Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:40]1[CH:45]=[CH:44][C:43]([C:46]2[S:50][S:49][C:48](=[S:51])[CH:47]=2)=[CH:42][CH:41]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[S:50][S:49][C:48](=[S:51])[CH:47]=2)=[CH:44][CH:45]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(-c2cc(=S)ss2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To the solution of 1 (acetylsalicylic acid, 416 mg, 2.31 mmol) in 40 mL of dimethylformamide, hydroxybenzotriazole (343 mg, 2.54 mmol) and DCC (523 mg, 2.54 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 5-p-hydroxyphenyl-1,2-dithiole-3-thione (2; 574 mg, 2.54 mmol) was added and stirred for 1 h at 0° C. and 3 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product was loaded on a silica gel open column and eluted with ethyl ether/petroleum ether (1/1), from which 4-(5-thioxo-5H-1,2-dithiol-3-yl)phenyl 2-acetoxybenzoate (3) was obtained (354 mg, 40% yield).
Reaction SMILES: N[C:2]1[C:7]2[N:8](C3C=CC=CC=3)[CH:9]=N[C:6]=2[CH:5]=[C:4](C#N)[CH:3]=1.Cl[C:20]1[C:25]([N+:26]([O-])=O)=[CH:24][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:22][C:21]=1[N+:33]([O-])=O>>[NH2:26][C:25]1[C:20]2[N:8]([C:7]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:9]=[N:33][C:21]=2[CH:22]=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:24]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: N#Cc1cc(N)c2c(c1)ncn2-c1ccccc1
Product: Nc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12

Procedure:
This was prepared in analogy with 7-amino-5-cyano-1-phenylbenzimidazole using 4-chloro-3,5-dinitrobenzotrifluoride as the starting material (11 g, 75%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[C:23](Br)[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]1([S:35]([O-:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Na+].CNCCNC>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([F:27])=[C:23]([S:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)(=[O:37])=[O:36])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(CC(=O)N2CCc3cc(F)c(Br)cc32)CCN1C(=O)OC(C)(C)C
Reactant: O=S([O-])c1ccccc1
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(CC(=O)N2CCc3cc(F)c(S(=O)(=O)c4ccccc4)cc32)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
A mixture of (R)-4-[2-(6-bromo-5-fluoro-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.137 g, 0.30 mmol), sodium phenylsulfinate (0.064 g, 0.39 mmol), copper (1) trifluoromethylsulfonate-benzene complex (0.0045 g, 0.009 mmol), N,N′-dimethylethylenediamine (0.29 g, 0.33 mmol) and dimethyl sulfoxide (1.5 mL) was stirred at 150° C. under nitrogen for 18 h in a sealed vessel. The resulting mixture was partitioned between water (50 mL) and 1:1 Et2O− EtOAc (30 mL) and the organic phase was washed with water (2×20 mL), dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography (SiO2; gradient elution with 0-100% EtOAc in petrol) gave the title compound (0.031 g, ˜25%). MS: [M+H]+=518.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[N:8]O)[CH2:4][CH2:3]1.Cl>C(O)C.[Ni].CCOCC>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=NO)CC1
Agent: [Ni]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC1(C)CCC(N)CC1

Procedure:
A solution of 4,4-dimethylcyclohexanone oxime (D52) (10 g) in ethanol (100 ml) was hydrogenated over Raney nickel at 50 psi for 3 days. 1M HCl in ether (100 ml) was added and the solvent removed to afford the amine as the hydrochloride salt. The title compound (D53) was liberated prior to use by dissolving in water and making strongly basic (KOH pallets), extracting with DCM (2×), drying with (Na2SO4) and evaporating the solvent carefully.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.[CH3:25][NH2:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:26][CH3:25])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CN
Product: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1F

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and methylamine (2M in THF).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[O:21][N:22]=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:4]1[CH:25]=[CH:24][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[O:21][N:22]=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cnoc2-c2ccccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCc3cnoc3-c3ccccc32)cc1
Yield: 219.6 %

