Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][C:7]([CH3:30])=[N:6]1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:39][C:40]([NH:42][CH2:43][CH3:44])=[O:41]>C(Cl)Cl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:43]([NH:42][C:40](=[O:41])[CH2:39][N:27]1[CH2:28][CH2:29][CH:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[C:7]([CH3:30])[N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:25][CH2:26]1)[CH3:44]
Reactant: CCNC(=O)CCl
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)CN1CCC(c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 54.3 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (150 mg, 0.35 mmol) in DCM (2 mL) was added triethylamine (107 μL, 0.77 mmol). The resultant mixture was stirred for 10 minutes before the addition of 2-chloro-N-ethyl-acetamide (46 mg, 0.38 mmol) and tetrabutylammonium iodide (13 mg, 0.04 mmol). The reaction was stirred at RT for 4 days before the reaction was washed with sodium hydrogen carbonate solution (sat. aq.). The aqueous phase was extracted with 10% MeOH in DCM (×3) and the combined organic layers dried (Na2SO4) then concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM) affording 276 (91 mg, 0.19 mmol, 55%). LCMS: RT=2.75 min, [M+H]+=478. 1H NMR δ (ppm) (CDCl3): 8.43 (1H, d, J=8.29 Hz), 7.59 (1H, s), 7.16 (1H, s), 7.00 (1H, dd, J=8.34, 1.81 Hz), 6.88 (1H, d, J=1.76 Hz), 5.91-5.80 (1H, m), 4.48-4.44 (2H, m), 4.42-4.37 (2H, m), 3.37-3.26 (2H, m), 3.06-2.88 (4H, m), 2.57-2.47 (1H, m), 2.38 (3H, s), 2.30 (2H, s), 1.87 (2H, d, J=12.74 Hz), 1.76 (2H, s), 1.54 (6H, d, J=6.65 Hz), 1.15 (3H, t, J=7.26 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH3:11])[CH2:3]1.C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>O1CCOCC1>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[CH3:11])[CH2:3]2)=[O:25])=[CH:22][CH:21]=1
Reactant: Cc1cccc2c1CC(N)C2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1cccc2c1CC(NC(=O)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
370 mg (2.52 mmol) 2-amino-4-methylindane and 257 mg (2.52 mmol) triethylamine were dissolved in 5 ml dioxane, 400 mg (2.52 mmol) 4-fluorobenzoylchloride were added, and the mixture was stirred for 2 h at room temperature (RT).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:14][C:15]([F:39])([F:38])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]>>[F:14][C:15]([F:38])([F:39])[CH2:16][NH:17][C:18]([C:20]1([CH2:33][CH2:34][CH2:35][CH2:36][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19]
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(F)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(4-fluorophenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=C[C@@H]1CCCCN1C(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC[C@@H]1CCCCN1C(=O)OC(C)(C)C
Yield: 74.9 %

Procedure:
To a solution of (S)-2-(2-methoxycarbonylvinyl)-piperidine-1-carboxylic acid t-butyl ester (1.46 g, 5.41 mmol) in 1:1 methanol:methylene chloride (40 mL) was added 10% palladized charcoal (0.129 g). The mixture was hydrogenated (59 psi) for 5.5 h. The catalyst was removed by filtration through a bed of celite and the solution concentrated in vacuo. Purification by silica gel chromatography provided the product (1.10 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Br[C:28]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:31]=[CH:30][C:29]=1[CH3:39].COCCOC.C([O-])([O-])=O.[Cs+].[Cs+]>O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:31]=[CH:30][C:29]=3[CH3:39])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1cnn(-c2ccccc2)c1Br
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1cnn(-c2ccccc2)c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 130 °C
Yield: 12 %

