Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C:33](=[O:45])[CH2:34][C:35](=[O:44])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C>C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:31][CH2:32][C@@H:33]([OH:45])[CH2:34][C@@H:35]([OH:44])[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:10]([CH:28]([CH3:30])[CH3:29])=[C:11]([C:19](=[O:27])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCC(=O)CC(=O)CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
An argon inerted reactor was charged with 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dioxo-heptanoic acid, t-butyl ester (V-A, 100.0 mmol, prepared as indicated in U.S. Pat. No. 6,476,235) and toluene (245 ml). To the reaction mixture was added triethyl amine (55 ml), followed by slow addition of formic acid (7.5 ml). The vessel and its contents was degassed via three vacuum/argon purges. Under a steady flow of argon, the complex of Ruthenium, [N-[(1R,2R)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2,3,4,5,6-η)-1,3,5-trimethylbenzene]-(1.25 g) was added, and the vessel and its contents were degassed via one vacuum/argon purge. The reaction mixture was stirred for 24 hours and condensed to a foamy solid. The crude (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid, t-butyl ester may be carried on through subsequent steps without purification, or optionally, can be isolated via flash column chromatography on silica gel, eluting with ethyl acetate-heptane mixtures. HPLC analysis (YMC ODS AQ S5; 1 ml/min; 30° C.; 254 nm: CH3CN/H2O w/0.1% formic acid, 60:40 (0–5 min) to 100:0 (15–22 min) to 60:40 (25 min) indicated a syn:anti ratio of 6:1 tr(syn)=13.9 min tr(anti)=13.5 min
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)[CH3:2].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: Oc1ccccc1Br
Reactant: CCc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
To a solution of 2-ethylphenylboronic acid (4.50 g, 30 mmol), 2-bromophenol (3.54 g, 20 mmol), and Cu(OAc)2 (1.86 g, 10 mmol) in anhydrous CH2Cl2 (50 mL) were added activated 4 Å molecular sieves (˜0.5 g), followed by anhydrous Et3N (7.0 mL, 50 mmol). The resulting dark green solution was stirred at rt for 48 h. The solvent was removed under vacuum and the residue was triturated several times with ether (˜200 mL). The combined organic solutions were washed with satd aq NH4Cl, and 1 N aq HCl aqueous solution, and solvent was removed under vacuum to give a crude product. Flash column chromatography gave 1-bromo-2-(2-ethylphenoxy)benzene (1.72 g, 31%) as a clear oil; 1H NMR (CDCl3, 400 MHz) δ: 7.62 (dd, 1H), 7.28 (m, 1H), 7.22-7.08 (m, 3H), 6.96 (m, 1H), 6.78 (m, 2H), 2.64 (q, 2H), 1.22 (t, 3H); MS no ionization was observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[CH:6][CH2:7]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: ClCC=Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(Cl)c1)CC2
Yield: 20 %

Procedure:
Prepared from 3-chloro-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform in the presence of 1 equivalent of potassium carbonate. Yield: 20% of theory, Melting point: 132°-136° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23](C#N)#[N:24].N1C=CC=CC=1.CN1CCCC1=O>Cl>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:24]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(Br)cc3)CC2)CC1
Reactant: N#CC#N
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)CC1

Procedure:
A mixture of 36.3 g of trans-1-p-bromophenyl-4-(trans-4-propylcyclohexyl)-cyclohexane, 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated to 160° for 2 hours. The mixture is cooled, a solution of 120 g of FeCl3.6H2O in 600 ml of 20% hydrochloric acid and the mixture is warmed to 70° for 1.5 hours, while stirring, and worked up in the customary manner to give trans-1-p-cyanophenyl-4-(trans-4-propylcyclohexyl)-cyclohexane, m.p. 55°, c.p. 184°.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(N(CC)CC)C.Cl.[C:32]1([CH3:46])[CH:37]=[CH:36][C:35]([C:38]2([C:41](=N)OCC)[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C(O)(=O)C>C(O)C>[N:19]1([C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:11]([C:7]3[N:8]=[C:9]4[NH:10][C:41]([C:38]5([C:35]6[CH:34]=[CH:33][C:32]([CH3:46])=[CH:37][CH:36]=6)[CH2:39][CH2:40]5)=[N:3][C:4]4=[CH:5][CH:6]=3)[CH2:12]2)=[O:18])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(c2ccc(C)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)cc1
Temperature: 130 °C

