Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:4]=1.ClCC1N(C)N=C(C)N=1.[CH:22]1([C:27]2([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])[CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([C:27]2([CH2:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[O:32][C:31](=[O:33])[C:30]([CH2:2][C:3]3[O:7][N:6]=[C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])[CH:4]=3)=[C:29]([OH:34])[CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)Nc1cc(CBr)on1
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Agent: Cc1nc(CCl)n(C)n1
Product: COC(=O)Nc1cc(CC2=C(O)CC(CCc3ccc(OC)cc3)(C3CCCC3)OC2=O)on1
Yield: 13 %

Procedure:
The title compound was prepared as described in Example B(53), using methyl 5-(bromomethyl)isoxazol-3-ylcarbamate (prepared as described: Sircar, J. C.; Capiris, T. U.S. Pat. No. 4,489,077, Dec. 18, 1984) in place of 5-(chloromethyl)-1,3-dimethyl-1H-1,2,4-triazole, and using 6-cyclopentyl-6-[2-(4-methoxyphenyl)ethyl]dihydro-2H-pyran-2,4(3H)-dione in place of 6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione. Yield: 13%. 1H NMR (300 MHz, DMSO-d6) δ 1.15-1.65 (m, 8H), 1.80 (m, 2H), 2.25 (m, 1H), 2.39-2.51 (m, 3H, overlap with DMSO-d5), 2.68 (d, J=17.4 Hz, 1H), 3.51 (s, 2H), 3.56 (s, 3H), 3.61 (s, 3H), 6.24 (s, 1H), 6.72 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 10.47 (s, 1H), 11.15 (br s, 1H). LC-MS (APCI) calcd for C25H30N2O7: 470.21; found (M+H+) 471.1 m/z.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][NH:6][C:7]([O:9][CH3:10])=[O:8])[CH3:2].C=O.[C:14](OC(=O)C)(=O)C.[P:21]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:22]C1C=CC=CC=1>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][N:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:14][P:21]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:22])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: C=O
Solvent: CC(=O)O
Product: CCOC(=O)CN(CP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)OC
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A mixture of N-carbomethoxy glycine ethyl ester (10.0 g, 0.06 mole), paraformaldehyde (2.0 g, 0.06 mole), acetic anhydride (96%, 4.0 g, 0.06 mole) and acetic acid (20 ml) was stirred for 3 hrs. at 60°-70° C. under nitrogen. Triphenyl phosphite (19.2 g, 0.03 mole) was slowly added then the reaction mixture was refluxed for 2 hrs. at 110°-200° C. The reaction was cooled and the solvent was evaporated under vacuum. The resulting oily material was dissolved in chloroform and washed with water. The product was confirmed by nmr. Yield 70.5%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=O)[C:5](=[O:11])[NH:6][C:7]=1[CH:8]([F:10])[F:9].[NH2:16][CH:17]([CH3:21])[CH2:18][O:19][CH3:20].Cl>>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:16][CH:17]([CH3:21])[CH2:18][O:19][CH3:20])=[O:14])[C:5](=[O:11])[NH:6][C:7]=1[CH:8]([F:9])[F:10]
Reactant: COC(=O)c1cc(Br)c(C(F)F)[nH]c1=O
Reactant: COCC(C)N
Agent: Cl
Product: COCC(C)NC(=O)c1cc(Br)c(C(F)F)[nH]c1=O

Procedure:
At room temperature, 334 mg (1.19 mmol) of methyl 5-bromo-6-(difluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate in 3.3 ml (41 mmol) of 2-amino-1-methoxypropane were stirred for 14 h. The pH was then adjusted to 2 by addition of 1N hydrochloric acid, and the mixture was extracted with dichloromethane. Drying and concentration of the extract gave 360 mg (89% of theory) of the product.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[I:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1N>ClCCl>[F:1][C:10]1[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:9]=1[I:8]
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: N#[O+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(F)c(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
A solution of nitrosonium tetrafluoroborate (24 g, 0.21 mol) in dichloromethane (200 mL) at 0° C. was treated with a solution of 2-iodo-4-nitroaniline (50 g, 0.19 mol) in dichloromethane (350 mL) and stirred at 0° C. for 1 h. The dichloromethane was concentrated to about half volume and the reaction mixture was treated with 1,2-dichlorobenzene (300 mL). The remaining dichloromethane was further concentrated in vacuo. The resultant 1,2-dichlorobenzene suspension was heated at 110° C. for 1 h, cooled to 20° C., and treated with water (200 mL) and dichloromethane (500 mL). The reaction mixture was filtered over celite and the celite was washed with dichloromethane and water. The aqueous layer of the filtrate was separated and extracted with dichloromethane (2×). The combined organic layers were washed with 20% sodium thiosulfate and brine, dried over anhydrous sodium sulfate, and filtered. The dichloromethane was removed under standard conditions while the 1,2-dichlorobenzene was removed via vacuum distillation to give a crude dark oil. This material was purified by distillation to give the desired product (19 g, 38%) as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[C:21]([CH:24]([CH3:26])[CH3:25])[S:22][CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:41]([C:40]3[CH:39]=[CH:38][C:37]([CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)=[CH:44][CH:43]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)c1nc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)cs1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)c1nc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(CN6CCOCC6)cc5)nc34)CC2)cs1
Temperature: 85 °C
Yield: 39.1 %

Procedure:
To a mixture of 5-bromo-4-(4-((2-isopropylthiazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.066 g, 0.15 mmol), EtOH (2.6 mL) and DMF (0.35 mL), 4-(morpholinomethyl)-benzaldehyde (0.034 g, 0.165 mmol) was added, followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.035 g, 39%); 1H-NMR (500 Mz, DMSO-d6): δ 1.33 (d, J=7.0 Hz, 6H, iPr—CH3), 2.34-2.42 (m, 4H), 2.68 (m, 4H), 3.22-3.32 (m, 1H), 3.54 (s, 2H), 3.59 (d, J=4.5 Hz, 4H), 3.62-3.70 (m, 6H), 7.35 (s, 1H, thiazole 5-H), 7.47 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.14 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.55 min—596/598 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 596.18.07, calculated for C28H35BrN7OS (M+H)+: 596.1793.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH2:20][CH2:21][C:22](OCC)=[O:23])=[CH:11][NH:12]2>C1COCC1>[CH3:7][C:8]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH2:20][CH2:21][CH2:22][OH:23])=[CH:11][NH:12]2
Reactant: CCOC(=O)CCc1c[nH]c2ccc([N+](=O)[O-])c(C)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c([N+](=O)[O-])ccc2[nH]cc(CCCO)c12
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a suspension of 95% LiAlH4 (0.378 g, 9.44 mmol) in 10 mL of dry THF was added a solution of ethyl 4-methyl-5-nitro-3-indolepropionate (0.650 g, 2.36 mmol) in 2 mL of dry THF, at 0° C. under Ar. After 5 min the cooling bath was removed and stirring was continued at room temperature for 30 min. The reaction was then quenched by the sequential addition of 0.4 mL of water, 0.4 mL of 15% aqueous NaOH and finally 1.2 mL of water. The resulting suspension was diluted with ethyl acetate and then it was filtered and the filtercake was washed with additional ethyl acetate. The filtrate was evaporated and the residue was chromatographed (SiO2 /dichloromethane-ethyl acetate, 2:1) to give the title compound (0.458 g, 83%) as a solid. An analytical sample was crystallized from ethyl acetate-hexane to give yellow-orange needles, mp 129°-130° C.: IR (KBr) 3543, 3210, 1616, 1520, 1330 cm- ; 1H NMR (DMSO-d6, 200 MHz) δ 11.43 (br s, 1H), 7.63 (d, J=8.9 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 7.29 (s, 1H), 4.51 (t, J=5.2 Hz, 1H), 5.20 (dt, J=6.2, 5.4 Hz, 2H), 2.91 (t, J=7.7 Hz, 2H), 2.78 (s, 3H), 1.78 (m, 2H). Anal. Calcd for C12H14N2O3 : C, 61.52; H, 6.02; N, 11.96. Found: C, 61.23; H, 5.85; N, 11.90.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].Br[CH2:10][C:11]#[C:12][CH2:13][CH3:14].[C:15]12([C:25]([OH:27])=O)[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2>>[CH3:1][C:2]1[N:3]([CH2:10][C:11]#[C:12][CH2:13][CH3:14])/[C:4](=[N:8]/[C:25]([C:15]23[CH2:16][CH:17]4[CH2:18][CH:19]([CH2:20][CH:21]([CH2:23]4)[CH2:22]2)[CH2:24]3)=[O:27])/[S:5][C:6]=1[CH3:7]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1nc(N)sc1C
Reactant: CCC#CCBr
Product: CCC#CCn1c(C)c(C)s/c1=N\C(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
4,5-Dimethylthiazol-2-ylamine, 1-bromo-pent-2-yne and 1-adamantane carboxylic acid were processed according to the method of Example 47 to afford the title compound. 1H NMR (CDCl3, 500 MHz) δ ppm 1.03 (t, J=7.49 Hz, 3H) 1.64-1.75 (m, 6H) 1.84 (d, J=2.50 Hz, 6H) 1.94-2.02 (m, 3H) 2.16 (s, 3H) 2.16-2.22 (m, 2H) 2.28 (s, 3H) 5.00 (t, J=2.18 Hz, 2H); MS (ESI) m/z 357 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:14]([CH3:33])=[C:13]([CH3:34])[N:12]=1>COCCOCCOC>[CH3:34][C:13]1[C:14]([CH3:33])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCCc2cccnc2)c1C
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCCc2cccnc2)c1C
Temperature: 90 °C
Reaction time: 1.25 h

