Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[F:16][C:17]([F:27])([F:26])[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[OH:19].[H-].[Na+].[Cl-].[NH4+]>C1COCC1>[Cl:12][C:11]1[C:2]([O:19][CH:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:17]([F:16])([F:26])[F:27])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2
Reactant: OC(c1cccnc1)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2nc(OC(c3cccnc3)C(F)(F)F)c(Cl)nc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
In THF (200 mL) was dissolved 2,3-dichloro-6-nitroquinoxaline (4.00 g, 16.4 mmol) and the mixture was cooled to −78° C. To the solution were added 2,2,2-trifluoro-1-(pyridin-3-yl)ethanol (3.05 g, 17.2 mmol) obtained in Step 1 and sodium hydride (1.31 g, 32.8 mmol) and the mixture was stirred at −78° C. allowing the temperature to rise slowly to −30° C. over 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/0 to 3/2) to give 3-chloro-6-nitro-2-(2,2,2-trifluoro-1-(pyridin-3-yl)ethoxy) quinoxaline (3.98 g, 63% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([C:22]([OH:24])=[O:23])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([C:22]([O:24][CH3:25])=[O:23])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(C(=O)O)c2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c2c(nc3ccccc13)CCN(C(=O)OC(C)(C)C)C2
Yield: 93.4 %

Procedure:
2-t-Butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine-10-carboxylic acid (500 mg, 1.523 mmol) was dissolved in N,N-dimethylformamide (3 ml), followed by adding thereto potassium carbonate (315.1 mg, 2.28 mmol) and methyl iodide (0.13 ml, 2.06 mmol), and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the desired compound (487 mg, 93.4%) as a brown oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[C:20]=1[CH3:26].Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[OH:25][C:21]1[C:20]([CH3:26])=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(N)cccc1O
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3cccc(O)c3C)c2cc1OC
Yield: 51.9 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.123 g of 3-amino-o-cresol, 20 mg of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.174 g of 4-(3-hydroxy-2-methyl-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 255-257° C.; mass spectrum (electrospray, m/e): M+H 335.9.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[C:20]([Cl:35])[CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:35][C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[NH:17]2)=[CH:22][C:21]=1[O:25][CH:26]1[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)[nH]c3cc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCNCC4)[nH]c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.2 %

Procedure:
To a cold (0° C.) solution of 4-[6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester (example 3, 547 mg, 1.0 eq.) in dichloromethane was added trifluoroacetic acid (1.23 mL, 10 eq.) dropwise. The reaction mixture was stirred 3 h at room temperature. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and a saturated aqueous sodium carbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and the solvents removed in vacuo. The residue was purified by flash chromatography on silica gel with a 90:9:1 dichloromethane/methanol/ammonia eluant to afford 413 mg (94%) of the title compound as a light-yellow solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:34][C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:24][CH2:25][CH:20]([C@@:18]3([CH3:26])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:33][CH:32]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3ncc(Cl)cn3)CC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 32; the configuration of the stereocenter is arbitrarily assigned) and 2,5-dichloro-pyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 6): tR=1.78 min; Mass spectrum (ESI+): m/z=485 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[C@H:15]([CH3:16])[C@@:14]3([O:25][CH3:26])[CH:17]=[C:18]([CH2:22][CH2:23][CH3:24])[C:19](=O)[CH:20]=[C:13]3[O:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[O:28]([NH2:30])[CH3:29]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[C@H:15]([CH3:16])[C@@:14]3([O:25][CH3:26])[CH:17]=[C:18]([CH2:22][CH2:23][CH3:24])[C:19](=[N:30][O:28][CH3:29])[CH:20]=[C:13]3[O:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCCC1=C[C@@]2(OC)C(=CC1=O)O[C@H](c1ccc(OC)c(OC)c1)[C@@H]2C
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CCCC1=C[C@@]2(OC)C(=CC1=NOC)O[C@H](c1ccc(OC)c(OC)c1)[C@@H]2C

