Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:44]([O:51][C:52]1[CH:59]=[CH:58][C:55]([CH:56]=[O:57])=[C:54]([CH3:60])[CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:56]([C:55]1[CH:58]=[CH:59][C:52]([O:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:53][C:54]=1[CH3:60])[OH:57])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1C
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 97 %

Procedure:
(S)-4-Benzyl-3-ethoxyacetyl-oxazolidin-2-one (12.45 g, 47 mmol) (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was dissolved in dry dichloromethane (270 ml) under an argon atmosphere and the solution was cooled to −78° C. Triethylamine (7.98 ml, 57 mmol) was added, followed by the slow addition, over approximately 20 min, of di-n-butylboron triflate (1 M solution in dichloromethane, 50 ml, 50 mmol) such that the reaction temperature was kept below −70° C. The mixture was stirred at −78° C. for 50 min, the cooling bath was replaced with an ice bath and the mixture stirred at 0° C. for additional 50 min before being recooled to −78° C. A solution of 4-benzyloxy-2-methyl-benzaldehyde (10.7 g, 47 mmol) in dry dichloromethane (130 ml) was added over ca. 45 min, such that the reaction temperature was maintained below −70° C. The resulting mixture was stirred at −78° C. for 45 min, warmed from −78° C. to 0° C. and stirred at 0° C. for a further 1.5 h. The reaction mixture was poured onto ice water/brine and extracted two times with dichloromethane. The combined extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, cyclohexane/AcOEt) to give 22.3 g (45.6 mmol, 96%) of the title compound as colorless oil. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: [O:1]1CCCC1.S(=O)(=O)(O)O.[OH:11][C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[C:13]#[CH:14]>O>[OH:11][C:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH:15]([CH3:17])[CH3:16])[C:13](=[O:1])[CH3:14]
Reactant: C1CCOC1
Reactant: C#CC(O)(c1ccccc1)C(C)C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)C(O)(c1ccccc1)C(C)C
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a refluxing mixture of tetrahydrofuran (70 ml), water (5 ml), and conc. sulfuric acid (1.5 g) is added 1 g of red mercuric oxide and the reflux is continued for 5 min. Then, the inside temperature is adjusted to 60°-62° C. and 10 g of 3-hydroxy-4-methyl-3-phenyl-1-pentyne (described in Example 1) is added. The reaction is exothermic (spontaneous mild reflux) and there is a noticeable clearing of the mixture. Another 1 g of mercuric oxide is added, and the solution is refluxed for 30 min. The reaction mixture is stirred at 60° C. for an additional 3 hr, during which time the precipitation of a mercury sludge occurred. After cooling, the slurry is diluted with 100 ml of diethyl ether and filtered through diatomaceous earth. The filter cake is washed with 200 ml of diethyl ether, and the combined filtrates are washed repeatedly with water, dried over magneisum sulfate, filtered, and evaporated to give 10.6 g of the title product, ir (CDCl3) 3470 and 1715-1710 cm-1 and nmr (CDCl3) δ 0.91(d), 2.15(s), 2.79(heptuplet), 4.39(s) and 7.20-7.65(m).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8](O)=[O:9])(=[O:4])=[O:3].CN(C=O)C.O=S(Cl)[Cl:25]>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([Cl:25])=[O:9])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cc(C(=O)Cl)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (70 mg, 0.26 mmol) in toluene (5 mL) were added catalytic amount of DMF and SOCl2 (0.2 mL, 2.61 mmol) and the reaction mixture was heated to reflux for 6 hours. The solvent was evaporated and the resulting 3-methanesulfonyl-5-trifluoromethyl-benzoyl chloride (70 mg, crude) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:12][CH:11]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1ccc(F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 4-fluorophenol and N-(3-{1-[5-(4-fluorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 7.62–6.70 (m, 12H), 5.10–5.00 (m, 1H) 3.71–3.56 (m, br, 2H), 3.04–2.82 (br, 2H), 2.78–2.64 (m, br, 3H), 2.64–2.48 (m, br, 3H), 2.05–1.82 (m, br, 6H), 1.62–1.42 (m, br, 2H), 1.25 (d, 6H, J=6.0 Hz); ESMS m/e: 521.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:37])[C:20]([C:22]1[N:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27](Cl)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]>>[CH3:18][N:19]([CH3:37])[C:20]([C:22]1[N:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:25]2[N:26]=[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]4)=[CH:6][N:7]=3)[N:28]=[CH:29][C:24]=2[CH:23]=1)=[O:21]
Reactant: N#CCCN1CCN(c2ccc(N)nc2)CC1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCC#N)CC4)cn3)nc2n1C1CCCC1
Yield: 10.2 %

