Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S@@:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Br:8][C:9]1[N:14]=[C:13]([C:15](=O)[CH2:16][CH2:17][O:18][CH3:19])[C:12]([F:21])=[C:11]([Si:22]([CH2:27][CH3:28])([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:10]=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+].O>[Br:8][C:9]1[N:14]=[C:13](/[C:15](=[N:7]/[S@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])/[CH2:16][CH2:17][O:18][CH3:19])[C:12]([F:21])=[C:11]([Si:22]([CH2:27][CH3:28])([CH2:23][CH3:24])[CH2:25][CH3:26])[CH:10]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)CCOC)c1F
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)c1cc(Br)nc(/C(CCOC)=N/[S@@](=O)C(C)(C)C)c1F
Temperature: 60 °C
Reaction time: 34 h
Yield: 63.5 %

Procedure:
A mixture of titantetraethoxide (11.03 g, 48.4 mmol), (S)-tert.-butylsulfinamide (3.52 g, 29 mmol) and 1-(6-Bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-3-methoxy-propan-1-one (9.1 g, 24.18 mmol) in THF (100 ml) was stirred at 60° C. under a nitrogen atmosphere for 34 hours. The cold reaction mixture was diluted with ethyl acetate and poured onto icecold brine (200 ml) with gentle stirring. The precipitate was filtered through a pad of hyflo and washed with ethyl acetate. The filtrate was diluted with ethyl acetate and washed with brine, dried over sodium sulfate, filtered and evaporated. The crude yellowish-brown oil (10.67 g) was chromatographed over silica gel (Redisep column 120 g, cyclohexane/ethyl acetate 95:5) to give the title compound as a yellow-orange oil. 7.51 g (63.5% yield).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:25])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22](Br)[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[N:26]1[CH:31]=[CH:30][C:29]([C:22]2[N:23]=[C:17]3[CH:16]=[C:15]([NH:14][C:12]([C:11]4[N:10]([CH3:25])[N:9]=[CH:8][C:7]=4[C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])=[O:13])[CH:20]=[CH:19][N:18]3[N:21]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccncc1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(Br)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3ccncc3)nc2c1
Yield: 18.8 %

Procedure:
Through a mixture of 4-(azetidine-1-carbonyl)-N-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (150 mg, 371 μmol) and pyridin-4-ylboronic acid (68.4 mg, 557 μmol) in dioxane (4 ml) and sat. sodium carbonate solution (1 ml) was bubbled nitrogen for 10 minutes, then 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride/dppf (15.2 mg, 18.6 μmol) was added and the resulting mixture was refluxed for 18 hours under nitrogen atmosphere. The solvent was evaporated and the residue was diluted with ethyl acetate and washed with water, the organic layer was separated, dried over magnesium sulfate, filtrated and evaporated. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using ethyl acetate/methanol 2-5% as eluent affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (28 mg, 18.8%) as a white solid. mp: >250° C., MS: m/z=403.0 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>ClCCl.C(OCC)(=O)C>[C:23]([NH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: Nc1cccc2c1-c1ccccc1C2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(=O)Nc1cccc2c1-c1ccccc1C2=O
Yield: 65.3 %

Procedure:
To a stirred solution of 4-amino-9-fluorenone (0.20 g, 1.0 mmol) in dichloromethane (40 ml) was added triethylamine (0.5 ml, 3.5 mmol), followed by propionyl chloride (0.5 ml, 5.8 mmol). After 20 min the mixture was diluted with ethyl acetate (150 ml) and washed with 2N HCl (100 ml) followed by saturated sodium carbonate (100 ml). The organic phase was separated, dried (MgSO4) and the solvent removed in vacuao. The residue was purified by flash chromatography (silica, heptane:ethyl acetate 7:3) to give 164 mg (63%) of the desired material as a yellow oil.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([CH3:20])([O:15][Si](C)(C)C)[CH3:14])[CH:7]=[CH:6][C:5]=12.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:21])[C:11]#[C:12][C:13]([OH:15])([CH3:14])[CH3:20])[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C#CC(=O)c1ccc2nonc2c1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccc2nonc2c1
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a stirred solution of 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-methyl-4-(trimethylsilyloxy)pent-2-yn-1-one (0.45 g, 1.490 mmol) in DCM (15 mL) was added p-TSA (0.341 g, 1.790 mmol) at RT and the reaction mixture was stirred for 3 h. The reaction mixture was then diluted with water (5 mL) and the layers were separated. The combined organic layers were washed with a saturated NaHCO3 solution and water, dried over Na2SO4, filtered, and then concentrated in vacuo to afford 1-(benzo[c][1,2,5]oxadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.3 g, 87%) as an oil.
