Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.C([Li])(C)(C)C.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.Cl>O1CCCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: Cn1cccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1cccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution (50 ml) of 1-methylpyrrole (4.44 ml) in tetrahydrofuran was added dropwise t-butyl lithium (1.7 M solution in pentane, 30.0 ml) under an argon atmosphere at −78° C. This mixed solution was heated to room temperature, and a solution (100 ml) of zinc chloride (75.0 g) in tetrahydrofuran was added. This mixture was stirred for 1 hr., and 1-bromo-4-trifluoromethylbenzene (3.50 ml) and tetrakis(triphenylphosphine)palladium (0.722 g) were added. This mixture was stirred overnight under an argon atmosphere, and poured into 0.5 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, volume ratio) to give 1-methyl-2-(4-trifluoromethylphenyl)pyrrole (4.01 g, yield 71%) as a colorless crystalline powder. melting point: 39–40° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]([N:6]([C:13]1[C:18]([C:19](=[O:25])[CH2:20][CH2:21][CH:22]2[CH2:24][CH2:23]2)=[CH:17][CH:16]=[C:15]([CH3:26])[N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.CO.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[C:18]([C:19](=[O:25])[C:20]=1[CH2:21][CH:22]1[CH2:23][CH2:24]1)=[CH:17][CH:16]=[C:15]([CH3:26])[N:14]=2)=[O:27]
Reactant: COC(=O)C(=O)N(c1ccccc1)c1nc(C)ccc1C(=O)CCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1c(CC2CC2)c(=O)c2ccc(C)nc2n1-c1ccccc1
Temperature: 80 °C

Procedure:
To N-[3-(3-cyclopropyl-propionyl)-6-methyl-pyridin-2-yl]-N-phenyl-oxalamic acid methyl ester (˜0.3 g) dissolved in toluene was added MeOH (5 mL) and K2CO3 (0.3 g). The mixture was heated to 80° C. for 30 min, cooled to RT, then taken up in EtOAc and washed 2× with LiCl (0.3 wt %, aq). The product was dried over MgSO4, filtered and concentrated, then purified by prep TLC (1:4 EtOAc/hexane) to provide 3-cyclopropylmethyl-7-methyl-4-oxo-1-phenyl-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (compound 142).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(-c3ccccc3)n2)cc(OC)c1OC
Yield: 36.2 %

Procedure:
Using Method C with 200 mg (0.68 mmol) 2a and 100 mg (0.82 mmol) phenylboronic acid, 83 mg (22.9%) pure title compound were obtained after preparative HPLC (eluent: AcOEt) purification of the whole batch. Reaction time: 20 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 3.64 (s, 3H, CH3O(4′)), 3.83 (s, 6H, CH3O(3′+5′)), 7.26 (s, 2H, Harom(2+6)), 7.51 (m, 3H, Harom 3′+4′+5′), 8.14 (m, 2H, Harom2′+6′), 8.16 (s, 1H, HP5), 8.52 (s, 1H, HP3), 9.58 (s, 1H, NHamine); MS, (C19H19N3O3), m/z: 338 [M++1, 100].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[CH:10]=2)=O)C.[NH3:18]>CO>[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[CH:10]=2)(=[O:3])[NH2:18]
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1
Reactant: N
Solvent: CO
Product: COc1ccc2cc(C(N)=O)cnc2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
3-Ethoxycarbonyl-7-methoxyquinoline (28 g, 120 mmol) was added to a methanol solution saturated with ammonia. The suspension was stirred at ambient temperature in a glass pressure vessel for 2 weeks. The white solid was collected by filtration, washed with methanol and dried under vacuum to give 3-carbamoyl-7-methoxyquinoline (21 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][N:20]([C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([CH3:32])=[CH:24][CH:25]=3)=[O:31])[CH2:21][CH2:22]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a suspension of 5-amino-7-(piperazin-1-yl)-2-(pyridine-3-yl)thiazolo[5,4-d]pyrimidine (150 mg, 0.48 mmol) in dioxane (10 ml) was added 4-tolyl isocyanate (63 μl, 0.5 mmol). The resulting reaction mixture was stirred at room temperature for 30 minutes. The solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/25), yielding the pure title compound as a yellowish solid (170 mg, 79%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[O:9])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH:18]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[OH:27])([CH3:20])[CH3:19]>O>[CH:18]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]1[O:27][C:8](=[O:9])[NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=1)([CH3:20])[CH3:19]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CC(C)C1CCCCC1O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)OC2CCCCC2C(C)C)cc1
