Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1.Br[C:23]1C=C(NCC2C=CC3N=C(SC)SC=3C=2)C(N)=CC=1OC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:23]=[N:21][C:4]=2[CH:3]=1
Reactant: COc1cc(N)c(NCc2ccc3nc(SC)sc3c2)cc1Br
Reactant: CSc1nc2ccc(CNc3ccc(Br)cc3N)cc2s1
Product: CSc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1

Procedure:
6-((5-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole was synthesized as a white solid (630 mg, 57%) using a procedure analogous to that described in Step 3 of Example 41, substituting 4-bromo-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine from Step 3 of this Example for 4-bromo-5-methoxy-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.00 (s, 1H), 7.75-7.91 (m, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.33-7.45 (m, 2H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 389 and 391 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][CH2:32]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][CH2:32][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(CCc2ccccc2OCCC2CCCCN2C(=O)OC(C)(C)C)c1
Yield: 32.7 %

Procedure:
Following a procedure similar to that described in Example 36(a), 1.00 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 1.51 g of 1-t-butoxycarbonyl-2-(2-hydroxyethyl)piperidine, 1.72 g of triphenylphosphine and 1.14 g of diethyl azodicarboxylate were reacted in 20 ml of methylene chloride. The mixture was then worked up as described in Example 36(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.630 g (yield 32%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=1[O:35][CH3:36].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[C:27]([O:35][CH3:36])[CH:28]=2)[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Reactant: COc1cc(B(O)O)ccc1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 168 h
Yield: 51.7 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 196, 200 mg) in CH2Cl2 (4 ml) were added 4-fluoro-3-methoxyphenylboronic acid (282 mg), copper-(II)-acetate (307 mg), molecular sieve and pyridine (219 mg). The mixture was stirred at room temperature under an air atmosphere with exclusion of moisture for 7 days. The mixture was filtered, diluted with CH2Cl2 and washed with 1M aqueous HCl. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (139 mg) as an off-white solid. MS (m/e)=486.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[Br:31]N1C(=O)CCC1=O>C(OCC)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][Br:31])=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2CBr)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a heterogeneous, refluxing solution of 2-(4-fluorophenyl)-4-methyl-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (590 mg, 1.65 mmol) and carbon tetrachloride (24 mL) was quickly added N-bromosuccinimide (yield: 308 mg, 1.73 mmol) followed by benzoyl peroxide (12 mg, 0.05 mmol). After 1 hour the reaction had only run to near 50% completion. Additional benzoyl peroxide (12 mg, 0.05 mmol) was added, and the reaction checked after another 1 hour. The reaction was still not complete, and so more benzoyl peroxide (4 mg, 0.017 mmol) was added. After 30 minutes, the reaction was completed. The mixture was cooled to 23° C. and diluted with ethyl acetate. The acetate solution was washed with saturated NaHCO3, water, and brine. The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes gradient 1:1 to 4:1) to provide the product (yield: 530 mg, 74%). 1H NMR (300 MHz, CDCl3) δ 3.16 (s, 3H), 4.34 (s, 2H), 7.20 (dd, J=8.8, 8.8 Hz, 2H), 7.67-7.74 (m, 2H), 7.82 (d, J=8.7 Hz, 2H), 7.86 (s, 1H), 8.17 (d, J=8.7 Hz, 2H), MS (APCI+) m/z 437 (M+H)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[CH2:10]=[C:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1>C1COCC1.II>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([C:14]2([OH:17])[CH2:15][CH2:16][C:11](=[CH2:10])[CH2:12][CH2:13]2)=[CH:4][CH:5]=1
Reactant: C=C1CCC(=O)CC1
