Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[NH:17][C:18]([CH:20]([C:22]3[N:23]([CH3:34])[C:24]4[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH3:21])=[N:19][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42].C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>C(Cl)CCl.CN(C=O)C>[CH3:44][O:43][C:41]([C:40]1[CH:45]=[CH:46][CH:47]=[CH:48][C:39]=1[O:38][CH2:37][CH2:36][NH:35][C:31]([C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([CH:20]([C:18]3[NH:17][C:14]4[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[O:10])[CH2:12][C:13]=4[N:19]=3)[CH3:21])[N:23]([CH3:34])[C:24]=2[CH:30]=1)=[O:32])=[O:42]
Reactant: COC(=O)c1ccccc1OCCN
Reactant: CC(c1nc2c([nH]1)CCN(C(=O)OCc1ccccc1)C2)c1nc2ccc(C(=O)O)cc2n1C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1OCCNC(=O)c1ccc2nc(C(C)c3nc4c([nH]3)CCN(C(=O)OCc3ccccc3)C4)n(C)c2c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
A mixture comprising 2-[1-(5-benzyloxycarbonyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)ethyl]-3-methyl-3H-benzoimidazole-5-carboxylic acid (0.75 g, 1.6 mmol), DMF (6.5 mL), methyl 2-(2-aminoethoxy)benzoate (0.38 g, 1.6 mmol) and HOBT (0.22 g, 1.6 mmol) was cooled under nitrogen to −40° C., treated with EDC (0.32 g, 1.6 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.6 mmol) and 15 minutes later with additional N,N-diisopropylethylamine (0.29 mL), allowed to warm to 20° C. and stirred for 16 hours. The mixture then was cooled to −40° C., treated with additional EDC (0.080 g) and N,N-diisopropylethylamine (0.050 mL), stirred for 15 minutes at −40° C. and 2 hours at 20° C. and concentrated by shortpath distillation. The residue was partitioned between chloroform and sodium bicarbonate and the organic layer was washed with sodium chloride, 0.5M potassium sulfate and sodium chloride, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl3/MeOH/AcOH: 95/5/1) to provide benzyl 2-(1-{6-[2-(2-methoxycarbonylphenoxy)ethylcarbamoyl]-1-methyl-1H-benzoimidazol-2-yl}ethyl)-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylate (0.69 g, 66%) as a glassy brown foam; 1H-NMR (300 MHz, DMSO-d6) d ppm: 11.92 (s, 1H), 8.49 (t, 1H, J=5.0 Hz), 8.02 (s, 1H), 7.69 (d, 1H, J=9.9 Hz), 7.60 (m, 2H), 7.50 (t, 1H, J=8.3 Hz), 7.30 (m, 5H), 7.19 (d, 1H, J=9.9 Hz), 6.99 (t, 1H, J=8.3 Hz), 5.04 (s, 2H), 4.61 (q, 1H, J=8.8 Hz), 4.30 (br s, 2H), 4.20 (t, 2H, J=5.0 Hz), 3.74 (s, 3H), 3.68 (s, 3H), 3.63 (m, 4H), 2.55 (br s, 2H), 1.67 (d, 3H, J=8.8 Hz).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]([NH:15][C@@H:16]([CH2:20][NH:21][C:22]([C:24]3[S:25][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]4[NH:34][CH2:35][CH2:36][CH2:37][N:38]=4)=[CH:27][CH:28]=3)=[O:23])[C:17]([OH:19])=[O:18])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(Cl)(Cl)=O>C(O)C(C)C>[CH2:2]([O:18][C:17](=[O:19])[C@@H:16]([NH:15][C:13]([O:12][CH2:11][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:14])[CH2:20][NH:21][C:22]([C:24]1[S:25][C:26]([CH2:29][CH2:30][C:31](=[O:39])[NH:32][C:33]2[NH:34][CH2:35][CH2:36][CH2:37][N:38]=2)=[CH:27][CH:28]=1)=[O:23])[CH:1]([CH3:10])[CH3:8]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCC23CC4CC(CC(C4)C2)C3)C(=O)O)s1)NC1=NCCCN1
Solvent: O=S(Cl)Cl
Solvent: CC(C)CO
Product: CC(C)COC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)s1)NC(=O)OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 139.2 %

