Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[S:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(#N)C>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:21]3[CH2:22][CH2:23][S:19][CH2:20]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: C1CSCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCSC3)cc21
Temperature: 25 °C
Yield: 10.1 %

Procedure:
A solution of 1.01 g (4.0 mmol) of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.79 ml (10 mmol) of thiazolidine, 20 ml of acetonitrile and 20 ml of N,N-dimethylformamide was heated at reflux for 16 hours. The reaction was cooled to room temperature and the solid which formed was removed by filtration. After triturating with hot methanol, the residue was recrystallized from N,N-dimethylformamide to give 0.13 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-thiazolidinyl)-3-quinolinecarboxylic acid; mp 270°-273° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[N:5]([CH2:8][CH2:9][CH:10]([N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:11])[C:6]=1[CH3:7].NN>C(O)C>[NH2:12][CH:10]([CH3:11])[CH2:9][CH2:8][N:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[CH:3]=[C:4]1[C:23]#[N:24]
Reactant: Cc1c(Cl)cc(C#N)n1CCC(C)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: Cc1c(Cl)cc(C#N)n1CCC(C)N
Temperature: 25 °C

Procedure:
A solution of 3.2 g (9.4 mmol) of 4-chloro-1-[3-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butyl]-5-methyl-1H-pyrrole-2-carbonitrile and 4.8 mL (94 mmol) of hydrazine in ethanol was heated at reflux for 60 min and cooled to room temperature. Precipitated solids were filtered and rinsed with ethyl acetate and the filtrate was concentrated to afford 1-(3-aminobutyl)-4-chloro-5-methyl-1H-pyrrole-2-carbonitrile as an oil. Step D: Preparation of 2-cyano-3,4,4-trimethylpentanoic acid
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.[I-].[Na+].C(N(CC)CC)C>CN(C=O)C.O>[CH3:15][C@@H:16]1[N:21]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=3)[CH2:4][CH2:3]2)[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:17]1
Reactant: FC(F)(F)c1ccc2c(c1)C(Cl)CC2
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1CCc2ccc(C(F)(F)F)cc21
Temperature: 25 °C

Procedure:
A solution of 1-chloro-6-(trifluoromethyl)indane (1.52 g, 6.89 mmol), tert-butyl (3S)-3-methylpiperazine-1-carboxylate (2.1 g, 10 mmol), sodium iodide (3 g, 20 mmol) and triethylamine (3 g, 30 mmol) in DMF (20 mL) was stirred at 60° C. overnight. After cooling to room temperature, water was added. The resulting solution was extracted with EtOAc twice. The combined extracts were washed with water and brine, dried over MgSO4 and concentrated. Column chromatography on silica (10%-30% EtOAc in hexane) afforded two isomers. Isomer 1: 0.52 g (brown oil). MS calculated for C20H27F3N2O2: (M+H)+ 385; found 385.2. Isomer 2: 0.41 g (brown oil). MS: (M+H)+ 385.2
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([CH:24]1[CH2:28][N:27]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([F:36])[CH:30]=2)[C:26](=[O:37])[CH2:25]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOC(C)=O>[C:16]([CH:24]1[CH2:28][N:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[C:31]([F:36])[CH:30]=2)[C:26](=[O:37])[CH2:25]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccccc1)C1CC(=O)N(c2ccc(O)c(F)c2)C1
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N4CC(C(=O)c5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 160 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.38 g, 1.67 mmol), 4-benzoyl-1-(3-fluoro-4-hydroxyphenyl)pyrrolidin-2-one (Step 3, 0.40 g, 1.67 mmol) and DMAP (0.204 g, 1.67 mmol) in 4 mL of dioxane (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 160° C. for 1 h. The mixture was cooled to RT and diluted with 50 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% to 100% EtOAc in hexanes then to 5% MeOH/EtOAc) to provide a white solid. MS (ESI pos. ion) m/z: 487.4 (M+H). Calc'd Exact Mass for C28H23FN2O5: 486.49.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([Cl:27])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C(OC([NH:36][C@H]1CCN(S(C2C3C(Cl)=CN=C(Cl)C=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:28])=[CH:20][N:21]=[C:22]([NH2:36])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Product: Cl
Product: Nc1ncc(Cl)c2c(S(=O)(=O)N3CCC(N)C3)cccc12

