Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:24](=[O:25])[NH:23][CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCC(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-piperidin-4-yl-piperazine-1-carboxylic acid tert-butyl ester (108 mg, 0.4 mmol, example 27) in dichloromethane (2 mL) was added isopropyl isocyanate. The mixture was stirred for 1 h and quenched with water. After aqueous workup with water and dichloromethane, the organic layers was dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was concentrated to give 4-(1-isopropylcarbamoyl-piperidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a viscous oil.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:35]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.O>CN(C=O)C>[CH:35]1([NH:41][C:3]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[NH:12][C:13]4[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[CH:9][CH:10]=2)=[O:4])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: NC1CCCCC1
Reactant: COC(=O)c1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccc(C(=O)NC4CCCCC4)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-methoxycarbonyl-phenyl)-3H-benzoimidazole-5-carboxylic acid (5.0 g) in DMF (250 mL) and CDI (7.1 g) was stirred at RT for 3.0 hours and then treated with cyclohexyl amine (2.0 g) and refluxed for 96 hours. The reaction mixture was cooled and then poured into water (2.0 L) and stirred at RT for 16 hours. The product was filtered, washed with water and ether and then recrystallized from THF, methanol and ether. Yield 0.4 g. TLC one spot (9:1)-CH2Cl2—CH3OH.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=O)[CH:11]=2.[O:30]([NH2:32])[CH3:31].[OH-].[Na+]>CCO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=[N:32][O:30][CH3:31])[CH:11]=2
Reactant: CON
Reactant: O=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)C2CC2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)C2CC2)C1
Reaction time: 18 h
Yield: 61 %

Procedure:
Combine cyclopropanecarboxylic acid[9-(3-fluoro-benzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Preparation 70) (0.32 g, 0.82 mmol), methoxylamine (0.21 g, 2.4 mmol), and sodium hydroxide (0.049 g, 1.3 mmol) in EtOH (15 mL). Add enough water to dissolve the sodium hydroxide and stir for 18 h. Dilute with water and extract with EtOAc. Dry EtOAc extracts over Na2SO4 and filter twice through a pad of silica to give 0.21 g (61%) of an off-white solid. MS (ES): m/z 420 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.[N:16]([Si](C)(C)C)=[N+:17]=[N-]>CC#N.CCOC(C)=O>[N:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)=[N+:16]=[N-:17]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Nc1ccc(I)cc1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-iodobenzenamine (2.38 g, 10.9 mmol) in MeCN (20 mL) at 0° C. was added tert-butyl nitrite (1.95 mL, 1.69 g, 16.4 mmol) and azidotrimethylsilane (1.70 mL, 1.49 g, 12.9 mmol). The reaction mixture was warmed to room temperature and stirred for 6 h, heated to 40° C. for 18 h, and diluted with EtOAc. The aqueous phase was washed with water (2×), brine (1×), dried over MgSO4, filtered, and concentrated to give 1-azido-4-iodobenzene which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[S:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:34]>ClCCl>[CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9](=[O:28])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[S:20]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:34])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccc(C(F)(F)F)cc1Sc1ccc(Cl)cc1)c1cnoc1C1CC1
Solvent: ClCCl
Product: O=C(c1ccc(C(F)(F)F)cc1S(=O)c1ccc(Cl)cc1)c1cnoc1C1CC1
Temperature: -12 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
A mixture of 5-cyclopropyl-4-[2-(4-chlorophenylsulphenyl)-4-trifluoromethylbenzoyl]isoxazole (1.14 g) and 3-chloroperoxybenzoic acid (0.84 g) in dichloromethane was stirred at -12° C. for 15 minutes. The precipitate was filtered and the filtrate was washed with aqueous sodium metabisulphite, aqueous sodium bicarbonate and a solution of brine and ammonium chloride, dried over anhydrous sodium sulphate and filtered. The dichloromethane was evaporated and the residue was crystallised from ethanol to give 5-cyclopropyl-4-[2-(4-chlorophenylsulphinyl)-4-trifluoromethylbenzoyl]isoxazole (compound 9, 0.86 g) as white crystals, m.p. 151° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:34])[N:25]([CH2:31][CH2:32][CH3:33])[CH:26]2[CH2:30][CH2:29][CH2:28]C2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:23][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:22]=1)[C:24]([N:25]([CH:26]1[CH2:38][CH2:37][CH2:28][CH2:29][CH2:30]1)[CH2:31][CH2:32][CH3:33])=[O:34]
Reactant: CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCCC1
Reaction time: 1 h

