Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:27]4[CH2:29][CH2:28]4)[C:11]=3[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)c3[nH]nc(C)c3C2c2ccc(Cl)cc2)cc1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Product: COc1ccc(CN2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)-5-(4-methoxybenzyl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 85.4) (8.76 g, 23.82 mmol) in 1,2-dichloroethane (100 mL) were added cyclopropylboronic acid (4.09 g, 47.6 mmol), copper (II) acetate (5.19 g, 28.6 mmol), Na2CO3 (5.05 g, 47.6 mmol) and 2,2′-bipyridine (3.72 g, 23.82 mmol) and the resulting mixture was stirred 16 h at 70° C. The reaction mixture was quenched with a saturated aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with saturated aq. NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane/EtOAc 15-30%) to afford the title product (3.27 g, 7.62 mmol, 32% yield) as yellow solid. tR: 5.77 min (HPLC 1); tR: 1.27 min (LC-MS 2); ESI-MS: 408 [M+H]+ (LC-MS 2); Rf=0.65 (hexane/EtOAc 1:1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[CH3:2].[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[CH3:2]
Reactant: CCc1cc(N)ccc1[N+](=O)[O-]
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])c(CC)c1

Procedure:
N-(3-Ethyl-4-nitrophenyl)-2-methylacrylamide was prepared as described in Example 1a starting from 3-ethyl-4-nitrophenylamine (W. Pfleiderer et al. U.S. 2002/0146737 A1) and methacryloyl chloride. The crude product was purified by flash chromatography using heptane/ethyl acetate (9:1) as an eluent. 1H NMR (400 MHz, DMSO-d6): 1.22 (3H, t, 3J=7.4 Hz), 1.97 (3H, s), 2.87 (2H, q, 3J=7.4 Hz), 5.62 (1H, s), 5.88 (1H, s), 7.81 (1H, dd, 3J=8.9 Hz, 4J=2.3 Hz), 7.83 (1H, d, 4J=2.2 Hz), 8.00 (1H, d, 3J=8.8 Hz), 10.21 (1H, s, —NHCO—).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.Br[CH:9]([CH3:13])[C:10](=O)[CH3:11]>>[CH3:13][C:9]1[N:1]=[C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]2[C:10]=1[CH3:11]
Reactant: Nc1cnccn1
Reactant: CC(=O)C(C)Br
Product: Cc1nc2cnccn2c1C

Procedure:
Similarly, condensation of the 2-aminopyrazine with 3-bromo-2-butanone gives the 2,3-dimethylimidazo[1,2-a]pyrazine as shown in the following reaction Scheme IV. ##STR16##
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7](=[NH:9])[N:6]([CH2:10][CH:11]3[CH2:15][CH2:14][CH2:13][O:12]3)[N:5]=2)[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22](/[N:9]=[C:7]1\[S:8][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][N:6]\1[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1)=[O:23]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: N=c1sc(C2CC2)nn1CC1CCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C2CC2)nn1CC1CCCO1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of the compound from Example 2A (70 mg, 0.31 mmol), 5-chloro-2-methoxy-benzoic acid (64 mg, 0.34 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (185 mg, 0.46 mmol) and triethylamine (130 L, 0.93 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 12 hour. The mixture was diluted with water, and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluting with ethyl acetate/hexanes 2:3) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95-1.01 (m, 2H) 1.14-1.21 (m, 2H) 1.67-1.78 (m, 1H) 1.79-1.93 (m, 2H) 1.91-2.00 (m, 1H) 2.30-2.39 (m, 1H) 3.65 (dd, J=13.81, 7.06 Hz, 1H) 3.77 (dd, J=13.50, 6.75 Hz, 1H) 3.80 (s, 3H) 4.21 (dd, J=13.20, 4.60 Hz, 1H) 4.31-4.38 (m, 1H) 4.43 (dd, J=12.89, 7.36 Hz, 1H) 7.13 (d, J=8.90 Hz, 1H) 7.49 (dd, J=8.90, 2.76 Hz, 1H) 7.73 (d, J=2.76 Hz, 1H); MS (ESI+) m/z 394 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH:7]([OH:11])[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:22]O>>[Br:1][C:2]1[C:3]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH:7]([OH:11])[C:8]([O:10][CH3:22])=[O:9]
Reactant: CO
Reactant: Cc1cccc2sc(C(O)C(=O)O)c(Br)c12
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1sc2cccc(C)c2c1Br
Yield: 88 %

