Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)(O)[O-].[Na+]>>[CH3:14][O:13][C:11](=[O:12])[CH2:10][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([I:1])[CH:3]=1
Reactant: COC(=O)CCl
Reactant: Nc1cccc(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CNc1cccc(I)c1
Yield: 150.5 %

Procedure:
3-Iodoaniline (40.0 g), methyl chloroacetate (37.12 g) and sodium bicarbonate (30.75 g) were treated according to the method of Intermediate 5 to give an oil (ca. 80 g), a sample of which (1.2 g) was purified by FCC eluting with System A (7:3) to give the title compound (0.8 g) as a solid, m.p. 83°.
Reaction SMILES: [NH3:1].[ClH:2].[F:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](=[NH:10])O)=[CH:6][CH:5]=1>C(O)C>[ClH:2].[F:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:1])=[NH:10])=[CH:6][CH:5]=1
Reactant: N=C(O)c1ccc(F)cc1
Reactant: N
Agent: Cl
Solvent: CCO
Product: N=C(N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
310 cm3 of ethanol saturated with ammonia was added to 83 g (0.41 mol) of 4-fluorobenzimidate hydrogen chloride and stirred at room temperature for one day and night. Approximately half of the ethanol was distilled off and the residue was recrystallized to yield 70 g (0.40 mol) of 4-fluorobenzamidine hydrogen chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30]1([N:36]=[C:37]=[S:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:37]([NH:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[S:38])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=S)Nc2ccccc2)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin 3-yl]-phenyl-methanone and phenyl isothiocyanate according to the procedure of Example 65. MS (ESI) m/z 526.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1Br)[N:11]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:10][C@H:9]([CH3:22])[N:8]2[C:23](=[O:25])[CH3:24])(=[O:3])[CH3:2].[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:32]1[CH:31]=[N:30][N:29]([CH2:28][C:27]([OH:44])([CH3:43])[CH3:26])[CH:33]=1)[N:11]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:10][C@H:9]([CH3:22])[N:8]2[C:23](=[O:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)Nc1cc2c(cc1Br)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)Nc1cc2c(cc1-c1cnn(CC(C)(C)O)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Temperature: 90 °C

Procedure:
A mixture of isopropyl (S)-6-acetamido-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.011 g, 0.027 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (0.0085 g, 0.032 mmol), cesium carbonate (0.026 g, 0.080 mmol), XPhos (0.001 g, 0.003 mmol) and tris(dibenzylideneacetone)dipalladium (0.001 g, 0.002 mmol) in 1,4-dioxane (0.25 mL) and water (0.05 mL) was heated for 16 h at 90° C. The reaction was cooled to rt and concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was concentrated and the residue was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford isopropyl (S)-6-acetamido-4-acetyl-7-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 472 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C@@H:11]1/[CH:17]=[CH:18]/[C@@H:19]([OH:25])[CH2:20][CH2:21][CH:22]1[CH2:24][CH2:23]1.[OH-].[Na+]>CO>[CH:22]1([CH2:21][CH2:20][C@H:19]([OH:25])/[CH:18]=[CH:17]/[C@H:11]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[N:10]2[CH2:9][CH2:8][S:7][CH2:6][CH2:5][CH2:4][C:3]([OH:26])=[O:2])[CH2:23][CH2:24]1
Reactant: COC(=O)CCCSCCN1C(=O)CCC[C@@H]1/C=C/[C@@H](O)CCC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCSCCN1C(=O)CCC[C@@H]1/C=C/[C@@H](O)CCC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A methanol (10 mL) solution of 4-{2-[(R)-2-((S)-(E)-5-Cyclopropyl-3-hydroxy-pent-1-enyl)-6-oxo-piperidin-1-yl]-ethylsulfanyl}-butyric acid methyl ester from step (4, 98 mg, 0.25 mmol) was treated with sodium hydroxide (0.3 mL, 5 M aqueous) and stirred at ambient temperature for 3 hours. The volatiles were removed under a stream of nitrogen and the mixture was partitioned between water and ethyl ether. The aqueous layer was rendered acidic with hydrochloric acid (12 M aqueous) and extracted with ethyl acetate (3×15 mL). The combined organic extracts was stored over anhydrous sodium sulfate. 4-{2-[(R)-2-((S)-(E)-5-Cyclopropyl-3-hydroxy-pent-1-enyl)-6-oxo-piperidin-1-yl]-ethylsulfanyl}-butyric acid (94 mg, 0.25 mmol) was obtained following filtration and removal of the volatiles as an oil: 1H NMR (300 MHz, CDCl3) δ 6.7 (br.s, 1 H), 5.58-5.63 (m, 2 H), 4.18-4.22 (m, 1 H), 4.02-4.07 (m, 1 H), 3.87-3.98 (m, 1 H), 2.98-3.08 (m, 1 H), 2.62-2.72 (m, 2 H), 2.59 (t, J=6.9 Hz, 2 H), 2.36-2.49 (m, 4 H), 1.61-1.99 (m, 8 H), 1.22-1.30 (m, 2 H), 0.59-0.71 (m, 1 H), 0.40-0.46 (m, 2 H), 0.00-0.06 (m, 2 H); MS: m/z M+1, 370.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]([Si:44]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[O:45][CH:46]1[CH2:51][CH2:50][CH:49](O)[CH2:48][CH2:47]1)([CH3:43])([CH3:42])[CH3:41].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CN(C=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:49]3[CH2:48][CH2:47][CH:46]([O:45][Si:44]([C:40]([CH3:43])([CH3:42])[CH3:41])([C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[C:53]4[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=4)[CH2:51][CH2:50]3)=[CH:17][CH:18]=1)[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](OC1CCC(O)CC1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCC(Oc2ccc(C(=O)NC3C4CC5CC(C4)CC3C5)cc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 52.8 %

Procedure:
To a stirred solution of N-adamantan-2-yl-4-hydroxy-benzamide (4 g, 14.74 mmol) in dry THF (100 mL) and DMF (75 mL) was added triphenyl phosphine (5.8 g, 22.11 mmol) and 4-(t-butyl-diphenyl-silanyloxy)-cyclohexanol (6.27 g, 17.69 mmol). The reaction mixture was cooled to 0° C. and DEAD (3.48 mL, 22.11 mmol) was added dropwise from an addition funnel over a period of 30 min. The reaction was gradually brought to room temperature and stirring continued for 16 hrs. The solvent was removed under vacuum and ether (100 mL) was added and cooled to 0° C. The solid formed was filtered off and the clear filtrate concentrated and purified by column chromatography using DCM as solvent to give 4.73 g (53%) of N-adamantan-2-yl-4-[4-(t-butyl-diphenyl-silanyloxy)-cyclohexyloxy]-benzamide as an oil.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:20]3[CH2:19][CH2:18][C:17]4[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=4[C:15](=[O:25])[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C.C1(C)C=CC=CC=1>[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH:29][C:22]1[CH:23]=[CH:24][C:16]2[C:15](=[O:25])[C:14]3[CH:20]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:11]=[CH:12][C:13]=3[CH2:19][CH2:18][C:17]=2[CH:21]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C1c2ccccc2CCc2c(OCCN3CCOCC3)cccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2ccc(OCCN3CCOCC3)cc21
Yield: 76 %

Procedure:
For the preparation of the compound by method C, 0.67 g (1.8 mmol) of 2-chloro-7-(2-morpholin-4-yl-ethoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.70 g (6.2 mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield: 76%; C24H21F2NO4 (Mr=425.44)
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[NH:21][CH3:22])[N:17]([CH3:23])[C:16](=[O:24])[C:15]3([CH3:26])[CH3:25])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C>[CH3:22][N:21]1[C:20]2[C:12](=[CH:13][C:14]3[C:15]([CH3:26])([CH3:25])[C:16](=[O:24])[N:17]([CH3:23])[C:18]=3[CH:19]=2)[N:11]=[C:9]1/[CH:8]=[CH:7]/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNc1cc2c(cc1NC(=O)/C=C/c1ccccc1)C(C)(C)C(=O)N2C
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)c2cc3nc(/C=C/c4ccccc4)n(C)c3cc21
Temperature: 0 °C
Yield: 91.5 %

