Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[C:11]([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:17]([C:28](O)=[O:29])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12].Cl.[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[C:37]([C@@H:39]([NH:41][C:42](=[O:44])[CH3:43])[CH3:40])[CH:38]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O>[C:11]([N:15]1[CH2:19][C@@H:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])[C@H:17]([C:28]([N:48]2[CH2:47][CH2:46][CH:45]([C:36]3[CH:35]=[CH:34][C:33]([Cl:32])=[CH:38][C:37]=3[C@@H:39]([NH:41][C:42](=[O:44])[CH3:43])[CH3:40])[CH2:50][CH2:49]2)=[O:29])[CH2:16]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCNCC1
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)N[C@@H](C)c1cc(Cl)ccc1C1CCN(C(=O)[C@@H]2CN(C(C)(C)C)C[C@H]2c2ccc(F)cc2F)CC1
Reaction time: 18 h
Yield: 99.1 %

Procedure:
N,N-diisopropylethylamine (5.86 mL, 33.6 mmol) was added to a stirred suspension of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid hydrochloride (3-9) (3.07 g, 9.61 mmol), N-[(1S)-1-(5-chloro-2-piperidin-4-ylphenyl)ethyl]acetamide hydrochloride (3.05 g, 9.61 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate (4.38 g, 11.5 mmol) in N,N-dimethylfoimamide (20 mL) at ambient temperature. After approximately 18 h, the reaction mixture was poured water and extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) provided 3-10 (5.2 g) as a foam m/z (ES) 546 (MH+).
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C:15](=O)[CH2:14][O:13][C@@H:12]([CH3:17])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[O:1]([CH2:9][C@H:10]1[C:15](=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][O:13][C@@H:12]([CH3:17])[O:11]1)[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: C[C@@H]1OCC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CO[C@@H](C)O[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.9 %

Procedure:
A mixture of (2R,4S)-4-t-butyldimethylsiloxymethyl -2-methyl-1,3-dioxan-5-one (2.50 g) and carboethoxymethylenetriphenylphosphorane (4.00 g) in tetrahydrofuran (25 ml) was stirred at room temperature for 24 hours and the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column (50 g) with a mixture of n-hexane and ethyl acetate (10:1) as an eluent to give (2R,4R)-4-t-butyldimethylsiloxymethyl-5-ethoxycarbonylmethylene-2-methyl-1,3-dioxane (2.09 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([O:36][CH3:37])[CH:28]=1>CN(C=O)C>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:29]([O:36][CH3:37])[CH:28]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using DMF as reaction solvent. Off-white solid (38%). MS (ESI): m/z=473.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4](O)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: CSc1ncc(C#N)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc(C#N)c(Cl)n1
Temperature: 25 °C

Procedure:
A mixture of 5-cyano-4-hydroxy-2-methylsulfanyl-pyrimidine (48.33 g) from Example 1 and phosphorus oxychloride (150 mL) was heated at reflux for 3 hours. The reaction mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated to dryness under vacuum. The residue was partitioned between methylene chloride and ice water. The organic layer was separated, washed with water, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was heated to reflux in hexane (750 mL) w ith stirring. Th e hot hexane so lution was decanted from the insoluble material and allowed to cool to room temperature to afford 32 g of the title compound 4-chloro-5-cyano-2-methylsulfanyl-pyrimidine.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1.[CH3:25]CO>>[CH2:9]([N:8]([CH2:25][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CCO
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: c1ccc(CN(Cc2ccccc2)Cn2nnc3ccccc32)cc1
Reaction time: 24 h

