Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:27])[F:28])=[N:20][C:21]([C:22]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCOCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 88.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (60 mg, 0.109 mmol), morpholine (19 mg, 0.218 mmol) and bis(2-oxo-3-oxazolidinyl) phosphonic chloride (53.5 mg, 0.218 mmol) were dissolved in 5 mL of dichloromethane under stirring, and triethylamine (0.1 mL, 0.65 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight until thin lay chromatography showed the starting material disappeared, and was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(morpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 3a (60 mg, yield 89%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=O)[O:5][C:6]2=[O:12].C([O-])(=O)C.[Na+].C(O)(=O)C.[NH2:23][NH2:24]>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4](=[O:5])[NH:23][NH:24][C:6]2=[O:12]
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Reactant: NN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c(F)ccc(F)c12
Temperature: 25 °C

Procedure:
To 4,7-difluoroisobenzofuran-1,3-dione (1.00 g, 5.43 mmol) and sodium acetate (0.535 g, 6.52 mmol) was added water (14 mL), acetic acid (7.15 ml, 125 mmol) and hydrazine (0.205 ml, 6.52 mmol) (slowly). A water condenser was attached and the mixture was heated to reflux for 20 hours. Cooled to RT and filtered the resulting solid. Washed with water and dried to yield 5,8-difluoro-2,3-dihydrophthalazine-1,4-dione as a white solid. MS m/z=199 [M+1]+. Calc'd for C8H4P2N2O2: 198.13.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C@@H:20]3[CH2:24][C@H:23]([S:25][C:26]4[C@H:27]([CH3:50])[C@@H:28]5[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]5[C:30]=4[C:31]([O:33]CC4C=CC([N+]([O-])=O)=CC=4)=[O:32])[CH2:22][N:21]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:19])[CH2:13]2)=O)=CC=1)([O-])=O.[ClH:66]>O1CCCC1.O>[ClH:66].[NH:12]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C@@H:20]2[CH2:24][C@H:23]([S:25][C:26]3[C@H:27]([CH3:50])[C@@H:28]4[C@@H:45]([C@H:46]([OH:48])[CH3:47])[C:44](=[O:49])[N:29]4[C:30]=3[C:31]([OH:33])=[O:32])[CH2:22][NH:21]2)=[O:19])[CH2:13]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N[C@@H]4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N[C@@H]4CCNC4)C3)[C@H](C)[C@H]12

Procedure:
500 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[(3R)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylaminocarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.47 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 1 g of 10% w/w palladium-on-charcoal. The reaction mixture was then worked up and purified by the same procedure as described in Example 18(b), to give 43 mg of the title compound as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:9]2=[O:12])=[CH:4][CH:3]=1.C1(N[S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[N:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([O:1][S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(O)cc3c2=O)c1
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(OS(=O)(=O)C(F)(F)F)cc3c2=O)c1
Temperature: 120 °C
Yield: 81.2 %

Procedure:
Methyl 3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzoate (529 mg), N-phenyltrifluoromethanesulfonamide (612 mg) and potassium carbonate (709 mg) were stirred in THF (15 ml) and heated under microwave irradiation (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 120° C. for 10 minutes. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and washed with water (×2), brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography with a gradient of iso-hexane to 30% ethyl acetate/iso-hexane yielded methyl 4-methyl-3-[1-oxo-7-{[(trifluoromethyl)sulfonyl]oxy} isoquinolin-2(1H)-yl]benzoate as a white solid (613 mg); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 3.86 (s, 3H), 6.89 (d, 1H), 7.50 (d, 1H), 7.60 (d, 1H), 7.90 (s, 1H), 7.93 (d, 1H), 8.00 (m, 2H), 8.20 (s, 1H); Mass Spectrum: M+Na+ 464.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])=[CH:10][CH:9]=1>C(#N)C>[CH3:6][O:7][C:8]1[CH:13]=[C:12]2[C:11]([CH2:14][CH2:15][N:16]=[C:17]2[CH3:18])=[CH:10][CH:9]=1
Reactant: COc1ccc(CCNC(C)=O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1ccc2c(c1)C(C)=NCC2
Temperature: 120 °C
Yield: 45.3 %

