Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:19][O:20][C:21](=[O:45])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32](=[O:44])[N:33]([CH3:43])[C:34](=[O:42])[N:35]([CH3:41])[C:36]=2[C:37]([F:40])([F:39])[F:38])=[CH:27][CH:26]=1)[NH2:23].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:19][O:20][C:21](=[O:45])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[C:32](=[O:44])[N:33]([CH3:43])[C:34](=[O:42])[N:35]([CH3:41])[C:36]=2[C:37]([F:40])([F:38])[F:39])=[CH:29][CH:30]=1)[NH:23][C:4]([C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])=[O:6]
Reactant: Cc1cccc(Cl)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)n(C)c(=O)n(C)c2=O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A solution of 2-chloro-6-methylbenzoic acid (190 mg, 1.14 mmol) in dichloromethane (7 mL) containing DMF (4 drops) was treated with oxalyl chloride (0.42 mL, 4.8 mmol) and the mixture was stirred for 2 h. The mixture was concentrated, azeotroping with toluene to remove traces of oxalyl chloride and the residue was used directly in the next step. A mixture of the above prepared acid chloride, 4-(1,3-dimethyl-2,4-dioxo-6-(trifluoromethyl)-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (423 mg, 1.003 mmol) in dichloromethane (5 mL) was treated with DIPEA (0.625 mL, 4.46 mmol) and the resulting light brown solution was stirred for 3 days. The mixture was concentrated, diluted with ethyl acetate, washed with 1 N HCl and brine solution and was dried over magnesium sulfate. Filtration and evaporation afforded a residue, which was purified by silica gel chromatography using a Biotage column (40s) to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-[1,3-dimethy-2,4-dioxo-6-(trifluoromethyl)-5-pyrimidinyl]-L-phenylalanine methyl ester as a white foam (179 mg, 33%). ES-HRMS m/e calcd for C25H23ClN3O5 (M+Na) 560.1171, found 560.1172.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[C:37]=2[CH3:46])=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][C:43](=[O:45])[CH3:44])[C:37]=2[CH3:46])=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(=O)Nc1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1C
Yield: 91.7 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using N-[4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-methyl[1,1′-biphenyl]-3-yl]acetamide (1.10 g) and pyridine hydrochloride (378 mg), the colorless amorphous title compound (605 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[CH3:77][N:78]1[C:82]([CH3:83])=[C:81](B2OC(C)(C)C(C)(C)O2)[CH:80]=[N:79]1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:81]5[CH:80]=[N:79][N:78]([CH3:77])[C:82]=5[CH3:83])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Product: Cc1c(-c2cccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc23)cnn1C
Yield: 78 %

Procedure:
Following the procedure of (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester to give the title compound (40 mg, 78%). LCMS (Method G): RT=4.12 min, [M+H]+=562.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[N:14]1([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:23]3[CH2:24][CH2:25][CH:20]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)[CH2:21][CH2:22]3)=[CH:7][CH:6]=2)[CH:9]=1
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: C1CCN(C2CCNCC2)CC1
Product: c1cncc(-c2ccc(N3CCC(N4CCCCC4)CC3)nn2)c1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 3-chloro-6-(pyridin-3-yl)-pyridazine and 4-piperidinopiperidine. 1H NMR (400 MHz, CD3OD) δ 9.47 (d, 1H), 9.11 (dt, 1H), 8.93 (d, 1H), 8.40 (d, 1H), 8.15 (q, 1H), 7.94 (d, 1H), 4.66 (d, 2H), 3.66 (m, 1H), 3.58 (d, 2H), 3.36 (t, 2H), 3.08 (t, 2H), 2.38 (d, 2H), 1.80-2.00 (m, 7H), 1.54 (m, 1H).
Reaction SMILES: N[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[I:12]CI.N(OCCC(C)C)=O>C(OCC)(=O)C>[I:12][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1
Reactant: ICI
Reactant: CCOC(=O)c1c[nH]nc1N
Agent: CC(C)CCON=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c[nH]nc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.1 %

