Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:31]C(=O)C)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](S(C3C=CC(C)=CC=3)(=O)=O)[CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:10]=12.[OH-].[Na+]>C(O)C>[NH2:31][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][CH:16]=[C:17]([CH2:18][CH2:19][OH:20])[C:10]=23)=[C:2]([F:1])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(CCO)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3[nH]cc(CCO)c23)c(F)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
470 mg (0.97 mmol) of N-[3-fluoro-4-({3-(2-hydroxyethyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo-[2,3-b]pyridin-4-yl}oxy)phenyl]acetamide are dissolved in 25 ml of ethanol. 10 ml of 20% strength aqueous sodium hydroxide solution are added, and the reaction mixture is stirred at 90° C. overnight. Most of the solvent is removed under reduced pressure, the residue is taken up in ethyl acetate and partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution and extracted. The organic phase is washed with 1N aqueous sodium hydroxide solution and dried over magnesium sulfate, and the solvent is removed under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]([CH2:23]/[CH:24]=[CH:25]/[C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5](=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:12]=1.CI.[H-].[Na+].[C:37](OCC)(=O)C>O1CCCC1.O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:32])[C:4]([CH3:37])([CH2:23]/[CH:24]=[CH:25]/[C:26]#[C:27][C:28]([CH3:29])([CH3:31])[CH3:30])[C:5](=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:12]=1
Reactant: COC(=O)C(C/C=C/C#CC(C)(C)C)C(=O)CCCCOc1cccc(-c2ccsc2)c1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CI
Product: COC(=O)C(C)(C/C=C/C#CC(C)(C)C)C(=O)CCCCOc1cccc(-c2ccsc2)c1
Yield: 92 %

Procedure:
750 mg of (E)-2-(6,6-dimethyl-2-hepten-4-ynyl)-7-[3-(3-thienyl)phenoxy]-3-oxoheptanoic acid methyl ester is dissolved in 10 ml of tetrahydrofuran, 0.16 ml of methyl iodide and 85 mg of 60% oily sodium hydride are added under ice cooling and stirring, and the mixture is stirred for 3 hours under ice cooling. The reaction solution is diluted with water, acetic acid is added for neutralization to pH 7, extraction is made with ethyl acetate, the extract is washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [Wako gel C-200, 30 g; hexane/ethyl acetate=6/1] to obtain 705 mg (yield: 92%) of (E)-2-methyl-2-(6,6-dimethyl-2-hepten-4-ynyl)-7-[3-(3-thienyl)phenoxy]-3-oxoheptanoic acid methyl ester as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>CN(C)C=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:28][CH:27]=[CH2:26])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.79 g, 2.50 mmol) and sodium hydride (0.13 g, 60% n in oil, 3.254 mmol) in dimethylformamide (10 mL). After 30 minutes add allyl bromide (0.35 mL, 3.25 mmol). Heat to 75° C. After 4 hours, cool the reaction mixture, dilute with dichloromethane, and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.83 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide 90/10/0.1).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][CH:10]=[CH:11][N:12]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:6]([C:7]1[C:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9][CH:10]=[CH:11][N:12]=1)#[CH:5]
Reactant: CCOC(=O)Cc1nccnc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1nccnc1CC(=O)OCC
Reaction time: 0.03 h
Yield: 74.8 %

Procedure:
Ethyl 2-(3-((trimethylsilyl)ethynyl)pyrazin-2-yl)acetate (I100) (0.386 g, 1.47 mmol) in THF (15 mL) was cooled to 0° C. and a 1.0 M solution of TBAF in THF (1.84 mL, 1.84 mmol) was added. The mixture was stirred for two minutes then poured into water (150 mL). The resulting mixture was extracted with diethyl ether (2×150 mL) and the combined ether phases washed with brine, dried (sodium sulphate) and evaporated to give the title compound (I101) (0.209 g, 75% yield) as a yellow-brown oil; 1H NMR (400 MHz, CDCl3) δ 8.50-8.47 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 4.08 (s, 2H), 3.49 (s, 1H), 1.26 (t, J=7.1 Hz, 3H). LCMS Method C: rt 4.88 min; m/z 191.1 [M+H]+.
Reaction SMILES: C([O:4][CH:5]=[CH:6][C@@H:7]([CH3:14])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])(=O)C.P(=O)(O)(O)O.O>C1(C)C=CC=CC=1>[CH3:13][C:11]1([CH3:12])[CH2:10][CH2:9][CH2:8][C@H:7]([CH3:14])[C@H:6]1[CH:5]=[O:4]
Reactant: CC(=O)OC=C[C@@H](C)CCC=C(C)C
Agent: O=P(O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1CCCC(C)(C)[C@@H]1C=O
Temperature: 100 °C

