Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH:17]=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[N:1]1([CH2:14][CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: O=CCCCn1cnc2cnc3ccccc3c21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OC(CCCn1cnc2cnc3ccccc3c21)c1ccccc1

Procedure:
The general method described in Step 7 of Example 1 was used to react 4-(1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (7.94 g, 33.2 mmol) with phenylmagnesium bromide (33.2 mL of a 1 M solution in THF, 33.2 mmol) to provide 4-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-ol (7.2 g) as an off-white solid that was used directly in the next step without further purification.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[O:6]=[N+:7]1[CH:12]=[N:11][CH:10]=[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][N:8]12.C[I:18].[CH2:19](N(CC)CC)C>C(#N)C>[I-:18].[CH3:19][C:12]1[N+:7](=[O:6])[N:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]2=[CH:10][N:11]=1
Reactant: CCN(CC)CC
Reactant: O=[n+]1cncc2ccccn21
Reactant: CI
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: Cc1ncc2ccccn2[n+]1=O
Product: [I-]
Yield: 80 %

Procedure:
6.0 g (0.024 moles) of 1-oxo-pyrido[2,1-f]-as-triazinium perchlorate are boiled in acetonitrile in the presence of 6 ml of methyl iodide and 3.4 ml of triethylamine for an hour. 5.6 g of desired compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13].[NH:27]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:32]=O.[C:34]([BH3-])#[N:35].[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:3][C:4]2[NH:5][CH:6]=[CH:34][N:35]=2)[CH2:32][C:28]2[NH:29][CH:30]=[CH:31][N:27]=2)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCN(CCC)CCCCN(CC(=O)OC)Cc1ccc(CN)cc1
Reactant: O=Cc1ncc[nH]1
Reactant: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(CC(=O)OC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.6 %

Procedure:
The compound (1.4928 g) obtained in Example 64-1 was dissolved in anhydrous methanol (59.6 ml) and added with 2-imidazole carboxaldehyde (1.1848 g) and sodium cyanoborohydride (1.0331 g). After the solution was adjusted to pH 5 with acetic acid, the whole was stirred at room temperature for 3 days. After completion of the reaction, the resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (705.7 mg) of the subject compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[N:24]=[C:25]([Si](C)(C)C)[S:26][CH:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[F:39][C:40]([F:52])([F:51])[C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>Cl.O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21]([C:23]5[N:24]=[CH:25][S:26][CH:27]=5)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:47]([C:44]2[CH:43]=[CH:42][C:41]([C:40]([F:39])([F:51])[F:52])=[CH:46][CH:45]=2)(=[O:49])=[O:48])[CH2:16][CH2:15]4)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2csc([Si](C)(C)C)n2)C1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(c1cscn1)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
A solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-(2-(trimethylsilyl)thiazole-4-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (76 mg, 0.103 mmol) in 4 M HCl/dioxane (3 mL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo (azeotroping twice with toluene (˜4 mL)) to give a dark orange oil. This was dissolved in dichloromethane (3 mL) and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (30.3 mg, 0.124 mmol) was added followed by diisopropylethylamine (90 μl, 0.516 mmol). The reaction mixture was stirred at room temperature for 0.5 hour. The solvent was removed in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-4-yl)methanone as a white solid (44 mg). LCMS (Method F, ES-API): RT 2.65 min, m+H=589.2; 1H NMR (400 MHz, CDCl3): δ 8.86 (1H, d, J=2.1 Hz), 8.23 (1H, d, J=2.1 Hz), 7.84-7.82 (2H, m), 7.74-7.72 (2H, m), 7.45-7.40 (2H, m), 7.28 (1H, s), 7.19-7.13 (2H, m), 6.51 (1H, d, J=2.1 Hz), 5.48 (1H, dd, J=12.5, 2.1 Hz), 4.15 (1H, d, J=16.6 Hz), 3.92-3.87 (1H, m), 2.93-2.85 (2H, m), 2.72 (1H, d, J=12.6 Hz), 2.56-2.49 (2H, m).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH2:33][CH3:34].Cl>C(O)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH2:33][CH3:34])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 43.8 %

