Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:12]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][CH:2]=1
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: O=Cc1ccc2[nH]cc(Cl)c2c1
Reaction time: 4 h
Yield: 105.6 %

Procedure:
To a stirred solution of 1H-indole-5-carbaldehyde (0.50 g, 3.44 mmol) in DCM (25 mL) was added N-chlorosuccinimide (0.44 g, 3.27 mmol). After 4 h, the mixture was washed with water (50 mL) and the organic layer was dried and concentrated to obtain the crude residue (0.62 g), which was used without purification. 1H NMR (CDCl3): 10.04 (s, 1H), 8.17-8.15 (m, 1H), 7.79 (dd, J=8.6, 1.5 Hz, 1H), 7.46 (d, J=8.6 Hz, 1), 7.29-7.28 (m,1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4](C2C=CC(F)=CC=2C)[CH:3]=1.[Cl:34][C:35]1[C:36](I)=[CH:37][C:38]([F:41])=[N:39][CH:40]=1>CCCCCCC.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=2)=[C:4]([C:36]2[C:35]([Cl:34])=[CH:40][N:39]=[C:38]([F:41])[CH:37]=2)[CH:3]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1cc(I)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1cc(F)ncc1Cl

Procedure:
The title compound was prepared in analogy to example 73, from N-(6-chloro-4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 72, intermediate) and 5-chloro-2-fluoro-4-iodopyridine (CAS RN 659731-48-3) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic separation. Colorless oil (89%). MS (ESI): m/z=511.009 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.CCOCC>[N:25]([CH:8]([C:6]1[C:5]([O:11][CH3:12])=[C:4]([CH:13]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]2)[C:3]([F:24])=[C:2]([Cl:1])[CH:7]=1)[CH3:9])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COc1c(C(C)N=[N+]=[N-])cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate (0.070 g, 0.18 mmol) and sodium azide (0.036 g, 0.56 mmol) in DMF (0.66 mL) was stirred at room temperature overnight. After diluting with ether, the mixture was washed with water, dried over MgSO4 and concentrated to give the crude azide which was used in the next step without further purification. LCMS calculated for C17H22ClFN4O3Na (M+Na)+: m/z=407.1. found: 407.0.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])[CH2:9]1)=[N+]=[N-].[H][H]>CO.[Pd]>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:23]=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=2)=[N:17][C:16]=1[CH2:15][O:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([O:7][CH2:6][CH2:5][CH2:4][NH2:1])[CH2:9]1
Reactant: Cc1cccc(-c2nc(CO[C@@H]3CCC[C@H](OCCCN=[N+]=[N-])C3)c(C)o2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCCN)C3)c(C)o2)c1

