Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:18][C:19]1[CH:20]=[CH:21][C:22](F)=[C:23]([CH:26]=1)[C:24]#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:13]([O:12][C:11](=[O:17])[NH:10][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:26][C:23]=2[C:24]#[N:25])[CH:3]=1)[CH3:9])([CH3:16])([CH3:15])[CH3:14]
Reactant: N#Cc1cc(Cl)ccc1F
Reactant: CC(NC(=O)OC(C)(C)C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)c1cccc(Oc2ccc(Cl)cc2C#N)c1
Temperature: 100 °C
Yield: 97.5 %

Procedure:
tert-Butyl [1-(3-hydroxyphenyl)ethyl]carbamate (0.025 g, 0.11 mmol) was dissolved in acetonitrile (1.0 mL) with 5-chloro-2-fluorobenzonitrile (Aldrich, Cat. #548693) (0.034 g, 0.22 mmol) and cesium carbonate (0.073 g, 0.22 mmol) in a sealed tube. The reaction was heated to 100° C. for 2 h. and was complete. The reaction was taken up in ethyl acetate, filtered and concentrated under reduced pressure to give crude tert-butyl{1-[3-(4-chloro-2-cyanophenoxy)phenyl]ethyl}carbamate (0.040 g) as a clear oil. Analytical LCMS (M+H-Boc)+: m/z=272.9.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:33]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1(C)C=CC=CC=1>[CH2:33]([N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCNCCCC
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 41.5 %

Procedure:
Operations are carried out as for Example 7, starting from 2.5 g of 1-phenyl isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.66 g of dibutylamine in 100 ml of toluene. After chromatography and recrystallization in petroleum ether, 1.5 g of N,N-dibutyl 1-phenyl isoquinoline 3-carboxamide melting at 62° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:13]1([S:19]([C:22]2[CH:23]=[C:24]([S:27](Cl)(=[O:29])=[O:28])[S:25][CH:26]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([C:22]2[CH:23]=[C:24]([S:27]([NH:1][C:2]3[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=3)(=[O:28])=[O:29])[S:25][CH:26]=2)(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cc(S(=O)(=O)c2ccccc2)cs1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(S(=O)(=O)c3ccccc3)cs2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-benzenesulfonylthiophene-2-sulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (29.5 mg) with purity >90%. MS (pos) m/z 473.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15](O)=[O:16])[CH:6]=2.[CH:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([NH:26][CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:16])[CH:6]=2
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2cc(N)ncc2c1
Reactant: NC1CCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CCC2)cc1-c1ccc2cc(N)ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.2 %

Procedure:
A mixture of 3-(3-aminoisoquinolin-7-yl)-4-methylbenzoic acid (43.0 mg; 0.155 mmol), cyclobutylamine (27 μL; 0.310 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (129.5 mg; 0.2384 mmol), N,N-diisopropylethylamine (0.1 mL; 0.6 mmol), 4-(dimethylamino)pyridine (0.1 equiv.; 0.0155 mmol) and N,N-dimethylformamide (2.0 mL; 26 mmol) was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water (2×) and brine, dried over magnesium sulfate, and filtered through a plug of silica gel, rinsing with additional ethyl acetate. The filtrate was evaporated in vacuo to yield 53.6 mg crude product. 20.2 mg of crude product was purified via preparatory reverse-phase HPLC and lyophilized to yield 4.2 mg of the title compound. LCMS (ESI): RT (Min)=2.88, M+H=327.3, method=H; 1H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.56 (d, J=8.0 Hz, 1H), 7.82-7.74 (m, 3H), 7.60 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 6.67 (s, 1H), 5.95 (s, 2H), 4.50-4.34 (m, 1H), 2.31 (s, 3H), 2.26-2.13 (m, 2H), 2.06 (m, 2H), 1.73-1.57 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH2:31]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][CH3:43])[CH2:38][CH2:37]1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=3[C:27]([F:28])([F:30])[F:29])[N:8]=[CH:9]4)[C:18](=[O:24])[N:19]=2)[CH3:43])[CH2:40][CH2:41]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)N1CCC(NC)CC1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CCOC(=O)N1CCC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
