Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:44])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29]([N:31]5[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:42])[C@H:11]3[OH:43])[C:5]=2[N:6]=1.[CH:45]1[CH:50]=[N+:49]([C@@H:51]2[O:55][C@H:54]([CH2:56][O:57][P:58]([O:61][P:62]([O:65][CH2:66][C@H:67]3[O:71][C@@H:70]([N:72]4[C:76]5[N:77]=[CH:78][N:79]=[C:80]([NH2:81])[C:75]=5[N:74]=[CH:73]4)[C@H:69]([OH:82])[C@@H:68]3[OH:83])([OH:64])=[O:63])([OH:60])=[O:59])[C@@H:53]([OH:84])[C@H:52]2[OH:85])[CH:48]=[C:47]([C:86]([NH2:88])=[O:87])[CH:46]=1>>[CH:1]1[N:2]=[C:3]([NH2:44])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([O:20][P:21]([O:24][CH2:25][C@H:26]4[O:30][C@@H:29]([N:31]5[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H:28]([OH:40])[C@@H:27]4[OH:41])([OH:23])=[O:22])([OH:19])=[O:18])[C@@H:12]([OH:42])[C@H:11]3[O:43][P:58]([OH:60])([OH:59])=[O:57])[C:5]=2[N:6]=1.[CH:45]1[CH:50]=[N+:49]([C@@H:51]2[O:55][C@H:54]([CH2:56][O:57][P:58]([O:61][P:62]([O:65][CH2:66][C@H:67]3[O:71][C@@H:70]([N:72]4[C:76]5[N:77]=[CH:78][N:79]=[C:80]([NH2:81])[C:75]=5[N:74]=[CH:73]4)[C@H:69]([O:82][P:17]([OH:19])([OH:18])=[O:16])[C@@H:68]3[OH:83])([OH:64])=[O:63])([OH:60])=[O:59])[C@@H:53]([OH:84])[C@H:52]2[OH:85])[CH:48]=[C:47]([C:86]([NH2:88])=[O:87])[CH:46]=1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Product: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To 0.9 ml of each of the above substrate solutions containing NADH or NAD+ was added 0.1 ml of 23 U/ml of the present enzyme, and the reaction was carried out at 30° C. for 20 minutes. Then, the reaction was terminated by heat treatment at 100° C. for 2 minutes, and the denatured protein was removed, after which the amount of NADPH or NADP+ produced by the reaction of the corresponding substrate was measured as follows. As a control solution, there was used a mixture of each substrate solution and the present enzyme in which the reaction had been terminated immediately after mixing them.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([C:10]([F:22])([C:18]([F:21])([F:20])[F:19])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=[C:6]([CH3:23])[C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[Br:30][C:31]1[C:39]([N+:40]([O-:42])=[O:41])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34].CN(C)C(=O)C>O1CCCC1>[CH2:1]([C:3]1[CH:9]=[C:8]([C:10]([F:22])([C:18]([F:19])([F:20])[F:21])[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13])[CH:7]=[C:6]([CH3:23])[C:4]=1[NH:5][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][CH:38]=[C:39]([N+:40]([O-:42])=[O:41])[C:31]=1[Br:30])[CH3:2]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Br
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
To a solution of 2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylaniline (preparation as described in WO 08/074427) (106 mg, 0.3 mmol) in tetrahydrofuran (0.5 ml) was added pyridine (72.6 μl, 0.9 mmol) at 0 to 5° C. A solution of 2-bromo-3-nitrobenzoic acid chloride (87 mg, 0.33 mmol) in tetrahydrofuran (0.5 ml) was added. The reaction mixture was stirred at ambient temperature for 3 hours, then at reflux for 15 hours. After 15 hours, the reaction was not complete so N,N-dimethylacetamide (“DMA”) (0.1 equivalents) and more 2-bromo-3-nitrobenzoic acid chloride (0.2 equivalents) were added. The reaction mixture was stirred at ambient temperature for 41 hours. After 41 hours, the reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (10 ml) and the mixture extracted twice with ethyl acetate (2×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 6:1) to give N-[2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylphenyl]-2-bromo-3-nitrobenzamide (0.133 g, 76% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(OC(=O)[NH:16][OH:17])(C)(C)C>>[ClH:1].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:17][NH2:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NO
Reactant: Clc1ccc(CBr)cc1
Product: Cl
Product: NOCc1ccc(Cl)cc1

