Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]=2[CH:23]=O)[CH2:7][CH2:6]1)=[O:4].[CH3:25][NH:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[CH2:33]2)(=[O:29])=[O:28]>>[CH3:25][NH:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])/[C:33]/2=[CH:23]\[C:15]1[NH:16][C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[C:14]=1[CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][OH:1])[CH2:10][CH2:9]1)(=[O:29])=[O:28]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(C(=O)CO)CC1)CCCC2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C(=O)CO)CC1)CCCC3)C(=O)N2
Yield: 35.7 %

Procedure:
3-{3-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (134 mg, 0.3 mmol) was condensed with 5-methylaminosulfonyloxindole (76 Mg, 0.33 mmol) following the procedure used in Example 1 to give 58 mg of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](C2CCCC2N)C=[C:6]([F:8])[CH:7]=1.[CH2:15]1[CH2:25][CH2:24][N:23]2[C:18](=NCCC2)[CH2:17][CH2:16]1.[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27]>C(Cl)Cl>[F:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:18]=1[C@H:17]1[CH2:16][CH2:15][CH2:25][C@H:24]1[NH:23][S:29]([CH:26]([CH3:28])[CH3:27])(=[O:31])=[O:30]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NC1CCCC1c1cc(F)cc(F)c1
Reactant: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stirrer was charged with (+,−) cis-[2-(3,5-difluoro-phenyl)-cyclopentylamine (83 mg, 0.42 mmol), methylene chloride (5.0 mL) and the solution cooled to 0° C. DBU (0.08 mL, 0.51 mmol) and isopropylsulfonyl chloride (0.06 mL, 0.51 mmol) were added. The reaction was then stirred at 0° C. for 60.0 minutes and brought to room temperature with stirring overnight. The reaction was diluted with methylene chloride and washed with 1N HCl, brine and the organic layer dried over sodium sulfate. The title compound was purified by radial chromatography eluting with methylene chloride to give 83 mg (65%) of the purified title compound. The nmr was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].ClC(Cl)(O[C:29](=[O:35])[O:30][C:31](Cl)(Cl)Cl)Cl.[CH3:37][O:38][C:39]1C=[CH:43][CH:42]=[CH:41][C:40]=1O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:30][C:31]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:38][CH3:37])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1ccccc1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4OC)c(C)c3C)c2cc1OC
Yield: 42.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-methoxyphenol (29 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (31 mg, yield 41%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[CH3:27][O:28][CH2:29]C(Cl)=O.[CH:33]1([NH2:36])[CH2:35][CH2:34]1>>[CH:33]1([NH:36][C:24]([C@@H:9]2[CH2:10][C:11](=[N:13][O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[CH2:12][N:8]2[C:6](=[O:7])[CH2:29][O:28][CH3:27])=[O:26])[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)O
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CC(=NOCc2ccc(Cl)c(Cl)c2)C[C@H]1C(=O)NC1CC1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(3,4-dichlorobenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, methoxyacetyl chloride, and cyclopropylamine the title compound was obtained in 54% purity by LC/MS. MS(ESI+): m/z=414.6.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[O:13]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1CCCCC1.O.C(Cl)Cl>[O:13]([C:20]1[CH:21]=[C:22]([NH:23][CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Nc1cccc(Oc2ccccc2)c1
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: O
Product: COC(=O)c1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
EX-612A) Methyl 3-(bromomethyl)benzoate (7.2 g, 0.031 mol) was added dropwise to a solution of 3-phenoxyaniline (20.5 g, 0.11 mol) in 160 mL of cyclohexane. The reaction mixture was refluxed overnight then cooled to room temperature and diluted with water and methylene chloride. The layers were separated, and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a dark oil. The crude product was purified by reverse phase HPLC eluting with 20% to 90% acetonitrile in water to afford 6.2 g (59%) of the desired methyl 3-[[(3-phenoxyphenyl)amino]methyl]benzoate product as a yellow oil. ESMS m/z=334 [M+H]+.
Reaction SMILES: [Na+].[I-:2].CNCCNC.Br[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([N:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)[CH:14]=[C:13]2[CH3:27].CCOC(C)=O>O1CCOCC1.[Cu]I>[I:2][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([N:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)[CH:14]=[C:13]2[CH3:27]
Reactant: [I-]
Reactant: Cc1cc(N2CCC(C)CC2)nc2ccc(Br)cc12
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCC(C)CC2)nc2ccc(I)cc12
Temperature: 110 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 39 mg (0.2 mmol) of CuI, 0.6 g (4.0 mmol) of NaI, and 43 μL N,N′-dimethylethylenediamine are added to a solution of 0.69 g (2.0 mmol) of 6-bromo-4-methyl-2-(4-methylpiperidin-1-yl)quinoline in 2 mL of 1,4-dioxane and the reaction mixture is shaken for 14 hours at 110° C. After cooling, it is combined with 60 mL of EtOAc, and the organic phase is washed twice with 20 mL of 5% NH3 solution and dried over magnesium sulfate. After the desiccant and solvent have been eliminated, the residue is reacted further without purification. Yield: 0.65 g (88% of theoretical); C16H19IN2 (M=366.240); calc.: molpeak (M+H)+: 367; found: molpeak (M+H)+: 367; HPLC-MS: 7.0 min (method A).
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4](S)[N:3]=1.[OH-:18].[Na+].OO.Cl>CO>[OH:18][C:4]1[N:3]=[C:2]([OH:1])[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[N:5]=1
Reactant: Oc1nc(S)nc2c(-c3ccccc3)cnn12
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CO
Product: Oc1nc(O)n2ncc(-c3ccccc3)c2n1

