Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][CH:24]([OH:44])[CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:32]=1>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][C@H:24]([OH:44])[CH2:25][O:26][C:27]4[CH:28]=[CH:29][C:30]([OH:43])=[C:31]([NH:33][S:34]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)(=[O:35])=[O:36])[CH:32]=4)[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NCC(O)COc1ccc(O)c(NS(=O)(=O)c2ccccc2)c1
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c(NS(=O)(=O)c5ccccc5)c4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-(3-amino-2-hydroxy-propoxy)-2-hydroxy-phenyl]-benzenesulfonamide (which was obtained in Example 21) according to the procedure of Example 73 as an off-white solid; mp>120° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.30–1.55 (m, 2 H), 1.80–2.00(m, 2 H), 2.50–4.00(m, 12 H), 4.55(dd, J=9.6, 4.0 Hz, 1 H), 6.49(dd, J=8.7, 2.9 Hz, 1 H), 6.61(d, J=8.7 Hz, 1 H), 6.77(d, J=2.9 Hz, 1 H), 6.86(d, J=8.7 Hz, 2 H), 7.05(d, J=8.7 Hz, 2 H), 7.40–7.60(m, 3 H), 7.70–7.80(m, 2 H); MS (ES) m/z: 627.0 (MH+, 100%); HRMS Calcd. for C30H35N4O7S2 (MH+): 627.1941. Found: 627.1954.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5]([NH:6][CH:7]=[N:8][C:9]=2[Cl:11])=[N:4][CH:3]=1.O[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:19][CH2:20]2)[CH:3]=1
Reactant: Clc1nc[nH]c2ncc(Br)c1-2
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCn2cc(Br)c3c(Cl)ncnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To 5-bromo-4-chloro-1H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.860 mmol) in Tetrahydrofuran (THF) (10 mL) was added 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate (592 mg, 2.58 mmol) and polymer bound triphenylphosphine (574 mg, 1.721 mmol) resin. To the mixture was then added dropwise DEAD (0.272 mL, 1.721 mmol). The stir bar was then removed from the reaction and the reaction was then placed on to a horizontal shaker and the reaction was agitated at room temp overnight. The resin was filtered off and the filtrated was concentrated then loaded on to a 10 g Biotage SNAP column and eluded with 0 to 45% EtOAc in Hexane to give 1,1-dimethylethyl 4-[2-(5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (326 mg, 85% yield) as a white solid. LC-MS (ES) m/z=443.4 [M+H]+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O:23][B:24](OC)[O:25]C.Cl>C(OCC)C>[CH2:15]([O:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[B:24]([OH:25])[OH:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ccc(OCc2ccccc2)c(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of butyl lithium (1.6M in hexane) (50 ml) was added dropwise to a stirred solution of the product from step (i) (23 g) in diethylether (300 ml) at −70° C. After 1 h a further 18 ml of butyl lithium was added, left for 0.75 h, then trimethylborate (10 ml) added and the mixture warmed to RT and left for 16 h. 2M Hydrochloric acid (100 ml) was added, stirred for 1 h then the organic layer separated and extracted with aqueous sodium hydroxide solution. The basic layer was acidified with 2M hydrochloric acid solution, extracted with diethylether which was dried and evaporated under reduced pressure. The residue was triturated with iso-hexane and filtered. Yield 10.8 g
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C(N(CC)CC)C.[CH:39](=O)[CH2:40][CH3:41].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:39][CH2:40][CH3:41])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: CCC=O
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCN1CC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)C1
Reaction time: 0.5 h
Yield: 50.5 %

Procedure:
In a 2 mL flask, 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 15 mg, 0.035 mmol) was suspended in acetonitrile (350 μL, 0.035 mmol). To this was added triethylamine (19 μL, 0.14 mmol), followed by propionaldehyde (25 μL, 0.35 mmol). After stirring for 30 minutes, NaBH(OAc)3 (37 mg, 0.17 mmol) was added. After the reaction was complete, it was quenched with saturated bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient to afford 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo-[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-propylazetidin-3-yl)acetonitrile (7.1 mg, 51% yield) as a white solid. MS (apci) m/z=402.2 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=O)(=[O:3])[CH3:2].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[NH2:26]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([NH:26][C:25]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:23]([C:22]([F:21])([F:34])[F:35])[CH:24]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 63.1 %

