Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:24]([C:25]5[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=5)=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].CCOC(C)=O>CO>[C:41]([N:5]1[CH2:4][CH2:3][N:2]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:24]([C:25]5[CH:26]=[CH:27][C:28]([C:29]([NH2:31])=[O:30])=[CH:32][CH:33]=5)=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6]1)(=[O:43])[CH3:42]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1ccc(-c2c[nH]c3ncc(-c4ccc(C(=O)N5CCNCC5)cc4)cc23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N1CCN(C(=O)c2ccc(-c3cnc4[nH]cc(-c5ccc(C(N)=O)cc5)c4c3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a solution of 4-{5-[4-(piperazine-1-carbonyl)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-benzamide, hydrochloride salt (19 mg, 0.041 mmol) in MeOH (2 ml) was added triethylamine (400 μl, 2.88 mmol) and acetic anhydride (100 μl, 1.06 mmol). The mixture was stirred for 1 hr at room temperature. EtOAc was added and washed with saturated aqu. NaHCO3, water, brine and dried and evacuated. Purification on silica gel employing 0-10% MeOH:DCM provided 4.7 mg (25%) of the title compound. MS ESI (m/z): 468.3 (M+1)+, calc. 467.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]([C:18](OC)=[O:19])=[C:16]([C:22](OC)=[O:23])[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:19])[NH:31][NH:32][C:22](=[O:23])[C:16]=4[N:15]=[CH:14]3)=[CH:26][CH:27]=2)=[O:7])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ncn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C(=O)OC
Reactant: NN
Solvent: O
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3c(=O)[nH][nH]c(=O)c32)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
To a solution of 1-[4-(4-chlorobenzoyl)benzyl]-4,5-dimethoxycarbonylimidazole (3.31 g) in methanol (20 ml) was added hydrazine monohydrate (1.68 g) and the mixture was refluxed for 5 hours. The resulting crystals were harvested by filtration and suspended in water (100 ml) and, after addition of concentrated HCl (10 ml), the suspension was stirred at 80° C. for 30 minutes. The resulting crystals were collected by filtration and dried in vacuo to provide 2.67 g (yield 88%) of the title compound. 1H-NMR (DMSO) δ: 5.78(2H,s), 7.45-7.77(8H,m), 8.49(1H,s).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[CH:5]=[C:6]([N:11]([CH3:18])[C:12]2[CH:17]=[N:16][CH:15]=[N:14][CH:13]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: Clc1cc(Br)cc(Nc2cncnc2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(c1cncnc1)c1cc(Cl)cc(Br)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
NaH (24 mg, 1.0 mmol, 1.1 eq) was added to a flame-dried round-bottom flask and anhydrous THF (2.2 mL) was added. The slurry was cooled to 0° C. and compound 34 (255 mg, 0.896 mmol, 1.00 eq) was added as a solution in THF (2.2 mL). After stirring at 0° C. for 30 minutes methyl iodide (61.5 μL, 1.00 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 248 mg (93%) of the title compound as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.64 (s, 1H), 7.25 (t, J=1.7 Hz, 1H), 7.16 (t, J=1.9 Hz, 1H), 7.07 (t, J=1.9 Hz, 1H), 3.32 (s, 3H); ES-MS [M+1]+: 298.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.Br[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>>[Cl:9][C:5]1[C:6]([O:8][CH:12]([CH3:14])[CH3:13])=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: CC(C)Br
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)Oc1cc(N)c(F)cc1Cl
Yield: 62 %

Procedure:
A stirring mixture of 5-amino-2-chloro-4-fluorophenol (22.0 g, 136.19 mmol), 2-bromopropane (38.4 mL, 50.25 g, 408.57 mmol) and potassium carbonate (37.6 g, 273.0 mmol) was heated at reflux for 17 h. The reaction mixture was cooled and filtered. The filtrate was evaporated to dryness under reduced pressure. Flash chromatography yielded the title compound of Step A as a brown oil (17.2 g). 1H NMR (CDCl3): δ7.02 (d, 1H), 6.44 (d, 1H) 4.38 (q, 1H), 3.81 (br s,2H), 1.33 (d,6H). IR (cm-1): 3378.4, 3475.6.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[C:40]#[N:41])=[CH:4][C:5](=[O:32])[N:6]([CH:8]([CH2:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[C:40]#[N:41])=[CH:4][C:5](=[O:32])[N:6]([CH:8]([CH2:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(C[C@@H]2CCCCO2)n2cc(Cl)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cl)cc1-c1cc(=O)n(C(C[C@@H]2CCCCO2)C(=O)Nc2ccc(C(=O)O)cc2)cc1Cl

