Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:9]=[C:8]([CH3:10])[N:7]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:6]=1)[NH2:4].C(N(CC)CC)C.[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=O)=[CH:31][CH:30]=1>ClCCl>[CH3:10][C:8]1[N:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:6]=[C:5]([C:3]2[N:4]=[C:33]([C:32]3[CH:36]=[CH:37][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:30][CH:31]=3)[O:1][N:2]=2)[CH:9]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccc(Cn2nc(C(N)=NO)cc2C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(Cn2nc(-c3noc(-c4ccc(OC(F)(F)F)cc4)n3)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred solution of N′-hydroxy-5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboximidamide (Intermediate KK, 110 mg, 0.45 mmol) and triethylamine (188 μL, 1.35 mmol) in dichloromethane (4 mL) was added 4-(trifluoromethyoxy)benzoyl chloride (101 mg, 0.45 mmol) at a temperature of 0° C. After stirring at rt for 1 h, when analytical HPLC indicated complete conversion of the starting materials, all volatiles were removed in vacuo. The residue was re-dissolved in DMSO (6 mL) and heated to 140° C. for 30 minutes in a microwave oven (CEM Discover). Then, the reaction mixture was diluted with a few mL of methanol and subjected to preparative HPLC. The title compound was obtained in pure form (110 mg, 59%): 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 2H), 7.37 (d, 2H), 7.12 (d, 2H), 7.05 (d, 2H), 6.71 (s, 1H), 5.40 (s, 2H), 2.31 (s, 3H), 2.23 (s, 3H); ES-MS m/z 415 (MH)+; HPLC RT (Method K) 1.58 min.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[S:14](Cl)([CH3:17])(=[O:16])=[O:15]>C(Cl)Cl>[CH3:17][S:14]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:16])=[O:15]
Reactant: OC1CCOC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
A solution of tetrahydrofuran-3-ol (25.0 g, 283 mmol) in 150 ml of DCM was cooled to 0° C., to this was added triethylamine (59 ml, 425 mmol) and mesylchloride (26.0 ml, 340 mmol), stirred the reaction mixture for 4 h at room temperature. TLC indicated reaction completion, it was diluted with DCM (100 ml), washed with water and brine solution, dried over anhydrous sodium sulfate, organic layer was evaporated to yields (44.0 g) of title product which was used as such for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:27][CH:26]=2)[C:21](O)=[O:22])=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:37][O:38][CH2:39][C@@H:40]([NH2:42])[CH3:41].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[CH3:37][O:38][CH2:39][C@@H:40]([NH:42][C:21]([C@@H:20]([NH:19][C:17]([C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:10])=[O:9])=[O:18])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:27][CH:26]=1)=[O:22])[CH3:41]
Reactant: COCCCOc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)O)cc1
Reactant: COC[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COCCCOc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)N[C@@H](C)COC)cc1

Procedure:
To (S)-2-{[(S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-[4-(3-methoxy-propoxy)-phenyl]-propionic acid (98 mg, 0.19 mmol) in dichloromethane (2 mL) was added 2-methoxy-1-(S)-methyl ethyl amine (19 mg, 0.19 mmol), 1-hydroxybenzotriazole hydrate (36 mg, 0.27 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (47 mg, 0.25 mmol) at room temperature. Upon reaction completion water was added. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (dichloromethane/ethyl acetate, 80/20 as eluant) to produce 87 (77%) mg of (S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carboxylic acid {(S)-1-((S)-2-methoxy-1-methyl-ethylcarbamoyl)-2-[4-(3-methoxy-propoxy)-phenyl]-ethyl}-amide. LC/MS rt=3.95, 536 m/e (M+H). 1H NMR (300 MHz, dmso-d6) 7.90 (d, J=8 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.48-7.37 (m, 4H), 7.13 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 4.50 (m, 1H), 4.28 (m, 1H), 3.96 (t, J=6.4 Hz, 2H), 3.79 (m, 1H), 3.63 (m, 1H), 3.42 (t, J=6.2 Hz, 2H), 3.30-3.21 (m, 9H), 3.17-3.05 (m, 2H), 3.90-3.82 (m, 1H), 3.75-3.65 (m, 1H), 1.98-1.85 (m, 2H), 1.45-1.10 (m, 4H), 1.00 (d, J=6.7 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:11](F)=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(OC(=O)[NH:20][C@H:21]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23][CH2:22]1)(C)(C)C.C(OC(=O)N[C@H]1CC[C@H](OC2C(Cl)=C3C(=CC=2)C=NC=C3)CC1)(C)(C)C>>[F:1][C:2]1[C:11]([O:27][C@@H:24]2[CH2:25][CH2:26][C@H:21]([NH2:20])[CH2:22][CH2:23]2)=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Reactant: Fc1cc2cnccc2c(F)c1F
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2ccc3cnccc3c2Cl)CC1
Product: N[C@H]1CC[C@@H](Oc2c(F)cc3cnccc3c2F)CC1