Procedure:
To a mixture of 4-hydroxy-2-mercapto-8-phenylpyrazolo[1,5-a]-1,3,5-triazine (130 mg), 0.25N sodium hydroxide solution (4 ml) and methanol (3 ml) is with stirring added 30% hydrogen peroxide (1 ml) under ice cooling. The mixture is reacted for one hour, and the reaction mixture is adjusted to pH 1-2 with conc. hydrochloric acid. The resulting precipitate is separated by filtration, washed with water and methanol and dried to give the title compound (25.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22].C(Cl)[Cl:30].Cl>C(OCC)(=O)C.CCOCC>[ClH:30].[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: ClCCl
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1-c1ccccc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1C
Yield: 85 %

Procedure:
[4-Nitro-2-(2-methylphenyl)benzoyl]methionine methyl ester was reduced to a corresponding amine by stannous chloride in ethyl acetate at 78° C. The free amine was treated with methylene chloride and 3 N HCl in ether to give [4-amino-2-(2-methylphenyl)benzoyl]methionine methyl ester hydrochloride (85% yield); [α]25D=−28.3 (c=1.0, methanol); 1H NMR (CD3OD) δ 7.74 (d, J=8.2 Hz, 1H), 7.47 (d, J=8.2 Hz, 1H), 7.23-7.30 (m, 5H), 4.47 (m, 1H), 3.69 (s, 3H), 2.06-2.18 (m, 4H), 1.99 (s, 3H), 1.97 (m, 2H), 1.74 (m, 1H); 13C NMR (CD3OD) δ 173.3, 170.8, 143.3, 139.7, 138.1, 137.2, 133.5, 131.49 130.8, 130.6, 129.6, 128.8, 126.2, 123.1, 66.9, 52.9, 31.5, 30.8, 20.4, 15.1.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][CH2:9][N:10]([CH2:16][CH:17]=O)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].[C:21]([O:25][C:26]([N:28]1[CH2:35][CH:34]2[O:36][CH:30]([CH2:31][NH:32][CH2:33]2)[CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)C.[BH3-]C#N.[Na+]>ClCCl.O>[C:21]([O:25][C:26]([N:28]1[CH2:29][CH:30]2[O:36][CH:34]([CH2:33][N:32]([CH2:17][CH2:16][N:10]([CH2:9][CH2:8][O:7][C:6]3[CH:19]=[CH:20][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:31]2)[CH2:35]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: CN(C)C(=O)N(CC=O)CCOc1ccc(C#N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)N(CCOc1ccc(C#N)cc1)CCN1CC2CN(C(=O)OC(C)(C)C)CC(C1)O2
Reaction time: 1 h
Yield: 102.5 %

