Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1.[CH3:21][C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][C:25](O)=[O:26]>>[F:20][C:2]([F:19])([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:25](=[O:26])[CH2:24][CH2:23][C:22]([CH3:29])([CH3:28])[CH3:21])[CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)(C)CCC(=O)O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)C1CCNCC1
Product: CC(C)(C)CCC(=O)N1CCC(C(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Yield: 89 %

Procedure:
This material was prepared in analogy to example 8 step C) from piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.144 g) and 4,4-dimethyl-pentanoic acid (0.065 g) to give the desired 1-(4,4-dimethyl-pentanoyl)-piperidine-4-carboxylic acid (4-trifluoromethoxy-phenyl)-amide (0.178 g) as an off-white solid. MS (ESI): 401.25 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[C:28]([O:37][CH3:38])(=[O:36])[C:29]1[C:30](=[CH:32][CH:33]=[CH:34][CH:35]=1)O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:38][O:37][C:28](=[O:36])[C:29]1[CH:30]=[CH:32][CH:33]=[CH:34][C:35]=1[O:15][CH2:14][CH:13]([N:12]1[C:11]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccccc1OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and methyl salicylate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (50%). MS (Turbo Spray): m/z=525.0 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-])=O.C(O)C.O.NN>[C].[Pd].O>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(ccc3ccccc32)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
First, 134 g of 2-nitrophenanthrene, 1.00 g of palladium carbon, and 1.2 L of ethanol were loaded, and then 70 mL of hydrazine monohydrate were added to the mixture. The reaction solution was stirred for 4 hours under heating ref lux. After having been cooled to room temperature, the reaction solution was poured into 3 L of water. Then, the mixture was extracted with 2 L of toluene. After the water layer had been removed, the organic layer was dried with magnesium sulfate. After magnesium sulfate had been separated by filtration, the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 100 g of a pale yellow solid were obtained (in 86% yield).
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:5]=1[CH2:6][N:7]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)=[O:15])[CH2:10][CH2:9][C@H:8]1[C:32]([O:34]C)=[O:33].Cl>C1COCC1.CO.CCOCC>[F:3][C:4]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:5]=1[CH2:6][N:7]1[CH2:12][C@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)=[O:15])[CH2:10][CH2:9][C@H:8]1[C:32]([OH:34])=[O:33]
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CN1Cc1c(F)cccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: COc1cccc(F)c1CN1C[C@H](NC(=O)c2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
LiOH (1M, aqueous) (3.0 ml, 3.00 mmol) was added to a stirred mixture of (2S,5R)-methyl 1-(2-fluoro-6-methoxybenzyl)-5-(3-(2-methylpyridin-4-yl)-1H-indazole-5-carboxamido)piperidine-2-carboxylate (1 g, 1.881 mmol) in THF (30 ml) & MeOH (10 ml) and the mixture was stirred at room temperature for Overnight. The reaction LCMS showed most starting material (M+1=532), but tlc showed product, another 3 ml of LiOH was added to the r×n, stirred for one day, LCMS gave M+H at 518, tlc showed completion. The reaction was treated 1 N HCl in ether, 6 ml, 1 eq, and rotovap to dryness and the residue was purified by column chromatography on silica gel Biotage 40M, eluting with 20% MeOH/CH2Cl2 to give the titled compound as a off-white (0.67 g, 68.8% yield).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([OH:23])[C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[CH3:27][S:28]([O:23][CH:12]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2)[C:11]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:26][CH:25]=1)=[O:24])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)c1ccc(CNC(=O)C(O)c2cccc3cnccc23)cc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(CNC(=O)C(OS(C)(=O)=O)c2cccc3cnccc23)cc1
Reaction time: 0.5 h

Procedure:
The product from Example 277B (1.00 g, 2.87 mmol) in pyridine (5 mL) was treated with methanesulfonyl chloride (5.56 μL, 7.17 mmol). After stirring for 30 minutes, the mixture was concentrated under reduced pressure and diluted with CH2Cl2 (50 mL). The organic layer was washed with water (50 mL×3), dried (Na2SO4), filtered, and the filtrate concentrated under reduce pressure to provide the title compound. MS (ESI+) m/z 427 (M+H)+; MS (ESI−) m/z 425 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.27 (s, 9H), 2.37 (s, 3H), 4.27 (dq, J1 14.9, J2 6.1, 2H), 6.84 (s, 1H), 7.17 (d, J 8.5, 2H), 7.38 (d, J 8.5, 2H), 8.07 (m, 2H), 8.37 (d, J 8.1, 1H), 8.60 (d, J 6.1, 1H), 8.97 (m, 1H), 9.21 (t, J 6.1, 1H), 9.96 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(C(C)C)CC)(C)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(OCC)(=O)C>ClCCl.O>[CH2:33]([N:21]1[CH2:22][CH2:23][CH:18]([C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:19][CH2:20]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: COc1ncccc1-c1[nH]c2ccccc2c1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ncccc1-c1[nH]c2ccccc2c1C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(2-methoxy-pyridin-3-yl)-3-piperidin-4-yl-1H-indole (0.13 g, 0.42 mmol) in dichloromethane (5 ml) was added diisopropylethylamine (0.22 ml, 1.25 mmol) followed by the benzyl bromide (0.075 g, 0.44 mmol). The reaction was stirred at room temperature for 2 h followed by addition of ethyl acetate and water. The organic layer was separated and washed with water, dried using Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography (SiO2, 100% EtOAc). The desired product was obtained as a yellow solid (0.080 g, 48%). M.p.=97-101° C.; 400 M Hz 1H NMR (DMSO-d6) 10.99 (s, 1H), 8.24 (dd, J1=7.2 Hz, J2=2.0 Hz, 1H), 7.70 (m, 2H), 7.34-7.24 (m, 6H), 7.13 (dd, J1=7.6 Hz, J2=5.2 Hz, 1H), 7.07 (m, 1H0, 6.98 (m, 1H), 3.86 (s, 3H), 3.48 (s, 2H), 2.92 (m, 2H), 2.56 (m, 1H), 2.15 (m, 2H), 1.93 (m, 2H), 1.64 (m, 2H); LCMS: 398.76 (M+1).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:35][C:36]1([CH2:42][OH:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:39]3[CH2:40][CH2:41][C:36]([CH2:42][OH:43])([CH3:35])[CH2:37][CH2:38]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CC1(CO)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCC(C)(CO)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with (4-methyl-piperidin-4-yl)-methanol trifluoroacetate and N-ethyldiisopropylamine in chloroform [α]D20=+24.1° (c=1.02, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:19])=[C:8]([CH3:18])[CH2:9][CH2:10][CH2:11][CH2:12]CS([O-])(=O)=O.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]([OH:31])=[O:30].C(=O)([O-])O.[Na+]>O>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29]([O:31][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([CH3:18])=[C:7]([F:6])[F:19])=[O:30]
Reactant: CC(CCCCCS(=O)(=O)[O-])=C(F)F
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CCCCOC(=O)c1cc2ccccc2[nH]1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To 20 ml of N,N-dimethylformamide were dissolved 1.50 g (6.6 mmol) of 6,6-difluoro-5-methyl-5-hexenylmethanesulfonate and 1.30 g (8.1 mmol) of 1H-indole-2-carboxylicacid, followed by the addition of 1.40 g (17 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 1.70 g (yield: 88%) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-2-carboxylate.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-])=O)=[C:7]([CH:9]=1)[NH2:8])[CH3:2].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:10])=[C:7]([NH2:8])[CH:9]=1)[CH3:2]
Reactant: CCc1ccc([N+](=O)[O-])c(N)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(N)c(N)c1
Yield: 85.4 %

Procedure:
A stirred solution of 5-ethyl-2-nitro-aniline [200 mg, Reference Example 30(a)] and tin chloride (2.75 g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140° C. for 10 minutes. The reaction mixture was basified to pH 8 by addition of saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to give 4-ethyl-phenylene diamine (140 mg) as a pale orange solid, which was used without future purification. MS: 137.2 (M+H)+. HPLC (METHOD H): RT=2.91 minutes.
