potassium carbonate (3.7 g) and 1,2-dibromoethane (0.6 ml) were added to dimethylformamide (20 ml), and the same manner to Example 2-13 step (i) was conducted to give the titled compound as a cream colored solid. Yield: 1.2 g (62%).
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:11]([OH:13])=[O:12].[CH2:21]([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>CS(C)=O>[CH2:21]([O:28][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]([F:20])([F:19])[F:18])[C:11]([OH:13])=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium tert-butoxide (816 mg, 7.28 mmol) was added to a solution of 3-fluoro-4-trifluoromethyl-benzoic acid (682 mg, 3.28 mmol) and benzyl alcohol (471 mg, 4.36 mmol) in DMSO (7.3 ml), and the mixture was stirred at room temperature for 16 hours. The reaction solution was made acidic by adding concentrated hydrochloric acid, and the precipitated insoluble matter was then filtered off. The resulting solid was washed with water and then dried to give 3-benzyloxy-4-trifluoromethyl-benzoic acid as a crude compound.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:15]=[C:14]([C@H:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17])[O:13][N:12]=3)[NH:8][C:7]=2[CH:26]=1>C(O)(C(F)(F)F)=O>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11]3[CH:15]=[C:14]([C@H:16]([NH2:18])[CH3:17])[O:13][N:12]=3)[NH:8][C:7]=2[CH:26]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cc(-c2nc3ccc(C(F)(F)F)cc3[nH]2)no1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)c1cc(-c2nc3ccc(C(F)(F)F)cc3[nH]2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
A mixture of (R)-tert-butyl 1-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)isoxazol-5-yl)ethylcarbamate (86.5 g, 0.22 mol) in TFA (300 mL) was stirred at RT for 2 hr. The reaction mixture was concentrated in vacuo and re-dissolved in ethyl acetate. The ethyl acetate solution was washed with K2CO3 and water, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography to afford compound Na, (R)-1-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)isoxazol-5-yl)ethanamine (30.2 g, 46.7%). 1H NMR (DMSO-d6) δ7.98 (s, 1H), 7.78 (d, 1H), 7.56 (d, 1H), 6.94 (s, 1H), 4.16 (q, 1H), 1.36 (d, 3H).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:13][CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:24]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28]>CCOC(C)=O.[Pd]>[NH:24]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:25]([C:30]([N:1]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:32])[CH2:26][CH:27]([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A suspension of CBZ-L-Pip-OtBu (0.52 g, 1.6 mmol) and Pd on C (10%, 0.10g) in EtOAc was stirred under a hydrogen atmosphere (balloon) for 1h. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The resulting oil was coupled with CBZ-L-Leu (0.43 g, 1.6 mmol) using the procedure described in Example 1 for the preparation of ethyl-3-[BOC-L-N-Me-Phe-L-(Tr-Gln)]-E-propenoate, to provide CBZ-L-Leu-L-Pip-OtBu (0.57 g, 83%) as a colorless oil after column chromatography on silica (20% EtOAc/hexanes): IR (thin film) 3300, 1726, 1642 cm-1 ; 1H NMR (CDCl3) δ 0.93 (d, 3H, J=6.5 Hz), 1.03 (d, 3H, J=6.5 Hz), 1.46 (s, 9H), 1.50-1.60 (m, 2H), 1.64-1.83 (m, 2H), 2.23-2.27 (m, 2H), 3.19-3.28 (m, 2H), 3.77-3.81 (m, 2H), 4.76-4.83 (m, 2H), 5.10 (s, 2H), 5.26 (d, 1H, J=4.7 Hz), 5.60 (d, 1H, J=8.7 Hz), 7.27-7.36 (m, 5H); Anal. (C24H36N2O5) C, H, N.
