Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Cl:24][CH2:25][CH:26]([OH:49])[CH2:27][CH:28]([C:40]1[CH:45]=[C:44]([F:46])[C:43]([F:47])=[C:42]([F:48])[CH:41]=1)[C:29]([NH:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[Si:5]([O:49][CH:26]([CH2:25][Cl:24])[CH2:27][CH:28]([C:40]1[CH:45]=[C:44]([F:46])[C:43]([F:47])=[C:42]([F:48])[CH:41]=1)[C:29]([NH:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])([C:1]([CH3:4])([CH3:3])[CH3:2])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)C(CC(O)CCl)c1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)C(CC(CCl)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
tert-Butyldiphenylchlorosilane (0.889 mL), imidazole (233 mg) and DMAP (41.9 mg) were added to a solution of tert-butyl N′-[5-chloro-4-hydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate (680 mg) in DMF (5 mL). The reaction solution was stirred at 60° C. for two hours and then left to cool to room temperature. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 831 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:46])=[N:17][C:18]([CH3:45])=[C:19]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:31][CH:30]=2)[C:20]=1[N:21]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:28][CH2:27]2)[CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:46])=[N:17][C:18]([CH3:45])=[C:19]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:34]=2)[C:20]=1[N:21]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:28][CH2:27]2)[CH2:22]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C3CC3)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C3CC3)C2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 18 h
Yield: 68.3 %

Procedure:
The 0.40 mL of 1M sodium hydroxide (15.93 mg, 0.40 mmol) was added to a solution of (2S)-isopropyl 2-(tert-butoxy)-2-(4-(3-cyclopropylpyrrolidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (60 mg, 0.10 mmol) in ethanol (2.5 mL) and stirred for 18 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to afford (2S)-2-(tert-butoxy)-2-(4-(3-cyclopropylpyrrolidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid 38.3 mg (69%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.39-7.36 (m, 2H), 7.20-7.19 (m, 1H), 7.15-7.11 (m, 2H), 7.03-6.97 (m, 3H), 5.62/5.61 (s, 1H), 4.21 (t, J=6.6 Hz, 2H) 3.21-2.58 (series m, 6H), 2.44/2.43 (s, 3H), 2.06/2.04 (s, 3H), 1.69-1.64 (m, 1H), 1.41-1.22 (m, 2H), 1.10/1.09 (s, 9H), 0.51-0.45 (m, 1H), 0.32-0.23 (m, 2H), −0.50-0.15 (m, 2H). UPLC (M+H)=603.5.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>O1CCCC1>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 64 %

Procedure:
Into 30 ml of tetrahydrofuran were suspended 1.3 g of 5-fluorouracil. To this suspension were added 1.4 g of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 5 hours at 170° C. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 1 whereby 0.30 g of the starting 5-fluorouracil was recovered as a substance insoluble in chloroform and 1.28 g of 1-(2-tetrahydrofuryl)-5-fluorouracil were obtained. The yield of the end product was 83.2% based on the consumed 5-fluorouracil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]1=[O:24].C(N(CC)CC)C.[F:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>O1CCCC1>[Cl:10][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:2]([NH:1][C:35](=[O:36])[C:34]2[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:33]=2[F:32])[C:7]=1[O:8][CH3:9]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c1NC(=O)c1ccc(F)cc1F
Yield: 80.2 %

Procedure:
3-(2-Amino-4-chloro-6-fluoro-3-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (2.0 g, 5.4 mmol) and triethylamine (0.66 g, 6.5 mmol) were dissolved in anhydrous tetrahydrofuran (30 ml) and stirred under ice cooling. To this solution was slowly added 2,4-difluorobenzoyl chloride (0.96 g, 5.4 mmol) and solution refluxed for 2 hr. Another batch of 2,4-difluorobenzoyl chloride (0.19 g, 1.1 mmol) was added and solution refluxed for 2 hr. Solvent was removed in vacuo and the product purified by column chromatography on silica gel using hexane-ethyl acetate (3:1) as the eluent to afford the title compound (2.2 g).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8]([N:35]3[CH2:36][CH2:37][CH:32]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:33][CH2:34]3)=[O:26])[CH:15]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(N2CCCC2)CC1
Reaction time: 0.83 h

