Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[C:8]([Cl:10])[CH:9]=1)[CH:6]=[O:7].[C:12]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.CCOC(C)=O>[Cl:10][C:8]1[CH:9]=[C:2]([Cl:1])[CH:3]=[C:4]([O:11][CH3:12])[C:5]=1[CH:6]=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc(Cl)c1C=O
Temperature: 50 °C

Procedure:
To a soln. of 4,6-dichlorosalicylaldehyde (2.69 mmol) in 5 mL DMF was added K2CO3 (5.39 mmol) followed by iodomethane (2.96 mmol). The reaction mixture was heated to 50° C. for 3.5 h. At RT, the mixture was diluted with EtOAc and washed 3 times with water and then with brine. The comb. org. layers were dried over MgSO4 and conc. in vacuo to give the desired product as beige solid.
Reaction SMILES: [Cl-].[C:2]([CH2:5][O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[NH3+:13])([OH:4])=[O:3].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>[OH-].[Na+].C(OCC)C>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([NH:13][C@@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:7]2[O:6][CH2:5][C:2]([OH:4])=[O:3])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: [NH3+][C@@H]1CCCC[C@H]1OCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.6 %

Procedure:
To a solution of trans-2-carboxymethoxy-cyclohexyl ammonium chloride (1.048 g, 5 mmoles) in 1N NaOH (15 ml), there was aded a solution of p-toluenesulphonyl chloride (1.048 g, 5.5 mmoles) in diethyl ether (20 ml). The mixture was vigorously stirred for 20 hours at room temperature. The aqueous phase was separated, washed with diethyl ether (20 ml), acidified with HCl 18% to pH 2 and extracted with diethyl ether (5×20 ml). The organic extracts were dried with MgSO4, the drying agent was filtered off and filtrate was evaporated in vacuo. The residue was recrystallized from diisopropyl ether. Thus, there were obtained 1.09 g (67%) of the title compound in the form of white crystals, melting point 56°-58° C.
Reaction SMILES: [CH:1]([N:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12]Br)[CH:5]=[CH:4]1)=[O:2].[N-:14]=[N+:15]=[N-:16].[Li+]>CO>[CH:1]([N:3]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][N:14]=[N+:15]=[N-:16])[CH:5]=[CH:4]1)=[O:2]
Reactant: O=CN1C=CC=C(OCCBr)C=C1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CO
Product: [N-]=[N+]=NCCOC1=CC=CN(C=O)C=C1

Procedure:
To a solution of (E) (2.7 g) in methanol (15 ml), lithium azide (1.65 g) was added. The solution was refluxed for 6 hours and left over night at room temperature. The solvent was removed in vacuo, and the residue was extracted with three 15 ml portions of chloroform to give crude (F) which was purified by chromatography on silica gel with ethyl acetate as eluent. Pure (F) was obtained as a colourless oil. The IR spectrum (chloroform) showed strong bands at 2100 and 1650 cm-1.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5].[C:16]([N:20]=[C:21]=[S:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>C(O)C>[C:16]([NH:20][C:21]([NH:2][C@@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)[CH2:4][OH:5])=[S:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=S)N[C@H](CO)Cc1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
The process is performed as in Example 2, starting with 5.65 g of (2S)-2-amino-3-(3-nitrophenyl)-1-propanol hydrochloride, 3.7 cm3 of tert-butyl isothiocyanate and 3.41 cm3 of triethylamine in 60 cm3 of ethanol, After stirring for 3 days at a temperature in the region of 20° C. and then heating for 30 minutes at a temperature in the region of 60° C., 3.7 cm3 of tert-butyl isothiocyanate are added to the reaction medium and heating is then continued for a further 3 hours at the same temperature. After an identical work-up, 6.45 g of N-(tert-butyl)-N′-[(1S)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea are obtained in the form of a yellow foam. (Rf=0.61 in a 40/5/0.5 by volume mixture of dichloromethane/methanol/aqueous ammonia, on a Merck 60F254R silica plate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:18]=[O:19])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH3:20][Li].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:18]([OH:19])[CH3:20])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=Cc1cc(-c2cccc(Cl)c2)c2ncccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cc(-c2cccc(Cl)c2)c2ncccc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
8-(3-Chlorophenyl)-6-quinolincarbaldehyde (0.8 g) was dissolved in 20 mL of tetrahydrofuran and cooled to -78° C. Methyllithium (4.5 mL, 1.4M) in diethyl ether was added dropwise to the solution over 5 minutes, stirred for 20 minutes, poured into 50 mL of saturated ammonium chloride, and stirred for 5 minutes. The solution was extracted with ethyl acetate (2×75 mL). The extracts were combined and dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (30:70 ethyl acetate:hexanes) to obtain 0.72 g of 8-(3-chlorophenyl)-6-(1-hydroxyethyl)quinoline as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:20]2[CH2:28][C@@H:27]3[C@@H:22]([CH2:23][CH2:24][CH2:25][NH:26]3)[CH2:21]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C[Si](NC(=O)C(F)(F)F)(C)C.Cl[CH2:41][C:42]1[CH2:49][S:48][C@H:47]2[N:44]([C:45](=[O:60])[C@H:46]2[NH:50][C:51](=[O:59])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:43]=1[C:61]([O:63][CH:64]([C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62].[Na+].[I-].Cl>ClCCl.CC(C)=O.O>[CH:64]([O:63][C:61]([C:43]1[N:44]2[C@H:47]([S:48][CH2:49][C:42]=1[CH2:41][N:26]1[CH2:25][CH2:24][CH2:23][C@@H:22]3[C@H:27]1[CH2:28][N:20]([C:3]1[C:2]([Cl:1])=[C:11]4[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]4[CH:12]4[CH2:14][CH2:13]4)=[CH:5][C:4]=1[F:19])[CH2:21]3)[C@H:46]([NH:50][C:51](=[O:59])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:45]2=[O:60])=[O:62])([C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(N3C[C@@H]4CCCN[C@@H]4C3)c(F)cc2c1=O
Agent: C[Si](C)(C)NC(=O)C(F)(F)F
Agent: Cl
Agent: [I-]
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CN3CCC[C@H]4CN(c5c(F)cc6c(=O)c(C(=O)O)cn(C7CC7)c6c5Cl)C[C@H]43)CS[C@H]12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under an N2 atmosphere, 160 mg (0.4 mmol) of 8-chloro-1-cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo[4.3.0]non-8-yl]-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are suspended in 2.25 ml of dichloromethane. 283 μl (1.6 mmol) of trimethylsilyltrifluoroacetamide are added and the mixture is stirred at room temperature for 20 minutes; 0.5 g of 3 Å molecular sieves is then added, and the mixture is stirred at room temperature for one hour, and the solution is evaporated to dryness. Subsequently, a solution of 151 mg (0.283 mmol) of benzhydryl [6R,7R]-3-chloromethyl-8-oxo-7-phenylacetylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate in 2.25 ml of acetone is added. After addition of 46.6 mg (0.367 mmol) of NaI, the mixture is stirred overnight (20 hours), poured into water, adjusted to pH=4 with 1N HCl, and extracted 3× with ethyl acetate. The organic phase is washed with water, dried over MgSO4 and evaporated to dryness. 96 mg (0.106 mmol) (38% of theory) of the title product are obtained by chromatography on silica gel using CH2Cl2 /CH3OH (30:1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:26]([N+:27]([O-])=O)=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)#[N:2].C.O.NN>CO.C1COCC1>[NH2:27][C:26]1[C:17]([NH:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1

Procedure:
A mixture of methyl 2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate (10 g), FeCl3.6H2O (0.1 g), activated charcoal (1 g) in a mixture of methanol (100 ml) and THF (50 ml) was heated under reflux for 30 min. Hydrazine hydrate (7.2 ml) was added dropwise to the reaction mixture and the mixture was then heated under reflux for 14 hours. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. Aqueous sodium bicarbonate was added to the resulting residue and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel to give crystals. Recrystallization from isopropyl ether afforded pale yellow needles (6.0 g, 64%), m.p. 110°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH:18]([CH3:20])[CH3:19])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH:18]([CH3:19])[CH3:20])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CC(C)n1ccc2ncnc(Oc3ccc(N)cc3F)c21
Solvent: C1CCOC1
Product: CC(C)n1ccc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Reaction time: 3 h
Yield: 24.7 %

Procedure:
To a suspension of 248 (10 mg, 0.035 mmol) in THF (1 mL) was added 2-phenylacetyl isothiocyanate (0.007 mL, 0.038 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by flash chromatography, eluent EtOAc/hexane (1:1) and preparative HPLC (C-18 Aquasyl column, gradient: 60% to 95% MeOH in water, 45 min), to afford title compound 249 (4 mg, 26% yield) as a white solid. 1HNMR: (CD3OD) δ (ppm): 8.35(s, 1H), 8.03 (d, J=12.4 Hz, 1H), 7.96(d, J=3.13 Hz, 1H), 7.44-7.26(m, 6H), 6.69 (d, J=3.13 Hz, 1H), 5.29 (quintuplet, J=6.65 Hz, 1H), 3.75(s, 2H), 3.60 (d, J=10.96 Hz, 3H), 1.63(d, J=6.65 Hz, 6H). MS (m/z): 464.2 (M+1).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>>[CH3:19][O:18][C:15]1[N:14]=[N:13][C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCN(c2ccc(OC)nn2)CC1
Agent: [Li]O
Solvent: O
Product: COc1ccc(N2CCC(C(=O)O)CC2)nn1

Procedure:
In analogy to the procedure described for the synthesis of 5′-Fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid the title compound was prepared from 1-(6-Methoxy-pyridazin-3-yl)-piperidine-4-carboxylic acid ethyl ester through saponification with LiOH.H2O. The title compound was isolated as orange solid. MS m/e: 236.2 [M−H].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH:13]=[N:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:16]([O:15][N:14]=[CH:13][CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C=NOCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(=NOCc1ccccc1)C1CCCN1

Procedure:
The solution of 2-(benzyloxyimino-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.50 g, 4.92 mmole) and TFA (10 ml) in dichloromethane (10 ml) is stirred for 2 hours at room temperature. Solvent is removed. The crude product is carried to next step without further purification. M+H+=205.1
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12]CC)[CH3:11].Cl>C(O)C>[ClH:1].[CH2:10]([O:12][C:6](=[NH:7])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=N)c1ccc(Cl)cc1
Reaction time: 72 h

Procedure:
10 g of 4-chlorobenzonitrile was suspended in 12 ml of ethanol and dissolved by adding diethyl ether. While being cooled in an ice bath, it was saturated with HCl gas. After 72 hours, precipitated product was suctioned out. The product was washed with diethyl ether.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]12[CH2:12][CH2:11][C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2.[Cr](Cl)([O-])(=O)=[O:20].[NH+]1C=CC=CC=1>C(Cl)Cl>[C:13]1([C:8]23[CH2:7][CH2:6][C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:20])([CH2:12][CH2:11]2)[CH2:10][CH2:9]3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC=CC12CCC(c3ccccc3)(CC1)CC2
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a stirred solution of 4-[2-methoxyethenyl]-1-phenylbicyclo[2.2.2]octane (Intermediate 7; 12.6 g, 51.99 mmol) in DCM (200 mL) was added pyridinium chlorochromate (33.6 g, 155.97 mmol) in portions and the reaction mixture was allowed to stir at ambient temperature for 2 hrs. Further pyridinium chlorochromate (12 g, 55.99 mmol) was added and stirring was continued for a further 1 hr. The mixture was filtered and the filtrate was concentrated under reduced pressure, ether (200 mL) was added and the organic phase was washed with water (200 mL). Water (200 mL) and ether (2×200 mL) were added to the filtered solid and the mixture was filtered through a pad of celite. The organic extracts were combined, dried (MgSO4) and concentrated to leave a brown gum. This was purified on a 330 g Crawford silica cartridge, loading the sample in DCM and eluting with 5-10-20% EtOAc-isohexane to provide the title compound as a cream solid (7.89 g, 30.53 mmol, 59%); 1H NMR (CDCl3) δ 1.63-1.71 (6H, m), 1.83-1.93 (6H, m), 2.17 (2H, s), 3.67 (3H, s), 7.14-7.19 (1H, m), 7.29-7.32 (4H, m); GC-MS EI m/e M+ 258.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.[Cl:12][C:13]([O:16]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:13]([Cl:12])=[O:16])[CH2:8]2
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-adamantanol (0.912 g, 6 mmol) in dry CH2Cl2 (15 mL) was added bis(trichloromethyl)carbonate (0.653 g), pyridine in dry CH2Cl2 (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for two hours. The solvent was removed in vacuo at 30° C., taken up in ethyl acetate (30 mL) and stirred for 10 minutes. The pyridinium hydrochloride precipitate was filtered off and the solvent removed in vacuo at 30° C., to give an oil which solidified upon standing (1.29 g, 100%). IR (film) 1778 cm-1 ; NMR (CDCl3) δ1.55-1.65 (2H, m), 1.70-1.80 (4H, m), 1.85-1.95 (4H, m), 2.00-2.10 (2H, m), 2.15-2.20 (2H, m), 5.02 (1H, 6, J 3.3 Hz CHOCOCl).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:24])[CH:20]([CH3:23])[CH2:21][CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH3:24][N:19]([CH:20]([CH3:23])[CH2:21][CH3:22])[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CCC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(C)N(C)c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 8-benzyl-N-methyl-N-(1-methylpropyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (0.64 g) in methanol (20 mL) was added 20% Pd(OH)2/C (0.13 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (20 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (540 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (0.44 g, 82%) as a pale-yellow powder.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[SH:18][CH2:19][C:20]([NH2:22])=[O:21].[OH-].[K+]>CN(C)C=O.O>[NH2:13][C:12]1[C:11]2[C:2](=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=3)[S:18][C:19]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)CS
Reactant: COc1cc2cc(C#N)c(Cl)nc2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2cc3c(N)c(C(N)=O)sc3nc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 20 g of 2-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 500 ml of dimethylformamide was added 20 g of 2-mercaptoacetamide. To the resultant mixture was added dropwise a solution of 15 g of potassium hydroxide in 100 ml of water. The mixture was stirred at room temperature for 30 minutes and enough additional water was added to give a homogeneous solution. The mixture was stirred at room temperature for 16 hours and then poured into 4 liters of water. The yellow precipitate which formed was separated by filtration and dried to give 3-amino-6,7-dimethoxy thieno[2,3-b]quinoline-2-carboxamide melting at about 278.5°-279.5° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:11][CH:12]=[C:13]([C:19]([O-])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]2[OH:11]
Reactant: Nc1ccccc1Br
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Product: CCOC(=O)c1cnc2c(Br)cccc2c1O
Yield: 80.8 %

