Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH:8]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[O:9][CH3:10].[C-:16]#[N:17].[Na+]>CN(C)P(=O)(N(C)C)N(C)C>[C:16]([CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][CH:8]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[O:9][CH3:10])#[N:17]
Reactant: [C-]#N
Reactant: COC(CC#CCCCCl)c1ccco1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(CC#CCCCC#N)c1ccco1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A stirred mixture of 0.45 g of 7-chloro-1-(2-furyl)-1-methoxy-3-heptyne, 0.20 g of sodium cyanide, and 4.0 ml of hexamethylphosphoric triamide was maintained at 25° C. for 22 hours. The mixture was partitioned with water and 1:1 hexaneether. The organic layer was washed with water and brine, dried and concentrated. The resulting oil was distilled at 0.30 mm on a Kugelrohr at 105°-110° C., giving 0.38 g of the desired compound as an oil; PMR δ 2.36 (2H, t, CH2CN).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][CH:13]=[CH:14][C:15]([C:16]([OH:18])=O)=[C:4]2[NH:3]1.C1C=CC2N(O)N=[N:25]C=2C=1.[NH4+].[Cl-].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN1C(=O)CCC1.[Cl-].[Na+].O.O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][CH:13]=[CH:14][C:15]([C:16]([NH2:25])=[O:18])=[C:4]2[NH:3]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cccc2c1[nH]c(=O)c1ccncc12
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1cccc2c1[nH]c(=O)c1ccncc12
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-7-carboxylic acid (1.0 eq, 1.91 g, 7.96 mmol) was mixed with HOBt.H2O (2.0 eq, 2.15 g, 15.91 mmol) and NH4Cl (8.0 eq, 3.41 g, 63.6 mmol) in NMP (30 ml). DIEA (4.0 eq, 5.5 ml, 31.57 mmol) and EDCI (2.0 eq, 3.05 g, 15.91 mmol) was added and the mixture was stirred in a closed vessel at 80° C. for 2.5 hours. Water and brine were added. The solid was filtered, washed with water, washed with methanol and dried in a vacuum oven. 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-7-carboxamide was isolated as an off-white solid (1.81 g, 96% yield). LCMS (ES): m/z 240 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]([OH:11])[CH2:9][OH:10])[CH3:2].C(N(CC)CC)C.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31].CCCCC>C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:8]([OH:11])[CH2:9][O:10][Si:30]([CH3:32])([CH3:31])[CH3:29])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCOc1ccccc1OC(c1ccccc1)C(O)CO
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CCOc1ccccc1OC(c1ccccc1)C(O)CO[Si](C)(C)C
Temperature: -17 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenylpropanol from Example 2 (1.44 g, 5 mmole) and triethylamine ((0.77 mL, 5.5 mmole) were dissolved in ethyl acetate (15 ml) and cooled to −17° C. Trimethylsilyl chloride (0.64 mL, 5.0 mmole) dissolved in 5 mL of ethyl acetate was added over 10 minutes keeping the temperature below −15° C. a white precipitate formed during this addition. The mixture was stirred below −15° C. for 15 minutes, and 20 mL of pentane was added. The solids were removed by filtration and the filtrate was concentrated under vacuum to a cloudy oil. The oil was chromatographed on silica (230-400 mesh) eluting with 4:1 heptane-ethyl acetate. The product-containing fractions were concentrated to yield 1.80 g (88.5%) of the title compound as a clear colorless oil; 1H NMR (400.13 MHZ, CDCl3) d 0.09 (s, 9H), 1.47 (t, J=6.8 Hz, 3H), 2.82 (d, J=5.2, 1H), 3.80 (m, 3H), 4.0-4.11 (m, 4H), 5.08 (d, J=6.0, 1H), 6.76 (m, 2H), 6.85 (m, 2H), 7.2-7.45 (m, 5H); 13C NMR (100.62 MHZ, CDCl3) d 0.0, 15.54, 63.34, 65.06, 75.22, 83.71, 114.28, 118.60, 121.51, 122.95, 127.84, 128.49, 128.84, 138.93, 148.34, 150.40; MS (ei) m/e 360.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[C:8]([CH3:16])[C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C1COCC1>[OH:1][C:2]1[C:7]2=[C:8]([CH3:16])[C:9]([C:11]([OH:13])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(O)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cn2ncnc(O)c12
Temperature: 60 °C