4-({5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-piperidine-1-carboxylic acid ethyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and 4-methylamino-piperidine-1-carboxylic acid ethyl ester following General Procedure B.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:9]=1[C:10]([OH:12])=[O:11].Cl[N:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[NH:20]1.Cl>CN(C)C=O.O>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][N:19]2[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[NH:24]2)[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: O=C(O)c1c(O)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1=CC(OC)=NN(Oc2cccc(Cl)c2C(=O)O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
At 25° C., 20.2 g of potassium tert-butylate is added in portions to 15.5 g of 2-chloro-6-hydroxybenzoic acid in 50 ml of dimethylformamide. Subsequently, 15.7 g of 2-chloro-4,6-dimethoxytriazine is added. The mixture is stirred for 12 hours at 25° C. and poured into cold water, and the resulting mixture is acidified with hydrochloric acid. Extraction is then carried out with ethyl acetate, and the extract is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is stirred with a small amount of diethyl ether, followed by filtration. The residue is dried under reduced pressure (m.p. 128°-131° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([C:14]([C:16]1[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3Cl)[CH:17]=1)=[O:15])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([NH2:37])=[CH:32][CH:31]=2>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([C:14]([C:16]1[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[NH:37][C:33]3[CH:34]=[C:35]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]([CH3:27])=[CH:36]4)[CH:17]=1)=[O:15])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC21
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC6C(C5)C6NC(=O)OC(C)(C)C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from {3-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamic acid tert-butyl ester and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 504 (MH+); HPLC Rf: 5.31 min.; HPLC purity 95%.
Reaction SMILES: [CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16].Br[CH2:18][CH2:19][CH2:20][OH:21].C(N(CC)CC)C.CCOCC>C(O)C>[CH3:1][N:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:10][CH2:9]2)=[CH:6][C:5](=[O:14])[N:4]([CH3:15])[C:3]1=[O:16]
Reactant: OCCCBr
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cn1c(N2CCN(CCCO)CC2)cc(=O)n(C)c1=O
Yield: 69.9 %

Procedure:
14.1 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione (compound b), 11.7 g of 3-bromo-1-propanol and 13 g of triethylamine were heated under reflux in 250 ml of ethanol for 20 hours to carry out reaction. After completion of the reaction, the resultant reaction mixture was then concentrated to dryness, and the resultant residue was dissolved in 300 ml of chloroform and then washed with 100 ml of water twice. The washed organic layer was dried over anhydrous magnesium sulfate and then treated with under reduced pressure, and the solvent was distilled off, thereby obtaining 20.5 g of a crude product. Next, ether was added to this crude product so as to achieve crystallization. The resultant crystals were recovered, washed and then dried to obtain 12.4 g (yield 69.8%) of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound a).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:8][CH:7]=1)C>CN(C)C=O.C(OCC)(=O)C>[O:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[O:18][CH2:17][CH2:16][O:15][C:9]1[C:10]2[CH:11]=[CH:12][O:13][C:14]=2[C:6]([CH2:5][C:4]([OH:25])=[O:3])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(OCCOC2CCCCO2)c2ccoc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(OCCOC2CCCCO2)c2ccoc12
Temperature: 25 °C
Yield: 73.4 %

Procedure:
Add to a cooled solution (0° C.) of {4-[2-(tetrahydropyran-2-yloxy)ethoxy]-benzofur-7-yl}acetic acid ethyl ester (1.363 g, 3.912 mmol) in dimethylformamide (20 ml) 2M aqueous sodium hydroxide (10 ml), and stir the mixture for 1½ hours at room temperature. Dilute the mixture with ethyl acetate and extract with water. Dilute with methylene chloride (50 ml) and neutralize using 0.1M aqueous hydrochloric acid (100 ml). Separate the layers are separated and extract the water layer with methylene chloride. Combine the methylene chloride layers, dry over sodium sulfate, filter, and concentrate to obtain 0.920 g (68%) of the title compound as an oil. Mass spectrum: electrospray (m/z) 319 (M−1).
