Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1.O>[CH2:17]([O:16][C:14]([N:4]1[CH2:5][CH2:6][C@@H:2]([OH:1])[CH2:3]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred mixture of (R)-3-hydroxypyrrolidine (4.35 g, 50 mmol) in THF (50 mL) and aqueous sodium carbonate (10.6 g, 100 mmol in 50 mL water) cooled to 0° C. was added a solution of benzyl chloroformate in THF (60 mmol, 8.6 mL in 10 mL THF) over a period of 5-10 min. After stirring at 0° C. for 2 h, the reaction mixture was diluted with 200 mL water and extracted with methylene chloride (3×100 mL). The combined extracts were washed with 1N sulfuric acid (3×75 mL) followed by brine solution (3×50 mL). This extract was then dried over anhydrous sodium sulfate and the solvent evaporated to give a light yellow oil (10.5 g, 95% yield) which was used for the next reaction without any purification.
Reaction SMILES: C1(C)C=CC=CC=1.CC(C)=O.Cl.[CH2:13]([OH:25])[C@H:14]([OH:24])[C@@H:15](O)[C@H:16]([OH:22])[C:17]([C:19]([OH:21])=[O:20])=[O:18]>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.O>[O:20]=[C:19]1[O:21][C@H:15]([C@H:14]([CH2:13][OH:25])[OH:24])[C:16]([OH:22])=[C:17]1[OH:18]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 6 h
Yield: 86.2 %

Procedure:
To a mixture solvent of toluene (570 ml) and acetone solution containing 23.5 weight % of hydrogen chloride (65 ml as acetone) was added 2-keto-L-gulonic acid (content 91.2%, water content 8.4%)(100 g). To this solution were further added water (7.7 ml) and trimethylcetylammonium chloride (110 mg)(water content was 1.90 times as much in molar ratio relative to 2-keto-L-gulonic acid). The reaction mixture was stirred for six hours while heating at 60° C., which was then cooled to 20° C. The resultant was poured into water (1 l), and the mixture was stirred, which was then left standing, followed by separating the aqueous layer. To the organic layer was added water (400 ml) for re-extraction. The aqueous layers were combined and subjected to quantitative determination by means of a high performance liquid chromatography to reveal the existence of L-ascorbic acid[78.2 g (yield 94.5%)], while unreacted 2-keto-L-gulonic acid remaining in an amount of 2.7%. The absorbance (E430nm1%) of this aqueous layer was 0.160.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:37][CH2:36][CH2:35][CH:34]([C:38]([OH:40])=[O:39])[CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=C(O)C1CCCNC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: O=C(O)C1CCCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)C1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl) benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and piperidine-3-carboxylic acid (125 mg; 0.97 mmol) to give Example 158 as a yellow solid. 1H NMR: (DMSO-d6, 400 MHz) δ 12.25 (1H, br s), 8.75 (2H, dd, J=4.5, 1.6 Hz), 7.97-7.88 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.7 Hz), 7.57-7.47 (4H, m), 3.59 (2H, t, J=14.7 Hz), 2.85 (1H, d, J=11.0 Hz), 2.68 (1H, d, J=11.2 Hz), 2.50-2.42 (1H, m), 2.28-1.95 (2H, m), 1.84 (1H, d, J=12.1 Hz), 1.68 (1H, dd, J=12.2, 4.7 Hz), 1.58-1.31 (2H, m). LC/MS (Method C): 526 (M+H)+. HPLC (Method F) Rt 2.83 min (Purity: 98.7%).
Reaction SMILES: N1(C2C=CC(NC3C4N(C=CN=4)C(C4C=CNC(=O)C=4)=CN=3)=CC=2)CCOCC1.Br[C:31]1[N:36]2[CH:37]=[CH:38][N:39]=[C:35]2[C:34]([NH:40][C:41]2[CH:57]=[CH:56][C:44]([C:45]([NH:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=3)=[O:46])=[CH:43][CH:42]=2)=[N:33][CH:32]=1.CC1(C)C(C)(C)OB([C:66]2[CH:67]=[N:68][NH:69][CH:70]=2)O1.CC([O-])(C)C.[Na+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:55][C:52]1[CH:53]=[CH:54][C:49]([CH2:48][NH:47][C:45](=[O:46])[C:44]2[CH:56]=[CH:57][C:41]([NH:40][C:34]3[C:35]4[N:36]([CH:37]=[CH:38][N:39]=4)[C:31]([C:66]4[CH:67]=[N:68][NH:69][CH:70]=4)=[CH:32][N:33]=3)=[CH:42][CH:43]=2)=[CH:50][CH:51]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(NCc1ccc(O)cc1)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)cc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(O)cc1)c1ccc(Nc2ncc(-c3cn[nH]c3)n3ccnc23)cc1

Procedure:
In the same way as described for Compound 85, step 1, using 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)-N-(4-hydroxybenzyl)benzamide (47 mg, 0.11 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (25 mg, 0.13 mmol), Pd(PPh3)4 (12 mg, 0.011 mmol) and NaOtBu (41 mg, 0.43 mmol) in DMF/water (3:1). The crude residue is chromatographed on silica gel, eluting with petrol:EtOAc (50:50 followed by 0:100) and then EtOAc:MeOH (95:5). The fractions containing the desired product are combined and evaporated, to afford the title compound as a solid. HPLC (254 nm): Rt 2.38 min (90.9%); m/z (APCI) 426 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH-:30].[Na+]>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[OH:30])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2O)cn1)c1ccc(Cl)s1
Yield: 6.2 %

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared in Example 11 (80 mg, 0.19 mmol) and 5 N aq. NaOH (0.5 mL, 2.5 mmol) in DMSO (2 mL) in a sealed tube was heated at 130° C. overnight. The mixture was purified by HPLC to give the title compound (5 mg). MS 427.0 and 429.0 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[F:16][C:17]1([F:23])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([N:20]2[CH2:21][CH2:22][C:17]([F:23])([F:16])[CH2:18][CH2:19]2)=[O:15])=[CH:4][N:3]=1
Reactant: FC1(F)CCNCC1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)N3CCC(F)(F)CC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and 4,4-difluoropiperidine by following the similar procedure as described for intermediate-11a.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(O)(=O)C.[N:20]([O-])=[O:21].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([NH:20][OH:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(NO)C(=O)c1ccc(Br)cc1
Reaction time: 1.5 h

