Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[F:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:29]=1[CH2:43][OH:44].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C.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>[ClH:1].[F:27][C:28]1[CH:33]=[C:32]([C:2]2[C:3]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15]4[CH:16]=[N:17][N:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:19]=4[CH3:20])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH:31]=[CH:30][C:29]=1[CH2:43][OH:44]
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1-c1ccccc1
Reactant: CC1(C)OB(c2ccc(CO)c(F)c2)OC1(C)C
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: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(CO)c(F)c3)CC2)cnn1-c1ccccc1
Product: Cl
Temperature: 25 °C
Yield: 82 %

Procedure:
Stir together 3′-chloro-4-(5-methyl-1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (184 mg, 0.50 mmol), [2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanol (151 mg, 0.60 mmol), potassium carbonate (166 mg, 1.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.006 g, 0.003 mmol) and water (1 mL), in N,N-dimethylacetamide (2 mL) at room temperature under nitrogen, then heat at 120° C. for 3 hr. Cool to room temperature, add water (20 mL) and extract with DCM (3×20 mL). Pass the combined DCM extracts through an IST Phase Separator Frit®, concentrate and purify (silica gel chromatography, eluting with 5:95 to 15:85 methanol:DCM). Dry in a vacuum oven over night, then dissolve the yellow powder in acetonitrile. Add 2 M aq. HCl and water then lyophilize to give the title compound as light yellow powder (203 mg, 82%). MS (ES): m/z=459 [M+H].
Reaction SMILES: [CH:1]([O:14][C:15]([CH2:17][O:18]/[N:19]=[C:20](/[C:52]1[N:53]=[C:54]([NH:57][C:58]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[S:55][CH:56]=1)\[C:21]([NH:23][CH:24]1[C:50](=[O:51])[N:26]2[C:27]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:28]([CH2:32]Cl)[CH2:29][S:30](=[O:31])[C@H:25]12)=[O:22])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:77].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>CC(C)=O>[CH:1]([O:14][C:15]([CH2:17][O:18]/[N:19]=[C:20](/[C:52]1[N:53]=[C:54]([NH:57][C:58]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[S:55][CH:56]=1)\[C:21]([NH:23][CH:24]1[C:50](=[O:51])[N:26]2[C:27]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:28]([CH2:32][I:77])[CH2:29][S:30](=[O:31])[C@H:25]12)=[O:22])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in (A) was dissoved in 380 ml of acetone, and 7.4 g (49 mmol) of sodium iodide was added thereto. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 300 ml of a 10% sodium thiosulfate aqueous solution and 1150 ml of ethyl acetate were added for extraction. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flush column chromatography (ethyl acetate/n-hexane =1/1) to obtain 22.4 g of a powder of the above-identified compound (yield from the previous step: 86.7%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:18]([C:22]1[CH:23]=[CH:24][C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:29])=[N:26][CH:27]=1)[CH2:19][CH2:20][CH3:21].B(Br)(Br)Br.C(Cl)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:14]([NH2:26])[CH:15]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:18]([C:22]1[CH:23]=[CH:24][C:25]([C:28]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[C:34]([NH2:7])[CH:35]=2)=[O:29])=[N:26][CH:27]=1)[CH2:19][CH2:20][CH3:21]
Reactant: ClCc1ccccc1
Reactant: COc1ccc(C(=O)c2cccc(C)n2)cc1
Reactant: CCCCc1ccc(C(=O)c2ccc(OC)cc2)nc1
Agent: BrB(Br)Br
Product: CCCCc1ccc(C(=O)c2ccc(OCc3ccccc3)c(N)c2)nc1
Product: Cc1cccc(C(=O)c2ccc(OCc3ccccc3)c(N)c2)n1