Procedure:
A solution of crude product of Example 1a (6.36 g, 32.4 mmol) in toluene (11 mL) (15.7 g) was added 85% phosphoric acid (12 mL). The mixture was heated to 100° C. for 4 hours. The reaction mixture was cooled to room temperature and toluene (12 mL) along with water (24 mL) was added and the layers were separated. The aqueous layer was extracted with toluene (12 mL×2). The combined organic layers were washed with saturated aqueous sodium bicarbonate (50 mL×2) and brine (50 mL×2). Concentration and distillation under reduced pressure (b.p. 65-70° C.) afforded the title compound as a 9:1 mixture of epimers as a colorless oil (2.51 g, Yield: 50%). 1H NMR (400 MHz, CDCl3) (Major) δ 9.63 (d, J=5.2 Hz, 1H), 2.03-1.91 (m, 1H), 1.83-1.75 (m, 1H), 1.64-1.60 (m, 1H), 1.54-1.48 (m, 1H), 1.40-1.35 (m, 1H), 1.24-1.14 (m, 1H), 1.02 (s, 3H), 0.97 (s, 3H), 0.95-0.84 (m, 2H), 0.81 (d, J=6.4 Hz, 3H) ppm. [α]D24=+5.20° (c=1.00, dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:25])[CH:17]=4)=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.CI.[C:30](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:26][CH3:27])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH2:24][OH:25])[CH:17]=4)=[N:14][N:13]([CH3:30])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: COc1cc2ncc3[nH]nc(-c4ccc(C#N)c(CO)c4)c3c2cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2ncc3c(c(-c4ccc(C#N)c(CO)c4)nn3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
4-(7,8-Dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (78 mg, 216 μmol) is dissolved in N,N-dimethylformamide (1.0 ml) under argon, and methyl iodide (34 μl, 541 μmol) and potassium carbonate (60 mg, 433 μmol) are subsequently added. The suspension is stirred at room temperature for 1 h. For purification, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness in vacuo. The residue is purified by chromatography (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), and the product fractions are lyophilised, giving 4-(7,8-dimethoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-1-yl)-2-hydroxymethylbenzonitrile (41 mg, 110 μmol) as a solid. MS: 375.2 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]([S:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([F:23])[F:22]>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[C:25]([S:24][C:21]([F:23])([F:20])[F:22])[CH:26]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1cccc(SC(F)(F)F)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)Sc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(trifluoromethylsulfanyl)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 3-(trifluoromethyl)-6-[4-[[3-(trifluoromethylsulfanyl)phenyl]methyl]piperazin-1-yl]-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH:7]1[CH2:35][CH2:34][C:10]2([C:14](=[O:15])[N:13]([C:16]3[C:17]([CH3:33])=[N:18][C:19]([N:22]4[CH2:26][CH2:25][C@@H:24]([N:27]5[CH2:31][CH2:30][CH2:29][C@@H:28]5[CH3:32])[CH2:23]4)=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:9][CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[OH:6][CH:7]1[CH2:8][CH2:9][C:10]2([C:14](=[O:15])[N:13]([C:16]3[C:17]([CH3:33])=[N:18][C:19]([N:22]4[CH2:26][CH2:25][C@@H:24]([N:27]5[CH2:31][CH2:30][CH2:29][C@@H:28]5[CH3:32])[CH2:23]4)=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:34][CH2:35]1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N1CCC2(CCC(O)CC2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.4 %

Procedure:
To a solution of 8-(tert-butyl-diphenyl-silanyloxy)-2-[2-methyl-6-((2S,3′R)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-pyridin-3-yl]-2-aza-spiro[4.5]decan-1-one (89 mg, 0.14 mmol) in tetrahydrofuran (2 mL) was added 1 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (0.15 mL, 0.15 mmol). The resulting mixture was stirred for 24 hours at ambient temperature and then added additional 1 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (0.15 mL, 0.15 mmol). The resulting mixture was heated to 70° C. for 30 hours then allowed the mixture to cool to ambient temperature. Water (10 mL) was added to the reaction mixture, extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to afford a crude solid which was then purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to provide 17 mg (29% yield) of the title compound as a solid.
Reaction SMILES: C(NC(C)C)(C)C.O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[CH2:22][CH3:23].[CH3:33][CH:34]([CH3:47])[C:35](=[O:46])[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.CCCCCC.C(OCC)(=O)C>[CH:34]([C:35]([OH:46])([CH:22]([CH3:23])[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])([CH3:47])[CH3:33]
Reactant: CCC(=O)OCc1ccccc1
Reactant: CC(C)C(=O)C(=O)OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)C(O)(C(=O)OCc1ccccc1)C(C)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65.9 %