Reaction SMILES: O=C1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:5]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=2)[CH:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][N:29]=2)[O:3]1.[OH-].[Na+].O>CO>[OH:3][CH:4]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:30][N:29]=1)[CH:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)OC(c2ccc(Oc3ccccc3)cn2)C1Cc1cccc(OC(F)(F)C(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (4RS,5RS)-2-oxo-5-(5-phenoxypyridin-2-yl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidine-3-carboxylate (1.00 g, 1.78 mmol) in methanol (12 ml) was added a solution (4.3 ml, 2.13 mmol) of 0.5N sodium hydroxide in methanol, and the mixture was stirred at room temperature for 1 hr. To the reaction solution was added water (50 ml), and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give-the objective substance (0.81 g, 85%).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([C:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=1)=[CH:7][NH:8]2
Reactant: CN1CCC(=O)CC1
Reactant: Fc1cccc2[nH]ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3cccc(F)c23)CC1
Reaction time: 28 h
Yield: 68.7 %

Procedure:
To a solution of 1.18 gm (21.0 mMol) potassium hydroxide in 10 mL methanol were added 1.00 gm (7.4 mMol) 4-fluoro-1H-indole and 1.82 mL (14.8 mMol) 1-methyl-4-piperidone. The reaction mixture was stirred for 28 hours at reflux and then was allowed to cool. The crystals which formed were filtered, washed with methanol and dried under vacuum at 60° C. to give 1.17 gm (69%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:32][CH:33]([CH3:34])[CH3:35])[S:40]([CH3:39])(=[O:42])=[O:41])[C@H:14]2[CH3:36])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CNc1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)CN(c1ccc(OC(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C)S(C)(=O)=O
Temperature: 65 °C
Reaction time: 4 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(isobutylamino)-5-(trifluoromethoxy)benzyl]-4-methyl-1,3-oxazolidin-2-one (9.2 mg, 0.0165 mmol) in pyridine (300 μL) was added methanesulfonyl chloride (100 μL, 1.29 mmol) and excess 4-dimethylaminopyridine. The reaction was stirred at 65° C. for 4 hours and then diluted with EtOAc (15 mL), and washed with 1 N HCl (2×10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (60% EtOAc/hexanes) N-[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]-N-isobutylmethanesulfonamide. Rf=0.25 (60% EtOAc/hexanes). LCMS=637.4 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.80 (s, 2H), 7.34-2.46 (m, 3H), 5.79-5.76 (m, 1H), 4.90-4.58 (m, 2H), 4.19-4.14 (m, 1H), 3.51-3.46 (m, 1H), 3.34-3.32 (m, 1H), 2.97 (m, 3H), 1.25 (m, 1H), 0.93-0.87 (m, 6H), 0.70-0.66 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[H-].[Na+].[N:17]1([C:23]([O-:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:20]3[CH2:21][CH2:22][N:17]([C:23]([O:25][C:2]([CH3:14])([CH3:6])[CH3:1])=[O:24])[CH2:18][CH2:19]3)[CH:10]=2)[O:3]1
Reactant: O=C([O-])N1CCCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.12 g, 21.2 mmol, Aldrich, Cat. 525057) in N,N-dimethylformamide (20 mL) was added sodium hydride (1.78 g, 44.5 mmol) at 0° C. The resulting solution was stirred at r.t. for one hour, and then tert-butyl 4-[methylsulfonyl)oxy]piperidine-1-carboxylate (6.3 g, 22 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 90° C. overnight. Then the reaction mixture was cooled to r.t., quenched with water, and extracted with AcOEt. The organic layer was washed with NaHCO3 aqueous solution and brine successively, dried with MgSO4, and concentrated. The residue was purified by flash column chromatography on a silica gel column using 30% ethyl acetate in hexane as eluent to afford the desired compound (2.30 g, 28.74%). LCMS (M+H)+: m/z=378.4.
Reaction SMILES: [CH:1](OC(=NC(C)C)NC(C)C)([CH3:3])[CH3:2].[CH3:14][C:15]1([CH3:30])[C@@H:17](/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21])[C@H:16]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C(OCC)(=O)C>[CH3:14][C:15]1([CH3:30])[C@@H:17](/[CH:18]=[CH:19]\[C:20]([O:22][CH:1]([CH3:3])[CH3:2])=[O:21])[C@H:16]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)N=C(NC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
2 g of O-isopropyl-N,N'-diisopropyl-isourea were added to a mixture of 2.7 g of the product of Step A and 10 ml of ethyl acetate and the mixture was stirred at room temperature for one hour, refluxed for 90 minutes and then cooled to 20° C. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The 3.5 g of oil residue were chromatographed over silica gel and eluted with a 7-3 benzene-cyclohexane mixture to obtain 1 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-(isopropoxycarbonyl)-ethenyl]-cyclopropane-carboxylate which was used as is for the next step.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=1>>[C:27]([C:25]1[N:26]=[C:22]([NH:21][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:23][CH:24]=1)#[N:28]
Reactant: N#Cc1csc(N)n1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2nc(C#N)cs2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-Amino-4-thiazolecarbonitrile instead of 3-chloroaniline to yield the final compound as a off-white solid, MS (ISP): m/e=356.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:23][N:24]1[CH2:28][CH2:27][CH2:26][C:25]1=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.[O-]CC.[Na+].Cl>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[N:16]=2)=[C:25]2[CH2:26][CH2:27][CH2:28][N:24]2[N:23]=1
Reactant: CC(C)c1nnc2ccc(CC(=NN3CCCC3=O)c3ccc(F)cc3F)nn12
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nn4c3CCC4)nn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.3 %

Procedure:
A mixture of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.20 g, 0.63 mmol, Preparation #K.1), 1-aminopyrrolidin-2-one hydrochloride (0.13 g, 0.95 mmol, prepared according to WO02/094833 Preparation #38), pyridine (0.15 mL, 1.9 mmol), and HOAc (1.2 mL) was sonicated to give a solution in a sealed vial. After stirring for about 16 h, additional 1-aminopyrrolidin-2-one hydrochloride (0.086 g, 0.632 mmol) was added and the resulting solution was stirred at ambient temperature for about 2 d. The reaction was then concentrated under reduced pressure and purified via silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give impure 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.16 g) as an oil that was carried on without further purification. A 10 mL round-bottomed flask equipped with reflux condenser and outfitted with a nitrogen inlet adapter was charged with 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.060 g, 0.15 mmol) in toluene (1.5 L) to give a yellow solution. Sodium ethoxide (0.020 g, 0.30 mmol) was added in one portion to give a yellow suspension. The reaction mixture was heated to reflux for about 5 h. The reaction mixture was allowed to cool to ambient temperature and continued stirring for about 2 d. The reaction mixture was diluted with water (5 mL) adjusted to about pH 2 with 6 N HCl. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried with MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM. The product-containing fractions were concentrated under reduced pressure and the resulting material was crystallized from EtOAc/heptane to give the title compound (0.031 g, 54%) as orange needles: LC/MS (Table 1, Method b) Rt=2.44 min; MS m/z: 381.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([C:10](=[O:12])[CH3:11])=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[Br:15]Br>C(O)(=O)C>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[O:6][C:7]([C:10](=[O:12])[CH2:11][Br:15])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CC(=O)c1oc2ccc(F)cc2c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1c(C(=O)CBr)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
In this Reference Example, 38.4 g of 5-fluoro-3-methyl-2-acetylbenzo [b] furan is dissolved in 200 ml of acetic acid and 32.0 g of bromine is addeddropwise thereto at room temperature. The mixture solution is then stirred for 30 minutes at room temperature, whereby the color of bromine disappears and crystals are deposited from the solution. Then, the solution is filtered to obtain 38.0 g of 5-fluoro-3-methyl-2-(α-bromoacetyl) benzo [b] furan as crystals. (Yield: 70%). Melting point of the desired compound recrystallized from ethanol is 120°-123° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]([NH:15][C:16]3[CH:21]=[N:20][CH:19]=[CH:18][N:17]=3)=[O:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C@H:22]12[CH2:28][C@H:25]([NH:26][CH2:27]1)[CH2:24][N:23]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[NH:15][C:13](=[O:14])[NH:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([N:26]3[CH2:27][C@@H:22]4[CH2:28][C@H:25]3[CH2:24][N:23]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: O=C(Nc1cnccn1)Nc1ccnc2cc(Br)ccc12
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccc2c(NC(=O)Nc3cnccn3)ccnc2c1

Procedure:
The compound was prepared by the method described for Example 1 using 1-(7-bromoquinolin-4-yl)-3-(pyrazin-2-yl)urea and (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]-heptane-2-carboxylate as starting compounds.