Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]#[N:8])=[N:4][NH:5][CH:6]=1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.[H-].[Na+]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][O:9]2)[C:3]=1[C:7]#[N:8]
Reactant: N#Cc1n[nH]cc1Br
Reactant: C1=COCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(Br)cnn1C1CCCCO1
Temperature: 95 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
4-Bromo-1H-pyrazole-3-carbonitrile (150 mg, 0.87 mmol) is dissolved in 3,4-dihydro-2H-pyran (25 mL, 2.6 mmol) in the presence of a catalytic amount of TFA (1 mg, 0.009 mmol). The reaction mixture is stirred at 95° C. for 1 hour, cooled and then quenched using NaH (1.2 mg, 0.052 mmol). After removing the solvent, the residue is purified by silica gel column chromatography eluting with a mixture of 3:1 petroleum ether-dichloromethane, followed by 10:1 petroleum ether-ethyl acetate. The fractions containing the desired compounds are collected and concentrated in vacuo to afford the title compound as a colorless oil (90 mg, 40%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH:16]=[CH:15]1.C(N(CC)CC)C>ClCCl>[C:9](/[CH:8]=[CH:7]/[C:6]1[CH:5]=[CH:4][C:3]([NH:2][C:14](=[O:20])/[CH:15]=[CH:16]\[C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)([OH:11])=[O:10]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)/C=C\C(=O)Nc1ccc(/C=C/C(=O)O)cc1

Procedure:
The method of Example 1 was employed using 4-aminocinnamic acid hydrochloride (10.0 g, 0.0501 mol) and maleic anhydride (5.00 g, 0.0509 mol). Triethylamine (7.00 ml, 0.0502 mol) in dichloromethane (100 ml) was added to generate the free amine. The yellow maleamic acid was obtained. H.p.l.c. 100%. 1H-n.m.r. (DMSO): δ 10.51 (1H, s, NH); 7.65 (4H, bs, ar H's); 7.55 (1H, d, pH-CH); 6.44 (2H, t, HO2C CH=CH; CO, PhCH=CH); 6.30 (1H, d, HO2C CH=CH CO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1.[F-].[Cs+].C[Si](C)(C)[C:38]([F:41])([F:40])[F:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[CH:16]=[C:15]4[C:17]5([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[CH2:25][CH2:24][C:23]([C:38]([F:41])([F:40])[F:39])([OH:26])[CH2:22][CH:18]5[CH2:19][CH2:20][CH2:21][C:14]4=[CH:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: O=C1CCC2(Cc3ccccn3)c3cn4cnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: OC1(C(F)(F)F)CCC2(Cc3ccccn3)c3cn4cnc(-c5ccc(F)cc5)c4cc3CCCC2C1
Temperature: -10 °C

Procedure:
rac-(4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-4,4a,5,6,7,13 b-hexahydro-1H-benzo[3,4]cyclohepta[1,2-d]imidazo[1,5-a]pyridin-3 (2H)-one (149, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.291 g, 0.662 mmol) was suspended in DME (7 mL) then CsF (0.060 g, 0.397 mmol) was added. The mixture was cooled to about −10° C. then trimethyl(trifluoromethyl)silane (0.185 g, 1.30 mmol) was added. After 15 min TBAF (1 M in THF) (0.695 mL, 0.695 mmol) was added and the mixture was allowed to warm to rt. The mixture was concentrated under reduced pressure then water (25 mL) was added to the material and the resulting solids collected by filtration. The material was purified on silica gel (12 g) using a gradient from 0-10% MeOH in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-(3R,4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-3-(trifluoromethyl)-2,3,4,4a,5,6,7,13b-octahydro-1H-benzo[3,4]cyclohepta[1,2-d]imidazo[1,5-a]pyridin-3-ol (151, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl, R3=Trifluoromethyl) (0.185 g, 55%); LC/MS, method 2, Rt=2.54 min, MS m/z 510 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.39-8.37 (m, 1H), 8.18 (s, 1H), 7.98-7.89 (m, 3H), 7.74 (s, 1H), 7.40-7.36 (m, 1H), 7.27-7.18 (m, 2H), 7.09-7.03 (m, 1H), 6.47 (d, J=7.8 Hz, 1H), 5.97 (s, 1H), 3.59 (d, J=13.2 Hz, 1H), 3.43-3.32 (m, 1H), 3.15 (d, J=13.4 Hz, 1H), 3.08-3.03 (m, 1H), 2.23-2.17 (m, 1H), 2.13-2.07 (m, 1H), 2.04-1.86 (m, 3H), 1.83-1.67 (m, 5H), 1.46-1.36 (m, 1H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11][CH2:10]1)(C(C)(C)C)(C)C.CC(O)=O.[BH4-].[Na+]>CO>[F:20][C:16]1[CH:15]=[C:14]([C@@H:12]2[NH:11][CH2:10][C@H:9]([OH:8])[CH2:13]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CN=C(c2cccc(F)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O[C@H]1CN[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Yield: 95 %

