Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OP([O-])(O)=O.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:23]#[N:24])([CH2:21][CH3:22])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=1>[OH-].[Na+]>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:23]#[N:24])([CH2:21][CH3:22])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=1
Reactant: CCC(C#N)(CCC(=O)OC)c1ccc(N)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Product: CCC(C#N)(CCC(=O)O)c1ccc(N)cc1
Temperature: 30 °C
Yield: 38.2 %

Procedure:
A 500 ml jacketed biotransformation vessel as charged with 0.1M KH2PO4, pH 7.0 (250 ml) and methyl 4-(4-aminophenyl)4-cyanohexanoate (5.0 g, 20.3 mmol). Candida cylindracea lipase (CCL; 5.0 g) was introduced and the mixture was agitated using an overhead stirrer. Temperature was maintained at 30° C. with the aid of a thermocirculator and the pH controlled by a probe linked to an autotitrator. The biotransformation was allowed to proceed until 10 ml of 1M NaOH had been added (equivalent to 50% conversion). This took about 3 hours. At this point, the biotransformation was quenched by the addition of NaCl (25 g) and the resulting mixture was extracted with diethyl ether (250 ml×4). The pH of the aqueous solution was then adjusted to 3 using conc. HCl and the mixture extracted with ethyl acetate (400 ml×3). The extracts were pooled, dried and concentrated under reduced pressure, yielding 1.8 g (38%) of 4-(4-aminophenyl)-4-cyanohexanoic acid, enriched in the (R)-enantiomer, in the form of a brown oil. Without further treatment, a sample of this material was reacted as described in Example 10.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[NH2:13][C:14]1[C:15]([NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.[CH:30]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[CH2:28]([S:25]([NH:24][C:15]1[C:14]([NH:13][C:36]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:37])=[CH:19][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:17][N:16]=1)(=[O:27])=[O:26])[CH3:29]
Reactant: O=C(O)C1CCCCC1
Reactant: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1NC(=O)C1CCCCC1
Reaction time: 10 h
Yield: 62.5 %

Procedure:
An alternative process will be described. In 20 ml of methylene chloride, 0.5 g of 4-diemthylaminopyridine was dissolved, and 0.78 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and dissolved. Then, 1 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was added thereto, and 30 minutes later, 0.52 g of cyclohexanecarboxylic acid was added thereto, and stirring was conducted for 10 hours. After completion of the reaction, 40 ml of methylene chloride was added to the reaction product, and the reaction product was washed with 10% hydrochloric acid and then washed with an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. From the extract layer, solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 0.88 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[CH3:30][N:31](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:30]#[N:31])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(Br)cc2)nc1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(C#N)cc2)nc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[6-(4-bromo-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.28 g, 0.53 mmol), zinc cyanide (0.037 g, 0.32 mmol), tetrakistriphenylphosphine palladium (0) (0.024 g, 0.021 mmol) and 0.66 mL of dimethylformamide was heated to 80° C. for 24 hours. An additional 37 mg of zinc cyanide and 24 mg of tetrakistriphenylphosphine palladium (0) was added and the mixture was stirred at 80° C. for an additional 48 hours. After cooling to room temperature, the mixture was diluted with toluene and was washed with 2M ammonium hydroxide (twice), brine, dried over sodium sulphate, filtered and concentrated in vacuo. Purification by radial chromatography (ethyl acetate-hexanes, then methanol) afforded 58 mg of 1-[6-(4-Cyano-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup. 1H NMR (CDCl3, 500 MHz): 8.07 (d, 1H, J=3.5 Hz), 7.80 (dd, 1H, J=2.5, 9.0 Hz), 7.69 (d, 2H, J=9.0 Hz), 7.25 (d, 2H, J=9.0 Hz), 7.02 (d, 1H, J=9.0 Hz), 4.21 (q, 4H, J=7.5 Hz), 2.74 (m, 2H), 2.66 (m, 2H), 1.19 (t, 6H, J=7.0 Hz) ppm. MS (APCl, m/z): 424 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]([O:23][C@H:24]2[O:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]3[N:32]=[N:33][NH:34][C:35]=3[CH2:36][N:37]([CH3:39])[CH3:38])[C@H:25]2[C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]([O:23][C@H:24]2[O:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]3[N:32]=[N:33][NH:34][C:35]=3[CH2:36][N:37]([CH3:39])[CH3:38])[C@H:25]2[C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C)Cc1[nH]nnc1CN1CCO[C@H](O[C@H](CO[Si](C)(C)C(C)(C)C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)Cc1[nH]nnc1CN1CCO[C@H](O[C@H](CO)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1c1ccc(F)cc1

