Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[I:14]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[I:14]
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(N)c(I)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 165.9 %

Procedure:
To a stirred solution of 4-amino-N,N-dimethylbenzenesulfonamide (3.0 g, 14.98 mmol) in EtOH (165 mL) at 50° C. was added a slurry of iodine (1.3 g, 4.99 mmol) and silver sulfate (2.8 g, 9.00 mmol) in EtOH (40 mL). The same addition was repeated after 1 h of stirring at 50° C., then the reaction mixture was stirred at 50° C. for 16 h. Iodine (0.76 g, 3.00 mmol) was again added, and the mixture stirred at 50° C. for 2 h before being filtered through Celite®. The filtrate was concentrated in vacuo, and EtOH (70 mL) was added. The suspension was stirred at 50° C. for 1 h, cooled to r.t., then filtered to give the title compound (2.7 g, 55%) as a brown solid that was used without further purification. δH (DMSO-d6) 7.81 (1H, d, J 2.1 Hz), 7.42 (1H, dd, J 8.6 and 2.1 Hz), 6.83 (1H, d, J 8.6 Hz), 6.12 (2H, br. s), 2.58 (6H, s). LCMS (ES+) 326.9 (M+H)+, RT 2.50 minutes (Method 3).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.Cl[C:46]1[N:51]=[C:50]([NH2:52])[C:49]([N+:53]([O-:55])=[O:54])=[C:48]([CH3:56])[N:47]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:46]2[N:51]=[C:50]([NH2:52])[C:49]([N+:53]([O-:55])=[O:54])=[C:48]([CH3:56])[N:47]=2)=[N:6]1
Reactant: Cc1nc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: Fc1ccccc1Cn1nc(I)c2cccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: C1COCCO1
Product: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under argon, 1.50 g (4.25 mmol) of the compound from Example 33A were initially charged in 1,4-dioxane (37.5 ml), and the reaction mixture was purged with argon for 10 min. Thereafter, 3.22 ml (6.37 mmol) of hexabutylditin and 881 mg (4.67 mmol) of 2-chloro-6-methyl-5-nitropyrimidin-4-amine were added. Subsequently, 1.49 g (2.12 mmol) of bis(triphenylphosphine)palladium(II) chloride were added and the reaction mixture was heated to reflux overnight. Thereafter, the mixture was cooled to RT and filtered through Celite, and the filtrate was washed through with methanol. The solids formed were filtered off and discarded. The remaining filtrate was concentrated, ethyl acetate was added, and the solids formed were filtered off and dried under high vacuum. This gave 640 mg (69% purity, 27% of theory) of the title compound. The crude product was converted further without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9](S(C)(=O)=O)[S:10]([CH3:13])(=[O:12])=[O:11])=[C:4]([F:18])[CH:3]=1.[OH-].[Na+].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][S:10]([CH3:13])(=[O:11])=[O:12])=[C:4]([F:18])[CH:3]=1
Reactant: CS(=O)(=O)N(c1c(F)cc(Br)cc1F)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1c(F)cc(Br)cc1F
Yield: 89.7 %

Procedure:
A mixture of N-(4-bromo-2,6-difluorophenyl)-N-(methylsulfonyl)methanesulfonamide (2.20 g, 6.04 mmol) and sodium hydroxide (pellet) (1.20 g, 30.0 mmol) in tetrahydrofuran. (30 ml) and water (10 ml) was stirred for 2 hours at ambient temperature. After the solvent was evaporated in vacuo and the residue was acidified to pH 2 with 2M hydrochloride aqueous solution. The aqueous solution was extracted with ethyl acetate and the combined solution was washed with brine, dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was recrystallized from ethyl acetate and hexane to furnish 1.55 g (90% yield) of the title compound as a white solid.
Reaction SMILES: O[N:2]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:3]1[CH:11]=[C:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([N:21]4[CH:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29](CC6C=CC=CC=6)[CH:30]=5)[N:23]=[CH:22]4)=[C:15]3[C:14]([CH:38]([CH3:40])[CH3:39])=[N:13]2)[CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].C1CCCCC=1.C([OH:55])C>[OH-].[Pd+2].[OH-]>[NH:29]1[CH:30]=[C:26]([C:24]2[N:23]=[CH:22][N:21]([C:20]3[CH:19]=[CH:18][N:17]=[C:16]4[N:12]([C:10]5[CH:9]=[CH:8][C:4]([C:5]([NH2:7])=[O:6])=[C:3]([NH:2][CH:41]6[CH2:46][CH2:45][CH:44]([OH:55])[CH2:43][CH2:42]6)[CH:11]=5)[N:13]=[C:14]([CH:38]([CH3:39])[CH3:40])[C:15]=34)[CH:25]=2)[CH:27]=[N:28]1
Reactant: CCO
Reactant: CC(C)c1nn(-c2ccc(C(N)=O)c(N(O)C3CCCCC3)c2)c2nccc(-n3cnc(-c4cnn(Cc5ccccc5)c4)c3)c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NC3CCC(O)CC3)c2)c2nccc(-n3cnc(-c4cn[nH]c4)c3)c12
Temperature: 80 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
Compound (93) (0.010 g) was dissolved in ethanol (1.0 mL). Palladium hydroxide (0.020 g) and cyclohexene (0.5 mL) were added to the resulting solution, followed by stirring under a nitrogen atmosphere at 80° C. for 24 hr. The reaction solution was filtered through celite, and the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (95) (0.005 g, 56%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([Cl:12])=[CH:5][C:3]=1[NH2:4].[ClH:13].O.OO>C(O)C>[Cl:13][C:5]1[C:6]([Cl:12])=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4]
Reactant: Cl
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: OO
Solvent: O
Solvent: CCO
Product: Nc1c(Cl)cc([N+](=O)[O-])c(Cl)c1Cl
Temperature: 50 °C
Yield: 88 %

