Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](O[C@@H]1[C@@H](CO[Si](C(C)(C)C)(C)C)O[C@@H](N2C3N=CN=C(OC)C=3N=C2)C1)([C:4](C)([CH3:6])[CH3:5])(C)C.N1([O:43][C:44]2[C:45]3[N:46]=[CH:47][N:48]([C:71]=3[N:72]=[CH:73][N:74]=2)[C@@H:49]2[O:70][C@H:60]([CH2:61][O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[C@@H:51]([O:52][Si:53]([C:56]([CH3:59])([CH3:58])[CH3:57])([CH3:55])[CH3:54])[CH2:50]2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(O)C>[Si:63]([O:62][C@@H:61]1[C@@H:60]([CH2:51][O:52][Si:53]([C:56]([CH3:57])([CH3:59])[CH3:58])([CH3:54])[CH3:55])[O:70][C@@H:49]([N:48]2[C:71]3[N:72]=[CH:73][N:74]=[C:44]([O:43][CH:4]([CH3:6])[CH3:5])[C:45]=3[N:46]=[CH:47]2)[CH2:50]1)([C:66]([CH3:67])([CH3:69])[CH3:68])([CH3:64])[CH3:65]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: COc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CC(C)Oc1ncnc2c1ncn2[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Yield: 84 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-methyl-2′-deoxyinosine, the isopropyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol) and 2-propanol (1 mL) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) over 10 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 44.1 mg (84% yield) of the title compound as a clear gum. Rf (20% EtOAc in hexanes)=0.31. 1H NMR (500 MHz, CDCl3): δ 8.50 (s, 1H, Ar—H), 8.23 (s, 1H, Ar—H), 6.49 (t, 1H, H-1′, J=6.3), 5.67 (septet, 1H, —CH—, J=6.3), 4.61 (m, 1H, H-3′), 4.02 (m, 1H, H-4′), 3.87 (dd, 1H, H-5′, J=11.2, 3.9), 3.78 (dd, 1H, H-5′, J=10.7, 2.9), 2.63 (app quint, 1H, H-2′, Japp˜6.3), 2.44 (ddd, 1H, H-2′, J=13.2, 5.9, 3.9), 1.47 (d, 6H, CH3, J=6.5), 0.91 (s, 18H, tert-Bu), 0.10, 0.09 (2 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 160.5, 152.0, 151.5, 140.3, 122.0, 87.9, 84.4, 71.9, 71.2, 62.8, 41.4, 26.0, 25.7, 22.0, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C25H47N4O4Si2 (M++H) 523.3136. found 523.3130.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[O:19])[CH2:14][CH2:13]2)[CH2:6][CH2:5]1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[CH:34][C:29]=2[O:28][CH2:27]1>>[Cl:25][C:22]1[S:21][C:20]([C:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C@H:7]3[CH2:8][CH2:9][C@H:4]([NH:3][C:35]([C:33]4[CH:32]=[CH:31][C:30]5[O:26][CH2:27][O:28][C:29]=5[CH:34]=4)=[O:36])[CH2:5][CH2:6]3)[CH2:13][CH2:14]2)=[O:19])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)s3)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)s3)CC2)CC1)c1ccc2c(c1)OCO2