Procedure:
A solution of (E)-3-phenyl-N-(1,3,3-trimethyl-6-methylamino-2-oxo-2,3-dihydro-1H-indol-5-yl)-acrylamide (288 mg) in acetic acid (6 ml) is heated under reflux for 1 h. After recooling the mixture is poured into ice-water whereupon the desired compound (250 mg) is precipitated.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[NH4+].[Cl-]>CCO.O.[Fe]>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:22]([F:25])([F:23])[F:24]
Reactant: O=[N+]([O-])c1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ccnc12
Yield: 64.7 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-4 using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)-8-nitroquinoline (380 mg, 1.07 mmol), iron powder (604 mg, 10.79 mmol), and NH4Cl (461 mg, 8.63 mmol) in EtOH (10 mL) and water (3 mL) to afford 223 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.55 (d, J=4.8 Hz, 1H), 7.75 (d, 1H), 7.67 (d, J=7.5 Hz, 2H), 7.34 (d, J=4.5 Hz, 2H), 6.92 (t, 1H), 6.68 (d, J=4.8 Hz, 1H), 5.98 (s, 2H); MS (m/z): 323.28 (M+H)+.
Reaction SMILES: C([O:7][C@@H:8]1[C@@H:13]([O:14]C(=O)C(C)(C)C)[C@H:12]([O:21]C(=O)C(C)(C)C)[C@@H:11]([CH2:28][O:29]C(=O)C(C)(C)C)[O:10][C@H:9]1[O:36][C:37]1[C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:50][CH:49]=2)[NH:39][N:38]=1)(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:68][CH2:69][CH2:70][C:71]([O:73][CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)=[O:72].[I-].[Na+]>CC(C)=O>[CH2:74]([O:73][C:71]([CH2:70][CH2:69][CH2:68][N:39]1[C:40]2=[N:41][CH:42]=[CH:43][C:44]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:53]=3)=[C:45]2[C:37]([O:36][C@@H:9]2[O:10][C@H:11]([CH2:28][OH:29])[C@@H:12]([OH:21])[C@H:13]([OH:14])[C@H:8]2[OH:7])=[N:38]1)=[O:72])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1
Reactant: O=C(CCCBr)OCc1ccccc1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Oc1ccc(CCc2ccnc3c2c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn3CCCC(=O)OCc2ccccc2)cc1
Yield: 101.8 %

Procedure:
To a solution of benzyl alcohol (1 mL) and triethylamine (2.69 mL) in dichloromethane (15 mL) was added 4-bromobutyryl chloride (1.68 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1) to give benzyl 4-bromobutyrate (2.45 g). To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.17 g) in acetone (3 mL) were added cesium carbonate (0.16 g), benzyl 4-bromobutyrate (0.1 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature for 2 days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1-3/1) to give 1-(3-benzyloxycarbonylpropyl)-3-(β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (0.14 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution was added 10% palladium-carbon powder (50 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2-dichloromethane/methanol=15/1) to give the title compound (95 mg).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]=O)=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl.O[NH3+:15].S(Cl)(Cl)=O.O>CN1CCCC1=O>[Cl:1][C:2]1[C:9]([C:10]#[N:15])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)c(C=O)c1Cl
Reactant: [NH3+]O
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: N#Cc1ccc(F)c(C#N)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of 2-chloro-4-fluoro-3-formylbenzonitrile (597 mg) in 1-methyl-2-pyrrolidone (10 mL) was added hydroxyammonium hydrochloride (310 mg), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled at 0° C., and thionyl chloride (0.735 mL) was added dropwise thereto. The mixture was stirred at the same temperature for 30 min, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane to give the title compound as yellow crystals (yield: 503 mg).
Reaction SMILES: C(O[C:5]1[C:6](=[O:20])[C:7](=[O:19])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(C)C.[C:21]([NH2:26])([CH2:24][CH3:25])([CH3:23])[CH3:22]>>[F:18][C:15]([F:16])([F:17])[C:12]1[CH:11]=[CH:10][C:9]([C:8]2[C:7](=[O:19])[C:6](=[O:20])[C:5]=2[NH:26][C:21]([CH3:23])([CH3:22])[CH2:24][CH3:25])=[CH:14][CH:13]=1
Reactant: CC(C)Oc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O
Reactant: CCC(C)(C)N
Product: CCC(C)(C)Nc1c(-c2ccc(C(F)(F)F)cc2)c(=O)c1=O

