Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]2[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4].C1C(=O)N([Cl:30])C(=O)C1>C(Cl)Cl.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:30])=[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]2[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22])=[O:4]
Reactant: COC(=O)c1cc2ccncn2c1Nc1ccc(I)cc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(Cl)c2ccncn2c1Nc1ccc(I)cc1F
Yield: 48.1 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-pyrrolo[1,2-c]pyrimidine-6-carboxylic acid methyl ester (576 mg, 1.40 mmol) in DCM (10 mL) was added NCS (206 mg, 1.54 mmol) and the reaction heated at reflux for 3 hours. More NCS (37 mg, 0.28 mmol) was added and the reaction heated at reflux for 2 hours. The reaction mixture was diluted with water and the product extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-40% ethylacetate in cyclohexane) to yield the title compound as an off-white solid (300 mg, 48%). LCMS (Method B): RT=4.11 min, M+H+=446.
Reaction SMILES: [Cl-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[O:8][C:9]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:10]=1[CH2:11][CH:12](C(OCC)=O)[C:13]([O:15]CC)=[O:14])#[N:4]>CS(C)=O.O>[C:3]([C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[O:8][C:9]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:10]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14])#[N:4]
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1Oc1cccc(C#N)c1)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cccc(Oc2cc(C(F)(F)F)ccc2CCC(=O)O)c1
Temperature: 120 °C

Procedure:
Sodium chloride (0.1 g) was added to a solution of the product from step (iv) (0.6 g) in DMSO (5 ml) and water (1 ml) then heated at 120° C. for 12 hours. The mixture was cooled and partitioned between 2M sodium hydroxide and diethylether. The aqueous layer was acidified with 2M hydrochloric acid, extracted with ethyl acetate and the organic layer dried and evaporated under reduced pressure. The residue was purified by reverse phase HPLC. Yield 0.108 g.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[C:16]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=3)=[N:25][C:26]([S:30][CH3:31])=[N:27]2)=[C:22]([NH2:39])[C:21]=1[C:40]([NH2:42])=[O:41])([CH3:19])([CH3:18])[CH3:17]>CC(C)=O>[C:16]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)[CH:33]=3)=[N:25][C:26]([S:30][CH3:31])=[N:27]2)=[C:22]([NH2:39])[C:21]=1[C:40]([NH2:42])=[O:41])([CH3:19])([CH3:17])[CH3:18]
Reactant: ClCCN1CCCC1
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(N)=O)c(C(C)(C)C)cc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1nc(-c2cccc(OCCN3CCCC3)c2)c2c(N)c(C(N)=O)c(C(C)(C)C)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of K2CO3 (1.0 g), 1-(2-chloroethyl)pyrrolidine hydrochloride (66 mg) and tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-quinazoline-6-carboxamide (example 26a, 121 mg) in acetone was heated overnight at reflux. The mixture was cooled to room temperature, the solids were removed by filtration and the filtrate concentrated under reduced pressure. The residue was taken up in EtOAc and washed with water and brine. The organic phase was dried (MgSO4) and concentrated in vacuo. The title compound was purified by HPLC using a Luna C-18 column with the following gradient: 10% aq. CH3CN/CH3CN/0.1% aq. TFA=72/25/3 to 27/70/3 (v/v/v) in 30 min. The title compound was lyophilized from a nixture of water, TFA is and CH3CN.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH2:31]([O:35]C1C=CC(O)=CC=1)[CH2:32][CH2:33][CH3:34].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:31]([O:35][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(O)cc1
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(Br)cc3)nc(C)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(-c2nc(C)c3c(n2)sc2c(OCC)nc(N4CCNCC4)nc23)cc1
Temperature: 180 °C

