Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[S:10][C:9]2[C:4](=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=2)[CH:3]=1.C([Li])CCC.[Cl:17]N1C(=O)CCC1=O>C1COCC1.C(NC(C)C)(C)C>[Cl:17][C:3]1[C:4]2=[N:5][C:6]([CH3:11])=[CH:7][CH:8]=[C:9]2[S:10][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2sc(F)cc2n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1ccc2sc(F)c(Cl)c2n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
To a solution of 461 mg (2.74 mmol) of 2-fluoro-5-methylthieno [3.2-b]pyridine (Example 7, Step 1) and 14 μl (0.1 mmol) of diisopropylamine in 12 mL of THF was added 2.15 mL of n-butyl lithium (1.4M in hexane) at -78° C. After stirring at -78° C. for 10 min, a solution of 585 mg (4.4 mmol) of N-chlorosuccinimide in 10 mL of THF was added at -78° C. The mixture was stirred at -78° C. for 20 min, warmed up to 0° C., stirred at 0° C. for 30 min, and then partitioned between aqueous ammonium chloride and ethyl acetate. Chromatographic purification on silica gel with hexane/ethyl acetate=8:1 gave 350 mg (63%) of the title product.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.OO.Cl>CO.O>[CH2:1]([O:8][C@@H:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)OCc1ccccc1
Agent: Cl
Agent: OO
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](OCc1ccccc1)C(=O)O
Reaction time: 24 h

Procedure:
To the above methyl (2S)-2-benzoxy-4-methylpentanoate (0.69 g, 2.92 mmol) in MeOH/H2O (5 mL/1 mL) was added LiOH.H2O (0.28 g, 11.7 mmol) and 30% H2O2 (0.3 mL, 11.7 mmol). After stirring the reaction mixture for 24 h, the mixture was treated with 1N HCl (pH=3) and the methanol was removed in vacuo. The aqueous layer was extracted with EA (4×15 mL). The combined organic layers were washed with 1N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated. (2S)-2-benzoxy-4-methylpentanoic acid was isolated as a colorless oil (0.65 g, 100%): 1H NMR (CDCl3, 300 MHz) δ 0.82-1.60 (m, 6 H), 1.53-1.62 (m, 1 H), 1.73-1.90 (m, 2 H), 3.99-4.50 (m, 1 H), 4.46 (d, 1 H, J=12.0 Hz), 4.72 (d, 1 H, J=12.0 Hz) 7.10-7.26 (m, 5 H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl.O>C1(C)C=CC=CC=1>[CH3:12][N:2]([CH3:1])[C:3](=[O:11])[CH:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:16][CH2:15][N:14]([CH3:18])[CH3:13]
Reactant: CN(C)C(=O)Cc1ccccc1
Reactant: CN(C)CCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCC(C(=O)N(C)C)c1ccccc1
Yield: 76.8 %

Procedure:
To a mechanically-stirred, refluxing suspension of 5.85 g (0.15 mol) of NaNH2 in 150 ml of toluene, was added dropwise under N2, 50 ml of a toluene solution consisting of 16.3 g (0.1 mol) of N,N-dimethyl-phenylacetamide (prepared by reaction of phenylacetyl chloride and N,N-dimethylamine in CH2Cl2 solvent) in toluene, and the mixture was stirred at reflux for 4 hr. Then, 16.5g (0.15 mol) of 2-(dimethylamino)ethyl chloride in 100 ml of toluene was added dropwise. The mixture was refluxed for 6 hr and then stirred at RT for 16 hr. Water (150 ml) was added to the mixture, and then the organic layer was separated and extracted with 1N HCl. The acid extract was basified in the cold with 2.5N NaOH and the basic solution extracted with Et2O. The ether extract was dried (Na2SO4), concentrated, and distilled to afford 18 g (76.8%) of N,N-dimethyl-4-dimethylamino-2-phenylbutanamide as a colorless oil, bp 108°-110°/0.2 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:6][CH:7]=1.O1CCOCCOCCOCCOCC1.[H-].[Na+].[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51](=O)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:51]2[CH2:52][CH2:53][N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[CH2:49][CH2:50]2)=[N:4][CH:3]=1
Reactant: CCOP(=O)(Cc1cccc(Oc2ncc(Br)cn2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ncc(Br)cn3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
Diethyl 3-(5-bromopyrimidin-2-yloxy)benzylphosphonate (0.700 g, 1.74 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.017 mL, 0.087 mmol) were suspended in THF (2 mL). The mixture was cooled to 0° C. and sodium hydride (84 mg, 60% dispersion in mineral oil, 2.1 mmol) was added. The reaction was warmed to room temperature, stirred for 30 min and then cooled back to 0° C. A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.452 g, 2.27 mmol) in THF (1.5 mL) was added and the reaction was warmed to room temperature. After 40 h, water was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to an orange oil (about 1 g). This material was purified by flash chromatography on silica (10-40% EtOAc:heptane) to afford the title compound (0.285 g, 37% yield). MS (APCI) M−100=346; 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 2.30-2.37 (m, 2H) 2.43-2.52 (m, 2H) 3.37-3.45 (m, 2H) 3.48-3.55 (m, 2H) 6.36 (s, 1H) 6.99-7.07 (m, 2H) 7.11 (d, J=7.80 Hz, 1H) 7.39 (t, J=7.90 Hz, 1H) 8.58 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=[C:5]2[N:4]=[N:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12](=[S:22])[NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:5]2[N:4]=[N:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cn1nnc2c(C(=O)Nc3ccccc3)ncn2c1=O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Product: Cn1nnc2c(C(=S)Nc3ccccc3)ncn2c1=O