Procedure:
Intermediate 26 can be used in the method of Example 39-1 instead of Intermediate 26a to obtain the title compound as hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15](Br)=[C:16]([CH3:17])[C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1.COCCOC>C(#N)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>[NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[C:16]([CH3:17])[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1N
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: CC#N
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1c(C)nc2sc(-c3cccnc3)c(C)c2c1N
Temperature: 70 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
A mixture of ethyl 4-amino-2-bromo-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (260 mg, 0.790 mmol) (Description 31), tetrakis(triphenylphosphine)palladium(0) (45.6 mg, 0.039 mmol), sodium carbonate (167 mg, 1.580 mmol) and 3-pyridineboronic acid (116 mg, 0.948 mmol) in acetonitrile (3 mL) and water (0.75 μl) was heated at 70° C. under nitrogen, for 30 min. 1,2-Dimethoxyethane (2 mL) was added and the mixture was stirred at 80° C. for 18 h. The reaction mixture was cooled to RT and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in DCM, afforded the title compound (141 mg). LCMS (A) m/z: 328 [M+1]+, Rt 0.88 min (acidic), Rt 1.14 min (basic).
Reaction SMILES: C1(N([C@H]2CC[C@H](CC)CC2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][C:16](O)=O)=[CH:12][N:13]=2)CCCC1.[C:28]([CH:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH:39]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1)([CH3:31])([CH3:30])[CH3:29].C([O:48][C:49](=[O:59])CCSC1SC(N)=NC=1)C>>[C:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([N:38]([CH:39]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[C:7](=[O:19])[NH:8][C:9]2[S:10][C:11]([S:14][CH2:15][CH2:16][C:49]([OH:59])=[O:48])=[CH:12][N:13]=2)[CH2:34][CH2:33]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Reactant: CC(C)(C)C1CCC(NC2CCCCCC2)CC1
Reactant: CCOC(=O)CCSc1cnc(N)s1
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclopentyl-3-(trans-4-ethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via (4-tert-butyl-cyclohexyl)-cycloheptyl-amine and 3-(2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: [CH3:1][N:2](CC1C=CC=CC=1)[C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=[O:21])[CH:4]=1.[H][H]>[Pd].CO>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)[N:6]=[C:5]([C:20]([OH:22])=[O:21])[CH:4]=1
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Agent: [Pd]
Solvent: CO
Product: CNc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1

Procedure:
4-[methyl(phenylmethyl)amino]-6-[3-(trifluoromethyl) phenoxy] picolinic acid (0.42 g, 0.0010 mol) and a small amount of 10% palladium/carbon were added to about 30 ml of methanol. The obtained mixture was stirred at room temperature for about 10 hours in a hydrogen atmosphere. The obtained reaction solution was filtered using High-Flow Super Cell, and then concentrated, thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:23])=[CH:5][C:6]([OH:22])=[C:7]([C:9](=[O:21])[CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[CH:8]=1)[CH3:2].N1C=CC=C[CH:25]=1.C(OC)(OC)OC>N1CCCCC1.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[OH:23])[O:22][CH:25]=[C:10]([C:11]1[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=1)[C:9]2=[O:21])[CH3:2]
Reactant: c1ccncc1
Reactant: CCc1cc(C(=O)Cc2ccc3ccccc3c2)c(O)cc1O
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CCc1cc2c(=O)c(-c3ccc4ccccc4c3)coc2cc1O
Temperature: 120 °C

Procedure:
To 1-(5-ethyl-2,4-dihydroxy-phenyl)-2-naphthalen-2-yl-ethanone (c, 0.50 g) was added a mixture of pyridine (2 mL), trimethyl orthoformate (2 mL) and piperidine (2 drops), and the mixture was heated at 120° C. for 12 h. The mixture was cooled to room temperature, diluted with EtOAc (100 mL) then washed with 1 N HCl (100 mL). The organic layer was washed with water and dried. The oil obtained on concentration of the organic layer was crystallized in EtOAc/hexanes to give 6-ethyl-7-hydroxy-3-naphthalen-2-yl-chromen-4-one (d, 0.36 g).
Reaction SMILES: [CH2:1]([NH:4][C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].C([Li])CCC.[C:18]1([CH2:24][CH:25]=[CH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([N:4]([C@@H:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@@H:25]([CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[CH:2]=[CH2:3]
Reactant: C=CCN[C@@H](C)c1ccccc1
Reactant: CC(C)(C)OC(=O)C=CCc1ccccc1
Agent: [Li]CCCC
Product: C=CCN([C@H](CC(=O)OC(C)(C)C)Cc1ccccc1)[C@@H](C)c1ccccc1
Yield: 82.3 %

