Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(Cl)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-chlorophenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.87 (dd, J=6.60, 3.18 Hz, 6H), 1.41-1.51 (m, 1H), 1.65 (ddd, J=13.69, 7.21, 6.97 Hz, 1H), 1.95 (ddd, J=13.57, 7.70, 7.58 Hz, 1H), 3.74 (t, J=7.83 Hz, 1H), 7.33-7.40 (m, 2H), 7.50-7.59 (m, 4H), 7.65 (s, 1H), 7.67 (d, J=1.47 Hz, 2H), 7.75 (d, J=8.31 Hz, 2H); Calcd for C25H22ClF3O2 (M+H) 447.13, Found 447.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:19][CH:20]=3)[C:9]2=[O:12])=[CH:4][N:3]=1
Reactant: Oc1nccc2cnc(Br)cc12
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Cn2ccc3cnc(Br)cc3c2=O)cc1

Procedure:
The alkylation of 7-bromo-1-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 4-bromomethyl-benzene sulfonamide (1.67 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product. Step (2): 4-[1-oxo-7-(3-phenyl-prop-1-ynyl)-1H-6-azaisoquinolin-2-ylmethyl]benzenesulfonamide
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[CH:6][C:7]=1[C:8](Cl)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[NH4+:30].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[CH:6][C:7]=1[C:8]([NH2:30])([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]1[S:10][CH:11]=[CH:12][N:13]=1
Reactant: O=c1cnn(-c2ccc(C(Cl)(c3ccc(Cl)cc3)c3nccs3)c(Cl)c2)c(=O)[nH]1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(c1ccc(Cl)cc1)(c1nccs1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of compound (36) (0.00425 mol) in THF (20 ml) was added dropwise at 5° C. to NH4OH (20 ml) and the mixture was stirred at RT for 2 hours, then poured out on ice, neutralized with HCl 6N and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was repurified by column chromatography over Kromasil C18 (eluent: CH3OH/H2O/HOAc 70/30/1). The pure fractions were collected and the solvent was evaporated. The residue was taken up in H2O and NH4OH (pH=8) was added. The precipitate was filtered off, washed with H2O and diethyl ether, and dried, yielding 0.3 g (±)-2-[3-chloro-4-[amino-(4-chlorophenyl)-2-thiazolylmethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 35).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:40][C:41]1[C:42]([C:49]2[C:54]([Cl:55])=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:56])=[N:43][O:44][C:45]=1[CH:46]1[CH2:48][CH2:47]1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:40][C:41]2[C:42]([C:49]3[C:50]([Cl:56])=[CH:51][CH:52]=[CH:53][C:54]=3[Cl:55])=[N:43][O:44][C:45]=2[CH:46]2[CH2:48][CH2:47]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.2 %

Procedure:
To a solution of 13.05 g (64.83 mmol) of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester in THF (120 mL) is added at 0° C. (ice bath) 18-crown-6 (19.6 g, 73.48 mmol) and potassium tertiary butoxide (8.68 g, 73.48 mmol). The resulting mixture is stirred for 20 min at room temperature, and added dropwise to a solution of 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (15 g, 43.22 mmol) in 75 mL of THF. The resulting mixture was stirred at room temperature for 14 h. To the reaction mixture is added water (500 mL), and it is extracted with EtOAc (3×200 mL). The organics are washed with brine (2×250 mL), dried (Na2SO4), filtered and concentrated to afford a crude which is purified by flash chromatography eluting with Hexanes/EtOAc 8:2, to obtain the title compound as a pale yellow oil (16 g (79%)). MS (m/e): 467 (M+1)
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([C@H:12]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:14](=[O:27])[C@H:13]1[NH2:28])=[O:11].[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:8][O:9][C:10]([C@H:12]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:14](=[O:27])[C@H:13]1[NH:28][C:36](=[O:37])[CH2:35][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:11]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)[C@@H]1[C@H](N)C(=O)N1Cc1ccc(OC)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1[C@H](NC(=O)Cc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 1 h