Procedure:
To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (10.0 g, 64.5 mmol) in diiodomethane (130 mL, 1.61 mol) at −10° C. was added isoamyl nitrite (156.0 mL, 1.16 mol). The mixture was allowed to warm to ambient temperature then heated to 100° C. After 2 h, ethyl acetate was added. The mixture was washed with saturated aqueous Na2SO3, HCl (1N in water) then water. The organic layer was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (9.63 g). MS 267.1 (M+1).
Reaction SMILES: [CH2:1]([Li])CCC.CNCCN(C)C.[C:13]1([C:19]2[C:20]([CH:24]=[O:25])=[CH:21][O:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>CCCCCC.O1CCCC1>[CH3:1][C:21]1[O:22][CH:23]=[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20]=1[CH:24]=[O:25]
Reactant: [Li]CCCC
Reactant: O=Cc1cocc1-c1ccccc1
Agent: CNCCN(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: Cc1occ(-c2ccccc2)c1C=O
Reaction time: 0.5 h

Procedure:
n-Butyllithium (a 1.6 m solution in hexane, 2.43 ml, 3.89 mmol) was added to a solution of trimethylethylenediamine (397 mg, 3.89 mmol) in tetrahydrofuran (25 ml) at 0 degrees under argon. After 20 minutes the solution was cooled to-78 degrees and 4-phenyl-3-furaldehyde (Compound 54, 608 mg, 3.35 mmol) was added. This mixture was allowed to gradually warm to-20 degrees and stirred for 1 1/2 hours, then recooled to-78 degrees before n-butyllithium (a 1.6 M solution in hexane, 2.43 ml, 3.89 mmol) was added dropwise. The stirring mixture was again gradually warmed to-20 degrees and stirred for 2 hours before iodomethane (2.56 g 17.67 mmol) was added. After stirring for 18 hours at-20 degrees the reaction was quenched with ice-cold 10% (v/v) hydrochloric acid and the organics were extracted into ethyl ether. The combined fractions were washed with saturated sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 20% ethyl ether/hexanes to give the title aldehyde.
Reaction SMILES: O[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O.[NH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(N(CC)CC)C>C(O)C>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:19]1[NH:18][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1sc2ncnc(O)c2c1C
Reactant: NC1Cc2ccccc2C1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: Cc1sc2ncnc(NC3Cc4ccccc4C3)c2c1C
Yield: 64 %

Procedure:
Using 4-hydroxy-5,6-dimethylthieno[2,3-d]pyrimidine (180 mg, 1.0 mmol), phosphorus oxychloride (1.0 ml), 2-aminoindan (270 mg, 2.0 mmol), triethylamine (0.84 ml, 6.0 mmol) and dry ethanol (5 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (190 mg, 0.64 mmol) having the following physical properties:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[Br:18][CH2:19][C:20](Br)=[O:21].C(N(C(C)C)CC)(C)C>C1COCC1.C(OCC)(=O)C>[Br:18][CH2:19][C:20]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:21]
Reactant: O=C(Br)CBr
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.6 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (2 g, 9.04 mmol) in THF (50 mL), bromoacetyl bromide (0.83 mL, 9.5 mmol) was added, followed by diisopropylethylamine (DIEA, 1.8 mL, 10.85 mmol), at room temperature. The reaction mixture was stirred at room temperature for 24 hrs, the slurry was diluted with ethyl acetate and the organic phase was washed with water (50 mL). The insoluble solid was filtered and analysed to afford 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (700 mg, 22% yield). The mother liquer was evaporated in vacuo to afford a second batch of 2-bromo-N-(3-(quinoxalin-2-yl)phenyl)acetamide (1.8 g, 58% yield). LCMS calculated for C18H15N3O (M+H): 290.33. found 290.24. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.62 (1H, br.), 9.52 (1H, s), 8.55 (1H, m), 8.12-8.18 (2H, m), 8.05-8.08 (1H, m), 7.80-7.95 (3H, m), 7.55-7.60 (1H, m), 4.12 (2H, s).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.CCCCCC.C(OCC)(=O)C.CN(C)C=O>[C:11]1([N:1]2[CH:9]=[C:8]3[C:4](=[N:5][CH:6]=[N:7]3)[N:3]=[CH:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Ic1ccccc1
Reactant: c1ncc2[nH]cnc2n1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(-n2cnc3ncnc-3c2)cc1
Yield: 69.3 %