Procedure:
The procedure of Example 1 was repeated using (S)-N-allyl-α-methylbenzylamine (2) (0.750 g, 4.7 mmol), 1.6M butyllithium (2.52 ml, 4.0 mmol) and t-butyl 4-phenyl-2-butenoate (17) (0.678 g, 3.1 mmol) as the Michael acceptor. Flash chromatography on silica gel [ethyl acetate/petroleum ether (1:49)] afforded the title compound (Rf 0.20) as a colourless oil (0.968 g, 82%). δH (300 MHz; CDCl3) 7.40-7.15 (5H, m, Ph), 5.96-5.82 (1H, m, NCH2CH=CH2), 5.19 (1H, dd, J=17.3 and 1.3, trans CH=CH2), 5.09 (1H, dd, J=10.1 and 1.3, cis CH=CH2), 3.95 (1H, q, J=6.7, PhCHCH3), 3.67-3.56 (1H, m, PhCH2CH), 3.38-3.13 (2H, m, NCH2), 2.77 (1H, dd, J=14.7 and 7.1, CH2CO2), 2.55 (1H, dd, J=14.7 and 6.0, CH2CO2), 2.08 (2H, d, J=7.1, PhCH2), 1.42 (9H, s, (CH3)3C), 1.20 (3H, d, J=6.7, PhCHCH3).
Reaction SMILES: [CH2:1]([C@@H:3]1[NH:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(=O)(OC1C=CC(S(N2C3C(=CC=C(F)C=3)NC(=O)[C@@H]2CC)(=O)=O)=CC=1)OCC>>[CH2:1]([C@@H:3]1[N:12]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:14])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@@H]1Nc2ccc(F)cc2NC1=O
Agent: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)ccc3NC(=O)[C@@H]2CC)cc1
Product: CC[C@H]1C(=O)Nc2cc(F)ccc2N1S(=O)(=O)c1ccc(OC)cc1

Procedure:
(3S)-3-Ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one was treated with 4-methoxybenzenesulfonyl chloride according to the procedure for the preparation of ethyl 4-{[(2S)-2-ethyl-7-fluoro-3-oxo-3,4-dihydroquinoxalin-1 (2H)-yl]sulfonyl}phenyl carbonate (see Example 20) to yield (3S)-3-ethyl-7-fluoro-4-[(4-methoxyphenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one. [α]D25=−12.1° (c=0.006 G/ML, DMSO); MS (ESI) m/z 365 ([M+H]+); MS (ESI) m/z 363 ([M−H]−); Anal. Calcd for C17H17FN2O4S: C, 56.03; H, 4.70; N, 7.69. Found: C, 55.99; H, 4.57; N, 7.62.
Reaction SMILES: [CH3:1]N1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.Br[C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:42][C:43]2[CH:44]=N[C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]([CH3:57])[CH3:56])[CH2:51][CH2:50]3)=[CH:47][CH:48]=2)=[N:35][CH:34]=1.CC1(C)C(C)(C)OB([C:66]2[CH:67]=[C:68]([C:71]([NH2:73])=[O:72])[O:69][CH:70]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[CH:55]([N:52]1[CH2:51][CH2:50][N:49]([C:46]2[CH:1]=[CH:44][C:43]([NH:42][C:36]3[C:37]4[N:38]([N:39]=[CH:40][N:41]=4)[C:33]([C:66]4[CH:67]=[C:68]([C:71]([NH2:73])=[O:72])[O:69][CH:70]=4)=[CH:34][N:35]=3)=[CH:48][CH:47]=2)[CH2:54][CH2:53]1)([CH3:56])[CH3:57]
Reactant: CC1(C)OB(c2coc(C(N)=O)c2)OC1(C)C
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cn2)CC1
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: [Na+]
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4coc(C(N)=O)c4)n4ncnc34)cc2)CC1

