Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18]Cl>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[S:18][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: ClSc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc[nH]c1
Solvent: ClCCl
Product: COC(=O)c1c[nH]c(Sc2ccc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen, methyl pyrrole-3-carboxylate (3.75 g.) was dissolved in 100 ml. of methylene chloride and cooled in an ice-water bath. To the cold, stirred solution, 2,4-dichlorobenzenesulfenyl chloride (6.39 g., 30 mmoles) was added dropwise. The bath was removed and the reaction stirred at room temperature for 1 hour. An equal volume of ether was added, the mixture filtered and the filtrate evaporated in vacuo to crude product (9.0 g., oil). The oil was chromatographed on 300 g. of silica gel with 200 ml. fractions of the ethyl acetate-1/hexane-7 eluant collected. Fractions 6 to 10 were combined and evaporated to yield purified methyl 5-(2,4-dichlorophenylthio)pyrrole-3-carboxylate (3.7 g., solid, m/e 302).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:29]([O:1][CH2:2][C:3]1[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1)([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30]
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a flask containing a solution of methyl 2-(hydroxymethyl)-1-((2-(tri-methylsilyl)-ethoxy)methyl)-1H-imidazole-4-carboxylate (1 g, 3.49 mmol) in DMF (25 ml), imidazole (0.490 g, 6.91 mmol), catalytic DMAP and TBDMSCl (0.790 g, 5.27 mmol) were added. The resulting mixture was stirred at RT for 12 h. The reaction mixture was quenched with saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography. Yield 800 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.04 (s, 9H), 0.05 (s, 6H), 0.80 (t, 2H), 0.86 (s, 9H), 3.49 (t, 2H), 3.74 (s, 3H), 4.71 (s, 2H), 5.41 (s, 2H), 8.02 (s, 1H). LC-MS: [M+1]=401.10.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][C:35]([F:39])([F:38])[CH2:34]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][C:35]([F:38])([F:39])[CH2:34]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CCC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CCC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Reaction time: 1 h
Yield: 43.3 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3,3-difluoropyrrolidin-1-yl)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (91.4 mg, 135 μmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo. 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane was added, and the reaction mixture stirred for 1 h then concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-{5-Difluoromethoxy-1-[3-(3,3-difluoro-pyrrolidin-1-yl)-propyl]-1H-indazol-3-yl}-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (32 mg, 43%). MS (M+H)+=548; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.38 (s, 1H), 8.21 (d, J=2.3 Hz, 2H), 7.88 (s, 2H), 7.86 (s, 1H), 7.36-7.43 (m, 1H), 6.92-7.49 (m, 1H), 4.59 (t, J=6.8 Hz, 2H), 2.84 (t, J=13.6 Hz, 2H), 2.64 (t, J=7.0 Hz, 2H), 2.43 (t, J=6.7 Hz, 1H), 2.15-2.29 (m, 2H), 2.08 (t, J=7.0 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:35](=[O:37])[CH3:36])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:19][C@@H:18]2[CH3:38])=[O:16])=[CH:11][CH:10]=1)=[O:7].[H-].[Na+].I[CH3:43]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:35](=[O:37])[CH3:36])[C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:19][C@@H:18]2[CH3:38])=[O:16])=[CH:13][CH:14]=1)[CH3:43])=[O:7]
Reactant: COC(=O)CCC(=O)Nc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(=O)N(C)c1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
To a solution of (2S,4R)-N-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-succinamic acid methyl ester (55 mg, 0.100 mmoles) in DMF was added sodium hydride (60% dispersion in oil). After 30 minutes, iodomethane (16 uL, 0.11 mmoles) was added to the reaction mixture and stirred at room temperature overnight. Reaction was quenched with water and extracted with ethyl acetate. Combined organics were washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Product was purified on silica gel by flash chromatography using 100% ethyl acetate and 90% ethyl acetate/10% methanol to afford (2S,4R)-N-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-N-methyl-succinamic acid methyl ester (16 mg, 26%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.C(Cl)Cl.[C:15]([Mg]Br)#[CH:16].P([O-])(O)(O)=O.[Na+]>O1CCCC1>[F:11][C:2]([F:10])([F:1])[C:3]1[O:7][C:6]([CH:8]([OH:9])[C:15]#[CH:16])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)o1
Reactant: C#C[Mg]Br
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C#CC(O)c1ccc(C(F)(F)F)o1
Reaction time: 0.25 h