Procedure:
6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (30 mg, 0.084 mmol) and 5-bromo-4-methyl-1-phenyl-1H-pyrazole (30 mg, 0.13 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 ml) and water (1 ml). To the above mixture were added PEPPSI-Ipr (5.4 mg, 0.008 mmol) and Cs2CO3 (83 mg, 0.25 mmol). The reaction mixture was heated at 130° C. in microwave reactor for 30 mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 3.9 mg product 6-(3,5-dimethylisoxazol-4-yl)-4-(4-methyl-1-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one (yield=12%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:7]=2[CH:29]=1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:8]2[C:7]3[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[O:11][CH2:10][C:9]2=[O:12])[CH2:20][CH2:19]1
Reactant: COc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2

Procedure:
tert-Butyl {1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-4-yl}carbamate (Intermediate 47) (510 mg, 1.26 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=O)[O:9][CH:8]2O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:18][NH2:19].C(O)(=O)C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=[O:9])[NH:19][N:18]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(c1)C(O)OC2=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
1.2 g (5.4 mmol) of 5-tert-butyl-7-fluoro-3-hydroxy-3H-isobenzofuran-1-one was weighed into a 25 mL round bottom flask fitted with a stir bar, condenser, and nitrogen inlet. Added 7.5 mL (100 mmol) of hydrazine monohydrate. Added 10 mL of glacial acetic acid. Stirred under nitrogen at 100° overnight. Poured the reaction mixture into 100 ml, of stirred water. Extracted the aqueous mixture with 2×50 mL CH2Cl2. Dried the combined extracts over Na2SO4 and removed the solvent on the rotavap. Purified by silica gel flash chromatography using gradient elution with 0→100% EtOAc/CH2Cl2 to obtain 898 mg of the title compound as an off-white solid. MS (ESI) 221 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]4[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1>C(Cl)Cl>[CH3:30][S:31]([NH:29][C:27]1[CH:26]=[CH:25][C:23]2[N:24]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]4)=[N:15][CH:16]=3)[S:21][C:22]=2[CH:28]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc(N)cc4s3)cn2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc(NS(C)(=O)=O)cc4s3)cn2)CC1
Yield: 48.8 %

Procedure:
To 4-[5-(6-amino-benzothiazol-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (12.7 mg, 0.031 mmol) in DCM (1 mL) was added methanesulfonyl chloride (3 μL, 0.034 mmol) followed by pyridine (3 μL, 0.034 mmol). The r.m. was stirred o.n. at r.t. The crude mixture was purified by flash column chromatography (heptane:ethyl acetate; 50:50 to 40:60), to give intermediate tert-butyl 4-(5-{6-[(methylsulfonyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)piperazine-1-carboxylate (7.4 mg) as a solid. MS m/z (M+H) 490, (M−H) 488. This intermediate was dissolved in DCM (1 mL) and TFA (300 μL) was added. The reaction mixture was thereafter stirred for three hours at r.t. The solvent was removed in a stream of nitrogen and the residue was dissolved in DMF (400 μL) and purified by prep. HPLC, to give the title compound (3 mg) as a white solid. 1H NMR δ 8.71 (d, 1 H) 8.09 (dd, 1 H) 7.72-7.86 (m, 2 H) 7.27 (dd, 1 H) 6.88 (d, 1 H) 3.63-3.77 (m, 4 H) 2.95-3.08 (m, 4 H) 2.90 (s, 3 H); MS m/z M+H 390, M−H 388.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH:24]([OH:33])[C:25]2[N:26]3[CH:32]=[N:31][CH:30]=[C:27]3[S:28][CH:29]=2)[CH2:22][C@@H:21]([OH:34])[CH2:20]1)=[O:18])[CH:14]=[CH2:15].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:13]([O:16][C:17]([N:19]1[C@H:23]([CH:24]([OH:33])[C:25]2[N:26]3[CH:32]=[N:31][CH:30]=[C:27]3[S:28][CH:29]=2)[CH2:22][C@@H:21]([O:34][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:20]1)=[O:18])[CH:14]=[CH2:15]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(O)c1csc2cncn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1C(O)c1csc2cncn12
Reaction time: 0.5 h