Procedure:
To a suspension of 2,5-dichloro-4-nitroaniline (4.0 g, 19.3 mmol) in ethanol (50 ml) was added concentrated hydrochloric acid (20 ml) and water (20 ml). The mixture was heated to 50° C. and 27.5% hydrogen peroxide (6 ml) added over 15 min. The mixture was maintained at this temperature for a further 2 h, cooled to room temperature, and the solid filtered and washed with water (2×20 ml) to give the title compound (D11) (4.1 g, 88%), MH+ 241/243.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH3:13][C:14]1([CH3:29])[CH:19]2[CH2:20][CH:16]([CH2:17][CH2:18]2)[CH:15]1[C:21]1([CH:27]=[O:28])[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1>C1(C)C=CC=CC=1>[CH3:13][C:14]1([CH3:29])[CH:19]2[CH2:20][CH:16]([CH2:17][CH2:18]2)[CH:15]1[C:21]1([CH2:27][OH:28])[CH2:26][CH2:25][CH:24]=[CH:23][CH2:22]1
Reactant: CC1(C)C2CCC(C2)C1C1(C=O)CC=CCC1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(C)C2CCC(C2)C1C1(CO)CC=CCC1
Temperature: 20 °C
Reaction time: 2.5 h
Yield: 126.1 %

Procedure:
A 1-L reaction flask equipped with a stirrer, a thermometer, a reflux condenser, a heating mantle, and an addition funnel was charged with Vitride (226 g, 0.73 mol) and toluene (226 g). The resulting mixture was stirred at 20° C. The Diels-Alder product containing 1-(3,3-dimethyl-bicyclo[2.2.1]hept-2-yl)-cyclohex-3-enecarbaldehyde (310 g, 1.32 mol, synthesized as above in EXAMPLE II) was added over about 2 hours. The temperature was allowed to rise to 45° C. The reaction mass was aged for 2.5 hours. The excessive Vitride reagent was quenched with ethyl acetate (CH3CO2CH2CH3, 44 g), followed by sodium hydroxide (NaOH, 25%, 467 g). The temperature was allowed to rise to 50° C. and stirred for another 0.5 hours. The organic phase was diluted with toluene (100 mL), washed with hot water (1 L) twice, and then concentrated to yield the crude product [1-(3,3-dimethyl-bicyclo[2.2.1]hept-2-yl)-cyclohex-3-enyl]-methanol (390 g) having a boiling point of 153° C. at a pressure of 1.7 mmHg.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([F:20])=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]=O>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:23]([CH2:22][CH2:21][C:14]3[CH:15]=[C:16]([F:20])[CH:17]=[C:18]([F:19])[C:13]=3[F:12])[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: O=CCCc1cc(F)cc(F)c1F
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1cc(F)cc(F)c1F

