Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9](F)[C:8]=2[F:16])[CH2:6][CH2:5]1.O>CO>[CH:4]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[C:9]([O:2][CH3:1])[C:8]=2[F:16])[CH2:6][CH2:5]1
Reactant: O=Cc1ccc(C2CC2)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1c(C=O)ccc(C2CC2)c1F
Reaction time: 15 h
Yield: 91.6 %

Procedure:
Sodium methoxide (28% methanol solution, 3.43 g) was added at room temperature to a methanol (100 mL) solution of 4-cyclopropyl-2,3-difluorobenzaldehyde (2.16 g), and the mixture was stirred at 70 C for 15 hours in a nitrogen atmosphere. Water was added to the reaction mixture, and methanol was distilled off under reduced pressure. The residue was subjected to extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.11 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:5]([O:7][CH3:8])=[O:6].CO.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[F:1]
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(F)c1

Procedure:
Into a 2000-mL round-bottom flask maintained with a nitrogen atmosphere, was placed a solution of methyl 3-fluoro-4-nitrobenzoate (98 g, 492.46 mmol, 1.00 equiv) in ethyl acetate:methanol=1:1 (1000 mL). Then Pd/C (10 g, 10 wt %, Degussa type) was added. The flask was fitted with a balloon of hydrogen, and the heterogeneous reaction mixture was stirred fo(16 h under a hydrogen atmosphere at 30°C. The catalyst solids were filtered off and the filtrate was concentrated under vacuum to give the deisred product methyl 4-amino-3-fluorobenzoate.
Reaction SMILES: C(OCCC#C[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:11][CH:10]=1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][C:12]1[CH:11]=[CH:10][CH:9]=[CH:14][C:13]=1/[CH:9]=[CH:10]/[CH2:11][CH2:12][OH:15]
Reactant: CC(=O)OCCC#Cc1ccc(OC2CCCCO2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC/C=C/c1ccccc1OC1CCCCO1
Yield: 193.5 %

Procedure:
To an anhydrous tetrahydrofuran solution containing 2.4 g of 4-[4-(2-tetrahydropyranyloxy)phenyl]-3-butynyl acetate was added 1 g of lithium aluminium hydride and the mixture was refluxed for 12 hours. After the reaction was completed, an aqueous solution saturated with sodium sulfate was slowly added to the reaction mixture, and the precipitation formed were removed by filtration, then the filtrate was dried with anhydrous sodium sulfate, and concentrated to dryness. The residue thus obtained was purified by means of a silica gel column chromatography to yield 2 g of 4-[(2-tetrahydropyranyloxy)phenyl]-3(E)-butenyl alcohol as in the form of colorless oily substance.
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[O:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C(C1C(C2C=C(N)C=CC=2)=C2C=CC=CN2N=1)(C)C>>[CH:11]([C:3]1[C:2]([C:23]2[CH:22]=[CH:21][C:20]([N:17]3[CH2:16][CH2:15][O:14][CH2:19][CH2:18]3)=[CH:25][CH:24]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)c1nn2ccccc2c1I
Agent: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Product: CC(C)c1nn2ccccc2c1-c1ccc(N2CCOCC2)cc1

Procedure:
2-Isopropyl-3-(4-morpholin-4-yl-phenyl)-pyrazolo[1,5-a]pyridine was prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and 4-morpholinophenylboronic acid following the method used in Step 3 of the synthesis of 3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example 59) (157 mg, 16%). 1H-NMR (250 MHz, DMSO-d6) δ 8.61 (d, J=6.3 Hz, 1H), 7.45 (d, J=9.0 Hz, 1H), 7.30 (d, J=7.0 Hz, 2H), 7.15-7.06 (m, 3H), 6.81 (t, J=6.5 Hz, 1H), 3.79-3.75 (m, 4H), 3.25 (sept, J=6.3 Hz, 1H), 3.22-3.15 (m, 4H), 1.27 (d, J=6.8 Hz, 6H); LC/MS 322.3 m/z (M+H+). Compound 1102.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]([OH:19])=O.C(N(CC)CC)C.C(C(Cl)=O)C.[CH:32]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.C(OCC)(=O)C.CCCCCC.O>[CH:32]([N:45]1[CH2:50][CH2:49][N:48]([C:17](=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][C:4]2[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])[CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(C=CC=CC(=O)O)c(OC)c1OC
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COc1ccc(C=CC=CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Temperature: 0 °C
Yield: 72.8 %

