Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][CH2:7][C:8](=[O:20])[C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10]([OH:12])=O.Cl.[NH2:22][CH:23]1[C:48](=[O:49])[N:25]2[C:26]([C:32]([O:34][CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])=[C:27]([CH:30]=[CH2:31])[CH2:28][S:29][C@H:24]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[Cl:6][CH2:7][C:8](=[O:20])[C:9](=[N:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10]([NH:22][CH:23]1[C:48](=[O:49])[N:25]2[C:26]([C:32]([O:34][CH:35]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:33])=[C:27]([CH:30]=[CH2:31])[CH2:28][S:29][C@H:24]12)=[O:12]
Reactant: COC(=O)CON=C(C(=O)O)C(=O)CCl
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)C(=O)CCl)[C@H]2SC1
Yield: 93.7 %

Procedure:
Vilsmeir reagent prepared from N,N-dimethylformamide (3.4 g) and phosphorus oxychloride (7.1 g) was suspended in dry tetrahydrofuran (30 ml). To the suspension was added 4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyric acid (syn isomer) (10 g) under ice-cooling, and the mixture was stirred at the same temperature for an hour to prepare the activated acid solution. This solution was added at a time to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (16.3 g) and trimethylsilylacetamide (40 g) in ethyl acetate (163 ml) at -30° C. After the reaction mixture was stirred at -15° C. for an hour, the resultant solution was poured into water (100 ml) and then extracted with ethyl acetate (200 ml). The extract was washed with a saturated aqueous sodium bicarbonate and a saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give benzhydryl 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (21.8 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[NH:45]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C@H:46]([C:52]([OH:54])=[O:53])[CH2:47][CH2:48][CH2:49][CH2:50][NH2:51]>CN(C=O)C>[C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:23])[NH:51][CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]([NH:45][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[C:52]([OH:54])=[O:53])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O

Procedure:
Hexadecanedioic acid mono-tert-butyl ester can be activated with TSTU in similar fashion to the method described in Example 1, Step 6. The product can be reacted with Boc-Lys-OH in DMF at RT for 16 h. After concentrating under vacuum, AcOEt can be added the residue and the mixture can be washed with 0.2 N HCl. The organic phase is then dried over MgSO4 and concentrated under vacuum to yield the crude product, 15-((S)-5-tert-Butoxycarbonylamino-5-carboxypentylcarbamoyl)pentadecanoic acid tert-butyl ester. This can either be used without further purification or purified by flash chromatography. This compound can be activated with TSTU in similar fashion to the method described in Example 1, Step 6 to yield 15-[(S)-5-tert-butoxycarbonylamino-5-(2,5-dioxopyrrolidin-1-yloxycarbonyl) pentylcarbamoyl]pentadecanoic acid tert-butyl ester, and this compound can be coupled to insulin and deprotected to yield the title compound as described in Example 1, Step 7 using prepatative HPLC to isolate the product.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:14]([C:15](OCC)=[O:16])=[CH:13][N:12]=[C:11]2[NH:20][CH:21]=[CH:22][C:10]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:8][C:9]1[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[C:11]2[NH:20][CH:21]=[CH:22][C:10]=12
Reactant: CCOC(=O)c1cnc2[nH]ccc2c1N[C@H]1CCCC[C@H]1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CCCC[C@@H]1Nc1c(CO)cnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
To a solution of ethyl 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (50 mg) in tetrahydrofuran (1 mL) was added lithium aluminum hydride (21 mg) at 4° C. The reaction mixture was stirred at the same temperature for an hour, at ambient temperature for an hour, and at 60° C. for 2 hours. After cooled to ambient temperature, to the mixture was added water (0.021 ml), 15% NaOH solution (0.021 ml), water (0.063 ml) one after another. The precipitate was filtered through a celite pad. The filtrate was concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with chloroform:methanol=8:1 to give (4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (15.6 mg) as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[OH:16][C:17]1[C:22]2[O:23][C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:25][C:21]=2[CH:20]=[C:19]([C:38](Cl)=[O:39])[CH:18]=1>C(Cl)Cl>[OH:16][C:17]1[C:22]2[O:23][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:25][C:21]=2[CH:20]=[C:19]([C:38]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:39])[CH:18]=1
Reactant: O=C(Cl)c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.8 %

