Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:20])([F:19])[C:12]1[N:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:20][C:11]([F:10])([F:19])[C:12]1[N:13]=[CH:14][C:15]([O:18][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:16][N:17]=1
Reactant: Oc1cnc(C(F)(F)F)nc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)cc1
Temperature: 130 °C
Yield: 71.6 %

Procedure:
A mixture of 4-fluorobenzaldehyde (0.196 mL, 1.828 mmol), 2-(trifluoromethyl)-5-pyrimidinol (300 mg, 1.828 mmol), and K2CO3 (505 mg, 3.66 mmol) in DMF (2 mL) was heated with a microwave reactor at 130° C. for 1 h. After removing the solvent, the residue was diluted with water, extracted with DCM. The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification via flash chromatography then afforded the title compound (351 mg, 1.309 mmol, 71.6% yield). LCMS: rt=2.97 min, [M+H+]=269
Reaction SMILES: N#N.[CH3:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[O:13][CH3:14].N1C(C)=CC(C)=CC=1C.[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27]>C(#N)C>[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:26](=[O:27])[C:25]([Cl:30])([Cl:29])[Cl:24])=[CH:10][CH:9]=[CH:8][C:7]=2[O:13][CH3:14]
Reactant: COc1cccc2cc(C)[nH]c12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: N#N
Solvent: CC#N
Solvent: Cc1cc(C)nc(C)c1
Product: COc1cccc2c(C(=O)C(Cl)(Cl)Cl)c(C)[nH]c12
Yield: 100.5 %

Procedure:
To a 2 L round-bottomed flask equipped with a magnetic stirrer and a N2 bubbler were added 2-methyl-7-methoxyindole (12 g, 74 mmol), acetonitrile (125 mL) and collidine (15 mL, 113 mmol). The mixture was stirred to give a solution and was cooled with an ice water bath. Trichloroacetyl chloride (14 mL, 112 mmol) was added. The cooling bath was removed and the reaction mixture stirred at RT for 3 h. 1N HCl (500 mL) was then added over 10 minutes. The resulting slurry was stirred at RT for 30 minutes and filtered. The cake was washed with DI water (3×50 mL) and suction dried for 17 h to give 2-methyl-3-trichloroacetyl-7-methoxyindole (22.8 g, 96% yield). 1H NMR (CDCl3) δ2.79 (s, 3H), 3.96 (s, 3H), 6.71 (d, J=7.9 Hz, 1H), 7.19 (dd, J=7.9, 8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 8.92 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[O:13]([CH2:21][CH2:22][CH2:23][NH2:24])[Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>O1CCCC1>[O:13]([CH2:21][CH2:22][CH2:23][NH:24][S:9]([CH3:8])(=[O:11])=[O:10])[Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCCN
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.16 ml, 16 mmol), followed by methanesulfonyl chloride (Compound 19, 1.48 ml, 19.2 mmol) was added to a solution of 3-tert-butyldimethylsiloxy-1-propylamine (Compound 29, 2.80 g, 16 mmol) in tetrahydrofuran (60 ml) at 0° C. under argon. After stirring at room temperature overnight, the mixture was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate and brine. Evaporation of the dried (magnesium sulfate) organic phase gave the title sulfonamide. 1HNMR(CDCl3): 0.04 (s, 6H), 0.87 (s, 9H), 1.76 (p, 2H, J=6.4 Hz), 2.91 (s, 3H), 3.24 (q, 2H, J=6.2 Hz), 3.74 (t, 2H, J=5.52 Hz) and 5.05 (br t, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.Cl[C:31](Cl)([O:33]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([NH2:51])[CH3:50])=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([NH:51][C:31]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:33])[CH3:50])=[CH:45][CH:44]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 114.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1S)-1-(4-chlorophenyl)ethylamine (36 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (61 mg, yield 54%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].C1(C)C=CC(S(O[CH2:28][C@H:29]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)(=O)=O)=CC=1.O>CN(C)C=O>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][C@@H:29]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:28][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=3)=[CH:10][CH:11]=2)[CH:33]=1
Reactant: N#Cc1cccc(-c2ccc(O)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)OC(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(OC[C@@H](CCc3cccnc3)OC(=O)c3ccccc3)cc2)c1
