Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([C:13]1[CH:14]=[C:15]([C:22](OC)=[O:23])[C:16]2[O:20][CH:19]=[CH:18][C:17]=2[CH:21]=1)(=[O:12])=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([C:13]1[CH:14]=[C:15]([CH2:22][OH:23])[C:16]2[O:20][CH:19]=[CH:18][C:17]=2[CH:21]=1)(=[O:11])=[O:12]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(C)ccc2OC)cc2ccoc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C)cc1S(=O)(=O)c1cc(CO)c2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 5-[(2-methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-carboxylate (400 mg, 1.1 mmol; Intermediate 67) was dissolved in dry THF (3 mL) and 1 M lithium aluminiumhydride in THF (0.3 mL) was slowly added. The mixture was stirred at room temperature overnight. After this time, water (0.15 mL) was added and stirring was continued for 10 min, followed by the addition of 2 M aqueous NaOH (0.15 mL) and water (0.45 mL). The precipitate formed was filtered off and the solvent was evaporated. The crude product was used in the next step without further purification. MS (ESI+) for C17H16O5S m/z 333 (M+H)+.
Reaction SMILES: [Na+].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH2:10][S:11]([O-:14])(=[O:13])=[O:12].Cl>CO>[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[CH2:10][S:11]([OH:14])(=[O:13])=[O:12]
Reactant: Cc1cccc(C)c1CS(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C)c1CS(=O)(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
Methanol (2.2 L) and (2,6-dimethyl-phenyl)-methanesulfonic acid sodium salt (185 g) were combined in a multi-necked 5 L flask equipped with overhead stirring. The mixture was cooled to 0° C. and hydrogen chloride (112 g) was passed through the mixture, maintaining an internal temperature of <10° C. The mixture was stirred for 2 h and allowed to warm to room temperature. The mixture was clarified by filtration. The filtrate was concentrated to 600 mL volume at ambient pressure and azeotroped with toluene (3×600 mL). Heptane (1.1 L) was added to the mixture as it cooled to <10° C. The solid product was collected by filtration and washed with heptane (100 mL). The product was dried at 40° C. in vacuo to constant weight to give (2,6-dimethyl-phenyl)-methanesulfonic acid (149 g, 89%). 1H NMR (300 MHz, DMSOd6): δ 7.0-6.91 (m, 3H, ArH), 4.40 (s, 2H, CH2), and 2.34 (s, 6H, CH3).
Reaction SMILES: N1CCCCC1.FC(F)OC1C=CC(C=O)=CC=1OC.C(CC(N[C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=O)(O)=O>C1(C)C=CC=CC=1>[C:30]([OH:32])(=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:28]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: COc1cc(C=O)ccc1OC(F)F
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
Piperidine (0.25 mL, 2.6 mmol) was added to a suspension of 4-(difluoromethoxy)-3-methoxybenzaldehyde (0.52 g, 2.6 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.52 mg, 2.6 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5 mL) and water (2 mL) and the solution was acidified with 50% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water, filtered and washed with water to afford (E)-2-[[3-methoxy-4-(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (259 mg, 71%) as a colourless crystalline solid; mp 172-174° C.; δH (500 MHz, DMSO-d6) 3.90 (s, 3H, OCH3), 6.94 (d, J=15.6 Hz, 1H, CH═CHCO), 7.12 (t, J=75 Hz, 1H, OCHF2), 7.17 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.20 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.32 (dd, J5′,6′=8.0, J2′,6′=2.0 Hz, 1H, H6′), 7.56 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (dt, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.33 (s, 1H, NH), 13.60 (br s, 1H, CO2H); δC (125 MHz, DMSO-d6) 56.1, 112.3, 114.5, 116.5 (t, J=256 Hz), 116.8, 120.4, 120.8, 121.4, 122.7, 122.9, 131.1, 132.9, 134.0, 140.6, 140.8, 150.7, 163.7, 169.4; HRMS (ESI−) calculated for C18H15F2NO5 [M-H ]− 362.0835, found 362.0839; νmax 1032, 1260, 1586, 1604, 1661, 2988, 3509 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[C:12](=[O:23])[C:13]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][N:15]([CH3:17])[CH:16]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[CH2:24](O)[CH2:25][CH2:26][CH2:27][CH2:28]C>O1CCCC1.[Ti]>[CH2:1]([O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[C:12](=[O:23])[C:13]([N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:14][N:15]([CH3:17])[CH:16]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)c1cccc(-c2cn(C)cc(-n3cccn3)c2=O)c1
Reactant: CCCCCCO
Agent: [Ti]
Solvent: C1CCOC1
Product: CCCCCCOC(=O)c1cccc(-c2cn(C)cc(-n3cccn3)c2=O)c1
Yield: 21.4 %

