Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[C:43]([S:45]([CH:48]([CH3:50])[CH3:49])(=[O:47])=[O:46])[CH:42]=[CH:41][C:40]=1[Cl:51]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:41]1[CH:42]=[C:43]([S:45]([CH:48]([CH3:49])[CH3:50])(=[O:46])=[O:47])[CH:44]=[CH:39][C:40]=1[Cl:51])([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CC(C)S(=O)(=O)c1ccc(Cl)c(Br)c1
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)S(=O)(=O)c1ccc(Cl)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-bromo-1-chloro-4-(isopropylsulfonyl)benzene (Intermediate 129), the title compound was obtained as a white solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38](C(OC(C)(C)C)=O)[CH:39]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[F:26][C:21]1[CH:20]=[C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:39]3[NH:38][N:37]=[CH:36][CH:35]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)c(F)c1
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: COCCOC
Product: O=C(Nc1cccnc1)c1cc(-c2ccn[nH]2)ccc1OCc1ccc(F)c(F)c1
Temperature: 120 °C

Procedure:
To a microwave vial was added 5-bromo-2-{[(3,4-difluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in Example 60; 120 mg, 0.29 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (93 mg, 0.32 mmol), 1,2-dimethoxyethane (2 ml), 1M sodium carbonate (0.57 ml, 0.57 mmol) and tetrakis(triphenylphosphine)palladium(0) (19.85 mg, 0.02 mmol). The vial was sealed and heated to 120° C. for 25 min under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3×10 ml). The organics were combined, evaporated under reduced pressure and the residue was purified using MDAP to yield the title compound. 65 mg.
Reaction SMILES: [OH:1][CH:2]1[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH2:3]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:12][CH2:11][CH2:10][CH2:9][N:4]1[CH2:3][CH:2]([OH:1])[C:6]2([CH2:7][CH2:8]2)[CH2:5]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCN1CC(O)C2(CC2)C1
Solvent: ClCCl
Product: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propanol (1.14 g, 6.67 mmol) and Et3N-(1.35 g, 13.34 mmol) in CH2Cl2 (20 mL) was added methanesulfonyl chloride (1.15 g, 10 mmol) dropwise at 0° C. The reaction was then stirred at 0° C. for 3 hrs. The reaction mixture was washed with cold water (10 mL) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the title compound as orange oil. The crude product was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[OH:28][CH2:29]C1C=C(B(O)O)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[OH:28][CH2:29][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=[O:21])=[O:22])[CH2:18][CH2:19]1
Reactant: OCc1cccc(B(O)O)c1
Reactant: COCCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COCCCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(CO)cc23)CC1
Yield: 67.5 %

Procedure:
Following the general procedure of Example 65, a mixture of 5-bromo-3-(1-{[3-(methyloxy)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 25) (30 mg, 0.065 mmol), [3-(hydroxymethyl)phenyl]boronic acid (40 mg, 0.26 mmols), cesium carbonate (42.5 mg, 0.13 mmol), and Pd(PPh3)4 (22 mg) in dioxane/water (2 mL/0.7 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (18.0 mg, 14%)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH3:33])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][C@@H:35]1[N:40]([CH3:41])[CH2:39][CH2:38][N:37]([CH2:42][CH2:43][OH:44])[CH2:36]1.[CH3:45][C@H:46]1N(C)[C@@H](C)CN(CCO)C1>>[CH:30]1([C:26]2[N:25]=[C:24]([CH2:23][N:18]3[C:19]4[C:15](=[C:14]([NH:13][C:11]([C:8]5[N:5]6[CH:6]=[CH:7][C:2]([O:44][CH2:43][CH2:42][N:37]7[CH2:38][CH2:39][N:40]([CH3:41])[C@@H:35]([CH3:34])[CH2:36]7)=[CH:3][C:4]6=[N:10][CH:9]=5)=[O:12])[CH:22]=[CH:21][CH:20]=4)[C:16]([CH3:33])=[N:17]3)[CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:46][CH2:45][CH2:31]1
Reactant: Cc1nn(Cc2cccc(C(C)C)n2)c2cccc(NC(=O)c3cnc4cc(Cl)ccn34)c12
Reactant: C[C@@H]1CN(CCO)C[C@H](C)N1C
Reactant: C[C@H]1CN(CCO)CCN1C
Product: Cc1nn(Cc2cccc(C3CCCC3)n2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)[C@@H](C)C5)ccn34)c12
Yield: 17 %

