Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:15]#[N:16])[CH2:6]C(C#N)C(OCC)=O)[CH3:2].C[O-].[Na+].C(OC(=O)CCCC(OC#N)=O)#N>CO.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:15]#[N:16])=[CH2:6])[CH3:2]
Reactant: CCOC(=O)C(C#N)CC(C#N)C(=O)OCC
Agent: *CO*
Agent: C[O-]
Agent: N#COC(=O)CCCC(=O)OC#N
Solvent: O
Solvent: CO
Product: C=C(C#N)C(=O)OCC
Reaction time: 0.75 h
Yield: 59.6 %

Procedure:
494.0 g (2.074 moles) of 2,4-dicyanoglutaric acid diethyl ester were reacted in the absence of water with 44.8 g of polyoxymethylene (92%; 1.372 moles) and 3 g of a 30% solution of sodium methylate in methanol (0.0167 mole). The quantity of sodium methylate used corresponded to an excess of 1.25 millimoles per mole of dicyanoglutarate. The reaction was carried out over a period of 45 minutes at a temperature of 100° C.-130° C. The water present was then removed using an oil pump vacuum. Thermolysis produced 154.5 g (1.236 moles) of 2-cyanoacrylic acid ethyl ester after distillation. The yield thus amounted to 31.3% by weight, based on 2,4-dicyanoglutarate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20](=[O:21])[C:11]3=[CH:12][NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.S(OC)(O[CH3:26])(=O)=O>>[CH3:26][N:9]1[C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[C:20](=[O:21])[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccc(Cl)cc1
Reactant: COS(=O)(=O)OC
Product: Cn1c2c(cnc3ccccc32)c(=O)n1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
The mixture of 3.0 g of 2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one and 100 ml of dimethyl sulfate is stirred at 110°-130° for 2 hours and evaporated. The residue is dissolved in N aqueous sodium hydroxide, the solution extracted with methylene chloride and the extract evaporated. The residue is recrystallized from diethyl ether, to yield the 1-methyl-2-(p-chlorophenyl)-pyrazolo[4,3-c]quinolin-3-one melting at 158°-161°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][S:2]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1)(=[O:4])=[O:3]
Reactant: c1ccc2[nH]nnc2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.3 %

Procedure:
Methanesulphonyl chloride (9.3 ml, 0.12 mol) in toluene (30 ml) was added dropwise to a solution of benzotriazole (11.9 g, 0.1 mol) and pyridine (12 ml, 0.16 mol) in toluene (120 ml). The reaction was stirred at room temperature for 20 h, diluted with ethyl acetate (150 ml), washed with water (2×100 ml), brine (150 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum to give 1-(methylsulphonyl)-1H-benzotriazole (19 g). NMR: ∂H CDCl3 8.17,(1H, m), 8.02,(1H, m), 7.69,(1H, m), 7.55,(1H, m), 3.52,(3H, s).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:16])[CH:13]=2)[O:8][C:7]1([CH3:18])[CH3:17])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)C>[NH2:1][CH2:4][CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:16])[CH:13]=2)[O:8][C:7]1([CH3:18])[CH3:17]
Reactant: CC1(C)Oc2ccc(F)cc2CC1CCN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Oc2ccc(F)cc2CC1CCN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.0 g (16 mmol) of 3-(2-azidoethyl)-2,2-dimethyl-6-fluorochroman in 30 ml of absolute tetrahydrofuran is added dropwise within a period of 30 minutes to a suspension of 0.61 g (16 mmol) of lithium aluminium hydride in 30 ml of absolute diethyl ether. The reaction mixture is then stirred for 2 hours at room temperature and then carefully decomposed with 0.61 ml of water, 0.61 ml of sodium hydroxide solution (15%) and 1.83 ml of water. The resulting precipitate is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether and the solution is extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline with sodium hydroxide solution (30%) while cooling with ice and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and concentrated by evaporation in vacuo, yielding 3.21 g (90% of the theoretical yield) of 3-(2 -aminoethyl)-2,2-dimethyl-6-fluoro-chroman in the form of a yellow oil. 3-(2-aminoethyl)-2,2-dimethyl-6-fluoro-chroman hydrochloride, prepared therefrom with hydrochloric acid in diethyl ether, crystallises from methanol/diethyl ether and has a melting range of from 249° to 251°.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:14]([O:23][CH3:24])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17]>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[C:9]([C:8]1[CH:12]=[CH:13][C:5]([S:2]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[C:14]([O:23][CH3:24])=[O:22])(=[O:4])=[O:3])=[CH:6][CH:7]=1)([OH:11])=[O:10]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(C(=O)O)cc1
Reaction time: 16 h