Procedure:
A solution of 2-bromoaniline (2.5 g, 14.62 mmol) and ethyl ethoxymethylenemalonate (3.16 g, 14.62 mmol) was heated at 100° C. for 3 h. Then the volatiles were removed by passing a stream of nitrogen and the molten mass was added slowly onto boiling diphenyl ether (10 mL) and the mixture was heated at reflux for 2 h. Then petroleum ether was added to the reaction mixture at rt and the precipitated solid was collected by filtration and dried to afford 3.5 g of the title product. 1H NMR (300 MHz, DMSO d6): δ 11.65 (br s, 1H), 8.45 (s, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.39-7.34 (t, J=7.8 Hz, 1H), 4.26-4.19 (q, J=7.2, 14.1 Hz, 2H), 1.30-1.26 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15](Br)=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[CH:15]=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2cc3n(c2c1)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Reaction time: 6 h
Yield: 49 %

Procedure:
To a solution of 1.52 g (R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 15 ml ethanol was added 0.15 g 10% palladium on charcoal and the mixture was stirred under a hydrogen atmosphere for 6 h. A further 0.15 g 10% palladium on charcoal was added and the mixture was stirred a further 6 h under a hydrogen atmosphere. Again 0.15 g 10% palladium on charcoal was added and the mixture was stirred a further 6 h under a hydrogen atmosphere . The catalyst was removed by filtration over dicalite and the filtrate was evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate=4:1 to yield 0.59 g (R)-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester as a white foam. MS: (M+H)=301.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36].[OH-].[K+]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:2]2[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[C:4]([CH2:5][O:6][CH2:7][C:8]3([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]3)[CH:3]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2)CC1
Temperature: 120 °C

Procedure:
tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (130.0 mg, 0.24 mmol), 4-cyanophenylboronic acid (140.0 mg, 0.95 mmol), and tetrakis(triphenylphosphine) palladium(0) (37.1 mg, 0.024 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. The mixture was flushed with nitrogen. To this was added potassium hydroxide (1 N in water, 0.75 mL, 0.75 mmol). The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and purified by flash chromatography on silica gel (25% ethyl acetate/hexanes) to afford 61.0 mg (48%). 1H-NMR (CDCl3, 500 MHz) δ 7.74-7.76 (m, 2H), 7.67 (s, 1H), 7.57-7.60 (m, 2H), 7.41 (s, 1H), 7.40 (s, 1H), 7.29-7.32 (m, 2H), 6.98-7.02 (m, 2H), 4.47 (s, 2H), 3.71-3.74 (m, 2H), 3.43 (s, 2H), 3.01-3.06 (m, 2H), 2.14-2.17 (m, 2H), 1.82-1.88 (m, 2H), 1.42 (s, 9H). Mass spec.: 569.25 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH:18]=[CH:17]4)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].BrC[CH2:47][O:48][C:49](=[O:51])[CH3:50].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:10]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)[CH:18]=[CH:17]4)[N:11]2[CH2:50][C:49]([O:48][CH3:47])=[O:51])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(=O)OCCBr
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc4nc(-c5cc(OC)ccc5-c5ccc(Cl)cc5)ccc4c3)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
To a mixture of intermediate 15-2 (1.024 g, 1.7 mmol) and bromoethylacetate (388 mg, 1.5 eq) in dry DMF (30 mL) was added NaH (60% dispersion in mineral oil, 122 mg, 1.8 eq) at 0° C. After stirring for 20 min at this temperature, the reaction mixture was warmed up to room temperature. After 24 h, the reaction mixture was poured into 300 mL of ice-cold water. The formed yellow solid was filtered off, washed with petroleum ether and purified by column chromatography (CH2Cl2) to give 450 mg (39%) of 2-[2-(4′-Chloro-4-methoxy-biphenyl-2-yl)-quinolin-6-yl]-3-cyclohexyl-1-methoxycarbonylmethyl-1H-indole-6-carboxylic acid methyl ester 15-3; m/z=674 (M+H+).