Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[CH2:12][CH:13]=[O:14].CC(=CC)C.P([O-])(O)(O)=[O:22].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[CH2:12][C:13]([OH:22])=[O:14]
Reactant: Cc1cc(C)c(CC=O)c(OC(F)F)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CC(=O)O)c(OC(F)F)c1
Reaction time: 4 h
Yield: 12.1 %

Procedure:
19.2 g of 2-difluoromethyloxy-4,6-dimethylphenylacetaldehyde (XXXIV-c-1) as the crude product were dissolved in 270 ml of tert-butanol, the solution was mixed with 90.4 g of 2-methyl-2-butene, and a solution of 90 g of sodium dihydrogen phosphate and 42 g of sodium chlorite in 353 ml of water was subsequently added dropwise at room temperature. The mixture was stirred for four hours and then stirred into 400 ml of ethyl acetate, and the phases were separated. The aqueous phase was extracted two more times using ethyl acetate, and the combined organic phases were dried over magnesium sulphate and concentrated. After stirring with hexane, 11 g of solid were isolated, from which 2.5 g (14% of theory via 2 steps) of 2-difluoromethyloxy-4,6-dimethylphenylacetic acid of melting point 124-127° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[I:20]N1C(=O)CCC1=O>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][C:19]=1[I:20])[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Solvent: C1CCOC1
Product: Nc1cc2c(cc1I)C[C@]1(C2)C(=O)Nc2ncccc21
Reaction time: 18 h

Procedure:
To a solution of (2R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (4.00 g, 15.9 mmol, described in Intermediate 1) in THF (64 mL) at ambient temperature was added N-iodosuccinimide (3.58 g, 15.92 mmol). The reaction mixture was stirred for 18 h, then purified by silica gel chromatography, eluting with EtOAc:hexanes—70:30, to give the title compound. MS: m/z=378 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[N+:11]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24])([O-:13])=[O:12]>>[OH:24][C:17]1([C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[O:9][CH3:10])[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([N+:11]([O-:13])=[O:12])[CH:15]=2)[NH:19][C:18]1=[O:23]
Reactant: COc1ccc(C)cc1Br
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C1=O
Product: COc1ccc(C)cc1C1(O)C(=O)Nc2ccc([N+](=O)[O-])cc21
Yield: 95.8 %

Procedure:
With 10.0 g of 2-bromo-4-methyl anisole and 6.00 g of 5-nitroisatin as starting materials, 9.40 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]([OH:25])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[O:25])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:15]=3)[N:10]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: OC(Cc1ccccc1)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1ccc2c(c1)c(-c1ccc(F)cc1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
A suspension of 1-[3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazol-5-yl]-2-phenylethan-1-ol (0.223 g, 0.54 mmol) and pyridinium chlorochromate (1.0 g, 4.6 mmol) in dried dichloromethane (10 mL) under nitrogen was stirred at ambient temperature for 6 hours. It was diluted with dichloromethane and washed with saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.112 g, 51% yield): 1H NMR (CDCl3) δ 8.62 (d, 1H), 8.10 (dd, 1H), 7.85-7.90 (m, 2H), 7.65 (dd, 1H), 7.19-7.37 (m, 7H), 5.77 (dd, 1H), 4.35 (s, 2H), 4.06 (m, 1H), 3.77 (m, 1H), 2.59 (m, 1H), 2.14 (m, 2H), 1.70 (m, 3H); ES-MS (m/z) 415 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12][C:13]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#N.[OH-:25].[Na+].C1(C)C(C)=CC=CC=1>C(O)(=O)C.S(=O)(=O)(O)O.O>[F:23][C:21]([F:24])([F:22])[C:20]1[C:13]2[S:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[NH:1][C:15](=[O:25])[C:14]=2[CH:17]=[CH:18][CH:19]=1
Reactant: [OH-]
Reactant: N#Cc1cccc(C(F)(F)F)c1Sc1ccc(C(F)(F)F)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1Nc2cc(C(F)(F)F)ccc2Sc2c1cccc2C(F)(F)F
Temperature: 0 °C

Procedure:
2-(2-Amino-4-trifluoromethylphenylthio)-3-trifluoromethylbenzonitrile (5.43 g, 15 mmol) was dissolved in a mixture of glacial acetic acid (60 ml), concentrated sulphuric acid (55 ml) and water (60 ml) and then heated under reflex for 8 hours. The cooled mixture was added to ice water (500 ml) and brought to pH 4 by addition of 10N aqueous sodium hydroxide. Extraction with dichloromethane followed by filtration, drying (sodium sulphate) and evaporation of the organic layer afforded a residue which was put into xylene (500 ml) and refluxed for 72 hours with azeotropic removal of water. The resulting solution was evaporated and the residue was recrystallised twice from ethanol to give the product as colourless needles (4.30 g, m/s, M+ =363).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:24])=[C:6]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][CH2:10][N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:7]=1.C[I:26].[C:27](#N)C>C1(C)C=CC=CC=1>[I-:26].[OH:24][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=1[C@@H:8]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][CH2:10][N+:11]([CH:12]([CH3:13])[CH3:14])([CH:15]([CH3:17])[CH3:16])[CH3:27]
Reactant: CC#N
Reactant: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reactant: CI
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c([C@H](CC[N+](C)(C(C)C)C(C)C)c2ccccc2)c1
Product: [I-]
Temperature: 22.5 °C

Procedure:
To tolterodine free base (from Example 1, 0.5 M, 2.5 ml) in toluene is added methyl iodide (1 ml). Acetonitrile (5 ml) is added to the mixture and stirred over night at 20-25° C. The solvent is removed by blowing dry nitrogen. Acetone (1 ml) and hexane (2 ml) are added and the mixture is filtered at 20-25° C. to give the title compound. Anal Calcd for C23H34INO: C, 59.10; H, 7.33; N, 3.00. Found: C, 59.00; H, 7.44; N, 3.00. The identity of the compound has been further verified and characterised by NMR analysis, mass spectrometry, and melting point determination.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:24])[C:15]=2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:10]([CH2:25][CH2:26][CH3:27])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31](=[O:36])[C:32](Br)([CH3:34])[CH3:33])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:36])[C:32]([O:24][C:14]1[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:25][CH2:26][CH3:27])[CH:9]=[C:8]2[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:34])[CH3:33])[CH3:29]
Reactant: CCCn1cc(Cc2ccccc2)c2c(Cc3ccccc3)c(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1cc(Cc2ccccc2)c2c(Cc3ccccc3)c(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3,4-dibenzyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:27])[C:5]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F-].[CH2:29]([N+](CCCC)(CCCC)CCCC)[CH2:30]CC.C(B1OC(C)(C)C(C)(C)O1)=C>C1COCC1>[F:27][C:4]1[C:5]([N:8]2[CH2:13][CH:12]=[C:11]([C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=[C:2]([CH:29]=[CH2:30])[CH:3]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O=C(Nc1nc2ccc(F)cc2s1)C1=CCN(c2ncc(Br)cc2F)CC1
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: [F-]
Solvent: C1CCOC1
Product: C=Cc1cnc(N2CC=C(C(=O)Nc3nc4ccc(F)cc4s3)CC2)c(F)c1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
687 mg of 1-(5-bromo-3-fluoropyridin-2-yl)-N-(6-fluorobenzo[d]thiazol-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide 29 (1.52 mmol) and 0.05 eq. PdCl2dppf catalyst ([1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), 0.08 mMol, Sigma-Aldrich) were placed in a 50 mL vial with a screw-top septum and suspended in 2 mL dry THF. 2 Eq. 1M tetrabutylammonium fluoride in THF (3.04 mL, Sigma-Aldrich) were then added and the vial heated to 65° C. 1.1 Eq. vinylboronic acid pinacol ester (1.6 mMol, Sigma-Aldrich) were added to the vial via a syringe and the reaction progressed over 18 hours. The reaction mixture was transferred to a 500 mL extraction funnel and diluted with 250 mL water. The compound was extracted with 2×100 mL EtOAc. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was chromatographed with a gradient of EtOAc in hexane. The fractions containing desired product (visualized by LC/MS) were concentrated and used without further purification or characterization.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]([O:33]C)=[O:32])=[N:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[C:13]([O:12][C:11]([NH:10][C:9]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31]([OH:33])=[O:32])=[N:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@H](CCCCNC(=O)[C@H](CCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
A solution of methyl ester 20 (6.00 g, 8.21 mmol) in MeOH/THF/H2O (100 mL/100 mL/50 mL) was charged with NaOH (1.64 g, 41.1 mmol) and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the pH of the solution was adjusted to 5 with 1 N HCl. The suspension was partitioned between CH2Cl2 (150 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×150 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford compound 21 (5.50 g, 94%) as a white solid, which was used directly in the next step: 1H NMR (400 MHz, CD3OD) δ 4.06-4.00 (m, 1H), 4.00-3.93 (m, 1H), 3.35 (t, J=7.3 Hz, 2H), 3.26-3.07 (m, 2H), 1.85-1.56 (m, 6H), 1.53-1.32 (m, 6H), 1.52 (s, 9H), 1.46 (s, 9H), 1.438 (s, 9H), 1.435 (s, 9H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34](F)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C(=O)CCC1.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]2)[CH2:51]1.C(C1C=CC=CC=1)C1C=CC=CC=1>O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([N:50]4[CH2:53][CH:52]([N:54]5[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]5)[CH2:51]4)[N:33]=3)[C:19](=[O:30])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:29])[N:15]2[C:14](=[O:39])[CH2:13][N:12]1[CH2:40][CH:41]=[CH2:42])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C2CNC2)CC1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(N4CC(N5CCN(C)CC5)C4)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 52.6 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (40.0 mg, 0.0694 mmol) described in Production Example 1-1-6 and NMP (2.0 mL) was added a mixture (112 mg) of 1-(azetidin-3-yl)-4-methylpiperazine and benzylbenzene described in Production Example 3-2 at room temperature, and the resultant mixture was irradiated with a microwave at 140° C. for 12 hours. After the mixture was cooled to room temperature, water was added to the reaction mixture, the resultant solution was extracted with ethyl acetate, and an organic layer was washed with water and then with saturated brine. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) and then further purified by NH silica gel thin-layer chromatography (ethyl acetate) to give the title compound (26.0 mg, yield: 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[NH3:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH2:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=S(=O)(Cl)CCc1ccc(F)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-flourophenyl)ethanesulfonyl chloride (0.7 g, 3.3 mmol) and concentrated aqueous ammonia (0.88 specific gravity, 10 ml) in ethanol (5 ml) was stirred at room temperature overnight. The reaction mixture was diluted with water (10 ml), acidified to pH 4 with citric acid (1.0 M) and then extracted with dichloromethane. The organic extracts were dried by filtering through an organic-only, permeable membrane and then concentrated under vacuum. The residue was purified by chromatography on a Biotage® Flash 40 (s) column (40 g silica) using 10-20% ethyl acetate/dichloromethane as eluant to give the title compound as an off white solid, (0.66 g).
Reaction SMILES: NC1C=CC(C#N)=C(Cl)C=1.CC1(C)C(=O)N(C2C=C(C3C=CC(F)=CC=3)C(C#N)=CC=2)C(=O)N1.Br[C:36]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:37]=1[CH2:38][N:39]1[C:43]([CH3:45])([CH3:44])[C:42](=[O:46])[N:41]([C:47]2[CH:52]=[C:51]([C:53]3[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=3)[C:50]([C:60]#[N:61])=[CH:49][CH:48]=2)[C:40]1=[O:62].[F:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:70]=1[NH2:76]>>[F:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[CH:71][C:70]=1[NH:76][C:36]1[CH:66]=[C:65]([F:67])[CH:64]=[CH:63][C:37]=1[CH2:38][N:39]1[C:43]([CH3:45])([CH3:44])[C:42](=[O:46])[N:41]([C:47]2[CH:52]=[C:51]([C:53]3[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=3)[C:50]([C:60]#[N:61])=[CH:49][CH:48]=2)[C:40]1=[O:62]
Reactant: Nc1ccc(F)cc1F
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(-c3ccc(F)cc3)c2)C(=O)N1Cc1ccc(F)cc1Br
Agent: CC1(C)NC(=O)N(c2ccc(C#N)c(-c3ccc(F)cc3)c2)C1=O
Agent: N#Cc1ccc(N)cc1Cl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(-c3ccc(F)cc3)c2)C(=O)N1Cc1ccc(F)cc1Nc1ccc(F)cc1F

Procedure:
The compound of Example 253 (5-{3-[2-(2,4-difluorophenylamino)-4-fluorobenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-4′-fluorobiphenyl-2-carbonitrile, molecular weight 558.16 (C31H22F4N4O2); retention time Rt=2.38 min. [B]; MS (ESI): 559.15 (MH+)) was obtained similarly to the manner described for the preparation of the compound of Example 223 via the sequence of 4-amino-2-chlorobenzonitrile→5-amino-4′-fluorobiphenyl-2-carbonitrile (253.3, 1H NMR: 7.54-7.49, m, 3H, 7.31, t, 2H, 6.61, m, 2H, 6.25, s, 2H)→5-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)-4′-fluorobiphenyl-2-carbonitrile (253.1, 1H NMR: 8.73, s, 1H; 8.09, d, 1H, 7.74, s, 1H, 7.65, m, 3H, 7.41, m, 2H, 1.42, s, 6H)→5-[3-(2-bromo-4-fluorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-4′-fluorobiphenyl-2-carbonitrile (253.2, 1H NMR: 8.1, d, 1H, 7.8, s, 1H, 7.75, d, 1H, 7.69-7.59, m, 4H; 7.41, t, 1H, 4.61, s, 2H, 1.4, s, 6H) δ 253 (from 253.2 by reaction with 2,4-difluorophenylamine).
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:6]=1.Cl[C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:31]([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl.C(O)(C)C>[OH:1][CH:2]([CH2:15][O:16][C:18]1[CH:23]=[CH:22][C:21]([S:24]([C:27]([F:29])([F:30])[F:28])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:31]([O-:33])=[O:32])[CH2:3][NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH2:12])(=[O:10])=[O:11])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: NS(=O)(=O)c1ccc(NCC(O)CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(NCC(O)COc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
A mixture of N4-(2,3-dihydroxypropyl)sulfanilamide (82 mg, 0.33 mmol), 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (135 mg, 0.47 mmol) and potasium carbonate (190 mg, 1.33 mmol) in acetonitrile (2 mL) was heated to reflux for 2 days. The reaction was diluted with chloroform/isopropanol mixture, washed with brine, dried, concentrated and column chromatographed to give the title compound (mono-arylated) and 4-[2,3-bis-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-propylamino]-benzenesulfonamide (di-arylated) example 62. 1H NMR (300 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.35 (dd, 1H), 7.75 (d, 1H), 7.63 (d, 2H), 6.68 (d, 2H), 4.35 (d, 2H), 3.98 (t, 1H), 3.2 (m, 2H). MS −ve APCI 498 [M−1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:3][CH:2]=1.Cl.O1CCOCC1.P(Cl)(Cl)([Cl:28])=O.C([O-])(O)=O.[Na+]>C(#N)C.O>[Cl:28][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: Clc1nnc(Cc2ccncc2)c2ccccc12
Temperature: 50 °C
Reaction time: 27 h

Procedure:
Under exclusion of air, 29 g (122 mmol) 4-(4-pyridylmethyl)-1 (2H)-phthalazinone [for preparation, see German Auslegeschrift no. 1061788 (published 23.7.1959)] in 450 ml acetonitrile is mixed with 61 ml HCl/dioxane 4N and 28 ml (306 mmol) phosphoryl chloride and stirred for 27 h at 50° C. To the white suspension, 119 g NaHCO3 in 1.45 l water is then added dropwise under ice cooling, and the mixture is stirred and the title compound filtered off. Anal. calc. (C14H10N3Cl) C 65.76%, H 3.94%, N 16.43%, Cl 13.86%; found C 65.40%, H 4.12%, N 16.45%, Cl 13.66%; FAB MS (M+H)+=256.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:30][Si](C)(C)C>CC(CC)=O>[ClH:30].[CH3:29][N:2]([CH3:1])[C:3]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCc2c[nH]c3ccccc23)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-phenylcyclohexylidene)-N-(1H-indol-3-ylmethyl)acetamide (120 mg, 0.309 mmol) was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.058 ml, 0.46 mmol) was added. After 1.5 h the hydrochloride was isolated with an m.p. of 173-185° C. in a yield of 63% (82 mg).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([OH:20])=O)=[O:12].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH:35]1[CH2:41][CH2:40][CH2:39][C@H:36]1[CH2:37][OH:38]>C(Cl)Cl>[CH2:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:35]1[CH2:41][CH2:40][CH2:39][C@H:36]1[CH2:37][OH:38])=[O:20])=[O:12]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
3-(Indan-2-ylacetyl)-L-thioproline (11.7 g) and triethylamine (5.6 ml) were dissolved in 100 ml of methylene chloride, followed by dropwise addition of 4.95 g of pivaloyl chloride under agitation while cooling in ice for 15 minutes. Subsequently, 4.05 g of L-prolinol and 5.6 ml of triethylamine were added dropwise and stirred at room temperature for another one hour. The reaction solution were washed in 1N HCl, saturated aqueous solution of sodium bicarbonate and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, followed by distillation of the solvent under reduced pressure. The resulting residue was purified by column chromatography to obtain 8.80 g of 1-[3-(indan-2-ylacetyl)-L-thioprolyl]-L-prolinol. Yield; 59%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][C:13]#[N:14].[C:15]([O-])(=[O:17])[CH3:16].[Na+].[H][H]>[Ni].C(OC(=O)C)(=O)C.O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: [H][H]
Reactant: N#CCCC1COc2ccccc2O1
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCCCC1COc2ccccc2O1

Procedure:
0.53 g (2.82 mmol) of the nitrile obtained in Step D is added to a suspension of 0.25 g (4.23 mmol) of Raney nickel and 0.34 g (4.23 mmol) of sodium acetate in 8 ml of acetic anhydride. The reaction mixture is subjected to hydrogen pressure of 50 psi at 50° C. for 6 hours. The remaining catalyst is then filtered off over Celite; the solvent is then evaporated in vacuo. The residue obtained is taken up in water; the reaction medium is then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium hydrogen carbonate and then dried over magnesium sulphate. After filtration and evaporation of the solvent under reduced pressure, the residue obtained is purified on a silica column (eluant: ethyl acetate) to result in the title amide in the form of a clear syrup.