Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[C:22](#[N:25])[CH2:23][OH:24].Cl>C1(C)C=CC=CC=1>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[O:24][CH2:23][C:22]#[N:25])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Reactant: N#CCO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 1,5-difluoro-2,4-dinitrobenzene (7.4 g) and triethylamine (4.4 g) in toluene (74 g) kept at room temperature, a mixture of glycolonitrile (3.1 g) and toluene (6.2 g) was dropwise added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into 5% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and concentrated to give 2,4-dinitro-5-fluorophenoxyacetonitrile (8.2 g; yield, 93.8%). M.P., 112°-113° C. (recrystallized from ethyl acetate-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2([CH3:14])[CH2:13][CH2:12]2)[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:11]2([CH3:14])[CH2:12][CH2:13]2)[C:5]([O:10][CH3:15])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: CC1(c2cc(Br)cc(C=O)c2O)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(C=O)cc(Br)cc1C1(C)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
step 3—To a solution of 130 (0.44 g, 1.7 mmol) in DMF (4 mL) was added K2CO3 (0.60 g, 4.4 mmol) and iodomethane (0.32 g, 2.3 mmol). The resulting mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to RT and partitioned between water and Et2O. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated to afford 0.47 g (96%) of 5-bromo-2-methoxy-3-(1-methylcyclopropyl)benzaldehyde (132) as a light yellow solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C:16]=2[CH:29]=1.CC(C1C=C(C(C)C)C(S([N:45]=[N+:46]=[N-:47])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:45]([CH:19]1[N:18]=[C:17]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[C:16]2[CH:29]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:46]=[N-:47]
Reactant: CN1C(=O)CN=C(c2ccsc2)c2cc(Cl)ccc21
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: CN1C(=O)C(N=[N+]=[N-])N=C(c2ccsc2)c2cc(Cl)ccc21
Yield: 97.4 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (10.4 mL of 0.5 M in toluene, 5.20 mmol), 7-chloro-1,3-dihydro-1-methyl-5-(3-thienyl)-2H-1,4-benzodiazepin-2-one (1.44 g, 4.95 mmol), trisyl azide (3.83 g, 12.4 mmol) and acetic acid (1.25 mL, 21.8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (7:3 hexanes:EtOAc) provided the title compound as a pale yellow solid (1.60 g, 98%). 1H-NMR (CDCl3): δ 7.61-7.55 (m, 4H), 7.40 (dd, J=2.9 Hz, J=5.1 Hz, 1H), 7.33 (dd, J=1.0 Hz, J=8.2 Hz, 1H), 4.54 (s, 1H), 3.44 (s, 3H). MS (ESI) (M+H)+=332.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[C:10]([C:24]#[N:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH2:36])=[CH:30][CH:29]=1.C(NC(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][NH:36][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:22]=[CH:23][C:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26])=[CH:9][C:10]=3[C:24]#[N:25])=[CH:21][CH:20]=2)=[O:18])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)O)cc2)c(C#N)c1
Reactant: NCCc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoic acid (0.34 g, 0.962 mmol), 2-(4-chlorophenyl)ethanamine (0.165 g, 1.06 mmol) in DMF (5 ml) was added diisopropylamine (0.200 ml, 1.15 mmol) and HBTU (0.149 g, 1.15 mmol). The reaction was stirred at ambient temperature for 90 minutes. The reaction was diluted with water and the product extracted into ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated to give tert-butyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-cyanophenyl)acetate (0.40 g, 85%) as a white solid after column chromatography.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@:9]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2.[F:28][C:29]([F:35])([F:34])[S:30](Cl)(=[O:32])=[O:31].CCCCCC.C(OCC)(=[O:44])C>ClCCl>[CH3:8][C@@:9]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@H:21]1[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:27])=[CH:17][C:18]=3[CH2:19][CH2:20]1)[CH2:11][CH2:10]2.[O-:31][S:30]([C:29]([F:35])([F:34])[F:28])(=[O:44])=[O:32]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCOC(C)=O
Agent: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