Procedure:
H-Benzotriazole-l-methanol (51.0 g, 0.342 mol) was weighed into a round bottom flask and solubilized in EtOH (800 mL). Dibenzylamine (67.5 g, 0.342 mol) was added slowly (over 5 min) to the rapidly stirred solution. Formation of a white precipitate was observed shortly after starting addition. The solution was abandoned to stir for 24 h. At this time the reaction is judged complete by NMR (product fragments on LCMS to show only benzotriazole). The majority of the solvent was removed by rotovap and diethyl ether (1 L) was added to the residue with vigorous stirring. This mixture was filtered, the filtrand washed with ether and dried under vacuum to yield N-(dibenzylaminomethyl)benzotriazole as a fluffy white solid (112 g, quat. yield). 1H NMR (400 MHz, chloroform-d) δ ppm 3.80 (s, 4 H) 5.48 (s, 2 H) 7.21 (d, J=8.34 Hz, 1 H) 7.34-7.43 (m, 11 H) 7.49 (d, 1 H) 8.09 (d, J=7.83 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([CH2:25][CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32](Cl)=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[CH:23][CH:22]=1>CS(C)=O.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH2:26][NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:2]=3[Cl:1])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[O:39])=[CH:40][CH:41]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2[N+](=O)[O-])c(Cl)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
Methyl 2-(3-chloro-4-hydroxyphenyl)acetate (177 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K2CO3 (122 mg, 0.885 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (300 mg, 0.885 mmol) (synthesized in step C). The reaction was heated to 85° C. and stirred for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over H2SO4, filtered and concentrated. The material was purified using a biotage 40S cartridge eluting with DCM:MeOH (99:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3-chlorophenyl)acetate (206 mg, 46.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:21][CH:22]([CH2:25][OH:26])[CH2:23][OH:24])=[O:15])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Br)cc1
Reactant: NC(CO)CO
Product: COc1ccc(C(=O)NC(CO)CO)cc1/C=C/c1ccc(Br)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-bromophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-43 and 2-amino-1,3-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][C:11]([OH:13])=O)[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][C:19]=1[O:31][CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][C:11]([N:27]3[CH2:28][CH2:29][C:24]([C:21]4[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([O:31][CH3:32])[CH:20]=4)([OH:30])[CH2:25][CH2:26]3)=[O:13])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C2(O)CCNCC2)ccc1Cl
Reactant: O=C(O)Cn1c(=O)oc2cc(Cl)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C2(O)CCN(C(=O)Cn3c(=O)oc4cc(Cl)ccc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(6-chloro-2-oxobenzo[d]oxazol-3(2H)-yl)acetic acid (22.7 mg, 0.1 mmol, 1 equiv), 4-(4-chloro-3-methoxy-phenyl)-piperidin-4-ol hydrochloride (69) (27.7 mg, 1 equiv), BOP (58 mg, 1.3 equiv), triethylamine (56 μL, 4 equiv) in 1 ml of DMF was stirred at room temperature for overnight. The solution was then diluted with EtOAc (50 mL) and washed with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography to provide 6-chloro-3-{2-[4-(4-chloro-3-methoxy-phenyl)-4-hydroxy-piperidin-1-yl]-2-oxo-ethyl}-3H-benzooxazol-2-one (70): MS (ES) [M+H]+ expected 451.1, found 451.1.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:13][C:14]([C:16]2(CC(Cl)=C)[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[C:9]([NH:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.[O:31]=[O+][O-].C[C:35]([CH3:37])=[O:36]>>[C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([NH:13][C:14]([C:16]2([CH2:37][C:35]([OH:31])=[O:36])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[C:9]([NH:11][CH3:12])=[O:10])=[CH:3][CH:2]=1
Reactant: C=C(Cl)CC1(C(=O)N[C@@H](Cc2ccc(-c3ccccc3)cc2)C(=O)NC)CCCC1
Reactant: CC(C)=O
Reactant: O=[O+][O-]
Product: CNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)C1(CC(=O)O)CCCC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)—N-(3-(biphenyl-4-yl)-1-(methylamino)-1-oxopropan-2-yl)-1-(2-chloroallyl)cyclopentanecarboxamide (38 mg, 0.09 mmol) in acetone (5 mL) at −78° C. was bubbled ozone for 1 minute with a persistent pale blue color. The mixture was stirred at −78° C. for 5 minutes. To the mixture was bubbled oxygen for 10 minutes then added dimethyl sulfide (0.5 mL) followed by 1 mL of water. The mixture was stirred for 1 hr at room temperature and concentrated under reduced pressure. The obtained mixture was diluted in EtOAc and acidified with 1 M HCl. The organic layer was washed with water, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified with RP-HPLC (SunFire C8, H2O (0.1% TFA)/CH3CN) to give (S)-2-(1-(3-(biphenyl-4-yl)-1-(methylamino)-1-oxopropan-2-ylcarbamoyl)cyclopentyl)acetic acid (27 mg). HPLC retention time=1.44 minutes (condition B); MS (m+1)=409.0; 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 1.33-1.63 (m, 6H), 1.72-1.94 (m, 2H), 2.60 (d, J=16.4 Hz, 1H), 2.73 (d, J=4.8 Hz, 3H), 2.73 (d, J=16.4 Hz, 1H), 2.97 (dd, J=14.1, 10.4 Hz, 1H), 3.39 (dd, J=14.1, 4.5 Hz, 1H), 4.58-4.76 (m, 1H), 6.70 (d, J=7.6 Hz, 1H), 7.09 (br. s., 1H), 7.34 (d, J=8.3 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 7.43-7.51 (m, 2H), 7.59 (d, J=8.1 Hz, 2H), 7.62-7.67 (m, 2H).
Reaction SMILES: [O-]CC.[Na+].Cl[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[N+:16]([CH:19]([CH3:21])[CH3:20])([O-:18])=[O:17]>C(O)C>[CH3:20][C:19]([N+:16]([O-:18])=[O:17])([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(Cc1ccc([N+](=O)[O-])cc1)[N+](=O)[O-]
Yield: 76 %

