Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]2[N:11]=[C:12]([CH3:23])[C:13]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[CH3:22])=[C:9]2[N:8]=[C:7]([CH3:24])[CH:6]=1.[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[O:25]1[CH2:30][CH2:29][CH:28]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:10]3[N:11]=[C:12]([CH3:23])[C:13]([C:14]4[C:15]([CH3:22])=[CH:16][C:17]([Cl:21])=[CH:18][C:19]=4[CH3:20])=[C:9]3[N:8]=[C:7]([CH3:24])[CH:6]=2)[CH2:27][CH2:26]1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(NCCN)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(NCCNC2CCOCC2)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
Dissolve 7-(2-aminoethylamino)-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo [1,5-a] pyrimidine (0.183 g, 5.4×10−4 mol, 339.2 g/mol) in dichloroethane (5 mL) and add tetrahydro-4H-pyran-4-one (0.068 g, 0.060 mL, 100.12 g/mol) and sodium triacetoxyborohydride (0.172 g, 211.94 g/mol). To the resultant slurry, add glacial acetic acid (0.032 mL, 5.4×10−4 mol) and stir at ambient temperature under N2 for 3 hours. Partition between CH2Cl2 (3 mL) and 1.0 N NaOH (10 mL), then separate the layers and chromatograph the CH2Cl2 layer using [10% (2.0M NH3 in MeOH)/90% CH2Cl2] as eluent. Obtained 0.16 g white solid-foam upon evaporation. TLC: Rf=0.65. LCMS=422.5 (MH+); 420.5 (M−). 1H-NMR (CDCl3): 6.67 (s, 2H); 5.79 (d, 1H, J=8.8 Hz); 3.98 (br. d, 2H, J=12 Hz); 3.78 (s, 3H); 3.52 (t, 2H, J=6 Hz); 3.39 (br. t, 2H, J=12 Hz); 3.37 (s, 1H); 3.04 (t, 2H, J=6 Hz); 2.75-2.81 (m, 2H); 2.40 (s, 3H); 2.18 (s, 3H); 2.00 (s, 6H); 1.89 (br. d, 2H, J=12 Hz); 1.47-1.53 (m, 2H).
Reaction SMILES: C[Si](Cl)(C)C.[OH:6][C:7]1([C:10]([OH:12])=O)[CH2:9][CH2:8]1.C(Cl)(=O)C(Cl)=O.[CH3:19][NH:20][CH3:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.N1C=CC=CC=1.CN(C)C=O.CO>[OH:6][C:7]1([C:10]([N:20]([CH3:21])[CH3:19])=[O:12])[CH2:9][CH2:8]1
Reactant: O=C(O)C1(O)CC1
Reactant: CNC
Agent: C[Si](C)(C)Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CN(C)C(=O)C1(O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17.1 ml of trimethylsilyl chloride are added dropwise to a solution of 6 g of 1-hydroxy-cyclopropanecarboxylic acid in 120 ml of dichloromethane and 10.5 ml of pyridine. After stirring for 4 hours at ambient temperature, the mixture is cooled to 0° C., and 10 drops of dimethylformamide and then 5.4 ml of oxalyl chloride are added. The reaction mixture is stirred at 0° C. for 1 hour and at ambient temperature for 1 hour; a solution of 2.4 g of dimethylamine in 10 ml of pyridine is then added. Stirring is continued for 20 hours and then, after cooling to 0° C., 14 g of citric acid in 120 ml of methanol are added. After returning to ambient temperature for one hour, the reaction mixture is washed with 1N hydrochloric acid solution and then with NaHCO3-saturated solution and then NaCl-saturated solution. The organic phase is treated in conventional manner and chromatography over silica gel (dichloromethane/tetrahydrofuran: 90/10) allows the expected product to be isolated.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]2=[CH:23][CH:22]=[CH:21][N:9]12
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2F)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccccc2F)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(2-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 360 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][N:7]=2)[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20]
Reactant: O=C(NCCc1ccccc1)c1ccc(C(F)(F)F)c(F)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Fc1cc(C2=NCCc3ccccc32)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 74.1 %

Procedure:
To a stirred mixture of 3-fluoro-N-phenethyl-4-(trifluoromethyl)benzamide (1.27 g, 4.08 mmol) in 30 mL of toluene, phosphorus pentoxide (1.751 g, 12.3 mmol) and phosphorus oxychloride (1.90 mL, 20.4 mmol) were added. The mixture was refluxed for overnight. The reaction mixture was cooled to RT. Supernatant was removed and the ice-water was added to the flask containing the residue. The mixture was stirred to break the chunks into powder. EtOAc was added and the pH was adjusted to ˜12 with 3N aqueous potassium hydroxide. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford 0.887 g of yellow viscous oil. The crude product was purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford the title compound as a clear oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.63-7.73 (m, 1H) 7.39-7.54 (m, 3H) 7.31 (d, J=7.60 Hz, 2H) 7.16-7.24 (m, 1H) 3.84-3.96 (m, 2H) 2.77-2.89 (m, 2H).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][C:9]([C:16]([OH:18])=[O:17])=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[Na+:27].[Na+]>>[CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][C:9]([C:16]([O-:18])=[O:17])=[CH:10][CH:11]=3)[C:6](=[O:19])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:20]([O-:22])=[O:21].[Na+:27].[Na+:27]
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccc(C(=O)O)cc1C2=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C([O-])c1ccc2c(c1)C(=O)c1ccc(C(=O)[O-])cc1C2=O

Procedure:
Anthraquinone-2,6-dicarboxylic acid (0.50g) was dissolved in sodium carbonate solution (1 equivalent of sodium carbonate, 0.18g, in water, 100 ml) with warming. As the di-sodium salt did not separate on cooling, the solution was evaporated to approximately 1/3 volume and heavily diluted with ethanol. The solid which separated was filtered off, dried at 100°C. and analysed for the dihydrate. Analysis: Required Carbon 51.09, Hydrogen 2.68, Found Carbon 50.67, Hydrogen 2.78.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:3]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:24][S:25]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:3]1)(=[O:27])=[O:26]
Reactant: N#Cc1ccc(-c2ccc3nc(N4CC[C@H](O)C4)sc3c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)O[C@H]1CCN(c2nc3ccc(-c4ccc(C#N)cc4)cc3s2)C1
Reaction time: 8 h

Procedure:
A stirred, 0° C. solution of (S)-4-(2-(3-hydroxypyrrolidin-1-yl)benzo[d]thiazol-6-yl)benzonitrile (Reference Example 13b, 75 mg, 0.23 mmol) in pyridine (2.5 mL) was treated with methanesulfonyl chloride (0.022 mL, 0.280 mmol). The ice bath was removed and stirring was continued at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give (S)-1-(6-(4-cyanophenyl)benzo[d]thiazol-2-yl)pyrrolidin-3-yl methanesulfonate that was used without further purification. 1H NMR (300 MHz, CDCl3) δ ppm 2.36-2.50 (m, 1H), 2.53-2.63 (m, 1H), 3.10 (s, 3H), 3.84-4.15 (m, 4H), 5.47-5.52 (m, 1H), 7.60 (dd, J=2, 8 Hz, 1H), 7.67-7.75 (m, 4H), 7.79 (d, J=8 Hz, 1H), 7.85 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 400 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[C:15](O)=[O:16])[CH3:2].F[P-](F)(F)(F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(CC)CC.[OH-].[NH4+]>CN(C)C=O.CN(C1C=CN=CC=1)C.O>[CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]1[C:15]([NH2:28])=[O:16])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(Cn1c(C(=O)O)cc2c1CCCC2)OCC
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(Cn1c(C(N)=O)cc2c1CCCC2)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a mixture of 195c (2.8 g, 10.0 mmol) in N,N-dimethylformamide (30 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (5.7 g, 15.0 mmol), Et3N (1.5 g, 15.0 mmol), and DMAP (128 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for overnight. Saturated ammonium hydroxide (30 mL) was added and the resulting mixture was further stirred for 2 h. It was then diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic phase was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (6:1 to 3:1) to afford 195d (2.7 g, 96%). MS-ESI: [M-EtOH+H]+ 235. 1H NMR (500 MHz, DMSO) δ 7.35 (bs, 1H), 6.70 (bs, 1H), 6.60 (s, 1H), 4.60 (t, J=5.5 Hz, 1H), 4.18 (d, J=4.0 Hz, 2H), 3.57-3.56 (m, 2H), 3.25 (m, 2H), 2.57 (t, J=6.0 Hz, 2H), 2.40 (t, J=6.0 Hz, 2H), 1.71 (t, J=5.0 Hz, 2H), 1.64 (t, J=5.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([SH:15])=[C:10]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=2)=[O:5])[CH3:2].N1C=CC=CC=1.[S:26](Br)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15][S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])=[C:10]([C:16]([CH3:18])([CH3:17])[CH3:19])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(S)c(C(C)(C)C)cc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(SS(=O)(=O)c3ccc(C)cc3)c(C(C)(C)C)cc2[nH]1