Procedure:
In a manner similar to Example 1, Step 2, 3-isopropoxy-4-(4-trifluoromethyl-phenyl)-cyclobut-3-ene-1,2-dione (0.30 g, 1.056 mmol) and tert-amylamine (0.86 mL, 7.39 mmol) were converted to the title compound. Recrystallization from hot ethyl acetate afforded 0.250 g (76%) of compound as a tan solid: m.p. 115.4-119° C. (dec); 1H NMR (DMSO-d6); δ8.60(br s,1H), 8.15(ABq,2H), 7.86(ABq,2H), 1.81(q,2H), 1.43(s,6H), 0.88(s,3H); IR (KBr) 3170, 2980, 1770, 1720, 1580, 1310, 1170, 1125, 1060, 1010, 850 cm−1; MS (m/z) 311 [M+].
Reaction SMILES: [CH3:1][Ge:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=O.Cl>C(O)(C)C.O1CCCC1.[OH-].[K+]>[CH3:13][Ge:2]([CH3:12])([CH3:1])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH:10]=[CH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc([Ge](C)(C)C)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[Ge](C)(C)c1cccc(C(=O)C=Cc2ccc(C(=O)O)cc2)c1
Reaction time: 8 h
Yield: 23 %

Procedure:
3'-Trimethylgermylacetophenone (49 mg,0.2 mmol) and methyl 4-formylbenzoate (37 mg,0.23 mmol) was dissolved in 5 ml of a mixture of 50% isopropanol and tetrahydrofuran, 1 ml of 1N aqueous potassium hydroxide solution was added, and the mixture was stirred overnight. The reaction mixture was adjusted to pH1 with 2N hydrochloric acid and extracted with AcOEt. The extract was evaporated and the residue was purified by column chromatography on silica gel (eluent: MeOH-methylene chloride) and recrystallized from a mixture of AcOEt and n-hexane to give 17 mg of pale yellow prisms, m.p.186°-188° C. (yield 22%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:23]3[CH:24]=[N:25][N:26](CC4C=CC(OC)=CC=4)[CH:27]=3)[C:13]=2[CH3:37])[CH:6]=1)[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:23]3[CH:27]=[N:26][NH:25][CH:24]=3)[C:13]=2[CH3:37])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(Cc4ccc(OC)cc4)c3)c3c(F)c(Cl)ccc23)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cn[nH]c3)c3c(F)c(Cl)ccc23)c1