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Solid 3'-cyanobiphenyl-4-ol (0.20 g, Example 36b)) was added to a suspension of sodium hydride (60%, 0.049 g) in dimethylformamide (5 ml) and the resulting solution stirred for 30 minutes. Solid (2R)-2-benzoyloxy-4-(3-pyridyl)-1-butyl para-toluenesulfonate (0.43 g) was then added and the mixture stirred at 60° C. for 2 hours. The mixture was cooled, poured into water (50 ml) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting with diethyl ether to give the sub-title compound as an oil (0.34 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1.[H-].[Na+].Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26])[CH:7]=[C:6]2[C:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][N:19]=[C:14]2[CH:13]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc2[nH]cc(-c3cc4nccnc4[nH]3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2CC(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A stirred solution of 6-(5-methoxy-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine [70 mg, Example 11] in dry dimethylformamide (10 mL) was treated with sodium hydride (21.6 mg, 60% dispersion in mineral oil). After stirring for 30 minutes this mixture was treated with a solution of 4-(2-chloroacetyl)morpholine (44.1 mg) in dimethylformamide (1 mL) and stirring was continued for a further 3 hours. The reaction mixture was poured into water (20 mL) and then extracted three times with ethyl acetate (30 mL). The combined extracts were dried over sodium sulfate and then evaporated. The residue was triturated with diethyl ether to give the title compound (55 mg) as a yellow solid, m.p. 263-267° C. MS: 392.21 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:63][N:64]([CH3:74])[CH2:65][CH2:66][CH2:67][CH:68]1[CH2:73][CH2:72][CH2:71][CH2:70][NH:69]1.FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][CH2:73][CH:68]1[CH2:67][CH2:66][CH2:65][N:64]([CH3:74])[CH3:63])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(C)CCCC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCCC3CCCN(C)C)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N,N-dimethyl-N-(3-piperidin-2-yl-propyl)-amine in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:13][C:11]=2[NH2:12])[CH:6]=[CH:7][CH:8]=1.[CH:26](=O)[CH3:27].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:10]2[N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:26]([CH3:27])=[N:12][C:11]=2[CH:13]=1
Reactant: COc1cccc(Nc2ccc(-c3nc4ccccc4o3)cc2N)c1
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(-n2c(C)nc3cc(-c4nc5ccccc5o4)ccc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a solution of 2-(2-(3-methoxyphenyl)aminoanilin-5-yl)benzoxazole (see Working Example 31-1) (55.0 mg, 0.166 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 31.2 μL, 0.405 mmol) and oxone (66.3 mg, 0.108 mmol), and this was stirred at room temperature for 3 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (17.3 mg, 29% yield) as light brown crystals.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[Br:19][C:17]1[C:16]([F:20])=[CH:15][C:14]([F:21])=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=1
Reactant: O=C(NC(=S)Nc1cc(Br)c(F)cc1F)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Nc1cc(Br)c(F)cc1F
Temperature: 70 °C
Reaction time: 15 h
Yield: 81.4 %

Procedure:
To a solution of 1-benzoyl-3-(5-bromo-2,4-difluoro-phenyl)-thiourea II (1.70 g, 4.60 mmol) in THF (35.0 mL) was added a solution of NaOH (0.97 g, 24.25 mmol) in water (13.0 mL). The resulting reaction mixture was stirred at 70° C. for 15 h. After the completion of the reaction (TLC monitoring), THF was evaporated, added water and extracted with EtOAc (3×50 mL). The combined organics was washed with brine and concentrated to obtain the desired compound (1.0 g, 83%). MS: 267.03 (M+H)+.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=1.[CH:21]1([CH:24]=[O:25])[CH2:23][CH2:22]1>C1COCC1.O>[CH:21]1([CH:24]([C:19]2[C:14]([Cl:13])=[N:15][CH:16]=[N:17][C:18]=2[Cl:20])[OH:25])[CH2:23][CH2:22]1
Reactant: O=CC1CC1
Reactant: Clc1cc(Cl)ncn1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: OC(c1c(Cl)ncnc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
Add slowly n-BuLi (2.37 g, 36.0 mmol) to a cooled solution of diisopropylamine (3.72 g, 36.0 mmol) in 50.0 mL THF at −78° C. under nitrogen atmosphere. Stir the reaction mixture for 30 min at the same temperature, then add 4,6-dichloropyrimidine (5.0 g, 33.0 mmol) dissolved in 15 mL of THF. Stir the resultant reaction mixture for an additional 30 min at −78° C., then add cyclopropane carbaldehyde (2.58 g, 36.8 mmol). Allow the reaction mixture to warm up to room temperature. Add 50.0 mL of water and extract the organic with ethyl acetate (3×50 mL), wash with saturated aqueous sodium chloride, then dry over anhydrous sodium sulfate. Concentrate under reduced pressure under vacuum to give Cyclopropyl-(4,6-dichloro-pyrimidin-5-yl)-methanol (4.0 g, 54% yield). MS (APCI): m/z=220 [M+H]
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:8][C:7]1[C:2]([C:12]2[CH:13]=[C:14]([CH:16]=[CH:17][C:11]=2[CH3:10])[NH2:15])=[N:3][CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: Fc1cnc(Cl)c(F)c1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(N)cc1-c1ncc(F)cc1F

Procedure:
To a round bottom flask is added 2-chloro-3,5-difluoropyridine (1.5 g, 10 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.2 g, 10 mmol), Pd(PPh3)4 (300 mg, 0.26 mmol), toluene (60 mL), ethanol (20 mL) and 2M Na2CO3 (20 mL, 40 mmol). The reaction is stirred under reflux condition for 15 hours. After cooling, the reaction mixture is diluted with ethyl acetate, washed with brine and dried over Na2SO4. The organic phase is then dried by rotary evaporation. The crude product is purified by silica gel flash chromatography to afford 3-(3,5-difluoropyridin-2-yl)-4-methylaniline as a light brown solid. MS m/z 221.1 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:33])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=2)=[O:33])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: O=C(Nc1nc(CCO)cs1)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 12B-a, 86 mg, 0.18 mmol) in diethyl ether (5 mL) was cooled to 0° C. and then treated with lithium aluminum hydride (10 mg, 0.27 mmol). The reaction mixture was slowly warmed to 25° C. where it was stirred for 16 h. At this time, the reaction mixture was slowly diluted with water (5 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-[4-(2-hydroxy-ethyl)-thiazol-2-yl]-2-(4-phenoxy-phenyl)-propionamide (21 mg, 27%) as an off-white solid: FAB-HRMS m/e calcd for C25H28N2O3S (M+H)+ 437.1899, found 437.1900.
Reaction SMILES: [N+:1]([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)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
To a solution of 1-(3-nitrophenyl)piperazine (12.0 g; 58 mmol) in DMF (60 ml) was added sodium hydride (2.55 g; 64 mmol, 60% dispersion in mineral oil) in portions over 30 min. The mixture 20 was kept under nitrogen. Ethyl 2-bromoacetate (7.1 ml; 64 mmol) was added, the mixture was stirred at ambient temperature for one hour and then poured into water (250 ml). The oily precipitate was filtered off, re-dissolved in ethyl acetate and washed with water. The organic phase was dried over magnesium sulphate and evaporated to dryness to leave 6b (11.0 g; 65%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[OH:26])[CH:21]=[C:22]([F:24])[CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([O:26][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: OC(c1cccc(F)c1)c1cc(F)cc(F)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OC(c1cccc(F)c1)c1cc(F)cc(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3,5-difluoro-phenyl)-(3-fluoro-phenyl)-methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].[NH2:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][NH:22]2)=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>CO>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][C:16]2[CH:24]=[C:23]3[C:19]([CH:20]=[N:21][NH:22]3)=[CH:18][CH:17]=2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccc2cn[nH]c2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
To the solution of 4-chloro-2-methylthio-5-pyrimidine carboxylic acid ethyl ester (5 g) and 6-aminoindazole (3.15 g) in methanol (70 ml) was added N,N-diisopropylethylamine (4.2 ml), and then the solution was reacted at 30-35° C. for 4 hr. The reaction mixture was cooled, and then stirred at 20° C. for 1 hr. The reaction mixture was filtered, washed with methanol (20 ml) and dried at 40-50° C. in vacuo to obtain the desired compound (5.8 g, 82%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[O:16]=[C:3]1[C:2]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[NH:4]1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCC3)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.84 mmol) in DMSO (2 mL) was added pyrrolidine (90 mg, 1.27 mmol) and DIEA (163 mg, 1.26 mmol). After stirring overnight at 70° C., the reaction mixture was dissolved in water (50 mL), then filtered to afford methyl 2-oxo-3-(pyrrolidin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (200 mg, 87%).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[C:14]([NH:16][C@@H:17]([C:20](OC)=O)[CH2:18][OH:19])=O)C=CC=CC=1>CCO.CO.[Pd]>[CH2:10]1[C@@H:9]2[CH2:14][NH:16][C@H:17]([CH2:18][OH:19])[CH2:20][N:8]2[CH2:13][CH2:12][O:11]1
Reactant: COC(=O)[C@@H](CO)NC(=O)[C@H]1COCCN1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: OC[C@@H]1CN2CCOC[C@@H]2CN1
Temperature: 50 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
Methyl N-{[(3R)4-(phenylmethyl)-3-morpholinyl]carbonyl}-D-serinate (D48, 3.72 g, 11.55 mmol) was dissolved in EtOH (50 mL), treated with 10% Pd on C (450 mg) then placed under an atmosphere of hydrogen over the weekend. Left stirring for further 6 hours. Added 10% Pd on C (200 mg) and left under an atmosphere of hydrogen overnight. Catalyst removed by filtration through kieselguhr washed with acid, washing well with EtOH. Solvent removed under reduced pressure to afford a colourless oil. Oil dissolved in dry MeOH (15 mL) and heated at 50° C. overnight. Left heating for a further 3 hours before cooling to R.T. Solvent removed under reduced pressure. Residue triturated with DCM to afford the title compound as an off white solid in 35% yield over the 2 steps.
