Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:17](=O)[CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(O)(O)(=O)=O.[CH3:25][O:26][C:27](=[NH:29])[NH2:28].C([O-])(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[NH:29][C:17]([CH3:18])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:28]=1
Reactant: COC(=N)N
Reactant: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A reaction mixture containing 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid, ethyl ester (2.62 g, 10.0 mmole), 2-methylpseudourea sulfate (1.72 g, 10.0 mmole), and sodium acetate (1.8 g, 22.0 mmole) in tetrahydrofuran (10 ml) is heated under reflux for 4 hours. The reaction mixture is allowed to cool to room temperature, diluted with ethyl acetate, and filtered. The filtrate is washed with sodium bicarbonate and brine, and then dried over anhydrous magnesium sulfate. Evaporation of the solvent gives a yellow oil which is purified by flash chromatography (5% ethyl acetate in dichloromethane). The resulting foam is crystallized from isopropyl ether-hexanes to provide 1.53 g of 1,4-dihydro-2-methoxy-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester as a colorless crystalline product; m.p. 103.5°-105°. TLC (silica gel; ethyl acetate:hexanes, 50:50) Rf =0.31.
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:6]1.[OH-].[K+]>C(O)C.O>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:6]1
Reactant: CCOC(=O)CCc1cn(CC(=O)N(C)CCc2ccccc2)c2ccc(OCc3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(CCc1ccccc1)C(=O)Cn1cc(CCC(=O)O)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 0.7 g (1.4 mmol) of N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carbethoxyethyl)indol-1-yl]acetamide in 20 ml of ethanol is added a solution of 0.2 g of potassium hydroxide in 3 ml of water. The mixture is stirred at room temperature for 18 hours and concentrated in vacuo. The residue is dissolved in water and the resulting solution adjusted to pH 4 with 1N aqueous HCl solution. The precipitate which forms is extracted into ethyl acetate. The organic solution is washed with brine, dried over magnesium sulfate and concentrated in vacuo to give N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-carboxyethyl)indol-1-yl]acetamide as a beige powder (m.p. 122°-125° C.).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH:9]=[CH2:10].[CH2:11]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([OH:22])[CH:16]=1)[CH3:12]>CC(C)=O>[CH2:11]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH2:10][CH:9]=[CH2:8])[CH:16]=1)[CH3:12]
Reactant: CCOC(=O)c1ccc(Cl)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OCC)ccc1Cl
Temperature: 25 °C

Procedure:
K2CO3 (78.5 mmol) and 3-bromo-1-propen (52.3 mmol) are added to a solution of 4-chloro-3-hydroxy-benzoic acid ethyl ester (26.2 mmol) in acetone (50 mL). The mixture is heated to reflux for 16 h and cooled to RT. The solvents are removed in vacuo to give the desired product which is used without further purification. LC-MS: tR=1.05 min; [M+H]+=240.9.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[OH-].[Li+:12]>O>[C:1]([O-:10])(=[O:9])[CH:2]([CH:4]([C:6]([O-:8])=[O:7])[OH:5])[OH:3].[Li+:12].[Li+:12]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Yield: 109.3 %