Procedure:
4-Methoxyphenyl (6-methyl-2-pyridyl) ketone and 4-methoxyphenyl (5-n-butyl-2-pyridyl) ketone are nitrated, cleaved with BBr3, treated with benzyl chloride and reduced according to the procedures of Example 1 to give 3-amino-4-benzyloxyphenyl (6-methyl-2-pyridyl) ketone and 3-amino-4-benzyloxyphenyl (5-n-butyl-2-pyridyl) ketone. These compounds are substituted for 3-amino-4-benzyloxyphenyl 2-pyridyl ketone in Example 2 to give α-(4-hydroxy-3-ureidophenyl)-6-methyl-2-piperidylcarbinol hydrochloride and α-(4-hydroxy-3-ureidophenyl)-5-n-butyl-2-piperidylcarbinol hydrochloride. The analogous methylureido compounds are prepared as described in Example 2.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17]C1C=NC(Br)=CN=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl.C(OCC)(=O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][NH2:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cnc(Br)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(CN)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of 3-cyclopentyloxy-4-methoxy-benzaldehyde (417 mg, 1.895 mmol), 2-amino-5-bromopyrazine (300 mg, 1.724 mmol), sodium triacetoxyborohydride (1.5 eq) and glacial acetic acid (3 eq) in dichloromethane (10 ml) was stirred at room temperature overnight. Then the reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by ISCO (SiO2 flash column chromatography) (Hexane/ethyl acetate=100/0 to 3/2) to give about 400 mg of 6-bromo-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine. Yield: 61%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2.[CH3:20][O:21][CH2:22][CH2:23]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.COCO>C1C=CC=CC=1.CCCCCC>[CH3:20][O:21][CH2:22][CH2:23][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Agent: CCCCP(CCCC)CCCC
Agent: COCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COCCOc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (0.1 g, 0.4 mmol) in benzene (5 mL) was added 2-methoxyethanol (0.09 ml, 1 mmol) and tri-n-butylphosphine (0.1 ml, 0.6 mmol). The resulting mixture was cooled to 0° C. followed by adding 1.1′-(azodicarbonyl)dipiperidine (0.1 g, 0.6 mmol). After 10 min, ice bath was removed; the reaction mixture was warmed up to rt. After 2 h, TLC showed there still existed 50% starting material. More methoxymethanol (2 eq, 0.06 mL) was added. The reaction mixture was continued to stir for 20 h. Hexane was added to the reaction mixture and dihydro-ADDP separated out was filtered off. The filtrate was concentrated. The crude product was purified using SiO2 chromatography (Teledyne Isco RediSep®, P/N 68-2203-027, 40 g SiO2, hexane:acetone=85%:15%, Flow=40 mL/min) to afford the desired product as colorless liquid. MS m/z: 318.4 (M+H). Calc'd. for C18H23NO4—317.38.
Reaction SMILES: C([O:4][C@@H:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]([NH2:18])=[O:17])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[CH2:6]1)(=O)C.C(O[C@H]1C2C=CC=CC=2N(C(N)=O)C2C=CC=CC=2C1)(=O)C.O[C@@H]1C2C=CC=CC=2N(C(N)=O)C2C=CC=CC=2C1.O[C@H]1C2C=CC=CC=2N(C(N)=O)C2C=CC=CC=2C1>>[O:4]=[C:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]([NH2:18])=[O:17])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]=2[CH2:6]1
Reactant: CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Agent: CC(=O)O[C@@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Agent: NC(=O)N1c2ccccc2C[C@@H](O)c2ccccc21
Agent: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Product: NC(=O)N1c2ccccc2CC(=O)c2ccccc21

Procedure:
In an another embodiment, the invention provides a process for preparing (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide, or (R)-(+)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide from (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide or (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz[b,f]azepine-5-carboxamide, which are obtained by enantioselective reduction of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide or derivatives thereof in presence of sodium borohydride and tartaric acid derived ester of phenyl boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:5].C(N(CC)C(C)C)(C)C.[Cl:35][C:36]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[CH:17]1[C:8]2[CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:21]=[CH:22][C:23]([NH:25][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:43]([Cl:45])=[CH:44][C:36]=4[Cl:35])=[CH:24][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.50 g of 5-(2-chloro-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.28 g of N,N-diisopropylethylamine and 0.45 g of 2,4-dichlorobenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water, saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. The filtrate is evaporated in vacuo to give the desired product as a solid residue, m.p., 150°-165° C.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[CH3:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[Cl:43]CCl>>[ClH:43].[C:18]1([C@H:17]([NH:24][C@H:2]([CH3:15])[CH2:3][C:4]2[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCl
Reactant: COC(=O)Cc1cccc(CC(C)=O)c1
Reactant: C[C@@H](N)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(C[C@@H](C)N[C@H](C)c2ccccc2)c1
Product: Cl

Procedure:
A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 24) (8.50 g, 41.2 mmol), (R)-α-methyl benzylamine (4.8 mL, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) and acetic acid (2.2 mL, 38 mmol) in dichloromethane (400 mL) was stirred at room temperature for 48 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (200 mL) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with dichloromethane (100 mL). The combined organic extracts were dried (magnesium sulfate) and reduced in vacuo. Purification by flash column chromatography eluting with dichloromethane:methanol: ammonia (99:1:0.1 to 95:5:0.5 by volume) gave a 4:1 mixture of diastereomers (R,R major) as a pale yellow oil (8.71 g). Treatment with hydrogen chloride (40 mL of a 1M solution in methanol, 40 mmol) followed by three successive crystallisations (diisopropylether/ methanol) gave the title compound as a white crystalline solid (5.68 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][CH2:28]O)[CH:24]=[CH:23][N:22]=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12>C1COCC1>[CH3:20][C:21]1[CH:26]=[C:25]([CH2:27][CH2:28][N:34]2[C:30](=[O:40])[C:31]3[C:32](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:33]2=[O:35])[CH:24]=[CH:23][N:22]=1
Reactant: Cc1cc(CCO)ccn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CCN2C(=O)c3ccccc3C2=O)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triphenylphosphine (3.18 g, 12.12 mmol) and diisopropylazodicarbocylate (2.39 μL, 12.12 mmol) in 10 mL of THF was stirred at 0° C. for 30 min and combined with a solution of 2-(2-methyl-pyridin-4-yl)-ethanol and phthalimide (1.33 g, 9.7 mmol) in 10 mL of THF. The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and the organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions. The organic layer was dried over sodium sulfate and concentrated in vacuo. Flash chromatography on silica using a dichloromethane/methanol gradient (2–10%) gave 2.5 g of the title product.
Reaction SMILES: [CH2:1]([NH:13][C:14]([C:16]1[CH:44]=[CH:43][C:19]([CH2:20][N:21]([CH2:29][CH:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]2)[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:45]>C(Cl)Cl.O1CCOCC1>[ClH:45].[CH2:26]([O:25][C:23](=[O:24])[C:22]([N:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:15])=[CH:44][CH:43]=1)[CH2:29][CH:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1)=[O:28])[CH3:27]
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C(=O)OCC)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN(CC2CCNCC2)C(=O)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a cold (0° C.) solution of tert-butyl 4-({{4-[(dodecylamino)carbonyl]benzyl}[ethoxy(oxo)acetyl]amino}methyl)piperidine-1-carboxylate (3.84 g, 6.24 mmol) in DCM (25 mL) was added a 4 N solution of HCl in dioxane (31.1 mL) and the resulting reaction mixture was stirred 4 h at 0° C. Evaporation of the solvents gave a white amorphous solid (73%). 1H NMR (DMDO-d6, 300 MHz) δ 9.03 (m, 0.5H), 8.70 (m, 0.5H), 8.50 (m, 1H), 7.85 (m, 2H), 7.33 (m, 2H), 4.56 (d, 2H, J=8.9 Hz), 4.40-4.20 (m, 2H), 3.35-3.10 (m, 7H), 2.80 (m, 2H), 1.70 (m, 2H), 1.52 (m, 2H), 1.43-1.15 (m, 21H), 0.86 (m, 3H). M−(LC/MS(ESI)): 514.4; M+(LC/MS(ESI)): 516.4. HPLC (Condition A), Rt: 4.68 min (HPLC purity: 99.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[ClH:15].[ClH:15].[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CNCCc1ccc(F)cc1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1ccc(F)cc1)CC2
Product: Cl

Procedure:
This compound was prepared analogous to Example 5(b) by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(4-fluoro-phenyl)-ethyl]-amine.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:19]=O)=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]=2[C:7]1=[O:21])[CH3:2].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCCC1>C(O)C>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:19]=[C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([F:24])[CH:26]=4)[NH:30][C:29]3=[O:34])=[C:14]([C:15]([F:16])([F:18])[F:17])[C:8]=2[C:7]1=[O:21])[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C(F)(F)F)c2C1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C(F)(F)F)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (40 mg, 0.121 mmol), 5-fluoro-1,3-dihydro-indol-2-one (18 mg, 0.12 mmol) in 0.4 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with anhydrous ethanol (1 ml×3), purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-trifluoromethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (46 mg, 83.6%) as a yellow solid
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH2:12][CH:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12]([OH:11])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:19]=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOCC(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2cc(F)ccc2c1O
Temperature: 100 °C
Yield: 67.6 %

