Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[CH:9]=[C:8]([CH3:10])[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]1[C:13](=[CH2:17])[CH2:14][CH2:15][OH:16].[CH3:19]I>CCCCCC.C1COCC1>[CH3:19][O:16][CH2:15][CH2:14][C:13](=[CH2:17])[CH:5]1[C:6]([CH3:11])([CH3:12])[CH2:7][C:8]([CH3:10])=[CH:9][C:4]1([CH3:18])[CH3:3]
Reactant: C=C(CCO)C1C(C)(C)C=C(C)CC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(CCOC)C1C(C)(C)C=C(C)CC1(C)C
Yield: 465.3 %

Procedure:
Sodium hydride (0.6 g of 60% oil dispersion, 0.015 mol) was washed with hexane (2×3 mL) and suspended in THF (10 mL). A solution of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol (1.11 g, 0.005 mol) in THF (5 mL) was added, followed by methyl iodide (1.4 g, 0.001 mol). The mixture was heated at reflux for 4 hr. Afterwhich, work-up, chromatography and kugelrohr distillation gave 1.10 g of 2,2,4,6,6-pentamethyl-γ-methylene-3-cyclohexene-1-propanol methyl ether. 1H-NMR (60 MHz, CDCl3) δ0.95 (6H, s), 1.03 (6H, broad s), 1.63 (3H, broad s), 1.5-2.6 (5H, m), 3.33 (3H, s) 3.58 (2H, t, J=7 Hz), 4.85-5.15 (3H, m); IR (film) vmax 2960, 1640, 1440, 1380, 1360 cm-1 ; MS m/e 236, 221, 204, 189, 140, 125, 96.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27]Br>C1COCC1>[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C#CCCCCC
Reactant: COC(CBr)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCC#CCC(OC)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
1-Heptyne (50 ml, 381 mmole) is dissolved in 360 ml dry THF in a flame dried 2000 ml 3-neck round bottom flask under nitrogen. The solution is cooled to 0° C. and treated with n-butyllithium (232 ml, 360 mmole) dropwise over 40 minutes via a dropping funnel. The reaction mixture is stirred 30 minutes at 0° C., treated with hexamethylphosphoric triamide (68 ml, 391 mmole), and stirred an additional 30 minutes at 0° C. 1,1-Dimethoxy-2-bromoethane (43 ml, 364 mmole) is added dropwise to the reaction mixture over 10 minutes at 0° C. The reaction mixture is stirred 3 hours at 0° C. and an additional 72 hours at room temperature. The mixture is subsequently quenched with 5 ml water and the THF removed in vacuo. The amber oily residue is dissolved in 200 ml diethyl ether and poured into 100 ml 50% saturated sodium chloride. The aqueous layer is extracted with 3×75 ml diethyl ether. The organics are combined, washed with 6×50 ml 50% saturated sodium chloride, and dried over anhydrous magnesium sulfate. The diethyl ether is removed in vacuo and the red oily residue distilled under reduced pressure. After a 5 ml forerun, the fraction boiling at 65°-67° C. (0.5 mm) is collected to provide 42 g of the title compound as a colorless oil. Following the above procedure gives the title compound having the physical characteristic described below:
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cc2cc(C(=O)N3CCC[C@H]3CN3CCCC3)ccc2n1CC(F)(F)F)N1CCC(F)(F)CC1
Yield: 85 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 44), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a white foam (85%).
Reaction SMILES: C([NH:8][C:9]1[C:18]([Cl:19])=[C:17]2[C:12]([C:13](=[O:41])[C:14]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][N:16]2[C:20]2[CH:25]=[C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([F:34])=[CH:22][C:21]=2[F:35])=[CH:11][C:10]=1[F:42])C1C=CC=CC=1.C(O)(=O)C.[H][H]>ClCCCl.[OH-].[Pd+2].[OH-]>[NH2:8][C:9]1[C:18]([Cl:19])=[C:17]2[C:12]([C:13](=[O:41])[C:14]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:15][N:16]2[C:20]2[CH:25]=[C:24]([NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C:23]([F:34])=[CH:22][C:21]=2[F:35])=[CH:11][C:10]=1[F:42]
Reactant: [H][H]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(NCc3ccccc3)c(F)cc2c1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(Cl)c(N)c(F)cc2c1=O
Temperature: 25 °C
Yield: 91.9 %

