Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([N:52]([CH2:57][CH2:58][CH3:59])[CH2:53][CH2:54][CH2:55][NH2:56])[CH2:50][CH3:51]>CN(C=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:56][CH2:55][CH2:54][CH2:53][N:52]([CH2:57][CH2:58][CH3:59])[CH2:49][CH2:50][CH3:51])=[O:21])=[CH:22][CH:23]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCCN(CCC)CCCN
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (190 mg) obtained in Example 2-2 was dissolved in DMF (3.0 ml) and added with DCC (189 mg), HOBt (124 mg), and the compound (96.9 mg) obtained in Example 22-3, followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by separating the solution into layers by the addition of 1 mol/l hydrochloric acid. The aqueous layer was made basic with a 1 mol/l sodium hydroxide aqueous solution. Then, the solution was subjected to extraction with chloroform. The extract was washed with saturated saline solution and the organic layer was then dried with anhydrous sodium sulfate. The solvent was distilled off. Subsequently, the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (84.8 mg) of the subject compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:28]2[CH2:27][CH2:26][NH:25][CH:24]([CH3:23])[CH2:29]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21

Procedure:
7-Fluoro-1-methylamino-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5 but starting from 3.2 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4 g of 2-methylpiperazine in 40 cm3 of pyridine. The crude product obtained is taken up in 30 cm3 of water and 7 cm3 of 2 N aqueous potassium hydroxide solution. A very small amount of insoluble matter is removed by filtration through diatomaceous silica. The filtrate is washed with twice 20 cm3 of diethyl ether and the product is then precipitated by adding 3.5 cm3 of 4 N methanesulphonic acid. The precipitate obtained is drained and washed with 3 times 20 cm3 of water and 3 times 20 cm3 of ethanol 2.2 g of 7-fluoro-1-methylamino-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a deep yellow solid melting at 343°-345° C., solvated by 3.7% of water.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH2:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[CH:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:27][Si:28]([CH3:37])([CH3:36])[C:29]#[C:30][C:31](OCC)=[O:32]>C1COCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([CH:8]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:31](=[O:32])[C:30]#[C:29][Si:28]([CH3:37])([CH3:36])[CH3:27])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#C[Si](C)(C)C
Reactant: Fc1cccc(F)c1Cc1ccc(Cl)nn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CC(=O)C(c1ccc(Cl)nn1)c1c(F)cccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 111 %

Procedure:
To a solution of 3-chloro-6-(2,6-difluorobenzyl)pyridazine (5.7 g, 23.7 mmol) in THF (300 mL) was added LHMDS (71.2 mL, 71.2 mmol, 1M solution in THF) via cannula at −78° C. After stirring for 0.5 hr at −78° C., ethyl 3-(trimethylsilyl)propynoate (6.66 mL, 35.5 mmol) was added. The reaction was allowed to warm from −78° C. to −10° C. over 3 hours. The reaction was known to be complete by LCMS analysis; and then quenched with aqueous NH4Cl, extracted with ethyl acetate. The organic layers were combined, washed with 0.5 N HCl, water, brine, dried over MgSO4, and condensed in vacuo to yield an oil. The crude material was purified via silica gel chromatography (EtOAc/Hex) to yield the title compound (9.6 g).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH:24]=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[CH3:28][C@H:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][NH:36][C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:28])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=CC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](NCC1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(F)cc2)CC1)c1ccccc1
Reaction time: 14 h

Procedure:
1-(1-(4-fluorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carbaldehyde (35 mg, 0.096 mmol) was dissolved in THF (2 mL) and (S)-α-methylbenzylamine (0.013 mL, 0.115 mmol) was added. The solution was stirred at rt for 10 h, at which time the THF was removed in vacuo and the residue dissolved in EtOH (5 mL), and sodium cyanoborohydride (13 mg, 0.192 mmol) and a catalytic drop of glacial acetic acid were added. Stirring was permitted for 14 h, at which time the solvent was removed in vacuo, the residue was taken up in EtOAc. The organic phase was washed with 10% aq. sodium carbonate, dried over magnesium sulfate, and concentrated. Purification was accomplished via silica gel flash chromatography (30 g silica gel, 5:95 7M methanolic ammonia:ethyl acetate.) The title compound was obtained as a yellow oil. (Yield: 21 mg, 0.045 mmol, 47%) 1H NMR (400 MHz, CDCl3) 7.62, 7.39-7.23, 7.14, 7.09-7.02, 6.86, 6.57, 5.45, 4.59, 4.06, 3.76-3.63, 2.74, 2.39-2.15, 1.76-1.52, 1.33, 0.98, 0.63
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: COC(=O)CCS
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 3.5 h