Procedure:
Starting from 5,6,7-trifluoro-isoquinoline (101) and cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester, the Boc-protected intermediate was prepared by the method described for trans-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (10). Deprotection using standard procedures (see 11 or 13) gave the title compound, which was isolated as trifluoro acetate after prep. HPLC. Subsequent treatment of the obtained trifluoro acetate with 2N HCl, followed by lyophilisation gave the corresponding HCl-salt. Rt=0.86 min (Method #1). Detected mass: 279.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[C:14]1([C@@H:20]([NH:22][C:23]2[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=2)[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([C@@H:20]([NH:22][C:23]2[N:24]=[C:25]([N:8]3[C:4]4[CH:3]=[C:2]([NH2:1])[C:10]([CH3:11])=[CH:9][C:5]=4[N:6]=[CH:7]3)[CH:26]=[CH:27][N:28]=2)[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@H](Nc1nccc(Cl)n1)c1ccccc1
Reactant: Cc1cc2nc[nH]c2cc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ncn(-c3ccnc(N[C@@H](C)c4ccccc4)n3)c2cc1N
Temperature: 90 °C
Reaction time: 7 h
Yield: 16 %

Procedure:
To a stirred solution of 5-amino-6-methybenzimidazole (28 mg, 0.19 mmol, 1 eq) in DMF was added NaH (60% dispersion in oil, 7.6 mg, 0.19 mmol, 1 eq). After gas evolution ceased, 2-[(S)-1-phenylethylamino]-4-chloro-pyrimidine (45 mg, 0.19 mmol, 1 eq) was added and the mixture was warmed to 90° C. and stirred 7 h. The heating bath was turned off and the mixture was allowed to stir overnight at room temperature. The DMF was removed under reduced pressure. The residue was diluted with water and extracted wth CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The products were purified by preparative thin layer chromatography to afford 10.5 mg of 2-[(S)-1-phenylethylamino]-4-[5-methyl-6-amino-benzimidazol-1-yl]pyrimidine 1H NMR (500 MHz, CDCl3): δ 1.64 (3H, d, J=7 Hz), 2.27 (3H, s), 3.59 (2H, br s), 5.23 (1H, br m), 5.75 (1H, br s), 6.71 (1H, d, J=5.5 Hz), 7.04 (1H, br), 7.31 (1H, t, J=7.5 Hz), 7.40 (2H, t, J=7.5 Hz), 7.47 (2H, d, J=7.5 Hz), 8.25 (1H, br s), 8.35 (1H, d, J=5.5 Hz). Mass spectrum (ESI) 345.2 (M+1). and 10.3 mg of 2-[(S)-1-phenylethylamino]-4-[5-amino-6-methyl-benzimidazol-1-yl]pyrimidine 1H NMR (500 MHz, CDCl3): δ 1.65 (3H, d, J=7 Hz), 2.31 (3H, s), 3.68 (2H, br s), 5.26 (1H, m), 5.74 (1H, br s), 6.75 (1H, d, J=5.5 Hz), 7.11 (1H, s), 7.28 (1H, m), 7.37 (2H, t, J=7 Hz), 7.75 (2H, d, J=7 Hz), 7.75 (1H, br s), 8.34 (1H, d, J=5.5 Hz), 8.38 (1H, br s). Mass spectrum (ESI) 345.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH:21][C:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([CH3:24])[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CCOC(C)=O>[OH:20][C@H:3]([CH2:2][NH:1][CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:22]([OH:21])([CH3:23])[CH3:24])[CH:26]=1)[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Reactant: CC(C)(O)c1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A solution of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (230 mg, 0.82 mmol) in THF was added 3-(2-hydroxypropan-2-yl)benzaldehyde (180 mg, 01.06 mmol) and stirred for 30 min at room temperature, NaB(OAc)3H (302.5 mg, 1.43 mmol) was then added portionwise in 30 min, and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was separated and dried (Na2SO4). Concentration in vacuo, followed purification with flash chromatography to give the desired product as a white solid (230 mg, 65% yield). 1H NMR (CDCl3): d: 8.514 (m, 2H), 7.717 (s, 1H), 7.321-7.203 (m, 5H), 3.831 (s, 3H), 3.580 (m, 1H), 2.978 (m, 1H), 2.890-2.755 (m, 3H), 1.724 (d, J=11.1 Hz, 6H), 1.364 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c1) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.C([O:12][CH:13]([C:19]([CH3:21])=O)[C:14](OCC)=[O:15])(=O)C>CC(N(C)C)=O>[Cl:8][C:5]1[S:4][C:3]2=[N:2][C:19]([CH3:21])=[C:13]([OH:12])[C:14](=[O:15])[N:7]2[CH:6]=1
Reactant: Nc1ncc(Cl)s1
Reactant: CCOC(=O)C(OC(C)=O)C(C)=O
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1nc2sc(Cl)cn2c(=O)c1O
Temperature: 100 °C
Reaction time: 6 h
Yield: 46.2 %