Reaction SMILES: C(OCC1ON=C(CO[NH:13][C:14]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[N:18](C3CCCCC3NS(C)(=O)=O)[CH:17]2C2C=CC(Cl)=CC=2Cl)=[O:15])N=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[O:26]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]([C:14]([NH2:13])=[O:15])[CH2:17][NH:18]1
Reactant: CC(=O)OCc1nc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)C1CNC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 323 mg of (3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazol-5-yl)methyl acetate in 6.5 ml of methanol was added 66 mg of potassium carbonate, followed by stirring at room temperature for 3 hours. To the reaction solution was added ethyl acetate, followed by washing with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and then recrystallized from ethyl acetate to obtain 157 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-N-{[5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl]methoxy}-2-{(1SR,2SR)-2-(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[N:29]2[C:24]([CH:25]=[N:26][C:27]([S:30][CH3:31])=[N:28]2)=[CH:23][CH:22]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]([CH2:46][CH2:47][C:48]#[N:49])[CH:43]=[CH:44][CH:45]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:31][S:30][C:27]1[N:26]=[CH:25][C:24]2=[CH:23][CH:22]=[C:21]([C:40]3[CH:41]=[C:42]([CH2:46][CH2:47][C:48]#[N:49])[CH:43]=[CH:44][CH:45]=3)[N:29]2[N:28]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: CC1(C)OB(c2cccc(CCC#N)c2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ncc2ccc(-c3cccc(CCC#N)c3)n2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.6 %

Procedure:
Into a 8-dram vial, Palladium Acetate (0.057 g, 0.26 mmol) and Triphenylphosphine (0.19 g, 0.00072 mol) were added. The mixture was purged under an atmosphere of Nitrogen for 10 minutes. 1,4-Dioxane (19.4 mL) was added and stirred for 10 minutes at room temperature. 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.623 g, 2.55 mmol), 3-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionitrile (1.31 g, 5.10 mmol), N,N-Dimethylformamide (39 mL), and 1.50 M of Sodium carbonate in Water (15.3 mL, 0.0230 mol) were added. The reaction was heated at 90° C. for 3 hours. The reaction was partitioned with water and EtOAc. The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via column chromatography with DCM and Methanol as eluant (1 to 8% MeOH). The collected fractions afforded a solid. The solid was triturated with Et2O and filtered to give 3-[3-(2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-propionitrile as a yellow solid (560 mg, 64%).
