Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=[CH2:3])=[N-].CCOCC.[Cl:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:11]=1[C:12]([CH3:23])=[C:13]([C:20]([OH:22])=[O:21])[NH:14]2>CCOCC>[Cl:9][C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:11]=1[C:12]([CH3:23])=[C:13]([C:20]([O:22][CH3:3])=[O:21])[NH:14]2
Reactant: C=[N+]=[N-]
Reactant: Cc1ccc(Cl)c2c(C)c(C(=O)O)[nH]c12
Solvent: CCOCC
Product: COC(=O)c1[nH]c2c(C)ccc(Cl)c2c1C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
An excess diazomethane ether solution was added to an ether solution of 0.50 g (2.24 mmol) of 4-chloro-3,7-dimethylindole-2-carboxylic acid under ice-cooling. The reaction mixture was allowed to stand for 30 minutes and then washed with 1N HCl aqueous solution and aqueous saturated sodium chloride solution. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide white crystals. The crude crystals were purified by silica gel column chromatography to provide 0.41 g of white crystals. Yield: 77%
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].[C:22](=O)(O)[O-].[Na+]>C(OC(=O)CC)(=O)CC>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13](=[O:14])[CH2:15][CH3:22])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: O=C([O-])O
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Product: CCC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Temperature: 0 °C

Procedure:
29.1 gm of 4,4-dimethyl-7-acetamino-8-nitro-2H,4H-isoquinoline-1,3-dione were refluxed for 4 hours with 50 ml of propionic acid anhydride. The mixture was then poured into ice water and neutralized with sodium bicarbonate. The obtained precipitate was purified on a silicagel column (eluant: chloroform/acetone 19:1).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[C:19]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH:18]=[CH:17][N:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:22][CH2:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:13]([N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:31][CH:30]=3)[CH2:8][CH2:9]2)=[O:14])[CH:20]=1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccnc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of tert-butyl ((2-(4-(4-chlorophenoxy)piperidine-1-carbonyl)pyridin-4-yl)methyl)carbamate (165 mg, 0.37 mmol, Step-1), trifluoroacetic acid (2 mL), and dichloromethane (2 mL) was stirred at room temperature for 1 hour. After removal of the solvent, the residue was purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX) to give 128 mg (>99%) of the title compound as colorless syrup. 25 mg of this material was further purified by preparative LC-MS to give 16.9 mg (68% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][C:4]=1[F:32].[C:33]([O:37][C:38]([NH:40][S:41](N1C=CC(=[N+](C)C)C=C1)(=[O:43])=[O:42])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(N(CC)CC)C>ClCCl>[F:32][C:4]1[CH:5]=[C:6]([CH:9]([CH3:31])[C:10](=[O:11])[NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][S:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])(=[O:42])=[O:43]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)c(F)c2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)c(F)c2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-(4-(Aminomethyl)-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide and intermediate (A) are dissolved in dichloromethane, dropwise triethylamine (0.1 equiv.). The reaction is stirred for 15 h at room temperature and quenched with water. The organic layer is extracted by dichloromethane and concentrated. After purification, tert-butyl N-(2-fluoro-4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate is obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:5]=1.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22](O)=[O:23])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([N:9]1[CH2:8][CH2:7][C:6]2[N:5]=[C:4]([C:3]([F:2])([F:14])[F:15])[CH:13]=[CH:12][C:11]=2[CH2:10]1)=[O:23])([CH3:18])[CH3:17]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: FC(F)(F)c1ccc2c(n1)CCNC2
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2nc(C(F)(F)F)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine hydrochloride (CA [741736-98-1]; WO2004069162) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 443.5 (M+H+).
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:19][NH2:20]>C(O)C>[CH:1]1([C:7]2[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[NH:20][N:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: O=C(O)c1ccccc1C(=O)C1CCCCC1
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(C2CCCCC2)c2ccccc12
Yield: 63.6 %

