Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][C:7]2[N:8]=[C:9]([NH:11][C@H:12]([C:20](O)=[O:21])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[Li]C.[CH3:27]COCC.Cl[Si](C)(C)C>C1COCC1>[CH:1]([C:4]1[CH:24]=[CH:23][C:7]2[N:8]=[C:9]([NH:11][CH:12]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20](=[O:21])[CH3:27])[S:10][C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(C)c1ccc2nc(N[C@@H](Cc3ccccc3)C(=O)O)sc2c1
Agent: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C(Cc1ccccc1)Nc1nc2ccc(C(C)C)cc2s1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A solution of 2 g N-(6-isopropylbenzothiazol-2-yl)phenylalanine (5.9 mmol) in 60 mL THF was cooled on an ice-salt bath to -5° C., under nitrogen. A solution of 1.4N MeLi in ether (26 mL, 36.4mmol) was added via syringe over about one minute. After two hours 10 mL chlorotrimethylsilane (78 mmol) was added rapidly and the reaction warmed up to room temperature. The reaction was quenched with 1N HCl and the product extracted into ether, dried (Na2SO4) and concentrated. The product was purified by flash chromatography thru silica gel, eluting with CH2Cl2. Recrystallization from EtOH gave 0.75g product (2.2 mmol, 38%), mp 107°-110° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][N:15]3[C:19]4=[N:20][C:21]([C:24]5[CH:25]=[CH:26][C:27]([F:32])=[C:28]([CH:31]=5)[C:29]#[N:30])=[CH:22][N:23]=[C:18]4[N:17]=[N:16]3)[CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:39][C:40]1[CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:45]=[CH:44][C:41]=1[CH:42]=[O:43]>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.O1CCOCC1>[F:32][C:27]1[CH:26]=[CH:25][C:24]([C:21]2[N:20]=[C:19]3[N:15]([CH2:14][C@H:10]4[O:11][CH2:12][CH2:13][N:8]([C:5]5[N:4]=[CH:3][C:2]([C:46]6[CH:45]=[CH:44][C:41]([CH:42]=[O:43])=[C:40]([F:39])[CH:47]=6)=[CH:7][N:6]=5)[CH2:9]4)[N:16]=[N:17][C:18]3=[N:23][CH:22]=2)=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(Br)cn5)CCO4)c3n2)ccc1F
Reactant: CC1(C)OB(c2ccc(C=O)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(C=O)c(F)c6)cn5)CCO4)c3n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
In a pressure tube reactor, ((S)-5-(1-((4-(5-bromopyrimidin-2-yl)morpholine-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-2-fluorobenzonitrile (50 mg, 0.10 mmol) was added, and then 1M Na2CO3 (0.31 mL, 0.31 mmol) was added. Pd(PPh3)4 (6 mg, 0.005 mmol) was further added, and 1,4-dioxane (1 mL) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzaldehyde (38 mg, 0.15 mmol) were added. The mixture was stirred at room temperature for 10 minutes under nitrogen gas, and then stirred at 105° C. for 3 hours. When the reaction was completed, the organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. Solid was generated using ether and hexane, followed by filtration, to give (S)-2-fluoro-5-(1-((4-(5-(3-fluoro-4-formylphenyl)pyrimidin-2-yl)morpholin-2-yl)methyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)benzonitrile (49 mg, 0.091 mmol) with a yield of 90%.
Reaction SMILES: [I-].[C:2]([C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][NH+:6]=1)([OH:4])=O.[N:12]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[I:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:2]([N:15]2[CH2:16][CH2:17][CH2:18][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:14]2)=[O:4])[CH:10]=1
Reactant: O=C(O)c1cc(I)cc[nH+]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(I)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-carboxy-4-iodopyridinium iodide (1 eq) in DMF were added tert-butyl 1-homopiperazinecarboxylate (2.05 eq), HBTU (2.05 eq) and DIPEA (2.05 eq) and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and washed with 0.5N HCl solution and brine. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The resulting crude was used as such in the next step without purification. MS (ES) C16H22IN3O3 requires: 431, found: 432 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[C:13]([NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][CH:23]=[N:22][C:21]=23)=[O:16])=[CH:12][NH:11][N:10]=1.IC.[C:28](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:10]([CH3:28])[N:11]=[CH:12][C:13]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=12)=[O:16]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C)c(-c2n[nH]cc2NC(=O)c2cnn3cccnc23)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(C)c(-c2c(NC(=O)c3cnn4cccnc34)cnn2C)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-(3-(2,5-dimethylphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.255 g, 0.767 mmol, 1 eq) in 10 mL N,N-dimethylformamide is added iodomethane (60.0 μL, 0.964 mmol, 1.26 eq) and cesium carbonate (0.562 g, 1.72 mmol, 2.25 eq). The reaction mixture is stirred at 40° C. for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, and concentrated. The mixture of regioisomeric products was separated and purified by flash chromatography on silica gel (20 to 90% ethyl acetate in dichloromethane) to yield: 84.3 mg (32%) of N-(3-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=347.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1H), 9.30 (d, 1H), 8.65 (s, 1H), 8.47 (d, 1H), 8.27 (s, 1H), 7.27 (d, 1H), 7.23-7.19 (m, 3H), 3.91 (s, 3H), 2.33 (s, 3H), 2.25 (s, 3H), and 81.8 mg (31%) of N-(5-(2,5-dimethylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=347.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 1H), 9.30 (d, 1H), 8.61 (s, 1H), 8.43 (d, 1H), 8.01 (s, 1H), 7.36 (d, 1H), 7.30 (d, 1H) 7.20 (m, 2H), 3.62 (s, 3H), 2.35 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]4[OH:25])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]4[OH:25])[C:14]([F:26])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](O)[C@H]4O)n3)c3cc(Cl)cnc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O[C@@H]1[C@H](O)CCC[C@@H]1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Reaction time: 1 h