Yield: 56.8 %

Procedure:
75.6 g (0.56 mol) of para-tolylisocyanate were placed with 500 ml toluene in a one litre vessel and subsequently 73.4 g (0.51 mol) of 2-isopropylcyclohexanol were added. The reaction mixture was heated to reflux for 6 hours. After cooling to room temperature 50 g of water were added and the mixture was refluxed for one more hour. After phase separation the solvent was stripped off and the crude product recrystallized from 235 g of n-heptane. The product (79.8 g) was obtained in form of off-white crystals in 99.2% purity. This corresponds to a theoretical yield of 56%.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17]CC2C=CC=CC=2)=[C:12]([CH2:25][CH3:26])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:25]([C:12]1[CH:11]=[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:15]=[C:14]([CH3:16])[C:13]=1[OH:17])[CH3:26]
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(OC(=O)c2ccccc2)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
Then, 8.4 g of crude 4-benzyloxy-3-ethyl-5-methylphenyl benzoate was dissolved in 100 ml of ethyl acetate, and the solution was put in a reaction vessel. The air in the reaction vessel was replaced with nitrogen gas. To the vessel was added 0.5 g of 10% palladium on carbon, and the nitrogen gas in the vessel was replaced with hydrogen gas, followed by vigorous stirring at room temperature for 24 hours. The hydrogen gas in the vessel was replaced with nitrogen gas, and the reaction mixture was filtered through cerite. The filtrate was concentrated under reduced pressure, which afforded 5.9 g of 2-ethyl-6-methyl-4-benzoyloxyphenol (yield, 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:26])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[N:61]1([CH2:67][C:68](O)=[O:69])[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:68](=[O:69])[CH2:67][N:61]2[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]2)=[C:21]([CH3:26])[CH:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)CN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(N(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)ccc1NC(=O)CN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0 %

Procedure:
To a solution of (4-amino-3-methylphenyl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (15.2 mg, 40 mol) in DMF (100 μL) was added a solution of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 27.4 mg, 72 mol) in DMF (100 μL), followed by i-Pr2NEt (25 μL, 144 mol) and piperidin-1-yl-acetic acid (8.6 mg, 60 mol). The resulting mixture was shaken at room temperature for 3 hours after which it was diluted with ethyl acetate (10 mL), washed with saturated aqueous ammonium chloride (2×10 mL), dried over sodium sulfate, and evaporated. The residue was purified on a FlashMaster system (silica, eluted with heptane/ethyl acetate mixtures) to yield [3-methyl-4-(2-piperidin-1-yl-acetylamino)-phenyl]-(4-trifluoromethylbenzyl)-carbamic acid tert-butyl ester as a white solid (10.7 mg, 53%). This was dissolved in dichloromethane (200 μL) and trifluoroacetic acid (200 μL), and the solution was kept at room temperature for 30 minutes, after which volatiles were evaporated and the residue was dried in vacuo at 0.1 mmHg and +40° C. for 1 hour. The resulting trifluoroacetic acid addition salt of the title compound was obtained as a yellow semisolid in quantitative yield.