Procedure:
To 7.3 g (27.6 mmol) of 5-(2,3,4-trimethoxyphenyl)-2,4-pentadienoic acid were added 300 ml of dry dichloromethane and 3.85 ml (27.6 mmol) of triethylamine, and the mixture was stirred at 0° C. To the resulting mixture was added 2,64 ml (27,6 mmol) of ethylcarbonyl chloride followed by stirring for 1 hour. To the mixture was added 8.36 g (33 mmol) of benzhydrylpiperazine in 50 ml of dry dichloromethane. Temperature of the mixture was raised to room temperature followed by stirring for additional 16 hours. After addition of water, the mixture was extracted with dichloromethane. The organic layer was washed successively with aqueous 1N-hydrochloric acid solution, a saturated aqueous sodium chloride solution and a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. There was obtained a residue, which was subjected to column chromatography on silica gel to give 10.0 g (20.1 mmol) of 1-benzhydryl-4-(5-(2,3,4-trimethoxyphenyl)-2,4-pentadienoyl)piperazine from eluates of ethyl acetate-hexane (1:1).
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[C:26](#[N:28])[CH3:27]>C(N(CC)CC)C.C(C1C=C(C=CC=1)N)#C.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.[Cu]I>[NH2:28][C:26]1[CH:24]=[C:12]([C:13]#[C:14][C:3]2[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]4[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=4)=[C:12]([CH3:24])[CH:11]=3)[C:4]=2[NH2:25])[CH:11]=[CH:10][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Reactant: CC#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#Cc1cccc(N)c1
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#Cc4cccc(N)c4)c3N)cc2C)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (200 mg) was dissolved in a mixed solvent of acetonitrile (7.6 mL)/triethylamine (5.72 mL), 3-ethynylaniline (0.0574 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (15.4 mg) and copper(I) iodide (5.3 mg) were sequentially added, and the mixture was stirred under a nitrogen stream at room temperature for 1.5 hrs. The reaction mixture was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→ethyl acetate:methanol=80:20) to give the title compound (157 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]CC)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:35]([Zn+])[CH:36]([CH3:38])[CH3:37]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH2:35][CH:36]([CH3:38])[CH3:37])[N:7]=3)=[CH:33][CH:32]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
Reactant: CC(C)C[Zn+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)Cc1cccc(NC(=O)c2ccc(Oc3cc4c(cc3Cl)C(C(=O)O)CCO4)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (Example 52, Step A, 0.021 g, 0.039 mmol) in THF (0.5 ml) was added 0.5 isobutylzinc bromide in THF (0.12 ml, 0.059 mmol) followed by bis(tri-t-butylphosphine)palladium (0) (0.0010 g, 0.0020 mmol) and the reaction was stirred at ambient temperature for 1 hour. The reaction was loaded onto silica gel and the product eluted using 3:1 hexanes/ethyl acetate. The resulting oil was dissolved in THF/MeOH/1N NaOH (0.5 ml/0.5 ml/0.25 ml) and stirred at ambient temperature for 3 hours. The reaction was diluted with DCM (35 ml) and washed with water with made acidic (pH=5) with 1N HCl. The organic layer was washed with brine (10 ml), dried over magnesium sulfate and concentrated to give the title compound (0.013 g, 0.027 mmol, 68% yield) as a white solid. MS (ESI) m/z=481.31 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.Cl[CH2:29][CH:30]1[CH2:34][O:33][C:32]([CH3:36])([CH3:35])[O:31]1.C(=O)([O-])[O-].[K+].[K+].[Br-].[Na+]>CN(C=O)C>[CH3:35][C:32]1([CH3:36])[O:31][CH:30]([CH2:29][O:27][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=2[C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:15]3[N:14]=2)[CH2:34][O:33]1
Reactant: CC1(C)OCC(CCl)O1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3O)nc12
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3OCC3COC(C)(C)O3)nc12
Temperature: 100 °C
Yield: 24.6 %

Procedure:
A mixture of (R)-ethyl 5-(2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (Example 86, Step C, 140 mg, 0.378 mmol), 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (114 mg, 0.756 mmol), potassium carbonate (261 mg, 1.89 mmol) and sodium bromide (77.8 mg, 0.756 mmol) in dry DMF (5 mL) was heated at 100° C. for 14 days. The mixture was concentrated and the residue purified by chromatography to afford the title compound (45 mg, 25% yield). MS (apci) m/z=485.0 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:14]\[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]2[N:34]=[CH:35][NH:36][CH:37]=2)=[O:30])=[CH:26][CH:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]2[N:34]=[CH:35][N:36]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/4=[N:14]\[C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[CH:4][CH:3]=3)[CH:37]=2)=[O:30])=[CH:26][CH:25]=1
Reactant: COc1ccc(/N=c2\ccccn2-c2ccc(I)cc2)cc1
Reactant: O=C(NCc1c[nH]cn1)c1ccc(Cl)s1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COc1ccc(/N=c2\ccccn2-c2ccc(-n3cnc(CNC(=O)c4ccc(Cl)s4)c3)cc2)cc1
Temperature: 130 °C
Yield: 28.5 %