Procedure:
To a solution of (1R,2S,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)cyclohexane-1,2-diol, 31c, (0.11 g, 0.21 mmol) in THF was added TBAF (0.23 g, 0.84 mmol). The reaction was aged at room temperature 1 hour, quenched with 1N HCl (1 ml), and purified via reverse phase chromatography (5-70% MeCN/H2O with 0.1% TFA). The product was desalted on an SPE bicarbonate cartridge, concentrated to dryness, and then triturated from MeOH to provide 18 mg of compound 632.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]3[CH:12]=[CH:13][C:14]([O:16]C)=[CH:15][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](I)(C)C>C(Cl)(Cl)Cl.CO.[Cl-].[Na+].O>[C:1]1([C:7]2[O:11][C:10]3[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc2oc(-c3ccccc3)cc2c1
Agent: C[Si](C)(C)I
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1ccc2oc(-c3ccccc3)cc2c1
Temperature: 50 °C
Yield: 87.5 %

Procedure:
A solution of 2-phenyl-5-methoxybenzo[b]furan (K K Thomas and M M Bokadia, J Indian Chem. Soc. 1966, 43, 713) (0.5 g, 2.23 mmol) in absolute chloroform (4 ml) was treated with trimethylsilyl iodide (0.44 ml, 3.09 mmol) and warmed at 50° C. for 48 h. A further quantity (0.22 ml) of trimethylsilyl iodide was added during this period. The reaction mixture was diluted with methanol (20 ml), treated with brine (40 ml) and extracted into diethyl ether (2×40 ml). The combined extracts were washed with aqueous sodium metabisulphite, followed by brine (40 ml) and dried over sodium sulphate. After concentration in vacuo the residue was distilled to give the title compound as a colourless solid (0.41 g, 88%) b.p. 250° C., 0.1 mm Hg (Kugelrohr).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].[N+](=[CH:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22])=[N-]>>[CH3:5]/[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:10])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])=[CH:3]\[CH2:2][O:1][CH2:19][P:20](=[O:25])([O:23][CH3:24])[O:21][CH3:22]
Reactant: COP(=O)(C=[N+]=[N-])OC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Product: COP(=O)(COC/C=C(\C)CC/C=C(\C)CCC=C(C)C)OC
Temperature: 25 °C
Yield: 36.4 %