Procedure:
2-amino-5-chloro-thiazole hydrochloride (10 g) was reacted with ethyl 2-acetoxy-acetoacetate (22 g) in dimethylacetamide (400 ml) containing polyphosphoric acid (71 g: 29 g of H3PO4 and 42 g of P2O5) under stirring at 100° C. for 6 hours. After cooling, dilution with ice water and neutralization with 37% NaOH, the precipitate was extracted with ethyl acetate and the organic solution was evaporated in vacuo to dryness. The residue was hydrolyzed by treatment with 35% HCl (50 ml) in dioxane (100 ml) at reflux temperature for 2 hours: after cooling the reaction mixture was diluted with ice water and neutralized with 37% NaOH and the precipitate was extracted with ethyl acetate. The organic solution was evaporated in vacuo to dryness and the residue was crystallized from methanol to give 5.85 g of 2-chloro-6-hydroxy-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 214°-217° C., which was dissolved in dimethylformamide (100 ml) and reacted with methyl iodide (15.4 g) in the presence of anhydrous K2CO3 (15 g) under stirring at 60° C. for 3 hours. After cooling the reaction mixture was diluted in ice water and neutralized with NaH2PO4 : the precipitate was filtered and the aqueous phase was extracted with ethyl acetate for the complete recovering of the product. On the whole it was obtained 5.1 g of 2-chloro-6-methoxy-7-methyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 138°-141° C., which was reacted with N-bromosuccinimide (17 g, added portionwise) in benzene (150 ml) at the reflux temperature for 40 hours. After cooling the reaction mixture was diluted with ethyl acetate and treated with aqueous NaHCO3 and then with water: the separated organic solution was evaporated in vacuo to dryness and the residue was crystallized from ethyl acetate to give 2.8 g of 7-bromomethyl-2-chloro-6-methoxy-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 160°-162° C., which was reacted with triphenylphosphine (2.6 g) in acetonitrile (50 ml ) at the reflux temperature for 3 hours. After cooling and evaporation in vacuo of the solvent, the residue was purified with ethyl acetate to give 3.8 g of (2-chloro-6-methoxy-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl)-methyl-triphenylphosphonium bromide, which was suspended in dimethylsulfoxide (45 ml) and treated with potassium tert-butoxide (0.75 g) dissolved in dimethylsulfoxide (20 ml) at room temperature under stirring for 10 minutes.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)[C:4]=1[CH3:16].Cl.[NH:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([CH2:26][OH:27])[CH2:21]1.C(N(CC)CC)C.C(Cl)(=O)C>C1COCC1>[OH:27][CH2:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:18])([F:17])[F:1])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:14])[CH2:21]1
Reactant: Cc1c(-c2ccc(C(=O)Cl)s2)noc1C(F)(F)F
Reactant: OC[C@H]1CCCNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](CO)C3)s2)noc1C(F)(F)F
Reaction time: 48 h
Yield: 70.5 %

