Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.N1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]1[C:32]1[C:33]([NH2:49])=[N:34][CH:35]=[C:36]([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[CH:42]=2)[CH:37]=1.[CH3:50][N:51]([CH3:56])[CH2:52][C:53](O)=[O:54].CN1CCOCC1>CN1C(=O)CCC1>[NH2:49][C:33]1[N:34]=[CH:35][C:36]([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:44][CH2:45][N:46]([C:53](=[O:54])[CH2:52][N:51]([CH3:56])[CH3:50])[CH2:47][CH2:48]3)[CH:42]=2)=[CH:37][C:32]=1[C:24]1[O:23][C:31]2[C:26]([N:25]=1)=[N:27][CH:28]=[CH:29][CH:30]=2
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ncccc2o1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CN(C)CC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ncccc5o4)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Benzotriazol-1-yl-[bis(dimethylamino)methylene]oxonium tetrafluoroborate (96 mg) was added to a stirred suspension of 3-oxazolo[4,5-b]pyridin-2-yl-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg), 2-dimethylaminoacetic acid (27.0 mg) and 4-methylmorpholine (0.055 ml) in NMP (1 ml) at 25° C. The resulting solution was stirred at 25° C. for 2 hours. The reaction mixture was purified by preparative HPLC using a Waters OBD reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness, the solid was taken up in dichloromethane, dried over Magnesium sulphate, filtered and concentrated. A precipitate appeared which was diluted with diethyl ether, the solid was collected by filtration, washed with petroleum ether then triturated several hours with acetonitrile, filtered and dried under vacuum at 50° C. overnight to afford 1-[4-[4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)pyrazol-1-yl]-1-piperidyl]-2-dimethylamino-ethanone (50.0 mg) as a solid. NMR Spectrum: (DMSOd6) 1.74-1.85 (m, 1H), 1.86-1.97 (m, 1H), 2.05-2.15 (m, 2H), 2.21 (s, 6H), 2.72-2.83 (m, 1H), 3.01-3.10 (m, 1H), 3.12-3.23 (m, 2H), 4.14-4.25 (m, 1H), 4.39-4.52 (m, 2H), 7.48 (dd, 1H), 7.68 (bs, 2H), 7.95 (s, 1H), 8.23 (dd, 1H), 8.36 (s, 1H), 8.47 (d, 1H), 8.56 (dd, 1H), 8.59 (d, 1H); Mass spectrum: M+H+ 447;
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[S:12]([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:29].[K+].C(Cl)(Cl)Cl>C(O)(=O)C.O>[C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[S:12]([CH2:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22](=[O:27])[CH2:21][CH2:20]3)=[O:16])(=[O:29])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=C1CCc2cc(C(=O)CS(=O)c3nccn3-c3ccccc3)ccc2N1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C1CCc2cc(C(=O)CS(=O)(=O)c3nccn3-c3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3.79 Grams (10 mM) of 6-[2-(1-phenyl-2-imidazolyl)sulfinylacetyl]-3,4-dihydrocarbostyril was dissolved in a mixture of 240 ml of acetic acid with 100 ml of water, then 5.06 g (32 mM) of potassium permanganate was added thereto. This mixture was stirred at room temperature for 2 days. After the reaction was completed, chloroform was added to the reaction mixture and filtered with Celite (a trademark for distomaceous earth product, manufactured by Johns-Manville Proudcts Corp.). The filtrate was washed with water and dried with anhydrous magnensium sulfate. The residue obtained by removing the solvent was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=30:1), and recrystallized from ethanol-chloroform to yield 0.6 g of 6-[2-(1-phenyl-2-imidazolyl)sulfonylacetyl]-3,4-dihydrocarbostyril. Light yellow granular substance. Melting point: 199°-201° C.
