Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[OH:8][C:9]1C(=O)N(CC2C=CC(OC)=CC=2)CCC=1C(=O)CC.COS(OC)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:9][O:8][C:3]1[C:2](=[O:7])[NH:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1cccc[nH]1
Reactant: CCC(=O)C1=C(O)C(=O)N(Cc2ccc(OC)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc[nH]c1=O
Reaction time: 16 h

Procedure:
said pyridinone compound of Formula (6.0.0) by methylation with dimethylsulfate; wherein a reaction mixture is established with dimethylformamide (DMF) solvent in the presence of cesium carbonate, Cs2CO3, with gradual addition of said dimethylsulfate over a period of 30 minutes, while said reaction mixture temperature is kept at from 20° to 25° C.; and thereafter, said reaction mixture is maintained at said temperature and stirred for 16 hours; whereby there is produced a 3-methoxy-pyridinone compound N-protected by p-methoxybenzyl, of Formula (7.0.0):
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH2:16][CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH:20]=2)=[CH:11][C:10]=1[C:28]1[O:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:31][N:32]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[CH2:53]([S:55](Cl)(=[O:57])=[O:56])[CH3:54]>C(Cl)Cl>[CH2:53]([S:55]([N:18]1[CH2:19][CH:20]=[C:15]([C:12]2[CH:11]=[C:10]([C:28]3[O:29][C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[N:31][N:32]=3)[C:9]([NH2:8])=[N:14][CH:13]=2)[CH2:16][CH2:17]1)(=[O:57])=[O:56])[CH3:54]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1-c1nnc(-c2ccccc2)o1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccccc4)o3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
tert-Butyl 4-[6-(tert-butoxycarbonylamino)-5-(5-phenyl-1,3,4-oxadiazol-2-yl)-3-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (141.7 mg, 0.2727 mmol) was dissolved in DCM (2 mL) and treated with TFA (373.1 mg, 252.1 μL, 3.272 mmol) at ambient temperature. The reaction was allowed to stir at ambient temperature for 3 hours and then concentrated in vacuo. The resultant residue was redissolved in DCM and treated with triethylamine (55.19 mg, 76.02 μL, 0.5454 mmol) followed by ethanesulfonyl chloride (17.54 mg, 12.93 μL, 0.1364 mmol). The mixture was allowed to stir at ambient temperature for 16 hours and then concentrated in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as an off-white solid (47 mg, 42% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.25 (t, 3H), 2.67 (br s, 2H), 3.16 (br s, 2H), 3.47 (br s, 2H), 3.94 (br s, 2H), 6.25 (br s, 1H), 7.44 (s, 2H), 7.64-7.69 (m, 3H), 8.22-8.24 (m, 2H), 8.29 (s, 1H) and 8.39 (s, 1H) ppm; MS (ES+) 411.95.
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][N:18]=[C:13]2[CH:12]([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC(C1C=C(C(C)C)C(S([N:68]=[N+:69]=[N-:70])(=O)=O)=C(C(C)C)C=1)C.CC(O)=O>C1COCC1.CCOC(C)=O>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:41])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][N:18]=[C:13]2[C@@:12]([N:68]=[N+:69]=[N-:70])([CH3:42])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
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: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@@]1(N=[N+]=[N-])C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1cccc(C(F)(F)F)c1)C(=O)OCc1ccccc1)c2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
To a solution of the methyl diastereomers (12c) (1.02 g, 1.78 mmol) in 10 mL THF at −78° C., was added LiHMDS (1M in THF, 3.73 mL, 3.73 mmol). The red solution was stirred at −78° C. for 10 min, then a solution of trisyl azide (606 mg, 1.96 mmol) in 2 mL THF was added. The reaction was stirred at −78° C. for 1.5 h, then was quenched with the addition of AcOH (459 μL, 8.01 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with sat. NH4Cl and brine, dried (Na2SO4), and concentrated. The product was purified by flash chromatography (30 to 35% EtOAc/hexanes) to afford 784 mg (71%) of azide (12d). 1H NMR (300 MHz, CDCl3) δ9.26 (br s, 1H), 7.82 (br s, 1H), 7.51-7.25 (m, 13H), 7.10 (t, J=7.3, 1H), 5.23 (m, 3H), 4.91-4.77 (m, 2H), 2.90 (d, J=13.9, 1H), 2.43 (dd, J=13.6, 9.2, 1H), 1.87 (s, 3H); MS (ESI) 640.4 (M+Na+), 616.4 (M−H+).
Reaction SMILES: CN1CCNCC1.CO[CH:10](OC)[N:11]([CH3:13])C.NC(C)CO.[F-].[K+].[C:23]1([CH3:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.CN(C=O)C>[N:11]1[C:10]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:29][CH:13]=1
Reactant: Cc1ccccc1
Reactant: COC(OC)N(C)C
Agent: CC(N)CO
Agent: CN1CCNCC1
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCO
Product: c1ccc2ncccc2c1