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[NH:12][C:11](=[O:13])[CH:10]=[CH:9][NH:8]1.Br[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:19]([O:18][C:16]([CH2:15][N:8]1[CH:9]=[CH:10][C:11](=[O:13])[NH:12][C:7]1=[O:6])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(=O)[nH]c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.3 %

Procedure:
To anhydrous dimethylformamide solution (10 ml) containing 2,4-dioxopyrimidine (1.0 g) are added benzyl bromoacetate (2.5 g) and potassium carbonate (2.5 g), and the mixture is stirred at room temperature for 15 hours. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed with a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure, and the precipitated crystals are washed with diethyl ether to give the desired 1-benzyloxycarbonylmethyl-2,4-dioxopyrimidine (1.4 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[C:5]([NH2:21])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].[C:26](C1NC=CN=1)(C1NC=CN=1)=[O:27].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:22]([F:23])([F:25])[F:24])=[CH:4][C:5]2[NH:21][C:26](=[O:27])[N:8]([CH:9]3[CH2:10][CH2:11][N:12]([CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:13][CH2:14]3)[C:6]=2[CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: Nc1cc(C(F)(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(C(F)(F)F)c(Cl)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 5-chloro-N-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-trifluoromethyl-1,2-benzenediamine (D52) (0.34 g, 0.9 mmol) in anhydrous tetrahydrofuran (40 ml) was treated with carbonyl diimidazole (0.29 g, 1.80 mmol)—added in portion over 5 minutes. The mixture was stirred at room temperature under argon for 4 hours. The mixture was warmed to a gentle reflux. After 18 hours, a further 0.29 g, 1.8 mmole of carbonyl diimidazole was added and the mixture maintained at reflux for another 24 hours. The mixture was cooled to room temperature and was treated with ethyl acetate (40 ml) and washed with water and brine then dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 1 to 10% methanol in dichloromethane to afford 6-chloro-5-trifluoromethyl-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one, which was subsequently converted to the hydrochloride salt and isolated as a cream powder. 0.25 g, 73%. MH+=404 and 406
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[C:9](=[O:19])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([OH:18])=[CH:13][CH:12]=2)[C:4]([OH:6])=[O:5].[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([C:25](N2C3C=CC=CC=3OC2=S)=[O:26])=[CH:23][CH:22]=1>CN1CCCC1=O>[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([C:25]([NH:2][CH:3]([CH2:7][C:8]2[C:9](=[O:19])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([OH:18])=[CH:13][CH:12]=3)[C:4]([OH:6])=[O:5])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(c1ccc(Cl)cc1)n1c(=S)oc2ccccc21
Reactant: NC(Cc1cc2cc(O)ccc2[nH]c1=O)C(=O)O
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=C(NC(Cc1cc2cc(O)ccc2[nH]c1=O)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2 Grams of 2-amino-3-(6-hydroxy-2-quinolon-3-yl)propionic acid hydrochloride was suspended in 50 ml of 1-methyl-2-pyrrolidone, then 2.2 g of 3-(4-chlorobenzoyl)benzoxazoline-2-thione was added thereto and stirred at a room temperature for 3 days. The reaction mixture was poured in ice-water and the crystals precipitated were collected by filtration. The crystals were dissolved in 1N-sodium hydroxide aqueous solution, and acidified with 10%-hydrochloric acid, then the crystals precipitated were collected by filtration. The crystals were dried and washed with chloroform. Recrystallized from methanol-water to obtain 1.5 g of 2-(4-chlorobenzoylamino)-3-(6-hydroxy-2-quinolon-3-yl)propionic acid in the form of light yellowish powdery product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][C:7](=O)[CH2:8]Br.[C:12]([NH:19][C:20]([NH2:22])=[NH:21])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[Na+].[I-]>CN(C=O)C>[C:15]([O:14][C:12]([N:19]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[N:21]=[C:20]1[NH2:22])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)NC(=N)N
