Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.N1(O)C2C=CC=CC=2N=N1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.[NH2:22][C:23]1[N:27]([C@@H:28]2[CH2:33][CH2:32][C@H:31]([C:34]([NH:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[C:26]2[CH:40]=[C:41]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:42]=[CH:43][C:25]=2[N:24]=1>C(Cl)Cl>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](/[N:22]=[C:23]2\[NH:24][C:25]3[CH:43]=[CH:42][C:41]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:40][C:26]=3[N:27]\2[C@H:28]2[CH2:33][CH2:32][C@@H:31]([C:34](=[O:35])[NH:36][CH:37]([CH3:39])[CH3:38])[CH2:30][CH2:29]2)=[O:18])=[CH:15][CH:14]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2c(N)nc3ccc(N4CCOCC4)cc32)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(N4CCOCC4)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of TEA (0.091 mL, 0.654 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (100 mg, 0.654 mmol) in DCM (2 mL) was added 4-fluorobenzoyl chloride (0.064 mL, 0.545 mmol) dropwise, and the reaction was stirred at RT for 30 minutes. After 30 minutes, the suspension was added to a solution of cis-4-(2-amino-6-morpholino-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide (210 mg, 0.545 mmol) in DCM (5 mL). The reaction was stirred at RT. After 3 days, the reaction mixture was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-10% MeOH in DCM, to provide (E)-4-fluoro-N-(1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-6-morpholino-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a grey powder (95 mg, 34.4% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.57 (s, 1H), 8.29 (dd, J=6.1, 8.8 Hz, 2H), 7.73 (d, J=7.5 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.24 (dd, J=8.8 Hz, 8.8 Hz, 2H), 6.87, (d, J=8.8 Hz, 1H), 4.94 (brs, 1H), 3.90-3.99 (m, 1H), 3.78 (t, J=4.7 Hz, 4H), 3.18 (t, J=4.8 Hz, 4H), 2.74-2.84 (m, 2H), 2.55 (brs, 1H), 2.03-2.11 (m, 2H), 1.67-1.78 (m, 2H), 1.54-1.63 (m, 2H), 1.10 (d, J=6.5 Hz, 6H). MS, m/z (C28H34FN5O3): calcd, 507.3. found, 507.9 [M+H].
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9]([CH:13]=O)[CH2:8][CH2:7]1.[OH:25][C:26]([CH3:36])([CH3:35])[CH2:27][NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C.C(OCC)(=O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:4]=1[CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][CH:9](/[CH:13]=[C:33]2/[C:29]([NH:28][CH2:27][C:26]([OH:25])([CH3:36])[CH3:35])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)(O)CNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC(C)(O)CNC1=NC(=O)S/C1=C\C1CCCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]azepane-4-carbaldehyde (133.2 mg) in 2-propanol (1.89 mL) were added 4-[(2-hydroxy-2-methylpropyl)amino]-1,3-thiazol-2(5H)-one (142 mg) and piperidinium acetate (54.7 mg). The reaction mixture was stirred at 60° C. overnight, cooled to room temperature, and diluted with ethyl acetate. The mixed solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (86.3 mg).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[N:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.[C:32]([N:39]1[CH:43]=[CH:42]N=[CH:40]1)(N1C=CN=C1)=[O:33].[CH3:44][C:45]1[CH:46]=[C:47]([CH:52]2CCNC[CH2:53]2)[C:48](=[O:51])[NH:49][N:50]=1>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[N:24][N:25]=[C:20]2[C@H:19]([NH:31][C:32]([N:39]2[CH2:40][CH2:53][CH:52]([C:47]3[C:48](=[O:51])[NH:49][N:50]=[C:45]([CH3:44])[CH:46]=3)[CH2:42][CH2:43]2)=[O:33])[CH2:18][CH2:17]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Reactant: Cc1cc(C2CCNCC2)c(=O)[nH]n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C2CCN(C(=O)N[C@@H]3CC[C@@H](c4cccc(F)c4F)Cn4c(CC(F)(F)F)nnc43)CC2)c(=O)[nH]n1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
Triethylamine (42 μL, 0.298 mmol) was added to a solution of the bis hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (50 mg, 0.119 mmol) and 1,1′-carbonyldiimidazole (34 mg, 0.209 mmol) in tetrahydrofuran (2 mL) at 0° C. After 15 min, additional 1,1′-carbonyldiimidazole (10 mg, 0.062 mmol). After 30 min, 6-methyl-4-piperidin-4-ylpyridazin-3(2H)-one (28 mg, 0.143 mmol) and dichloromethane (3 mL) were added and the mixture heated to 60° C. After 1 h, the reaction mixture was allowed to cool to ambient temperature and concentrated. Purification by reverse phase HPLC (C-18, 10% acetonitrile/water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (54 mg). MS 566.2313 (M+1).
Reaction SMILES: ICI.[CH2:4]([Zn]CC)C.[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:35])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]([CH3:34])=[CH2:33])[C:13]2=[CH:12][CH:11]=1.[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39]>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:35])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]3([CH3:4])[CH2:34][CH2:33]3)[C:13]2=[CH:12][CH:11]=1.[CH3:36][O:37][CH:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])[CH3:39]
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reactant: CC[Zn]CC
Agent: COC(C)[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: ICI
Product: CC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
A solution of diiodomethane (3.7 g, 0.013 mmol) in toluene (10 mL) was cooled in ice-salt bath. Then diethylzinc (1.1M in toluene, 10 mL, 11 mmol) was added dropwise into the above solution slowly. After the addition, the mixture was stirred for 10 min. To the resulting mixture was added a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane prepared in Example 267a (800 mg, 1.4 mmol) in toluene (10 mL). The mixture was then allowed to warm to room temperature and stirred for 3 h, quenched with aqueous NH4Cl. The organic layer was separated, washed with water, dried over Na2SO4, purified by column chromatography to give title compound (800 mg).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[OH:25]>>[OH:25][C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[NH:15][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:9]
Reactant: Cc1cc(C(=O)O)c(Br)s1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2cc([N+](=O)[O-])ccc2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amino-4-nitrophenol, N-(2-hydroxy-5-nitrophenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)=[CH:6][C:5]([CH3:18])=[CH:4][C:3]=1[CH2:19]O.[BrH:21].S(=O)(=O)(O)O>>[Br:21][CH2:19][C:3]1[CH:4]=[C:5]([CH3:18])[CH:6]=[C:7]([C:8]23[CH2:17][CH:12]4[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]4)[CH2:9]2)[CH2:15]3)[C:2]=1[OH:1]
Reactant: Cc1cc(CO)c(O)c(C23CC4CC(CC(C4)C2)C3)c1
Reactant: Br
Agent: O=S(=O)(O)O
Product: Cc1cc(CBr)c(O)c(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
4 (0.802 g, 2.94 mmol) was placed into a round bottom flask. Hydrobromic acid (18 mL of a 48 wt % aqueous solution) was added. Concentrated sulfuric acid (3 mL) was added dropwise to the stirring mixture. The reaction mixture was heated to 80° C. for 3 hours. The reaction mixture was allowed to cool and contents filtered. The resulting solids were dried for 30 minutes and the solid was slurried in diethyl ether. Most of the solids dissolved to give a yellow solution. The solution was dried over MgSO4 and filtered. The volatiles were removed under vacuum to give a yellow sticky solid (1.01 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH3:16])[N:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:26])[N:15]([C:13]2[CH:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:10]=[CH:11][N:12]=2)[CH3:16])[CH:21]=[CH:22][CH:23]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CNc1cc(Nc2ccc(F)cc2)ncn1
Product: CN(C(=O)Nc1cccc(Cl)c1)c1cc(Nc2ccc(F)cc2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 121 from N-(4-fluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine and 3-chlorophenyl isocyanate.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=O)C.CC([O-])(C)C.[K+].C(O)(C(F)(F)F)=O>C1COCC1.ClCCl>[CH2:24]([O:23][C:21]([C:20]1[N:19]=[CH:18][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[S:10][C:6]=2[C:4]=1[OH:3])=[O:22])[CH3:25]
Reactant: CCOC(=O)CN(Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)OCC)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2nc(-c3ccc(Cl)cc3)sc2c1O
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 0 %

Procedure:
A mixture of 4-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-2-(4-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (964 mg, 2.00 mol) in THF (7.2 mL) was added drop wise a solution of 1 M KOtBu in THF (2.8 mL, 0.02 mmol) at −78° C. The red solution was stirred at −78° C. for 20 min, warmed to room temperature and stirred at that temperature for two hours before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a yellow oil. It was dissolved in dichloromethane (4 mL) and TFA (1 mL) was added. The mixture was stirred at room temperature for 1 h before it was concentrated in vacuo. It was redissolved in dichloromethane, triethylamine (1.4 mL) was added. The mixture was stirred under air overnight before it was partitioned between ethyl acetate and water, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (59 mg): MS: (+) m/z 335.0 M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:25][CH2:24][C@H:23]([CH2:26][NH:27]C(=O)OCC4C=CC=CC=4)[CH2:22][CH2:21]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1>Cl.O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:20]3[CH2:21][CH2:22][C@H:23]([CH2:26][NH2:27])[CH2:24][CH2:25]3)=[N:9][C:10]=2[C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c1c(-c1cc3ccccc3[nH]1)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: O
Product: NC[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1

Procedure:
A solution of benzyl {[trans-4-(8-amino-1-(1H-indol-2-yl)imidazo [1,5-a]pyrazin-3-yl)cyclohexyl]methyl}carbamate (0.163 g, 0.330 mmol) in conc. HCl (5 ml) was stirred at rt overnight. The reaction mixture was diluted with H2O (20 mL), washed with Et2O (30 mL), then basified with 1N NaOH (aq) and extracted with DCM (3×20 mL). The combined extracts were washed with water then dried over Na2SO4 and concentrated in vacuo To afford 0.085 g of desired compound. MS (ES+): m/z 361.30 [MH+].
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](I)=[CH:4][C:3]=1[O:11][CH3:12].[C:13]([CH:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])#[CH:14].O1[CH2:34][CH2:33][CH2:32][CH2:31]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[CH2:16]([CH:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:13]#[C:14][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:31]#[C:32][CH:33]([CH2:34][CH2:17][CH2:16][CH2:15][CH2:13][CH3:14])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[CH:4][C:3]=1[O:11][CH3:12])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CC(CCCCCC)CCCCCCCC
Reactant: C1CCOC1
Reactant: COc1cc(I)c(OC)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCCCCCCC(C#Cc1cc(OC)c(C#CC(CCCCCC)CCCCCCCC)cc1OC)CCCCCC
Temperature: 60 °C
Reaction time: 17 h
Yield: 84 %

Procedure:
1,4-Diiodo-2,5-dimethoxy-benzene (3.750 g; 9.616 mmol), 7-ethynyl-pentadecane (4.2) (5.116 g; 21.637 mmol), PdCl2(PPh3)2 (0.169 g; 240 μmol) and copper iodide (0.092 g; 481 μmol) are dissolved into tetrahydrofuran (50 cm3) and triethylamine (50 cm3). The resulting mixture is degassed for 30 minutes and then stirred at 60° C. for 17 hours. The solvent is removed in vacuo and the crude product purified by column chromatography (gradient from 100:00 to 75:25, Petroleum ether (40-60° C.) and dichlorobenzene) to afford a light yellow oil which crystallises upon standing (4.90 g, Yield: 84%). NMR (1H, 300 MHz, CDCl3): δ 6.83 (s, 2H); 3.81 (s, 6H); 2.59 (m, 2H); 1.53 (m, 16H); 1.31 (m, 32H); (m, 12H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:20](Br)[CH:21]=[CH2:22]>CN(C)C=O.O>[CH2:22]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 70 °C

Procedure:
Potassium carbonate (28.0 g.) was added to a stirred solution of t-butyl ethyl malonate (37.6 g.) in dry N,N-dimethylformamide (DMF) (100 ml.). After 1 hour allyl bromide (34 ml.) was added. The mixture was heated at 70° C. for 66 hours, cooled to room temperature and diluted with water (900 ml.). The mixture obtained was extracted with ethyl acetate (3×200 ml.). The extracts were dried (MgSO4) and evaporated. The oil obtained was purified by flash column chromatography eluting with 1:15 v/v ethyl acetate/petroleum ether (b.p. 60°-80° C.) to give t-butyl ethyl 2-allylmalonate as a colourless oil (15.6 g.), b.p. 70°-72° C. at 0.2 mmHg; NMR: 1.21 (3H,t), 1.42 (9H,s), 2.66 (2H,m), 3.28 (1H,m), 4.16 (2H,q), 5.06 (2H,m) and 5.76 (1H,m) ppm.