Procedure:
5 g (0.016 mole) of 5-(3-methoxycarbonylphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone and 16.32 g (0.16 mole) of n-hexanol are extracted under reflux together with 3.64 g (0.016 mole) of titanium tetraethylate in 50 ml of absolute tetrahydrofuran for 12 hours over a Soxhlet extractor filled with 4 Å zeolite. The reaction mixture is concentrated to dryness, the residue is taken up in water and the mixture is extracted three times with methylene chloride; the combined organic phases are dried over sodium sulphate and concentrated in vacuo. The oil which remains is purified chromatographically over a silica gel column (eluant: cyclohexane/ethyl acetate 1:1) and the product is crystallized from ether. 1.3 g (21.4% of theory) of 5-(3-n-hexyloxycarbonylphenyl)-1-methyl-3-(pyrazol-1-yl)-4-pyridone of melting point 96°-97° C. are obtained.
Reaction SMILES: C(OC([N:11]1[C@H:15]([CH3:16])[C@@H:14]([C:17]([O:19][CH3:20])=[O:18])[C@H:13]([NH:21][CH2:22][C:23]2[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=2[O:34][CH3:35])[C@@H:12]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O)C1C=CC=CC=1.COC1C=CC(OC(F)(F)F)=CC=1CN[C@H]1[C@H](C(OC)=O)[C@@H](C)N[C@H]1C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:35][O:34][C:24]1[CH:25]=[CH:26][C:27]([O:29][C:30]([F:31])([F:33])[F:32])=[CH:28][C:23]=1[CH2:22][NH:21][C@H:13]1[C@@H:14]([C:17]([O:19][CH3:20])=[O:18])[C@@H:15]([CH3:16])[NH:11][C@H:12]1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)[C@H]1[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)[C@@H]1C
Agent: [Pd+2]
Agent: COC(=O)[C@H]1[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N[C@@H]1C
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1[C@H](NCc2cc(OC(F)(F)F)ccc2OC)[C@H](c2ccccc2)N[C@@H]1C
Yield: 26.8 %

Procedure:
20% Pd(OH)2 --C (Pearlman's cat., 600 mg) was added to a solution of (2S*,3S*,4S*,5R*)-1-benzyloxycarbonyl-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine 1.08 g, 1.89 mmol) and HCO2NH4 (714 mg, 11.3 mmol) in methanol (25 ml). The reaction mixture was stirred and heated at a gentle reflux for 30 min. The catalyst was filtered off by the aid of a Celite pad, and washed with MeOH. The combined filtrate and washings were concentrated in vacuo. The residue was basified to pH 10-11 with 10% NaOH aq. solution, and extracted with CH2Cl2 (60 ml×4). The combined CH2Cl2 extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give a crude mixture of (2S*,3S*,4R*,5R*)-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine and (2S*,3S*,4R*,5R*)-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine (794 mg) as a yellow oil. This was purified by column chromatography on silica gel (45 g) with hexane-ethyl acetate (1:1) to give (2S*,3S*,4S*,5R*)-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)amino]-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine (222 mg, 27.3%) as a pale yellow solid, which was recrystallized from hexane-ethyl acetate to give (2S*,3S*,4S*,5R*)-3-[N-(2-methoxy-5-trifluoromethoxybenzyl)-amino]-4-methoxycarbonyl-5-methyl-2-phenylpyrrolidine (127 mg, 1st crop) as a white solid: mp 81-82° C.
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[CH:17][C:16]1=[O:40])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].CC(O)=O>CC#N.O>[P:1]([OH:8])([OH:3])([O:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[CH:17][C:16]1=[O:40])=[O:2]
Reactant: Cc1cc(F)ccc1Oc1cc(Cl)ccc1C(=O)Nc1ccn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)c1
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(F)ccc1Oc1cc(Cl)ccc1C(=O)Nc1ccn(COP(=O)(O)O)c(=O)c1
Yield: 43.5 %