Procedure:
0.38 g (0.7 mmol) of (2S)-2-(1-adamantylmethoxycarbonylamino)-3-((5-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-thiophene-2-carbonyl)-amino)-propionic acid (example 15) were dissolved in 7 ml of isobutanol. Under an inert gas atmosphere and under external ice cooling 0.19 ml of thionyl chloride were cautiously added. After stirring for 8 hours at room temperature the reaction was complete. The solvents were removed in vacuo to give a colourless foam which was purified by chromatography (silica gel; isopropanol/ethyl acetate/water (4/3/1; v/v/v)). The fractions containing the title compound were lyophilized to give 0.30 g of a colourless solid.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:20][C:19]2[CH:18]=[C:17]([O:21][CH3:22])[CH:16]=[CH:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH:6]=1)[CH3:2].[Li].N.CC(O)C>O1CCCC1>[CH2:1]([C@@H:3]1[CH2:20][C:19]2[CH2:18][C:17]([O:21][CH3:22])=[CH:16][CH2:15][C:14]=2[C@@H:13]2[C@@H:4]1[C:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH:6]=1)[CH3:2]
Reactant: CC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC[C@@H]1CC2=C(CC=C(OC)C2)[C@H]2CC[C@@]3(C)C(=CC[C@@H]3O)[C@H]12
Temperature: -35 °C
Reaction time: 4.5 h

Procedure:
x)—The alcohol obtained in the previous step (1.5 g) in dry tetrahydrofuran (24 ml) was added to a refluxing solution of lithium (2.12 g) in liquid ammonia (98 ml). After 4.5 h stirring at −35° C., 2-propanol was added in 30 min. and the ammonia was allowed to evaporate. Water was added and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure, to give (7α,17β)-7-ethyl-3-methoxyestra-2,5(10),14-trien-17-ol (1.65 g). The product was used in the following step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:13]([CH3:15])=[CH2:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2]>C(O)C.[Pd]>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:2]
Reactant: C=C(C)c1cccc2ccc(C#N)cc12
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cccc2ccc(C#N)cc12
Reaction time: 1 h
Yield: 86.1 %

Procedure:
2-Cyano-8-isopropenylnaphthalene (0.23 g) and 10% palladium/carbon (containing 50% of water) (50 mg) were suspended in 20 ml of ethanol and the resulting suspension was subjected to catalytic hydrogenation at ordinary temperature under normal pressure for one hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give a crude product. This crude product was purified by silica gel column chromatography to give 0.20 g of the title compound as an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=O)[N:9]=[CH:8]2)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[Cl:18])(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc2[nH]c(=O)ncc2c1
Product: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Temperature: 105 °C
Yield: 74 %

Procedure:
In a 100 mL flask equipped with a reflux condenser, 6-acetoxyquinazolone 3.06 g (15 mmol), phosphoryl chloride (35 mL) were added. The mixture was refluxed at 105° C. for 2 h, and then was taken out and poured into 150 mL of ice water carefully. A large amount of solid was deposited slowly, which was filtered, dried, and identified as the title compound. Yield: 74%.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][C:8]1([CH3:49])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([CH2:24][CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[O:23])[C:11](=[O:34])[N:10]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[C:37]([C:44]([F:47])([F:46])[F:45])[CH:36]=2)[C:9]1=[O:48].O>C1COCC1>[CH3:7][C:8]1([CH3:49])[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([CH2:24][CH2:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])(=[O:1])=[O:23])[C:11](=[O:34])[N:10]([C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[C:37]([C:44]([F:46])([F:47])[F:45])[CH:36]=2)[C:9]1=[O:48]
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)(=O)CCCC(F)(F)C(F)(F)F
Temperature: 23 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Oxone® (566 mg, 0.93 mmole) is added to a solution of the compound of Example 2 (200 mg, 0.31 mmole) in THF (6 ml). The reaction mixture is completed with water (3 ml) and stirred at 23° C. for 3 h 30, the time necessary for the total conversion of the starting product. The mixture is then poured into water (25 ml) and extracted with AcOEt (2×25 ml). After decantation, the organic phases are combined and washed with salt water (20 ml), dried over Na2SO4, filtered and concentrated to dryness under vacuum. The evaporation residue is purified on a silica column (eluent: Heptane/AcOEt: 1/1 to 3/7). The expected compound is obtained in the form of a colourless oil with a yield of 89% (185 mg).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[C:12]2[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>C1C=CC=CC=1>[CH3:1][O:2][N:3]=[C:4]([C:8]1[C:12]2[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]=1)[C:5]([Cl:21])=[O:6]
Reactant: CON=C(C(=O)O)c1csc2cccc(Cl)c12
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CON=C(C(=O)Cl)c1csc2cccc(Cl)c12

