Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:14]1(=[O:23])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccncc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 17.8 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 15.52 g (55 mmol) of N-(4-bromobutyl)phthalimide in 80 ml of DMF was added 8.23 ml (5 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene. The mixture was stirred at room temperature for 7 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.63 g of the desired compound (yield: 17.2%, colorless crystals).
Reaction SMILES: [CH:1]1([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:3][CH2:2]1.Br[CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1.C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>CCCCCC.C(OCC)(=O)C.O.C1COCC1>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[O:16][CH2:15][CH2:14][CH2:13][CH2:12][C:1]1([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C1CC1
Reactant: BrCCCCOC1CCCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C1(CCCCOC2CCCCO2)CC1
Temperature: -65 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
Under the argon atmosphere, tert-butyl cyclopropylcarboxylate (3.76 g) and 2-(4-bromobutoxy)tetrahydro-2H-pyran (7.52 g) were dissolved in anhydrous/THF (106 mL), followed by cooling to an inner temperature of −65° C. A lithium diisopropylamide solution (2.0M, THF:heptane:ethylbenzene solution) (19.8 mL) was added dropwise over 15 minutes. After completion of addition, the mixture was stirred at room temperature for 8 hours. An aqueous saturated ammonium chloride solution was added to stop the reaction, and water, and hexane:ethyl acetate (1:1) were added, followed by extraction. The organic layer was washed with dilute hydrochloric acid, water and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The residue obtained by concentration was purified by silica gel column chromatography (hexane:ethyl acetate, 98:2→90:10) to obtain the title compound (3.86 g) having the following physical property values.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:18])[CH2:9][CH:8]3[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C1CC(c2cccc(Cl)c2)c2ccccc2N1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: O=C1CC(c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)cc3)ccc2N1
Temperature: 0 °C
Yield: 2.4 %

Procedure:
Intermediate (1-a) (58.6 g), 4-chlorobenzoic acid (71.2 g) and polyphosphoric acid (580 g) were stirred at 140° C. for 48 hours. The mixture was poured into ice water and filtered off. The precipitate was washed with water, then with a diluted NH4OH solution and taken up in DCM. The organic layer was dried (MgSO4), filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99/1/0.1). The pure fractions were collected and evaporated, and recrystallized from CH2Cl2/CH3OH/DIPE, yielding 2.2g of (±)-6-(4-chlorobenzoyl)-4(3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone (interm. 1-b, mp. 194.8° C.).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][O:6][CH:7]=1)[CH3:2].[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25](Br)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]>>[CH2:8]([O:10][C:11](=[O:32])[N:12]([C:21]1[CH:26]=[C:25]([C:5]2[O:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=2)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[CH3:9]
Reactant: CCc1cocn1
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(-c2nc(CC)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-ethyl-oxazole (47 mg) and (2-amino-6-bromo-3-nitro-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (100 mg), giving the product (74 mg) as a yellow gum.
Reaction SMILES: [C:1]1([OH:7])C=CC=CC=1.[C:8]1([CH:15]=[CH:14][CH:13]=[C:11](O)[CH:10]=1)[OH:9].C1(C=CC(O)=CC=1)O.OC1C=CC(CC2C=CC(O)=CC=2)=CC=1.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.BrC1C=C(C(C2C=C(Br)C(O)=C(Br)C=2)(C)C)C=C(Br)C=1O.C1C(O)=CC=C(S(C2C=CC(O)=CC=2)(=O)=O)C=1>>[CH2:1]=[O:7].[C:8]1([OH:9])[CH:15]=[CH:14][CH:13]=[CH:11][CH:10]=1
Reactant: Oc1cccc(O)c1
Agent: CC(C)(c1cc(Br)c(O)c(Br)c1)c1cc(Br)c(O)c(Br)c1
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: Oc1ccccc1
Product: C=O

