Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH3:14])([CH3:13])[O:9]2)[CH2:5][O:4]1>O.C1COCC1>[CH2:2]=[C:3]1[O:4][CH2:5][CH:6]2[CH:10]([O:9][C:8]([CH3:14])([CH3:13])[O:7]2)[CH2:11][O:12]1
Reactant: CC1(C)OC2COC(CBr)OCC2O1
Solvent: O
Solvent: C1CCOC1
Product: C=C1OCC2OC(C)(C)OC2CO1
Yield: 69 %

Procedure:
0.943 mol (105.8 g) of potassium tert.butylate were dissolved in 800 ml of water-free THF. A solution of 865 mmol (231 g) of 4-bromomethyl-9,9-dimethyl-3,5,8,10-tetraoxabicyclo[5.3.0]decane in 800 ml of THF were added dropwise within 90 minutes with stirring and the mixture was subsequently heated for 6 h under reflux. The resulting KBr was filtered and the THF was subsequently distilled under a filter pump vacuum. The dark brown residue underwent fractional distillation under vacuum. 111.2 g of colourless clear 4-methylene-9,9-dimethyl-3,5,8,10-tetraoxabicyclo[5.3.0]decane (yield 70%) go over at between 45° and 49° C. (0.2 mbar).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1>CN1C(=O)CCC1>[CH3:1][S:2][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: Nc1ccnc(Cl)c1
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CSc1cc(N)ccn1
Temperature: 200 °C
Yield: 265.2 %

Procedure:
Sodium thiomethoxide (140 mg, 1.98 mmol) was added to a solution of 2-chloropyridin-4-amine (150 mg, 1.17 mmol) in NMP (0.65 mL) in a pressure vessel. The vessel was sealed and heated in a microwave to 200° C. for 800 sec. Purification by silica flash chromatography eluting with 8% MeOH/DCM afforded 2-(methylthio)pyridin-4-amine (435 mg, 50% yield). LC/MS (m/z): 140.9 (MH+), Rt 0.59 minutes.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.[CH:24]1[CH:29]=[CH:28][CH:27]=CC=1>>[CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:3][C:4]([O:6][CH2:27][CH:28]1[CH2:24][CH2:29]1)=[O:5]
Reactant: c1ccccc1
Reactant: CC(=CC(=O)O)CCCC(C)CCCC(C)C
Agent: O=C(Cl)C(=O)Cl
Product: CC(=CC(=O)OCC1CC1)CCCC(C)CCCC(C)C
Reaction time: 2 h

Procedure:
To 1.56 g. of 3,7,11-trimethyldodec-2-enoic acid, under nitrogen, is added dry benzene and oxalyl chloride (2.4 g.). The mixture is stirred 2 hours and then concentrated in vacuo. To the concentrate is added fresh dry benzene and 1.6 g. of cyclopropylmethyl alcohol and the mixture stirred overnight at room temperature. The reaction is worked up by pouring into water and extracting with ether. The organic phase is washed with brine, stirred over neutral alumina (Act. III), concentrated under reduced pressure and purified by distillation to yield cyclopropylmethyl 3,7,11-trimethyldodec-2-enoate, b.p. 90° (bath) at 0.005 mm.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15](=S)[NH:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=1>O1CCOCC1.FC(F)(F)C([O-])=O.[Hg+2].FC(F)(F)C([O-])=O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[C@H:3]([C:15]2[N:19]3[C:20]4[CH:26]=[CH:25][N:24]([S:27]([C:30]5[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=5)(=[O:28])=[O:29])[C:21]=4[N:22]=[CH:23][C:18]3=[CH:17][N:16]=2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)[C@@H]4CN(C(=O)OC(C)(C)C)CC[C@@H]4C)cnc32)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [Hg+2]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@@H]4CN(C(=O)OC(C)(C)C)CC[C@@H]4C)n23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A round bottom flask was charged with cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (5.62 g, 10.6 mmol, prepared using O from 4-methylnicotonic acid, M, H from Example #5, Step C, HATU and DIEA) and Lawesson's reagent (3.0 g, 7.4 mmol) in 1,4-dioxane (100 mL). The reaction was heated at about 80° C. for about 1 h, cooled to ambient temperature, and concd under reduced pressure. The crude product was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (3×100 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (5.2 g, 90%): LC/MS (Table 1, Method b) Rt=2.65 min; MS m/z: 544 (M+H)+. A round bottom flask was charged with cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (2.6 g, 4.8 mmol) and mercury (II) trifluoroacetate (2.1 g, 4.8 mmol) in 1,4-dioxane (72 mL) and stirred at ambient temperature for about 1 h. The reaction mixture was filtered through a pad of Celite®. The Celite® pad was rinsed with DCM (30 mL) and EtOAc (30 mL). The filtrate was concd under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with saturated aqueous sodium thiosulfate (10 mL), and saturated aqueous NaHCO3 (25 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford cis-tert-butyl-4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (2.2 g, 90%): LC/MS (Table 1, Method b) Rt=2.57 min; MS m/z: 510 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:11])[CH2:9][OH:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O.C(Cl)(Cl)Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH3:11])[CH2:9][O:10][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: C[C@H](CO)OC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)OC2CCCCO2)cc1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A solution of 2-O-tetrahydropyranyl-(R)-propane-1,2-diol(67.2 g, 0.42 mol) in pyridine (600 ml) was placed in a 2 l round-bottom flask with magnetic stirring rod and 500 ml dropping funnel with a side-tubing, protected by calcium chloride tube. 4-Dimethylaminopyridine (2 g) was added, the flask was placed in an ice-water cooling bath and a solution of p-toluenesulfonyl chloride (91 g, 0.477 mol) in pyridine (300 ml) was added over 1 hour under stirring. The mixture was stirred under ice-cooling for additional 3 hours and left to stand overnight in a refrigerator at 4° C. Water (20 ml) was then added to the mixture and, after standing for 1 hour, pyridine (approx. 300 ml) was distilled off in vacuo. The residue was diluted by ethyl acetate (2.5 l) and shaken with water (300 ml). After separation of the lower aqueous layer, the organic phase was washed with water (two 300 ml portions), evaporated in vacuo and the residue co-evaporated with toluene (four 250-ml-portions) in vacuo. The remaining amber oil was purified by chromatography over silica gel (eluting with chloroform) to afford 122 g (0.39 mol, 93%) of (R)-2-O-tetrahydropyranyl-1-O-p-toluenesulfonylpropane-1,2 diol as a thick colorless oil, RF 0.60 (TLC, chloroform). This product was stored at +4° C. for several months without obvious decomposition. For C15H22OS (MW 314,4) calculated: C,57.30; H,7.05; S,10.20. Found: C,57.15; H,7.22; S,10.52.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:12]C(=O)OC)=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH3:17].[BrH:18]>C(O)(=O)C>[BrH:18].[NH2:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:2]([CH3:1])[N:3]([CH3:17])[CH2:4][CH2:5]2
Reactant: COC(=O)Nc1ccc2c(c1)CCN(C)C2C
Agent: Br
Solvent: CC(=O)O
Product: CC1c2ccc(N)cc2CCN1C
Reaction time: 1.5 h

Procedure:
A mixture of 110 mg (0.47 mmol) methyl (1,2-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)-carbamate, 2.0 MI 33% HBr in glacial acetic acid and 2.0 ml glacial acetic acid are heated to boiling for 1.5 h. Then the mixture is concentrated in vacuo, mixed with water and the aqueous phase is separated off and freeze-dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=O)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]1([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:34][C:28]1([C:24]2[S:23][CH:27]=[CH:26][CH:25]=2)[CH2:29][CH2:30][N:31]([C:19](=[O:21])[CH2:18][O:17][CH2:16][CH2:15][N:13]([CH3:14])[S:10]([C:6]2[C:5]([CH3:22])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH3:9])(=[O:11])=[O:12])[CH2:32][CH2:33]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Reactant: OC1(c2cccs2)CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(c3cccs3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (77 mg, 0.475 mmol) was added to a solution of 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)-ethoxy)acetic acid (acid unit S2) (150 mg, 0.453 mmol) in methylene chloride (7 ml) and the mixture was stirred for 1 h at room temperature. A solution of 4-(thiophen-2-yl)piperidin-4-ol (A7) (82 mg, 0.453 mmol) in methylene chloride (3 ml) was subsequently added and the reaction mixture was stirred for 15 h at room temperature. Thereafter, saturated sodium bicarbonate solution (10 ml) was added to the reaction mixture and the aqueous phase was subsequently extracted with methylene chloride (20 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ethyl acetate/methanol/ammonia solution (25% aq.) (100:10:1).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[K+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O.CN(C)C=O>[CH3:31][S:32]([C:2]1[CH:3]=[CH:4][C:5]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCc2c(C(=O)CCN3CCN(c4ccccc4)CC3)ccc(O)c2N1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)CCN2CCN(c3ccccc3)CC2)c2c1NC(=O)CC2