Procedure:
(E,E)-Farnesol, (5.0 mmol, 1.11 g, 1.26 ml) was stirred under argon in 10 ml of dry deoxygenated benzene (10 ml) and treated in one portion with ##STR87## (1.0 mmol, 0.442 g). The dark blue/green solution was stirred at room temperature and a solution of (1.5 g, 10.0 mmol) of dimethyl diazomethylphosphonate (prepared according to D. Seyferth et al, J. Org. Chem., 1971, vol. 36, No. 10, pages 1379 to 1386) in 20 ml of dry, deoxygenated benzene was added dropwise over 4 hours via syringe pump. After addition, the reaction mixture was stirred an additional 45 minutes. The reaction mixture was stripped of solvent and applied as a 75% ethyl acetate/Hexane solution to a flash chromatography column (50 mm diameter, 6" of silica gel) eluted with 75% ethyl acetate/hexane to afford 0.627 g, (36% yield), of the ether as a dark blue/green oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]2[NH:25][C:26]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=3[N:28]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.CCOCC>CCCCCC>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:33][C:31]1[CH:30]=[CH:29][C:27]2[N:28]=[C:24]([S:23][CH2:22][CH2:21][N:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[NH:25][C:26]=2[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCSc2nc3ccc(F)cc3[nH]2)CC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: Fc1ccc2nc(SCCN3CCNCC3)[nH]c2c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
While trifluoroacetic acid (17 mL) was stirred under cooling with ice, 1-tert-butoxycarbonyl-4-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazine (6.50 g, 17.08 mmol) was added to the acid over 30 minutes and dissolved thereto. The temperature of the mixture was allowed to room temperature, and the mixture was stirred for 30 minutes. Thereafter, ether and hexane were added thereto, and the formed solid was collected through filtration. The collected product was washed with ether, to thereby yield 1-[2-(5-fluorobenzimidazol-2-ylthio)ethyl]piperazine tris(trifluoroacetic acid) salt (10.50 g, yield 99%) as a brown powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH2:20][NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:17]=[N:18][CH:19]=1.[CH3:27]C(C)([O-])C.[K+].CI.O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:14]1[CH:15]=[C:16]([CH2:20][N:21]([CH3:27])[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:17]=[N:18][CH:19]=1
Reactant: CCS(=O)(=O)NCc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)Cc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a solution of ethanesulfonic acid [5-(7-fluoro-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 16, 0.15 g, 0.39 mmol) in DMF (5 mL) was added potassium tert-butoxide (67.2 mg, 0.60 mmol) at 0° C. The resulting mixture was stirred for 30 minutes at 0° C. before methyl iodide (84.6 mg, 0.6 mmol) was added dropwise. After stirring for 2 hours, the mixture was treated with water, and extracted with EtOAc. The combined organic layers were then washed with water and brine in sequence, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 5% methanol in dichloromethane) to afford the title compound (93 mg, 60%) as a white solid. MS: 392.1 (M+H+)+.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]1[S:14][C:13]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)=[O:17])=[N:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:46])C=1>ClCCl>[C:2]1([CH2:1][S:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C@H:24]4[CH2:29][CH2:28][C@H:27]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25]4)=[CH:22][CH:23]=3)=[O:17])=[N:12][N:11]=2)=[O:46])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CSCc4ccccc4)s3)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CS(=O)Cc4ccccc4)s3)cc2)CC1
Reaction time: 2 h

Procedure:
0.1 g of tert-butyl trans-{4-[4-(5-benzylsulfanylmethyl[1.3.4]thiadiazol-2-ylcarbamoyl)-phenyl]cyclohexyl}acetate (0.11 mmol, 1 eq.) is placed in 10 mL of dichloromethane with stirring. 0.027 g of 70% meta-chloroperbenzoic acid (0.11 mmol, 1 eq.) is added. After 2 hours, 0.01 g of 70% meta-chloroperbenzoic acid (0.41 mmol, 0.37 eq.) is added. After 16 hours, the reaction medium is diluted with dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic phase is dried and evaporated. The residue is triturated in ethyl acetate to give 0.072 g of tert-butyl trans-{4-[4-(5-phenylmethanesulfinylmethyl[1.3.4]thiadiazol-2-ylcarbamoyl)-phenyl]cyclohexyl}acetate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](O)=O)=[CH:5][C:4]([CH3:17])=[N:3]1.O=P(Cl)(Cl)[Cl:20].[NH4+].[OH-]>>[CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:9]([C:10]([Cl:20])=[C:5]2[C:4]([CH3:17])=[N:3]1)=[CH:13][CH:14]=[CH:15][CH:16]=3
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Nc2ccccc2C(=O)O)n(C)n1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nn(C)c2nc3ccccc3c(Cl)c12
Temperature: 0 °C

