Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][CH2:23][C:24]4[N:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:17][C:16]=3[C:31]3[C:32]([C:38]([OH:40])=[O:39])=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].C(C1C=C2C(C(CC3C=CC(C(=O)NCC4C=NC=CC=4)=CC=3C3C(C(O)=O)=CC(C)=CC=3)=CN2CC)=CC=1)(=N)[NH2:42].C(O)(=O)C(O)=O.NCC1N=CC=CN=1>>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:30])[NH:22][CH2:23][C:24]4[NH:29][CH2:28][CH2:27][CH2:26][N:25]=4)=[CH:17][C:16]=3[C:31]3[C:32]([C:38]([OH:40])=[O:39])=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)(=[NH:42])[NH2:2]
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3ncccn3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C#N)cc21
Reactant: CCn1cc(Cc2ccc(C(=O)NCc3cccnc3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C(=N)N)cc21
Agent: NCc1ncccn1
Agent: O=C(O)C(=O)O
Product: CCn1cc(Cc2ccc(C(=O)NCC3=NCCCN3)cc2-c2ccc(C)cc2C(=O)O)c2ccc(C(=N)N)cc21
Yield: 55 %

Procedure:
Part A. 2′-(6-cyano-1-ethyl-1H-indol-3-ylmethyl)-4-methyl-5′-[(pyrimidin-2-ylmethyl)-carbamoyl]-biphenyl-2-carboxylic acid: The amide was prepared in 55% yield from the acid of Example 37, Part D following the procedure of Example 37, Part E using 2-aminomethylpyrimidine oxalate in place of 3-aminomethylpyridine. 1H NMR (500 MHz, CDCl3) δ ppm 1.38 (t, J=7.42 Hz, 3H) 2.41 (s, 3H) 3.79 (s, 2H) 4.03 (q, J=7.15 Hz, 2H) 4.86 (m, 2H) 4.96 (m, 2H) 6.67 (s, 1H) 7.03 (m, 3H) 7.17 (dd, J=15.40, 8.25 Hz, 2H) 7.24 (m, 5H) 7.41 (t, J=12 Hz, 1H) 7.56 (s, 1H) 7.60 (s, 1H) 7.74 (d, J=9.90 Hz, 1H) 7.84 (s, 1H) 8.71 (d, J=0.40 Hz, 2H). LC/MS m/z 620.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[CH:7]=1.[C:14]1([CH3:24])[CH:19]=[CH:18]C(S(O)(=O)=O)=CC=1>C(O)CCC>[CH2:3]([O:12][C:11]([C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]([O:10][CH2:24][CH2:14][CH2:19][CH3:18])=[O:9])[CH:5]=1)=[O:13])[CH2:2][CH2:7][CH3:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1cc(C(=O)O)cc(C(=O)O)c1
Solvent: CCCCO
Product: CCCCOC(=O)c1cc(N)cc(C(=O)OCCCC)c1
Temperature: 97 °C
Yield: 181.7 %

Procedure:
A mixture of 5-amino-1,3-benzenedicarboxylic acid (632 g, 3.49 mol), n-butyl alcohol (7.5 L) and p-toluenesulphonic acid (860 g, 4.52 mol) is loaded into a 10 L reaction vessel and heated to 97° C. under stirring under a reduced pressure of about 450 mBar removing the azeotrope n-butyl alcohol/water that forms. After 11 hours of heating the reaction mixture is concentrated to 2.4 L, cooled to 60° C. and neutralised by the addition of 5M NaOH (0.9 L). The mixture is further cooled to about 10° C. and diluted with water 3.4 L). After 15 hours at room temperature the solid is recovered by filtration, washed with water (2×1 L) and dried yielding the 5-amino-1,3-benzenedicarboxylic acid di-n-butyl ester (930 g, 3.17 mol, yield: 91%).
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[S:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1>CN1CCCC1=O>[CH3:23][N:20]1[CH2:19][CH2:18][CH:17]([S:16][C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:4]#[N:5])[CH:8]=3)[NH:12][CH:11]=2)[CH2:22][CH2:21]1
Reactant: CN1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Product: CN1CCC(Sc2c[nH]c3ccc(C#N)cc23)CC1
Yield: 5.1 %

Procedure:
A suspension of copper cyanide (17.7 g) and 5-bromo-3-[(1-methylpiperidin-4-yl)thio]-1H-indole (35.5 g, prepared in Example 44) in 1-methylpyrrolidin-2-one (45 ml) is refluxed for 24 hours. After dilution with water, the brown precipitate is separated off and then taken up with a mixture of water (110 ml) and ethylenediamine (170 ml). The blue solution is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The residual oil is chromatographed on silica gel (eluent: AcOEt/iPrNH2 95/5) to give 3-[(1-methylpiperidin-4-yl)thio]-1H-indole-5-carbonitrile (1.5 g), which is converted to the oxalate in ethanol.
Reaction SMILES: [OH:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([OH:21])[CH:3]=1.[H-].[Na+].[CH2:24]([N:26]([CH2:31][CH3:32])[S:27](Cl)(=[O:29])=[O:28])[CH3:25]>CS(C)=O>[CH2:24]([N:26]([CH2:31][CH3:32])[S:27]([O:1][C:2]1[C:19]2[C@@H:18]3[C@@H:9]([C@H:10]4[C@@:14]([CH2:16][CH2:17]3)([CH3:15])[C:13](=[O:20])[CH2:12][CH2:11]4)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][S:27]([N:26]([CH2:31][CH3:32])[CH2:24][CH3:25])(=[O:29])=[O:28])[CH:3]=1)(=[O:29])=[O:28])[CH3:25]
Reactant: C[C@]12CC[C@@H]3c4c(O)cc(O)cc4CC[C@@H]3[C@@H]1CCC2=O
Reactant: CCN(CC)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN(CC)S(=O)(=O)Oc1cc2c(c(OS(=O)(=O)N(CC)CC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Temperature: 25 °C
Reaction time: 25 h

Procedure:
A solution of 250 mg. of 1,3-dihydroxy-8α-estra-1,3,5(10)-trien-17-one in 6.5 ml. of dimethyl sulfoxide is mixed under cooling and nitrogen with 250 mg. of NaH (50% suspension in oil), and agitated for 30 minutes at room temperature. A solution of 1.05 g. of diethylaminosulfonyl chloride in 2 ml. of dimethyl sulfoxide is then added to the mixture, and the latter is agitated for 25 hours at room temperature. The mixture is introduced into acetic ice water (NaCl), the organic substances are extracted with ether, and the extracts are washed, dried, and evaporated. After purificationby chromatography, 150 mg. of 1,3-bis(diethylaminosulfonyloxy)-8α-estra-1,3,5(10)-trien-17-one is produced.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH2:11])=[CH:9][N:10]=2.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([N:12]=1)=[N:7][C:8]([NH:11][C:16]([NH:15][CH2:13][CH3:14])=[O:17])=[CH:9][N:10]=2
Reactant: Nc1cnc2ccc(Cl)nc2n1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cnc2ccc(Cl)nc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
A total of 5.0 g 6-Chloro-pyrido[2,3-b]pyrazin-3-ylamine (27.7 mmol; 1 eq) was suspended in 150 mL of dry 1,4-dioxane. 2.63 g (33.2 mmol; 1.2 eq) ethyl isocyanate was added and the reaction mixture was stirred at 100° C. for 4 hours. Additional 1.97 g (27.7 mmol; 1 eq) of ethyl isocyanate were added and the resulting solution was stirred at 100° C. for further 4 hours. After cooling to room temperature, the precipitate was filtered of and dried in vacuo to afford 6.5 g (93.3% yield) of 1-(6-Chloro-pyrido[2,3-b]pyrazin-3-yl)-3-ethyl-urea.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1([C@H]([NH2:23])C)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C@H:12]([NH2:23])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1ccc(CC(C)=O)cc1OC
Product: COc1ccc(C[C@@H](C)N)cc1OC
Yield: 71.6 %

Procedure:
Using 10 ml of the above cell-free extract, the mixture was reacted in a 100 ml reaction mixture comprising 0.1 M Tris-hydrochloric acid buffer (pH 8.5) containing 0.5 g 1-(3,4-dimethoxyphenyl)-2-propanone and 0.34 g (R)-1-phenylethylamine at 30° C. for 24 hours. As a result, 0.36 g (R)-(3,4-dimethoxyphenyl)-2-aminopropane was formed.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[C:5](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([Cl:11])[CH:10]=1)[NH2:6].[Li+].[OH-].Cl>C1COCC1.O>[Cl:11][C:9]1[CH:10]=[C:4]([C:3]([OH:15])=[O:2])[C:5]([NH2:6])=[CH:7][C:8]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1cc(Cl)c([N+](=O)[O-])cc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc([N+](=O)[O-])c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
To a solution of 5-chloro-4-nitroanthranilic acid methyl ester (10.0 g, 43 mmol) in THF (120 mL) was added LiOH (2.7 g, 65 mmol) dissolved in water (40 mL). The reaction mixture was stirred at room temperature for 18 h and acidified to pH 4 with 1 N HCl. The aqueous layer was extracted with EtOAc (2×150 mL); the combined organic layers were dried over Na2SO4, filtered, and concentrated to give 5-chloro-4-nitroanthranilic acid (8.7 g, 88%) as an orange solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=2[NH2:19])=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#N.O.S(=O)(=O)(O)[OH:24].[OH-].[Na+]>C(O)(=O)C>[CH3:18][C:14]1[C:13]2[NH:19][C:6](=[O:24])[C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:21])([F:20])[F:1])[C:4]=3[S:11][C:12]=2[CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(Sc2c(C#N)cccc2C(F)(F)F)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2c1NC(=O)c1cccc(C(F)(F)F)c1S2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Trifluoromethyl-2-(3-methyl-2-aminophenylthio) benzonitrile (2.53 g, 8 mmol) was dissolved in acetic acid (25 ml), water (25 ml) and concentrated sulphuric acid (25 ml) and the mixture stirred and heated under reflux for 7.5 hours, then at ambient temperature for 15 hours before further sulphuric acid (25 ml) was added and the mixture stirred and heated under reflux for a further 8.5 hours. The mixture was allowed to stand at ambient temperature overnight then poured onto crushed ice (200 ml) and basified to pH 4 with aqueous sodium hydroxide (10N). The mixture was extracted with dichloromethane (3×200 ml) and the combined organic fractions dried (magnesium sulphate) and evaporated. The residue was dissolved in xylene (400 ml) and heated under reflux for 72 hours in a Dean-Stark apparatus, before being allowed to cool. After evaporation of the xylene, recrystallisation from toluene, followed by recrystallisation from ethanol, the title compound was obtained as an off-white solid (1.02 g, m.p. 273°-277°).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[CH:3]=1.[I:22]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([O:14][C:15]([F:17])([F:16])[F:18])=[CH:9][C:8]=2[Cl:19])[N:5]=[C:4]([C:20]#[N:21])[C:3]=1[I:22]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)n1
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(OC(F)(F)F)cc2Cl)c(N)c1I

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethoxyphenyl)pyrazole (4.17 g) in acetonitrile (20 ml) at room temperature was added N-iodosuccinimide (2.79 g). After 15 minutes the mixture was evaporated to dryness and the residual orange solid was taken up in dichloromethane. The solution was washed with water, then brine, then dried (Na2SO4) and evaporated to provide the title compound as a pale orange solid, m.p. 149.5-150.0° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][O:39][N:40]([CH3:50])[C:41](=[O:49])[CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([N:40]([O:39][CH3:38])[CH3:50])=[O:49])[CH2:48][CH2:47]3)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CON(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)OC)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-methoxy-N-methyl-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-methoxy-N-methyl-2-piperazin-1-yl-acetamide (example 16b) in an analogous manner as described in example 25. LR-MS: 725.3 [(M+H)+]
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C.CCCP(=O)=O>CN(C=O)C.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:25])[NH:10][C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: Nc1ccc2ncsc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCCP(=O)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc3ncsc3c2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.9 %

