Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:17][CH:18]=1)=[O:13].Br[C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][C:30]([CH3:37])([CH3:36])[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3cccc(C(F)(F)F)c3)s2)c(Cl)c1Cl

Procedure:
Ethyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoate is prepared from 3-(2,3-dichloro-4-hydroxy-phenyl)-1-(5-(3-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and ethyl bromo-isobutyrate according to general procedure D.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]>>[Cl:42][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]3[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)[CH:32]=[C:27]([Cl:26])[C:28]=1[OH:43]
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure M, 1-(6-bromo-4-((trans-4-(dimethylamino)cyclohexyl)amino)quinolin-3-yl)propan-1-one (125 mg, 0.31 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (98 mg, 0.34 mmol) to afford the desired product (74 mg, 49%) as a yellow solid. 1H NMR (500 MHz, DMSO d6) δ 10.58 (d, J=7.9 Hz, 1H), 8.96 (s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.03 (dd, J=8.7, 1.9 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.771 (s, 2H), 4.19-4.15 (br s, 1H), 3.13 (q, J=7.2 Hz, 2H), 2.56-2.51 (m, 1H), 2.32 (s, 6H), 2.26-2.22 (m, 2H), 1.96-1.89 (m, 2H), 1.56-1.47 (m, 4H), 1.14 (t, J=7.2 Hz, 3H). APCI MS m/z 486 [C26H29Cl2N3O2+H]+; HPLC>99% (AUC), tR=8.28 min.
Reaction SMILES: [NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:35][C@H:36]([C:41]([CH3:43])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39].Br.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N[C@H](C(N[C@H](C(C)=O)CC(C)C)=O)C)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:35][C@H:36]([C:41]([CH3:43])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:23])[CH2:18][CH:19]([CH3:20])[CH3:21])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(=O)[C@@H](N)CC(C)C
Agent: Br
Agent: CC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Product: CC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
Z-Phe-Gly-Leu-LeuCH3 was prepared by coupling Z-Phe-Gly-Leu-OH (2.23 g, 4.76 mmol) to H-LeuCH3.HBr by a procedure substantially similar to that described for preparation of Z-Phe-Gly-Ala-LeuCH3 in Example 1, above. Product was recrystallized from ethyl acetate to yield 2.34 g of Z-Phe-Gly-Leu-LeuCH3 (m.p. 165.5°-166.5°).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2[CH:11]=[C:12]([C:19]([N:21]([CH:35]([CH3:37])[CH3:36])[C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]3)=[O:20])[C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]=2[O:8][C:7]([CH3:39])([CH3:38])[C:6]1=[O:40])[CH2:2][CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:49])C=1.O>ClCCl>[CH3:39][C:7]1([CH3:38])[C:6](=[O:40])[N:5]([CH2:1][CH2:2][CH:3]2[CH2:4][O:49]2)[C:10]2[CH:11]=[C:12]([C:19]([N:21]([CH:35]([CH3:36])[CH3:37])[C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23]3)=[O:20])[C:13]([C:15]([F:17])([F:16])[F:18])=[CH:14][C:9]=2[O:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Solvent: ClCCl
Solvent: O
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2CCC1CO1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a solution of tert-butyl (3R)-3-[{[4-but-3-en-1-yl-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (1.7 g) in dichloromethane (15 ml) was added m-chloroperbenzoic acid (775 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (780 mg).
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=3)[CH:16]=2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[CH:16]=2)[C:11]([N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[O:13])=[CH:26][CH:27]=1)#[N:2]
Reactant: CCNCC
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CCN(CC)C(=O)c1cc(Oc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1
Yield: 72.3 %

Procedure:
Following the procedure of Example 5(c) 3,5-bis-(4-cyano-phenoxy)-benzoic acid 1.2 g (3.36 mmol) and diethyl-amine (0.245 g, 3.36 mmol) were used to afford 1.0 g of the required product. 1H NMR (DMSO-d6): δ 1.15 (6H, m), 3.22 (2H, m), 3.40 (2H, m), 6.94 (2H, d), 7.05 (1H, t), 7.25 (2H, d), 7.88 (2H, d).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][N:6]=[CH:5][N:4]=1)#[CH:2].Cl[C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[N:17]=1.C(N(CC)CC)C.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:8]1[C:3]([C:1]#[C:2][C:20]2[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:16][N:17]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]4)=[CH:29][CH:28]=3)[N:19]=2)=[N:4][CH:5]=[N:6][CH:7]=1)[CH3:14]
Reactant: C#Cc1ncncc1CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cncnc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 27.8 %