Procedure:
In methanol (10 ml) were dissolved (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (0.40 g), methyl 3-mercaptopropionate (1.42 ml) and 28% sodium methoxide-methanol (1.25 ml) and the solution was refluxed. After 2 and after 3.5 hours, (0.53 ml and 0.32 ml each of) methyl 3-mercaptopropionate were added, and after 2.5 minutes, 28% sodium methoxide-methanol (0.63 ml) was added. At 4.5 hours after the beginning of heating, the oil bath was removed and the reaction mixture was cooled, neutralized with 1N hydrochloric acid (9.6 ml) and extracted with dichloromethane (100 ml). The extract was washed with saturated aqueous sodium chloride solution (20 ml) and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane-ethyl acetate=1:3). The desired fraction was concentrated and the resulting crystals were collected and washed with isopropyl ether to give (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 43:0.22 g) as colorless needles. m.p. 176°-178° C.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][O:19][CH3:20])[C:12]=1[C:21](=[CH2:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O>[CH3:20][O:19][CH2:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][O:8][CH3:7])[C:12]=1[C:21]1([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:2][CH2:27]1
Reactant: C=C(C(=O)OCC)c1c(OCOC)cccc1OCOC
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(c2c(OCOC)cccc2OCOC)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of trimethylsulfoxonium iodide (1.805 g, 8.20 mmol) in dry dimethyl sulfoxide (20 mL) sodium hydride 60% dispersion in mineral oil (0.310 g, 7.75 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. A solution of ethyl 2-(2,6-bis{[(methyloxy)methyl]oxy}phenyl)-2-propenoate (Intermediate 81, 1.35 g) in dry dimethyl sulfoxide (10 mL) was slowly added and the reaction mixture was stirred for 1 hour at room temperature. The reaction was quenched with an aqueous saturated solution of ammonium chloride (10 ml), diluted with water (20 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was washed with water (50 ml), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 50 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents affording the title as a colourless oil (1.14 g).
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(O)O.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[N:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])=[CH:15][CH:16]=1
Reactant: Brc1ccncc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1cccc(-c2ccncc2)c1
Yield: 83.7 %

Procedure:
To a solution of 3-boronobenzoic acid (1.5 g, 9 mmol) and 4-bromopyridine (1.5 g, 9.9 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was stirred under reflux overnight. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.5 g 3-(pyridin-4-yl)benzoic acid. Yield: 83%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH2:17][O:18][CH3:19])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([OH:12])=O.CCN=C=NCCCN(C)C.Cl.Cl.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>CN(C)C=O.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:17][O:18][CH3:19])[NH:5][C:6]=1[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10]([N:33]1[CH2:38][CH2:37][CH:36]([C:39]2[CH:46]=[CH:45][C:42]([C:43]#[N:44])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1)=[O:12]
Reactant: COCc1nc(Cl)c(-c2cc(C(=O)O)ccc2C)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COCc1nc(Cl)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.7 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(4-chloro-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 27.5, 20 mg, 0.07 mmol) in N,N-dimethylformamide (3 mL). 4-Dimethylaminopyridine (17.4 mg, 0.14 mmol), EDC.HCl (27 mg, 0.14 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 15.5 mg, 0.07 mmol, 1.00 equiv) were added and the resulting solution was stirred for 12 h at room temperature. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (35% CH3CN up to 50% in 7 min, up to 100% in 3 min, down to 35% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield 15 mg (47%) of the title compound as a white solid. m/z (ES+) 449 (M+H)+.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25]([CH2:28]O)=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:23]=[N:24][C:25]([CH2:28][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:26][CH:27]=2)=[CH:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(CO)nc3)nc3ccccc3c2=O)cc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)c1ccc(-n2c(-c3ccc(CN4CCOCC4)nc3)nc3ccccc3c2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 984 %

