Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[C:6]=1C=O.ClC1C=CC=C(C(OO)=[O:27])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[C:6]=1[OH:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCOc1cc(OC)c(OC)c(OC)c1C=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1cc(OC)c(OC)c(OC)c1O
Temperature: 25 °C

Procedure:
12.8 g of 2-methoxymethyloxy-4,5,6-trimethoxybenzaldehyde prepared in Referential Example 11 was dissolved in 100 ml of dichloromethane, and 8.7 g of m-chloroperbenzoic acid was added thereto at room temperature while stirring. The mixture was refluxed for 30 min and cooled with ice, and 100 ml of a saturated aqueous sodium thiosulfate solution was added thereto. The precipitated crystals were separated by filtration. The mother liquor was washed with a saturated aqueous sodium hydrogen-carbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was mixed with 50 ml of ethanol, 40 ml of water and 21.3 g of potassium hydroxide, and the mixture was stirred for 1 hr under reflux. The reaction mixture was cooled, poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off to prepare 11.5 g of the product compound (light yellow oleaginous) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:14].[Cl:15][C:16]1[CH:17]=[C:18]([C:28](O)=O)[N:19]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:14][C:3]1[CH:4]=[C:5]2[CH:6]=[N:7][NH:8][C:9]2=[C:10]2[C:2]=1[N:1]=[C:28]([C:18]1[N:19]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:20]=[C:16]([Cl:15])[CH:17]=1)[O:12][C:11]2=[O:13]
Reactant: O=C(O)c1cc(Cl)nn1-c1ncccc1Cl
Reactant: Nc1c(Cl)cc2cn[nH]c2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc3cn[nH]c3c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.8 %

Procedure:
To a suspension of 1.00 g (4.58 mmol) of 6-amino-5-chloro-1H-indazole-7-carboxylic acid in 40 mL of anhydrous acetonitrile is added 1.18 g (4.58 mmol) of 5-chloro-2-(3-chloro-pyridin-2-yl)-2H-pyrazole-3-carboxylic acid followed by 1.7 mL (20.6 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 1.25 mL (16.0 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at ambient temperature for 6 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated, washed with cold water and dried. Purification by flash chromatography (SiO2, toluene/methylene chloride/ethyl acetate 10:10:3) affords 910 mg (39%) of the product as a yellowish solid; LC/MS:433/435 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.BrC[CH2:16][CH2:17][O:18][CH2:19]CCBr>>[CH3:19][O:18][CH2:17][CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: BrCCCOCCCBr
Product: COCCn1cnc(-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 2-bromo-ethylmethylether according to the procedure for the preparation of Example 35, part A. [M+H] Calc'd for C12H12N4O, 229. Found, 229.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([NH:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)ncc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cnc(N)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-diamino-4-picoline, prepared as shown in Example 30, (50 mg, 0.41 mmol) in methylene chloride (1.0 mL) were added triethylamine (70 uL, 0.49 mmol) and acetic anhydride (43 uL, 0.45 mmol). After stirring 0.5 h at room temperature, the reaction mixture 25 was evaporated to dryness and purified by silica gel chromatography using 40:10:1 chloroform-methanol-water as eluant to give the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1.O=S(Cl)[Cl:19]>C(Cl)(Cl)Cl>[Cl:19][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:11]=2)[CH:8]=1
Reactant: CCOC(=O)c1cn2cc(CO)ccc2n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn2cc(CCl)ccc2n1
Yield: 97.8 %

Procedure:
By the method of Example 5, the product from Example 10 (2.52 g, 11.4 mmol) dissolved in CHCl3 (100 mL) was reacted with SOCl2 (1.5 g, 12.6 mmol). Final workup provided 2.66 g (98%) of title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([CH:11]([CH3:13])[CH3:12])[C:9]([C:14]2[C:19]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:18][C:17]([Cl:34])=[CH:16][N:15]=2)=[N:8][N:7]=1)=O)C.[CH3:35][NH:36][CH3:37].[C-]#N.[K+]>C1COCC1>[CH3:35][N:36]([CH3:37])[C:4]([C:6]1[N:10]([CH:11]([CH3:13])[CH3:12])[C:9]([C:14]2[C:19]([NH:20][S:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:28][CH:29]=3)(=[O:23])=[O:22])=[CH:18][C:17]([Cl:34])=[CH:16][N:15]=2)=[N:8][N:7]=1)=[O:3]
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C(C)C
Reactant: CNC
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)n1c(C(=O)N(C)C)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A 25 mL scintillation vial was charged with 5-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-4-isopropyl-4H-[1,2,4]triazole-3-carboxylic acid ethyl ester (prepared according to general procedure B, 11 mg, 0.02 mmol), dimethylamine in THF (2 mL, 2.0 M), and KCN (1 mg, 0.01 mmol). The vial was sealed and stirred at 50° C. for 16 h. The volatiles were then evacuated in vacuo and the residue was purified via preparatory HPLC to afford 4-tert-butyl-N-[6-chloro-2-(4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-enzenesulfonamide as a white powder: MS (ES) M+H expected 505.2. found 505.5.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1.[OH-].[Na+].ClCCl.[Br:32][CH2:33][CH2:34]Br>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Br:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:9]2=[O:26])=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: O=c1n(-c2ccc(O)cc2)ccn1-c1ccc(Oc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(Oc2ccccc2)cc1
Temperature: 75 °C