Procedure:
Piperidine (0.3 ml, 2 mmol) and ethyl diisopropylamine (0.5 ml, 3 mmol) were dissolved in methylene chloride (10 ml). 7-Hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl chloride (353 mg, 1 mmol) dissolved in methylene chloride (3 ml) was added dropwise at room temperature. The reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was extracted with 1N aqueous HCl solution, brine, dried over sodium sulfate and filtered. The solvent was evaporated and the residue purified by column chromatography on silica gel (20 g, 5% methanol in dichloromethane eluant) to yield the phenol as a white solid (180 mg, 45%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:16]([CH2:24][C:25](=[O:29])/[CH:26]=C/C)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]([CH:13]1[CH2:15][CH2:14]1)=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)C(=O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[C:11]([CH:13]2[CH2:15][CH2:14]2)=[CH:26][C:25](=[O:29])[CH2:24][N:16]1[C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: C=C(C1CC1)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)/C=C/C)C(=O)OC(C)(C)C
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Product: CC(C)(C)OC(=O)N1CC(=O)C=C(C2CC2)[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 110 °C

Procedure:
The title compound was prepared from (S,E)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-yl(2-oxopent-3-enyl)carbamate (Intermediate 236, 4 g, 9.44 mmol) following the procedure described for Intermediate 7, except the reaction mixture was heated at 110° C. overnight. The desired product was obtained as a light brown oil (2.97 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([CH3:22])[CH:3]=1.[H-].[Na+].I[CH3:26].[NH4+].[Cl-]>C1COCC1>[C:17]([O:16][C:15](=[O:21])[N:14]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:22])[CH3:26])([CH3:18])([CH3:19])[CH3:20]
Reactant: CI
Reactant: Cc1cc(F)ccc1-c1ccncc1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1ccncc1N(C)C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a stirring solution of tert-butyl 4-(4-fluoro-2-methylphenyl)pyridin-3-ylcarbamate (230 mg, 0.76 mmol) in THF (5 mL) under argon was added NaH (23.9 mg, 1 mmol). After 15 min iodomethane (62 μL, 1 mmol) was added and the reaction mixture was stirred for 1 h. The reaction mixture was poured into saturated aqueous NH4Cl solution and extracted three times with EtOAc. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure gave the N-methylated product [4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-carbamic acid tert-butyl ester as a light brown oil. This oil was treated with 4M HCl in dioxane for 1 h. Removal of volatiles gave an oily solid which was suspended in CH2Cl2 and washed with 1M aqueous K2CO3 solution. The aqueous phase was extracted twice more with CH2Cl2 and the combined organic phases were dried over MgSO4. Filtration followed by removal of volatiles gave the desired product (113 mg, 69%) which was pure enough for the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].I[C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=[N:18][C:19]=1[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:20][C:19]1[N:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)=[CH:15][C:14]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1I
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ncc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Yield: 74.7 %

Procedure:
(3-Nitrophenyl)boronic acid (0.086 g, 0.52 mmol) was mixed with N-(5-iodo-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide (0.21 g, 0.52 mmol) and potassium carbonate (0.13 g, 0.91 mmol) in toluene (3.8 mL), ethanol (0.56 mL) and water (0.5 mL) and the solution was degassed. Into the reaction was added tetrakis(triphenylphosphine)palladium(0) (0.025 g, 0.022 mmol) and was refluxed for 18 hours. The reaction was extracted with EtOAc and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and stripped in vacuo. The residue was purified by column chromatography using 40% EtOAc/hexanes to give the product (0.156 g, 75% yield). 1H NMR (400 MHZ, CDCl3): δ 8.67 (d, 1H), 8.28 (m, 2H), 8.16 (brs, 1H), 8.11 (m, 1H), 7.99 (brs, 1H), 7.85 (m, 1H), 7.69 (m, 4H), 2.52 (s, 3H); MS (ES) (M+H)=402.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]3[O:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:13]=1)=[N:7]2.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][N:40](C(OC(C)(C)C)=O)[CH:41]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:15]1[CH:14]=[CH:13][C:12]([C:6]2[C:5]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[N:11][C:2]=3[C:37]3[CH:38]=[N:39][NH:40][CH:41]=3)[N:7]=2)=[CH:17][CH:16]=1
Reactant: Clc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1ccc(-c2cc3c(-c4cn[nH]c4)nccc3nc2-c2ccc(C3OCCO3)cc2)cc1
Temperature: 100 °C