Yield: 270.7 %

Procedure:
A mixture of 3-methyl-4-oxo-N-phenyl-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (430 mg, 1.59 mmol), phosphorus pentasulfide (212 mg, 0.48 mmol) and hexamethyldisiloxane (680 μL, 3.18 mmol) in DCM (20 mL) was refluxed overnight. The crude product was absorbed on silica and was purified by flash chromatography using a gradient elution of DCM:MeOH (100:0 to 98:2) to give 372 mg of 3-methyl-4-oxo-N-phenyl-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide as a 1.5:1 inseparable mixture with the starting material.
Reaction SMILES: C([CH2:8][NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][C@@H:23]([C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:27]([NH2:29])=[O:28])[CH2:22]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>C(O)(C)C.[Pd]>[CH3:8][NH:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:25][CH2:24][C@@H:23]([C:26]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:27]([NH2:29])=[O:28])[CH2:22]2)=[CH:16][CH:17]=1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCCc2ccc(CCNCCc3ccccc3)cc2)C1
Agent: [Pd]
Solvent: CC(C)O
Product: CNCCc1ccc(CCCN2CC[C@@H](C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 2.5 h
Yield: 9 %

Procedure:
A stirred solution of the intermediate from Step E (0.8 g, 1.46 mmol) in isopropanol (100 mL) was flushed with nitrogen gas and then palladium (80 mg; 10 wt. % (dry basis) on activated carbon) was added. The reaction flask was then placed under vacuum and then flushed with hydrogen gas (3 cycles). The reaction mixture was then stirred for 2.5 hours and then was flushed with nitrogen gas, filtered and the solvent removed under reduced pressure. To the residue was added a 1:1 mixture of acetic acid/water (1.0 mL) and this mixture was then chromatographed on reverse-phase silica gel (gradient elution, 10-50% ACN/water) to provide 60 mg of the title compound (6% yield) as a bis(trifluoroacetate) salt. MS m/z: [M+H+] calc'd for C30H37N3O 456.3; found 456.3. Retention time=3.04 min (10-70% ACN: H2O, reverse phase HPLC).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C:10]([OH:12])=[O:11])[O:5][N:4]=1.CCN(CC)CC.[CH3:29][C:30]([O:33][C:34](ON=C(C1C=CC=CC=1)C#N)=[O:35])([CH3:32])[CH3:31]>O1CCOCC1.O>[C:30]([O:33][C:34]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:9][C:10]([OH:12])=[O:11])[O:5][N:4]=1)=[O:35])([CH3:32])([CH3:31])[CH3:29]
Reactant: NCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
A solution of (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoic acid (preparation 163) (177 mg, 0.53 mmol) and Et3N (186 μl, 1.33 mmol) in dioxan (500 μl) and H2O (500 μl) was treated with Boc-ON (145 mg, 0.58 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with H2O and extracted with EtOAc (×2). The organic extracts were combined and the solvent removed under reduced pressure. The crude material was purified on a silica column eluting with DCM:MeOH (100:0) gradually changing to (90:10) to afford the title compound as a colourless gum (115 mg, 55%).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9](=O)[CH2:10][CH2:11][CH:12]=[CH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>C(O)C>[CH2:10]([C:9]1[NH:18][N:17]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)[CH2:11][CH:12]=[CH2:13]
Reactant: NN
Reactant: C=CCCC(=O)CC(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: C=CCCc1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1-phenylhept-6-ene-1,3-dione (3 g, 14.83 mmol) in ethanol (50 mL) was added hydrazine hydrate (2.228 g, 44.5 mmol) at room temperature. The reaction was refluxed for 10 h, cooled to room temperature and concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic extract was dried over MgSO4 and concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=199.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.65-2.78 (m, 2H), 4.01-4.12 (m, 2H), 4.83-4.95 (m, 2H), 5.82-5.93 (m, 1H), 6.42 (s, 1H), 7.23-7.82 (m, 5H), 12.6 (s, 1H).