Procedure:
A mixture of (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)-4-methoxybenzenamine (90 mg, 0.17 mmol), 5-Chloro-N-((1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 3-1 (62 mg, 0.17 mmol), 8-hydroxyquinoline (14 mg, 0.096 mmol) and K2CO3 (100 mg, 0.72 mmol) in DMSO (2 mL) was degassed with Ar before being charged with CuI (20 mg, 0.10 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the titled compound (25 mg). MS 516.0 and 518.1 (M+H, Cl pattern).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH:17][C:18]([C:20]2[C:21]([NH2:27])=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=2)=O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CCN2C(=NCCC2)CC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)Cl>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[O:15][C:18]([C:20]3[C:21]([NH2:27])=[N:22][CH:23]=[C:24]([Br:26])[CH:25]=3)=[N:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)c2cc(Br)cnc2N)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[N′-(2-amino-5-bromo-pyridine-3-carbonyl)-hydrazinocarbonyl]-piperidine-1-carboxylic acid tert-butyl ester (1.3 g, 2.939 mmol) in ACN (50 mL) were added DBU (1.68 g, 11.035 mmol), PPh3 (1.95 g, 7.434 mmol) and CCl4 (4 mL, 41.558 mmol) at RT. The reaction mixture was stirred for 18 h at RT. The reaction mixture was poured into ice-water (30 mL), extracted with ethyl acetate (3×50 mL), organic layer was washed with brine dried over anhydrous sodium sulphate concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel. The column was eluted with 40% EtOAc in petroleum ether to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([O:19]C)=O)=[CH:4][CH:3]=1.[OH-].[Na+].[NH:23]1[C:31]2[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=2)[CH:25]=[N:24]1.N=C=N>CO.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([NH:32][C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[NH:23][N:24]=[CH:25]3)=[O:19])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(F)cc1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: N=C=N
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(F)cc2)CC(=O)N1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 0.4 %

Procedure:
The product of Step 1 (1.58 g, 5.70 mmol, 1 equiv) was dissolved in methanol (24 mL) and 2.5 N NaOH (8 mL) was added. The reaction was heated to 60° C. for 3 h. Upon cooling, the resulting mixture was partitioned between EtOAc and water. The aqueous layer was acidified to pH 1 and extracted with EtOAc. The phases were separated and the organic phase was concentrated in vacuo. The resulting residue (1.50 g, 5.70 mmol, 1.1 equiv) was dissolved in DMF (30 mL). 1H-indazol-5-amine (700 mg, 5.18 mmol, 1.0 equiv) and PS-carbodiimide resin (8.27 g, 7.77 mmol, 1.5 equiv) were added and the mixture stirred overnight at room temperature. The resin was removed by filtration and washed alternately with methanol and CH2Cl2, followed by diethyl ether. The filtrate was concentrated en vacuo to remove the volatile solvents. The residue was dissolved in EtOAc, washed twice with water and once with satd. NaHCO3. The organic phase was concentrated in vacuo and the residue was purified by reverse phase HPLC (Xterra Prep 19×50, 25 mL/min, 10-90% 5 mM aq. NH4HCO3/CH3CN over 9 minutes) to provide 8 mg (0.4%) of a white crystalline solid. MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([C:23]2[CH:24]=[N:19][CH:20]=[N:21][CH:22]=2)[CH:7]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Cl)cc(-c2cncnc2)n1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 30.2 %

Procedure:
210 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 91 mg of pyrimidine-5-boronic acid, 304 mg of potassium carbonate and 60 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex were added in turn to a degassed mixed solution of 3 ml of 1,4-dioxane and 1 ml of water, and the mixture was stirred at 90° C. for 6 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 73 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4,5′-bipyrimidine-2-amine as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H][H].CC(C)=O>C(O)C.[C].[Pd]>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[CH:10]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)=O
Product: Nc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In ethanol (250 mL) was dissolved 100 g (F.W. 201.57, 496 mmol) of 2-chloro-4-nitrobenzoic acid (1) and after replacing with argon, a 10% palladium carbon catalyst (4.0+1.5 g) was added thereto. After replacing with hydrogen, the mixture was stirred at room temperature for 72 hours. The formed crystal was dissolved with acetone and filtered to remove the catalyst. The solvent was distilled under reduced pressure to quantitatively obtain 88 g of the target 4-amino-2-chlorobenzoic acid (2).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1)(=O)[CH3:2].[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([CH:1]([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=2)[CH3:2])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(=O)c1ccnc(NC(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)N1CCN(C(C)c2ccnc(NC(=O)OC(C)(C)C)c2)CC1
Temperature: 50 °C

Procedure:
To a suspension of tert-butyl 4-acetylpyridin-2-ylcarbamate (16-3, 187 mg, 0.79 mmole) in MeOH (3 mL) was added 1-acetylpiperazine (304 mg, 2.37 mmole), glacial HOAc (0.14 mL, 2.37 mmole), and NaBH3CN (149 mg, 2.37 mmole) then the mixture was heated to 50° C. After 6 hr additional NaBH3CN (149 mg, 2.37 mmole) was added and heating continued. After 18 hr the mixture was cooled to RT, diluted with saturated NaHCO3, and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-10% EtOH/EtOAc) gave the titled compound as an oil: 1H-NMR (500 MHz, CDCl3) δ 8.17 (d, 1 H, J=5.13 Hz), 7.87 (s, 1H), 7.52 (bs, 1 H), 6.97 (d, 1 H, J=5.13 Hz), 3.64-3.57 (m, 2 H), 3.45-3.39 (m, 3 H), 2.49-2.35 (m, 4 H), 2.06 (s, 3 H), 1.54 (s, 9 H), 1.35 (d, 3 H, J=6.59 Hz).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl:29][C:30]1[CH:31]=[N:32][CH:33]=[N:34][CH:35]=1>C1COCC1.C(OCC)(=O)C.O>[C:13]([O:17][C:18]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23]([C:31]1[C:30]([Cl:29])=[CH:35][N:34]=[CH:33][N:32]=1)([OH:28])[CH2:24]2)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: Clc1cncnc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncncc1Cl)C2
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
n-Butyl lithium (2.5 M, 1.2 mL, 3.00 mmol) was added dropwise to a solution of diisopropylamine (0.406 mL, 3.0 mmol) in THF (5 mL) at 0° C. under nitrogen and stirred for 30 minutes. The mixture was then added to a solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.675 g, 3.0 mmol) and 5-chloropyrimidine (0.343 g, 3.0 mmol) in THF (1.5 mL) and stirred at 0° C. for 1 hour. Water and ethyl acetate were added, the organics separated, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 20-30% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.14 g). LCMS m/z 340.3 [M+H]+. R.T.=3.70 min (Analytical Method 3).
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([O:17][C@@H:18]1[C@@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:22]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:21]([CH2:40][O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:20][C@H:19]1[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=[CH2:56])[CH:50]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:66]1[CH:75]=[C:74]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=[CH:73]2)[C:67]=1[C:76]([O:78][CH3:79])=[O:77]>Cl[Pd]Cl.C1(P[C-]2C=CC=C2)C=CC=CC=1.[C-]1(PC2C=CC=CC=2)C=CC=C1.[Fe+2].O.CN(C=O)C.C1COCC1>[CH2:10]([O:17][C@@H:18]1[C@@H:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:22]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:21]([CH2:40][O:41][CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[O:20][C@H:19]1[C:49]1[CH:50]=[C:51]([CH2:55][CH2:56][C:66]2[CH:75]=[C:74]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=[CH:73]3)[C:67]=2[C:76]([O:78][CH3:79])=[O:77])[CH:52]=[CH:53][CH:54]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1c(Cl)cc2cccccc1-2
Reactant: C=Cc1cccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(CCc2cccc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c2)cc2cccccc1-2
Temperature: 50 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A THF solution (8.0 ml) of 9-borabicyclo[3.3.1]nonane was added to (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-(3-vinylphenyl)-D-glucitol (1.0 g) and the mixture was refluxed with heating for four hours. Next, a 3 M aqueous solution of potassium phosphate (1.3 ml) and DMF (12 ml) were added to the reaction mixture. Methyl 2-chloroazulene-1-carboxylate (0.35 g) and 1,1′-diphenylphosphinoferrocene dichloropalladium (II) (0.12 g) were further added to the mixture, followed by stirring at 50° C. for two hours. After cooling to room temperature, the reaction mixture was poured into ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated brine in that order and dried over anhydrous sodium sulfate. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain methyl 2-[2(3-[(2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl]phenyl)ethyl]azulene-1-carboxylate (0.88 g).