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5])#[N:2].[Se](=O)=O>ClC1C=CC=CC=1>[C:1]([C:3](=[CH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: N#CC(CC(=O)c1ccccc1)C(=O)O
Agent: O=[Se]=O
Solvent: Clc1ccccc1
Product: N#CC(=CC(=O)c1ccccc1)C(=O)O
Temperature: 135 °C

Procedure:
A mixture of 11.5 g of 16A, 5.5 g of selenium dioxide and 30 ml of chlorobenzene was refluxed at 135° C. Then the chlorobenzene was distilled off under reduced pressure. The residue was extracted with hot hexane. The hexane was evaporated from the extract under reduced pressure. 30 ml of chlorobenzene was added to the residue and the mixture was refluxed overnight. The chlorobenzene was evaporated under reduced pressure. The residue was extracted with ether. The extract was cooled to give a solid, which was recrystallized from hexane to give the E-isomer of the ethyl ester of 2-cyano-4-oxo-4-phenyl-2-butenoic acid (16B) mp: 74°-75° C.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].C([Li])CCC.CCCCCC.[CH2:16]([S:24]C#N)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:16]([S:24][C:3]#[C:2][CH2:1][OH:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: C#CCO
Reactant: CCCCCCCCSC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCCC
Product: CCCCCCCCSC#CCO
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-propynol (0.65 g/0.68 ml, 11.7 mmol) in 25 ml of tetrahydrofuran (THF), cooled to -60°, is slowly added butyllithium in hexane (14.6 ml, 23.3 mmol) over 5 min. About 5 ml of HMPA is added and the mixture is warmed to -20° and stirred for 5 min. The mixture is then cooled again to -60° and octylthiocyanate (2.0 g, 11.7 mmol) in 3 ml of THF is added over 1 min. The mixture is allowed to warm to RT over 1 hour and is stirred at RT for an additional hour. It is then cooled to -10° and quenched with water. The reaction mixture is diluted with ether, washed with water and brine and dried to give 3-octylthio-2-propynol.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][O:7][CH2:6][C@@H:5]1[O:9][Si:10]([CH3:13])([CH3:12])[CH3:11])=[N+]=[N-]>CC(C1C=C(C(C)(C)C)C(=O)/C(=C/N[C@H]2[C@H](N/C=C3/C=C(C(C)(C)C)C=C(C(C)(C)C)C/3=O)CCCC2)/C=1)(C)C.[Co].[Pd].C1COCC1>[CH3:11][Si:10]([CH3:13])([CH3:12])[O:9][C@H:5]1[CH2:6][O:7][CH2:8][C@@H:4]1[NH2:1]
Reactant: C[Si](C)(C)O[C@H]1COC[C@@H]1N=[N+]=[N-]
Agent: [Co]
Agent: [Pd]
Agent: CC(C)(C)C1=C/C(=C/N[C@@H]2CCCC[C@H]2N/C=C2\C=C(C(C)(C)C)C=C(C(C)(C)C)C2=O)C(=O)C(C(C)(C)C)=C1
Solvent: C1CCOC1
Product: C[Si](C)(C)O[C@H]1COC[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of [(3R,4S)-4-azidotetrahydrofuran-3-yl]oxy-trimethyl-silane (870 mg, 4.2 mmol; prepared according to the exact procedure found in Jacobsen, E. N.; Larrow, J. F.; Schaus, S. E. J. Org. Chem. 1997, 62, 4197-4199; except that commercially available (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis(3,5-di-t-butylsalicylidene)cobalt (II) is used as catalyst), 10% palladium on carbon (230 mg, 216 μmol), and THF (22 mL) is stirred at room temperature under hydrogen (60 psi) for 16 h. The reaction is filtered through a pad of diatomaceous earth and the pad is rinsed with THF (50 mL). The filtrate is concentrated in vacuo to give the title compound as a brown oil (825 mg, quantitative). LC-ES/MS m/z 176 (M+1).