Procedure:
Following Buchwald Procedure A, 3-[4-(6-amino-pyridin-3-yl)-piperazin-1-yl]-propionitrile (173 mg, 0.751 mmol) and 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.683 mmol) gave 2-{5-[4-(2-cyano-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (34 mg, 10%) [following purification by preparative LCMS]. MS (ESI) m/z 488.2 (M+H)+ (method B).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][C:4]([NH2:8])=[C:3]([OH:9])[CH:2]=1.Cl.Cl.[C:12]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C:20]2[O:9][C:3]3[CH:2]=[CH:1][C:6]([NH2:7])=[CH:5][C:4]=3[N:8]=2)=[CH:23][CH:24]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(O)c(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1ccc(-c2nc3cc(N)ccc3o2)cc1
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 93.9 %

Procedure:
8 mmol of 2,4-diaminophenol.2HCl and 8 mmol of 4-tert-butyl-benzoic acid were dissolved in 10 g of PPA, and then, the mixed solution was stirred at a temperature of 180° C. for 3 to 4 hours. After completion of the reaction, the reaction solution was cooled, neutralized with 10% NaOH, and filtered by using distilled water for recrystallization in a slow manner, thereby obtaining 2.0 g of 2-(4-tert-butylphenyl)benzo[d]oxazole-5-amine (Derivate #4) (yield: 94%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:36]>C(=O)([O-])[O-].[Na+].[Na+]>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:32])([CH3:33])[C:30]([NH2:31])=[O:36])[CH2:25][CH2:24]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][C:6]([CH3:34])=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)C#N)CC4)cc2OCC3)n(C(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(C)(C)C(N)=O)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 9 %

Procedure:
To 2-{-4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (140 mg, 0.31 mmol) was added concentrated sulfuric acid (1.75 mL). The mixture was stirred at RT for 3.5 hours before the reaction was diluted with ice and neutralised with sodium carbonate. The aqueous mixture was extracted with 10% MeOH in DCM (×5) before the organic phase was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM). The material was triturated with diethyl ether before being purified by reverse phase HPLC (C18, gradient 20-70% MeOH/0.1% formic acid in water/0.1% formic acid). The resultant residue was taken up into MeOH (1.2 mL) and treated with 0.2 M HCl in diethyl ether. The solution was concentrated in vacuo affording 289 (14 mg, 0.03 mmol, 9%). LCMS: RT=2.65 min, [M+H]+=478. 1H NMR δ (ppm) (DMSO-d6): 9.50 (1H, m), 8.33 (1H, d, J=8.29 Hz), 7.97 (1H, s), 7.93 (1H, s), 7.86 (1H, s), 7.02 (1H, dd, J=8.36, 1.75 Hz), 6.87 (1H, d, J=1.71 Hz), 5.78-5.71 (1H, m), 4.50-4.44 (4H, m), 3.19-3.04 (2H, m), 2.91-2.80 (1H, m), 2.25 (3H, s), 2.12 (2H, d, J=13.49 Hz), 1.98 (2H, d, J=13.54 Hz), 1.51 (6H, s), 1.43 (6H, d, J=6.59 Hz). 2H obscured by solvent.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]([CH2:14][CH2:15]O)[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:5]([N:12]([CH2:14][CH2:15][Cl:3])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CN(CCCl)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (2 ml) was added dropwise to a stirred, ice cooled solution of 2-[N-benzyl-N-methylamino]ethanol (4 g) obtained in preparation 8, in dry benzene (10 ml). The resulting mixture was stirred at 0° C. for 2 h and then diluted with ethyl acetate (40 ml), washed with saturated aqueous sodium bicarbonate solution (2×25 ml), water (50 ml), brine (50 ml) and dried. The ethyl acetate layer was evaporated and the residue was chromatographed on silica gel with 20% ethyl acetate in petroleum ether as eluent to give 2.6 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1F)[NH2:7])([O-:3])=[O:2].[CH3:12][O-:13].[Na+].Cl.O>CO>[CH3:12][O:13][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(N)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 21 h
Yield: 97.3 %