Procedure:
Prepared according to Example 7, Step F, substituting 7-chloro-N-(1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide for 7-chloro-N-(1-((6-isopropylpyridin-2-yl)methyl)-3-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide and (S)-2-(3,4-dimethylpiperazin-1-yl)ethanol for 2-((3R,5S)-3,4,5-trimethylpiperazin-1-yl)ethanol to give the title compound (17%). MS (APCI), positive scan, m/z=607.1 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:12]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:11]=2[O:10][C:4]2([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:3]1.S(Cl)([Cl:27])(=O)=O>ClCCl>[Cl:27][C:14]1[C:15]([O:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16][C:11]2[O:10][C:4]3([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:3][C:2](=[O:1])[C:12]=2[CH:13]=1
Reactant: CCOC(=O)COc1ccc2c(c1)OC1(CCCCC1)CC2=O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)COc1cc2c(cc1Cl)C(=O)CC1(CCCCC1)O2
Yield: 75 %

Procedure:
Ethyl 2-{(3,4-dihydro-4-oxospiro[2H-1-benzopyran-2,1'-cyclohexan]7-yl)oxy}acetate prepared in Preparation 28) (0.72 g, 2.26 mmol) is dissolved in dry dichloromethane (7.2 ml). To the solution is added dropwise 1M sulfuryl chloride solution in dichloromethane (2.3 ml, 2.3 mmol) at -40° C. with stirring. After 2 hours stirring at -40° to -10° C., the solvent is removed by distillation. The residue is dissolved in dichloromethane, and the solution is washed with water, dried, and concentrated. The residue is applied to a Lober column and eluted with a mixture of ethyl acetate and hexane (1:2). The resulting crude product is recrystallized from a mixture of diethyl ether and hexane to yield the title compound (0.6 g, yield 75%, m.p.=116°-117° C.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[F:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33][S:34][C:35]1[N:40]=[C:39]([NH:41][S:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)(=[O:44])=[O:43])[CH:38]=[C:37]([O:51][CH3:52])[N:36]=1.CN1CCOCC1>CN(C=O)C>[F:25][C:26]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:33][S:34][C:35]1[N:40]=[C:39]([NH:41][S:42]([N:45]2[CH2:46][CH2:47][N:48]([C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:49][CH2:50]2)(=[O:43])=[O:44])[CH:38]=[C:37]([O:51][CH3:52])[N:36]=1
Reactant: COc1cc(NS(=O)(=O)N2CCNCC2)nc(SCc2cccc(F)c2F)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: COc1cc(NS(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(tert-butoxycarbonyl)glycine (0.11 g) in DMF (10 mL) was added 1,3-Dicyclohexycarbodiimide (0.14 g) and 1-hydroxybenzotriazole hydrate (94 mg). After stirring at room temperature for 1 h, a solution of N-[2-[[(2,3-Difluorophenyl)methyl]thio]-6-methoxypyrimidin-4-yl]piperazine-1-sulfonamide, hydrochloride salt (the product of step i, 0.27 g) and N-methylmorpholine (78 μL) in DMF (5 mL) was added dropwise and stirring continued at room temperature for 24 h. The mixture was filtered, rinsed with DCM and the filtrate evaporated. The crude material was purified by column chromatography on silica gel using EtOAc/isohexane (3:2) as eluent to give the subtitle compound as a foam. Yield: 0.24 g
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[S:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH2:23][CH2:22]1>CN(C)C=O.C(OCC)C>[S:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]([CH2:12][C:10]([OH:11])([CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[C:13]([F:16])([F:15])[F:14])[CH2:23][CH2:22]1
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: c1ccc2c(c1)NCCS2
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCSc2ccccc21)C(F)(F)F