Procedure:
To the solution of ethyl 3-(4-bromophenyl)-3-oxopropanoate in THF (prepared in step A above), add acetic acid (160 L) and water (73 L) at an internal temperature of 8° C. To this mixture, add a solution of sodium nitrite (6.35 kg, 92.00 mol, 1.25 eq) in water (30 L) at an internal temperature of 6 to 9° C. during 90 min and stir at this temperature for 90 min. At an internal temperature of 4 to 7° C., add water (147 L) over 30 min to the reaction mixture and stir the resulting suspension for 30 min. Filter the suspension and wash the filter cake with water (59 L) and heptane (60 L). Dry the filter cake under a constant flow of nitrogen for 13 h to obtain the title compound: 18.731 kg according to loss of drying (23.044 kg wet); white powder; 1H NMR (DMSO-d6, 500.0 MHz): δ 1.22 (t, J=7.1 Hz, 3H), 4.27 (q, J=7.1 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H, 7.83 (d, J=8.8 Hz, 2H), 13.18 (s, 1H); 13C NMR (DMSO-d6, 125.7 MHz): δ 14.36, 62.27, 129.68, 131.09, 133.08, 133.36, 148.44, 161.17, 191.08; Anal. Calcd for C11H10BrNO4: C, 44.02; H, 3.36; Br, 26.63; N, 4.67; O, 21.32. Found: C, 43.98; H, 3.31; Br, 26.65; N, 4.59; MS (ES−) 299; IR (KBr): 3281, 3219, 3049, 2983, 2870, 1728, 1680, 1586, 1446, 1400, 1302, 1262, 1029, 944 cm−1.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH3:15].CO>CO>[CH3:14][O:13][C:10]1[CH:9]=[C:4]2[C:3]([CH2:2][NH:15][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(OC)ccc1CBr
Reactant: N
Solvent: CO
Product: COc1ccc2c(c1)C(=O)NC2
Temperature: 125 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
A solution of methyl 2-(bromomethyl)-5-methoxybenzoate ((75), 5.0 g, 19.3 mmol) in MeOH was placed in pressure flask and to it ammonia/methanol (2M, 30 ml) was added. Resulting mixture was stirred at 125° C. for 2 hr. The solvent and excess NH3 was removed in vacuo and the residue was triturated with Hexane/EtOAc (1:2 ratio). The compound was filtrated under vacuum and air-dried for 2 hr to give the title compound (2.51 g, 65%) as a pale yellow solid. The filtrated was concentrated and purified on silica gel (Hexane/EtOAc/MeOH 3:1:0.5 ratio) to yield another 270 mg of desired compound. Combined yield was 86%. MS (ES) m/z 164.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[NH:30][N:29]=2)[C:24]([C:36]#[C:37][Si](C)(C)C)=[CH:23][N:22]=1.C1(C2NN=C(NC3C(C#C)=CN=C(C4C=C(S(N)(=O)=O)C=CC=4)N=3)C=2)CC1>[Pd]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:21]2[N:26]=[C:25]([NH:27][C:28]3[NH:29][N:30]=[C:31]([CH:33]4[CH2:35][CH2:34]4)[CH:32]=3)[C:24]([C:36]#[CH:37])=[CH:23][N:22]=2)=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC1(C)OB(c2ccc(Cl)c(C(N)=O)c2)OC1(C)C
Agent: [Pd]
Agent: C#Cc1cnc(-c2cccc(S(N)(=O)=O)c2)nc1Nc1cc(C2CC2)[nH]n1
Product: C#Cc1cnc(-c2ccc(Cl)c(C(N)=O)c2)nc1Nc1cc(C2CC2)n[nH]1
Yield: 13 %

Procedure:
2-chloro-5-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5-ethynylpyrimidin-2-yl) benzamide (Compound 128) (40 mg, 13%) was prepared from 2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide and 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl) pyrimidin-4-amine using the same Pd cataliysed condition as described in Compound 110. LC-MS (m/z)=378.9 [M+H1H NMR (400 MHz, DMSO-d6): δ 0.75-0.76 (m, 2H), 0.98-0.99 (m, 2H), 1.89-1.97 (m, 1H), 4.87 (s, 1H), 6.41 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.72 (s, 1H), 8.05 (s, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.33 (d, J=1.6 Hz, 1H), 8.58 (s, 1H), 8.75 (s, 1H), 12.33 (s, 1H).
Reaction SMILES: [ClH:1].[OH:2][C@@H:3]([CH2:19][N:20]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[ClH:1].[OH:2][C@@H:3]([CH2:19][N:20]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:30]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)COc1ccc(N(CC(C)C)C[C@H](O)COc2cccc3[nH]c4ccccc4c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OCC(=O)O)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
A solution of the free base (0.25 g, 0.47 mmol) from example 93 in ethanol/THF (50 mL/50 mL) was treated with 1N NaOH (14.1 mL, 14.1 mmol) and refluxed with stirring for 1 h, the reaction was neutralized with 1N HCl (13.6 mL, 13.6 mmol, 29 eq), and concentrated in vacuo. The resulting residue was slurried in ether (30 ml) and anhydrous HCl in ether (30 ml) was added. The resulting slurry was concentrated in vacuo. The residue was dissolved in EtOAc and filtered. The filtrate was concentrated in vacuo to provide 0.08 g (35%) of a tan solid. MS (FD+): m/z 463. Anal Calcd for C27H31N20O5Cl: C, 64.99; He 6.26; N, 5.61. Found: C, 65.29; H, 6.55; N, 5.35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:31]=1.[BH4-].[Na+]>CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]4[S:21][C:22]5[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[C:23]=5[N:24]=4)[C:15](=[O:30])[CH2:14]3)(=[O:11])=[O:12])[S:7][C:6]=2[CH:31]=1
Reactant: O=C1CCCc2sc(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)nc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1nc2c(s1)CCCC2O

Procedure:
To the suspension of 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-ylmethyl]-6,7-dihydro-5H-benzothiazol-4-one (7 mg, 0.01 mmol) in EtOH (1 mL) is added sodium borohydride (3 mg, 0.08 mmol). After 15 min the reaction is diluted with EtOAc and washed with 1N HCl, NaHCO3 and brine. The solution is dried (MgSO4) and concentrated to provide 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-(4-hydroxy-4,5,6,7-tetrahydro-benzothiazol-2-ylmethyl)-piperazin-2-one. 1H NMR (300 MHz, CDCl3) δ 7.88-7.82 (m, 3H), 7.46 (dd, 1H), 4.83-4.81 (m, 1H), 4.76 (s, 1H), 4.75 (s, 1H), 3.92 (s, 1H), 3.91 (s, 1H), 3.62-3.55 (m, 2H), 3.47-3.41 (m, 2H), 2.76-2.62 (m, 2H), 2.05-1.78 (m, 4H); MS (Ion Spray) 498 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[F-:11].[K+]>CS(C)=O.[Cl-].[Na+].O.C(OCC)(=O)C>[F:11][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: [F-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(F)nc1
Temperature: 70 °C
Yield: 84.8 %

Procedure:
To 100 g of 2-chloro-5-nitropyridine (Aldrich) in 600 mL of dimethyl sulfoxide under an inert atmosphere was added 100 g of anhydrous KF. The reaction was heated at 70° C. for 18 hours before cooling and diluting with 500 mL each of brine, ethyl acetate, and hexanes. This mixture was filtered through a pad of celite, the organic phase was separated, and the aqueous phase was extracted three times with equal volumes of ethyl acetate and hexanes. The pooled organic phases were washed with brine, dried with anhydrous sodium sulfate, and stripped of the solvents. This crude product was passed through a plug of silica gel with a gradient of 10-30% ethyl acetate/hexanes and stripped to constant weight on a rotary evaporator to give 76 g (84%) of 2-fluoro-5-nitropyridine as an oil, which was used in the following procedure.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:19](N=[N+]=[N-])=[O:20].C(OC(C)C)(C)C>C1C=CC=CC=1>[CH2:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:19](=[O:20])[C:18]2[CH:17]=[C:16]([O:15][CH3:14])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: COc1cc(C(=O)N=[N+]=[N-])cc(OC)c1OC
Solvent: c1ccccc1
Solvent: CC(C)OC(C)C
Product: COc1cc(C(=O)NC2CCN(Cc3ccccc3)C2)cc(OC)c1OC
Temperature: 60 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A mixture of 1.8 g (0.01 mole) of 3-amino-1-benzylpyrrolidine, 2.4 g. (0.01 mole) of 3,4,5-trimethoxybenzoyl azide, and 25 ml. of dry benzene was stirred 16 hours at room temperature followed by stirring for one hour at about 60° C. The mixture was cooled and 50 ml. of isopropyl ether added to the mixture. The crude crystalline product was separated by filtration and recrystallized from ethyl acetate-isopropyl ether mixture, giving 2.2 g. (60% yield). The melting point of the product after a second recrystallization from the same solvent was 128°-129° C.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[O:4].[NH2:27][CH2:28][C:29]([OH:31])=[O:30]>>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[C:14]([OH:15])=[C:5]([C:3]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:26]
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3OC)cccc2c1O
Reactant: NCC(=O)O
Product: COc1ccccc1Oc1cccc2c(O)c(C(=O)NCC(=O)O)nc(C#N)c12