Procedure:
A solution of di-tert-butyl [4-[[4-chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (23) (35 mg, 0.05882 mmol) in CH3CN (700.0 μL), water (700.0 μL) and AcOH (0.7 mL, 12.31 mmol) was heated at 90° C. for 20 min then evaporated and co-evaporated with CH3CN (3×). The material was triturated with CH3CN, filtered, washed with CH3CN and desiccated to give [4-[[4-chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl dihydrogen phosphate (13) (13 mg, 0.02558 mmol, 43.5%) as a white solid. ESI-MS m/z calc. 482.0446, found 483.4 (M+1)+; Retention time: 1.41 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.30 (dd, J=8.2, 2.0 Hz, 1H), 7.21 (d, J=9.3 Hz, 1H), 7.16-7.05 (m, 2H), 6.89 (d, J=2.3 Hz, 1H), 6.74 (d, J=2.0 Hz, 1H), 6.44 (dd, J=7.6, 2.3 Hz, 1H), 5.51 (d, J=9.7 Hz, 2H), 2.16 (s, 3H) ppm. 31P NMR (162 MHz, DMSO-d6-85% H3PO4 aq. as internal standard—0 ppm) δ −2.15 (t, J=9.7 Hz) ppm.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19](F)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([O:10][C:11]3[CH:20]=[C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(F)cc1Oc1cnc2[nH]ccc2c1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCNCC2)cc1Oc1cnc2[nH]ccc2c1
Temperature: 25 °C

Procedure:
A mixture of EXAMPLE 3H (20.5 g) and piperazine (37.0 g) in dimethylsulfoxide (200 mL) was heated to 110° C. for 24 hours, and the mixture was allowed to cool to room temperature. The mixture was poured into water (1 L), extracted three times with dichloromethane, and the combined extracts were washed with 2× water, and brine and filtered and concentrated to give the pure product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N+:9]2[O-])([O-:3])=[O:2].C1(C)C(S(Cl)(=O)=O)=CC=CC=1.C(N(CC)CC)C.[CH3:33][OH:34]>>[CH3:33][O:34][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: CO
Reactant: O=[N+]([O-])c1cccc2c1ccc[n+]2[O-]
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c([N+](=O)[O-])cccc2n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 1 g (5 mmol) of 5-nitroquinoline-1-oxide, 1.23 g (6.4 mmol) of toluenesulfonic acid chloride and 1.4 ml (9.9 mmol) of triethylamine in 30 ml of MeOH is stirred for 20 hours at room temperature. The solid is suctioned off and washed with MeOH: 565 mg of light yellow product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:6][CH2:5][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: OCCc1ccccc1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccccc2Br)cc1

Procedure:
The reaction and work up was conducted as described in the preparation of compound 163 using 2-bromophenethyl alcohol (5 g, 25 mmol) in pyridine (12 mL) and p-toluenesulfonyl chloride (5.2 g, 27.5 mmol). The crude product was purified by flash chromatography eluting with EtOAc/petroleum ether 1:4. This afforded the title compound as a colourless crystalline compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc(N)n2)cn1
Yield: 100.6 %