Reaction SMILES: C[NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Cl:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40]([OH:42])=O)[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>ClCCl.C(OCC)(=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[CH2:38][CH2:37][C@@H:36]([CH2:39][C:40](=[O:42])[NH:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=3[CH2:18][C:19]([O:21][CH3:22])=[O:20])[N:28]3[C:29](=[O:35])[C:30](=[O:34])[NH:31][C:32]([CH:33]=1)=[C:27]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Reactant: CNc1ccc(CNC(=O)OC(C)(C)C)cc1CC(=O)OC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Reaction time: 4.5 h
Yield: 74.6 %

Procedure:
A mixture of methyl 4-tert-butoxycarbonylaminomethyl-2-methoxycarbonylmethylaniline (1.20 g, 4.27 mmol), (S)-9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (1.26 g, 4.27 mmol), triethylamine (1.49 mL, 10.7 mmol), and Bop-Cl (1.19 g, 4.69 mmol) in dichloromethane (26 mL) was stirred for 4.5 h at 0° C. to room temperature and diluted with ethyl acetate. The mixture was washed successively with 5% potassium hydrogen sulfate, water, 1/15 phosphate buffer (pH 7.5), water, and brine, dried over magnesium sulfate, and concentrated. The residual solid was washed with a 1:1 mixture of diethyl ether and dichloromethane, and dried to give 1.82 g of the title compound (74%).
Reaction SMILES: BrCCCCCCOCCC#CC1C=C([N:19]2C(=O)CNC2=O)C=CC=1.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][C:36]#[C:37][C:38]1[CH:39]=[C:40]([N:44]2[C:48](=[O:49])[CH2:47][NH:46][C:45]2=[O:50])[CH:41]=[CH:42][CH:43]=1.[NH2:51][CH2:52][C@@H:53]([C:55]1[CH:66]=[CH:65][C:58]2[O:59][C:60]([CH3:64])([CH3:63])[O:61][CH2:62][C:57]=2[CH:56]=1)[OH:54]>CN(C=O)C>[NH3:19].[CH3:63][C:60]1([CH3:64])[O:59][C:58]2[CH:65]=[CH:66][C:55]([C@@H:53]([OH:54])[CH2:52][NH:51][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][C:36]#[C:37][C:38]3[CH:39]=[C:40]([N:44]4[C:48](=[O:49])[CH2:47][NH:46][C:45]4=[O:50])[CH:41]=[CH:42][CH:43]=3)=[CH:56][C:57]=2[CH2:62][O:61]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Reactant: O=C1CNC(=O)N1c1cccc(C#CCCOCCCCCCBr)c1
Reactant: O=C1CNC(=O)N1c1cccc(C#CCCOCCCCCCI)c1
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCC#Cc3cccc(N4C(=O)CNC4=O)c3)ccc2O1
Product: N
Temperature: 20 °C
Reaction time: 22 h

Procedure:
A mixture of 3-(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione and 3-(3-{4-[(6-iodohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione (760 mg, 22:3), (1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (800 mg) in DMF (5 ml) was stirred at 20° C. for 22 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc and washed with water, brine and dried (MgSO4). The solution was concentrated and purified by chromatography on Biotage (40 g) eluting with dichloromethane:MeOH:1M ammonia in methanol (98:1:1 to 95:4:1) to give the title compound (368 mg) LCMS RT=2.59 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH:19]=O)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:26]([NH2:30])(=[O:29])[CH2:27][CH3:28].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:22]([F:24])([F:25])[F:23])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([CH2:19][NH:30][C:26](=[O:29])[CH2:27][CH3:28])=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCC(N)=O
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCC(=O)NCc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 49.7 %

Procedure:
A mixture of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carbaldehyde (120 mg), propionamide (66 mg), trifluoroacetic acid (68 μl) and triethylsilane (144 μl) in toluene (2 ml) is refluxed overnight. After 20 hours the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-ylmethyl}-propionamide (68 mg, compound 1.5 in Table 1) as a white foam. MS (HPLC/MS): 465 (MH+). Retention time: 1.98 min.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[C:24]4[C:23]([O:25][CH2:26][CH3:27])=[N:22][CH:21]=[N:20][C:19]=4[NH:18][CH:17]=3)=[C:11]([F:28])[N:10]=2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.O>O1CCCC1>[CH2:26]([O:25][C:23]1[C:24]2[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:5]4[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=4)=[N:10][C:11]=3[F:28])=[CH:17][NH:18][C:19]=2[N:20]=[CH:21][N:22]=1)[CH3:27]