Procedure:
A solution of (3-bromo-4-methyl-benzo[b]thiophen-2-yl)-hydroxy-acetic acid (23g) (270 mg, 0.9 mmol) and sulfuric acid (500 μL) in methanol (5 mL) was refluxed for 1 hour. The reaction mixture was then concentrated and the residue was diluted with ethyl acetate (20 mL). The organic layer was washed with water (2×20 mL), a saturated aqueous solution of sodium bicarbonate (20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired product (23h) as a orange solid (250 mg, 0.79 mmol, 88%) without further purification.
Reaction SMILES: [O:1]1[C@@H:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@@H:2]1[C:3]([O:5]CC)=[O:4].[OH-].[K+]>C(O)C>[CH2:12]([O:11][C:9](=[O:10])[C@@H:8]1[O:1][C@H:2]1[C:3]([OH:5])=[O:4])[CH3:13]
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)[C@@H]1O[C@H]1C(=O)O
Yield: 42.7 %

Procedure:
In 50 ml of ethanol is dissolved 13.1 g (69.7 mmole), of diethyl (2R,3R)-epoxysuccinate, and a solution of 3.94 g of potassium hydroxide in 120 ml of ethanol is added dropwise to the solution under ice-cooling with stirring. After the stirring under ice-cooling for 3 hours, the ethanol is distilled off under reduced pressure. 50 ml of water and 100 ml of ether are added to the residue to a solution, and the aqueous layer is separated. The ether layer is extracted three times with dilute aqueous sodium chloride solution, and the aqueous layers are combined and acidified with 3N hydrochloric acid. The solution, after being saturated with sodium chloride, is extracted four times with ethyl acetate, and the extract is washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is distilled under reduced pressure to give 4.76 g (42.7%) of (2R,3R)-epoxysuccinic acid monoethyl ester as a colorless oil having a boiling point of 121°-122° C. (0.85 mmHg). The product, upon standing, crystallizes, and the crystals are recrystallized from isopropyl ether-petroleum ether (1:2) to give colorless crystals.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]2[C:12](=[O:13])[CH2:11][CH2:10][N:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:19]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C@H:8]2[C@@H:12]([OH:13])[CH2:11][CH2:10][N:9]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)N1CCC(=O)C1C(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)N1CC[C@H](O)[C@@H]1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of 2-(diphenylmethyl)-1-ethoxycarbonylpyrrolidin-3-one (Example 1c, 5.75 g, 18 mmol) in ethanol (50 ml) was added sodium borohydride (1.00 g, 26 mmol) and the mixture was stirred under nitrogen for 60 h at room temperature. The reaction mixture was partitioned between 10% citric acid/ethyl acetate, the organic phase washed with saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue chromatographed on silica gel using ethyl acetate/hexane (2:3) as eluant. Recrystallisation from ethyl acetate/hexane gave cis-2-(diphenylmethyl)-3-hydroxy-1-ethoxycarbonylpyrrolidine, m.p.=104°-105° C. 1H NMR (360 MHz, CDCl3) δ7.00-7.50 (10H, m), 4.78 (1H, dd, J=9 Hz and J=7 Hz), 4.46 (1H, dd, J=8.0 Hz and J=7.0 Hz), 4.32 (1H, d, J=9 Hz), 3.83 (2H, m), 3.47 (2H, m), 3.31 (1H, m), 2.10 (1H, m), 1.95 (1H, m), 1.00 (3H, t, J=7.0 Hz).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.C(N(CC)CC)C.[C:30]([NH:38][NH2:39])(=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[NH:6][C:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[N:38][N:39]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NNC(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2n[nH]c3ccc(-c4nnc(-c5ccccc5)[nH]4)cc23)cc1
Yield: 47.7 %