At room temperature, triethylamine (1.0 mL, 7.2 mmol, 1.2 equiv.) was added to a solution prepared by dissolving estrone (1.62 g, 6.0 mmol) in 10 mL of dichloromethane. The mixture was cooled to 0° C., and then trifluoromethanesulfonyl chloride (760 pt, 7.2 mmol, 1.2 equiv.) was added to the mixture over 3 minutes or more with stirring to effect a reaction. After 6 hours, the reaction was quenched by adding a saturated sodium hydrogen carbonate aqueous solution (10 mL) to the reaction mixture, and the reaction mixture was separated into two layers. The organic layer (dichloromethane solution) was isolated preparatively, and 20 mL of dichloromethane was added to the aqueous layer to extract the product. The above operation was repeated twice. An excess amount of anhydrous magnesium sulfate was added to the collected organic layer (dichloromethane solution), and the mixture was filtered. The solvent was evaporated under reduced pressure to obtain a concentrate including a crude product. The concentrate was subjected to silica gel flash column chromatography (eluant: hexane/ethyl acetate=5/1) to obtain estrone triflate (Rf=0.36, white solid, 1.98 g) (see below). The yield thereof was 82%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:4][CH:3]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]1[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=1)OC1C=CC=CC=1)#[N:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:28]([NH:27][C:25]#[N:26])=[N:36][CH2:37][CH2:38][S:39][CH2:40][C:41]2[N:42]=[C:43]([NH:46][C:47]([NH2:49])=[NH:48])[S:44][CH:45]=2)[CH3:18])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: CN(CCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Product: CN(CCCCCNC(=NCCSCc1csc(NC(=N)N)n1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.75 g (2.1 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,5-pentanediamine and 0.81 g (2.1 mmol) of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam; MS (+FAB method): m/z (rel. int.[%])=627 ([M+H]+, 3), 230 (100); IR (KBr): 2162 cm-1 (C≡N). For analytical purposes a sample is converted into the maleic acid salt and recrystallised from ether/ethanol; m.p.: 87°-90° C.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[S:8][CH:9]=[C:10](Br)[N:11]=1)[CH2:2]2.C(O)C.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[S:8][CH:9]=[C:10]([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][C:21]=3[F:23])[N:11]=1)[CH2:2]2
Reactant: Brc1csc(N2CC3CC3C2)n1
Reactant: OB(O)c1ccc(F)cc1F
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2csc(N3CC4CC4C3)n2)c(F)c1
Temperature: 92.5 °C
Yield: 77.4 %

Procedure:
To a solution of 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-bromothiazole (Step-1 of compound 66, 0.29 g, 1.16 mmol) in a mixture of toluene: ethanol (4 ml:16 ml) were added (2,4-difluorophenyl) boronic acid (0.20 g, 1.28 mmol) and potassium carbonate (0.32 g, 2.32 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.067 g, 0.058 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite; residue was washed with ethyl acetate (2×10 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.25 g, 77.0%). MS: m/z 279 (M+1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][C@@H:10]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:16]([OH:18])=O)[CH3:11].[NH2:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:11][C@H:10]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=1)[C:16]([NH:30][C:31]1[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=1)=[O:18])[CH2:9][O:8][CH3:7]
Reactant: Cc1cnc(N)cn1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.9 %

Procedure:
Oxalyl chloride (2.1 mL, 24.0 mmol) was added to a solution of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (6.32 g, 20.0 mmol) in DCM (100 mL) and the mixture stirred at RT for 4 hours. The mixture was evaporated in vacuo to a residue, which was taken up in DCM (25 mL) and added to a stirred mixture of 2-amino-5-methylpyrazine (2.29 g, 21.0 mmol) and pyridine (1.94 mL, 24.0 mmol) in DCM (100 mL) at 5° C.-10° C. The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo. The residue was partitioned between water (50 mL) and ethyl acetate (150 mL), the organic layer washed with brine, dried (MgSO4) and evaporated to a residue, which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (7.0 g). 1H NMR δ (CDCl3): 1.3 (d, 3H), 2.5 (s, 3H), 3.3 (s, 3H), 3.4-3.5 (m, 2H), 4.5 (m, 1H), 5.0 (s, 2H), 6.7 (s, 1H), 7.0 (s, 1H), 7.05 (s, 1H), 7.35 (m, 5H), 8.05 (s, 1H), 8.3 (s, 1H) and 9.5 (s, 1H). m/z 408 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][O:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1)=[O:11].[CH2:18](OCC)C>>[CH2:6]([O:5][C:3]([CH2:2][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:10]([O:9][CH2:8][CH3:18])=[O:11])[CH2:13]1)=[O:4])[CH3:7]