Procedure:
Ethyl 7-benzylamino-1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-8-chloro-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (3.2 g) was dissolved in 1,2-dichloroethane (40 ml). An acetic acid suspension (10 ml) of 20% palladium hydroxide (300 mg) was added to this solution, and the mixture was stirred overnight at 60° C. in a hydrogen atmosphere. An acetic acid suspension (4 ml) of 20% palladium hydroxide (100 mg) was additionally added, and the resultant mixture was stirred overnight at the same temperature. After the reaction mixture was cooled back to room temperature, palladium hydroxide was removed by filtration. After the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and solids were collected by filtration to obtain the title compound (2.5 g) as an amorphous substance.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C1COCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2-c1cccc(OCCn2ccnc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1cccc(O)c1)cn2-c1cccc(OCCn2ccnc2)c1

Procedure:
1.85 g of 5-(3-benzyloxyphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]-pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 80 h in 40 ml of THF in the presence of 0.4 g of 5% palladium/carbon. After filtration through Celite and crystallization from ethanol, 5-(3-hydroxyphenyl)-7-[3-(2-(1-imidazolyl)-ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having a melting point of 165°-167° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8]
Reactant: COc1cc(C(=O)O)ccn1
Reactant: Nc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)Nc2ccccc2)ccn1
Temperature: 0 °C
Reaction time: 6 h
Yield: 83.9 %

Procedure:
To a solution of 2-methoxyisonicotinic acid (2.00 g, 13.06 mmol) in anhydrous tetrahydrofuran (80 mL) was added 4-methyl morpholine (1.84 g, 18.28 mmol). After cooling to 0° C., isobutyl chloroformate (2.31 g, 16.98 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 6 hours, followed by the addition of aniline (1.70 g, 18.28 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 mL) and washed with saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford 2-methoxy-N-phenylisonicotinamide (2.50 g, 86%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 11.85 (s, 1H), 10.31 (s, 1H), 7.75-7.60 (m, 2H), 7.47 (d, J=4.6 Hz, 1H), 7.35-7.20 (m, 2H), 7.12-7.04 (m, 1H), 6.83-6.80 (m, 1H), 6.54-6.42 (m, 1H); MS (ES+) m/z 229.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)([C:6]([NH2:8])=[O:7])[C:3]([NH2:5])=[O:4]>[Pd].C(OCC)(=O)C.C(O)C>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:2]([CH3:1])([C:3]([NH2:5])=[O:4])[C:6]([NH2:8])=[O:7])=[CH:15][CH:14]=1
Reactant: CC(Cc1ccc([N+](=O)[O-])cc1)(C(N)=O)C(N)=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(Cc1ccc(N)cc1)(C(N)=O)C(N)=O
Reaction time: 6 h
Yield: 46.2 %

Procedure:
A 250-mL round bottom flask was charged with 2-methyl-2-(4-nitrobenzyl)malonamide (0.69 g, 2.74 mmol) and 10% palladium on carbon (0.17 g) in 1:2 ethyl acetate/ethanol (30 mL). This mixture was vigorously stirred under H2 (1 atm) for 6 h. The mixture was then filtered through celite to afford the title compound (0.28 g, 46%) as an off-white solid. MW=221.26. 1H NMR (DMSO-d6, 300 MHz) δ 7.15 (s, 2H), 7.08 (s, 2H), 6.80 (d, J=8.1 Hz, 2H), 6.41 (d, J=8.1 Hz, 2H), 4.87 (s, 2H), 2.86 (s, 2H), 1.07 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of ethyl 2-(4-methoxyphenyl)acetate (12 g, 0.06 mol) in MeOH (150 mL) was added dropwise a solution of NaOH (9.8 g, 0.24 mol) in water (50 mL). The mixture was then stirred at RT for 1 h and concentrated in vacuo, the residue was acidified with HCl (1N) and extracted with EtOAc (2×400 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4-methoxyphenyl)acetic acid (10 g, 67%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([O:7][CH2:8][CH2:9][OH:10])[C:3]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:34](OC(=O)C)(=[O:36])[CH3:35]>O1CCCC1>[C:34]([O:10][CH2:9][CH2:8][O:7][C:4]1[C:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:2]([NH2:1])[O:6][N:5]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)c1c(OCCO)noc1N
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCOc1noc(N)c1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a stirring solution of tert-butyl 5-amino-3-(2-hydroxyethoxy)-4-isoxazolecarboxylate (R. Neidlein, J.Heterocyclic Chem., 1989, 26,1335) (5.60 g) and triethylamine (3.36 ml) in tetrahydrofuran (50 ml) at room temperature was added dimethylaminopyridine (280 mg) followed by acetic anhydride (2.81 g). The reaction was stirred for 2 hours at room temperature. The solvent was removed in vacuo to yield the crude material (6.0 g). The crude material was purified using the Biotage™ Flash 40i System (silica, 90 g), eluting with ethyl acetate:hexane (1:1) to yield the product as an off white solid (5.0 g)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](Cl)([Cl:11])[C:9](=O)[CH2:8][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[NH:6]1)=[O:4].Cl.[NH2:25][OH:26].N1C=CC=CC=1>CO>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[CH2:8][C:9](=[N:25][OH:26])[C:10]=1[Cl:11])=[O:4]
Reactant: NO
Reactant: COC(=O)C1NC(c2ccc(Cl)c(OC)c2F)CC(=O)C1(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: COC(=O)C1=C(Cl)C(=NO)CC(c2ccc(Cl)c(OC)c2F)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.5 %