Procedure:
Under ice-cooling and stirring, 2.10 ml of triethylamine is added to a solution of 2.94 g of cis-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester in 40 ml of methylene chloride, and a solution of 2.31 g of phenylacetyl chloride in 15 ml of methylene chloride is then added dropwise over 1 hour. The stirring is continued for another one hour under ice-cooling, and the reaction mixture is then washed successively with dilute hydrochloric acid, 5% aqueous sodium hydrogen carbonate and an aqueous sodium chloride solution, and dried over magnesium sulfate, and the solvent is distilled off in vacuo. Ether is added to the residue and the precipitated crystals are collected by filtration to give cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 124°-126° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:14]1[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=1.[N:24]1([CH2:30][C:31]2[CH:32]=[C:33]([NH2:43])[CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:36]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>O1CCOCC1.C(OCC)(=O)C>[N:24]1([CH2:30][C:31]2[CH:32]=[C:33]([NH:43][C:14]3[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[CH:34]=[C:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:36]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(CN2CCOCC2)cc(-c2ccccc2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccnc(Nc2cc(CN3CCOCC3)cc(-c3ccccc3)c2)n1
Temperature: 80 °C

Procedure:
p-Toluenesulfonic acid monohydrate (75 mg, 0.395 mmol) was added to a solution of 2-chloro-4-(trifluoromethyl)pyrimidine (36 mg, 0.198 mmol) and 5-(morpholin-4-ylmethyl)biphenyl-3-amine (53 mg, 0.198 mmol) in dioxane (1.98 mL) and heated to 80° C. for 14 hours, then allowed to cool to room temperature. The mixture was diluted with ethyl acetate (30 mL) and washed with saturate aqueous NaHCO3 (30 mL) and 1:1 water: brine (2×30 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (thyl acetate/hexanes) provided N-[5-(morpholin-4-ylmethyl)biphenyl-3-yl]-4-(trifluoromethyl)pyrimidin-2-amine. MS ESI calc'd. for C22H22F3N4O [M+H]+ 415, found 415. 1H NMR (400 MHz, CDCl3): δ 8.67 (d, J=4.9 Hz, 1H); 7.90 (s, 1H); 7.66 (d, J=7.7 Hz, 2H); 7.58 (s, 1H); 7.51-7.42 (m, 3H); 7.39 (t, J=7.4 Hz, 1H); 7.33 (s, 1H); 7.06 (d, J=4.9 Hz, 1H); 3.76 (t, J=4.5 Hz, 4H); 3.61 (s, 2H); 2.54 (t, J=4.2 Hz, 4H).
Reaction SMILES: [CH:1]12[NH:27][CH2:26][CH:5]([N:6]([C:8]3[C:17]([F:18])=[C:16]4[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]4[CH2:19][CH3:20])=[CH:10][C:9]=3[F:25])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[CH2:28]=O>C(O)=O>[CH2:19]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([F:25])=[C:8]([N:6]3[CH2:7][CH:1]4[N:27]([CH3:28])[CH2:26][CH:5]3[CH2:4][CH2:3][CH2:2]4)[C:17]=2[F:18])[C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14]1)[CH3:20]
Reactant: C=O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCCC3CN4)c(F)c21
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCCC3CN4C)c(F)c21

Procedure:
A mixture of 0.20 g (0.52 mmol) of 7-(6,8-diazabicyclo[3.2.2]non-6-yl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5 ml of 37% formaldehyde solution, and 5 ml of formic acid was heated under reflux for 3.6 hr. The reaction mixture was evaporated to dryness and the residue was suspended in ethanol/HCl. The solid was collected by filtration to give 0.16 g of the title compound as the hydrochloride salt, mp >300°.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8](OC3C=CC=CC=3)[C:7]=2[N:21]=1)[CH3:2].[NH3:26]>CO>[CH2:1]([NH:3][C:4]1[N:5]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]=[C:8]([NH2:26])[C:7]=2[N:21]=1)[CH3:2]
Reactant: CCNc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)C
Reactant: N
Solvent: CO
Product: CCNc1nc2c(N)nc(C)c(C)c2n1CC(C)C
Temperature: 170 °C

Procedure:
N-Ethyl-6,7-dimethyl-1-(2-methylpropyl)-4-phenoxy-1H-imidazo[4,5-c]pyridin-2-amine (1.3 g, 3.8 mmol) and ammonia (25 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 170° C. for four days. The resulting solution was allowed to cool to ambient temperature and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with 2-4% methanol in dichloromethane with 1% aqueous ammonium hydroxide added) to provide 294 mg of N2-ethyl-6,7-dimethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]pyridine-2,4-diamine as a yellow powder, mp 168-170° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Temperature: 80 °C
Yield: 18.5 %