Procedure:
Tartaric acid (15.0 g, 0.1 mole) is dissolved in 40 ml. water and treated with lithium hydroxide (8.4 g, 0.2 mole). The resulting solution is evaporated to a small volume under reduced pressure and the residue is treated with p-dioxane. The resulting precipitate is filtered and dried under vacuum to give the di-lithium tartarate (17.7 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=4)[N:13]=[C:12]([NH:21][C:22]4[CH:30]=[C:29]5[C:25]([C:26](=[O:31])[NH:27][NH:28]5)=[CH:24][CH:23]=4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CS(C)=O.C1([O-])C=CC=CC=1.[K+].O>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:18]=4)[N:13]=[C:12]([NH:21][C:22]4[CH:30]=[C:29]5[C:25]([C:26](=[O:31])[NH:27][NH:28]5)=[CH:24][CH:23]=4)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(I)ccc4n3)ccc12
Agent: [K+]
Agent: [O-]c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)c4cc(-c5ccccc5)ccc4n3)ccc12
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To 6-[4-(5-Cyclopropyl-2H-pyrazol-3-ylamino)-6-iodo-quinazolin-2-ylamino]-1,2-dihydro-indazol-3-one (300 mg, 0.48 mmol), and phenyl boronic acid (88 mg, 0.72 mmol) in DMSO and 1.5 M potassium phenolate (2.6 mL) was added PdCl2 (dppf)2 (175 mg) and the solution was heated to 100° C. in a sealed tube. After 12 hr, the solution was diluted with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated. The title compound was isolated by preparative HPLC as a white solid (0.82 mg). HPLC tr=5.14 min (10% to 90% MeCN over 8 min, total time 12 min, 3×150 mm C18 column) FIA m/e 475.55 (M+H), 473.55 (M-H).
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1)=[C:2]=[S:3].[CH3:14][C:15]1[O:19][C:18]([CH2:20][NH:21][C:22]2[C:23]([NH2:28])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1>O1CCCC1>[CH3:14][C:15]1[O:19][C:18]([CH2:20][NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[NH:28][C:2]([NH:1][CH:4]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]2)=[S:3])=[CH:17][CH:16]=1
Reactant: Cc1ccc(CNc2ccccc2N)o1
Reactant: CCOC(=O)N1CCC(N=C=S)C1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(NC(=S)Nc2ccccc2NCc2ccc(C)o2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 80 parts of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate, 88.8 parts of N1 -[(5-methyl-2-furanyl)methyl]-1,2-benzenediamine and 560 parts of tetrahydrofuran was stirred for 2 hours at reflux temperature. After cooling to room temperature, the reaction mixture was evaporated, yielding 144.9 parts (100%) of ethyl 3-[[[[2-[[(5-methyl-2-furanyl)methyl]amino]phenyl]amino]thioxomethyl]amino]-1-pyrrolidinecarboxylate as a residue (interm. 7).
Reaction SMILES: [Br-].[Li+].C[C:4]1[CH:9]=[CH:8][C:7]([Mg]Br)=[CH:6][CH:5]=1.CCOCC.[CH2:17]([C:21]1[S:25][C:24]([C:26](=[O:30])[C:27](Cl)=[O:28])=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20].Cl>[Cu](Br)Br.C1COCC1>[CH2:17]([C:21]1[S:25][C:24]([C:26](=[O:30])[C:27]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:28])=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CCCCc1ccc(C(=O)C(=O)Cl)s1
Agent: Br[Cu]Br
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1ccc(C(=O)C(=O)c2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into a flask containing THF (60 mL) was added copper (II) bromide (5.7 g, 40 mmol) followed by lithium bromide (6.8 g, 80 mmol). The reaction was cooled to 0° C. and a solution of 4-methyl-phenylmagnesium bromide (1N) in ether (48 mmol) was added dropwise. The reaction was stirred 10 min and a solution containing (5-butyl-thiophen-2-yl)-oxo-acetyl chloride was added dropwise over 20 min at 0° C. The reaction was poured into HCl 1N (aqueous) and extracted with ether. The organic layer was separated and washed with NaOH 2.5N (aqueous), then brine and dried over MgSO4, filtered and stripped. MS m/e 273 (M)−; 1HNMR (DMSO-d6, 300 MHz) δ 0.9 (t, 3H), 1.3 (m, 2H), 1.6 (m, 2H), 2.8 (t, 2H), 7.0 (s, 1H), 7.6 (t, 2H), 7.7 (s, 1H), 7.8 (m, 1H), 7.9 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[N:11][OH:12])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(=NO)CC1
Temperature: 25 °C