Procedure:
A solution of 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (110 mg, 0.188 mmol) in TFA (10 mL) was heated at 80° C. for 16 h. The orange mixture was concentrated to a slurry, diluted with saturated NaHCO3 (5 mL), and filtered. The solid was washed with water, MeOH, and (3:1) hexane-EtOAc to give the product as a brown solid (65 mg). LCMS (ES, pos.): calcd for C15H14ClN7O: 343.1. found: 344.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.69 (br. s., 1H); 8.72 (br. s., 1H); 8.50 (d, J=3.33 Hz, 1H); 8.31 (br. s., 1H); 8.09 (br. s., 1H); 7.94 (br. s., 1H); 7.80 (br. s., 1H); 6.84 (br. s., 2H); 3.85 (br. s., 3H); 2.43 (br. s., 3H).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=[C:8]([C:22]([OH:24])=O)[C:7]=2[C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]1[C:29](=[O:38])[NH:30][C:31]([CH3:37])=[CH:32][C:33]=1[CH2:34][CH2:35][CH3:36]>>[CH3:37][C:31]1[NH:30][C:29](=[O:38])[C:28]([CH2:27][NH:26][C:22]([C:8]2[C:7]3[C:6]([CH3:25])=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:12]=3[CH:11]=[C:10]([C:13]3[CH:14]=[C:15]4[CH:21]=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:9]=2)=[O:24])=[C:33]([CH2:34][CH2:35][CH3:36])[CH:32]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: Cc1nn(C(C)C)c2cc(-c3cnc4[nH]ccc4c3)cc(C(=O)O)c12
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1c(C)nn2C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was prepared in the same manner as described for example 80 (step c) from 1-isopropyl-3-methyl-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-indazole-4-carboxylic acid (50 mg, 0.149 mmol) and 3-(aminomethyl)-6-methyl-4-propylpyridin-2(1H)-one (26 mg, 0.149 mmol) wherein the contents were stirred at RT for 5 h. The crude product was washed with DCM, filtered, and dried to afford the title compound as an off-white solid. (48 mg, 64%). 1H NMR (DMSO-d6, 400 MHz): δ 0.930 (t, J=7.6 Hz, 3H), 1.468 (d, J=6.4 Hz, 6H), 1.544-1.601 (m, 2H), 2.123 (s, 3H), 2.452 (s, 3H), 2.501 (s, 2H), 4.394 (d, J=4 Hz, 2H), 5.060-5.093 (m, 1H), 5.902 (s, 1H), 6.526 (s, 1H), 7.420 (s, 1H), 7.528 (s, 1H), 7.996 (s, 1H), 8.348 (s, 1H), 8.445 (s, 1H), 8.656 (s, 1H), 11.490 (brs, 1H), 11.735 (brs, 1H). LCMS (ES+) m/z: 497.49
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>O1CCCC1>[C:9]([NH:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[CH:3][N:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ncc(N)cn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1ncc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 9.1 %

Procedure:
To a solution of N-(5-aminopyrimidin-2-yl)acetamide (450 mg, 2.96 mmol) and pyridine (0.718 ml, 8.87 mmol) in tetrahydrofuran (10 ml) was added 2,2,2-trichloroethyl chloroformate (0.612 ml, 4.44 mmol) with ice-cooling, the mixture was stirred for 1 hour with ice-cooling and then at room temperature for 2 hours, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (88.3 mg, 9.1%) as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([NH:17][C:18]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)=[O:19])=[C:11]2[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1ccc2c(NC(=O)C3CCNCC3)ccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2c(NC(=O)C3CCN(Cc4ccccc4)CC3)ccnc21
Temperature: 0 °C
Yield: 47.6 %

Procedure:
A solution of N-(1-tert-butoxycarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-piperidinecarboxamide (500 mg), benzyl bromide (370 mg) and potassium carbonate (300 mg) in dimethylformamide (10 ml) was stirred at 80° C. for 4 hours. The reaction mixture was poured into ice-water and extracted with chloroform. The residue obtained by water washing, drying and then concentration under reduced pressure was purified by silica gel column chromatography to give 300 mg of N-(1-tert-butoxycarbonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-benzyl-4-piperidinecarboxamide.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH2:28]([C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1)[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.CO.S1C=CC=C1C([O-])=O.[Cu+]>[CH2:28]([C:30]1[N:31]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[N:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Agent: [Cu+]
Agent: O=C([O-])[O-]
Agent: O=C([O-])c1cccs1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)sc2n1
Yield: 35.9 %

