Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Si:8]([N:15]1[CH2:21][C:19](=[O:20])[N:18]([Si](C(C)(C)C)(C)C)[C:16]1=[O:17])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].CN(C)P(=O)(N(C)C)N(C)C.[CH2:40]([O:43][C:44]([N:46]1[CH2:50][C@@H:49]([S:51][C:52]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:48][C@H:47]1[CH2:71]I)=[O:45])[CH:41]=[CH2:42].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:40]([O:43][C:44]([N:46]1[CH2:50][C@@H:49]([S:51][C:52]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:48][C@H:47]1[CH2:71][CH:21]1[N:15]([Si:8]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10])[C:16](=[O:17])[NH:18][C:19]1=[O:20])=[O:45])[CH:41]=[CH2:42]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Reactant: CC(C)(C)[Si](C)(C)N1CC(=O)N([Si](C)(C)C(C)(C)C)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1C(=O)NC(=O)N1[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
A 1.6M n-butyllithium-hexane solution (4.1 ml, 6.56 mmol) was dropwise added to a solution of diisopropylamine (1 ml, 7.14 mmol) in tetrahydrofuran (5 ml) under a nitrogen stream at -78° C., and the reaction solution was stirred at the same temperature for 10 minutes and under cooling with ice for 30 minutes. A solution of N,N'-bis(tert-butyldimethylsilyl)hydantoin (1.65 g, 5.02 mmol) in tetrahydrofuran (2 ml) was dropwise added to this reaction solution at -78° C. This solution was stirred at the same temperature for 1 hour. Then, hexamethylphosphoric triamide (1.75 ml, 10 mmol) was added to this reaction solution, and the mixture was stirred for 10 minutes. Then, a solution of (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (2.28 g, 4.00 mmol, compound of Reference Example 21-2) in tetrahydrofuran (3 ml) was dropwise added thereto. The reaction solution was stirred at the same temperature for 2 hours. To the reaction solution, a saturated ammonium chloride aqueous solution (10 ml) and ethyl acetate (300 ml) were added. The organic layer was washed sequentially with a 1N potassium hydrogen sulfate aqueous solution, water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (Wakogel™ C-300, hexane-ethyl acetate) to obtain (2R,4S)-N-allyloxycarbonyl-2-(1-tert-butyldimethylsilyl-2,4-dioxoimidazolidin-5-ylmethyl)-4-tritylthiopyrrolidine (1.19 g, yield: 45%).
Reaction SMILES: [Na].[CH2:2]([O:4][C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16](=[O:26])[NH:15][C:14]1=[O:27])=[O:6])[CH3:3].[CH2:28](Br)[CH2:29][CH2:30][CH3:31]>C(O)C>[CH2:28]([N:15]1[C:14](=[O:27])[CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:16]1=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCN1C(=O)NC(=O)C1CCCCCCC(=O)OCC
Reactant: CCCCBr
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCN1C(=O)N(CCCC)C(=O)C1CCCCCCC(=O)OCC

Procedure:
To a solution of sodium (308 mg) in ethanol (40 ml) was added 5-(6-ethoxycarbonylhexyl)-1-octylhydantoin (see Example 29b), followed by butyl bromide (1.8 g), and the solution was refluxed for 24 hours. The solvent was evaporated, water was added and the insoluble oil was extracted with ether. The washed and dried extract was evaporated to give 3-butyl-5-(6-ethoxycarbonylhexyl)-1-octylhydantoin.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][CH2:6][CH2:7][CH2:8][CH:9]([CH:23]1[CH2:28][C:27](=[O:29])[NH:26][C:24]1=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:30]1([C:36]2[NH:37][C:38]3[C:43]([C:44]=2[NH2:45])=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[N+:46]([C:49]1[CH:50]=[C:51]([S:55](Cl)(=[O:57])=[O:56])[CH:52]=[CH:53][CH:54]=1)([O-])=O.Cl>[Zn].O.CC(C)=O.N1C=CC=CC=1>[CH3:5][CH2:6][CH2:7][CH2:8][CH:9]([CH:23]1[CH2:28][C:27](=[O:29])[NH:26][C:24]1=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:30]1([C:36]2[NH:37][C:38]3[C:43]([C:44]=2[NH:45][S:55]([C:51]2[CH:52]=[CH:53][CH:54]=[C:49]([NH2:46])[CH:50]=2)(=[O:57])=[O:56])=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1c(-c2ccccc2)[nH]c2ccccc12
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: CCCCCCCCCCCCCC(CCCC)C1CC(=O)NC1=O
Agent: Cl
Agent: [Zn]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: Nc1cccc(S(=O)(=O)Nc2c(-c3ccccc3)[nH]c3ccccc23)c1
Reaction time: 4 h
Yield: 179 %

Procedure:
To 200 cc of a chloroform were added 22.28 g (0.04 mole) of 5-octadecyl succinimide-2-phenyl-3-aminoindole and 9.1 g (0.01 mole) of m-nitrobenzene sulfonic acid chloride, and to the mixture solution were dropwise added 3.24 g of pyridine under nitrogen gas flow, and stirred over a period of 4 hours, and the thus deposited Precipitate was filtered, whereby 18 g of crude crystals of 5-octadecyl succinimide-2-phenyl-3-{N-(3-nitrobenzene sulfonyl)amino}indole were obtained. 16 g of the obtained crystals were added to 140 ml of acetone, and to the solution were added 3.5 g of zinc powder and 7 ml of hydrochloric acid at a temperature of from 15° to 20° C. and, keeping the temperature, further added alternately 5.7 g of zinc powder and 15 ml of hydrochloric acid. This was stirred for 30 minutes after the addition and was added with stirring to 100 ml of water to deposit crystals. The crystals were centrifugally separated, stirred, washed, refined by column chromatography, and then dried, thereby obtaining 12.8 g of an objective product.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[CH2:19]([N:21](CC)CC)[CH3:20].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:21][CH2:19][CH3:20])=[O:4]
Reactant: COC(=O)CC[C@H](N)C(=O)O
Reactant: CCN(CC)CC
Agent: CCN
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
First, 320 g (1.983 mol) of L-glutamic acid-γ-methyl ester was suspended in 500 g of methanol. To this, 219 g (2.186 mol, 1.1 eq.) of acetylacetone and 200 g (1.983 mol, 1 eq.) of triethylamine were added. The mixture was stirred at 60° C. for one hour. Subsequently, 1,277 g (19.8 mol) of 70% ethylamine was added to the mixture. After the mixture was allowed to react for 6 hours, the reaction solution was heated under normal pressure. In this manner, 667 g of excessive ethylamine was recovered and deprotection was performed at the same time. To the slurry of the theanine precipitated, 1 L of 2-propanol was added. The crystal was filtrated by suction and washed with 200 mL of 99.5% ethanol to obtain theanine (314.3 g) as a white crystal substance (yield: 91%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[C:5]([C:20]#[N:21])[C:4]1=[O:22].[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].CCN(C(C)C)C(C)C>ClCCl>[C:23]([N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]([CH3:2])[C:4](=[O:22])[C:5]=2[C:20]#[N:21])[CH2:19][CH2:18]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: C=CC(=O)Cl
Reactant: Cn1c(=O)c(C#N)c(NC2CCNCC2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCC(Nc2c(C#N)c(=O)n(C)c3ccccc23)CC1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of 1-Methyl-2-oxo-4-(piperidin-4-ylamino)-1,2-dihydro-quinoline-3-carbonitrile hydrochloride salt (leg, 0.020 g, 0.07 mmole) in dichloromethane at −10° C. was added acryloyl chloride (1.1 eq, 0.007 g, 0.077 mmole) followed by the addition of N,N′-diisopropylethylamine (1.5 eq, 0.014 g, 0.011 mmole, 0.02 mL). The resulting solution stirred at −10° C. for 1 hour then warmed to RT and stirred for an additional 2 hours. The reaction was quenched into ice cooled water and extracted with ethyl acetate (25 mL×3). Combined organic phase was washed consecutively with water, brine before drying over sodium sulfate. Organic phase was evaporated and the residue was purified by flash chromatography to afford 4-(1-Acryloyl-piperidin-4-ylamino)-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carbonitrile as a yellow solid (0.004 g, 32% calc M+H 337, obs M+H 337).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][C:17]=2[NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][C:17]=2[NH:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]([CH3:39])[CH3:38])=[CH:34][CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c(Nc2ncnc3cc(C(C)C)ccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2c1