Procedure:
364 mg (0.61 mmol) of tert-butyl 4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-3-[(2S)-tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoate (mixture of enantiomerically pure diastereomers 1 and 2) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative flash chromatography (silica gel 50, eluent: dichloromethane/methanol gradient). Yield: 264 mg (76% of theory)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].C1C=CC(N[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=CC=1>C1COCC1>[F:34][C:33]([F:36])([F:35])[S:30]([O:22][C:19]1[CH2:18][CH2:17][N:16]([C:13](=[O:15])[CH3:14])[CH2:21][CH:20]=1)(=[O:32])=[O:31]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (18.0 mL, 128 mmol) was taken up in 50 mL of THF and chilled to −78° C. Butyllithium, 2.5 M in hexanes (51.0 mL, 128 mmol) was added dropwise. After 10 min, 1-acetylpiperidin-4-one (15.0 g, 106 mmol) was added in 60 mL of THF with rigorous stirring. After 30 min, n-phenyltriflamide (41.8 g, 117 mmol) was added in 120 mL of THF. The reaction mixture was stirred at −78° C. to RT for 16 h. The reaction mixture was quenched by saturated NaHCO3, followed by extraction with EtOAc and 5% citric acid. The organic layer was washed with 1 N NaOH (2×), water (2×), and brine, then dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0% to 60% EtOAc/hexanes) afforded 1-acetyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate as a yellow oil.
Reaction SMILES: C([N:3](CC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:12][C:13]([N:16](CC)CC)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)C>CS(C)=O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:21]3[C:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: CCN(CC)c1ccc(-c2ccc(N(CC)CC)cc2-c2ccccc2-c2ccccc2)cc1
Solvent: CS(C)=O
Product: Nc1ccc(-c2ccc(N)cc2-c2ccccc2-c2ccccc2)cc1

Procedure:
The NMR spectrum in dimethyl sulfoxide included an aromatic singlet 7.52 to low field of an A2B2 quartet 7.37, 7.22, 6.59 and 6.44 with integrated intensities in the ratio 1:1. N,N,N', N'-Tetraethyl-4,4'-diamino-quarterphenyl may be prepared from the diamino derivative of Example 5 by following the procedure outlined in Example 6.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8]12[CH:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][NH:10][CH2:9]2)([CH3:4])([CH3:3])[CH3:2].C=O.[BH3-][C:51]#N.[Na+].CCOC(C)=O>CC(O)=O>[C:1]([SiH2:5][O:6][C:7]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:8]12[CH:23]([O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH:12]([CH:13]([N:15]3[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]3=[O:22])[O:14]1)[O:11][N:10]([CH3:51])[CH2:9]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C12CNOC(C(n3ccc(=O)[nH]c3=O)O1)C2OCc1ccc2ccccc2c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CC2(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)OC(n3ccc(=O)[nH]c3=O)C(O1)C2OCc1ccc2ccccc2c1

Procedure:
To a solution of compound 52 (1 mmol) in CH3COOH (5 mL) and trithylortoformate (1 mL), 20% aq. HCHO (0.16 mL, 1.1 mmol) was added at 0° C. After 15 minutes NaBH3CN (2 mmol) is added. After an additional 1 hour the mixture is poured into EtOAc (250 mL), washed with saturated aqueous NaHCO3 (2×250 mL), dried over anhydrous Na2SO4, filtered and evaporated. Purification by silica gel chromatography gave compound 53 in 90% isolated yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:16]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH3:16])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Fc1ccc(-c2cc[nH]n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(-c2ccc(F)cc2)n1
Yield: 29.5 %

Procedure:
Treat a solution of 3-(4-fluorophenyl)pyrazole (7.17 g, 44.2 mmol) in dry DMF (60 mL) with NaH (2.2 g, 92.8 mmol) at 0° C. for 15 min. Add iodomethane (3.3 mL, 53.04 mmol) and slowly warm to RT. Quench the reaction mixture with methanol (5 mL) and dilute with water (100 mL). Extract with EtOAc (3×70 mL), dry (MgSO4) and concentrate and purify (Biotage system eluting with dichloromethane:methanol 50:1) to give desired compound as a white solid (2.3 g, 29% yield).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=[C:6]([CH3:17])[C:5]=1[C:18]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:19]=1[CH2:20][CH2:21][C@H:22]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([O:39]C)=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1>CO>[CH3:17][C:6]1[CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[C:4]([CH3:3])[C:5]=1[C:18]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]2[C:19]=1[CH2:20][CH2:21][C@H:22]2[O:28][C:29]1[CH:42]=[CH:41][C:32]2[C@H:33]([CH2:36][C:37]([OH:39])=[O:38])[CH2:34][O:35][C:31]=2[CH:30]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(CCCS(C)(=O)=O)cc5C)ccc(F)c43)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(CCCS(C)(=O)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1 M aqueous NaOH solution (50 μL) is added to a solution of methyl 2-((S)-6-((R)-4-(2,6-dimethyl-4-(3-(methylsulfonyl)propyl)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (20 mg) in methanol (2 mL). The mixture is stirred at room temperature for 12 hours and at 50° C. for 2 days. 1 M aqueous NaOH solution (18 μL) is added and the mixture is stirred at 50° C. for 2 hours. Methanol is evaporated in vacuo, the residue is diluted with water and neutralized with 1 M aqueous HCl. The resulting mixture is extracted with ethyl acetate, and the organic phase is dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 7 mg; LC (method 8): tR=0.34 min; Mass spectrum (ESI+): m/z=553 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:12][CH2:13][C:14]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17]3)[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC3(C=Cc4ccccc43)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCC3(CCc4ccccc43)CC2)cc1
Reaction time: 3 h

Procedure:
1'-((4-Methylphenyl)sulfonyl)spiro(1H-indene-1,4'-piperidine) (57.7 mg, 0.17 mmol), prepared as in example 2, was dissolved in absolute ethanol (4 ml), treated with 10% Palladium on carbon (14.2 mg), and hydrogenated at 40 psi, ambient temperature, for 3 hr. The mixture was filtered through Solka floc and the filtrate was evaporated to dryness in vacuo. The residue was crystallized from ether to provide the title compound: (m.p. 140°-142°).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[N:37](C(OC(C)(C)C)=O)[CH:38]=[CH:39][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>CCO.O>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:36]3[NH:37][CH:38]=[CH:39][CH:40]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc[nH]2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 25.1, 100 mg, 0.216 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (127 mg, 0.433 mmol) Pd(PPH3)2Cl2 (15.18 mg, 0.022 mmol), Na2CO3 (92 mg, 0.865 mmol), DME (918 μL), water (262 μL) and EtOH (131 μL) were added to a MW vial, which sealed, evacuated/purged with argon and the RM was stirred at 80° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW irradiation at 150° C. for 5 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 91 mg, 0.130 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, cyclohexane/EtOAc from 40% to 100% EtOAc) followed by preparative SFC (Column DEAP, from 24% to 29% in 10 min) to afford the title compound as a grey solid. UPLC-MS (Condition 3) tR=1.10 min, m/z=449.2 [M+H]+, m/z=447.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74 (dd, J=6.48, 2.57 Hz, 1H) 1.83 (dd, J=8.68, 4.28 Hz, 1H) 2.98 (d, J=11.98 Hz, 1H) 3.22-3.29 (m, 2H) 3.37-3.50 (m, 1H) 4.19 (d, J=2.45 Hz, 1H) 4.81 (d, J=3.42 Hz, 1H) 5.94-6.17 (m, 2H) 6.67-6.87 (m, 1H) 7.67 (d, J=8.80 Hz, 2H) 7.83-7.99 (m, 2H) 8.02 (d, J=2.45 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.25 (s, 1H) 11.11 (br. s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([F:17])[CH:11]=2)[N:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]=1)=[O:4].[OH-].[K+].CO>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]2[N:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH2:9]2)=[CH:11][C:12]=1[F:17]
Reactant: COC(=O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=NN(c2ccccc2Cl)C(c2ccc(Br)c(F)c2)C1
Temperature: 70 °C
Reaction time: 4 h
Yield: 103.1 %

Procedure:
5-(4-Bromo-3-fluoro-phenyl)-1-(2-chloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid methyl ester (830.0 mg, 2.0 mmol) prepared in Step 3 and a solution of potassium hydroxide (226.0 mg, 4.0 mmol) in distilled water (10.0 mL) were added to methanol (10.0 mL). The reaction mixture was stirred at 70° C. for 4 hours and then concentrated under reduced pressure to discard methanol. The resulting residue was washed with diethyl ether, acidified by a 1N hydrochloric acid solution, and then extracted with ethyl acetate. The extract was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 820.0 mg of the titled compound as a pale yellow solid.
Reaction SMILES: C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C([O:15][C:16]([CH:18]1[CH2:33][N:32]([CH:34]2[CH2:36][CH2:35]2)[C:21]2[N:22]=[C:23]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[N:24]=[C:25]([CH3:26])[C:20]=2[C:19]1=[O:37])=[O:17])C>C1(C)C=CC=CC=1>[N:27]1([C:23]2[N:24]=[C:25]([CH3:26])[C:20]3[C:19](=[O:37])[C:18]([C:16]([OH:17])=[O:15])=[CH:33][N:32]([CH:34]4[CH2:36][CH2:35]4)[C:21]=3[N:22]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)C1CN(C2CC2)c2nc(N3CCCC3)nc(C)c2C1=O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: Cc1nc(N2CCCC2)nc2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 51.6 %

Procedure:
100 ml of toluene and 2.5 g of chloranil are added to 3.4 g of 2-pyrrolidino-4-methyl-8-cyclopropyl-5-oxo-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. The mixture is warmed at 80°-90° C. for 30 minutes, the solvent is stripped off in vacuo and the residue is recrystallised from acetonitrile. The resulting 2.2 g of the ester with a melting point of 170°-175° C. are heated with 20 ml of ethanol and a solution of 1.2 g of potassium hydroxide in 60 ml of H2O for 2.5 hours at the boil under reflux. The alcohol is distilled off, the filtered solution is acidified with glacial acetic acid and the precipitate is filtered off, washed with water and dried. 1.6 g of 2-pyrrolidino-4-methyl-8-cyclopropyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid with a melting point of 253° C. are obtained. (Example 2 (in Table 1)).
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]2[O:19][CH2:18][C:8]3([C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]3=[O:17])[C:6]=2[CH:7]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.BrCC1CCCCO1>>[CH2:22]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2([C:6]3[CH:7]=[C:2]([F:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=3[O:19][CH2:18]2)[C:9]1=[O:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1F)C1(CO2)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: COc1cc2c(cc1F)C1(CO2)C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and benzylbromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-benzyl-5-fluoro-6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (86%) as a colorless solid: mp 160-162° C.; 1H NMR (300 MHz, CDCl3) δ7.39-7.26 (m, 5H), 7.20 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.16-7.09 (m, 1H), 7.06-6.97 (m, 1H), 6.79 (d, J=7.8 Hz, 1H), 6.61 (d, J=6.8 Hz, 1H), 6.43 (d, J=10.1 Hz, 1H), 5.05 (d, J=15.5 Hz, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.83 (d, J=15.5 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ182.3, 173.3, 166.3, 165.6, 147.9, 137.5, 133.7, 128.5, 128.0, 126.1, 124.9, 124.6, 114.2, 97.5, 84.9, 77.3, 62.0, 47.6, 33.5; MS (ES+) m/z 376.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20]C)=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.O[Li].O>C1COCC1.O>[F:22][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)c[nH]c2c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(-c3cccc(C(F)(F)F)c3)c[nH]c2c1
Yield: 94 %

Procedure:
A solution of compound 15d (TFA salt, 500 mg, 1.15 mmol), and LiOH.H2O (132.7 mg, 3.16 mmol) in THF/H2O (10 mL/10 mL) was stirred at 45° C. overnight. The resulting mixture was concentrated and diluted with water. The aqueous layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give compound 15e (330 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 306.0.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12](=[O:32])[CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:14][C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:23]#[N:24])[CH3:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:26]1([C:13]2[N:14]=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:22])[C:23]#[N:24])[O:32][C:12]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C#N)CCCCCC(=O)NC(C(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C#N)CCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
7.3 g of phosphorus oxychloride are added to a solution of 5.75 g of (RS)-1,2-diphenyl-2-(7-cyanooctanamido)ethanone in 30 cm3 of toluene, and the mixture is heated to 80° C. for 6 hours. After treatment, the product obtained is chromatographed on a column 2 cm in diameter containing 60 g of silica gel (50 to 200μ). The column is eluted with 0.6 liter of diisopropyl ether, collecting 50 cm3 fractions. The fractions emerging at between 0.1 liter and 0.6 liter are concentrated under reduced pressure (0.2 kPa). 4.2 g (76%) of (RS)-7-(4,5-diphenyl-2-oxazolyl)-2-methylheptanenitrile are obtained in the form of an oil, which is used directly in the subsequent reaction.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28]([OH:30])=O)([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:2].S(Cl)(Cl)=O.[CH3:39][O:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:33]([O:32][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28]([NH:45][C:44]2[CH:46]=[CH:47][C:41]([O:40][CH3:39])=[CH:42][CH:43]=2)=[O:30])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:34]
Reactant: COc1ccc(N)cc1
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(OC)cc2)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
(RS)-1-(2,2-diethoxyethyl)-3-(hydroxycarbonylmethyl)-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one in 50 ml of dichloromethane were added successively 0.140 g of 4-dimethylaminopyridine and 0.090 ml of thionyl chloride at 0° C., followed by stirring at 0° C. for 30 minutes. To the mixture were further added 0.140 g of 4-dimethylaminopyridine and 0.190 g of 4-methoxyaniline at 0° C. The resulting mixture was stirred at room temperature for 1 hour, and then washed with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.54 g (88%) of the title compound.