Procedure:
Phosphorus oxychloride (22.5 mL) was added to a solution of N-[2-(4-methoxy-phenyl)-ethyl]-acetamide (6.5 g) in acetonitrile (200 mL). The mixture was heated at 120° C. in a sealed tube for 16 h. The solvent was evaporated. The residue was dissolved in dichloromethane (200 mL) and washed with aqueous sodium bicarbonate (saturated, 100 mL) and brine (100 mL). The dichloromethane layer was dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (5% methanol in dichloromethane) to afford 7-methoxy-1-methyl-3,4-dihydro-isoquinoline (2.67 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[CH:8][C:9]=1[OH:10].[Br:15]Br>O>[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:11](=[O:14])[CH2:12][CH3:13])[CH:7]=[C:8]([Br:15])[C:9]=1[OH:10]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(O)c(CN)c1
Agent: Cl
Solvent: O
Product: CCC(=O)c1cc(Br)c(O)c(CN)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of 22 g of 3'-aminomethyl-4'-hydroxypropiophenone hydrochloride in 300 ml of ice-cold water is added dropwise 17 g of bromine with stirring under ice cooling for about 10 minutes. After addition, the reaction mixture is stirred under ice cooling for 3 minutes and then at room temperature for 5 minutes. To the resulting mixture is added 200 ml of water and insoluble substances are filtered off. The filtrate is neutralized with powdery sodium hydrogencarbonate and the liquid layer is adjusted pH to about 7 to precipitate fine powder. The powder is collected by filtration and dried to give 25 g of 3'-aminomethyl-5'-bromo -4'-hydroxypropiophenone, melting at 186°-187° C. with decomposition.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[NH:17][C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[CH:13]=1>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:11][C:12]1[N:17]([CH2:2][C:3]#[N:4])[C:16](=[O:18])[N:15]([CH2:19][CH2:20][CH3:21])[C:14](=[O:22])[CH:13]=1
Reactant: CCCn1c(=O)cc(Cl)[nH]c1=O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCn1c(=O)cc(Cl)n(CC#N)c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Chloroactonitrile (16.5 g) and potassium carbonate (29.3 g) were added to a solution of 6-chloro-3-propylpyrimidine-2,4(1H,3H)-dione (20 g) in DMF (200 ml), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated and evaporated to dryness to obtain a residue. A resulting residue was dissolved in chloroform and H2O, and the organic layer was washed with water and dried. The solvent was evaporated to dryness to give a syrup, which was purified by column chromatography on silica gel to give a crystalline product. Recrystalization of the crude crystals from ethyl acetate-isopropylether gave colorless prisims (21.1 g, 87%), mp. 83°-84° C.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52](Br)[CH:53]=1.O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:44][O:45][C:46](=[O:55])[CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])[CH:53]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
A solution of t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 22.0 mg, 0.036 mmol) in N,N-dimethylformamide (0.3 mL) was added to 5-bromopyridine-3-acetic acid methyl ester (Example 24-(2); 19.2 mg, 0.083 mmol) and a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (3.2 mg, 0.0039 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 76 to 84° C. for five hours and 30 minutes. Water was added to the reaction mixture, followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (17.2 mg, 76%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](N)[S:9][CH:10]=1)=[O:5])[CH3:2].N([O-])=O.[Na+].[BrH:16]>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:16])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)c1csc(N)n1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1csc(Br)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A solution of 30 g (174.3 mmol) ethyl-2-aminothiazole-4-carboxylate [prepared as in Example 1a)] in a mixture of 100 ml HBr (65%) and 100 ml of water was cooled to -15° C. and a solution of 12.03 g (174.3 mmol) sodium nitrite in 40 ml water was added over a period of 30 minutes and the mixture stirred for another 30 minutes at -15° C. After warming to room temperature, the solid was collected, washed with 50 ml cold water and dried to give 23.7 g (57.6%) ethyl-2-bromothiazole-4-carboxylate m.p. 63°-65° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14]([CH3:16])=[O:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1.FC1C=C(N[C:44]([NH:46][C:47](=[O:55])[CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[S:45])C=CC=1OC1C2SC(SC)=CC=2N=CN=1>>[F:1][C:2]1[CH:20]=[C:19]([NH:21][C:44]([NH:46][C:47](=[O:55])[CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[S:45])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([S:14]([CH3:16])=[O:15])=[CH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: CS(=O)c1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: CSc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Product: CS(=O)c1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Yield: 36 %