Procedure:
A solution of 1-(4-hydroxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (4.7 g) in 1,2-dibromoethane (23.6 ml) was mixed with sodium hydroxide solution (3N, 9.1 ml) and tetrabutylammonium hydrogen sulfate (232 mg). The mixture was heated at 75° C. for 2 hours. After cooling, the reaction mixture was mixed with dichloromethane and washed with sodium hydroxide solution (1N), hydrochloric acid (1N) and saturated brine. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 9:1). The product with the molecular weight of 451.32 (C23H19BrN2O3); MS (ESI): 451 ([M+H]+), was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:15][CH2:14][CH2:13][CH2:12]1)[C:7](=[O:16])[C:6]([C:17](OCC)=[O:18])=[C:5]2[OH:22].Cl.[C:24]([O:28][C:29](=[O:32])[CH2:30][NH2:31])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]1([CH2:12][CH2:13][CH2:14][CH2:15]1)[C:7](=[O:16])[C:6]([C:17]([NH:31][CH2:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])=[O:18])=[C:5]2[OH:22]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCCC2)C1=O
Temperature: 85 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
A mixture of ethyl 6′-chloro-4′-hydroxy-2′-oxo-spiro[cyclopentane-1,1′-naphthalen]-3′-carboxylate (0.66 g, 2 mmol) and glycine tert-butyl ester hydrochloride (0.5 g, 3 mmol) in 10 mL dioxane was treated with DIPEA (1 mL, 6 mmol). The mixture was warmed to 85° C. and stirred for 4 hours, M+1=406. The mixture was then cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with 10-30% EtOAc hexane to give the title compound (0.8 g) as a pale yellow solid. MS (m/z)=406 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:5]([C@@H:8]([NH:18]C(=O)OC(C)(C)C)[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[OH:48][C:42]([C:44]([F:47])([F:46])[F:45])=[O:43].[NH2:1][C:2]1[CH:3]=[C:4]([C:26]2[CH:27]=[CH:28][C:29]([Cl:41])=[C:30]3[C:34]=2[N:33]([CH3:35])[N:32]=[C:31]3[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:5]([C@@H:8]([NH2:18])[CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3cc(N)cnc3[C@@H](N)Cc3cc(F)cc(F)c3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 49A (60 mg) was dissolved in 2 mL of DCM and to it was added 0.3 mL of TFA. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed to afford the title product. MS (m/z): 507.00 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:24]#[C:25][CH2:26][CH2:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH3:28])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CCCC#Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [Pd]
Solvent: CCO
Product: CCC/C=C\c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Yield: 55.7 %

Procedure:
To a solution of 2-(3-methyl-2-pent-1-ynyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (122) (300 mg, 0.77 mmol) in absolute EtOH (18 mL) is added the catalyst, Pd—C (50% wetted powder, 10% Pd, 30 mg, 1.4% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 50 psi, room temperature, overnight. The catalyst is removed by the filtration through a pre-column (10 g silica gel) and washed by EtOH. The combined EtOH solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product as white solid (168 mg, 56%).
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19]([C:33]2[CH2:42][CH2:41][C:36]3(OCC[O:37]3)[CH2:35][CH:34]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.CC(O)=O.O.[OH-].[Na+]>CCOC(C)=O>[NH2:8][C:16]1[N:17]=[CH:18][C:19]([C:33]2[CH2:42][CH2:41][C:36](=[O:37])[CH2:35][CH:34]=2)=[N:20][C:21]=1[C:22]1[O:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:25][N:26]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C2=CCC3(CC2)OCCO3)nc1-c1nnc(-c2ccccc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ncc(C2=CCC(=O)CC2)nc1-c1nnc(-c2ccccc2)o1
Yield: 82 %

