Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9]2.[Br:16]Br.Cl>ClC(Cl)C.C(OCC)C>[Br:16][C:7]1[C:6]([F:5])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:15]
Reactant: O=C1CCc2cc(F)ccc21
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: O=C1CCc2c1ccc(F)c2Br
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
A solution of aluminum trichloride (11.10 g, 83.00 mmol) in dichloroethane (100 mL) was slowly added a solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (5 g, 33.3 mmol) in dichloroethane (10 mL) at ambient temperature and stirred for 5 minutes, followed with the addition of bromine (2.57 mL, 50.0 mmol). The resulting dark red mixture was heated at 70° C. for 2 hours. The reaction mixture was cooled to ambient temperature and poured into a mixture of ice and HCl (1N, 50 mL). Diethyl ether (300 mL) was added and the mixture was partitioned. The organic portion was washed with water (75 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed on silica gel (gradient elution: 0-10% EtOAc/hexanes) to provide the title compound mixed with inseparable bisbrominated side product (4,7-dibromo-5-fluoro-2,3-dihydro-1H-inden-1-one). MS (DCI) m/z 246 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH2:13][N:12]([C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][C:9]=2N2CCCCC2)=O)=[CH:4][CH:3]=1.CCN(CC)CC.Cl.[CH3:33][CH:34]([CH3:38])[C:35](=[NH:37])[NH2:36]>C(O)(CC)(C)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[C:8]3[CH2:13][N:12]([C:14](=[O:16])[CH3:15])[CH2:11][CH2:10][C:9]=3[N:37]=[C:35]([CH:34]([CH3:38])[CH3:33])[N:36]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(N2CCCCC2)=C(C(=O)c2ccc(F)cc2)C1
Reactant: CC(C)C(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCC(C)(C)O
Product: CC(=O)N1CCc2nc(C(C)C)nc(-c3ccc(F)cc3)c2C1
Temperature: 25 °C

Procedure:
A solution of crude 1-[5′-(4-fluoro-benzoyl)-3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl]-ethanone in t-amyl alcohol (1.5 L) was treated with Et3N (108 mL, 0.78 mol) and 2-methyl propanimidamide hydrochloride (82.6 g, 0.67 mol). The reaction mixture was heated at reflux for 16 h and then was cooled to rt. The mixture was concentrated, and the residue was diluted with water (2 L) and extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated to afford the crude title compound, which was used in next reaction without further purification. HPLC: RT=8.11 min. MS (ESI): exact mass calcd. for C18H20FN3O, 313.16; m/z found, 314.0 [M+H]+. 1H NMR (CDCl3; mixture of rotamers): 7.60-7.50 (m, 2H), 7.24-7.12 (m, 2H), 4.71 (s, 1.4H), 4.56 (s, 0.6H), 3.93 (t, J=6.2, 0.6H), 3.80 (t, J=6.2, 1.4H), 3.18 (sept, J=6.8, 1H), 3.07 (t, J=6.2, 1.4H), 3.02 (t, J=6.2, 0.6H), 2.15 (s, 2.1H), 2.00 (s, 0.9H), 1.34 (d, J=6.8, 6H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[C:43]([F:48])=[CH:44][CH:45]=[C:46]([F:47])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: OB(O)c1c(F)ccc(F)c1F
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)ccc(F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,3,6-trifluorophenyl)boronic acid gave 332. 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.81 (s, 1H), 7.63-7.51 (m, 3H), 7.31-7.23 (m, 1H), 4.79 (dd, J=10.7, 3.5 Hz, 1H), 4.46-4.29 (m, 2H), 4.24-4.11 (m, 1H), 4.09-3.92 (m, 1H), 3.75 (s, 3H), 2.08-2.00 (m, 1H), 1.84-1.75 (m, 1H), 1.74-1.66 (m, 2H). LCMS (ES+) m/z 485 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH:11](Cl)Cl)[CH:3]=1.O.[NH2:15][NH2:16]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:7])[NH:16][N:15]=[CH:11]2
Reactant: O=C(O)c1ccc(Cl)cc1C(Cl)Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]ncc2cc(Cl)ccc12
Yield: 63.1 %

Procedure:
A solution of 23.9 g (0.1 mole) of 4-chloro-2-dichloromethylbenzoic acid and 16 g (0.32 mole) of hydrazine hydrate in 200 ml of ethanol was heated under reflux for 3 hours. The ethanol was evaporated under reduced pressure, and the residue recrystallized from ethanol to give 11.4 g (yield: 63%) of 6-chloro-1-phthalazinone having a melting point of 272°-273° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C@H:19]([OH:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:26])=[CH:7][CH:8]=2)[N:3]=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:37][CH3:38])=[C:32](B(O)O)[CH:33]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>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.O>[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:37][CH3:38])=[C:30]([C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C@H:19]([OH:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][C:6]([CH3:26])=[CH:7][CH:8]=3)[N:3]=2)[CH:29]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(Cl)nc2c1
Reactant: COc1ccc(F)cc1B(O)O
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: CC#N
Solvent: O
Product: COc1ccc(F)cc1-c1nc(N2CCN(C(=O)[C@H](O)CC(C)C)CC2)c2ccc(C)cc2n1
Temperature: 160 °C
Yield: 70 %

Procedure:
(R)-1-(4-(2-Chloro-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (50 mg, 0.13 mmol), 5-fluoro-2-methoxyphenylboronic acid (27 mg, 0.16 mmol), Pd(Ph3P)4 (9.2 mg, 0.008 mmol), and K2CO3 (37 mg, 0.27 mmol) were placed into a microwave tube charged with a stir bar. Acetonitrile (2 mL) and H2O (400 μL) were added, and the vessel was capped and heated at 160° C. for 12 minutes in the microwave reactor. The reaction was partitioned between EtOAc and H2O, the layers were separated, and the aqueous layer was extracted once more with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to an orange gel. The reaction was purified by silica gel chromatography using 10%-30% EtOAc in CH2Cl2/hexanes (2:1) to afford (R)-1-(4-(2-(5-fluoro-2-methoxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one as a white foam (70%). LC/MS: m/z 467.30 (M+H)+ at 2.38 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [H-].[Na+].CCOP(OCC)([CH2:8][C:9]#[N:10])=O.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=O)=[CH:18][CH:17]=1.O>O1CCCC1>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][CH2:22][C:23]2=[CH:8][C:9]#[N:10])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(=CC#N)CCC2
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a solution of 60% sodium hydride (6.24 g, 156 mmol) in tetrahydrofuran (100 ml) was gradually added dropwise, under ice-cooling, diethyl cyanomethyl phosphonate (30.4 g, 172 mmol). The mixture was stirred for 15 minutes. To the reaction mixture was then added dropwise a solution of 7-methoxy-1-tetralone (25.2 g, 143 mmol) in THF (50 ml). The reaction mixture was heated for 3 hours under reflux. The reaction mixture was poured into water, and the organic layer was subjected to extraction with chloroform. The extract solution was washed with brine and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane:ethyl acetate=9:1) to give the above-titled compound (a mixture of isomers) (28 g, yield 98%, oil). The above-titled compound (a mixture of isomers) was further purified by a silica gel column chromatography (hexane:ethyl acetate=98:2) to fractionally refine the respective isomers.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[O:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN1CCCC1=O>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[CH:3]=3)[O:9][C:10]=2[C:16]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: C1COCCN1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(C2CCOCC2)c2oc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Temperature: 140 °C
Yield: 29.3 %

Procedure:
A stirred suspension of 460 mg (1.06 mmol) 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-isonicotinamide, 693 mg (2.13 mmol) cesium carbonate and a few crystals of 2,6-di-tert-butyl-p-cresol in 2.78 ml (3.19 mmol) morpholine and 2 ml N-methylpyrrolidone in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (2/98 methanol/dichloromethane) followed by trituration in ether afforded 136 mg (29%) N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzooxazol-2-yl]-2-morpholin-4-yl-isonicotinamide as a white crystalline solid. ES-MS m/e (%): 439 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.I[CH:25]([OH:27])[CH3:26].C(N=C1CCN(C)P(N(CC)CC)N1C)(C)(C)C.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][CH2:26][CH2:25][OH:27])[S:3][C:4]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[N:9]=1
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: CC(O)I
Agent: CCN(CC)P1N(C)CCC(=NC(C)(C)C)N1C
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1nc(NCCO)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Temperature: 124 °C

Procedure:
To a mixture of [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(3-nitro-phenyl)-amine (0.33 g, 1.0 mmol) and iodoethanol (0.44 g, 2.6 mmol) in dry DMF (2 mL) was added tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3-diazaphosphorine (0.5 mL). The reaction mixture was heated at 124° C. for 20 h. The product was isolated as a brown solid by preparative RP-HPLC (Vydac 218TP1022, 9 mL/min) using a gradient from 10-70% MeCN in 0.1% aq CF3COOH over 40 min. Anal. RP-HPLC: tR=14.30 min (Vydac 218TP54, 0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, 25° C., purity >97%). 1H-NMR (CD3OD) δ: 3.30 (s, 3H, CH3), 3.91 (t, 2H, J=4.6 Hz, CH2), 4.25 (t, 2H, J=4.6 Hz, CH2), 7.21(d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.54 (m, 1H, Ph-H), 7.89 (m, 2H, Ph-H), 8.59 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.90 (s, 1H, Ph-H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])C1C=CC=CC=1.[C:37]([O:41][C:42](=[O:49])[C@H:43]([CH2:45][CH:46]([CH3:48])[CH3:47])[NH2:44])([CH3:40])([CH3:39])[CH3:38]>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:24])[CH3:25])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][NH:44][C@H:43]([C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:49])[CH2:45][CH:46]([CH3:47])[CH3:48])[CH2:30][CH2:29]1)=[O:27]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CC(C)C[C@H](NCCC1CCN(C(=O)c2cc(C(C)C)c(O)cc2O)CC1)C(=O)OC(C)(C)C