Procedure:
Starting from the compound 285 and following the procedure described above for the synthesis of compound 283 (scheme 64, step 4, example 225), title compound 286 was obtained in 36% yield as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.45 (s, 1H), 11.83 (s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 7.93(dd, 1H, J1=2.3 Hz, J2=10.9 Hz), 7.55 (t, 1H, J=8.6 Hz), 7.48 (m, 1H), 7.34-7.31 (m, 4H), 7.28-7.25 (m, 1H), 3.81 (s, 2H), 3.08 (s, 3H). MS (m/z): 501.0 (M+H) (found).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.C[O:15][C:16](=O)[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28]2)[CH2:24][CH2:23][CH2:22][N:21]3[CH:20]=1)=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:12])[NH:13][C:16](=[O:15])[C:17]=2[C:19]2[C:29]3=[C:30]4[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28]3)[CH2:24][CH2:23][CH2:22][N:21]4[CH:20]=2)=[CH:2]1
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cc(OC)cc13)CCC2
Product: COc1cc2c3c(c1)c(C1=C(c4c[nH]c5ccccc45)C(=O)NC1=O)cn3CCC2

Procedure:
Beginning with indole-3-acetamide and (8-methoxy-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N:7][CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].C(O)(=[O:16])CC.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N+:7]([O-:16])[CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2]
Reactant: CCc1nc2nccc(C)c2[nH]1
Reactant: CCC(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c([nH]1)c(C)cc[n+]2[O-]

Procedure:
A solution of 28 g (174 mmol) of 2-ethyl-7-methylimidazo[4,5-b]pyridine prepared according to Example 1, Steps A and B, but substituting propionic acid in place of butyric acid in Step B (described in European Patent Application No. 400,974, May 12, 1990) and m-chloroperbenzoic acid (80-90%, 44.6 g) in CHCl3 (300 mL) was heated at reflux for 0.5 hours. The mixture was concentrated and purified (SiO2, 100% CH2Cl2 gradient to 30% CH2Cl2 /MeOH) to give 29.8 g of the title compound as a solid.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>>[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2ccccc2)n1

Procedure:
Phenyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combined according to literature procedures to yield 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine. See WO 2006/071940.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]3=[N:12][C:13](Cl)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:36]([O:39][C:40]([CH3:60])([CH3:59])[C:41](=[O:58])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=1)(=[O:38])[CH3:37].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:36]([O:39][C:40]([CH3:60])([CH3:59])[C:41]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:13]2[N:12]=[C:11]3[N:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([NH:28][C:29]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:35])[CH2:27][CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[C:8]([C:7]4[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=4)=[N:9][C:10]3=[CH:15][CH:14]=2)[CH:44]=1)=[O:58])(=[O:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Reactant: CC(=O)OC(C)(C)C(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OC(C)(C)C(=O)Nc1cccc(-c2ccc3nc(-c4cccnc4N)n(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c3n2)c1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
To a suspension of tert-butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (50 mg) and 1,1-dimethyl-2-oxo-2-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino}ethyl acetate (71 mg) and potassium phosphate (65 mg) and PdCl2(dppf)CH2Cl2 (8 mg) in dioxane (2 mL) and H2O (0.2 mL) was degassed for 5 minutes and then heated to 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (2 times: 0-10% methanol in chloroform then 0-10% methanol in ethyl acetate) gave the product (44 mg, 64%).
Reaction SMILES: [CH2:1]([C:3]([C:14]1[CH:27]=[CH:26][C:17]([O:18][CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:16]([CH3:28])[CH:15]=1)([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH3:13])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:29][C:30]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])[CH3:31]>>[C:30]([Si:33]([CH3:35])([CH3:34])[O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]([C:14]2[CH:27]=[CH:26][C:17]([O:18][CH2:19][C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])=[C:16]([CH3:28])[CH:15]=2)([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]=1[CH3:13])([CH3:32])([CH3:31])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Yield: 90.2 %