Procedure:
A mixture of 0.050 g of 5,6-dihydro-6-(4-nitrobenzoyl)-4H-isoxazolo[4,5-d][1]benzazepine and 0.169 g of SnCl2 2H2O in 2 ml of ethyl alcohol is heated at reflux under argon for 1 hour. Water and 10% NaHCO3 is added until basic. The volatiles are evaporated in vacuo to a residue which is stirred with 1:1 chloroform-methanol and filtered. The filtrate is evaporated in vacuo to a residue which is dissolved in methyl alcohol, treated with activated carbon, filtered through diatomaceous earth and concentrated in vacuo to give 100 mg of the desired product as a white crystalline solid. CIMS(CH4):MH+ =306.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[C:8]1[CH:9]2[C:17](=[O:18])[O:16][C:14](=O)[CH:10]2[CH2:11][CH2:12][CH:13]=1.[C:19](OCC)(=O)C.O>O1CCCC1>[CH3:19][C:12]1[CH2:11][C@H:10]([CH2:14][OH:16])[C@H:9]([CH2:17][OH:18])[CH2:8][CH:13]=1
Reactant: CC1=CCCC2C(=O)OC(=O)C12
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1=CC[C@@H](CO)[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 300 ml of tetrahydrofuran at 0° C. was added 16.0 g (0.42 mol) lithium aluminum hydride portionwise keeping the reaction temperature between 0° C. and 5° C. A solution of 33.0 g (0.20 mol) of 4-methyl-4-cyclohexene-2,3-dicarboxylic anhydride in 100 ml of tetrahydrofuran was added dropwise over 2 hours keeping the temperature between 0° C. and 10° C. The reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction was cooled to 0° C. and 35 ml of ethyl acetate was added dropwise, followed by dropwise addition of 35 ml isoropanol and 35 ml water. The reaction mixture was filtered through celite using acetone, dried with MgSO4, filtered, and concentrated to 33.0 g of oil. Flash chromatography in 3:1 hexanes-ethylacetate, followed by 1:1 hexanes-ethylacetate and finally ethylacetate alone yielded 18.2 g of oil.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: Ic1ccccn1
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Product: CCOC(=O)c1cc2cccnc2n1-c1ccccn1

Procedure:
This compound was prepared according to the experimental protocol described in Example 6.1, starting with ethyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate obtained according to the protocol described in step 3.2 and 2-iodopyridine. A beige-colored solid is obtained.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]([C:30]([O:32]CC)=[O:31])=[C:23]([C:25](=[O:29])[NH:26][CH2:27][CH3:28])[N:24]=3)[CH2:16][C@H:15]2[O:35][CH2:36][CH3:37])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]>CO>[Cl:3][C:4]1[N:5]=[C:6]([C:11]([NH:13][C@H:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]([C:30]([OH:32])=[O:31])=[C:23]([C:25](=[O:29])[NH:26][CH2:27][CH3:28])[N:24]=3)[CH2:16][C@H:15]2[O:35][CH2:36][CH3:37])=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCNC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)sc1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)sc1C(=O)O
Reaction time: 5.5 h
Yield: 78.1 %

Procedure:
A 2 N aqueous lithium hydroxide solution (2.41 mL, 4.82 mmol) was added to a solution of ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-4-(ethylcarbamoyl)-1,3-thiazole-5-carboxylate obtained in Example (247a) (254 mg, 0.48 mmol) in methanol (5 mL) at room temperature, followed by stirring for 5.5 hours. The reaction solution was concentrated under reduced pressure, and then a 1 N aqueous hydrochloric acid solution was added to the resulting residue at 0° C. The precipitated solid was collected by filtration, and then washed with water and ethyl acetate to obtain 187 mg of the title compound as a white solid (78%).
Reaction SMILES: O[C:2]1[C:7](C)=[CH:6][C:5]([O:9][CH3:10])=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH2:15](Cl)[Cl:16]>>[Cl:16][CH2:15][C:2]1[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: COc1cnc(O)c(C)c1
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(CCl)nc1

Procedure:
To a solution of 2-hydroxy-methyl-5-methoxy-pyridine (0.68 g, 4.9 mmol) in dry DCM was added dropwise excess thionyl chloride (2.0 mL), and the mixture was refluxed for 2 hours. The solvent was removed in vacuo, and the residue was taken up in EtOAc and washed with NaHCO3 (aq), dried (MgSO4, and concentrated in vacuo. The extremely volatile 2-chloromethyl-5-methoxy-pyridine was obtained as a solution in ethyl acetate to give (984.0 mg, 83.5%) yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]2[N:10]=[CH:11][N:12]([CH3:13])[C:4]=2[CH:3]=1.[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.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]>[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]3[N:10]=[CH:11][N:12]([CH3:13])[C:4]=3[CH:3]=2)=[CH:20][C:19]=1[C:27]([F:28])([F:29])[F:30]
Reactant: Cn1cnc2c(C#N)nc(Cl)cc21
Reactant: OCCOc1ccc(B(O)O)cc1C(F)(F)F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCO)c(C(F)(F)F)c3)cc21
Temperature: 100 °C
Yield: 75.8 %