Reactant: COC(=O)CCCC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
6-bromo-5-oxo-hexanoic acid methyl ester (2.30 g, 10.3 mmol), Boc-guanidine (4.92 g, 30.9 mmol),32 and NaI (3.07 g, 20.6 mmol) were dissolved in DMF (30 mL) and allowed to stir at room temperature. After 24 h the DMF was removed under reduced pressure and the residue was taken up in ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL) before being dried (Na2SO4), filtered and evaporated to dryness. The resulting oil was purified by flash column chromatography (50-100% EtOAc/Hexanes) to obtain a yellow oil. Trituration of the viscous oil with cold hexanes (20 mL) produced a precipitate, which upon filtration yielded 18 (1.89 g, 65%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.53 (s, 1H), 5.6 (br s, 2H), 2.41 (t, 2H, J=7.2 Hz), 2.37 (t, 2H, J=7.2 Hz), 1.93 (quint., 2H, J=7.2 Hz), 1.58 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 174.09, 150.11, 149.61, 138.39, 107.15, 84.81, 51.56, 33.65, 28.18, 27.68, 23.82; HRMS (ESI) calcd for C13H22N3O4 (MH)+284.1604, found 284.1606.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][O:11][CH:10]([CH2:15][Cl:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17]C1C=CC(CNCCCO)=CC=1>>[Cl:17][C:5]1[CH:4]=[CH:3][C:2]([CH2:1][N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH:10]([CH2:15][Cl:16])[CH2:9]2)=[CH:7][CH:6]=1
Reactant: ClCC1CN(Cc2ccccc2)CCCO1
Reactant: OCCCNCc1ccc(Cl)cc1
Product: ClCC1CN(Cc2ccc(Cl)cc2)CCCO1
Yield: 29 %

Procedure:
(±)-4-(4-Chlorobenzyl)-2-(chloromethyl)perhydro-1,4-oxazepin was prepared analogously to the method for the preparation of (±)-4-benzyl-2-(chloro-methyl)perhydro-1,4-oxazepin described in K. Araki et al. J. Med. Chem. 36, 1356 (1993), using N-(4-Chlorobenzyl)-N-(3-hydroxypropyl)amine as starting material. Yield 29%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:8]1=[O:20].O1C[CH2:31][CH2:30][CH2:29]1.C([Li])(CC)C.C(Br)C=C>C(OCC)(=O)C.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)([CH2:31][CH:30]=[CH2:29])[C:8]1=[O:20]
Reactant: C1CCOC1
Reactant: COc1cc(CN2CCC(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Agent: [Li]C(C)CC
Solvent: C=CCBr
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCC1(Cc2ccc(F)cc2)CCN(Cc2cc(OC)c(OC)c(OC)c2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine (0.93 g, 2.86 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyl lithium (2.64 mL, 1.3 M in hexane, 3.43 mmol). After 30 minutes, add allyl bromide (0.42 g, 3.43 mmol). After the addition is complete, warm to ambient temperature. After 3 hours, add water and extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with ethyl acetate/hexane 1/4 to give the title compound.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([O:7][P:8]([CH:13]([F:19])[C:14](OCC)=[O:15])([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]>CCO.CCO.CCO.CCO.[Ti]>[CH2:5]([O:7][P:8]([CH:13]([F:19])[C:14]([O:4][CH2:1][C:2]#[CH:3])=[O:15])([O:10][CH2:11][CH3:12])=[O:9])[CH3:6]
Reactant: C#CCO
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Ti]
Solvent: CCO
Product: C#CCOC(=O)C(F)P(=O)(OCC)OCC
Temperature: 100 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
45.31 g (826 mmol) of propargyl alcohol and 0.94 g (4.1 mmol of tetraethyl titanate were added to 10.00 g (41.3 mmol) of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate, and heated under reflux at 100° C. for 10 hours. Subsequently, ethanol and propargyl alcohol were evaporated away under reduced pressure at a temperature falling within a range of from 70° C. to 100° C., taking 10 hours, and then the residue was cooled down to room temperature. 0.18 g of water was added to the reaction liquid, the formed precipitate was filtered away, and the filtrate was purified through silica gel column chromatography (ethyl acetate/hexane=1/1 for elution) to give 8.96 g (yield 86%) of the intended 2-propynyl 2-(diethoxyphosphoryl)-2-fluoroacetate. The obtained 2-propynyl 2-(diethoxyphosphoryl)-2-fluoroacetate was analyzed through 1H-NMR to confirm the structure thereof. The results are shown below.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.Cl[C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)=[O:29].C(N(CC)CC)C.O>ClCCl>[C:18]1([C:17]([NH:16][CH:12]2[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:15][N:14]([C:28]([N:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[O:29])[CH2:13]2)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CC(NC(=O)c3ccccc3)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Temperature: 25 °C