Procedure:
A solution of {2-[3-(propyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.07 g) in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.036 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[C@@H:10]([CH:19]([CH3:21])[CH3:20])[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH2:1]([O:8][C:9](=[O:22])[C@@H:10]([CH:19]([CH3:20])[CH3:21])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](N)C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 6 h

Procedure:
N-Tert-butoxycarbonyl-D-valine benzyl ester (70.7 g, 0.23 mol) was dissolved in a mixture of trifluoroacetic acid and methylene chloride (150 mL in 1:4 ratio) and the reaction mixture was heated at 50-60° C. After 6 h, the reaction mixture was concentrated to give D-valine benzyl ester trifluoroacetic acid salt (156.8 g) as a viscous oil which was converted to the free amine just prior to use.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2Cl)[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1.[NH3:22]>O1CCOCC1>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:22])[N:4]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[N:3]=1
Reactant: N
Reactant: Clc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(Br)nn2C1CCC2(CC1)OCCO2
Yield: 61 %

Procedure:
3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate W) (8.2 g, 21 mmol), conc. ammonia (100 mL) and dioxan (100 mL) were heated in a Parr pressure vessel at 120° C. for 20 hrs. The solvents were evaporated and the residue partioned between EtOAc and water. The EtOAc layer was dried over NASO4, filtered and evaporated to leave 3-bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine as a solid (4.7 g, 61%) which was used without further purification. 1H NMR (400 MHz, d6-DMSO): 8.21 (1H, s), 4.71 (1H, m), 3.90 (4H, m), 2.11(2H, m), 1.72-1.88 (6H, m ) HPLC: Tr=11.84 mins, 92.1%.
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[C:16]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CCOCC>C1COCC1>[CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][O:4][C:5](=[O:13])[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([O:26][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:35][CH:34]=2)=[CH:10][CH:11]=1
Reactant: CCC(C)COC(=O)c1ccc(O)cc1
Reactant: O=C(OCc1ccccc1)Oc1ccc(C(=O)Cl)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(C)COC(=O)c1ccc(OC(=O)c2ccc(OC(=O)OCc3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
A solution of 16 m moles (3.3 g) of the above 4-hydroxybenzoic acid 2-methylbutyl ester in 20 ml of THF and 40 ml of pyridien was cooled, and a THF solution of 10 m moles (2.9 g) of the above 4-carbobenzoxyoxybenzoyl chloride was added dropwise. The mixture was returned slowly to room temperature, then stirred for 8 hours. After the reaction, the reaction mixture was ether extracted and concentrated, and then purified by column chromatography to obtain 2.9 g of 4-(4'-carbobenzoxyoxybenzoyloxy)benzoic acid 2-methylbutyl ester [m.p. 64.4°-65.4° C⟧ (yield: 63%)
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH:6]1[C:23]2=[C:24]3[C:13]([C:14]4[C:25]5[C:22]2=[CH:21][CH:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]=5[C:17]([C:29](O)=[O:30])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([C:32](=N)[OH:33])[C:9]3=[C:8]([C:35](=N)[OH:36])[CH:7]=1>>[CH:15]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]4[C:32]([O:2][C:35](=[O:36])[C:8]5[C:9]=4[C:24]=3[C:23](=[CH:6][CH:7]=5)[C:22]3[C:25]=2[C:18]2[C:19]([C:26]([O:28][C:29](=[O:30])[C:17]=2[CH:16]=1)=[O:27])=[CH:20][CH:21]=3)=[O:33]
Reactant: O=S(=O)(O)O
Reactant: N=C(O)c1ccc2c3ccc(C(=O)O)c4c(C(=O)O)ccc(c5ccc(C(=N)O)c1c25)c43
Product: O=C1OC(=O)c2ccc3c4ccc5c6c(ccc(c7ccc1c2c73)c64)C(=O)OC5=O
Temperature: 220 °C