Procedure:
To a solution of 4,4-dimethylcyclohexanone (3.0 g, 0.024 mole) and hydroxylamine hydrochloride (2.2 g, 0.031 mole) in ethanol (15 mL) and water (20 mL) at room temperature was added a solution of sodium carbonate (3.3 g, 0.031 mol) in water (10 mL), dropwise. The mixture was heated under reflux for 3 hr, cooled to room temperature and ethanol was removed in vacuo. The aqueous residue was extracted several times with ethyl acetate, combined extracts were dried over MgSO4 and concentrated in vacuo affording the title compound as a white solid, used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.93 (s, 6H), 1.28 (t, J=6.6 Hz, 2H), 1.35 (t, J=6.6 Hz, 2H), 2.11 (t, J=6.6 Hz, 2H), 2.36 (t, J=6.6 Hz, 2H), 10.12 (s, 1H).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[C:8]([O:17][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=2[CH3:25])=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][C:35]=1[C:36](Cl)=[O:37]>O>[Cl:6][C:7]1[C:8]([O:17][C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:36](=[O:37])[C:35]3[CH:39]=[C:40]([N+:43]([O-:45])=[O:44])[CH:41]=[CH:42][C:34]=3[Cl:33])=[CH:20][C:19]=2[CH3:25])=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1cc(N)ccc1Oc1ncc(C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2cc([N+](=O)[O-])ccc2Cl)ccc1Oc1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 670 mg of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-3-methylaniline and 270 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 490 mg of 2-chloro-5-nitrobenzoylchloride was dropwise added, followed by stirring for about 30 minutes, and then water was added, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 700 mg of N-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-3-methylphenyl)-2-chloro-5-nitrobenzamide (Compound No. 106) having a melting point of from 230 to 232° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[S:8]([N:11]([CH3:26])[C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[SH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].O>CN(C)C=O>[CH3:26][N:11]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[CH:17]2)[S:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:2][S:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])(=[O:10])=[O:9]
Reactant: COC(=O)CS
Reactant: CN(c1cccc2cc(-c3nccs3)[nH]c12)S(=O)(=O)c1ccsc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CSCc1sccc1S(=O)(=O)N(C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 50 °C
Reaction time: 10 h
Yield: 67 %

Procedure:
To a solution of 2-(chloromethyl)-N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-3-sulfonamide (450 mg) in N,N-dimethylformamide (5 mL) were added potassium carbonate (150 mg) and methyl mercaptoacetate (130 μL), and the mixture was stirred at 50° C. for 10 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (348 mg, yield 67%) as pale-yellow crystals. melting point 126° C.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[N:10][C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)=[CH:8][N:7]=1)C.O[Li].O>C1COCC1.CO.O.O>[N:12]1([C:9]2[N:10]=[CH:11][C:6]([CH2:5][C:4]([OH:17])=[O:3])=[N:7][CH:8]=2)[CH:16]=[N:15][N:14]=[N:13]1
Reactant: CCOC(=O)Cc1cnc(-n2cnnn2)cn1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)Cc1cnc(-n2cnnn2)cn1
Reaction time: 0.5 h

Procedure:
A mixture of ethyl[5-(1H-tetrazol-1-yl)pyrazin-2-yl]acetate (2.0 g, 8.5 mmol) in 60 mL of THF/MeOH/H2O (2:2:1) was added LiOH.H2O (540 mg, 12.8 mmol) portionwise and stirred for 30 minutes before diluting with 200 mL of water and washing with ether (30 mL×3). The water layer was acidified to pH=4 with diluted HCl and extracted with EtOAc (50 mL×5). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to afford title compound: 1H-NMR (400 MHz, d6-DMSO) δ ppm 12.93 (brs, 1H), 10.22 (s, 1H), 9.25 (d, J=1.2 Hz, 1H), 8.71 (d, J=1.2 Hz, 1H), 3.98 (s, 2H).
Reaction SMILES: Cl[CH2:2][CH:3]([NH:7][C:8]([C:10]1[C:14]2[CH:15]=[C:16]([N:19]3[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]3=[O:31])[CH:17]=[CH:18][C:13]=2[S:12][N:11]=1)=[O:9])[CH:4]([CH3:6])[CH3:5].[H-].[Na+]>O1CCCC1>[CH:4]([CH:3]1[CH2:2][O:9][C:8]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:30])[C:20]4=[O:31])[CH:17]=[CH:18][C:13]=3[S:12][N:11]=2)=[N:7]1)([CH3:5])[CH3:6]
Reactant: CC(C)C(CCl)NC(=O)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1COC(c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)=N1