Procedure:
(R)-3-(tert-butyldimethylsilyloxy)-5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (5.0 g, 17.0 mmol) was dissolved in 50 mL methanol and 10 mL AcOH and cooled to −40° C. NaBH4 (1.6 g, 43 mmol) was slowly added in small portions. The reaction was allowed to warm to ambient temperature. Most of the solvent was removed by rotary evaporation. The reaction was taken up in 200 mL of EtOAc, washed with 1 N NaOH, and filtered through Phase Separator filter paper, and concentrated. The crude product was taken up in 20 mL of 2 N HCl in dioxane. The reaction was concentrated, taken up in 200 mL of EtOAc, washed with 1 N NaOH, filtered, and concentrated, yielding the crude product, which was carried to the next step without further purification (2.93 g, 95% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.[I-].[Na+].[Na].[CH3:22][CH:23]1[CH2:27][CH2:26][CH:25]([CH3:28])[NH:24]1>C(#N)C.C(OCC)(=O)C.O>[CH3:22][CH:23]1[CH2:27][CH2:26][CH:25]([CH3:28])[N:24]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=2)=[CH:8][CH:7]=1
Reactant: CC1CCC(C)N1
Reactant: CC1(C)COC(c2ccc(OCCCCl)cc2)=N1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC1CCC(C)N1CCCOc1ccc(C2=NC(C)(C)CO2)cc1
Yield: 41 %

Procedure:
2-[4-(3-chloropropoxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax10 (500 mg, 1.87 mmol, 1 eq), sodium iodide (0.56 mg, 3.74 mmol, 2 eq), sodium hydrogenocarbonate (0.31 mg, 3.74 mmol, 2 eq) and 2,5-dimethylpyrrolidine (0.24 ml, 2.8 mmol, 1.5 eq) are stirred at reflux overnight in dry acetonitrile (10 ml). Water and ethyl acetate are added to the mixture and the layers are separated. The organic layer is dried with brine, sodium sulfate and evaporated under vacuum. Flash chromatography over silica with ethyl acetate as the eluent gives 0.253 g of 2-(4-{3-[2,5-dimethylpyrrolidin-1-yl]propoxy}phenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole 18 as a free base.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[N:19]=[C:18]3[CH2:20][CH2:21][CH2:22][C:17]3=[CH:16][CH:15]=2)[CH:3]=1.CO.[NH3:25]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:25])=[O:9])=[C:4]([NH:13][C:14]2[N:19]=[C:18]3[CH2:20][CH2:21][CH2:22][C:17]3=[CH:16][CH:15]=2)[CH:3]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc2c(n1)CCC2
Reactant: N
Solvent: CO
Product: NC(=O)c1nnc(Cl)cc1Nc1ccc2c(n1)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
Ethyl 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxylate (554 mg, 1.74 mmol) was suspended in ammonia 7M in methanol (11.8 g, 15.0 mL, 105 mmol). The flask containing the mixture was sealed and stirred at room temperature for 18 h. The precipitated off-white solid was separated by filtration and dried under high vacuum to give 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxamide (375 mg, 75%) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.92 (s, 1H), 8.95 (s, 1H), 8.83 (s, 1H), 8.18 (s, 1H), 7.63 (d, J=7.9 Hz, 1H), 6.84 (d, J=7.9 Hz, 1H), 2.78-3.00 (m, 4H), 2.07 (quin, J=7.6 Hz, 2H); LC-MS 290.0 [M+H]+.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:60]#[N:61])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([C:60]#[N:61])=[C:53]([O:58][CH3:59])[CH:54]=4)[O:49][C:48]=3[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2cc1C#N