Procedure:
4-Chlorosulfonylbenzoic acid (2.21 g, 10 mmol) is added to a solution of the methyl anthranilate (1.51 g, 10 mmol) in 20 mL of DCM at RT. The reaction is stirred 16 h and then filtered to give a white solid. The solid is dissolved in diluted aqueous potassium carbonate and extracted with EtOAc. The aqueous phase is added slowly to an excess (25 mL) of 1 N aqueous HCl. A white solid precipitates and is collected by filtration, washed with water, and dried under vacuum to give methyl 2-(4-carboxybenzene-sulfonylamino)-benzoate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO>[N:11]1([CH2:14][C:15]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: N#CC1(CN2CCN(Cc3ccccc3)CC2)CCCCC1
Solvent: CO
Product: N#CC1(CN2CCNCC2)CCCCC1
Reaction time: 6 h

Procedure:
A suspension of 1-[(4-benzyl-1-piperazinyl)methyl]cyclohexanecarbonitrile (2.23 g/7.51 mmol) and Pd(OH)2-C (1.1 g) in methanol (40 ml) was stirred under H2 (4 Kg/cm−2) for 6 hours. After filtration through a pad of Celite, the filtrate was concentrated and the resulting residue was purified by column chromatography to give a white solid (1.1 g/71%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:21])[CH:3]=1.BrC1C=C(C)C(C(O)=O)=C(C)C=1.N1(CCO)CCCNCC1.BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.[F:66][C:67]([F:79])([F:78])[O:68][C:69]1[CH:70]=[C:71](B(O)O)[CH:72]=[CH:73][CH:74]=1>>[CH3:21][C:4]1[CH:3]=[C:2]([C:71]2[CH:72]=[CH:73][CH:74]=[C:69]([O:68][C:67]([F:66])([F:78])[F:79])[CH:70]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][OH:20])[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCCN(CCO)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)O
Agent: OCCN1CCCNCC1
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)cc(C)c1C(=O)N1CCCN(CCO)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-[4-(2-hydroxy-ethyl)-[1,4]diazepan-1-yl]-methanone (prepared from 4-bromo-2,6-dimethyl-benzoic acid and 2-[1,4]diazepan-1-yl-ethanol in analogy to the procedure described for the preparation of intermediate 1) was reacted with 3-trifluoromethoxy-phenyl boronic acid to give the title compound as light yellow amorphous solid. MS: 437.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17](Br)[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1.CN(C=O)C.C(NC(C)C)(C)C.[CH3:34][C:35]([OH:39])([C:37]#[CH:38])[CH3:36]>O.[Cu]I.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>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:38]#[C:37][C:35]([OH:39])([CH3:36])[CH3:34])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:21])=[CH:10][CH:11]=3)[N:6]=1
Reactant: C#CC(C)(C)O
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ncc(Br)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2

Procedure:
A 25-mL flask was charged with (S)-2′-amino-3-bromo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (1.012 g, 2.91 mmol), copper(i) iodide (0.055 g, 0.291 mmol), and tetrakis(triphenylphosphine)palladium (0.034 g, 0.029 mmol). The vial was flushed with Ar(g), then a septum was attached. DMF (5.81 mL), diisopropylamine (6.11 mL, 43.6 mmol), and 2-methylbut-3-yn-2-ol (1.137 mL, 11.63 mmol) were added in sequence to give a clear, brown solution. A reflux condenser was attached, and the flask was placed in a 75° C. oil bath for 4 hours. The mixture was diluted with water (35 mL) and extracted with DCM (4×20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue, which contained a considerable amount of DMF, was loaded onto a 10-g SCX-2 column with the aid of methanol. The column was eluted with methanol to remove impurities, then with 2M ammonia in methanol to elute the product. The filtrate was evaporated, and the residue was chromatographed on an 80-g Redi-Sep column, eluting with 0-10% MeOH/DCM to give (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][CH2:10][CH2:11][CH2:12][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: BrCCCBr
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccccc1OCCCBr
Temperature: 80 °C
Yield: 100.8 %

Procedure:
A mixture of 2-fluorophenol (2.24 g, 20.0 mmol), 1,3-dibromopropane (20.3 mL, 200 mmol), and potassium carbonate (2.76 g, 20.0 mmol) in acetonitril (30 mL) was heated at 80° C. overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 4.70 g of the title compound as a light yellow oil with a purity of ca. 80%. The product was used in the subsequent reaction step without further purification.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([CH2:20][OH:21])[C@@H:17]([CH3:19])[OH:18])=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.C1(SC)C=CC=CC=1.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl.C(OCC)C>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([CH2:20][OH:21])[C@@H:17]([CH3:19])[OH:18])=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.[F:40][C:39]([C:37]([OH:43])=[O:38])([F:42])[F:41]
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CSc1ccccc1
Product: Cc1ccc(CSC[C@H](N)C(=O)N[C@H](CO)[C@@H](C)O)cc1
Reaction time: 0.33 h