Procedure:
Triethylamine (0.25 ml) and 0.12 ml of methanesulfonyl chloride are successively added to a solution of 457 mg of crude (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]pyrrolidine (stereoisomer A) in 12 ml of dry THF in an argon atmosphere at 3° C., and the mixture is stirred in this state for 30 min. A 5% aqueous sodium hydrogencarbonate solution (30 ml) is added thereto, and the mixture is extracted with 100 ml of ethyl acetate. The organic layer is washed with saturated saline, dried over magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure to give a slightly cloudy orange brown oil. This oil is purified by flash column chromatography on silica gel (ethyl acetate:methanol=92:8) to give 344 mg of crude (3R,5S)-1-allyloxycarbonyl-5-[1-hydroxy-1-(imidazo[5,1-b]thiazol-3-yl)methyl]-3-methanesulfonyloxypyrrolidine (stereoisomer A) as a milky white amorphous material.
Reaction SMILES: Cl[C:2]1[C:3](=[O:27])[O:4][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23][CH3:24])=[CH:18][C:17]=2[O:25][CH3:26])([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)OC(CCC2C=CC(OC)=C(Cl)C=2)(C2CCCC2)CC=1O.[Cl:53][C:54]1[CH:64]=[CH:63][C:57]2[N:58]([CH3:62])[C:59]([SH:61])=[N:60][C:56]=2[CH:55]=1.ClC1C=CC2N(C(C)C)C(S)=NC=2C=1>>[Cl:22][C:20]1[C:19]([O:23][CH3:24])=[CH:18][C:17]([O:25][CH3:26])=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:27])[C:2]([S:61][C:59]3[N:58]([CH3:62])[C:57]4[CH:63]=[CH:64][C:54]([Cl:53])=[CH:55][C:56]=4[N:60]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Reactant: Cn1c(S)nc2cc(Cl)ccc21
Agent: CC(C)n1c(S)nc2cc(Cl)ccc21
Agent: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Sc3nc4cc(Cl)ccc4n3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example C(40), where 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]-6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one was substituted in place of 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]6-cyclopentyl-4-hydroxy-5,6-dihydro-2H-pyran-2-one and 5-chloro-1-methyl-1H-benzimidazole-2-thiol was substituted in place of 5-chloro-1-isopropyl-1H-benzimidazole-2-thiol.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][N:4]([CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH3:5].[CH3:17][NH:18][CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1>C1C=CC=CC=1>[OH:1][CH:2]([CH2:16][N:18]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[CH3:17])[CH2:3][N:4]([CH3:5])[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Reactant: CN(CC1CO1)C1CC(C)(C)NC(C)(C)C1
Solvent: c1ccccc1
Product: CN(CC(O)CN(C)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h

Procedure:
A mixture of 2.2 g of 4-[N-(2,3-epoxypropyl)-N-methylamino]-2,2,6,6-tetramethylpiperidine and 1.7 g of 4-methylamino-2,2,6,6-tetramethylpiperidine in 20 ml of benzene was refluxed, with stirring, for 3 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and then the resulting residue was distilled in vacuo, giving the desired compound in the form of a colourless, viscous oil boiling at 194°-196° C. at 0.2 mmHg.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:37])[CH:10]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:49]([O-])=[O:50].[Na+]>>[CH2:1]([N:8]([N:49]=[O:50])[C:9](=[O:37])[CH:10]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)[CH:11]1[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: O=C(NCc1ccccc1)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=NN(Cc1ccccc1)C(=O)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a ice-cold solution of 3.10 g (5.85 mMol) N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-acetamide in 19.1 ml (333 mmol) acetic acid and 40.14 ml (708 mmol) acetic anhydride were added in portions over 20 min. 2.02 g (29.25 mmol) sodium nitrite. The reaction mixture was stirred overnight at room temperature and evaporated. The residue was taken up in saturated aqueous sodium bicarbonate solution and ethyl acetate and the pH was adjusted to 7 by adding solid sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. Yellow foam (85%). MS (Turbo Spray): m/z=559.2 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12].BrCCC.OC1C=CC(C=O)=CC=1>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:11]=[O:12]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CCCCCBr
Agent: O=Cc1ccc(O)cc1
Solvent: CCCBr
Product: CCCCCOc1ccc(C=O)cc1Cl
Yield: 96 %