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2cc1C#N
Yield: 71 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(7-cyano-6-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a pale yellow solid (23 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.65 (s, 1H), 7.43-7.32 (m, 7H), 7.16-7.12 (m, 2H), 4.02 (s, 3H), 2.42-2.35 (m, 2H), 2.17-2.09 (m, 2H), 2.06-1.96 (m, 1H), 1.72-1.62 (m, 1H). LCMS (Method E): RT=3.67 min, [M+H]+=423.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:46][C@@H:47]1[CH2:51][NH:50][C@H:49]([C:52]#[N:53])[CH2:48]1.CN1CCOCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([N:50]3[CH2:51][C@@H:47]([F:46])[CH2:48][C@H:49]3[C:52]#[N:53])=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)N1C[C@@H](F)C[C@H]1C#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 15.5 %

Procedure:
(R)-2-(6-Chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (10 mg, 0.032 mmol)), HATU (15 mg, 0.039 mmol), (2S,4S)-4-fluoropyrrolidine-2-carbonitrile (4 mg, 0.032 mmol), and N-methylmorpholine (90 μL, 0.097 mmol) were combined in THF (0.5 mL). The reaction mixture was stirred under nitrogen at 40° C. for 10 min and then at room temperature for 30 min. The solution was concentrated and purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA) to afford the title compound as a white solid (2 mg, 12%). 1H NMR (500 MHz, CD3OD) δ 0.94 (d, J=6.3 Hz, 3H), 1.05 (d, J=6.3 Hz, 3H), 1.03-1.15 (m, 1H), 2.56-2.65 (m, 3H), 23.89-3.91 (m, 1H), 4.25-4.30 (m, 1H), 4.83-4.87 (m, 1H), 5.09-5.13 (m, 1H), 5.39-5.41 (m, 1H), 5.47-5.66 (m, 1H), 7.87 (s, 1H), 8.27 (s, 1H). [M+H] calc'd for C19H19ClFN5O2, 404; found, 404.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[N+:17]([C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[CH:23]=[CH:24][C:25](O)=O)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)/[CH:23]=[CH:24]/[C:25]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1)([O-:19])=[O:18]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc([N+](=O)[O-])c3)nc2n(CCC)c1=O
Yield: 56.9 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 4.0 g (17.7 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.8 g (19.5 mmol) of 3-nitrocinnamic acid. Then, the resultant crude crystals were recrystallized from toluene to give 3.86 g (yield 57%) of Compound 35 as pale yellow needles.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:30]([O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)(=[O:32])[CH3:31]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:38][C:37]5[CH:36]=[CH:35][C:34]([O:33][C:30](=[O:32])[CH3:31])=[CH:41][CH:40]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: CC(=O)Oc1ccc(CBr)cc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(OC(C)=O)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-acetoxy-benzyl bromide following a procedure analogous to that described for Intermediate 7. LC (method 8): tR=1.27 min; Mass spectrum (ESI+): m/z=541 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:42][CH2:43][NH2:44])[CH2:38][CH2:37]1>>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[CH:26]=[CH:25][N:24]=[C:23]3[C:18]=2[C:19]2[CH:31]=[CH:30][C:29]([C:32]([NH:44][CH2:43][CH2:42][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)=[O:33])=[CH:28][C:20]=2[C:21](=[O:27])[NH:22]3)=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)c(=O)[nH]c1nccc(Nc3ccc(NC(=O)c4ccccc4)cc3)c12
Reactant: CN1CCN(CCN)CC1
Product: CN1CCN(CCNC(=O)c2ccc3c(c2)c(=O)[nH]c2nccc(Nc4ccc(NC(=O)c5ccccc5)cc4)c23)CC1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 269 using 268 (30 mg, 0.07 mmol) and 2-(4-methyl-piperazin-1-yl)-ethylamine to provide 271. LC-MS (M+H=576, obsd.=576).