Procedure:
A solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]carbamate in (40 mg, 0.069 mmol) AcOH (832 mg, 788 μL, 13.85 mmol) and H2O (50 mg, 50 μL, 2.8 mmol) was heated at 80° C. for 2 h. The reaction mixture was diluted with 10 ml of EtOAc and pH was adjusted to 8 with 1N NaOH. The reaction mixture was washed with 20 ml of NaHCO3. The layers were separated and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to obtain 4-[5-amino-6-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]cyclohex-3-en-1-one (19 mg, 82%), which was used as crude for the next step. LC/MS m/z 334.0 [M+H]+.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[N:11][C:12]([O:15][CH2:16][C:17]2[N:18]([CH3:29])[N:19]=[N:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:13][CH:14]=1)=[O:8])C>O.C1COCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([C:21]2[N:20]=[N:19][N:18]([CH3:29])[C:17]=2[CH2:16][O:15][C:12]2[N:11]=[N:10][C:9]([C:7]([OH:8])=[O:6])=[CH:14][CH:13]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
A solution of lithium hydroxide monohydrate (111 mg, 3.09 mmol) in water (5 mL) was added dropwise to a suspension of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (471 mg, 1.32 mmol) in THF (5 mL). The reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (430 mg, 99%) as a white solid after trituration with ethyl acetate. MS: m/e=328.3 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:31][OH:32])=[C:8]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=[O:5])[CH3:2]>C(Cl)(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:31]=[O:32])=[C:8]2[C:13]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[C:12]([C:28]#[N:29])[CH:11]=[N:10][N:9]2[CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1C=O
Temperature: 55 °C
Yield: 93.8 %

Procedure:
To a solution of compound 16C (21.4 mg, 0.05 mmol) in chloroform (1 mL) was added MnO2 (<5 micron, activated, 17 mg, 0.20 mmol). The reaction was heated at 55° C. overnight, cooled to room temperature and purified by flash chromatography on a silica gel column (0-2% EtOAc/CH2Cl2) to give compound 18 as a yellow solid (20 mg, 94%). HPLC: 94% at 2.20 min (retention time) (PrimeSphere 5u C18-HC column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 200 nm). MS (ES): m/z 427.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:15][CH:14]3[N:16]([CH3:17])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)=[C:4]([CH2:18][CH:19](OC)OC)[CH:3]=1>Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH:9]1[CH2:15][CH:14]3[N:16]([CH3:17])[CH:11]([CH2:12][CH2:13]3)[CH2:10]1)[CH:19]=[CH:18]2
Reactant: COC(Cc1cc(Br)ccc1NC1CC2CCC(C1)N2C)OC
Agent: Cl
Solvent: CO
Product: CN1C2CCC1CC(n1ccc3cc(Br)ccc31)C2
Yield: 127.1 %

Procedure:
Compound 83 (118 mg, 0.308 mmol) was dissolved in anhydrous 1M HCl/methanol (10 mL) in a dry argon purged flask, refluxed for 1 hour, concentrated under reduced pressure to yield a shiny brown solid, 84 (125 mg, 100%) as a 5:1 or 1:5 mixture of endo/exo stereoisomers. 1H NMR (major isomer-DMSO-d6) δ 1.85-1.96 (m, 2H), 2.15-2.26 (m, 2H), 2.31-2.40 (m, 2H), 2.66 (d, 3H, J=4.9 Hz), 2.76-2.93 (m, 2H), 3.87-3.96 (m, 2H), 4.99-5.11 (m, 1H), 6.49 (d, 1H, J=3.4 Hz), 7.24-7.34 (m, 1H), 7.49 (d, 1H, J=8.8 Hz), 7.76 (d, 1H, J=1.6 Hz), 7.79 (d, 1H, J=2.9 Hz); ESI-MS (m/z, %): 319/321 (MH+, 100%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.Cl.Cl.[N:16]1([C:22]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[C:1]1([S:7]([N:19]2[CH2:20][CH2:21][N:16]([C:22]([O:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[CH2:17][CH2:18]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(Oc1cccnc1)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Oc1cccnc1)N1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (0.23 ml) and benzenesulfonyl chloride (0.075 ml) were added to a dichloromethane (5 ml) solution containing 3-pyridyl 1-piperazinecarboxylate dihydrochloride (150 mg), followed by stirring overnight at room temperature. The reaction solution was diluted with chloroform, the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform), and the resulting solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-(phenylsulfonyl)-1-piperazinecarboxylate (130 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:18]([CH:15]2[CH2:17][CH2:16]2)=[O:19])[CH:5]=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cnc(-c2ccncc2)c(Cl)n1
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2ccncc2)c(Cl)n1)C1CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a stirred solution of 6-chloro-5-pyridin-4-ylpyrazin-2-amine (Preparation 7, 0.73 g, 3.56 mmol) in pyridine (15 mL) was added cyclopropanecarbonyl chloride (648 μL, 7.1 mmol). The solution was stirred at 70° C. for 1 h 30 min, evaporated, partitioned between dichloromethane and a 4% sodium bicarbonate aqueous solution, the aqueous phase extracted twice with dichloromethane, the organic layers washed with brine, dried (MgSO4) and evaporated. The residue was triturated with diethyl ether and methanol and the precipitate was collected by filtration and dried to furnish the title compound as a light brown solid (0.69 g, 70%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([NH:26][C:27]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=2[Cl:35])=[N:19][CH:20]=[N:21]3)[CH2:10][CH2:9]1)=O)(C)(C)C.C=O>C(O)=O>[Cl:35][C:28]1[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=1[NH:26][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:25][C:16]=2[O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)[N:21]=[CH:20][N:19]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cccc(OCC4CCN(C(=O)OC(C)(C)C)CC4)c23)c1
Agent: C=O
Solvent: O=CO
Product: COc1ccc(Cl)c(Nc2ncnc3cccc(OCC4CCN(C)CC4)c23)c1
Temperature: 100 °C