Procedure:
Same procedure as described for preparation 8. Starting materials: 4-Chlorobenzyl bromide and tert-butyl-N-hydroxycarbamate. 1H-NMR (DMSO-d6) δ 11.18 (bs, 3H), 7.44-7.51 (m, 4H), 5.06 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)([CH3:11])[CH2:5][CH:6](OC)[O:7]C.Cl>C1COCC1.O>[CH3:1][O:2][C:3](=[O:20])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)([CH3:11])[CH2:5][CH:6]=[O:7]
Reactant: COC(=O)C(C)(CC(OC)OC)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(CC=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
A mixture of 6 g (19 mmol) 2-(3,4-dichloro-phenyl)-4,4-dimethoxy-2-methyl-butyric acid methyl ester and 28 mL 2N HCl aq. in 60 mL THF and 60 mL water was stirred at room temperature for 20 h. The mixture was extracted with diethyl ether. The combined organic phases were washed with sat. NaCl aq., dried with Na2SO4 and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and hexane. The product containing fractions were evaporated to yield 3 g (58%) of the title compound as light yellow oil.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:15]C3CCCCO3)[CH:9]=[C:10]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]=2[CH:4]([CH2:22][C:23]([O:25]CC)=[O:24])[O:3]1.[OH-].[Li+].Cl>CCO.O>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:15])[CH:9]=[C:10]([O:11][CH:12]([CH3:14])[CH3:13])[C:5]=2[CH:4]([CH2:22][C:23]([OH:25])=[O:24])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(OC(C)C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of ethyl 2-(1-hydroxy-4-isopropoxy-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (110 mg, 0.29 mmol) in EtOH (4 mL) was added an aqueous solution of lithium hydroxide (25.2 mg, 0.60 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 30 min and acidified with 1N HCl to pH=4. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep HPLC to give the title compound as a white powder (40 mg. Yield: 51.8%). 1H NMR (400 MHz, CDCl3) δ12.2 (s, 1H), 9.38 (s, 1H), 9.08 (s, 1H), 6.64 (3, 1H), 6.46 (s, 1H), 5.29-5.32 (m, 1H), 3.55 (m, 2H), 3.06-3.10 (m, 1H), 2.00-2.02 (m, 1H), 1.29-1.33 (m, 3H). MS (ESI) m/z=267 [M+H]+.
Reaction SMILES: CSC.B.[F:5][C:6]1[CH:7]=[C:8]([CH2:13][C:14](O)=[O:15])[CH:9]=[CH:10][C:11]=1[F:12].CO>C1COCC1>[F:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][OH:15])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: OCCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of borane dimethyl sulfide (2M in THF, 18.30 mL) was added cautiously to a solution of 2-(3,4-difluorophenyl)acetic acid (2.1 g) in THF (20 mL) at 0° C. The resulting mixture was allowed to warm to RT and stirred for 1 h. The reaction was cooled in an ice bath and methanol (5 mL) was added dropwise. The reaction was stirred until bubbling ceased and the solvent evaporated in vacuo. Purification was by silica gel chromatography eluting with isohexane to 4:1 isohexane:ethyl acetate. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a clear oil. Yield 1.92 g.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:2][CH3:3].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][C:4]([CH2:1][CH2:2][CH3:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCCC(Cc1ccc(OCc2ccccc2)cc1)(C(=O)OCC)C(=O)OCC
Yield: 99.5 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using diethyl 2-propylmalonate (5.00 g), 4-benzyloxybenzyl chloride (6.32 g) and sodium hydride (55% suspension in oil, 1.13 g) and the reaction mixture was treated to afford the desired compound (9.80 g) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2([CH2:10][C:11]([OH:13])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:25][N:26]1[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:40]>ClCCl>[O:40]=[C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]([C:36]([F:37])([F:39])[F:38])=[N:35][N:26]1[NH:25][C:11](=[O:13])[CH2:10][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: O=C(O)CC1(c2ccccc2)CC1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CC1(c2ccccc2)CC1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A solution of 2-(1-phenylcyclopropyl)acetic acid (0.063 g, 0.36 mmol) and oxalyl dichloride (0.042 mL, 0.48 mmol) in dichloromethane (1 mL) with a catalytic amount of DMF was stirred for 90 minutes, and concentrated. The material was re-dissolved in dichloromethane (1 mL) and the product from Example 11B (0.080 g, 0.35 mmol) was added, stirred for 2 hours, and concentrated. The residue was chromatographed on SiO2 (0-2% diethyl ether/dichloromethane) to give the title compound (52 mg) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 8.41-8.45 (m, 1H), 8.10-8.16 (m, 1H), 7.97-8.07 (m, 2H), 7.32-7.40 (m, 2H), 7.23-7.29 (m, 2H), 7.13-7.20 (m, 1H), 2.74 (s, 2H), 1.04-1.10 (m, 2H), 0.84-0.89 (m, 2H); MS (ESI−) M/Z 386 (M−H)−.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C@H:12]1[CH2:16][C@H:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@H:14]([CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[C@H:13]1[CH2:36][OH:37].OS([O-])(=O)=O.[K+]>C(Cl)Cl.C(N(CC)CC)C>[F:11][C@H:12]1[CH2:16][C@H:15]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C@H:14]([CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[C@H:13]1[CH:36]=[O:37]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CO)[C@@H](F)C[C@@H]1OC1CCCCO1
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@@H](F)C[C@@H]1OC1CCCCO1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
Oxalyl chloride (25 mL, 50 mmol) was dissolved in DCM (400 mL) and cooled to −78° C. under a nitrogen atmosphere, to which a solution consisting of DMSO (4.5 mL) in DCM (150 mL) was added. The reaction mixture was stirred for 15 minutes at −78° C. and a solution consisting of (Z)-isopropyl 7-((1R,2S,3S,5S)-3-fluoro-2-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoate (prepared in Step F, 12.94 g, 33.36 mmol) in DCM was subsequently added slowly. The reaction mixture was stirred for 40 minutes and triethylamine (28 mL) was subsequently added. Stirring was continued as the reaction mixture was allowed to warm to room temperature for 2 hours, monitoring by TLC. The reaction was acidified with 5% KHSO4, extracted with DCM, and the organic layers were washed twice with brine. After drying over sodium sulfate, filtration, and solvent removal under reduced pressure, the crude product was purified on silica gel, eluted with hexanes-ethyl acetate (85:15) to afford the title intermediate (10.31 g, 80%).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[H][H]>C(O)C.[Pd]>[CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCN
Reaction time: 4 h