Procedure:
At 0° C., 220 mg (0.55 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 3 ml of dichloromethane, and 273 mg (1.10 mmol) of tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate and 116 μl (0.82 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 88 mg (28% of theory)
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[N:16][CH:17]=3)[CH:10]=2)[N:5](C2CCCCO2)[N:4]=1)=O.[S].[F:32][C:33]1[CH:34]=[C:35]([C:39]2[C:40]([NH2:46])=[C:41]([NH2:45])[CH:42]=[N:43][CH:44]=2)[CH:36]=[CH:37][CH:38]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(O)CCC>[F:32][C:33]1[CH:34]=[C:35]([C:39]2[C:40]3[N:46]=[C:1]([C:3]4[C:11]5[C:6](=[N:7][CH:8]=[C:9]([C:12]6[CH:13]=[C:14]([NH:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:21])[CH3:23])[CH:15]=[N:16][CH:17]=6)[CH:10]=5)[NH:5][N:4]=4)[NH:45][C:41]=3[CH:42]=[N:43][CH:44]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: Nc1cncc(-c2cccc(F)c2)c1N
Reactant: CC(C)(C)C(=O)Nc1cncc(-c2cnc3c(c2)c(C=O)nn3C2CCCCO2)c1
Agent: CC[SiH](CC)CC
Agent: [S]
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Nc1cncc(-c2cnc3[nH]nc(-c4nc5c(-c6cccc(F)c6)cncc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A solution of N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide (LXV) (75 mg, 0.18 mmol), sulfur (64 mg, 0.20 mmol) and 5-(3-fluorophenyl)pyridine-3,4-diamine (XL) (41 mg, 0.20 mmol) in n-butanol (10 mL) was refluxed overnight under argon. The solution was cooled and filtered and dried under vacuum for 1 h. The residue was taken in dry DCM (5 mL). Triethylsilane (72 μL, 0.45 mmol) followed by TFA (2.5 mL) was added to the solution and stirred for 2 h at room temperature. The solvent was removed under vacuum. Water was added to the residue, sonicated briefly and basified with a 5N NH4OH solution. The solids formed were filtered, washed with cold water and dried at room temperature. The solids were boiled in DCM, cooled to room temperature and sonicated briefly. The solids were filtered, washed with DCM and dried under vacuum to give N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)pivalamide (2) as a brown solid (66 mg, 0.13 mmol, 72% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 1.30 (s, 9H), 7.22 (t, 1H), 7.57-7.66 (m, 1H), 8.25 (d, 1H), 8.36 (d, 1H), 8.55 (s, 1H), 8.74 (s, 1H), 8.78 (s, 1H), 8.89 (s, 1H), 8.97 (s, 1H), 9.04 (s, 1H), 9.07 (s, 1H), 9.61 (s, 1H), 13.92 (brs, 1H), 14.63 (brs, 1H); ESIMS found C28H23FN8O m/z 507.5 (M+H).
Reaction SMILES: O[CH2:2][CH:3]([NH:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C.C(Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C.O.ClCCl>[CH3:7][O:6][C:4]([CH:3]1[CH2:2][O:10][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:8]1)=[O:5]
Reactant: COC(=O)C(CO)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)C1COC(C2CCN(C(=O)OC(C)(C)C)CC2)=N1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[[[1-(hydroxymethyl)-2-methoxy-2-oxoethyl]amino]carbonyl]-1-piperidinecarboxylate (i.e. the product of Example 7, Step A) (6.58 g, 19.92 mmol) in 70 mL of dry acetonitrile and 20 mL of dry dichloromethane was added triphenylphosphine (7.8 g, 29.87 mmol) and then 4.12 g (31.87 mmol) of N,N-diisopropylethylamine. The reaction mixture was stirred until homogeneous, and 4.59 g (29.87 mmol) of carbon tetrachloride was added dropwise over 5 minutes. The reaction mixture was stirred for 2.5 h at room temperature, cooled to 0° C. and diluted with 170 mL of ethyl acetate followed by 50 mL of saturated aqueous sodium bicarbonate solution. The mixture was stirred for 10 minutes, poured into 120 mL of water, and the organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure to give a yellow oil. The oil was purified by silica gel chromatography using 75-100% ethyl acetate in hexanes as eluant to give 2.95 g of the title compound as an oil containing traces of triphenylphosphine.