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carbonyl chloride (74 mg, 0.25 mmol, as prepared in Example 2 Method B) and (S)-1-piperidin-3-yl-methanol, hydrochloride (76 mg, 0.5 mmol) by the method used in Example 46 for the achiral isomer. Gummy solid (70 mg, 74%). LC/MS 5.85 min, [M+1]+ 375. mg, 0.2 mmol) in THF (2 mL) was treated with triethylamine (70 μL, 0.5 mmol) followed by acetyl chloride (22 μL, 0.3 mmol). The reaction mixture was allowed to stir 48 hr, evaporated and chromatographed on silica gel with EtOAc then MeOH/EtOAc (10%) as eluant to afford product as a colorless solid (66 mg, 83%). 1H NMR (CDCl3) 1.65 (m, 2 H), 1.81 (m, 1 H), 1.95 (s, 3 H), 2.00 (obs m, 1 H), 2.33 (d, J=1.3, 3 H), 3.30 (m, 2 H), 3.98 (m, 2 H), 4.10 (br d, J=11.0, 1 H), 6.10 (br d, J=6.6, 1 H), 7.43 (d, J=4.0, 1 H), 7.49 (br s, 1 H). 13C NMR 7.9, 23.5, 30.1, 46.5, 51.0 (br), 114.8, 118.7 (q, J=271), 128.3, 129.7, 131.7, 140.1, 155.2 (J=40), 157.9, 163.3, 170.3 19F NMR −63.1. LC/MS 5.72 min, [M+1]+ 402.
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1[CH2:21][C:19](=[O:20])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:16]1=[S:17].N1CCCCC1>C(O)C>[NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[C:21]2[S:15][C:16](=[S:17])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:19]2=[O:20])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1csc(Nc2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 24, the desired compound was prepared from 440 mg of 2-anilinothiazole-4-carbaldehyde, 412 mg of rhodanine-3-acetic acid, 0.5 ml of piperidine and 10 ml of ethanol. The resulting product was a yellowish-brown powder having the following physical properties.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:34][C:35]1[C:40]([C:41]([C:43]2[N:44]([CH2:48][CH3:49])[N:45]=[CH:46][CH:47]=2)=O)=[CH:39][C:38]([Br:50])=[CH:37][N:36]=1>O1CCCC1>[Br:50][C:38]1[CH:39]=[C:40]([C:41]([C:43]2[N:44]([CH2:48][CH3:49])[N:45]=[CH:46][CH:47]=2)=[CH:2][O:3][CH3:4])[C:35]([NH2:34])=[N:36][CH:37]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCn1nccc1C(=O)c1cc(Br)cnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1nccc1C(=COC)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
To a solution of (methoxymethyl)triphenylphosphonium chloride (866 mg, 2.53 mmol) in tetrahydrofuran (20 ml) was added potassium bis(trimethylsilyl)amide (5.0 ml, 0.5M, 2.5 mmol). The red-orange reaction mixture was stirred at room temperature for 45 minutes. A solution of (2-amino-5-bromo-pyridin-3-yl)-(2-ethyl-2H-pyrazol-3-yl)-methanone (339 mg, 1.15 mmol) in tetrahydrofuran (10 ml) was added to the reaction mixture. The combined solution was stirred for 4 hours, and then quenched with saturated, aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo. The crude material was purified by flash chromatography (0 to 100% [10% methanol in ethyl acetate] in hexanes) to give 280 mg (75%) of 5-bromo-3-[1-(2-ethyl-2H-pyrazol-3-yl)-2-methoxy-vinyl]-pyridin-2-ylamine. MS: m/z 323.2+325.2 (M+H+).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]#[C:7]1)[CH2:2][CH:3]=[CH2:4].[CH2:14]([O:16][SiH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH3:15]>>[CH:6]1([O:5][CH2:1][CH2:2][CH2:3][CH2:4][Si:17]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[O:16][CH2:14][CH3:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]#[C:7]1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCOC1C#CCCCCC1
Product: CCO[Si](CCCCOC1C#CCCCCC1)(OCC)OCC
Yield: 97 %

Procedure:
The compound 3 (1.28 g, 7.18 mmol) is mixed with triethoxysilane (3.6 ml). The Karstedt catalyst is added very slowly in a catalytic amount (10 drops). The reaction takes place at 45° C. over three days. The product is purified by flash chromatography (100% AcOEt) to give a brown liquid (2.4 g, 7 mmol, 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=4I)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1.CO[CH2:29][CH2:30]OC>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:13][CH:12]3[CH2:14][N:15]([C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=4[C:30]4[CH:29]=[CH:6][CH:7]=[CH:2][N:3]=4)=[O:18])[CH2:16][CH:11]3[CH2:10]2)[N:3]=1
Reactant: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4I)CC3C2)n1
Reactant: COCCOC
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4-c4ccccn4)CC3C2)n1
Temperature: 160 °C