Reactant: COC(=O)C1CCCNC1
Reactant: CCOC(=O)CBr
Reactant: CCOCC
Product: CCOC(=O)CN1CCCC(C(=O)OCC)C1

Procedure:
Ethyl bromoacetate (21.2 g, 0.127 mol) was added dropwise to a solution of 3-methoxycarbonylpiperidine (40 g, 0.254 mol) in diethyl ether (250 ml) at 0° C. The reaction was heated under reflux for 1 hour and the resulting precipitate filtered off and washed with diethyl ether. The ethereal solution was concentrated under reduced pressure to give the title compound (27.6 g); δ (60 MHz, CDCl3) 1.25 and 1.27 (each 3H, each t, J=7 Hz, 2×OCH2CH3). 1.40-3.70 (9H, m, 2CH2, 3CH, 4CH2, 5CH2 and 6CH2), 3.20 (2H, s, NCH2CO2), 4.10 and 4.15 (each 2H, each q, J=7 Hz, 2×NCH2CO2).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[SH:20][C:21]1[N:25]=[CH:24][NH:23][N:22]=1>>[N:23]1[N:22]=[C:21]([S:20][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[CH:4][N:3]=[C:2]3[NH:13][C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[NH:25][CH:24]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Sc1nc[nH]n1
Reactant: Nc1cnccn1
Product: c1cnc(Nc2ncnc3ccc(Sc4nnc[nH]4)cc23)cn1

Procedure:
The compound of Example 5 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, 2-amino-pyrazine and 3-mercapto-1,2,4-triazole.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[Si:16]([O:10][CH2:9][CH2:8][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCNc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCNc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of 2-anilinoethanol (5.82 g, TCI) in anhydrous DMF (50 ml) was added with imidazole (3.23 g, TCI), added dropwise with a solution of t-butyldiphenylsilyl chloride (12.48 g, TCI) in DMF (50 ml) under ice cooling, stirred for 30 minutes, then warmed to room temperature, and further stirred for 3.5 hours. The reaction mixture was added with water (100 ml), and extracted with ethyl acetate (100 ml). The organic layer was washed successively with water and saturated brine, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (Intermediate 46, 15.61 g).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[O:14]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][NH2:30])=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:30]([CH2:29][CH2:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCCCc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cccc2CN1CCCc1ccc(Oc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.106 g, 0.3 mmol), 3-(4-phenoxy-phenyl)-propylamine (0.136 g, 0.6 mmol), and K2CO3 (0.110 g, 0.8 mmol) in toluene (5 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-iodo-2-[3-(4-phenoxy-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.025 g, 18%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.01 (m, 2H), 2.68 (t, 2H), 3.67 (t, 2H), 4.28 (s, 2H), 6.86-7.42 (m, 11H), 7.88 (d, 1H).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].O=[CH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:1][O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1.[C:1]([O:4][CH:5]1[C:14]2[C:9](=[N:10][C:11]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:13]=2)[N:8]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCNc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CCC(OC(C)=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Product: COC(=O)CCCCCCN1CCC(OC)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazin-8-yl acetate ((prepared according to the preparation procedures disclosed in PCT patent application PCT/EP2011/062028, Intermediate HF) (209 mg, 0.560 mmol) in DCE (dry) (10 ml) was added ethyl 7-oxoheptanoate (289 mg, 1.679 mmol) followed by sodium triacetoxy borohydride (356 mg, 1.679 mmol). The mixture was left to stir overnight at room temperature under an atmosphere of nitrogen. The resulting mixture was diluted with water (20 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was passed through an Isolute® SCX-2 SPE cartridge and was loaded onto a primed (with MeOH 20 ml) SCX-2 cartridge. The methanolic ammonia fractions were concentrated under reduced pressure to afford the titled compound as a mixture with rac-ethyl 7-(8-acetoxy-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate; The mixture was used in the next step without further purification;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[Na].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: C=CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCOc1ccc(Cl)cc1C