Reactant: CCOc1ncnc2[nH]cc(Cc3ccc(Nc4ccc(Br)nc4)nc3F)c12
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ncnc2[nH]cc(Cc3ccc(Nc4cccnc4)nc3F)c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To (6-bromo-pyridin-3-yl)-[5-(4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-6-fluoro-pyridin-2-yl]-amine (P-4020, 0.040 g, 0.090 mmol) in 5.0 mL of tetrahydrofuran under nitrogen at −78° C., tert-butyllithium (0.531 mL, 1.70 M in hexane, 0.903 mmol) is added. The reaction is stirred at −78° C. for 30 minutes, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified with silica gel column chromatography, eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-4021, 25.7 mg). MS (ESI) [M+H+]+=364.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1C(=O)C(I)=C(C1C=CC=CC=1)O2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:20])[C:47]4[C:46](=[CH:45][CH:44]=[CH:39][C:38]=4[F:37])[O:28][C:27]=3[C:26]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2cccc(F)c12
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cccc(F)c4c3=O)cc2)CCC1
Yield: 26 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 5-fluoro-3-iodo-2-phenyl-chromen-4-one (55 mg, 0.15 mmol) was reacted to give the title compound (19 mg, 26%). 1H NMR (400 MHz, CDCl3): δ 7.65-7.57 (m, 1H), 7.41-7.29 (m, 6H), 7.28-7.22 (m, 2H), 7.21-7.16 (m, 2H), 7.09-7.03 (m, 1H), 5.03 (s, 1H), 2.61-2.29 (m, 4H), 2.21-2.00 (m, 1H), 1.88-1.74 (m, 1H), 1.48-1.18 (m, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: ClCCCBr
Reactant: COc1cc(O)ccc1C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OCCCCl)ccc1C(C)=O

Procedure:
In a 250 mL round bottom flask, 1-(4-hydroxy-2-methoxy-phenyl)ethanone (5.0 g, 30.0 mmol), 1-bromo-3-chloro-propane (3.27 mL, 33.1 mmol), and potassium carbonate (4.75 g, 33.1 mmol) in acetonitrile (100 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, separated, dried over MgSO4. Purification with silica gel chromatography eluting with hexanes/ethyl acetate (3:1) produced 6.18 g (85%). Mp 51-53° C. MS m/z 243 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([CH3:17])=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[N:3]=1.N1C=CC=CC=1.O.[NH2:25][NH2:26]>CO>[Cl:12][C:11]1[C:2]([NH:25][NH2:26])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:13]([O:15][CH3:16])=[O:14])=[C:6]([CH3:17])[CH:5]=2
Reactant: COC(=O)c1cc2nc(Cl)c(Cl)nc2cc1C
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2nc(Cl)c(NN)nc2cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3.57 g of methyl 2,3-dichloro-7-methylquinoxaline-6-carboxylate in 214 mL of methanol were added 7.0 mL of pyridine and 2.34 mL of hydrazine monohydrate at 0° C., and then the mixture was stirred at room temperature overnight. The mixture was concentrated until its total amount reached about 100 mL, and water was added thereto, followed by stirring at room temperature for 1 hour. The precipitate was collected by filtration, washed with water and ethanol, and dried under reduced pressure to obtain 2.94 g of methyl 3-chloro-2-hydrazino-7-methylquinoxaline-6-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][C:18]([CH:21]=[O:22])([CH3:20])[CH3:19]>C1COCC1>[CH3:17][C:18]([CH3:20])([CH3:19])[CH:21]([C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1)[OH:22]
Reactant: CC(C)(C)C=O
Reactant: CCCSc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCSc1ccc(C(O)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 90.9 %

Procedure:
To a stirred solution of 1-bromo-4-(propylthio)benzene (500 mg, 2.16 mmol) in THF (10 ml) at −78° C. was added n-butyllithium (2.5 M in hexanes, 0.91 ml, 2.27 mmol). The resulting yellow solution was stirred at −78° C. for 15 minutes then pivaldehyde (0.29 ml, 2.59 mmol) was added. The mixture was allowed to warm to room temperature, during which time the solution turned colourless. The mixture was partitioned between ethyl acetate (60 ml) and water (30 ml). The organic phase was separated, washed with brine (30 ml), dried over MgSO4 filtered and evaporated to give a colourless oil. The crude product was chromatographed on silica eluting with 5% ethyl acetate in hexanes to give the title product as a pale yellow oil (468 mg). 1H NMR δ (CDCl3) 7.28-7.20 (4H, m), 4.36 (1H, s), 2.89 (2H, t, J=7.3 Hz), 1.84 (1H, s), 1.71-1.63 (2H, m), 1.02 (3H, t, J=7.3 Hz), 0.91 (9H, s).