Procedure:
A mixture of [4-(methylthio)phenyl]boronic acid (16.8 mg, 0.1 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (36 mg, 0.10 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) was heated at 80° C. overnight. The reaction was cooled to ambient temperature, transferred onto a 1 mL Varian Chem Elut column, eluted with EtOAc, and the filtrate concentrated. The crude product was purified by reverse-phase preparative HPLC using a MeOH:H2O gradient (20:80 to 100:0) with 0.1% formic acid as a modifier to afford the title compound (7.4 mg, 12%). LRMS (ESI), m/z 422 (M+Na).
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1)=[O:5].[CH:25]([NH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1)=[O:26]>N1C=CC=CC=1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:2]=1[NH:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([NH:27][CH:25]=[O:26])[CH2:29][CH2:30]1
Reactant: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2F)cc1OC
Reactant: N[C@H]1CC[C@H](NC=O)CC1
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2N[C@H]2CC[C@H](NC=O)CC2)cc1OC
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 2-fluoro-N-(3,4-dimethoxybenzyl)-5-nitrobenzamide (200 mg) and trans-4-formamidocyclohexylamine (170 mg) in pyridine (2 mL) was stirred for 4 hours at 50° C. The mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with 1N HCl and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 5% methanol in chloroform. The obtained product was recrystallized from acetone (2 mL) to give N-(3,4-dimethoxybenzyl)-2-[(trans-4-formamidocyclohexyl)amino]-5-nitrobenzamide as yellow crystals (164 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][S:15]([CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)(=[O:17])=[O:16])[C:10]([O:12][CH3:13])=[O:11])=O)(C)(C)C.Cl.O1CCOCC1>C1COCC1>[NH2:8][C@@H:9]([CH2:14][S:15]([CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)(=[O:16])=[O:17])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@H](CS(=O)(=O)Cc1cnccn1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CS(=O)(=O)Cc1cnccn1
Reaction time: 48 h

Procedure:
Methyl 2(R)-tert-butoxycarbonylamino-3-(pyrazin-2-ylmethanesulfonyl)propionate was dissolved in THF (5 mL) and a solution of HCl/dioxane (4.0 M, 2.9 mL) was added. After stirring for 48 h, the solvent was removed in vacuo and the residue was precipitated with diethyl ether and dried under vacuum to give methyl 2(R)-amino-3-(pyrazin-2-ylmethanesulfonyl)propionate which was converted to the title compounds utilizing the procedure described in Example 4 above.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C(N(CC)CC)C.Cl[C:22](=O)[CH:23]([CH3:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[CH3:1][N:2]1[C:3]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)[N:13]=[C:22]1[CH:23]([CH3:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CC(C)C(=O)Cl
Reactant: CNc1ccc2ncccc2c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(C)c1nc2c3cccnc3ccc2n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.4 %

Procedure:
To a solution of N6-methylquinoline-5,6-diamine (914 mg, 5.28 mmol) in DCM (30 mL) was added triethylamine (1.07 g, 10.57 mmol). A solution of methyl 4-chloro-3-methyl-4-oxobutanoate (1.3 g, 7.90 mmol) in DCM (10 mL) was added dropwise to the above solution over 5 min. The resulting mixture was stirred at room temperature for 20 min. The mixture was concentrated to dryness. To the residue was added acetic acid (10 mL). The solution was stirred at 60° C. for 2 h. The solvent was removed under reduce pressure and to the residue was added saturated sodium bicarbonate aqueous solution (20 mL). The mixture was extracted with DCM (3×40 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to dryness to give the crude product, which was purified by silica gel column chromatography (DCM/MeOH v/v 30:1) to give the title compound as a yellow solid (560 mg 33% yield). ESI MS: m/z 284.1 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.94-8.88 (m, 2H), 7.95 (d, J=9.2 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.50 (dd, J=4.4, 8.4 Hz, 1H), 3.94 (s, 3H), 3.70-3.63 (m, 4H), 3.28 (d, J=8.4 Hz, 0.5H), 3.23 (d, J=8.4 Hz, 0.5H), 2.86 (d, J=6.0 Hz, 0.5H), 2.82 (d, J=6.0 Hz, 0.5H), 1.47 (d, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C[N:12](C=O)C.N[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24]>C(N(CC)CC)C>[OH:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[C:6]([NH2:12])=[O:7])=[C:18]([CH3:24])[CH:19]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(O)ccc1N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(N)=O)c(-c2ccc(O)cc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
4-Methylbenzoyl chloride was added to a DMF solution of a mixture of 4-amino-3-methylphenol and triethylamine, and stirred at room temperature for 30 minutes. The relative amount of each compound used, and the purification of the product. is described in Production Example 4. Thus was obtained the intended product, 4-hydroxy-2-methylphenyl-4-methylbenzamide (yield: 12%).
Reaction SMILES: O.[CH3:2][C:3]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:5]=[O:6]>[Ni].CO>[CH3:2][CH:3]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:15])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:4][CH2:5][OH:6]
Reactant: CC(=CC=O)CCC=C(C)CC(C)C
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CC(=CCCC(C)CCO)CC(C)C