Procedure:
100 mg (0.21 mmol) 7-(4-bromophenyl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine, 51 mg (0.31 mmol) 4-n-butoxyphenol, 134 mg (0.41 mmol) Cs2CO3, 1 μl (5 mole %) ethyl acetate and 1.5 mg (5 mole %) CuBr were suspended in 5 ml absolute toluene and heated in a microwave oven at 180° C. for 17 h. Thereafter, the solvent was removed and the residue was purified by means of flash chromatography. 4 mg (3%) of the title substance is obtained. ESI-MS [m/z]: 571
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH3:18][CH:19]([CH3:45])[CH:20]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1[C:33]1[CH:32]=[CH:31][C:30]([CH:20]([CH:19]([CH3:45])[CH3:18])[CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[CH:35][CH:34]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C(CNC(=O)OC(C)(C)C)C(C)C)cc1
Yield: 20 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-thieno[2,3-c]quinolin-4(5H)-one) (800 mg, 2.58 mmol) was reacted with tert-butyl 3-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butylcarbamate (1.2 g, 3.09 mmol) to afford the desired product (250 mg, 20%) as a yellow solid: ESI MS m % z 493 [C28H32N2O4S+H]+.
Reaction SMILES: [CH3:1][N:2]([C:12]1[S:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[N:17]=1)[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][CH:4]=1.[H][H]>[Ni].CN(C=O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([C:12]2[S:13][C:14]3[N:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[N:17]=2)[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(c1ccc([N+](=O)[O-])cc1)c1nc(=O)c2cccnc2s1
Reactant: [H][H]
Agent: [Ni]
Solvent: CN(C)C=O
Product: CN(c1ccc(N)cc1)c1nc(=O)c2cccnc2s1
Yield: 72.2 %

Procedure:
A mixture of 1.505 g (4.79 mmol) of 2-[N-methyl-N-(4-nitrophenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one obtained in Example 63, 50 ml of DMF and about 1.5 g of Raney nickel was stirred in an atmosphere of hydrogen for 5 hours. The resulting insoluble matters were then removed by filtration. The resulting filtrate was then concentrated under reduced pressure. The residue was then recrystallized from ethanol to obtain 984 mg of 2-[N-(4-aminophenyl)-N-methylamino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:26][NH2:27])[CH2:24][CH3:25]>>[CH2:1]([N:8]1[C:12]([CH2:13][C:14]2[C:19]([CH2:20][CH3:21])=[N:27][N:26]([CH2:23][CH2:24][CH3:25])[C:15]=2[CH2:16][CH3:17])=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1cncn1Cc1ccccc1)C(=O)CC
Reactant: CCCNN
Product: CCCn1nc(CC)c(Cc2cncn2Cc2ccccc2)c1CC

Procedure:
4-(3-Benzyl-3H-imidazol-4-ylmethyl)-3,5-diethyl-1-propyl-1H-pyrazole was prepared from 4-(3-benzyl-3H-imidazol-4-ylmethyl)-heptane-3,5-dione and propylhydrazine in analogy to Example 55 b): off-white solid; MS (ISP): 337.1 ((M+H)+.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].[Si:10]([O:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[NH:34][C:35](=[O:44])[C:36]2[CH:41]=[C:40](I)[CH:39]=[CH:38][C:37]=2[F:43])[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>CC#N.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>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:40]2[CH:39]=[CH:38][C:37]([F:43])=[C:36]([CH:41]=2)[C:35]([NH:34][C:25]2[CH:26]=[C:27]([C:30]([F:31])([F:32])[F:33])[CH:28]=[CH:29][C:24]=2[N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([O:17][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12])[CH2:19]2)=[O:44])=[CH:4][N:5]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(I)ccc2F)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCCN(c2ccc(C(F)(F)F)cc2NC(=O)c2cc(C#Cc3cnc(N)nc3)ccc2F)C1
Temperature: 70 °C