Reaction SMILES: Br[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])=[O:4].C(N(CC)CC)C.Cl.[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([CH:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:7])=[O:4])[CH2:31][CH2:30]1
Reactant: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Reactant: FC1(F)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](OC(=O)C(c1ccccc1)N1CCC(F)(F)CC1)c1ccccc1
Temperature: 55 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
To a solution of the product from Example 138A (1.00 g, 3.13 mmol) in tetrahydrofuran (20 mL) at room temperature was added triethylamine (1.75 mL, 12.5 mmol) and tetrabutylammonium iodide (0.46 g, 1.25 mmol). The mixture was stirred for 5 minutes and then 4,4-difluoropiperidine hydrochloride (0.74 g, 4.70 mmol) was added as the free base in THF. The mixture was stirred for 1 hour at room temperature and then heated to 55° C. overnight. The cooled mixture was washed with brine, concentrated, then purified by column chromatography (EtOAc-hexane) to provide the title compound (1.04 g, 92% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:22][CH:21]=1
Reactant: NCCc1ccncc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccncc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(pyridin-4-yl)-ethyl-amine to afford the title compound. MS: m/e=363 (M+H). 1H NMR (δ ppm): 11.72 (s, 1H); 8.87 (d, 1H, J=2.1 Hz); 8.77 (t, 1H, J=5.4 Hz); 8.67 (d, 1H, 2.1 Hz); 8.47 (m, 2H); 8.04 (t, 1H, J=2.1 Hz); 7.29 (m, 3H); 3.57 (q, 2H, J=7.1 Hz); 2.89 (t, 2H, J=7.1 Hz); 2.42 (q, 2H, J=7.4 Hz); 2.17 (s, 3H); 1.11 (t, 3H, J=7.4 Hz).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](OC3C=CC=CC=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[C:16]1[CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=1)[NH2:36].Cl.N1C=CC=CC=1.C1(O)C=CC=CC=1>ClCCl>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:36][C:35]3[CH:37]=[CH:38][C:39]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[CH:43]=4)=[C:33]([Cl:32])[CH:34]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[C:16]1[CH3:31])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: Cc1cc2ncnc(Oc3ccccc3)c2n1CCOCCOC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: Oc1ccccc1
Product: Cc1cc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2n1CCOCCOC(=O)c1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 26.2 %

Procedure:
A mixture of 2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (92.3 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (86.3 mg), pyridine hydrochloride (81.6 mg) and phenol (156.1 mg) was stirred at 120° C. for 3 hrs, and at 140° C. for 5.5 hrs. Further, pyridine hydrochloride (77.6 mg) and phenol (188.7 mg) were added, and the mixture was stirred at 140° C. for 22.5 hrs. The reaction mixture was diluted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=50:50→0:100) to give the title compound (33.3 mg) as a purple oil.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@@H:18]([CH2:20][N:21]=[N+:22]=[N-:23])[O:17][C:16]3=[O:24])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:25].CSC.C(Cl)(=O)C>O1CCCC1>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:19][C@@H:18]([CH2:20][N:21]=[N+:22]=[N-:23])[O:17][C:16]3=[O:24])=[CH:13][CH:14]=2)[CH2:5][CH:4]1[F:25]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2)CC1F
Solvent: CSC
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(N3CCC(=O)C(F)C3)cc2)C(=O)O1
Temperature: 40 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
