Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.BrC1NC2C=CC=CC=2N=1.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:6]=2[CH:11]=1
Reactant: Cc1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: Brc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A mixture of 6-bromo-2-methyl-4-nitro-1H-benzo[d]imidazole, prepared as described in Example 1 (22 g), (bromomethyl)benzene (15 g) and K2CO3 (35 g) in DMF (250 mL) was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was then poured into water. It was then filtered to afford a solid and the solid was washed with water and then dried in-vacuo to afford the desired product (28 g, 93%). 1H NMR (300 MHz, DMSO-d6): δ ppm 2.60 (s, 3H), 5.62 (s, 2H), 7.12-7.15 (m, 2H), 7.29-7.39 (m, 3H), 8.12 (d, 1H, J=1.8 Hz), 8.32 (d, 1H, J=1.8 Hz); LC-MS: m/e=346 [M+1]+.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH3:24])[C:13]3[C:18]([S:19][C:20]=2[CH:21]=1)=[CH:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=3.[CH:25](N1CCCCC1)=[O:26].Cl>C(OCC)C.O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH3:24])[C:13]3[C:18]([S:19][C:20]=2[C:21]=1[CH:25]=[O:26])=[CH:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=3
Reactant: COc1ccc2c(c1)Sc1cc(OC)ccc1N2C
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)Sc1c(ccc(OC)c1C=O)N2C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 179.9 %

Procedure:
16.25 ml of n-butyllithium solution (1.6M in hexane) were added dropwise at -78° under argon to a solution of 5.46 g (10.0 mmol) of 3,7-dimethoxy-10-methylphenothiazine in 100 ml of diethyl ether/tetrahydrofuran (4:1). The reaction mixture was stirred at -70° for 15 minutes, brought slowly to 0°, stirred for 2 hours and then treated at 0° with 3.39 g (30.0 mmol) of N-formylpiperidine. After stirring at 0° for 2 hours the mixture was poured into 500 ml of ice-water, whereupon it was acidified slightly with 0.5N hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases were extracted with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was crystallized from acetone, whereupon, after drying, 5.42 g (90%) of 3,7-dimethoxy-10-methyl-phenothiazine-4-carbaldehyde were obtained as a red solid of m.p. 150°.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl.[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22](Cl)=[O:23])[CH:17]=1>C1COCC1.CCOC(C)=O>[Cl:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:23])[CH:17]=1
Reactant: NC1CC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 116 %

Procedure:
A 0° C. solution of cyclopropylamine (0.645 g, 11.30 mmol) and DIEA (1.973 mL, 11.30 mmol) in THF (15 mL) was treated with 4-chloropicolinoyl chloride hydrochloride (0.8 g, 3.77 mmol) in one portion, stirred at RT for 2 h, diluted with EtOAc and washed with satd. NaHCO3, then brine. The organic layer was dried over Na2SO4 and concentrated to dryness to afford 4-chloro-N-cyclopropylpicolinamide (0.86 g, 116%). 1H NMR (400 MHz, DMSO-d6): δ 8.83 (d, J=5.0 Hz, 1H), 8.58 (d, J=5.3 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 7.74 (dd, J=5.3, 2.2 Hz, 1H), 2.89-2.88 (m, 1H), 0.68-0.66 (m, 4H); MS (ESI) m/z: 197.1 (M+H+).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:26][CH3:27])[C:10]1=[O:28])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:26]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:28])[CH3:27]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)cc21
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 99.2 %