Procedure:
From {1-[2-(trans-4-amino-cyclohexyl)-ethyl]-piperidin-4-yl}-(5-chloro-thiophen-2-yl)-methanone dihydrochloride (100 mg) and benzo[1,3]dioxole-5-carboxylic acid (45 mg) by procedure C. Yield: 62 mg (52%). Off-white solid. MS (m/z): 503.2 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:45]=4[N+:53]([O-:55])=[O:54])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C)C=O.O1CCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:57])[CH2:34][CH2:35][NH:36][C:37](=[O:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]4[CH:49]=[CH:48][C:47]([N+:50]([O-:52])=[O:51])=[CH:46][C:45]=4[N+:53]([O-:55])=[O:54])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 23 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
To a slurry of N-{3-[(3-{(3β)-cholest-5-en-3-yl[(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}-6-[(2,4-dinitrophenyl)amino]hexanamide (20, 121 mg, 0.124 mmol) and K2CO3 (137 mg, 0.991 mmol) in N,N-dimethylformamide (8 mL) and tetrahydrofuran (4 mL) was added thiophenol (100 μL, 0.971 mmol). After stirring at 23° C. for 18 h, the mixture was filtered and solvent removed in vacuo. Flash column chromatography (MeOH/triethylamine/CH2Cl2, 3:5:100) afforded 3 (50 mg, 51%) mp 157-158° C.; 1H NMR (360 MHz, CDCl3) δ 9.12 (d, J=2.6 Hz, 1H), 8.55 (t, J=5.0 Hz, 1H), 8.26 (dd, J=2.6 Hz, J=9.5 Hz, 1H), 6.91 (d, J=9.6 Hz, 1H), 6.62 (t, J=5.5 Hz, 1H), 5.30 (d, J=4.7 Hz, 1H), 3.51 (dt, J=5.8 Hz, J=5.7 Hz, 2H), 3.41 (dt, J=7.0 Hz, J=5.5 Hz, 2H), 3.33 (dt, J=5.9 Hz, J=5.7 Hz, 2H), 2.74 (t, J=6.0Hz, 2H), 2.38-2.31 (m, 3H), 2.21-2.14 (m, 3H), 2.01-1.00 (m, 37H), 0.97 (s, 3H), 0.90 (d, J=6.5 Hz, 3H), 0.86 (d, J=1.4 Hz, 3H), 0.84 (d, J=1.4 Hz, 3H), 0.66 (s, 3H); 13C NMR (125.8 MHz, CDCl3) δ 172.6, 171.8, 148.5, 141.6, 136.2, 130.6, 130.5, 124.6, 121.2, 114.1, 58.4, 57.0, 56.3, 50.5, 45.7, 43.5, 42.5, 40.4, 40.0, 39.7, 39.5, 38.2, 37.2, 36.5, 36.4, 36.0, 35.7, 35.5, 32.1 (×2), 29.9, 29.1, 28.6, 28.4, 28.2, 26.7, 25.2, 24.5, 24.0, 23.0, 22.7, 21.2, 19.6, 18.9, 12.0; IR (film) νmax 3354, 3299, 2933, 2868, 1647, 1620, 1335 cm−1; CI m/z 793.5584 (MH+, C45H73N6O6 requires 793.5592).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.I.[OH-].[Na+]>C(O)(=O)CC.O>[CH3:1][C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[CH3:16])[C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)-c1cccc(C)c1C2=O
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(=O)O
Product: Cc1cc(C)c2c(c1)-c1cccc(C)c1C2

Procedure:
1,3,8-Trimethylfluoren-9-one (53) was reduced according to the general procedure of Carruthers et al. (W. Carruthers, D. Whitmarsh, J. Chem. Soc. Perkin Trans, I 1973, 1511). 1,3,8-Trimethylfluoren-9-one (53) (2.74 g, 12.3 mmol) was dissolved in propionic acid (235 ml). Red phosphorus (3.0 g) and concentrated HI (40 ml) were added and the reaction mixture was refluxed for 24 h. Quantitative conversion was shown by TLC. The reaction mixture was diluted with water (250 ml), neutralized with NaOH and extracted with Et2O (4×125 ml). The combined organic layers were washed with brine (2×125 ml), dried over MgSO4, filtered and the volatiles removed in vacuo to afford 2.56 g (quant.) 54 as a white solid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:13]=[C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].Cl>C(O)C>[F:3][C:4]1[CH:13]=[C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Cc2cccc(F)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2cccc(F)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of sodium hydroxide 2M (1 mL; 2 mmol) was added to a solution of methyl 2-fluoro-4-(3-fluorobenzyl)benzoate (0.151 g; 0.576 mmol) in ethanol (1 mL). The mixture was stirred at room temperature for 1 hour and the pH of the solution was adjusted to 1 by addition of a solution of 6N hydrochloric acid. The precipitate was collected by filtration and dried under reduced pressure to give 0.141 g (99%) of 2-fluoro-4-(3-fluorobenzyl)benzoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16]([NH2:18])=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.NC[C:36](N)=[O:37]>>[NH2:18][C:16]([C@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Cl:1])=[C:3]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])[N:4]=[CH:5]2)[CH:10]=1)[CH2:36][OH:37])=[O:17]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)N[C@H](CO)C(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting L-serinamide HCl for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.98 (m, 1H), 7.85 (m, 1H), 7.61 (q, 1H, J=8.4 Hz), 7.55 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.60 (m, 2H), 4.63 (m, 1H), 3.89 (d, 2H, J=5.6 Hz), 2.21 (s, 3H). ESHRMS m/z 493.1129 (M+H calculated for C22H20ClF2N4O5 requires 493.1085).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][S:17][C:16]([CH3:25])([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[S:15]2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)Cl>[C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:13][CH:14]2[CH2:18][S:17][C:16]([CH3:25])([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[S:15]2)=[O:40])=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSCC2CSC(C)(CCCC(=O)O)S2)ccc(C(C)=O)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)CC2CSC(C)(CCCC(=O)O)S2)ccc(C(C)=O)c1O
Yield: 41.8 %

Procedure:
The title compound was prepared according to the procedure of Example 48 using the sulfide obtained in Example 61 (0.15 g, 0.0003 mol) and m-chloroperbenzoic acid (0.063 g, 0.0003 mol) in methylene chloride (3 ml). The crude product was chromatographed on silica gel using ethyl acetate containing 1% acetic acid to give 0.063 g (45%) of the desired product as an oil containing one molar equivalent of acetic acid.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[CH:19]1([C:22]([NH2:24])=[NH:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[N:23]=[CH:4][C:5]3[CH2:6][C:7](=[O:17])[NH:8][C:9]4[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=4[C:11]=3[N:24]=2)[CH2:21][CH2:20]1
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Reactant: N=C(N)C1CC1
Agent: Cl
Product: O=C1Cc2cnc(C3CC3)nc2-c2ccccc2N1
Yield: 62 %

Procedure:
Analogous to Scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and cyclopropanecarboxamidine hydrochloride. Yield: 62%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:36])([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[CH3:28])=[C:23]([F:37])[CH:22]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([CH:14]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:28])([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[CH3:36])=[C:23]([F:37])[CH:22]=3)[CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(C(C)(C)OC4CCCCO4)c(F)c3)cc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc2[nH]c(C(CC3CCCC3)c3ccc(C(C)(C)OC4CCCCO4)c(F)c3)cc2c1
Temperature: 50 °C
Yield: 59.7 %

Procedure:
A mixture of 2-(2-cyclopentyl-1-{3-fluoro-4-[1-methyl-1-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl}-vinyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (3 g, 5.93 mmol) and 10% palladium on activated carbon (900 mg) in methanol (600 mL) was heated at 50° C. under hydrogen (50 bar) for 5 h. The resulting mixture was cooled to 25° C., the catalyst was removed by filtration, washed with ethyl acetate and concentrated in vacuo to afford 2-(2-cyclopentyl-1-{3-fluoro-4-[1-methyl-1-(tetrahydro-pyran-2-yloxy)-ethyl]-phenyl}-ethyl)-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (1.8 g, 60%) as a white solid which was used in the next step without further purification: LC/MS m/e calcd for C30H37FN2O4 [M+H]+ 509.64, observed 508.9.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]#[N:13])[C:8](=[O:14])[C:7]=2[CH:15]=1)[CH3:2].C1C(=O)N([Br:23])C(=O)C1>ClC(Cl)(Cl)Cl>[Br:23][CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]=[C:9]([C:12]#[N:13])[C:8](=[O:14])[C:7]=2[CH:15]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc2occ(C#N)c(=O)c2c1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc2occ(C#N)c(=O)c2c1

Procedure:
A mixture of 9.95 parts of 6-ethyl-4-oxo-4H-1-benzopyran-3-carbonitrile 8.90 parts of NBS and 300 parts by volume of tetrachloromethane is refluxed under stirring and irradiation of infrared ray (100 volt, 375 WR) for 2 hours. The tetrachloromethane is distilled off and the solid residue is well shaken with 500 parts by volume of ethyl acetate and 100 parts by volume of water. The ethyl acetate layer is collected and shaken with 100 parts by volume of water. In this manner, the ethyl acetate layer is repeatedly washed with water until the solid residue disappears. The ethyl acetate layer is dried on Na2SO4, concentrated and cooled. The procedure yields 12.11 parts of 6-(1-bromoethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile as colorless crystals. Melting point: 162-164° C
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:11]2)[CH:3]=1.[C:27]([C:29]1[C:34]([F:35])=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:39])#[N:28].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[C:27]([C:29]1[C:34]([F:35])=[CH:33][C:32]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:11]3)[CH:3]=2)=[CH:31][C:30]=1[F:39])#[N:28]
Reactant: N#Cc1c(F)cc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 100 °C

Procedure:
(3S,6R)-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (100 mg, 0.267 mmol) and (4-cyano-3,5-difluorophenyl)boronic acid (73.4 mg, 0.401 mmol) were dissolved in 1,4-Dioxane (2 mL) in a 5 mL sealable vial then added saturated NaHCO3 (1 mL). Nitrogen gas was bubbled through the mixture for 10 min. Then Pd(Ph3P)4 (37.1 mg, 0.032 mmol) was added and nitrogen gas bubbled for an additional 5 min. The vial was capped the reaction was heat at 100° C. overnight. The reaction was diluted with water (5 mL) and then extracted with EtOAc (3×10 mL). Organic were combined, dried over MgSO4, filtered and concentrated. The yellow oil was then purified on a 10 g Biotage SNAP column with gradient of 0 to 40% EtOAc in Hexane. LC-MS (ES) m/z=477 [M+H]+.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:23])[CH3:22])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)[CH3:22])[CH2:11]2
Reactant: COC(=O)c1c(Cl)cccc1CBr
Reactant: CC(N)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(c1ccc(Cl)cc1)N1Cc2cccc(Cl)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
A mixture of 2-bromomethyl-6-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), 1-(4-chlorophenyl)-ethylamine (0.117 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-chloro-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.132 g, 86%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.66 (d, 3H), 3.95 (d, 1H), 4.34 (d, 1H), 5.84 (q, 1H) 7.26-7.46 (m, 7H). GC-MS: m/z 306 (M)+.
Reaction SMILES: [C:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(C)=O)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.9 %

