Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.C(O)(C)C>[C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: O=C1CCCc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Yield: 49.3 %

Procedure:
1-Phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.600 g) is dissolved in a minimum volume of chloroform and isopropanol is added to give a final volume of 15 mL. The solution is injected onto a 5×50 cm column of 20 micron Chiralcel OD (Chiral Technologies) held at 30° C. The sample is eluted with 30% isopropanol in heptane (V/V) at 75 mL/min while monitoring at 245 nm using a Merck/Sepracor ST-140 HPLC with closed loop peak shaving and recycling capability. About 70% of the front part of the broad peak that eluted between 25-32 minutes is collected and about 40% of the tail of the second peak that eluted between 29-37 minutes is collected. The central portions of these overlapping peaks are recycled and complete resolution is obtained on the second pass. The appropriate fractions are pooled and the solvent is removed on a rotary evaporator. The residues are assayed on a 0.46×25 cm Chiralcel OD-H column at ambient temperature using 25% isopropanol in heptane at 0.5 mL/min and detection at 244 nm. The earlier eluting enantiomer (0.297 g, Rt=21.7 min) assayed for 97.6% ee. Chromatography on silica gel using acetone/hexane (20/80) gave 0.296 g of (R)-(−)-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one; [α]D=−81° (CH2Cl2). The later eluting enantiomer (0.261 g, Rt=26.8 min) assayed for >99% ee. Chromatography on silica gel using acetone/hexane (20/80) gave 0.254 g of (S)-(+)-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one. [α]D=+84° (CH2Cl2).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)=[C:2]=[S:3].C(N(C(C)C)CC)(C)C.Cl.[NH:23]([CH2:25][C:26](OCC)=[O:27])[NH2:24]>ClCCl>[NH2:24][N:23]1[CH2:25][C:26](=[O:27])[N:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=2)[C:2]1=[S:3]
Reactant: O=C(O)c1ccc(N=C=S)cc1
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NN1CC(=O)N(c2ccc(C(=O)O)cc2)C1=S
Yield: 52.5 %

Procedure:
179 mg (1 mmol) of 4-isothiocyanatobenzoic acid and 523 μl (3 mmol) of diisopropylethylamine were stirred in 8 ml of dichloromethane and then with 155 mg (1 mmol) of ethyl hydrazinoacetate hydrochloride at room temperature for 96 hours. After the solvent was concentrated, the mixture was partitioned between ethyl acetate and 30% acetic acid. The aqueous layer was extracted with ethyl acetate again, and the organic layers were combined, washed with water and then with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated. The resulting solid was mixed with a 190:10:0.8 liquid mixture of ethyl acetate, methanol and acetic acid, and the insoluble was dried to obtain 132 mg of the desired product (yield 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:19].[K+].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([OH:19])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
39.5 g of the 2-benzyloxy-4-fluoronitrobenzene (0.16 mol) prepared as described in Example 1 are added to a mixture of an aqueous potassium hydroxide solution prepared from 27.2 g of potassium hydroxide (0.48 mol) and 180 ml of distilled water, and 150 ml of dimethyl sulfoxide in a three-neck flask fitted with reflux condenser, stirrer and nitrogen inlet, and the mixture is then heated to 100° C. After 4 hours, the reaction solution is allowed to cool to room temperature, and the residue is filtered off via a fluted filter. The dark-orange solution is then added to 800 ml of water, and concentrated hydrochloric acid is added with vigorous stirring until the mixture is acidic. Within about 1 hour, a white-yellowish, flaky reaction product precipitates; this is filtered off via a Büchner funnel and washed three times with water. The reaction product is recrystallized from ethanol and then dried for 48 hours under nitrogen at 40 ° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19]I.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:19][N:11]1[CH:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)[nH]1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(C)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.5 g of ethyl 2-phenyl-1H-5-imidazolecarboxylate was dissolved in 30 ml N,N-dimethylformamide. 0.71 g of sodium hydride was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction solution was ice-cooled again and 1.5 ml methyl iodide was added, followed by stirring at room temperature for 30 minutes. Water and aqueous ammonium chloride solution were added to the reaction solution, followed by extracting with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography, to give 0.6 g of ethyl 1-methyl-2-phenyl-1H-4-imidazole carboxylate with hexane:ethyl acetate=8:1 and 2.2 g of ethyl 1-methyl-2-phenyl-1H-5-imidazolecarboxylate with hexane:ethyl acetate=1:1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[O:19])[CH2:10][CH:11]([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[CH3:24]I.O>O1CCCC1>[CH3:24][C:11]([CH2:10][C:9]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:21][CH:20]=1)=[O:19])([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CI
Reactant: COC(=O)C(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
0.65 g (2.1 mmol) of methyl 2-(4-methylsulfonylphenacyl)acetoacetate [prepared as described in Example 43(ii)] was dissolved in 20 ml of anhydrous tetrahydrofuran, and 92 mg (2.3 mmol) of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to the resulting solution, whilst ice-cooling and under a nitrogen atmosphere. The mixture was stirred for 10 minutes, after which 1.1 ml (2.5 mmol) of methyl iodide were added, whilst ice-cooling, and the mixture was stirred for 2 hours. At the end of this time, water was added to the mixture, which was then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 2:3 by volume mixture of ethyl acetate and hexane, to give 0.54 g (yield 80%) of the title compound as a slightly yellow powder.
Reaction SMILES: Cl.C(OC([N:9]1[C:17]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=2[CH:11]=[C:10]1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([S:33]([C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([Cl:46])[CH:42]=3)[CH:37]=2)(=[O:35])=[O:34])[CH2:29][CH2:28]1)=[O:26])=O)(C)(C)C>C(O)C>[ClH:46].[Cl:46][C:41]1[CH:42]=[C:43]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[C:36]([S:33]([N:30]1[CH2:31][CH2:32][N:27]([C:25]([C:10]3[NH:9][C:17]4[CH2:16][CH2:15][NH:14][CH2:13][C:12]=4[CH:11]=3)=[O:26])[CH2:28][CH2:29]1)(=[O:35])=[O:34])[CH:45]=[CH:44]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)n2C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: O=C(c1cc2c([nH]1)CCNC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Reaction time: 1 h

Procedure:
A saturated solution of hydrochloride in ethanol (25 ml) was added to 1,5-bis(t-butoxycarbonyl)-2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (300 mg) at room temperature, followed by stirring for 1 hour. The reaction mixture was concentrated and water was added to the concentrate. The resulting mixture was concentrated under reduced pressure. To the residue, a saturated solution of hydrochloride in methanol (25 ml) was added at room temperature, followed by stirring for 1 hour. After concentration of the reaction mixture, water was added and the resulting mixture was concentrated under reduced pressure, whereby the title compound (200 mg) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:9]=[C:8]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[NH:18]3)=[CH:14][CH:13]=2)=[O:11])[S:7][C:6]=1[Br:27].Br[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45]>CC#N>[Br:27][C:6]1[S:7][C:8]([C:10]([C:12]2[CH:20]=[C:19]3[C:15]([CH:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:18]3[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][CH:35]3[C:36](=[O:45])[C:37]4[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:43]3=[O:44])=[CH:14][CH:13]=2)=[O:11])=[CH:9][C:5]=1[CH2:4][C:3]([O:2][CH3:1])=[O:28]
Reactant: O=C1c2ccccc2C(=O)C1NCCCCBr
Reactant: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)[nH]c3c2)sc1Br
Solvent: CC#N
Product: COC(=O)Cc1cc(C(=O)c2ccc3cc(-c4ccccc4)n(CCCCNC4C(=O)c5ccccc5C4=O)c3c2)sc1Br
Yield: 41.8 %

Procedure:
To a stirred solution of 453 mg (1 mmol) of methyl-(2-bromo-5-(2-phenyl-1H-indole-6-carbonyl)thiophene-3-yl)acetate in 10 mL of anhydrous CH3CN was added 1.25 g of CsF-Celite under N2, and then followed by 295 mg (1 mmol) 2-(4-bromobutylamino)-1H-indene-1,3(2H)-dione. The resulting mixture was refluxed for 5 h. The mixture was filtered and washed with CH3CN (5 mL×3), the filtrate was evaporated under reduced pressure, and the residue was purified by MPLC (EtOAc/Hex 1:4) to give 280 mg product as a yellow solid (yield 42%).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH3:15])([CH3:14])[S:4]1)[OH:2].[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([O:2][N:1]=[C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH3:15])([CH3:14])[S:4]1)=[O:19]
Reactant: CN=C=O
Reactant: CC1(C)SC(=NO)N=C1c1ccccc1
Product: CNC(=O)ON=C1N=C(c2ccccc2)C(C)(C)S1

Procedure:
2-oxo-4-phenyl-5,5-dimethyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4-phenyl-5,5-dimethyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 135°-137° C. The 2-oxo-4-phenyl-5,5-dimethyl-3-thiazoline-oxime starting material (m.p. 147°-149° C.) was prepared from 2-methyl-1-phenyl-2-thiocyanato-1-propanone (b.p. [0.02 mm] 98°-100° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[NH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][CH2:20][CH2:21][CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCCN
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCCNc1c(C(=O)OCC)cnc2c(OC)cccc12

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with 1-aminopropane following general procedure B to afford 8-methoxy-4-propylamino-quinoline-3-carboxylic acid ethyl ester (260 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into 8-methoxy-4-propylamino-quinoline-3-carboxylic acid ethylamide (200 mg) following general procedure E. The above ethylamide (0.70 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-7-methoxy-1-propyl-1H-pyrimido[5,4-c]quinoline-2,4-dione (26 mg). LCMS: m/z 314 [M+1]+.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[C:14]2[S:13][N:12]=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=O>O1CCCC1>[S:13]1[C:14]2[C:6]([C:4]([NH2:1])=[O:3])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=[N:12]1
Reactant: N
Reactant: COC(=O)c1cccc2nnsc12
Solvent: C1CCOC1
Product: NC(=O)c1cccc2nnsc12

Procedure:
In an autoclave, under pressure and at room temperature, 17 g of ammonia ispassed into a solution of 19.4 g of benzo-1,2,3-thiadiazole-7-carboxylic acid methyl ester in 70 ml of tetrahydrofuran. The solution is then heatedand maintained at 80°-90° C. for approximately 20 hours, an internal pressure of 55·105Pa max. building up. Partial concentration by evaporation is then carried out and the resulting precipitate is filtered off, washed with cold tetrahydrofuran and dried. 14.9 g of beige crystals having a melting point of 270°-272°C. are obtained.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[N:11]=[C:10]([NH2:12])[N:9]2[N:13]=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:8]2[N:7]=1.C(O)(C(F)(F)F)=O.O.[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.N1CCNCC1.BrC1C=CC(F)=CC=1F.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[N:39]1[CH2:40][CH2:41][N:42]([CH2:3][CH2:4][NH:5][C:6]2[N:11]=[C:10]([NH2:12])[N:9]3[N:13]=[C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:8]3[N:7]=2)[CH2:43][CH2:44]1
Reactant: Fc1ccc(N2CCNCC2)c(F)c1
Reactant: COC(CNc1nc(N)n2nc(-c3ccco3)nc2n1)OC
Agent: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Fc1ccc(Br)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1nc(NCCN2CCN(c3ccc(F)cc3F)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The dimethyl acetal intermediate (40 mg, 0.13 mmol) from subpart (a) above was suspended in 2 mL of CH2Cl2 and 0.2 mL of 2:1 solution of TFA/H2O was added. The resulting reaction mixture was stirred at room temperature for 4 hours. It was then neutralized with 0.25 mL of triethylamine. 1-(2,4-Difluoro-phenyl)-piperazine (40 mg, 1.5 eq., prepared by reacting piperazine with 1-bromo-2,4-difluorobenzene according to the procedure described in WO 01/92264 A1), was added, followed by 140 mg of Na(OAc)3BH. The resulting reaction mixture was stirred at room temperature for 2 hours. It was then concentrated and then purified by preparative HPLC to afford N5-{2-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-ethyl}-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine. 1H NMR (DMSO-d6) δ 7.90 (br s, 2H), 7.80 (d, J=1.0 Hz, 1H), 7.05 (d, J=3.6 Hz, 1H), 7.10-7.50 (m, 3 H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H) 3.20-2.75 (m, 12 H) ppm. MS: m/z: 442 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[CH2:1]([NH:8][C:9](=[O:10])[NH:11][N:12]([CH2:14][C:15]([NH:18][C@@H:19]([CH3:43])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21])=[O:17])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)N
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](C)NC(=O)CN(C)NC(=O)NCc1ccccc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 99 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-11) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8]Br.[CH3:11][N:12]([CH3:20])[C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]([CH3:20])[CH3:11])=[CH:14][CH:15]=1
Reactant: COC(=O)C=CC=CCBr
Reactant: CN(C)c1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C=CC=CCSc1ccc(N(C)C)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 6-bromo-hexa-2,4-dienoic acid methyl ester (1.15 g, 5.6 mmol) and 4-dimethylamino-benzenethiol (0.86 g, 5.6 mmol) in tetrahydrofuran (30 mL) was added dropwise triethylamine (1.6 mL, 11.4 mmol) under an atmosphere of argon. The mixture was stirred at 20° C. for 30 minutes, then filtered. The filtrate was concentrated under reduced to pressure and the residue was dissolved in ethyl acetate (100 mL). This solution was washed with saturated aqueous sodium hydrogen carbonate (50 mL), demineralised water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a yellow oil that was purified by column chromatography (9:1 to 7:3 60-80° C. petroleum ether:diethyl ether, all eluant containing 1% triethylamine by volume). The solid was recrystallised from diethyl ether/petroleum ether to give the title compound (1.0 g, 64%) as a white solid, mp 68-70° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[NH2:11].[CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23]([NH:11][C:10]3[CH:9]=[CH:8][S:7][C:6]=3[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccsc1-c1nccs1
Reactant: O=C(O)Cc1cccc2cnccc12
Product: O=C(Cc1cccc2cnccc12)Nc1ccsc1-c1nccs1

Procedure:
The title compound was prepared from 2-(thiazol-2-yl)thiophen-3-amine and 2-(isoquinolin-5-yl)acetic acid according to protocol A. Preparative HPLC gave 2-(isoquinolin-5-yl)-N-(2-(thiazol-2-yl)thiophen-3-yl)acetamide. Method[7], MS (ESI) 352.1 [M+H], Retention time=2.59 min; 1H-NMR (300 MHz, CDCl3) δ 11.32 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.10-8.09 (m, 1H), 8.07 (s, 1H), 7.94 (t, J=7.7 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.31-7.24 (m, 4H), 7.10 (d, J=3.3 Hz, 1H), 4.33 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([N:12]1[CH2:16][CH2:15][NH:14][C:13]1=O)(=O)C>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:13]1[NH:14][CH2:15][CH2:16][N:12]=1
Reactant: Nc1ccccc1Cl
Reactant: CC(=O)N1CCNC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccccc1NC1=NCCN1

Procedure:
12.75 g of o-chloroaniline and 14.09 g of 1-acetylimidazolidin-2-one in 144 ml of POCl3 are stirred for 71 hours at 60°C. The mixture is worked up as described in Example 19 and 15.45 g, that is to say 65.3%, of the acetyl derivative of 2-(2'-chlorophenylamino)-2-imidazoline are obtained as a crystalline product, which, for analysis, is recrystallised from i-propanol and toluene. Melting point: 142°-143°C
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].BrC1C(O)=C([C:18]([O:21][CH3:22])=CC=1)C(O)=O>N1C2C(=CC=CC=2)C=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:18][O:21][CH3:22]
Reactant: COc1ccc(Br)c(O)c1C(=O)O
Reactant: COc1ccc(Br)c(O)c1
Solvent: c1ccc2ncccc2c1
Product: COCOc1cc(OC)ccc1Br

Procedure:
1-Bromo-2-hydroxy-4-methoxybenzene. 3-Bromo-2-hydroxy-6-methoxybenzoic acid [T. de Paulis et. al. J. Med. Chem., (1985), 28, 1263-1269](5 g, 0.02 mol) was heated in quinoline (200 mL) at 160° C. for 1 h. On cooling, the product was partitioned between Et2O and 3M HCl. The organic extract was washed with water and brine then dried (MgSO4), filtered and evaporated to give the title compound which was recrystallized from 5% ethyl acetate/hexane (4 g, 97%); m.p. 40-42° C. Anal. Calc. for C7H7BrO2: C, 41.41; H, 3,48. Found C, 41.39; H, 3.37.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[NH:8][CH:7]=1.S(C)C>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[NH:8][CH:7]=1
Reactant: CNC(=O)CC(c1ccccc1)c1c[nH]c2cccnc12
Solvent: C1CCOC1
Solvent: CSC
Product: CNCCC(c1ccccc1)c1c[nH]c2cccnc12
Temperature: 25 °C

Procedure:
To a RT solution of N-methyl-3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propionamide (25.3 mg, 0.091 mmol) in THF (5 mL) was added BH3.SMe2 (10 M in THF, 18 μL). The resulting mixture was refluxed for 2 h, cooled to RT, and quenched by addition of MeOH and HCl (concentrated, 3 drops). The mixture was then heated at reflux for 15 min, cooled to RT, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH), affording N-Methyl-[3-phenyl-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)-propyl]-amine. MS M+H=266.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.P([O-])(O)(O)=[O:35].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[C:31]([OH:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=O)c2ncc(C=O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.7 %

Procedure:
To a stirred solution of 6-benzyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde (55 mg, 0.13 mmol) in t-butanol (2 mL) and water (2 mL) solution was added sodium dihydrogenphosphate monohydrate (71.1 mg, 0.52 mmol), 2-methyl-2-butene (0.087 mL, 0.77 mmol) and sodium chlorite (69.9 mg, 0.77 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in methanol to afford 6-Benzyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (35 mg, 62% yield) as a light yellow solid. HR-MS m/e calcd for C26H21N1O6 (M−H+) 444.1442, found 444.1442; 1H NMR (300 MHz) compatible.