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4, using 5-bromo-N-(6-(4-isopropylpiperazin-1-yl)pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine (80 mg, 0.21 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-furan-2-carboxylic acid amide (101 mg, 0.42 mmol), and Pd(PPh3)4 (62 mg, 0.053 mmol) in 1.5M Na2CO3 (aq) (1.143 mL, 1.71 mmol), and dioxane (4 mL). The crude product is purified by silica gel column chromatography eluting with DCM and 97:3 DCM:NH3 (7M in MeOH). The title compound is isolated after trituration with diethyl ether (35.4 mg, 42%). Conversion into the mesylate salt using 1M methanesulfonic acid in MeOH (0.0793 mL) affords the title compound as a solid (35 mg).
Reaction SMILES: Cl.CO[C:4]1[CH:17]=[CH:16][C:7]([C:8](C2CCNCC2)=[O:9])=[CH:6][CH:5]=1.COC([C:22]1[CH:23]=[CH:24][C:25](C(O)=O)=[N:26][CH:27]=1)=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:8]([N:26]1[CH2:27][CH2:22][CH2:23][CH2:24][CH2:25]1)(=[O:9])[C:7]1[CH:6]=[CH:5][CH:4]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 161.5 %

Procedure:
To a mixture of 4-(4-methoxybenzoyl)piperidine hydrochloride (2.00 g, 7.82 mmol, 1.0 eq) and 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.42 g, 7.82 mmol, 1.0 eq) in dimethylformamide (55 mL) was added triethylamine (2.72 mL, 19.55 mmol, 2.5 eq) followed by HATU (2.97 g, 7.82 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL). The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 4-5% MeOH—CH2Cl2) yielded the coupled product (2.39 g, 80%) as a white foam; 1H nmr (CDCl3) δ 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.60 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s, 1×OCH3), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m, 1H of BzpipH-3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); 13C nmr (CDCl3) δ 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5, 126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m/z: 383 [M+H]+ (found [M+H]+, 383.1515, C21H22N2O5 requires [M+H]+ 383.1602).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1(OB(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]1([C:7]2[O:8][CH:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:13])[N:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NN=C(c2ccccc2)OC1c1ccccc1
Reactant: OB(O)Oc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(c2ccccc2)OC(c2ccccc2)=NN1c1ccccc1
Yield: 36.9 %

Procedure:
A mixture of 2,6-diphenyl-4H-1,3,4-oxadiazine-5-one (0.1 g), phenyl boric acid (0.13 g), copper acetate (0.18 g) and triethylamine (0.12 g) was stirred vigorously in methylene chloride (15 ml) overnight at room temperature. The reaction in solution was purified directly by silica gel chromatography (ethyl acetate/hexane, 1:2), to give the title compound as a white powder (0.048 g, 37%).
Reaction SMILES: O[CH2:2][C:3]1[C:4]([CH3:8])=[N:5][S:6][CH:7]=1.Cl.[NH2:10][CH2:11][CH2:12][SH:13].[BrH:14]>>[BrH:14].[CH3:8][C:4]1[C:3]([CH2:2][S:13][CH2:12][CH2:11][NH2:10])=[CH:7][S:6][N:5]=1
Reactant: NCCS
Reactant: Cc1nscc1CO
Agent: Br
Agent: Cl
Product: Cc1nscc1CSCCN

Procedure:
Reacting 4-hydroxymethyl-3-methylisothiazole (3.0 g) with cysteamine hydrochloride (2.8 g) in 48% aqueous hydrobromic acid (50 ml) by the procedure of Example 42(ii) gives 3-methyl-4-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide. The base is obtained by basifying with aqueous potassium carbonate, extracting with chloroform, drying the extracts over magnesium sulphate and concentrating. Using the amine (5.0 g) as the starting material in the procedure of Example 72(ii) yields the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=1[N:43]=[C:44]=O.[F:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:49][C:48]=1[CH3:59]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:14]=[C:44]([N:56]1[CH2:55][CH2:54][N:53]([C:50]3[CH:51]=[CH:52][C:47]([F:46])=[C:48]([CH3:59])[CH:49]=3)[CH2:58][CH2:57]1)[N:43]([C:37]1[C:36]([O:35][CH3:34])=[CH:41][CH:40]=[C:39]([CH3:42])[CH:38]=1)[CH:8]2[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COc1ccc(C)cc1N=C=O
Reactant: COC(=O)/C=C/c1cccc(F)c1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(N2CCNCC2)ccc1F
Product: COC(=O)CC1c2cccc(F)c2N=C(N2CCN(c3ccc(F)c(C)c3)CC2)N1c1cc(C)ccc1OC