Reaction SMILES: Cl.[CH2:2]([C@@H:9]1NC(C)(C)N(C)[C:10]1=[O:17])[C:3]1C=CC=CC=1.[C:18]1([C:24]2[O:25][C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:27]3[C:32]=2[CH:31]=[CH:30][CH:29]=[CH:28]3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CO.C(=O)/C=C/C>CN(C=O)C.CCOCC>[C:18]1([C@@:24]23[O:25][C@@:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C@@H:9]([CH:10]=[O:17])[C@@H:2]2[CH3:3])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]3=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(-c2oc(-c3ccccc3)c3ccccc23)cc1
Reactant: CN1C(=O)[C@H](Cc2ccccc2)NC1(C)C
Agent: C/C=C/C=O
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@H]1[C@H](C=O)[C@]2(c3ccccc3)O[C@@]1(c1ccccc1)c1ccccc12
Temperature: 10 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a 10° C. solution of 5 (13 mg, 0.058 mmol), 1,3-diphenylisobenzofuran (162 mg, 0.60 mmol), and MeOH (12 μL, 0.30 mmol) in DMF/1H2O (95/5 v/v, 1.0 M) was added (E)-crotonaldehyde (25 μL, 0.30 mmol). The solution was stirred at 10° C. for 24 h. The reaction mixture was then diluted with Et2O (10 mL) and washed with H2O (10 mL). The aqueous layer was extracted with Et2O (10 mL×2) and the combined organics were dried (Na2SO4), and concentrated. Purification by silica gel chromatography (7% EtOAc/hex) afforded the title compound as a yellow solid in 75% yield (76 mg, 0.22 mmol); 35:1 exo:endo; 96% ee. Product ratios were determined, after reduction to the corresponding alcohol (4 eq NaBH4, EtOH (0.1 M)), by HPLC (Chiralcel OD-H column, 3% EtOAc/hex, 1.0 mL/min) exo isomers tr=14.1 min and 15.3 min, endo isomers tr=16.5 min and 20.8. IR (CH2Cl2) 3066, 3041, 2828, 2729, 1722, 1603, 1499, 1457, 1448, 1381, 1355, 1309 cm−1; 1H NMR (500 MHZ, CDCl3) δ 9.36 (d, J=5.8 Hz, 1H, CHO), 7.73-7.78 (m, 2H, ArH), 7.43-7.57 (m, 7H, ArH), 7.35-7.40 (m, 1H, ArH), 7.16-7.26 (m, 3H, ArH), 7.04-7.08 (m, 1H, ArH), 3.08 (dq, J=6.9, 4.1 Hz, 1H, CHCH3), 2.56 (dd, J=5.8, 4.2 Hz, 1H, CHCHO), 0.96 (d, J=6.9 Hz, 3H, CH3); 13C NMR (125 MHZ) δ 201.9, 147.4, 145.0, 145.0, 136.6, 135.7, 135.5, 128.8, 128.6, 128.0, 127.4, 127.3, 127.0, 126.0, 125.5, 121.7, 118.5, 91.4, 89.2, 66.0, 43.0, 34.2, 30.3, 16.5; HRMS exact mass calcd for (C24H20O2) requires m/z 341.1541, found m/z 341.1542; [α]D=−82.4 Ĉ=1.0, CHCl3).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1B1OC(C)(C)C(C)(C)O1)(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[OH:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:27][O:26][CH2:25]4)[CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Clc1cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c2nccn2n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C1c2cc3c(n2CCN1c1nccc(-c2cc(Nc4ccc(N5CCN(C6COC6)CC5)cn4)c4nccn4n2)c1CO)CCCC3
Temperature: 130 °C
Yield: 4 %

Procedure:
A sealed tube was charged with 6-chloro-N-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-yl)imidazo[1,2-b]pyridazin-8-amine 105a (200 mg, 0.5 mmol), 114e (200 mg, 1.0 eq., 0.5 mmol), Pd2(dba)3 (46 mg, 0.1 eq., 0.05 mmol), PCy3 (40 mg, 0.2 eq., 0.1 mmol), cesium carbonate (325 mg, 2 eq., 1.0 mmol), and dioxane (10 mL). After three cycles of vacuum/argon flash, the mixture was heated at 130° C. for 14 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) and further purified with reverse-phase prep-HPLC to afford 114 (13 mg, 4%). LCMS: [M+H]+ 647. 1H NMR (500 MHz, DMSO) δ 9.96 (s, 1H), 8.56 (d, J=5.0, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.99 (d, J=2.5, 1H), 7.68 (s, 1H), 7.45-7.50 (m, 3H), 6.58 (s, 1H), 4.72 (t, J=5.0, 1H), 4.55-4.59 (m, 3H), 4.45-4.47 (m, 2H), 4.37-4.40 (m, 1H), 4.19-4.29 (m, 2H), 4.08-4.10 (m, 1H), 3.91-3.94 (m, 1H), 3.42-3.45 (m, 1H), 3.14-3.16 (m, 4H), 2.52-2.63 (m, 2H), 2.46-2.47 (m, 2H), 2.36-2.40 (m, 4H), 1.76-1.78 (m, 2H), 1.66-1.70 (m, 2H)
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16][CH2:15][CH2:14]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][S:16][CH2:17][CH2:18]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(C2CCSCC2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1sc(C2CCSCC2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a mixture of 4-({cyclohexyl[2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methyl}amino)benzoic acid (250 mg) synthesized in Example 272-(5), ethyl 3-(methylamino)propanoate (88.7 mg), 1-hydroxybenzotriazole monohydrate (104 mg) and triethylamine (94 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (130 mg), and the mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (230 mg, 77%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:43])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([CH2:34][NH:35]C(OC(C)(C)C)=O)=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:43])[C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([CH2:34][NH2:35])=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)NCc1ncccc1-c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ncccc1-c1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Yield: 93.1 %

Procedure:
To a solution of 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(2-tert-butyloxycarbonylaminomethyl-pyridyl)benzoyl]piperazine (90 mg, 1.45 mmol) in tetrahydrofuran (2 ml) was added ˜4M methanolic HCl (2 ml) and the resultant mixture stirred for four hours at ambient temperature. Removal of the solvent, after filtration, gave 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(2-aminomethyl-pyridyl)benzoyl]piperazine (75 mg, 1.35 mmol).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:54])([C:50]([F:53])([F:52])[F:51])[C:24]([F:49])([F:48])[C:25]([F:47])([F:46])[O:26][C:27]([F:45])([F:44])[C:28]([F:43])([F:42])[O:29][C:30]([F:41])([F:40])[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][O:32][CH2:31][C:30]([O:29][C:28]([F:42])([F:43])[C:27]([F:44])([F:45])[O:26][C:25]([F:46])([F:47])[C:24]([F:48])([F:49])[C:23]([F:22])([F:54])[C:50]([F:52])([F:53])[F:51])([F:41])[F:40])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: FC(F)(COCCCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.01 g, 3.55 mmol) and 6-(2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromohexane (2.4 g, 4.03 mmol; prepared by combining 1,6-dibromohexane and 2-(2-(nonafluorobutoxy)tetrafluoroethoxy)-2,2-difluoroethanol). The resulting crude product was isolated and further purified essentially as described in Example 3, eluting with 1 vol. % ethyl acetate/toluene