Yield: 88 %

Procedure:
The product of Example 432D (0.505 g, 0.927 mmol) was suspended in 1,4-dioxane (6 mL), treated with a solution of lithium hydroxide monohydrate (0.078 g, 1.85 mmol) in water (3 mL) at room temperature, then heated at 50° for one hour. The reaction was diluted with water (25 mL), adjusted to pH 1 with 1N aqueous HCl, and extracted with ethyl acetate (50 mL). The organic extract was washed with water (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to afford the title compound as a light yellow solid (0.433 g, 0.816 mmol, 88%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31 (d, J=6.99 Hz, 6 H) 1.48 (s, 9 H) 2.98-3.23 (m, 1 H) 6.92 (d, J=8.09 Hz, 1 H) 7.36 (d, J=8.46 Hz, 2 H) 7.54 (d, J=8.82 Hz, 2 H) 7.59 (d, J=11.77 Hz, 1 H) 7.73 (d, J=8.09 Hz, 1 H) 7.89 (s, 1 H) 8.34-8.49 (m, 2 H) 9.61 (s, 1 H) 9.94 (s, 1 H). MS (ESI+) m/z 531 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:13][C:14]([CH3:16])=O.N1CCCC1.CCOCC>CO.O>[CH3:7][C:2]([C:8]1[CH:12]=[CH:11][C:10](=[C:14]([CH3:16])[CH3:13])[CH:9]=1)([CH3:1])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CC(C)(C)C1=CC=CC1
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: CCOCC
Solvent: CO
Product: CC(C)=C1C=CC(C(C)(C)CC(C)C)=C1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a solution of 3.00 g (18.3 mmol) of (1,1,3-trimethylbutyl)cyclopentadiene in 30 ml of methanol, 13.4 ml (182.5 mmol) of acetone and 3.1 ml (36.6 mmol) of pyrrolidine were added with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with % 100 ml of ether, 50 ml of water was added. The organic phase was separated, washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (130° C./1 mmHg) to obtain 3.50 g (17.1 mmol) of a yellow liquid (yield: 94%). The analyzed values are given below.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:25])[F:26])[CH:16]=1)(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Brc1cccc2[nH]ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)n1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
Aq. 2.5M NaOH (5 mL) was added to a stirring mixture of 4-bromo-1H-indole (1000 mg, 5.3 mmol), 3-(trifluoromethyl)benzenesulfonyl chloride (1300 mg, 5.6 mmol) and tetrabutylammonium hydrogen sulfate (173 mg, 0.5 mmol) in DCM (10 mL). The reaction mixture was stirred at ambient temperature overnight. The mixture was diluted with DCM and water and the layers were separated. DCM was washed with water 2 times, dried (MgSO2) and concentrated to give 1.6 g of crude material that was purified using flash chromatography (SiO2, eluent EtOAc:hexane 9:1) giving the title product (0.91 g, 44%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([O:21][CH3:22])[C:15]([O:23][CH3:24])=[CH:14]2.[N:25]([O-])=O.[Na+].O.C(OCC)(=O)C>C(O)(=O)C.Cl>[CH3:22][O:21][C:16]1[C:15]([O:23][CH3:24])=[CH:14][C:13]2[C:18]([CH:17]=1)=[CH:19][CH:20]=[C:11]1[C:12]=2[N:25]=[N:1][C:2]2[CH:7]=[C:6]3[O:8][CH2:9][O:10][C:5]3=[CH:4][C:3]1=2
Reactant: COc1cc2ccc(-c3cc4c(cc3N)OCO4)cc2cc1OC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc2ccc3c4cc5c(cc4nnc3c2cc1OC)OCO5
Reaction time: 8 h
Yield: 46 %

Procedure:
6-(2-Amino-4,5-methylenedioxyphenyl)-2,3-dimethoxy-naphthalene (13, 40 mg, 0.13 mmol) in acetic acid (2 mL) and concentrated hydrochloric acid (0.3 mL) was cooled to 0° C. and diazotised with a solution of sodium nitrite (0.09 g in 1.5 mL water). The diazonium solution was allowed to rise slowly to room temperature and left overnight. Water (50 mL) was added to the red solution with some precipitate. The resulting mixture was extracted with ethyl acetate, washed with diluted sodium hydroxide solution, then with water, dried (anhydrous Na2SO4) and rotaevaporated to give the crude product. Chromatography on silica gel using 40:60 hexanes:ethyl acetate afforded the title compound (20 mg) in 50% yield; 1H NMR (CDCl3) d 4.09(3H, s), 4.22(3H, s), 6.24(2H, s), 7.31(1H, s), 7.80(1H s), 7.95(1H, s), 8.00(1H, d, J=9.2), 8.13(1H, d, J=8.9), 9.14(1H, s); 13C NMR d 56.5 56.9, 98.1, 102.9, 104.6, 107.5, 107.9, 117.1, 119.6, 120.6, 126.8, 128.5, 131.7, 141.9, 145.6, 150.2, 151.2, 152.1.