Procedure:
2 g of oleylamine in 120 ml of ethanol are hydrogenated at 30° C. under 8 bar of hydrogen in the presence of palladium-on-charcoal. After reacting for 4 h and evaporating the solvent, 1.6 g of product are obtained in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[CH:9][C:10]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:11][C:5]=2[CH:4]2[O:21][CH:3]12.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[N+:30]([C:27]1[CH:28]=[CH:29][C:24](=[O:23])[N:25]([C@H:4]2[C@H:3]([OH:21])[C:2]([CH3:1])([CH3:22])[O:7][C:6]3[CH:8]=[CH:9][C:10]([S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)(=[O:14])=[O:13])=[CH:11][C:5]2=3)[CH:26]=1)([O-:32])=[O:31]
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2C2OC21
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)Oc2ccc(S(=O)(=O)c3ccccc3)cc2[C@@H](n2cc([N+](=O)[O-])ccc2=O)[C@@H]1O

Procedure:
4.00 g (12.6 mmol) of 3,4-dihydro-2,2-dimethyl-3,4-epoxy-6-(phenylsulfonyl)-2H-benzo[b]pyran and 1.77 g (12.6 mmol) of 2-hydroxy-5-nitropyridine are suspended in a little absolute THF, and 16.7 ml (12.6 mmol) of a 1 M solution of lithium bis-trimethylsilylamide are added dropwise under argon with stirring and ice cooling. The mixture is stirred at room temperature for a further 72 hours, hydrolyzed and extracted three times with ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution and dried over sodium sulfate. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel (ethyl acetate/ cyclohexane 1:1). The compound can be crystallized in ethyl acetate.
Reaction SMILES: C(O)=O.[CH2:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH2:29])=[CH:23][CH:22]=3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=2)=[CH:8][CH:7]=1)[CH3:5].C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:20]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][CH2:58][C@H:56]([OH:57])[CH2:55][O:54][C:51]4[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=4)=[CH:25][CH:26]=3)[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]=2)=[CH:10][CH:11]=1)[CH3:5]
Reactant: CCc1ccc(-c2nc3cccnc3n2-c2ccc(CCN)cc2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: O=CO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2nc3cccnc3n2-c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)cc1
Yield: 34.8 %