Procedure:
Using the general procedure, purine (0.120 g, 1.00 mmol) was coupled with iodobenzene (225 μL, 2.00 mmol) using CuI (9.5 mg, 0.050 mmol, 5.0 mol %), Cs2CO3 (2.1 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (32 μL, 0.20 mmol, 20 mol %) and dimethylformamide (1.0 mL) to give the crude product. Column chromatography (2×15 cm, hexane:ethyl acetate 1:2) provided 0.136 g (69% yield) of the product as a white solid. 1H NMR (400 MHz, CDCl3): δ8.00 (d, J=0.9 Hz, 1H), 7.52 (m, 3H), 7.42 (m, 5H), 6.73 (dd, J=0.6 Hz and J=3.3 Hz, 1H), 7.60 (m, 2H), 7.48 (m, 1H).
Reaction SMILES: O1CCCC1.C([O:8][C:9]([C:11]1[O:12][C:13]2[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[CH:16][C:14]=2[CH:15]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH2:21]([O:20][C:18]1[CH:17]=[CH:16][C:14]2[CH:15]=[C:11]([CH2:9][OH:8])[O:12][C:13]=2[CH:19]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a tetrahydrofuran (370 mL) solution of 6-benzyloxy-benzofuran-2-carboxylic acid ethyl ester (18.4 g, 62.1 mmol) described in Production Example 1-2-1 was added lithium aluminum hydride (7.07 g, 186 mmol) at 0° C., which was stirred at room temperature for 4 hours. To the reaction mixture were added water (7.07 mL), 5 N aqueous sodium hydroxide solution (7.07 mL) and water (21.2 mL) at 0° C. After filtering the mixture through Celite, the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (14.2 g, 90%) as a white solid.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[H-].[Na+].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Cl.[I-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1][CH2:2][C:3]1=[O:11]
Reactant: CN(C)CCCCl
Reactant: O=C1CSc2ccccc2N1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)CCCN1C(=O)CSc2ccccc21

Procedure:
The title product is prepared by reacting sixty grams (0.36 mole) of 1,4-benzothiazin-3(4H)-one in 360 of DMF with 18 g (0.37 mole) of 50% NaH, 260 ml (0.55 mole) of a 2.1 N toluene solution of 3-dimethylaminopropyl chloride, and 4 g of sodium iodide according to the procedure described in Example 1, part A; yield, 57.7 g; bp 157°-160°/0.2 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.[Cl-].[Cl:20][CH:21]=[N+:22]([CH3:24])[CH3:23]>ClCCCl>[Cl-:20].[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10]([CH:21]=[N+:22]([CH3:24])[CH3:23])=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2cc3cc(Br)ccn3n2)cc1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc(-c2nn3ccc(Br)cc3c2C=[N+](C)C)cc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of 5-bromo-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (200 mg, 0.66 mmol) in 1,2-dichloroethane (6 mL) was added N-(Chloromethylene)-N-methylmethanaminium chloride (195 mg, 1.5 mmol). The mixture was stirred at 20° C. for 20 h then heated to 50° C. for 1 h at which time monitoring the reaction by LC indicated all starting material had converted to the title compound. The solids were collected by filtration and dried under reduced pressure to afford the title compound as a solid (260 mg, 100%). LCMS m/z 331.0, 333.0 (M-(CH3)2NH+H2O)+, ret. time=2.13 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12)[NH2:5].[NH2:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH:23]=[C:22](Cl)[N:21]=1>>[NH2:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH:23]=[C:22]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)=[C:2]([F:1])[CH:3]=2)[N:21]=1
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: N#Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Product: N#Cc1ccc(Nc2cc(Nc3ccc(Oc4ccnc5[nH]ccc45)c(F)c3)nc(N)n2)cc1