Procedure:
The title compound was prepared according to General Method 15 using (6-tert-Butyl-5-mercapto-1H-indole-2-carboxylic acid ethyl ester (prepared in Example AAA), pyridine, tosyl bromide, carbon tetrachloride, and EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:12][CH2:11][C:8]2([O:10][CH2:9]2)[CH2:7][CH2:6]1.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CCO>C(O)C.C(OCC)(=O)C.CN(C)C=O>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:12][CH2:11][C:8]([CH2:9][N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[O:17])([OH:10])[CH2:7][CH2:6]1
Reactant: Fc1ccccc1CN1CCC2(CC1)CO2
Reactant: Oc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1ccccn1CC1(O)CCN(Cc2ccccc2F)CC1
Yield: 60.8 %

Procedure:
23.00 g (0.104 mol) of N-(2-fluorobenzyl)-1-oxa-6-azaspiro[2,5]-octane and 10.30 g (0.108 mol) of 2-hydroxy-pyridine were weighed and added into 80 mL N,N-dimethylformamide, and then 1.00 g (0.007 mol) potassium carbonate was added. The reaction was stirred and reacted at a bath temperature of about 80° C. for 1 day, and the solvent was recovered. Potassium carbonate aqueous solution was added into the residue The mixture was extracted with dichloromethane twice, combined, washed with water, and dried. The solvent was recovered, crystallized with petroleum ether-ethyl acetate to obtain colorless flake-like crystal, 22.80 g, yield 69.3%. 1H-NMR (CDCl3, ppm) δ: 7.372 (2H, m), 7.228 (2H, m), 7.092 (1H, t, J=7.56 Hz), 7.020 (1H, t, J=8.96 9.24 Hz), 6.639 (1H, d, J=9.24 Hz), 6.228 (1H, t×d, J1=6.72 Hz, J2=1.12 Hz), 4.720 (1H, s), 4.036 (2H, s), 3.603 (2H, s), 2.69 (2H, dd, J1=7.84 Hz, J2=3.64 Hz), 2.46 (2H, t×d, J1=8.40 Hz, J2=2.80 Hz), 1.55-1.74 (4H, m). The product was heated and dissolved in ethanol-ethyl acetate, salified with HCl-EtOH while warm and naturally cooled to obtain a colorless fine granular crystal, which was dried under vacuum to obtain 20.00 g product. Melting point: 249-251° C.
Reaction SMILES: [C:1]1([C:7]2([CH:12]=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:15][NH3+:16].N1C=CC=CC=1>C(O)C>[C:1]1([C:7]2([CH:12]=[N:16][OH:15])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1(c2ccccc2)CCCC1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: ON=CC1(c2ccccc2)CCCC1
Yield: 66 %