Procedure:
3-(4-sec-butylphenyl)-2-(6-(hydroxymethyl)pyridin-3-yl)quinazolin-4(3H)-one (0.176 g, 0.46 mmol) was dissolved in CH2Cl2 (30 mL) under nitrogen and cooled to 0° C. Hünig's base (0.160 mL, 0.92 mmol) was added, followed by MsCl (0.042 mL, 0.55 mmol), and the mixture was stirred for 15 min at 0° C. Morpholine (0.400 mL) was added, the reaction was warmed to room temperature, and stirred for 2 hours, before concentration and purification by flash chromatography on silica gel, eluting with 100% ethyl acetate to 10% methanol/ethyl acetate, afforded the title compound (0.175 g, 984%). 1H-NMR (300 MHz, DMSO-6): δ8.48 (s, 1H), 8.22 (d, J=7.9 Hz, 1H), 7.90-7.95 (m, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.60-7.68 (m, 2H), 7.22-7.27 (m, 3H), 7.10-7.16 (m, 2H), 3.49-3.54 (m, 6H), 2.55-2.63 (m, 1H), 2.19-2.29 (m, 4H), 1.33-1.56 (m, 2H), 1.13 (d, J=6.8 Hz, 3H), 0.62 (t, J=7.2 Hz, 3H). MS (APCI) m/z: 455 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21]2)=[O:19])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH2:37][CH:38]3[CH2:40][CH2:39]3)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:24][CH2:25]2)=[O:19])[CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](CC(=O)O)Cc2ccc(Cl)cc2)CC1

Procedure:
A solution of tert-butyl (3S)-3-[(4-chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)-amino]phenyl}piperazinyl)-4-oxobutanoate (Step 5) (0.16 g, 0.27 mmol) in 10 mL of 50% TFA in CH2Cl2 mixture was stirred at RT for 2 h. The volatile solvent was removed in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo. (3S)-3-[(4-Chlorophenyl)-methyl]-4-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)-amino]phenyl}piperazinyl)-4-oxobutanoic acid was obtained as a light yellow solid (0.14 g) MS (ESI, pos. ion) m/z: 534.4 (M+1). Calc'd for C26H32ClN3O5S: 533.18. Anal. Calc'd for C26H32ClN3O5S.1.5H2O: C, 55.66; H, 6.29; N, 7.49; Cl, 6.32. Found: C, 55.51; H, 5.85; N, 7.35; Cl, 6.12.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([CH3:8])[N:6]2[C:9]3[N:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:5]2[C:4](=[O:21])[NH:3]1.[OH-].[Na+]>C(O)C>[CH3:1][C@H:2]1[C@@H:7]([CH3:8])[N:6]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:5]2[C:4](=[O:21])[NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2n1)[C@H](C)[C@H](C)NC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1NC(=O)c2cc3ccc(C(=O)O)nc3n2[C@@H]1C
Temperature: 50 °C
Yield: 94.8 %

Procedure:
To a suspension of ethyl cis-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylate (1.04 g, 3.62 mmol) in ethanol (30 mL) is added 1M aqueous NaOH (9.05 mL, 9.05 mmol). The reaction mixture is heated at 50° C. for 90 min and is cooled to room temperature. The ethanol is removed in vacuo and the aqueous mixture is acidified with 1N aqueous HCl. The resulting solid is collected by filtration and dried in vacuo to afford the title compound as a white solid (890 mg, 95%). LCMS: 260.65 (M+H+).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2Cl)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccccc2Cl)ccn1)NO
Reaction time: 22 h
Yield: 44 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (19 mg, 0.043 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 22 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a pale blue oil (8 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)(C)C)cn1
Yield: 76 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using tert-butylamine instead of 3-methoxypropylamine, to the title compound (89 mg, 76%) which was obtained as an off white solid. MS: m/e=366.3 [M+H]′.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][C:6]#[N:7].[CH3:11][C:12]([CH3:25])([CH2:19][C:20](OCC)=[O:21])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[Na]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([C:6]#[N:7])[C:20](=[O:21])[CH2:19][C:12]([CH3:25])([CH3:11])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][CH:10]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: CCOC(=O)CC(C)(C)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(C)(C)CC(=O)C(C#N)c1cccc(Cl)c1
Yield: 67.9 %