Procedure:
A mixture of benzothiazol-6-ylamine (0.15 g, 1 mmol) and piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.23 g, 1 mmol) in DMF (3 ml) was treated with DIPEA (5 eq.) and propylphosphonic anhydride (1 eq, 50% solution in EA). The mixture was stirred at rt for 72 h, diluted with water and extracted with EA. The org. layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (hex/EA 1:1, EA) to give the coupling product as a colourless oil (0.22 g, 61% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CC(C)=O>[C:19]1([C:16]2[S:17][CH:18]=[C:14]([CH2:13][O:1][C:2]3[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=3)[N:15]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#CCc1cccc(O)c1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCc1cccc(OCc2csc(-c3ccccc3)n2)c1
Yield: 43.5 %

Procedure:
To a solution of 14.0 g (0.105 mol) of 3-hydroxyphenylacetonitrile in 500 ml of acetone were added 25.9 g (0.105 mol) of 4-chloromethyl-2-phenylthiazole hydrochloride and 34.2 g (0.105 mol) of cesium carbonate and 1 g of potassium iodide and the slurry is heated to reflux for 20 hours. The mixture is filtered and the solution is concentrated in vacuo to obtain crystals. Recrystallization from ethyl acetate gives 14.0 g (43%) crystals, m.p. 108°-110° C. The product is used without further purification in subsequent reactions.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:15][C:16]1[CH:17]=[CH:18][C:19]2[C:23]([O:24][C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)=[C:22]([C:40]3[CH:45]=[CH:44][C:43]([S:46]([CH3:49])(=[O:48])=[O:47])=[CH:42][CH:41]=3)[S:21][C:20]=2[CH:50]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[CH3:49][S:46]([C:43]1[CH:42]=[CH:41][C:40]([C:22]2[S:21][C:20]3[CH:50]=[C:16]([OH:15])[CH:17]=[CH:18][C:19]=3[C:23]=2[O:24][C:25]2[CH:39]=[CH:38][C:28]([O:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:27][CH:26]=2)=[CH:45][CH:44]=1)(=[O:47])=[O:48]
Reactant: CS(=O)(=O)c1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CS(=O)(=O)c1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 68.2 %

Procedure:
Dissolve the compound of Example 90 (85 mg, 0.14 mmol) in methanol (14 mL) and ethyl acetate (14 mL). Add ammonium formate (262 mg, 4.2 mmol) and palladium hydroxide (90 mg) and heat to reflux for 1 hour. Filter the reaction mixture and concentrate in vacuo. Partition the residue between ethyl acetate:methanol (5:1, 6 mL) and saturated aqueous sodium bicarbonate:brine (1:1, 6 mL). Wash the organic layer with brine, and dry with sodium sulfate. Concentrate in vacuo to give 50 mg of the title compound (68%): 1H NMR (CDCl3): δ 7.85 (s, 4H), 7.18 (d, J=8.2 Hz, 1H), 7.14-7.12 (m, 1H), 6.78-6.74 (m, 3H), 6.59-6.55 (m, 2H), 4.07 (t, J=5.4 Hz, 2H), 3.05 (s, 3H), 2.92-2.88 (m, 2H), 2.69 (bs, 4H), 1.74-1.68 (m, 4H), 1.50 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:17][N:18]([CH3:34])[C:19](=[O:33])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29]Br)=[C:22]([O:31][CH3:32])[CH:21]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:34][N:18]([CH3:17])[C:19](=[O:33])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][N:12]2[CH2:11][CH2:10][CH:9]([C:6]3[C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)[CH2:14][CH2:13]2)=[C:22]([O:31][CH3:32])[CH:21]=1
Reactant: COc1cc(C(=O)N(C)C)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(=O)N(C)C)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.9 g, 17.7 mmol), N,N-dimethyl-4-bromopropoxy-3-methoxybenzamide (5.54 g, 17.5 mmol) and K2CO3 (3 g) in acetonitrile (250 ml) was heated at reflux for one hour. At the end of the reaction, the insolubles were filtered and washed with dichloromethane. The solvent was removed on a rotary evaporator. The residue was purified by flash chromatography over a silica gel column. The product thus obtained as an oil weighed 7 g. Crystallization from hot ethanol (45 ml) afforded analytically pure N,N-dimethyl-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxybenzamide, 3.95 g, 50%, as light yellow crystals, m.p.=126°-127° C.
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.O[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:18]=[C:17]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[CH:16]=1.[O:39]1[CH2:43][CH2:42][NH:41][C:40]1=[O:44].[H-].[Na+]>C(Cl)Cl>[O:44]=[C:40]1[N:41]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[N:18]=[C:17]([O:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]3)[CH:16]=2)[CH2:42][CH2:43][O:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO)cc(C(F)(F)F)n2)CC1
Reactant: O=C1NCCO1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CN3CCOC3=O)cc(C(F)(F)F)n2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (220 μL, 1.6 mmol) and then methanesulfonyl chloride (82 μL, 1.1 mmol) were added to a solution of tert-butyl 4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (0.20 g, 0.53 mmol, from Step 2) in methylene chloride (2 mL) at 0° C. After stirring at this temperature for 30 minutes, the reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude mesylate intermediate was dissolved in N,N-dimethylformamide (2.0 mL), and oxazolidin-2-one (230 mg, 2.6 mmol) was added. The mixture was cooled to 0° C. and sodium hydride (53 mg, 1.3 mmol, 60% in mineral oil) was added. The reaction was warmed to room temperature and stirred for 40 minutes, then was quenched with water, and extracted with EtOAc. The organic extract was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-70% EtOAc in hexanes afforded product (95 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 7.14 (s, 1H), 6.79 (s, 1H), 5.27 (tt, J=7.7, 4.1 Hz, 1H), 4.44 (s, 2H), 4.44-4.38 (m, 2H), 3.80-3.68 (m, 2H), 3.58-3.47 (m, 2H), 3.31 (ddd, J=13.6, 8.5, 3.6 Hz, 2H), 1.99 (ddt, J=13.2, 6.3, 3.0 Hz, 2H), 1.78-1.67 (m, 2H), 1.47 (s, 9H); 19F NMR (376 MHz, CDCl3) 5-68.89 (s); LCMS (M+Na)+: 468.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([O:24]C)=O)[N:9]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33]/[C:34](=[N:36]/O)/[NH2:35].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]1[N:35]=[C:22]([CH2:21][N:10]2[C:11](=[O:20])[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:16])([F:18])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)[O:24][N:36]=1
Reactant: COC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O
Reactant: N/C(Cc1ccccc1Cl)=N\O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1n(Cc2nc(Cc3ccccc3Cl)no2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F

Procedure:
50 mg (0.13 mmol) of the compound from Example 7A were dissolved in 2 ml of toluene, 51 mg (0.28 mmol) of (1Z)-2-(2-chlorophenyl)-N′-hydroxyethaneimidamide and 38 mg (0.28 mmol) of potassium carbonate were added and the mixture was heated under reflux for 6 h. For work-up, 10 ml of water were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The combined organic phases were washed once with 10 ml of water and 10 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 40 mg (59% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[N:15]([CH3:24])[N:14]=3)[CH2:10][C@H:9]2[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1CN(c2ccc(=O)[nH]n2)C[C@H]1c1ccc(Cl)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1CN(c2ccc(=O)n(C)n2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
Methyl (3S,4R)-4-(4-chlorophenyl)-1-(6-oxo-1,6-dihydropyridazin-3-yl)pyrrolidine-3-carboxylate obtained in Step A of Preparation 22 was dissolved in DMF (5 ml). Cs2CO3 (1.11 g, 3.41 mmol) was added, and methyl iodide (0.71 mL, 11.40 mmol) was added dropwise. The reaction mixture was stirred at 20-30° C. for 2 hours and concentrated in vacuo. The obtained residue was diluted with EtOAc, washed with water and purified by column chromatography (eluent: EtOAc/Hex=1/1) to give the title compound (0.55 g, 70%).