Procedure:
The epoxide compounds may also derive from monocyclic phenols, for example from phenol, resorcinol or hydroquinone; or they are based on polycyclic phenols, for example bis(4-hydroxyphenyl)methane, 2,2-bis(4-hydroxyphenyl)propane, 2,2-bis(3,5-dibromo-4-hydroxyphenyl)propane, 4,4′-dihydroxydiphenyl sulphone, or condensation products, obtained under acidic conditions, of phenols with formaldehyde, such as phenol novolacs.
Reaction SMILES: [CH2:1](N1CCCC(CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)C1)[CH3:2].[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:54][CH3:55])[N:41]2[CH2:44][CH2:45][CH2:46][CH2:47][CH:48]2[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]2)=[C:37]([NH2:56])[N:36]=1)[CH2:31][CH2:32][CH3:33].ICC>>[CH2:1]([N:50]1[CH2:51][CH2:52][CH2:53][CH:48]([CH2:47][CH2:46][CH2:45][CH2:44][N:41]2[C:40]([O:54][CH3:55])=[N:39][C:38]3[C:42]2=[N:43][C:35]([O:34][C@@H:30]([CH3:29])[CH2:31][CH2:32][CH3:33])=[N:36][C:37]=3[NH2:56])[CH2:49]1)[CH3:2]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[NH2:27][C:28]([CH3:37])([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>O1CCCC1.C(#N)C>[CH3:36][C:28]([NH:27][C:23](=[O:24])[CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1)([CH3:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)NC(C)(C)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (40 mg, 0.119 mmol), tert-butyl 2-amino-2-methylpropanoate hydrochloride (27.8 mg, 0.142 mmol), and TEA (0.050 mL, 0.356 mmol) in tetrahydrofuran (1 mL) and acetonitrile (1 mL) was added HATU (54.1 mg, 0.142 mmol). The reaction mixture was stirred at 60° C. for 1.5 h and 1M HCl was added to neutralize the reaction solution. The resulting mixture was purified by HPLC to give the title compound. LCMS m/z=479.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.27 (d, J=6.9 Hz, 0.4H), 1.37 (s, 6H), 1.41 (s, 9H), 1.46 (d, J=6.5 Hz, 2.6H), 1.70-1.82 (m, 1H), 2.01-2.12 (m, 2H), 2.23-2.33 (m, 1H), 2.45 (t, J=7.8 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 3.05-3.22 (m, 4H), 3.39-3.48 (m, 1H), 3.53-3.62 (m, 1H), 3.72-3.82 (m, 1H), 6.60 (s, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CO.[CH3:14][Si](C=[N+]=[N-])(C)C.C(OCC)C>ClCCl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccc(O)cc1C(=O)O
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cc(O)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 49 %

Procedure:
To a stirred solution of 5-hydroxy-2-methylbenzoic acid (WO 9619437, 1.11 g, 6.69 mmol), in dichloromethane (6 mL) and methanol (6 mL) was added a 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether (7.31 mL, 14.7 mmol) at 0° C. The mixture was stirred at room temperature for 3 days, and the mixture was diluted with dichloromethane (200 mL). The solution washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluting with hexane/ethyl acetate (10/1) to afford 545 mg (49%) of the title compound:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1O)([O-:3])=O.[OH-].[Na+].C1C2C(=[O:42])C3C(=CC=CC=3)C=2C=CC=1.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.C(O)CCCCCCC>[OH:42][C:13]1[C:14]([C:22]([CH3:25])([CH3:23])[CH3:24])=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:3])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(N=Nc2ccccc2)cc1
Solvent: CCCCCCCCO
Solvent: O
Product: CC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Temperature: 50 °C