Procedure:
When the 1-bromopentane and 3-chloro-4-hydroxybenzaldehyde was substituted for 1-bromopropane and 4-hydroxybenzaldehyde in Example 50 Step A the identical process afforded the title compound in 96% yield, as light yellow oil. 1H-NMR (CDCl3) 0.9 (tr, 3H, J=7.05 Hz); 1.34-1.39 (m, 4H); 1.41-1.45 (m, 2H); 4.07 (tr, 2H, J=3.66 Hz); 6.97 (d, 1H, J=8.49 Hz); 7.7 (dd, 1H, J=2.01, 8.46 Hz); 7.85 (d, 1H, J=2.04 Hz); 9.81 (s, 1H).
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:10]([N:20]1[C:28]2[C:23](=[N:24][C:25]([NH2:29])=[CH:26][N:27]=2)[CH:22]=[CH:21]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(O)CCC>O1CCOCC1>[S:10]([N:20]1[C:28]2[N:27]=[CH:26][C:25]3[N:24]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8][N:29]=3)[C:23]=2[CH:22]=[CH:21]1)([C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[CH:18][CH:19]=1)(=[O:11])=[O:12]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(N)cnc32)cc1
Solvent: C1COCCO1
Solvent: CCCCO
Product: CCOC(=O)c1cnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of ethyl 2-chloro-3-oxopropanoate (1.60 g, 7.65 mmol, prepared as described in US2009005359A1) and 1,4-dioxane (10.0 mL) was added to 5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-amine (1.45 g, 5.03 mmol, Preparation #E.1.1) under nitrogen. Anhydrous butan-1-ol (30.0 mL) was added, a reflux condenser was attached, and the system was sealed. After about 30 min, the mixture was warmed to about 80° C. The solution was allowed to cool to ambient temperature. A solution of ethyl 2-chloro-3-oxopropanoate (2.78 g, 13.3 mmol) and 1,4-dioxane (5 mL) was added. After about 30 min, the reaction mixture was warmed to about 80° C. After about 30 min, the mixture was warmed to about 125° C. After about 48 h, the brown solution was allowed to cool to ambient temperature. The volatiles were removed under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 5-50% EtOAc in heptane to give ethyl 3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-carboxylate (1.16 g, 60%): LC/MS (Table 1, Method b) Rt=2.52 min; MS m/z 385 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCN(C(C)C)C(C)C>ClCCl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH:22]([CH3:24])[CH3:23])[C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[CH2:17][CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)NC1CCN(Cc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C(=O)CCCCl)C1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
A solution of 4-chlorobutyryl chloride (5.3 mL, 47.4 mmol) in dichloromethane (400 mL) was added dropwise to a mixture of 1-benzyl-4-(isopropylamino)piperidine (10 g, 43.07 mmol) and DIPEA (9.0 mL, 51.7 mmol) in dichloromethane (200 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min and then at room temperature for 2 h. The solution was then washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexane/triethylamine: 42.5/56.5/1) to give 5.0 g of the title intermediate as viscous oil (35% yield).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[O:7])[CH:2]=1.NC1[S:15][C:16]2C=C[CH:20]=[CH:19][C:17]=2N=1>C(#N)C>[S:15]1[C:16]2[CH:17]=[CH:19][CH:20]=[CH:9][C:10]=2[N:11]=[C:12]1[NH:8][C:6]([N:3]1[CH:2]=[CH:1][N:5]=[CH:4]1)=[O:7]
Reactant: Nc1nc2ccccc2s1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: O=C(Nc1nc2ccccc2s1)n1ccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
To CDI (1.6 g, 10 mmol) in acetonitrile (30 mL) was slowly added 2-aminobenzothiazole (1.0 g, 6.6 mmol) and allowed to stir at rt for 48 hours. The reaction mixture was filtered, washed with acetonitrile, and dried to provide 1.44 g (88%) of the desired product N-(benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide (1M): LC/MS (APCI): m/z 245.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.O1CCCC1.[CH2:25]([Mg]Br)[CH:26]([CH3:28])[CH3:27].[BH4-].[Na+]>CO>[CH3:25][CH:26]([CH3:28])[CH2:27][CH:8]([C:6]1[CH:5]=[CH:4][C:3]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][CH:11]=2)=[C:2]([CH3:1])[CH:7]=1)[NH2:9]
Reactant: CC(C)C[Mg]Br
Reactant: Cc1cc(C#N)ccc1-c1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(N)CC(C)C)ccc1-c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 76.6 %