Procedure:
To a solution of N-[1-(chloromethyl)-2-methylpropyl]-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-carboxamide(1.25 g, 2.63 mmol) in anhydrous tetrahydrofuran is added sodium hydride (60% oil dispersion, 0.116 g, 2.90 mmol). The resultant mixture is stirred 1.5 hour at room temperature, quenched with saturated ammonium chloride, diluted with diethyl ether, washed with saturated ammonium chloride and brine, and dried over anhydrous magnesium sulfate. Concentration in vacuo affords a yellow syrup, which is combined with material from a previous run and chromatographed on silica gel to afford the title compound as a white crystalline solid (mp 100-105° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[Cl:7][C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1Cl.BrC1C(Cl)=C(Cl)N=NC=1>O1CCCC1>[Cl:7][C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[O:3][CH2:2][CH2:1][OH:4]
Reactant: Clc1cc(Cl)c(Cl)nn1
Reactant: OCCO
Agent: Clc1nncc(Br)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)nnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of ethylene glycol (55 ml) in tetrahydrofuran (200 ml) was treated at around 0° C. (ice bath cooling) with sodium hydride (60% dispersion in oil, 5.9 g) over 40 minutes. After the addition was complete, 3,4,6-trichloropyridazine (27 g) containing isomers of bromo-dichloropyridazine as impurity was added portionwise and washed in with more dry THF (50 ml) and the mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. The mixture was concentrated (to ⅓ volume) then diluted with aqueous sodium bicarbonate solution and extracted with chloroform (5×) and ethyl acetate (3×). The combined organic extracts were washed with water, dried over sodium sulphate and evaporated and the solids filtered off and washed with CHCl3 (×3) and dried in a vacuum oven overnight at 40° C. affording a white solid (25.5 g, 83%), containing some bromo-derivative (10-15%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:33](O)=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C.CC1(C)[O:41][CH:40]([CH2:42][NH:43][CH2:44][CH2:45][CH3:46])[CH2:39][O:38]1>>[NH2:8][C:9]1[CH2:10][C:11]([C:33]([N:43]([CH2:42][CH:40]([OH:41])[CH2:39][OH:38])[CH2:44][CH2:45][CH3:46])=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:27])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Reactant: CCCNCC1COC(C)(C)O1
Product: CCCN(CC(O)CO)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(N)C1

Procedure:
The title compound was prepared by the procedures as described in Example 101 (Step H and I) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)propan-1-amine.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH2:25][C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44]I>>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([CH3:44])[C:24]1=[O:43])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Reactant: CI
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a −78° C. solution of 3.19 g (5.05 mmol) of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one (Example 121, Step I) and 347 μL (5.55 mmol) of methyl iodide in dry, degassed THF (40 mL) was added 6.82 mL (6.82 mmol) of a 1 M solution of lithium bis(trimethylsilyl)amide in THF slowly via syringe over 2 min. The yellow solution was warmed to 0° C. and stirred for 1.5 h, and then was warmed to room temperature and stirred for an additional 15 min. The reaction was quenched with saturated aqueous ammonium chloride, and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (0-15% MeOH/DCM, gradient elution) provided the title compound (mixture of C-3 epimers) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:17]2[CH:16]=[N:15][C:14]([O:13][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:19][CH:18]=2)=[N:7][CH:6]=1
Reactant: CCCCOc1ccc(B(O)O)cn1
Reactant: Brc1cnc(Br)nc1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCOc1ccc(-c2ncc(Br)cn2)cn1
Yield: 36.9 %