Procedure:
2-nitro-2'-hydroxy-3',5'-di-t-butylazobenzene 23.7 g was added to a mixture of n-octanol 50 g, water 14 g and 97% sodium hydroxide 8.2 g, and the resultant mixture was heated to 65° C. The mixture was then cooled to 50° C., and 9-fluorenone 2.0 g was added thereto. The resultant mixture was stirred at 90°~97° C. for 2 hours, thus almost all of the azobenzene having disappeared to produce 2-(2-hydroxy-3,5-di-t-butylphenyl)benzotriazole-N-oxide. Thus, the reaction of Process (b) was completed.
Reaction SMILES: [Cl-].[Li+].O.[CH:4]([O-:6])=[O:5].[Li+].I[C:9]1[C:17]2[C:16]([CH:18]=[O:19])=[CH:15][CH:14]=[N:13][C:12]=2[N:11]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:10]=1.C(OC(=O)C)(=O)C.CCN(C(C)C)C(C)C>CO.C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH:18]([C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:11]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:10]=[C:9]([C:4]([OH:6])=[O:5])[C:17]=12)=[O:19]
Reactant: O=C[O-]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(C=O)ccnc32)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(C=O)ccnc32)cc1
Temperature: 56 °C
Yield: 89.2 %

Procedure:
Lithium chloride (358 mg, 8.45 mmol) and lithium formate monohydrate (591 mg, 8.45 mmol) were combined in a dry sealable tube under nitrogen. DMF (12 mL), 3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (1.2 g, 2.82 mmol), acetic anhydride (532 mL, 5.63 mmol) and palladium acetate (63 mg, 0.28 mmol) were added. DIPEA (981 μL) was added, and the reaction tube was sealed and heated at 56° C. for 4 h. The reaction mixture was taken up in MeOH/DCM (20%) and filtered to remove the insoluble black carbon material. The yellow solution was concentrated in vacuo, dissolved in MeOH/DCM (10%), and washed with aqueous HCl (0.1N). The aqueous layer was extracted twice with MeOH/DCM (10%). The organics were combined, dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (10-15% MeOH/DCM) gave the title compound as a tan solid (866 mg, 89%). 1H NMR (500 MHz, DMSO-d6) δ 2.35 (s, 3H), 7.45 (d, J=8.5 Hz, 2H), 7.62 (d, J=5.0 Hz, 1H), 8.11 (d, J=8.5 Hz, 2H), 8.58-8.62 (m, 2H), 11.02 (s, 1H), 13.20 (br s, 1H). [M+H] calc'd for C16H12N2O5S, 345; found, 345.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:4]=[CH:3]1.[Br:15]N1C(=O)CCC1=O>ClCCl>[Br:15][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1
Solvent: ClCCl
Product: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of 2-(1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (100 mg, 0.54 mmol) in dichloromethane (5 mL) was added N-bromosuccinimide (102 mg, 0.57 mmol). The reaction mixture was stirred at r.t. for 3 hrs. It was then purified by flash column chromatography (EtOAc/Hexane) to afford 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (140 mg, quantitative yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 3.67 (3H, s), 7.70 (1H, d, J=4.8 Hz), 8.04 (1H, s), 8.19 (1H, s), 8.81 (1H, d, J=4.2 Hz). [M+H] Calc'd for C10H7BrN4, 264. Found, 263, 265.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7](=[O:34])[C@H:8]([CH2:31][CH2:32][CH3:33])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18](C3C=CC(S(C)(=O)=O)=CC=3)=[CH:17][CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH2:5][CH2:4]1)#[N:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[F:42].BrC1C=CC([C@H](N[C@H](C(NC2(C#N)CC2)=O)CCC)C(F)(F)F)=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([C:3]1([NH:6][C:7](=[O:34])[C@@H:8]([NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:39]=[CH:40][C:41]([F:42])=[C:36]([Cl:35])[CH:37]=3)=[CH:17][CH:16]=2)[C:11]([F:12])([F:14])[F:13])[CH2:31][CH2:32][CH3:33])[CH2:5][CH2:4]1)#[N:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CCC[C@H](N[C@@H](c1ccc(-c2ccc(S(C)(=O)=O)cc2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCC[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Product: CCC[C@H](N[C@@H](c1ccc(-c2ccc(F)c(Cl)c2)cc1)C(F)(F)F)C(=O)NC1(C#N)CC1