Procedure:
The mixture of approximately 1.78 g of the product of Stage D and approximately 20 ml of methylene chloride was cooled to +5° C. and 27 ml of ethynylmagnesium bromide as a 0.5M solution in tetrahydrofuran were added over 15 minutes. The mixture was stirred for 15 minutes at +5° C., poured into an aqueous sodium dihydrogenphosphate solution and extracted with methylene chloride. The extract was dried, the solvent was evaporated at 30° C. and the residue was chromatographed on silica (eluent: methylene chloride) to obtain 0.87 g of the expected product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](OC(CC(C)C)CCN(CC3C=CC=CC=3)C)=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:27]([O:31][C:32](=[O:46])[N:33]([CH2:35][CH2:36][CH:37]([OH:45])[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)[CH3:34])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:46])[N:33]([CH2:35][CH2:36][CH:37]([O:45][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1)[CH2:38][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)[CH3:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Reactant: CN(CCC(O)CC1CCCCC1)C(=O)OC(C)(C)C
Product: CN(CCC(CC1CCCCC1)Oc1cccc2sccc12)C(=O)OC(C)(C)C

Procedure:
Using a method similar to that for [3-(Benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine, (4-cyclohexyl-3-hydroxy-butyl)-methyl-carbamic acid tert-butyl ester affords the title compound: mass spectrum (ion spray) m/z=418 (M+1); 1H NMR (CDCl3) δ 7.49-7.47 (d, 1H), 7.43-7.41 (d, 1H), 7.31-7.30 (d, 1H), 7.24 (t, 1H), 6.72 (d, 1H), 4.59-4.52 (m, 1H), 3.34-3.27 (m, 2H), 2.80 (s, 3H), 1.98-0.92 (m, 24).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[C:4]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:2].F[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([N:14]2[CH2:13][CH2:12][N:11]([C:4]3[C:5]([NH2:10])=[N:6][C:7]([NH2:9])=[N:8][C:3]=3[CH2:1][CH3:2])[CH2:16][CH2:15]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: N#Cc1ccc(F)cc1
Reactant: CCc1nc(N)nc(N)c1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1nc(N)nc(N)c1N1CCN(c2ccc(C#N)cc2)CC1
Temperature: 140 °C
Yield: 68.3 %

Procedure:
A mixture of 2.2 g (0.010 mole) of 6-ethyl-5-(1-piperazinyl)-2,4-pyrimidinediamine, 1.33 g (0.011 mole) of a 4-fluorobenzonitrile and 1.52 g (0.011 mole) of potassium carbonate in 20 ml of dimethyl sulfoxide was heated under reflux at 140° C. for two hours. The reaction mixture was cooled and poured into 100 ml of ice water. The solid was collected and recrystallized from N,N dimethyl formamide to give 2.21 g of the product as a white solid, mp>310° C.
Reaction SMILES: [CH:1](/[OH:6])=[CH:2]/[CH2:3][CH2:4][OH:5].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Si:12]([O:6][CH2:1]/[CH:2]=[CH:3]\[CH2:4][OH:5])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: O/C=C\CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC/C=C\CO
Temperature: 0 °C
Reaction time: 6 h
Yield: 73 %

Procedure:
To a solution of cis-1,4-butene diol (6) (20.0 g, 227.27 mmol) in dry CH2Cl2 (700 mL) at 0° C. was added imidazole (23.21 g, 340.91 mmol) and tert-butyldimethylsilyl chloride (37.68 g, 250.0 mmol). The reaction mixture was stirred at 0° C. for 6 h. After completion of reaction (monitored by TLC), it was diluted with CH2Cl2 (500 mL) washed with water, brine and dried over anhydrous Na2SO4. Removal of solvent under reduced pressure gave the crude product which was then purified by column chromatography with petroleum ether/EtOAc (9:1 v/v) to give (7) as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14]CC=C)=[CH:9][C:10]=2[O:12][CH3:13])[O:5][C:4](=[O:18])[CH:3]=1.[CH3:19][CH2:20][CH2:21]CCC>CCN(C1C=CC=CC=1)CC>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:21][CH:20]=[CH2:19])[C:8]([OH:14])=[CH:9][C:10]=2[O:12][CH3:13])[O:5][C:4](=[O:18])[CH:3]=1
Reactant: CCCCCC
Reactant: C=CCOc1cc(OC)c2c(C)cc(=O)oc2c1
Solvent: CCN(CC)c1ccccc1
Product: C=CCc1c(O)cc(OC)c2c(C)cc(=O)oc12