Procedure:
2-Methoxyethyl ether (diglyme) (50 ml) and sodium hydride (60% in oil) (5.77 g) were combined. Under a nitrogen atmosphere, a solution of phenol (13.58 g) and diglyme (250 ml) was added slowly over 10 minutes to allow for controlled gas evolution. 2-chloro-5,6-dimethyl-3-nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]pyridin-4-amine (35.1 g) from Part A was then added and the reaction mixture was heated to 90° C. After 1.25 hours, the reaction mixture clouded and the temperature was increased to 110° C. After an additional 3.75 hours, HPLC and TLC analysis indicated the reaction was complete. The reaction mixture was cooled and the solvent was removed under reduced pressure. The resulting oil was dissolved in ethyl acetate and washed once with 20% potassium hydroxide, once with 1N potassium hydroxide, 3 times with water, and 3 times with brine. The combined organic layers were dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography over silica, eluting with 90/10 ethyl acetate/hexane. The fractions containing purified product were concentrated under reduced pressure and dried under vacuum at 70° C. overnight. NMR analysis of the resulting yellow oil indicated sufficient purity for use of the product in the next step.
Reaction SMILES: C(N1CCO[C@H]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]O)[CH:16]=2)C1)(OC(C)(C)C)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][C:31]1=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC1C=C(C=CC=1)CBr>>[CH2:23]([N:30]1[CH2:35][CH2:34][O:33][CH:32]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[C:31]1=[O:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1COCCN1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1
Agent: Cc1cccc(CBr)c1
Product: Cc1cccc(CC2OCCN(Cc3ccccc3)C2=O)c1

Procedure:
N-Benzyl-2-(3-methylbenzyl)-morpholin-3-one was prepared as described for example 70, intermediate (b), but using 4-benzylmorpholine-3-one and 3-methylbenzyl bromide and was isolated as a pale yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]([CH3:18])=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCOCC1.O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([CH:16]([OH:17])[CH3:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2ccc(C(C)=O)o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2ccc(C(C)O)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring mixture of 22 g (0.090 mole) of methyl 5-(p-acetamido-phenyl)-2-furyl ketone and 345 ml of 95% dioxane/H2O was added portionwise 3.4 g (0.090 mole) of NaBH4 while maintaining the temperature at 15°-20°. The resulting mixture was stirred overnight at room temperature and then added to ice/water. The solid was filtered and dried at 60° to yield 21 g (95%), m.p. 175°-177°, of title compound.
Reaction SMILES: [C:1](=O)([O:5]CC)[O:2][CH2:3][CH3:4].CCOCC.[CH3:14][C:15]1([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[O:19][CH2:18][CH2:17][O:16]1>C(O)C>[CH2:3]([O:2][C:1](=[O:5])[CH2:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][C:15]1([CH3:14])[O:16][CH2:17][CH2:18][O:19]1)[CH3:4]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)CCCC1(C)OCCO1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CC(=O)CCCC1(C)OCCO1

