Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2.[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32]>>[CH3:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][CH:6]([CH3:26])[CH2:7]2)=[O:32]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(C(=O)NC[C@@H]2[C@H]3CC(C)C[C@H]3CN2C(=O)c2nc(C)sc2-c2cccc(C)c2)c1

Procedure:
prepared by reaction of [(1S,2S,5R)-2-aminomethyl-7-methyl-3-aza-bicyclo[3.3.0]oct-3-yl]-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-methyl-benzoic acid.
Reaction SMILES: [C:1]([O:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O)(=O)[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)C.[NH4+:25]>C(O)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:25]=[C:1]([CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:10][CH:11]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCC(=O)OCC(=O)c1ccc(Cl)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1nc(-c2ccc(Cl)cc2)co1
Temperature: 110 °C
Yield: 31.3 %

Procedure:
A mixture of 2-(4-chlorophenyl)-2-oxoethyl ethyl succinate (7.6 g), ammonium acetate (9.8 g) and acetic acid (80 ml) was stirred for an hour at 110° C. and refluxed for 2 hours. The solvent was distilled off. The residue was diluted with water, made basic by addition of aqueous sodium hydrogen carbonate solution and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried over MgSO4. After removal of the solvent, the oily residue was subjected to a silica gel column chromatography. Crystals of ethyl 4-(4-chlorophenyl)-2-oxazolepropionate (2.23 g, 31%) were obtained from the fraction eluted with ethyl acetate-hexane (1:3, V/V). Recrystallization from ethyl acetate-hexane gave colorless plate crystals of mp 65°-66° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])[CH2:4][CH2:3]1.Cl[C:16]1[N:34]=[C:19]2[C:20]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[CH:21][CH:22]=[CH:23][N:18]2[N:17]=1>>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][NH:24][C:20]2[C:19]3[N:18]([N:17]=[C:16]([NH:11][C:10]4[CH:12]=[CH:13][CH:14]=[C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:9]=4)[N:34]=3)[CH:23]=[CH:22][CH:21]=2)=[CH:31][CH:30]=1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: COc1ccc(CNc2cccn3nc(Cl)nc23)cc1
Product: COc1ccc(CNc2cccn3nc(Nc4cccc(N5CCN(C)CC5)c4)nc23)cc1