Procedure:
The product of Step C, above, (0.2 g) was stirred in anhydrous tetrahydrofuran (2 ml) with tetrabutylammonium fluoride (1.0M) in tetrahydrofuran (0.42 ml) for 30 minutes. The mixture was partitioned between ammonium chloride solution and ethylacetate, and the organic layer washed (H2O, brine), dried (MgSO4) and evaporated in vacuo. Purification by gravity silica column eluting with 4-10% MeOH/0.1% NH4OH/dichloromethane afforded the title compound. 1H NMR (250 MHz, CDCl3) δ 2.26 (6H, s), 2.51 (1H, m), 3.09 (2H, m), 3.35 (2H, m), 3.51-3.63 (4H, m), 3.78 (2H, d, J=13.8 Hz), 4.30-4.36 (2H, m), 4.88 (1H, m), 7.01-7.10 (4H, m), 7.50 (2H, vbr s), 7.59 (1H, br s).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][CH:13]=[CH2:14])[S:4](=[O:16])(=[O:15])[N:3]=1.[BH4-].[Na+].[H-].[Na+].O.[CH2:22](O)C>CN(C)C=O>[CH3:22][N:3]1[CH:2]([CH3:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][CH:13]=[CH2:14])[S:4]1(=[O:16])=[O:15]
Reactant: CCO
Reactant: C=CCN1c2ccccc2C(C)=NS1(=O)=O
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1c2ccccc2C(C)N(C)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(2 g) was dissolved in ethanol(50 ml) and treated with sodium borohydride (350 mg) at room temperature. After 15 minutes, the solvent was removed in vacuo and water added(200 ml). The product was extracted with chloroform(3×100 ml), dried, filtered and evaporated in vacuo to give a solid. This was dissolved in dry dimethylformamide (35 ml) and treated with sodium hydride (350 mg) at room temperature for 30 minutes followed by methyl iodide(600 μl). The reaction was stirred at room temperature for 1 hour, poured into water(250 ml), extracted with ether (3×75 ml), dried, filtered and the solvent removed to give 3,4-dihydro-3,4-dimethyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. This product was dissolved in dioxan (25 ml) and treated with osmium tetroxide (2 crystals) and sodium periodate(3.6 g) in water(25 ml) and stirred at room temperature overnight. Water was added(100 ml) and the product extracted with ether(3×100 ml), dried, filtered and the solvent removed to give an oil. This was dissolved in methanol(50 ml) and treated with 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridine (1.2 g) at room temperature overnight in the presence of acetic acid(1 ml) and 3A molecular sieves(2 g). Sodium cyanoborohydride(1 g) was then added and the reaction stirred for 4 hours. A further quantity of acetic acid (1 ml) and sodium cyanoborohydride(1 g) were added and stirred at room temperature for 18 hours. Saturated sodium bicarbonate (250 ml) was added and the mixture extracted with ethyl acetate (3×100 ml). After drying, filtering and removal of solvent, flash chromatography on the residue eluting with chloroform/ethyl acetate to ethyl acetate gave product, 3,4-dihydro-1-{2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-3,4-dimethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide, m.p.105-108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH2:23][CH3:24])([O-:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:23]([N+:20]([O-:22])=[O:21])[CH3:24])[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: CC[N+](=O)[O-]
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cc(C=C(C)[N+](=O)[O-])cc(OC)c1OC
Temperature: 105 °C
Yield: 50 %

