Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Yield: 67 %

Procedure:
As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted using morpholine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 20:80, 165 mg, 67%) which was obtained as a white solid. MS: m/e=380.3 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:9]2[C@H:8]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:6]12[CH3:7])[C@:20]1([CH3:21])[C:15]([CH2:16][C@@H:17]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18][CH2:19]1)=[CH:14][CH2:13]3)(=[O:3])[CH3:2].C(Cl)(Cl)(Cl)Cl.C([OH:43])(C)(C)C.C(OC(=O)C)(=O)C>C(Cl)Cl.[O-2].[Cr+6].[O-2].[O-2].C(O)(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]2[CH2:11][C@H:9]2[C@H:8]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:6]12[CH3:7])[C@:20]1([CH3:21])[C:15]([CH2:16][C@@H:17]([O:25][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:18][CH2:19]1)=[CH:14][C:13]3=[O:43])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H]2C[C@H]2[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: CC(C)(C)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H]2C[C@H]2[C@H]2[C@@H]3C(=O)C=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 80 °C
Reaction time: 32 h

Procedure:
6.9 g of 17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5-androstene was combined with 69 ml of carbon tetrachloride with an acetic tert.-butyl chromate solution prepared from 10.35 g of chromium(VI) oxide, 90 ml of carbon tetrachloride, 28.2 ml of tert.-butyl alcohol, 37.2 ml of acetic acid, and 134 ml of acetic anhydride. The reaction solution was then stirred for 32 hours at 80° C., diluted with methylene chloride, and washed with sodium acetate solution, sodium bicarbonate solution, and water. After drying and evaporation, the resultant residue was chromatographed on silica gel, thus obtaining 4.4 g of 17β-acetoxy-3β-benzoyloxy-15β,16β-methylene-5-androsten-7-one, mp 245°-246° C. (acetone-diisopropyl ether).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][C:7]([O:14][CH:15]([CH3:17])[CH3:16])=[N:6][C:5]=1[NH2:18].[OH-].[Li+]>CO.O>[NH2:18][C:5]1[N:6]=[C:7]([O:14][CH:15]([CH3:16])[CH3:17])[CH:8]=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:4]=1[C:3]([OH:19])=[O:2]
Reactant: COC(=O)c1c(OC(C)C)cc(OC(C)C)nc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc(OC(C)C)c(C(=O)O)c(N)n1
Temperature: 50 °C

Procedure:
To the solution of 2-amino-4,6-diisopropoxy-nicotinic acid methyl ester (1.6 g, 5.97 mmol) in methanol (9.0 mL) and water (1.0 mL), was added lithium hydroxide (750 mg, 17.91 mmol). The reaction mixture was heated to 50° C. for 8 hours. The solvent was removed; the residue was diluted with water and neutralized with 2 N HCl. The product was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, then brine, dried over Na2SO4, and evaporated, to give crude 2-amino-4,6-diisopropoxy-nicotinic acid as a light yellow solid. Yield: 1.48 g (98%, crude).
Reaction SMILES: C([O:8][C:9]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:12]2[N:13]([CH2:22][O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[CH:10]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:12]2[N:13]([CH2:22][O:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH2:14][CH2:15][CH2:16][CH:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[CH:10]=1
Reactant: COC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(OCc1ccccc1)c1ccccc21
Agent: [Pd]
Product: COC(=O)C1CCCN(COS(C)(=O)=O)c2c1cc(O)c1ccccc21