Procedure:
To a solution of ethyl 4-hydroxy-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (442 mg, 2.0 mmol) (see example 6 of US Pat. App. 2003/0186982, the disclosure of which is herein incorporated by reference ) in 10 mL of THF was added a solution of NaOH (1 N, 6.0 mL). The mixture was heated at 60° C. overnight and HPLC analysis indicated the completion of the reaction. After cooling down, the solution was neutralized with 6.0 mL of 1 N HCl. The organic solvent was then removed and the solid was collected after filtration to the title compound (350 mg, 91%). MS(ESI+) m/z 194.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[F:21][C:22]([F:38])([F:37])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)=[CH:26][CH:25]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:22]([F:38])([F:37])[F:21])=[CH:29][CH:28]=2)[CH2:31][C:32]2[NH:36][CH:35]=[CH:34][N:33]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: FC(F)(F)Oc1ccc(NCc2ncc[nH]2)cc1
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2ccc(OC(F)(F)F)cc2)[C@H]1O
Yield: 40.5 %

Procedure:
The title compound (155 mg, 40%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (200 mg, 0.71 mmol) and 4-trifluoromethoxyphenyl-1H-imidazol-2-ylmethylamine (183 mg, 0.71 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[CH2:28](B(O)O)[CH2:29][CH3:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:28]([C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1)[CH2:29][CH3:30]
Reactant: CCCB(O)O
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Br)cn2COCC[Si](C)(C)C)c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 38.1 %

Procedure:
To 2.37 g (5.00 mmol) of 3-bromo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 20-(a) were added 1.76 g (20 mmol) of propylboronic acid, 4.25 g (20 mmol) of potassium phosphate, 15.8 ml of toluene, 0.95 ml of water, 56 mg of palladium acetate and 179 mg of butyl-di-1-adamantylphosphine, and the mixture was degassed under reduced pressure, replaced with argon and stirred at 100° C. for 5.5 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with toluene. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=7:1→5:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 834 mg of the title compound as a pale brownish solid. (Yield: 38%)
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:5]2[C:6]([C:12](O)=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C[CH2:19][N:20]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN.Cl>CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]1[C:16]([Br:17])=[CH:15][C:5]2[C:6]([C:12]([NH:20][CH3:19])=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: Nc1cc2oc(C3CC3)c(C(=O)O)c2cc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(C2CC2)oc2cc(N)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 714.3 %

Procedure:
To a solution of 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylic acid (6.5 g, 22 mmol) in dry DMF (500 mL) were added EDCI (2.98 g, 2.4 mmol) and HOBT (6.33 g, 3.6 mmol). The reaction mixture was stirred at room temperature for 2 h, and then Et3N (20 mL) and MeNH2.HCl (7.3 g, 110 mmol) were added to the reaction mixture. After stirring for another 2 hours, the reaction mixture was concentrated in vacuum and Na2CO3 (a.q., 300 mL) was added to the mixture. The resulting solid was filtered to give the crude product, which was purified by column chromatography (DCM:MeOH=30:1) to give the product of 6-amino-5-bromo-2-cyclopropyl-N-methylbenzofuran-3-carboxamide (5.3 g, yield: 78%). 1H-NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 6.77 (s, 1H), 5.88 (s, 1H), 4.11 (s, 2H), 3.04 (d, J=4.8 Hz, 3H), 2.69˜2.73 (m, 1H), 1.10˜1.16 (m, 2H), 1.07˜1.09 (m, 2H). MS (M+H)+: 309/311.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][OH:10])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](OCC(F)(F)F)=[O:12]>O1CCCC1>[OH:10][N:9]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH:11]=[O:12]
Reactant: C[C@H](NO)c1ccccc1
Reactant: O=COCC(F)(F)F
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N(O)C=O
Temperature: 65 °C
Yield: 89 %

Procedure:
A solution of Example 2B (1.5 g, 10.95 mmol) in tetrahydrofuran (15 mL, 10 vols) was treated with the 2,2,2-trifluoroethyl formate reagent (92% wt, 7.6 g, 54.7 mmol, 5 equiv). The resulting mixture was heated at 65° C. for 18 hours and concentrated. The concentrate was distilled under vacuum (170° C. at 1.6 mm Hg) to provide 1.6 g (89%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.00 (s, 1H), 7.54-7.30 (m, 5H), 4.93 (q, 1H, J=7 Hz), 1.82 (d, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[S:10].[C:11]([NH:19][NH2:20])(=O)[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:19][N:20]=[C:9]1[SH:10]
Reactant: S=C=Nc1ccccc1Cl
Reactant: NNC(=O)c1ccncc1
Solvent: CC#N
Product: Sc1nnc(-c2ccncc2)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.2 %

Procedure:
A mixture of 1-chloro-2-isothiocyanatobenzene 1 (3 g, 17.68 mmol) and isonicotinohydrazide 2 (2.43 g, 17.68 mmol) in acetonitrile was stirred at ambient temperature for 18 hours, concentrated to dryness, and 100 mL of 10% K2CO3 (aq.) was added. The resulting mixture was stirred under reflux for 6 hours. The clear solution was cooled to ambient temperature, washed with ether and acidified with 1N HCl. The solid was collected, washed with H2O and ether, and dried to afford compound 4 (4.3 g). Yield: 86%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][C:21](=[O:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:23]=3[CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2cccc(Nc3ncc(-c4ccc(Cl)cc4)o3)c2C1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: OC1CCc2cccc(Nc3ncc(-c4ccc(Cl)cc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 2, substituting the product of Example 6C for the product of Example 1I. 1H NMR (DMSO-d6) δ 9.16 (s, 1H), 7.43-7.57 (m, 6H), 7.09 (t, 1H, J=7.4 Hz), 6.83 (d, 1H, J=7.0 Hz), 4.80 (d, 1H, J=3.7 Hz), 3.92 (m, 1H), 2.72-2.98 (m, 4H), 1.86 (m, 1H), 1.61 (m, 1H); MS (ESI+) m/z 341/343 (M+H, 35Cl/37Cl).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([OH:21])=[O:20].[O:22]1[C:26](B(O)O)=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2>>[O:22]1[C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[CH:25]=[C:26]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)Cc1cn(Cc2ccccc2)c2ccc(Br)cc12
Reactant: OB(O)c1cc2ccccc2o1
Product: O=C(O)Cc1cn(Cc2ccccc2)c2ccc(-c3cc4ccccc4o3)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo-1-benzyl-1H-indol-3-yl]acetic acid and benzo[b]furan-2-boronic acid were used.
Reaction SMILES: [CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15](I)[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:39]([Zn]CC)[CH3:40]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:21][CH2:22][CH:23]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:16]5=[C:15]([CH2:39][CH3:40])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:35]([F:38])([F:37])[F:36])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CC1CCn2c1c(I)c1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Reactant: CC[Zn]CC
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: CCc1c2n(c3ccc(OCc4ccc(C5CCCC5)c(C(F)(F)F)c4)cc13)CCC2CC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 45.1 %

Procedure:
To a solution of tert-butyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-9-iodo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (17 mg, 0.027 mmol) in THF (0.500 mL) in a 0.5-2.0 mL heavy-walled microwave sealed tube under N2 was added diethylzinc (0.074 mL, 0.037 mmol) and bis(tri-t-butylphosphine)palladium(0) (1.223 mg, 2.393 μmol). The reaction was then heated to 70° C. for 2 h. The reaction mixture was quenched with saturated NaHCO3, filtered by vacuum filtration through Celite®, and washed with EtOAc (2×5 mL). The filtrate was then extracted with EtOAc (3×5 mL). The organic layers were combined and washed with saturated NaCl (1×10 mL), dried (MgSO4), and filtered by vacuum filtration through a glass fiber paper. The solvent was removed under reduced pressure. The residue was purified by preparative TLC to give the title compound (6.6 mg) as an amber oil. LCMS m/z=542.6 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:10])=[C:4]([F:22])[CH:3]=1.[CH3:23][O:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1>>[F:8][C:6]1[CH:7]=[C:2]([C:28]2[CH:27]=[N:26][C:25]([O:24][CH3:23])=[N:30][CH:29]=2)[CH:3]=[C:4]([F:22])[C:5]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2cc(F)c(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)cn1

Procedure:
The title compound is prepared in a manner substantially analogous to Example 14 via Procedure F′ from (4-bromo-2,6-difluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 2-methoxypyrimidine-5-boronic acid (CAS 628692-15-9). MS (FIA) 403 (MH+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[C:14](=[O:27])[NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[CH2:17][OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]COC(C)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]2[C@H:10]([CH2:11]2)[C@H:9]1[C:14](=[O:27])[NH:15][C@@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])[CH2:17][O:18][CH3:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@@H]2[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Product: COC[C@@H](NC(=O)[C@@H]1[C@H]2C[C@H]2CN1C(=O)OC(C)(C)C)c1cccc(Cl)c1F

Procedure:
was prepared according to Scheme B9 (Step B) from (1S,2S,5R)-2-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester. TLC, Rf (EtOAc): 0.65; MS (UPLC/MS): 413.4/415.4 [M+H]+, 457.4/459.4 [M+HCOO]−; tR (HPLC conditions a): 3.67 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([Cl:24])[CH:3]=1.[CH3:25][N:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[Cl:24][C:4]1[CH:3]=[C:2]([N:28]2[CH2:29][CH2:30][N:26]([CH3:25])[C:27]2=[O:31])[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3Cl)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3Cl)CC2)c(C)c1
Yield: 6.1 %