Procedure:
5.00 g (25.5 mmol) 3,4,5-trimethoxybenzaldehyde (Aldrich, Milwaukee, Wis.), 9.82 g (127 mmol) ammonium acetate (Fluka), and 50 g (670 Mmol) nitroethane, 98% (Aldrich) were combined in a 100 ml round bottom flask equipped with magnetic stirrer and nitrogen inlet. The reaction mixture was heated to 105° C. for 90 minutes and the solvent was removed under vacuum to give a crude product which was recrystallized from cold methyl alcohol three times to give yellow needles in 50% yield. 1H NMR spectra is shown in FIG. 4.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19][CH3:20])[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:22]=[CH:21][C:15]3[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(SC)sc3c2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reaction time: 1 h

Procedure:
To the solution of 4-(2-methylsulfanyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide from step 3 (3.88 g, 11.72 mmol, 1.0 eq) in DCM (20 mL) at 0° C., was added MCPBA (77%, 2.88 g, 1. eq). The mixture was stirred at this temperature for one hour. Saturated sodium bicarbonate solution (100 mL) was added. The aqueous layer was extracted with DCM (3×150 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated in vacuo to yield 4-(2-methanesulfinyl-benzothiazol-6-yloxy)-pyridine-2-carboxylic acid methylamide as white powder in quantitative yields. The crude product was used in the next step without purification. M+H=348.0.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][C:10]=1[Cl:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[Cl:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CO)cc1Cl
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a stirred and cooled (0° C.) solution of 8.00 g (26.7 mmol) of the product of Step A dissolved in 50 mL of anhydrous THF was added 53.3 mL (53.3 mmol) of a 1M solution of lithium aluminum hydride in THF. After the addition was complete the reaction mixture was allowed to warm to room temperature and stirred 2 hours. The stirred reaction was then quenched by dropwise addition of 2.5 mL water, then 2.5 mL of 15% NaOH, and finally 7.5 mL water. The reaction mixture was then filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 1N HCl, saturated NaHCO3, dried (MgSO4), and evaporated in vacuo to afford 4.0 g (53%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([CH2:37][N+:38]([O-])=O)([C:33]([F:36])([F:35])[F:34])[CH2:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[C:19]2([CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[O:18][CH2:17]3)=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]>C(O)C>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]2([C:33]([F:34])([F:36])[F:35])[CH2:11][C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19]3([CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:25]3)[O:18][CH2:17]4)=[N:38][CH2:37]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)c(F)c(Cl)c3)C(F)(F)F)ccc12
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C3=NCC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Yield: 40.7 %

Procedure:
To the solution of tert-butyl 5′-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-3-(nitromethyl)butanoyl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-carboxylate (Preparation 7, 1.2 g, 1.98mmol) in ethanol (10 mL) nitrogen was purged for 30 minutes and was added pre-washed Raney-Nickel (0.24 g, 50% suspension in water). Resulting reaction mixture was stirred under hydrogen atmosphere using balloon for 16 hours at room temperature. After complete conversion of starting material, the reaction mixture was filtered through celite bed. The bed was washed with 10% MeOH in DCM (30 mL). Combined filtrate was concentrated under vacuum to get 1.1 g of crude, off white solid. Crude compound was purified by column chromatography on silica gel (230-400 mesh). Desired compound was eluted in 7% EtOAc in n-Hexane to afford off white semi solid (451 mg, 40.63%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.44 (d, J=17.2 Hz 1H), 3.76-3.81 (m, 1H), 4.13 (d, J=9.68 Hz, 2H), 4.32 (d, J=9.68 Hz, 2H), 4.42 (d, J=17.12 Hz 1H), 4.84-4.89 (m, 1H), 5.13 (s, 2H), 7.32 (d, J=5.96 Hz, 2H), 7.54 (d, J=7.92 Hz 1H), 7.73 (s, 1H), 7.83 (d, J=7.88 Hz 1H). LC-MS (m/z): 558.8 (M+H).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH:10][NH2:11])[CH:5]=1.C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C>C(O)C>[NH2:21][C:20]1[N:10]([C:6]2[CH:5]=[C:4]([O:3][CH:2]([F:1])[F:12])[N:8]([CH3:9])[N:7]=2)[N:11]=[CH:16][C:17]=1[C:18]#[N:19]
Reactant: CCOC=C(C#N)C#N
Reactant: Cn1nc(NN)cc1OC(F)F
Solvent: CCO
Product: Cn1nc(-n2ncc(C#N)c2N)cc1OC(F)F