Procedure:
The title compound was prepared in similar manner to that described for N1-(1-cyanocyclopropyl)-N2-{(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}-L-norvalinamide via Suzuki cross-coupling between 3-chloro-4-fluorophenylboronic acid and N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-norvalinamide in the presence of [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), dichloromethane complex.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=[C:9]2I.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CN(C)CC(O)=O.[F:38][C:39]1[CH:40]=[C:41]([OH:46])[CH:42]=[C:43]([F:45])[CH:44]=1>O1CCOCC1.[Cu]I>[F:38][C:39]1[CH:40]=[C:41]([CH:42]=[C:43]([F:45])[CH:44]=1)[O:46][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)[CH:7]=2)[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2cc(C3OCCO3)ccc21
Reactant: Oc1cc(F)cc(F)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(Oc2cc(F)cc(F)c2)c2cc(C3OCCO3)ccc21
Temperature: 140 °C
Reaction time: 2 h

Procedure:
To a microwave-flask containing 300 mg (0.672 mmol) 5-(1,3-dioxolan-2-yl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A), 438 mg (1.344 mmol) cesium carbonate and 19 mg (0.134 mmol) N,N-dimethylglycine hydrochloride in 1,4-dioxane (3 ml) were added 131 mg (1.008 mmol) 3,5-difluorophenol and 13 mg (0.067 mmol) copper(I) iodide. The flask was placed in an ultrasonic bath, and argon was bubbled through for a period of five minutes. The flask was then sealed and heated to 140° C. for 2 h using microwave irradiation. After this time, the same amounts of N,N-dimethylglycine hydrochloride and copper(I) iodide were added again, and heating was continued for further 2 h. This procedure was repeated one more time. Then, the reaction mixture was filtered, and the filtrate was purified by preparative RP-HPLC (acetonitrile/water+0.05% TFA gradient) to afford 43 mg (14% of th.) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([N:16]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](I)[CH:25]=3)C(OC(C)(C)C)=O)[N:12]3[N:31]=[CH:32][CH:33]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([NH:16][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:36]4[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=4)[CH:25]=3)[N:12]3[N:31]=[CH:32][CH:33]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: OB(O)c1cccnc1
Reactant: Cc1c(N[C@H]2CC[C@H](N)CC2)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1cccc(I)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(N[C@H]2CC[C@H](N)CC2)nc2ccnn2c1Nc1cccc(-c2cccnc2)c1

Procedure:
The title compound and Boc protected intermediate were synthesised in the same manner as above using N-{5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(tert-butoxy)-N-(3-iodophenyl)carboxamide, pyridine-3-boronic acid, Na2CO3 palladium (II) acetate and triphenylphosphine. The title compound (6.1 mg, 15% yield as 3 trifluoroacetic acids salt) was obtained. The HPLC retention time and ESI/MS data for this compound are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:11](OCC)=[O:12])[CH2:5]2.BrC1C=C2C(=CC=1)C(=O)CC2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([CH2:11][OH:12])[CH2:5]2
Reactant: CCOC(=O)C1Cc2ccc(Br)cc2C1
Agent: O=C1CCc2cc(Br)ccc21
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Ethyl 5-bromo-2,3-dihydro-1H-indene-2-carboxylate (prepared from 5-Bromo-2,3-dihydro-1H-inden-1-one, following similar procedure of US2005/0075366, compound 148) in 100 mL of anhydrous THF was added LiAlH4 (4.94 g, 130 mmol) portionwise at 0° C. The mixture was warmed slowly to RT and stirred overnight. The reaction mixture was quenched with water (5 mL) and diluted with EtOAc (200 mL) and then filtered. The filtrate was washed with water (300 mL) and brine (300 mL), dried over Na2SO4 and concentrated to dryness to obtain the title compound. 1H-NMR (300 MHz, CDCl3) δ 7.33 (s, 1H), 7.24 (d, J=7.9 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 3.64 (d, J=6.4 Hz, 2H), 2.96-3.09 (m, 2H), 2.65-2.77 (m, 3H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])#[N:2].[N-:24]=[N+:25]=[N-:26].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:24]1[C:1]([CH:3]2[CH2:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[N:2][N:26]=[N:25]1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(C#N)C1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn[nH]2)C1
Temperature: 95 °C
Yield: 98.6 %

