Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:28][CH3:29])[N:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:28][CH3:29])[N:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CCn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.249 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (47.9 mg, 0.250 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (˜5 mL) and Hexane (˜40 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (10 mL) to afford the title compound in 36% yield (0.0515 g, 0.089 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=[O:6].ClC1C=C(C=CC=1OCC)C=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:19])=[O:6]
Reactant: CCOc1ccc(C=O)cc1Cl
Reactant: CCCOc1ccc(C=O)cc1Cl
Product: CCCOc1ccc(C(=O)O)cc1Cl
Yield: 95 %

Procedure:
When the product of Step B was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49, Step A the identical process afforded the title compound in 95% yield, as a colourless solid. 1H-NMR (CDCl3) 1.00 (tr, 3H, J=7.38 Hz); 1.73-1.87 (m, 2H); 3.98 (tr, 2H, J=6.47 Hz); 6.85 (d, 1H, J=8.65 Hz); 7.84 (dd, 1H, J=2.09, 8.68 Hz); 7.98 (d, 1H, J=2.07 Hz).
Reaction SMILES: [C:1]1(=[O:13])[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1.[CH3:14][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1(C)C=CC=CC=1>[OH:13][C:1]1([CH3:14])[C:5]2=[CH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]2[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: O=C1CCn2c1cc1ccccc12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(O)CCn2c1cc1ccccc12
Reaction time: 0.08 h

Procedure:
To 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-one (613 mg, 3.58 mmol) suspended in toluene (12 mL), at 0° C. there was added methyl magnesium bromide 1.5M in toluene/THF (75:25) (3.0 mL, 4.5 mmol). The mixture was stirred at 0° for 5 minutes, then at room temperature for 20 minutes. After quenching with saturated aqueous NH4Cl solution, the mixture was partitioned between H2O and EtOAc. The crude product obtained from the organic fraction was chromatographed on a column of silica gel eluting with a 1:2 mixture of EtOAc and hexane to afford the title product as a yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Yield: 92.3 %

Procedure:
4-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine (135 mg, 0.4 mmol) was dissolved in 5 ml THF and triethylamine was added (112 μL, 0.8 mmol). Trimethyl acetyl chloride (49.3 μL, 0.4 mmol) was added under stirring and the reaction stirred at room temperature overnight. The reaction mixture was concentrated under nitrogen and dissolved in 5 ml methylene chloride and then washed with water. The organic layer was concentrated and evaluated by LCMS. The mixture was purified by MPLC using a Biotage 40s prepacked silica gel cartridge eluting with 3% methanol in methylene chloride. N-{4-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-2,2-dimethyl-propionamide (156 mg) was isolated in 98.2% purity @ 254 nm; LCMS (APCI): 423 [M+H]+
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[NH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([S:17]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])=[O:18])=[CH:12][N:11]=1.CCOCC>CN(C=O)C>[CH3:6][N:4]([CH:3]=[N:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([S:17]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:18])=[O:19])=[CH:12][N:11]=1)[CH3:5]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(N)nc1O
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=Nc1ncc(S(=O)(=O)NC(C)(C)C)c(O)n1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Dimethylformamide dimethyl acetal (304 mL, 2.28M) was added to a suspension of 2-amino-4-hydroxy-N-(1,1-dimethylethyl)-5-pyrimidinesulfonamide (304 g, 1.23M) in DMF (3000 mL). Stirring was continued for 1/2 hour after precipitate formation and then the reaction slurry was concentrated in vacuo. Trituration of the resulting white solid with ether afforded the desired compound (362 g, yield 97%, m.p. 258°-261° C.). The compound was dried in vacuo at 40° C. for 16 hours.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][NH:29][CH2:30][CH2:31][CH3:32]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][N:29]([CH3:28])[CH2:30][CH2:31][CH3:32])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCCNC
Solvent: CC#N
Product: CCCN(C)CC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), N-methyl-propan-1-amine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.5), 288 (8), 86 (bp), 84 (6), 58 (8).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=1)[C:8]([OH:10])=O)([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:23]=1>>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][C:22]1[N:23]=[C:19]([NH:18][C:8](=[O:10])[C:7]2[CH:11]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[CH:13]=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:6]=2)[S:20][CH:21]=1)[CH3:29]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(C)Oc1cc(OC(C)C)cc(C(=O)O)c1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(OC(C)C)cc(OC(C)C)c2)n1