Procedure:
A mixture of the above aldehyde (3.4 g, 20 mmol) and hydroxylammonium chloride (2.9 g, 42 mmol) in a mixture of absolute ethanol (30 ml) and pyridine (3.3 g, 42 mmol) was heated at reflux for 2 h. The solvent was evaporated in vacuo, the residue was treated with absolute ethanol (50 ml) and the suspension filtered. The solvent was evaporated from the filtrate in vacuo and the residue crystallised from a 4/1 mixture of n-heptane and ethyl acetate to give 2.5 g of 1-phenyl-1-cyclopentanecarboxaldehyde oxime.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:4]=1)#[N:2].C[N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([NH2:35])=[O:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C(N)=O)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The reaction was carried out under argon. (4S)-4-[4-Cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (696 mg, 1.45 mmol; Example 5A) and HATU (2 eq., 1104 mg, 2.9 mmol) were initially charged in dry DMF (35 ml) at 0° C., and after brief stirring (20 min) ammonium chloride (5 eq., 388 mg, 7.26 mmol) and DIEA (7 eq., 1314 mg, 10.16 mmol) were added. The mixture was stirred at RT for 4 h (monitored by HPLC). The mixture was then concentrated, and the residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (612 mg, 88% of theory).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[C:25]1(=[O:34])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][NH:26]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>C(OCC)(=O)C.[Cu](I)I.C1(C)C=CC=CC=1>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([N:26]3[CH2:27][C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25]3=[O:34])[N:3]=2)[N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:9]=1)=[O:16]
Reactant: O=C1NCc2ccccc21
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(N3Cc4ccccc4C3=O)nc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
Toluene was added to a mixture of 1-[2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.250 g, 0.606 mmol), 2,3-Dihydro-isoindol-1-one (0.097 g, 0.727 mmol), copper iodide (11.6 mg, 0.061 mmol), and potassium carbonate (0.168 g, 1.212 mmol) under argon. Dimethyl ethylenediamine (0.013 mL; 0.011 g, 0.121 mmol) was subsequently added and the reaction was stirred for 16 h at 110° C. The reaction was diluted with ethyl acetate and filtered through a silica plug before being concentrated in vacuo. Silica gel chromatography (0->25% EtOAc/hexanes over 30 minutes) afforded 0.2206 g (78% yield) of 2-[7-(2,2-Dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-2,3-dihydro-isoindol-1-one. MS (E/I): 465 (M+H)
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:11][CH2:10][CH2:9]O1.[I:20](O)(=O)=O>>[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[CH:11][CH2:10][CH2:9][I:20]
Reactant: Cc1ccccc1C1(c2ccccc2C)CCCO1
Reactant: [O-][I+2]([O-])O
Product: Cc1ccccc1C(=CCCI)c1ccccc1C

Procedure:
A solution of 2,2-di-(2-tolyl)-tetrahydrofuran 33a (40 g) in 57% aqueous iodic acid (250 mL) was boiled under reflux for 30 min. The cooled solution was extracted with diethyl ether. The combined organic phases were washed with water and a saturated aqueous solution of NaCl, dried (Na2SO4) and evaporated in vacuo. The residue was subjected to CC (n-heptane/ethyl acetate 15:1) to give the title compound 36a as an oil (44 g). 1H NMR (CDCl3) 67 2.10 (s,3H), 2.30 (s,3H), 2.65 (q,2H), 3.19 (t,2H), 5.73 (t, 1H), 7.05-7.22 (m,8H)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(Cl)(=[O:11])C>[OH-].[Na+].O.O1CCCC1>[C:5]([OH:11])(=[O:6])[CH3:7].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Hydroquinone (440 g) was dissolved in a solution of sodium hydroxide (160 g) in water (1600 ml) and to the resulting solution was added dropwise a solution of acetyl chloride (346 g) in tetrahydrofuran (346 g), while maintaining the temperature at 0° C. with ice-cooling. After addition, the mixture was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with a small amount of water. Ethyl acetate was removed and the residue was distilled under a reduced pressure to give hydroquinone monoacetate (188 g). b.p. 144°-147° C./4 mmHg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][OH:11])=[O:9])[CH:3]=1.OO.S(=O)(=O)(O)O.C(O)(=O)C>>[CH:3]1[C:4]([C:8]([O:10][OH:11])=[O:9])=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Product: O=C(OO)c1ccccc1