Procedure:
Under a nitrogen atmosphere, 3-fluoroaniline (50.0 g, 0.45 mol) and diethyl ethoxymethylmalonate (91 mL, 0.45 mol) were combined and heated at 100° C. for 3 hours. The reaction was allowed to cool to ambient temperature and it solidified. Dowtherm A (200 mL) was added and the reaction mixture was heated at 240° C. for 4 hours. The reaction mixture was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, washed with hexane and then dried in a vacuum oven to provide 71.5 g of ethyl 7-fluoro-4-hydroxy-3-quinolinecarboxylate.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:10][C:11]([Cl:16])(Cl)[C:12](Cl)=[O:13].P(Cl)(Cl)(Cl)=O>C(OCC)C.[Cu].[Zn]>[CH2:1]([CH:2]1[CH2:3][C:12](=[O:13])[C:11]1([Cl:16])[Cl:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CCc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1CC(Cc2ccccc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To a room temperature mixture containing allylbenzene (1.84 g, 15.6 mmol), zinc-copper couple (5.1 g, 78 mmol) and diethylether (60 ml) was added dropwise a solution of trichloroacetylchloride (2.96 ml, 26.5 mmol) and phosphorus oxychloride (2.46 ml, 26.5 mmol) in diethylether (20 ml). The reaction mixture was stirred at room temperature for 1 hour, filtered and the filtrate was partially concentrated. The residue was neutralized with saturated NaHCO3. The aqueous phase was extracted with diethylether. The combined organic phases were washed successively with H2O and brine, dried over Na2SO4, and concentrated. The residue was chromatographed over silica gel (hexane) to provide (RS)-3-benzyl-2,2-dichlorocyclobutanone (0.71 g, 20%) as a yellow oil, MS: m/e=228.1 (M-H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](=O)[CH3:14])[N:12]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[Na+].CO>CCOC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH:10]=[C:11]([C:13](=[N:33][OH:34])[CH3:14])[N:12]=1
Reactant: CC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2Cl)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=NO)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(-c2ccccc2Cl)n1
Yield: 50.8 %

Procedure:
To a 50 mL RB flask attached with Vigreux column was added compound 1-[2-(2-Chloro-phenyl)-1-(3′-methanesulfonyl-biphenyl-4-yl)-1H-imidazol-4-yl]-ethanone (162 mg, 359 μmol), hydroxylamine-HCl (200 mg, 2.87 mmol), sodium acetate (238 mg, 2.90 mmol), MeOH (12 mL) and H2O (6 mL). The reaction solution was allowed to stir at reflux for 2 hrs prior to TLC analysis. The reaction solution was diluted with EtOAc (150 mL), washed with aq. NaCl (100 mL), partitioned, dried over Na2SO4, filtered, and concentrated on the Rotavapor. The crude product was chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 80% EtOAc to afford 85 mg (51% yield) of the title compound as a mixture of E and Z isomers. The isomers were separated by chromatography with a Reverse Phase HPLC using a C18 Preparative column. Characterization for one single oxime isomer: 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.15 (t, 1H), 8.02 (d, 1H), 7.90 (d, 1H), 7.85 (s, 1H), 7.80 (d, 2H), 7.72 (t, 1H), 7.64 (d, 1H), 7.47-7.44 (m, 3H), 7.35 (d, 2H); MS (ES): 466.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([CH2:18]OS(C)(=O)=O)[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][CH2:33][C:32]1([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>C1COCC1.O>[C:24]([O:28][C:29]([N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([CH2:18][C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[C:6]3[N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[N:9]=[C:10]([CH3:11])[C:5]=23)[CH2:33][C:32]1([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1nn(C2CCCCO2)c2nc(Br)cc(COS(C)(=O)=O)c12
Reactant: CCC1(CC)CNC(C)(C)CN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CC)CN(Cc2cc(Br)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Temperature: 160 °C
Yield: 51.6 %

Procedure:
A mixture of 500 mg of methanesulfonic acid 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl ester, 400 mg of 2,2-diethyl-5,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester and 0.43 ml of DIPEA in 8 ml of dry THF was heated to 160° C. for 30 min in a microwave reactor. For workup the mixture was taken up in water and ethyl acetate, the phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo and the resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate). 369 mg (50%) of the title compound were obtained.