Procedure:
A mixture of N-(1,3-dimethyl-pyrazol-5-yl)anthranilic acid (7 g, 0.03 mol) and POCl3 (40 ml) was heated on a steam bath for 3 hours. The reaction mixture was then poured into ice-water (600 ml) and then basified with NH4OH. The mixture was extracted with ether (3×200 ml) and the combined ether layers were dried over MgSO4 and evaporated to afford 7.0 g of 1,3-dimethyl-4-chloro-1H-pyrazolo [3,4-b]quinoline, m.p. 127-129° C.
Reaction SMILES: C(OC([NH:11][C@@H:12]([C:14]([N:16]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH:17][C:18](=[O:39])[C@@H:19]([CH:24]([C:28](=[O:38])[NH:29][O:30]CC1C=CC=CC=1)[CH2:25][CH:26]=[CH2:27])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@@H:12]([C:14]([N:16]([CH2:40][CH:41]([CH3:42])[CH3:43])[NH:17][C:18](=[O:39])[C@@H:19]([CH:24]([C:28](=[O:38])[NH:29][OH:30])[CH2:25][CH2:26][CH3:27])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13]
Reactant: C=CCC(C(=O)NOCc1ccccc1)[C@@H](CC(C)C)C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCC(C(=O)NO)[C@@H](CC(C)C)C(=O)NN(CC(C)C)C(=O)[C@@H](C)N
Yield: 136.9 %

Procedure:
A solution of 0.560 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-[(benzyloxy)carbamoyl]-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 25 ml of methanol was hydrogenated in the presence of 0.150 g of 5% palladium-on-carbon for 2 hours. The catalyst was removed by filtration and the solvent was evaporated. The residue was triturated with diethyl ether to give 0.480 g of 2′-(D-alanyl)-2(R)-[1(RS)-(hydroxycarbamoyl)butyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid. This solid was then dissolved in 2 ml of dioxan and the solution was treated with 0.5 ml of 4M hydrogen chloride in dioxan. The mixture was stirred at room temperature for 15 minutes and then diluted with diethyl ether. Filtration and drying gave 0.188 g of 2′-(D-alanyl)-2(R)-[1(RS)-(hydroxycarbamoyl)butyl]-2′-isobutyl-4-methylvalerohydrazide hydrochloride in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH:5][CH:6]=[C:7]1[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]1=[O:16].Cl.Cl[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[I-].[K+]>[O:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][O:1][C:2]2[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[NH:5][CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:14])([CH3:15])[O:9][C:8]2=[O:16])[CH2:28][CH2:29]1
Reactant: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1O
Reactant: ClCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1OCCCN1CCOCC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 5-((3-hydroxy-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione, (prepared as described for the starting material in Example 3), 4-(3-chloropropyl)morpholine hydrochloride (680 mg, 3.57 mmol), (J. Amer. Chem. Soc. 1945, 67, 736), in DMF (25 ml) containing potassium carbonate (940 mg, 7.48 mmol) and potassium iodide (56 mg, 0.34 mmol) was stirred at 60° C. for 2 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4), the insoluble materials were removed by filtration and the volatiles were removed by evaporation. The residue was triturated with ether, collected by filtration and dried under vacuum to give 5-((3-(3-morpholinopropoxy)-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione 2735 mg, 5 1%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([OH:19])([CH2:16][CH:17]=[CH2:18])[C:4]#[C:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[H-].[Na+].[N+:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O-:26])=[O:25]>CN(C=O)C.O>[N+:24]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:19][C:3]([C:2]([F:1])([F:20])[F:21])([C:4]#[C:5][Si:6]([CH:13]([CH3:14])[CH3:15])([CH:10]([CH3:11])[CH3:12])[CH:7]([CH3:8])[CH3:9])[CH2:16][CH:17]=[CH2:18])=[O:32])=[CH:34][CH:35]=1)([O-:26])=[O:25]
Reactant: C=CCC(O)(C#C[Si](C(C)C)(C(C)C)C(C)C)C(F)(F)F
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(C#C[Si](C(C)C)(C(C)C)C(C)C)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 0.67 h
Yield: 96.5 %