Procedure:
A mixture of 6-chloro-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.75 g), 4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenylboronic acid (1.46 g), tris(dibenzylideneacetone)dipalladium (0.18 g), tricyclohexylphosphine (0.13 g) and tribasic potassium phosphate (1.65 g) in dioxane (7.5 ml) and water (3 ml) was heated at 100° C. under N2 for 3 hours. The mixture was then diluted with ethyl acetate (100 ml), organic layer seperated and solvent removed under reduced pressure, the residue was then columned on silica gel using DCM-MeOH (3%) as eluant to give 6-[4-(2-hydroxyethoxy)-3-(trifluoromethyl)-phenyl]-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (1.07 g).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:32])=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[C:22]([Cl:21])[CH:23]=[CH:24][C:25]=1[O:32][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 99.3 %

Procedure:
To a solution of (2R, 5S)-2-chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (2.75 g, 9.2 mmol) in butanone (50 ml) was added methyl 5-chloro-2-hydroxybenzoate (1.55 g, 9.2 mmol), potassium carbonate (2.54 g, 18.4 mmol) and potassium iodide (1.52 g, 9.2 mmol). The resulting mixture was stirred at reflux for 6 hours. The reaction was then cooled, diluted with ethyl acetate, and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. Chromatography on silica gel gave the title compound (4.1 g, 100% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][C:4]1[N:5]=[C:6]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)=[CH2:16])[N:7]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:8]=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]([CH3:31])([CH3:32])[CH2:3][C:4]1[N:5]=[C:6]([CH:15]([CH3:16])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:7]([S:9]([N:12]([CH3:14])[CH3:13])(=[O:10])=[O:11])[CH:8]=1
Reactant: C=C(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)cn1S(=O)(=O)N(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)cn1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pd(OH)2 (5 mg) was added to a solution of 4-(2,2-dimethylpropyl)-2-{1-[4-(5-fluoropyridin-2-yl)benzyl]vinyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide in methanol. After stirring under an atmosphere of hydrogen (balloon) at ambient temperature for 1 h, the reaction mixture was filtered through a silica plug (rinsing with ethyl acetate) and concentrated in vacuo. Purification of the resulting crude product by silica preparatory plate chromatography eluting with 40% ethyl acetate/hexanes afforded 4-(2,2-dimethylpropyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-methylethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: Br[C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][N:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>C(#N)C.O1CCOCC1.O>[Cl:12][C:11]1[C:2]([C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[N:15][CH:16]=2)=[CH:3][C:4]2[O:8][C:7]([CH3:9])=[N:6][C:5]=2[CH:10]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1nc2cc(Cl)c(Br)cc2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1nc2cc(Cl)c(-c3ccc(N)nc3)cc2o1
Temperature: 85 °C
Yield: 60.1 %

Procedure:
A mixture of 6-bromo-5-chloro-2-methylbenzoxazole (35) (123 mg, 0.5 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (130 mg, 0.6 mmol), Bis(dicyclohexyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (35 mg) and K3PO4 (106 mg, 0.5 mmol) in 1 ml ACN, 1 ml dioxane, 0.25 ml H2O was bubbled with argon before heated at 85° C. for 6 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. The resulting red solid was dissolved in DCM and subjected to silica gel column purification using 0-100% B (A: hexane; B: EA) to furnish 78 mg 36 as off-white solid (yield: 60%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:24][N:25]([CH:32]([CH3:34])[CH3:33])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:29](=[O:30])/[CH:28]=[CH:27]/[CH2:26][N:25]([CH3:24])[CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:22][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)N(C)C/C=C/C(=O)O
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CNCC4)cc1Cl
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1CCc2sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c3c2C1

Procedure:
The title compound was synthesized in analogy to Example 89 from N-(3,4-dichlorophenyl)-5,6,7,8-tetrahydropyrido[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 76A (100 mg, 0.29 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (77 mg, 0.40 mmol) to yield 56 mg (40%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:22])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Reactant: COCCN
Product: COCCNC(=O)c1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1

Procedure:
This material was prepared by a method analogous to that described for Example 21, starting from 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino] phenoxy}pyridine-2-carboxylic acid and 2-methoxyethylamine.
Reaction SMILES: [CH3:1][CH:2]([S:5]([NH2:8])(=[O:7])=[O:6])[CH2:3][CH3:4].C[O-].[Na+].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.Cl>CO>[F:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:8][S:5]([CH:2]([CH2:3][CH3:4])[CH3:1])(=[O:7])=[O:6])=[O:21])=[CH:15][CH:14]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CCC(C)S(N)(=O)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCC(C)S(=O)(=O)NC(=O)Nc1ccc(F)cc1