Procedure:
m-Chloroperbenzoic acid (MCPBA) or a mixture of hydrogen peroxide/sulfuric acid/acetic acid is preferably used for the oxidation.
Reaction SMILES: [C:1]([C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].[NH2:10][C:11]([CH:38]1[CH2:40][CH2:39]1)([CH:35]1[CH2:37][CH2:36]1)[C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]([NH:24][C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH:20]=[C:21]([CH3:23])[CH:22]=2)=[CH:15][N:16]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH:38]1([C:11]([CH:35]2[CH2:36][CH2:37]2)([C:12]2[S:13][C:14]([C:17]3[CH:18]=[C:19]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][N:26]=4)[CH:20]=[C:21]([CH3:23])[CH:22]=3)=[CH:15][N:16]=2)[NH:10][C:7]([C:4]2([C:1]([NH2:2])=[O:3])[CH2:6][CH2:5]2)=[O:9])[CH2:39][CH2:40]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(N)(C3CC3)C3CC3)s2)c1
Reactant: NC(=O)C1(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(NC(=O)C3(C(N)=O)CC3)(C3CC3)C3CC3)s2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
A flask was charged with 1-carbamoylcyclopropanecarboxylic acid (16.23 mg, 0.126 mmol), N-(3-{2-[amino(dicyclopropyl)methyl]-1,3-thiazol-5-yl}-5-methylphenyl)-4-(trifluoromethyl)-pyrimidin-2-amine (56 mg, 0.126 mmol), BOP (83 mg, 0.189 mmol), DIPEA (43.9 μL, 0.251 mmol) and DMF (10 mL). The reaction was stirred at room temperature for 90 minutes. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered, and concentrated to afford N-{dicyclopropyl[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}cyclopropane-1,1-dicarboxamide (67.6 mg, 0.121 mmol, 97% yield) as an off white solid. MS ESI: [M+H]+ m/z 557.1. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.81 (s, 1H), 8.83 (d, 1H), 8.01 (s, 1H), 7.91 (s, 1H), 7.44 (s, 1H), 7.29 (m, 3H), 7.15 (s, 1H), 2.31 (s, 3H), 1.67-1.46 (m, 2H), 1.28-1.20 (m, 4H), 0.7-0.65 (m, 2H), 0.56-0.54 (m, 2H), 0.44-0.38 (m, 4H). rhSYK activity=+++
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2([OH:46])[CH2:32][N:31](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:30]2)=[C:25]([F:47])[CH:24]=1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C1C=CC=CC=1>[C:2]([N:31]1[CH2:32][C:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])=[CH:24][C:25]=2[F:47])([OH:46])[CH2:30]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1)OCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Nc1ccc(C2(O)CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1

Procedure:
Benzyl chloroformate (3.8 mL, 26.6 mmol) was added to a solution of 3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)-3-hydroxy-1-(1,1-diphenylmethyl)azetidine (Example 81, Step 2, 1.60 g, 3.32 mmol) in benzene (30 mL) and then heated under reflux under nitrogen for 2 hr. The benzene was evaporated and the residue chromatographed over silica gel (150 g, 40-60 μm) eluting with 20-60% ethyl acetate-hexane. The title compound was obtained as a white foam. 1H NMR δ (CDCl3): 3.32, 4.19, 4.42, 5.08, 5.17, 6.98, 7.11, 7.19, 7.24-7.43.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(N(C)C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(N(C)C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-ethoxycarbonyl-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.