Procedure:
To a nitrogen de-gassed solution of ethyl 2-(4-ethynylpyrimidin-5-yl)acetate (I110) (0.146 g, 0.766 mmol) and tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (0.250 g, 0.547 mmol) in dry DMF (15 mL) were added triethylamine (0.305 mL, 2.19 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.016 g, 0.055 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.019 g, 0.027 mmol) and Cu(I)I (0.010 g, 0.055 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated in vacuo to give a brown gum. The crude material was purified by silica gel chromatography (Isolera Biotage, 40 g Si cartridge, 0-70% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I111) (0.093 g, 27% yield) as a yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.50 (s, 1H), 9.23 (s, 1H), 8.97 (s, 1H), 8.88 (s, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 4.14-4.04 (m, 4H), 3.96 (s, 2H), 2.81 (br s, 2H), 2.70-2.61 (m, 1H), 1.75 (d, J=11.9 Hz, 2H), 1.53-1.37 (m, 11H), 1.14 (t, J=7.1 Hz, 3H). LCMS Method C: it 6.64 min; m/z 609.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:15][CH3:16])=[C:5](C(O)=O)[NH:6]2.[H-].[Na+].[CH3:19][C@@H:20]1[CH2:22][O:21]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:15][CH3:16])=[CH:5][N:6]2[CH2:19][C@H:20]([OH:21])[CH3:22]
Reactant: CCc1c(C(=O)O)[nH]c2ccc(F)c(Cl)c12
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cn(C[C@@H](C)O)c2ccc(F)c(Cl)c12
Reaction time: 4 h
Yield: 80 %

Procedure:
A suspension of 1.2 g of 4-chloro-5-fluoro-3-ethyl-indole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 4 hours and, after cooling to 0°, diluted with 24 ml of tetrahydrofuran. 186 mg of sodium hydride dispersion were added and the mixture was stirred for one hour. Subsequently, 0.5 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 114 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium surfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with hexane-toluene (1:2) and subsequently with toluene-ethyl acetate (9:!). 102 g (80%) of (R)-1-(4-chloro-5-fluoro-3-ethylindol-1-yl)-propan-2-ol were obtained as pale brown crystals with m.p. 87°-88°.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[I:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]([NH:14][NH:13][C:11](=[O:12])[C:10]2[CH:15]=[CH:16][C:17]([CH3:18])=[C:8]([I:7])[CH:9]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(C(=O)NN)cc1I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NNC(=O)C2CC2)cc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of cyclopropanecarbonyl chloride (1.81 mL, 20.0 mmol) in dichloromethane (20 mL) was added dropwise to a stirred solution of 3-iodo-4-methylbenzohydrazide (preparation 55b, 5.00 g, 18.1 mmol) and triethylamine (2.78 mL, 20.0 mmol) in dichloromethane (80 mL) at 0° C. After 2 hours stirring at ambient temperature, the mixture was concentrated in vacuo and water was added to the residue. The resultant precipitate was filtered and was washed with water and diethyl ether to give the title compound (4.75 g, 76%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][C:38]1[S:42][N:41]=[C:40]([C:43](=[N:67][O:68][CH3:69])[C:44]([NH:46][C@@H:47]2[C:65](=[O:66])[N:49]3[C:50]([C:62]([O-:64])=[O:63])=[C:51]([CH2:54][N+:55]4([CH3:61])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]4)[CH2:52][S:53][C@H:48]23)=[O:45])[N:39]=1.C[Si](C)(C)NC(=O)C.C(OC(C)C)(C)C>CS(C)=O>[NH2:37][C:38]1[S:42][N:41]=[C:40]([C:43](=[N:67][O:68][CH3:69])[C:44]([NH:46][C@@H:47]2[C:65](=[O:66])[N:49]3[C:50]([C:62]([O-:64])=[O:63])=[C:51]([CH2:54][N+:55]4([CH3:61])[CH2:60][CH2:59][N:58]([C:9]([C:4]5[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][N:5]=5)=[O:11])[CH2:57][CH2:56]4)[CH2:52][S:53][C@H:48]23)=[O:45])[N:39]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCNCC3)CS[C@H]12)c1nsc(N)n1
Reactant: O=C(O)c1cc(O)c(O)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)N[Si](C)(C)C
Agent: On1nnc2ccccc21
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCN(C(=O)c4cc(O)c(O)cn4)CC3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a solution of 4,5-dihydroxy-2-pyridinecarboxylic acid (3.1 g) and 1-hydroxybenzotriazole (4.0 g) in dimethyl sulfoxide (30 ml) was added N,N'-dicyclohexylcarbodiimide (6.2 g). After being stirred at room temperature for 1 hour, the reaction mixture was added to a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (10.0 g) and N-trimethylsilylacetamide (3.0 g) in dimethyl sulfoxide (50 ml), and the stirring was continued for 30 minutes. The mixture was added dropwise to diisopropyl ether (1.5 l) and the resulting precipitate was collected by filtration, which was dissolved in an aqueous solution of sodium bicarbonate, After the insoluble material was filtered off, the filtrate was adjusted to pH 3.0 with 1N hydrochloric acid and subjected to column chromatography on "Diaion HP-20" with 5% aqueous isopropyl alcohol as an eluent. The eluate was lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-[1-methyl-4-(4,5-dihydroxy-2-pyridylcarbonyl)-1-piperazinio]methyl-3-cephem-4-carboxylate (syn isomer) (0.5 g).
Reaction SMILES: O(C)[Na].[C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])#[N:5].Cl.Cl.[NH2:17][C:18]1[CH:19]=[C:20]([CH3:26])[C:21]([CH3:25])=[CH:22][C:23]=1N.O>CO>[CH3:26][C:20]1[C:21]([CH3:25])=[CH:22][C:23]2[NH:5][C:4]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:17][C:18]=2[CH:19]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CC(C)(C)OC(=O)NCC#N
Agent: CO[Na]
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cc2nc(CNC(=O)OC(C)(C)C)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.3 g of a 30% NaOCH3 solution were added to tert-butyl cyanomethylcarbamate (0.4 g; 25.6 mmol) in 10 ml of CH3OH, and the mixture was stirred at room temperature for 1 h. After addition of 5.15 g of 4,5-diamino-ortho-xylene bishydrochloride, the reaction mixture was stirred overnight and then added to 100 ml of H2O, and the solid obtained by filtration was dried at 30° C. in vacuo. 0.5 g; ESI-MS [M+H+]=276
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][O:36][CH:37]([CH3:39])[CH3:38]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][O:36][CH:37]([CH3:39])[CH3:38])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: CC(C)OCCBr
Product: CC(C)OCCN1CCN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CC1
Yield: 86.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.229 mmol) and 2-(2-bromoethoxy)propane (200 mg, 0.252 mmol) gave 7-cyclopentyl-2-{5-[4-(2-isopropoxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (103 mg, 86%). MS (ESI) m/z 521.3 (M+H)|
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[CH:18])[CH:14]=[CH:13][C:12]=2[Cl:19])[CH:9]=1)[C:5]#[N:6].I[C:21]1[C:29]2[C:24](=NC=CC=2)[N:23]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:22]=1>CN(C=O)C.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[C:33]([O:32][C:30]([N:23]1[C:24]2[CH:3]=[CH:4][CH:5]=[N:6][C:29]=2[C:21]([C:18]#[C:17][C:15]2[CH:14]=[CH:13][C:12]([Cl:19])=[C:11]([O:10][C:8]3[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=3)[CH:16]=2)=[N:22]1)=[O:31])([CH3:34])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cccnc21
Reactant: C#Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(C#Cc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c2ncccc21

