Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[O:15])[CH3:14])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][Mg]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1.O>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])([CH3:17])[CH3:14])[N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Mg]Br
Reactant: CC(=O)c1csc(NC(=O)OC(C)(C)C)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1nc(C(C)(C)O)cs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
(4-Acetyl-thiazol-2-yl)-carbamic acid tert-butyl ester (500 mg, 2.06 mmol) was taken in to dry tetrahydrofuran (8 mL) and cooled in an ice bath. To this was added a 3 M solution of methyl magnesium bromide (2.752 mL, 8.256 mmol) in diethyl ether over 5 minutes. After 30 minutes, more 3 M solution of methyl magnesium bromide (1 mL, 3 mmol) in diethyl ether was added. After 30 minutes, an additional aliquot of 3 M methyl magnesium bromide (1 mL, 3 mmol) in diethyl ether was added. No further change in the reaction mixture composition was observed after an additional 30 minutes. The reaction mixture was diluted with tetrahydrofuran (5 mL) and allowed to warm to room temperature. After 2 hours thin layer chromatography indicated no change in the composition of the reaction mixture. The reaction mixture was cooled in an ice bath and saturated aqueous ammonium chloride was added slowly. The mixture was diluted with water, extracted with ethyl acetate and washed with brine. The combined organic extracts were dried over sodium sulfate and concentrated to give a viscous oil. The crude product was purified by chromatography over silica gel gradient eluted from 1:19 upto 1:4 ethyl acetate/dichloromethane to give [4-(1-hydroxy-1-methyl-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester as a white foam (250 mg, 47%).
Reaction SMILES: C(Cl)(=[O:8])C1C=CC=CC=1.[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH3:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10].[C:21]1([OH:8])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCCCCCCCCCCC
Product: Oc1ccccc1
Temperature: 210 °C
Reaction time: 2.5 h
Yield: 27680 %

Procedure:
4,4′-methylene diphenyl dicarbamate (38 g, 86.8 mmole) and inhibitor benzoyl chloride (0.09 g, 0.6 mmole) were charged to 500 ml three-neck bottle with solvent n-dodecane (250 ml, 189.19 g). The mixture was stirred with a magnetic stirbar and heated to 210° C. with an oil bath. One neck of the bottle was equipped with a thermometer and charged with nitrogen, and another neck was connected to a divide tube which was further connected to a condenser to charge with cold water. The upper end of the condenser was connected to a grease seal. The reaction was carried out for 2.5 hours. The progress of the reaction was monitored by FT-IR. It was observed that the absorption peak at 1720 cm−1 and the absorption peak at 3335 cm−1 disappeared completely, and the absorption peak appeared at 2270 cm−1. After part of n-dodecane (100 ml) and produced phenol (15.63 g) was retrieved from the divide tube, the heating was stopped and the reaction ended.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[N:4](COCC[Si](C)(C)C)[C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]([CH3:31])[CH3:30])[CH:21]=1.ClC1C2C(=O)NN=CC=2N(COCC[Si](C)(C)C)C=1C1C=CC(OC(F)F)=C(OC(C)C)C=1>>[Cl:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[NH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH:29]([CH3:31])[CH3:30])[CH:21]=1
Reactant: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC(C)C
Agent: CC(C)Oc1cc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)ccc1OC(F)F
Product: COc1ccc(-c2[nH]c3cn[nH]c(=O)c3c2Cl)cc1OC(C)C
Yield: 74.8 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 40-(b) except for using 305 mg (0.657 mmol) of 3-chloro-2-(3-isopropoxy-4-methoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 48-(a) in place of 3-chloro-2-(4-difluoromethoxy-3-isopropoxyphenyl)-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 164 mg of the title compound was obtained as a white solid. (Yield: 75%)
Reaction SMILES: C([O:3][C:4](=O)[C@:5]([O:11][CH2:12][C:13]([C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([Br:35])[N:29]=1)([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.CO.[NH3:39]>>[Br:35][C:30]1[N:29]=[C:28]([C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:9])([F:8])[F:7])[C:4]([NH2:39])=[O:3])[C:33]([F:34])=[CH:32][CH:31]=1
Reactant: N
Reactant: CCOC(=O)[C@@](C)(OCC(C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1nc(Br)ccc1F)C(F)(F)F
Solvent: CO
Product: CC(CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1nc(Br)ccc1F
Yield: 73 %