Procedure:
N-methylpiperazine was first introduced into compound XXXXVIII which was converted to enaminoketoester L on treatment with N,N-dimethylformamide dimethyl acetal in toluene followed by the reaction with 2-amino-1-propanol in ethanol. Reaction of enaminoketoester L with potassium fluoride in DMF gave quinoline LI which was cyclized with strong base such as sodium hydride to give the ester LII. Alternatively, enaminoketoester L may be reacted with sodium hydride in dioxane to yield the ester LII which was hydrolyzed with sodium hydroxide to give Ofloxacin.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12]O.[CH2:14]([NH2:21])[CH2:15][S:16]S(O)(=O)=O>>[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12][S:16][CH2:15][CH2:14][NH2:21]
Reactant: NCCSS(=O)(=O)O
Reactant: Cc1nc[nH]c1CO
Agent: O=S(=O)(O)O
Product: Cc1nc[nH]c1CSCCN
Yield: 97.2 %

Procedure:
4.8 g of 4-methyl-5-hydroxymethylimidazole sulfate is reacted with 5.2 g of 2-aminoethanethiolsulfuric acid according to the procedure described in Example 1 (i), yielding 3.8 g of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole as an oily product (yield: 73.3%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:6]1)[CH3:4].[C:19]([C:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]>>[C:19]([C:22]1[CH:26]=[C:25]([C:27]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:6]2)[CH3:4])=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 18.2 %

Procedure:
(S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (217 mg, 0.416 mmol) was coupled with 3-acetyl-1H-pyrazole-5-carboxylic acid (128 mg, 0.832 mmol) using the method of Example 34(d). Crude product was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN in water) to yield 30 mg (18%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.62 (d, 3H), 2.55 (s, 3H), 3.74-3.83 (m, 1H), 3.90-3.99 (m, 1H), 4.58-4.69 (m, 1H), 6.61 (d, 1H), 7.29 (bs, 1H), 7.50 (d, 1H), 7.68 (d, 1H), 7.77 (dd, 1H), 8.09 (s, 1H), 11.1 (bs, 1H).
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[C:11]([NH:12][C:13]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[S:18][CH:19]=2)=O)=[C:10]([CH3:26])[C:9]([O:27][CH3:28])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>N1C=CC=CC=1.CCO>[CH:20]1([C:17]2[S:18][CH:19]=[C:15]([C:13]3[CH:4]=[C:3]([OH:5])[C:6]4[C:11](=[C:10]([CH3:26])[C:9]([O:27][CH3:28])=[CH:8][CH:7]=4)[N:12]=3)[N:16]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2csc(C3CCCCC3)n2)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc2c(O)cc(-c3csc(C4CCCCC4)n3)nc2c1C
Temperature: 150 °C
Yield: 253.9 %

Procedure:
Freshly grounded KOH (2 mmol, 112 mg) was added to a solution of 2-cyclohexyl-thiazole-4-carboxylic acid (6-acetyl-3-methoxy-2-methylphenyl)amide (118, 373 mg, 2 mmol) in pyridine (20 mL). The mixture was divided into several batches and each batch was individually heated by microwave irradiation at 150° C. for 30 min. Then, the different batches were combined and pyridine was evaporated. The residue was treated with aqueous citric acid to give a suspension, which was subsequently diluted with a small volume of EtOH, then partitioned between water and CH2Cl2. Organic layer was dried (Na2SO4), and evaporated. The residue was purified by column chromatography (gradient of CH2Cl2:MeOH, 1:0 to 93:7) to give 1.8 g (72.5%) of the title compound 119 as a white powder: m/z=355 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[C-:17]#[N:18].[Na+]>C(O)C.O>[F:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:17]#[N:18]
Reactant: Fc1cccc(Oc2ccccc2CCl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccccc1Oc1cccc(F)c1