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:8]=[C:9]([NH:14][C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)=[CH:5][N:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C1COCC1.[Br-].[CH3:60][O:61][C:62](=[O:67])[C@H:63]([CH3:66])[CH2:64][Zn+]>[NH4+].[Cl-].O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:64][C@H:63]([CH2:66][C:2]1[S:3][C:4]([C:7]2[CH:8]=[C:9]([NH:14][C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=3)[CH:10]=[C:11]([CH3:13])[CH:12]=2)=[CH:5][N:6]=1)[C:62]([O:61][CH3:60])=[O:67]
Reactant: COC(=O)[C@H](C)C[Zn+]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(Br)s2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)Cc1ncc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
N-[3-(2-Bromo-1,3-thiazol-5-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (INTERMEDIATE 9, 1.50 g, 3.61 mmol), Pd(OAc)2 (81 mg, 0.361 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (297 mg, 0.722 mmol) were combined in a vial, sealed, and purged with nitrogen (2×). Degassed THF (15 mL) and (S)-(−)-3-methoxy-2-methyl-3-oxopropylzinc bromide (0.5 M in THF, 28.9 mL, 14.45 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated aqueous NH4Cl and water and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (0-50% ethyl acetate in hexanes) afforded methyl(2R)-2-methyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoate (1.37 g, 87%) as a yellow gum. MS ESI: [M+H]+ m/z 437.0. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.80 (d, J=4.8, 1H), 7.93 (s, 2H), 7.43 (s, 1H), 7.25 (d, J=4.9, 1H), 7.12 (s, 1H), 3.58 (s, 3H), 3.25 (dd, J=7.8, 15.2, 1H), 3.09 (dd, J=6.2, 15.2, 1H), 3.00-2.91 (m, 1H), 2.29 (s, 3H), 1.15 (d, J=7.0, 3H). rhSYK activity=+++
Reaction SMILES: [N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=[O:20].[CH2:23]([N:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][C:37]=2[N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)[C:32]([CH3:49])=[C:31]1[CH3:50])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)(=O)C.O>[CH2:23]([N:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][C:37]=2[N:39]2[CH2:48][CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40]2)[C:32]([CH2:49][OH:20])=[C:31]1[CH3:50])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)ccnc12
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(CO)c2nccc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
The compound prepared in Example 6 (501.1 mg, 1.23 mmol) was treated with a saturated sodium bicarbonate solution to obtain 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (433.6 mg, 1.18 mmol). Ammonium cerium (IV) nitrate (1.94 g, 3.54 mmol) was added at room temperature to a solution of 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine (433.6 mg, 1.18 mmol) in acetic acid (10 ml). The reaction mixture was stirred for 4 hours at 55° C., cooled to room temperature, poured in water, and then extracted with ethyl acetate. The resulting organic layer was washed with a saturated sodium chloride solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol (20 ml). 2N Lithium hydroxide (5.0 ml) was added to the solution, which was then stirred for 1 hour at room temperature. The reaction mixture was neutralized with 1N hydrochloric acid, concentrated under reduced pressure to discard methanol, and then extracted with ethyl acetate. The resulting organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography to give 1-benzyl-7-(1,2,3,4-tetrahydroisoquinolin-2-yl)-3-hydroxymethyl-2-methyl-1H-pyrrolo[3,2-b]pyridine, which was then dissolved in ethyl acetate. The solution was saturated with hydrochloric acid gas and then filtered to give the titled compound as a white solid (69 mg, 13.9%).