Reaction SMILES: C(N(CC)CC)C.C(O)=O.C([O:14][C:15]([C:17]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1)([CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])C(OCC=C)=O)=[O:16])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH:17]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=1)[C:15]([OH:16])=[O:14])[CH3:32]
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CCOC(=O)CCCCC(Cc1ccc(C#N)cc1)C(=O)O
Temperature: 10 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of 24.21 ml (173.69 mmol) of triethylamine and 4.96 ml (131.58 mmol) of formic acid in 500 ml of dioxane is added to a solution of 22.5 g (52.63 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonyl-2-(4-cyanobenzyl)-heptanedioate from Example 108A, 970 mg (3.68 mmol) of triphenylphosphine and 240 mg (1.05 mmol) of palladium acetate in 500 ml of dioxane at room temperature. The reaction mixture is then stirred at 10° C. for 2 hours. After conversion is complete, the reaction solution is cooled, and the solvent is removed in vacuo. The residue is then taken up in ethyl acetate and water and acidified with 1 N hydrochloric acid, and the organic phase is separated off. The aqueous phase is extracted three times more with ethyl acetate, and the organic phases are then combined, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solution is concentrated in vacuo. 17.5 g (87% yield, 80% purity) of a colorless solid are obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][C@H:25]2[CH2:29][CH2:28][O:27][CH2:26]2)[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].Br[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]2.CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.[Cu]I>[CH3:20][C:17]1[N:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:10]2[CH:21]=[C:22]([O:24][C@H:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[CH:23]=[C:8]([O:7][C:31]3[CH:32]=[C:33]4[C:38](=[CH:39][CH:40]=3)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]4)[CH:9]=2)=[N:15][CH:16]=1
Reactant: O=C1NCCc2cc(Br)ccc21
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)cn1
Agent: [Cu]I
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc4c(c3)CCNC4=O)cc(O[C@H]3CCOC3)c2)cn1
Temperature: 160 °C

Procedure:
Cesium carbonate (812 mg, 2.50 mmol) was added to a solution of 3-hydroxy-N-(5-methylpyrazin-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (262 mg, 0.83 mmol), 6-bromo-3,4-dihydro-2H-isoquinolin-1-one (226 mg, 1.0 mmol), copper (I) iodide (158 mg, 0.83 mmol) and 2,2,6,6 tetramethyl-3,5-heptanedione (0.7 mL, 3.3 mmol) in NMP (9 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 8 hours. The reaction mixture was filtered through diatomaceous earth and the filter pad washed thoroughly with DCM and methanol. The filtrate was concentrated in vacuo, water (20 mL) was added to the residue and the mixture extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with water (2×10 mL), brine (20 mL), dried (MgSO4) and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound a white solid (190 mg). 1H NMR δ (CDCl3): 2.17 (1H, m), 2.22-2.29 (1H, m), 2.56 (3H, s), 2.94-3.02 (2H, m), 3.49-3.59 (2H, m), 3.90-4.01 (4H, m), 5.00 (1H, s), 6.01 (1H, s), 6.77-6.80 (1H, m), 6.83 (1H, s), 6.96 (1H, d), 7.16 (1H, s), 7.26 (1H, d), 8.06 (1H, d), 8.15 (1H, s), 8.49 (1H, s), 9.54 (1H, s); m/z 461 (M+H)+, 459 (M−H)−
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12](C(OC(C)(C)C)=O)[CH:13]=2)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:29]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[C:31]([CH3:38])[CH:30]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:38][C:31]1[CH:30]=[C:29]([C:9]2[CH:13]=[N:12][NH:11][CH:10]=2)[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2cn[nH]c2)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (8.17 g, 27.8 mmol), tetrakis(triphenylphosphine)palladium(0) (2.67 g, 2.31 mmol) and potassium carbonate (12.8 g, 93.0 mmol) were added to a solution of 1-bromo-3-methyl-5-nitrobenzene (5.0 g, 23.1 mmol) in dioxane (7.5 mL). The mixture was degassed with nitrogen for 5 minutes and stirred at 100° C. for 18 h. The mixture was passed through CELITE, washed with methanol and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/Hexane) to afford 4-(3-methyl-5-nitrophenyl)-1H-pyrazole. MS ESI calc'd. for C10H10N3O2 [M+H]+ 204. found 204.