Procedure:
Five percent Pd/BaSO4 (60 mg) was added to a solution of 3-benzyloxy-1-ethyl-6-fluoro-7-pyrrolidinyl-1H-quinazoline-2,4-dione (Example E, 0.21 g, 0.55 mmol) in 16 mL of THF. The mixture was shaken under 50 PSI of hydrogen for 31 hours, filtered, and concentrated to afford 0.16 g of a solid. This solid was dissolved in 1N sodium hydroxide and washed with chloroform. The chloroform layer was back extracted with sodium hydroxide, and the combined basic extracts were acidified to pH 3. The aqueous layer was extracted with chloroform, dried over magnesium sulfate, and concentrated to give 0.11 g of the title compound as a solid, mp 170-171 ° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][C:7]([NH:9][C@H:10]([C:17]([OH:19])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1)=[O:8])[C:2]([NH2:4])=[NH:3].C(SC(=N)N)C.[OH:26]S(O)(=O)=O.NCCC(N[C@H](C(O)=O)CC1N=CNC=1)=O>O>[NH:1]([CH2:5][CH2:6][C:7]([OH:8])=[O:26])[C:2]([NH2:4])=[NH:3].[NH2:9][C@H:10]([C:17]([OH:19])=[O:18])[CH2:11][C:12]1[N:16]=[CH:15][NH:14][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: N=C(N)NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CCSC(=N)N
Agent: NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Solvent: O
Product: N=C(N)NCCC(=O)O
Product: N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
To prepare beta-guanidinopropionyl-L-histidine.H2O, (n=2) S-ethylisothiourea.H2SO4 (5.0 g) and βAla-His (5.3 g) were reacted by the procedure described in Example 1: yield, 38.8%; mp, 121°-124° C., decomp. Hydrolysis as described in Example 1 gave beta-guanidinopropionic acid and histidine tlc.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH3:14].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>C1COCC1>[C:41]([O:40][C:38](=[O:39])[CH2:37][CH:17]([C:16]([O:15][CH2:13][CH3:14])=[O:35])[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)CCCOc1ccc(-c2ccc(C#N)cc2)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(CCOc1ccc(-c2ccc(C#N)cc2)cc1)CC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
To a -78° C. solution in THF (100 mL) of diisopropylamine (0.94 mL, 7.15 mmol) was added n-butyllithium (25M in hexanes, 2.86 mL, 7. 15 mmol) and the mixture was stirred for 15 minutes. A solution in THF (25 mL) of 4-[4-(4-cyanophenyl)phenoxy]butanoic acid ethyl ester (2.01 g, 6.5 mmol), prepared as in step 1, was added dropwise and the reaction mixture was stirred for 15 minutes. Neat t-butyl bromoacetate (1.03 mL, 6.8 mmol) was added rapidly and the reaction mixture was stirred at -78° C. for 2 hours, then for 0.5 hours at ambient temperature. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted twice with ethyl ether. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Successive chromatographies on silica gel (dichloromethane, then 1:3 ethyl acetate-hexanes) gave 3-carboethoxy-5-[4(4-cyanophenyl)phenoxy]pentanoic acid tert-butyl ester (0.91 g, 33%).
Reaction SMILES: CCN(C1C=C[C:9]2[CH:12]=[C:13](/[CH:17]=[N:18]\[NH:19][C:20]3[N:25]=CC=CC=3)C([O:16][C:8]=2C=1)=O)CC.[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:34])=O)[CH:27]=1.FC1C=CC=CC=1C1[O:52]C(C(Cl)=O)=CC=1>>[O:16]1[CH:8]=[CH:9][CH:12]=[C:13]1[C:17]1[O:52][C:20]([NH:25][C:32]([C:28]2[CH:27]=[C:26]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:34])=[N:19][N:18]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CCN(CC)c1ccc2cc(/C=N\Nc3ccccn3)c(=O)oc2c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2F)o1
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cccc(-c2ccccc2)c1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ic-2 described below, using an acid chloride which can be prepared from commercially available 3-biphenylcarboxylic acid by a routine method instead of 5-(2-fluorophenyl)-2-furancarbonyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:58][CH2:59][C:60]1[C:61](=[O:68])[NH:62][C:63]([CH3:67])=[CH:64][C:65]=1[CH3:66]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH2:14][C:15]([F:16])([F:17])[F:18])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:58][CH2:59][C:60]1[C:61](=[O:68])[NH:62][C:63]([CH3:67])=[CH:64][C:65]=1[CH3:66])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(N(CC(F)(F)F)C2CCOCC2)c1C
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(CC(F)(F)F)C3CCOCC3)c2C)c(=O)[nH]1
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
A stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzoate (250 mg, 0.63 mmol) in dry DMF (3.0 ml) at 0° C. under a balloon of nitrogen, was treated with HATU (288 mg, 0.76 mmol) and DIPEA (220 μl, 1.3 mmol) dropwise. The resulting solution was stirred for 5 minutes and then treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 119 mg, 0.69 mmol). The resulting suspension was stirred at 0° C. for 20 minutes and then stirred at room temperature for 16.5 hours. The reaction mixture was treated with 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (30 mg). Stirring was continued for further 23 hours and the reaction mixture was then partitioned between water (30 ml) and CH2Cl2 (20 ml). The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×20 ml). The combined organics were washed with a saturated solution of NaHCO3 (aq) (50 ml), water (60 ml), brine (2×40 ml), dried over MgSO4, filtered and concentrated in-vacuo. The crude residue was purified by flash column chromatography (10 g SNAP cartridge, Isolera, 0-10% MeOH/CH2Cl2) and triturated from ether (10 ml) with sonication. The resulting precipitate was collected by filtration and dried in-vacuo to give the title compound (249 mg, 74%) as a white solid. LC-MS 100%, 4.08 min (7 minute LC-MS method), m/z=530.0, 531.0, 532.0, 533.0; 1H NMR (500 MHz, Acetone) δ 10.67 (s, 1H), 7.55 (d, J=1.8 Hz, 2H), 7.27 (d, J=1.9 Hz, 1H), 5.90 (s, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.90 (dd, J=11.2, 4.6 Hz, 4H), 3.28 (t, J=11.6 Hz, 2H), 3.07-2.97 (m, 1H), 2.32 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H), 1.76 (dd, J=12.3, 1.6 Hz, 2H), 1.61 (qd, J=12.0, 4.5 Hz, 2H).
Reaction SMILES: I.[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8][C:7]1=[NH:15])[CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:32]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[CH2:2]([N:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[S:8]/[C:7]/1=[N:15]\[C:29](=[O:30])[C:28]1[CH:32]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=1[O:33][CH3:34])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1cc(C(C)(C)C)sc1=N
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 6A (1.4 g, ˜4 mmol) and triethylamine (1.4 mL, 10 mmol) in CH2Cl2 (35 mL) at 0° C. was added 5-chloro-2-methoxy-benzoyl chloride (820 mg, 4 mmol), the mixture was allowed to warm to room temperature was stirred for 14 hours. The mixture was washed sequentially with water, brine, dried with anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography (6:2:2 Hexane-EtOAc-CH2Cl2) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 0.94 (t, J=7 Hz, 3H), 1.30 (m+s, 11H), 1.75 (m, 2H), 3.77 (s, 3H), 4.14 (t, J=7 Hz, 2H), 7.10 (d, J=9 Hz, 1H), 7.31 (s, 1H), 7.43 (d-d, J=9 Hz, 3 Hz, 1H), 7.65 (d, J=3 Hz, 1H); MS (ESI+) m/z 381 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:17][CH:1]3[C:10]4[C:5]([CH:4]=[CH:3][N:2]3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]2=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:14][CH:13]=1
Reactant: c1ccc2cnccc2c1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1ccc(Cl)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc(C2OC3c4ccccc4C=CN3c3ccccc32)cc1
Yield: 81 %