Procedure:
Starting with 75.0 g (0.495 mol) of 3-chlorobenzyl cyanide, 160.58 g (0.743 mol) of diethyl 3,3-dimethylglutarate, 14.80 g (0.643 mol) of sodium, and 260 ml of dry ethanol a total of 108.08 g (71% yield) of the desired product was obtained using the procedure described in Example I, Part A.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][CH:14]=O)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH2:1]([O:8][C:9]([N:11]([CH2:13][CH2:14][N:16]1[CH2:21][CH2:20][C:19](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:18][CH2:17]1)[CH3:12])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C=C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C=C1CCN(CCN(C)C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a stirred solution of 2-(N-benzyloxycarbonyl-N-methylamino)acetaldehyde (2.07 g, 10.0 mmol) and ethyl 4-piperidinylideneacetate (1.69 g, 10.0 mmol) in MeOH—AcOH (10:1, v/v, 22 ml) was added NaBH3CN (1.32 g, 20 mmol) and the stirring was continued overnight. The mixture was quenched by addition of sat. NaHCO3 (200 ml) and extracted with CHCl3 (3×150 ml). The combined extracts were dried over MgSO4 and evaporated. The residue was chromatographed on silica-gel with CHCl3—EtOH (40:1, v/v) to give ethyl 1-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]4-piperidinylideneacetate (1.71 g, 47%) as a colorless oil. 1H-NMR (CDCl3) δ1.25 (t, J=7.3 Hz, 3 H), 2.16 (m, 2 H), 2.57 (m, 4 H), 2.95 (m, 7 H), 3.44 (m, 2 H), 4.13 (q, J=7.3 Hz, 2 H), 5.12 (s, 2 H), 5.49-5.53 (m, 1 H), 7.35 (m, 5 H).
Reaction SMILES: I[CH2:2][I:3].N(OCCC(C)C)=O.NC1[N:21]=[C:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[F:38])[N:23]=2)[N:19]=[C:18]2[C:14]=1[N:15]([CH:40]([CH3:42])[CH3:41])[C:16](=[O:39])[NH:17]2>>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:24]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:30]2[C:22]([C:20]2[N:19]=[C:18]3[C:14]([N:15]([CH:40]([CH3:42])[CH3:41])[C:16](=[O:39])[NH:17]3)=[C:2]([I:3])[N:21]=2)=[N:23]1
Reactant: ICI
Reactant: CC(C)n1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Agent: CC(C)CCON=O
Product: CC(C)n1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a mixture of 2.59 ml (32.20 mmol) of diiodomethane and 2.78 ml (20.61 mmol) of isoamyl nitrite were added 539 mg (approx. 1.08 mmol) of the compound from example 115, and the reaction mixture was stirred at 85° C. overnight. The mixture was concentrated, and the residue was stirred with dichloromethane and filtered. The solids were washed with dichloromethane and dried under high vacuum. 330 mg of the title compound were obtained (92% purity; 53% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6][CH2:5]2.Cl.[NH2:14][OH:15].C([O-])(=O)C.[Na+]>C(O)C.O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[N:14][OH:15])[CH2:7][CH2:6][CH2:5]2
Reactant: NO
Reactant: Nc1ccc2c(c1)CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CCCC2=NO
Temperature: 25 °C
Yield: 83 %

Procedure:
6-Aminotetralone (1.98 g, 12.3 mmol), hydroxylamine hydrochloride (0.85 g, 12.3 mmol), sodium acetate (2.52 g, 30.7 mmol), and water (3.3 ml) were dissolved in ethanol (10 ml), and the mixture was heated to reflux 4 hours. After cooling to room temperature, the mixture was diluted with water (20 ml), and the resulting precipitate was filtered to obtain 6-Amino-3,4-dihydro-2H-naphthalen-1-one oxime as a light brown solid, 1.80 g. (83% yield) 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 7.48-7.53 (m, 1H), 6.36-6.40 (m, 1H), 6.27 (s, 1H), 5.20 (s, 2H), 2.44-2.53 (m, 4H), 1.60-1.69 (m, 2H); MS (m/e) 177 (M+1).