Procedure:
Using 5-acetyl-2-benzyloxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound (5.47 g, 63.1%) as a slight yellowish green solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:8][C:9](=O)[C:10]3[CH2:15][CH2:14][CH2:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19].C([O-])(O)=O.[Na+]>>[Cl:19][C:9]1[C:10]2[CH2:15][CH2:14][CH2:13][C:11]=2[N:12]=[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(Cl)s2)nc2c1CCC2
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
An 18-mL vial was charged with 2-(5-chloro-2-thienyl)-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one (180 mg, 0.71 mmol). POCl3 (1 ml) was added. The resulting mixture was stirred at 90 C for 4 hr. After cooling to room temperature, the mixture was added dropwise slowly to cold NaHCO3 aq. Dichloromethane was added. The organic layer was separated and passed through a plug of silica gel, using dichloromethane as eluent to give 4-chloro-2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (178 mg, 92% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].CN(C)C=O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2c1ccc(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (5.0 g), lithium hydride (0.37 g), and dimethylformamide (200 ml) was stirred at 25° C. for 3 hrs. Benzyl bromide (5.5 g) was added and the mixture was stirred for 20 hrs. Water was added, and the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The layers were separated and combined organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with hexanes to provide 4.5 (58%) of 5,6,7,8-tetrahydro-5-oxo-1-phenylmethyl-2(1H)-quinolinone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40](Br)[CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[C:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=1)#[CH:47].N(CC)CC.CN(C=O)C>C(O)=O.[Cu]I.CC#N>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([C:47]#[C:46][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1cccc(Br)c1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COC(=O)N[C@H](C(=O)NN(Cc1cccc(C#Cc2ccccn2)c1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was synthesized according to Method C using compound 26 (79.4 mg, 0.117 mmol), 2-(ethynyl)pyridine (15.3 mg, 0.148 mmol), Et2NH (0.105 mL, 1.01 mmol) Pd(PPh3)2Cl2 (6.50 mg, 0.00926 mmol), CuI (1.50 mg, 0.00788 mmol) and DMF (2 mL). RP-LC-MS (35 min gradient of 0-100% CH3CN in 0.05% aqueous formic acid) gave the product (15.9 mg, 19%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17](Cl)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH:22]([CH3:24])[CH3:23].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:21]([CH3:20])[CH:22]([CH3:24])[CH3:23])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reactant: CNC(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 14 %

Procedure:
A suspension of 8-benzyl-3-chloro-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (498 mg), N-methylpropan-2-amine (0.29 mL), Pd2(dba)3 (50 mg), XPhos (104 mg) and sodium tert-butoxide (348 mg) in toluene (5 mL) was stirred under an argon atmosphere with heating at 100° C. for 3 hr. Water was added to the reaction mixture, the aqueous layer was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 9→50% ethyl acetate/hexane), and further by preparative HPLC to give the title compound (79 mg, 14%) as a pale-yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>CCO>[F:14][C:15]([F:25])([F:26])[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23]/[N:24]=[CH:1]/[C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(/C=N/Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