Procedure:
Following the general procedure detailed for 85, 93 (0.028 g, 0.060 mmol, 1 equiv) was treated with 10% Pd—C (0.010 g, 0.009 mmol, 0.16 equiv) followed by aqueous HCO2NH4 (0.265 mL, 25% w/v, 18 equiv). Filtration and concentration gave 95 as an analytically pure white solid (0.0204 g, 0.0225 g theoretical, 91%): mp 113-115° C.; 1H NMR (500 MHz, CD3OD) major rotamer δ 8.25 (d, J=7.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.55-7.45 (m, 2H), 6.60 (s, 1H), 4.41-4.33 (m, 4H), 3.66 (s, 3H), 2.85-2.79 (m, 1H), 2.64 (s, 3H), 2.35-2.20 (m, 1H), 2.13-1.95 (m, 1H), 1.71-1.67 (m, 2H); 13C NMR (125 MHz, CD3OD) major rotamer δ 157.2, 154.4, 140.9, 134.8, 128.3, 126.2, 125.8 (2C), 124.5, 124.3, 123.9, 72.5, 53.6, 49.9, 37.3, 36.9, 27.9, 25.5; IR (film) νmax 3283, 2938, 2857, 1672, 1621, 1591 cm31 1; FABHRMS (NBA-NaI) m/z 379.1081 (M+, C18H21NO6S requires 379.1090).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]2[C:22](=[O:23])[C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[S:19]2(=[O:29])=[O:28])[CH2:11]1)=[O:7])(C)(C)C.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34](C(O)=O)=[C:33]([O:41][CH3:42])[CH:32]=1>>[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:34]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[S:19]3(=[O:28])=[O:29])[CH2:11]2)=[O:7])=[C:33]([O:41][CH3:42])[CH:32]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCN2C(=O)c3ccccc3S2(=O)=O)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN2C(=O)c3ccccc3S2(=O)=O)C1

Procedure:
3-tert-Butoxycarbonylaminomethyl-1-(3-(1,1,3-trioxo-2,3-dihydro-1,2-benzisothiazol-2-yl)propyl)pyrrolidine (0.28 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.13 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(3-(1,1,3-trioxo-2,3-dihydro-1,2-benzisothiazol-2-yl)propyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc(Br)ccc1SC
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
To a solution of 4-bromo-2-methoxybenzenethiol (1.21 g, 5.52 mmol) in DMF (5 mL) was added potassium carbonate (2.29 g, 16.5 mmol) under argon. The resulting mixture was stirred for 10 min, and then iodomethane (3.44 mL, 55.2 mmol) was slowly added over 2 min. The resulting mixture was stirred at r.t. overnight. Then the reaction mixture was poured into water (75 ml), and extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated, the residue was purified by flash chromatography on silica gel with n-heptane/ethyl acetate (7:3) to give 920 mg (72%) of the subtitle compound.
Reaction SMILES: [C:1]([CH2:11][C:12]([O:14]CC)=[O:13])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:17]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1)=[N+:18]=[N-:19].[O-]CC.[Na+].O>C(O)C>[CH2:27]([NH:26][C:24]([C:23]1[CH:29]=[CH:30][C:20]([N:17]2[C:1](/[CH:2]=[CH:3]/[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[C:11]([C:12]([OH:14])=[O:13])[N:19]=[N:18]2)=[CH:21][CH:22]=1)=[O:25])[CH3:28]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Reactant: CCOC(=O)CC(=O)C=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
Ethyl cinnamoylacetate (1.17 g, 4.82 mmol, 1.2 eq.) obtained in Example 106a) and 4-azido-N-ethylbenzamide (0.750 g, 3.94 mmol) were dissolved in ethanol (25 ml), sodium ethoxide (373 mg, 4.93 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 30 min, and then at 60° C. for 10.5 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (2:1, 40 ml), acidified (pH<3) with 6N hydrochloric acid, and extracted with ethyl acetate (25 ml×3). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and ethyl acetate was added. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a pale-brown powder (627 mg, 1.73 mmol, 43.9%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[O:10]1[CH:12]([CH2:13][C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:11]1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH2:11][CH:12]([OH:10])[CH2:13][C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:18])([F:20])[F:19])[CH2:3][CH2:2]1
Reactant: OCCN1CCOCC1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CC1CO1
Product: OC(COCCN1CCOCC1)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 80 °C
Reaction time: 10 h
Yield: 73 %