Reaction SMILES: FC(F)(F)C(O)=O.O.[C:9]([C:13]1[CH:64]=[CH:63][C:16]2[NH:17][C:18]([CH2:20][CH2:21][CH:22]3[CH2:25][CH:24]([N:26]([CH2:31][C@@H:32]4[C@H:36]5[O:37]C(C)(C)[O:39][C@H:35]5[C@H:34]([N:42]5[C:46]6[N:47]=[CH:48][N:49]=[C:50]([NH:51]CC7C=CC(OC)=CC=7OC)[C:45]=6[CH:44]=[CH:43]5)[CH2:33]4)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23]3)=[N:19][C:15]=2[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:51][C:50]1[C:45]2[CH:44]=[CH:43][N:42]([C@@H:34]3[CH2:33][C@H:32]([CH2:31][N:26]([CH:24]4[CH2:23][CH:22]([CH2:21][CH2:20][C:18]5[NH:17][C:16]6[CH:63]=[CH:64][C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:14][C:15]=6[N:19]=5)[CH2:25]4)[CH2:27][CH:28]([CH3:29])[CH3:30])[C@@H:36]([OH:37])[C@H:35]3[OH:39])[C:46]=2[N:47]=[CH:48][N:49]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC(C)C)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)CN(C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O)C1CC(CCc2nc3cc(C(C)(C)C)ccc3[nH]2)C1
Reaction time: 8 h
Yield: 47.8 %

Procedure:
Trifluoroacetic Acid (20 ml, 300 mmol) added to a mixture of Water (2 ml, 100 mmol) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(isobutyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.9 g, 1 mmol) at RT. The reaction was stirred overnight and Triethylsilane (0.38 ml, 2.4 mmol) was added. The volatiles were removed in vacuo and resulting residue was taken up in MeOH (15 ml), 500 mgs of K2CO3 and 8 drops H2O were added and reaction stirred at RT for 1 hour. The mixture was filtered and filter cake washed with 10 ml MeOH. The filtrate was concentrated and the resulting residue purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to yield the desired product (0.274 g) as an off white foam. MS (ESI+) for C23H47N7O2 m/z 574.6 [M+H]+; MS (ESI−) for C33H45N7O2 m/z 572.4 [M−H]−; HPLC purity >86% (ret. time, 2.918 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.078 (s, 1H), 7.497 (s, 1H), 7.416-7.396 (m, 1H), 7.305-7.284 (m, 1H), 7.216-7.200 (m, 1H), 6.621-6.612 (d, J=3.6 Hz, 1H), 4.368-4.334 (m, 1H), 3.930-3.894 (m, 1H), 2.934-2.918 (m, 1H), 2.866-2.797 (m, 2H), 2.652-2.583 (m, 1H), 2.444-2.361 (m, 2H), 2.287-2.199 (m, 2H), 2.166-2.119 (m, 3.5H (contains methine of trans isomer)), 2.048-2.012 (m, 1H), 1.921-1.748 (m, 3.5H (contains methine of cis isomer)), 1.622-1.494 (m, 2H), 1.380 (s, 9H), 1.269-1.252 (m, 1H), 0.932-0.879 (m, 6H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]([N:9](CC#C)[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH2:8].CN(C)P(N(C)C)(N(C)C)=O.IC>O1CCCC1.CCCCCC>[CH2:6]([N:9]([CH2:1][C:2]#[C:3][CH3:4])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH2:8]
Reactant: C#CCN(CC=C)C(=O)OC(C)(C)C
Reactant: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CI
Product: C=CCN(CC#CC)C(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 75.7 %

Procedure:
A 2.5 M hexane solution of n-butyllithium (40.8 mL, 102 mmol) was added dropwise over 30 min to a solution of tert-butyl allyl(prop-2-ynyl)carbamate (17.3 g, 89 mmol) in tetrahydrofuran (100 mL) at −10° C. After 5 min at −10° C., hexamethyl phosphoramide (17.73 mL, 102 mmol) and iodomethane (7.20 mL, 115 mmol) were added sequentially. The resultant mixture was stirred at −10° C. for 1 h, at ambient temperature for 1 h and quenched with saturated ammonium chloride (50 mL). After evaporation of the tetrahydrofuran solvent in vacuo, the residue was diluted with ethyl acetate (400 mL), washed with water, brine, dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-100% dichloromethane in hexanes, gave tert-butyl allyl(but-2-yn-1-yl)carbamate (14.1 g, 76% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 5.62-5.92 (1 H, m), 4.93-5.40 (2 H, m), 3.63-4.11 (4 H, m), 1.81 (3 H, s), 1.48 (9 H, s).