Procedure:
A solution of (R)-2-[2-(6-bromo-3-fluoro-pyridin-2-yl)-2-(2-nitro-benzenesulfonylamino)-propoxy]3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (720 mg, 1.195 mmol) in NH3 7N in methanol (19 ml, 133 mmol) was stirred at 50° C. for 2 days in a sealed 25 ml microwave vial. The solvent was removed in vacuo and the residue (987 mg) was chromatographed over silica gel (cyclohexane/ethyl acetate) affording the title compound as a mixture of two diastereoisomers (500 mg, 73% yield). TLC (cyclohexane/ethyl acetate 1:1) Rf=0.30; LC-MS RtH5=1.05 min (ES+573, 575).
Reaction SMILES: [CH2:1]([C@@H:4]1[C@H:10]2[C@H:8]([O:9]2)[CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[CH2:5]1)[CH:2]=[CH2:3].[N-:15]=[N+:16]=[N-:17].[Na+].[NH4+].[Cl-]>CO.O>[CH2:1]([C@H:4]1[CH2:5][C:6]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C@H:8]([N:15]=[N+:16]=[N-:17])[C@H:10]1[OH:9])[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CC[C@H]1CC(C(=O)OC)=C[C@H]2O[C@@H]12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=CC[C@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1O

Procedure:
A solution of Example 1I, sodium azide (2.8 g, 43.1 mmol) and NH4Cl (1.0 g, 18.8 mL) in methanol (30 mL) and H2O (10 mL) was refluxed for 5 hours, diluted with H2O and extracted with ethyl acetate. The combined ethyl acetate layers were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (1/1) to afford 1.4 g (67% over steps I and J) of the desired product as a colorless oil.
Reaction SMILES: O1C[CH2:4][CH2:3][CH2:2]1.[C:6]1([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrCCC[N:44]1[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]2[C:45]1=[O:54]>C(OCC)(=O)C>[C:12]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:19]=[CH:18][C:15]([CH:16]=[CH:2][CH2:3][CH2:4][C:52]2[CH:53]=[C:46]3[C:45](=[O:54])[NH:44][C:48](=[O:49])[C:47]3=[CH:50][CH:51]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C1CCOC1
Agent: [Br-]
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: O=C1NC(=O)c2cc(CCC=Cc3ccc(-c4ccccc4)cc3)ccc21
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A suspension of 150 ml of tetrahydrofuran, 5.46 g of 4-phenylbenzaldehyde and 15.9 g of N-(3-bromopropyl)-phthalimide triphenyl phosphonium bromide was cooled to -40° C. and 3.37 g of potassium terbutylate was then introduced. The temperature was allowed to rise to -15° C. and the mixture was stirred at -15° C. for one hour. The mixture was poured over ice and extraction was carried out with ethyl acetate. The extracts were washed with water and the organic phases were dried over Na2SO4, filtered and concentrated to obtain 19 g of product which was dissolved in methylene chloride. Chromatography on silica was carried out, eluting with an ethyl acetate - hexane mixture (3-7) and the residue was concentrated, impasted in hexane, followed by separation and drying under reduced pressure to obtain 8.5 g of the desired product melting at approximately 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([OH:21])=O)[C:4]=12.Cl.[C:24]1([N:30]2[C:34]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:33][N:32]=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)=[C:5]2[NH:15][CH:16]=[C:17]([C:18](=[O:22])[C:19]([N:38]3[CH2:39][CH2:40][N:35]([C:34]4[N:30]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:31]=[N:32][N:33]=4)[CH2:36][CH2:37]3)=[O:21])[C:4]=12
Reactant: c1ccc(-n2nnnc2N2CCNCC2)cc1
Reactant: COc1cnc(-c2cncnc2)c2[nH]cc(C(=O)C(=O)O)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cnc(-c2cncnc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.2 %

Procedure:
To a suspension of 2-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (50 mg, 0.168 mmol), 1-(1-phenyl-1H-tetrazol-5-yl)piperazine hydrochloride (40.2 mg, 0.151 mmol) and 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (59.2 mg, 0.184 mmol) in DMF (1 ml) was added N,N-Diisopropylethylamine (0.146 ml, 0.838 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with 150 ml of CH2Cl2 and washed with 5% NaHCO3 (30 ml), brine (30 ml). The organic layer was dried over Na2SO4 and concentrated to give a residue, which was purified by prep. HPLC to give 1-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (10 mg, 0.020 mmol, 11.68% yield) (light tan solid). LCMS: m/e 511.4 (M+H)+, ret time 1.25 min. 1H NMR (500 MHz, MeOD) δ ppm 9.30 (s, 1H) 9.17 (s, 2H) 8.38 (s, 1H) 8.16 (s, 1H) 7.58-7.65 (m, 5H) 4.09 (s, 3H) 3.80-3.83 (m, 2H) 3.57-3.60 (m, 2H) 3.38-3.42 (m, 2H) 3.31-3.33 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[NH2:15][C:16]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][C:17]=1[OH:23].O1CCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:15][C:16]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][C:17]=1[OH:23])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Nc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.6 %