Procedure:
1-[2-(4-Cyanophenoxy)ethyl]-3,3-dimethyl-1-(2-oxoethyl)urea (4.5 g; see Preparation G above) was taken in dichloromethane (100 mL). 9-Oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (2.9 g, 0.013 mol; see WO 01/28992), followed by glacial acetic acid (1.47 g, 0.0245 mol), was added, and reaction mixture was stirred for 1 h. NaBH3CN (1.54 g, 0.024 mol) was added at 0° C., and stirring was continued overnight at room temperature. The reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent evaporation, followed by purification by column chromatography, yielded the title compound (6.5 g).
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1O)[OH:2].[OH-:10].[Na+].[CH2:12]1[O:14][CH2:13]1>>[OH:10][CH2:3][CH2:1][O:2][C:8]1[CH:7]=[C:5]([O:6][CH2:7][CH2:5][OH:6])[CH:3]=[C:1]([O:2][CH2:13][CH2:12][OH:14])[CH:9]=1
Reactant: Oc1cccc(O)c1O
Reactant: C1CO1
Reactant: [OH-]
Agent: [Na+]
Product: OCCOc1cc(OCCO)cc(OCCO)c1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
Pyrogallol (378.3 g., 3 moles) and sodium hydroxide (0.5 g.) are charged into a one-liter autoclave. The mixture is heated to 140° C., purged three times with nitrogen and subjected to a vacuum of 20 mm Hg for one-half hour. Ethylene oxide (396 g., 9 moles) is then added at 30 psig; after all the ethylene oxide is consumed, the autoclave is purged two times with nitrogen and cooled to 30° C. Two hundred grams of the product is withdrawn and 10 g. of potassium hydroxide pellets is added to the autoclave. The autoclave is purged three times with nitrogen at 150° C. Acetylene (100 psig.) then is added and heating is continued for 16 hours to provide the trivinyl ether of 1,3,5-tris-(2-hydroxyethoxy) benzene, having the formula: ##STR3##
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.CC([O-])(C)C.[K+].CS(C)=O.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[C:34](=[CH:35][C:36](F)=[CH:37][CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:39]3[C:34](=[CH:35][C:36]([O:6][CH:4]4[CH2:5][NH:2][CH2:3]4)=[CH:37][CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: OC1CNC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OC4CNC4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106 %

Procedure:
A mixture of Azetidin-3-ol hydrochloride (Oakwood) (461 mg, 4.21 mmol), KOtBu (1.02 g, 9.11 mmol), and dry DMSO (4.2 mL) was stirred at rt for 30 min until a translucent solution resulted. Then 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.46 g, 4.41 mmol), as prepared in Example 65b, was added, and the resulting opaque orange mixture (no visible precipitate) was stirred at rt for 3.5 hr. The reaction was then shaken with water (40 mL) and extracted with DCM (1×20 mL) and 9:1 DCM/MeOH (1×20 mL). The combined organic layers were washed with 0.2 M K2CO3 (3×20 mL), dried (Na2SO4), and concentrated to give 1.715 g of the title compound as an off-white solid (“106%” crude yield). LC/MS (ESI): calcd mass 384.2, found 385.3 (MH)+.
Reaction SMILES: [Na].CC1C(C[S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=O)=NC=CC=1OCC1(C)OCC2(OCCO2)CO1.C[C:35]1(C)[O:40]CC(COC2C=CN=C(CO)C=2C)C[O:36]1>>[O:36]1[C:31]2[C:32](=[CH:33][C:27]3[NH:26][C:25]([SH:23])=[N:29][C:28]=3[CH:30]=2)[O:40][CH2:35]1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Cc1c(OCC2COC(C)(C)OC2)ccnc1CO
Agent: [Na]
Product: Sc1nc2cc3c(cc2[nH]1)OCO3