Reaction SMILES: [C:1]([N:5]=[CH:6][N:7]=[CH:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].[Li].[Cl-].[Cr+2:15].[Cl-]>O1CCCC1.C1C=CC=CC=1>[C:1]([N:5]=[C:6]([Cr:15][C:6]([N:7]=[CH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][C:1]([CH3:2])([CH3:3])[CH3:4])[N:7]=[CH:8][C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: [Cr+2]
Reactant: CC(C)(C)C=NC=NC(C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)(C)C=NC(=NC(C)(C)C)[Cr]C(N=CC(C)(C)C)=NC(C)(C)C
Reaction time: 6 h

Procedure:
A 100 mL Schlenk flask, equipped with a magnetic stir bar and a rubber septum, was charged with 1,4-di-tert-butyl-1,3-diazabutadiene (1.000 g, 5.94 mmol) and tetrahydrofuran (20 mL). To this stirred solution at ambient temperature was slowly added freshly cut lithium metal (0.042 g, 6.000 mmol) and the resultant dark brown solution was stirred for 6 h. This solution was then added dropwise by cannula over a 30 min period to a stirred suspension of anhydrous chromium(II) chloride (0.365 g, 2.970 mmol) in tetrahydrofuran (40 mL). The resultant deep purple solution was stirred for 6 h at ambient temperature. The volatile components were then removed under reduced pressure and the resultant dark purple powder was dissolved in toluene (50 mL). The solution was filtered through a 1-cm pad of Celite on a coarse glass frit, and toluene was then removed under reduced pressure. Dark purple crystals of 1 were obtained by sublimation at 85° C./0.05 Torr (0.442 g, 38%): mp 95-97° C.; IR (Nujol, cm−1) 1704 (w), 1628 (w), 1538 (w), 1246 (m), 1209 (s), 1132 (m), 1104 (m), 1034 (m); μeff=2.83 and 2.84 BM in the solid state and in benzene solution, respectively. Anal. Calcd for C20H40CrN4: C, 61.82; H, 10.38; N, 14.42. Found: C, 61.71; H, 10.06; N, 14.37.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.C1N=CN([C:29]([N:31]2[CH:35]=N[CH:33]=[CH:32]2)=[O:30])C=1.N1CC[C@H:38]([OH:41])C1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:29]([N:31]3[CH2:32][CH2:33][C@H:38]([OH:41])[CH2:35]3)=[O:30])=[C:16]2[N:15]=1
Reactant: O[C@H]1CCNC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12)N1CC[C@H](O)C1
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 30 mg, 0.095 mmol) was added CDI (31 mg, 0.19 mmol) at ambient temperature in one portion. After stirring two hours, (S)-pyrrolidin-3-ol (17 mg, 0.19 mmol) [purchased from Suven Life Sciences] was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 50% acetonitrile/water to yield the final product as a yellowish foamy powder (30 mg, 74% yield). MS (apci) m/z=429.2 (M+H).
Reaction SMILES: [Br:1]C[C:3]1[N:7]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1[C:19]#[N:20].C(O[CH2:24][CH3:25])C>N1C=CC=CC=1>[Br-:1].[C:19]([C:4]1[CH2:3][N:7]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][N:9]=2)[NH:6][C:5]=1[CH2:8][N+:7]1[CH:25]=[CH:24][CH:5]=[CH:4][CH:3]=1)#[N:20]
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1CBr
Reactant: CCOCC
Solvent: c1ccncc1
Product: N#CC1=C(C[n+]2ccccc2)NN(c2ncc(C(F)(F)F)cc2Cl)C1
Product: [Br-]

Procedure:
A solution of 13.6 grams (0.044 mole) of 5-bromomethyl-4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazole in 41 mL of pyridine was stirred at ambient temperature for three hours. After this time, the reaction mixture was slurried in 350 mL of diethyl ether and filtered. The filter cake was washed with additional diethyl ether. The filter cake was dried, yielding 11.9 grams of 1-[4-cyano-2-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-ylmethyl]pyridinium bromide. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5]([N:14]=1)=[N:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[CH:13]=2.[S:15]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)([O:18][CH3:19])(=[O:17])=[O:16]>>[S:15]([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)([O-:18])(=[O:17])=[O:16].[CH3:1][CH:2]1[NH+:14]=[C:5]2[N:6]([CH3:19])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=[C:4]2[O:3]1
Reactant: Cc1nc2nc3ccccc3cc2o1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: CC1[NH+]=C2C(=Cc3ccccc3N2C)O1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
A mixture of 0.6 g of 2-amino-3-hydroxyquinoline, 3.8 mL of trimethylorthoacetate and 0.1 g of p-toluenesulfonic acid is heated at 60° C. for 7 hours. The reaction mixture is then diluted with ethyl acetate, washed with sodium bicarbonate, and purified by column chromatography on silica gel to yield 0.28 g of 2-methyloxazolo[4,5-b]quinoline. The quinoline is heated with one equivalent of methyl tosylate at 70° C. for one hour to generate the product.
Reaction SMILES: [C:1]([OH:5])(C)([CH3:3])[CH3:2].[CH2:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:19])[CH:11]=1)CC=C.S([O-])([O-])=[O:21].[Na+].[Na+]>O>[CH3:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:6][CH2:2][C@H:1]([OH:5])[CH2:3][OH:21])=[CH:11]1
Reactant: O=S([O-])[O-]
Reactant: C=CCCc1cn(C)c2ccccc12
Reactant: CC(C)(C)O
Agent: [Na+]
Solvent: O
Product: Cn1cc(CC[C@H](O)CO)c2ccccc21
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a mixture of tert-butyl alcohol (14 ml) and water (14 ml) was added AD-mix-a (4.0 g). The mixture was stirred at room temperature until both phases are clear, and then cooled to 0° C. 3-(3-butenyl)-1-methylindole (530 mg, 2.86 mmol) was added, and the heterogeneous slurry was stirred vigorously at 0° C. for 4 hours. While the mixture was stirred at 0° C., solid sodium sulfite (4.29 g) was added and the mixture was allowed to warm to room temperature and stirred for 1 hour. This mixture was extracted with ethyl acetate, and the extracts were washed with brine, dried (magnesium sulfate) and evaporated in vacuo. The residue was purified by silica gel (15 g) chromatography eluting with chloroform/methanol (100:1 to 20:1) to give (S)-4-(1-methylindol-3-yl)butane-1,2-diol (602 mg, 96.1%).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)Cl.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>O>[C:27]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)(=[O:30])[CH2:28][CH3:29]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.4 %

Procedure:
A solution of benzyl piperazine-1-carboxylate (16, 10.0 g, 45.4 mmol), triethylamine (6.89 g, 68.0 mmol) and dry CH2Cl2 (150 mL) was cooled to 0° C. and propionyl chloride (4.62 g, 50.0 mmol) was added dropwise over 10 min. The reaction was kept under nitrogen and allowed to warm to room temperature. After stirring at rt for 17 h, water (50 mL) was added and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The solution was dried over Na2SO4, filtered and concentrated to a yellow oil. The product was purified by silica gel chromatography eluting with 0-3% CH3OH in CH2Cl2 to afford the title compound (9.08 g, 72%) as a clear, colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 5.15 (s, 2H), 3.70-3.35 (m, 8H), 2.35 (q, J=7.5 Hz, 2H), 1.15 (t, J=7.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[F:15][C:16]([F:28])([F:29])[C:17]1[CH:18]=[C:19]([NH:20][C:12]([C:3]2[C:2]([OH:1])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[O:14])[CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1
Reactant: O=C(O)c1nc2ccccc2nc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nc2ccccc2nc1O
Yield: 2.7 %

Procedure:
Using 3-hydroxyquinoxaline-2-carboxylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.