Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24].O.O.C([O-])(=O)C.[Zn+2:52].C([O-])(=O)C.O>CC(C)=O>[Zn:52].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H]1O[C@@H](CC(=O)OO)[C@H](C)C[C@@H]1C)[C@H]1O[C@](C)([C@]2(O)O[C@](CC)([C@@H](O)CC)C[C@H]2C)C[C@@H]1C
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: [Zn]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 13.0 g of sodium lysocellin and 5.0 g zinc acetate dihydrate in 150 ml of acetone was stirred at ambient temperature for approximately 18 hours. Stirring was continued and two volumes of water were added slowly to precipitate the zinc salt. The product was isolated and dried (14.0 g). The zinc salt was recrystallized from acetone. The resulting solid product had a melting point of 102.0° C. Analysis: % Zn calculated (4.95); Found (4.37).
Reaction SMILES: C(=O)([O-])[O-].[Zn+2:5].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9]([OH:11])=[O:10]>O>[Zn:5].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: [Zn+2]
Agent: N[C@@H](CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Product: [Zn]

Procedure:
20 g of zinc carbonate (zinc content: 32%) was dispersed in 500 ml of water and dissolved therein by stirring, and 60 g of aspartic acid was added thereto to perform a reaction, then the solution was continually stirred until the zinc carbonate and aspartic acid were entirely dissolved. Bubbles were generated in the initial stage of the reaction but they disappeared after a certain time. The resulting reaction solution was centrifuged to remove insoluble materials, and the clear supernatant was separated. The supernatant was freeze-died to obtain about 72 g of zinc-aspartic acid chelate.
Reaction SMILES: [CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].[CH3:40][S:41]([OH:44])(=[O:43])=[O:42].[Cl-].[Zn+2:46].[Cl-].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>[Cl-].[Cl-].[Zn+2].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>[Zn:46].[CH3:1][C:2]([N:4]([OH:39])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([CH2:13][CH2:14][C:15]([N:17]([OH:38])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([CH2:26][CH2:27][C:28]([N:30]([OH:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH2:36])=[O:29])=[O:25])=[O:16])=[O:12])=[O:3].[CH3:40][S:41]([OH:44])(=[O:43])=[O:42]
Reactant: [Zn+2]
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Agent: CS(=O)(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: [Zn]

Procedure:
10 ml of sterile solution containing 500 mg Desferal, 10.4 mg zinc chloride and 1 gr of glucose is prepared by dissolving the contents of one vial of Desferal in ZnCl2 /glucose sterile solution.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>CCCCCC>[CH3:8][C:6]1[CH:7]=[C:2]([B:15]([OH:20])[OH:16])[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C)cc(B(O)O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-m-xylene (1.5 g in 15 mL of dry tetrahydrofuran) at -78° C. was added 6.4 mL of a 1.4M solution of butyllithium in hexane and the mixture stirred for 20 minutes. At this time triisopropyl borate (2.8 mL) was added and the mixture allowed to warm to room temperature. After 1.5 hours the reaction was concentrated in vacuo to 1/3 volume then cooled to 0° C. and treated with 2N hydrochloric acid (9 mL) followed by warming to room temperature. After 4 hours the mixture was made basic by the addition of 2.5M sodium hydroxide and partitioned between ethyl ether (75 mL) and 1.25M sodium hydroxide. The organic layer was extracted with 1.25M sodium hydroxide (2×) and the aqueous portion then cooled to 0° C. and acidified to pH 3 by the dropwise addition of conc. hydrochloric acid. The white slurry was dissolved in methylene chloride, the organic portion dried over magnesium sulfate and concentrated in vacuo to provide the title compound (960 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[OH:18][C:19]1[CH:20]=[C:21]([O:33][CH:34]([CH3:36])[CH3:35])[CH:22]=[C:23]([CH:32]=1)[C:24]([NH:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1)=[O:25].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:18][C:19]2[CH:32]=[C:23]([C:24](=[O:25])[NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)[CH:22]=[C:21]([O:33][CH:34]([CH3:36])[CH3:35])[CH:20]=2)=[N:6][CH:5]=1
Reactant: CC(C)Oc1cc(O)cc(C(=O)Nc2nccs2)c1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Oc2cc(OC(C)C)cc(C(=O)Nc3nccs3)c2)nc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
After adding 123 mg (0.72 mmol) of 6-chloronicotinic acid methyl ester and 199 mg (1.44 mmol) of potassium carbonate to a solution of 100 mg (0.36 mmol) of the obtained amide compound in N,N-dimethylformamide (10.0 ml), the mixture was stirred at 80° C. for 18 hours under a nitrogen atmosphere. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was dried and then concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain the title compound as a white solid. The analysis data for the compound obtained in Production Example 65 are shown below.
Reaction SMILES: [CH:1]1[C:23]2=[C:24]3[C:4]4[C:5]([CH:17]=[CH:18][C:19]3=[C:20](S([O-])(=O)=O)[CH:21]=[C:22]2[OH:25])=[C:6](S([O-])(=O)=O)[CH:7]=[C:8](S([O-])(=O)=O)[C:3]=4[CH:2]=1.[Na+:30].[Na+].[Na+].[S:33](=O)(=[O:36])([OH:35])[OH:34]>>[OH:25][C:22]1[CH:21]=[CH:20][C:19]2[C:24]3=[C:4]4[C:5]([CH:6]=[CH:7][CH:8]=[C:3]4[C:2]([S:33]([O-:36])(=[O:35])=[O:34])=[CH:1][C:23]=13)=[CH:17][CH:18]=2.[Na+:30]
Reactant: O=S(=O)([O-])c1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34
Reactant: O=S(=O)(O)O
Agent: [Na+]
Product: O=S(=O)([O-])c1cc2c(O)ccc3ccc4cccc1c4c32
Yield: 10 %