Procedure:
800 g of 95% strength sulfuric acid are initially taken and 200 g of 89.4% strength perylene-3,4,9,10-tetracarboxylic acid diimide are introduced at room temperature. The temperature of the mixture is then raised to 220° C., and this temperature is maintained for two hours. The mixture is then allowed to cool to room temperature and the precipitate which has been formed is filtered off with suction and washed first with 280 g of 80% strength sulfuric acid and then with water until it is neutral. Drying at 80° C. gives 174.3 g of crude perylene-3,4,9,10-tetracarboxylic dianhydride. This is introduced, with exclusion of light, into a solution composed of six liters of water and 140 g of 85% strength potassium hydroxide. While blanketed with nitrogen, the solution is heated to 80°-90° C., and stirring is continued for a further 90 minutes at this temperature. The mixture is then allowed to cool to 25° C., the pH is adjusted to a value of 8-9 and the solid residue is filtered off with suction and washed with 100 ml of water. (The residue is 38.7 g of perylene-3,4,9,10-tetracarboxylic acid diimide which has only been half-saponified, i.e. perylene-3,4,9,10-tetracarboxylic acid monoanhydride-monoimide, and this is expediently added to the next batch.) 60 g of 85% strength potassium hydroxide and 60 g of animal charcoal are introduced into the filtrate, with exclusion of light, and the mixture is then blanketed with nitrogen. After a further hour's stirring at 25° C., a solution of 48.8 g of copper carbonate and 600 ml of water is added dropwise, the mixture is stirred for a further hour at 25° C. and is clarified, and the filtrate is then added dropwise to 600 g of concentrated hydrochloric acid, the mixture is kept at 80°-90° C. for one hour and the precipitate is filtered off with suction, washed with water until it is neutral and dried at 80° C. This gives 133.7 g of perylene-3,4,9,10-tetracarboxylic dianhydride having the following extinction values:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:16]1[C:17]2[CH2:37][N:36]([C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][C:18]=2[N:19]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[O:33][CH:32]=[N:31][CH:30]=3)=[CH:25][CH:24]=2)[N:21]=1)(=O)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[N:1]1([C:16]2[C:17]3[CH2:37][N:36]([C:38](=[O:40])[CH3:39])[CH2:35][CH2:34][C:18]=3[N:19]=[C:20]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[O:33][CH:32]=[N:31][CH:30]=4)=[CH:27][CH:28]=3)[N:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(OS(=O)(=O)C(F)(F)F)c2C1
Reactant: c1ccc2c(c1)CCN2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N3CCc4ccccc43)c2C1
Yield: 19.1 %

Procedure:
1-(4-(Indolin-1-yl)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanone (14.3 mg, 19.1%) was prepared from indoline and 6-acetyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl trifluoromethanesulfonate (example 88a) according to the general procedure for amine substitution of tosylate on pyrimidines. MS (ES+) m/z 453.3 (M+H)+
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[C:12]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:11]1)C1C=CC=CC=1>C(O)C>[OH:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[C:12]([CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:11]1
Reactant: CC(C)CC1=C[C@H](COCc2ccccc2)OC1=O
Solvent: CCO
Product: CC(C)CC1=C[C@H](CO)OC1=O
Yield: 99 %

Procedure:
2.3 g of [R]-5-benzyloxymethyl-3-isobutyl-2(5H)-furanone, 150 mg of PdOH/C in 50 ml of ethanol was stirred at RT over night under H2 atmosphere. Then the catalyst was filtered out and filtrate was evaporated to dryness to give the pure compound in yield of 99%.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=1[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:19]1CCOCC1.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>O1CCCC1.O>[C:12]([C:11]1[CH:15]=[CH:16][C:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:9]([CH3:17])[CH:10]=1)(=[O:13])[NH2:19]
Reactant: CN1CCOCC1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(N)=O)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-tert-butoxycarbonyl-3-methyl-benzoic acid (40 g) was suspended in tetrahydrofuran (160 mL). This solution was cooled to −30 C then N-methyl morpholine (18.7 mL) followed by isobutylchloroformate (24.2 mL) were added. A white precipitate appeared. The solution was stirred for 8 hours then a solution of ammonium hydroxide (100 mL) was added. The reaction mixture was slowly allowed to warm to room temperature over 48 hours. Then water was added and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over sodium sulfate and concentrated to give a solid which was further triturated with a mixture of dichloromethane/ethyl acetate, filtered, to give tert-butyl 4-carbamoyl-2-methyl-benzoate (29.9 g) as a white solid. 1H-NMR (CDCl3, 400 MHz): 7.90 (d, 1 H), 7.72 (s, 1 H), 7.65 (d, 1 H), 2.63 (s, 3 H), 1.62 (s, 9 H).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].Cl[C:6]([O:8][CH2:9][Cl:10])=[O:7].N1C=CC=CC=1>CCOCC>[CH:2]([O:4][C:6](=[O:7])[O:8][CH2:9][Cl:10])([CH3:3])[CH3:1]
Reactant: O=C(Cl)OCCl
Reactant: CC(C)O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)OC(=O)OCCl
Temperature: 0 °C
Yield: 91.9 %