Reactant: Brc1ccc(Br)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=C1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a flask charged with dry, freshly ground magnesium turnings (1.1 g, 45 mmol) and iodine (25 mg, 0.1 mmol) in THF (50 mL) was added a solution of 1,4-dibromobenzene (10.6 g, 45.0 mmol) in THF (30 mL) slowly by dropping funnel over 30 min. The resulting mixture was stirred at rt for 1 hr. The resultant grey Grignard solution was cooled to −78° C. and to it was added a solution of 4-methylenecyclohexanone (3.3 g, 30 mmol) in THF (20 mL) slowly dropwise over 20 min. The reaction was stirred at −78° C. for 30 min before being allowed to stir and warm to rt for 3 h. The resulting reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with methyl tert-butyl ether. The combined organic phases were washed with a saturated aqueous NaCl solution, dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification of the crude material by column chromatography (80 g silica gel, 0-50% EtOAc:Hept, monitor for 225 nm) afforded 2.94 g of a colorless oil that was used without further purification. ESI-MS m/z: not ionized [M+H]+, retention time 1.50 min (condition E).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].C([Li])CCC.[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[C:39]([OH:45])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClCCl>C1COCC1>[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[CH:2][CH2:3][CH3:4])=[C:39]([OH:45])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a flame dried 500 mL 3-neck flask under an atmosphere of argon, was charged n-propyltriphenylphosphonium bromide (12.66 g, 32.85 mmol) dissolved in anhydrous THF (85 mL), followed by the dropwise addition of n-butyllithium 16.4 mL, 26.28 mmol). The dark red mixture was stirred at ambient temperature for 1 h. 15 min. Next 4-benzyloxy-2-hydroxybenzaldehyde (1.5 g, 6.57 mmol) (Synth. Commun., 26(3), 593-601, (1996) was added followed by the addition of anhydrous dichloromethane (27 mL). The mixture was stirred at ambient temperature for 18 h. The solvents were removed in vacuo, and the residue was partitioned between ethyl acetate and water (500 mL each). The organic layer was washed with brine (500 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified using the Biotage FlashElute chromatography system using a 65M normal phase cartridge, eluting with 15% ethyl acetate/Hex to give a yellow solid (1.50 g, 90%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 5H), 7.19 (d, J=8.3 Hz, 1H), 6.52 (dd, J=8.8, 2.4 Hz, H), 6.46 (d, J=2.4 Hz, 1H), 6.43 (s, 1H), 6.14-6.07 (m, 1H), 5.03 (s, 2H), 4.98 (s, 1H), 2.25 (quintet, J=7.6 Hz, 2H), 1.09 (t, J=7.3 Hz, 3H), MS (ES) m/e 255 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH:25]([NH:28][CH3:29])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:28]([CH:25]([CH3:27])[CH3:26])[CH3:29])=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Reactant: CNC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)N(C)C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, N-isopropylmethylamine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.49 minutes; C20H20Cl2N4O2 (419.31); mass spectrum: (M+H)+=419.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[OH-].[Na+].[C:19](=O)([O-])O.[Na+]>CO>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:10][C:6]=1[C:7]([O:9][CH3:19])=[O:8]
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(N)ccc1O
Yield: 45 %

Procedure:
5-Amino-2-hydroxybenzoic acid (200 g, 1.31 mole) was suspended in methanol (2 1), concentrated sulphuric acid (120 ml) was slowly added and the reaction mixture was refluxed for 48 hours under nitrogen. Subsequently the reaction mixture was brought to room temperature and neutralized with 33% aqueous sodium hydroxide (120 ml) and 1M aqueous sodium hydrogen carbonate (to neutral reaction). The reaction mixture was extracted with ether (3×400 ml), the ethereal solution was washed with 1M aqueous sodium hydrogen carbonate (2×100 ml) and water (2×100 ml) and dried over anhydrous magnesium sulphate (50 g) and the ether evaporated. The remaining product was recrystallized from hexane, with activated carbon, to give methyl 2-hydroxy-5-aminobenzoate (98.3 g, 45%), m.p. 93°-95° C. Found (Calc. for C8H9NO3) C 57.38 (57.48), H 5.41 (5.39), N 8.38 (8.38).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:9]1[CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])([CH3:8])([CH3:7])[CH3:6].[CH3:23]O>>[C:5]([C:9]1[CH:10]=[C:11]([N+:20]([O-:22])=[O:21])[C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([O:16][CH3:23])=[O:15])([CH3:8])([CH3:6])[CH3:7]