Procedure:
2-{4-[2-(4-Ethylphenyl)-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}-1-ethanamine formate (0.27 g, 0.746 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.2 g, 0.5 mmol) according to Procedure G (eluant: 20:1 going to 5:1 chloroform-methanol) to give the title compound (0.13 g, 0.174 mmol).
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.C(=O)=O.CC(C)=O.[CH2:19]([NH:21][C:22]([C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)=[O:23])[CH3:20].CN(CCN(C)C)C.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>C1COCC1>[CH2:19]([NH:21][C:22]([C:24]1[CH:28]=[CH:27][S:26][C:25]=1[Si:38]([CH3:40])([CH3:39])[CH3:37])=[O:23])[CH3:20]
Reactant: CCNC(=O)c1ccsc1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CCNC(=O)c1ccsc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
1.3M s-BuLi in cyclohexane (37.23 mL, 48.4 mmol) was added dropwise to a dry-ice/acetone cooled solution of N-ethyl-3-thiophenecarboxamide (3.41 g, 22 mmol) and TMEDA (5.62 g, 48.4 mmol) in THF (100 mL). After stirring for 30 min at -78° C., TMSCl (5.26 g, 48.4 mmol) was added in a single portion. The reaction was allowed to slowly warm to -10° C. over 1 h, then was quenched with dilute aq citric acid and extracted with ethyl acetate (3×). The combined organic solutions were dried (MgSO4), concentrated, and purified by HPLC with 3:7 EtOAc/hexanes to give 1.4 g of the title compound as a white solid, a 28% yield. m.p. 114-116° C.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][C@H:15]([C:19]([NH:21][C@H:22]([C@H:30]([OH:49])[C@@H:31]([OH:48])[C@@H:32]([NH:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17].N=[C:51]=[NH:52]>>[N:52]1[C:51]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:1]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C@H:30]([OH:49])[C@@H:31]([OH:48])[C@@H:32]([NH:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:45])[CH3:46])[NH:43][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: N=C=N
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1ccc2ccccc2n1
Product: CC(C)[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1ccc2ccccc2n1)C(C)C

Procedure:
Quinaldic acid was coupled to the resultant compound of Example 317 using the carbodiimide coupling procedure of Example 55 to provide the desired compound.
Reaction SMILES: C(OC(=O)[N:7]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]2[C:36]3[C:31](=[C:32]([Cl:37])[CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][C:28]2=[O:38])[CH2:21][CH2:20]1)[CH2:8][C:9]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1)(C)(C)C.Cl.O1CCOCC1>O1CCOCC1>[ClH:37].[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[CH:30]=[CH:29][C:28](=[O:38])[N:27]2[CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([NH:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[O:13][CH2:14][CH2:15][O:16][C:11]=3[CH:10]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(Cl)cccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc2c(Cl)cccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.1 %

Procedure:
To 0.28 g of tert-butyl(1-(2-(5-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 6 mL of 1,4-dioxane and 2 mL of 4 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The resulting solid was filtered to give 0.16 g of 5-chloro-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)quinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[CH3:23])[CH:18]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:15]([F:14])[CH:16]=2)[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: Cc1ccc(C=O)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(C)c(F)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 44.2 %

Procedure:
(1S,2R,3 S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 300 mg, 1.637 mmol) was suspended in ethanol (5 mL). 3-Fluoro-4-methyl-benzaldehyde (0.2 mL, 1.637 mmol) was added followed by glacial acetic acid (0.1 mL, 3.724 mmol) and 4 Å powdered molecular sieves (0.6 g). Sodium cyanoborohydride (0.593 g, 9.406 mmol) was added and the mixture was stirred under nitrogen at 50° C. for 18 h. Upon cooling, the mixture was filtered through Celite. The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×75 mL). The layers were separated and the organic layer was washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes) afforded the desired product, (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (221 mg, 0.724 mmol, 44%), as a clear thick oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.15 (2H, m), 1.21 (1H, d, J=10.1 Hz), 1.29 (3H, t, J=7.1 Hz), 1.42-1.63 (4H, m), 1.94 (1H, dt, J1=10.2 Hz, J2=2.0 Hz), 2.25 (3H, s), 2.43 (1H, d, J=3.5 Hz), 2.59 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 2.93 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 3.65 (1H, d, J=13.4 Hz), 3.79 (1H, d, J=14.2 Hz), 4.15 (2H, q, J=7.1 Hz), 6.94 (1H, d, J=7.9 Hz), 6.98 (1H, d, J=10.9 Hz), 7.08 (1H, t, J=7.8 Hz). LC-MS (ESI) calcd for C18H24FNO2 305.18. found 305.9 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26](F)[CH:25]=2)=[CH:4][CH:3]=1.[CH3:31][O-:32].[Na+].O>CN1CCCC1=O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:32][CH3:31])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(F)c4)n3n2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN1CCCC1=O
Product: COc1cc(-c2c(-c3ccc(F)cc3)nc3ccc(N4CCN(C)CC4)nn23)ccn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution under argon of 0.10 g (0.25 mmol) of 2-(4-fluorophenyl)-3-(2-fluoropyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine in N-methylpyrrolidone is added 0.65 mL (3.4 mmol) of sodium methoxide at 30% by weight in methanol. After stirring for 4 days at room temperature, the medium is poured into 200 mL of water and the product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure to give a pale yellow solid.