Procedure:
A solution of 4-methyl-5-methoxy-7-allyloxycoumarin (XXXVI; 4.0 g) in diethylaniline (80 ml) was refluxed for 3 h. After cooling, n-hexane (400 ml) was added and the precipitate was collected, washed several times with n-hexane and crystallized twice from EtOAc to give 4-methyl-5-methoxy-7-hydroxy-8-allylcoumarin (XXXVII: 2.8 g; m.p. 198° C.) free from its isomer, the 4-methyl-5-methoxy-6-allyl-7-hydroxycoumarin (which during the successive steps can lead to the formation of a linear furocoumarin). ##STR40##
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([C:21]([OH:23])=[O:22])[CH:12]([C:18]([OH:20])=[O:19])[C:13]([C:15]([OH:17])=[O:16])=[CH2:14].OS(O)(=O)=O>O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH:12]([C:18]([OH:20])=[O:19])[CH2:11][C:21]([OH:23])=[O:22]
Reactant: Sc1nc2ccccc2s1
Reactant: C=C(C(=O)O)C(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC(C(=O)O)C(CSc1nc2ccccc2s1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.45 g of 2-mercaptobenzothiazole and 5 g of but-3-ene-1,2,3-tricarboxylic acid are ground together in a mortar. The powdered mixture is introduced in portions into 60 ml of 70% H2SO4 at 48°-50° in the course of 1 hour, with stirring. After a further 3 hours at 48°-50°, the reaction mixture is cooled to room temperature and diluted with 250 ml of water at 25°-30°, with stirring. The aqueous solution is decanted from a little glutinous sediment and diluted with a further 200 ml of water. After stirring for 1 hour, the precipitate is filtered off and dried. The 4-(benzothiazol-2-ylthio)-butane-1,2,3-tricarboxylic acid obtained has a melting point of 188°-190°, after recrystallisation from methanol/water.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@H:35]([C:40](O)=[O:41])[CH2:36][CH:37]([CH3:39])[CH3:38])(OCC1C=CC=CC=1)=O>>[NH2:34][C@@H:35]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:40]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:41]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 5 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-L-leucine as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.18-3.98 (m, 1H), 3.83 (t, 1H), 3.52-3.38 (m, 1H), 3.35-3.20 (m, 1H), 1.95 (br d, 2H), 1.83-1.58 (m, 9H), 1.52 (dd, 2H), 1.42-1.15 (m, 3H), 1.10-0.95 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 41. LCMS m/z: [M+H]+=349.2.
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1.[CH3:14][O:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH2:21][CH:22]1[O:24][CH2:23]1>C(O)C>[CH3:14][O:15][CH2:16][CH2:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[O:20][CH2:21][CH:22]([OH:24])[CH2:23][NH:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: CC(C)(N)COc1ccc(Cl)nn1
Reactant: COCCc1ccccc1OCC1CO1
Solvent: CCO
Product: COCCc1ccccc1OCC(O)CNC(C)(C)COc1ccc(Cl)nn1
Yield: 38.7 %

Procedure:
A mixture of 4.83 g of 3-(2-amino-2-methylpropoxy)-6-chloropyridazine obtained in Example 1(a), 5.0 g of 1-[2-(2-methoxyethyl)phenoxy]-2,3-epoxypropane and 200 ml of ethanol was refluxed for 4 hours, and the solvent was evaporated under reduced pressure. A solution of the residue in benzene was extracted with 1N hydrochloric acid. The aqueous layer was extracted with chloroform, washed successively with 5% sodium carbonate and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated to give 3.8 g of 1-[2-(2-methoxyethyl)phenoxy]-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinyloxy)ethylamino]-2-propanol.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[N:13]([CH3:17])[CH2:14][CH2:15]O>C(Cl)Cl.CN(C=O)C>[Br:12][C:10]1[CH:11]=[C:6]([NH2:5])[C:7]([N:13]([CH2:14][CH2:15][Cl:3])[CH3:17])=[CH:8][CH:9]=1
Reactant: CN(CCO)c1ccc(Br)cc1N
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCCl)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Thionyichloride (0.78 g, 6.74 mmol) was added dropwise to a solution of 2-((2-amino-4-bromophenyl)(methyl)amino)ethanol (25C) (1.376 g, 5.62 mmol) in DCM (50 mL) and DMF (10 drops) at 0° C. The mixture was allowed to warm up to rt and stirred for 1 hour. Then, the mixture was heated to 35° C. for 2.5 hours, concentrated, diluted with 1N NaOH, and extracted with DCM. The organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with a gradient of PE:EtOAc 100:0-85:15, to provide 0.611 g (41%) of the desired product 4-bromo-N1-(2-chloroethyl)-N1-methylbenzene-1,2-diamine (25D): 1H NMR (300 MHz, CDCl3) δ 6.88-6.79 (3H, m), 4.20 (2H, bs), 3.56 (2H, t), 3.17 (2H, t), 2.67 (3H, s).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO>[CH3:13][O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH:9]=1)=[O:12]
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc2nc[nH]c2c1