Procedure:
3-Chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-3-chloro-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (33; 1.612 g, 4.63 mmol) was suspended in MeOH (20 mL). Hydroxylamine hydrochloride (966 mg, 13.9 mmol) was added followed by pyridine (3 mL). The reaction mixture was stirred for 18 h at room temperature and then for 4 h at 40° C. The solvent was removed by rotary evaporation. H2O (100 mL) was added, and the resulting solid was filtered, washed with H2O followed by MeOH to give 3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-hydroxyimino-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (34; 1.353 g, 81%) as a white powder: mp 174-176° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H, NOH), 7.35 (dd, JF-H=1.5 Hz, JH-H=8.7 Hz, 1H, aromatic), 7.17 (dd, JF-H=JH-H=8.7 Hz, 1H, aromatic), 6.93 (br s, 1H, NH), 4.69 (m, 1H, H6), 3.88 (s, 3H), 3.79 (s, 3H), 3.03 (dd, J=4.5, 16 Hz, 1H, H5a), 2.74 (dd, J=9.0, 16 Hz, 1H, H5b); Anal. Calcd for C14H13Cl2FN2O4: C, 46.30; H, 3.61; N, 7.71. Found: C, 46.77; H, 3.64; N, 7.42.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C([O-])(=O)C.[Rh+].C(Cl)Cl>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[CH:34][N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g), rhodium(I) acetate (0.023 g) and methylene chloride (10 mL) was added dropwise ethyl diazoacetate (0.64 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.68 g, 59%).
Reaction SMILES: [C:1]([OH:7])([C:3](F)(F)F)=O.[N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3([C:21]4[N:25]5[N:26]=[C:27]([C:30]6[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=6)[CH:28]=[N:29][C:24]5=[N:23][CH:22]=4)[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>>[N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3([C:21]4[N:25]5[N:26]=[C:27]([C:30]6[CH:38]=[CH:37][C:33]([C:34]([NH:8][CH:9]7[CH2:3][CH2:1][O:7][CH2:11][CH2:10]7)=[O:35])=[CH:32][CH:31]=6)[CH:28]=[N:29][C:24]5=[N:23][CH:22]=4)[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Reactant: O=C(O)C(F)(F)F
Product: O=C(NC1CCOCC1)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1

Procedure:
This compound was prepared as a TFA salt starting from 4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoic acid using procedures analogous to those for Example 105. LCMS: (M+H)=491.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](I)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24].CC1(C)C(C)(C)OB([C:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH:45]=2)O1>>[C:18]([NH:17][C:15]1[N:16]=[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=4)(=[O:25])=[O:24])[CH:4]=3)=[N:13][N:12]2[C:14]=1[C:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH:45]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1I
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Yield: 25.9 %

Procedure:
Following the procedure described in Example 49, N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (370.0 mg, 583 μmol)was combined with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (216 mg, 699 μmol, (Carbocore, The Woodlands, Tex.) to afford tert-butyl 4-(2-acetamido-6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (104 mg, 25.9% yield) as a yellow solid. LCMS (ESI positive ionization) m/z: 691 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13].[N+:17](=[CH2:19])=[N-:18]>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH:19]=[N+:17]=[N-:18])=[CH:4][C:3]=1[S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13]
Reactant: C=[N+]=[N-]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl

Procedure:
14.1 g of 4-chloro-3-dimethylsulfamoylbenzoyl-chloride were reacted as prescribed in Example 66(b) with diazomethane in diethyl ether and the crystalline product was filtered off. Melting point: 136°-137° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 13 g. of 4-[[bis(p-chlorphenyl)methyl]amino]benzoic acid, ethyl ester, 9 g. of potassium hydroxide, and 150 ml. of 95% ethanol is heated at 70° C. for 4 hours, cooled, diluted with 300 ml. of water, and adjusted to pH 6.5 with 37% hydrochloric acid. The solid is collected, dried, and crystallized from ethanol and then acetic acid, giving 5.52 g. of the desired product as yellow crystals, m.p. 245°-247° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[CH3:15][C:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:25])[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(OCC)(=O)C>[CH3:25][C:16]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH3:15])[CH2:17][CH2:18][N:19]1[CH2:20][CH2:21][N:22]([C:12]([CH:10]2[CH2:9][S:8][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11]2)=[O:14])[CH2:23][CH2:24]1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: CC(C)(CCN1CCNCC1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CCN1CCN(C(=O)C2CSC(c3cccnc3)N2)CC1)c1ccccc1
Yield: 99 %

Procedure:
A solution of 2-(3-pyridyl)thiazolidin-4-carboxylic acid (0.81 g), 1-(3-methyl-3-phenylbutyl)-piperazine (0.73 g), 1-hydroxybenzotriazole (0.50 g) and dicyclohexylcarbodiimide (0.76 g) in N,N-dimethylformamide (7 ml) was stirred under room temperature for 12 hours. To the reaction solution was added ethyl acetate (10 ml) and the insoluble matter was filtered off. To the filtrate was added 0.5N sodium hydroxide and the solution was extracted with ethyl acetate. The ethyl acetate layer was extracted with 1N hydrochloric acid. The aqueous layer was made basic with potassium carbonate and extracted with ethyl acetate. The resultant ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and elution with an ethyl acetate-methanol (10:1) mixture gave 1.32 g of 1-(3-methyl-3-phenylbutyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[Si:22]([NH:9][CH:8]([CH3:10])[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(N)c1ccc(F)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(N[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of racemic 4-fluoro-α-methylbenzenemethanamine (2.95 g, 21.2 mmol) and triethylamine (4.3 mL, 30.9 mmol) in acetonitrile (75 mL) in a flame-dried flask under nitrogen was added dropwise t-butylchlorodiphenylsilane (5.5 mL, 21.1 mmol). The mixture was stirred at room temperature overnight and then filtered to remove the insoluble white precipitate (triethylamine hydrochloride). After removal of the solvent in vacuo, the crude product was taken up in ether and washed sequentially with H2O, saturated NaHCO3 solution and brine. The solution was dried (Na2SO4 /K2CO3) and concentrated to leave a clear oil which was distilled under high vacuum. The major fraction consisting of the pure title compound (3.8 g, 47%) distilled from 123° to 143° C. at 0.15 mm Hg.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[I-:15].[Na+]>C(C(C)=O)C>[CH3:1][C:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][I:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [I-]
Reactant: CCOC(=O)CC(C)(C)CCCCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)CC(C)(C)CCCCI

Procedure:
To a solution of 3.57 g. (0.0162 mole) of ethyl 3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone is added 4 g. of sodium iodide and the mixture heated at reflux for 18 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between ether and water. The aqueous phase is extracted several times with ether. The extract is washed with sodium bisulfite solution, water and saline. The organic solution is dried over magnesium sulfate and concentated to give 4.182 g. of a yellow oil. The material is purified by distillation, b.p. 86°-87°C. (0.18 Torr).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: Cc1ccc(Cl)c(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)c(Cl)c1Cl
Yield: 85.5 %

Procedure:
2,3,4-Trichlorotoluene (2.00 g) was dissolved in carbon tetrachloride (20 ml), and 2,2′-azobis(2,4-dimethyl-4-methoxyvaleronitrile) (158 mg) and N-bromosuccinimide (2.00 g) were added thereto. The mixture was refluxed under heating for 2 hr, and hexane was added, which was followed by stirring under cooling for 30 min. The mixture was filtrated and an insoluble matter on a filter paper was washed with small amounts of hexane. The filtrates were combined and concentrated under reduced pressure. Diisopropyl ether was added to the residue and the mixture was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to give a mixture (2.40 g) of the objective compound and 2,3,4-trichlorotoluene as brown crystals.