Procedure:
To a solution of sodium ethoxide (3.5 g, 50 mmol) in ethanol (100 mL), 1-(chloromethyl)-4-nitrobenzene (8.6 g, 50 mmol) and 2-nitropropane (2.2 g, 250 mmol) were added at room temperature, and the mixture was heated under reflux for 18 hours. The reaction solution was filtered, concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain 1-(2-methyl-2-nitropropyl)-4-nitrobenzene (8.52 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:25]1[CH:26]=[CH:27][C:28]2[S:32][CH:31]=[CH:30][C:29]=2[CH:33]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:25]2[CH:26]=[CH:27][C:28]3[S:32][CH:31]=[CH:30][C:29]=3[CH:33]=2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCOC(=O)C(N)c1ccc2sccc2c1
Product: CCOC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1ccc2sccc2c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and ethyl 2-amino-2-(benzothiophen-5-yl)acetate (prepared as described in S. Kukolja et al., J. Med. Chem., 1985, 28, 1896-1903), the title compound was prepared as a solid (mp=126.5-127.5° C.). The product was purified by preparative LC 2000 chromatography using 1:1 hexanes/EtOAc as the eluent.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.C(OCC)C>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:2]4[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=C(C1CCNCC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reactant: Cc1nccc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nccc(N2CCC(C(=O)N3CCN(S(=O)(=O)c4ccc(Br)cc4)CC3)CC2)n1
Yield: 30 %

Procedure:
4-Chloro-2-methylpyrimidine (135 mg) was added to a solution of 1-(4-bromophenylsulphonyl)-4-(4-piperidylcarbonyl)piperazine (415 mg) in THF (15 ml) containing triethylamine (0.2 ml). The mixture was heated under reflux for 16 hours. After cooling, the THF was evaporated. The residue was treated with H2O(20 ml) and the aqueous extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with saturated brine (1×20 ml) dried and evaporated to give an oil which was purified by chromatography on silica gel. Elution with dichloromethane/methanol/0.88 NH3 (96:3:1) gave an oil. Trituration with diethyl ether (10 ml) gave, as a colourless solid, l-(4-bromophenylsulphonyl)-4-[1-(2-methylpyrimidyl)-4-piperidylcarbonyl]piperazine (152 mg), mp 200-202° C.; NMR: 1.39-1.48 (m, 2H), 1.55-1.69 (m, 2H), 2.30 (s, 3H), 2.80-3.00 (m, 7H), 3.45-3.67 (m, 4H), 4.32 (m, 2H), 6.57 (d, 1H), 7.65 (d, 2H), 7.83 (d, 2H), 8.03 (d, 1H); EI-MS m/z 508 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38](O)=[O:39])=[CH:32][CH:31]=1)(=[N:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]3[O:25][CH:26]=[CH:27][C:28]=3[CH3:29])=[O:23])[CH:16]=2)[CH:12]=1)=[O:6])=[O:3].[CH3:41][NH:42][CH2:43][CH:44]([OH:47])[CH2:45][OH:46]>>[OH:47][CH:44]([CH2:45][OH:46])[CH2:43][N:42]([CH3:41])[C:38](=[O:39])[CH2:37][CH2:36][C:33]1[CH:32]=[CH:31][C:30]([S:2]([CH3:1])(=[O:3])=[N:4][C:5](=[O:6])[C:7]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([C:24]4[O:25][CH:26]=[CH:27][C:28]=4[CH3:29])=[O:23])[CH:16]=3)[CH:10]=[N:9][CH:8]=2)=[CH:35][CH:34]=1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)O)cc3)c2)c1
Reactant: CNCC(O)CO
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(C)(=O)c3ccc(CCC(=O)N(C)CC(O)CO)cc3)c2)c1
Yield: 34.6 %

Procedure:
In a manner similar to that described in Example 485, 3-[4-(S-methyl-N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}-ethynyl)pyridin-3-yl]carbonyl}sulfonimidoyl)-phenyl]propanoic acid (0.050 g, 0.090 mmol) and 3-methylamino-propane-1,2-diol (0.050 mL, 0.520 mmol) were reacted to give the title compound (0.020 g, 35%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31].[CH:32](=O)[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[F:31])[CH3:33]
Reactant: CC=O
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCNc1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Reaction time: 1 h