Procedure:
To a suspension of benzimidazole-5-carboxylic acid (100 mg, 0.616 mmol, 1 eq) in MeOH (4 mL) was added a 2N solution of trimethylsilyldiazomethane in hexanes (3×0.3 mL, 1.8 mmol, 3 eq). Nitrogen evolution was evident. Eventually a yellow color persisted. The reaction was quenched by the addition of a small amount of acetic acid. The MeOH was removed under reduced pressure and the mixture was purified by preparative thin layer chromatography (eluted with 7% MeOH in CH2Cl2) giving 66 mg of the desired product.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C(Br)c1ccc(OC)cc1
Reactant: Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C(Nc1ccccc1)c1ccc(OC)cc1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
Methyl 2-bromo-2-(4-methoxyphenyl)acetate (1.10 g, 4.25 mmol), DIPEA (0.89 mL, 5.09 mmol), and aniline (0.43 mL, 4.67 mmol) are dissolved in acetonitrile (12 mL). The reaction is heated for 18 minutes at 100° C. under microwave irradiation. Acetonitrile is evaporated and the residue is diluted with DCM and washed with water and brine, dried over Na2SO4, filtered and evaporated to dryness. The crude is purified by flash chromatography (Petroleum Ether/EtOAc=9/1) to give intermediate I139 as a yellow oil (745 mg, 65% yield).
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:30])[C:13]([CH2:28][OH:29])([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:33](I)[CH3:34]>O1CCCC1>[C:1]12([NH:11][C:12](=[O:30])[C:13]([CH2:28][O:29][CH2:33][CH3:34])([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)C(CO)(Cc1ccncc1)Cc1ccncc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
To a well-stirred suspension of N-adamantan-1-yl-2-hydroxymethyl-3-pyridin4-yl-2-pyridin-4-ylmethyl-propionamide (40 mg, 0.1 mmol) in anhydrous tetrahydrofuran (0.50 ml), sodium hydride (7.8 mg of 60% mineral oil dispersion; 0.2 mmol of sodium hydride) was added. After stirring at ambient temperature for 15 minutes, ethyl iodide (15.8 μl, 0.20 mmol) was added. After stirring for 2 hours at ambient temperature, the reaction was quenched by the addition of dilute aqueous sodium bicarbonate/methylene chloride (10 ml of each). The mixture was then extracted with three 10 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil (54 mg). Flash chromatography (silica gel, 40 micron mesh; elution with methanol/ethyl acetate=1:9 in volume) afforded the title compound (free base) (19 mg) as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:15]=3[N:16]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>CN(C=O)C>[CH2:34]([O:33][C:31]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[C:15]3[N:16]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[S:9][C:10]=3[N:11]=[C:12]([NH2:23])[N:13]=2)[CH2:22][CH2:21]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)sc2n1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Nc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)c2nc(-c3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 2-(4-fluorophenyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine (50 mg, 0.15 mmol) and pyridine (18 μl, 0.23 mmol) in DMF (1 ml) was added benzyl chloroformate (24 μl, 0.17 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched with water, extracted with EtOAc, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 100:1) to yield the title compound as a white solid (54 mg, 77%).
Reaction SMILES: [F:1][C:2]1([CH2:18][OH:19])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:1][C:2]1([CH2:18][O:19][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(F)(CO)CC1
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(F)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of benzyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 3.7 mmol) in CH2Cl2 (10 mL) at RT was added MsCl (0.29 mL, 3.7 mmol) and TEA (1.04 mL, 7.5 mmol). The reaction mixture was stirred at RT for 5 min, and partitioned between EtOAc and H2O. The organic layer was dried over Na2SO4, filtered, concentrated and purified on silica gel (10:1 to 1:2 hexanes:EtOAc) to give benzyl 4-fluoro-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate.
Reaction SMILES: O[CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[Br:16][C:17]1[CH:18]=[N:19][NH:20][CH:21]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCCC1>[Br:16][C:17]1[CH:18]=[N:19][N:20]([CH2:2][C@H:3]2[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]2)[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Reactant: Brc1cn[nH]c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Br)cn2)C1
Reaction time: 192 h

Procedure:
Tetrahydrofuran was added to a mixture of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (250 mg, 1.15 mmol), 4-bromo-1H-pyrazole (186 mg, 1.27 mmol), di-tert-butyl azodicarboxylate (530 mg, 2.30 mmol), and triphenylphosphine resin (3 mmol/g loading, 601 mg, 2.30 mmol) under argon. The resulting suspension was stirred for 8 days and then filtered through CELITE. The supernatant was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel (5-100% ethyl acetate/hexanes) to afford tert-butyl (2S)-2-[(4-bromo-1H-pyrazol-1-yl)methyl]morpholine-4-carboxylate. ESI calc'd. for C9H13BrN3O3 [M+H t-Bu]+ 289 and 291. found 289 and 291. 1H NMR (500 MHz, CDCl3) δ 7.49 (s, 1H), 7.46 (s, 1H), 4.22-4.08 (m, 2H), 4.04-3.78 (m, 3H), 3.76-3.69 (br s, 1H), 3.52-3.46 (m, 1H), 2.99-2.82 (br s, 1H), 2.63-2.51 (br s, 1H), 1.45 (s, 9H).