Procedure:
5 g. of Raney nickel are suspended in 200 ml. of methanol and treated slowly with a solution of 2.5 g. of soda in 5 ml. of water. To this mixture are added 97 g. of 3,7,9-trimethyl-2,6-decadien-1-al dissolved in 0.8 liters of methanol and the resulting mixture is hydrogenated. After uptake 2 of equivalents of hydrogen, the catalyst is filtered off, rinsed with 50 ml. of methanol and the filtrate evaporated. The residue is taken up in 300 ml. of ether, washed three times with 200 ml. of water each time, dried over sodium sulphate and evaporated. By distillation there is obtained pure 3,7,9-trimethyl-6-decen-1-ol of boiling point 90° C/0.7 mm. Hg; nD25 = 1.4570.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:12]=[C:11]([OH:22])[C:10]([OH:23])=[N:9]2>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13]([N:12]=[C:11]([OH:22])[C:10]([OH:23])=[N:9]2)=[C:14]([N+:1]([O-:4])=[O:2])[C:15]=1[NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Nc1cc2nc(O)c(O)nc2cc1Cl
Solvent: CC(=O)O
Product: CCOC(=O)Nc1c(Cl)cc2nc(O)c(O)nc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To an ice-cooled mixture of 50 ml 100% nitric acid and 100 ml glacial acetic acid was added gradually 10 g 6-chloro-7-ethoxycarbonylamino-2,3-dihydroxyquinoxaline. Stirring was continued at 0° C. for 90 min. The reaction mixture was poured into 500 ml ice-water to give 10 g (86%) 7-chloro-6-ethoxycarbonylamino-5-nitro-2,3-dihydroxyquinoxaline as yellow crystals, m.p.>300° C. NMR (DMSO-d6): 12.2 (1H, broad s), 11.7 (1H, broad m), 9.3 (1H, broad s), 7.33 (1H,S), 4.0 (2H,q), 1.2 (3H,t).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1.B(O)(O)O.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][NH2:28]>O>[CH3:23][O:24][CH2:25][CH2:26][CH2:27][NH:28][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[OH:18].[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([OH:18])=[CH:4][CH:3]=1
Reactant: COCCCN
Agent: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Agent: OB(O)O
Solvent: O
Product: COCCCNc1cc(O)c2c(c1O)C(=O)c1ccccc1C2=O
Temperature: 65 °C

Procedure:
2-(methoxypropylamino)-1,4-dihydroxyanthraquinone was prepared as follows: 60 grams of 1,4-dihydroxyanthraquinone, 15.5 grams of boric acid, and 89 grams of methoxypropylamine were slurried in 125 ml of water. The slurry was stirred and heated to 65° Celsius, and a strong stream of air was bubbled through it. These conditions were maintained about nine hours, or until thin layer chromatography of the reaction mixture failed to isolate any, 1,4-dihydroxyanthraquinone.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:6]([CH3:9])=[N:7][CH:8]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:6]([CH3:9])=[N:7][CH:8]=1)=[O:1]
Reactant: Cc1ncc(CO)c(C)c1OCc1ccc(C#N)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1ncc(C=O)c(C)c1OCc1ccc(C#N)cc1
Yield: 64.4 %

Procedure:
A solution of 4-(5-hydroxymethyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (22) (5.6 g, 21 mmol) and manganese (IV) dioxide (9.1 g, 0.105 mol) in toluene (250 mL) was stirred at 60° C. for about 18 hours. Excess manganese (IV) dioxide was filtered through a celite pad and washed with ethyl acetate. The filtrate was evaporated to give 4-(5-formyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (23) (3.6 g, 65% yield) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH2:15][CH2:14]1)=[O:12].[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>>[CH:28]1([CH2:31][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[O:12])[CH2:14][CH2:15]2)[CH2:30][CH2:29]1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: O=CC1CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCN(CC2CC2)c2ccccc21

Procedure:
The title compound was prepared in analogy to Example 5, from [4-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (Example 3), cyclopropanecarboxaldehyde (commercially available; CAS RN 1489-69-6), dibutyltin dichloride and phenylsilane. Light brown solid (53%). MS (ESI): m/z=454.109 [M+H]+.