Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)[N:23]=1>>[N:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([N:8]([C@@H:9]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)[C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)=[O:36])=[CH:38][CH:39]=2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Reactant: O=C(O)c1ccc(-n2nnc3cccnc32)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](N(C(=O)c2ccc(-n3nnc4cccnc43)cc2)c2ncccc2Cl)C1
Yield: 78.9 %

Procedure:
Prepared according to General Procedure A and C starting from Preparation 1 tert-butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (26.7 g, 85.5 mmol) and Preparation 5 4-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)benzoic acid (20.1 g, 83.5 mmol) to provide 35.2 g (79%) of the product as a solid.
Reaction SMILES: C[O-].[Na+].[CH:4]([O:7][C:8](=[O:23])[C:9](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[C:10]([CH3:12])=O)([CH3:6])[CH3:5].C(O)(=O)C.[CH:28]([N:41]1[CH2:44][CH:43]([O:45][C:46](=[O:51])[CH2:47][C:48](=[NH:50])[NH2:49])[CH2:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)(C)C>[CH:4]([O:7][C:8]([C:9]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:47]([C:46]([O:45][CH:43]2[CH2:42][N:41]([CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:44]2)=[O:51])=[C:48]([NH2:49])[NH:50][C:10]=1[CH3:12])=[O:23])([CH3:6])[CH3:5]
Reactant: N=C(N)CC(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC2CN(C(c3ccccc3)c3ccccc3)C2)=C(N)N1
Yield: 88.2 %

Procedure:
According to Japanese Examined Patent Publication (Kokoku) No. Hei 3-31715, sodium methoxide (0.27 g) was added to a solution of 2-(3-nitrobenzylidene)acetoacetic acid isopropyl ester (1.39 g) and amidinoacetic acid (1-benzhydryl-3-azetidinyl) ester acetate (1.62 g) in isopropyl alcohol (80 ml) and the mixture was heated under reflux for 4 hours. After the reaction mixture was cooled, insoluble material was removed and the solvent was evaporated under reduced pressure. The thus obtained residue was dissolved in ethyl acetate and the mixture was washed with water, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography (toluene:ethyl acetate=3:1) to obtain pale yellow (±)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenylmethylazetidin-3-yl) ester 5-isopropyl ester (2.17 g, 74%).
Reaction SMILES: FC1C=CC([N+]([O-])=O)=C(C=1)C(OCC)=O.[F:16][C:17]1[CH:18]=[CH:19][C:20]([N+:29]([O-])=O)=[C:21]([CH:28]=1)[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23]>>[F:16][C:17]1[CH:28]=[C:21]([C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23])[C:20]([NH2:29])=[CH:19][CH:18]=1
Reactant: CCCOC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: CCOC(=O)c1cc(F)ccc1[N+](=O)[O-]
Product: CCCOC(=O)c1cc(F)ccc1N

Procedure:
If the isomerically pure ethyl 5-fluoro-2-nitrobenzoate is replaced by aliquot parts of a correspondingly prepared, isomerically pure n-propyl 5-fluoro-2-nitrobenzoate, and the same procedure is employed, then the isomerically pure n-propyl 5-fluoroanthranilate is obtained in comparable yield and quality.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]([CH3:24])[CH:26]=3)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cn(C)c4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1-methyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=489.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(OCC)(=O)C>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[O:25])[CH:11]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Fc1ccc(NCc2cccnc2)cc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)N(Cc1cccnc1)c1ccc(F)cc1

Procedure:
N-[(3-pyridyl)methyl]-N-(4-fluorophenyl)-(4-chlorophenylamino)carboxamide was prepared by the method of Example 21 by reacting 5.0 g. of N-(4-fluorophenyl)-[(3-pyridyl)methyl]amine with 3.76 g. of 4-chlorophenylisocyanate in 200 ml. of ethyl acetate. Weight 1.8 g. M.P. 95°-96° C.
Reaction SMILES: CO[CH:3](OC)[CH:4]([C:18]#[N:19])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[CH:7]=1.S(O)(O)(=O)=O.[OH:27][CH2:28][CH2:29][NH:30][C:31]([NH2:33])=[NH:32].C[O-].[Na+]>C(O)C>[OH:27][CH2:28][CH2:29][NH:30][C:31]1[N:33]=[C:18]([NH2:19])[C:4]([CH2:5][C:6]2[CH:7]=[C:8]([O:16][CH3:17])[C:9]([O:14][CH3:15])=[C:10]([O:12][CH3:13])[CH:11]=2)=[CH:3][N:32]=1
Reactant: N=C(N)NCCO
Reactant: COc1cc(CC(C#N)C(OC)OC)cc(OC)c1OC
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCO)nc2N)cc(OC)c1OC
Yield: 68.2 %

Procedure:
6.4 g of α-cyano-β-(3,4,5-trimethoxyphenyl)-propionaldehyde dimethylacetal, 3 g of β-hydroxyethylguanidine sulfate and 1.1 g of sodium methylate in 100 ml of ethanol were refluxed for 5 hours. The ethanol was then distilled off and the residue was dissolved in 100 ml of water. On extracting the solution with chloroform, 3.4 g (50% of theory) of 2-(β-hydroxyethylamino)-4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidine were obtained, melting at 146° C. after recrystallization from isopropanol.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[NH:19][C:18]2=[O:27])[CH:11]=1.CO.[Li+].[OH-].Cl>O>[F:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:27])[C:17]2=[CH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[O:28]
Reactant: COC(=O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.9 %

Procedure:
5-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)pentanoic acid methyl ester (396 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (294 mg, 77% yield) as a brown solid. LC-MS (m/z) 383 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Si:7]([O:14][C@@H:15]1[N:21]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:50])[C@@H:34]([NH:36][C:37](=[O:49])[C@@H:38]([NH:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])[CH:39]([CH3:41])[CH3:40])[CH3:35])=[CH:28][CH:27]=2)=[O:23])[C:20]2[CH:51]=[C:52]([OH:57])[C:53]([O:55][CH3:56])=[CH:54][C:19]=2[C:18](=[O:58])[N:17]2[CH:59]=[C:60](/[CH:62]=[CH:63]/[CH3:64])[CH2:61][C@@H:16]12)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Si:65]([O:72][C@@H:73]1[N:79]([C:80]([O:82][CH2:83][CH:84]=[CH2:85])=[O:81])[C:78]2[CH:86]=[C:87]([O:92][CH2:93][CH2:94][CH2:95]I)[C:88]([O:90][CH3:91])=[CH:89][C:77]=2[C:76](=[O:97])[N:75]2[CH:98]=[C:99](/[CH:101]=[CH:102]/[CH3:103])[CH2:100][C@@H:74]12)([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66]>CC(C)=O>[CH2:46]([O:45][C:43]([NH:42][C@H:38]([CH:39]([CH3:41])[CH3:40])[C:37]([NH:36][C@H:34]([CH3:35])[C:33]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([N:21]2[C:20]3[CH:51]=[C:52]([O:57][CH2:95][CH2:94][CH2:93][O:92][C:87]4[C:88]([O:90][CH3:91])=[CH:89][C:77]5[C:76](=[O:97])[N:75]6[CH:98]=[C:99](/[CH:101]=[CH:102]/[CH3:103])[CH2:100][C@H:74]6[C@H:73]([O:72][Si:65]([C:68]([CH3:71])([CH3:69])[CH3:70])([CH3:67])[CH3:66])[N:79]([C:80]([O:82][CH2:83][CH:84]=[CH2:85])=[O:81])[C:78]=5[CH:86]=4)[C:53]([O:55][CH3:56])=[CH:54][C:19]=3[C:18](=[O:58])[N:17]3[CH:59]=[C:60](/[CH:62]=[CH:63]/[CH3:64])[CH2:61][C@H:16]3[C@@H:15]2[O:14][Si:7]([C:10]([CH3:11])([CH3:12])[CH3:13])([CH3:8])[CH3:9])=[O:23])=[CH:31][CH:30]=1)=[O:50])=[O:49])=[O:44])[CH:47]=[CH2:48]
Reactant: C=CCOC(=O)N1c2cc(OCCCI)c(OC)cc2C(=O)N2C=C(/C=C/C)C[C@H]2[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(O)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O[Si](C)(C)C(C)(C)C)cc1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOC(=O)N[C@@H](C(=O)N[C@H](C)C(=O)Nc1ccc(COC(=O)N2c3cc(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/C)C[C@H]4[C@H](O[Si](C)(C)C(C)(C)C)N5C(=O)OCC=C)c(OC)cc3C(=O)N3C=C(/C=C/C)C[C@H]3[C@@H]2O[Si](C)(C)C(C)(C)C)cc1)C(C)C
Temperature: 75 °C
Yield: 35 %

Procedure:
Potassium carbonate (0.030 g, 0.21 mmol, 1.0 eq) was added to a solution of the phenol 18 (0.175 g, 0.21 mmol, 1.0 eq) and the iodo linker 49 (0.214 g, 0.32 mmol, 1.5 eq) in acetone (10 mL). The reaction mixture was heated under a nitrogen atmosphere at 75° C. in a sealed flask for 17 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified by flash chromatography (silica gel, 2/98 v/v methanol/DCM to 5/95 v/v methanol/DCM) to afford the product as a pale yellow solid (0.100 g, 35%). LC/MS (4.293 min (ES+)), m/z: 1359.13 [M]+.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:3]1=[O:19]>C1COCC1.[Zn]>[CH3:16][Si:15]([CH3:18])([CH3:17])[CH2:14][CH2:13][O:12][CH2:11][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[CH2:2][C:3]1=[O:19]
Reactant: C[Si](C)(C)CCOCN1C(=O)C(Br)(Br)c2cccnc21
Agent: [Zn]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Reaction time: 3 h

Procedure:
Zinc (10 g, 1.54 mol) was added to a solution of 3,3-dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (65 g, 0.154 mol) in THF (880 mL) and saturated aqueous NCl (220 mL). After 3 h, the reaction mixture was filtered and concentrated in vacuo. The residue was partitioned between EtOAc and H2O which resulted in the formation of a white precipitate. Both layers were filtered through a Celite pad and the layers were separated. The aqueous layer was washed with EtOAc (2×500 mL) and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with CH2Cl2:EtOAc-90:10, to give the title compound. MS: m/z=265 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]([CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[C:7]([O:14][CH3:15])=[CH:6][CH2:5][CH:4]=1.C([Li])(CC)C.Br[CH2:22][C@@H:23]1[O:25][C@:24]1([CH2:27][CH2:28][CH2:29][C:30]([O:33][CH3:34])([CH3:32])[CH3:31])[CH3:26]>CCOC(C)=O.CCCCCC.C1COCC1.C1CCCCC1>[CH3:15][O:14][C:7]1[C:8]([CH2:22][C@@H:23]2[O:25][C@:24]2([CH2:27][CH2:28][CH2:29][C:30]([O:33][CH3:34])([CH3:32])[CH3:31])[CH3:26])([CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[CH:4][CH2:5][CH:6]=1
Reactant: COC(C)(C)CCC[C@]1(C)O[C@H]1CBr
Reactant: COC1=CCC=C(OC)C1CC=C(C)C
Agent: [Li]C(C)CC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: COC1=CCC=C(OC)C1(CC=C(C)C)C[C@@H]1O[C@@]1(C)CCCC(C)(C)OC
Temperature: -30 °C
Yield: 67 %

Procedure:
A THF (100 mL) solution of 11 (4.35 g, 20.9 mmol, 1 equiv.) was cooled to −78° C. in a 250-mL round-bottom flask, and a cyclohexane solution of sec-butyllithium (1.21 M, 21.6 mL, 26.1 mmol, 1.25 equiv.) was added slowly over 5 min. The resulting yellow slurry was warmed to −30° C. over 40 min and maintained at that temperature for an additional 15 min. The resulting dark orange-red slurry was cooled to −78° C., and a THF (20 mL) solution of 29 (4.98 g, 18.8 mmol, 0.9 equiv.) was added, followed by two THF (10 mL) rinses of the flask that contained 29. At the end of the initial addition of 29, the slurry became faint yellow, and it was allowed to warm slowly to 0° C. over 3.5 h. The slurry was then quenched with H2O at 0° C., producing a mild effervescence. The mixture was warmed to room temperature and extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow oil. Flash column chromatography (400 mL SiO2, 9:1 to 8:2 hexane:EtOAc) afforded 4.95 g (12.6 mmol, 67% yield) of 30 as a colorless oil. TLC Rf 0.38 (8:2 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 4.89 (t, J=7.3 Hz, 1H), 4.76 (t, J=3.5 Hz, 1H), 4.72 (t, J=3.5 Hz, 1H), 3.51 (s, 3H), 3.46 (s, 3H), 3.15 (s, 3H), 2.75 (t, J=3.6 Hz, 2H), 2.61 (dd, J=8.0, 3.9 Hz, 1H), 2.34-2.27 (m, 2H), 2.03 (dd, J=13.7, 3.9 Hz, 1H), 1.76 (dd, J=13.7, 8.0 Hz, 1H), 1.62 (s, 3H), 1.54 (s, 3H), 1.51 (m, J=11.0, 5.5, 2.8 Hz, 1H), 1.42-1.37 (m, 2H), 1.35-1.30 (m, 2H), 1.27-1.22 (m, 1H), 1.17 (s, 3H), 1.12 (s, 6H). 13C NMR (126 MHz; CDCl3): δ 154.07, 154.01, 132.5, 120.7, 93.04, 92.93, 74.6, 61.46, 61.26, 54.5, 54.1, 49.3, 46.2, 40.10, 39.90, 34.6, 34.1, 26.1, 25.22, 25.16, 24.2, 19.8, 17.8, 16.8. FTIR (thin film) νmax: 2972, 2912, 2828, 1695, 1659, 1453, 1381, 1364, 1223, 1206, 1151, 1124, 1084, 1033, 973, 952, 849, 779, 689 cm−1. HRMS-ESI (m/z): [M+H]+ calculated for C24H40O4, 393.2999. found, 393.3000.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH:9]([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]1[OH:11].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:12][C:13]1[CH:18]=[C:17]([O:11][CH:5]2[CH2:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH:4]2[CH3:3])[N:16]=[CH:15][N:14]=1
Reactant: CC1CCCC(O)C1C
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1CCCC(Oc2cc(Cl)ncn2)C1C
Temperature: 25 °C
Yield: 89.1 %

Procedure:
In 5 ml of tetrahydrofuran was suspended 0.19 g of sodium hydride (60% in oil), to which 0.5 ml of a tetrahydrofuran solution containing 0.48 g of 2,3-dimethylcyclohexanol (mixture of isomers) was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 10 minutes and then cooled to 0° C., to which 1.5 ml of a tetrahydrofuran solution containing 0.5 g of 4,6-dichloropyrimidine was slowly added dropwise, followed by further stirring at room temperature for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.72 g of 4-chloro-6-(2,3-dimethylcyclohexyloxy)pyrimidine.
Reaction SMILES: [Br:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[C:15]([CH2:14][N:8]2[C:7](=[O:12])[CH:6]=[C:5]3[C:10]([N:11]=[C:2]([Br:1])[CH:3]=[CH:4]3)=[CH:9]2)[CH:16]=1
Reactant: Oc1cc2ccc(Br)nc2cn1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cc3nc(Br)ccc3cc2=O)c1

Procedure:
The alkylation of 7-bromo-3-hydroxy-8-azaisoquinoline (1.00 g, 4.46 mmol) using methyl 3-(bromomethyl)benzoate (1.53 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.C(N(CC)CC)C.Cl[CH:29]1[CH2:33][CH2:32][CH2:31][O:30]1.C(Cl)(Cl)Cl.C(O)C>CC(N(C)C)=O>[O:30]1[CH2:31][CH2:32][CH2:33][CH:29]1[N:5]1[C:4](=[O:18])[C:3]([C:2]([F:1])([F:19])[F:20])=[CH:16][N:7]([C@@H:8]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]2)[C:6]1=[O:17]
Reactant: ClC1CCCO1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=c1c(C(F)(F)F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1C1CCCO1
Reaction time: 8 h

Procedure:
5.92 Grams of 2'-deoxy-5-trifluoromethyluridine was dissolved in 40 ml of dry dimethylacetamide. Thereto was added 2.23 g of triethylamine and the mixture was ice-cooled. Thereto was added dropwise a dry dimethylacetamide solution containing 2.34 g of 2-chlorotetrahydrofuran prepared just prior to use, and the mixture was stirred overnight. The reaction mixture was subjected to filtration and the resulting filtrate was subjected to evaporation. The residue was extracted with chloroform and the extract was dried with anhydrous sodium sulfate. The solvent in the extract was removed by evaporation to obtain an oily residue. The residue was treated by a silica gel column chromatography (developing solvent: chloroform/ethanol =20/1). The eluate was recrystallized from ethanol-petroleum ether to obtain 2.80 g of the desired product. Melting point: 127°-128° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.Cl.[C:23]1([C:29]2[N:30]=[N:31][N:32]([CH:34]3[CH2:38][CH2:37][NH:36][CH2:35]3)[CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[N+](=C1CCCCCCCCCC1C1CCCCCCCCCC1)=[N-]>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:36]2[CH2:37][CH2:38][CH:34]([N:32]3[CH:33]=[C:29]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:30]=[N:31]3)[CH2:35]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1ccc(-c2cn(C3CCNC3)nn2)cc1
Agent: Cl
Agent: [N-]=[N+]=C1CCCCCCCCCC1C1CCCCCCCCCC1
Solvent: c1ccncc1
Product: Nc1c(F)c(N2CCC(n3cc(-c4ccccc4)nn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 90 °C
Yield: 9.8 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (100 mg, 0.33 mmol), 3-(4-phenyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (160 mg, 0.42 mmol) and diazobicycloundecane (102 mg, 0.67 mmol) in pyridine (5 ml) was heated at 90° C. for 20 hrs. The reaction mixture was concentrated and the residue was diluted with water. The separated solid was filtered, washed with water, methanol and then with CHCl3, followed by acetonitrile to get 16 mg (10%) of title compound, m.p. 265° C. 1H NMR (TFA) δ: 0.92-1.43 (m, 4H), 2.51-2.80 (m, 2H), 3.57-4.59 (m, 5H), 5.43-5.62 (m, 1H), 7.44 (dd, 5H), 8.50 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].[CH3:24]I>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[C:8]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH3:24]
Reactant: CC(=O)c1cc(Cl)c2cn[nH]c2c1-c1cc(F)cc(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(Cl)c2cnn(C)c2c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a mixture of 1-[4-chloro-7-(3,5-difluorophenyl)-1H-indazol-6-yl]ethanone (1.0 g, 3.3 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (200 mg, 4.9 mmol). After being stirred at room temperature for 30 minutes, to the resulting mixture was added methyl iodide (0.30 mL, 4.9 mmol). The reaction was stirred at room temperature for another 30 minutes, then quenched with sat. ammonium chloride and extracted with Ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate, then concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 30% ethyl acetate in hexane, to give the desired product (0.438 g, 42%). LCMS calculated for C16H12ClF2N2O (M+H)+: m/x=321.1; Found: 321.0. The other isomer, 1-[4-chloro-7-(3,5-difluorophenyl)-2-methyl-2H-indazol-6-yl]ethanone, was also isolated in a yield of 47%.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][N:22]=2)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[O:7])=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH:26](O)[CH3:27]>C(O)CO>[CH2:25]1[O:29][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:10]2[CH:20]=[CH:21][N:22]=[C:8]([C:6](=[O:7])[C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)[O:12][CH:26]1[CH3:27]
Reactant: CC(O)CO
Reactant: O=C(Nc1ccccc1)c1ccnc(C(=O)c2ccc(Cl)cc2)c1
Solvent: OCCO
Product: CC1COC(Nc2ccccc2)(c2ccnc(C(=O)c3ccc(Cl)cc3)c2)O1
Yield: 80 %

Procedure:
2-(4-Chlorobenzoyl)-isonicotinanilide (11 g) was treated as in Synthesis 16 except that ethylene glycol was replaced by propylene glycol. The titled compound was obtained in an amount of 10.5 g (yield: 80%). m.p. 125°-126° C.
Reaction SMILES: [F:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:21]=[C:22]([NH2:33])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1>CN1C(=O)CCC1>[F:1][CH:2]1[CH2:4][CH:3]1[C:5]1[O:7][N:33]=[C:22]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=2)[N:21]=1
Reactant: Cc1ccc(C(N)=NO)cc1[N+](=O)[O-]
Reactant: O=C(O)[C@@H]1C[C@H]1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: Cc1ccc(-c2noc(C3CC3F)n2)cc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 0.05 h

Procedure:
To a stirring solution of trans-2-Fluoro-cyclopropanecarboxylic acid (0.38 g, 3.68 mmol) in anhydrous NMP (12 mL) was added 1,1′-carbonyldiimidazole (CDI) (0.59 g, 3.68 mmol). The reaction was stirred for 3 minutes. N′-hydroxy-4-methyl-3-nitrobenzimidamide (27) (0.72 g, 3.68 mmol) was added and the reaction was stirred for minutes then heated in the microwave at 120° C. for 15 minutes. The crude product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified on silica gel using ethyl acetate and hexane to yield 5-(2-fluorocyclopropyl)-3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazole (129). MS m/z 264.1 (M+1)+.