Procedure:
A solution of 147 mg (0.51 mmol) of 3-chloro-5-(2-chloro-5-ethynylphenoxy)benzonitrile, 166 mg (0.48 mmol) of tert-butyl 3-iodo-1H-pyrazolo[3,4-b]pyridine-1-carboxylate, 17 mg (0.03 mmol) of bis(triphenylphosphino)palladium (II) chloride, and 9.00 mg (0.05 mmol) of CuI in 2.5 mL DMF/5 mL triethylamine under nitrogen was stirred at room temperature for one hour. The reaction mixture was concentrated in vacuo to a dark oil. The crude oil was purified by flash chromatography over silica gel with 2.5:1 hexanes/EtOAc to provide the desired product as a yellow oil/foam. M+=405 (M−100, loss of Boc). 1H NMR (CDCl3): 1.75 (s, 9H), 7.10 (m, 1H), 7.19 (m, 1H), 7.36 (m, 1H), 7.39 (m, 2H), 7.50 (dd, 1H), 7.56 (dd, 1H), 8.21 (dd, 1H), 8.82 (dd, 1H).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13](=[O:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1>C(O)(=O)C.C([O-])(=O)C.[Ag+]>[I:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[CH2:11][CH2:12][C:13](=[O:15])[CH3:14]
Reactant: COc1cccc(CCC(C)=O)c1
Reactant: II
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(I)c(CCC(C)=O)c1
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Samples of iodine (42.4 g, 0.167 mole) and silver acetate (27.87 g, 0.167 mole) were added in portions to a solution of 29.8 g (0.167 mole) of 1-(3-methoxyphenyl)- butane-3-one in 167 ml of glacial acetic acid. The mixture was stirred one hour. The silver iodide was removed by filtration and washed with acetic acid. The filtrate was partitioned between ether and water. The ether layer was washed with water, sodium bicarbonate solution and sodium thiosulfate solution. The ether solution was dried with MgSO4 and evaporated to dryness in vacuo. There was obtained 41.8 g (82% yield) of oily 1-(2-iodo-5-methoxyphenyl)butane-3-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49](Br)[CH:50]=3)[CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[C:49]([C:22]#[C:21][C:18]4[NH:17][C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:23])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=4)[CH:50]=3)[CH:45]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc3cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc3c2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (53 mg, 0.166 mmol), (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (100 mg, 0.200 mmol), Pd(PPh3)4 (19 mg, 0.0166 mmol), CuI (3 mg, 0.0166 mmol) and triethylamine (0.230 mL, 1.66 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 1 hours then cooled to RT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (24 mg, 20%). (DMSO-d6, 400 MHz) 12.00-11.85 (m, 2H), 7.99-7.83 (m, 4H), 7.64 (s, 1H), 7.48 (m, 1H), 7.42 (s, 1H), 7.29 (m, 2H), 5.10 (m, 1H), 5.03 (m, 1H), 4.06 (m, 2H), 3.82-3.76 (m, 4H), 3.54 (s, 6H), 2.15-1.97 (m, 10H), 0.94-0.81 (m, 12H); MS (ESI) m/z 737 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][N:8]=1.O>CC(N(C)C)=O>[I:13][C:10]1[CH:11]=[CH:12][C:7]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:8][CH:9]=1
Reactant: C1CCNC1
Reactant: Clc1ccc(I)cn1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Ic1ccc(N2CCCC2)nc1
Temperature: 120 °C

Procedure:
Pyrrolidine (1.74 ml) was added to 2-chloro-5-iodopyridine (1 g) in dimethylacetamide (5 ml) and the solution heated at 120° C. for 4 h. After cooling, the reaction mixture was poured into water (60 ml) and the solid precipitate collected by filtration. Recrystallisation from ethyl acetate gave the product as off-white needles (0.33 g); the remaining material was adsorbed onto silica and purified by column chromatography eluting with 0 to 3% ethyl acetate in hexane to give a white solid (0.65 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].C1OCCOCCOCCOCCOCCOC1.CC([O-])(C)C.[K+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CCOCC>[CH2:36]([N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)C(=O)c1ccc[nH]1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)C(=O)c1cccn1Cc1ccccc1
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
A suspension of 10 g (65 mmol) of methyl pyrrol-2-ylglyoxylate in 100 ml of ether is added to a solution of 1.7 g (6.5 mmol) of 18-crown-6 with 7.3 g (65 mmol) of potassium tert-butylate in 100 ml of ether, stirring is carried out for 30 minutes and 11.1 g (65 mmol) of benzyl bromide in 50 ml of ether are then added dropwise. Stirring is carried out overnight at room temperature, the mixture is poured onto water and extracted with ether and the organic phase is dried and evaporated down. Chromatography over silica gel with hexane/ethyl acetate gives 6.7 g (42%) of the title compound as a reddish brown oi.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[Cl:12][C:13]1[C:14]([CH:23]([CH3:25])[NH2:24])=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([NH:24][CH:23]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:16][N:15]=2)[CH3:25])=[O:5])=[C:7]([Cl:11])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(Cl)c1c(Cl)ccnc1Cl
Reactant: CC(N)c1ncc(C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)c1c(Cl)ccnc1Cl)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 8 h

Procedure:
2,4-Dichloronicotinoyl chloride (0.40 g), made as in Example 1, Step C, was added to a solution of the amine intermediate from Step A (0.66 g) and triethylamine (0.70 g) in 30 mL of methylene chloride at room temperature followed by stirring overnight. The reaction mixture was distilled under vacuum to remove the solvent, giving an oil that was filtered through silica gel using 100% methylene chloride as the eluent. The solvent was then removed under vacuum to give the title compound, a compound of the invention, as a red oil.