Procedure:
37.9 Grams of 8-hydroxy-5-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyril and 5.9 g of potassium hydroxide were dissolved in 400 ml of water and the solution was concentraed under a reduced pressure to obtain a residue. The residue was dissolved in 400 ml of dimethylformamide and the 12.0 g of methane-sulfonyl chloride was added dropwise to the solution under cooling condition. One hour after the addition either was added to the reaction mixture to obtain crystals. The crystals were collected by filtration and washed with acetone, then recrystallized from isopropanol to obtain 35.9 g of 8-methanesulfonyl-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril in light brown needle-like crystals. Melting point: 165°-167° C.
Reaction SMILES: [CH2:1]([C:4]1([CH:33]([CH3:35])[CH3:34])[CH2:8][CH:7]([OH:9])[N:6]([CH2:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=2O[Si](C(C)C)(C(C)C)C(C)C)[C:5]1=[O:32])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O>C1COCC1.CCOC(C)=O>[CH2:1]([C:4]1([CH:33]([CH3:34])[CH3:35])[C:5](=[O:32])[N:6]2[CH:7]([O:9][C:12]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]=3[CH2:10]2)[CH2:8]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(C)C)CC(O)N(Cc2cc(C(F)(F)F)ccc2O[Si](C(C)C)(C(C)C)C(C)C)C1=O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: C=CCC1(C(C)C)CC2Oc3ccc(C(F)(F)F)cc3CN2C1=O
Reaction time: 0.5 h
Yield: 51 %