Procedure:
N(8)-(4-Methoxy-benzyl)-N(2)-[3-(4-methyl-piperazin-1-yl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 3-(4-Methylpiperazin-1-yl)aniline (74.2 mg, 0.388 mmol) and (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(4-methoxy-benzyl)-amine (99.9 mg, 0.346 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (9.16 mg, 6%). 1H NMR (400 MHz, CD3OD, δ, ppm): 7.85 (d, J=5.9 Hz, 1H), 7.33 (m, 3H), 7.19-7.08 (m, 2H), 6.90 (d, J=8.0 Hz, 2H), 6.76 (t, J=14.4, 7.5 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 6.44 (d, J=7.4 Hz, 1H), 4.42 (s, 2H), 3.78 (s, 3H), 3.23 (s, 4H), 2.64 (s, 4H), 2.37 (s, 3H). MS=444 (MH)+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:11]([C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH3:21])[C:14]=1[NH2:15])[CH3:12].[NH2:22][C:23]1[N:32]=[CH:31][C:30]2[CH2:29][CH2:28][C:27]3[C:33]([C:37](OCC)=[O:38])=[N:34][N:35]([CH3:36])[C:26]=3[C:25]=2[N:24]=1>C1COCC1>[NH2:22][C:23]1[N:32]=[CH:31][C:30]2[CH2:29][CH2:28][C:27]3[C:33]([C:37]([NH:15][C:14]4[C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:13]=4[CH2:11][CH3:12])=[O:38])=[N:34][N:35]([CH3:36])[C:26]=3[C:25]=2[N:24]=1
Reactant: CCOC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Reactant: CCc1cccc(CC)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
Sodium hexamethyldisilazide (NaHMDS) in THF (1.0 M, 11.0 mL, 11.0 mmol) was added over 30 min to a solution of 2,6-diethylaniline (1.2 mL, 8.32 mmol) and ethyl 8-amino-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxylate (0.760 g, 2.77 mmol) in THF (30 mL) at 0° C. The resulting brown solution was stirred at 0° C. for 10 min and allowed to warm to room temperature over a period of 30 min. After stirring at room temperature for 3 h, the reaction was quenched by the addiction of saturated acquesous NH4Cl (10 mL). The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The acqueos layer was extracted with ethyl acetate (2×30 mL). The combined organic solution was washed with brine (50 mL), dried over Na2SO4, filtered and evaporated to dryness, the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol 95/5) to afford 0.830 g (80% yield) of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([NH:24][C:25](=[O:38])[CH:26]([CH2:30][O:31]CC[Si](C)(C)C)[CH:27]([CH3:29])[CH3:28])[CH2:21][C@@H:20]([C:39](=[O:62])[N:40]([CH:59]4[CH2:61][CH2:60]4)[C:41]4[CH:42]=[CH:43][C:44]5[O:49][C:48]([CH3:51])([CH3:50])[C:47](=[O:52])[N:46]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:45]=5[CH:58]=4)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.O>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@@H:22]([NH:24][C:25](=[O:38])[CH:26]([CH2:30][OH:31])[CH:27]([CH3:29])[CH3:28])[CH2:21][C@@H:20]([C:39](=[O:62])[N:40]([CH:59]4[CH2:60][CH2:61]4)[C:41]4[CH:42]=[CH:43][C:44]5[O:49][C:48]([CH3:51])([CH3:50])[C:47](=[O:52])[N:46]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:45]=5[CH:58]=4)[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NC(=O)C(COCC[Si](C)(C)C)C(C)C)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Solvent: ClCCl
Solvent: O
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(N(C(=O)[C@@H]3C[C@H](NC(=O)C(CO)C(C)C)CN(C(=O)OCC4c5ccccc5-c5ccccc54)C3)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-di hydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-5-[3-methyl-2-(2-trimethylsilanyl-ethoxymethyl)-butyrylamino]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester in CH2Cl2 is added BF3 Et2O at room temperature, then the mixture is stirred at room temperature. After 1.5 h, the reaction mixture is diluted with H2O (10 mL) and extracted with CH2Cl2 (20 mL). The organic phase is washed with 5% aqueous KHSO4 (10 mL), 5% aqueous NaHCO3, H2O, and brine, then dried over Na2SO4. The solution is filtered and the solvent is evaporated in vacuo to give the title compound as white amorphous material. MS: 767 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 1.55 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:16][NH:17][NH2:18]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:17]([CH3:16])[NH2:18])[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNN
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Solvent: CCO
Product: Cc1nc(N(C)N)nnc1-c1ccccc1
Yield: 70.2 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (20 g) and methylhydrazine (15.3 g) in ethanol (30 ml) was heated under reflux for 66 hours. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. The solution was washed with water and brine successively, dried over sodium sulfate, and then evaporated. The residue was crystallized with diethyl ether, washed with diethyl ether, and dried to give 5-methyl-3-(1-methylhydrazino)-6-phenyl-1,2,4-triazine (13.91 g).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]([O:7][Si](C)(C)C)=[CH2:6].[O:12]([CH2:19]C=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[O:12]([CH2:19][CH:1]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3][O:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=CCOc1ccccc1
Reactant: C=C(C=COC)O[Si](C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1C=COC(COc2ccccc2)C1
Temperature: -5 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
1-Methoxy-3-(trimethylsilyloxy)-1,3-butadiene (4.95 ml; 26 mmol) was added to a solution of phenoxyacetaldehyde (3.56 g, 26 mmol) in DCM (40 ml). The solution was cooled to −5° C. A 2.3 M solution of zinc chloride in DCM (5.6 ml, 13 mmol) was added. The reaction mixture was stirred for 16 hours, while it was warming up to room temperature. It was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (100 ml). The aqueous phase was extracted with ethyl acetate (100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (200 g), using ethyl acetate/heptane (1:1) as eluent, to give 2.36 g of 2-phenoxymethyl-2,3-dihydropyran-4-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)[O:9][N:8]=1.[C:17]([O:21][C:22]([NH:24][C:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=NS(C(F)(F)F)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:38]([O:37][C:35]([NH:34][C:25]([N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[C:10]1[O:9][N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:11]=1)=[N:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: c1ccc(-c2cc(C3CCCN3)on2)nc1
Reactant: CC(C)(C)OC(=O)NC(=NS(=O)(=O)C(F)(F)F)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCCC1c1cc(-c2ccccn2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
2-[3-(Pyrid-2-yl)isoxazol-5-yl]pyrrolidine (Method 12) (1.5 g, 7 mmol) was added to a solution of N,N′-di(tertbutyloxycarbonyl)-N″-(trifluoromethylsulphonyl)guanidine (2.59 g, 6.6 mmol) and triethylamine (0.975 ml) in DCM and the mixture stirred at ambient temperature for 8 hours. The mixture was then washed with water, dried (MgSO4) and the volatiles removed by evaporation. The residue was purified by chromatography on silica gel eluting with DCM/methanol (100:0 increasing in polarity to 98:2) to give the title compound (2.3 g, 70%).
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5][CH3:6])=[O:4].[CH2:11]=[CH:12][C:13]([Cl:15])=[CH2:14]>>[Cl:15][C:13]1[CH2:14][C:1]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH2:11][CH:12]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=C)Cl
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)C1=C(C(=O)OC)CC(Cl)=CC1
Yield: 100 %

Procedure:
Dimethyl acetylenedicarboxylate (6.3 g) and chloroprene (6.2 g) were heated at 50° C. for 25 hours. The reaction mixture was distilled under reduced pressure and the fraction boiling at 135° to 138° C. at 2.5 torr was collected. The thick oil weighed 4.6 g (100% yield based on unreacted dimethyl acetylenedicarboxylate).
Reaction SMILES: [C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:9]([NH:11][C:12]2[CH:23]=[CH:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14][CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:30][C:31]1([Cl:38])[CH2:33][C:32]1([CH3:37])[C:34](O)=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[C:1]([C:3]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8][CH2:7][N:6]([C:9]([NH:11][C:12]2[CH:23]=[CH:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH:18][C:34]([C:32]3([CH3:37])[CH2:33][C:31]3([Cl:38])[Cl:30])=[O:35])=[CH:14][CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2ccccc2)CCN(C(=O)Nc2ccc(C[C@H](N)C(=O)O)cc2)CC1
Reactant: CC1(C(=O)O)CC1(Cl)Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(C(=O)N[C@@H](Cc2ccc(NC(=O)N3CCC(C#N)(c4ccccc4)CC3)cc2)C(=O)O)CC1(Cl)Cl
Reaction time: 3 h

Procedure:
A suspension of 4-[[(4-cyano-4-phenyl-1-piperidinyl)carbonyl]amino]-L-phenylalanine on Wang resin (0.30 g, 0.228 mmol), 2,2-dichloro-1-methylcyclopropane carboxylic acid (0.19 g, 1.14 mmol), BOP (0.50 g, 1.14 mmol) and DIPEA (0.26 mL, 1.5 mmol) in N-methylpyrrolidinone (3 mL) was agitated for 3 hr. The mixture was filtered and washed with dichloromethane and methanol. Cleavage from the resin was effected by treatment with 90% TFA in dichloromethane for 3 min. The mixture was filtered and the filtrate evaporated to give 4-[[(4-cyano-4-phenyl-1-piperidinyl)carbonyl]amino]-N-[(2,2-dichloro-1-methylcyclopropyl)carbonyl]-L-phenylalanine. FAB MS m/z 543 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[Cl:10].C(N(CC)CC)C.O1CCCC1.[S:23]1[C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=[C:24]1[C:37](Cl)=[O:38]>>[Cl:10][C:4]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:3]=1[N:2]([CH3:1])[C:37]([C:24]1[S:23][C:27]2[C:28]3[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=3[O:30][CH2:31][CH2:32][C:26]=2[CH:25]=1)=[O:38]
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Reactant: CNc1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccc(Cl)cc1Cl

Procedure:
To a solution of N-methyl-2,4-dichloroaniline (0.133 g, 0.755 mmol) and triethylamine (0.105 mL, 0.755 mmol) in tetrahydrofuran (1.5 mL, 18 mmol) was added 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (0.100 g, 0.378 mmol) portion wise as a solid. Reaction was stirred at room temperature with monitor for formation of desired product. The reaction was stirred overnight. After aqueous workup, the crude was taken into DMF at a concentrated of 100 mg/ml and purified by preparative RP-HPLC to give 108. Yield=30% of theoretical. MS: (ESI+) 405.5
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[F:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][N:5]=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:9]([F:8])[CH:10]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Product: COc1ccc(C=NCC(OC)OC)cc1F

Procedure:
2,2-Dimethoxyethylamine (13.85 ml, 0.13 mol) is added to a solution of 3-fluoro-4-methoxybenzaldehyde (20 g, 0.13 mol) in toluene (200 ml). The resulting solution is flushed with nitrogen gas and then heated overnight under reflux in a Dean-Stark apparatus. The solvent is then removed under reduced pressure to yield (2,2-dimethoxy-ethyl)-[1-(3-fluoro-4-methoxy-phenyl)-methylidene]-amine. This intermediate (31 g, 0.13 mol) is dissolved in ethylacetate and acetic anhydride (13.1 g, 0.13 mol) added. Platinum oxide (0.3 g) is then added, under a blanket of nitrogen, and the resulting mixture is stirred under a hydrogen atmosphere until uptake is complete. Filtration, washing with saturated aqueous NaHCO3 (3×100 ml), brine and water, drying over MgSO4 and concentration then gives N-(2,2-dimethoxy-ethyl)-N-(3-fluoro-4-methoxy-benzyl)-acetamide. This intermediate (38.9 g, ca 0.13 mol) is dissolved in anhydrous CH2Cl2 and then added slowly over 20 mins to a stirred mixture of AlCl3 (90 g) and CH2Cl2 under an atmosphere of nitrogen. The total volume of CH2Cl2 is 250 ml. The mixture is stirred for a further 10 mins at room temperature and is then cooled with an ice bath during the addition of aqueous 40% NaOH. The mixture is further diluted with water (250 ml), filtered through glass wool, the organic phase separated and the aqueous phase further extracted with CH2Cl2 (2×200 ml). Drying over MgSO4 and evaporation under reduced pressure yields a crude oil which is purified by flash silica chromatography (eluant: 1% methanol in CH2Cl2) to give as one of the products 1-(7-fluoro-6-methoxy-1H-isoquinolin-2-yl)-ethanone. This intermediate (0.60 g, 2.7 mmol) is mixed with glyoxylic acid (0.325 g, 3.5 mmol) and water (10 ml) and the resulting mixture is stirred at room temperature for 20 min. Concentrated hydrochloric acid (10 ml) is then added and the mixture heated to reflux for 1 h. Concentration and purification by preparative HPLC gives (7-fluoro-6-methoxy-isoquinolin-4-yll)-acetic acid, [MH]+ 236.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:11][CH2:12][CH2:13][N:14]=[C:15]=[O:16]>CC(C)=O>[Cl:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: O=C=NCCCl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CC(C)=O
Product: O=C(NCCCl)Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
To a solution of 2 g of 5-aminoindole in 125 mL of anhydrous acetone is added dropwise 1.25 g of 2-chloroethyl isocyanate. This solution was stirred for 16 h at room temperature, cooled at -20° C., and filtered. The solvent is evaporated and the residue was crystallized from methanol and washed with ether to give a brownish solid, yield 30%, mp 159°-161° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=[O:13])(=[O:7])=[O:6].CC(C)=[O:26]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:12]([OH:26])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)=O
Reactant: CC(C)(COS(=O)(=O)CCCCl)C(C=O)OCc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)C(OCc1ccccc1)C(=O)O
Yield: 96 %

Procedure:
Following the general procedure of the oxidation of aldehydes to carboxylic acids of Description 13, (3R/S)-2,2-dimethyl-4-oxo-3-(phenylmethoxy)butyl (3-chloropropyl)sulfonate (12b) (7.6 g, 21 mmol) dissolved in 100 mL of acetone was reacted with 10.5 mL of Jones-reagent (2.0 M in water). After work-up, 7.6 g (96% yield) of the title compound (12) was obtained as a colorless oil. The analytical data was consistent with the proposed structure and with the data obtained for the enantiopure compound (11).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.S(Cl)([Cl:29])=O>CN(C=O)C>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([Cl:29])=[O:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: CN1CCN(c2ccc(-c3nc4ccc(C(=O)O)cc4s3)cn2)CC1
Agent: Cl
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(-c3nc4ccc(C(=O)Cl)cc4s3)cn2)CC1
Temperature: 70 °C