Procedure:
12.0 g of o-(cyclohexanoyl) benzoic acid and 3.1 g of hydrazine hydrate were dissolved in 60 ml of ethanol, and the solution was refluxed for 4 hours. Ethanol was distilled off and the remaining solution was crystallized by adding ether, thereby obtaining 7.5 g of 4-cyclohexyl-1-phthalazinone.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(C(F)(F)F)cc43)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4ccc(C(F)(F)F)cc43)nc12
Reaction time: 15 h
Yield: 26.2 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-(trifluoromethyl)-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (110 mg, 207 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-4% over 15 min (methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(6-trifluoromethyl-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (21.8 mg, 26%). MS (M+H)+=403; 1H NMR (DMSO-d6) δ: 8.93 (s, 1H), 8.78 (s, 1H), 8.71 (d, J=0.8 Hz, 1H), 8.46 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.68 (dd, J=8.5, 1.3 Hz, 1H), 7.62 (s, 1H), 1.41 (s, 9H).
Reaction SMILES: [P:1]([O:19][C:20]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22](=[O:39])[CH:23]=[C:24]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[NH:25]2)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].P(OC1C2C(=CC=C(OC)C=2OP(O)(O)=O)N=C(C2C=CC=C(F)C=2)C=1)(O)(O)=O>>[P:1]([OH:11])([OH:3])([O:19][C:20]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22](=[O:39])[CH:23]=[C:24]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[NH:25]2)=[O:2]
Reactant: COc1ccc2[nH]c(-c3cccc(F)c3)cc(=O)c2c1OP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: COc1ccc2nc(-c3cccc(F)c3)cc(OP(=O)(O)O)c2c1OP(=O)(O)O
Product: COc1ccc2[nH]c(-c3cccc(F)c3)cc(=O)c2c1OP(=O)(O)O
Yield: 63.7 %

Procedure:
Compound 51 (0.25 g, 0.46 mmol) was allowed to react in the same manner as described in the preparation of compound 49 to give 52. Yellow solid; yield: 63.7%; mp 179-181° C.; MS (ESI): m/z 366 (M+H)+; 1H-NMR (D2O+NaOD, 200 MHz): δ 3.76 (s, 3H), 6.53 (s, 1H), 7.05 (1, =8.4 Hz, 1H), 7.24-7.60 (m, 5H); Anal. (C16H13FNO6P) C, H, N.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[C:22]([C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:23]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
Phenylacetic acid (8.09 g, 59.46 mmoles) was dissolved in 15 ml dichloromethane. To this mixture, oxalylchloride (5.2 ml, 59.46 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 15 ml dichloromethane. To this mixture, 4-fluoroanisole (5.0 g, 39.64 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (7.92 g, 59.46 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (5.1 g, 56% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.43(s,1H), 7.77(dd, J=9.5,3.2 Hz, 1H), 7.42(dt, J=8.7,3.2 Hz, 1H),7.33(t, J=7.3 Hz, 2H), 7.26(m, 3H), 7.01(q, J=4.6 Hz, 1H),4.42(s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][CH:12]([OH:23])[CH2:11][O:10]1.C(#N)C.C(O)(=O)C.CC(O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH2:13][C:12](=[O:23])[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(O)CO[C@@H]1c1cc(F)ccc1F
Solvent: CC#N
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)CO[C@@H]1c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To 46.8 kg (142 mol) of tert-butyl [(2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl]carbamate in a stirred vessel was added acetonitrile (150 kg), acetic acid (50 kg), and water (25 kg). After dissolving at room temperature, the solution was cooled to 0° C. and RuCl3.3H2O (250 g, 956 mmol) in water (50 kg) was added under nitrogen. Then, NaBrO3 (11.7 kg, 77.5 mol) was added in six portions every 1.5 h under nitrogen. After stirring at 0° C. for 6 h, 2-propanol (31 kg) was added over 30 min. at 0° C. Then, water (720 kg) was added at this temperature over 5 h. The resulting slurry was stirred overnight, filtered, and cake washed with water. The solids were then dried under vacuum at 40-60° C. to give tert-butyl [(2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl]carbamate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH:20]=[CH:21][N+:22]([O-])=O)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]>C(O)C.[H][H].S(=O)(=O)(O)O.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[C:15]([CH2:20][CH2:21][NH2:22])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(C=C[N+](=O)[O-])c3c2c1C
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3cccc(CCN)c3c2c1C
Yield: 65.6 %

Procedure:
5-(2-Nitrovinyl)-4-methyl-beta-carboline-3-carboxylic acid ethyl ester (1 g) is dissolved in ethanol (20 ml) and in a hydrogen atmosphere with stirring is slowly added drop by drop to a suspension of 10% palladium carbon (0.25 g) in ethanol (50 ml) and sulfuric acid (0.1 ml). In the end, it is stirred for another half hour more. Then the catalyst is suctioned off and the filtrate evaporated. After the usual working up, 0.6 g of the title compound is obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=O)#[N:2].[N-:18]=[N+:19]=[N-:20].[Na+].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[C:1]([CH2:3][CH2:4][N:5]1[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:20][N:19]=[N:18]1)#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cccc(C(=O)NCCC#N)c1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnnn2CCC#N)c1
Yield: 41.2 %