Procedure:
2-Propanol (73.14 mmole, 5.6 mL) was added to a solution of chloromethyl chloroformate (73.85 mmole, 6.5 mL) in ether (100 mL). The reaction mixture was cooled to 0° C. and pyridine (74.18 mmole, 6 mL) was dropwise added with stirring. Thereafter, the reaction mixture was stirred at ambient temperature for 20 hours. The formed solids were filtered and the filtrate was washed with citric acid (1% aqueous), water, sodium bicarbonate solution (1%) and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness to yield 10.26 g (92%) of a colorless oil. MS (ES+): m/e 152 (M+H).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:15])[CH:6]2[O:13][CH3:14].[Li]CCCC.[CH2:21]1[O:23][CH2:22]1.O>C1COCC1>[CH3:14][O:13][CH:6]1[C:7]2[C:3](=[C:2]([CH2:21][CH2:22][OH:23])[C:10]([CH3:11])=[C:9]([CH3:12])[CH:8]=2)[CH2:4][CH:5]1[CH3:15]
Reactant: COC1c2cc(C)c(C)c(Br)c2CC1C
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC1c2cc(C)c(C)c(CCO)c2CC1C
Temperature: -110 °C
Reaction time: 0.67 h

Procedure:
To a solution of 52.77 g (196.0 mmol) of 4-bromo-1-methoxy-2,5,6-trimethylindane in 300 ml of THF 156.8 ml of 2.5 M (392.1 mmol) n-BuLi in hexanes was added for 20 min at −80° C. This mixture was stirred for 40 min at this temperature, cooled to −110° C., and 17.27 g (392.1 mmol) of ethylene oxide was added by one portion at vigorous stirring. The resulting mixture was stirred for 12 h at room temperature, and then 10 ml of water was added. The organic layer was separated and evaporated to dryness. To the residue 200 ml of water was added, and the crude product was extracted with 3×100 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The product was isolated by flash chromatography using short column with Silica Gel 60 (40-63 um, d 110 mm, l 90 mm; eluent: hexanes/ether=20/1). Yield 36.66 g (80%) of a ca. 1 to 1.7 mixture of two diastereomers.
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:11]=2[O:15][CH2:16][CH2:17][CH3:18])[N:6]1[C:25](=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:2]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:11]([O:15][CH2:16][CH2:17][CH3:18])=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]([C:25](=[O:27])[CH3:26])[C@@H:5]([CH3:4])[CH2:14][CH2:13]3)[CH2:20][CH2:21]1)[CH3:3]
Reactant: CCI
Reactant: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(C2CCN(CC)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
Iodoethane (5 μl, 0.06 mmol) was added to a solution of (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethanone (20 mg, 0.06 mmol) and potassium carbonate (38 mg, 0.27 mmol) in DMF (1.0 mL), and the reaction was stirred at room temperature overnight. The reaction was quenched via the addition of water (5 mL) and extracted with ethyl acetate (2×10 mL). The organic layer was collected and further washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 50-80% methanol in ethyl acetate) to afford (S)-1-(6-(1-ethylpiperidin-4-yl)-2-methyl-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (10 mg, 51%) as a light yellow oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96-1.06 (m, 6H), 1.15 (t, J=7.04 Hz, 3H), 1.15-1.26 (m, 1H), 1.38-1.61 (m, 4H), 1.66-1.89 (m, 2H), 2.20 (s, 3H), 2.16-2.28 (m, 2H), 2.52 (m, 2H), 2.67-2.80 (m, 2H), 2.83-2.94 (m, 1H), 2.92-3.07 (m, 3H), 3.58-3.72 (m, 2H), 4.40-4.63 (br d, J=6.75 Hz, 1H), 7.03 (br s, 2H). MS (ESI, pos. ion) m/z 359 [M+H]+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[NH:3][CH:2]=1.[N:11]1[S:12][N:13]=[C:14]2[CH:19]=[C:18]([CH2:20]Br)[CH:17]=[CH:16][C:15]=12.C([O-])([O-])=O.[K+].[K+]>>[N:11]1[S:12][N:13]=[C:14]2[CH:19]=[C:18]([CH2:20][N:10]([CH2:20][C:18]3[CH:17]=[CH:16][C:15]4=[N:11][S:12][N:13]=[C:14]4[CH:19]=3)[C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)[CH:17]=[CH:16][C:15]=12
Reactant: BrCc1ccc2nsnc2c1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1nc2cc(N(Cc3ccc4nsnc4c3)Cc3ccc4nsnc4c3)ccc2[nH]1