Procedure:
α-Methoxyimino-α-(4-chloro-3-benzothienyl)acetic acid was reacted with oxalyl chloride and N,N-dimethylformamide in benzene to give α-methoxyimino-α-(4-chloro-3-benzothienyl)acetyl chloride. A solution of 1.47 g (5.45 mM) of the acid chloride in 30 ml of acetone was added dropwise over ten minutes to a cold (5° C.) stirred solution of 1.22 g (5.7 mM) of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 30 ml of water and 30 ml of acetone containing 1.37 g (16.35 mM) of sodium bicarbonate. The reaction mixture was stirred at 0°-5° C. for thirty minutes following the addition, and then was warmed to 20° C. and stirred for an additional two hours. The reaction mixture was concentrated to a volume of about 30 ml, diluted with 20 ml of water, and washed several times with ethyl acetate. The aqueous mixture was layered with 50 ml of fresh ethyl acetate and acidified to pH 2.5 by addition of 1N hydrochloric acid. The organic layer was separated, washed with fresh water and with brine, dried and the solvent was removed by evaporation to give 2.1 g (83% yield) of 7-[α-methoxyimino-α-(4-chloro-3-benzothienyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. NMR (DMSOd6): δ 2.03 (s, 3H); δ 3.51 (broad s, 2H); δ 3.98 and 4.10 (two singlets, 3H); δ 5.11 (d, 1H); δ 5.68 (dd, 1H); δ 7.3-8.1 (m, 4H); δ 8.78 and 8.95 (two d, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([N:8]=[C:9]=[S:10])[CH:5]=[CH:6][CH:7]=1.Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([N:8]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:9]2=[S:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1N=C=S
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1N1C(=O)CN(C)C1=S
Yield: 83.3 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 13.2 g of 3-chloro-2-methylphenyl-isothiocyanate, 11.0 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from diethyl ether afforded the title compound (15.2 g) as a tan solid, m.p. 122°-124° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.96; H, 4.21; N, 11.05. Mass spectrum (EI, M.+) m/z 254/256.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1>CN(C=O)C>[CH3:20][S:19][C:15]1[N:16]=[C:17]([N:2]2[CH:3]=[C:4]3[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]3)=[N:1]2)[CH:18]=[CH:13][N:14]=1
Reactant: CSc1nccc(Cl)n1
Reactant: c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2cc3ccccc3n2)n1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 77.8 %

Procedure:
A solution of 1H-indazole (2.36 g, 20.0 mmol) in anhydrous DMF (100 mL) was treated with NaH (60% dispersion in mineral oil, 1.60 g, 40.0 mmol) at RT for 10 min. 4-Chloro-2-methylthiopyrimidine (2.55 ml, 22.0 mmol) was then added in one portion at RT, and the resulting mixture stirred at 70° C. for 2.5 h. The reaction mixture was cooled to RT, quenched with aqueous HCl (1 M), and extracted with EtOAc. The layers were separated, the organic layer washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was absorbed onto silica gel and purified by flash chromatography (ethyl acetate/hexane, gradient from 5:95 to 25:75) to afford a mixture of 1-(2-methyl-sulfanyl-pyrimidin-4-yl)-H-indazole and 2-(2-methylsulfanyl-pyrimidin-4-yl)-2H-indazole (3.77 g, 78% yield) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10]S(C(C)(C)C)=O)[CH3:9])=[N:6][CH:7]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1
Reactant: C[C@@H](NS(=O)C(C)(C)C)c1ccc(F)cn1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)c1ccc(F)cn1
Reaction time: 0.5 h