Procedure:
A solution of 3-allyl-5-hydroxy-3-isopropyl-1-(5-(trifluoromethyl)-2-(triisopropylsilyloxy)benzyl)pyrrolidin-2-one (approximately 525 mg, 1.02 mmol) in THF (13 mL) was charged with tris(dimethylamino)sulfonium difluorotrimethylsilicate (366 mg, 1.33 mmol) and the resulting mixture was stirred for 30 min. At this time the mixture was charged with TFA (0.394 mL, 5.11 mmol) and 4 angstrom molecular sieves (500 mg). This solution was stirred for 12 h, at which time it was diluted with EtOAc and washed 2× with brine. The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified using a 12 g silica gel cartridge and 20:1 Hex/EtOAc to 3:1 Hex/EtOAc to elute 2-allyl-2-isopropyl-7-(trifluoromethyl)-2,3,3a,9-tetrahydro-1H-benzo[e]pyrrolo[2,1-b][1,3]oxazin-1-one (177 mg, 0.52 mmol, 51% yield) as a clear oil, 1:1 mixture of diastereomers. LC/MS [M+H]+=340.15, HPLC tR=1.99 min [Waters Sunfire C18 4.6×50 mm column, 3 min gradient from 10/90/0.1 MeOH/H2O/TFA to 90/10/0.1 MeOH/H2O/TFA at 4 mL/min flow rate]. 1H-NMR (400 MHz, CDCl3) δ=7.26 (d, J=8.0 Hz, 1H), 7.21 (s, 1H), 6.80 (d, J=8.0 Hz, 1H), 5.56 (m, 1H), 5.2-4.8 (m, 3H), 4.16 (m, 1H), 2.3-1.8 (m, 5H), 0.8-0.6 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=1.[H-].[Na+].[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=3)=[N:8]2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1C
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1C
Yield: 578 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxy-3-methylphenyl)-1H-indazole (0.76 g, 0.4 mmol), sodium hydride (60% in oil, 0.120 g, 3.0 mmol) cyclopentyl bromide (0.321 mL, 3.0 mmol) to give the title compound (0.75 g).
Reaction SMILES: C(=O)(O)[O-].[Na+].[O-:6][C:7]#[N:8].[K+].O.Cl.[NH2:12][CH2:13][CH2:14][N:15]1[C:19]([S:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[N+:30]([O-:32])=[O:31])=[N:18][N:17]=[N:16]1>C(O)(=O)C>[N+:30]([C:22]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=1[S:20][C:19]1[N:15]([CH2:14][CH2:13][NH:12][C:7]([NH2:8])=[O:6])[N:16]=[N:17][N:18]=1)([O-:32])=[O:31]
Reactant: NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: N#C[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
To a solution of 0.84 g. (0.010 mol.) of sodium bicarbonate and 0.81 g. (0.010 mol.) of potassium cyanate in 35 ml. of water containing 2.5 ml. of glacial acetic acid was added 3.15 g. (0.010 mol.) of 1-(2-aminoethyl)-5-(2,4-dinitrophenylthio)tetrazole hydrochloride. The mixture was refluxed for 2.5 hours, then it was filtered and the solid product was washed with water and recrystallized from methanol-acetone to give 5-(2,4-dinitrophenylthio)-1-(2-ureidoethyl)tetrazole, m.p. 190°-191° (d).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[NH:8][C:9]2=[O:13])=[CH:4][C:3]=1[Br:17].[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>CC#N.CN(C=O)C>[Br:17][C:3]1[C:2]2[N:1]=[C:23]([C:22]3[CH:25]=[CH:26][C:19]([CH3:18])=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=3)[NH:12][C:11]=2[C:10]2[C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]([CH3:15])([CH3:16])[C:5]=2[CH:4]=1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CC1(C)C(=O)NC(=O)c2c1cc(Br)c(N)c2N
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1ccc(-c2nc3c(Br)cc4c(c3[nH]2)C(=O)NC(=O)C4(C)C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a solution of 7,8-diamino-6-bromo-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (1.40 g, 4.70 mmol) in MeCN (47 mL) and DMF (3 mL) was added 4-methyl-3-nitro-benzaldehyde (814.2 mg, 4.93 mmol) and p-chloranil (1.21 g, 4.93 mmol). The reaction mixture was stirred at 60° C. for 8 h. The cooled mixture was diluted with MeCN (50 mL) and the suspension was filtered. The solid was dried to give the title compound (1.65 g, 79% yield).
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH3:36])[NH:5][C:6](=[O:35])[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1.[OH-].[Li+]>O1CCOCC1.O>[CH3:32][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:22]2[C:21](=[O:33])[NH:20][C:19](=[O:34])[C:18]=2[C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:8][CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:37])=[O:2])[CH3:36])=[O:35])[CH:10]=2)=[CH:24]1
Reactant: COC(=O)[C@H](C)NC(=O)CCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](NC(=O)CCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-[3-[4-(1-Methylindol-3-yl)-1H-pyrrole-2,5-dion-3-yl)-indol-1-yl]-propionyl-L-alanine methyl ester 100 mg (0.2 mmol) are dissolved in a mixture of 4 mL dioxane and 1 mL of water, mixed with 36 mg (1.5 mmol) lithium hydroxide, and stirred for 18 hours at ambient temperature. The solvent is subsequently distilled off in a vacuum and the residue is taken up in 30 mL ethylacetate, washed with 1N hydrochloric acid, and dried over anhydrous sodium sulphate. The solvent is then distilled off in a vacuum and the residue separated by thick layer chromatography (silica gel, dichloromethane/methanol saturated with ammonia=90:10%). The product is separated with the first polar fraction, extracted, freed from solvent, and stirred up with a mixture of dichloromethane and diisopropyl ether (1:1). There are obtained 65 mg (67% of theory) of the desired product;
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:31])[CH2:10][C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:30])[CH:12]=1.Cl.[CH3:33][N:34]([CH3:38])[CH2:35][CH2:36]Cl.O>CN(C=O)C>[CH3:7][O:8][C:9](=[O:31])[CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH2:36][CH2:35][N:34]([CH3:38])[CH3:33])[CH:14]=[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:21][C:20]=2[Cl:30])[CH:12]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(O)cc(CC(=O)OC)c2)c(Cl)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc(OCCN(C)C)c2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
Potassium carbonate (0.46 g) was added to a solution of the product from step (i) (1.10 mmol) and 2-dimethylamino ethyl chloride hydrochloride (0.16 g) in DMF at RT. After 1 h no reaction was evident so the mixture was heated to 60° C. for 18 h. Water was added and the mixture extracted with ethyl acetate, washed (brine) and the organics dried (MgSO4) and concentrated to a green oil which was purified by flash column chromatography (eluent 1% triethylamine and 2% methanol in ethyl acetate) to give the subtitle compound as a coulourless oil (100 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[C:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18]([CH:24]=[C:25]([CH3:27])[CH3:26])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
The mixture 2-[3-methyl-2-(2-methyl-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (134) (283 mg, 0.75 mmol) and KOH (600 mg, 10.7 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (135) as white solid (250 mg, 95%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)=[C:5]([N+:19]([O-])=O)[CH:4]=1)=[O:2].[H][H]>[Pd].CCOC(C)=O>[NH2:19][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[CH:8]=[CH:7][C:6]=1[N:9]1[CH2:10][CH2:11][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: COC(=O)C1CCN(c2ccc(C=O)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ccc(C=O)cc2N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.8 %