Procedure:
1-Benzyl 4-ethyl 2-cyanopiperidine-1,4-dicarboxylate (2.5 g, 7.90 mmol) was dissolved in toluene (50 mL) and sodium azide (0.822 g, 12.64 mmol) and triethylamine hydrochloride (1.740 g, 12.64 mmol) were added and the mixture was heated at 95° C. overnight. The reaction mixture was allowed to cool to room temperature and was washed with 2 M HCl. The aqueous phase was extracted with EtOAc and the combined organic phase was dried over Na2SO4 and evaporated to yield 1-benzyl 4-ethyl 2-(1H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (2.8 g, 99%). MS m/z 360 (M+H)+
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C@@H:14]2[CH2:16][C@H:15]2[C:17]([OH:19])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:44][C@H:45]([C:48]1[CH:49]=[N:50][C:51]([O:54][CH2:55][CH2:56][CH3:57])=[CH:52][CH:53]=1)[CH2:46][OH:47]>CN(C=O)C.[Cl-].[Na+].O.CCOC(C)=O>[OH:47][CH2:46][C@H:45]([NH:44][C:17]([C@H:15]1[CH2:16][C@@H:14]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:19])[C:48]1[CH:49]=[N:50][C:51]([O:54][CH2:55][CH2:56][CH3:57])=[CH:52][CH:53]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: CCCOc1ccc([C@@H](N)CO)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reaction time: 0.01 h
Yield: 29 %

Procedure:
Triethylamine (0.384 mL, 2.75 mmol) was added to a mixture of trans-2-phenyl-1-cyclopropanecarboxylic acid IM46 (223 mg, 1.38 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (522 mg, 1.38 mmol) suspended in DMF (2 mL) in a small vial. The vial was vigorously agitated for 30 seconds and then left for 5 minutes. This mixture was added drop wise to (R)-2-Amino-2-(6-propoxy-pyridin-3-yl)-ethanol IM38 (270 mg, 1.4 mmol) dissolved in DMF (3 mL). Alter 1 h the mixture was poured into a mixture of EtOAc (40 mL) and brine (20 mL). The organic layer was dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, 10-100% EtOAc in heptanes) gave the title compound as a white solid (0.134 g, 29%). LC-MS (m/z) 341.0 (MH+), tR=1.52 min (method A). 1H-NMR (800 MHz, DMSO) δ 8.53 (d, J=8.2 Hz, 1H), 8.04 (br a, 1H), 7.64-7.57 (m, 1H), 7.30-7.23 (m, 2H), 7.19-7.14 (m, 1H), 7.10 (d, J=7.3 Hz, 2H), 6.74 (d, J=8.5 Hz, 1H), 4.96-4.90 (m, 1H), 4.88-4.80 (m, 1H), 4.16 (t, J=6.7 Hz, 2H), 3.61-3.49 (m, 2H), 2.23-2.15 (m, 1H), 2.04-1.95 (m, 1H), 1.74-1.64 (m, 2H), 1.40-1.32 (m, 1H), 1.23-1.13 (m, 1H), 0.84 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[NH4+].[Cl-].C[N:15](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(Br)cc1N

Procedure:
A solution of 2-amino-4-bromobenzoic acid (1 g, 4.63 mmol), NH4Cl (1.8 g, 32.41 mmol), TBTU (1.5 g, 4.63 mmol) and diisopropylethylamine (1.2 g, 9.26 mmol) in DMF (30 mL) was stirred at room temperature overnight. Then the mixture was adjusted to pH 8.0 with saturated Na2CO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to give the desired yellow product. MS (ESI): 215, 217 (MH+).