Procedure:
The synthesis of mono-CysMA is given in Scheme 1. Reaction of HPTS with 30% sulfuric acid at 150° C. for 20 min gave sodium 3-hydroxypyrene-5-sulfonate 1 in 10% yield. Acetylation of 1 followed by chlorination of 2 gave intermediate 3. The polymerizable group was attached via the cysteic acid moiety in compound 4 and reacted with 3 to give compound 5. Chlorosulfonation of 5 was achieved without affecting the polymerizable group and after purification on polystyrene beads gave mono-CysMA in 50% yield over two steps. The dye was characterized by 1H NMR, HPLC, and MS.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH2:13](Br)[C:14]#[CH:15]>CC(C)=O>[N:7]1([CH2:15][C:14]#[CH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C#CCBr
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of cesium carbonate (1.6 g) and morpholine (0.437 ml) in acetone (10 ml) was added propargyl bromide (557 μl of 80% wt. in toluene) dropwise. The mixture was stirred at room temperature for 18 hours. The insoluble material was removed by filtration and the filtrate concentrated. The residue dissolved in ethyl acetate, washed with saturated NaHCO3 solution, dried (magnesium sulfate) and concentrated to yield 3-(4-morpholinyl)-1-propyne as a brown oil (494 mg); NMR Spectrum: (DMSOd6) 2.19 (t, 1H), 2.50 (m, 4H), 3.22 (d, 2H), 3.67 m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH3:7])[C:4](=[O:6])[CH3:5].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:5][C:4](=[O:6])[C:3]([O:8][CH3:9])([O:2][CH3:1])[CH3:7]
Reactant: COC(OC)N(C)C
Reactant: COC(C)(OC)C(C)=O
Product: COC(C)(OC)C(=O)C=CN(C)C
Temperature: 10 °C
Reaction time: 42 h
Yield: 99.5 %

Procedure:
A mixture of 100 g of 3,3-dimethoxy-2-butanone and 99.2 g of N,N-dimethylformamide dimethylacetal was stirred at 10° C. for 42 hours. After cooling the reaction mixture, the mixture was concentrated under reduced pressure to give 141 g of 1-dimethylamino-4,4-dimethoxy-1-penten-3-one.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8](O)[CH:9]=1)[CH2:5][OH:6].C(O)C1C=CC=CC=1.[C:19]([O-:27])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:5]([O:27][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:6])[C:4]1[CH:7]=[CH:8][CH:9]=[CH:2][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: OCc1cc(O)cc(O)c1
Agent: CN(C)c1ccncc1
Solvent: OCc1ccccc1
Solvent: c1ccncc1
Product: O=C(OC(=O)c1ccccc1)c1ccccc1