Procedure:
Analogously to example 25, the title compound is synthesized from 51 mg (0.21 mmol) of [3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)phenyl]amine (from example XIX) and 54 mg (0.22 mmol) of 4-[(2-amino-6-chloropyrimidin-4-yl)amino]benzonitrile (from example XLVII). Purification by preparative HPLC gives the product.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+](C1C=C([N+]([O-])=O)C=CC=1C(NCC(OCC1C=CC=CC=1)=O)=O)([O-])=O.[Cl:46][C:47]1[CH:55]=[CH:54][C:50]([C:51](Cl)=[O:52])=[CH:49][C:48]=1[N+:56]([O-:58])=[O:57]>>[Cl:46][C:47]1[CH:55]=[CH:54][C:50]([C:51]([NH:1][CH2:2][C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[O:52])=[CH:49][C:48]=1[N+:56]([O-:58])=[O:57]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC(=O)OCc1ccccc1
Agent: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])OCc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1)OCc1ccccc1

Procedure:
The reaction of 4-chloro-3-nitrobenzoyl chloride (prepared from 4-chloro-3-nitrobenzoic acid, 1.0 g and SOCl2, 10 mL) with benzyl glycinate.PTS salt (2.0 g, 5.9 mmol) in the presence of triethylamine (2.0 mL, 14.88 mmol) as described in intermediate 1 gave the title compound as a pale green color solid (1.38 g, 80%), mp 84-86° C. 1H NMR (400 MHz, CDCl3): δ 8.31 (1H, d, J=2.0 Hz), 7.95 (1H, dd, J=8.4, 2.0 Hz), 7.65 (1H, d, J=8.4 Hz), 7.38 (5H, br s), 6.73 (1H, br s), 5.24 (2H, s), 4.29 (2H, d, J=4.8 Hz); LC-MS (negative ion mode): m/z 347 (M−H)−.
Reaction SMILES: C([Mg]Br)(C)C.[CH3:6][N:7]1[C:12]2=[CH:13][N:14]([CH2:22][CH2:23][C:24](OC)=[O:25])[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]2[C:10](=[O:28])[N:9]([CH3:29])[C:8]1=[O:30].Cl.[CH3:32][NH:33][O:34][CH3:35]>C1COCC1>[CH3:6][N:7]1[C:12]2=[CH:13][N:14]([CH2:22][CH2:23][C:24]([N:33]([O:34][CH3:35])[CH3:32])=[O:25])[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:11]2[C:10](=[O:28])[N:9]([CH3:29])[C:8]1=[O:30]
Reactant: COC(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Reactant: CNOC
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)CCn1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isopropylmagnesium bromide solution (2.9M, 3.03 mL, 8.79 mmol) was added slowly to a suspension of methyl 3-(1,3-dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)propanoate (Example 11.0 step 1) (1.5 g, 4.39 mmol) and commercially available N,O-dimethylhydroxylamine hydrochloride (0.514 g, 5.27 mmol) in THF (50 mL) at 0° C. The mixture was warmed to room temperature and stirred for 30 mins. A further portion of isopropylmagnesium bromide solution (2.9M, 3.03 mL, 8.79 mmol) was added slowly and the mixture stirred for a further 60 mins. The reaction was quenched with saturated NH4Cl(aq) and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 50-100% EtOAc/hexane, then 1-8% MeOH/EtOAc afforded the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[CH:6]=1.[CH2:14](O)[CH2:15][OH:16]>C1C=CC=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>[CH3:12][C:11]1([C:7]2[CH:6]=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=[CH:9][CH:8]=2)[O:16][CH2:15][CH2:14][O:13]1
Reactant: OCCO
Reactant: COCOc1cccc(C(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COCOc1cccc(C2(C)OCCO2)c1
Yield: 60 %