Procedure:
cis-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.177 mmol) was suspended in 1,2-dichloroethane (6 mL). A solution of acetaldehyde (12 mg, 0.266 mmol) in 1,2-dichloroethane (0.300 mL) and acetic acid (42 mg, 0.708 mmol) was added and the mixture was stirred for 1 hour. Sodium triacetoxyborohydride (75 mg, 0.354 mmol) was added. After 16 hours, more sodium triacetoxyborohydride (37 mg, 0.175 mmol) was added and the reaction continued for another 3 hours. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in dichloromethane (75 mL) then washed with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product (80 mg) was collected as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:31])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]4=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[OH:32].[CH:33](OC)(OC)[O:34]C.CC(O)=O.[O:44]1[CH2:47][C:46](=O)[CH2:45]1>CO.CN(C=O)C>[Cl:31][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][C@H:2]3[N:1]([CH:46]4[CH2:45][O:44][CH2:47]4)[C:33](=[O:34])[O:32][C@@H:3]3[CH2:4]2)=[CH:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=1[NH:16][C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]2=[N:26][CH:27]=[C:28]([C:29]#[N:30])[N:19]2[N:18]=1
Reactant: COC(OC)OC
Reactant: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](N)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Reactant: O=C1COC1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H]4[C@@H](C3)OC(=O)N4C3COC3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(+/−)-2-((3-((3R,4R)-4-amino-3-hydroxypiperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg, 0.177 mmol) was taken up in MeOH (1.0 mL) and DMF (1.0 mL) and trimethyl orthoformate (1.464 mL, 13.25 mmol), AcOH (0.040 mL, 0.707 mmol), and oxetan-3-one (0.113 mL, 1.766 mmol) were added. The reaction was stirred at room temperature for 2 h, then NaCNBII3 (111 mg, 1.766 mmol) was added and the reaction stirred at 25° C. overnight.
Reaction SMILES: CNC1[C:8](C(O)=O)=[CH:7][N:6]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1.[CH3:18][N:19]([CH3:22])[CH:20]=[O:21].C1(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(N(CC)CC)C>[CH3:18][N:19]1[C:20](=[O:21])[NH:37][C:8]2[C:22]1=[N:4][C:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[N:6][CH:7]=2
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CNc1nc(-c2ccccc2)ncc1C(=O)O
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(=O)[nH]c2cnc(-c3ccccc3)nc21
Reaction time: 0.17 h

Procedure:
To a mixture of 4-methylamino-2-phenylpyrimidine-5-carboxylic acid (7 g) and dimethylformamide (50 ml) is added triethylamine (3.1 g) at room temperature, and the mixture is stirred for 10 minutes, and thereto is added diphenylphosphoryl azide (8.4 g) at the same temperature. The reaction mixture is stirred at 120° C. for four hours, and concentrated under reduced pressure. The residue is poured into ice-water, and the precipitates are collected by filtration, washed with water, washed with ethanol, and recrystallized from chloroform to give the desired compound (5 g).
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)=[CH:9][N:8]=1>C1COCC1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[O:15][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[C:7]([S:5][CH2:3][CH3:4])=[N:8][CH:9]=1
Reactant: CCS
Reactant: N#Cc1cc(Oc2ccc(Cl)c(Cl)c2)cnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCSc1ncc(Oc2ccc(Cl)c(Cl)c2)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
THF (25 ml), and NaOH (0.8 g) were mixed in a reaction flask to which was added 1.24 g of ethanethiol (previously chilled in an ice-salt bath). This mixture was stirred at room temperature until all of the NaOH was dissolved. Separately, 4.5 g of 2-chloro-5-(3,4-dichlorophenoxy)-3-pyridinecarbonitrile was dissolved in 25 ml of THF and then added to the previously prepared ethanethiol mixture. This combination was then stirred at room temperature for 30 minutes and then heated to boiling for 2 hours after which it was allowed to cool and then poured into 300 g of ice. A precipitate formed which was collected by filtration and subsequently recrystallized from a CH2Cl2 /hexane mixture to give 4.3 g of the desired 5-(3,4-dichlorophenoxy)-2-ethylthio-3-pyridinecarbonitrile, m.p. 80°-81° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:14](=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: CNCc1sc2ccccc2c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1sc2ccccc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine (1.95 g, 11.4 mmol) in CH2Cl2 (40 mL) was treated with acryloyl chloride (1.2 mL, 14 mmol) and triethylamine (3.2 mL, 22 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with CH2Cl2 (100 mL). The solution was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (silica gel, EtOAc/hexanes, 40/60) gave the title compound (2.10 g, 75%) as a pale yellow solid: MS (ESI) m/e 246 (M+H)+.