Procedure:
The synthesis of organotelluride catalysts based on 3,5-dihydroxybenzyl alcohol (1) is shown in FIG. 11. 3,5-Bis[3-(tert-butyldimethylsilyloxy)propyl-1-oxy]benzyl alcohol (5) (Francavilla et al., J. Am. Chem. Soc., 123:57 et al. (2001), which is hereby incorporated by reference in its entirety) was converted to the corresponding benzoate 6 in 99% isolated yield with benzoic anhydride and pyridine in the presence of catalytic DMAP. The silyl protecting groups were removed with HF-pyridine to give diol 7 in 89% isolated yield. Diol 7 was converted to the corresponding dibromide 8 in two steps (Wendler et al., Tetrahedron, 3:144 et al. (1958), which is hereby incorporated by reference in its entirety). The mesylate was first prepared, but not isolated, and was then treated in situ with lithium bromide to give dibromide 8 in 87% isolated yield. The addition of PhTeNa to 8 gave 9a with two phenyltelluro groups in 65% isolated yield; 4-Me2NC6H4TeNa, 9b with two dimethylaminophenyltelluro groups in 92% isolated yield; and n-C6H13TeNa, 9c with two hexyltelluro groups in 62% isolated yield.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(Cn2cnnc2[C@H]2CCCN2)cc1

Procedure:
De-Boc by TFA procedure: A solution of Boc-protected triazole from Example 3 (0.35 g, 0.9645 mmol) in 10 mL of TFA and 10 mL of CH2Cl2 was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and then treated with saturated aqueous Na2CO3 (30 mL), extracted with CH2Cl2 (4×40 mL), dried over Na2SO4, and concentrated in vacuo. The desired product was obtained as a pale yellow oil (0.13 g, 51.3%).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][CH:14]=3)[C:9]2=[O:23])=CC=1.[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.O>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][CH:14]=2)[C:9](=[O:23])[NH:8][CH2:17]1
Reactant: COc1ccc(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CNC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.7 %

Procedure:
A solution of 2-(4-methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (1.2 g, 3.52 mmol) and cerium ammonium nitrate (5.78 g, 10.56 mmol) in acetonitrile (30 ml) and water (15 ml) was stirred at 0° C. for 1 hrs, after this time the reaction was warmed to room temperature and stirred for a further 15 h. The solvent was evaporated in vacuo and dichloromethane added. The organic phase was separated, washed with saturated aqueous ammonium chloride solution and brine, then dried and evaporated in vacuo. The crude residue was purified by flash column chromatography (15% ethyl acetate in dichloromethane) to afford the title compound (300 mg, 39%). HPLC retention time 3.71 min. Mass spectrum (ES+) m/z 221 (M+H).
Reaction SMILES: [F:1][C:2]([F:11])([CH2:7][C:8]([O-])=[O:9])[C:3]([O:5][CH3:6])=[O:4].CO>O1CCCC1>[F:1][C:2]([F:11])([CH2:7][CH2:8][OH:9])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)(F)CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(F)(F)CCO
Temperature: 80 °C

Procedure:
In a 4 L flask equipped with a reflux condenser and 1 L dropping funnel, a solution of BH3.Me2S complex (10M, 88 mL) in dry dicholoromethane (1 L) is slowly added over a 2 hour period to a stirred solution of the methyl 2,2-difluorosuccinate (120 g, 0.714 moles) in dry tetrahydrofuran at 20° C. After refluxing (bath temperature 80° C.) for about 15 hours, the mixture is allowed to cool to room temperature and methanol (1 L) is slowly added. Evaporation yields methyl 2,2-difluoro-4-hydroxybutyrate as an oil which is stripped with methanol (1 L) and finally with CCl4 to yield a yellow oil: 100 g (92%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[N:9]=[CH:8][NH:7][C:6]2=[O:15].COC1C=CC=C2C=1C(OC)=NC(=O)N2.Br.N>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][NH:7][C:6]2=[O:15]
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Agent: Br
Agent: COc1cccc2[nH]c(=O)nc(OC)c12
Agent: N
Product: O=c1[nH]cnc2cc(O)c(O)cc12
Temperature: 100 °C
Yield: 84 %

Procedure:
To 6,7-dimethoxy-4(3H)-quinazolinone, 10 (3.0 g, 14.5 mmol) was added 48% HBr (36 mL) and the solution was heated to reflux at 100° C. for 12 h. The reaction mixture was cooled to room temperature and the solids were filtered. The solid obtained was neutralized with aq. NH3 (pH=8) and the solution was filtered and washed with water and dried to give 6,7-dihydroxy-4(3H)-quinazolinone, 11 as a off-white crystalline solid (2.20 g, 84%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.Cl.[CH2:12](O)[CH3:13]>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:12][CH3:13])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl
Product: CCOC(=O)c1cccc(Br)n1
Yield: 92 %