Procedure:
To a solution of N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-2-methylpropane-2-sulfinamide (34.3 g, 140 mmol) in methyl alcohol (700 mL) at 0 was added hydrogen chloride (4.0 M in dioxane; 105 mL, 421 mmol). After 30 min, the mixture was concentrated to dryness. The residue was recrytalized using ethyl alcohol (15 mL) and ether (40 mL). The white solid was filtered and dried under reduced pressure to give the hydrochloride salt of the title compound. MS 141.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[NH2:21][CH2:22][C:23]([NH2:26])([CH3:25])[CH3:24].CO.C(Cl)(Cl)Cl>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:21][CH2:22][C:23]([CH3:25])([NH2:26])[CH3:24])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: CC(C)(N)CN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCC(C)(C)N)c1C
Reaction time: 24 h
Yield: 57.6 %

Procedure:
A stirred solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (4.42 g, 20.0 mmol) in 50 mL of anhydrous DMF, under N2, was treated with triethylamine (5.58 mL, 40.0 mol) and 1,2-diamino-2-methylpropane (2.10 mL, 20.0 mmol). After stirring for 24 h, the reaction mixture was concentrated under reduced pressure. The resulting oil was treated with CH2Cl2 (200 mL) and H2O (100 mL). The aqueous layer was made basic (pH˜12) by addition of concentrated NH4OH solution. The layers were separated and the aqueous portion was extracted with an additional 100 mL of CH2Cl2. The combined organic portions were washed with H2O (2×) and brine. The organic portion was dried with Na2SO4 and concentrated to give an orange oil that solidified on standing. Column chromatography (SiO2, 2% MeOH/CHCl3) gave N1-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-2-methylpropane-1,2-diamine (3.14 g) as a yellow solid.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:35][CH2:34]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccccc1N1CCNCC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate(0.29 g, 1.0 mmol) and 1-(2-methoxyphenyl)piperazine(0.19 g, 1.0 mmol) were dissolved in tetrahydrofuran(10 ml) and DBU(0.15 g, 1.0 mol) was added thereto and the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was concentrated and chromatographed to obtain 0.33 g of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6]([CH2:14][C:15]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:16][C:17](OCC)=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:31][NH2:32]>O>[CH3:1][N:2]1[CH2:30][CH2:29][C:5]2[N:6](/[CH:14]=[C:15](/[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)\[CH2:16][C:17]([NH:32][CH3:31])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)C=C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Reactant: CN
Solvent: O
Product: CNC(=O)C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
Ethyl 4-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-(4-fluorophenyl)but-2-enoate (50 mg, 0.123 mmol; prepared according to General Method 5) in 40% aqueous methyl amine (1 mL) was heated overnight at 100° C. The reaction mixture was cooled to RT and diluted with water (5 mL). A white solid precipitated out which was filtered and dried under vacuum. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.60 (m, 2H), 7.30 (d, 1H), 7.20 (m, 3H), 7.10 (m, 1H), 7.0 (d, 1H), 4.70 (m, 1H), 4.35 (m, 1H), 3.80 (m, 2H), 3.60 (m, 2H), 3.30 (m, 3H), 3.15 (s, 3H), 2.55 (s, 3H), 2.40 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC=CC=1.[Li]CCCC.[C:32](=[O:34])=[O:33]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[C:5]([C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1)[C:32]([OH:34])=[O:33]
Reactant: O=C=O
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)c(C(=O)O)c1NC(=O)C(C)(C)C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
N-(2-methoxy-5-(trifluoromethyl)phenyl) pivalamide (1 eq) was azeotrope with toluene (x=3). Dissolved in THF, cooled to −50° C. and added n-BuLi (2 eq, 2.5M solution in hexane) dropwise. The reaction mixture was stirred at −50° C. for 1 h then warmed to −10° C. in 30 min. Stirred at this temperature for 30 min then CO2 gas was passed through cylinder into the reaction mixture at −10 to 0° C. for 1 h. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was poured to water and extracted with ethyl acetate. (EtOAc extracts contained starting material). The aq layer pH was adjusted to 1-2 and product was extracted with ethyl acetate (x=3). The ethyl acetate extracts were combined, washed with brine and dried over sodium sulfate.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[CH:5][CH:4]=[C:3]1[C:12]([O:14]CC)=[O:13].[OH-].[Na+]>CO>[O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[CH:5][CH:4]=[C:3]1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2ccccn2c1=O
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a suspension of ethyl 4-oxo-4H-quinolizine-3-carboxylate (1) (100 mg, 0.46 mmol) in 4 ml methanol was added 300 μl NaOH (3 M). The reaction mixture was stirred overnight, followed by evaporation of the solvent in vacuo. The remaining solid was dissolved in 4 ml water and the clear solution was acidified to pH 1, with 1 M HCl. The resulting suspension was filtered, and the residue was dried in vacuo over P2O5 to give yellow plates of 4-oxo-4H-quinolizine-3-carboxylic acid (1a) (63 mg, 72%). M.p. 235-240° C. 1H NMR (δ, DMSO-d6): 7.26 (d, J=8 Hz, 1H), 7.64 (dd, J=7 Hz, J=7 Hz, 1H), 8.03 (dd, J=7 Hz, J=7 Hz, 1H), 8.14 (d, J=9 Hz, 1H), 8.39 (d, J=9 Hz, 1H), 9.27 (d, J=7 Hz), 14.13 (s, 1H). MS: m/z 189.0433; required for C12H11NO3: 189.0428.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14]P([O-])(O)=O.[K+].[O-]Cl=O.[Na+].[OH-].[Na+]>C1COCC1.CC(O)(C)C.O>[C:1]1([C:7]2[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(-c2ccccc2)s1
Reactant: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 120 h
Yield: 51 %