Procedure:
Following the general procedure, treatment of isoquinoline (0.064 g, 59 μL, 0.50 mmol) and 4-chlorobenzaldehyde (0.105 g, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoro-methane sulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=93/07) of the crude reaction mixture afforded 6-(4-chlorophenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline as inseparable mixture of diastereomers as a yellow solid (0.140 g, 81% yield, dr determined by 1H NMR analysis of crude reaction mixture is 3:2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][N+:3]=1[O-:12].[CH3:13][NH2:14].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:14][CH3:13])=[CH:4][N+:3]=1[O-:12]
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])cc1F
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNc1c[n+]([O-])c(Br)cc1[N+](=O)[O-]

Procedure:
2-Bromo-5-fluoro-4-nitropyridine 1-oxide (11.2 g, 47 mmol) and 2 N methylamine (solution in THF) (48 mL, 96 mmol) in 150 mL THF was stirred for 5 min at ambient temperature. Water was poured into the mixture and THF was removed i.vac. The solid was filtered, washed with water and dried at 50° C. i. vac.
Reaction SMILES: C(O)=[O:2].[CH:4]1([N:10]=[C:11]=[N:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([NH:10][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of formic acid (0.504 mL, 13.36 mmol) in chloroform (37 mL) was added dropwise dicyclohexylcarbodiimide (DCC) (2.75 g, 13.36 mmol) in chloroform (37 mL) at 0° C. After 5 min., the above solution was added to the compound 9 (2.5 g, 6.68 mmol) in pyridine (20 mL). The mixture was then stirred for 1 hours at room temperature. Evaporation of solvent was followed by addition of ether gave dicyclohexylurea which was removed via filtration and the solid was washed with ether. The combined filtrate was concentrated and purified by flash column chromatography to give the compound 11, R1 =C5H11 (EM-401) (2.5 g, 93%) The NMR spectroscopy analysis gave a (4:1) mixture of two conformers, M.P. 149°-151° C.; 1H NMR (CDCl3): δ 0.67 (s ,3H), 0.86 (s, 3H), 0.82-1.19 (m, 6H), 1.21-1.42 (m, 11H), 1.56-1.57 (m, 2H), 1.69-1.91 (m, 4H), 1.92-1.97 (m, 3H), 2.38-2.43 (m, 2H), 2.89 (s, 3H ), 3.0 (dd, 1H, J=3.2, 12.4 Hz), 3.21-3.28 (m, 3H), 8.14 (s, 0.8H), 8.2 (s, 0.2H); 13C NMR (CDCl3):δ 170 .56, 164.8, 162.97, 68.54, 65.58, 61.98, 51.93, 51.66, 51.24, 46.69, 44.28, 37.24, 36.8, 36.37, 34.07, 32.83, 32.12, 29.64, 29.13, 29.04, 28.8, 28.19, 25.15, 24.33, 23.22, 22.84, 22.36, 20.51, 13.94, 12.75, 12.32;HRMS: calcd for C25H42O2N2, 402.3245, found 402.3242.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:21])=[C:13]([CH3:20])[C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:15]1[C:14]2[C:13]([CH3:20])=[C:12]([CH3:21])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: N#Cc1ccncc1
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C