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (2.331 mmol) and 3-(2,3,5-trifluoro-phenyl)-propionaldehyde (0.600 g; 3.189 mmol) afforded 3-ethyl-1-iodo-8-[2-(2,3,5-trifluoro-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.69 min.; [M+H]+=436.23 g/mol.
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH3:24])=[C:9]([NH:11][C:12]([C:14]2[N:18]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[CH:10]=1)#[N:4]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C:12]([NH:11][C:9]3[CH:10]=[C:5](/[C:3](=[N:1]/[OH:2])/[NH2:4])[CH:6]=[CH:7][C:8]=3[CH3:24])=[O:13])=[CH:15][N:16]=2)[CH:19]=1
Reactant: NO
Reactant: Cc1ccc(C#N)cc1NC(=O)c1cnc2ccc(F)cn12
Product: Cc1ccc(/C(N)=N/O)cc1NC(=O)c1cnc2ccc(F)cn12
Temperature: 60 °C

Procedure:
NH2OH (5 mL, 16.1 mmol) was added in one portion to a stirred suspension of N-(5-cyano-2-methylphenyl)-6-fluoroimidazo[1,2-a]pyridine-3-carboxamide (39) (0.95 g, 3.23 mmol). The resulting suspension was heated at 60° C. overnight and then cooled to 0° C. The product, (Z)-6-fluoro-N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (40) was collected by filtration. MS m/z 328.1 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:20]=[CH:21][CH:22]=1
Reactant: Clc1cccc(CBr)c1
Reactant: CCOC(=O)c1cc(O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2cccc(Cl)c2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.7 %

Procedure:
A suspension of ethyl 5-hydroxy-2-methylbenzoate (39.06 g, 217 mmol), 3-chlorobenzyl bromide (31.3 ml, 238 mmol) and potassium carbonate (44.9 g, 325 mmol) in N,N-dimethylformamide (1000 ml) was stirred at room temperature for 18 hours. The reaction was then filtered, diluted with ethyl acetate (2 L), washed with water (2 L then 3×1 L) and brine (1 L), filtered through a hydrophobic frit and concentrated to give the title compound as a dark yellow oil (68.61 g) which was used without further purification. MS (ES+) [C17H1735ClO3+H]+ 305. 1H-NMR (400 MHz, d6-DMSO) δ 1.31 (3H, t, J 7.2), 2.42 (3H, s), 4.28 (2H, q, J 7.2), 5.14 (2H, 2), 7.13-7.16 (1H, m), 7.19-7.23 (1H, m), 7.33-7.45 (4H, m), 7.54-7.55 (1H, m).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@H:13]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C1COCC1.[Pd]>[NH2:1][C@@H:2]([C:10]([N:12]1[CH2:23][CH2:22][CH2:21][C@H:13]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[O:11])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)[C@H](N)CC1CCCCC1
Yield: 100 %

Procedure:
Z-DCha-Pro-OtBu (made by standard peptide coupling reactions) was hydrogenated in THF over 5% Pd-C at standard temperature and pressure for 24 h. Filtration and evaporation provided H-DCha-Pro-OtBu (oil, 100%).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:23])[CH2:22][CH2:21][CH2:20][CH:19]3[CH:15]2[CH2:16][CH2:17][NH:18]3)=[CH:10][CH:9]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([OH:23])[CH2:22][CH2:21][CH2:20][CH:19]3[CH:15]2[CH2:16][CH2:17][N:18]3[C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])=[CH:12][CH:13]=1
Reactant: O=C(Cl)C1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCCC2NCCC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC2C1CCCC2(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The starting material was produced as follows: 2.74 g of Cyclopropanecarboxylic acid chloride was added dropwise to a solution of 7.2 g of (3aRS, 4SR, 7aRS)-4-p-chlorophenylhexahydro-4-indolinol and 2.5 ml of pyridine in 30 ml of methylene chloride at 0° to 10°. The mixture was stirred at room temperature for 1 hour, and then was washed first with a 10% tartaric acid solution, then with a sodium bicarbonate solution, then with a saturated salt solution. The organic phase was dried over sodium sulphate and concentrated to afford (3aRS, 4SR, 7aRS)-4-p-chlorophenyl-1-cyclopropylcarbonylhexahydro-4-indolinol. (M.P. 167°-169°).
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:27](=[O:41])[N:28]([CH:38]3[CH2:40][CH2:39]3)[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=3[Cl:37])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25]O)[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].[Cl:51][C:52]1[C:57]([CH3:58])=[CH:56][C:55]([OH:59])=[CH:54][C:53]=1[CH3:60]>>[C:45]([O:44][C:42]([N:12]1[CH2:13][CH:14]2[N:9]([C:7]([O:6][C:3]([CH3:5])([CH3:4])[CH3:2])=[O:8])[CH:10]([CH2:17][C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:59][C:55]4[CH:56]=[C:57]([CH3:58])[C:52]([Cl:51])=[C:53]([CH3:60])[CH:54]=4)[CH:19]=3)=[C:15]2[C:27](=[O:41])[N:28]([CH:38]2[CH2:39][CH2:40]2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[Cl:37])[CH2:11]1)=[O:43])([CH3:46])([CH3:47])[CH3:48]
Reactant: Cc1cc(O)cc(C)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCO)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Product: Cc1cc(OCCCc2cc(C3=C(C(=O)N(Cc4cccc(Cl)c4Cl)C4CC4)C4CN(C(=O)OC(C)(C)C)CC(C3)N4C(=O)OC(C)(C)C)on2)cc(C)c1Cl