To the mixture of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-azide (0.5 mmol), freshly fused zinc chloride (1.5 mmol), dimethyl sulphide (2.5 mmol), acetyl chloride (1.5 mmol) in tetrahydrofuran (50 ml) was stirred at 40° C. for 4 days. To this reaction mixture extracted with the ethyl acetate water mixture and organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel afforded title compound in 67% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[CH:11]([N:14]([CH:18]([CH3:20])[CH3:19])[C:15](Cl)=[O:16])([CH3:13])[CH3:12].N1C=CC=CC=1.Cl>>[CH:11]([N:14]([CH:18]([CH3:20])[CH3:19])[C:15](=[O:16])[O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:13])[CH3:12]
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: OCCc1ccccc1F
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)N(C(=O)OCCc1ccccc1F)C(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 8.0 g (57.1 mmol) of 2-(2-fluorophenyl)ethanol, 9.34 g (57.1 mmol) of diisopropylcarbamoyl chloride and 6.93 ml (85.7 mmol) of pyridine was heated to 90° C. and stirred overnight. After cooling to room temperature, the mixture was treated with 1 N—HCl, extracted 3 times with ethyl acetate, washed with water, saturated NaHCO3, water and brine and then dried over sodium sulfate. After the solvent was distilled off, purification of the residue by silica gel chromatography gave 14.0 g of the title compound. (Yield: 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2].CN(C)C1C=CC=CC=1.[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>C(#N)C>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([NH:10][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(N)c([N+](=O)[O-])c2)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a mixture of 2-nitro-benzene-1,4-diamine (10 g, 65.30 mmol) and N,N-dimethylaniline (8.7 g, 71.83 mmol) in acetonitrile (310 ml) at 0° C. 4-isopropyl-benzenesulfonylchloride (13.85 g, 63.34 mmol) was added over a period of 1 h. The mixture was stirred at 0° C. for 1 h and for 16 h at room temperature. After concentrating the mixture in vacuo the obtained oil was triturated with water. The precipitate was collected, washed with ethanol and dried in vacuo to give the product as a yellow powder (11.76 g, 54%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10].C([O-])(=O)C.[Na+]>C(O)C.[Pd]>[CH3:7][N:6]1[CH:2]=[C:3]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[C:4]([CH3:8])=[N:5]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)Nc1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)cc1C(=O)Nc1ccccc1
Yield: 85.9 %

Procedure:
5-chloro-1,3-dimethyl-N-phenyl-4-pyrazolecarboxamide (2.7 g) was dissolved in ethanol (100 ml) and anhydrous sodium acetate (2 g) added. The mixture was hydrogenated at room temperature and 2 atmospheres pressure using palladium on carbon catalyst. On completion of the reaction, the catalyst was removed by filtration through celite and the filtrate evaporated in vacuo. Water (50 ml) was added and the product extracted with chloroform (3 × 25 ml). The combined extracts were washed with water, dried and evaporated. The product was crystallised from ethanol and 1,3-dimethyl-N-phenyl-4-pyrazolecarboxamide (2 g, 96%) was obtained as colourless needles, m.p. 91-92° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[NH:5][C:4](=[O:18])[C:3]=1[C:19]([OH:21])=[O:20].OS(O)(=O)=O.[CH3:27]O>>[CH3:27][O:20][C:19]([C:3]1[C:4](=[O:18])[NH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)=[CH:7][C:2]=1[CH3:1])=[O:21]
Reactant: CO
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)[nH]c(=O)c1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)[nH]c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of 0.30 g (1.0 mmol) of 4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid in 15 ml of MeOH was treated with 0.06 ml=0.01 g (0.1 mmol) of H2SO4 (98%) and the reaction mixture was heated up to reflux. After 4 hours, it was cooled down to RT, poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.24 g (77%) of the title compound as off-white solid. MS: 312.0 (MH+).