Procedure:
(2S,3S,3aS)-2-(3,4-Dimethoxyphenyl)-3a-methoxy-3-methyl-5-n-propyl-2,3,3a,6-tetrahydro-6-methoxyiminobenzofuran was prepared from (2S,3S,3aS)-2-(3,4-dimethoxyphenyl)-3a-methoxy-3-methyl-5-n-propyl-2,3,3a,6-tetrahydro-6-oxobenzofuran and methoxylamine hydrochloride in pyridine at room temperature for 3 days. The product was purified by flash column chromatography on silica gel (hexane-ethyl acetate, 9:1, v/v) followed by HPLC to afford (2S,3S,3aS)-2-(3,4-dimethoxyphenyl)-3a-methoxy-3-methyl-5-n-propyl-2,3,3a,6-tetrahydro-6-methoxyiminobenzofuran, n.m.r. (CDCl3): δ0.98 (t, J 7.5 Hz, CH2CH2CH3), 1.11 (d, CH3 --3), 1.64 (m, CH2CH2CH3), 2.52 (m, CH2CH2CH3), 3.0 (s, OCH3), 3.84 (s, Ar--OCH3), 4.04 (s, NOCH3), 5.07 (s, H-2), 5.72 (s, H-7) 6.48 (s, H-4), 6.87-7.12 (m, Ar--H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([N+:12]([O-])=O)=[N:4][CH:3]=1.[H][H]>C(O)(=O)C.C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-]>[NH2:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([F:1])=[CH:3][N:4]=1
Reactant: COC(=O)c1nc(F)cnc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: COC(=O)c1nc(F)cnc1N
Yield: 11.8 %

Procedure:
In 1.0 mL of acetic acid was dissolved 20 mg of methyl 6-fluoro-3-nitro-2-pyrazinecarboxylate. After adding 6 mg of lead-poisoned palladium-calcium carbonate, hydrogen gas was introduced into the mixture at room temperature under a pressure of 1 atmosphere, until the mixture became absorbing no further quantity of hydrogen gas. The insoluble matter was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=5:1] to obtain 2 mg of methyl 3-amino-6-fluoro-2-pyrazinecarboxylate as a light yellow-colored solid product.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[CH:1]1([C:4]2[C:5]([O:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][C:22]([F:27])([F:26])[CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCCC(F)(F)C2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(C2CC2)c(OCC2CCCC(F)(F)C2)cc1F
Reaction time: 3 h

Procedure:
A solution of tert-butyl 5-cyclopropyl-4-((3,3-difluorocyclohexyl)methoxy)-2-fluorobenzoate (191 mg) in dichloromethane (1.0 mL) and trifluoroacetic acid (0.5 mL) was stirred at 0° C. for 30 min then at rt for 3 h. The contents were concentrated. The residue was suspended in toluene and concentrated. The beige solid was dried under vacuum (162 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[C:5](N(OC)C)=[O:6].[CH3:15][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:15])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: CON(C)C(=O)c1ccc(F)c(Br)c1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(F)c(Br)c1
Reaction time: 1 h

Procedure:
A solution of 3-bromo-4-fluoro-N-methoxy-N-methylbenzamide (50 g, 0.19 mol) in 500 mL of THF was cooled to 0° C. in ice bath, and then the mixture was added MeMgCl (27.3 g, 0.21 mol) dropwise. The reaction mixture was stirred under N2 for 1 h. The reaction mixture was quenched with sat. NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography to give 1-(3-bromo-4-fluorophenyl)ethanone.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[S:6][CH:7]=1.[I-:18].[Na+].O>CC(C)=O>[I:18][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[S:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)cs2)c1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(-c2nc(CI)cs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
To a solution (10 mL) of the compound (1.0 g, 3.6 mmol) obtained in Example 21a in acetone was added sodium iodide (1.6 g, 11 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=70/30) to give the title compound (370 mg, 28%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][NH:20][C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22]>>[CH3:19][NH:20][C:21]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:25][CH2:24]1)=[O:22]
Reactant: CNC(=O)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CNC(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Reaction between 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 and piperidine-4-carboxylic acid methylamide, using General Procedure B-3 yielded 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidine-4-carboxylic acid methylamide.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]1([N:7]([CH2:19][C:20]2[CH:21]=[C:22]([O:30][CH3:31])[C:23]([O:28][CH3:29])=[C:24]([O:26][CH3:27])[CH:25]=2)[C:8](=[O:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C#Cc1ccccc1)Nc1ccccc1
Reactant: COc1cc(CBr)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.7 %

Procedure:
3-Phenyl-propynoic acid phenylamide (951.4 mg, 4.3 mmol), 5-bromomethyl-1,2,3-trimethoxy-benzene (1.35 g, 5.16 mmol), and Cs2CO3 (2.1 g, 6.45 mmol) were dissolved in DMF (20 ml). The mixture was stirred at room temperature for 16 h. The mixture was poured into water and extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification was by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenyl-(3,4,5-trimethoxy-benzyl)-amide 1.03 g (65%).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:16])[C:7]([CH3:9])([CH3:8])[O:6][B:5]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[O:4]1.CCN(CC)CC.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[CH3:9][C:7]1([CH3:8])[C:3]([CH3:16])([CH3:2])[O:4][B:5]([C:10]2[CH2:11][CH2:12][N:13]([C:24](=[O:26])[CH3:25])[CH2:14][CH:15]=2)[O:6]1
Reactant: CC(=O)Cl
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (2.9 g, 11.8 mmol) in DCM (30 mL) were added Et3N (3.6 g, 35.4 mmol) and acetyl chloride (AcCl) (932 mg, 11.8 mmol). The reaction mixture was stirred at room temperature for 1 hour, then diluted with DCM (20 mL), washed with H2O (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, and filtered, evaporated to give the crude product (3.2 g, crude). ESI-MS (M+1): 252 calc. for C13H22BNO3 251.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14](OC)=[O:15])[N+:10]([O-:18])=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1>CN(C)C=O>[N:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[N:10]3[O:18][C:14](=[O:15])[N:13]=[C:11]3[N:12]=2)[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OC)[n+]1[O-]
Solvent: CN(C)C=O
Product: COC(=O)Nc1cc(N2CC=CCC2)nc2nc(=O)on12

Procedure:
50 G. of dimethyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide are heated to 140° C. under an argon atmosphere in 300 ml. of dimethylformamide while stirring for 30 minutes. The dimethylformamide is evaporated under reduced pressure and the residue is recrystallized from methanol/methylene chloride. There is obtained methyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]-oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 213°-215° C. (decomposition).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:19][CH2:18][CH:17]([CH3:20])[NH:16]1.[Cl-].[NH4+]>>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:16]2[CH:17]([CH3:20])[CH2:18][CH2:19][CH:15]2[CH3:14])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: CC1CCC(C)N1
Agent: [Cl-]
Agent: [NH4+]
Product: CC#CCOc1ncnc(N2C(C)CCC2C)c1F
Reaction time: 18 h
Yield: 95.2 %

Procedure:
0.2 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine and 0.30 g of 2,5-dimethylpyrrolidine were mixed and left for 18 hours at room temperature. Into the reaction mixture was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.25 g of 4-(2-butynyloxy)-5-fluoro-6-(2,5-dimethyl-1-pyrrolidinyl)pyrimidine (hereinafter, referred to as Compound (6)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]3[CH2:21][CH3:22])=[C:8]([C:23]([NH2:25])=[O:24])[CH:7]=[N:6][N:5]2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH2:40][CH2:41][C:42]#[N:43])[CH:39]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[C:42]([CH2:41][CH2:40][N:38]1[CH:39]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9]([NH:10][C@@H:11]4[CH2:16][CH2:15][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]4[CH2:21][CH3:22])=[C:8]([C:23]([NH2:25])=[O:24])[CH:7]=[N:6][N:5]3[CH:26]=2)[CH:36]=[N:37]1)#[N:43]
Reactant: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Reactant: CC[C@@H]1CN(S(C)(=O)=O)CC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H]1CN(S(C)(=O)=O)CC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CCC#N)c3)cc12
Temperature: 100 °C
Yield: 55.9 %

Procedure:
To a vial charged with 6-bromo-4-(((3R,4R)-3-ethyl-1-(methylsulfonyl)piperidin-4-yl)amino) pyrrolo[1,2-b]pyridazine-3-carboxamide (15 mg, 0.034 mmol), 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (16.68 mg, 0.068 mmol) and PdCl2(dppf)-CH2Cl2 Adduct (3.61 mg, 4.42 μmol) were added 1,4-dioxane (225 μl) and a 2M solution of potassium phosphate (50.6 μl, 0.101 mmol). The suspension was purged with nitrogen for 5 minutes. The vial was sealed and heated at 100° C. for 2 hrs. The reaction mixture was diluted with methanol (10 ml), filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm). The collected fractions were combined and dried via centrifugal evaporation, yielding 6-(1-(2-cyanoethyl)-1H-pyrazol-4-yl)-4-(((3R,4R)-3-ethyl-1-(methylsulfonyl)piperidin-4-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (9.3 mg, 0.019 mmol, 56.9% yield) as a white solid. 1H NMR (500 MHz, 1:1 Chloroform-d/Methanol-d4) δ 8.12 (s, 1H), 7.93 (s, 1H), 7.82 (s, 1H), 7.75 (d, J=1.5 Hz, 1H), 6.91 (d, J=1.0 Hz, 1H), 4.48 (t, J=6.4 Hz, 2H), 4.11 (td, J=8.4, 4.0 Hz, 1H), 3.79-3.61 (m, 2H), 3.25-3.17 (m, 1H), 3.05 (t, J=6.4 Hz, 2H), 2.97-2.85 (m, 4H), 2.43-2.34 (m, 1H), 1.88-1.76 (m, 3H), 1.51-1.40 (m, 1H), 1.04-0.97 (m, 3H). LCMS (Method K) m/z 485.0 ([M+H]+). HPLC (Method F) Rt: 1.14 min.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](Cl)=[O:12])[CH3:9].CN(C1C=CC=CN=1)C.[Si]([O:30][C:31]1[CH:36]=[C:35]([O:37][Si](C(C)(C)C)(C)C)[CH:34]=[CH:33][C:32]=1[C@H:45]1[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47][CH2:46]1)(C(C)(C)C)(C)C>ClCCl>[C:11](=[O:12])([O:10][CH2:8][CH3:9])[O:51][C@H:48]1[CH2:47][CH2:46][C@H:45]([C:32]2[CH:33]=[CH:34][C:35]([OH:37])=[CH:36][C:31]=2[OH:30])[CH2:50][CH2:49]1
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Triethylamine (0.5 ml), ethylchloroformate (0.5 ml) and dimethylaminopyridine (cat.) were added to a stirred solution of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (250 mg) in anhydrous dichloromethane (5 ml). After 72 hr at room temperature, the reaction mixture was partitioned between-ethyl-acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in methanol (5 ml) and was stirred with fluoride resin (500 mg) for 16 h at room temperature. The resin was filtered through a pad of celite, which was washed well with methanol. The combined filtrates were concentrated in vacuo. The residue was purified using flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v), and then preparative HPLC to give the title compound (4 mg, 3%) as a cream solid. δH (CD3OD) 1.20-1.30 (3H, m), 1.40-1.60 (4H, m), 1.80-1.95 (2H, m), 2.00-2.20 (2H, m), 2.70-2.84 (1H, m), 4.06-4.20 (2H, m), 4.50-4.60 (1H, m), 6.20-6.30 (2H, m), 6.86 (1H, d); m/z (ES−) 279 (M−H−).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[N+](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[CH3:13]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCC1CC1
Agent: [Rh]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)COCC1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
To a solution of cyclopropylmethanol (720 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 5 min. The reaction mixture is diluted with heptane, filtered through Celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.22 g of the product 462. 1H NMR (CDCl3) δ 4.2 (q, 2H), 4.09 (s, 2H), 3.37 (d, 2H), 1.27 (t, 3H), 1.09 (m, 1H), 0.56-0.51 (m, 2H), 0.25-0.2 (m, 211); MS: m/z 191 (M+)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[N:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][N:9]=1
Reactant: COCOc1ccc(O)nc1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(OCOC)cn1
Temperature: 60 °C
Yield: 26.9 %

Procedure:
To a mixture of 5-(methoxymethoxy)pyridin-2-ol (1.35 g, 8.71 mmol, 1 eq.) and K2CO3 (6.01 g, 43.6 mmol, 5.0 eq.) in DMF (30.0 mL) was added 1-bromo-2-methoxyethane (3.61 g, 26.1 mmol, 3 eq.). The mixture was heated at 60° C. for 2 h, cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 2-(2-methoxyethoxy)-5-(methoxymethoxy)pyridine (500 mg, 27%) as a colorless oil. NMR (400 MHz, CDCl3) δ 7.94 (d, J=3.0 Hz, 1H), 7.35 (ddd, J=8.9, 3.0, 1.0 Hz, 1H), 6.76 (dd, J=8.9, 1.0 Hz, 1H), 5.11 (s, 2H), 4.48-4.40 (m, 2H), 3.79-3.71 (m, 2H), 3.50 (s, 3H), 3.45 (s, 3H). MS (ESI) m/z 214.1 [M+H]+.