Procedure:
In a 16×120 mm resealable pyrex tube, 5-ethynylpyrimidin-2-amine (0.080 g, 0.67 mmol), (R)—N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluoro-5-iodobenzamide (0.210 g, 0.34 mmol), Bis(triphenylphosphine)palladium(II) dichloride (0.012 g, 0.017 mmol), and Copper(I) iodide (0.0032 g, 0.017 mmol) were taken up in CH3CN and Triethylamine (0.71 ml, 5.1 mmol) was added, and the tube was flushed with nitrogen. The tube was sealed and the reaction heated to 70° C. overnight. The reaction was cooled, and transferred to a 50 mL RBF with EtOAc. The mixture was concentrated in vacuo, and the resulting solid was treated with 10% MeOH in CH2Cl2 and adsorbed onto 1.5 g silica gel and passed through a Redi-Sep® pre-packed silica gel column (40 g) eluting with 0-60% EtOAc/hexane. The product-containing fractions were concentrated to afford (R)-5-(2-(2-aminopyrimidin-5-yl)ethynyl)-N-(2-(3-(tert-butyldimethylsilyloxy)piperidin-1-yl)-5-(trifluoromethyl)phenyl)-2-fluorobenzamide as an off-white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[Br:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14](Cl)=[N:15][CH:16]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH2:8]([O:7][C:3](=[O:6])[CH2:4][O:5][C:14]1[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][C:11]([Br:10])=[CH:16][N:15]=1)[CH3:9]
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CCOC(=O)CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
Sodium hydride (55% dispersion in mineral oil, 603 mg, 13.8 mmol) was added to a solution of ethyl glycolate (1.43 g, 13.8 mmol) in 1,4-dioxane, and the reaction mixture was heated at 70° C. for 1 h, then 5-bromo-2-chloro-3-nitropyridine (Eur. Pat. Appl. EP 122109 (1984); 1.64 g, 6.91 mmol) was added, and stirring was continued at 70° C. for 1 h and at room temperature for 16 h. The reaction mixture was then neutralized with sat. aq. sodium hydrogencarbonate solution and extracted three times with dichloromethane. The organic layers were pooled, dried (Na2SO4), and evaporated. Chromatography (SiO2, hexane-ethyl acetate gradient) furnished (5-bromo-3-nitropyridin-2-yloxy)-acetic acid ethyl ester (1.03 g, 49%). Light yellow liquid, MS (ISP)=305.1 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[C:12]([C:19]([F:22])([F:21])[F:20])[CH:11]=2)=[CH:6][CH:5]=1.C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[Br:1][C:11]1[C:12]([C:19]([F:22])([F:20])[F:21])=[C:13]([C:15]([F:16])([F:17])[F:18])[NH:14][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)[nH]c1C(F)(F)F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1[nH]c(-c2ccc(Cl)cc2)c(Br)c1C(F)(F)F
Reaction time: 2 h
Yield: 65.4 %

Procedure:
Bromine (0.527 g, 3.3 mmol) is added to a room temperature solution of 5-(p-chlorophenyl)-2,3-bis(trifluoromethyl)pyrrole (0.9 g, 3.0 mmol), acetic acid (5 mL) and sodium acetate (0.492 g, 6 mmol). After stirring for 2 hours the reaction mixture is diluted with water and extracted with ether. The combined organic extracts are washed sequentially with water, sodium metabisulfite solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. Crystallization of the solid from hexanes gives the title product as white crystals (0.77 g, mp 64.5°-65.0° C., 65%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:12][C:13](=O)[CH3:14]>C(O)C>[CH3:14][C:13]1[N:1]=[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]2[CH:12]=1
Reactant: CC(=O)CBr
Reactant: Nc1ncccc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1cn2cccc([N+](=O)[O-])c2n1

Procedure:
20.0 g of 2-amino-3-nitropyridine and 22 g of bromoacetone are boild in 1 l ethanol for 55 hours under reflux. The mixture is then cooled in an icebath, the crystalline hydrobromide filtered off under suction and washed with ethanol. After drying in a vacuum at 50° C. the yield of the title compound of m.p. 300° C. (decomposition) is 17.2 g.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[C:2]=1[CH:13]=[O:14].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[C:15]1([CH:13]([C:2]2[C:3]([CH:11]([OH:12])[C:1]3[CH:10]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[OH:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1cc2ccccc2cc1C=O
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1)c1cc2ccccc2cc1C(O)c1ccccc1
Yield: 86.6 %

Procedure:
2,3-Naphthalenedicarboxaldehyde (10.0 g) in dry tetrahydrofuran (100ml) was added to phenylmagnesium bromide [derived from bromobenzene (53 g) and magnesium (8 g)] in dry tetrahydrofuran (500 ml) over 1 hr. and the solution was refluxed for a further 3 hr. On cooling, water (500 ml) was added and the ethereal layer was decanted. The aqueous slurry was washed with ether (4 × 500 ml) and the combined ethereal extracts were dried (magnesium sulphate) and evaporated to dryness. The residue was purified by chromatography on silica gel and recrystallised from dichloromethane/petroleum ether (b.p. 40°-60°) to yield two isomers of 2,3-bis(1-phenyl-1-hydroxymethyl)naphthalene (III) (8.0 g. m.p. 145° and 3.0 g, m.p. 164°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][O:13][CH3:14].O1CCCC1.C(OP([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:5][C:4]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COCOc1cc(C=O)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OC)c(OCOC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 4.2 %