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH:41]4[CH2:43][CH2:42]4)[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:46]([N:50]=[C:51]=[O:52])([CH3:49])([CH3:48])[CH3:47].CCN(C(C)C)C(C)C.ClCCCl>C(Cl)Cl>[CH:41]1([N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:29]=2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:51]([NH:50][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:52])[CH2:20][NH:19][CH2:24]2)=[O:44])[CH2:42][CH2:43]1
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1C
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)NC(C)(C)C)C2)C2CC2)ccc1C
Temperature: 50 °C
Reaction time: 14 h

Procedure:
A mixture of (3R*,5S*)-3-amino-5{-cyclopropyl-[3-(3-methoxy-propoxy)-4-methyl-benzyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (110 mg, 0.173 mmol), tert-butyl isocyanate (40 μl, 0.35 mmol), DIPEA (34.2 μl, 0.2 mmol) and 1,2-dichloroethane (2 ml) is shaken for 14 h at 50° C. The mixture is diluted with CH2Cl2 and washed with NaHCO3 solution. The organic layer is dried (Na2SO4) and evaporated. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 1 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL 1 min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a colorless resin. MS: 475.6 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.14 min.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=1.[C:26]([C:28]1[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=1)#[CH:27].C(N(CC)CC)C>O>[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]3[CH:27]=[C:26]([C:28]4[C:29]([NH2:35])=[N:30][C:31]([NH2:34])=[CH:32][CH:33]=4)[O:24][N:23]=3)=[CH:17][CH:16]=2)[CH:8]=1
Reactant: C#Cc1ccc(N)nc1N
Reactant: Cc1ccnc(OCc2ccc(CC(Cl)=NO)cc2)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccnc(OCc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a tetrahydrofuran (5.00 mL) solution of (4-(4-methyl-pyridin-2-yloxymethyl)phenyl)-acetohydroximoyl chloride (130 mg, 0.447 mmol) described in Manufacturing Example 43-1-5 and 3-ethynyl-pyridin-2,6-diamine (30.0 mg, 0.226 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (126 μL, 0.903 mmol) at room temperature, which was stirred for 1 hour at room temperature. Water was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (37.4 mg, 42.7%).
Reaction SMILES: C([O-])C.[Na+].OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(OCC)=O.C(I)C.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:47]([O-:49])=[O:48])[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([O-:37])=[O:36])[CH3:30].[Na+]>C(O)C>[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:38]=[C:39]([N+:47]([O-:49])=[O:48])[C:40]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]([OH:37])=[O:36])[CH3:30]
Reactant: CCOc1cc(C(=O)[O-])cc([N+](=O)[O-])c1-c1ccccc1
Agent: CCOC(=O)c1cc(O)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCI
Product: CCOc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1

Procedure:
To a solution of sodium ethanolate (prepared from 0.5 g of sodium) in dry ethanol (40 ml), ethyl 3-hydroxy-5-nitro-4-phenylbenzoate (4.4 g) is added followed by ethyl iodide (2.5 ml), and the resulting solution is refluxed for 20 hours. After about 6 hours an additional amount of sodium ethanolate (prepared from 0.25 g of sodiumn) in dry ethanol (10 ml) is added followed by ethyl iodide (1.3 ml). The mixture is evaporated in vacuo, 2 N sodium hydroxide (25 ml) is added to the residue, and the mixture is heated on a steam bath for 30 minutes to form a clear solution. On cooling, sodium 3-ethoxy-5-nitro-4-phenylbenzoate separates. It is collected by filtration, and washed with a small amount of icecold water. After drying, the sodium salt is dissolved in hot water (50 ml), and the 3-ethoxy-5-nitro-4-phenylbenzoic acid is precipitated by addition of 4 N hydrochloric acid (5 ml). After cooling, the acid is collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, it is obtained with a melting point of 174°-176° C.