Procedure:
A mixture 2-[1-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperidin-4-yl]propan-2-ol (100 mg, 0.24 mmol), 2-ethyl-1H-benzoimidazole (42 mg, 0.29 mmol), copper(I) thiophene-2-carboxylate (9 mg, 0.048 mmol) and cesium carbonate (119 mg, 0.36 mmol) in NMP (0.5 mL) was stirred at 110° C. for 18 hours. The reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed and the residue was subjected to flash chromatography (Si—PCC, 0-20% MeOH in EtOAc) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 332 as a beige solid (45 mg, 36%). LCMS (Method G): RT 7.37 min; [M+H]+ 522. 1H NMR (400 MHz, CHCl3-d): δ 8.03-7.98 (m, 1 H); 7.77-7.73 (m, 1 H); 7.32-7.24 (m, 2 H); 4.41 (m, 4H); 3.90-3.85 (m, 6 H); 3.35 (q, J=7.5 Hz, 2 H); 3.11 (m, 2 H); 2.33-2.12 (m, 2 H); 1.79 (m, 2 H); 1.57 (m, 2 H); 1.44 (t, J=7.5 Hz, 3 H); 1.34 (m, 1 H); 1.22 (s, 6 H)
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][N:8]=1.[Li][CH2:15]CCC.CI.[NH4+].[Cl-]>CCOCC>[Cl:13][C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:6]2[CH:5]=[CH:4][S:3][C:2]=2[CH3:15])[CH:12]=1
Reactant: [Li]CCCC
Reactant: Clc1ccnc(-c2ccsc2Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: Cc1sccc1-c1cc(Cl)ccn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2-bromo-thiophen-3-yl)-4-chloro-pyridine (80 mg, 0.3 mmol) in Et2O (3 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 0.2 mL). After 10 min, MeI (70 mg, 0.5 mmol) was added. The resulting mixture was maintained at −78° C. for 2 h, then was warmed to room temperature and stirred for 3 h. The reaction mixture was treated with 2 M aqueous NH4Cl and extracted with EtOAc. The organic layer was dried and concentrated to yield a residue. The residue was purified by preparative TLC (hexanes/EtOAc) to yield 4-chloro-2-(2-methyl-thiophen-3-yl)-pyridine as a solid.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:9]=2)[N:4]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.O.C(#N)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:9]=2)[N:4]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[N:3]=1
Reactant: Cn1cc(-c2cc3c(Cl)nn(C4CCCCO4)c3cn2)cn1
Reactant: COc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(F)c(-c2nn(C3CCCCO3)c3cnc(-c4cnn(C)c4)cc23)c1
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
In a microwave vial was charged with 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (29.4 mg, 0.093 mmol), 2-(2-fluoro-5-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (35.0 mg, 0.139 mmol), potassium acetate (13.6 mg, 0.14 mmol), sodium carbonate (14.7 mg, 0.14 mmol), and bis(diphenylphosphino)ferrocene]dichloropalladium (II), complexed with dichloromethane (1:1) (7.5 mg, 9.2E−3 mmol). Degassed acetonitrile (0.8 mL) and water (0.3 mL) were added. Nitrogen was passed through the mixture for 15 minutes and the vial was capped. The reaction mixture was subjected to microwave irradiation at 125° C. for 25 min. The reaction mixture was filtered through a pad of Celite® and diluted with water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified using flash chromatography (Si-PPC gradient elution, solvent: 10-100% ethyl acetate in heptanes) to give 3-(2-fluoro-5-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine as a foam (37.3 mg, 98.9%). 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 7.95 (s, 1H), 7.90 (s, 1H), 7.81 (d, J=2.8 Hz, 1H), 7.32 (dd, J=5.5, 3.2 Hz, 1H), 7.15 (t, J=9.4 Hz, 1H), 6.97-6.89 (m, 1H), 5.86 (dd, J=8.7, 2.1 Hz, 1H), 4.07-3.98 (m, 1H), 3.93 (s, 3H), 3.86-3.74 (m, 4H), 2.64-2.47 (m, 1H), 2.16 (d, J=9.7 Hz, 2H), 1.83-1.66 (m, 3H). LC/MS: m/z 408.2 [M+1].