Procedure:
[2-(3,5-Diisopropoxy-benzoylamino)-thiazol-4-yl]acetic acid ethyl ester was prepared from 3,5-diisopropoxybenzoic acid (prepared as described in general synthetic descriptions B, using 2-bromopropane as alkylhalid) and ethyl 2-aminothiazol-4-ylacetate following synthetic description A.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:17][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[C:28](Cl)(=[O:32])[O:29][CH2:30][CH3:31].[H-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:17][S:18][C:19]2[N:20]([C:28]([O:29][CH2:30][CH3:31])=[O:32])[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Cc1c(SCCN2CCOCC2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)n1c(SCc2nccc(SCCN3CCOCC3)c2C)nc2ccccc21

Procedure:
2-((3-Methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole (10 g) was reacted with 1.1 equivalents of ethyl chlorocarbonate in dimethylformamide in the presence of 1.1 equivalents of sodium hydride at room temperature. After the completion of the reaction, the solvent was distilled away and water was added to the residue, followed by extraction with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 11 g of ethyl 2-((3-methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole1-carboxylate as crystals, melting point 145°-147° C.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[C:3]#[N:4].[S:6](=[O:10])(=[O:9])([OH:8])[OH:7].[CH3:11][OH:12]>>[S:6]([OH:10])([OH:9])(=[O:8])=[O:7].[CH3:1][N:2]([CH3:5])[C:3](=[NH:4])[O:12][CH3:11]
Reactant: CO
Reactant: CN(C)C#N
Agent: O=S(=O)(O)O
Product: COC(=N)N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of dimethylcyanamide (10.0 g, 142.7 mmol) in methanol (50 mL) was added dropwise sulfuric acid (14.0 g, 142.7 mmol) over 2 hours at 20-30° C. The mixture was stirred at 20-30° C. for 4 hours and then concentrated in vacuo. To the residue was added acetone (50 mL) and stirred at 20-30° C. After crystallized, the mixture was stirred at 20-30° C. for 30 minutes, then at 0-10° C. for 1 hour and filtered. The crystals were washed with acetone (20 mL) and dried in vacuo to give N,N,O-trimethylisourea sulfate (22.86 g, 80.0% yield) as white granulated solids.
Reaction SMILES: C([O:4][CH:5]([CH2:26][O:27]C(=O)C)[C:6]([NH:8][C:9]1[C:10]([I:25])=[C:11]([CH2:20][O:21]C(=O)C)[C:12]([I:19])=[C:13]([C:17]=1[I:18])[C:14](Cl)=[O:15])=[O:7])(=O)C.[OH:31][CH:32]([CH2:35][OH:36])[CH2:33][NH2:34].[Br-].[Li+].C(N(CC)CC)C>O1CCCC1>[OH:4][CH:5]([CH2:26][OH:27])[C:6]([NH:8][C:9]1[C:10]([I:25])=[C:11]([CH2:20][OH:21])[C:12]([I:19])=[C:13]([C:17]=1[I:18])[C:14]([NH:34][CH2:33][CH:32]([OH:31])[CH2:35][OH:36])=[O:15])=[O:7]
Reactant: NCC(O)CO
Reactant: CC(=O)OCc1c(I)c(NC(=O)C(COC(C)=O)OC(C)=O)c(I)c(C(=O)Cl)c1I
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC(O)CO)c1c(I)c(CO)c(I)c(NC(=O)C(O)CO)c1I
Temperature: 65 °C
Reaction time: 26 h
Yield: 83 %