Procedure:
A solution of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (118 mg) and 3,4-dihydro-2H-1,4-benzothiazine (H. I. El-Subbagh et al., Arch. Pharm. Med. Chem., 1999, 332, pp. 19-24) (122 mg) in dimethylformamide (1 mL) was heated at 140° C. for 73 hours. The resulting mixture was diluted with diethyl ether, washed with saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by radial chromatography with a chromatotron (eluted with 0% to 1% ethyl acetate-hexanes) to give the title compound as a white solid (53.5 mg), m.p. 103° C.-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:29].[F:37][C:38]1[CH:60]=[CH:59][C:41]([CH2:42][N:43]2[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=3[N:45]=[C:44]2[C:52]2([OH:58])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:55]2[CH2:56][CH2:57][C:52]([C:44]3[N:43]([CH2:42][C:41]4[CH:59]=[CH:60][C:38]([F:37])=[CH:39][CH:40]=4)[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=4[N:45]=3)([OH:58])[CH2:53][CH2:54]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:8]1=[O:29]
Reactant: COc1ccc(CC2(CCS(C)(=O)=O)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1OC
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Product: COc1ccc(CC2(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(3,4-dimethoxy-phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.58 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][O:19][C:20]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:21]=1[NH2:22]>>[NH2:22][C:21]1[CH:23]=[CH:24][C:25]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:26][C:20]=1[O:19][CH3:18]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1cc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)ccc1N
Yield: 60.5 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (100 mg, 0.30 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (150 mg, 0.50 mmol) to afford the desired product (64 mg, 60%) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 7.61 (d, J=5.3 Hz, 1H), 7.58-7.53 (m, 2H), 7.41 (d, J=5.3 Hz, 1H), 7.16 (s, 1H), 7.01 (d, J=5.3 Hz, 1H), 6.09 (d, J=5.1 Hz, 1H), 3.93 (s, 3H), 3.77 (s, 3H).
Reaction SMILES: C(C1C=CC(C2C=CC(C(C)(C)C)=CC=2)=CC=1)(C)(C)C.Br[CH2:22][CH:23]1[CH2:25][CH2:24]1.[O:26]=[C:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>C1COCC1>[CH:25]1([CH2:24][C:27]2([OH:26])[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:31][CH2:32]2)[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2)CC1
Temperature: -78 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a suspension of 4,4′-di-tert-butylbiphenyl (DTBB, 30.33 mg, 0.114 mmol) and Li (56.7 mg, 8.09 mmol) in 50 mL of anhydrous THF was added dropwise a solution of (bromomethyl)cyclopropane (307.9 mg, 2.28 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.5 mmol) in anhydrous THF (5 mL) at −78° C. under N2. The resulting mixture was stirred at −78° C. under N2 for 8 h. The reaction mixture was quenched by satd. NH4Cl solution at −78° C. The resulting mixture was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 262.5 mg of title compound as a colorless oil. 1H NMR (CHLOROFORM-d) δ: 3.90-3.78 (m, 2H), 3.25-3.12 (m, 2H), 1.60 (dd, J=9.4, 4.3 Hz, 4H), 1.48 (s, 9H), 1.42 (d, J=6.9 Hz, 2H), 0.82-0.70 (m, 1H), 0.57-0.47 (m, 2H), 0.16-0.06 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[C:11](=[N:16][NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([OH:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:12]([O:14]C)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1)[NH2:30].Cl.[CH2:41](O)[CH3:42]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11](=[N:16][NH:17][C:18]3[CH:19]=[CH:20][C:21]([S:24]([OH:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[C:12](=[O:14])[N:29]([C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH2:41][CH3:42])=[O:36])=[CH:38][CH:39]=3)[N:30]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(=NNc1ccc(S(=O)(=O)O)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCO
Reactant: NNc1ccc(C(=O)O)cc1
Agent: Cl
Product: CCOC(=O)c1ccc(N2N=C(c3ccc([N+](=O)[O-])cc3)C(=NNc3ccc(S(=O)(=O)O)cc3)C2=O)cc1

Procedure:
The crude product methyl 3-(4-nitrophenyl)-3-oxo-2-(2-(4-sulfophenyl)hydrazono)-propanoate (200 mg, 0.49 mmol) (synthesized as described for II -1) was dissolved in ethanol (10 ml), and 4-hydrazinobenzoic acid (90 mg, 0.59 mmol) and hydrochloric acid (37%, 0.2 ml) were added. The product 4-((1,5-dihydro-3-(4-nitrophenyl)-5-oxo-1-(4-ethoxycarbonyl phenyl)-4H-pyrazol-4-ylidene)-hydrazino)-benzenesulfonic acid was isolated by filtration as an orange solid (yield 54%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][N:5]2[N:6]=[C:7]([CH2:9][OH:10])[CH:8]=[C:4]2[CH2:3]1>C(Cl)(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1([CH3:12])[CH2:11][N:5]2[N:6]=[C:7]([CH:9]=[O:10])[CH:8]=[C:4]2[CH2:3]1
Reactant: CC1(C)Cc2cc(CO)nn2C1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CC1(C)Cc2cc(C=O)nn2C1