Procedure:
To a 1M solution of 3-nitro-4-fluoroaniline (16.7 g, 107 mmol, from Aldrich Chemical Co., Milwaukee, Wis. USA) in anhydrous methanol at ambient temperature was added sodium methoxide (23.1 g, 428 mmol) and the resulting solution was refluxed with stirring for 21 hours. The reaction mixture was then cooled to 0° C. and a 12M solution of HCl (13.4 mL) was added dropwise followed by water (250 mL). The crude mixture was extracted three times with Et2O (200 mL). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum to yield 17.5 g (97%) of product as a dark brown solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J=9 Hz, 1H), 7.01 (dd, J=2.8, 1.3 Hz, 1H), 6.85 (ddd, J=9, 2.8, 1.4 Hz, 1H), 5.2 (s, 2H), 3.75 (s, 3H).
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:22]1([C:25]([NH2:33])([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH3:26])[CH2:24][CH2:23]1>>[CH:22]1([C:25]([NH:33][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:5][O:4][CH2:3]3)=[CH:11][N:10]=2)=[O:14])([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH3:26])[CH2:24][CH2:23]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Product: Cc1nc(C(C)(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)COC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (Example 142b) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (32.6 mg, 37%); MS (ESI, m/z): 459.5 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:15][N:16]1CCCC1=O.[C-]#N.[Na+]>O>[C:15]([C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)#[N:16]
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1c(Cl)ccc2ccncc12
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2ccncc2c1[N+](=O)[O-]

Procedure:
7-Chloro-8-nitroisoquinoline (0.125 mole) and cuprous cyanide (0.225 mole) are refluxed in 125 ml. of distilled N-methylpyrrolidinone under a nitrogen atmosphere for 16 hours. The reaction mixture is poured into a solution of 40 g. of sodium cyanide in 120 ml. of water. The mixture is cooled and extracted with benzene. The benzene extracts are combined, washed with water, dried over sodium sulfate and evaporated. The residue is recrystallized from benzene to give 7-cyano-8-nitroisoquinoline.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[CH:18]([NH2:20])=[S:19]>C1COCC1.C(OCC)(=O)C>[S:19]1[CH:2]=[C:3]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[N:20]=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cscn2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
The title compound from Step B above (500 mg, 1.63 mmol) was combined with thioformamide (100 mg, 1.63 mmol) in 5 mL of THF, warmed to 60° C., and stirred overnight. The mixture was cooled to RT and diluted with ethyl acetate. The solution was then washed with water followed by brine. The organics were dried over magnesium sulfate, filtered and concentrated under vacuum. Purification via preparative TLC plates (3×1000 μM) eluting with 60% ethyl acetate/hexane afforded the title compound (282 mg, 63%) as a clear oil. ESI-MS calculated for C13H20N2O2S: Exact Mass: 268.12. Found: 169.12 (M-Boc)+ and 291.14 (MNa)+.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:8][CH:7]([CH2:9][OH:10])[CH2:6][NH:5][CH:4]1[CH3:11].N1C=CC=CC=1.Cl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>CN(C)C=O>[OH:10][CH2:9][CH:7]1[CH2:6][NH:5][CH:4]([CH3:11])[CH:3]([O:2][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:8]1
Reactant: CC1NCC(CO)CC1O
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1NCC(CO)CC1OC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 0.9 g. of 3-hydroxy-5-hydroxymethyl-2-methylpiperidine hydrochloride in 10 ml. of pyridine was added to a solution of 0.9 g. of isonicotinoyl chloride hydrochloride in 25 ml. of dimethylformamide under cooling. The resulting mixture was stirred at room temperature for 16 hours. Then, the reaction mixture was poured into ice-water and extracted with chloroform. The extracted was washed with water, dried and the solvent was distilled off to give a crystalline substance. The substance was recrystallized from a mixture of ethyl acetate and hexane to give 0.7 g. of the desired product. m. p. 126° - 128°C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:16][NH2:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]=O>C(Cl)Cl.CCOC(C)=O>[CH3:18][NH:17][CH2:16][C:10]1([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: NCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1
Reactant: C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNCC1(c2ccc([N+](=O)[O-])cc2)CCOCC1