Reactant: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(C)(C)C)cc([N+](=O)[O-])c1OC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2.3 ml of thionyl chloride are added dropwise to an ice-cooled solution of 5.40 g 5-tert-butyl-2-methoxy-3-nitro-benzoic acid in 50 ml of methanol. The cooling bath is removed and the solution is heated to 60° C. The solution is stirred overnight at 60° C. and then cooled to ambient temperature. The solution is evaporated down completely and the residue is mixed with water. The aqueous mixture is extracted with ethyl acetate, and the combined extracts are dried (MgSO4). The solvent is removed, and the residue is chromatographed on silica gel with cyclohexane/ethyl acetate (98:2→60:40).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[S:21][CH:20]=[C:19]([C:22]#[N:23])[C:18]=1[C:24]1[S:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1>>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[C:18]1[C:19]([C:22]#[N:23])=[CH:20][S:21][C:17]=1[NH:16][C:13](=[O:15])[CH2:12][N:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1=[O:1]
Reactant: N#Cc1csc(N)c1-c1nc2ccccc2s1
Reactant: O=C(O)Cn1c(=O)ccc2ncccc21
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3ncccc32)c1-c1nc2ccccc2s1

Procedure:
The title compound was prepared from 2-(2-oxo-1,5-naphthyridin-1(2H)-yl)acetic acid (0.040 g, 0.19 mmol) and 5-amino-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile (0.073 g, 0.28 mmol) according to protocol A. The crude product was purified by prep HPLC. LCMS retention time (min)=5.122, method [12], MS (ESI) 446.1 (M+H). 1H NMR (CDCl3) δ 13.38 (s, 1H), 8.32 (d, J=5.6 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.94 (d, J=7.5 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.47-7.42 (m, 1H), 7.35-7.30 (m, 1H), 4.95 (s, 2H), 3.33-3.28 (m, 2H), 2.99-2.94 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([C:28](O)=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][CH2:24][C:25]([CH3:26])([CH3:27])[C:28](=[O:29])[N:41]4[CH2:45][CH2:44][CH2:43][CH2:42]4)[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:5]2=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC(C)(C)C(=O)N2CCCC2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 17.9 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxycarbonyl-2-methyl-propoxy)-phenyl]-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.07 mmol), pyrrolidine (0.0083 mL, 0.1 mmol), EDC.HCl (20 mg, 0.1 mmol), and HOBt (14 mg, 0.1 mmol) in THF (5 mL) was added DIPEA (0.018 mL, 0.2 mmol) at rt. The reaction mixture was stirred for 4 h, then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep-HPLC to give the title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1)([O:8][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])[C:4]([F:7])([F:6])[F:5].CCN(C(C)C)C(C)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH:22][S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])[CH2:18][CH2:17]1)([O:8][Si:9]([CH2:10][CH3:11])([CH2:14][CH3:15])[CH2:12][CH3:13])[C:4]([F:7])([F:6])[F:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N)CC1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[Si](CC)(CC)OC([C@H]1CC[C@H](NS(=O)(=O)c2ccccc2)CC1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.71 g (1.87 mmol) of trans 4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexylamine in 5 mL of CH2Cl2 was treated with 0.64 mL (3.74 mmol) of DIPEA and 0.24 mL (1.87 mmol) of benzenesulfonylchloride and stirred at RT for 3 hrs. Distribution of the crude mixture between a diluted aqueous solution of HCl and Et2O, drying of the combined organic phases over Na2SO4 and chromatography on silica gel with EtOAc/heptane 1:1 gave 0.9 g (93%) of trans-N-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexyl]-benzenesulfonamide as a light yellow semisolid, MS: 518 (M−H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:29])=[O:28])=[CH:22][CH:21]=1>>[Cl:18][C:14]1[CH:13]=[C:12]([C:4]2[N:3]=[C:2]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH2:29])=[O:28])=[CH:24][CH:25]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccc(Cl)c2)n1
Reactant: NC(=O)Cc1ccc(N)cc1
Product: NC(=O)Cc1ccc(Nc2cc(C(F)(F)F)nc(-c3cccc(Cl)c3)n2)cc1
Yield: 30.4 %

Procedure:
Following General Procedure A2, 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine (0.100 g, 0.34 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.103 g, 0.68 mmol) to afford the title compound (0.042 g, 56%) as an off-white solid. MW=406.79. 1H NMR (DMSO-d6, 500 MHz) δ 10.24 (s, 1H), 8.33-8.25 (m, 2H), 7.74-7.58 (m, 4H), 7.33 (d, J=8.5 Hz, 2H), 7.09 (s, 1H), 6.88 (s, 1H), 3.39 (s, 2H), 2.70 (s, 1H); APCI MS m/z 407 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[C:5]([O:11][CH3:12])[CH:4]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(CBr)ccc1CO