Procedure:
5-[N-(2,3-Diacetoxypropionyl)amino]-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride (7.71 g, 9.9 mmol), 2,3-dihydroxypropylamine (1.48 g, 16.2 mmol), lithium bromide (90 mg, 1 mmol) and triethylamine (2.27 ml, 16.2 mmol) were mixed in tetrahydro-furan (55 ml) at ambient temperature. The temperature was increased to 65° C. and held there for 26 h with efficient stirring, and the mixture was then evaporated to dryness. The residue was dissolved in a mixture of water and methanol (6:1, 70 ml) and treated with a strongly basic anion exchange resin (Dowex 1×8) for 2.5 h. The resin was filtered off, the solution diluted with further water (50 ml) and treated with a strongly acidic cation exchange resin (Amberlyst 15) to bring the pH of the solution to 5.5-6.0. The resin was filtered off and the solution was treated with activated charcoal (0.35 g), filtered and evaporated to a light yellow to white solid residue. This was triturated with acetonitrile (20 ml) for 12 h, giving 5.8 g (70%) of a white crystalline residue.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]=O)=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].N1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.[CH3:54][O:55][NH2:56]>C(O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH:35]=[N:56][O:55][CH3:54])=[CH:31][CH:32]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CON
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Yield: 64.5 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-oxoethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (145 mg, 0.25 mmol), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.099 mL, 1.28 mmol), sodium acetate (201.3 mg, 2.45 mmol) and O-methylhydroxylamine hydrochloride (102 mg, 1.22 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (50 mL). The organic layer was separated, washed with water (2×10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 1.8:8.2 Acetone:Pet. Ether) to afford title compound (100 mg, 64.4%).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:45])[CH:6]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:42])[CH:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH:20]([CH2:43][CH3:44])[CH2:19]1)[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.Cl>C1COCC1.O>[C:38]([O:37][C:35]([NH:34][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:24]([N:21]1[CH2:22][CH2:23][N:18]([CH:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:45])=[O:4])[CH2:19][CH:20]1[CH2:43][CH3:44])=[O:42])=[O:36])([CH3:39])([CH3:40])[CH3:41]
Reactant: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC1CN(C(Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)C(Cc1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
LiOH (0.2 g, 7.9 mmol) is added to the cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-propionyl]-3-ethyl-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 42, (1.0 g, 1.6 mmol) in THF/H2O (2/1, 30 mL). The reaction mixture is stirred overnight. The reaction mixture is cooled in ice bath and the pH is adjusted to 3 with 1M HCl. The aqueous layer is extracted with EtOAc (3×75 mL) and dried over Na2SO4. The organic layers are concentrated in vacuo to afford 1.0 g (quantitative yield) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[I:11])(=[O:20])=[O:19])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1I
Reactant: COc1nc(C)cnc1N
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1I

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 2-iodobenzenesulphonyl chloride.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C@@H:21]([CH2:24][OH:25])[O:20][C:19]=3[CH:26]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C@@H:21]([CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])[O:20][C:19]=3[CH:26]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)O[C@H](CO)CO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1COc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Methanesulfonyl chloride (0.550 g; 0.0048 mol) at 0° C. was added drop-wise to a solution of (7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(R)-yl)-methanol (0.73 g; 0.00238 mol) and triethyl amine (0.48 g; 0.0048 mol) in dichloromethane (10 mL). The mixture was stirred at 0° C. for 45 minutes, and then diluted with dichloromethane (20 mL), washed with water, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 1:1) to give methansulfonic acid 7-benzenesulfonyl-2,3-dihydro-benzo[1,4]dioxin-2(S)-yl-methyl ester as a foam (0.67 g; 73%): MS (M+H)+ 385.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[CH3:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:28][C:27]2[CH:29]=[CH:30][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Reactant: COc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(N=C(C)c2cccc(C(C)=Nc3c(C)cc(C)cc3C)n2)cc1
Reaction time: 144 h

Procedure:
Monoimine (1, 280 mg, 1 mmol) and 4-methoxyaniline (123 mg, 1 mmol) were dissolved in 20 ml of toluene. To this solution 4 Å molecular sieves were added. After standing for 6 days at room temperature the reaction mixture was filtered and the solvent was removed in vacuo. The residue was recrystallised from ethanol. Yield 148 mg (38%) of mixed diimine (6). 1H-NMR (CDCl3) δ 8.42 (dd, 1H), 8.34 (dd, 1H), 7.86 (t, 1H), 6.93 (d, 2H), 6.88 (s, 2H), 6.81 (d, 2H), 3.82 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H), 2.22 (s, 3H), 2.00 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=2)[NH:22][CH:21]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([F:29])[CH:27]=3)[NH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: Fc1ccc2[nH]cc(CCCCCl)c2c1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Product: Fc1ccc2[nH]cc(CCCCN3CCN(c4cccc(Cl)c4Cl)CC3)c2c1