Procedure:
The sub-title compound was prepared according to the method described in Example 27(i) above from 4-chloro-2-methylphenol (4.99 g; 35.0 mmol), sodium (0.055 g; 2.4 mmol), ethanol (1.5 mL) and ethyl acrylate (4.1 g; 41 mmol). The crude product (1.98 g; 23%) was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH:11]1([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:18][CH:19]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C2CCCCC2)cc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
6-Chloronicotinoyl chloride (0.24 g) was dissolved in toluene (5 mL), and the solution was cooled to 0° C. 4-Cyclohexylaniline (0.47 g) was added thereto at 0° C., and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added thereto, and the organic layer was washed with a 1 N aqueous sodium hydroxide solution and water and dried over sodium sulfate. After concentration under reduced pressure, the obtained solid was collected by filtration and washed with diethyl ether. The solid was dried under reduced pressure to obtain the title compound (0.40 g) as a white solid (yield: 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:16])[C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.BrBr.[CH3:25][NH:26][C:27]([NH2:29])=[S:28].CO.[CH2:32](OCC)[CH3:33]>>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:9]2[N:29]=[C:27]([NH:26][CH3:25])[S:28][C:10]=2[CH2:11][C:12]([O:14][CH2:32][CH3:33])=[O:13])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOCC
Reactant: CC(C(=O)CCC(=O)O)c1ccc(-c2ccccc2)c(F)c1
Reactant: CNC(N)=S
Agent: BrBr
Solvent: CO
Product: CCOC(=O)Cc1sc(NC)nc1C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 35 %

Procedure:
To an ice-cooled solution of 5-(2-fluoro-4-biphenylyl)-4-oxohexanoic acid (500 mg, 1.52 mmoles) in diethyl ether (10 ml) was added dropwise bromine (243 mg, 1.52 mmoles) and the resulting mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. A mixture of the afforded residue, N-methylthiourea (164 mg, 1.82 mmoles) and methanol was stirred at 50° C. for 2 hours and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was washed with water, dried over sodium sulfate and concentrated under reduce pressure. Purification of the residue by medium pressure silica gel column chromatography gave the desired ethyl 2-(4-(1-(2-fluoro-4-biphenylyl)ethyl)-2-methylamino-5-thiazolyl)acetate (209 mg, 0.524 mmole, yield 35%) as a yellow oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1([C:17]2[S:18][C:19]3[C:24](=[O:25])[N:23]=[CH:22][NH:21][C:20]=3[N:26]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.Br[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36]>O1CCCC1>[N:11]1([C:17]2[S:18][C:19]3[C:24](=[O:25])[N:23]=[CH:22][N:21]([CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:36])([F:37])[F:38])[C:20]=3[N:26]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O=c1nc[nH]c2nc(N3CCOCC3)sc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1ncn(Cc2ccccc2C(F)(F)F)c2nc(N3CCOCC3)sc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (0.755 mL, 0.755 mmol) was added to a suspension of 2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (90 mg, 0.378 mmol) in tetrahydrofuran (THF) (3 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min before the addition of 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.069 mL, 0.453 mmol). The mixture was warmed up to RT and stirred overnight. The solvent was removed and the residue was partitioned between DCM and brine. The organic layer was concentrated and the residue was purified on a biotage column (5% MeOH/DCM) to give 80 mg (55%) of the product (the undesired regioisomer (24 mg, 17%) was less polar on silica gel). LCMS (ES) m/z=397.0 (M+H)+, 1H NMR (400 MHz, CDCl3-d1) δppm 8.05 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.45˜7.55 (m, 2H), 7.05 (d, J=7.6 Hz, 1H), 5.54 (s, 2H), 3.80 (m, 4H), 3.58 (m, 4H).