Procedure:
4-Acetylaniline (0.159 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=1:2) to obtain the titled compound (0.160 g, 0.326 mmol, 61%).
Reaction SMILES: N#N.[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](O)=[O:19])[CH:13]=1)=[O:6].CO>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1)=[O:6]
Reactant: COC(=O)c1ncoc1-c1cccc(C(=O)O)c1
Agent: N#N
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ncoc1-c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 5-(3-carboxy-phenyl)-oxazole-4-carboxylic acid methyl ester (500 mg, 2.02 mmol) in THF (14.0 mL) at 0° C. was treated dropwise with BH3 (10.1 mL of a 1M solution in THF, 10.11 mmol). The resulting mixture was stirred at 0° C. for 4 h. MeOH (14 mL) was then added dropwise. After 30 min, the solvent was removed under reduced pressure. EA (20 mL) was added and the organic phase was washed with 1N NaOH (10 mL), water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (93:7 CH2Cl2-MeOH) gave the title compound as a white solid. TLC:rf (93:7 CH2Cl2-MeOH)=0.32. LC-MS-conditions 02: tR=0.76 min, [M+H]+=234.39.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]2[O:18][CH2:19][C:20](=[O:27])[C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:3][CH2:2]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][N:35]=2)[C:30]([CH:37]=O)=[CH:29]1.[OH-].[Na+]>C(O)C.Cl>[NH:28]1[C:36]2=[N:35][CH:34]=[CH:33][CH:32]=[C:31]2[C:30]([CH:37]=[C:19]2[O:18][C:17]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]2=[O:27])=[CH:29]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2OCCN2CCOCC2)OCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccccc2OCCN2CCOCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a solution of ethyl 2-{[2-(2-morpholinoethoxy)phenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.021 g, 0.054 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0070 g, 0.048 mmol) in ethanol (0.5 mL), 2M hydrochloric acid in ethanol (0.024 mL, 0.048 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. The reaction mixture was cooled with ice bath. Aqueous 2M sodium hydroxide solution (0.024 mL, 0.048 mmol) was added dropwise to neutralize and the mixture was stirred for 1 h. The precipitate was collected by filtration then purified by preparative HPLC to afford the titled compound as solid (0.0054 g, y. 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:4][C:3]=1[F:13].[NH:14]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([N:14]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16][CH2:15]2)=[O:10])=[CH:4][C:3]=1[F:13]
Reactant: O=C(O)/C=C/c1ccc(Cl)c(F)c1
Reactant: O=C1CCNCCN1
Product: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(F)c2)CCN1

Procedure:
In analogy to the procedure described for intermediate 1A, (E)-4-chloro-3-fluorocinnamic acid and 2,3,6,7-tetrahydro-(1H)-1,4-diazepin-5(4H)-one gave the title compound as white solid. MS: 297.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.[CH3:15][NH:16][C:17]([C:19]1[N:20]([CH3:25])[N:21]=[CH:22][C:23]=1[NH2:24])=[O:18]>>[CH3:25][N:20]1[C:19]([C:17](=[O:18])[NH:16][CH3:15])=[C:23]([NH:24][C:12]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([C:8]([OH:11])([CH3:9])[CH3:10])[N:4]=2)=[O:14])[CH:22]=[N:21]1
Reactant: CNC(=O)c1c(N)cnn1C
Reactant: CC(C)(O)c1ncc(Br)c(C(=O)O)n1
Product: CNC(=O)c1c(NC(=O)c2nc(C(C)(C)O)ncc2Br)cnn1C

Procedure:
The product was obtained starting from 5-bromo-2-(2-hydroxypropan-2-yl)pyrimidine-4-carboxylic acid (150 mg, 0.575 mmol) and 4-amino-2-methyl-2H-pyrazole-3-carboxylic acid methylamide (106 mg, 0.69 mmol) according to the method described in example 64, step 6 after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light brown waxy solid (31 mg, 13%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:28]>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[O:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)OCc1ccc(F)cc1
Reactant: CCNCc1ccc(C)cc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2CN(CC)C(=O)OCc2ccc(F)cc2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-5′-methyl-biphenyl-3-yl)-acetic acid ethyl ester and 4-fluorobenzyl chloroformate.