Procedure:
472 mg of ((1R,3S)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propyl 4-chloromethanesulfonate are dissolved in 3 ml of N-methylpyrrolidone, and 200 mg of sodium azide are added. The mixture is stirred at 60° C. for 3 h and, after cooling, taken up in 20 ml of ethyl acetate/20 ml with sat. NaCl solution. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. This gives 4-((1R,3S)-[3-(3-azidopropoxy)cyclohexyloxymethyl]-5-methyl-2-m-tolyloxazole as a colorless oil. C21H28N4O3 (384.48), MS (ESI): 385 (M+H+). The crude azide is taken up in 20 ml of methanol and hydrogenated with 50 mg of Pd/C 10% at a hydrogen atmosphere of 1 bar for 3 h. The catalyst is filtered off, giving (1R,3S)-3-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]propylamine as a colorless oil. C21H30N2O3 (358.48), MS (ESI): 359 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH:19]([O:18][CH:12]([CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([CH2:2][O:1][C:31]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[O:32])[CH:4]=1)[C:13]([OH:15])=[O:14])([CH3:20])[CH3:21]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Reactant: COc1ccc(N=C=O)cc1
Product: COc1ccc(NC(=O)OCc2cc(CC(OC(C)C)C(=O)O)ccc2OC)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: C1COCCN1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCOCC2)no1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.3 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was cooled to 0° C. then treated with morpholine (0.066 ml, 7.60 mmol). The resulting mixture was warmed to room temperature and stirred under a nitrogen atmosphere for 17 hours. Further morpholine (0.53 ml, 6.08 mmol) was added and the mixture heated to 60° C. for 8 hours. The mixture was cooled and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (80:20) to afford title compound as a yellow oil (269 mg)
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]([OH:16])=[O:15])=[O:11])=[N:5][CH:4]=1)=[O:2].[C:30]([OH:32])([C:29]([F:34])([F:33])[F:28])=[O:31]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)CNc1ncc(C=O)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cnc(NCC(=O)N[C@@H](Cc2ccccc2)C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of material from Example 10 (27 mg, 0.07 mmol) in CH2Cl2 (6 mL) is added trifluoroacetic acid (2.5 mL, 32.4 mmol). The resulting solution is stirred at room temperature for 1 h, then evaporated to dryness over 18 h to give the title compound as a TFA salt that is used crude, and in its entirety in the next step. LC/MS (Condition A): ret. T=2.45 min, (M+1-H)+ 334.08.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH2:11])=[S:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH:13]([CH2:17][CH3:18])[C:14](O)=[O:15]>>[CH:1]1([NH:8][C:9]2[S:10][CH:13]([CH2:17][CH3:18])[C:14](=[O:15])[N:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: CCC(Br)C(=O)O
Product: CCC1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-cycloheptylthiourea and 2-bromobutyric acid according to Method C.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=O>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[C:2]([S@@:5](/[N:7]=[CH:8]/[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:12][CH2:11]1)=[O:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(/C=N/[S@@](=O)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A solution of (S)-2-methylpropane-2-sulfinamide (2.0 g, 16.50 mmol) in THF (8.0 ml) and titanium(IV) ethoxide (17.3 ml, 82.51 mmol) were added sequentially to a solution of tert-butyl 4-formylpiperidine-1-carboxylate (3.70 g, 17.33 mmol) in THF (8.0 ml). The resulting mixture was stirred at r.t for 2 hours. The reaction mixture was poured into ice/water and the suspension filtered. The filtrate was extracted with EtOAc and the organic layer was dried with MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was dried under vacuum to provide the title compound (4.45 g, yield: 85%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].Br[CH2:26][CH2:27][CH2:28][Cl:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: ClCCCBr
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
A suspension of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (321 mg, 1 mmol), (prepared as described in Example 49), 1-bromo-3-chloropropane (120 μl, 1.2 mmol) and potassium carbonate (359 mg, 2.6 mmol) in DMF (5 ml) was stirred at ambient temperature overnight. After addition of water, the precipitate was collected by filtration, washed with water and dried over phosphorus pentoxide at 60° C. to give 7-(3-chloropropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (280 mg, 70%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[NH2:31][OH:32]>CS(C)=O.O>[OH:32][N:31]=[C:27]([C:26]1[CH:29]=[CH:30][C:23]([CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([CH2:14][O:13][C:12]4[CH:15]=[C:16]5[C:20](=[CH:21][C:11]3=4)[CH2:19][CH2:18][O:17]5)[C:2]2=[O:1])=[CH:24][CH:25]=1)[NH2:28]
Reactant: NO
Reactant: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Solvent: O
Solvent: CS(C)=O
Product: NC(=NO)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirred solution of 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (1.30 g, 32.9 mmol) in dimethyl sulfoxide (10 mL) was added 50% wt solution of hydroxylamine in water (2 mL). The reaction was heated with stirring at 80° C. for 1 h, then cooled to ambient temperature and the product was precipitated by adding distilled water (25 mL). The solid was filtered and air dried to afford N′-hydroxy-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide (1.32 g, 93%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 9.17 (s, 1H), 7.40-7.03 (m, 13H), 6.99-6.92 (m, 2H), 6.79-6.74 (m, 2H), 6.58-6.50 (m, 1H), 5.10 (s, 1H); MS (ES+) m/z 428.0 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([F:15])=[C:10]([Cl:16])[CH:9]=2)=[O:5])C.Br[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>>[Cl:16][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:3])=[O:5])[N:7]2[CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[F:15]
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cc(F)c(Cl)cc2[nH]1
Product: O=C(O)c1cc2cc(F)c(Cl)cc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 6-chloro-5-fluoro-1H-indole-2-carboxylic acid ethyl ester (Lit. 7) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 352.0 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:20])CCOC>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][F:20])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: FCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 4-bromobenzylalcohol (561 mg) in methylene chloride (3 mL) was added [bis-(2-methoxyethyl)amino]sulfur trifluoride (590 μL) over a period of 5 minutes under ice-cooling and the mixture was stirred at the same temperature for 1 hours and then stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=100:0→95:5) to give 1-bromo-4-fluoromethyl-benzene (340 mg, yield: 60%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:14].N1C(C)=CC=CC=1C>C(OCC)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH:7]([OH:14])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: O=S1CCC2(CC1)OCCO2
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: OC1CC2(CCS1)OCCO2
Temperature: 150 °C

Procedure:
A mixture of 0.88 g of product from Example 393, 5.0 ml of acetic anhydrideand 2.0 ml of lutidine is heated at 110°-115° C. for 2.5 hours, followed by increasing the temperature to 150° C. and then heated for 3 hours. The reaction mixture is diluted with ethyl acetate, washed 2 X with 1N hydrochloric acid, water, saturated sodium chloride, dried and concentrated in vacuo. The residue is dissolved in methylene chloride, filtered through a pad of hydrous magnesium silicate and reconcentrated in vacuo to give 0.569 g of the desired product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[I:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:8][CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: NCCN1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: O=S(=O)(NCCN1CCCC1)c1ccc(I)cc1

Procedure:
The title compound was prepared from [2-(1-pyrrolidinyl)ethyl]amine and 4-iodobenzenesulfonyl chloride using a similar procedure to that described for Description 30.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)[C@H:3]([OH:27])[CH2:4][N:5]([CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22][C:23]#[N:24])[S:6]([C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1)(=[O:8])=[O:7].[O:43]1[CH2:47][CH2:46][C@H:45]([O:48][C:49](ON2C(=O)CCC2=O)=[O:50])[CH2:44]1.C(NC(C)C)(C)C.C(#N)C>>[O:13]1[C:12]2[CH:16]=[CH:17][C:9]([S:6]([N:5]([CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:4][C@@H:3]([OH:27])[C@@H:2]([NH:1][C:49](=[O:50])[O:48][C@H:45]3[CH2:46][CH2:47][O:43][CH2:44]3)[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:34]=3)(=[O:8])=[O:7])=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Reactant: CC(C)(CCCC#N)CN(C[C@@H](O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)(CCCC#N)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
N-{(2R,3S)-3-Amino-4-[4-(benzyloxy)phenyl]-2-hydroxybutyl}-N-(5-cyano-2,2-dimethylpentyl)-1,3-benzodioxole-5-sulfonamide was treated with 1-({[(3S)-tetrahydro-3-furanyloxy]carbonyl}oxy)-2,5-pyrrolidinedione/diisopropylamine/acetonitrile as previously described to provide the title product as a solid foam. 1H NMR (DMSO-d6): δ 0.88 (3H, s), 0.90 (3H, s), 1.3 (2H, dd), 1.5-1.6 (2H, m), 1.7-1.8 (1H, m), 2.0-2.2 (1H, m), 2.37 (1H, t), 2.4 (2H, t), 2.75-2.85 (3H, m), 2.9 (1H, dd), 3.30-3.45 (3H, m), 3.55 (1H, dd), 3.65 (1H, dd), 3.7 (2H, dd), 4.9 (1H, s), 4.98 (1H, d), 5.0 (2H, s), 6.15 (2H, s), 6.8 (2H, d), 7.0 (2H, d), 7.06 (2H, d), 7.24 (1H, s), 7.25-7.42 (6H, m); MS: 708 (MH+);
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1.Cl[CH2:15][C:16](Cl)=[O:17].Cl>[Na]>[C:16]([NH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1)(=[O:17])[CH3:15]
Reactant: Cc1cc(C)c2c(c1O)C(N)CC2
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na]
Product: CC(=O)NC1CCc2c(C)cc(C)c(O)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.77 Grams of 1-amino-4,6-dimethyl-7-hydroxyindane was dissolved in 100 ml of 0.2N-sodium hdyroxide aqueous solution, then 1.7 g of α-chloroacetyl chloride was added thereto under an ice-cooling condition. Then the reaction mixture was stirred at a room temperature for 2 hours. The reaction mixture was acidified by adding a diluted hydrochloric acid, then extracted with chloroform. The chloroform layer was washed with water, dried, then the solvent was removed by evaporation. Recrystallized from ethanol to obtain 2.34 g of 1-acetylamino-4,6-dimethyl-7-hydroxyindane in the form of colorless needle-like crystals. Melting point: 131°-132° C.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[NH2:6].[F:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23]>CCOCC>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:4]=[C:5]([NH:6][C:25]([NH:24][C:22](=[O:23])[C:21]2[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:20]=2[F:19])=[O:26])[CH:7]=[CH:8][C:9]=1[O:10][C:11]([F:16])([F:15])[CH:12]([F:13])[F:14]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: Nc1ccc(OC(F)(F)C(F)F)c(C(F)(F)F)c1
Solvent: CCOCC
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1ccc(OC(F)(F)C(F)F)c(C(F)(F)F)c1