Procedure:
The same procedure as in the steps (5f) to (5h) of Example 5 was repeated using (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methanol obtained in the step (12b) above and 5H-[1,3]dioxolo[4,5-f]benzimidazole-6-thiol obtained in the step (78c) above to obtain the title compound (347 mg, total 51.9% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=O)[CH2:11][CH3:12].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH2:11][CH3:12])=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CC(=O)CC
Reactant: COc1ccccc1N
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=C(CC)Nc1ccccc1OC
Yield: 49.4 %

Procedure:
A mixture of o-anisidine (15.11 g), ethyl propionylacetate (17.69 g) and acetic acid (0.5 ml) in benzene (30 ml) was refluxed removing water for 24 hours. The solvent was removed in vacuo, and the residue was dissolved in toluene (30 ml). The reaction mixture was refluxed for an additional 8 hours. The solvent was removed in vacuo. The residue was purified by column chromatography (hexane--ethyl acetate) to give ethyl 3-(2-methoxyanilino)-2-pentenoate (15.11 g) as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:11](=O)[CH2:12]Br)[NH:9][CH:10]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:8]3[NH:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOC(=O)c1c[nH]c(C(=O)CBr)c1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cc(C(=O)O)c[nH]3)cs2)cc1OCC

Procedure:
4-Ethoxycarbonyl-2-(α-bromoacetyl)pyrrole and 3,4-diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-pyrrolyl)thiazole.
Reaction SMILES: [CH:1]1([C:10]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)([CH3:12])[CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.C1(C(C2C3C(=CC=CC=3)C=C2)(C)C)C2C(=CC=CC=2)C=C1.[Li].[Li].[Si:50](Cl)([CH3:53])([CH3:52])[CH3:51]>CCOCC.CCCCC>[CH3:51][Si:50]([CH3:53])([CH3:52])[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:10]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([Si:50]([CH3:53])([CH3:52])[CH3:51])=[CH:2]2)([CH3:11])[CH3:12])[CH:14]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(C1C=Cc2ccccc21)C1C=Cc2ccccc21
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C1C=C([Si](C)(C)C)c2ccccc21)C1C=C([Si](C)(C)C)c2ccccc21

Procedure:
5.45 g (20 mmol) of 2,2-bis(indenyl)propane was dissolved in 100 ml of ether. The solution thus obtained was taken to -20° C., and 22 ml of a 2.0 M solution of n-butyl-lithium in pentane was added, thus giving a suspension of dilithium-2,2-(indenyl)propane. 8.77 g (30.85 mmol) of dilithium 2,2-bis(indenyl)propane was dissolved in 100 ml of ether, and 10 ml of Me3SiCl (excess) was added at a temperature of -40° C. The resulting mixture was allowed to return to room temperature. The organic phase was then separated off, the solvent removed and the product dried in vacuo.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[Cl:24][C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:31]([C:26]5[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][N:27]=5)=[O:32])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: O=C(O)c1ncccc1Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Product: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4NC(=O)c3ncccc3Cl)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 13, coupling of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with 3-chloro-pyridine-2-carboxylic acid gave the title compound as colorless solid. MS: 447.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13](N)=[C:12]([CH3:17])[CH:11]=1.O.C(#[N:21])C>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:3]([C:2]([CH3:8])([CH3:7])[CH3:1])[C:4]([NH2:21])=[O:5])=[C:12]([CH3:17])[CH:11]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC#N
Solvent: O
Product: Cc1cc(Br)ccc1C(C(N)=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
3,3-Dimethylbutanoyl chloride (724 mg, 0.75 mL, 5.4 mmol) was added to a solution of 4-Bromo-2-methyl-phenylamine (1.0 g, 5.4 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (830 mg, 56% yield).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].IC.[F:9][C:10]1[C:11]([N+:19]([O-:21])=[O:20])=[CH:12][C:13](O)=[C:14]([CH:17]=1)[CH:15]=[O:16].O>CN(C)C=O>[F:9][C:10]1[C:11]([N+:19]([O-:21])=[O:20])=[CH:12][C:13]([O:4][CH3:1])=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(F)c([N+](=O)[O-])cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc([N+](=O)[O-])c(F)cc1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
To a suspension of 0.524 g (3.80 mmole) of potassium carbonate, 0.5 mL of iodomethane and 8 mL of dimethylformamide was added, dropwise, a solution of 0.141 g (0.76 mmole) of 5-fluoro-2-hydroxy-4-nitro-benzaldehyde (IV.46b) in 1 mL of dimethylformamide. The resulting dark red solution was stirred at room temperature for 3 hours. The mixture was poured into 50 mL of water and extracted three times with 25 mL of ethyl acetate. The combined organic layers were washed three times with 25 mL of water, once with 25 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.143 g of 5-fluoro-2-methoxy-4-nitro-benzaldehyde (IV.46c) as a yellow solid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[CH:12]=[N:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].Br.C([OH:17])C>>[C:7]1(=[O:17])[C:6]2[C:5](=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][NH:8]1
Reactant: CCO
Reactant: CN(C)/C=C/c1cnccc1C#N
Agent: Br
Product: O=c1[nH]ccc2cnccc12
Temperature: 25 °C