Procedure:
A solution of C-[4-(4-nitro-phenyl)-tetrahydro-pyran-4-yl]-methylamine (as prepared in Example 73, step (b)) in DCM is treated with formaldehyde according to the literature procedure found in J. Org. Chem., 61, 3849-3862, (1996). The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: C([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]3[N:16]=[C:15]2[CH2:25][CH3:26])=[CH:10][CH:9]=1)(=O)CC.[Li+].[OH-]>CO.C1COCC1>[CH2:25]([C:15]1[N:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][OH:5])=[CH:13][CH:12]=2)[C:18]2=[N:19][C:20]([CH3:24])=[CH:21][C:22]([CH3:23])=[C:17]2[N:16]=1)[CH3:26]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)cc(C)nc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
To a solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl propionate (step 5, 1.75 g, 5.1 mmol) in methanol/THF (v/v, 1:1, 28 mL) was added 4N aqueous LiOH (4.6 mL, 18.4 mmol) and the resulting mixture was stirred at room temperature. After 3 h, the mixture was concentrated. The residue was dissolved in water (30 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 2:1 to 0:1) to afford 1.3 g (86%) of the title compound as pale brown solids: 1H-NMR (CDCl3) δ 7.40 (2H, d, J=8.4 Hz), 7.31 (2H, d, J=8.4 Hz), 6.91 (1H, s), 3.81-3.75 (2H, m), 3.47 (1H. br.s), 2.92 (2H, t, J=6.9 Hz), 2.81 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.51 (3H, s), 1.27 (3H,
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH3:10].[C:11]([C:14]1[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][S:17][CH:18]=1)([OH:13])=[O:12]>CN(C=O)C.O>[CH2:8]([O:13][C:11]([C:14]1[C:15]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][S:17][CH:18]=1)=[O:12])[CH2:9][CH3:10]
Reactant: CCCI
Reactant: COC(=O)Cc1cscc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(=O)c1cscc1CC(=O)OC
Reaction time: 3 h

Procedure:
Potassium carbonate (670 mg) and, after 15 minutes, 1-iodopropane (0.26 ml) were added successively to a stirred solution of methyl (4-carboxy-3-thienyl)acetate (490 mg) in DMF (10 ml). After 3 h, the resulting mixture was diluted with water and extracted with ether. The extracts were washed with water, dried, and concentrated to give methyl [4-(prop-1-yloxycarbonyl)-3-thienyl]acetate (600 mg, quantitative yield) as a yellow liquid, pure by GC, IR (film): 1735, 1710 cm-1, 1H nmr: delta 1.00 (3H, t), 1.75 (2H, q), 3.69 (3H, s), 3.92 (2H, s), 4.20 (2H, t), 7.13 (1H, d J 3.5 Hz), 8.12 (1H, d J 3.5 Hz) Ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C(N1C2C(=CC=C(C3C=CC=CN=3)C=2)[C:24](=[O:37])C(C(O)=O)=C1)C.NC1C=C(C2C=CN=CC=2)C=CC=1C(O)=O.C(Cl)(Cl)=O>>[N:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:4]3[NH:1][C:24](=[O:37])[O:8][C:6](=[O:7])[C:5]3=[CH:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1[N+](=O)[O-]
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccccn3)cc21
Agent: Nc1cc(-c2ccncc2)ccc1C(=O)O
Agent: O=C(Cl)Cl
Product: O=c1[nH]c2cc(-c3ccncc3)ccc2c(=O)o1

Procedure:
It was found that the 2-nitro-4-(4-pyridinyl)benzoic acid prepared in the preceding examples could be converted to 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acid by (a) reducing it to 2-amino-4-(4-pyridinyl)benzoic acid, (b) reacting the 2-amino-4-(4-pyridinyl)benzoic acid with phosgene to form 4-(4-pyridinyl)isatoic anhydride, (c) alkylating the 4-(4-pyridinyl)isatoic anhydride with ethyl bromide to produce N-ethyl-4-(4-pyridinyl)isatoic anhydride, (d) reacting the N-ethyl-4-(4-pyridinyl)isatoic anhydride with the potassium salt of ethyl formyl acetate to form ethyl 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylate, and (e) hydrolyzing that ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:13][C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=[C:16]([NH2:32])[N:15]=1)(=[O:12])=[O:11].[NH:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[NH2:32][C:16]1[N:15]=[C:14]([O:13][S:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])(=[O:11])=[O:12])[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:33]3[CH2:37][CH2:36][CH2:35][C@@H:34]3[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Product: COc1cc(CN2CCC[C@@H]2C(=O)OC(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 91.2 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (vii) from the product of example 1 step (v) (200 mg) and (R)-tert-butyl pyrrolidine-2-carboxylate (108 mg). The sub-title compound (234 mg) was obtained as a colourless amorphous solid; LC-MS: m/z 611.
Reaction SMILES: CC(C)=O.Cl[C:6]1[N:11]=[C:10]([Cl:12])[N:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1.[CH:19]12[O:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][NH:21][CH2:20]2>C(N(CC)CC)C>[Cl:12][C:10]1[N:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=[C:6]([N:21]2[CH2:20][CH:19]3[O:26][CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[N:11]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: C1CC2CNCC1O2
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: Clc1nc(N2CCOCC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred acetone/crushed ice suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.5 g, 6.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (980 mg, 6.5 mmol) and triethylamine (3 ml) was added and stirred at room temperature for 6 hours. At the end, the separated solid was filtered and washed with water. The crude product was found to be pure enough for further transformations. Yield: 2.0 g (99%); mp. 118; (M+H) 313.1