Procedure:
5.4 g of 3-trifluoromethyl-4-(1,1,2,2-tetrafluoroethoxy)-aniline are placed into 20 ml of abs. ether, and 3.7 g of 2,6-difluorobenzoylisocyanate dissolved in 10 ml of abs. ether are subsequently added dropwise at room temperature. The solid which has precipitated is filtered off with suction after 1 hour; it is then washed with abs. ether and dried in air. Recrystallisation from toluene yields N-[3-trifluoromethyl-4-(1,1,2,2-tetrafluoroethoxy)-phenyl]-N'-(2,6-difluorobenzoyl)-urea having a melting point of 182°-185° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]3[CH:29]=[C:30]([O:36][CH2:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[CH:32][C:27]=3[C@H:26]3[C@H:21]([CH2:22][CH2:23][N:24]([CH3:39])[CH2:25]3)[N:20]=2)=[CH:15][CH:14]=1>ClCCl.N1C=CC=CC=1>[CH2:37]([O:36][C:30]1[C:31]([O:33][CH2:34][CH3:35])=[CH:32][C:27]2[C@H:26]3[C@H:21]([CH2:22][CH2:23][N:24]([CH3:39])[CH2:25]3)[N:20]=[C:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])=[CH:14][CH:15]=3)[C:28]=2[CH:29]=1)[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1cc2c(cc1OCC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1cc2c(cc1OCC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.7 %

Procedure:
A solution of 2.3 g p-toluenesulfonic acid chloride in 5 ml absolute dichloromethane is added dropwise to a solution of 3.5 g (−)-cis-6-(4-Aminophenyl)-8,9-diethoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo-[c][1,6]naphthyridine in 20 ml absolute pyridine, and the mixture is then stirred at room temperature for a further 3 h. After the evaporation of the solvents, the residue is extracted with dilute sodium hydroxide solution and dichloromethane. The organic phase is then washed with water, dried over sodium sulfate and concentrated. 5.4 g of the title compound are obtained as rough product, which is recrystallised twice in ethyl acetate/methanol. Yield: 4.3 g yellowish crystalls. M.p. 267-268° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][S:15]([C:18]1[CH:37]=[CH:36][C:21]([C:22]([NH:24][CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][C@H:29]2[C:33]([OH:35])=O)=[O:27])=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:33]([C@@H:29]2[CH2:30][CH2:31][CH2:32][N:28]2[C:26](=[O:27])[CH2:25][NH:24][C:22](=[O:23])[C:21]2[CH:36]=[CH:37][C:18]([S:15](=[O:17])(=[O:16])[NH:14][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:19][CH:20]=2)=[O:35])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@@H]2CCCN2C(=O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccccc3Oc3ccccc3)cc2)CC1

Procedure:
The title compound was prepared from (S)-1-{2-[4-(2-phenoxy-phenylsulfamoyl)-benzoylamino]-acetyl}-pyrrolidine-2-carboxylic acid and piperazine-1-carboxylic acid tert-butyl ester according to the method described in Example 1.1/d. MS (EI) 714.3 (M+Na+).
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:3][C:2]([CH3:19])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][N:16]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:17][CH2:18]2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C3CCCCC3)CC2)CC1
Yield: 99 %

Procedure:
Prepared analogously to Example A19a) from 1-(1,1-dimethyl-ethoxycarbonyl)-4-(4-piperidinyl)piperazine and cyclohexanone in a yield of 99% of theory. Colourless, highly viscous oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[N:6]=[C:5]2[NH:24][CH2:25][C:26]([F:29])([F:28])[F:27].[F:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[N:6]=[C:5]3[NH:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: NS(=O)(=O)c1ccc(CNc2nc(NCC(F)(F)F)c3cc(Br)ccc3n2)cc1
Product: NS(=O)(=O)c1ccc(CNc2nc(NCC(F)(F)F)c3cc(-c4ccc(F)cc4)ccc3n2)cc1

Procedure:
The title compound was synthesized by analogy to Example 51 using 4-{[6-bromo-4-(2,2,2-trifluoro-ethylamino)-quinazolin-2-ylamino]-methyl}-benzenesulfonamide and 4-fluorobenzene boronic acid. The resulting product was characterized as follows: MS (m/z): 506 ([M+H]+, 100); HPLC Rt=2.85 minutes (Method A).