Procedure:
(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-iodophenyl)methanone (51 mg, 0.11 mmol) and 2-tributylstannane pyridine (57 mg, 0.13 mmol) were combined and dissolved in degassed DME then purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 and then purged with bubbling for 5 minutes in a sealed vessel and then heated to 160° C. in microwave for 90 min. Reaction was filtered through celite, concentrated and purified on 16 g SiO2 with 0-3.5% NH3 MeOH/CH2Cl2. MS (ESI) mass calcd. for C24H24FN5O, 417.49; m/z found, 418.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.71-7.64 (m, 1H), 7.57-7.52 (m, 1H), 7.46 (dddd, J=8.2, 5.6, 2.8, 1.2 Hz, 1H), 7.37 (td, J=7.9, 5.5 Hz, 1H), 7.30-7.24 (m, 2H), 7.20 (ddd, J=9.0, 2.5, 1.5 Hz, 1H), 7.11 (tdd, J=8.4, 2.6, 1.0 Hz, 1H), 6.31 (s, 1H), 3.97 (dd, J=12.7, 7.8 Hz, 1H), 3.89 (dd, J=11.5, 7.7 Hz, 1H), 3.82-3.70 (m, 2H), 3.70-3.60 (m, 2H), 3.50 (dd, J=11.5, 4.6 Hz, 1H), 3.40 (dd, J=10.9, 5.4 Hz, 1H), 3.07 (d, J=7.2 Hz, 1H), 3.03-2.94 (m, 1H), 2.30 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Li].BrC1C=CC=CN=1.C([Li])CCC.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([C:26]([NH:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]=[O:32])=[O:27])=[CH:24][CH:23]=1>O1CCCC1.CCCCCC.CCOCC>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]([OH:32])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:27])=[CH:37][CH:38]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2C=O)cc1
Reactant: [Li]c1ccccn1
Agent: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2ccccc2C(O)c2ccccn2)cc1
Reaction time: 0.33 h
Yield: 46 %

Procedure:
Pyridyl lithium, prepared by adding 2-bromopyridine (30.0 g., 0.19 mole) in 200 ml. of ether to 131 ml. of a hexane solution of 1.6 molar n-butyl lithium (0.2 mole) at -70°C., is added in 25 min. to a solution of o-(4-methoxybenzamido)benzaldehyde (8.6 g., 0.035 mole) in 300 ml. of tetrahydrofuran at -25°C. over a 20 min. period with stirring. Stirring is continued for 20 min. at -25°C. 1 hr. at -10°C. and then at 0°C. for 30 min. The reaction mixture is poured into 1500 ml. of cold 1N hydrochloric acid, the aqueous layer separated, washed with ethyl acetate, made strongly basic with concentrated ammonium hydroxide and extracted with ethyl acetate. The ethyl acetate extract is washed with water, brine, dried over sodium sulfate and concentrated and the residue thus obtained triturated with ether to provide a 46% yield of 4-methoxy-2'-[hydroxy(2-pyridyl)methyl]benzanilide, m.p. 127.5°-128.5°C. (corr.).
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.ClCCl.Br[CH2:22][CH2:23][Cl:24].C(N(CC)CC)C>CCCCCC>[Cl:24][CH2:23][CH2:22][N:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=2)[CH2:11][CH2:12]1
Reactant: ClCCBr
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: FC(F)(F)c1cccc(N2CCN(CCCl)CC2)c1
Temperature: 25 °C

Procedure:
To a 100 mL flask was added 4-(3-trifluoromethylphenyl)piperazine HCl (5035 mg, 18.88 mmol) and 60 mL dichloromethane. 1-Bromo-2-chloroethane (1730 μl, 20.78 mmol, 1.10 eq) was added, then triethylamine (5.25 mL, 37.7 mmol, 2.00 eq). The solution was refluxed for 9 hours, then cooled to 25° C. 100 mL of hexane was then added, and the resulting suspension was vacuum filtered. The filtrate was concentrated in vacuum and purified by column chromatography using dichloromethane as eluant resulting in an oil of 1-(2-Chloroethyl)-4-(3-trifluoromethylphenyl)piperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:30])=[O:25])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(N)=O)cc2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid (76 mg, 0.209 mmol) in DMF (2 mL) was added CDI (41 mg, 0.251 mmol) and the resulting mixture stirred at 60° C. for 1 h. After cooling to room temperature ammonium hydroxide (330 μL, 2.09 mmol) was added and reaction mixture was stirred for 1 h and then evaporated. Purification by crystallization afforded the title compound (64 mg, 84%) as a white solid. MS: m/e=363.2 [M+H]+.