Procedure:
The title compound was synthesized from 1-cyano-4-hydroxy-8-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=392.5.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>C(O)(=O)C>[C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:20][CH:21]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(OCC2CCN(c3ccncc3)CC2)cc1

Procedure:
A solution of 4-[(4-aminophenoxy)methyl]-1-[4-pyridyl]piperidine (see Preparation 4) (0.57 g), acetic anhydride (1 ml) and acetic acid (1 ml) was heated on a steam bath for 3 hours and then evaporated. The residue was dissolved in water (2 ml) and the solution was made basic with sodium bicarbonate solution. The solid was filtered off, washed with water, dried and then chromatographed on silica gel eluting with dichloromethane/methanol (20:1). Earlier fractions contained impurity and pure product was eluted in the later fractions. The product fractions were combined and evaporated. The solid was crystallised from methanol to give the title compound, (0.34 g), m.p. 226°-228°.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)C>N1C=CC=CC=1>[CH2:1]([O:17][CH2:18][CH:19]([CH2:21][O:22][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 70 %

Procedure:
1-hexadecyl glycerol (105 g, 0.33 mol) and 93 g (0.33 mol) tritylchloride were dissolved in 300 ml of pyridine. The mixture was heated at 100° C. for 16 hours. After cooling to room temperature 1500 ml of ethyl ether was added and the slurry washed 3 times with cold 0.5N H2SO4, 5% sodium bicarbonate and 2 times with water. The organic phase was dried over MgSO4, the ether removed on a rotary evaporator and the residue recrystallized from ethanol, yielding the intermediate 1-hexadecyl-3-trityl glycerol (129 g, 70%). The 2 position of this intermediate was alkylated with tetradecyl bromide in the same manner (powdered KOH in toluene) as described earlier for the dialkylation of benzyl glycerol in the preparation of 1,2-dihexadecyl glycerol. The resulting 1-hexadecyl-2-tetradecyl-3-trityl glycerol (128g) was dissolved in 300 ml of petroleum ether. At room temperature 30g of anhydrous hydrogen chloride was added. A precipitate formed within a short time. The slurry was stirred at room temperature for 4 hours and then filtered. The solids were recrystallized from acetone (10° C.) to give 45.6g of product, m.p. 42°-3° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH2:46][C:47]5[CH2:48][C:49]6([CH2:54][CH2:55][C:56]=5[C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=5)OCC[O:50]6)[CH2:42][CH2:41]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:41][CH2:42][N:43]([CH2:46][C:47]5[CH2:48][C:49](=[O:50])[CH2:54][CH2:55][C:56]=5[C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=5)[CH2:44][CH2:45]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(C3)OCCO4)CC2)cc1Oc1ccc2[nH]ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)C1

Procedure:
A mixture of EXAMPLE 249E (20 mg) and pyridinium p-toluenesulfonate (16.8 mg) in acetone/H2O (1:1, 3 mL) was heated in a microwave to 135° C. for 8 minutes.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([NH2:27])=[O:26]>>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NC(=O)CBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 33.1 %

Procedure:
The mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (6.77 g, 30.7 mmol), K2CO3 (5 g, 36.2 mmol) and 2-bromoacetamide (4.46 g, 32.3 mmol) in acetrontrile (250 ml) was heated to reflux for 4 hours. The insolubles were filtered and rinsed with dichloromethane (DCM). The solvents were removed. The residual solid was dissolved in DCM and upon concentration of this solution, 2.3 g of product crystallized out and was collected when the volume was reduced to about 50 ml. The rest of the product in DCM was purified by flash chromatography over a silica gel column (80 gm, SiO2; eluted with DCM and 1% C;H3OH in DCM). The total product (4.2 g) thus purified was recrystallized from ethanol to yield 2.82 g of white crystals, m.p. 170°-172° C. dec.