Procedure:
To a solution of 5-chloro-2-[4-(1,3-dioxolan-2-yl)phenyl]-3-phenyl-1,6-naphthyridine (1-1, Reference: WO2006135627A2, Dec. 21, 2006) (1.7 g, 4.2 mmol) in DMF (100 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (2.5 g, 8.6 mmol), cesium carbonate (4.2 g, 13 mmol) and Pd(Ph3P)2Cl2 (0.030 g, 0.042 mmol). The reaction mixture was heated at 100° C. under an atmosphere of N2 for 1 hour. The reaction was cooled to room temperature, poured into saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (EtOAc in hexane) gave 2-[4-(1,3-dioxolan-2-yl)phenyl]-3-phenyl-5-(1H-pyrazol-4-yl)-1,6-naphthyridine (1-2) as a white solid. MS (M+H)+: calculated 421.47; found 421.51
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]2[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=2)[CH:35]=1)[C:12](=[O:32])[CH2:13][NH:14]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OCC)(=O)C>C(#N)C.N1CCCCC1>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]2[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([O:46][CH3:47])[CH:45]=2)[CH:35]=1)[C:12](=[O:32])[CH2:13][NH2:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)ccn2)cc(OC)c1OC
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)CN)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[2-(tert-butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-Nα-(9-fluorenylmethoxycarbonyl)glycine amide (5.15 g) was dissolved in a 20% acetonitrile solution (40 mL) of piperidine, and the solution was stirred at room temperature for 4 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to obtain the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6].[CH2:12]([OH:17])[C:13]([F:16])([F:15])[F:14]>C1COCC1.CCOC(C)=O>[CH:10]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[O:17][CH2:12][C:13]([F:16])([F:15])[F:14])=[O:11]
Reactant: N#Cc1ccc(C=O)c(F)c1
Reactant: OCC(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C=O)c(OCC(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of 3-fluoro-4-formyl-benzonitrile (CAS 105942-10-7, 1 g) in THF (25 ml) was cooled to 0° C. under argon. Trifluoroethanol (3.36 g) and potassium tert.-butylate (0.83 g) were added subsequently. The mixture was stirred for 2 h. The mixture was diluted with EtOAc and washed with water. The organic phase was dried, filtered and concentrated. The product was purified by flash chromatography (SiO2, cyclohexane/EtOAc 1:1) to give 4-formyl-3-(2,2,2-trifluoro-ethoxy)-benzonitrile. Yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:26]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:25])=[C:15]([NH:17]C(=O)OC(C)(C)C)[CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.FC(F)(F)C(O)=O>CN(C)C(=O)C>[NH2:17][C:15]1[CH:16]=[C:11]([CH:12]=[CH:13][C:14]=1[F:25])[O:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:30]([CH:27]3[CH2:29][CH2:28]3)=[O:31])[N:26]=2)[CH:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3nc(N)nn3c2)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)ccc1F
Yield: 77.2 %

Procedure:
In the same manner as in Example 66-2 and using tert-butyl {5-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-2-fluorophenyl}carbamate (8.99 g, 25.0 mmol), cyclopropanecarbonyl chloride (3.82 mL, 42.0 mmol), N,N-dimethylacetamide (60 mL) and trifluoroacetic acid (50 mL) as starting materials, the title compound (6.32 g, 77%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:21]2[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
p-Acetoxybenzoic acid (11 g, 61.1 mmol) was dissolved in methylene chloride (100 ml), to which DMF (3 drops) and thionyl chloride (5.54 ml, 76.3 mmol) were added, and the mixture was heated under reflux for 2 hours. The mixture was cooled in an ice-bath, to which a solution of tert-butyl piperazine-1-carboxylate (10.3 g, 55.5 mmol) and pyridine (12 ml, 0.15 mol) in methylene chloride (100 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride, and the mixture was washed with water, 10% hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford tert-butyl 4-(4-acetoxybenzoyl)piperazine-1-carboxylate (18.5 g, yield 87%) as a colorless crystalline powder.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])=O)(C)(C)C.[ClH:20].NCCCC(OC1C(C)=CC=CC=1C)=O>>[ClH:20].[NH2:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)Oc1ccccc1
Agent: Cc1cccc(C)c1OC(=O)CCCN
Agent: Cl
Product: NCCC(=O)Oc1ccccc1

Procedure:
The title compound was prepared from phenyl N-(tert-butoxycarbonyl)-β-alaninate in a similar manner as described for 2,6-dimethylphenyl 4-aminobutanoate hydrochloride. 1H NMR (400 MHz, CDCl3): δ 7.36-7.40 (t, 2H), 7.22-7.25 (t, 1H), 7.12-7.14 (d, 2H), 4.82 (s, 3H), 3.27-3.30 (m, 2H), 2.99-3.03 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[F:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[F:33]
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N45-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 96.4%, 424.0482 (M−H)−.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[C:20]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=[CH:18][C:4]=1[O:5][CH2:6][C:7]1[N:11]=[CH:10][N:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:33]1[N:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][N:34]=1>CN(C)C=O>[CH2:39]([C:36]1[CH:35]=[N:34][C:33]([N:15]2[CH2:16][CH2:17][CH:12]([N:9]3[CH:10]=[N:11][C:7]([CH2:6][O:5][C:4]4[CH:18]=[CH:19][C:20]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:21][C:3]=4[F:2])=[N:8]3)[CH2:13][CH2:14]2)=[N:38][CH:37]=1)[CH3:40]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(OCc2ncn(C3CCNCC3)n2)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cnc(N2CCC(n3cnc(COc4ccc(S(C)(=O)=O)cc4F)n3)CC2)nc1
Temperature: 90 °C

Procedure:
A mixture of 4-[3-(2-fluoro-4-methanesulfonyl-phenoxymethyl)-[1,2,4]triazol-1-yl]-piperidine hydrochloride salt (Intermediate 6, 0.100 g, 0.256 mmol), potassium carbonate (0.106 g, 0.768 mmol) and 2-chloro-5-ethyl-pyrimidine (0.062 mL, 0.512 mmol) in dimethylformamide (2 mL) was heated at 90° C. for 4 hours or until the starting material was consumed. The reaction was cooled to room temperature, the solution was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and concentration in vacuo. The residue was chromatographed on silica gel (1:1 Hex/EtOAc) to afford the desired product. 1H NMR (CDCl3): δ 8.22 (2H, s), 8.17 (1H, s), 7.68 (2H, m), 7.38 (1H, m), 5.28 (2H, s), 4.92 (2H, d), 4.47 (1H, m), 3.08 (3H, s), 2.94 (2H, m), 2.48 (2H, q), 2.27 (1H, m), 2.18 (1H, m), 1.98 (2H, m), 1.20 (3H, t).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:4]=1OCC1CCNC1.[OH:20][CH2:21][CH:22]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]1>>[ClH:2].[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][CH:3]=[CH:4][C:12]=1[O:20][CH:21]1[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: FC(F)(F)c1ccc(Cl)c(OCC2CCNC2)c1
Agent: Cl
Product: FC(F)(F)c1ccccc1OC1CCNCC1
Yield: 72 %

Procedure:
The synthesis of intermediate 1n is performed starting with 3-hydroxymethyl-1-BOC-pyrrolidine following the operating mode described for the synthesis of 1a (white solid, total yield 72%). TLC silica gel 60 F 254 Merck, CH2Cl2-MeOH—AcOH: 90:9:1, Rf=0.10
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]([CH3:21])([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[C:7]([NH2:9])=[O:8])([CH3:5])[CH3:4].[CH3:22][OH:23]>>[C:7]([C:6]([NH:10][C:11]([C:12]1[N:13]=[CH:14][CH:15]=[CH:16][C:17]=1[C:18]([O:23][CH3:22])=[O:19])=[O:20])([CH3:21])[CH:3]([CH3:5])[CH3:4])(=[O:8])[NH2:9]
Reactant: CC(C)C(C)(C(N)=O)N1C(=O)c2cccnc2C1=O
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cccnc1C(=O)NC(C)(C(N)=O)C(C)C
Reaction time: 8 h

Procedure:
Sodium hydride (0.47 g of a 50% suspension in mineral oil) is reacted with 500 mL dry methanol under nitrogen. To this is added 51.4 g of 5,7-dihydro-alpha-isopropyl-alpha-methyl-5,7-dioxo-6H-pyrrolo [3,4-b]pyridine-6-acetamide and the mixture stired at room temperature overnight. The mixture is concentrated, the residue dissolved in methylene chloride and the solution washed first with 150 mL water followed by 150 mL brine. After drying (Na2SO4), the organic phase is concentrated and the residue crystallized from ether to give 47.85 g of product which is analytically pure mp 108°-145° C. with decomposition.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12]SCCCCCC)[NH:4][N:3]=1.[CH2:20](SCCCl)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC>>[NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[NH:4][N:3]=1
Reactant: CCCCCCCCSCCCl
Reactant: CCCCCCSCCSCCSc1nc(N)n[nH]1
Product: CCCCCCCCSCCSc1nc(N)n[nH]1
Yield: 96 %

Procedure:
Compound 7 was prepared by using the procedure used for Compound 12, but with 2-chloroethyl octyl sulfide as the starting material. The yield was 96%. A portion was recrystallized from ligroin/ethyl acetate to obtain a solid, m.p. 85°-86° C. Analysis: Calculated for C12H24N4S2 : C, 49.96; H, 8.39; N, 19.42. Found: C, 49.54; H, 8.12; N, 19.29.