Procedure:
A mixture of 13.1 g of 2-morpholinoethanol and 27.6 g of 1,2-epoxy-4,4,5,5,6,6,7,7,7-nonafluoroheptane was stirred at 80° C. for 10 hours. The reaction mixture was directly purified by silica gel column chromatography. There was obtained 29.7 g of 1-(2-morpholinoethoxy)-4,4,5,5,6,6,7,7,7-nonafluoro-2-heptanol (yield 73%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]N=C(OCC)C(=O)CCC)=[CH:6][CH:5]=1)([O-:3])=[O:2]>Cl>[CH2:5]([C:4]1[C:6]2[C:7](=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:10][CH:9]=1)[CH3:6]
Reactant: CCCC(=O)C(=NNc1ccc([N+](=O)[O-])cc1)OCC
Agent: Cl
Product: CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Yield: 89.7 %

Procedure:
The 4-nitrophenylhydrazone of ethyl 2-oxopentanoate (D29) (0.72 g, 2.60 mM) was heated to reflux for 16 h in concentrated hydrochloric acid. After cooling to room temperature the precipitated solid was filtered off. Chromatography on silica using dichloromethane as eluant gave the title compound as a yellow solid (0.22 g; 45%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CO>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[CH2:7][OH:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc([N+](=O)[O-])c(CO)c1
Reaction time: 4 h

Procedure:
60 ml of borane-dimethyl sulphide complex are added over the course of 30 minutes to a boiling solution of 100 g of 5-methyl-2-nitrobenzoic acid in 750 ml of tetrahydrofuran. The reaction solution is boiled for 4 hours under reflux conditions. Then, 200 ml of methanol are added with cooling, and the solution is left to stand for 30 minutes at room temperature. It is then evaporated in a vacuum until dry and the residue thus obtained is partitioned between chloroform and sodium carbonate solution. The organic phase is washed with water, dried over sodium sulphate and evaporated, whereupon the heading compound is obtained as a crystalline solid having a low melting point.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:15])=[N:10][CH:11]=2.[C:16](OC(=O)C)(=[O:18])[CH3:17]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:16]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH2:15])=[N:10][CH:11]=2)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc2ncn(COCCO)c2n1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OCCOCn1cnc2cnc(N)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 0.82 g (3.92 mM) of 9-(2-hydroxyethoxymethyl)-2-amino-9H-purine, 48 mg (0.392 mM) of a 4-dimethylaminopyridine and 0.75 ml (7.84 mM) of acetic anhydride in 18 ml of dry dimethylformamide was stirred at room temperature for two days. The reaction mixture was evaporated in vacuo and the residue dissolved in ethyl acetate and absorbed on silica gel. The solvent was removed by flash evaporation and the residual powder added to a column prepared for flash chromatography. Elution with 5% methanol in dichloromethane gave 1.0 g of a semicrystalline oil which on recrystallization from benzene-hexane gave analytically pure 9-(2-acetoxyethoxymethyl)-2-amino-9H-purine, mpt. 115°-118° C. An additional crop was obtained from the mother liquor.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:20](OCC)(OCC)OCC>>[N:12]1([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:20]1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Product: CCOC(=O)CCn1cnc2cnc3ccccc3c21
Reaction time: 3 h

Procedure:
The method described in Part A of Example 10 was used to treat ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (10.0 g, 38.6 mmol, prepared in Part A of Example 18) with triethyl orthoformate (8.98 mL, 54.0 mmol). The reaction was complete in three hours. The reaction mixture was filtered to remove a precipitate and then subjected to the work-up procedure to provide 9.7 g of ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)propanoate.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:24]3[S:25][C:26]([CH3:29])=[CH:27][N:28]=3)[CH2:20][C:21]([O-:23])=[O:22])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([C:24]3[S:25][C:26]([CH3:29])=[CH:27][N:28]=3)[CH2:20][C:21]([OH:23])=[O:22])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1cccc(CCOc2ccc(CC(CC(=O)[O-])c3ncc(C)s3)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1cccc(CCOc2ccc(CC(CC(=O)O)c3ncc(C)s3)cc2)n1
Reaction time: 18 h
Yield: 62 %

Procedure:
To a solution of methyl (±)-[4-[4-[2-(6-methylaminopyridin-2-yl)-1-ethoxy]phenyl]-3-(5-methylthiazol-2-yl)butanoate (0.85 mmole) in 1:1 THF/H2O (5 mL) was added 1.0 N NaOH (1.28 mL, 1.28 mmole). After 18 hr the mixture was acidified to pH 6 using 10% HCl then concentrated to dryness. The residue was chromatographed on silica gel (EtOH) to give the title compound as a yellow solid (217 mg, 62% over 2 steps). MS (ES) m/e 412 (M+H)+. Anal. Calcd for C22H25N3O3S 1.2H2O: C, 61.01; H. 6.38; N. 9.70. Found: C, 61.25; H. 6.06; N, 9.32.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].Br[CH:19]([CH2:21][CH2:22][CH3:23])[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH3:20][CH:19]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(C)Br
Reactant: O=Cc1cccc2[nH]ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(C)n1ccc2c(C=O)cccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1H-indole-4-carbaldehyde (1) (1.0 g, 6.88 mmol) in dimethylformamide (DMF, 35 mL) was added potassium t-butoxide (KOtBu, 1.16 g, 10.32 mmol) at 0° C. After the resulting solution was stirred for 30 min at 0° C., 2-bromopentane (2) (1.05 ml, 8.27 mmol) was added dropwise, and the reaction solution was warmed up to room temperature gradually and stirred for 12 h at room temperature. Water (5 ml) was added to quench the reaction. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with H2O (40 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (6:1 hexane/ethyl acetate) recovered 1H-indole-4-carbaldehyde (1) (500 mg) and gave 1-(pentan-2-yl)-1H-indole-4-carbaldehyde (3) mixed with residual 2-bromopentane (2), which was used in the following step directly.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH4+:23].[OH-]>CC(O)C>[NH2:23][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: [NH4+]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N
Temperature: 120 °C
Yield: 61 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 51 mg, 0.172 mmol) and NH4OH (670 μl, 17.21 mmol) in propan-2-ol (1.7 ml) and heating in a microwave reactor (Biotage Initiator) at 120° C. for 10 min. Purification by silica gel (100% DCM to 5% MeOH/DCM) provided 2-(3-amino-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.52 (s, 3H) 2.94 (t, J=6.85 Hz, 2H) 3.44 (td, J=6.80, 2.25 Hz, 2H) 6.94 (br. s., 1H) 6.98 (d, J=2.15 Hz, 1H) 7.15 (br. s., 2H) 7.29 (t, J=7.82 Hz, 1H) 7.54 (dd, J=8.02, 0.98 Hz, 1H) 7.91 (dd, J=7.53, 1.08 Hz, 1H) 12.45 (br. s., 1H). MS (ESI, pos. ion) m/z: 294.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[F:17][C:18]([F:31])([F:30])[C:19]1[NH:20][C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([CH2:28][NH2:29])=[CH:23][CH:22]=2.C(N(CC)CC)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:29][CH2:28][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:18]([F:31])([F:17])[F:30])=[CH:27]3)=[O:10])=[CH:6][N:7]=1
Reactant: O=C(O)c1cnc(Cl)nc1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1cnc(Cl)nc1
Reaction time: 2 h
Yield: 56.5 %

Procedure:
2-Chloro-pyrimidine-5-Carboxylic acid (209 mg, 1.317 mmol) was stirred in dichloromethane (20 ml). Oxalyl chloride (0.210 ml, 2.394 mmol) then DMF (4.63 μl, 0.060 mmol) was added. The reaction mixture was then left to stir for 2 h under Argon gas. The reaction mixture was then evaporated to dryness and the resulting residues were then dissolved in dichloromethane (20 ml). A solution of {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 300 mg, 1.197 mmol) in DCM (10 mL) was added then triethylamine (0.500 ml, 3.59 mmol) was added. The reaction mixture was then left to stir at room temperature for 24 h. The reaction mixture was evaporated to dryness. The resulting residues where then partitioned between 2M HCl (50 ml) and ethyl acetate (50 ml). The organic layer was collected, dried (MgSO4), filtered and the solvent was removed. The resulting residues where then purified on the MDAP to give the title compound (240 mg);
Reaction SMILES: [K].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1>C(O)(C)(C)C>[C:2]([CH:4]([C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3]
Reactant: CCOC(=O)CC#N
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [K]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C#N)c1ncccc1[N+](=O)[O-]
Yield: 64.8 %

Procedure:
Potassium (2.5 g, 63 mmol) was carefully added in small lumps to dry t-butanol (80 mL, distilled from calcium hydride). Upon complete addition, the reaction was warmed to 50° and stirred until all the potassium was consumed. Ethyl cyanoacetate (6.71 mL, 63 mmol) was added and a thick white precipitate was formed. 2-Chloro-3-nitropyridine (5 g, 31.5 mmol) was added in hot (60° C.) t-butanol (80 mL) and the reaction turned dark orange upon addition. The reaction was heated to reflux for two hours, the t-butanol was removed and the residue partitioned between hydrochloric acid (1N) and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was dried over magnesium sulfate, filtered and the solvent removed. The brown solid residue was recrystallized from ethyl acetate to give the desired product as red needles (4.8 g, 65%); m.p. 133-134° C.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[C:9]([O:16]C)[CH:10]=[CH:11][C:12]=2[O:14]C)[N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[N+]([O-])([O-])=O.[NH4+].[Ce]>CC#N>[N+:1]([C:4]1[C:13]2[C:12](=[O:14])[CH:11]=[CH:10][C:9](=[O:16])[C:8]=2[N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COc1ccc(OC)c2c([N+](=O)[O-])ccnc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1C=CC(=O)c2c([N+](=O)[O-])ccnc21
Reaction time: 0.25 h

Procedure:
400 mg (1.71 mmol) of 4-nitro-5,8-dimethoxyquinoline are dissolved in 10 mL of CH3CN and 5 mL of water at room temperature. 2.8 g (5.2 mmol) of cerium ammonium nitrate are added and the reaction medium is stirred for 15 min. After evaporating off the CH3CN on a rotary evaporator, 10 mL of water are added and the medium is extracted with CH2Cl2 (3 times 20 mL). After drying the organic phases and evaporating off the solvent on a rotary evaporator, 290 mg of 4-nitroquinoline-5,8-dione are obtained in the form of an orange powder.
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:27]#[N:28])([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:29])(OC)=O.CS(C)=O.[Cl-].[Na+]>O>[C:27]([C:9]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:19])[F:20])=[C:13]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:12]=2)[CH2:10][CH2:5][C:6](=[O:29])[CH2:7][CH2:8]1)#[N:28]
Reactant: COC(=O)C1CC(C#N)(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCC(=O)CC1
Temperature: 145 °C
Yield: 23.9 %

Procedure:
A mixture of 2-carbomethoxy-4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)cyclohexan-1-one (0.98 g, 2.4 mmole), dimethyl sulfoxide (10 mL), water (0.62 mL) and sodium chloride (0.62 g) under an argon atmosphere was heated at 145° C. for 5 h. The reaction mixture was cooled to room temperature and concentrated. The residue was partitioned between ether and water, the organic layer washed with water, was dried (magnesium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 20-30% ethyl acetate/hexanes. The isolated residue was dissolved in ethyl acetate, this was washed twice with dilute sodium hydroxide, once with water, once with brine and then was dried and evaporated to yield a solid (0.2 g, 23.6%): m.p. 76°-78.5° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:23]1[CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CS(C)=O.O>[N:23]1([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCC3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (100 mg, 0.32 mmol) in DMSO (2 mL) was added azetidine (37 mg, 0.65 mmol) and DIEA (81 mg, 0.63 mmol). After stirring for 2 hours at 70° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford a residue, which was purified via silica gel column chromatography (2% dichloromethane in petroleum ether) to afford methyl 3-(azetidin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a light yellow solid (60 mg, 56%).