Procedure:
To anhydrous tetrahydrofuran (5 mL) was added diisopropylamine (759 mg, 7.5 mmol) under nitrogen stream, and the mixture was cooled to −78° C. To the solution was added a 1.58 M n-butyl lithium-hexane solution (4.3 mL, 6.8 mmol), and the mixture was stirred at −78° C. for 5 min, and then at 0° C. for 15 min. The solution of lithium diisopropylamide tetrahydrofuran was cooled to −78° C., and a solution of benzyl propionate (821 mg, 5.0 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise over 1 h, and the reaction mixture was further stirred at −78° C. for 1 h. The enolate thus prepared was added via a cannula to a solution of benzyl 3-methyl-2-ketobutyrate (1.24 g, 6.0 mmol) in anhydrous tetrahydrofuran (5 mL) having been cooled to −78° C. After stirring at −78° C. for 2 h, the reaction mixture was diluted with a 10% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 9:1) to give 1.22 g of dibenzyl 2-isopropyl-2-hydroxy-3-methylsuccinate as oil (yield: 66%) in the form of a diastereomer mixture.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:29][O:30][C:31]1[CH:37]=[C:36]([C:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH:43]=2)[C:35]([N+:45]([O-:47])=[O:46])=[CH:34][C:32]=1[NH2:33].CC(O)CCC>CN(C=O)C>[CH3:29][O:30][C:31]1[CH:37]=[C:36]([C:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH:39]=2)[C:35]([N+:45]([O-:47])=[O:46])=[CH:34][C:32]=1[NH:33][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1N
Reactant: Clc1nccc(-c2cnn3ccccc23)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC(C)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C2=CCN(C)CC2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Yield: 65.6 %

Procedure:
A solution of 3-(2-chloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine (Intermediate 152, 256 mg, 1.00 mmol), p-toluene sulphonic acid monohydrate (271 mg, 1.43 mmol) and 2-methoxy-4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-5-nitroaniline (Intermediate 3, 250 mg, 0.95 mmol) and 2-pentanol (12 mL) was heated at reflux for 4 h under an atmosphere of N2. The mixture was then concentrated in vacuo and the residue was dissolved in CH3OH. This solution was purified by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia. Fractions containing the desired product were concentrated in vacuo to give a residue that was dissolved into hot DMF (10 mL). This solution was filtered and concentrated in vacuo to provide a gum that was triturated with CH3CN (10 mL) to give the title compound (285 mg, 66%) as a yellow powder; 1H NMR: 2.36 (5H, s), 2.67 (2H, s), 3.07 (2H, s), 4.02 (3H, s), 5.66 (1H, s), 7.00 (1H, s), 7.12 (1H, t), 7.41 (1H, m), 7.45 (1H, m), 8.45 (2H, t), 8.59 (1H, d), 8.83 (2H, t), 8.90 (1H, s); m/z: ES− M-H− 456.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:28]1([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][C:12]([N:31]2[CH2:30][CH2:29][N:28]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:33][CH2:32]2)=[CH:11][C:10]=1[O:16][C:17]([F:20])([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)Oc1cc(Br)ccc1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N(Cc3ccccc3)Cc3ccccc3)c(OC(F)(F)F)c2)CC1
Temperature: 100 °C

Procedure:
A mixture of the product of EXAMPLE 45A (7.92 g, 18.21 mmol), tert-butyl piperazine-1-carboxylate (3.73 g, 20 mmol), palladium diacetate (205 mg, 0.91 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (850 mg, 1.36 mmol) and cesium carbonate (11.88 g, 36 mmol) in toluene (200 mL) was heated under nitrogen at 100° C. for 20 hours. After cooling to ambient temperature, the mixture was concentrated and the residue was diluted with dichloromethane (300 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 10/1 petroleum ether/ethyl acetate to give the title compound. MS: 542 (M+H+).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[C:53]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[NH:63][CH:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)([CH3:56])([CH3:55])[CH3:54]>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:67]2[CH2:68][CH2:69][CH:64]([NH:63][C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=3[C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:65][CH2:66]2)=[O:12])=[CH:5][CH:6]=1
Reactant: CC(C)(C)c1ccccc1NC1CCNCC1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1NC1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.091 g, 0.00036 mole) in DMF (1 mL) was added DIPEA (0.211 g, 0.0016 mole), HOBt (0.048 g, 0.00036 mole) and EDCI.HCl (0.125 g, 0.00065 mole). After 2 minutes (2-tert-butyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00033 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (1% methanol in chloroform) afforded 0.062 g (40%) of N-biphenyl-4-yl-3-[4-(2-tert-butyl-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 470.27 (M+1)+, 96.38%, 1H NMR (DMSO-d6): δ 7.8-7.6 (m, 6H), 7.5 (t, 2H), 7.3 (d, 1H), 7.1 (d, 1H), 7.0 (t, 1H), 6.8 (d, 1H), 6.6 (t, 1H), 4.3 (d, 1H), 3.9 (d, 2H), 3.7 (s, 1H), 3.6 (s, 2H), 3.2 (t, 1H), 2.9 (t, 1H), 2.0 (t, 2H), 1.5 (t, 1H), 1.4 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH:7]([CH2:22][CH3:23])[C:8]([C:10]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]3[C:11]=2[CH2:12][CH2:13][C:14](=[O:21])[NH:15]3)=[O:9])[CH2:3][CH2:2]1.Br.[H][H]>O.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([CH:7]([CH2:22][CH3:23])[CH:8]([C:10]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]3[C:11]=2[CH2:12][CH2:13][C:14](=[O:21])[NH:15]3)[OH:9])[CH2:3][CH2:2]1
Reactant: CCC(C(=O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: O
Product: CCC(C(O)c1ccc(O)c2c1CCC(=O)N2)N1CCOCC1
Yield: 69.6 %

Procedure:
1.0 g of 5-(2-morpholinobutyryl)-8-hydroxy-3,4-dihydrocarbostyril (IIb) hydrobromide was dissolved in 70 ml of water and 0.2 g of palladium-on-carbon and 0.3 g of palladium black were added to the solution followed by allowing the mixture to catalytically reduce under atmospheric pressure in a hydrogen atmosphere for 10 days at a temperature of 70° C while shaking. After completion of the reduction, the reaction mixture was filtered to remove the catalysts by filtration, and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was dissolved in acetone by heating followed by allowing the solution to cool. The precipitate formed upon cooling was recrystallized from ethanol to obtain 0.7 g of white amorphous 5-(2-morpholino-1-hydroxybutyl)-8-hydroxy-3,4-dihydrocarbostyril (I) hydrobromide 1/2 hydrate having a melting point of 183° - 185° C (with decomposition). The product thus obtained was confirmed by NMR and IR spectral analyses and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[CH:4]([OH:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[O:19][CH3:20].[CH:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]([OH:21])[C:3]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:2]=2[NH:1][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:6]([O:19][CH3:20])[CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc(OCc2ccccc2)ccc1C(O)c1cc(Cl)ccc1N
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(OCc2ccccc2)ccc1C(O)c1cc(Cl)ccc1NCC(C)(C)C
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-α-(4-benzyloxy-2-methoxyphenyl)-5-chlorobenzyl alcohol (9.5 g), pivalaldehyde (3.35 ml), acetic acid (1.85 g) and ethanol (200 ml) was stirred for 30 min. To the mixture was added sodium cyanoborohydride (2.33 g) and the mixture was stirred for 24 h. After the mixture was concentrated in vacuo, the residue was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give α-(4-benzyloxy-2-methoxyphenyl)-2-neopentylamino-5-chlorobenzyl alcohol (10.0 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][C:10]=2[F:20])[S:6][C:5]=1[NH:21][C:22]1[CH:23]=[CH:24][C:25]2[N:26]([CH:28]=[C:29]([C:31](OCC)=[O:32])[N:30]=2)[N:27]=1)=[O:3].C[Al](C)C.Cl.[OH:41][CH:42]1[CH2:45][NH:44][CH2:43]1>O1CCCC1>[F:15][C:14]1[CH:13]=[C:12]([C:16]([OH:19])([CH3:18])[CH3:17])[CH:11]=[C:10]([F:20])[C:9]=1[C:7]1[S:6][C:5]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[N:26]([CH:28]=[C:29]([C:31]([N:44]4[CH2:45][CH:42]([OH:41])[CH2:43]4)=[O:32])[N:30]=3)[N:27]=2)=[C:4]([C:2]([NH2:1])=[O:3])[CH:8]=1
Reactant: CCOC(=O)c1cn2nc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)ccc2n1
Reactant: OC1CNC1
Agent: C[Al](C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc4nc(C(=O)N5CC(O)C5)cn4n3)s2)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)imidazo[1,2-b]pyridazine-2-carboxylate (33 mg, 0.07 mmol) was taken up in tetrahydrofuran and cooled to 0° C. Trimethylaluminum (0.53 ml, 1.06 mmol) was added dropwise, followed by 3-hydroxyazetidine hydrochloride (7 mg, 0.07 mmol). The reaction was stirred at 0° C. for one hour, warmed to room temperature and allowed to react overnight. The reaction was then quenched slowly with methanol, followed by stirring for 10 minutes at room temperature. The resulting mixture was filtered, washing the solids with ethyl acetate and water. The filtrate was collected, the phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were concentrated under and purified via flash chromatography (0-15% methanol in dichloromethane) to afford the title compound.