Procedure:
To a mixture of 10% palladium on carbon (1.67 g, 1.57 mmol) and methyl 1-(4-formyl-2-nitrophenyl)piperidine-4-carboxylate 58 (3.435 g, 11.8 mmol) was added EtOAc (100 mL). The nitrogen atmosphere was replaced by hydrogen from a double balloon and the reaction mixture was stirred at room temperature for 4 h, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 60% EtOAc in hexanes) gave methyl 1-(2-amino-4-formylphenyl)piperidine-4-carboxylate 59 (0.488 g, 15.8% yield) as a yellow solid. Mass spectrum: calculated for C14H18N2O3 262.1. found 263.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[H][H]>[Pd].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)c1cccc(N)c1N

Procedure:
A slurry of 1-(2-amino-3-nitro-phenyl)-ethanone (0.2 g, 1.11 mmol) and 10% palladium on carbon (0.020 g) in methanol (10 mL) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered and evaporated under vacuum to obtain the title compound as off white solid (0.120 g, 72.28%)
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[CH:13][N:12]=2)=[O:10])[CH2:4][CH2:3]1>CO.[Ni]>[CH3:1][C:2]1([CH3:21])[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][N:12]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: CC1(C)CCC(NC(=O)c2cc(N)c([N+](=O)[O-])cn2)CC1
Agent: [Ni]
Solvent: CO
Product: CC1(C)CCC(NC(=O)c2cc(N)c(N)cn2)CC1

Procedure:
The product obtained in 83c (100 mg, 0.34 mmol) in 10 mL methanol was mixed with Raney nickel (25 mg) and hydrogenated at 3.4 bar for 2.5 h in a Parr apparatus. The mixture was filtered and the filtrate concentrated i. vac.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]2[O:21]C(=O)[NH:19][C:16]2=[N:17][CH:18]=1.[OH-].[Na+]>>[Br:12][C:13]1[CH:14]=[C:15]([OH:21])[C:16]([NH:19][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[N:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)Nc2ncc(Br)cc2O)cc1

Procedure:
With 4-methylbenzenesulfonyl chloride, 6-bromo-[1,3]-oxazolo[4,5-b]pyridin-2(3H)-one (described in Heterocycles, 41, 2799 (1995)) was allowed to react. Then, with an aqueous solution of sodium hydroxide, the mixture was hydrolyzed to give the title compound having the following physical data.