Procedure:
[4-(4-Nitrophenoxy)pyridin-2-yl]carbamic acid phenyl ester (100 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogen atmosphere, and then 4-(pyrrolidin-1-yl)piperidine (148 mg) was added thereto, followed by stirring for 50 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:2 to 1:8). The solvent was evaporated under a reduced pressure to give a residue, which was then dried in vacuum to provide 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20]C1N=C(C(N)=N)C=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[N:3]=1
Reactant: Cc1cccc(C(=N)N)n1
Reactant: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Product: Cc1cccc(-c2nc(Cl)cc(-c3cccnc3)n2)n1

Procedure:
This compound is prepared analogously to Intermediate A by replacing pyridine-2-carboxamide (step 1) with 6-methyl-pyridine-2-carboxamidine (Intermediate B); [M+H]+=283.
Reaction SMILES: [CH2:1]([C:8](=[CH2:19])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(#N)C>[CH2:1]([CH:8]([CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: CC#N
Product: O=C(OCc1ccccc1)C(Cc1ccccc1)Cn1ccnc1
Yield: 94.7 %

Procedure:
The resultant compound from Example 73 (10.00 g, 36.93 mmol) and imidazole (5.40 g, 79.3 mmol) in acetonitrile (10 mL) were heated at reflux for 44 h. The mixture was evaporated and the residue was chromatographed on silica gel with 2% methanol in chloroform to afford 11.20 g (88%) of the desired product as an oil: TLC (5% methanol/95% chloroform) Rf =0.35; 1H-NMR (CDCl3) 7.38 (s, 1H), 7.38-7.05 (m, 10H), 7.00 (dd, 1H), 6.80 (dd, 1H), 5.03 (d, 1H), 4.99 (d, 1H), 4.25 (1H), 4.03 (dd, 1H), 3.22-3.09 (m, 1H), 3.02 (dd, 1H), 2.78 (dd, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([N:13]=NC2C=CC=CC=2)=[C:8]([CH3:21])[CH:7]=1)[CH2:2][CH2:3][CH3:4].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([NH2:13])=[C:8]([CH3:21])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(C)c(N=Nc2ccccc2)c(C)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOc1cc(C)c(N)c(C)c1

Procedure:
To a flask fitted with reflux condenser and stirrer containing 4-butoxy-2,6-dimethylazobenzene (53.4 g, 0.189 mole) was added 50% aqueous ethanol (480 ml). The mixture was heated close to boiling with stirring and sodium hydrosulfite (Na2S2O4, 121.4 g, 0.697 mole) was added in small portions over a period of 30 min. The mixture was refluxed for 75 min. Most of the alcohol was distilled off and the oily amine layer formed in the operation was taken up in ether. The aqueous phase was made alkaline with sodium hydroxide and was extracted with ether. All the combined ether extracts were dried (Na2SO4), were filtered, and all low-boiling components were evaporated at reduced pressure (solvent and aniline), after which the residue was fractionated by distillation in vacuo. The fraction boiling at 105°-108° (0.1 mm Hg) was collected. Yield: (63%); nD25 =1.5337. [Cf. E. Honkanen, Ann. Acad. Sci. Fennicae, Ser. AII, 99 (1960)].
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(F)(F)F)CC3)C=2)C=1)(C)CCC(O)=O.C(O)(C(F)(F)F)=O.[N+:37]([C:40]([C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:61][C@H:62]3[CH2:67][CH2:66][C@H:65]([C:68]([F:71])([F:70])[F:69])[CH2:64][CH2:63]3)[C:53]=2[C:57]([F:60])([F:59])[F:58])[CH:48]=1)([CH3:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])([O-])=O>>[NH2:37][C:40]([C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([O:61][C@H:62]3[CH2:63][CH2:64][C@H:65]([C:68]([F:69])([F:70])[F:71])[CH2:66][CH2:67]3)[C:53]=2[C:57]([F:59])([F:60])[F:58])[CH:48]=1)([CH3:46])[CH2:41][CH2:42][C:43]([OH:45])=[O:44]
Reactant: CC(CCC(=O)O)(c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CCC(=O)O)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1