Procedure:
2-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazole-6-carboxylic acid hydrochloride acid (46 mg, 0.12 mmol) was added to thionyl chloride (3 mL), followed by 3 drops DMF, before heating at 70° C. o.n. The solvent was thereafter evaporated in vacuo and once with toluene to give crude 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazole-6-carbonyl chloride. Ammonium hydroxide (conc., 3 mL) was added dropwise to this crude product and the mixture was thereafter stirred for 1 h at r.t. The r.m. was extracted twice with DCM, dried (Na2SO4), and evaporated in vacuo. The obtained residue was purified by prep. HPLC to give the title compound (7 mg) as a light yellow solid. 1H NMR δ 8.81 (d, 1H) 8.58 (s, 1H) 8.16 (dd, 1H) 8.07 (br. s., 1H) 7.99 (s, 2H) 7.45 (br. s., 1H) 7.00 (d, 1H) 3.61-3.71 (m, 4H) 2.37-2.46 (m, 4H) 2.23 (s, 3H) 1.89 (s, 3H); MS m/z (M+H) 354.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[H-].[Na+].[CH2:34](I)[CH2:35][CH3:36]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:12]([N:13]([CH:35]([CH3:36])[CH3:34])[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4ccccc4nc3OC)CC2)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)N(c3nc4ccccc4nc3OC)C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To 1-[(2-methoxyquinoxalin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine (216 mg, 0.51 mmol) dissolved in dimethylformamide (20 ml), 60% sodium hydride (20.4 mg, 0.51 mmol) was added and stirred at room temperature for 15 minutes, and thereto propyl iodide (86.7 mg, 0.51 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:63]([O-:65])=[O:64])=[C:47]([C:49]2[C:54]([O:55][CH3:56])=[CH:53][N:52]([CH:57]([CH3:61])[C:58](O)=[O:59])[C:51](=[O:62])[CH:50]=2)[CH:48]=1>CN(C=O)C>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([N+:63]([O-:65])=[O:64])=[C:47]([C:49]2[C:54]([O:55][CH3:56])=[CH:53][N:52]([CH:57]([CH3:61])[C:58]([NH:1][C:2]3[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=3)=[O:59])[C:51](=[O:62])[CH:50]=2)[CH:48]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon and at RT, 25 mg (0.13 mmol) of tert-butyl 4-aminobenzoate, 44 μl (0.26 mmol) of N,N-diisopropylethylamine and 74 μl (50% strength in DMF, 0.13 mmol) of T3P were added to a solution of 30 mg (0.09 mmol) of 2-[4-(5-chloro-2-nitrophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) in 2 ml of DMF, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 32 mg (71% of theory)
Reaction SMILES: [CH2:1]1[CH:8]([NH2:9])[C:6](=[O:7])[NH:5][C:3](=[O:4])[CH2:2]1.Cl.Br[CH2:12][C:13]1[C:22]([F:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:14]=1[C:15](OC)=[O:16].C(N(CC)CC)C>CN(C)C=O>[O:16]=[C:15]1[C:14]2[C:13](=[C:22]([F:23])[C:21]([F:24])=[C:20]([F:25])[C:19]=2[F:26])[CH2:12][N:9]1[CH:8]1[CH2:1][CH2:2][C:3](=[O:4])[NH:5][C:6]1=[O:7]
Reactant: NC1CCC(=O)NC1=O
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3c(F)c(F)c(F)c(F)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 16.25 g of 2,6-dioxopiperidin-3-ammonium chloride, and 30.1 g of methyl 2-bromomethyl-3,4,5,6-tetrafluorobenzoate, and 12.5 g of triethylamine in 100 mL of dimethylformamide is stirred at room temperature for 15 hours. The mixture is then concentrated in vacuo and the residue mixed with methylene chloride and water. The aqueous layer is separated and back-extracted with methylene chloride. The combined methylene chloride solutions are dried over magnesium sulfate and concentrated in vacuo to give 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4,5,6,7-tetrafluoroisoindoline.