Procedure:
The compound was synthesized starting from benzimidazol-5-amine (133 mg; 1 mmol; 1 eq.), benzo[c][1,2,5]thiadiazol-5-yl-methylbromide (504 mg; 2.2 mmol; 2.2 eq.) and K2CO3 (304 mg; 2.2 mmol; 2.2 eq.) according to method 5; Yield: 0.128 mg (29.8%); MS m/z: 430.4 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 5.01 (s, 4H); 6.78 (br s, 1H); 6.82-6.84 (m, 1H); 7.39-7.41 (m, 1H); 7.71-7.73 (m, 2H); 7.88 (s, 1H); 7.90 (s, 2H); 8.06-8.08 (m, 2H); 11.85 (br s, 1H); HPLC (METHOD [A]): rt 14.11 min (98.9%)
Reaction SMILES: B(Br)(Br)Br.CCCCCCC.C[O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)=[CH:16][CH:15]=1>C(Cl)Cl>[OH:29][C@H:26]1[CH2:27][CH2:28][C@H:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=2)[CH2:24][CH2:25]1
Reactant: COc1ccc(CCN[C@H]2CC[C@H](O)CC2)cc1
Agent: BrB(Br)Br
Solvent: CCCCCCC
Solvent: ClCCl
Product: Oc1ccc(CCN[C@H]2CC[C@H](O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add dropwise 1.0 M BBr3 in heptane (1.35 mL, 1.35 mmol) to a suspension of (±)-(trans)-4-[2-(4-methoxyphenyl)ethylamino]cyclohexanol (Part A, 153.2 mg, 0.61 mmol) in anhydrous CH2C12 (5.0 mL) at 0° C. Add another 1.0 mL of CH2Cl2 when the compound precipitates out. Stir the mixture at 0° C. for 30 minutes and at room temperature for 2 hours. Quench the reaction with 5 drops of H2O and concentrate. Purify the residue on an SCX column, washing with MeOH and then eluting with 2.0 M NH3 in MeOH to yield (±)-(trans)-4-[2-(4-hydroxycyclohexylamino)ethyl]phenol (121.2 mg).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[SH:21][CH:22]([CH2:25][SH:26])[CH2:23][OH:24]>>[OH:24][CH2:23][CH:22]([SH:21])[CH2:25][S:26][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: OCC(S)CS
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SCC(S)CO)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 2,3-dimercapto-1-propanol to provide 5-[2-[(3-hydroxy-2-mercaptopropyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.65 (m, 1H) and overlapping 1.65 and 1.68 (singlets, 3H), 1.92 (br s with fine structure, 1H), 2.65-2.80 (m, 2H), 2.89 (br s with fine structure, 1H), 3.10-3.28 (m, 2H), 4.43-4.60 (m, 1H), 5.38, 5.40 and 5.41 (singlets, 1H), 7.13-7.20 (m, 2H), 7.25-7.43 (m, 6H); MS (LR-ESI) m/z 407 (M+H calcd. for C20H23NO3S3 407).