Procedure:
6-Bromo-2-pyridinecarboxylic acid (925 mg, 4.95 mmol) (Aldrich) was dissolved in hydrochloric acid/ethanol (1.25 M, 20 ml) and stirred under reflux for 3 h. Then the solvent was evaporated under reduced pressure. The remaining residue was taken up with DCM and washed with saturated aqueous NaHCO3 solution. Evaporation of the solvent afforded the title compound (1.045 g, 92%). The material was used in the following step without any further purification; 1H-NMR (300 MHz, CDCl3) δ (ppm): 8.1-8.0 (m, 1H), 7.8-7.5 (m, 2H), 4.4 (q, 2H), 1.4 (t, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][Si:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][CH2:10][OH:11]>ClCCl>[CH3:6][Si:7]([CH3:13])([CH3:12])[CH2:8][CH2:9][CH2:10][OH:11].[CH3:1][S:2]([O-:4])(=[O:11])=[O:3]
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)CCCO
Solvent: ClCCl
Product: CS(=O)(=O)[O-]
Reaction time: 0.75 h

Procedure:
Methanesulfonylchloride (0.73 ml, 9 mmol) was added dropwise to a solution of 3-(trimethylsilyl)-1-propanol (1.2 ml, 7.56 mmol) cooled at 0° C. in 20 ml of dichloromethane. After 45 minutes stirring, the reaction mixture was partitioned between water and dichloromethane, the organic phase was separated, the solvent was evaporated under reduced pressure to afford the expected 3-(trimethylsilyl)-1-propanol, methanesulfonate in crude quantitative yield.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1ccccc1Br
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Product: N#Cc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Yield: 100 %

Procedure:
A mixture of 2-bromobenzonitrile (34.6 g, 190 mmol) and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (76.1 g, 285 mmol) were coupled as described in Example 2 to afford 2′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a beige solid (46 g, 100%): δH (360 MHz, CDCl3) 7.37-7.42 (1H, m), 7.53 (1H, d, J 8), 7.59 (1H, td, J 8 and 1), 7.75 (1H, td, J 8 and 1), 7.83 (1H, dd, J 8 and 1), 8.35-8.39 (2H, m).
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.ClCCl.Br[CH2:22][CH2:23][CH2:24][Cl:25].C(N(CC)CC)C>CCCCCC>[Cl:25][CH2:24][CH2:23][CH2:22][N:13]1[CH2:14][CH2:15][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:16])[F:17])[CH:5]=2)[CH2:11][CH2:12]1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCCCBr
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cccc(N2CCN(CCCCl)CC2)c1
Temperature: 25 °C

Procedure:
To a 100 mL flask was added 1-(3-trifluoromethylphenyl)piperazine HCl (5035 mg, 18.88 mmol) and 60 mL dichloromethane. 1-Bromo-3-chloropropane (1730 ul, 20.78 mmol, 1.10 eq) was added, then triethylamine (5.25 mL, 37.7 mmol, 2.00 eq). The solution was refluxed for 9 hours, then cooled to 25° C. 100 mL of hexane was then added, and the resulting suspension was vacuum filtered. The filtrate was concentrated in vacuum and purified by column chromatography using dichloromethane as eluant resulting in an oil of 1-(3-Chloropropyl)-4-(3-trifluoromethylphenyl)piperazine.
Reaction SMILES: C(N[C@H](C(O)=O)CCCCN)(OC(C)(C)C)=O.C([NH:25][C@H:26]([C:32]([OH:34])=[O:33])[CH2:27][CH2:28][C:29](=[O:31])[NH2:30])(OC(C)(C)C)=O>>[NH2:25][C@H:26]([C:32]([OH:34])=[O:33])[CH2:27][CH2:28][C:29](=[O:31])[NH2:30]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Product: NC(=O)CC[C@H](N)C(=O)O

Procedure:
To the product of Step (B) above, the P-nitrophenyl ester of Boc-L-Glutamine [Gln (ONp), Peninsula, supra.] is coupled following the procedure of Step (E), Example 1, supra.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:24]=[C:23]([NH:25][C@:26]([CH3:32])([CH2:30][CH3:31])[C:27](O)=[O:28])[CH:22]=[CH:21][N:20]=2)=[CH:11]1.CCCP(=O)=O.[F:39][C:40]([F:44])([F:43])[CH2:41][NH2:42]>O.ClCCl>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[N:24]=[C:23]([NH:25][C@:26]([CH3:32])([CH2:30][CH3:31])[C:27]([NH:42][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:28])[CH:22]=[CH:21][N:20]=2)=[CH:11]1
Reactant: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)O
Reactant: NCC(F)(F)F
Agent: CCCP(=O)=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@](C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)NCC(F)(F)F
Temperature: 0 °C