Procedure:
A mixture of 1.0 g (3.159 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.740 g (3.79 mmole) of 4-amino-3-ethoxybenzoic acid, 10 mL of ethanol and 40 mL of 1M hydrochloric acid was heated at reflux for 18 hours. The mixture was cooled and the white precipitate was collected by filtratration, washed with cold water and dried in vacuum to give 0.6391 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214) as off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2scnc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2scnc12
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
A solution of 4-Methyl benzothiazole (16.0 g, 107 mmol) in 535 mL of CCl4 was treated with NBS (19.0 g, 107 mmol) and AIBN (2.28 g, 13.9 mmol) at 20° C. and stirred at 70° C. for 2.5 h. The resulting mixture was filtered through Celite washing with Et2O (150 mL) and concentrated in vacuo. The residue was submitted to a silica gel column chromatography with toluene:Et2O=50:3 to 50:5 as eluate to afford 4-bromomethyl benzothiazole as a yellowish solid. (20.4 g, 89.9 mmol, 84%) Rf=0.61 (toluene-Et2O 10:1); 1H NMR (400 MHz, CDCl3) δ 9.07 (1H, s), 7.90 (1H, d, J=7.5 Hz), 7.55 (1H, d, J=7.5 Hz), 7.41 (1H, t, J=7.5 Hz), 5.08 (2H, s); 13C NMR (99.5 MHz, CDCl3) δ 154.1, 151.4, 134.3, 132.6, 127.0, 125.6, 122.3, 29.5.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([CH:9]1[CH2:10][CH2:11][N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:12])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCN1C1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2ccccc2)CCN1C1CCCCC1
Yield: 69.9 %

Procedure:
Place 1-cyclohexyl-pyrrolidin-2-one (400 mg, 2.4 mmol) in THF (30 mL) and cool to −78° C. Slowly add LDA (2.0 M, 2.4 mL, 4.8 mmol) and stir for 15 minutes. Add benzyl bromide (1.23 g, 7.2 mmol) and stir for 3 hours. Quench with ammonium chloride and extract with dichloromethane. Dry over sodium sulfate, filter, and concentrate. Purify by silica gel (20-50% ethyl acetate in hexanes) to afford 432 mg (70%) of the title compound. Mass spectrum (apci) m/z=258.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[H][H]>C(O)(=O)C.[Ni].CO>[ClH:1].[Cl:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: N#Cc1nccnc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Solvent: CO
Product: Cl
Product: NCc1nccnc1Cl
Temperature: 25 °C
Yield: 148.7 %

Procedure:
To a solution of 3-chloropyrazine-2-carbonitrile (160 g, 1.147 mol) in acetic acid (1.5 L) was added Raney Nickel (50% slurry in water, 70 g, 409 mmol). The resulting mixture was stirred under 4 bar hydrogen at room temperature overnight. Raney Nickel was removed by filtration over decalite and the filtrate was concentrated under reduced pressure and co-evaporated with toluene. The remaining brown solid was dissolved in ethyl acetate at 50° C. and cooled on an ice-bath. 2M hydrogen chloride solution in diethyl ether (1.14 L) was added in 30 min. The mixture was allowed to stir at room temperature over weekend. The crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40° C. The product brown solid obtained was dissolved in methanol at 60° C. The mixture was filtered and partially concentrated, cooled to room temperature and diethyl ether (1000 ml) was added. The mixture was allowed to stir at room temperature overnight. The solids formed were collected by filtration, washed with diethyl ether and dried under reduced pressure at 40° C. to give 153.5 g of (3-chloropyrazin-2-yl)methanamine.hydrochloride as a brown solid (74.4%, content 77%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1ccc([Mg]Cl)cc1
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)NC(=O)c1cnc(Cl)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
14.1 ml (14.1 mmol) 4-Fluoro-phenylmagnesium chloride solution (1M in THF) were added over 10 minutes to a solution of 1.0 g (4.7 mMol) N-tert.-butyl-6-chloro-nicotinamide in 5.0 ml THF cooled to 0° C. and the reaction mixture was stirred 18 hours at 35° C. After cooling to 0° C., 1.14 ml (28.2 mMol) methanol were added over 20 minutes, followed, after 15 minutes, by 1.17 g (5.2 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. After 30 minutes at room, temperature, the brown solution was concentrated under reduced pressure to about 10 g, heated to 50° C. and 20 ml tert.-butyl-methylether were added. The resulting suspension was stirred 1 hour at 55° C., then 1 hour at room temperature and filtered. The filtrate was concentrated under reduced pressure and digested in 5 ml n-hexane/ethyl acetate 4:1 to yield 0.69 g (48%) N-tert.-butyl-6-chloro-4-p-fluoro-phenyl-nicotinamide as a light brown powder of m.p.=168-173° C.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[S:15][N:14]=[C:13]([CH3:16])[N:12]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[F:8][C:7]1[C:2]([O:28][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][N:19]=[C:18]3[NH:10][C:11]2[S:15][N:14]=[C:13]([CH3:16])[N:12]=2)=[N:3][CH:4]=[C:5]([F:9])[CH:6]=1
Reactant: Cc1nsc(N)n1
Reactant: Oc1ccc2ncnc(Cl)c2c1
Reactant: Fc1cnc(F)c(F)c1
Product: Cc1nsc(Nc2ncnc3ccc(Oc4ncc(F)cc4F)cc23)n1

Procedure:
The compound of Example 90 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3,5-trifluoropyridine, 5-amino-3-methyl[1,2,4]thiadiazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][NH2:19])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20]([O-])(O)=[O:21].[Na+].C(Cl)(Cl)=O>C(Cl)Cl.O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]3[O:17][C:20](=[O:21])[NH:19][N:18]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])O
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]nc(OCC2c3ccccc3-c3ccccc32)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A suspension of N-[(9H-fluoren-9-ylmethoxy)carbonyl]hydrazine (141) (1.49 g, 5.78 mmol), CH2Cl2 (60 ml) and saturated NaHCO3 solution (60 ml) was stirred vigorously at 0° C. for 5 minutes, and the solution was then left for 5 minutes without stirring. Phosgene (1.89 M in toluene, 7.95 ml, 15.0 mmol) was then carefully added to the lower, organic phase using a syringe, and stirring of the reaction mixture was begun again immediately after the addition. After 10 minutes, water (20 ml) and CH2Cl2 (20 ml) were added to the reaction mixture. The phases were then separated rapidly, the aqueous phase was extracted with CH2Cl2 (50 ml), and the combined organic phases were dried over Na2SO4. Removal of the solvent under reduced pressure and drying gave a colourless solid (1.35 g, 4.82 mmol, 83%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[C:37]#[N:38].CCCCCC.C(OCC)(=O)C>C1COCC1.CCCCCC>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:34][C:35]2[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=2[C:37]#[N:38])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccccc2C#N)C(=O)O1

Procedure:
Analogously to Example 21 D) 1)c), 2.0 g (6.55 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-dihydrofuran-2-(3H)-one [Example 21 D) 1)b)] dissolved in 40 ml of THF are deprotonated with 13.1 ml of lithium bis(trimethylsilyl)amide 1M in THF and alkylated (75 min) with 1.4 g (7.2 mmol) of 2-bromomethylbenzonitrile (Fluka; Buchs/Switzerland). Column chromatography (SiO2, hexane/ethyl acetate 2:1) and stirring in hexane yields the pure title compound: TLC Rf (D)=0.45; tRet (I)=16.2 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][CH2:17][CH2:18][C:19]1[S:23][C:22]([NH:24][C:25]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:26])=[N:21][CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH4:1].[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:16][CH2:17][CH2:18][C:19]3[S:23][C:22]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=4)=[O:26])=[N:21][CH:20]=3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: NCCc1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C
Product: COC(=O)c1sc2ncnc(NCCc3cnc(NC(=O)Nc4cccc(C(F)(F)F)c4)s3)c2c1C
Temperature: 110 °C

Procedure:
A 20 mL vial was charged with 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (250 mg, 100 mol %), compound 38.1 (341 mg, 100 mole %), DIEA (1 mL) and DMF (2 mL). The resulting suspension was heated at 110° C. for 2 hours and cooled to room temperature. Concentration in vacuo provided 5-methyl-4-(2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-ethylamino)-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester; compound with methane (compound 43.1) as a solid that was used in the next reaction without further purification. LCMS [M+H]+ m/z 537.2
Reaction SMILES: [C:1]([N:4]1[CH:9]([CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][S:12]2(=[O:18])=[O:17])[CH2:8][N:7]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:6](=[O:27])[CH2:5]1)(=[O:3])[CH3:2].[C:28](OCC)(=[O:34])[C:29](OCC)=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[O:17]=[S:12]1(=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[CH2:10][CH:9]1[N:4]2[C:1](=[O:3])[CH:2]=[C:28]([OH:34])[C:29]([OH:30])=[C:5]2[C:6](=[O:27])[N:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:8]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)CC1CN1CCCCS1(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1c2c(O)c(O)cc(=O)n2C(CN2CCCCS2(=O)=O)CN1Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-5-[(1,1-dioxido-1,2-thiazinan-2-yl)methyl]-1-(4-fluorobenzyl)-piperazin-2-one (75 mg, 0.19 mmol) and diethyl oxalate (29 μL, 0.21 mmol) in DMF (3 mL) under an atmosphere of nitrogen, a solution of sodium bis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21 mmol) was added over a period of 0.5 h and stirred at the temperature for 30 min. Then additional sodium bis(trimethylsilyl)amide in THF (1M, 0.21 mL, 0.21 mmol) was added over a period of 0.5 h and stirred at the temperature for 1 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.O1CCCC1.CO.[BH4-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][OH:24])=[CH:25][CH:26]=1
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CO)cc1
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a mixture of 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzaldehyde (6.00 g), tetrahydrofuran (80 mL) and methanol (20 mL) was gradually added sodium borohydride (330 mg) at room temperature. After stirring for 30 min., water was added to the reaction mixture, and the precipitated crystals were collected by filtration and recrystallized from acetone-methanol to give colorless prism crystals (5.76 g, 95%) of 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]benzyl alcohol. melting point: 181-182° C.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[C:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16]=1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)Cl>[CH:1]1([NH:6][C:15]2[N:20]3[N:21]=[CH:22][N:23]=[C:19]3[N:18]=[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:16]=2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCCCCc1c(-c2ccccc2)nc2ncnn2c1Cl
Reactant: NC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1c(-c2ccccc2)nc2ncnn2c1NC1CCCC1
Yield: 86.7 %

Procedure:
With stirring, a mixture of 0.13 g (1.5 mmol) of cyclopentylamine and 0.15 g (1.5 mmol) of triethylamine in 10 ml of methylene chloride was added to a mixture of 0.52 g (1.5 mmol) of 7-chloro-6-octyl-5-phenyl-[1,2,4]-triazolo-[1,5-α]-pyrimidine (cf. Ex. 8) in 20 ml of methylene chloride. The reaction mixture was stirred at room temperature for 16 h, work-up was carried out analogously to Ex. 3. This gave 0.52 g (1.3 mmol) of the title compound (melting point 81° C.).
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].I[C:55]1[CH:60]=[CH:59][C:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[C:57]([CH3:68])[CH:56]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][C:24]([CH3:52])([CH3:23])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:55]1[CH:60]=[CH:59][C:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)=[C:57]([CH3:68])[CH:56]=1)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Reactant: Cc1cc(I)ccc1Oc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1Oc1ccccc1
Yield: 81.6 %

Procedure:
A mixture of palladium acetate (20 mg, 0.08 mmol) and tri-(2-methylphenyl)phosphine (50 mg, 0.16 mmol) was added to a stirred solution of tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (Preparation 2)(578 mg, 1.23 mmol), 1-iodo-3-methyl-4-phenoxybenzene (Preparation 11)(384 mg, 1.35 mmol), and triethylamine (300 μL, 2.14 mmol) in anhydrous acetonitrile (3 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 24 h. After being cooled, the mixture was poured into ethyl acetate (100 mL) and washed with saturated aqueous sodium chloride (2×50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with hexane:ethyl acetate=9:1 and then 4:1) to give mainly tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-({ [(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-(3-methyl-4-phenoxyphenyl)hex-5-enoate as an orange foam (615 mg). 1H nmr suggested that two alkene isomers, the (5Z) and (4E), together with the alkene starting material (10%) were also present. The mixture of alkenes was taken onto the next step (see b, below).