Procedure:
The compound (3.42 g, 17.4 mmol) of Example 9-1 was dissolved in N,N-dimethylformamide (30 ml) and tetrahydrofuran (30 ml) and then thereto were added ethyl diethylphosphonoacetate (3.91 g, 17.4 mmol) and sodium hydride (766 mg, 19.1 mmol). After stirring for 2 hours at 60° C., the mixture was allowed to cool to room temperature, and tetrahydrofuran was removed under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate-toluene (3:1). The organic layer was washed with water and an aqueous saturated sodium chloride solution in the order, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the subject compound (196 mg, 88.8%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[C:18](=[O:21])([O-])[O-].[K+].[K+].O>N1C=CC=CC=1.[Cu](I)I>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([O:21][C:18]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Reactant: O=C([O-])[O-]
Agent: I[Cu]I
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Oc2ccccc2)s1
Temperature: 125 °C
Reaction time: 65 h
Yield: 34.7 %

Procedure:
To a solution of (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) (463 mg) in pyridine (10 mL) phenol (158 mg), copper iodide (32 mg) and potassium carbonate (97 mg) were added. The mixture was stirred at 125° C. for 65 h under nitrogen. Water was added and the aqueous layer was extracted with chloroform. Following evaporation, the residue was purified by flash chromatography using 5-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound (80 mg); MS (ES+) 329 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[CH2:14][CH:13]3[N:15](C(OC(C)(C)C)=O)[CH:10]2[CH2:11][CH2:12]3)[N:2]=1.[ClH:23]>O1CCOCC1.CC(O)C>[ClH:23].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][CH:9]2[CH2:14][CH:13]3[NH:15][CH:10]2[CH2:11][CH2:12]3)[N:2]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(COc1cccnn1)C2
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: c1cnnc(OCC2CC3CCC2N3)c1
Temperature: 70 °C

Procedure:
To the title compound from step A (300 mg, 1 mmol) in 1,4-dioxane (3 mL) was added 6N HCl in iPrOH (1 mL). The reaction was heated to 70° C. for 3 h, cooled to rt and concentrated to give the title compound that was used without further purification. MS (ESI) mass calcd. for C11H15N3O, 205.1; m/z found 206.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])[CH3:11])=[N:8][CH:9]=1.[CH2:13](Cl)[O:14][CH3:15]>CN(C=O)C>[CH3:13][O:14][CH2:15][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:12])[CH3:11])=[N:8][CH:9]=1
Reactant: CC(=O)c1ccc(O)cn1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C(C)=O)nc1
Reaction time: 1 h
Yield: 84.8 %

Procedure:
NaH was added to a solution of 1 g (7.29 mmol) 1-(5-hydroxy-pyridin-2-yl)-ethanone (Anichem) in 15 ml DMF at 0° C. After stirring this mixture for 1 h, 0.78 ml (8.75 mmol) MOMCl was added at 0° C. Then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured on water and extracted 2 times with EtOAc. The combinded organic layers were washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel (EtOAc, heptane) to yield 1.12 g of the pure title compound as an oil. LCMS (method L): tR=0.66 min, M+H=182.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[OH:17])[N:6]=1.[H-].[Na+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>CN(C)C=O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][O:17][C:8]1[CH:9]=[CH:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:5]1[N:6]=[C:2]([NH2:1])[O:3][CH:4]=1
Reactant: COC(=O)CBr
Reactant: Nc1nc(-c2c(O)ccc3ccccc23)co1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2ccccc2c1-c1coc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(2-Amino-oxazol-4-yl)-naphthalen-2-ol (22, 190 mg) was dissolved in N,N-dimethylformamide and then sodium hydride (34 mg) was added in one portion to give a dark orange solution. Methyl bromoacetate (88 μL) was then added and the mixture was stirred at room temperature for 18 hours.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12](Cl)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:16]1[C:20]([C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[N:19][N:18]=[N:17]1>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[S:11][C:10]([S:12]([NH:27][C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]4[NH:19][N:18]=[N:17][N:16]=4)[CH:22]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc(S(=O)(=O)Cl)s2)cs1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1nc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)cs1
Yield: 25.7 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 5-(2-methylthiazol-4-yl)thiophene-2-sulphonylchloride (15 mg, 0.055 mmol) and [3-(1H-tetrazol-5-yl)phenyl]amine (8 mg, 0.05 mmol) giving 5.2 mg (26%) of the title compound. MS (ESI+) calcd for C15H12N6O2S3 404.0184, found 404.0182.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:21][CH:20]3[CH:16]([CH2:17][NH:18][CH2:19]3)[CH2:15]2)=[O:13])[NH:4][CH:5]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=1.CCN(C(C)C)C(C)C>C(#N)C>[N:1]1[N:2]=[C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([N:14]2[CH2:15][CH:16]3[CH:20]([CH2:19][N:18]([C:23]4[N:28]=[C:27]([CH3:29])[C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=4)[CH2:17]3)[CH2:21]2)=[O:13])[NH:4][CH:5]=1
Reactant: O=C(c1ccccc1-c1nnc[nH]1)N1CC2CNCC2C1
Reactant: Cc1nc(Cl)nc(C)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(N2CC3CN(C(=O)c4ccccc4-c4nnc[nH]4)CC3C2)nc(C)c1C
Yield: 28.8 %

