Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Cc1ccc(Cl)c(N)c1
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(C)ccc1Cl
Yield: 36.9 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.00 g, 24.1 mmol) and 2-chloro-5-methylaniline (8.54 g, 60.3 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (2.94 g, 37%) was obtained.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:28]3[C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[S:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)[CH:17]=[C:16]([Br:33])[C:15]=1[OH:34].O[C@@H:36]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.CCOCC>[CH3:40][O:39][C:37](=[O:38])[C@H:36]([O:34][C:15]1[C:14]([Br:13])=[CH:19][C:18]([C:20]2[C:28]3[C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[S:25][C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]=1[Br:33])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: Oc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2cccc3sc4ccccc4c23)cc1Br
Temperature: 80 °C
Reaction time: 4 h
Yield: 85301.9 %

Procedure:
Diethylazodicarboxylate (DEAD, 0.077 mL, 1.15 mmol) was added to a stirred, room temperature suspension of 2,6-Dibromo-4-(dibenzothiophen-1-yl)-phenol (0.250 g, 0.576 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.208 g, 1.15 mmol), triphenylphosphine (0.302 g, 1.15 mmol) in benzene (3 mL) under a dry nitrogen atmosphere. Dissolution occurred and the solution was heated in an 80° C. oil bath for 16 h. More diethylazodicarboxylate (DEAD, 0.039 mL, 0.576 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.104 g, 0.576 mmol) and triphenylphosphine (0.151 g, 0.576 mmol) were added and the solution was stirred an additional 4 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (98:2 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0. 293 g, 85%): NMR (CDCl3): δ 7.89 (dd, J=8, 1 Hz, 1H), 7.85 (ddd., J=8, 1, 1 Hz, 1H), 7.64 (d, J=2 Hz, 1H), 7.63 (d, J=2 Hz, 1H), 7.47 (dd, J=9, 8 Hz, 2H), 7.41-7.17 (m, 8H), 5.13 (dd, J=8, 6 Hz, 1H), 3.71 (s, 3H), 3.55 (dd, J=7, 4 Hz, 1H), 3.53 (dd, J=8, 4 Hz, 1H); MS (EI): [M+], 2 bromine isotope pattern, 594 (20%), 596 (40%) 598 (25%); Anal. Calc. for C28H20Br2O3S: C, 56.39, H, 3.38, N, 0.00. Found: C, 56.27, H, 3.21, N, 0.09.
Reaction SMILES: [CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].Br[C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].O>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>[CH3:1][C:2]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[CH:36]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COC(=O)c1cc(Br)ccn1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(B4OC(C)(C)C(C)(C)O4)cccc32)c1C
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: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
To a degassed solution of 4-(2,3-dimethylphenoxy)-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one (0.020 g, 0.045 mmol), methyl 4-bromopicolinate (0.019 g, 0.089 mmol) and potassium carbonate (0.018 g, 0.134 mmol) in dioxane (0.50 mL)/water (0.20 mL) was added tetrakis(triphenylphosphine)palladium (2.57 mg, 2.225 μmol). Upon completion of addition, the vial was purged with argon, sealed, and stirred at 90° C. for 16 h. After cooling to room temperature, the mixture was extracted with EtOAc. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (17.7 mg, 87% yield) as a clear colorless oil. LCMS, [M+H]+=459.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:10]([CH2:18][CH3:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: O=c1cc(Br)cc[nH]1
Product: CCC(C(=O)OC(C)(C)C)n1ccc(Br)cc1=O

Procedure:
348 mg (2.0 mmol) of 4-bromopyridin-2(1H)-one and 1.2 eq. of tert-butyl 2-bromobutanoate (racemate) were reacted according to General Method 4B at 120° C. After aqueous work-up, the desired product was reacted further as crude product. Yield: 608 mg (purity 82%, 79% of theory)
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][CH2:7][C:8]3([C:16]42[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]4)[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[C:29]#[N:30]>>[NH2:21][C:19]1[C:18]([CH3:22])=[N:17][C:16]2([C:23]3[C:5](=[CH:4][CH:3]=[C:2]([C:32]4[CH:31]=[C:28]([CH:27]=[C:26]([Cl:25])[CH:33]=4)[C:29]#[N:30])[CH:24]=3)[CH2:6][CH2:7][C:8]32[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)[N:20]=1
Reactant: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(N)=N3)CC1
Reactant: CC1(C)OB(c2cc(Cl)cc(C#N)c2)OC1(C)C
Product: COC1CCC2(CCc3ccc(-c4cc(Cl)cc(C#N)c4)cc3C23N=C(C)C(N)=N3)CC1

Procedure:
The title compound was prepared following the procedure described for Example 2, starting from 7′-bromo-4-methoxy-5″-methyl-3′,4′-dihydrodispiro[cyclohexane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 5, 125 mg, 0.32 mmol) and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (Intermediate 4, 93 mg, 0.35 mmol). The product was purified using preparative chromatography followed by concentration of the fractions, extraction of the remaining aqueous phase with DCM, washing the organic layer with water and concentration and drying in vacuo at 50° C. for 2 days to give:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]([N:22](COCC[Si](C)(C)C)COCC[Si](C)(C)C)=[CH:20][C:19]([CH:39]5[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]5)=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>O>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH:14]=[N:15][N:16]4[C:21]([NH2:22])=[CH:20][C:19]([CH:39]5[CH2:44][CH2:43][S:42](=[O:45])(=[O:46])[CH2:41][CH2:40]5)=[N:18][C:17]=34)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCS(=O)(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(C2CCS(=O)(=O)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12

Procedure:
3-(6-phenylpyridin-3-yl)-5-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (286.1 mg, 0.42 mmoL) was treated with 50% TFA in H2O (10 mL) until the disappearance of starting material in LCMS. Concentration afforded crude 3-(6-phenylpyridin-3-yl)-5-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine: LCMS tR=1.12 Min (5 min run, UV254nm). Mass calculated for, M+ 419.1, observed m/z 420.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:16][CH:17]=1
Reactant: O=C(CNc1ccc(Br)cc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CNc1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.7 %

Procedure:
A solution of 2-(4-bromoanilino)-1-phenyl-1-ethanone (3.50 g, 0.0121 mol) in anhydrous methanol (200 mL) was cooled to 0° C. and sodium borohydride (2.28 g, 0.0603 mol) was added at once. The mixture was allowed to warm up to ambient temperature while stirring under an atmosphere of nitrogen for three hours. The reaction was quenched by dropwise addition of acetic acid, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (120 mL) and water (85 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure to yield 2-(4-bromoanilino)-1-phenyl-1-ethanol (3.49 g, 0.0117 mol) as a yellow oil.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[CH3:9][CH:10]([CH3:34])[CH2:11][C:12]1([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25].C(Br)C=C>C1COCC1>[CH3:9][CH:10]([CH3:34])[CH2:11][C:12]1([CH:26]([C:3]([CH3:4])=[CH2:2])[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85.9 %

Procedure:
LDA (2.0M, 7.7 mL, 16 mmol) is added to a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 1, step 3; 4.62 g, 12.9 mmol) and THF (45 mL) at -78° C. The solution is stirred at -78° C. for 45 minutes and allyl bromide (1.3 mL, 16 mmol) is added. The solution is allowed to warm to 0° C. over 2 hours, and is allowed to stir overnight at room temperature. After quenching with saturated aqueous ammonium chloride, aqueous workup (EtOAc, MgSO4) and purification by column chromatography (2:1:17 v/v EtOAc:CH2Cl2 :hexane) gives 4.43 g (86%) of the title compound as yellow oil which solidified upon standing (mp 54.5°-56° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].IC.[C:27]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[CH:12]/[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH3:27])[C:16]2=[O:24])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(/C=C/C(=O)n2c(=O)[nH]c3ccccc32)cc1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(/C=C/C(=O)n2c(=O)n(C)c3ccccc32)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-1H-benzo[d]imidazol-2(3H)-one (240 mg, 0.75 mmol), iodomethane (68 uL, 1.1 mmol) and K2CO3 (204 mg, 1.5 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by recrystallisation from EtOH to afford (E)-1-(3-(3,4-dimethoxyphenyl)acryloyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (200 mg, 79%). 1H-NMR (400 MHz, CDCl3) δ 3.46 (s, 3H), 3.96 (s, 3H), 3.98 (s, 3H), 6.91 (d, J=8.4 Hz, 1H), 7.01 (dd, J=7.6, 0.8 Hz, 1H), 7.19-7.28 (m, 4H), 7.98 (d, J=15.6 Hz, 1H), 8.15 (d, J=15.6 Hz, 1H) 8.32 (dd, J=8.0, 0.8 Hz, 1H); LC-MS (ES-API); rt 9.05 min; m/z calculated for C19H18N2O4 [M+H]+ 339.1, found 339.0 and 361.0 ([M+Na]+).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25]1[O:29][C:28]2[CH:30]=[C:31]([Cl:36])[C:32]([CH2:34]Cl)=[CH:33][C:27]=2[O:26]1>CN(C=O)C>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:34][C:32]1[CH:33]=[C:27]3[O:26][CH2:25][O:29][C:28]3=[CH:30][C:31]=1[Cl:36])[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a stirring suspension of sodium hydride (2.03grams (hereinafter "g"), (60% in mineral oil), 50.8 millimoles (hereinafter "mmol")) in DMF (100 milliliters (hereinafter "mL")) was added ethyl 5-benzyloxyindole-2-carboxylate (10.0 g, 33.9 mmol). After 10 minutes (hereinafter "min"), 6-chloropiperonyl chloride (10.4 g, 50.8 mmol) was added. After 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4), filtered and concentrated to leave an oily pale yellow solid. The solid was recrystallized from ethanol to provide the title compound as a white solid (7.8 g, 50%). 1HNMR (400 MHz, CDCl3) d 7.49-7.33 (m, 6H), 7.19-7.08 (m, 3H), 6.87 (s, 1H), 5.86 (s, 2H), 5.78 (s, 1H), 5.77 (s, 2H), 5.11 (s, 2H), 4.33 (q, 2H), 1.36 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3C(C#N)[C:4]=2[CH:3]=1.O.Cl.[C:21]([OH:24])(=[O:23])[CH3:22]>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[S:6][CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:22]([C:21]([OH:24])=[O:23])[C:4]=2[CH:3]=1
Reactant: N#CC1c2ccccc2CSc2ccc(Br)cc21
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)C1c2ccccc2CSc2ccc(Br)cc21

Procedure:
After 4.72 g of 2-bromo-11-cyano-6,11-dihydrodibenzo[b,e]thiepine was dissolved in 90 ml of hydrochloric acid-acetic acid (1:2), the mixture was heated under reflux for 48 hours. The reaction mixture was allowed to stand at room temperature, and 50 ml of water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with water. The organic layer was extracted 3 times with saturated sodium bicarbonate aqueous solution. The aqueous layer was adjusted to pH 2 with 4N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride aqueous solution successively, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to obtain 2.68 g of 2-bromo-6,11-dihydrodibenzo[b,e]thiepin-11-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:28][CH2:27][C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:12][CH2:13][C:14]3([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH2:15]3)[CH2:27][CH2:28]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N)CC2)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (495.9 mg, 2.7 mmol) in ethanol (20 mL) were added tert-butyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate (1.08 g, 4.0 mmol) and Et3N (413.6 mg, 4.1 mmol). The mixture was stirred at room temperature for 12 h and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/7) to give the product as a light yellow solid (387.1 mg, 34.5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:14])=[CH:8]2)=[O:4].[Cl:15][C:16]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[OH-].[Na+].[I-].[Na+]>O.O1CCOCC1>[Cl:15][C:16]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:17]=1[CH2:18][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[NH:10][C:9]=1[CH3:14]
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Reactant: Clc1cc(-c2ccccc2)ccc1CBr
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2[nH]c(C)c(Cc3ccc(-c4ccccc4)cc3Cl)c2c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 5-methoxycarbonyl-2-methylindole (0.84 g), 2-chloro-4-phenylbenzyl bromide (2.0 g), L-tartaric acid (1.07 g), sodium hydroxide (0.37 g), sodium iodide (0.53 g), 1,4-dioxane (15 ml) and water (8 ml) is stirred at 90° C. for 4 hours. The reaction mixture is extracted with water and ethyl acetate added thereto, and the organic layer is washed with water, dried and concentrated. The resulting residue is purified through silica gel column chromatography (eluent: ethyl acetate/hexane=1/4 to 1/2), and crystallized from a mixed solution of hexane and ethyl acetate to obtain 3-(2-chloro-4-phenylbenzyl)-5-methoxycarbonyl-2-methylindole (144) (0.965).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[N:22][C:23]=3[CH3:27])[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:28]1([CH2:34]C=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:27][C:23]1[N:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[CH:25]=[CH:26][C:17]([NH:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:1][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:9][CH2:10]1)=[N:18]2
Reactant: O=CCc1ccccc1
Reactant: Cc1nccc2nc(NCCN3CCN(Cc4ccccc4)CC3)ccc12
Product: Cc1nccc2nc(NCCN3CCN(CCc4ccccc4)CC3)ccc12