Procedure:
With the procedure of Example 477, the reaction of 4-cyanopyridine and 2-amino-4,5-dimethyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:16]([F:19])([F:18])[F:17])[C:3]=1[NH2:4].[N+:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([O-:22])=[O:21].O.C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[C:7]([C:9]([F:14])([F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:16]([F:17])([F:18])[F:19])[C:3]=1[NH:4][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=1
Reactant: Nc1c(Br)cc(C(F)(F)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1c(Br)cc(C(F)(F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 5.7 %

Procedure:
To a solution of 2.50 g (6.99 mmol) of 2-bromo-4-(perfluoroethyl)-6-(trifluoromethyl)aniline in 20 ml of pyridine was added 2.72 g (14.7 mmol) of 3-nitrobenzoyl chloride, followed by stirring at 100° C. for 12 hours. To the reaction liquid were added water and ethyl acetate, followed by extraction with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. To the obtained residue were added THF and an aqueous sodium hydroxide solution, followed by stirring at room temperature for 8 hours. The reaction liquid was extracted/dried in the same manner as described above, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=7:1→5:1) to prepare 0.202 g (yield 6%) of a target compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17](Br)[C:11]=2[N:10]([CH3:31])[C:9]1=[O:32])(=[O:3])[CH3:2].[CH3:33][Sn](C)(C)C>CN(C=O)C.CC(=O)OCC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH3:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[C:17]([CH3:33])[C:11]=2[N:10]([CH3:31])[C:9]1=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2c(c(Br)c(-c3cccc(OC(F)(F)F)c3)n2C)n(C)c1=O
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCn1c(=O)c2c(c(C)c(-c3cccc(OC(F)(F)F)c3)n2C)n(C)c1=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To a solution of 3-(7-bromo-1,5-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (25 mg, 0.05 mmol) in DMF (1 mL) was added tetramethylstannane (26.7 mg, 0.15 mmol) and Pd(PPh3)2Cl2 (5 mg). The reaction was heated at 120° C. (MW) for 45 min, cooled to RT then diluted with EA (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 3-(1,5,7-trimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (20 mg, 91.8% yield) as an oil. LCMS: MH+ 454 and TR=1.625 min. Used without further purification.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([O:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCCl.C(Cl)Cl>[C:1]1([N:7]2[C:11]([NH:12][C:20](=[O:21])[O:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccnn1-c1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1ccnn1-c1ccccc1)Oc1ccccc1
Reaction time: 1 h

Procedure:
1-Phenyl-1H-pyrazol-5-amine (1 eq) was dissolved in DCE (0.1M), phenylchloroformate (1.1 eq) was added. The reaction was stirred 1 h, then diluted with DCM and washed with water and brine, dried and concentrated under reduced pressure to afford the product in quantitave yield.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[F:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:43][CH:44]2[CH2:53][CH2:52][C:51]3[C:50]([CH2:54][CH2:55][C:56]([O:58]C)=[O:57])=[CH:49][C:48]([CH2:60][CH2:61]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:47][C:46]=3[CH2:45]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1>CN(C=O)C>[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:43][CH:44]2[CH2:53][CH2:52][C:51]3[C:50]([CH2:54][CH2:55][C:56]([OH:58])=[O:57])=[CH:49][C:48]([CH2:60][CH2:61][N:22]4[CH2:23][CH2:24][CH:19]([C:17](=[O:18])[C:16]5[CH:15]=[CH:14][C:13]([F:12])=[CH:26][CH:25]=5)[CH2:20][CH2:21]4)=[CH:47][C:46]=3[CH2:45]2)(=[O:42])=[O:41])=[CH:38][CH:39]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: COC(=O)CCc1cc(CCOS(=O)(=O)c2ccc(C)cc2)cc2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1cc(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)cc2c1CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2

Procedure:
6.5 g (17.3 mmol) of 4-(4-fluorobenzoyl)piperidine tosylate and 2.4 g (17.3 mmol) of potassium carbonate are added to a solution of 3.5 g (5.7 mmol) of methyl 3-[6-{[(4-chlorophenyl)sulphonyl]amino}-3-(2-{[(4-methylphenyl)sulphonyl]oxy}ethyl)-5,6,7,8-tetrahydro-1-naphthyl]propanoate, described in Application EP 864 561, in 100 ml of DMF. The reaction mixture is heated at reflux for one hour, then concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried and concentrated and then purified by chromatography on silica gel, using as eluant a dichloromethane/methanol/ammonia mixture (98/2/0.2), to yield the expected compound.