Reaction SMILES: C[Si](C)(C)O[Si](C)(C)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[CH2:33][CH:34]2[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)=[C:27]([OH:48])[CH:26]=1.O>ClCCCl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]2[N:31]=[C:32]([CH2:33][CH:34]3[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]3)[O:48][C:27]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2ccc(Br)cc2O)CC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCCl
Product: Brc1ccc2nc(CC3CCNCC3)oc2c1
Yield: 45.4 %

Procedure:
Hexamethyldisiloxane (1.068 g, 6.58 mmol) was added to a solution of P2O5 (0.786 g, 5.54 mmol) in dry 1,2-Dichloroethane (2.9 mL) under argon and then heated to reflux for 10 min. A solution of tert-butyl 4-(2-(4-bromo-2-hydroxyphenylamino)-2-oxoethyl)piperidine-1-carboxylate (0.41 g, 0.992 mmol) in 1,2-Dichloroethane (2.9 mL) was added and the mixture was heated to reflux for 3 h. The mixture was poured into cool water (5 mL), extracted with CH2Cl2 (3×3 mL). The organic layers were discarded. The aqueous layer and the remaining solid were brought to pH=12 using aqueous NaOH (1 N). The mixture was extracted with CH2Cl2 (3×6 mL). The combined organic layers were dried (K2CO3), filtered, and concentrated to afford desired product as an orange oil (0.133 g, HPLC purify 95%, 43% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.65 (d, J=1.7 Hz, 1H), 7.48-7.56 (m, 1H), 7.38-7.46 (m, 1H), 3.01-3.15 (m, 2H), 2.80-2.89 (m, 2H), 2.63 (td, J=12.2, 2.1 Hz, 2H), 1.96-2.14 (m, J=15.0, 7.7, 7.6, 3.6, 3.4 Hz, 1H), 1.74 (d, J=12.7 Hz, 2H), 1.57 (br. s., 1H), 1.20-1.36 (m, 2H). LCMS (m/z)=295 (M+H)+.
Reaction SMILES: CC1C2C(=O)CCC=2N(S([C:13]2[CH:19]=[CH:18][C:16](C)=[CH:15][CH:14]=2)(=O)=O)C=1C(O)=O.O=[C:25]1[C:32]2[CH:31]=[C:30]([C:33]([O:35][CH3:36])=[O:34])[NH:29][C:28]=2[CH2:27][CH2:26]1.BrC1C=C(C=CC=1)C[Mg]Br.Br[C:48]1[CH:49]=[C:50]([CH:74]=[CH:75][CH:76]=1)/[CH:51]=[C:52]1\[CH2:53][CH2:54][C:55]2[N:56]([S:64]([C:67]3[CH:73]=[CH:72][C:70]([CH3:71])=[CH:69][CH:68]=3)(=[O:66])=[O:65])[C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:58][C:59]\1=2.C1(B(O)O)C=CC=CC=1>>[C:51]1([C:50]2[CH:49]=[CH:48][CH:76]=[CH:75][CH:74]=2)[CH:60]=[CH:57][CH:58]=[C:59]([CH2:55][CH:25]2[C:32]3[CH:31]=[C:30]([C:33]([O:35][CH3:36])=[O:34])[NH:29][C:28]=3[CH2:27][CH2:26]2)[CH:52]=1.[C:48]1([C:13]2[CH:19]=[CH:18][CH:16]=[CH:15][CH:14]=2)[CH:76]=[CH:75][CH:74]=[C:50](/[CH:51]=[C:52]2\[CH2:53][CH2:54][C:55]3[N:56]([S:64]([C:67]4[CH:73]=[CH:72][C:70]([CH3:71])=[CH:69][CH:68]=4)(=[O:65])=[O:66])[C:57]([C:60]([O:62][CH3:63])=[O:61])=[CH:58][C:59]\2=3)[CH:49]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2=O
Reactant: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c(C)c2C(=O)O)C(=O)CC3)cc1
Agent: Br[Mg]Cc1cccc(Br)c1
Agent: OB(O)c1ccccc1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(-c2ccccc2)c1
Product: COC(=O)c1cc2c(n1S(=O)(=O)c1ccc(C)cc1)CC/C2=C\c1cccc(-c2ccccc2)c1

Procedure:
The title compound was synthesized in four steps. First tosyl protected methyl 4-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (methyl 4-oxo-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) (1.50 g, 8.37 mmol) was reacted with 3-bromobenzylmagnesium bromide (15 mL, 3.75 mmol) according to General Procedure 3 to give exo olefin-containing compound (E)-methyl 4-(3-bromobenzylidene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, followed by coupling with phenylboronic acid (0.305 g, 2.50 mmol) according to General Procedure 9.2 to give (E)-methyl 4-(biphenyl-3-ylmethylene)-1-tosyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate, then tosyl deprotection according to General