Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:15])=[C:7]([CH:11]=[CH:12][C:13]=2[OH:14])[C:8]([NH2:10])=[O:9])[CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:36]=[CH:35][C:24]2[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[O:28][C:23]=2[C:22]=1[CH2:37][CH2:38][CH3:39]>C(OCC)(=O)C.CCCCCC>[NH2:10][C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:36]=[CH:35][C:24]3[CH2:25][CH2:26][CH:27]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[O:28][C:23]=3[C:22]=2[CH2:37][CH2:38][CH3:39])=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]=1[OH:15])=[O:9]
Reactant: NC(=O)c1ccc(O)c(CC2CC2)c1O
Reactant: CCCc1c(OCCCI)ccc2c1OC(CCC(=O)OC)CC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2

Procedure:
The compound of Example 66 and the compound of Example 3 are coupled under the conditions outlined in Example 60. Chromatography of the crude phenolic ester on silica gel using ethyl acetate/hexane (3:7) as eluant affords the product.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21](Cl)[N:20]=4)[C:15](=[O:26])[CH:14]=3)[CH:10]=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]([C:19]4[CH:24]=[N:23][CH:22]=[C:21]([C:29]#[N:30])[N:20]=4)[C:15](=[O:26])[CH:14]=3)[CH:10]=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=c1cc(Cn2cncc2Oc2ccc(Br)cc2)ccn1-c1cncc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cncc(-n2ccc(Cn3cncc3Oc3ccc(Br)cc3)cc2=O)n1

Procedure:
A mixture of 4-[5-(4-Bromophenoxy)imidazol-1-ylmethyl]-1-(6-chloropyrazin-2-yl)-1H-pyridin-2-one (79 mg, 0.17 mmol) and zinc cyanide (12 mg, 0.1 mmol) in DMF (1 mL) was purged with argon for 5 min. A solution of tetrakis(triphenylphosphine)palladium(0) (20 mg, 17 μmol) in DMF (0.5 mL) was added. The resultant mixture was stirred under argon at 80° C. overnight, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1:1 v/v 5% methanol in chloroform and chloroform saturated with ammonia gas. Collection, concentration of appropriate fractions, and trituration of the residue with anhydrous ether provided the titled compound as white solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1([O:13][CH2:12][CH2:11][O:10]1)[CH3:9])[C:5]([OH:7])=[O:6].CON=[C:17](C1(OCCO1)CCl)[C:18](O)=O.CON=C(C1(OCCO1)CBr)C(O)=O>>[CH3:1][O:2][N:3]=[C:4]([C:8]1([O:10][CH2:11][CH2:12][O:13]1)[CH3:9])[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: CON=C(C(=O)O)C1(C)OCCO1
Reactant: CON=C(C(=O)O)C1(CCl)OCCO1
Agent: CON=C(C(=O)O)C1(CBr)OCCO1
Product: CCOC(=O)C(=NOC)C1(C)OCCO1

Procedure:
Thus obtained product can be led to 2-methoxyimino-3,3-ethylenedioxybutyric acid (syn isomer) or 2-methoxyimino-3,3-ethylenedioxy-4-chlorobutyric acid (syn isomer) or 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyric acid (syn isomer) according to the manner described in Examples 1 or 2 or 3 or 4 or 5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.CCN(C(C)C)C(C)C.[NH2:22][CH2:23][CH:24]([OH:36])[CH2:25][N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[CH2:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH2:35][N:26]1[CH2:25][CH:24]([OH:36])[CH2:23][NH:22][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([F:1])[CH:3]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)COc1cccc(F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COc1cccc(F)c1)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
To a stirred mixture of 2-(3-fluorophenoxy)acetic acid (252 mg, 0.893 mmol) in DCM (5 mL) was added DIEA (173 mg, 1.34 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (183 mg, 0.893 mmol), and Bop-Cl (273 mg, 1.07 mmol). The mixture was stirred at 25° C. for 16 hours then quenched with water (20 mL), extracted with DCM (3×20 mL). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was then purified by prep-HPLC to afford the product (18 mg, Yield 5.6%). 1H NMR (400 MHz, METHANOL-d4) δ=7.26-7.29 (m, 1H), 7.13-7.02 (m, 4H), 6.76-6.69 (m, 3H), 4.55 (s, 2H), 4.06-4.00 (m, 1H), 3.71 (s, 1H), 3.47-3.31 (m, 2H), 2.91-2.90 (m, 2H), 2.86-2.77 (m, 2H), 2.61 (d, J=6.0 Hz, 2H). LCMS (m/z): 359.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([CH:18]([OH:21])[CH:19]=[CH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.[NH4+].[Cl-].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]1([C:18](=[O:21])[CH2:19][CH2:20][C:2]2[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C=CC(O)C1CCCC1
Reactant: CC(C)(O)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: CC(C)(O)c1ccc(CCC(=O)C2CCCC2)cc1F
Temperature: 140 °C
Yield: 35.9 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)propan-2-ol (5.8 g, 25.0 mmol) in anhydrous NMP (63 mL) was added 1-Cyclopentyl-2-propen-1-ol (3.15 g, 25.0 mmol), NaHCO3 (4.2 g, 50 mmol) and PdCl2(PPh3)2 (350 mg, 2 mol %). The mixture was heated to 140° C. for 4 hours before it was cooled down to room temperature. The reaction was diluted with aqueous NH4Cl, extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried with Na2SO4 and evaporated to dryness. The mixture was purified by flash column chromatography (10-50% EtOAc in hexanes) to give the product (2.5 g, 36% yield). 1H NMR (300 MHz, CDCl3) δ: 1.56-1.82 (m, 8H), 1.62 (s, 6H), 2.74-2.78 (m, 2H), 2.82-2.89 (m, 2H), 6.84-6.88 (m, 1H), 6.93-6.95 (m, 1H), 7.40-7.44 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH:20]=1)[C:6]([NH:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([OH:16])[C:10]=1[F:17])=O)#[N:2]>C1COCC1>[F:17][C:10]1[C:11]([OH:16])=[CH:12][CH:13]=[C:14]([F:15])[C:9]=1[NH:8][CH2:6][C:5]1[CH:4]=[C:3]([CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH:18]=1)[C:1]#[N:2]
Reactant: N#Cc1cc(C(=O)Nc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Solvent: C1CCOC1
Product: N#Cc1cc(CNc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 50 °C
Yield: 29267.9 %

Procedure:
To a solution of 3-Cyano-N-(2,6-difluoro-3-hydroxy-phenyl)-5-(3-fluorophenyl)benzamide (500 mg, 2.7 mmol, 1.0 eq) in THF (30 mL) at 0° C. was added a solution of BH3 (1M in THF, 10.8 mL, 10.8 mmol, 4.0 eq) dropwise. The reaction was then heated at 50° C. for 6 h. The reaction was cooled to room temperature and quenched by addition of aqueous NH4Cl. The aqueous layer was extracted with EtOAc and the combined organic extracts dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 7:1) to give the title compound as white solid (280 g, 58%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:21][NH2:22].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[Cl:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:10][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([CH2:2][NH:22][CH3:21])[C:4]=2[F:20])[CH:18]=1)[C:14]#[N:15]
Reactant: CN
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
A solution of 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (1.04 g, 2.77 mmol) in CH2Cl2 (10 mL) was added dropwise to a 2M solution of MeNH2 (13.9 mL, 27.73 mmol) in THF. The solution turned light yellow and the flask was stoppered and stirred at RT overnight. Ethyl acetate (200 ml) and saturated NaHCO3 solution (150 ml) were added. The organic layer was separated, washed with brine (150 mL), dried over MgSO4, filtered and concentrated to give the title compound (0.81 g, 90%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.30-7.33 (m, 1H), 7.24-7.30 (m, 2H), 7.11-7.14 (m, 1H), 6.98 (dd, 1H), 3.81 (s, 2H), 2.45 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1([CH3:37])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]2[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][C:23]1=2.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:26]3[CH:25]=[CH:24][C:23]4[C:22]([CH3:37])([CH3:21])[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:28]=4[CH:27]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)n2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
150 mg (0.44 mmol) of 4-(6-bromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester, 112 mg (0.48 mmol) of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylboronic acid and 202 mg (0.88 mmol) of tripotassium phosphate monohydrate are suspended in 6 ml of ethylene glycol monomethyl ether, degassed a number of times, and 25 mg (0.04 mmol) of bis(triphenylphosphine)-palladium(II) dichloride are added under nitrogen atmosphere. The reaction mixture is stirred at 80° C. for 16 h, cooled to RT, and 20 ml of water are added. This mixture is extracted three times with ethyl acetate, dried over Na2SO4 and evaporated. The crude product is purified by means of flash chromatography on silica gel.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])([O-])=O.[K+].[K+].[ClH:31]>CCOCC.CCOC(C)=O.O>[ClH:31].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([N:9]3[CH2:14][CH2:13][N:12]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCBr
Reactant: Fc1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN1CCN(c2nsc3cc(F)ccc23)CC1
Yield: 6.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperazinyl)-1,2-benzisothiazole (6.0 g, 25 mmol), ethyl 3-bromopropionate (4.5 g, 25 mmol), K2CO3 (3.5 g) CH3CN (100 ml) was stirred and refluxed for 16 hours. The reaction was poured into H2O, and after extractive workup with EtOAc, 6.0 g of am orange oil was realized. The oil was dissolved in Et2O and ethereal HCl was added to precipitate 6.3 g of a white hydrochloride salt. The salt was recrystallized from CH3CN to yield 6.0 g (6.4%) of the desired compound. An analytical sample was obtained by recrystallization of a 1.0 g sample from EtOH-Et2O to yield 0.8 g of a white solid, m.p.=197-199° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=2[Cl:47])[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1>>[Cl:47][C:41]1[C:42]([Cl:46])=[CH:43][CH:44]=[CH:45][C:40]=1[C:27]1([CH2:26][NH:25][C:22](=[O:24])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(Cl)c2Cl)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5cccc(Cl)c5Cl)CCNCC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(2,3-dichlorophenyl)piperidine-1-carboxylate (amine intermediate “J”) were reacted to give the title compound. LC/MS (M+H)+: 703. Ret. time: 2.01 min. (Condition M).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH:17]C(OCC2C=CC=CC=2)=O)([CH2:14][CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH2:17])([CH2:14][CH2:15][OH:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCO)(NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(N)(CCO)C1
Reaction time: 5 h
Yield: 98 %

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (27.2 g) in methanol (544 ml) was added 10% palladium carbon (2.7 g), and the mixture was hydrogenated under ordinary pressure for 5 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the titled compound (17.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([NH:21][C:22]3[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=3)[N:13]=2)[CH2:9][OH:10])=[N:6][CH:7]=1.[CH2:31](O)C.C(O)(=O)C.C(N)=N.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:11][C:12]2[N:13]=[C:14]3[N:21]([C:22]4[CH:26]=[C:25]([O:27][CH:28]([CH3:30])[CH3:29])[NH:24][N:23]=4)[CH:31]=[N:18][C:15]3=[CH:16][CH:17]=2)[CH2:9][OH:10])=[N:6][CH:7]=1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: N=CN
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(-n2cnc3ccc(N[C@@H](CO)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
(2R)-2-(5-fluoropyridin-2-yl)-2-({6-[(5-isopropoxy-1H-pyrazol-3-yl)amino]-5-nitropyridin-2-yl}amino)ethanol (Intermediate 24, 0.45 g) was dissolved into ethanol (20 mL) with Pd—C (90 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by a silica gel column (Ethyl acetate/MeOH) to afford 0.075 g of the title compound. MS (electrospray): 398 (M+1) for C19H20FN7O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.50 (d, 1H) 8.30 (s, 1H) 7.80 (d, 1H) 7.50 (dd, 1H) 6.70 (d, 1H) 6.05 (s, 1H) 5.20 (m, 1H) 4.65 (m, 1H) 4.00 (m, 2H), 1.55-1.35 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([O:16][CH3:17])[CH2:14][N:13]([C:18]4[N:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=4)[CH2:12]3)=[C:8]([C:26]([NH2:28])=[O:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH:30]1([NH:33][C:34]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)=[O:35])[CH2:32][CH2:31]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[C:24]([C:21]1[CH:20]=[N:19][C:18]([N:13]2[CH2:14][C@H:15]([O:16][CH3:17])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:29]=[C:2]([C:39]5[CH:38]=[CH:37][C:36]([C:34](=[O:35])[NH:33][CH:30]6[CH2:32][CH2:31]6)=[CH:41][CH:40]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:26]([NH2:28])=[O:27])[CH2:12]2)=[N:23][CH:22]=1)#[N:25]
Reactant: O=C(NC1CC1)c1ccc(B(O)O)cc1
Reactant: CO[C@H]1CN(c2ncc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CO[C@H]1CN(c2ncc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(C(=O)NC4CC4)cc3)cc12
Temperature: 140 °C
Reaction time: 0.42 h
Yield: 35.5 %

Procedure:
A solution of 6-bromo-4-(((3R,4S)-1-(5-cyanopyrimidin-2-yl)-4-methoxypyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.022 mmol) in 1,4-dioxane (0.5 mL), was added [1,1′-[bis(diphenylphosphino)ferrocene]-dicholorpalladium (II) (1.601 mg, 2.187 μmol), [4-(cyclopropylcarbamoyl)phenyl]-boronic acid (6.73 mg, 0.033 mmol) and potassium phosphate (2M, 0.033 mL, 0.066 mmol). The reaction vial was purged with nitrogen, sealed and heated at 140° C. for 1 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.2 mg, 35% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.57 (br. s., 1H), 8.51 (d, J=3.0 Hz, 1H), 8.13 (d, J=3.5 Hz, 1H), 7.95 (br. s., 1H), 7.87-7.75 (m, 2H), 7.73-7.66 (m, 2H), 7.62-7.55 (m, 2H), 7.18 (br. s., 1H), 5.09 (br. s., 1H), 4.33-4.22 (m, 2H), 4.02-3.94 (m, 1H), 3.93-3.84 (m, 1H), 3.77-3.69 (m, 1H), 3.52 (d, J=3.5 Hz, 3H), 2.89-2.80 (m, 1H), 0.80 (m, 4H). MS (ES+) m/z: 538.22 (M+H); LC retention time: 1.31 min (analytical HPLC Method I).
Reaction SMILES: [CH2:1]([NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:22]([CH:24]([CH3:29])[C:25](OC)=O)=[O:23]>>[CH2:1]([NH:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[CH:24]([CH3:29])[CH:25]=[N:21][CH2:20][CH2:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCNCCNCCN
Reactant: COC(=O)C(C)C=O
Product: CCCCCCCCCCCCCCNCCN1CCN=CC(C)C1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 299.5 g (1 mole) of N-tetradecyldiethylenetriamine and 116.1 g (1 mole) of methyl 2-formylpropionate. At 130° to 135° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-tetradecylaminoethyl-6-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[C:21](=[O:22])[N:9]2[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][C@@H:8]2[CH2:7]1.[ClH:26]>O1CCOCC1>[ClH:26].[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][CH:6]1[C:21](=[O:22])[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C@@H:8]2[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)C(Cc3cccc(F)c3)C[C@H]2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1C(Cc2cccc(F)c2)C[C@H]2CNCCN12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 213A (72 mg, 0.207 mmol) in 1,4-dioxane (1 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (1 mL, 4.0 mmol). The resulting mixture was stirred at room temperature for 90 minutes and concentrated and dried in vacuo to give the title compound (59 mg, quantitative).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[S:10][N:9]=[C:8]([CH3:11])[C:7]=1[CH2:12]O>C(Cl)(Cl)Cl>[Cl:3][CH2:12][C:7]1[C:8]([CH3:11])=[N:9][S:10][C:6]=1[Cl:5]
Reactant: Cc1nsc(Cl)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1nsc(Cl)c1CCl
Reaction time: 3 h
Yield: 100.2 %

Procedure:
3.26 g (27.44 mmoles) of thionyl chloride was added, at room temperature, to a solution of 1.50 g (9.15 mmoles) of (5-chloro-3-methyl-isothiazol-4-yl)-methanol dissolved in 10 ml of chloroform. The mixture was stirred for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was subjected to vacuum distillation to remove the solvent contained therein, to obtain 1.67 g (yield: quantitative) of 4-chloromethyl-5-chloro-3-methylisothiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9](=[N:22][NH2:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:10]1([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:22][NH:23][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1ccncc1Br
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccncc1NN=C(c1ccccc1)c1ccccc1
Yield: 59.9 %

Procedure:
3-Bromo-4-methyl-pyridine (1.0 g, 5.81 mmol) in 5 mL dry toluene was treated with benzophenone hydrazone (1.25 g, 6.39 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (335 mg, 0.58 mmol), and sodium tert-butoxide (840 mg, 8.72 mmol). The mixture was degassed with argon for 15 minutes. Added Pd(II)(OAc)2 (130 mg, 0.58 mmol) and stirred at 90° C. for 14 hours. Extracted using EtOAc/H2O (3×200 mL EtOAc, 1×100 mL H2O, 1×100 mL brine). Dried using Na2SO4 and then purified by flash chromatography (silica, 10-50% EtOAc/Hexane) to afford 3-(2-(diphenylmethylene)hydrazinyl)-4-methylpyridine (1.00 g, 3.48 mmol, 60%). 1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 7.97 (d, 1H), 7.67-7.52 (m, 6H), 7.45-7.36 (m, 5H), 7.06 (d, 1H), 1.91 (s, 3H); LC-MS (ESI) m/z 488 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[F:21][C:22]([F:34])([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:23]([NH2:25])=O.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[F:34][C:22]([F:21])([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:23]1[N:14]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[C:2]([F:1])[CH:3]=2)[C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[N:25]=1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Reactant: NC(=O)C(F)(F)Oc1cccc(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(C(F)(F)Oc2cccc(F)c2)n1
Temperature: 165 °C
Reaction time: 24 h
Yield: 39.5 %

Procedure:
A mixture of N-(3-fluoro-4-morpholinophenyl)-3-oxobutanamide (0.60 g, 2.14 mmol), 2,2-difluoro-2-(3-fluorophenoxy)acetamide (0.88 g, 4.29 mmol) and titanium tetraisopropanolate (4.87 g, 17.1 mmol) in xylene (20 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 60 mL of toluene and 80 mL of saturated NH4Cl aqueous solution were added. The resulting mixture was stirred at rt overnight and filtered and the filtrate was extracted with DCM (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.38 g, 40%). The compound was characterized by the following spectroscopic data: