Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:42]=[CH:41][C:5]([CH2:6][O:7][CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[CH:16][CH:15]=3)[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9]2)=[CH:4][C:3]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48].[F-].[Cs+].[CH:51]([Sn](CCCC)(CCCC)CCCC)=[CH2:52].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH:13]2[CH2:12][CH2:11][N:10]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:9][CH:8]2[O:7][CH2:6][C:5]2[CH:41]=[CH:42][C:2]([CH:51]=[CH2:52])=[C:3]([O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])[CH:4]=2)=[CH:15][CH:16]=1
Reactant: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=Cc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC

Procedure:
The solution of 0.155 g of tert-butyl 3-[4-chloro-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 31a), 0.008 g of caesium fluoride and vinyl tributyl tin in 1.0 ml of dioxane is initially charged under argon in a Schlenk apparatus with stirring. The mixture is admixed with the solution of 0.0027 g of tris(dibenzylidenacetone)dipalladium(II) and 0.0026 g of tri-tert-butylphosphine in 0.20 ml of dioxane (prepared in a Schlenk apparatus under argon). The reaction mixture is stirred at 100° C. over 24 hours, then cooled, admixed with 1M sodium hydrogencarbonate solution (20 ml) and extracted with tert-butyl methyl ether (2×25 ml). The organic phases are washed with brine (1×5 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.16 (6:1 toluene-methanol); Rt=29.41 (II).
Reaction SMILES: F[C:2]1[C:3]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(Cl)Cl>[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:2]2[C:3]([C:8]3([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:27][CH:26]=1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: OC1(c2nccnc2F)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OC1(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCOCC1
Temperature: 80 °C

Procedure:
To a solution of 4-(3-fluoropyrazin-2-yl)tetrahydro-2H-pyran-4-ol (0.1 g, 0.505 mmol) in DMSO (1 mL) was added 4-(benzo[d]thiazol-2-ylamino)phenol (0.183 g, 0.757 mmol) and cesium carbonate (0.329 g, 1.009 mmol). The resulting mixture was heated to 80° C. overnight. Reaction mixture was diluted with DCM and washed with alternating washes of water and brine to remove DMSO. Purification by Biotage (0-10% MeOH/DCM) produced product. MS (ESI, pos. ion) m/z: 421.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:25])[CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:10]([C:9](=[O:25])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[OH:11])=[CH:18][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)NCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(=O)NCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using N-Benzyl-2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-hydroxy-acetamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[C:9]([O:11]COC)[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:16]1>CO>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:16]1
Reactant: COCOc1ccc(C2CCCC(NS(C)(=O)=O)C2)c(OCOC)c1
Solvent: CO
Product: CS(=O)(=O)NC1CCCC(c2ccc(O)cc2O)C1
Yield: 38.5 %

Procedure:
(±)-N-{3-[2,4-Bis(methoxymethoxy)phenyl]cyclohexyl}methanesulfonamide (34 mg) was heated under reflux in methanol (2 ml) containing acidic ion exchange resin (0.3 g) for 5 hr. The reaction mixture was filtered and the resin was washed with methanol. The combined filtrate and washings were evaporated in vacuo and the crude residue was purified by preparative HPLC to furnish a mixture of diastereoisomers of the title compound as a pale pink solid (10 mg, 38%). δH (d4-MeOH) 1.20-2.00 (7H, overlapping m), 2.07 (1H, m), 2.90 (0.5H, m), 2.93 (1.5H, s), 2.97 (1.5H, s), 3.13 (0.5H, m), 3.30 (0.5H, m), 3.80(0.5H, m), 6.21-6.26 (1H, dd), 6.87 (0.5H, d), 6.89 (0.5H, d); m/z (ES−) 284 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]([CH:23]3[CH2:25][CH2:24]3)[CH3:22])[CH:15]=2)=[CH:8][CH:7]=1.[OH-].[K+].Cl>CO.O1CCCC1>[CH:23]1([N:21]([CH2:20][C:16]2[CH:15]=[C:14]([C:13]#[C:12][C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([OH:26])=[O:2])=[CH:7][CH:8]=3)[CH:19]=[CH:18][CH:17]=2)[CH3:22])[CH2:24][CH2:25]1
Reactant: COC(=O)/C=C/c1ccc(C#Cc2cccc(CN(C)C3CC3)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1cccc(C#Cc2ccc(/C=C/C(=O)O)cc2)c1)C1CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.8 %

Procedure:
A solution of (E)-3-(4-{3-[(cyclopropyl-methyl-amino)-methyl]-phenylethynyl}-phenyl)-acrylic acid methyl ester (Intermediate 92, 0.11 g, 0.32 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was treated with a 3M solution of potassium hydroxide (1 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 days. The reaction mixture was neutralized with 5% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography over silica gel (230–400 mesh) using 10% methanol in ethyl acetate as the eluent to afford the title product as a yellow solid (0.038 g, 36%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:31])([F:32])[F:30])=[CH:28][C:3]=3[C:2]([F:1])([F:34])[F:33])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44][C@@H:43]1[CH2:48][OH:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R)-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[S:19]([CH3:22])(=[O:21])=[O:20])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[OH:23][CH2:24][C@@H:25]1[O:29][C:28](=[O:30])[NH:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.[Cl-].[NH4+]>O1CCOCC1.[Cu](I)I>[OH:23][CH2:24][C@@H:25]1[O:29][C:28](=[O:30])[N:27]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[S:19]([CH3:22])(=[O:21])=[O:20])[NH:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[CH2:26]1
Reactant: CS(=O)(=O)c1ccccc1-c1cc2ccc(Br)cc2c(=O)[nH]1
Reactant: O=C1NC[C@H](CO)O1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccccc1-c1cc2ccc(N3C[C@H](CO)OC3=O)cc2c(=O)[nH]1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
The 7-bromo-3-(2-methylsulfonylphenyl)-2H-isoquinolin-1-one (7 mg, 0.019 mmol) prepared in step A, copper iodide (I) (3.5 mg, 0.019 mmol), (R)-5-hydroxymethyloxazolidin-2-one (2.2 mg, 0.019 mmol), and potassium carbonate (5.3 mg, 0.039 mmol) were suspended in 1,4-dioxane (0.5 ml). Thereafter, N,N′-dimethylethylenediamine (0.01 ml, 0.093 mmol) was added to the suspension. The obtained mixture was stirred under heating to reflux overnight. The reaction solution was cooled to a room temperature. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=100:1->30:1), so as to obtain 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-methanesulfonylphenyl)-2H-isoquinolin-1-one (2 mg, 26%) in the form of a colorless oil substance.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.N([O-])=O.[Na+].[I-:17].[K+]>C1COCC1.Cl.O.CCOC(C)=O>[OH:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][CH:3]=[C:2]2[I:17])=[CH:7][CH:8]=1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1ccc2cccc(I)c2c1
Reaction time: 0.25 h

Procedure:
To a solution of 8-amino-2-naphthol (10.0 g, 62.80 mmol) in THF (50 mL) and 3 N aqueous HCl (100 mL) at 0° C. was added a solution of NaNO2 (4.76 g, 69.08 mmol) in H2O (20 mL). The resulting mixture was stirred for 15 min, then a solution of potassium iodide (41.8 g, 251.8 mmol) in H2O (30 mL) was added. After 40 min, the reaction was diluted with EtOAc and filtered. The filtrate was extracted with EtOAc (2×), the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo in the presence of silica gel. The powder was chromatographed on silica gel, eluting with hexane—10% EtOAc, to yield the above-titled compound.
Reaction SMILES: N12CCCCC1C=NCCC2.Br[CH2:13][CH:14]1[CH2:29][N:17]2[CH2:18][CH2:19][CH2:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:16]2[C:15]1=[O:30].[C:31]([O-:34])(=[S:33])[CH3:32].[K+].C(O)(=S)C>O1CCOCC1.CC(C)=O.ClCCl>[C:31]([S:33][CH2:13][CH:14]1[CH2:29][N:17]2[CH2:18][CH2:19][CH2:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:16]2[C:15]1=[O:30])(=[O:34])[CH3:32]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)C1CCCN2CC(CBr)C(=O)N12
Agent: C1=NCCCN2CCCCC12
Agent: CC(O)=S
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)SCC1CN2CCCC(C(=O)OC(C)(C)C)N2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
2.3 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene in 10 ml of dioxan were added at 5° C. to a solution of 4.4 g of tert.butyl 2-bromomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]-pyridazine-5-carboxylate (diastereomer B) in 25 ml of dioxan. The mixture was left to stand at room temperature for 2 hours and then filtered. The filtrate was evaporated and the residue was dissolved in ethyl acetate. The solution was filtered through 6 g of silica gel and evaporated. The residue obtained was dissolved in 10 ml of acetone. The solution was treated with 1.6 g of potassium thioacetate and subsequently with 10 ml of thioacetic acid, whereupon the mixture was stirred overnight at room temperature. The mixture was diluted with 100 ml of dichloromethane and washed with 50 ml of saturated aqueous sodium bicarbonate. The separated organic phase was dried over magnesium sulfate and evaporated to give an oil which was chromatographed over 200 g of silica gel using diethyl ether/hexane for the elution. After recrystallization from ethyl acetate/hexane, there were obtained 1.69 g of tert.butyl 2-acetylthiomethyl-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (diastereomer A) and 0.9 g of the corresponding diastereomer B.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)=O.[CH2:28]([C:30]1[C:38]2[C:37]([NH2:39])=[CH:36][CH:35]=[CH:34][C:33]=2[N:32]([CH2:40][C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)[N:31]=1)[CH3:29]>CC(N(C)C)=O>[CH2:28]([C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[NH:39][C:20]([C:17]2[N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:12][C:13]3=[N:19][CH:18]=2)=[O:22])[N:32]([CH2:40][C:41]2[S:42][CH:43]=[C:44]([CH3:46])[N:45]=2)[N:31]=1)[CH3:29]
Reactant: CN1CCN(CCOc2ccn3c(C(=O)O)cnc3c2)CC1
Reactant: CCc1nn(Cc2nc(C)cs2)c2cccc(N)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCc1nn(Cc2nc(C)cs2)c2cccc(NC(=O)c3cnc4cc(OCCN5CCN(C)CC5)ccn34)c12
Temperature: 25 °C
Yield: 35.8 %

Procedure:
A solution of 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (0.346 g, 0.997 mmol) in DMA (5 mL) was cooled to 0° C. and treated with phosphorous oxychloride (0.182 mL, 1.99 mmol). The mixture was warmed up to ambient temperature and after stirring for an hour, the mixture was cooled to 0° C. again and treated with a solution of 3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-amine (0.181 g, 0.665 mmol) in DMA (2 mL). The mixture was allowed to warm up to ambient temperature and stirring continued overnight. The mixture was concentrated and then quenched with saturated aqueous lithium hydroxide, stirred at ambient temperature for 30 minutes and then diluted with DCM. The organic layer was filtered through glass fiber filter paper, concentrated under reduced pressure and purified by silica gel chromatography (2-10% 7N NH3/MeOH in DCM) to provide N-(3-ethyl-1-((4-methylthiazol-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (0.133 g, 36% yield) as beige solids. MS (APCI) m/z=559 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.C(=O)([O-])O.[Na+].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[F:34].CCOCC>C1(C)C=CC=CC=1.C(O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:30]1[CH:31]=[CH:32][C:33]([F:34])=[C:28]([Cl:27])[CH:29]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccc(F)c(Cl)c1
Reaction time: 8 h

Procedure:
To a rapidly stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.25 g) in toluene (2 ml) containing tetrakis(triphenylphosphine)palladium(0) (0.02 g) was added saturated aqueous sodium hydrogen carbonate solution (1 ml) and a solution of 3-chloro-4-fluorophenylboronic acid (0.22 g) in ethanol (1 ml). The mixture was heated under reflux for 3 hours, then left at room temperature overnight and then poured into ether (25 ml) and water (25 ml). The organic layer was separated, dried (MgSO4) and evaporated. The residue was taken up the minimum amount of ethyl acetate and purified by column chromatography on silica gel (20 g) eluted with dichloromethane:hexane (1:2). Combination and evaporation of suitable fractions followed by recrystallisation form ether/hexane gave the title compound as an off-white solid, m.p. 197-8° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2([C:16]([NH:18][C@H:19]([C:45]([OH:47])=[O:46])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=4[O:35][CH3:36])=[CH:23][C:22]=3[O:37]CC3C=CC=CC=3)=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd]>[C:1]1([S:7]([C:10]2([C:16]([NH:18][C@H:19]([C:45]([OH:47])=[O:46])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[C:28]([O:35][CH3:36])=[CH:29][CH:30]=[CH:31][C:32]=4[O:33][CH3:34])=[CH:23][C:22]=3[OH:37])=[O:17])[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)C2(S(=O)(=O)c3ccccc3)CCCNC2)C(=O)O)c(OCc2ccccc2)c1
Agent: [Pd]
Product: COc1cccc(OC)c1-c1ccc(C[C@H](NC(=O)C2(S(=O)(=O)c3ccccc3)CCCNC2)C(=O)O)c(O)c1

Procedure:
A mixture of N-(3-phenylsulfonyl-nipecotyl)-4-(2′,6′-dimethoxyphenyl)-2-benzyloxyphenylalanine (36 mg, 0.055 mmol) and 10% Pd/C (10 mg) were stirred vigorously under 1 atm of H2 until the starting material was consumed as judged by reverse phase HPLC analysis. The mixture was filtered through a pad of celite which was washed with MeOH and concentrated. The filtrate was triturated with Et2O to afford N-(3-phenylsulfonyl-nipecotyl)-4-(2′,6′-dimethoxyphenyl)-2-hydroxyphenylalanine as a solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][O:4][CH2:3]1.C(NC(C)C)(C)C.[Li].[N:16]1([C:21]2[C:30]3[C:25](=[N:26][C:27](Cl)=[C:28]([Cl:31])[N:29]=3)[N:24]=[C:23]([Cl:33])[N:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1.O>O1CCCC1>[Cl:33][C:23]1[N:22]=[C:21]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:30]2[C:25](=[N:26][C:27]([O:1][C@@H:2]3[CH2:7][CH2:6][CH2:5][O:4][CH2:3]3)=[C:28]([Cl:31])[N:29]=2)[N:24]=1
Reactant: O[C@@H]1CCCOC1
Reactant: Clc1nc(N2CCCC2)c2nc(Cl)c(Cl)nc2n1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Clc1nc(N2CCCC2)c2nc(Cl)c(O[C@@H]3CCCOC3)nc2n1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
a)+b) 170 mg (1.67 mmol) (R)-3-hydroxytetrahydropyran are dissolved in 5 ml of tetrahydrofuran and under protective gas at −10° C. mixed with 821 μl (1.64 mmol) of a 2 molar solution of lithium diisopropylamine in tetrahydrofuran. The mixture is stirred for 30 minutes at −10° C., then for one hour at ambient temperature. The mixture is cooled to −10° C. again and combined with a suspension of 500 mg (1.64 mmol) 4-pyrrolidin-1-yl-2,6,7-trichloropteridine in 15 ml of tetrahydrofuran. The mixture is stirred for one hour at −10° C., slowly allowed to come up to ambient temperature and stirred for another four hours. The reaction mixture is combined with approx. 100 ml of water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is taken up in approx. 50 ml diethyl ether and stirred for one hour. The solid is suction filtered, washed with diethyl ether and dried. Yield 320 mg (53% of theory). The (R)-2,6-dichloro-7-(3-tetrahydropyranyloxy)-4-pyrrolidin-1-yl-pteridine thus obtained is dissolved in 13 ml dioxane and slowly added dropwise to a solution of 372 mg (4.3 mmol) piperazine in 12 ml dioxane at a temperature of 80° C. The mixture is stirred for approx. another 16 hours at 80° C., cooled to ambient temperature and the reaction mixture is combined with water. It is extracted with dichloromethane, the organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is purified by chromatography. The product obtained is stirred with diethyl ether, the solid substance is suction filtered, washed with diethyl ether and dried. Yield 170 mg (47% of theoretical)
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]([O:16]CC)=[CH2:15])[N:11]=[C:10]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[N:9]=1)[CH2:4][F:5].O.Cl>O1CCOCC1>[F:5][CH2:4][CH:3]([O:6][CH2:7][C:8]1[N:9]=[C:10]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[N:11]=[C:12]([C:14](=[O:16])[CH3:15])[CH:13]=1)[CH2:2][F:1]
Reactant: C=C(OCC)c1cc(COC(CF)CF)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COC(CF)CF)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a solution of 4-((1,3-difluoropropan-2-yloxy)methyl)-6-(1-ethoxyvinyl)-N-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidin-2-amine (47 mg, 0.10 mmol) in dioxane (7.5 mL) was added water (0.5 mL) and HCl (conc., 0.025 mL, 0.31 mmol). The mixture was stirred at 50° C. for 20 minutes. The solvents were evaporated. Sodium bicarbonate solution (50% saturated) was added and the mixture was extracted with DCM. The organic phase was separated on phase separator and evaporated to give the title compound (34 mg, 77%).
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[C@H:5]([N:13]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C(O)(C(F)(F)F)=O>CO.O=[Pt]=O.[Pt]>[NH2:2][CH2:1][CH2:3][CH2:4][C@H:5]([N:13]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:26])([F:27])[F:25])(=[O:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CN([C@@H](/C=C/C#N)Cc1ccccc1)S(=O)(=O)c1ccccc1OC(F)(F)F
Agent: O=[Pt]=O
Agent: [Pt]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCOC(=O)CN([C@@H](CCCN)Cc1ccccc1)S(=O)(=O)c1ccccc1OC(F)(F)F
Reaction time: 12 h

Procedure:
To a solution of compound 31h (3.7 g, 7.7 mmol) in MeOH (200 mL) were added PtO2 (0.1 g), Pt/C (0.3 g) and TFA (1.9 g). The mixture was hydrogenated in a Parr shaker at 48 psi for 12 h. The mixture was filtered and concentrated. The product was directly used in the next reaction step without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[CH3:7][O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][NH:19][C:20]([C:22]3([NH2:25])[CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)=[C:11]([C:30]([F:33])([F:32])[F:31])[CH:10]=1>>[CH3:7][O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][NH:19][C:20]([C:22]3([NH:25][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:23][CH2:24]3)=[O:21])=[CH:16][CH:15]=2)=[C:11]([C:30]([F:31])([F:32])[F:33])[CH:10]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: N#CCC(=O)O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)CC#N)CC3)cc2)c(C(F)(F)F)c1

Procedure:
Prepared analogously to Example 85b) starting from cyanoacetic acid and 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide (from 85a). In addition, the residue was finally purified by chromatography (reversed phase).