Procedure:
11.8 Grams (0.1 moles) of diethyl carbonate in 12.5 ml. of anhydrous ether was added to 4.55 g. (0.1 moles) of a 53 percent dispersion of sodium hydride in mineral oil which was washed with anhydrous hexane and dried under nitrogen. This mixture was stirred under nitrogen and 8.6 g. (0.05 mole) of the ketal ketone, 5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone was added dropwise over a period of two hours. A gentle reflux was maintained throughout the addition and the refluxing was continued for an additional period of approximately 11/2 hours. The solution was then cooled with an ice bath, 20 ml. of anhydrous ether and 2 ml. of absolute ethyl alcohol was added and it was stirred for 45 minutes to destroy any unreacted sodium hydride. The suspension was diluted with an equal volume of ether and the ice cold suspension was then added to a rapidly agitated mixture of 6 ml. of glacial acetic acid and 200 ml of ice water. The etheral layer was separated, and the aqueous layer was additionally extracted twice with ether. The extract was washed with saturated sodium bicarbonate and with a saturated sodium chloride, dried with sodium sulfate, filtered and evaporated in vacuo to give the crude β-keto ester, 6-(2-methyl-1,3-dioxolan-2-yl)-3-oxo-hexanoic acid ethyl ester, b.p. 110°-112° C at 0.2 mm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[N:9][N:10]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH:11]=2)=[CH:3][CH:2]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:34][C:25]4[CH:26]=[N:27][C:28]5[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:24]=4)=[CH:21][CH:22]=3)=[N:9][N:10]([CH2:12][C:13]([F:15])([F:16])[F:14])[CH:11]=2)=[CH:3][CH:2]=1
Reactant: OCc1cnc2ccccc2n1
Reactant: Oc1ccc(-c2nn(CC(F)(F)F)cc2-c2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: FC(F)(F)Cn1cc(-c2ccncc2)c(-c2ccc(OCc3cnc4ccccc4n3)cc2)n1
Temperature: 60 °C
Yield: 47.3 %

Procedure:
To a solution of 4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenol (79 mg) and Quinoxalin-2-yl-methanol (50 mg) in dioxane (2 ml) was added triphenylphosphine (105 mg) and di-t-butyldiazacarboxalate (92 mg) and the reaction mixture heated at 60° C. After 18, the reaction mixture was poured into 1N NaOH, extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated. Purification with MPLC biotage eluting with 2% methanol/0.5% ammonium hydroxide/60% ethyl acetate/hexanes provided the title compound (54 mg). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.52 (m, 2H), 8.13 (m, 1H), 8.10 (m, 1H), 7.79 (m, 2H), 7.73 (s, 1H), 7.40 (d, J=8.7, Hz, 2H), 7.24 (m, 2H), 7.04 (d, J=8.7 Hz, 2H), 5.32 (s, 2H), 4.79 (q, J=8.3 Hz, 2H); MS: (M+H m/z=462.1).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH2:15].[C:16]1([CH3:23])[C:17](C)=[CH:18][CH:19]=[CH:20][CH:21]=1>>[C:16]1([CH:23]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:8]([OH:10])=[O:9])[CH2:12][C:11](=[O:13])[N:15]2[CH3:14])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CC(c2ccccc2)C(=O)O1
Reactant: CN
Reactant: Cc1ccccc1C
Product: CN1C(=O)CC(C(=O)O)(c2ccccc2)C1c1ccccc1
Yield: 86 %

Procedure:
57.5 g (0.327 mole) of phenylsuccinic anhydride and 39 g (0.327 mole) of Schiff base, prepared from benzyldehyde and methylamine according to the general procedure, are refluxed at 140° in 400 ml of xylene for 12 hr. After cooling to 0 C. the solid is collected and washed with xylene and ether: 83.2 g (86% yield) of 2,3-diphenyl-1-methyl-pyrrolidin-5-one-3 carboxylic acid mp 247°-52° (diastereomeric mixture), less polar minor isomer mp 290°-3°, more polar major isomer mp 295°-61° C. 14.7 g of the above acid (0.03 mole) are dissolved in 300 ml of THF and treated at 5°-10° with diborane, generated from 15 g of NaBH4 in 350 ml of diglyme and 101 ml of BF3 -etherate in 200 ml of diglyme. After completion of the reaction 250 ml of 6N HCl are added at first very slowly. After the addition of 300 ml of water the THF is removed in vacuo. The water solution is adjusted to pH 8-9 with 6N NaOH. After cooling to 0 the crystals are collected and dried: 9.7 g (74%) of title compound, mp 99°-102° (diastereomeric mixture).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:21]=2)[CH:15]=1
Reactant: COC(=O)c1ccccc1S
Reactant: COc1ccnc(C#N)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 80 %