Procedure:
Prepared from Intermediate D and L-leucine tert-butyl ester. 1H NMR (300 MHz, d3-MeOD) 6.95 (1H, s), 6.33 (1H, s), 4.17 (2H, m), 3.33 (1H, m), 3.28 (1H, m), 2.95 (2H, t, J=12.6 Hz), 2.65 (2H, m), 1.74 (4H, m), 1.57 (11H, m), 1.44 (4H, m), 1.20 (6H, d, J=9.0 Hz), 0.97 (6H, m). LC/MS: purity 96%, m/z 477 [M+H]+
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH:4]([C:6]1([OH:18])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:5].[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)(Cl)Cl>[C:20]([O:18][C:6]1([CH:4]([CH3:5])[CH2:3][N:2]([CH3:1])[CH3:19])[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:22])[CH3:21]
Reactant: CC(CN(C)C)C1(O)CCCCC1c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)OC1(C(C)CN(C)C)CCCCC1c1ccccc1
Temperature: 25 °C

Procedure:
(-)-1-(2-Dimethylamino-1-methylethyl)-2-phenycyclohexanol (8 gm) in 65 ml chloroform is cooled to 0° and 2.7 ml acetyl chloride is added at ≤5°. After warming to room temperature, the solution is extracted with dilute aqueous sodium hydroxide, washed with water and dried over magnesium sulfate. The dried chloroform solution is then cooled to 0° and treated with another 3.0 ml acetyl chloride at ≤5° and again allowed to warm to room temperature, extracted with dilute sodium hydroxide, washed with water and dried over magnesium sulfate. Removal of solvent leaves 9.3 gm of an oil which crystallizes spontaneously. This is recrystallized from 30 ml n-hexane (at -50°) yielding 5.7 gm product melting at 63°-66°. The optical rotation is as follows: ##EQU8##
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:20]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[C:8]([NH2:22])[N:7]=1)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[N:32]1([CH2:38][CH2:39][OH:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C=O)C.CS(C)=O>[NH2:22][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:20])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][N:35]1[CH2:36][CH2:37][N:32]([CH2:38][CH2:39][OH:40])[CH2:33][CH2:34]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: OCCN1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN3CCN(CCO)CC3)c2n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2-(Butyloxy)-9-(4-chlorobutyl)-8-(methyloxy)-9H-purin-6-amine (for example, as prepared for Intermediate 42) (100 mg, 0.305 mmol), DIPEA (0.160 mL, 0.915 mmol) and 2-(1-piperazinyl)ethanol (commercially available, for example, from Aldrich) (0.075 mL, 0.61 mmol) were dissolved in DMF (2.2 mL). The reaction mixture was stirred and heated at 50° C. under nitrogen overnight. Additional 2-(1-piperazinyl)ethanol (0.075 mL, 0.61 mmol) was added and the mixture heated at 80° C. for 20 hours. The reaction mixture was cooled down to room temp and partitioned between water (5 mL) and DCM (6 mL). The layers were separated using a hydrophobic frit and the aqueous washed with DCM (5 mL). The combined organics were concentrated under vacuum. The residues were dissolved in DMSO (1 mL) and purified by MDAP on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier. The desired fractions were combined and concentrated under nitrogen blowdown. The residue was dissolved in methanol (2 mL) and HCl 4M in dioxane (3 mL) was added. The reaction mixture was stirred for 30 mins and then left in solution at room temp for 1 hour. The reaction mixture was concentrated under nitrogen blowdown and then dissolved in MeOH and eluted through an NH2 (1 g). The columns were washed with MeOH (3 CV). The solvent was removed under nitrogen blowdown to give a brown solid. The samples were dissolved in DMSO (1 mL) and purified by MDAP on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier. The desired fractions were combined and concentrated under nitrogen blowdown to give the title compound as a white solid (0.0262 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[CH2:13]([N:16]=[C:17]=[O:18])[CH:14]=[CH2:15]>C1COCC1.C(OCC)C>[CH2:13]([NH:16][C:17]([NH:7][NH:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[Br:1])=[O:18])[CH:14]=[CH2:15]
Reactant: NNC(=O)c1ccc(Cl)cc1Br
Reactant: C=CCN=C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCNC(=O)NNC(=O)c1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A quantity of 10.0 g (40.1 mmol) of 2-bromo-4-chlorobenzhydrazide was suspended in 100 ml of THF at 50° C. and admixed with 3.59 ml (40.9 mmol) of allyl isocyanate in solution in 50 ml of THF. Stirring was continued for 16 h at 50° C. The batch was then allowed to cool to RT and diluted with 50 ml of diethyl ether. The precipitated solid was filtered off with suction, washed with a little diethyl ether and dried in an HV. This gave 11.30 g (85% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([C@H:42]([OH:47])[C@@H:43]([OH:46])[CH2:44][CH3:45])[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:40]3[CH:39]=[C:38]([CH:42]([OH:47])[CH:43]([OH:46])[CH2:44][CH3:45])[CH:37]=[CH:36][CH:41]=3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: CC[C@H](O)[C@@H](O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCOC1
Product: CCC(O)C(O)c1cccc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)c1