Procedure:
Compound 10 was prepared as described for compound 9, using phenylacetaldehyde in place of benzaldehyde. 1H NMR (CD3OD, 400 MHz) δ 8.20 (d, 1H, J=5.5 Hz), 8.10 (d, 1H, J=7.5 Hz), 7.10-7.40 (m, 6H), 6.85 (d, 1H, J=7.5 Hz), 3.65-3.75 (m, 2H), 2.50-2.90 (m, 17H). LCMS (EI) m/z 376 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[O:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>CCO>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: NC1CCOCC1
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(NC3CCOCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (60 mg, 0.16 mmol) and tetrahydro-2H-pyran-4-amine (2 ml, 19 mmol) in EtOH (3 mL). The vessel was sealed and the reaction mixture was irradiated (microwave) at 125° C. for 2 hr. and then at 170° C. for 1 hr. The mixture was concentrated to ca. 20% volume and NMP (2 mL) added to the reaction mixture. The contents were again irradiated (microwave) first at 180° C. for 2.5 h and then at 190° C. for 75 min. The mixture was evaporated under vacuum, and the resulting residue was purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOAc/hexanes (1:1), sonicated, and heated. After cooling, solids that precipitated were filtered and dried to afford the title compound (46 mg, 64%) as an off-white solid. LCMS E-S (M+H)=439.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (s, 1H) 8.44 (t, J=5.05 Hz, 1H) 7.83 (s, 1H) 7.20 (d, J=7.33 Hz, 1H) 6.63 (s, 1H) 5.89 (s, 1H) 4.93 (quin, J=6.69 Hz, 1H) 4.32 (d, J=5.05 Hz, 2H) 3.99-4.06 (m, 1H) 3.88 (dt, J=11.49, 3.47 Hz, 2H) 3.45 (td, J=11.37, 2.02 Hz, 2H) 2.21 (s, 3H) 2.13 (s, 3H) 1.95 (d, J=10.61 Hz, 2H) 1.41-1.51 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([F:9])[C:3]=1[Cl:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16]>>[Cl:1][C:2]1[C:3]([Cl:10])=[C:4]([F:9])[C:5]([CH3:8])=[CH:6][C:7]=1[C:15](=[O:17])[CH3:16]
Reactant: Cc1ccc(Cl)c(Cl)c1F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(C)c(F)c(Cl)c1Cl

Procedure:
Using 1,2-dichloro-3-fluoro-4-methylbenzene (12.0 g), anhydrous aluminum chloride (17.87 g) and acetyl chloride (5.26 g), the title compound was obtained as a pale-yellow oil (yield: 5.46 g) by an operation similar to that in Reference Example 9.
Reaction SMILES: B([C:4]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=1[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(O)O.Br[C:18]1[CH:32]=[CH:31][C:21]([C:22]([N:24]([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[O:23])=[C:20]([F:33])[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>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].O1CCOCC1>[CH3:27][CH:25]([N:24]([CH:28]([CH3:30])[CH3:29])[C:22]([C:21]1[CH:31]=[CH:32][C:18]([C:4]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:5]=2[O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:19][C:20]=1[F:33])=[O:23])[CH3:26]
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1F)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)N(C(=O)c1ccc(-c2cc(Cl)ccc2O[C@@H](C)C(=O)O)cc1F)C(C)C
Temperature: 25 °C

Procedure:
The product of step c) (200 mg), the product of step d) (200 mg), Pd(dppf)Cl2 (60 mg), sodium carbonate (350 mg) and dioxan (5 ml) were charged to a flask and heated at reflux for 24 h, then cooled to room temp and filtered (hyflo). The filtrate was concentrated in vacuo, then purified by reverse phase HPLC to give the title compound. Yield 22 mg
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][CH2:4][O:3]1.[N:7]([Si](C)(C)C)=[N+:8]=[N-:9]>Cl[Sn](Cl)(Cl)Cl>[N:7]([CH:2]([O:3][CH2:4][CH2:5][OH:6])[CH3:1])=[N+:8]=[N-:9]
Reactant: CC1OCCO1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CC(N=[N+]=[N-])OCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methyl dioxolane (0.897 ml, 10 mmol) and azidotrimethylsilane (1.6 ml, 12 mmol) was added SnCl4 (40 μl) at −78° C. After addition, the cooling bath was removed and the reaction was warmed up to room temperature. After 1 hr, the reaction was worked up by partitioning between DCM (50 ml) and saturated aqueous NaHCO3 (50 ml). The aqueous layer was further extracted with DCM (20 ml). All the DCM extracts were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was dissolved in 10% aqueous methanol. After 2 hr at room temperature, all the solvents were removed under reduced pressure. The title compound was obtained as a colourless oil (224 mg, 17.1%).
Reaction SMILES: S(O)(O)(=O)=O.N[C:7]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[C:9]([Br:21])[CH:8]=1.N(OCC)=O>[Cu].O>[Br:21][C:9]1[CH:8]=[CH:7][CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[C:10]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1c(Br)cc(N)cc1C(F)(F)F
Agent: [Cu]
Agent: CCON=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1c(Br)cccc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a suspension of 4'-amino-2'-bromo-6'-trifluoromethylacetanilide sulfate is added two molar equivalents of ethyl nitrite. The reaction mixture is cooled (0°) and stirred for 2 hours then allowed to warm to 25° and a catalytic amount of copper bronze is added. The mixture is stirred for 3 hours with the temperature maintained below 40°. The mixture is then refluxed briefly and cooled. Addition of water gives 2'-bromo-6'-trifluoromethylacetanilide which is collected by filtration.