Procedure:
This compound is prepared from compound E6 and 4-chloro-3,5-dimethylphenol, according to the above-described procedure A. LC-MS: tR=1.33 min, ES+: 933.35.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([CH2:22][CH3:23])[C:19]([OH:24])=[CH:18][C:17]=3[O:25][CH3:26])[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([C:29]1[NH:30][C:31]([CH:35]=O)=[C:32]([CH3:34])[N:33]=1)[CH3:28].CC1C=NC2N(N=C(C=O)N=2)C=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[C:20]([CH2:22][CH3:23])[C:19]([OH:24])=[CH:18][C:17]=3[O:25][CH3:26])[O:11][C:10](=[O:12])[C:9]([CH2:35][C:31]3[N:30]=[C:29]([CH2:27][CH3:28])[NH:33][C:32]=3[CH3:34])=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c(OC)cc1O
Reactant: CCc1nc(C)c(C=O)[nH]1
Agent: Cc1cnc2nc(C=O)nn2c1
Product: CCc1nc(CC2=C(O)CC(CCc3cc(CC)c(O)cc3OC)(C3CCCC3)OC2=O)c(C)[nH]1

Procedure:
The title compound was prepared analogously to Example A(126), where 6-Cyclopentyl-6-[2-(5-ethyl-4-hydroxy-2-methoxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione was substituted in place of 6-Cyclopentyl-6-[2-(3-ethyl-4-hydroxy-phenyl)-ethyl-dihydro-pyran-2,4-dione and 2-ethyl-5-formyl-4-methylimidazole was substituted in place of 6-Methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example. 1H NMR (400 MHz, DMSO-d6): δ 1.07–1.34 (m, 6H), 1.49–1.81 (m, 10H), 2.13 (s, 3H), 2.28–2.35 (m, 1H), 2.39–2.68 (m, 8H), 3.40 (d, J=6.9 Hz, 2H), 3.68 (s, 3H), 6.41 (s, 1H), 6.74 (s, 1H). Anal. Calcd. For C28H38N2O5.1H2O: C, 67.18; H, 8.05; N, 5.60. Found: C, 67.50; H, 8.09; N, 5.60. MS(ESI): 483.2 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.Cl.Cl.[CH3:19][NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([CH3:34])[CH:23]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH3:19][NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:30][CH2:29]2)=[C:24]([CH3:34])[CH:23]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(C)c1
Temperature: 95 °C
Reaction time: 15 h
Yield: 39.7 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (75.00 mg, 0.348 mmol), N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (133 mg, 0.436 mmol) and (cyanomethyl)trimethylphosphonium iodide (136 mg, 0.558 mmol) in Propiononitrile (Volume: 2.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.425 mL, 2.439 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide N,3-dimethyl-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.0594 g, 0.138 mmol, 39.6% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.26 (s, 3 H) 2.53-2.66 (m, 4 H) 2.75 (d, J=4.55 Hz, 3 H) 2.86-2.96 (m, 4 H) 3.64 (s, 2 H) 6.71-6.76 (m, 1 H) 7.03 (d, J=8.34 Hz, 1 H) 7.07 (dd, J=3.66, 1.64 Hz, 1H) 7.58 (d, J=1.77 Hz, 1 H) 7.59-7.66 (m, 2 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.19 (q, J=4.29 Hz, 1 H) 8.36 (d, J=1.52 Hz, 1 H) 11.58 (s, 1 H). ESI-MS: m/z 431.4 (M+H)+. mp=264.0-266.3° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:21][C:22]1[N:23]=[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([CH3:47])=[C:35]([NH:37][C:38]([C:40]4[N:44]([CH3:45])[N:43]=[C:42]([CH3:46])[CH:41]=4)=[O:39])[CH:36]=3)=[N:26][N:25]2[CH:48]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:45][N:44]1[C:40]([C:38]([NH:37][C:35]2[CH:36]=[C:31]([O:30][C:27]3[CH:28]=[CH:29][C:24]4[N:25]([CH:48]=[C:22]([NH:21][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[N:23]=4)[N:26]=3)[CH:32]=[CH:33][C:34]=2[CH3:47])=[O:39])=[CH:41][C:42]([CH3:46])=[N:43]1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Reactant: CS(=O)(=O)CC(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CS(C)(=O)=O)cn4n3)ccc2C)n(C)n1
Yield: 38.1 %