Procedure 10.1 to give (E)-methyl 4-(biphenyl-3-ylmethylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. Hydrogenation of (E)-methyl 4-(biphenyl-3-ylmethylene)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate according to General Procedure 6 (with 5% Pd/C), then purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-20% EtOAc/heptane afforded the title compound: 0.041 g. 1H NMR (400 MHz, ACETONE-d6) δ ppm 2.09-2.19 (m, 1H) 2.50-2.60 (m, 1H) 2.60-2.68 (m, 2H) 2.86 (d, J=1.85 Hz, 1H) 2.88 (s, 1H) 3.31-3.39 (m, 1H) 3.71-3.72 (m, 3H) 6.36 (d, J=1.90 Hz, 1H) 7.21-7.25 (m, 1H) 7.26-7.30 (m, 1H) 7.31-7.51 (m, 5H) 7.61-7.67 (m, 2H) 10.49 (br.s, 1H).
Reaction SMILES: C(O[C:6](=[O:15])[NH:7][CH2:8][CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])(C)(C)C.FC(F)(F)C(O)=O.COC([C:27]1[C:36]([OH:37])=[C:35]2[C:30]([CH:31]=[CH:32][C:33](=[O:45])[N:34]2[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:29][N:28]=1)=O>C(Cl)Cl.CCOC(C)=O>[CH3:14][S:11]([NH:10][CH2:9][CH2:8][NH:7][C:6]([C:27]1[C:36]([OH:37])=[C:35]2[C:30]([CH:31]=[CH:32][C:33](=[O:45])[N:34]2[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:29][N:28]=1)=[O:15])(=[O:12])=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNS(C)(=O)=O
Reactant: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCCNC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
(2-Methanesulfonylamino-ethyl)-carbamic acid tert-butyl ester (77 mg, 0.32 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed by evaporation, and the residue was taken up in EtOH (2 mL). NaOMe was added with vigorous stirring until pH about 8. The resulting cloudy solution was transferred to a microwave vial containing 1-benzyl-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (25 mg, 0.081 mmol), and the mixture was heated at 140° C. for 6 h in a microwave reactor. The mixture was diluted with EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The crude product was first purified by column chromatography (0-5% MeOH/CH2Cl2), then by preparative TLC (10% MeOH/CH2Cl2) to give 2.7 mg of the title compound as an off-white solid. MS: (+) m/z 417.30 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:23][C:24](=[O:31])[CH:25]([NH:29][CH3:30])[CH:26]([CH3:28])[CH3:27])[C:14](=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[NH:32]([C:45]([O:47][C:48]([CH3:51])(C)C)=[O:46])[C@H:33]([C:42]([OH:44])=O)[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1.O.[CH2:53]1COC[CH2:54]1>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH:13]([NH:23][C:24](=[O:31])[CH:25]([N:29]([C:42](=[O:44])[CH:33]([NH:32][C:45]([O:47][CH2:48][CH2:51][CH2:53][CH3:54])=[O:46])[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[CH3:30])[CH:26]([CH3:27])[CH3:28])[C:14](=[O:22])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: CNC(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)C(C)C
Solvent: O
Product: CCCCOC(=O)NC(Cc1ccc(F)cc1)C(=O)N(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)C(C)C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of 3-methyl-2-methylaminobutyric acid 2-(3-tert-butyl-4-hydroxyphenyl)-1-(2-pyridylcarbamoyl)ethylamide (1.25 g, 2.93 mmol), Boc-Phe(4-F)-OH (1.08 g, 3.81 mmol) and CMPI (973 mg, 3.81 mmol) in THF 19 ml, TEA (0.94 ml, 6.74 mmol) was added under cooling with ice and stirred for 4 hours under cooling with ice. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (1.72 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26](OC(C)(C)C)=[O:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.[C:33]([OH:39])(C(F)(F)F)=[O:34].[CH2:40](Cl)Cl>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:27])[C:33]([O:39][CH3:40])=[O:34])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1