Procedure:
6 g (30 mmol) of 1-chloro-2,6-dinitrobenzene and 4.8 g (30 mmol) of 4-aminoresorcinol hydrochloride were added to 300 ml of a mixture of tetrahydrofuran with dimethylformamide (1:1). After adding 7.8 g (60 mmol) of N,N-diisopropylethylamine thereto, the obtained mixture was stirred at room temperature for 24 hours. Then the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium chloride. Then it was dried over magnesium sulfate and concentrated and the residue was purified by silica gel column chromatography. Thus 6.95 g of 4-((2,6-dinitrophenyl)amino)resorcinol was obtained. This product was dissolved in 125 ml of dimethylformamide and 25 ml of N,N-diisopropylethylamine was added thereto. After heating at 100° C. for 2 hours, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and concentrated to dryness. Thus 5.4 g of the title compound was obtained.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:18]([OH:20])=O)[CH2:13][CH2:14][C:15]([OH:17])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=N[C:31]2[CH:32]=[CH:33][CH:34]=[N:35][C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)[CH:48]([CH3:50])[CH3:49]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:4]([O:3][C:1]([NH:11][CH:12]1[CH2:13][CH2:14][C:15](=[O:17])[N:35]([CH:34]([CH2:33][CH:32]2[CH2:31][CH2:30][CH2:50][CH2:48][CH2:49]2)[C:1]([O:3][CH3:4])=[O:2])[C:18]1=[O:20])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCCC1)N1C(=O)CCC(NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of (L) N-Cbz-glutamic acid (5.62 g; 20 mmol) in dry DMF (100 mL) was added HATU (8.36 g; 22 mmol) and DMAP (0.56 g) followed by the dropwise addition of TEA (6 mL; 44 mmol). The reaction mixture was stirred at room temperature for 1 h (solution A). In the meantime, to a solution of (L) cyclohexylalanine-OMe(HCl) (5.32 g; 24 mmol) in dry DMF (30 mL) was added DIEA (9.28 g; 72 mmol) and the reaction mixture was stirred for 15 min (solution B). Solution B was mixed with solution A and stirred overnight at room temperature. The solvent was removed on the rotary evaporator and the residue was taken up in ethyl acetate (300 mL). The organic layer was washed sequentially with saturated sodium bicarbonate (2×100 mL), 5% HCl (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated, yielding a crude product which was purified by flash chromatography (silica gel; hexane/ethyl acetate 75:25) to give 1 as a white solid (2.15 g; 32% yield). 1H NMR (CDCl3): δ 8.0 (s, 1H), 7.32 (m, 5H), 5.04 (m, 2H), 4.62 (m, 1H), 4.0 (m 1H), 3.73 (s, 3H), 2.3 (m, 2H), 2.0 (m, 2H), 1.65 (m, 6H), 1.46 (m, 1H), 1.18 (m, 4H), 0.89 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.Cl[CH2:11][C:12]#[N:13].C(N(CC)CC)C>CCOCC>[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:11][C:12]#[N:13])[CH2:2][CH2:3]1
Reactant: N#CCCl
Reactant: OCCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: N#CCN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.7 %

Procedure:
The title compound was prepared according to general procedure G described in Scheme 3. 2-(Piperidin-4-yl)ethanol (1.2 g, 9.3 mmol) was treated with 2-chloroacetonitrile (1.4 g, 18.6 mmol), triethylamine (10.4 mL, 74.3 mmol) and stirred at RT for 14 h. The crude reaction mixture was diluted with Et2O (25 mL) and washed with H2O (3×10 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a yellow oil (1.56 g, 100%), which was used without further purification.
Reaction SMILES: OP([O-])(O)=O.[K+].O=[CH:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17]O)O)[OH:14])O)O.[NH2:19][C@H:20](C(O)=O)CC(C)C.N[C@H:29]([C:36]([OH:38])=[O:37])[CH2:30]C1N=CNC=1>>[C:20]([C:29](=[CH:30][C:8]1[CH:9]=[CH:11][C:13]([OH:14])=[CH:15][CH:17]=1)[C:36]([OH:38])=[O:37])#[N:19]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Product: N#CC(=Cc1ccc(O)cc1)C(=O)O
Reaction time: 0.33 h

Procedure:
YNB-1 agar: 3.3 g/l KH2PO4, 16.7 g/l agar, pH adjusted to 7. Autoclaved for 20 min. at 121° C. After autoclaving, 25 ml of a 13.6% yeast nitrogen base without amino acids, 25 ml of a 40% glucose solution, 1.55 ml of a 1 % L-leucine solution and 1.55 ml of a 1% histidine solution were added per 450 ml agar.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9]([CH3:11])=[N:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)=[N:6][C:5]=2[S:4][C:3]=1[C:22]([NH2:24])=[O:23].[O:25]=[C:26](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[CH3:11][C:9]1[C:10]2[C:2]3[NH:1][C:26](=[O:25])[NH:24][C:22](=[O:23])[C:3]=3[S:4][C:5]=2[N:6]=[C:7]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=2)[N:8]=1
Reactant: Cc1nc(-c2ccc(OC(C)C)cc2)nc2sc(C(N)=O)c(N)c12
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2ccc(OC(C)C)cc2)nc2sc3c(=O)[nH]c(=O)[nH]c3c12
Temperature: 25 °C
Yield: 72.4 %