Reaction SMILES: [CH3:1][CH:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][CH:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:16])[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C1COCCN1
Reactant: CCCCCCC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCCCCCC(C)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 14 and morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[C:9]2[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:11][N:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1nn(C)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C)c(C)c1C(NCc1ccc(OC)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1,5-dimethyl-1H-pyrazole-3-carboxylate (Step 25.2) and 4-methoxybenzylamine. tR: 3.99 min (HPLC 1); tR: 0.86 min (LC-MS 2); ESI-MS: 428 [M+H]+ (LC-MS 2); Rf=0.59 (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[Cl-].[Ca+2].[Cl-]>C(O)C.O>[NH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][CH2:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])=[C:2]([Cl:1])[CH:17]=1
Reactant: N#Cc1ccccc1COc1ccc([N+](=O)[O-])cc1Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccccc1COc1ccc(N)cc1Cl
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 2-[(2-chloro-4-nitrophenoxy)methyl]benzonitrile (2.0 g) in ethanol/water (9:1, 40 mL) was added calcium chloride (90%, 427 mg), and the mixture was stirred at 100° C. for 10 min. Reduced iron (90%, 2.6 g) was added at room temperature, and the mixture was stirred at 100° C. for 3 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:methylene chloride=2:1:1) to give the title compound (1.2 g) as a white solid.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH2:35][C:36]1[CH:37]=[C:38]([CH:51]=[CH:52][C:53]=1[N:54]1[CH2:59][CH2:58][N:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])[CH2:56][CH2:55]1)[C:39]([NH:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50])=[O:40].Br[C:68]1[N:73]=[CH:72][CH:71]=[CH:70][N:69]=1>CC(O)(C)C.C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:50]=[C:46]1[CH2:47][CH2:48][CH2:49][N:45]1[CH2:44][CH2:43][CH2:42][NH:41][C:39](=[O:40])[C:38]1[CH:51]=[CH:52][C:53]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[CH3:66])[CH2:56][CH2:55]2)=[C:36]([NH:35][C:68]2[N:73]=[CH:72][CH:71]=[CH:70][N:69]=2)[CH:37]=1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: Brc1ncccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2Nc2ncccn2)CC1

Procedure:
N-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-3-(pyrimidin-2-ylamino)-4-(4-o-tolyl-piperazin-1-yl)-benzamide (compound no. 242) was prepared as follows: In a microwavable glass tube, Pd(OAc)2 (0.0025 g, 0.0115 mmol) and X—PHOS (5.4 mg, 0.0115 mmol) were taken in a mixture of t-BuOH:toluene (1:5) (2.0 mL) and stirred. This solution was evacuated for 5 min and purged with nitrogen. 3-Amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (0.05 g, 0.115 mmol) and 2-bromo-pyrimidine (2.7 mg, 0.172 mmol) were added to this, evacuated and nitrogen purged. This mixture was stirred at 140° C. under MW for 30 min. LC-MS indicated the product formation along with some other by-products. The reaction mixture was concentrated, dissolved in methanol and purified on preparative HPLC using water/methanol as eluent to give desire product (10.0 mg, 17%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[C:12]([OH:15])[CH:11]=[CH:10]2)(=[O:3])[CH3:2].S(OC)(O[CH3:20])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH:13]=[C:12]([O:15][CH3:20])[CH:11]=[CH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2ccc(O)cc12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc2cccc(NC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 8-Acetamido-2-naphthol (21 g, 0.104 mol), dimethyl sulfate (15.1 g, 0.12 mol) and potassium carbonate (41 g, 0.3 mol) in acetone (200 mL) was stirred at room temperature for 48 h. Solids were removed by filtration and washed with methanol, and the filtrate evaporated. The residue was washed in 1:1 hexane:toluene, collected by filtration and dried (24.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>>[CH2:28]([N:12]1[C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[C:19]2[C:14]([C:15]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:17]=[CH:18]2)=[N:13]1)[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Product: C=CCn1nc2c(C(F)(F)F)cccc2c1-c1ccc(OC)cc1OC
Yield: 34.9 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-(trifluoro-methyl)-1H-indazole (0.150 g, 0.49 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and allyl bromide (0.07 mL, 0.7 mmol) to give the title compound (0.062 g) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[NH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:19]=[N:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[F:4][CH2:3][CH2:2][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:19]=[N:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: FCCBr
Reactant: c1ccc2c(-c3cn(-c4ccc(C5CCNCC5)cc4)nn3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FCCN1CCC(c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)CC1
Temperature: 100 °C
Yield: 42.7 %

Procedure:
1-bromo-2-fluoroethane (30 mg; 0.24 mmol; 0.9 eq.) was added to a suspension of 3-[1-(4-piperidin-4-ylphenyl)-1H-1,2,3-triazol-4-yl]-1H-indazole (100 mg; 0.26 mmol; 1.0 eq.) and NaHCO3 (331 mg; 3.94 mmol; 15 eq.) in dry DMF (2 mL). The reaction mixture was heated in MW at 100° C. for 3 h. It was then diluted with water and extracted with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, gradient from 100:0 to 90:10) gave the title compound as a white solid (40 mg, 39%). 1H NMR (300 MHz, DMSO-d6) δ 13.36 (brs, 1H), 9.27 (s, 1H), 8.41-8.31 (m, 1H), 8.01-7.92 (m, 2H), 7.64-7.58 (m, 1H), 7.55-7.38 (m, 3H), 7.30-7.20 (m, 1H), 4.56 (dt, J=47.8, 4.9 Hz, 2H), 3.09-2.96 (m, 2H), 2.75-2.54 (m, 3H), 2.22-2.07 (m, 2H), 1.88-1.61 (m, 4H). HPLC (max plot) 99.8%; Rt 2.64 min. UPLC/MS: (MS+) 391.1, (MS−) 389.2
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].O1CCCC1.C(Cl)(Cl)=O.[OH-].[NH4+:23]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:23])=[O:5]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: [NH4+]
Agent: O=C(Cl)Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(F)c(F)cc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
A round-bottomed flask was charged with 2-amino-4,5-difluorobenzoic acid (2 g, 11.7 mmol) and 50 mL tetrahydrofuran (THF). The flask was cooled to 0° C., whereupon a 20% solution of phosgene (6.11 mL, 11.7 mmol) in toluene was added dropwise. The reaction was stirred for 15 min at 0° C., after which a large stoichiometric excess of ammonium hydroxide was added. The reaction was then warmed to room temperature, stirred for 18 h, then washed with water, and then extracted three times with ethyl acetate. Organic layers were combined and dried over sodium sulfate, then concentrated. The product was identified as 2-amino-4,5-difluorobenzamide (1.24 g, 7.2 mmol, 62% yield). MS: M(C7H6F2N2O)=172.13, (M+H)+=173.2.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[S:19][C:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][N:22]=1>N1C=CC=CC=1>[CH2:27]([O:26][C:24]([CH2:23][C:20]1[S:19][C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[N:22][CH:21]=1)=[O:25])[CH3:28]
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: CCOC(=O)Cc1cnc(N)s1
Agent: [I-]
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cnc(N=C2SC[C@@H]3Cc4ccccc4CN23)s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 77.2 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinolinium iodide (10 g) is added to a solution of ethyl (2-aminothiazol-5-yl)acetate (5.1 g) in pyridine (150 cc). After 48 hours at a temperature of the order of 20° C., the solution is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa). The residue is dissolved in a mixture of methylene chloride (200 cc) and N sodium hydroxide solution (100 cc). The organic phase is decanted off, washed with water (3×50 cc), dried over sodium sulphate and then concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. The residue is crystallised by dissolving it in boiling ethanol (100 cc) and cooling to 0° C. The resulting crystals are filtered off, washed with ethanol (30 cc) and diethyl ether (20 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(5-ethoxycarbonylmethylthiazol-2-yl)imino-]-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (7.9 g) m.p.=132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][NH:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.CN(C)C=O.[H-].[Na+].[CH2:26](Br)[C:27]#[CH:28]>O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]([CH2:28][C:27]#[CH:26])[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCc2cccnc2N1c1cccc(Br)c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCN1Cc2cccnc2N(c2cccc(Br)c2)C1=O
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 3.0 g of 1-(m-bromophenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 100 ml of dry dimethylformamide was added 0.6 g of 50% sodium hydride and the mixture was stirred for 30 minutes. To this was further added 3.5 g of propargyl bromide and the whole was reacted for one hour at room temperature. After the reaction was complete, the solvent was distilled off from the reaction mixture under reduced pressure. The residue thus obtained was diluted with water to release an oily product, which was then extracted with ether. The ether solution was dehydrated over magnesium sulfate, and separation and purification were accomplished by passing the solution through a column of alumina. The eluate thus obtained was concentrated to give 2.9 g of 1-(m-bromophenyl)-3-propargyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 118° - 119° C.
Reaction SMILES: [C:1]([NH:5][OH:6])(=[O:4])[CH2:2][CH3:3].[CH3:7][N:8]=[C:9]=[O:10]>C(N(CC)CC)C.C(Cl)Cl>[CH3:7][NH:8][C:9]([N:5]([O:6][C:9]([NH:8][CH3:7])=[O:10])[C:1](=[O:4])[CH2:2][CH3:3])=[O:10]
Reactant: CN=C=O
Reactant: CCC(=O)NO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N(OC(=O)NC)C(=O)NC
Reaction time: 48 h

Procedure:
Propiohydroxamic acid (4.5 grams), methyl isocyanate (6.0 grams), and a few drops of triethylamine were stirred for about one hour in about 50 ml of methylene chloride. The resulting solution was allowed to stand at room temperature for about 48 hours, after which the solvent was removed by evaporation leaving a residue. The residue was recrystallized from a mixture of methylene chloride and hexane leaving the desired, N-((methylamino)carbonyl)-N-(((methylamino)carbonyl)-oxy)propionamide as white crystals, m.p. 90.5°-92.5° C.