Procedure:
To a suspension of (E)-3-(2-(dimethylamino)vinyl)isonicotinonitrile (5 g, 28.9 mmol) in ethanol (50 mL) was added 49 mL of HBr (48% in water) dropwise over 20 minutes. The mixture was heated to reflux overnight for 19 h, and cooled to rt. Upon cooling, fine yellow crystals started to form. The mixture was cooled in the refrigerator for 1.5 h. The crystals were collected by filtration and were washed with ether. To the yellow solid was carefully added sat. aq. NaHCO3 until gas evolution ceased. The off-white solid that formed was collected by filtration and was washed with water to give 1.83 g of the expected product. The mother liquors from both filtrations were combined and were concentrated under reduced pressure. The residue was neutralized with sat. aq. NaHCO3, and the solvent removed under reduced pressure. The residue was diluted with 300 mL of dichloromethane and 300 mL of MeOH, and the mixture was warmed to reflux with a heat gun. The solids were removed by filtration, and the organic solution was concentrated under reduced pressure. The residue was purified by BIOTAGE® flash chromatography using a 0-6.5% MeOH in dichloromethane gradient. The expected product, was isolated as an off-white solid (0.96 g) and the two lots were combined to yield 2,6-naphthyridin-1(2H)-one (2.79 g, 19.1 mmol, 66% yield). LC/MS: m/z 147.04 (M+H)+, 1.407 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.63 (br. s., 1H) 9.07 (s, 1H) 8.62 (d, J=5.49 Hz, 1H) 7.98 (d, J=5.49 Hz, 1H) 7.33 (d, J=7.02 Hz, 1H) 6.67 (d, J=7.02 Hz, 1H).
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5]([OH:8])([CH3:7])[CH3:6].[Cl:9][C:10]1[N:15]=[N:14]C(C(OC)=O)=[CH:12][CH:11]=1.Cl>C1COCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:9][C:10]1[N:15]=[N:14][C:4]([C:5]([OH:8])([CH3:7])[CH3:6])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)nn1
Reactant: CC(C)(C)O
Agent: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccc(Cl)nn1
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
A solution of THF (2.5 mL) and toluene (10 mL), and methylmagnesium chloride (3.0 M, 9.7 mL) were stirred at −20° C. under N2 atmosphere followed by the addition of t-BuOH (0.5 mL, 5.79 mmol) in THF (7 mL) dropwise. The solution was allowed to stir for 30 min and warmed to 3° C. and cooled backed down to −20° C. followed by the addition of the methyl 6-chloropyridazine-3-carboxylate (1.0 g, 5.79 mmol) in portions. The solution quickly turned dark violet and was stirred at 0° C. for 30 min. The solution was then poured into a flask containing 1 N aqueous hydrochloric acid at −5° C., diluted with ethyl acetate, and stirred for 10 min. The layers were then separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine. The acidic aqueous layer was neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layers were combined and concentrated in vacuo. Purification via flash chromatography (silica, 0-100% ethyl acetate/hexanes) provided the title compound. LRMS (ESI) calcd for C7H10ClN2O [M+H]+: 173.1, Found: 173.1