Procedure:
1-(Chloromethyl)-2-(3-fluorophenoxy)benzene (26.5 g.) was dissolved in 300 ml of ethanol; a solution of sodium cyanide (7.8 g.) in 15 ml of water was added, and the resulting mixture was heated to reflux overnight. The ethanol was evaporated, the residue taken up in water, extracted with ether and the combined ether extracts were dried and concentrated to give the title compound. ##STR13##
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:12][CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[N:4]=[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH3:13]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: CCC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(=Nc1c(C)cc(C)cc1C)c1ccccc1
Temperature: 200 °C

Procedure:
2,4,6-Trimethylaniline (11.5 mL, 82 mmol, Aldrich) was mixed with propiophenone (10 mL, 74.5 mmol, Aldrich) and p-TsOH (1.4 g, 7.3 mmol, Aldrich). The resulting mixture was heated for 2 h at 200° C. under a slow stream of Ar to remove H2O which formed. After cooling to RT the reaction mixture was poured into hexanes (100 mL), filtered, the precipitate washed with additional hexanes (2×100 mL) followed by the evaporation of the filtrate. The residue was filtered through a 9×4.1 cm plug of silica gel in hexanes/ether 10/1 (300 mL collected). After evaporation of the solvent the unreacted starting materials were distilled off under vacuum (45–50° C./0.4 mm). The residue was crystallized from methanol. Product was isolated as large orange-yellow crystals, 4.8 g, (25.6%). 1H NMR (CDCl3) 8.00–7.94 (m, 2H); 7.51–7.45 (m, 3H); 6.89 (s, 2H); 2.50 (q, 2H; J=7.7 Hz); 2.31 (s, 3H); 2.04 (s, 6H); 0.98 (t, 3H; J=7.7 Hz).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7](=[N:20][CH:21]1[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C.C1(C)C=CC=CC=1>C1COCC1>[C:7](=[N:20][C:21]1([CH2:3][C:2]#[CH:1])[CH2:25][CH2:24][N:23]([CH3:26])[C:22]1=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: CN1CCC(N=C(c2ccccc2)c2ccccc2)C1=O
Agent: C#CCBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCN(C)C1=O
Temperature: -65 °C
Reaction time: 1 h