Procedure:
3-{6-Chloro-7-fluoro-1-[1-(4-methoxy-benzyl)-1H-pyrazol-4-yl]-2-methyl-1H-indol-3-ylsulfanyl}-benzoic acid ethyl ester (0.10 g, 0.18 mmol) was stirred in neat TFA (4 mL) for 18 hrs.
Reaction SMILES: OCCCN1C=C(C2C=C[C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3C=2[CH2:17][N:16](C)[C:15]3=[O:20])C=N1.NC1C(C(NC)=O)=[N:53][C:54]([Br:57])=[CH:55][CH:56]=1>>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:46]=[CH:47][C:33]([NH:32][C:24]2[N:23]=[C:22]([NH:21][C:13]3[C:14]([C:15](=[O:20])[NH:16][CH3:17])=[N:53][C:54]([Br:57])=[CH:55][CH:56]=3)[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][N:25]=2)=[C:34]([O:48][CH3:49])[CH:35]=1)(=[O:45])[O:39][CH2:40][CH3:41])[CH3:44]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc(Br)ccc1N
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC
Yield: 78 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 10 with 3-amino-6-bromo-N-methylpyridine-2-carboxamide (Compound 6D, 279 mg, 1.21 mmol). The reaction mixture was concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→5% MeOH in DCM] to afford 661 mg of the title compound (78%). 1H NMR (400 MHz, CD3OD) δ 8.94-9.11 (m, 1H), 8.37 (s, 1H), 7.68 (d, J=7.1 Hz, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.07 (t, J=2.0 Hz, 1H), 6.94 (td, J=2.4, 8.2 Hz, 1H), 4.04-4.16 (m, 4H), 3.88 (s, 3H), 3.33-3.34 (m, 1H), 3.28 (s, 1H), 2.94 (s, 3H), 1.29 (t, J=7.1 Hz, 6H). MS (ESI): m/z 647.53/649.53 [M+H]+. UPLC: tR=1.49 min (UPLC-TOF: polar—2 min).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:18]=[CH:19][N:20]=2)[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[CH3:21][C:22]1([CH3:35])[CH2:27][CH2:26][N:25]([C:28]2[N:33]=[C:32]([NH2:34])[CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH3:21][C:22]1([CH3:35])[CH2:23][CH2:24][N:25]([C:28]2[N:33]=[C:32]([NH:34][C:2]3[C:3]4[N:4]([CH:18]=[CH:19][N:20]=4)[N:5]=[C:6]([C:8]4[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=4)[C:11]([O:13][CH3:14])=[O:12])[CH:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:27]1
Reactant: CC1(C)CCN(c2cccc(N)n2)CC1
Reactant: COC(=O)c1cccc(-c2cc(Br)c3nccn3n2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCC(C)(C)CC4)n3)c3nccn3n2)c1
Temperature: 100 °C
Yield: 97.4 %

Procedure:
A mixture of methyl 3-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (0.15 g, 0.45 mmol), 6-(4,4-dimethylpiperidin-1-yl)pyridin-2-amine (93 mg, 0.46 mmol), Pd2(dba)3 (0.026 g, 0.046 mmol), BINAP (0.057 g, 0.09 mmol) and Cs2CO3 (0.442 g, 1.36 mmol) in dioxane (5 mL) was heated to 100° C. for 15 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, dichloromethane:MeOH=100:1) to afford methyl 3-(8-(6-(4,4-dimethylpiperidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (200 mg) as a brown liquid. LC-MS: [M+1]+=457.3, tR=2.145 min. This contained unidentified impurties and was used directly without further purification.
Reaction SMILES: [NH:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].I[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O>C(OC)(C)(C)C.O.O1CCCC1>[CH2:17]([N:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[CH2:18][CH3:19]
Reactant: N#CCCCCCNCCCCCC#N
Reactant: CCCI
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CCCN(CCCCCC#N)CCCCCC#N
Temperature: 60 °C
Yield: 81 %

Procedure:
A mixture of 6,6′-imino-bis-capronitrile (20.7 g, 100 mmol), 1-iodopropane (18.7 g 110 mmol), potassium carbonate (16.6 g, 120 mmol), and 100 mL of tetrahydrofuran was stirred and heated at 60° C. under nitrogen for three days. The product mixture was cooled to room temperature, and 25 mL of water was added to dissolve most of the solids. The aqueous layer was drawn off in a separatory funnel, a 125-mL portion of methyl t-butyl ether was added, and another small aqueous layer thus formed was drawn off. Gas chromatographic analysis of the product solution showed it to contain a small amount of unreacted secondary amine. Therefore, 10 g of anhydrous potassium carbonate and 2.5 g of 4-nitrobenzoyl chloride were added, and the mixture was stirred at room temperature for 30 minutes. Subsequent analysis by gas chromatography showed this treatment to have completely eliminated the unreacted starting material. The mixture was filtered, and solvent was removed by rotary evaporation at reduced pressure. Molecular distillation of the residue under high vacuum afforded 20.2 g (81 mmol, 81% of theory) of 6,6′-propylimino-bis-capronitrile.