Reaction SMILES: C([O:4][CH:5]([CH3:29])[CH2:6][C:7]([CH2:18][P:19]([O:25]C(C)C)([O:21]C(C)C)=[O:20])=[CH:8][CH:9]([NH:15]C=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)C.C(Cl)Cl.C[Si](C)(C)Br>C(O)C>[NH2:15][CH:9]([CH:8]=[C:7]([CH2:18][P:19]([OH:25])([OH:21])=[O:20])[CH2:6][CH:5]([OH:4])[CH3:29])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C=C(CC(C)OC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Agent: C[Si](C)(C)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(N)C=C(CC(C)O)CP(=O)(O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
11.5 g (26.4 mmol) of ethyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate are dissolved in 70 ml of abs. CH2Cl2 and to this solution are added 13.7 ml (105.6 mmol) of trimethylbromosilane. The reaction mixture is allowed to stand for 24 hours at room temperature and, after addition of 70 ml of abs. ethanol, allowed to stand again for 24 hours. The reaction mixture is concentrated by evaporation and the residue is dissolved in 70 ml of ethanol. A mixture of 70 ml of propylene oxide and 70 ml of ethanol is then added dropwise. The white suspension so obtained is stirred for 30 minutes at room temperature and for 30 minutes at 0° C. and then filtered with suction. The filter product is dried giving white crystals of ethyl 2-amino-6-hydroxy-4-phosphonomethyl-hept-3-enoate with a melting point of 211°-212° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[C:5]([CH3:14])[CH:4]=1.[Br:15]Br>CO>[Br:15][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:14])[C:10]1=[O:13]
Reactant: COc1cc(C)c2c(c1)C(=O)CCC2
Reactant: BrBr
Solvent: CO
Product: COc1cc(C)c2c(c1)C(=O)C(Br)CC2
Reaction time: 2 h

Procedure:
To the cold (−10° C.) solution of 7-methoxy-5-methyl-3,4-dihydro-2H-naphthalen-1-one (8.3 g, 0.04 mol) in methanol (20 mL), the solution of bromine (2.3 mL, 0.04 mol) in methanol (10 mL) was added dropwise and the mixture was stirred for 2 h while allowing the temperature to rise to room temperature. Methanol was evaporated in vacuo and the mixture was diluted with ethyl acetate and washed with aqueous sodium thiosulphate solution followed by saturated sodium bicarbonate, brine and dried. Evaporation of the solvent gave 2-bromo-7-methoxy-5-methyl-3,4-dihydro-2H-naphthalen-1-one as an off-white solid, 10 g, which was used as such in step 2. MS m/z 271 (M+2).
Reaction SMILES: C1(S([CH2:9][C:10]2[CH2:29][C@@H:28]3[C@:15]([CH3:32])([CH2:16][CH2:17][C@H:18]4[C@H:27]3[CH2:26][CH2:25][C:24]3[C@:19]4([CH3:31])[CH2:20][CH2:21][C:22](=[O:30])[CH:23]=3)[C:11]=2[C:12](=[O:14])[CH3:13])=O)C=CC=CC=1.CO.C(N(CC)CC)C.C[O:43]P(OC)OC>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CCCCCCC>[OH:43][C@:11]1([C@:15]2([CH3:32])[C@H:28]([C@H:27]3[C@H:18]([CH2:17][CH2:16]2)[C@:19]2([CH3:31])[C:24](=[CH:23][C:22](=[O:30])[CH2:21][CH2:20]2)[CH2:25][CH2:26]3)[CH2:29][C:10]1=[CH2:9])[C:12](=[O:14])[CH3:13]
Reactant: COP(OC)OC
Reactant: CC(=O)C1=C(CS(=O)c2ccccc2)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: CO
Product: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]2(C)[C@@]1(O)C(C)=O

Procedure:
The crude 16-(phenylsulfinylmethyl)pregna-4,16-diene-3,20-dione (VIA, Example 38) is slurried in toluene (300 ml) under a nitrogen atmosphere. Methanol (2 mmole), triethylamine (0.13 mmole) and then trimethylphosphite (0.79 mmole) are added. The reaction mixture is sealed and heated under pressure at 90° for 4 hours, then cooled to 20°-25°. The reaction mixture is subjected to acid hydrolysis of the access trimethylphosphite, base and buffer washes and finally crystallization from toluene/heptane to give the title compound. NMR (CDCl3) 0.82, 1.20, 1.30, 3.5, 5.04, 5.21 and 5.68 δ