Procedure:
A microwave reaction vial was charged with 2-methyl-4′-(trifluoromethyl)biphenyl-4-carbonitrile (500 mg, 1.91 mmol) and tetrahydrofuran (5 mL). To the mixture was added isobutylmagnesium bromide (2.87 mL, 5.74 mmol, 2M in THF). The reaction was heated at 100° C. in a microwave for 30 minutes. The reaction mixture was then carefully added to a solution of sodium borohydride (145 mg, 3.83 mmol) in methanol (5 mL). After stirring for 5 minutes, the mixture was concentrated to dryness. Purification by column chromatography gave 3-methyl-1-(2-methyl-4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (470 mg). 1H NMR (400 MHz, CD3OD, δ): 7.72 (d, 2H), 7.50 (d, 2H), 7.24 (s, 1H), 7.19 (d, 2H), 3.94 (m, 1H), 2.27 (s, 3H), 1.65 (m, 2H), 1.49 (m, 1H), 0.95 (d, 3H), 0.92 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(NC(C)C)(C)C.[NH2:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20]>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][CH2:18][C:19]([CH3:22])([OH:21])[CH3:20])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(O)CN
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)(O)CNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4-dichloro-5-fluoropyrimidine (2 g, 11.98 mmol) in acetonitrile (10 mL) was cooled to −40° C., avoiding freezing. To this solution was added diisopropylamine (3.82 mL, 21.88 mmol) followed by 1-amino-2-methylpropan-2-ol (1.5 g, 16.83 mmol). The reaction mixture was removed from the cooling bath, warmed to room temperature and allowed to stir overnight (˜18 hours). Solvents were removed in vacuo and the residue was taken up in a minimum of dichloromethane (˜1.5-2 mL) and diluted with heptane until slightly cloudy. This mixture was loaded onto a 40 gram BioRad silica gel cartridge. Purification by flash chromatography (Analogix System, 20 min gradient, 0-25% methanol/dichloromethane, 40 mL/min.) provided 1-(2-chloro-5-fluoropyrimidin-4-ylamino)-2-methylpropan-2-ol as a white solid. LCMS m/z 220.1, 221.8 (M+H)+, Rt 0.49 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH3:11])[O:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5])[CH3:2].[Br:16]N1C(=O)CCC1=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][Br:16])[O:8][C:7]=1[C:12]([F:15])([F:13])[F:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C)oc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(CBr)oc1C(F)(F)F
Temperature: 25 °C
Yield: 37.6 %

Procedure:
To a solution of 5-methyl-2-trifluoromethyl-furan-3-carboxylic acid ethyl ester (0.95 g, 4.5 mmol) in CCl4 (12 mL) was added N-bromosuccinimide (0.84 g, 4.8 mmol) followed by AIBN (0.004 g, 0.01 mmol). After refluxing for 2 h, analytical HPLC analysis confirmed the reaction was complete. The reaction was cooled to rt, then CH2Cl2 and sat'd NaHCO3 (aq.) were added. The organic portion was separated and dried to provide the crude residue as a yellow oil. This material was purified by RP HPLC to provide the title compound (510 mg, 38%). MS (ESI): mass calcd. for C9H8BrF3O3, 300.0; m/z found, 302.9 [M+H]+. 1H NMR (CDCl3): 6.84 (s, 1H), 4.44 (s, 2H), 4.34 (q, J=7.2 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H).