Reaction SMILES: [OH-].[Na+].N1([C:12]2[S:16][N:15]=[N:14][C:13]=2[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)C2C=CC=CC=2N=N1.C[CH:28]([SH:32])[C:29]([O-:31])=[O:30].Cl.[CH3:34]N(C=O)C>>[C:17]1([C:13]2[N:14]=[N:15][S:16][C:12]=2[S:32][CH2:28][C:29]([O:31][CH3:34])=[O:30])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(-c3nnsc3-n3nnc4ccccc43)cccc2c1
Reactant: CC(S)C(=O)[O-]
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)CSc1snnc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaOH (60% oil, 30 mg, 0.61 mmol) was added to a solution of 5-(1H-benzo[d][1,2,3]triazol-1-yl)-4-(naphthalen-1-yl)-1,2,3-thiadiazole and methylthioglycolate (64 mg, 0.61 mmol) in DMF (3 mL) and the mixture was stirred at room temperature for 2 h. 1N HCl was then added and the mixture was extracted with ethyl acetate, dried over Na2SO4 and concentrated. Purification by TLC (100% DCM) afforded methyl 2-(4-(naphthalen-1-yl)-1,2,3-thiadiazol-5-ylthio)acetate.
Reaction SMILES: Br[CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.C([Li])CCC.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.O>CCCCCC.C1COCC1>[CH2:3]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([B:28]([OH:29])[OH:27])[CH:10]=2)[O:5]1)[CH2:2][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCC(Br)CC1Cc2ccccc2O1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1Cc2cc(B(O)O)ccc2O1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
Then, 2.00 g (6.43 mM) of b-bromo-2-octylcoumaran and 28 ml of dry THF were placed in a 100 ml-three-necked flask. To the mixture, 4.5 ml (7.20 mM) of a 1.6M solution of butyllithium in hexane was added dropwise under stirring and nitrogen atmosphere on a dry ice-acetone bath at an inner temperature of -70° to -68° C., followed by stirring for 50 minutes at the same temperature. To the resultant mixture a solution of 3.2 ml (13.9 mM) of triisopropylborate in 5.7 ml of dry THF was added dropwise in 10 minutes at an inner temperature of -73° to -68° C., followed by stirring for minutes at the same temperature. Thereafter, the cooling bath was removed and the inner temperature was increased to room temperature, followed by gradual addition of 9.5 ml of 10%-hydrochloric acid. After the reaction, the reaction mixture was poured into water and subjected to extraction with isopropyl ether, followed by washing with water, drying with mirabilite and distilling-off of the solvent to obtain a residue. To the residue, hexane was added and the mixture was left standing in a freezer to precipitate a crystal. The crystal was recovered by filtration to obtain 1.19 g of 2-octylcoumaran-5-boronic acid (Yield: 67.1%).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:2]([CH3:4])([CH3:3])[C:1]#[N:5]
Reactant: CC(C)C#N
Reactant: BrCc1ccccc1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C#N)Cc1ccccc1Br
Reaction time: 0.33 h
Yield: 99.7 %

Procedure:
To a solution of isobutyronitrile (3.58 g, 52 mmol) in dry THF (30 mL) was added LiHMDS (1.0 M in THF) (80 mL, 80 mmol) at 0° C., stirred for 20 min, and to this solution was added 1-bromo-2-(bromomethyl)benzene (10 g, 40 mmol) in dry THF (70 mL). After 3 h at rt, the reaction mixture was quenched with saturated NH4Cl solution, extracted with EtOAc (2×), the combined organics were washed with H2O, brine, dried over Na2SO4, filtered and concentrated to give 9.5 g (99%) of Intermediate 24A as red wine liquid. 1H NMR (400 MHz, CDCl3) δ 7.57-7.60 (2H, m), 7.30-7.34 (1H, m), 7.12-7.17 (1H, m), 3.08 (2H, s), 1.4 (6H, s) ppm.