Procedure:
4-Amino-4-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid was synthesized as per 4-amino-4-[6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid (Example 282) in 56% yield (as TFA salt), using 4-nitro-4-[5-trifluoromethyl-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid as starting material. MS: m/z=500.20 [M+Na]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.23 (br. s., 1H), 8.53 (br. s., 3H), 8.22 (d, J=9.3 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.05 (d, J=1.5 Hz, 1H), 7.72-7.80 (m, 2H), 4.62-4.73 (m, 1H), 2.35-2.42 (m, 1H), 2.21-2.34 (m, 2H), 2.07-2.20 (m, 3H), 1.88-2.05 (m, 3H), 1.66-1.78 (m, 3H), 1.40-1.60 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[N:17]=[N:18][NH:19][C:20]=1[Si](C)(C)C.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[N:17]=[N:18][NH:19][CH:20]=1
Reactant: C[Si](C)(C)c1[nH]nnc1-c1ccncc1Nc1ccc(I)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Fc1cc(I)ccc1Nc1cnccc1-c1c[nH]nn1
Yield: 68.6 %

Procedure:
N-(2-fluoro-4-iodophenyl)-4-[5-(trimethylsilyl)-1H-1,2,3-triazol-4-yl]pyridin-3-amine (20 mg, 0.044 mmol) was added into a solution of NaOH (3.5 mg, 0.088 mmol) in THF (0.5 mL) for 5 days. The mixture was diluted with MeOH and neutralized to pH7 with acidic resin (Dowex). After filtration and the filtrate was concentrated to give pure product (11.5 mg, 69%). LC/MS [Method A: rt: 0.40 min; m/z: 381 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[C:21](OCC)(OCC)(OCC)[CH3:22]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:21]([CH3:22])=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1cc(-c2ccccc2Cl)c2cc(Cl)ccc2n1
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc(Cl)ccc3n12

Procedure:
In the manner given in Example 2, 6-chloro-4-(o-chlorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-chloro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline of melting point 257°-259° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]([O:11][CH3:12])=[O:10])=[CH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(Oc1ccc(C)cc1)c1ccccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1)c1ccccc1Cl
Yield: 76.5 %