Procedure:
The product of Step 1a (750 mg, 4 mmol) is dissolved in a mixture of THF, t-BuOH, and water (2:1:1, 60 mL). KH2PO4 (1.36 g, 10 mmol) is added followed by NaClO2 (900 mg, 10 mmol). The mixture is stirred at room temperature for 5 days. Aqueous NaOH (2M, 10 mL) is added, and a majority of the organic solvents are removed in vacuo yielding an aqueous suspension. This suspension is diluted with water and washed three times with CH2Cl2. The aqueous layer is acidified to pH<6 with 25% H2SO4 and the product is extracted three times with CH2Cl2. The combined organic washes are dried over Na2SO4, filtered and concentrated in vacuo to yield the desired product (417 mg, 51%). MS for C11H8O2S (ESI) (M−H)− m/z 203.
Reaction SMILES: C([O:8][C:9]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:10]=1[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C.CCCCCC>ClCCl>[Br:29][C:26]1[CH:27]=[CH:28][C:9]([OH:8])=[C:10]([CH:25]=1)[CH2:11][N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=1)[CH2:13][CH3:14]
Reactant: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(=O)OC)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.1 %

Procedure:
A solution of methyl 2-(N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]-5-pyridylcarboxylate (10.0 g, 22 mM) in dichloromethane (150 ml) was treated with boron trichloride dimethyl sulfide complex (40 ml, 2M, 80 mM). The reaction was stirred at ambient temperature for 48 hours. Saturated sodium bicarbonate solution was added and the layers were separated. The aqueous layer was washed with dichloromethane. The organic layers were combined, dried (MgSO4) and evaporated to give an off-white solid. The off-white solid was subjected to chromatography (diluted with ethyl acetate/hexane) to give the title product methyl 2-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]-pyridine-5-carboxylate (6.02 g, 75%).
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].Cl.NO.N1C=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50 mL round bottom flask was charged with 1 (680 mg, 2.5 mmol), hydroxylamine HCl (191 mg, 2.75 mmol), pyridine (0.25 mL, 3.0 mmol) and ethanol (10 mL). The resulting reaction mixture was stirred at rt overnight. The crude product was concentrated, absorbed onto silica gel, and purified by flash chromatography (97:3 CH2Cl2/MeOH to give 2 as an orange solid. LCMS m/z 289.2 (MH+), tR=2.06 min.