Reactant: ClCCl
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Product: COC(=O)C(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A solution of 1,1-dimethylethyl 4-[({6-[2-fluoro-4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.15 g, 0.32 mmol) in CH2Cl2 (10 mL) was treated with TFA (0.3 mL). The mixture was stirred at ambient temperature overnight. CH2Cl2 and excess of TFA were removed under reduced pressure. The residue was redissolved in CH2Cl2 (5 mL) and cooled in an ice bath. Diisopropylethylamine (1.5 mL) was added, followed by addition of methyl oxalyl chloride (34 μL, 0.36 mmol). The reaction mixture was allowed to warm up to ambient temperature and stirred overnight, quenched with aqueous NaHCO3 and extracted with EtOAc (50 mL×2). The combined organic extract was washed with brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a viscous brown oil. The crude material was purified by chromatography on a silica gel column eluted with 1:5 acetone/CH2Cl2 to give 0.112 g (77%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.42 (d, 1H, J=2.9 Hz), 8.23 (t, 1H, J=7.8 Hz), 7.85-7.80 (m, 2H), 7.73 (dd, 1H, Ja=10.3 Hz, Jb=1.5 Hz), 7.27 (dd, 1H, Ja=10.8 Hz, Jb=2.9 Hz), 4.65-4.55 (m, 1H), 4.00-3.90 (m, 2H), 3.88 (s, 3H), 3.80-3.70 (m, 1H), 3.25-3.10 (m, 1H), 3.09 (s, 3H), 2.80-2.70 (m, 1H), 2.25-2.10 (m, 1H), 200-1.90 (m, 2H), 1.50-1.35 (m, 2H); LRMS (APCI), m/z 451 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[CH3:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:29][CH2:28]5)=[N:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(C)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (120 mg. 0.187 mmol) was alkylated using (S)-2-methyloxirane (33 mg, 0.562 mmol), DIPEA (145 mg, 1.124 mmol) and ethanol (5 mL) to get 100 mg (crude) of the titled compound. MS: m/z=662.3 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH:16][NH2:17])=[CH:14][C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[CH2:1]([N:8]1[C:15]2[NH:16][N:17]=[C:22]([NH:23][CH3:24])[C:14]=2[C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH2:20][CH3:21])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: CCCCn1c(=O)cc(NN)n(Cc2ccccc2)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccccc2)c1=O
Yield: 66 %

Procedure:
A solution of 1-benzyl-3-butyl-6-hydrazinouracil (4.0 g, 13.9 mM) and methyl isothiocyanate (2.85 ml, 41.7 mM) in DMF (50 ml) was stirred at 120° C. for 20 hours. To the solution was added methanol (20 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol gave colorless crystals (3.0 g, 66%), m.p. 282°-284° C.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])[C:6]#[N:7].O.[NH2:20][NH2:21]>C(O)C>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][C:5]1[C:8]([C:9]([F:10])([F:11])[F:12])=[N:20][NH:21][C:6]=1[NH2:7]
Reactant: N#CC(Cc1cccc(Cl)c1Cl)C(=O)C(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1[nH]nc(C(F)(F)F)c1Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 15.3 %

Procedure:
To a solution of 2-(2,3-dichlorobenzyl)-4,4,4-trifluoro-3-oxobutanenitrile (10.0 g, 33.77 mmol) in ethanol (800 mL) was added hydrazine hydrate (1.86 g, 37.15 mmol) and the resulting solution was stirred under reflux for 16 h. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column (petroleum ether/ethyl acetate=2/1) and reverse-phase Prep-HPLC to provide the titled compound (1.6 g, 15%) as a yellow oil; LC/MS: MS (ES+) m/e 310 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.85 (s, 2H), 6.78 (dd, J=1.2, 7.8 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.47 (dd, J=1.2, 7.8 Hz, 1H).