Procedure:
A mixture of 5-[N-(tert-butoxycarbonyl)piperidin-4-ylmethoxy]-4-(2-chloro-5-methoxyanilino)quinazoline (0.2 g), a concentrated aqueous formaldehyde solution (37%, 0.4 ml) and formic acid (4 ml) was stirred and heated to 100° C. for 2.5 hours. The mixture was cooled to ambient temperature and evaporated. The residue was triturated under diethyl ether and the resultant solid was isolated and dried under vacuum. There was thus obtained 4-(2-chloro-5-methoxyanilino)-5-(N-methylpiperidin-4-ylmethoxy)quinazoline, as a formic acid salt (0.09 g); NMR Spectrum: (CDCl3) 1.8-2.0 (m, 2Et), 2.05-2.15 (m, 2H), 2.35 (m, 1H), 2.6 (t, 2H), 3.55 (d, 2H), 3.93 (s, 3H), 4.21 (d, 2H), 6.68 (m, 1H), 6.95 (d, 1H), 7.31 (d, 1H), 7.54 (d, 1H), 7.7 (m, 1H), 8.35 (br s, 1H), 8.39 (d, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 413.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[N:12]=2)=[CH:9][CH:10]=1)=[O:5])C.[Li+].[OH-].Cl>CO.O>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:13]2[N:12]=[C:11]([C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=3)[CH:16]=[CH:15][N:14]=2)[CH:19]=1
Reactant: CCOC(=O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccnc(Nc3cccnc3)n2)s1
Yield: 72.2 %

Procedure:
5-[2-(Pyridin-3-ylamino)-pyrimidin-4-yl]-thiophene-2-carboxylic acid ethyl ester (76 mg, 0.209 mmol) was saponified by treatment with 4 N LiOH (0.524 mL, 2.09 mmol) in MeOH (1.5 mL) at 40° C. for 15 h. 6 N HCl (2.09 mmol) was added and the mixture was diluted with water. The precipitate was collected by filtration, rinsed with EtOH and dried on vacuum to afford title compound (45 mg, 72%). The crude material was used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[Br:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][C:5]([CH3:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1cc(Oc2ccc(F)cc2F)c(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(F)cc2F)c(Br)cc1N
Reaction time: 16 h
Yield: 80.5 %

Procedure:
1-Bromo-2-(2,4-difluoro-phenoxy)-4-methyl-5-nitro-benzene (87.0 g, 253 mmol) was dissolved in THF (300 mL) and diluted with MeOH (900 mL). Zinc dust (82.7 g, 1.26 mol) was added and 1 L of saturated NH4Cl was added slowly so that the reaction temperature never exceeded 42° C. The reaction was mechanically stirred vigorously for 16 hours. The reaction was filtered through Celite and the filter cake was washed with ethyl acetate. The filtrate was then concentrated with 1.2 L of saturated NH4OAc. When the THF/MeOH was removed, the solids were collected and washed with water. The solids were then stirred in 1 L water for 30 min, then collected via filtration and rinsed with water (1 L) in three portions. The resulting solid was dried under high vacuum for 48 hours to produce 64 g of the desired product (81%yield). MS (ESI+)m/z 314,316 (M+1, Br pattern) detected; 1H NMR (400 mHz, CDCl3) δ 6.92 (m, 1H), 6.91 (s, 1H), 6.75 (m, 2H), 6.70 (s, 1H), 3.57 (br. s, 2H), 2.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].Cl[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]>>[CH3:15][O:14][C:12](=[O:13])[C:11]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1)=[O:16]
Reactant: COC(=O)C(=O)Cl
Reactant: Cc1cc(N)ccc1Cl
Product: COC(=O)C(=O)Nc1ccc(Cl)c(C)c1

Procedure:
In a manner similar to that employed in Referential Example 242, the title compound was prepared from 4-chloro-3-methylaniline and methyl chlorooxoacetate.