Procedure:
1.0 g (3 mmol) 5-amino-4-methyl-2-(4-iso-propoxy-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide was suspended in 200 ml dioxane, and following the addition of 0.73 ml (6 mmol) diphosgene the suspension is refluxed for 2 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was subsequently sucked off. 0.8 g (68%) 9-methyl-7-(4-iso-propoxy-phenyl)-thieno[2,3-d:4,5-d′]-dipyrimidine-2,4(1H,3H)-dione is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C@H:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:25](=O)(ON1C(=O)CCC1=O)[O:26]N1C(=O)CCC1=O.C(N(CC)CC)C>ClC(Cl)C>[OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:25]1=[O:26]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1O)C(C)(C)C
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2O)C1=O)C(C)(C)C
Yield: 67.3 %

Procedure:
A solution of Example 145A (180 mg, 0.521 mmol) and disuccinimidyl carbonate (0.16 g, 0.625 mmol) in dichloroethane (5 mL) was treated with triethylamine (87 μL, 0.625 mmol) at 25° C. for 16 h. The mixture was partitioned between 10% sodium carbonate and dichloromethane. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and the solvents were evaporated to give the crude residue which was purified using silica gel chromatography eluting with a gradient of 100% hexanes to 60% hexanes in ethyl acetate to give the title compound (0.127 g, 67%).
Reaction SMILES: C(O[C:4](=[O:24])[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([O:17][CH3:18])[CH:11]=1)([CH3:9])[CH3:8])C.C([Sn](CCCC)(CCCC)[C:30]([O:32]CC)=[CH2:31])CCC.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CN(C)C=[O:68]>>[C:30]([C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][C:5]([OH:23])([C:19]([F:22])([F:20])[F:21])[C:4]([OH:68])=[O:24])=[CH:11][C:12]=1[O:17][CH3:18])(=[O:32])[CH3:31]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)c(OC)c1)C(F)(F)F
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Product: COc1cc(C(C)(C)CC(O)(C(=O)O)C(F)(F)F)ccc1C(C)=O

Procedure:
Analogously to the compound above of 4-(4-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester, tributyl-1-ethoxyvinyltin, tri-o-tolylphosphine and bis-tri-o-tolylphosphine-palladium(II) chloride in dimethylformamide to 120° C., oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:3]=1.[CH3:37][N:38]1[CH:42]=[C:41]([S:43](Cl)(=[O:45])=[O:44])[N:40]=[CH:39]1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C)C1C=CN=CC=1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:4]1[CH:3]=[C:2]([NH:1][S:43]([C:41]2[N:40]=[CH:39][N:38]([CH3:37])[CH:42]=2)(=[O:45])=[O:44])[CH:11]=[C:10]2[C:5]=1[CH2:6][N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NS(=O)(=O)c4cn(C)cn4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-amino-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (150 mg, 0.278 mmol) (COMPOUND CCC4, STEP A) in 4 mL of THF cooled to 0° C. was added 1-methyl-1H-imidazole-4-sulfonyl chloride (100 mg, 0.556 mmol). A few crystals of 4-(dimethylamino)pyridine and diisopropylethylamine (53.9 mg, 0.417 mmol) were added. The resulting reaction mixture was stirred at 0° C. for 20 min, then heated to 70° C. for ca. 7.5 h. The reaction mixture was cooled to rt and partitioned between ethyl acetate and 1M aqueous HCl (added brine to improve the layer separation). The organic layer was concentrated under reduced pressure and triturated sequentially with Et2O, methanol, and CH2Cl2 to yield the N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methyl-1H-imidazole-4-sulfonamide. Mass spectrum (ESI) 682.0 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>O>[CH3:20][C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=1
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To 2,3-dichloro-5-trifluoromethylpyridine (25 g) were added 1-BOC-piperazine (23.84 g), potassium carbonate (32.08 g), N,N-dimethylformamide (50 mL) and toluene (50 mL), and the mixture was stirred at 100° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (45.71 g). To 4-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (11 g) were added palladium (II) acetate (0.726 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.692 g), potassium fluoride (15.06 g), methylboronic acid (7.88 g) and tetrahydrofuran (300 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g). To 4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (9.14 g) were added 4N hydrogen chloride/ethyl acetate (26 mL) and chloroform (64 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and sodium hydrogen carbonate, and the mixture was extracted with chloroform. The solvent was evaporated to give the title compound (6.38 g).