Procedure:
To a solution of 0.200 g (0.69 mmol) of the product of Step C dissolved in 2 mL of carbon tetrachloride was added 0.117 g (0.95 eq) of N-bromosuccinimide and ca. 10 mg (catalytic amount) of AIBN. The reaction mixture was stirred and refluxed under a nitrogen atmosphere for 30 minutes, then cooled and concentrated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.186 g (73%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8](=[O:16])[C@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][OH:11])=[CH:4][CH:3]=1.[Si]([N:23]=[N+:24]=[N-])(C)(C)C>CC#N>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:16])[C@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][OH:11])=[CH:17][CH:18]=1)=[N+:23]=[N-:24]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)N[C@H](CO)C(=O)NCc1ccc(N)cc1
Solvent: CC#N
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To a cooled (0° C.) CH3CN solution (70 mL) of (R)—N-(4-aminobenzyl)-2-acetamido-3-hydroxypropanamide (2.40 g, 9.56 mmol) maintained under Ar, t-BuONO (3.41 mL, 28.68 mmol) followed by TMSN3 (3.02 mL, 22.94 mmol) were slowly added. The resulting solution was allowed to stir at room temperature (16 h) under Ar. The solvent was removed in vacuo, and the product was purified by column chromatography (SiO2; 1/9 MeOH/CHCl3) to give 2.10 g (79%) of (R)—N-(4-azidobenzyl)-2-acetamido-3-hydroxypropanamide as a white solid: mp 161-163° C.; [α]26D +13.2° (c 1.0, MeOH); Rf=0.35 (1/9 MeOH/CHCl3); IR (nujol mull) 3268, 2924, 2128, 1649, 1553, 1459 cm−1; 1H NMR (DMSO-d6) δ 1.87 (s, CH3C(O)), 3.58 (t, J=5.7 Hz, CH2OH), 4.26-4.32 (m, CH2Ar and CH), 4.91 (t, J=5.7 Hz, OH), 7.03-7.08 (m, 2 ArH), 7.28-7.31 (m, 2 ArH), 7.94 (d, J=8.1 Hz, NHCH), 8.40 (t, J=6.0 Hz, NHCH2); 13C NMR (DMSO-d6) δ 22.7 (CH3C(O)), 41.5 (CH2Ph), 55.3 (CH), 61.7 (CH2OH), 118.9, 128.7, 136.5, 137.7 (C6H5), 169.4, 170.3 (2 C(O)); HRMS (ESI) 278.1249 [M+H+] (calcd. for C12H16N5O3 278.1253); Anal. (C12H15N5O3) Calcd.: C, 51.98%; H, 5.45%; N, 25.26%. Found: C, 51.93%; H, 5.47%; N, 24.98%.
Reaction SMILES: [Na].Cl[C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1.[CH2:14]([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:14]([O:20][C:3]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][S:5][N:4]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCCCCCO
Agent: [Na]
Product: CCCCCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in 1-hexanol (15 ml) was added 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (490 mg, 2.5 mmol). The mixturewas stirred at 50° C. for 2 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: [N:1]1([C:5]2[CH:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[N:8]=[C:7]([S:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[N:1]1([C:5]2[CH:10]=[C:9]([NH:11][C:12]3[NH:13][N:14]=[C:15]([CH3:17])[CH:16]=3)[N:8]=[C:7]([S:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:33][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:24])=[CH:21][CH:20]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)O)cc3)n2)[nH]n1
Reactant: NC1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(N3CCC3)nc(Sc3ccc(C(=O)NC4CCCC4)cc3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 25 ml round bottom flask was charged with 4-[4-azetidin-1-yl-6-(5-methyl-2H-pyrazol-3-ylamino)-pyrimidin-2-ylsulfanyl]-benzoic acid (200 mg, 0.48 mmol), cyclopentyl amine (85 mg, 1 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3,-tetramethyluroniumtetrafluoroborate (321 mg, 1 mmol), diisopropylethylamine (0.34 ml, 2 mmol) in dimethylformamide (5 ml), under nitrogen. The reaction mixture was stirred at room temperature for 18 hours and then was diluted with ethyl acetate (40 ml), washed with a saturated sodium hydrogen carbonate aqueous solution (40 ml) and brine (40 ml). The organic was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated in dichloromethane to afford the title compound. 1H NMR (DMSO-d6): 1.60-1.65 (4H, m), 1.70-1.80 (2H, m), 1.95-2.10 (5H, m), 2.20-2.30 (2H, m), 3.90-4.00 (4H, s), 4.30-4.35 (1H, m), 5.35-5.40 (1H, s), 7.70-7.75 (2H, d), 8.00-8.05 (2H, d), 8.45-8.50 (1H, d), 9.3 (1H, s). MS (ES+): 450.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)[C:28]1=[O:49].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:31]3[CH:30]=[C:29]([NH:42][C:43]4[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=4)[C:28](=[O:49])[N:27]([CH3:26])[CH:32]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: Cn1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)n1
Temperature: 100 °C
Yield: 53.1 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (359 mg, 1.0 mmol), 140b (660 mg, 2.0 mmol), K3PO4 (424 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (82 mg, 0.10 mmol), sodium acetate (164 mg, 2.0 mmol), and acetonitrile/water (15/0.2 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1.5 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (30 mL) and water (30 mL). The organic layer was separated and the aqueous extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 50/1) to afford 140c (280 mg, 53%) as yellow solid. MS-ESI: [M+H]+ 528.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C:12]([NH2:15])(=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.C1(C)C(C)=CC=CC=1>[CH3:9][Si:8]([CH3:11])([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:15][C:12](=[O:14])[CH3:13])=[CH:3][CH:4]=1
Reactant: CC(N)=O
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Product: CC(=O)Nc1ccc([Si](C)(C)C)cc1

Procedure:
Under a flow of argon, in a 1 L-recovery flask, 35 g of 1-bromo-4-(trimethylsilyl)benzene, 22.6 g of acetamide, 5.8 g of copper(I)iodide, 42.2 g of potassium carbonate, and 380 mL of xylene were placed. After stirring, 6.6 mL of N,N′-dimethylethylenediamine was added. The resultant was heated and stirred at reflux for 18 hours.
Reaction SMILES: Cl.[CH:2]([NH:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)([CH3:4])[CH3:3].C(N(CC)CC)C.ClCCl.Cl[S:27]([C:30]1[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=1)[C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])(=[O:29])=[O:28]>N1C=CC=CC=1>[CH:2]([N:5]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:8][CH2:7]1)[S:27]([C:30]1[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=1)[C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:40])[CH3:41])=[O:34])(=[O:28])=[O:29])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@H]1CC[C@H](NC(C)C)CC1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](N(C(C)C)S(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 734 mg of methyl trans-4-(isopropylamino)cyclohexane carboxylate hydrochloride, 0.90 mL of triethylamine, and 10 mL of dichloromethane was stirred at room temperature for 30 minutes, and 10 mL of pyridine and 1.00 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate were added thereto in this order, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 311 mg of 2-(trimethylsilyl)ethyl 3-{isopropyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoate as a pale yellow solid. ESI+: 484