Procedure:
Diisopropylethylamine (DIEA) (3.61 kg, 28.1 moles, 2.5 equiv.) was added to (R)-2-(2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-ylamino)-2-methylbutanoic acid (4a) (3.5 kg, 11.24 moles, 1.0 equiv.) in 7 volumes (32.6 kg) of dichloromethane (CH2Cl2 or DCM) while keeping the temperature at ≦30° C. Water (0.103 kg) was added to make 5.5±0.5% total water content for the reaction system, and the mixture was stirred at ≦30° C. for at least 30 minutes. The reaction mixture was cooled to 0±5° C. Propylphosphonic anhydride solution (17.9 kg, 28.1 moles, 2.5 equiv.) was added to the mixture while maintaining the temperature below 20° C. The mixture was agitated for at least an hour keeping the temperature at 20±5° C., then 2,2,2-trifluoroethylamine (1.68 kg, 16.86 moles, 1.5 equiv.) was added while maintaining the temperature below 20° C. The reaction mixture was warmed to 25±5° C. and agitated for 5 hours while holding the temperature. A 1.0 mL aliquot was removed and the reaction was determined to be 100% complete. Water (17.5 kg, 5 volumes) was added to the reaction mixture, and the resultant mixture was agitated for at least 30 minutes while maintaining the temperature below 30° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][N:10]([CH3:12])[CH:11]=1.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C(OCC)C>[CH3:12][N:10]1[CH:11]=[C:7]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]=[N:9]1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cn1cc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cnn(C)c1

Procedure:
To a precooled (<−10° C. internal temperature) solution of 1.6M n-butyl lithium in hexanes (100 ml) in anhydrous diethyl ether (100 ml) under argon was added a solution of 4-bromo-1-methyl-1H-pyrazole (23.42 g) from Example 111 in diethyl ether (50 ml) at a rate to maintain the temperature. The reaction was allowed to stir for a further 20 minutes before tributyltin chloride (43.4 ml) was added in diethyl ether (50 ml). The reaction temperature was allowed to rise to 20° C. The reaction was diluted with diethyl ether and the insoluble material removed by suction filtration. Evaporation of the solvent in vacuo afforded 56 g of the title compound as an oil. MS, m/z: 373 [M+H]+. Residual amounts of tin residues were removed from the oil by distillation using a kugelrohr apparatus under high vacuum at 170° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10](OC)=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
A solution of methyl 1H-indazole-5-carboxylate (825 mg, 4.68 mmol) in tetrahydrofuran (20 ml) was added to a solution of lithium aluminum hydride (580 mg, 14.1 mmol) in tetrahydrofuran (16 ml) at 0° C. and stirred at 0° C. for 1 hour. A mixture of tetrahydrofuran (10 ml) and water (10 ml) was added to the reaction solution and the resulting mixture was filtered. The filtrate was concentrated and the resulting residue was diluted with chloroform and washed with a 1N-aqueous sodium hydroxide solution and then a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby 1H-indazole-5-ylmethanol (260 mg, 38%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[NH:10][NH2:11].C(O[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18])C.C(O)(=O)C>O>[NH2:20][C:19]1[N:10]([C:3]2[CH:4]=[CH:5][C:6]([Cl:9])=[C:7]([Cl:8])[C:2]=2[Cl:1])[N:11]=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccc(Cl)c(Cl)c1Cl
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Temperature: 0 °C
Yield: 64.7 %

Procedure:
A solution of 15 g of 2,3,4-trichlorophenylhydrazine, 8.7 g of (ethoxymethylene)malononitrile, 100 ml of glacial acetic acid and 50 ml of water was refluxed for 3 hours. The reaction mixture was cooled, poured into ice water and the precipitated solid was collected by filtration and dried. This solid was dissolved in ethyl acetate and the resulting solution was washed twice with saturated sodium bicarbonate, once with 100 ml of water, once with 100 ml of saturated brine and dried over anhydrous magnesium sulfate. The organic phase was evaporated under reduced pressure and the residue was recrystallized from ethanol to give 13.2 g of 5-amino-1-(2,3,4-trichlorophenyl)-1H-pyrazole-4-carbonitrile. Yield 66%. mp=140°-142° C.