Procedure:
A mixture of 3-(acetyl)phenyl methoxymethyl ether (3.6 g, 20 mmol), ethylene glycol (3.72 g, 60 mmol) and pyridinium tosylate (0.075 g, 0.3 mmol, 3 mol %) in benzene (200 mL) was azeotropically refluxed for 8 h. The reaction was concentrated and the resulting residue was diluted with ethyl ether (150 mL) and washed with saturated aqueous bicarbonate (2×50 mL) and brine (100 mL). The ethyl ether solution was dried (K2 CO3) and concentrated. The residue was suspended in n-hexanes and the by-product was precipitated. The n-hexane solution was then separated and concentrated to obtain the desired product (2.69 g, 61%); TLC Rf: 0.5 (30% EtOAc/n-hexanes).
Reaction SMILES: C([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:44][CH3:45])[CH2:25][O:26][Si:27]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:5]1=[O:46])C=C.I([O-])(=O)(=O)=O.[Na+].Cl.[Na+].[Cl-].CC[O:58][C:59]([CH3:61])=[O:60]>O.C(#N)C.C(Cl)(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[Si:27]([O:26][CH2:25][C@@H:24]([N:6]1[C@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH2:9][C@@H:4]([CH2:61][C:59]([OH:58])=[O:60])[C:5]1=[O:46])[CH2:44][CH3:45])([C:40]([CH3:43])([CH3:42])[CH3:41])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(C)=O
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (816 mg, 1.216 mmol; Example 127, Step A) in water/acetonitrile/CCl4 (7 mL/5 mL/5 mL) at room temperature was added sodium periodate (1041 mg, 4.87 mmol) and ruthenium chloride hydrate (27.4 mg, 0.122 mmol). The mixture was stirred vigorously at room temperature for 3 h. The mixture was diluted with EtOAc and acidified with 1 M HCl. Sat. aq. NaCl solution was added and the mixture was filtered to remove the emulsion. The layers of the filtrate were separated. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (24 g column; eluent: 0 to 50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:31]3[CH:36]=[C:35]([CH3:37])[C:34]([O:38][Si](C(C)(C)C)(C)C)=[C:33]([CH3:46])[CH:32]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23]3[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=3)[C:15]2=[O:30])=[CH:9][C:8]=1[CH3:47])(C)(C)C.C[O-].[Na+].C1C[O:56][CH2:55]C1>CO>[OH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:31]3[CH:32]=[C:33]([CH3:46])[C:34]([OH:38])=[C:35]([CH3:37])[CH:36]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([O:56][CH3:55])[N:24]=3)[C:15]2=[O:30])=[CH:9][C:8]=1[CH3:47]
Reactant: C1CCOC1
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)N(c3ccnc(Cl)n3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(N2C(=O)C(c3cc(C)c(O)c(C)c3)(c3cc(C)c(O)c(C)c3)c3ccccc32)n1

Procedure:
Under an N2 atmosphere, combine 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1-(2-chloro-pyrimidin-4-yl)-1,3-dihydro-indol-2-one and sodium methoxide solution (0.5 M) in methanol (2.0 mL). Add THF (5.0 mL) and stir for 3 h at room temperature. Quench the reaction with saturated aqueous ammonium chloride (25 mL). Add ethyl acetate (25 mL) and separate the layers. Dry the organic layer with sodium sulfate and concentrate in vacuo. Dissolve the crude residue in THF (2 mL), and add a solution of tetrabutylammonium fluoride (1.0 M) in THF (0.84 mL). Stir the reaction at room temperature for 1 h. Quench the reaction with saturated aqueous ammonium chloride (25 mL). Add ethyl acetate (25 mL) and separate the layers. Dry the organic layer with sodium sulfate and concentrate in vacuo. Purify by flash column chromatography eluting with a gradient from 25% to 50% ethyl acetate in hexanes to give 0.289 g (%) of the title compound: mass Spectrum (ion spray): m/z=482(M+1); 1H NMR (DMSO-d6): δ8.67 (d, 1H), 8.29 (s, 2H), 8.21 (d, 1H), 7.36 (td, 1H), 7.30, (dd, 1H), 7.22 (td, 1H), 6.69 (s, 4H), 3.97 (s, 3H), 2.05 (s, 12H).