Procedure:
Using (4-bromo-2-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (204 mg) described in Preparation Example 119 and 1-methylimidazolidin-2-one (60 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (13 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccc3c2CCC3=O)cc1
Temperature: 25 °C
Reaction time: 4.25 h

Procedure:
22.9 g (0.109 mol) of 4-Bromo-indan-1-one, 23.18 g (0.130 mol) of 4-tert-butylphenylboronic acid, 23.0 g (0.217 mol) sodium carbonate, 67 ml water and 357 ml of ethylene glycol are placed into a round bottom flask with reflux condenser and stirrer. The flask is evacuated and refilled with argon three times to remove any oxygen. 49 mg (0.22 mmol) of Palladium(II) acetate and 1.4 ml (0.87 mmol) of a 0.6 M solution of NaTPPTS (tris-sodiumtriphenylphosphine-3,3′,3″-trisulfonate) are premixed in 2 ml of water and added to the reaction mixture which is subsequently heated to reflux. The progress of the reaction is monitored via TLC. Complete conversion should be achieved within 3.5 to 5 hours. The mixture is cooled to room temperature and water and toluene are added until two clearly discernible phases form. The layers are separated and the water phase is extracted three times with toluene. The combined organic layers are washed twice with a saturated sodium chloride solution, dried over anhydrous magnesium sulphate and the solvent is removed in a vacuum to yield an oily product. The GC-determined purity of the crude product is 92%. Pure product can be obtained by treating the oily residue with 35 ml of ethanol at room temperature. Solid 4-(4-tert-Butyl-phenyl)-indan-1-one precipitates and is filtered of. The filtrate still contains significant amounts of product which can be isolated by evaporating the filtrate to dryness mixing it with 50 ml of heptane and storing the mixture at −30° C. over night. The filtrate is filtered off, washed with two portions of cold (30° C.) heptane and dried in a vacuum (Combined yield: 23.71 g, 82%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][OH:5].[CH3:9][S:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:15]=2[N:16]=1.C(Cl)Cl>C1C=CC=CC=1>[CH3:8][O:7][C:3](=[O:6])[CH2:4][O:5][C:13]1[C:14]2[CH:19]=[C:18]([CH2:20][CH3:21])[N:17]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:15]=2[N:16]=[C:11]([S:10][CH3:9])[N:12]=1
Reactant: CCc1cc2c(Cl)nc(SC)nc2n1Cc1ccccc1-c1ccccc1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
To a suspension of 64 mg (2.66 mmol) of sodium hydride in 5 mL of benzene was added 200 mg (2.22 mmol) of methyl glycolate and a solution of 350 mg (0.89 mmol) of 2-(methylthio)-4-chloro-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine in 2.5 ml of benzene then the mixture heated to 60° C. The reaction was monitored for conversion to product by TLC (silica, methylene chloride). Additional sodium hydride (96 mg) and methyl glycolate (360 mg) were added in portions over 4 days. The reaction was cooled to ambient temperature and partitioned by the addition of 15 mL of 2 M sodium hydrogen sulfate and 15 mL of ethyl acetate. The aqueous phase was extracted twice with 7 mL portions of ethyl acetate. The combined organic phases were dried with sodium sulfate and concentrated. The product was purified by flash chromatography (53 g silica, hexanes-ethyl acetate gradient 100:0 to 85:15) to provide 187 mg (47%) of [[2-(methylthio)-6-ethyl-7-([1,1′-biphenyl]-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (300 MHz, CDCl3) δ1.10 (t, 3H), 2.16 (q, 2H), 2.52 (s, 3H), 3.80 (s, 3H), 5.03 (s, 2H), 5.32 (s, 2H), 6.25 (s, 1H), 6.62 (d, 1H), 7.1-7.6 (m, 8H)
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[NH2:60][CH:61]([C:64]1[CH:69]=[CH:68][C:67]([Cl:70])=[CH:66][CH:65]=1)[CH2:62][OH:63]>CN1C(=O)CCC1>[Cl:70][C:67]1[CH:66]=[CH:65][C:64]([CH:61]([NH:60][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:50])[CH2:62][OH:63])=[CH:69][CH:68]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(CO)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(CO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (148 mg, 0.39 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (134 mg, 0.37 mmol) and N-ethyldiisopropylamine (0.077 mL, 0.44 mmol) in NMP (3 mL). The mixture was treated with 2-amino-2-(4-chlorophenyl)ethanol (70 mg, 0.41 mmol) (CAS™ no. 179811-64-4, see US2006/0004045 for preparation). The dark solution was stirred for 16 hours at room temperature. The mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was washed twice with water and then brine. The organic solution was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash silica chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM). Product containing fractions were combined to give tert-butyl 4-(1-(4-chlorophenyl)-2-hydroxyethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (152 mg, 80%) as colourless solid.