Procedure:
Potassium tert-butoxide 1.7M in THF (602.08 mL, 1023.5 mmol) was added dropwise over a period of 2.5 h to a stirred solution of 3-(benzhydrylidene-amino)-1-methyl-pyrrolidin-2-one (259 g, 930.48 mmol) (which may be prepared as described in Description 5) and 80% solution of propargyl bromide in toluene (124.37 mL, 1116.6 mmol) in 3A-molecular-sieve-dried reagent grade THF (1900 mL) at −65° C. under nitrogen, in a 5 L flask equipped with an overhead stirrer. After the addition was complete, the mixture was stirred at −65° C. for a further 1 h. The cooling bath was removed and a saturated solution of NaHCO3 (140 ml) was added over 1 minute (at −60° C.). After a further 5 mins more sat NaHCO3 solution (1.4 L) was added followed by Et2O (1.4 L). The mixture was stirred for 1 h then transferred to a separating funnel and water (1.4 L) was added to dissolve all solids. The layers were separated and the aqueous further extracted with Et2O (2×1 L). The combined organic extracts were re-washed with sat. brine (700 ml), diluted with water (700 ml). The organic layer was dried (MgSO4) and evaporated to a volume of approx. 500-600 ml whereupon crystallization started to occur. To this stirred mixture was then added iso-hexane (1.6 L). After standing for 15 mins the cream solid was filtered under suction and washed with iso-hexane (500 ml) and dried at 50° C. under vacuum for 5 h. This afforded 3-(benzhydrylidene-amino)-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D6) (274 g, 93%). This was pure by NMR but contains some additional water;
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=3[F:21])[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[N:37]=[C:36]([O:38][CH3:39])[C:35](B(O)O)=[CH:34][N:33]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:20][C:16]1[C:15]([F:21])=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:35]4[C:36]([O:38][CH3:39])=[N:37][C:32]([O:31][CH3:30])=[N:33][CH:34]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)cc1)N(c1cccc(Cl)c1F)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cccc(Cl)c2F)C3=O)c(OC)n1
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 4-[2-bromo-5-(3-chloro-2-fluoro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-benzonitrile (Intermediate I) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The reaction was performed at 75° C. for 2 h and the product was purified by flash chromatography. The title compound was obtained as a white solid. tR=5.27 min (HPLC 4); ESI-MS: tR=1.13 min, [M+H]+ 532/534 (LC-MS 1); 1H-NMR (d6-DMSO, 600 MHz): 8.31 (s, 1H), 7.82 (m, 2H), 7.47 (m, 2H), 7.39-7.46 (m, 2H), 7.18 (m, 1H), 6.51 (s, 1H), 6.40 (s, 1H), 3.95 (m, 1H), 3.94 (s, 3H), 3.90 (s, 3H), 1.31 (m, 3H), 0.43 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[CH:7]=O.[Br-].[CH2:12]([O:14][C:15]([CH:17]=[C:18]([CH3:44])[CH:19]=[CH:20][CH:21]=[C:22]([CH3:43])[CH2:23][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:16])[CH3:13].CN(C)C=O.[Na]>C(O)C>[CH2:12]([O:14][C:15](=[O:16])[CH:17]=[C:18]([CH3:44])[CH:19]=[CH:20][CH:21]=[C:22]([CH3:43])[CH:23]=[CH:7][C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[CH3:1])[CH3:13]
Reactant: Cc1sc(C)c(C=O)c1C
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)sc(C)c1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.9 G. of 2,4,5-trimethyl-3-thiophenecarboxaldehyde and 6.75 g. of (7-ethoxycarbonyl-2,6-dimethyl-2,4,6-heptatrienyl)triphenyl phosphonium bromide are dissolved in 50 ml. of dry dimethylformamide. The solution is treated at 10° C. dropwise with a solution of 0.29 g. of sodium in 8 ml. of ethanol. The mixture is subsequently stirred for 4 hours at room temperature, then introduced into 100 ml. of methanol/water 60:40 parts by volume and thoroughly extracted with hexane. The hexane extract is washed with methanol/water (60:40 parts by volume, then with water, dried over sodium sulfate and evaporated. There is obtained 3,7-dimethyl-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester, which melts after recrystallization from hexane at 88°-89° C.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([C:9]#[N:10])[C:7]([NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>O1CCOCC1>[C:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=1[N:12]=[CH:15][N:16]([CH3:18])[CH3:17])#[N:10]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)C=Nc1ccc([N+](=O)[O-])cc1C#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 5-nitroanthranilonitrile (1.00 g, 6.13 mmol) in dioxane (25 mL) was added dimethylformamide dimethyl acetal (0.88 g, 7.36 mmol). Th reaction mixture was stirred at 100° C. for 2 h and then cooled to room temperature and refrigerated. The precipitate was filtered out, washed with cold ether several time, and then dried in vacuo to give 1.30 g (97%) of N′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][C:14]([CH3:16])=[CH2:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].O1CCCC1>[C].[Pd].CO>[OH:12][C:11]1[CH:2]=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][C:10]=1[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: C=C(C)Cc1cc(C(=O)OC)cc(Br)c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(O)c(CC(C)C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.2 %

Procedure:
Methyl 3-bromo-4-hydroxy-5-(2-methylprop-2-en-1-yl)benzoate (5.0 g, 24.2 mmol) and 10% palladium-carbon (50% water-containing product, 1.5 g) were added to a mixed solvent of tetrahydrofuran (70 mL) and methanol (70 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hr. The catalyst was filtered off, and the filtrate was concentrated to give the title compound (4.8 g, yield 95%) as colorless needle crystals.
Reaction SMILES: Br[C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7](=[O:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[CH3:15][N:16]([CH2:21][C:22]1[O:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[C:26]=1[CH3:27])[C:17](=[O:20])[CH:18]=[CH2:19].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:11][CH:10]1[CH2:9][CH2:8][C:7](=[O:12])[NH:6][C:5]2[N:13]=[CH:14][C:2](/[CH:19]=[CH:18]/[C:17]([N:16]([CH3:15])[CH2:21][C:22]3[O:23][C:24]4[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=4[C:26]=3[CH3:27])=[O:20])=[CH:3][C:4]1=2
Reactant: O=C1CCC(O)c2cc(Br)cnc2N1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)C(O)CCC(=O)N3)oc2ccccc12
Temperature: 130 °C
Yield: 72.5 %

Procedure:
A suspension of 3-bromo-5-hydroxy-6,7-dihydro-5H-pyrido[2,3-b]azepin-8(9H)-one (40 mg, 0.16 mmol), N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (71 mg, 0.31 mmol) and (i-Pr)2EtN (0.14 mL, 0.78 mmol) in 3 mL of DMF) was de-oxygenated with Ar for 30 min in a microwave reaction vial. The mixture was treated with Pd(OAc)2 (4.0 mg, 0.02 mmol) and P(o-tol)3 (9.0 mg, 0.04 mmol) then heated to 130° C. for 5 min in the microwave. The hot mixture was filtered through a pad of celite and washed liberally with ethyl acetate. The filtrate was diluted with 20 mL H2O then extracted with 2×20 mL ethyl acetate. The resulting crude product was subjected to prep HPLC purification to yield 47 mg of product (75% pure). A second prep HPLC purification was performed to obtain pure product as a fluffy white powder. Yield 5.1 mg (8%); 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.09 (s, 1H), 7.56 (d, J=7.4 Hz, 1H), 7.47 (m, 2H), 7.35-7.21 (m, 3H), 7.14 (d, J=15.2 Hz, 1H), 5.60 (s, 1H), 4.77 (s, 2H), 3.17 (s, 3H), 2.65 (s, 3H), 2.26 (m, 4H); ESI MS m/z 406 [C23H23N3O4+H]+
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:12]I>C(OCC)(=O)C>[CH3:12][N:5]1[CH2:6][CH:7]=[C:2]([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:4]1
Reactant: CI
Reactant: CCOC(=O)c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CCN(C)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of ethyl isonicotinate (151 g) in ethyl acetate (1000 mL) was added methyl iodide (126 mL), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was cooled, and an orange precipitate was collected by filtration. The precipitate was suspended in ethanol (1000 mL), sodium borohydride (37.8 g) was added with cooling at −40° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and ethanol was evaporated under reduced pressure. The residue was extracted with ethyl acetate-THF, the organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure to give ethyl 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate (85.8 g, 51%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#N)=[CH:14][N:13]=2)[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C.[OH:29]S(O)(=O)=O.C([O-])(O)=O.[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([CH:16]=[O:29])=[CH:18][CH:19]=2)[CH2:4][CH2:3]1
Reactant: O=S(=O)(O)O
Reactant: CN1CCC(CCCOc2ccc(C#N)cn2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1CCC(CCCOc2ccc(C=O)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a 0° C. solution of 6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (640 mg, 2.47 mmol) in toluene (20 mL) was added 1.0 M DIBAL-H in hexanes (3.70 mL, 3.70 mmol) dropwise. The mixture was warmed to rt and stirred for 2 h (complete by TLC). Methanol was added (5 mL) followed by 1.0 M H2SO4 (±0 mL). After stirring for 30 min the solution was neutralized with satd. aq. NaHCO3, diluted with satd. aq. sodium potassium tartrate (10 mL), and stirred an additional 30 min. The reaction was extracted with CHCl3 (3×50 mL) and the combined extracts were dried (Na2SO4), filtered, and concentrated, yielding the crude product, which was purified by Method 1 to afford 598 mg (92%) of a colorless oil. MS (ESI): mass calcd for C15H22N2O2, 262.17; m/z found, 263.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.87 (br s, 1H), 8.53 (d, J=2.3, 1H), 7.98 (dd, J=8.6, 2.3, 1H), 6.74 (d, J=8.6, 1H), 4.34 (t, J=6.6, 2H), 2.78-2.26 (m, 2H), 2.19 (s, 3H), 1.85-1.62 (m, 7H), 1.35-1.16 (m, 4H).