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cc(CBr)ccc1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of (4-bromomethyl-2-methoxy-phenyl)-methanol (1.1 g, 4.76 mmol) in dichloromethane (15 mL) is added imidazole (0.861 g, 5.71 mmol) and tert-butylchlorodimethylsilane (0.971 g, 12.98 mmol) at 0° C. The reaction mixture is allowed to warm to room temperature and stirred for one hour. The reaction mixture is quenched with water and concentrated. The residue is diluted with DCM, washed with water (15 mL) and brine (15 mL), dried over sodium sulfate, filtered, and concentrated to give the title compound (1.1 g, 66.9%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.41 (d, J=8 Hz, 1H), 7.00-6.98 (d, J=8 Hz, 1H), 6.94 (s, 1H), 4.73 (s, 2H), 4.50 (s, 2H), 3.83 (s, 3H), 0.95 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [CH3:1][C:2]([NH2:5])([CH3:4])[CH3:3].Cl[CH2:7][C:8]1[O:9][C:10]([CH3:13])=[N:11][N:12]=1>CN(C=O)C>[CH3:1][C:2]([NH:5][CH2:7][C:8]1[O:9][C:10]([CH3:13])=[N:11][N:12]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: Cc1nnc(CCl)o1
Solvent: CN(C)C=O
Product: Cc1nnc(CNC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
A suspension of 2-methylpropan-2-amine (75-64-9, 141 mg, 202 μL, 1.92 mmol) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (3914-42-9, 50 mg, 377 μmol) in DMF (200 μL) was stirred at ambient temperature for 16 h. The mixture was poured onto ice-water (20 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were washed with ice-water (20 mL), dried over Na2SO4 and concentrated in vacuo to give a yellow oil. The crude product was purified by preparative TLC (silica gel 1 mm, EtOAc/diethyl amine 95:5, elution with DCM/EtOAc 1:1) to give the title compound (45 mg, 71%) as yellow oil; MS (EI): m/e=170.2 [MH+].
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[F:32][C:33]([F:38])([F:37])[C:34](=O)[CH3:35].CO>C(Cl)(Cl)Cl>[F:32][C:33]([F:38])([F:37])[CH:34]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH3:35]
Reactant: CC(=O)C(F)(F)F
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(N1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 40 mg (0.098 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 1 mL chloroform was treated with 1 mL (large excess) trifluoracetone and 62 mg (0.29 mmol) NaBH3(CN), followed by addition of 1 mL methanol. The mixture was stirred at ambient temperature for 15 h when it was quenched before complete conversion to product. The reaction mixture was diluted with 20 mL DCM, washed with 20 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a mixture of diasteriomers (9:1 by HPLC). MS (ES+): 508 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:30])=[CH:10][N:11]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:19]([NH:21][CH:22]3[CH2:25][CH2:24][CH2:23]3)=[O:20])[C:12]2=[O:15])=[CH:7][CH:6]=1.[I-].[K+].[CH3:33][NH:34][CH:35]([CH3:37])[CH3:36]>CC(N(C)C)=O.C(OCC)(=O)C>[CH:22]1([NH:21][C:19](=[O:20])[C:18]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:16]([N:11]3[CH:10]=[C:9]([CH3:30])[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:34]([CH:35]([CH3:37])[CH3:36])[CH3:33])=[CH:6][CH:7]=4)[C:12]3=[O:15])[CH:17]=2)[CH2:23][CH2:24][CH2:25]1
Reactant: CNC(C)C
Reactant: Cc1ccc(C(=O)NC2CCC2)cc1-n1cc(C)c2ccc(OCCCl)cc2c1=O
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cc(C)c2ccc(OCCN(C)C(C)C)cc2c1=O
Temperature: 150 °C

Procedure:
A mixture of 3-[7-(2-chloroethoxy)-4-methyl-1-oxoisoquinolin-2(1H)-yl]-N-cyclobutyl-4-methylbenzamide (131 mg), potassium iodide (102 mg), and N-methylisopropylamine (0.19 ml) were stirred in DMA (2 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting using initially 10% methanol/ethyl acetate and then a 99:1 mixture of 10% methanol/ethyl acetate and aqueous ammonia solution gave N-cyclobutyl-3-[7-{2-[isopropyl(methyl)amino]ethoxy}-4-methyl-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzamide (74 mg) as a cream solid; NMR Spectrum: (DMSOd6) 0.98 (d, 6H), 1.68 (m, 2H), 2.06 (m, 2H), 2.11 (s, 3H), 2.21 (m, 2H), 2.25 (s, 3H), 2.28 (s, 3H), 2.77 (t, 2H), 2.84 (m, 1H), 4.15 (m, 2H), 4.43 (m, 1H), 7.09 (s, 1H), 7.45-7.51 (m, 2H), 7.71-7.74 (m, 2H), 7.80 (s, 1H), 7.89 (d, 1H), 8.60 (d, 1H); Mass Spectrum: M+H+ 462.