Procedure:
To a mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (0.3 g, 0.62 n mmol) and 1-(3-bromo-phenyl)-butane-1(S),2(S)-diol (0.152 g, 0.62 mmol) in a 20 mL microwave reaction flask was added THF (3 mL), acetonitrile (3 mL), and sodium carbonate (1 N in water, 3 mL, 6 n mmol). The resulting suspension was purged with nitrogen for 1 minute. Dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (22 mg, 27 μmol) was added and the purging was continued for another minute. The flask was sealed and irradiated in a microwave reactor to 90° C. for 10 minutes. The reaction mixture was neutralized to pH 7 using 1 N hydrochloric acid, extracted with ethyl acetate (10 mL×3). The combine organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexane to afford 1-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-butane-1,2-diol as a off white solid (171 mg, 53%). MS: m/z 520 (M+H+).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9](=[O:20])[CH2:10][NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[CH2:3]1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][N:28]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:24]=2[N:25]=[CH:26][N:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[Cl:19][C:14]1[CH:13]=[C:12]([NH:11][CH2:10][C:9]([N:4]2[CH2:5][CH2:6][CH:7]([CH3:8])[CH:2]([NH:1][C:22]3[C:23]4[CH:30]=[CH:29][N:28]([S:31]([C:34]5[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=5)(=[O:32])=[O:33])[C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:3]2)=[O:20])[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: CC1CCN(C(=O)CNc2cc(Cl)cc(Cl)c2)CC1N
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CN(C(=O)CNc5cc(Cl)cc(Cl)c5)CCC4C)ncnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 1-(3-amino-4-methylpiperidin-1-yl)-2-(3,5-dichlorophenylamino)ethanone (180 mg, 0.56 mmol) and 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (192 mg, 0.62 mmol) in DMF (5 mL), was added DIEA (0.15 mL, 0.85 mmol) and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc/water (1:2, 120 mL). The EtOAc layer was separated, dried over Na2SO4 and evaporated in vacuo to give a residue that was purified by column chromatography (silica gel, gradient EtOAc in hexanes) to afford the titled intermediate (120 mg, 35%). LC-MS: m/z [M+1]=587.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13].CCCCCCC.CCOC(C)=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:14]/[CH:12]=[O:13]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2ccccc2s1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C/C=C/c1cc2ccccc2s1
Yield: 28.9 %

Procedure:
A solution of benzothiophene-2-carboxaldehyde (3 g, 18.4 mmol) and formylmethylenetriphenylphosphorane (5.62 g, 18.4 mmol) in CH2Cl2 (100 ml) was treated as seen in preparation 1. After a chromatography on silicagel (n-heptane/EtOAc 4/1) pure title compound was obtained (1.00 g, 5.31 mmol, yield 28.9%) as yellow crystals, m.p.=88°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[NH2:6].C(O)(=O)C.[Br:16][C:17]1[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][N:18]=1.C([BH3-])#N.[Na+]>CO.O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][CH2:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Br:16])[CH:22]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=Cc1ccnc(Br)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1NCc1ccnc(Br)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
6.04 g (40 mmol) of anthranilic acid methyl ester in 600 ml of methanol is mixed with 3.2 ml of acetic acid and 7.4 g (40 mmol) of 2-bromopyridine-4-carbaldehyde and stirred overnight at 40° C. 3.8 g (60 mmol) of sodium cyanoborohydride is added thereto and stirred overnight at 40° C. 3.8 g (60 mmol) of sodium cyanoborohydride is added again and stirred over the weekend at 40° C. It is mixed with water and largely concentrated by evaporation. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are dried, filtered and concentrated by evaporation. The crude product is chromatographed on silica gel with a gradient that consists of hexane and hexane/ethyl acetate 1:3 and hexane/ethyl acetate 1:1 as an eluant. 10.0 g (78% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester is obtained as a colorless oil.