Procedure:
The general method of procedure B was followed with 2-butanesulfonamide (6.85 g), sodium methoxide (2.7 g), methanol (250 ml), and 4-fluorophenyl isocyanate (6.8 g) except 1N HCl was added to provide the free urea. The solid was recrystallized from benzene to provide 5.2 g of white powder with a melting point of 136-138° C.
Reaction SMILES: C(=O)([O-])O.[Na+].[CH3:6][C@H:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>O.CC(C)=O>[CH3:6][C@H:7]1[CH2:12][N:11]([S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH2:10][CH2:9][NH:8]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C[C@H]1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@H]1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
Sodium hydrogen carbonate (21.7 g) and acetone (50 ml) was added to a solution of (S)-(+)-2-methylpiperazine (6.0 g) in water (75 ml). The resulting suspension was cooled (0-5° C.) and a solution of 2-nitrobenzenesulphonyl chloride (15.9 g) in acetone (25 ml) was added, the reaction mixture was allowed to stir at ambient temperature overnight. Water (60 ml) was added and volatile material was removed by evaporation. The residue was acidified to pH 2 by the addition of HCl (2 M, 75 ml) and the mixture was extracted into DCM (2×100 ml). The aqueous phase was adjusted to pH 10-11 by the addition of NaOH (2 M, 50 ml) and extracted into EtOAc (2×150 ml). The organic washings were combined, dried and concentrated to leave the title compound (14.1 g) as a yellow oil. NMR: 1.06 (d, 3H), 2.35-2.43 (m,1H), 2.73-3.06 (m, 4H), 3.65-3.71 (m, 2H), 7.59-7.62 (m, 1H), 7.68-7.72 (m, 2H), 7.95-7.98 (m, 1H); m/z (+ve ESP): 286 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl-].[CH3:19][CH:20]([S:22]([CH2:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH3+:29])(=[O:24])=[O:23])[CH3:21]>C1COCC1.CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:26]([CH2:25][S:22]([CH:20]([CH3:21])[CH3:19])(=[O:24])=[O:23])[CH:27]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CC(C)S(=O)(=O)Cc1cccc([NH3+])c1
Agent: [Cl-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Yield: 268 %

Procedure:
To a stirred solution of 2,4-dichloro-1,3,5-triazine (150 mg, ABCR GmbH & CO. KG) in THF/i-PrOH (1:1; 1.9 mL) DIPEA (0.52 mL) was added at −40° C. Then a suspension of 3-[(propan-2-ylsulfonyl)methyl]anilinium chloride (250 mg) in THF/i-PrOH (1:1, 0.94 mL) was added at this temperature. Under stirring the temperature of the reaction mixture was slowly raised over 3 hours to 0° C. The reaction mixture was then concentrated in vacuo to give the crude title compound (876 mg) which was used without further purification.
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C1(C)C=CC=CC=1.[NH2:20][C:21]1[C:26]([C:27](OCC)=[O:28])=[C:25]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[O:38][CH2:37][CH2:36][CH2:35]3)[C:24]([C:42]([O:44][CH3:45])=[O:43])=[C:23]([CH3:46])[N:22]=1>O1CCCC1>[NH2:20][C:21]1[C:26]([CH2:27][OH:28])=[C:25]([C:32]2[CH:33]=[C:34]3[C:39](=[CH:40][CH:41]=2)[O:38][CH2:37][CH2:36][CH2:35]3)[C:24]([C:42]([O:44][CH3:45])=[O:43])=[C:23]([CH3:46])[N:22]=1
Reactant: CCOC(=O)c1c(N)nc(C)c(C(=O)OC)c1-c1ccc2c(c1)CCCO2
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C)nc(N)c(CO)c1-c1ccc2c(c1)CCCO2
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
An ice cooled solution of Red-Al, 65 wt % solution in toluene (12.58 mL, 41.3 mmol) in tetrahydrofuran (THF) (188 mL) was treated with a solution of 3-ethyl 5-methyl 2-amino-4-(chroman-6-yl)-6-methylpyridine-3,5-dicarboxylate (7.64 g, 20.63 mmol) in tetrahydrofuran (THF) (31.4 mL) and the mixture was stirred at 0° C. for 5 minutes. The mixture was quenched with water (32 mL) then 15% NaOH (16 mL) was added. The mixture was warmed to ambient temperature and stirred for 20 minutes (solids formed). The mixture was filtered and then filtrate was concentrated. The residue was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and then concentrated to afford the crude methyl 6-amino-4-(chroman-6-yl)-5-(hydroxymethyl)-2-methylnicotinate as a light brown solid which was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.87-6.72 (m, 3 H), 5.35-5.19 (m, 2 H), 4.50-4.41 (m, 2 H), 4.25-4.18 (m, 2 H), 3.50-3.45 (m, 3 H), 2.78 (t, J=6.4 Hz, 2 H), 2.38 (s, 3 H), 2.06-2.00 (m, 2 H); LC/MS (m/z) ES+=329.26 (M+1).