Procedure:
To a suspension of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (220 mg, 0.60 mmol) in ethanol (2 mL) was added triethylamine (250 μL, 1.8 mmol), a solution of ethyl 1-(p-tolyl)cyclopropanecarbimidate hydrochloride (140 mg, 0.58 mmol) in ethanol (1 mL), and acetic acid (0.5 mL, 8.70 mmol). The reaction mixture was heated in a microwave for 45 min at 130° C. The solvent was removed under reduced pressure. Ethyl acetate (10 mL) was added to the residue and the solution was washed with aqueous sodium hydroxide (1N, 5 mL). The aqueous layer was extracted with ethyl acetate (10 mL×3). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 430.2; HPLC retention time 2.51 min (Method A).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]([C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=2)[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=O)=O.Cl.[CH3:31][NH:32][CH3:33].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:31][N:32]([CH3:33])[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]([C:22]2[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[CH:24][N:23]=2)[C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: CNC
Reactant: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of 2-[1-(4-cyanopyridin-2-yl)-5-[(4-fluorophenyl)methoxy]pyrazol-4-yl]ethyl methanesulfonate (42 mg, 0.1 mmol) and dimethylamine hydrochloride (41 mg, 0.5 mmol) in ACN (3 mL) was added K2CO3 (276 mg, 2 mmol) and KI (62 mg, 0.4 mmol) at rt. The reaction mixture was heated to 80° C. and stirred overnight. Filtered, solvent removed and purified by prep-HPLC to give the title compound (16 mg, 44%). 1H NMR (400 MHz, CDCl3): δ 2.45 (6H, s), 2.56-2.61 (2H, m), 2.69-2.73 (2H, m), 5.16 (2H, s), 7.03-7.07 (2H, m), 7.35-7.41 (3H, m), 7.53 (1H, s), 8.03 (1H, s), 8.64 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H20FN5O, 366; Found, 366.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23]#[C:24][C:25]2(O)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:12]=[N:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.O>ClCCl>[CH2:16]([O:15][C:14]1[N:13]=[N:12][C:11]([C:23]#[C:24][C:25]2[CH2:30][CH2:29][O:28][CH2:27][CH:26]=2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)CCOCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C(#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)C1=CCOCC1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
4-{2-[5,6-bis(Benzyloxy)pyridazin-3-yl]ethynyl}oxan-4-ol (Intermediate 59; 2.0 g, 4.8 mmol) was dissolved in dichloromethane (20 ml). Triethylamine (2.94 g, 28.82 mmol, 6.0 equiv.) was added to the clear solution followed by the addition of methanesulfonyl chloride (1.64 g, 14.42 mmol, 3.0 equiv.) at room temperature. The reaction mixture was stirred for an hour at room temperature before the reaction mass was poured into water (200 ml) and product was extracted into ethyl acetate (100 ml×2). The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated in vacuo to get the crude title compound (1.0 g, 52% yield) which was used as such for the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][S:6][C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][S:6]([C:7]1[CH:16]=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1)=[O:30]
Reactant: CN(C)c1ccccc1CSc1cnc2ccccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccccc1CS(=O)c1cnc2ccccc2n1
Yield: 21.3 %

Procedure:
In 50 ml of chloroform was dissolved 1.47 g of 2-(2-dimethylaminobenzylthio)quinoxaline. To the chilled solution kept at --10° C. was portionwise added 1.54 g of m-chloroperbenzoic acid (purity: 80%). To the reaction liquid were washed successively with saturated aqueous NaHCO3 solution, water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (hexane/acetone) to give 330 mg of 2-(2-dimethylaminobenzylsulfinyl)quinoxaline as a yellow powder, m.p. 114°-115° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])[CH2:14][NH:13][C:12]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:42]1([S:48](Cl)(=[O:50])=[O:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[CH2:20][CH2:19]2)=[O:17])[CH2:14][N:13]([S:48]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:50])=[O:49])[C:12]1=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CNC(=O)N3C(=O)OCc3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3C(=O)OCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (S)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-2-oxo-imidazolidine-1-carboxylic acid benzyl ester (1.0 g), N-ethyl-diisopropylamine (0.43 mL) and 4-dimethylaminopyridine (0.14 g) in dichloromethane (15 mL) was added benzenesulfonyl chloride (0.35 mL) at 0° C. The mixture was stirred at ambient temperature for 3 h, a diluted aqueous solution of NaHCO3 was added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography (SiO2, dichloromethane/methanol 98:2) to yield (S)-3-benzenesulfonyl-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-2-oxo-imidazolidine-1-carboxylic acid benzyl ester (1.08 g) as a white solid. MS: 576.8, ([M+H]+)
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]([O:11][CH2:12][CH2:13][CH3:14])=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Br:15]CC1C(C(OCCC)=O)=CC=CC=1.BrCC1C(C(Cl)=O)=CC=CC=1.C1(C)C(C([O-])=O)=CC=CC=1.[Br-].CO[C:53]([C:55]1C=CC=C[C:56]=1[CH2:57][P+:58](CCCC)([CH2:63][CH2:64][CH2:65][CH3:66])[CH2:59][CH2:60][CH2:61][CH3:62])=O>C(O)CC>[Br-:15].[CH2:12]([O:11][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][P+:58]([CH2:59][CH2:60][CH2:61][CH3:62])([CH2:63][CH2:64][CH2:65][CH3:66])[CH2:57][CH2:56][CH2:55][CH3:53])=[O:10])[CH2:13][CH3:14]
Reactant: CCCOC(=O)c1ccccc1CCl
Reactant: CCCC[P+](CCCC)(CCCC)Cc1ccccc1C(=O)OC
Reactant: CCCOC(=O)c1ccccc1CBr
Agent: Cc1ccccc1C(=O)[O-]
Agent: O=C(Cl)c1ccccc1CBr
Agent: [Br-]
Solvent: CCCO
Product: CCCC[P+](CCCC)(CCCC)Cc1ccccc1C(=O)OCCC