Procedure:
The product of Step A (167 mg, 0.421 mmol), Intermediate 56 (66 mg, 0.421 mmol) and DIPEA (0.29 mL, 1.68 mmol) were heated for 2 h at 200° C. in ACN (1.4 mL) in the microwave. The mixture was concentrated in vacuo. The crude product was purified using Agilent HPLC (basic system) to yield impure material. This material was subsequently purified using normal phase chromatography (DCM to 8% 2M NH3 in MeOH/DCM) to afford the title compound (49 mg, 29%). MS (ESI) mass calculated for C22H25N7O, 403.49; m/z found, 404.2. 1H NMR (500 MHz, CDCl3): 8.16 (d, J=7.8 Hz, 1H), 8.06 (s, 1H), 7.54-7.49 (m, 1H), 7.48-7.44 (m, 1H), 7.35 (d, J=7.5 Hz, 1H), 3.96-3.89 (m, 1H), 3.85-3.77 (m, 1H), 3.74-3.68 (m, 1H), 3.68-3.55 (m, 2H), 3.42 (br s, 2H), 3.16 (br s, 1H), 3.04-2.96 (m, 1H), 2.89 (br s, 1H), 2.32 (s, 6H), 2.05 (s, 3H).
Reaction SMILES: [OH-:1].[K+].O.[OH:4][C:5]1([C:18](N)=[O:19])[C:14]2[C:9](=[C:10]([Cl:17])[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[O:8][CH2:7][CH2:6]1>CC(O)C>[Cl:17][C:10]1[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[C:14]2[C:9]=1[O:8][CH2:7][CH2:6][C:5]2([C:18]([OH:19])=[O:1])[OH:4]
Reactant: [OH-]
Reactant: COc1cc(Cl)c2c(c1)C(O)(C(N)=O)CCO2
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COc1cc(Cl)c2c(c1)C(O)(C(=O)O)CCO2

Procedure:
KOH (1.2 g; 21 mmol) and water (25 mL) were added to a solution of 4-hydroxy-8-chloro-6-methoxychroman-4-yl-carboxylic amide (0.39 g; 1.5 mmol; from step (iv) above) in i-PrOH (25 mL). The reaction mixture was refluxed overnight, i-PrOH was evaporated and the water solution was washed with ether. The reaction mixture was acidified with HCl (2M) and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated. Yield: 0.38 mg (97%).
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O.C>CC1C=CC=CC=1>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1Br
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a stirred suspension of 414 parts of 2-bromo-3-nitrobenzoic acid in 653 parts of methylbenzene there were added 440 parts of thionyl chloride. The whole was refluxed for 6 hours, cooled and left overnight. The reaction mixture was treated with activated charcoal, filtered over diatomaceous earth and evaporated. The residual oil was triturated with 396 parts of hexane (2×). The product was filtered off, washed with hexane and dried, yielding 363 parts (81.7%) of 2-bromo-3-nitrobenzoyl chloride (interm. 3).