Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Li+].CC([N-]C(C)C)C.[I:32]I>C1COCC1.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH:16]([I:32])[C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: II
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(I)C2
Temperature: 25 °C

Procedure:
A solution of 9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (134 mg, 0.43 mmol) in anhydrous THF (2.5 mL) was cooled in an ice bath, stirred under a nitrogen atmosphere, and treated with 0.4M LDA in THF (1.2 mL, 0.48 mmol). After stirring at 0° C. for 30 minutes, the enolate solution was cooled to −78° C. and treated with a solution of iodine (540 mg, 2.13 mmol) in THF. The resulting mixture was allowed to gradually warm to room temperature, then stirred at room temperature overnight. The mixture was diluted with EtOAc (50 mL), washed with 1N HCl, saturated aqueous Na2SO3 (2×30 mL), water, 5% NaHCO3, and brine, dried over MgSO4, filtered, and evaporated under vacuum to provide crude (2SR,9aRS)-9a-butyl-2-iodo-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a gum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](N2C(C)=CC=CC2=O)=O)=[CH:6][CH:5]=[C:4]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH2:20]2)[N:3]=1.CO.[CH2:34]([OH:38])[CH:35](C)[CH3:36].C[O-].[Na+]>O>[CH3:2][C:7]1[N:8]([CH2:9][C:9]2[NH:1][C:2]3=[N:3][C:4]([N:19]4[CH2:24][CH2:23][CH2:22][C@@H:21]([C:25]([N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)=[O:26])[CH2:20]4)=[CH:5][CH:6]=[C:7]3[N:8]=2)[C:34](=[O:38])[CH:35]=[CH:36][CH:6]=1
Reactant: Cc1cccc(=O)n1C(=O)Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CC(C)CO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc(=O)n1Cc1nc2ccc(N3CCC[C@@H](C(=O)N4CCCC4)C3)nc2[nH]1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Into a vial were added (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-6-methyl-2-oxopyridine-1(2H)-carboxamide (1 equiv) and a solution of methanol and isobutanol (1:1, 1.5 mL). Sodium methoxide (2.0 equiv) was added and the reaction mixture was shaken at 110° C. for 2 h. Water was added and the mixture was extracted with a mixture of methanol/dichloromethane (1:1). The organics were concentrated by Speedvac and the crude material was purified via preparative HPLC to afford the title compound. MS (ES+) (M+H) 421.4; UPLC 1.09 min (Method T).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[I:10]I.[I-].[K+].[OH-].[Na+]>C(O)C.O>[I:10][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: II
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Ic1c[nH]c2ncccc12
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of 7-azaindole (20.0 g, 169 mmol) in ethanol is treated with iodine (57.9 g, 228 mmol), potassium iodide (37.8 g, 228 mmol), and 1 N aqueous NaOH (204 mL, 204 mmol). After stirring for 4 h at 20° C., the reaction is diluted with water and extracted with ethyl acetate. The organic extracts are combined and concentrated in vacuo. The resultant residue is crystallized from methanol/water to afford the title compound as a pinkish-white solid, 35.4 g, mp 201-204° C., characterized by mass spectral and HNMR analyses.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][C:21]=2F)[N:18]([C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][OH:25])[CH:17]=[C:16]([C:30]([O:32]CC)=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:40]=2)[CH:7]=1)[CH3:2].[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[OH-].[Li+].CS(O)(=O)=O>C1COCC1.O>[CH2:1]([NH:3][C:4](=[O:45])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[N:20][C:21]=2[N:50]2[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]2)[N:18]([C@@H:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:24][OH:25])[CH:17]=[C:16]([C:30]([OH:32])=[O:31])[C:15]3=[O:35])=[C:8]([C:36]2[S:37][CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[N:40]=2)[CH:7]=1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)OCC)cn([C@H](CO)C(C)(C)C)c3nc2F)cn1
Agent: CS(=O)(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2cc3c(=O)c(C(=O)O)cn([C@H](CO)C(C)(C)C)c3nc2N2CCN(C)CC2)cn1
Temperature: 50 °C
Reaction time: 10 h
Yield: 22 %

Procedure:
To a solution of (S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-7-fluoro-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate Intermediate 76 (200 mg, 0.31 mmol, 1 equiv.) in THF (1.2 mL) was added 1-methylpiperazine (0.041 mL, 0.37 mmol, 1.2 equiv.). This reaction was stirred at 50° C. for 10 h. 2 M lithium hydroxide (0.307 mL) was added. The reaction was stirred at 50° C. for 2 h, cooled to room temperature, and diluted with water. 10% wt. sol. of methanesulfonic acid was added until pH 5-6 was reached. The precipitate was discarded. The solution was partitioned between water (10 mL) and ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL), and the aqueous layer was concentrated. The compound was purified (HPLC) and concentrated to provide (S)-6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxy-3,3-dimethylbutan-2-yl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid as a solid (52.8 mg, 22%). Calcd for C32H37F3N8O5S [M+H]+: 703.2. H1NMR (d6-DMSO) δ 15.18 (s, 1H), 9.51 (s, 1H), 8.8 (d, 1H), 8.51 (s, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 8.2 (s, 1H), 7.6 (m, 1H), 5.71-5.68 (m, 1H), 5.09-5.02 (m, 1H), 4.09-4.0 (m, 2H), 3.29-3.27 (m, 2H), 3.21-3.19 (m, 2H), 3.15-3.04 (m, 2H), 2.18-2.14 (m, 2H), 2.05 (s, 3H), 1.95-1.91 (m, 2H), 1.12 (t, 3H), 0.95 (s, 9H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]
Reactant: O=Cc1cccc(O)c1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 9.9 %

Procedure:
0.5 M solution of 1-bromomethyl-2-fluoro-benzene (1.50 g, 8.0 mmol) in DMF was added dropwise to a suspension of 3-hydroxy-benzaldehyde (0.89 g, 7.3 mmol), K2CO3 (1.51 g, 11 mmol) and KI (0.12 g, 0.73 mmol) in 100 ml DMF. The reaction mixture was stirred at 90° C. overnight. After cooling to room temperature, the solid residue was filtered off and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate, the organic layer washed twice with 1M NaOH, dried over Na2SO4 and evaporated to dryness. The residue was purified on silica gel, obtaining 167 mg of the title compound (quantitative yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11].[CH:15]#[C:16][CH:17]([OH:19])[CH3:18].[Cl-].[Na+]>[Cu]I.C(N(CC)CC)C>[F:14][C:5]1[CH:4]=[CH:3][C:2]([C:15]#[C:16][CH:17]([OH:19])[CH3:18])=[CH:13][C:6]=1[CH2:7][NH:8][C:9](=[O:12])[O:10][CH3:11]
Reactant: COC(=O)NCc1cc(Br)ccc1F
Reactant: C#CC(C)O
Agent: [Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: COC(=O)NCc1cc(C#CC(C)O)ccc1F
Temperature: 100 °C
Reaction time: 48 h
Yield: 41.1 %

Procedure:
A mixture comprising 1.60 g of methyl N-(5-bromo-2-fluorobenzyl)carbamate, 1.40 g of 1-butyn-3-ol, 0.20 g of palladium dichlorobis(triphenylphosphine), 0.10 g of copper(I) iodide and 10 ml of triethylamine, was stirred at 100° C. for 48 hours in an autoclave. The reaction solution was poured into a saturated sodium chloride aqueous solution and extracted with ethyl acetate, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.63 g of methyl N-[2-fluoro-5-(3-hydroxy-1-butynyl)benzyl]carbamate as a brown viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])[CH2:16][CH2:15][CH:14](CS(N3CCC[C@@H]3C(O)=O)(=O)=O)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:37]([NH2:41])([NH2:40])(=[O:39])=[O:38]>O1CCOCC1.C(OCC)(=O)C.CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])[CH2:16][CH2:15][CH:14]([NH:40][S:37](=[O:39])(=[O:38])[NH2:41])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CCCN1S(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: NS(N)(=O)=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 42 %

Procedure:
Intermediate R (100 mg, 0.26 mmol in dioxane (4 ml) was treated with sulfamide (125 mg, 1.30 mmol) and heated to reflux for 1 hour, then cooled to room temperature, diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Trituration of the residue in ether afforded the desired product (50 mg, 42% yield). 1H NMR (360 MHz, CDCl3) δ 7.40–7.30 (4H, m), 7.09–7.02 (2H, m), 6.90–6.80 (1H, m), 5.51–5.46 (1H, m), 5.14–5.07 (2H, broad, s) 3.70–3.61 (1H, m), 2.60–2.49 (3H, m), 2.19–2.10 (2H, m) and 1.99–1.45 (3H, m). m/z=465, 467 [MH]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([OH:10])=[O:9].[Cl:12][C:13]1[C:14]([O:22][CH:23]([F:25])[F:24])=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](F)=O.[OH-].[Na+].S(Cl)(Cl)=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCCl>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[O:9][C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[C:14]=3[O:22][CH:23]([F:25])[F:24])=[N:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(F)c1cccc(Cl)c1OC(F)F
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=c1oc(-c2cccc(Cl)c2OC(F)F)nc2cccc(Cl)c12
Yield: 98.9 %

Procedure:
When 42.9 g of 6-chloroanthranilic acid, 58.4 g of 3-chlorodifluoromethoxybenzoyl fluoride, 20.8 g of 50% strength sodium hydroxide solution, 0.45 g of benzyltrimethylammonium chloride, 700 g of 1,2-dichloroethane and 32.7 g of thionyl chloride are used as starting materials and the procedure described in Example 1 is employed, 88.6 g (99%) of 5-chloro-2-(m-chlorodifluoromethoxyphenyl)-4H-3,1-benzoxazin-4-one of melting point 112°-114° C. are obtained.
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.Br[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:30])[C:28]#[N:29])=[CH:23][CH:22]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Cl[C:55]1[C:56]([N:61]2[CH2:66][CH2:65][N:64]([CH2:67][C:68]3[CH:69]=[N:70][N:71]([CH3:74])[C:72]=3[CH3:73])[CH2:63][CH2:62]2)=[N:57][CH:58]=[CH:59][N:60]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:74][N:71]1[C:72]([CH3:73])=[C:68]([CH2:67][N:64]2[CH2:63][CH2:62][N:61]([C:56]3[C:55]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]([CH3:30])[C:28]#[N:29])=[CH:23][CH:22]=4)=[N:60][CH:59]=[CH:58][N:57]=3)[CH2:66][CH2:65]2)[CH:69]=[N:70]1
Reactant: Cc1c(CN2CCN(c3nccnc3Cl)CC2)cnn1C
Reactant: CC(C#N)c1ccc(Br)cc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1c(CN2CCN(c3nccnc3-c3ccc(C(C)C#N)cc3)CC2)cnn1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
Stir together bis(dibenzylideneacetone)palladium(0) (35 mg, 0.06 mmol) and tricyclohexylphosphine (39 mg, 0.06 mmol) in N,N-dimethylacetamide (4 mL) at room temperature under nitrogen for 20 min. Add racemic 2-(4-bromo-phenyl)-propionitrile (420 mg, 2.00 mmol), then 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (521 mg, 2.05 mmol) and potassium acetate (294 mg, 3.00 mmol) and stir at 80° C. for 16 hr. Cool reaction to room temperature, add 3′-chloro-4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (307 mg, 1.00 mmol), potassium carbonate (332 mg, 2.40 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0050 g, 0.0056 mmol) and water (2 mL), then stir at 120° C. for 8 hr. Cool to room temperature, purify by SCX-2® chromatography washing with methanol then eluting with 2 M ammonia in methanol. Further purify (silica gel chromatography, eluting with 0:100 to 20:80 methanol:DCM), to give the free base racemate 2-{4-[4-(1,5-dimethyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-yl]-phenyl}-propionitrile as a powder (433 mg, 107%). MS (ES): m/z=402 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[S:14]1[CH:18]=[N:17][N:16]=[C:15]1[NH2:19]>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:15]2[S:14][CH:18]=[N:17][N:16]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1nncs1
Product: O=C(Nc1nncs1)c1ccc(F)c([N+](=O)[O-])c1
Yield: 67 %

Procedure:
The product from Example 172a was reacted with [1,3,4]Thiadiazol-2-ylamine (149 mg, 1.474 mmol) according to the procedure from Example 172b to provide the title compound (272 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.5 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (73 mg, 59%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:5]([CH2:9][C:10]2[C:18]([Cl:19])=[CH:17][C:13]3[O:14][CH2:15][O:16][C:12]=3[CH:11]=2)[C:6]=1[CH:7]=[O:8].[H-].[Na+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>>[Cl:19][C:18]1[C:10]([CH2:9][N:5]2[C:6]([CH:7]=[O:8])=[C:2]([S:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[N:3]=[C:4]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:11][C:12]2[O:16][CH2:15][O:14][C:13]=2[CH:17]=1
Reactant: COc1ccc(S)cc1
Reactant: O=Cc1c(Br)nc(-c2ccccc2)n1Cc1cc2c(cc1Cl)OCO2
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Sc2nc(-c3ccccc3)n(Cc3cc4c(cc3Cl)OCO4)c2C=O)cc1

Procedure:
The operation is carried out as in Example 2 starting with 4 g of the product of Example 6 using 640 mg of sodium hydride at 50% in oil and 1.64 ml of 4-methoxy thiophenol and in this way 4.05 g of expected product is obtained. (M.p.=116° C.).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([NH:10][NH2:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:13][CH:14]([F:24])[O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>CO>[S:7]([NH:10][N:11]=[CH:4][C:3]1[CH:2]=[CH:1][CH:6]=[CH:5][C:20]=1[C:19]1[CH:22]=[CH:23][C:16]([O:15][CH:14]([F:24])[F:13])=[CH:17][CH:18]=1)([C:4]1[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=1)(=[O:8])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=Cc1ccc(OC(F)F)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NN=Cc2ccccc2-c2ccc(OC(F)F)cc2)cc1
Yield: 25.9 %

Procedure:
4-Tolylsulfonyl hydrazine (6.03 g, 182 mmol) was added to a stirred solution of 4-difluoromethoxy-benzaldehyde (5 g, 172 mmol) in methanol (6 ml). Everything dissolved. After two hours the solvent was evaporated to yield 9.8 g (99%) of a white solid.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:38]([CH3:39])[C:37]4[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[NH2:8].CC(C)([O-])C.[K+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>CC(N(C)C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([O:9][C:4]2[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([F:1])[CH:3]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A suspension of 3-fluoro-4-aminophenol (8.0 g, 63.0 mmol) in dimethylacetamide (80 mL) was de-gassed in vacuo and treated with potassium tert-butoxide (7.3 g, 65 mmol). The resultant mixture was stirred at RT for 30 min. 2,4-Dichloropyridine (8 g, 54 mmol) was added and the mixture was heated to 80° C. for 12 h. The solvent was removed under reduced pressure to give a residue which was partitioned between water and EtOAc (3×100 mL). The organic layers were washed with saturated brine, dried (MgSO4), concentrated in vacuo and purified by silica gel column chromatography to give 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (11 g, 86% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.24 (d, J=5.7 Hz, 1H), 7.00 (dd, J=9.0, 2.7 Hz, 1H), 6.89-6.73 (m, 4H), 5.21 (br s, 2H); MS (ESI) m/z: 239.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C1COCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[C:7]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Fc1ncccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccnc1F
Reaction time: 4 h
Yield: 94.6 %

Procedure:
A mixture of 2-fluoro-3-iodopyridine (5 g), trimethylsilylacetylene (2.86 g) copper(I) iodide (0.015 g) and bis(triphenylphosphine)palladium dichloride (0.06 g) in a mixture of THF (20 mL) and triethylamine (30 mL) was stirred under argon for 4 hours. The solvents were evaporated and the residue was taken up in water/ethyl acetate. The organic phase was separated, dried and evaporated. Distillation of the residue gave 2-fluoro-3-(trimethylsilylethynyl)pyridine as an oil (4.10 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[O:10]=[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[O:17][C:18](=O)[O:19]N1C(=O)CCC1=O.C(N(CC)CC)C>C(#N)C>[O:10]=[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[N:12]1[O:17][C:18](=[O:19])[O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC1(C)OCC(CO)O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)OCC(COC(=O)ON2C(=O)CCC2=O)O1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 122 %

Procedure:
To a solution of (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (0.4 g, 3.0 mmol) in acetonitrile (10 mL) was added carbonic acid bis-(2,5-dioxo-pyrrolidin-1-yl) ester (1.15 g, 4.5 mmol) and triethylamine (0.84 mL, 6.0 mmol). After stirring at ambient temperature for 10 min, the mixture was concentrated at reduced pressure, sat. NaHCO3 (50 mL)was added, and the solution was extracted with ethyl acetate and organic phase was separated and concentrated to obtain 1.0 g of crude product that was used without further purification in the next step. MS (APCI) m/z: 273 [M+H]+ 1H NMR (DMSO-d6) δ: 4.50 (m, 1H), 4.40-4.29 (m, 2H), 4.04 (m, 1H), 3.73 (dd, J=6.0 and 9.0 Hz, 1H), 2.80 (s, 4H), 1.35 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)[C@@H](C1C=CC=CC=1)CN>C(C(C)=O)C>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[C@H](CN)c1ccccc1
Solvent: CCC(C)=O
Product: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 10 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
(±)-2-(3-Benzoylphenyl)propionic acid (12.7 g, 50 mmol) was added to methyl ethyl ketone (hereinafter abbreviated to "MEK") (70 ml) and dissolved with heating. Then, (S)-(+)-3-methyl-2-phenylbutylamine (4.9 g, 30 mmol) was added dropwise with stirring. After completing the addition, the reaction solution was stirred at 35°C. to 40°C. for one hour and then at room temperature for 4 hours, and finally maintained at 10°C. for 3 hours. The crystal precipitated was filtered, and the filter cake was washed with cold MEK (35 ml) and dried to give a diastereomer salt (7.72 g) of (S)-(+)-2-(3-benzoylphenyl) propionic acid with (S)-(+)-3-methyl-2-phenylbutylamine. The yield of the product based on (S)-(+)-2-(3-benzoylphenyl) propionic acid contained in the starting material was 74%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[F:18])[C:4]=2[CH:3]=[CH:2]1.Cl[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=[C:22]([NH2:32])[N:21]=1.Cl.[OH-].[Na+]>O>[NH2:32][C:22]1[N:21]=[C:20]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:9]3[C:4]4[CH:3]=[CH:2][O:1][C:5]=4[CH:6]=[CH:7][CH:8]=3)=[C:12]([F:18])[CH:13]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[N:23]=1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Nc1ccc(Oc2cccc3occc23)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3cccc4occc34)c(F)c2)cc(-c2ccncc2)n1

Procedure:
32 mg (0.13 mmol) of 4-(1-benzofuran-4-yloxy)-3-fluorophenylamine (from example XXIII) and 28.5 mg (0.14 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidine-amine (from example XXIX) are suspended in 1.5 ml of water, and 19 μl of concentrated hydrochloric acid are added. The reaction mixture is heated at reflux overnight, resulting in the formation of a brown precipitate. Using 1N sodium hydroxide solution, the suspension is adjusted to pH 10. The precipitate is filtered off with suction and the filtrate is discarded. The crude product is purified by preparative HPLC.