To a magnetically stirred solution of methyl 4-formylbenzoate (1.71 g, 10.41 mmoL) dissolved in EtOH (mL) was added (4-(trifluoromethoxy)phenyl)-hydrazine hydrochloride (2 g, 10.41 mmoL) and the reaction was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and dried under high vacuum to give (E)-methyl 4-((2-(4-(trifluoromethoxy)phenyl)-hydrazono)methyl)benzoate (3.08 g, 87%): mp 142-145° C.; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.72-7.65 (m, 3H), 7.13 (q, J=8.9 Hz, 4H), 3.93 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.36; ESIMS m/z 338 ([M+H])+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:25])=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:13]3[CH3:18])=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:18][N:13]1[C:14]2[C:10](=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[CH:17]=[CH:16][CH:15]=2)[C:11]([CH3:25])=[C:12]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2cccc3c2c(C)c(-c2ccccc2)n3C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)n(C)c2cccc(-c3ccc(O)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 4 of example 3. Thus, 4-(4-methoxy-phenyl)-1,3-dimethyl-2-phenyl-1H-indole (1.227 g, 3.747 mmol) was reacted with BBr3 (4.5 ml of a 1M solution in CH2Cl2) to give the product (0.751 g, 2.396 mmol, 64%) as a white solid, mp 132-134° C. 1H NMR (DMSO-d6) δ 1.71 (s, 3H), 3.57 (s, 3H), 6.78-6.83 (m, 3H), 7.15-7.19 (m, 3H), 7.40-7.46 (m, 4H), 7.52 (t, J=7.2 Hz, 2H), 9.39 (s, 1H); IR (solid) 3480, 3430, 2920, 1605, 1520, 1480, 1450, 1310, 1270, and 1180 cm−1; [ESI(+)], m/z 314 (M+H)+; Anal. Calcd. for C22H19NO: C, 84.31; H, 6.11; N, 4.47; Found: C, 84.17; H, 6.10; N, 4.42.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].Cl>C(Cl)Cl>[CH3:13][C:12]1[CH:14]=[CH:15][C:9]([S:6]([O:4][CH2:3][CH:2]([F:5])[F:1])(=[O:8])=[O:7])=[CH:10][CH:11]=1
Reactant: OCC(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of compound 2,2-difluoroethanol (1 g, 12.2 mmol) in CH2Cl2 (15 mL) was added TsCl (3.5 g, 18.3 mmol) at 0° C. The mixture was stirred at room temperature overnight. Then aqueous HCl was added to the mixture to adjusted the mixture to pH<7 and the mixture was separated. The aqueous phase was extracted with EtOAc and the combined organic phases was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=15:1) to provide 2,2-difluoroethyl 4-methylbenzenesulfonate. (2.5 g, yield: 86.8%). 1H-NMR (CDCl3, 400 MHz) δ 7.78 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 5.75˜6.04 (m, 1H), 4.10˜4.18 (m, 2H), 2.44 (s, 3H). MS (M+H)+: 267.
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([C:43]4[S:44][C:45]5[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=5[C:47]=4[O:48][CH3:49])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:56][C@H:25]([CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:58][CH:57]=1)[CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:55]=[CH:54][C:33]([NH:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([C:43]3[S:44][C:45]4[CH:53]=[CH:52][CH:51]=[CH:50][C:46]=4[C:47]=3[O:48][CH3:49])=[O:42])[CH2:39][CH2:40]2)=[CH:32][CH:31]=1
Reactant: COc1c(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)sc2ccccc12
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1c(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)sc2ccccc12
Yield: 83 %

Procedure:
{4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}(3-methoxy-1-benzothiophen-2-yl)methanone (0.148 g, 0.182 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.087 g, 0.151 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])[C:4]([CH3:17])=[N:3]1.[F:18][C:19]1[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[CH:22]=[C:23]([F:26])[C:24]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:18][C:19]1[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[CH:22]=[C:23]([F:26])[C:24]=1[O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:17])[C:5]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: Cc1nn(C)c(O)c1-c1c(F)cc(F)cc1F
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c(Oc2c(F)cc([N+](=O)[O-])cc2F)c1-c1c(F)cc(F)cc1F
Temperature: 80 °C

Procedure:
1,3-Dimethyl-4-(2,4,6-trifluorophenyl)-1H-pyrazol-5-ol (i.e. the product of Step C) (0.310 g, 1.28 mmol), was combined with 3,4,5-trifluoronitrobenzene (157 μL, 1.35 mmol) and potassium carbonate powder (0.27 g, 2 mmol) in dry N,N-dimethylformamide (4 mL). This mixture was stirred and heated at 80° C. for 45 minutes and then allowed to cool. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic phase was washed with water and with brine, dried over MgSO4, and concentrated to leave a viscous residue. This residue was purified by column chromatography through silica gel eluted with a gradient of ethyl acetate (30% to 100%) in hexane to give the title product, a compound of the present invention, as an off-white solid (209 mg).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:28])[C:20]2[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:28])[C:20]2[C:25]([CH:26]=[CH:1][CH3:2])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(c1ncccc1C=O)C1CCN(Cc2ccccc2)CC1
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC=Cc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a stirring suspension of (ethyl)triphenylphosphonium bromide (1.75 g, 4.72 mmol) in dry THF (150 ml) at 20°-25° under nitrogen is added n-butyl lithium (1.6M in hexane, 2.95 ml, 4.72 mmol). The resulting mixture is stirred for 10 min followed by addition of 1-benzyl-4-[N-methyl-N-(3-formyl-2-pyridinyl)amino]piperidine (XXI, EXAMPLE 13, 1.40 g, 4.72 mmol) in THF (10 ml) under nitrogen. The mixture is stirred at 20°-25° for 1 hr and quenched with saturated aqueous ammonium chloride (50 ml). Water is added (100 ml) and the aqueous is extracted with ethyl acetate (3×75 ml). The organic phases are combined, dried over sodium sulfate and the solvent evaporated to dryness. The residue is purified via flash column chromatography (silica gel; hexane/ethyl acetate (6/1→1/1)) to give the title compound, NMR (CDCl3) 1.64, 1.81-1.93, 2.80, 2.91, 3.46, 5.77, 6.13, 6.26, 6.40, 6.78, 7.20-7.56 and 8.11δ; MS (EI, m/e) 321 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH:22]([C:26](O)=[O:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:26]([CH:22]3[O:23][CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21]3)=[O:27])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (350 mg, 1.52 mmol), 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (739 mg, 3.20 mmol), BOP-Cl (813 mg, 3.20 mmol), and triethylamine (1.06 mL, 7.61 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour. 3M LiOH (3 mL) was then added, and stirred for an additional 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the solid formed was filtered. The solid product was washed with DCM (10 mL) and dried to give tert-butyl 2-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate (660 mg, 97.9% yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH:9]2[CH3:12])=[CH:4][CH:3]=1.B(O)O>>[CH3:12][CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:5]3[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=3)[CH:11]=2)[CH2:6][CH2:7][NH:8]1
Reactant: CC1NCCc2ccc(Br)cc21
Agent: OBO
Product: CC1NCCc2ccc(-c3ccncc3)cc21

Procedure:
In close analogy to the procedure described above, 7-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline is reacted with the corresponding boronic acid to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[CH:9]=1)[CH3:2].[B-](F)(F)(F)[F:35].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:3][CH2:4][C@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[C:11]2[C:22](=[O:25])[NH:23][CH2:24][C:10]=2[C:9]=1[F:35])[CH3:2]
Reactant: CCOC[C@@H](CNc1cc2c(c(Nc3cccc(C)c3)n1)C(=O)NC2)NC(=O)OC(C)(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC[C@@H](CNc1nc(Nc2cccc(C)c2)c2c(c1F)CNC2=O)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a chilled solution of (R)-tert-butyl 1-ethoxy-3-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)propan-2-ylcarbamate (94.7 mg, 0.208 mmol) in CH2Cl2 (5 mL) at 0° C. was added SELECTFLUOR® (73.6 mg, 0.208 mmol). The mixture was left stirring in an ice bath and warmed slowly to RT for 6 h. Afterwards, the mixture was diluted with EtOAc (10 mL) and washed with saturated aq NaHCO3 (5 mL) followed by water (5 mL) and brine (5 mL). The organic layers were combined, dried over Na2SO4, and concentrated to a brown residue. The resulting crude material was reconstituted in MeOH/DCM (5 mL) and purified via preparative HPLC. The collected fractions were collected and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×200 mL), dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation to yield the title compound. [M+H] calc'd for C24H32FN5O4, 474; found, 474.