Procedure:
In the same manner as in Example 279 and using (methylsulfonyl)acetic acid (100 mg, 0.73 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (63 μL, 0.73 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (91 mg, 38%) was obtained as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[N:10][C:11]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:12]([N+:14]([O-])=O)[CH:13]=2)[CH2:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:23])[CH2:3][N:4]([C:8]2[CH:13]=[C:12]([NH2:14])[C:11]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[N:10][CH:9]=2)[CH2:5][CH2:6][O:7]1
Reactant: CC1(C)CN(c2cnc(N3CCOCC3)c([N+](=O)[O-])c2)CCO1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CN(c2cnc(N3CCOCC3)c(N)c2)CCO1

Procedure:
A solution of 2,2-dimethyl-4-(6-morpholino-5-nitropyridin-3-yl)morpholine (490 mg, 1.52 mmol; described herein) in 30 mL MeOH was reduced in a Thalles H-Cube® hydrogenator using a 10% Pd/C CatCart column (20 bar, 25° C., 1 mL/min flow rate.) The reaction mixture was then concentrated, diluted with EtOAc, and extracted with 1M HCl. The aq. layer was washed with DCM and basified with 1M NaOH. The product was extracted with EtOAc, dried (magnesium sulfate), and concentrated, affording 5-(2,2-dimethylmorpholino)-2-morpholinopyridin-3-amine as a beige powder. Mass Spectrum (ESI) m/e=293.2 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]C(=O)C)=[CH:12][CH:11]=1.[ClH:21]>>[ClH:21].[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:20])=[O:2])=[CH:15][CH:14]=1
Reactant: COC(=O)CCCCCOc1ccc(NC(C)=O)cc1
Agent: Cl
Product: Nc1ccc(OCCCCCC(=O)O)cc1
Temperature: 10 °C
Yield: 55.6 %

Procedure:
A mixture of 6-(4-Acetylaminophenoxy)hexanoic acid methyl ester 19 (290 grams, 1.04 mol) in concentrated hydrochloric acid (7.12 L) was refluxed for 48 hours. Excess concentrated hydrochloric acid was distilled off in vacuum and filtered hot. The mixture was cooled to 10° C., filtered and dried give pure 20 (150 g, 55.6%) as a brown powder. The melting point was found to be 155-160° C.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]([F:39])([F:38])[C:12]([CH2:33][NH:34][CH2:35][CH2:36][CH3:37])([OH:32])[CH2:13][NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[CH2:35]([N:34]([CH2:33][C:12]([CH2:13][NH:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:16]=1[CH:17]=[N:18][N:19]2[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)([OH:32])[C:11]([F:10])([F:38])[F:39])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:36][CH3:37]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccccc1
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])(C)C)(C)(C)C.C([Li])CCC.CCCCCC.CN(C)[CH:30]=[O:31].[BH4-].[Na+]>O1CCCC1.CO>[F:16][C:10]1[C:11]([CH2:30][OH:31])=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1c(F)ccc(O)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl(2,4-difluorophenoxy)dimethylsilane (J. Med. Chem. 1993, 36, 3947, 1.50 g, 6.14 mmol) in tetrahydrofuran (30 mL) was added a 1.57 M solution of n-butyllithium in hexane (4.69 mL, 7.37 mmol) at −78° C. over 10 minutes, and the mixture was stirred at −78° C. for 2 h. To the mixture, N,N-dimethylformamide (0.950 mL, 2.28 mmol) was added at −78° C. The mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature and stand at room temperature for 16 h. The mixture was diluted with methanol (20 mL), and to the mixture was added sodium borohydride (696 mg, 18.4 mmol) at 0° C. The mixture was stirred at room temperature for 1.5 h. The reaction was quenched by addition of aqueous ammonium chloride at 0° C. to be pH=7. The mixture was extracted with diethyl ether (200 mL) and the organic layer washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/ethyl acetate (2/1) to afford 410 mg (42%) of the title as a colorless oil: