Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH2:14])=O)[NH:3]1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]#[N:14])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1nc2ccccc2c(=O)[nH]1
Product: N#Cc1nc(Cl)c2ccccc2n1
Yield: 62 %

Procedure:
4-Oxo-3,4-dihydroquinazoline-2-carboxamide (40b, 0.51 g, 2.69 mmol) was heated to 100° C. in POCl3 (7.0 mL) for three hours. The solvent was removed under reduced pressure. Ice-cold water was carefully added to the flask, and the insoluble product was filtered off. The filtrate was extracted three times with chloroform. The combined organics were dried (MgSO4) and evaporated to give 4-Chloroquinazoline-2-carbonitrile (40c, 0.21 g). 95% pure by HPLC and used without further purification. The insoluble product was purified by flash silica gel chromatography eluting with 3-30% EtOAc/hexane to give an additional 0.22 g of 40c as a white solid for an overall yield of 62%. Rf=0.53 (30% EtOAc/hexane). 1H NMR (400 MHz, DMSO-d6): δ 8.07-8.11 (m, 1H), 8.24-8.31 (m, 2H), 8.41 (d, J=8.4 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([N+:15]([O-])=O)[C:9]2=[O:18])=[CH:5][CH:4]=1.[CH2:21]=O.C[O-].[Na+]>CS(C)=O.C(OCC)(=O)C>[NH2:15][C:10]1[C:9](=[O:18])[N:8]([CH2:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:13]=[CH:12][C:11]=1[CH2:14][CH3:21]
Reactant: C=O
Reactant: COc1ccc(Cn2ccc(C)c([N+](=O)[O-])c2=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1ccn(Cc2ccc(OC)cc2)c(=O)c1N
Reaction time: 2 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 1-(4-methoxybenzyl)-4-methyl-3-nitro-2-pyridone (1.38 g, 5.0 mmol) and paraformaldehyde (0.152 g) in dimethylsulfoxide (8 mL) was added sodium methoxide (0.018 g). After 2 hours, the mixture was diluted with ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was dried, filtered and evaporated. The residual solid was triturated with chloroform/ethyl acetate (10 mL, 1/1) and 1-(4-methoxybenzyl)-4-hydroxyethyl-3-nitro-2-pyridone was collected by filtration (0.496 g). Fractionation of the supernatant over silica gel (chloroform/ethyl acetate to ethyl acetate/methanol 99/1) gave additional product (0.404 g) (total yield, 2.96 mmol, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:24]([C:33]([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28].C1CCC([N:56]=C=NC2CCCCC2)CC1>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:33]([NH:24][C@H:25]([C:30]([NH2:56])=[O:32])[CH2:26][CH:27]([CH3:29])[CH3:28])([O:35][CH2:36][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:34]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Yield: 74.9 %

Procedure:
(Z)-1-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene (1.92 g, 6.1 mmols), 2.58 g (7.3 mmols) of Fmoc-L-Leu, 1.5 g (7.3 mmols) of DCC and 1.1 g (7.3 mmols) of HOBtH2O were dissolved in 40 ml of N,N-dimethylformamide, and the mixture was reacted at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate, then filtered and concentrated. The product was purified through silica-gel column chromatography (mixture of ethyl acetate and hexane at a ratio by volume of 1:2) to produce 3.05 g of the final product in a yield of 76.9%.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C@H:19]([CH2:21]OS(C)(=O)=O)[O:18][C:17]2=[O:27])=[CH:12][CH:11]=1>CN(C)C=O.O>[CH3:8][S:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][C@H:19]([CH2:21][N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)[O:18][C:17]2=[O:27])=[CH:14][CH:15]=1
Reactant: CSc1ccc(N2C[C@H](COS(C)(=O)=O)OC2=O)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(N2C[C@H](Cn3ccnc3)OC2=O)cc1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
Sodium hydride (80% in oil, 23 mg, 0.77 mM) was stirred under nitrogen in N,N-dimethylformamide (5 ml), imidazole (52 mg, 0.77 mM) added, and stirring continued for 10 minutes. (5R)-3-(4-Methylthiophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (200 mg, 0.63 mM) was dissolved in N,N-dimethylformamide (5 ml), added to the above, and the mixture stirred 18 hours at ambient temperature. After diluting with water (30 ml), the mixture was extracted with ethyl acetate (30 ml), the extract washed with brine (25 ml), dried (magnesium sulfate) and evaporated. The residue was triturated with diethyl ether, and filtered to give the desired product (129 mg, mp 129–131°).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(-c2ccc(C=O)s2)cc1
Product: COc1ccc(-c2ccc(C(O)c3ccccc3)s2)cc1
Yield: 64 %

Procedure:
The title compound was prepared from the product of step 1 (0.56 g, 2.55 mmol) and benzyl bromide (0.5 g, 3.2 mmol) using the procedure of Example 159, step 2 with 64% yield (0.6 g).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:18])([F:17])[F:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH3:19][NH2:20]>ClCCl.CO>[CH3:19][NH:20][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C:15]([F:18])([F:17])[F:16])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3]
Reactant: CN
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1OC(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(OC(F)(F)F)c(C(=O)O)c1
Reaction time: 0.03 h

Procedure:
To a solution of 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid (0.15 g) in dichloromethane (1.5 ml) was added a solution of methylamine in methanol (8M, 0.31 mL) and the reaction mixture was stirred for 2 minutes after precipitation was compete. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 1N NaOH (2 mL) and extracted with diethylether. The aqueous phase was then acidified using 3 N hydrochloric acid solution (2 mL) and the solution was extracted with dichloromethane (2×10 mL). The combined organic phases were dried with sodium sulfate and concentrated in vacuo to yield the title compound as a white solid (0.12 g). MS (m/e): 298.0 (M−H, 100%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[CH:14]=[N:13][C:12]([OH:15])=[N:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)C.CS(C)=O>[Cl:9][C:7]1[CH:6]=[C:5]([N:10]2[CH:14]=[N:13][C:12]([O:15][CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:23])=[N:11]2)[CH:4]=[C:3]([Cl:2])[CH:8]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2cc(Cl)cc(Cl)c2)n1
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2cc(Cl)cc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
A 1.8 g portion of sodium was dissolved in 75 ml of absolute ethanol, and the solution was added slowly with stirring to a solution of 18.5 g of 1-(3,5-dichlorophenyl)-3-hydroxy-1,2,4-1H-triazole in 200 ml of dimethylsulfoxide. The solution was stirred at 60° for 1 hour, 14.5 g of ethyl 2-bromopropionate was added, and the mixture was heated for 2 hours at 100°-110°. It was then poured over ice water, and the solid was collected, dried and recrystallized from ether to obtain 10 g of the desired product. The mother liquor was chromatographed to obtain 1.3 g of additional product.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].ON1C2C=CC=CC=2N=N1.[F:33][C:34]([F:47])([F:46])[C:35]1[N:39]2[CH2:40][CH2:41][NH:42][CH2:43][C:38]2=[C:37]([CH2:44][OH:45])[N:36]=1.C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([N:42]1[CH2:41][CH2:40][N:39]2[C:35]([C:34]([F:47])([F:33])[F:46])=[N:36][C:37]([CH2:44][OH:45])=[C:38]2[CH2:43]1)=[O:5]
Reactant: OCc1nc(C(F)(F)F)n2c1CNCC2
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCn2c(C(F)(F)F)nc(CO)c2C1
Reaction time: 12 h
Yield: 63.8 %

Procedure:
2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid 1a (372 mg, 1.25 mmol) was dissolved in 5 mL of N,N-dimethylformamide, followed by addition of N-hydroxybenzotriazole (85 mg, 0.63 mmol), [3-(trifluoromethyl)-5,6,7,8-tetrahydro imidazo[1,5-a]pyrazin-1-yl]methanol 6a (277 mg, 1.25 mmol), 1-ethyl-(3-dimethyl-aminopropyl) carbodiimide hydrochloride (359 mg, 1.88 mmol) and triethylamine (0.3 mL, 2.5 mmol). After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography with elution system A to obtain 4-[[4-fluoro-3-[1-(hydroxymethyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2H-phthalazin-1-one 6 (400 mg, yield 64.0%) as a white solid.
Reaction SMILES: [C:1](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[NH2:17][C@H:18]([C:20]([O-:22])=[O:21])[CH3:19].Cl>C(O)C.C(OC([C@@H](N[C@H](C(O)=O)C)CC(=O)C1C=CC=CC=1)=O)C>[CH2:14]([O:13][C:11]([CH:10]([NH:17][C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])[CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)/C=C/C(=O)c1ccccc1
Reactant: C[C@H](N)C(=O)[O-]
Agent: CCOC(=O)[C@H](CC(=O)c1ccccc1)N[C@@H](C)C(=O)O
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccccc1)N[C@@H](C)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68.2 %

Procedure:
To a solution of 25.9 g of ethyl trans-β-benzoylacrylate in 770 ml of ethanol was added a solution of 6.03 g of L-alanine lithium salt in 426 ml of ethanol over 30 minutes at room temperature. After completion of addition, the mixture was stirred for an additional 5 minutes, and then 5.29 ml of concentrated hydrochloric acid was added, followed by cooling with ice-water. As seed crystals, 679 mg of N-(1(S)-ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-alanine was added, and the mixture was stirred for 4 hours. The crystals separating out were collected by filtration, washed with ethanol, and dried, whereby 12.7 g of N-(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-alanine (1S/1R ratio=95/5) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[CH:16]=[N:15]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[N:14]([CH3:13])[N:15]=[CH:16]3)(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1
Reactant: Cn1ncc2cc(CN)ccc21
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Product: Cn1ncc2cc(CNS(=O)(=O)c3ccc(Br)cc3Cl)ccc21

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from 4-bromo-2-chlorobenzene-1-sulfonyl chloride and (1-methyl-1H-indazol-5-yl)methanamine.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[CH:11][CH:12]=O)[CH:5]=1>CC(O)(C)C>[N:2]1[NH:3][CH:10]([C:6]2[CH:5]=[N:4][CH:9]=[CH:8][CH:7]=2)[CH2:11][CH:12]=1
Reactant: O=CC=Cc1cccnc1
Reactant: NN
Solvent: CC(C)(C)O
Solvent: O
Product: C1=NNC(c2cccnc2)C1

Procedure:
Under N2 atmosphere, hydrazine hydrate (3.65 mL, 2 equiv.) was added to a solution of 3-(3-pyridyl)acrolein (5.0 g) in t-BuOH (25 mL). The mixture was refluxed for 3 days, followed by evaporation under reduced pressure. The residue was taken up in DCM and washed with 5% aqueous NaHCO3. The organic phase was dried over Na2SO4 and evaporated under reduced pressure. This gave 5.0 g of a red oil, containing 74% of the anticipated product and 26% of the hydrazone intermediate that failed to undergo ring-closure. This material was used in subsequent steps without further purification. Characteristic pyrazoline signals in 1H NMR (400 MHz, CDCl3): δ 2.63-2.75 (m, 1H), 3.13-3.25 (m, 1H) 4.72-4.82 (m, 1H), 6.85 (br s, 1H).
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[C:5]([O:9][C:10]([C:12]1[CH:22]=[C:21]([OH:23])[C:15]2[CH2:16][CH:17]([CH2:19][OH:20])[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:5]([O:9][C:10]([C:12]1[CH:22]=[C:21]([O:23][CH:2]([CH3:4])[CH3:3])[C:15]2[CH2:16][CH:17]([CH2:19][OH:20])[O:18][C:14]=2[CH:13]=1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)c1cc(O)c2c(c1)OC(CO)C2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(=O)OC(C)(C)C)cc2c1CC(CO)O2
Temperature: 60 °C
Yield: 86.4 %

Procedure:
A mixture of 2-iodopropane (0.826 mL, 8.26 mmol), 4-hydroxy-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (200f) (2.00 g, 7.51 mmol), and K2CO3 (1.56 g, 11.3 mmol) in DMF (20 mL) was heated to 60° C. overnight. Additional 2-iodopropane (0.9 mL) and K2CO3 (0.9 g) were added. The resulting mixture was heated to 50° C. for 4 days, then cooled to room temperature, quenched with H2O and extracted with 3×EtOAc. The organic layers were washed with 2× H2O, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography with 50-70% EtOAc in hexanes to give a yellow syrup (2.0 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ 7.11 (s, 1 H) 7.03 (d, J=1.01 Hz, 1 H) 4.90-5.05 (m, 1 H) 4.58-4.66 (m, 1 H) 3.81-3.88 (m, 1 H) 3.67-3.77 (m, 1 H) 3.21 (dd, J=16.42, 9.60 Hz, 1 H) 2.94 (dd, J=16.42, 7.07 Hz, 1 H) 1.60 (s, 9 H) 1.32-1.34 (m, 6 H); LCMS for C17H24O5 m/z 253.00 (M-tBu+H+).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[CH2:26][C:27]#[N:28])[C:10]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:30][OH:31].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[OH:31][NH:30][C:27](=[NH:28])[CH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:10]2[C:9]3[CH:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:17]=[CH:18]1
Reactant: N#CCc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21)NO

Procedure:
The title compound is prepared in analogy to Example 67 starting from 300 mg (0.832 mmol) of [2-(8-phenyl-imidazo[4,5-c]quinolin-1-yl)phenyl]-acetonitrile (Example 64), 346 mg (0.499 mmol) hydroxylamine hydrochloride in 7 ml DMF, and 465 mg sodium carbonate in 2.5 ml water. The compound is isolated as colorless powder. mp: 253-254° C.; MS: 394 (M+1); HPLC: tret=6.57 min (Grad 1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([CH3:21])[N:15]=1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>O1CCCC1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)=[N:15][C:16]=1[CH3:21]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1nc(N)ccc1Br
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(NCc2ccc(C(F)(F)F)cc2)ccc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of p-trifluoromethylbenzaldehyde (16, 1.00 g, 5.74 mmol) in tetrahydrofuran (9 mL) was added 2-amino-5-bromo-6-methylpyridine (33, 1.08 g, 5.77 mmol), followed by dibutyltin dichloride (40 mg, 0.13 mmol). The mixture was stirred for 5 minutes at 25° C and phenylsilane (0.69 g, 6.4 mmol) was added. The reaction was heated at 50° C. overnight, then the solvent was removed at reduced pressure. Ethyl acetate was added to the resulting solid which was washed with saturated sodium carbonate, dried over magnesium sulfate and filtered. Concentration under reduced pressure afforded a light yellow solid (34, 1.7 g, 4.93 mmol). MS(ESI) [M+H+]+=345.1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:21][CH2:22][CH2:23]O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([O:12][CH2:23][CH2:22][CH2:21][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Product: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-6-hydroxy-7-methoxy-quinazoline and 3-Morpholin-4-yl-propan-1-ol. LC/ESI-MS: m/z=338 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.N[C:35]1[C:40]([C:41]#N)=[C:39](N2CCC(C3N(CCNCC(C)C)C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=[CH:37][N:36]=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[N:18]([CH2:33][CH2:37][NH:36][CH2:35][CH:40]([CH3:41])[CH3:39])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:15][CH2:16]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: Cc1cc(-c2cn(CCNCC(C)C)c(C3CCN(c4ncnc(N)c4C#N)CC3)n2)ccc1F
Product: Cc1cc(-c2cn(CCNCC(C)C)c(C3CCN(c4ncnc(N)c4C(N)=O)CC3)n2)ccc1F

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-isobutylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=495, obsd.=495).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C:17]1[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=1)[C:11]([OH:13])=O.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31](=[N:33]O)[NH2:32])[CH:30]=1.CCN(C(C)C)C(C)C>>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([C:31]2[N:32]=[C:11]([C:10]3[CH:14]=[CH:15][C:16]([C:17]4[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=4)=[C:8]([CH3:7])[CH:9]=3)[O:13][N:33]=2)[CH:30]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: Cc1cc(C(=O)O)ccc1-c1cccnc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3cccnc3C)c(C)c2)n1

Procedure:
Oxalyl chloride (84 mg; 0.66 mmol; 3 eq.), Intermediate 37 (50 mg; 0.22 mmol; 1 eq.), Intermediate 23 (41 mg; 0.22 mmol, 1 eq.) and DIEA (85 mg; 0.66 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 90/10 then 85/15) afforded the title compound as a white solid.
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([O:21][CH2:22][CH2:23][CH3:24])[C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[O:11][C:9]=2[N:10]=1)(=O)=O.Cl.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C>CN(C=O)C>[CH2:22]([O:21][C:7]1[C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[O:11][C:9]=2[N:10]=[C:5]([NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:6]=1)[CH2:23][CH3:24]
Reactant: NC1CCOCC1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCOc1nc(NC2CCOCC2)nc2oc(-c3cccc(C)c3)nc12
Yield: 20.7 %

Procedure:
A mixture of 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine, 40 mg of 4-aminotetrahydropyran hydrochloride and 39 μl of triethylamine in 3 ml of DMF was heated for 8 h to 50° C. After filtration, the solvent was distilled off in vacuo, and the product was isolated via preparative HPLC to yield 22 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
2-Hydroxy-5-nitropyridine (50 g, 357 mmol) and N-chlorosuccinimide (55 g, 410 mmol) were suspended in anhydrous DMF (150 mL). The suspension was stirred at room temperature for 18 hours. The resulting homogeneous reaction mixture was diluted by the slow addition of water (750 mL), which resulted in a pale yellow precipitate. The solids were isolated via filtration and dried under high vacuum to provide 3-chloro-5-nitro-2-hydroxypyridine (59 g, 95% yield).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[CH3:9][S:10]([NH2:13])(=[O:12])=[O:11].[OH-].[Na+]>CC(C)=O.O>[CH3:9][S:10]([NH:13][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])(=[O:12])=[O:11]
Reactant: CS(N)(=O)=O
Reactant: FC(F)(F)CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CS(=O)(=O)NC(=S)NCC(F)(F)F
Yield: 19.2 %

Procedure:
A solution of 2,2,2-trifluoroethylisothiocyanate (1.4 g.) in acetone (20 ml.) was added to a solution of methanesulphonamide (0.95 g.) and sodium hydroxide (0.44 g.) in water (10 ml.) and the mixture stirred and heated under reflux for 18 hours, and then evaporated to dryness. The residue was dissolved in water and the solution washed with ethyl acetate and then acidified with concentrated hydrochloric acid. The mixture was extracted three times with ethyl acetate and the combined extracts dried and evaporated to dryness. The residue was triturated with acetonitrile and filtered and the filtrate evaporated to dryness. The residue was dissolved in ether, and the solution extracted with aqueous sodium bicarbonate solution. The extract was neutralised with N hydrochloric acid and the mixture extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to dryness to give 1-methanesulphonyl-3-(2,2,2-trifluoroethyl)thiourea (0.45 g.) which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11](C(C(=CN(C)C)C(OCC)=O)=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6](Cl)=[C:7](F)[CH:8]=2)[N:3]=1.C1([NH2:29])CC1>ClC(Cl)Cl>[CH2:10]1[CH2:11][CH2:2][N:3]2[C:7](=[N:29][CH2:6][CH2:5][CH2:4]2)[CH2:8][CH2:9]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: NC1CC1
Solvent: ClC(Cl)Cl
Product: C1CCC2=NCCCN2CC1
Yield: 122.8 %

Procedure:
A solution of 20.6 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate and 6 g of cyclopropylamine in 100 cm3 of trichloromethane is stirred at a temperature close to 20° C. for 24 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. The residue is taken up in 180 cm3 of ethanol and 10 g of DBU and the solution obtained is heated at a temperature close to 78° C. for 4 hours. After cooling to a temperature close to 20° C., the precipitate obtained is drained and washed with twice 60 cm3 of ethanol 13.65 g of 8-chloro-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a pale yellow solid melting at 256° C., which is used for the subsequent steps without further purification.