Procedure:
22.5 g (0.13 mol) 5-Difluoromethoxy-3-hydrazino-1-methyl-pyrazole was dissolved in 310 ml ethanol and treated with 15.4 g (0.13 mol) ethoxymethylenemalononitrile. After the mixture had been heated under reflux for one hour it was cooled. The precipitate was suction filtered and washed with a small amount of ethanol.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:22]4=[N:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH:72]1[CH2:77][CH2:76][CH:75]([OH:78])[CH2:74][CH2:73]1>CN(C=O)C.O>[CH2:29]([O:28][C:27]1[C:22]2[N:23]([C:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]4[CH2:10][CH2:11][CH:6]([C:4]([N:72]5[CH2:77][CH2:76][CH:75]([OH:78])[CH2:74][CH2:73]5)=[O:3])[CH2:7][CH2:8]4)[N:18]=3)=[CH:20][N:21]=2)[CH:24]=[CH:25][CH:26]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)C1CCC(Nc2nccc(-c3cnc4c(OCc5ccccc5)cccn34)n2)CC1
Reactant: OC1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(C1CCC(Nc2nccc(-c3cnc4c(OCc5ccccc5)cccn34)n2)CC1)N1CCC(O)CC1
Yield: 95 %

Procedure:
A mixture of 4-[4-(8-benzyloxy-imidazo[1,2-a]pyridine-3-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid ethyl ester (0.23 g) in DMF (10 mL) was treated with BOP (79 mg), then DIEA (0.345 g), then piperidin-4-ol (79 mg), and the mixture stirred at RT for 5 h. The reaction mixture was then diluted with water, and the resulting solid filtered, washed with water, and dried. The solid was then dissolved in hot EtOAc, MeOH, and DCM, and the solution filtered hot. The product was dried at 50° C. under vacuum overnight to provide {4-[4-(8-benzyloxy-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-2-ylamino]-cyclohexyl}-(4-hydroxy-piperidin-1-yl)-methanone (compound 6, 244 mg).
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:9][N:8]=1.Cl[C:21]1[N:26]=[N:25][C:24]([N:27]([CH2:35][C:36]2([C:40]3[C:45]([F:46])=[CH:44][CH:43]=[CH:42][N:41]=3)[CH2:39][CH2:38][CH2:37]2)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][CH:22]=1>[Cl-].[Zn+2].[Cl-].C1COCC1>[CH3:19][C:14]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:21]3[N:26]=[N:25][C:24]([N:27]([CH2:35][C:36]4([C:40]5[C:45]([F:46])=[CH:44][CH:43]=[CH:42][N:41]=5)[CH2:39][CH2:38][CH2:37]4)[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:23][CH:22]=3)=[N:8][CH:9]=2)[C:17]([CH3:18])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(Cl)nn1
Reactant: Cc1ccc(C)n1-c1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [Zn+2]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1ccc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)nc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 463.5 %

Procedure:
THF (8.5 mL) was cooled to −78° C. under a nitrogen atmosphere. tBuLi (1.7 mL, 2.9 mmol, 2.0 equiv) was added, followed by the addition of 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (370 mg, 1.47 mmol, 1.0 equiv dissolved in 2 mL THF) over 2 min. The reaction as stirred for 45 min at −78° C. Zinc chloride (510 mg, 3.75 mmol, 2.5 equiv dissolved in 5 mL of THF) was added and the reaction was allowed to warm to rt and stirred for 3 h. (t-Bu3P)2Pd (41 mg, 0.015 mmol, 0.10 equiv dissolved in 5 mL of THF) and t-butyl 6-chloropyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (393 mg, 0.1 mmol, 0.07 equiv dissolved in 5 mL of THF) were added and the reaction was refluxed for 4 h followed by dilution with sodium bicarbonate (20 mL), and extraction with ethyl acetate (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography (35% EtOAc/hexanes) to give 245 mg (46%) of tert-butyl 6-(5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate.
Reaction SMILES: BrC1C=C2C(C(CC([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=O)=CN2)=CC=1.[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36]([C:41](=O)[NH:42]C(C)(C)C)=[C:35]2[CH2:48][C:49]([OH:51])=O>>[Br:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36]([C:41]#[N:42])=[C:35]2[CH2:48][C:49]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]1[CH:19]=[C:20]([Cl:29])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:22]([Cl:24])[CH:23]=1)=[O:51]
Reactant: CC(C)(C)NC(=O)c1[nH]c2ccc(Br)cc2c1CC(=O)O
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c(C#N)[nH]c3ccc(Br)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetic acid (preparation J) in step 25 (A), the title compound was prepared. 1H-NMR (500 MHz, CD3OD) δ ppm 2.19 (d, J=12.82 Hz, 3 H) 3.79 (s, 2 H) 4.31 (s, 2 H) 7.00 (s, 1 H) 7.26 (s, 1 H) 7.35 (d, J=8.24 Hz, 1 H) 7.85 (s, 1 H).
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13][C:14]1[CH:21]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:19]=[C:18]([B:29]2[O:33][C:32](C)(C)C(C)(C)[O:30]2)[C:15]=1C=O>C1COCC1.[Zn]>[Cl:13][C:14]1[C:15]2[CH:32]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:33][B:29]([OH:30])[C:18]=2[CH:19]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:21]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)OB(c2cc(OC3CCCCO3)cc(Cl)c2C=O)OC1(C)C
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC3CCCCO3)cc(Cl)c21
Temperature: 55 °C
Reaction time: 0.25 h

Procedure:
To a suspension of powdered zinc dust (1.0 g, 2.73 mmol) in THF (3 mL) was added trimethylsilyl chloride (0.21 mL, 2.73 mmol) at 40° C. The mixture was stirred at 55° C. for 15 min. After cooled to 37° C., ethyl bromoacetate (1.21 mL, 13.65 mmol) was added slowly while maintaining the temperature between 37˜40° C. The resulting mixture was stirred at ambient temperature for an additional 30 min. To a solution of 2-chloro-4-(tetrahydro-2H-pyran-2-yloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)benzaldehyde (1 g, 2.73 mmol) in anhydrous THF (3 mL) cooled at −78° C., was added above freshly prepared zinc reagent. Upon completion of addition, the reaction mixture was warmed to room temperature and stirred for 30 min before quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was used directly in the next step reaction without further purification. MS (ESI) m/z=355 [M+H]+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[NH:28][NH2:29])[N:13]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:37](Cl)(Cl)=[O:38]>C(Cl)Cl.C1(C)C=CC=CC=1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:37]([OH:38])[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Oc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-[1,3]dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridin-5-yl]-hydrazine (3-4, 5.3 g, 13.8 mmol) in CH2Cl2 (anhydrous, 40 mL) at 0° C. was added triethylamine (9.7 mL, 68.9 mmol) followed by a rapid addition of phosgene in toluene (2M, 7.6 mL). After stirring for 10 min at room temperature, the mixture was concentrated and water (30 mL) was added. The solid was collected and dried with toluene azeotropically to give the title compound which was used for the next step without further purification. LRMS m/z (M+1) Calcd: 411.1. Found 411.2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].O>CN(C)C=O>[CH2:21]([O:20][C:18]([CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:19])[CH3:22]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (10 g) and potassium carbonate (17 g) in dimethylformamide (100 ml) was added ethyl bromoacetate (15 g) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (ethyl acetate:n-hexane, 1:4, V/V) to give 4-(ethoxycarbonylmethoxy)benzaldehyde (16 g).