Procedure:
To 3.19 g of the crude (5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-2-yl)methanol in 222 mL of CHCl3 was added activated MnO2 (18.5 g) under a nitrogen atmosphere at room temperature, and then refluxed for 1 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The residue was applied to silica-gel column chromatography, and then the column was eluted with hexane-AcOEt (3:1). The titled compound was obtained as a brown solid (2.48 g, 68.0% from the ester).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[CH2:20][CH2:19][C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccco1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccco1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-(furan-2-yl)propionyl chloride (396.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:2). The fractions containing the 1-(4-benzylpiperazin-1-yl)-3-(furan-2-yl)propan-1-one are collected and the solvent is removed in vacuo to give 497 mg of colorless oil.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:6]([NH:8][C@H:9]([C:19](O)=[O:20])[CH2:10][CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:44]1[CH2:79][CH2:78][CH2:77][C@H:45]1[C:46]([NH:48][C@H:49]([C:54]([N:56]1[CH2:76][CH2:75][CH2:74][C@H:57]1[C:58]([NH:60][C@H:61]([C:70]([O:72][CH3:73])=[O:71])[CH2:62][C:63]1[CH:68]=[CH:67][C:66]([OH:69])=[CH:65][CH:64]=1)=[O:59])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47]>O1CCCC1.CN(C)C=O>[NH:1]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C@H:2]([C:6]([NH:8][C@H:9]([C:19]([N:44]1[CH2:79][CH2:78][CH2:77][C@H:45]1[C:46]([NH:48][C@H:49]([C:54]([N:56]1[CH2:76][CH2:75][CH2:74][C@H:57]1[C:58]([NH:60][C@H:61]([C:70]([O:72][CH3:73])=[O:71])[CH2:62][C:63]1[CH:68]=[CH:67][C:66]([OH:69])=[CH:65][CH:64]=1)=[O:59])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])=[O:20])[CH2:10][CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
0.8 g of Boc-Val-Glu(OBut)-OH (1.9 mmol) is dissolved in 5 cm3 of tetrahydrofuran cooled to -15° C. 0.21 cm3 of N-methylmorpholine (1.9 mmol) and 0.25 cm3 of isobutyl chloroformate are added in succession. After 2 minutes, the solution of Pro-Ile-Pro-Tyr-OMe in 5 cm3 of dimethylformamide, prepared earlier, is added. The reaction mixture is stirred for 1 hour at -15° C. and then for 2 hours at 20° C. The solvents are removed under reduced pressure. The 1.2 g of crude product obtained are purified by chromatography on silica gel by eluting with mixtures of ethyl acetate and petroleum ether (1-1; 7-2 and 8-2 by volume). The main fraction is purified by chromatography on silica gel by eluting with methylene chloride containing 3% of methanol (by volume). In this way, 0.6 g of Boc-Val-Glu(OBut)-Pro-Ile-Pro-Tyr-OMe is obtained, the properties of which are as follows:
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:21].C(Br)(Br)(Br)[Br:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:23][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:21]
Reactant: O=C1N(CCO)CCC1(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1N(CCBr)CCC1(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 64A (0.3, 1.1 mmol) in methylene chloride was added carbon tetrabromide (0.7 g, 2.13 mmol) and triphenylphosphine (0.56 g, 2.13 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the obtained residue was chromatographed on silica gel eluting with 10-30% ethyl acetate/hexane to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.31 (m, 10H), 3.78 (t, J=6.44 Hz, 2H), 3.54 (t, J=5.59 Hz, 2H), 3.49 (t, J=5.76 Hz, 2H), 2.80 (t, J=6.44 Hz, 2H); MS (ESI+) m/z 345 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5](OC)([O:8][CH3:9])[O:6][CH3:7].CO.[C:14]([OH:18])([CH3:17])([CH3:16])[CH3:15]>C(O)(C)(C)C>[NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])([O:8][CH3:9])[O:6][CH3:7]
Reactant: CC(C)(C)O
Reactant: CO[Si](CCCN)(OC)OC
Solvent: CO
Product: CO[Si](CCCN)(OC)OC(C)(C)C
Yield: 94 %

Procedure:
Into a 500 ml 3-necked flask equipped with a magnetic stirrer, heating mantle, thermometers, a 12 in. distilling column packed with 1/8 in. glass helices, addition funnel, distilling head and receiver was added 179.3 g (1.0 mole) of 3-aminopropyltrimethoxysilane. The flask was heated to 160° C. and from the (heated) addition funnel 160 g (2.16 moles) of t-butanol was slowly added with the simultaneous distillation of methanol/t-butanol to the receivers. The rate of addition of t-butanol was kept slow in order to maintain as high a flask temperature as possible (150°-170° C). Periodic sampling of the flask and lites for gas chromotograph analysis indicated that after 2.16 moles t-butanol had been added, approximately an 80% conversion of 3-aminopropyltrimethoxysilane to Compound A* had been achieved. Distillation of this material with four cuts (94°-100° C. at 20 mm Hg) produced 100 g of 94% pure aminopropyl-t-butoxydimethoxysilane (combined cuts 2, 3, 4). Cut one, enriched in 3-aminopropyltrimethoxysilane was 30 grams.