Procedure:
Preparation H7, Step 2: To a soultion of methyl 3-((2-cyanoethyl)carbamoyl)benzoate (400 mg, 1.7 mmol) in MeCN (15 mL) at 0° C. was added NaN3 (111 mg, 1.7 mmol), and Tf2O (0.3 mL, 1.7 mmol). The mixture was stirred at rt for 16 h before aq NaHCO3 and EtOAc were added. The organic layer was separated and re-washed twice before it was collected, dried over Na2SO4, and concentrated to methyl 3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)benzoate as an oil (180 mg, 41% yield). MS found: (M+H)+=258.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(#N)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccc(F)cc1)c1ccccc1
Temperature: 100 °C
Yield: 72.3 %

Procedure:
4-Fluoroaniline (2.38 ml, 24.8 mmol) was added to a solution of ethyl 2-bromo-2-phenylacetate (4.34 ml, 24.8 mmol) in acetonitrile (50 ml). The reaction was heated under microwave irradiation at 100° C. for 30 minutes. Acetonitrile was evaporated, the residue was taken up with EtOAc and washed with 1N NaHCO3, 1N HCl and brine (100 ml). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (Petroleum ether/EtOAc=99/1 to 8/2) to afford ethyl 2-(4-fluorophenylamino)-2-phenylacetate (4.90 g, 72.3% yield).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH2:30]([N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH3:31]>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:44]3[CH2:45][CH2:46][N:41]([C:33]4[N:32]([CH2:30][CH3:31])[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=4)[CH2:42][CH2:43]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: CCn1c(N2CCNCC2)nc2ccccc21
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCn1c(N2CCN(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 1-ethyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][N:5]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:4]1.C(N(CC)CC)C.[S:34](Cl)([C:37]1[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>ClCCl.CN(C)C1C=CN=CC=1>[N:26]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:5]1[CH2:6][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[O:20][CH:3]([CH2:2][O:1][S:34]([C:37]2[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1ncccn1)CC(CO)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CN(c3ncccn3)CC3(CCN(C(=O)OC(C)(C)C)CC3)O2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a solution of tert-butyl 10-(hydroxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.45 g, 3.98 mmol) in dichloromethane (15 mL) was added triethylamine (1.66 mL, 11.9 mmol) and 4-(dimethylamino)-pyridine (195 mg, 1.59 mmol) at 0° C. Tosyl chloride (910 mg, 4.78 mmol) was then added in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with water and the layers were separated. The aqueous layer was extracted with dichloromethane, and the combined organic layers washed with saturated sodium bicarbonate solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Silica gel column chromatography (0-80% ethyl acetate/hexanes) provided tert-butyl 4-(pyrimidin-2-yl)-2-(tosyloxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (1.83 g, 3.53 mmol, 89%). ESI-MS m/z calc. 518.2. found 519.3 (M+1)+; Retention time: 1.83 minutes (3 min run). 1H NMR (400 MHz, MeOD) δ 8.31 (d, J=4.8 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 6.60 (t, J=4.8 Hz, 1H), 4.67-4.48 (m, 2H), 4.12 (d, J=4.6 Hz, 2H), 3.89 (ddd, J=12.0, 7.5, 4.6 Hz, 1H), 3.71-3.56 (m, 2H), 3.05 (ddd, J=20.6, 17.0, 8.8 Hz, 2H), 2.80-2.65 (m, 2H), 2.46 (s, 3H), 1.88 (d, J=14.1 Hz, 1H), 1.50 (dt, J=7.9, 4.0 Hz, 2H), 1.45 (s, 9H), 1.38-1.27 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].Br[CH2:11][CH2:12][CH2:13][OH:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9]
Reactant: Cc1occc(=O)c1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1occc(=O)c1OCCCO
Reaction time: 72 h
Yield: 7.3 %