Procedure:
Starting with 0.60 g (1.76 mmol) of the iminophosphorane from Example 10A, 376 mg (2.31 mmol) of 2-methoxy-5-methylphenyl isocyanate and 342 mg (1.76 mmol) of the phenylpiperazine from Example 13A, 183 mg (16% of theory) of product are obtained after purification by preparative HPLC.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[C:8](C2C=CC(O)=C(N)C=2)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.[C:25](=[O:28])([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:6][C:7]1([C:12]2[CH:11]=[CH:10][C:25]([OH:28])=[C:8]([NH:9][C:3](=[O:4])[CH2:2][Cl:1])[CH:7]=2)[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[N:9][CH2:8]1
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1O
Reactant: O=C(Cl)CCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCl)Nc1cc(C2(Cl)C=C(C(F)(F)F)C=NC2)ccc1O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
3.8 g (33.3 mmol) of chloroacetyl chloride were added dropwise at 0° C. to a mixture of 7.4 g (25.6 mmol) of 3-chloro-2-(3-amino-4-hydroxyphenyl)-5-trifluoromethylpyridine and 2.1 g (15.4 mmol) of potassium carbonate in 100 ml of anhydrous dimethylformamide. After stirring at 90° C. for three hours, the reaction mixture was allowed to cool and then poured into 500 ml of water. The solid portion was filtered off with suction, washed with water and dried under reduced pressure. Yield: 7.3 g (87%) of colorless crystals of m.p.: 205° C.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][CH2:4][NH2:5].[C:7]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-:15].[Na+]>C1COCC1.O.CO>[CH2:1]([NH:6][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][OH:15])[CH2:2][CH2:3][CH2:4][NH:5][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: O=C1CCCCCO1
Reactant: [OH-]
Reactant: NCCCCN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(CCCCCO)NCCCCNC(=O)CCCCCO
Yield: 70 %

Procedure:
To a solution of 8.35 gram (0.0949 mol) 1,4-butanediamine in a mixture of 25 ml THF and 5 ml H2O was added a solution of 21.66 gram (0.1897 mol) ε-caprolactone in 25 ml THF in 5 min. at room temperature while stirring. The reaction mixture was stirred for 16 hours, whereafter the solvent was evaporated under reduced pressure. The obtained crude product (light yellow oil) was dissolved in 150 ml methanol (p.a.) and brought to pH=11.5 by adding 1M NaOH. The obtained solution was stirred for 16 hours whereafter it was added slowly drop by drop to 500 ml THF (p.a.). The obtained white product was filtered off and dried. The product still contains crystallization water. Yield 70%; Tm=135-136° C. C16H32N2O4: C, H, N; calculated 60.71%, 10.20%, 8.86%; found 58.87%, 10.13%, 8.44%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=O)[C:5]([F:34])=[CH:4][N:3]=1.CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])([CH3:20])[CH2:9][O:10][C@@:11]([C:12]#[N:14])([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:5]([F:34])=[CH:4][N:3]=1
Reactant: CC(CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(CO[C@](C)(C#N)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ncc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dry solution of (R)-2-[(RS)-2-(2-bromo-5-fluoro-pyridin-4-yl)-2-(2-nitro-benzenesulfonyl-amino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide (860 mg, 1.35 mmol) in DCM (9 ml) was added at rt NEt3 (0.470 ml, 342 mg, 3.38 mmol). At 0° C., trifluoroacetic anhydride (0.229 ml, 340 mg, 1.62 ml) was added dropwise. The reaction mixture was allowed to warm to rt and to stir for 1.5 h. The reaction mixture was diluted with 1M aq. Na2CO3 soln. and DCM.