Procedure:
Using the procedure of Example V, but substituting a mixture of propyl α-chloro-o-toluate and propyl α-bromo-o-toluate, prepared from propyl alcohol and α-bromo-o-toluoyl chloride, for the toluate mixture of Example V provides an oil which upon triturating several times with ether and precipitating as an oil from ethyl acetate with ether and drying yields 18.7 g of o-propoxycarbonylbenzyltributylphosphonium bromide, an oil having a structure in accordance with formula (1) which is confirmed by nmr spectral analysis.
Reaction SMILES: BrC1[N:7]=[C:6]([CH2:8][O:9][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[CH:4]C=1.C1(S)C=CC=CC=1.[S:34]1[CH:38]=[CH:37][N:36]=[C:35]1CC(=O)C.[CH3:43][CH2:44][C:45](=[O:48])[CH2:46][CH3:47]>>[OH:48][C:45]([C:46]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:47]=1)([C:35]1[S:34][CH:38]=[CH:37][N:36]=1)[CH2:44][CH3:43]
Reactant: CC(C)(C)[Si](OCc1cccc(Br)n1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Cc1nccs1
Reactant: CCC(=O)CC
Agent: Sc1ccccc1
Product: CCC(O)(c1cccc(CO)n1)c1nccs1

Procedure:
Following the procedure described for Phenol 2, Step 2 and for Phenol 7, Step 3 but substituting 6-bromo(O-tert-butyldiphenylsilyl)pyridin-2-ylmethanol (from Alcohol 2, Step 4) for 1-bromo-3-(3,4-dimethoxy)benzyloxy-5-fluorobenzene and 1-(thiazol-2-yl)propanone (from Phenol 1, Step 2) for 3-pentanone the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][C@@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[CH:4]=1.C(N(CC)C(C)C)(C)C.[CH3:58][S:59](Cl)(=[O:61])=[O:60].CCOC(C)=O>C(Cl)Cl>[CH3:58][S:59]([O:1][CH2:2][C:3]1[CH:4]=[C:5]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]3[CH2:23][C:22]([CH2:46][C:47]#[N:48])([N:24]4[CH:28]=[C:27]([C:29]5[C:30]6[CH:37]=[CH:36][N:35]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:31]=6[N:32]=[CH:33][N:34]=5)[CH:26]=[N:25]4)[CH2:21]3)[CH2:16][CH2:15]2)[N:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)(=[O:61])=[O:60]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(COS(C)(=O)=O)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
{1-(cis-4-{[6-(Hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (110.0 mg, 0.1609 mmol) was dissolved in methylene chloride (2.22 mL) and was cooled to 0° C. To that was added N,N-diisopropylethylamine (45.8 μL, 0.263 mmol), followed by methanesulfonyl chloride (18 μL, 0.23 mmol). The reaction was stirred at 0° C. for 1 hour. The reaction was worked up using EtOAc and used in the next reaction. MS (ES): 762 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH:24]=O)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[NH2:26][CH2:27][CH:28]1[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1.CN(C=O)C.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][NH:26][CH2:27][CH:28]3[NH:32][C:31](=[O:33])[CH2:30][CH2:29]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Reactant: NCC1CCC(=O)N1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CNCC3CCC(=O)N3)s2)c1
Reaction time: 8 h
Yield: 24.7 %

Procedure:
To a flask was added 4 Å molecular sieves (200 mgs) and the product from Step 1 (0.050 g, 0.14 mmol), 5-(aminomethyl)pyrrolidin-2-one (0.016 g, 0.21 mmol) and a 95:5 solution of DMF: acetic acid (1.4 mL). The mixture was stirred overnight. Resin-bound sodium cyanoborohydride (0.44 g, 0.41 mmol, 0.93 mmol/g loading) was added and the reaction was stirred for 72 hours. The mixture was filtered and purified by reverse phase HPLC (12-100% acetonitrile gradient with water over 6 minutes with 0.1% formic acid buffer) to yield 5-[({[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}amino)-methyl]pyrrolidin-2-one (0.016 g, 25%). MS ESI: [M+H]+ m/z 463.1. 1H NMR (600 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.81 (d, J=5.2, 1H), 7.96 (s, 2H), 7.61 (s, 1H), 7.42 (s, 1H), 7.26 (d, J=5.1, 1H), 7.14 (s, 1H), 4.03 (s, 2H), 3.63 (s, 1H), 2.74-2.53 (m, 1H), 2.47 (m, 1H), 2.29 (s, 3H), 2.20-1.98 (m, 3H), 1.80-1.59 (m, 1H). rhSYK activity=+++
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH:4]=[CH:3]1.[CH2:9]([O:16][C:17](ON1C(=O)CCC1=O)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C=O)C.CCOCC>[OH:8][CH:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:17]([O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])[CH:3]=[CH:4]1
Reactant: N[C@H]1C=C[C@@H](O)CC1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NC1C=CC(O)CC1)OCc1ccccc1
Yield: 55.5 %

Procedure:
A solution of 4.64 g of cis-4-amino-2-cyclohexen-1-ol, 10.2 g of N-(benzyloxycarbonyloxy)succinimide and 5.7 ml of triethylamine in DMF is diluted with ether after stirring, washed with saturated sodium chloride solution, dried and concentrated. Chromatography of the residue on silica gel (ethyl acetate/hexane 2:1) gives 5.62 g of benzyl (1RS,4SR)-4-hydroxy-2-cyclohexene-1-carbamate. MS: 156 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([O:11]CC)=[O:10])[CH2:7][CH2:6][CH2:5][O:4][CH2:3]1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(CC)C(C)C)(C)C.[OH-].[Na+]>C(#N)C.CO>[CH2:18]([O:17][C:15]([NH:1][C:2]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][O:4][CH2:3]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC1(N)CCCOC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(O)CC1(NC(=O)OCc2ccccc2)CCCOC1
Yield: 28.8 %

Procedure:
Ethyl (3-aminotetrahydro-2H-pyran-3-yl)acetate (Preparation 32, 1.33 g, 7.109 mmol), benzyl chloroformate (1.53 g, 8.53 mmol) and N,N-diisopropylethylamine (3.72 mL, 21.3 mmol) were stirred in anhydrous acetonitrile (30 mL) for 18 hours at room temperature. The reaction was concentrated in vacuo then partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with heptane:ethyl acetate:methanol (100:0:0-0:90:10). The oil isolated was then dissolved in methanol (10 mL) and a 1M aqueous solution of sodium hydroxide (10 mL) and heated to 75° C. for 18 hours. The methanol was removed in vacuo and the mixture partitioned between dichloromethane (10 mL) and water. The aqueous layer was acidified with 2M aqueous hydrogen chloride and extracted with dichloromethane (4×10 mL). The organic layer was dried over MgSO4 to afford the title compound as a oil (0.6 g, 29% yield over 2 steps).
Reaction SMILES: Cl[C:2]1N=C(Cl)[C:5](OC)=[CH:4][N:3]=1.C[Al](C)C.[Cl-].[NH4+:16].C(Cl)(Cl)Cl.[CH2:21]1[CH2:25][O:24][CH2:23][CH2:22]1>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>[CH3:25][O:24][C:23]1[C:22]([CH3:21])=[N:16][C:4]([CH3:5])=[N:3][CH:2]=1
Reactant: [NH4+]
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1cnc(C)nc1C
Temperature: 75 °C
Reaction time: 8 h

Procedure:
2,4-Dichloro-5-methoxypyrimidine (5.3 g) was dissolved in THF (51.3 ml), and tetrakis(triphenylphosphine)palladium (1.71 g) and trimethylaluminum (2.0 M: 51.8 ml) were then added to the solution. The temperature of the obtained mixture was heated to 75° C., and the obtained mixture was then stirred overnight. Thereafter, 1 equivalent of trimethyl aluminum was added to the reaction solution, and the obtained mixture was then stirred for 6 hours. Thereafter, saturated ammonium chloride aqueous solution was added dropwise to the reaction solution under cooling on ice, and liquid separation and extraction were carried out with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate to ethyl acetate), so as to obtain the title compound (4.2 g).