Procedure:
A suspension of 3-hydroxy-2-methyl-4-pyrone (25 g, 200 mmol), 3-bromo-1-propanol (70 g, 500 mmol) and K2CO3 (111 g 800 mmol) in 600 ml acetone was stirred for three days. The solvent was evaporated and the residue partitioned between 300 ml methylene chloride and 500 ml 2.5% NaOH. The aqueous layer was separated and extracted with 2×300 ml methylene chloride. The organic phases were combined, dried over Na2SO4 and evaporated at 50° C. Eight grams of the residue (24 g) was chromatographed on silica gel with methanol/methylene chloride (5:95) as eluent which afforded 2.7 g (22%) of the desired product as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:34][C:35]([NH:37][CH:38]([CH3:40])[CH3:39])=[O:36])[C:29]([O:31]CC)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:41])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].OS([O-])(=O)=O.[K+]>C(O)C.O>[C:1]([O:5][C:6](=[O:42])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:34][C:35]([NH:37][CH:38]([CH3:39])[CH3:40])=[O:36])[C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:41])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)C(CC(=O)NC(C)C)CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)NC(=O)CC(CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)C(=O)O
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
2.6 g ethyl 2-{[(3S)-1-({[1-(2-tert.butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-(isopropylamino)-4-oxobutyrate (for preparation see Example 1) was dissolved in 52 ml of ethanol. A solution of 710 mg solid NaOH in 52 ml water was added to this receiving solution. After 30 minutes, it was acidulated with dilute aqueous KHSO4 solution to approximately pH 2 and the aqueous phase was extracted three times with 50 ml EA each time. The combined organic phases were dried over magnesium sulfate, the solvent was largely evaporated at reduced pressure and the remaining residue was chromatographed on silica gel (mobile phase: EA/cyclohexane 2:1 v/v). Drying the product fractions in an oil pump vacuum (5×10−2 mbar) yielded 2.2 g of the title compound as white foam resin, MS: [M+H]+: 558; m/z: 502,425, 397, 323.
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[Br:6][C:7]1[CH:8]=[CH:9][C:10](I)=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]>Cl>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:4][CH3:5])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(Br)ccc1I
Reactant: CC[Zn]CC
Agent: Cl
Product: CCc1ccc(Br)cc1C(=O)OC
Temperature: 62.5 °C
Reaction time: 2 h
Yield: 176.1 %

Procedure:
Add diethyl zinc (3050 mL, 3.05 mol, 1 M hexane) over 3 hours to a 5° C. solution of methyl 5-bromo-2-iodobenzoate (1876 g, 5.50 mol) and (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (40 g, 0.05 mol). Heat the mixture to 60-65° C. over 2 hours and stir for an additional 2 hours, then cool to 10-15° C. and pour into ice cold aqueous 1 M HCl (10 L). Separate the phases, extract the aqueous layer with methyl-tert-butyl ether (2×10 L), combine the organic phases, wash with saturated aqueous sodium chloride, dry over sodium sulfate, filter, and evaporate under reduced pressure. Dissolve in ethyl acetate (400 mL) and add petroleum ether (8 L), then let stand at 15-20° C. for 16 hours and filter through a pad of silica gel, wash with ethyl acetate/petroleum ether (1:20, 8 L) and evaporate the filtrate under reduced pressure to provide the title compound as a pale yellow oil (1306 g, 96%). ES/MS m/e: (79Br/81Br) 243/245 (M+H).
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([S:21][CH3:22])[CH:14]=1)[CH3:3].[OH:28]O>C(O)C>[ClH:1].[CH2:2]([O:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([S:21]([CH3:22])=[O:28])[CH:14]=1)[CH3:3]
Reactant: OO
Reactant: CCOc1ccccc1OCCNC(C)Cc1ccc(OC)c(SC)c1
Agent: Cl
Solvent: CCO
Product: CCOc1ccccc1OCCNC(C)Cc1ccc(OC)c(S(C)=O)c1

Procedure:
In 30 ml of ethanol was dissolved 1.0 g of 4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylthio)anisole hydrochloride and then 0.5 g of an aqueous 35% hydrogen peroxide solution was added to the solution with stirring. After stirring the mixture for 18 hours at room temperature, ethanol was distilled off under reduced pressure and the remaining sticky product was dispersed in 20 ml of water and extracted with 100 ml of ethyl acetate. The ethyl acetate layer was washed three times each time with 20 ml of water and after acidifying the solution with 0.2 ml of concentrated hydrochloric acid, the solvent was distilled off under reduced pressure. The remaining sticky material was applied to a silica gel column chromatography and eluted using a mixture of ethyl acetate and methanol (4:1 by volume ratio). The sticky product obtained was crystallized by the addition of 3 ml of isopropanol and the crystals thus formed were recovered by filtration to provide 0.4 g of 4-{2-[2-(2-ethoxyphenoxy)ethylamino]-2-methylethyl}-2-(methylsulfinyl)anisole hydrochloride.