Procedure:
Using a procedure analogous to Example 13A, 1-{(4-[1-Ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (Example 1B) (4.91 g, 12.83 mmol) and TBSCl (1.93 g, 12.83 mmol) give the title compound (5.74 g, 11.57 mmol, 90%). 1H NMR (CDCl3), δ 0.21 (s, 6H), 0.60 (t, J=7.5 Hz, 6H), 1.01(s, 9H), 1.26 (s, 9H), 2.01 (q, J=7.5 Hz, 4H), 2.16 (s, 3H), 2.24 (s, 3H), 4.83 (s, 2H), 6.50 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 6.82 (dd, J=8.4, 2.3 Hz, 1H), 6.87-6.93 (m, 3H). LC/MS (m/z): calcd for C31H52NO3Si (M+NH4)+: 514.8; found: 514.5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 537.0 (M+H)+.
Reaction SMILES: Cl[C:2](=[N:8][OH:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:10][CH2:11][C:12]#[CH:13].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[Br:10][CH2:11][C:12]1[O:9][N:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=1
Reactant: CCOC(=O)C(Cl)=NO
Reactant: C#CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(CBr)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.3 %

Procedure:
A solution of ethyl 2-chloro-2-(hydroxyimino)acetate (11 g; 70.41 mmol) in ethyl acetate (60 mL) was added dropwise at room temperature to a mixture of 3-bromoprop-1-yne (15.2 mL; 141 mmol), sodium bicarbonate (11.95 g; 141 mmol), ethyl acetate (400 mL), and water (4 mL). The mixture was stirred at room temperature for 24 h and the solid was removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent: 15 to 100% of dichloromethane in heptane) to give 14.38 g (87%) of ethyl 5-(bromomethyl)isoxazole-3-carboxylate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]Br)[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2.[C:21]([O-:24])(=[O:23])[CH3:22].[K+]>CN(C)C=O.C(OCC)C>[C:21]([O:24][CH2:11][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]2[C:8]=1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2)(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(CBr)c21
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (940 mg, 2.237 mmol) in dimethylformamide (10 mL) at room temperature was added potassium acetate (659 mg, 6.71 mmol). After 10 min, the reaction was placed in a 40° C. bath and stirred for 1 h. The reaction was cooled to room temperature, diluted with diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 1.04 g (quant.) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.95 (s, 1H), 7.86 (d, J=1.8, 1H), 7.55 (d, J=1.2, 1H), 5.81 (s, 2H), 5.52 (s, 2H), 3.49 (m, 2H), 2.08 (s, 3H), 0.84 (m, 2H), −0.09 (s, 9H; 13C NMR (126 MHz, CDCl3) δ ppm 170.2, 137.1, 133.4, 132.2, 128.1, 124.1, 120.9, 114.1, 79.6, 66.3, 63.0, 21.1, 17.8, −1.4.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.[CH3:17]O>C(OCC)C>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Br:6])[CH:8]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C

Procedure:
Concentrated sulphuric acid (588 μL) was added to a solution of 3-bromophenyl acetic acid (10 g, 46.5 mmol) in methanol (100 mL). The mixture was refluxed for 1.5 h and then cooled to ambient temperature and evaporated under reduced pressure to afford a residue. The residue was redissolved in diethyl ether (500 mL), washed with water (2×100 mL), brine (100 mL), dried (MgSO4) and then evaporated under reduced pressure to afford 3-bromophenyl acetic acid methyl ester (10.65 g). The 3-bromophenyl acetic acid methyl ester was dissolved in toluene (117 mL) then phenyl boronic acid (6.8 g, 55.69 mmol) added, followed by a aqueous solution of sodium carbonate (93 mL, 2M) and tetrakis(triphenylphosphine)palladium (1.6 g, 1.41 mmol). The mixture was stirred overnight then cooled to ambient temperature and an aqueous solution of saturated ammonium chloride (100 mL) added. The mixture was extracted with ethyl acetate (2×200 mL), died (Na2SO4) and evaporated under reduced pressure to afford a residue. Flash chromatography of the residue over silica (200 g) using ethyl acetate:heptane (3:48) as the eluent gave biphenyl-3-yl acetic acid methyl ester, yield 10.5 g, (99%), TLC (single UV spot, Rf=0.24, 10% ethyl acetate in heptane), analytical HPLC Rt=19.55 min, HPLC-MS (single main UV peak with Rt=9.35 min, 227.1 [M+H]+).