Procedure:
To a 0° C. solution of crude 3-(trifluoromethyl)-1-(triisopropylsilyl)hex-5-en-1-yn-3-ol from Step 1 (242 mg, 0.755 mmol) in DMF (2 mL) was added NaH (60% disp., 32 mg, 0.793 mmol) in two portions. The mixture was allowed to reach room temperature and stirred for 40 min. A solution of 4-nitrobenzoyl chloride (147 mg, 0.793 mmol) in DMF (1 mL) was added dropwise. After 1.5 h, the mixture was poured in H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O (3×) and brine, dried (Na2SO4) and concentrated, affording the title compound (342 mg).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10]([CH2:18][CH3:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]2)[S:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26]([NH:28][C:29]([NH:31][C:32]1[S:33][C:34]2[C:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:39][C:38](B(O)O)=[CH:37][C:35]=2[N:36]=1)=[O:30])[CH3:27]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:18]([C:10]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12][N:7]([C:5]2[S:4][N:3]=[C:2]([C:38]3[CH:39]=[C:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=4)[C:34]4[S:33][C:32]([NH:31][C:29](=[O:30])[NH:28][CH2:26][CH3:27])=[N:36][C:35]=4[CH:37]=3)[N:6]=2)[CH2:8][CH2:9]1)[CH3:19]
Reactant: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Reactant: CCOC(=O)C1(CC)CCN(c2nc(Cl)ns2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3nsc(N4CCC(CC)(C(=O)OCC)CC4)n3)cc(-c3ccccn3)c2s1
Temperature: 110 °C

Procedure:
Ethyl 1-(3-chloro-1,2,4-thiadiazol-5-yl)-4-ethylpiperidine-4-carboxylate (110 mg, 0.35 mmol), cesium carbonate (285.6 mg, 0.88 mmol), Pd(dppf)2Cl2 (20 mg, 0.03 mmol) and {2-[(ethylcarbamoyl)amino]-7-(pyridin-2-yl)-1,3-benzothiazol-5-yl}boronic acid (100 mg, 0.29 mmol) was suspended in a mixture of THF (9 mL) and water (1 mL) and heated in the microwave at 110° C. for 50 min. The reaction mixture was concentrated in vacuo and the residue partitioned between 10% IPA/DCM (10 mL) and water (10 mL). The organic layer was separated and the aqueous extracted with further 10% IPA/DCM (3×10 mL), the organic layers were combined, dried (MgSO4), filtered and concentrated to give a black solid which was pre-absorbed onto silica and purified by flash column chromatography (Biotage SP4 12 g, 2% MeOH/DCM-5% MeOH/DCM-8% MeOH/DCM) to give the desired product as a brown solid. MS: 566.11 [M+H]+.
Reaction SMILES: C(OCCCC)CCC.[Na].[Na+].[Na+].[Na+].[P-3].[C:15]1([P:21](Cl)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:29](Cl)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O>[CH2:29]([P:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCCCCCCl
Agent: [Na+]
Agent: [Na]
Agent: [P-3]
Solvent: O
Solvent: CCCCOCCCC
Product: CCCCCCP(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 88 %

Procedure:
Distilled di-n-butyl ether (2500 ml) and solid sodium metal (230 g, 10.0 moles) were placed in a 22 L round bottom flask. The flask was equipped as in the above Comparative Example C-1. The solution of the sodium phosphide salt was made by carefully adding diphenylphosphinous chloride (1100 g, 5.0 moles) to the refluxing solvent-sodium slurry as described in the previous example. Stirring and reflux was continued for 2 hours after addition of the diphenylphosphinous chloride was complete. The reaction mixture was cooled with further stirring to about 45° C. n-Hexyl chloride (603 g, 5 moles) was added over a 30 minute period. Stirring was continued for 30 minutes after this addition was complete. Water (2500 ml) was added with stirring and the inorganic salts dissolved. Stirring was stopped and the lower water layer drained off and discarded. The upper organic layer was concentrated under vacuum giving crude n-hexyldiphenylphosphine (1190 g) of about 87 percent yield based on diphenylphosphinous chloride. This material was found to be about 20 percent n-hexyldiphenylphosphine oxide by GLC analysis.