Procedure:
7.1 g BOC-Cys(MBzl)-Thr-ol and 5 ml thioanisole are dissolved in 25 ml methylene chloride. The solution is added to 50 ml TFA and allowed to stand for 20 minutes at room temperature. The mixture is diluted with ca. 1.5 liters ethyl-ether and the precipitated product filtered off and dried to yield the title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH2:24][C:25]#[N:26])=[N:7]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[C:11](=[O:12])[C:10]2[C:13]([O:22][CH3:23])=[C:14]3[C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH2:16][N:15]3[C:9]=2[C:8]([CH:24]([C:25]#[N:26])[CH2:42][C:43]([O:45][CH3:46])=[O:44])=[N:7]1
Reactant: COc1c2n(c3c(CC#N)nn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)CC(C#N)c1nn(Cc2ccc(F)c(Cl)c2)c(=O)c2c(OC)c3n(c12)CCN(C)C3=O
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-4-(cyanomethyl)-10-methoxy-8-methyl-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-dione (0.11 g, 0.25 mmol; Example 118, step 1) in anhydrous DMF (1 mL), a solution of lithium bis(trimethylsilyl)amide (0.28 mL, 0.28 mmol; 1M) in THF was added over a period of 5 minutes. The reaction solution was stirred at the same temperature for 30 minutes and treated with methyl bromoacetate (43 mg, 0.28 mmol). After stirring at room temperature for two hours, the product mixture was concentrated under vacuum. The residue was partitioned between dichloromethane and aqueous ammonium chloride. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 0 to 10% methanol in chloroform gradient. Collection and concentration of appropriate fractions afforded the title compound.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H][H]>[Rh].O>[NH2:15][CH:14]1[CH2:16][CH2:17][N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[NH:13]1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: [H][H]
Agent: [Rh]
Solvent: O
Product: NC1CCN([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C(=O)N1

Procedure:
A solution of 17.5 g. (72 millimoles) of cytidine in 540 ml. of water was hydrogenated in a Parr hydrogenator at 30 psi pressure, in the presence of 3.6 g. of 5% rhodium on alumina catalyst. Hydrogen uptake overnight (18-19 hours) was approximately 2 molar equivalents. The solution (pH 10.5) was filtered through a bed of Celite (diatomaceous earth) filter and lyophilized to yield 4-amino-1-β-D-ribofuranosyl-tetrahydro-2(1H)-pyrimidinone as a white amorphous solid. When examined by nuclear magnetic resonance the solid showed a doublet at 5.95 ppm. (anomeric proton); multiplet at 4.50 ppm. ##STR12## multiplets at 3.45 ppm. (--CH2N=) and 2.00 ppm. (C--CH2 --C) and a small amount of absorption at 2.75 ppm. ##STR13## Upon acidification, the 4.50 ppm. multiplet moved downfield to 5.08 ppm. ##STR14## and part of the 2.00 ppm. multiplet moved slightly downfield to 2.2 ppm. Peak locations are referred to the peak for sodium-2,2-dimethyl-2-silapentane-5-sulfonate (SDSS) as internal standard. Held in aqueous solution at pH 5.5 to 6 overnight, the solid was converted to and gave the analytical characteristics of 4-hydroxy-1-β-D-ribofuranosyl-tetrahydro-2(1H)-pyrimidinone.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][C:4](=[O:14])[CH2:3]1.[Br:16]C1CC(C(C)C)CCC1=O>>[Br:16][CH:5]1[CH2:6][CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([CH3:15])([CH3:1])[CH2:3][C:4]1=[O:14]
Reactant: CC1(C)CC(=O)CCC1c1ccccc1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: CC1(C)CC(=O)C(Br)CC1c1ccccc1

Procedure:
The bromination of 3,3-dimethyl-4-phenyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.O=O>C(O)(=O)C>[C:1]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccccc1
Agent: O=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: c1ccc(-c2ccccc2)cc1
Reaction time: 20 h
Yield: 21.3 %

Procedure:
10 c.c. of the catalyst thus prepared was fed into a 50 c.c. microbomb, together with 10 g of benzene, 5 g of acetic acid and 0.2 g of concentrated sulfuric acid, and the bomb was sealed. Oxygen was introduced therein through an upper valve till its pressure reached 40 kg/cm2. The bomb was then placed in an oil bath of shaking type whose temperature had been controlled to 100°C. After the reaction was carried out for 20 hours, the catalyst was separated and removed. The reaction mixture containing unreacted benzene and acetic acid was cooled and filtered. The resultant filtrate was evaporated to give 2.1 g of biphenyl
Reaction SMILES: [CH2:1]([O:3]CC)C.Br[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:11][CH:12]=1.C([Li])CCC.CN(C)C=O>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:10]2[N:11]=[CH:12][C:7]([CH:1]=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(OCc2ccc(Br)cn2)cc1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(COc2ccc(F)cc2)nc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 30.5 %