Procedure:
A mixture of methyl thiosalicylate (2.0 g, 11.7 mmol), 4-methoxy-2-cyanopyridine (1.5 g, 11.1 mmol), triethylamine (2.5 ml, 17.9 mmol) and toluene (5 ml) was refluxed for 12 hrs as described in Example 1. The precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (2.4 g, 81%).
Reaction SMILES: [CH3:1]C(C)CCN.[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)=[O:19])=[CH:12][C:11]=12.[N+:29]([C:32]1C=C[C:35]([C:36]([OH:38])=O)=[CH:34][CH:33]=1)([O-])=O>>[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:19])[C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:29]4[CH2:32][CH2:33][CH2:34][C@@H:35]4[CH2:36][O:38][CH3:1])=[O:25])=[CH:27][CH:28]=3)=[CH:12][C:11]=12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccn3ccnc3c2)cc1
Reactant: CC(C)CCN
Product: COC[C@H]1CCCN1C(=O)c1ccc(C(=O)NCc2ccn3ccnc3c2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting (2R)-2-(methoxymethyl)pyrrolidine for 3-methylbutan-1-amine and 4-(imidazo[1,2-a]pyridin-7-ylmethylcarbamoyl)benzoic acid for 4-nitrobenzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.18 (t, J=4.8 Hz, 1H), 8.49 (dd, J=7.0, 0.9 Hz, 1H), 7.95 (d, J=8.3 Hz, 2H), 7.88 (s, 1H), 7.57 (d, J=7.7 Hz, 2H), 7.52 (d, J=1.2 Hz, 1H), 7.40 (s, 1H), 6.86 (dd, J=7.0, 1.6 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H), 3.62-2.88 (br m, 8H), 2.05-1.64 (br m, 4H); MS (ESI(+)) m/e 393 (M+H)+.
Reaction SMILES: ClC1C=NC=C(Cl)C=1[NH:8][C:9]([C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](N)[CH:21]=3)[N:16]([CH3:25])[C:15]=2[C:14]([O:26][CH3:27])=[CH:13][CH:12]=1)=[O:10].[N:29]1C=C[CH:32]=[CH:31][CH:30]=1.C(Cl)(=[O:38])CC>C1COCC1>[CH3:27][O:26][C:14]1[C:15]2[N:16]([CH3:25])[C:17]3[C:22](=[CH:21][C:20]([NH:29][C:30](=[O:38])[CH2:31][CH3:32])=[CH:19][CH:18]=3)[C:23]=2[C:11]([C:9]([NH2:8])=[O:10])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(N)ccc3n(C)c12
Reactant: c1ccncc1
Reactant: CCC(=O)Cl
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc2c(c1)c1c(C(N)=O)ccc(OC)c1n2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-amino-9H-4-carbazolecarboxamide (75 mg, 0.00018 mol) was suspended in THF (5 ml) and added with pyridine (28 mg, 0.00036 mol) and stirred at room temperature for 10 minutes. The solution obtained, was added with a solution of propionyl chloride (24 mg, 0.00027) in dry THF (5 ml). The reaction mixture was stirred for 1 hr. THF was evaporated and the solid was washed with water to get crude solid which was column chromatographed using 10% methanol in chloroform to give N-3,5-dichloropyrid-4-yl)-1-methoxy-9-methyl-6-propionamido-9H-4-carbazolecarboxamide (20 mg), mp>250° C.
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([NH:19][NH2:20])(=[O:18])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>O1CCOCC1.O>[NH2:1][C:2]1[O:18][C:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:19][N:20]=1
Reactant: N#CBr
Reactant: CCCCCCCCCCCCCC(=O)NN
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCc1nnc(N)o1

Procedure:
Cyanogen bromide (2.9 g, 0.027 mol) was added to a mixture of the compound prepared in Step 1 above (6.1 g, 0.025) and KHCO3 (2.8 g, 0.028 mol) in dioxane/water (1:1, 50 mL) at room temperature. The mixture was refluxed for 1 hour, allowed to cool, filtered, washed with dioxane/water (1:1, 20 mL), then water (50 mL), and dried in vacuo. The solid was recrystallized from chloroform to yield 4.16 g, m.p. 147°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:10]([CH2:20][C:21](O)=[O:22])[N:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br.Br.[S:35]1[C:44]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39][C:38]=2[N:37]=[C:36]1[NH2:45].C(=O)([O-])O.[Na+]>CN(C=O)C.C(Cl)Cl>[NH2:45][C:36]1[S:35][C:44]2[CH2:43][CH2:42][N:41]([C:21](=[O:22])[CH2:20][N:10]3[C:11]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)=[N:12][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9]3)[CH2:40][CH2:39][C:38]=2[N:37]=1
Reactant: O=C(O)Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1nc2c(s1)CCN(C(=O)Cn1nc(-c3ccc(F)cc3)nc1-c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 53.7 %

Procedure:
350 mg (3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetic acid and 0.2 mL DIPEA were dissolved in 4.5 mL DMF. 570 mg PFTU was added to this solution and the mixture was stirred for 7 min at RT. Then, 333 mg 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepin-2-ylamine dihydrobromide and 0.4 mL DIPEA were added and the reaction was stirred over night at RT. Then, sodium hydrogencarbonate solution (10%) and CH2Cl2 were added, the organic phase was separated and the solvent was removed. The residue was purified by HPLC to yield 252 mg of the desired compound.