Procedure:
from 1-(2,3-dichlorophenyl)piperazine and 3-(4-chlorobutyl)-5-fluoro-1H-indole. Mp 147–148° C. 1H NMR (DMSO-d6): 1.45–1.55 (m, 2H); 1.60–1.70 (m, 2H); 2.35 (t, 2H); 2.50 (b s, 4H); 2.65 (t, 2H); 2.95 (b s, 4H); 6.85–6.95 (m, 1H); 7.10–7.15 (m, 1H); 7.20 (s, 1H); 7.25–7.35 (m, 4H); 10.85 (b s, 1H). Ms m/z: 420 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:19][N:18]([CH3:20])[CH2:17]3)[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([O:24][CH2:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][C:27]=1[N:41]1[CH2:53][CH2:52][N:44]2[C:45]3[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=3[CH:51]=[C:43]2[C:42]1=[O:54])(=[O:23])[CH3:22]>>[C:21]([O:24][CH2:25][C:26]1[C:27]([N:41]2[CH2:53][CH2:52][N:44]3[C:45]4[CH2:46][CH2:47][CH2:48][CH2:49][C:50]=4[CH:51]=[C:43]3[C:42]2=[O:54])=[CH:28][CH:29]=[CH:30][C:31]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:19][N:18]([CH3:20])[CH2:17]3)[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CC(c2cc(Nc3cc(Br)cn(C)c3=O)n[nH]2)C1
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C4CN(C)C4)[nH]n3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 20 %

Procedure:
Following Example 136e, 168b and 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a were reacted to give 168c in 20% yield.
Reaction SMILES: BrC1C=C([O:8]C)C=CC=1.C([Li])(CC)C.[CH2:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:19][CH2:18]1)[CH3:16]>O1CCCC1.CCCCCC>[CH2:15]([N:17]1[CH2:22][CH2:21][C:20]([OH:8])([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[CH2:19][CH2:18]1)[CH3:16]
Reactant: CCN1CCC(c2cccc(OC)c2)CC1
Reactant: COc1cccc(Br)c1
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCN1CCC(O)(c2cccc(OC)c2)CC1
Temperature: -50 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a stirred solution of 3-bromoanisole (12.83 g, 0.069 mol) in dry tetrahydrofuran (70 ml) at -50° C. under an atmosphere of nitrogen was added sec-butyllithium (1.3M in hexanes, 68.5 ml, 0.089 mol) dropwise, ensuring that the temperature in the reaction vessel did not rise above -50° C. After complete addition of the sec-butyllithium, a white precipitate formed, and the reaction was stirred for 1 hour at -50° C. N-Ethyl-4-(3-methoxyphenyl)piperidine (10.5 ml, 0.079 mol) in dry tetrahydrofuran (50 ml) was added dropwise at a rate to maintain the reaction temperature below -40° C., resulting in an orange solution. The reaction mixture was allowed to warm to -20° C. over 1.5 hours, and then to room temperature over a further 1 hour. After this time, the reaction mixture was quenched by the addition of saturated brine (21 ml) and water (30 ml). The quenched reaction was stirred for a further 30 minutes, and then the two phases separated, and the organic phase retained. The aqueous phase was extracted with dichloromethane (3×75 ml), and the two organics combined and washed with hydrochloric acid (1N, 2×50 ml). The aqueous layer was separated, basified with ammonium hydroxide to pH 10, and extracted with dichloromethane (3×40 ml). The dichloromethane extracts were concentrated to yield a thick oil, which was triturated in cold hexane until a solid was obtained. This crude solid was stirred in hot hexane, allowed to cool, and filtered to yield N-ethyl-4-hydroxy-4-(3-methoxyphenyl)piperidine (5.5 g, 33.7%) as a white solid. m.p.=86.7-91.1° C.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1)(O)=O.[CH3:20][NH:21][C:22](=[O:30])[C:23]1[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=1)[NH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:20][N:21]1[C:22](=[O:30])[C:23]2[C:24](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:25]=[C:1]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:18][CH:19]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2-4-dione obtained by following a procedure described in any of Examples 25-28 (100 g, 0.356 M), N-methyl anthranilamide (58.7 g, 0.391 M), and p-toluenesulphonic acid (200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (internal temperature 150-155° C., oil bath temperature 170-180° C.) for a period of 12-15 h while monitoring the reaction by TLC. After completion of the reaction, the reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (100 g , Y=71%, P=98%).