Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=3[CH:17]=2)[C:4](=[O:18])[CH2:3]1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH:33]=O)=[CH:23][CH:22]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([N:25]=[CH:26][C:27](=[O:35])[N:28]2[CH2:31][CH2:32][CH2:33][NH:1][C@H:2]2[CH2:6][N:5]([C:7]3[CH:8]=[CH:9][C:10]4[O:15][CH2:14][C:13](=[O:16])[NH:12][C:11]=4[CH:17]=3)[C:4](=[O:18])[CH2:3]2)=[CH:23][CH:22]=1
Reactant: N[C@@H]1CC(=O)N(c2ccc3c(c2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(CCC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCCN[C@@H]3CC(=O)N(c4ccc5c(c4)NC(=O)CO5)C3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-[(4R)-4-Amino-2-oxopyrrolidin-1-yl]-2H-1,4-benzoxazin-3(4H)-one (23.9 mg, 0.0967 mmol) and 3-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propanal (Reference Example 8; 22.4 mg, 0.0967 mmol) were dissolved in N,N-dimethylfomamide (0.5 ml). Sodium sulfate (100 mg) was added to the obtained solution, and the mixture was then stirred at room temperature overnight. Thereafter, sodium triacetoxy borohydride (30.7 mg, 0.145 mmol) was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 2 days. After completion of the reaction, dichloromethane and a saturated sodium hydrogen carbonate aqueous solution were added to the reaction solution, and the organic layer was separated. The organic layer was washed with water (4×) and saturated sodium chloride solution, and was then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (chloroform/methanol) to yield 18.4 mg (41%) of the above captioned compound in the form of a light brown solid.
Reaction SMILES: S(O[CH2:12][C@@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O>[N:26]([CH2:12][C@@H:13]1[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)=[N+:27]=[N-:28]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](CN=[N+]=[N-])C1

Procedure:
A solution of EXAMPLE 442A (1.66 g, 4.47 mmol) and sodium azide (0.581 g, 8.94 mmol) in anhydrous N,N-dimethylformamide (10 mL) was stirred at 90° C. for 4 hours. The mixture was cooled and concentrated to dryness. The residue was taken up in 5% aqueous sodium carbonate solution and extracted with methylene chloride. The combined organic layers was dried (MgSO4), filtered and concentrated to provide the title compound.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[S:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH:37]=[C:36]1[C:44](Cl)=[O:45]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:44]([C:36]3[S:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[CH:37]=3)=[O:45])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)c1cc2ccccc2s1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3cc4ccccc4s3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 1-benzothiophene-2-carbonyl chloride as a yellow oil (95%). HPLC, Rt: 6.04 min (Purity: 92.1%).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1/[CH:21]=[CH:22]/[C:23](Cl)=O.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51]>C(OCC)(=O)C>[C:49]([OH:54])(=[O:53])[C:50]([OH:52])=[O:51].[F:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:23](/[CH:22]=[CH:21]/[C:17]3[S:16][CH:20]=[CH:19][CH:18]=3)=[N:15][C:4]=2[CH:3]=1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/c1cccs1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(c1)nc(/C=C/c1cccs1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-3-(2-thienyl)acryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). The free base and oxalic acid were dissolved into ethyl acetate. Concentration and recrystallization from ethyl acetate/n-hexane yielded the titled compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CCOCC>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])[CH:7]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccnc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)ccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution containing 2-bromo-4-methylpyridine (1.46 g, 8.49 mmol) in ether (15 mL) at −78° C. was treated with n-butyllithium (5.57 mL, 1.6 M in hexanes) dropwise, stirred at −78° C. for 1 hour, treated with tributyltin chloride (3.45 mL, 12.74 mmol), stirred at 0° C. for 4 hours, quenched with saturated ammonium chloride solution and partitioned between ether and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on neutral alumina eluting with 10% ethyl acetate in dichloromethane to give the title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:38](=[O:39])[N:13]3[C:14]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)=[O:27])=[C:15](OS(C(F)(F)F)(=O)=O)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:40][C:41]#[C:42][CH3:43].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:40][C:41]1[C:15]2[C@H:16]([C:42]=1[CH3:43])[S:17][C@H:12]1[N:13]([C:38](=[O:39])[C@H:11]1[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]=2[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)=[O:27]
Reactant: CC#CC
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C3C(C)=C(C)[C@@H]3S[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoromethyl-sulphonyloxy)ceph-3-em-4-carboxylate (60 mg, 0.102 mmol) in dichloromethane (10 ml) was cooled to 0° C., 2-Butyne (1.2 ml, 15.3 mmol) was added followed by diisopropylethylamine (18 μl, 0.102 mmol). The mixture was stirred and allowed to warm to room temperature over 15 min. Chromatography gave the title compound (28.4 mg, 57%), (Found: M+, 490.1562. C27H26N2O5S requires M, 490.1562); νmax (CH2Cl2) 1783, 1716, 1684 cm-1 ; δH (CDCl3) 1.79 (3H, s), 1.97 (3H, s), 3.62 (2H, ABq, J 16.1), 3.79 (3H, s), 4.07 (1H, br s), 4.79 (1H, d, J 4.8), 5.21 (2H, ABq, J 11.8), 5.89 (1H, dd, J 8.6, 4.8), 6.06 (1H, d, J 8.6), 6.86 (2H, d, J 8.6), 7.30 (7H, m); δc (CDCl3) 12.5, 13.2, 43.3, 45.6, 55.3, 59.8, 62.3, 67.1, 111.8, 113.9 (2c), 127.4, 127.7, 129.2 (2c) 129.5 (2c), 130.8 (2c), 133.7, 135.4, 142.5, 149.1, 159.9, 161.4, 164.4, 171.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1.Cl.[CH:16]1([C:19]2[CH:20]=[C:21]([CH3:31])[C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][CH:24]=2)[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:29][CH2:30][N:25]([C:22]3[C:21]([CH3:31])=[CH:20][C:19]([CH:16]4[CH2:17][CH2:18]4)=[CH:24][N:23]=3)[CH2:26][CH2:27]2)=[O:8])=[C:4]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2S(C)(=O)=O)CC1
Yield: 94.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 4-bromo-2-methanesulfonylbenzoic acid (558 mg) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (508 mg) described in Preparation Example 49, the title compound (0.9 g) was obtained.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][NH:4][CH2:5][CH2:6][O:7][CH3:8].[C:15](=S)=[S:16]>C1(C)C(C)=CC=CC=1>[CH3:8][O:7][CH2:6][CH2:5][N:4]1[CH2:3][CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1][C:15]1=[S:16]
Reactant: COCCNCC(N)c1ccccc1
Reactant: S=C=S
Solvent: Cc1ccccc1C
Product: COCCN1CC(c2ccccc2)NC1=S
Temperature: 130 °C

Procedure:
The ethylamine product of Example IV in the amount of 6.85 g is dissolved in 20 ml xylene, and this is then stirred with 3 ml carbon disulfide at room temperature for two hours. The resulting slurry is then slowly heated to 130° C. and maintained at this temperature for four hours.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[O:18][C:19]4[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=4[C:21]=3[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:13]=2)[CH:8]=1)C.[OH-].[K+]>C1COCC1.O>[CH2:22]([C:21]1[C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][C:17]=1[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:6][CH2:5][C:4]([OH:31])=[O:3])[CH:16]=[CH:15]2)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCc1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCc1c(-c2ccc3cc(OCC(=O)O)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Step 4 of Example 6, [6-(3-Pentyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetic acid ethyl ester (0.34 g, 0.82 mmol), was hydrolyzed with potassium hydroxide (0.50 g, 8.9 mmol) in THF (20 mL) and water (10 mL). The title compound was obtained as an off-white solid (0.28 g), mp 163-165° C. Mass spectrum (+APCl, [M+H]+) m/z 389. 1HNMR (400 MHz, DMSO-d6): δ13.15 (br s, 1H), 8.24 (s, 1H), 7.99 (d, 1H, J=9.0 Hz), 7.93 (d, 1H, J=8.8 Hz), 7.85 (dd, 1H, J=8.5, 1.7 Hz), 7.69-7.66 (m, 1H), 7.59 (d, 1H, J=7.8 Hz), 7.35-7.25 (m, 4H), 4.82 (s, 2H), 2.98 (t, 2H, J=7.6 Hz), 1.72 (p, 2H, J=7.3 Hz), 1.42-1.27 (m, 4H), and 0.83 ppm (t, 3H, J=7.1 Hz). Elemental Analysis for C25H24O4.0.4H2O: Calculated: C, 75.89; H, 6.32; N, 0.00. Found: C, 75.9; H, 6.07; N, 0.17.
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](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH2:23]1[NH:28][C:26](=[O:27])[NH:25][CH2:24]1.N[C@@H]1CCCC[C@H]1N.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[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:25]4[CH2:24][CH2:23][NH:28][C:26]4=[O:27])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: O=C1NCCN1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(N3CCNC3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 110 °C
Yield: 6.9 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 prepared in Example 1 (80 mg, 0.18 mmol), ethyleneurea (40 mg, 0.47 mmol), 1,2-trans-diaminocyclohexane (15 μL, 0.12 mmol) and K2CO3 (100 mg, 0.72 mmol) in DMSO (1 mL) was degassed with Ar before being charged with CuI (20 mg, 0.11 mmol). The mixture in a sealed tube was heated at 110° C. overnight. It was then purified by HPLC to give the title compound (5 mg). MS 402.1 and 404.1 (M+H, Cl pattern).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].C1(O)C=CC=CC=1.C1(S([N:22]2[C:30]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=3[CH:24]=[C:23]2[CH2:32][N:33]2[CH2:38][CH2:37][N:36]([S:39]([C:42]3[S:46][C:45]4[CH:47]=[C:48]([Cl:51])[CH:49]=[CH:50][C:44]=4[CH:43]=3)(=[O:41])=[O:40])[CH2:35][C:34]2=[O:52])(=O)=O)C=CC=CC=1>>[NH2:5][C:26]1[C:25]2[CH:24]=[C:23]([CH2:32][N:33]3[CH2:38][CH2:37][N:36]([S:39]([C:42]4[S:46][C:45]5[CH:47]=[C:48]([Cl:51])[CH:49]=[CH:50][C:44]=5[CH:43]=4)(=[O:41])=[O:40])[CH2:35][C:34]3=[O:52])[NH:22][C:30]=2[CH:29]=[CH:28][N:27]=1
Reactant: [NH4+]
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2c(Cl)nccc2n1S(=O)(=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: Nc1nccc2[nH]c(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)cc12
Temperature: 100 °C

Procedure:
Anhydrous ammonium acetate (0.56 g, 7.2 mmol), phenol (0.45 g, 4.8 mmol) and 1-(1-benzenesulfonyl-4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-2-one (0.31 g, 0.48 mmol, prepared as described previously) are heated to 100° C. for 3.5 days. The mixture is cooled to RT then the crude product is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN then the appropriate product fractions are lyophilized to provide the title compound (1.29 g, 2.2 mmol) as a white solid (22.4 mg, 0.038 mmol). 1H NMR (DMSO-d6, 300 MHz) δ12.40 (bs, 1H), 12.00 (bs, 1H), 8.31 (d, 1H), 8.20 (s, 1H), 8.06 (d, 1H), 8.02 (bs, 2H), 7.57 (dd, 1H), 7.48 (m, 1H), 6.89 (d, 1H), 6.81 (s, 1H), 4.60 (s, 1H), 3.81 (s, 2H), 3.40 (m, 4H). LR-FAB MS, [M+H]+=476, 478.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:2]=1.CI.[OH-].[Na+].[C:20](O)(=O)C>O.C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11]([S:14][CH3:20])=[N:12][CH:13]=2)[CH:2]=1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cccnc1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Solvent: O
Product: CSc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
A solution of 5-(3-pyridylmethyl)-2-thiouracil (11.0 g), methyl iodide (7.1 g) and sodium hydroxide (4.2 g) in water (150 ml) and ethanol (150 ml) was stirred at 65° for 40 minutes, allowed to cool and acetic acid was added to pH5. The solution was partially evaporated, cooled and filtered to give 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p. 247°-9° (ex. ethanol-acetic acid).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:13]([O:14][CH3:15])[CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(O)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
A mixture of 5-hydroxypicolinic acid (5.00 g), N,O-dimethylhydroxylamine hydrochloride (3.86 g), TEA (11.1 mL), WSC (7.58 g) and HOBt (5.34 g) in DMF (100 mL) was stirred at room temperature for 24 h. The mixture was poured into 5% NaHCO3 aqueous solution and extracted with AcOEt (10 times). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (4.13 g).
Reaction SMILES: C(OC([C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8](=[N:10][OH:11])[NH2:9])=O)C.[OH-].[Na+].O.Cl.[CH2:20]([OH:22])C>>[C:7]1([C:8]2[N:9]=[C:20]([OH:22])[O:11][N:10]=2)[CH:6]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccccc1C(N)=NO
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In accordance with the known process [Yakugaku Zasshi, 84(11), 1061 (1964)], 27 g (0.13 mol) of o-ethoxycarbonylbenzamidoxime were added to a liquid mixture consisting of 10 g (0.25 mol) of sodium hydroxide, 600 ml of water and 150 ml of ethyl alcohol, followed by stirring at room temperature for 3 hours. The reaction mixture was neutralized with dilute hydrochloric acid. Crystals thus formed were collected by filtration and then washed with water, whereby the title compound was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:32][C:23]1[CH:28]=[CH:27][C:26]([C:29]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(CN2CCC(O)CC2)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CCC(OC(=O)c3ccc(C)cc3)CC2)cc1
Yield: 82.4 %

Procedure:
0.31 g (0.0015 mol) of 1-(4-methyl-benzyl)-piperidin-4-ol and 0.52 ml (0.00375 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.25 ml (0.001875 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:4). 0.4 g (83%) of 1-(4-methyl-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals; m.p. 66°-77°.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:46][CH2:47]I>O1CCOCC1>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O:25][CH2:47][Cl:46])=[O:24])=[O:17])[CH:13]([CH3:14])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)O
Reactant: ClCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)OCCl
Reaction time: 0.08 h
Yield: 59.6 %

Procedure:
To a solution of 5-(N-CBz-L-valyloxy)-2,2-dimethylvaleric acid (5.88 g, 15.5 mmol) in dioxane (100 mL), was added dropwise a 40% aqueous solution of tetrabutylammonium hydroxide (10.1 g). After stirring for 5 min, the solution was evaporated to dryness through co-evaporation with dioxane and toluene. The residue was dissolved in dichloromethane (100 mL) and then chloroiodomethane (11.3 mL, 155 mmol) was added and the solution was stirred for 6 h at room temperature. The solution was concentrated under reduced pressure and the residue was shaken with hexane/ethyl acetate (1:1 v/v, 200 mL). The yellow crystalline solid was filtered off and the filtrate was washed with aqueous solution of sodium thiosulfate (0.1 M) and the filtered through anhydrous sodium sulfate and evaporated to dryness. The residue was column chromatographed (silica gel, 1–4% MeOH in CH2Cl2), to give 3.95 g of chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:10]=[C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[C:8]([F:16])=[C:7]([NH:17]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1)C.OS(O)(=O)=O.CC#N>O>[NH2:17][C:7]1[C:8]([F:16])=[C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)[N:10]=[C:5]([CH:4]=[O:3])[CH:6]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(C2CCCO2)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: Nc1cc(C=O)nc(C2CCCO2)c1F
Yield: 95.7 %

Procedure:
Using the procedure of Example 12, 6-(diethoxymethyl)-3-fluoro-2-(tetrahydrofuran-2-yl)-N-tritylpyridin-4-amine (4.21 g, 8 mmol), conc H2SO4 (1 mL), CH3CN (35 mL) and H2O (35 mL) gave 4-amino-5-fluoro-6-(tetrahydrofuran-2-yl)picolinaldehyde (1.61 g, 95%) as a white solid: mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 7.28 (d, J=6.7 Hz, 1H), 5.26 (td, J=7.1, 1.7 Hz, 1H), 4.46 (br s, 2H), 4.17 (dt, J=7.9, 6.9 Hz, 1H), 3.98 (td, J=7.8, 5.6 Hz, 1H), 2.29 (m, 2H), 2.19 (m, 1H), 2.05 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 193.12, 148.75 (d, J=5.2 Hz), 148.60 (d, J=11.7 Hz), 148.53 (d, J=256.8 Hz), 142.02 (d, J=12.1 Hz), 108.33 (d, J=4.1 Hz), 75.70, 69.26, 30.78 (d, J=0.9 Hz), 26.28; 19F NMR (376 MHz, CDCl3) δ −144.90 (d, J=6.6 Hz); HRMS-ESI (m/z) [M+H]+ calcd for C10H11FN2O2, 210.0805. found, 210.0803.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][S:24]([CH3:27])(=[O:26])=[O:25])[O:20][CH3:21])[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].[CH2:28](SCC(CO)OCC)CCCCCCCCCCCCCCC.CS(Cl)(=O)=O>>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][S:24]([CH3:27])(=[O:26])=[O:25])[O:20][CH2:21][CH3:28])[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: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CO)OCC
Agent: CS(=O)(=O)Cl
Product: CCCCCCCCCCCCCCCCSCC(COS(C)(=O)=O)OCC
Yield: 94 %

Procedure:
This compound was prepared in an analogous manner to that of (±)-1-S-hexadecyl-2-O-methyl-3-O-mesylthioglycerol from 5.5 grams (0.016 mole) of (±)-1-S-hexadecyl-2-O-ethylthioglycerol and 2.2 grams (0.019 mole) of methanesulfonyl chloride. This resulted in 6.2 grams of product (94%) as an oil. 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 31H, (CH2)14, CH3 --CH2 --O], 2.58(m, 2H, S--CH2), 2.62(m, 2H, CH--CH2 --S), 3.08(s, 3H, SO2 --CH3), 3.40-3.50(m, 3H, CH, CH3 --CH2 --O), 4.35(m, 2H, CH2 --OSO2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:35])[C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][N:10]2[C:11](=[O:13])[N:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:35])[C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[NH:16][CH2:15][CH2:14][N:10]2[C:11](=[O:13])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cc(F)c(Oc3ccc(F)cc3)c(F)c1)nc2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1nc(OCc2cc(F)c(Oc3ccc(F)cc3)c(F)c2)cc2n1CCN2

Procedure:
Prepared in a manner similar to that described for E60 using tert-butyl 7-((3,5-difluoro-4-(4-fluorophenoxy)benzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carbo-xylate (150 mg, 0.306 mmol) and TFA (2 mL, 26.0 mmol) in DCM (10 mL).