Reaction SMILES: [Cl-].[F:2][C:3]([F:15])([F:14])[S:4]([O:7][C:8]1[CH2:9][CH2:10][NH2+:11][CH2:12][CH:13]=1)(=[O:6])=[O:5].[CH3:16][C@@:17]1([CH2:24][S:25](Cl)(=[O:27])=[O:26])[C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]1>>[F:15][C:3]([F:2])([F:14])[S:4]([O:7][C:8]1[CH2:13][CH2:12][N:11]([S:25]([CH2:24][C@:17]2([CH3:16])[C:21](=[O:22])[NH:20][C:19](=[O:23])[NH:18]2)(=[O:26])=[O:27])[CH2:10][CH:9]=1)(=[O:6])=[O:5]
Reactant: C[C@]1(CS(=O)(=O)Cl)NC(=O)NC1=O
Reactant: O=S(=O)(OC1=CC[NH2+]CC1)C(F)(F)F
Agent: [Cl-]
Product: C[C@]1(CS(=O)(=O)N2CC=C(OS(=O)(=O)C(F)(F)F)CC2)NC(=O)NC1=O

Procedure:
4-{[(Trifluoromethyl)sulfonyl]oxy}-1,2,3,6-tetrahydropyridinium chloride was reacted with [(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methanesulfonyl chloride (Example 1f) in the same way as for Example 1c.
Reaction SMILES: C(OC(=O)[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1)C.CC[O:15][CH2:16][CH3:17].[CH3:18][Mg]Br>O>[CH3:18][C:16]([OH:15])([CH3:17])[C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCOCC
Reactant: C[Mg]Br
Solvent: O
Product: CC(C)(O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 2.76 grams of ethyl-4-iodobenzoate in 10 ml. of ether is placed in a dry flask. The solution is cooled in an ice bath and is stirred. Over a 5 minute period, 26.5 ml. of a 1.52 M ethereal solution of methyl magnesium bromide is added. The solution is stirred for 3 hours while in the ice bath. Water (6 ml.) is added dropwise while stirring. The solution is filtered and the filter cake is washed with six 20 ml. portions of ether. The combined ether phases are dried over magnesium sulfate and filtered. Removal of the ether gives α,α-dimethyl-4-iodobenzyl alcohol as a clear, light yellow liquid.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[CH3:15].Cl[S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:1][CH:2]([CH3:16])[CH2:3][N:4]([C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[CH3:15])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:25][CH:26]=1)(=[O:20])=[O:19]
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(F)(F)F)cc1NCC(C)C
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(S(=O)(=O)N(CC(C)C)c2cc(C(F)(F)F)ccc2C)cc1
Reaction time: 0.5 h

Procedure:
To a solution of (2-methylpropyl)[2-methyl-5-(trifluoromethyl)phenyl]amine (50 mg, 0.216 mmol) in pyridine (5 mL) was added methyl 3-[4-(chlorosulfonyl)phenyl]propanoate (56.8 mg, 0.216 mmol). The mixture was stirred for 30 minutes to ensure dilution, then stood at room temperature, in air, for 16 hours. The solvent was evaporated in vacuo to give the crude product which was purified by MDAP (Method F) to give the required product, 21.5 mg. LCMS (M+1) 458, RT 1.39 mins.