Procedure:
A reaction of 109 mmol of 2,5-dibromopyrimidine, 109 mmol of 2-butoxypyridine-5-boronic acid, 218 mmol of sodium carbonate and 1.1 mmol of tetrakis(triphenylphosphine)palladium(0) in 200 ml of toluene, 100 ml of ethanol and 100 ml of water is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives 12.4 g (37%) of a colorless solid, m.p. 134-138° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][N:14]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CN(c2ccncc2)c2ccc(C#N)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(N(Cc2ccc(O)cc2)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.3 %

Procedure:
Then, 31 mg of 4-[N-[4-(tert-butyldimethylsilyloxy)benzyl]-N-(4-pyridyl)amino]benzonitrile was dissolved in 0.33 ml of tetrahydrofuran, and 0.15 ml of a 1 M tetrahydrofuran solution of tetrabutyl-ammonium fluoride was added thereto, followed by stirring at room temperature for 45 minutes. After water was added to the reaction mixture, the product was extracted with tetrahydrofuran-diethyl ether (1:1). After the extract was washed with water and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 9:1 mixture of chloroform and methanol as the developing solvent) to obtain 14 mg of 4-[N-(4-hydroxybenzyl)-N-(4-pyridyl)amino]benzonitrile.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH3:33])=[C:25]1[C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([CH:53]([OH:65])[CH2:54][O:55][CH2:56][C:57]1[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35]>CS(C)=O>[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH3:33])=[C:25]1[C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([C:53](=[O:65])[CH2:54][O:55][CH2:56][C:57]1[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35]
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Dess-Martin periodinane (195 mg) was added as a solid to a solution of N-[(1,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-(2′,6′-dichloro-benzyloxy)pentanoic acid, t-butyl ester (96 mg) in DMSO (1.5 ml). The resulting solution was stirred under a nitrogen atmosphere at room temperature for thirty minutes, then partitioned between EtOAc and water. The organic phase was washed with water (2×) and brine, dried (Na2SO4), and concentrated to give a white solid (83 mg). Flash chromotographic purification with EtOAc/hexanes (1:1) afforded the title product as a white solid (54 mg). TLC (EtOAc/hexanes; 1:1, silica gel): Rf=0.52.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[NH:12]C(=O)CCC.CC([O-])(C)C.[K+].O>CN(C=O)C>[C:2]([C:3]1[NH:12][C:6]2[C:5]([CH:4]=1)=[C:10]([F:11])[CH:9]=[CH:8][CH:7]=2)([CH3:19])([CH3:18])[CH3:1]
Reactant: CCCC(=O)Nc1cccc(F)c1C#CC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2c(F)cccc2[nH]1
Temperature: 90 °C
Yield: 151.6 %

Procedure:
To a solution of N-(2-(3,3-dimethylbut-1-ynyl)-3-fluorophenyl)butyramide (6.0 g, 20 mmol) in DMF (100 mL) was added t-BuOK (5.0 g, 50 mmol) at room temperature. The mixture was heated at 90° C. overnight before it was poured into water and extracted with EtOAc (100 mL×3). The organic layers were washed with sat. NaCl and water, dried over anhydrous Na2SO4, and evaporated under vacuum to give 2-tert-butyl-4-fluoro-1H-indole (5.8 g, 97%). 1H NMR (400 MHz, CDCl3) δ 8.17 (br s, 1 H), 7.11 (d,I=7.2 Hz, 1 H), 7.05-6.99 (m, 1 H), 6.76-6.71 (m, 1 H), 6.34 (m, 1 H), 1.41 (s, 9 H).