Procedure:
To a diethyl ether (100 mL) solution of 5-bromo-2-(4-fluoro-phenoxymethyl)-pyridine (4.00 g, 14.2 mmol) described in Manufacturing Example 72-1-1 was added dropwise n-butyl lithium (2.55 M n-hexane solution, 6.13 mL, 15.6 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere, which was stirred for 40 minutes at −78° C. N,N-dimethylformamide (1.32 mL, 17.0 mmol) was then added dropwise and stirred for 5 minutes at −78° C. The reaction solution was cooled to room temperature and water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:4) to obtain the title compound (1.00 g, 30.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8]C(=O)C)=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.ClC1C=C([N+]([O-])=O)C(OC)=CC=1NC(=O)C.Cl.[OH-].[Na+]>>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([N+:12]([O-:14])=[O:13])[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cl)c(NC(C)=O)c1[N+](=O)[O-]
Agent: COc1cc(NC(C)=O)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(Cl)c(N)c1[N+](=O)[O-]

Procedure:
A solution of 6.25 g of a mixture of N-(6-chloro-3-methoxy-2-nitro-phenyl)-acetamide and N-(2-chloro-5-methoxy-4-nitro-phenyl)-acetamide in 30 mL of 25%-HCl and 150 mL of 1M-HCl was refluxed for 2 h. The reaction mixture was basified with 2M-NaOH and extracted with EtOAc. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The crude product was purified by CC using EtOAc/heptane 1/3 to yield 819 mg of 6-chloro-3-methoxy-2-nitro-phenylamine as dark yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([O-:14])=[O:13].[Na+].C(=O)(O)[O-].[Na+]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=C([O-])CCl
Reactant: N#Cc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
54.0 g (0.46 mol) of 4-aminobenzonitrile and 106.5 g (0.92 mol) of sodium chloroacetate were suspended in 750 mL of water, and the resulting mixture was stirred at reflux temperature for 4 hours. After cooling to room temperature, pH was adjusted to 8-9 with sodium bicarbonate. The resulting solution was washed with 2×200 mL of ethyl acetate, and 5M hydrochloric acid was added to the aqueous phase until pH=3. The precipitated solid was isolated by filtration, washed with 100 mL of water and dried to yield 57.1 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 70.9%. Purity (HPLC, method 3): 88.4%.
Reaction SMILES: [C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=2)[C:9]([NH:11][C@@H:12]([CH:34]([CH3:36])[CH3:35])[C:13]([NH:15][C@H:16]([B:21]2[O:29][C@H]3[C@](C)([C@H]4C[C@@H](C3)C4(C)C)[O:22]2)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=[O:10])[CH:2]=1.Cl>CO.CCCCCC>[C:1]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:37][C:38]2[CH:39]=[C:40]([O:48][CH3:49])[C:41]([O:46][CH3:47])=[C:42]([O:44][CH3:45])[CH:43]=2)[C:9]([NH:11][C@@H:12]([CH:34]([CH3:36])[CH3:35])[C:13]([NH:15][C@H:16]([B:21]([OH:29])[OH:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])=[O:10])[CH:2]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B2O[C@@H]3C[C@@H]4C[C@@H](C4(C)C)[C@]3(C)O2)C(C)C)cc(OC)c1OC
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)B(O)O)C(C)C)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
I-BuB(OH)2 is added to a mixture of (S)-2-[(S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionylamino]-3-methyl-N-[(R)-3-methyl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-butyl]-butyramide, methanol (4.3 mL), hexane (4.3 mL) and 1N HCl (1.45 mL). The reaction mixture is stirred for 2 h at rt and then diluted with methanol (8 mL) and hexane (8 mL). The two layers are separated. The methanol layer is washed twice with hexane, diluted with CH2Cl2, washed with H2O, dried (Na2SO4), filtered and concentrated. The residue is dissolved in CH2Cl2 and purified by silica gel (20 g) column chromatography (CH2Cl2/MeOH, 80/20) to afford the title compound as a pale yellow foam.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[C:5]([C:15]2[N:16]=[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]3=[N:19][CH:20]=2)=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>>[CH3:32][S:33]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]2[C:5]([C:15]3[N:16]=[C:17]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:18]4=[N:19][CH:20]=3)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH2:10]1)(=[O:35])=[O:34]
Reactant: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCNC2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCN(S(C)(=O)=O)C2)n1

Procedure:
(1-Methanesulfonyl-piperidin-3-yl)-{6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from {6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-piperidin-3-yl-amine, and methanesulfonyl chloride, using 4 equivalents of DIPEA as base and following the general synthetic procedures described in the above Examples.