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[C:8](=[O:16])[NH:7][C:6]2[CH:17]=[CH:18][CH:19]=[N:20][C:5]1=2)=[O:3].[N:21]1([CH2:27][CH2:28][CH:29]2[O:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>>[CH3:15][C:13]1[CH:12]=[CH:11][C:10]2[N:4]([C:2]([N:31]3[CH2:32][CH2:33][O:34][CH:29]([CH2:28][CH2:27][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)[CH2:30]3)=[O:3])[C:5]3[N:20]=[CH:19][CH:18]=[CH:17][C:6]=3[NH:7][C:8](=[O:16])[C:9]=2[CH:14]=1
Reactant: Cc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)Cl
Reactant: C1CCN(CCC2CNCCO2)CC1
Agent: Cl
Product: Cc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)N1CCOC(CCN2CCCCC2)C1
Yield: 79 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-(1-piperidinyl)ethyl]morpholine in a yield of 79% of theory. Rf 0.43 (conditions as in Example 58). The colourless hydrochloride melted at 272°-273° C. with decomposition.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]([OH:18])=O)=[CH:14][N:15]=2)[CH2:7]1.C1C=CC2N(O)N=[N:31]C=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+].[Cl-].CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[S:12][C:13]([C:16]([NH2:31])=[O:18])=[CH:14][N:15]=2)[CH2:7]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)C2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{3-[2-(trifluoromethyl)phenoxy]pyrrolidin-1-yl}-1,3-thiazole-5-carboxylic acid (860 mg, 2.4 mmol), HOBt (324 mg, 2.4 mmol), HATU (1.5 g, 3.8 mmol) and NH4Cl (385 mg, 7.2 mmol) in DMF at rt was added DIPEA (2.1 mL, 12 mmol). The mixture was stirred at rt overnight. After dilution with water, the mixture was extracted twice with EtOAc. The EtOAc extracts were combined, washed twice with 0.5 N NaOH, diluted brine, dried (Na2SO4) and concentrated. The residue was triturated with Et2O:hexanes (1:1) to give the title compound as a pale yellow solid. 1H NMR (500 MHz, acetone-d6): δ 7.79 (s, 1 H), 7.68-7.64 (m, 2 H), 7.39 (d, 1 H), 7.15 (t, 1 H), 5.48 (s, 1 H), 3.91 (m, 1 H), 3.78-3.62 (m, 4 H), 2.57-2.49 (m, 1 H), 2.44-2.40 (m, 1 H). MS (+ESI) m/z 358 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[C:22](O)=[O:23])[CH2:2][CH2:3][CH3:4].S1C(B(O)O)=CN=C1.[CH3:33][N:34]1[CH:38]=[N:37][N:36]=[C:35]1[CH2:39][NH2:40]>>[CH2:1]([C:5]1[N:9]([C:10]2[N:15]=[C:14]([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[C:13]([CH3:21])=[CH:12][N:11]=2)[N:8]=[CH:7][C:6]=1[C:22]([NH:40][CH2:39][C:35]1[N:34]([CH3:33])[CH:38]=[N:37][N:36]=1)=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: Cn1cnnc1CN
Reactant: CCCCc1c(C(=O)O)cnn1-c1ncc(C)c(-c2cncs2)n1
Agent: OB(O)c1cncs1
Product: CCCCc1c(C(=O)NCc2nncn2C)cnn1-c1ncc(C)c(-c2cncs2)n1

Procedure:
Compound 27 was prepared from 5-butyl-1-(5-methyl-4-(thiazol-5-yl)pyrimidin-2-yl)-1H-pyrazole-4-carboxylic acid following procedures described in Example 1 with the exceptions of substituting thiophene-2-boronic acid with thiazole-5-boronic acid in Step 1 and substituting pyridine-4-ylmethylamine with (4-methyl-4H-1,2,4-triazol-3-yl)methanamine. 1H NMR (400 MHz, MeOD-d3) δ 0.85 (t, J=7.3 Hz, 3H), 1.36 (m, 2H), 1.61 (m, 2H), 2.69 (s, 3H), 3.56 (t, J=7.4 Hz, 2H), 3.97 (s, 3H), 4.81 (s, 2H), 7.63 (s, 1H), 8.15 (s, 1H), 8.61 (s, 1H), 8.81 (s, 1H), 8.98 (s, 1H), 9.17 (s, 1H). LCMS (ES+) m/z 438 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:24]=[CH:23][N:22]=[N:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[CH:23][N:22]=[N:21]1
Reactant: O=Cc1cccc(-n2ccnn2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2ccnn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 3-(1H-1,2,3-triazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.71 min.; [M+H]+: 393.08 g/mol.