Procedure:
The procedure described in example 119 using ethoxy[3-(4-fluorophenyl)(1H-indazole-5-yl)]methanimine hydrochloride (200 mg, 0.62 mmol), triethylamine (0.25 mL, 1.86 mmol) and benzoic hydrazide (170 mg, 1.25 mmol) was followed to yield the title compound (105 mg, 48% yield). 1H NMR (DMSO-d6) δ 13.5 (br s, 1H), 8.74 (s, 1H), 8.0–8.2 (m, 5H), 7.75 (d, 1H), 7.35–7.6 (m, 5H), ES-MS (m/z) 356 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])[C:19]2[C:14](=[CH:15][CH:16]=[N:17][C:18]=2[O:31][CH:32]([CH3:34])[CH3:33])[NH:13][C:12]=1[CH3:35])=[O:10])[C:2]1C=CC=CC=1.[Na]>C(O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:28])[F:29])[C:19]2[C:14](=[CH:15][CH:16]=[N:17][C:18]=2[O:31][CH:32]([CH3:34])[CH3:33])[NH:13][C:12]=1[CH3:35])=[O:10])[CH3:2]
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1ccccc1C(F)(F)F

Procedure:
1.44 g (+)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid benzyl ester is introduced into a solution of 100 mg sodium in 90 mL anhydrous ethanol and boiled under reflux for 20 hours. The reaction mixture is evaporated, the residue is taken up in 50 mL dichloromethane and extracted three times with 20 mL amounts of water. The organic phase is dried over anhydrous sodium sulfate and thereafter evaporated to dryness. The residue is recrystallized from 20 mL n-hexane. The filter cake is dried to constant weight at 30° C. in a vacuum drying cabinet. Yield: 850 mg (67.38% of theory); mp 130° C.; [α]D =+110° C. (c=0.5/dichloromethane).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]#[C:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:20]=[C:14]2[N:13]=[CH:12]1.CO.N1C2C(=CC=CC=2)C=CC=1.[H][H]>[Pd].CCOCC.C(Cl)(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]=[CH:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])[N:20]=[C:14]2[N:13]=[CH:12]1
Reactant: [H][H]
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(C#CCOC3CCCCO3)cnc-2n1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: c1ccc2ncccc2c1
Product: CC(C)(C)C(=O)Nc1cc2c(O)n(C=CCOC3CCCCO3)cnc-2n1

Procedure:
A mixture of 2 g of 3-(3-tetrahydropyr-2-yloxyprop-1-yn-1-yl)-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine, 40 ml of methanol, 20 ml of chloroform, 40 mg of 5% palladium on barium sulfate, and 40 mg of synthetic quinoline is stirred under 1 atmosphere hydrogen pressure for 40 min. The solvent then is removed by evaporation and the residue diluted with methylene chloride. The methylene chloride solution is filtered through silica gel with 2% methanol in methylene chloride to remove catalyst and the filtrate then concentrated to give an oil which upon adding ether yields 3-(3-tetrahydropyr-2-yloxyprop-1-en-1-yl)-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine which can be further purified through column chromatography eluting with ethyl acetate and recrystallization using ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:3]=[C:4]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[N:6][CH:7]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cncc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 5′-bromo-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,3′]bipyridinyl (example E.24) (0.200 g, 0.5 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.157 g, 0.6 mmol) according to the general procedure VI. Obtained as an off-white solid (0.182 g, 68%). MS (ISP) 526.3 [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:21])([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([NH2:29])[CH:26]=[N:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([CH3:21])([CH3:20])[C:17]([NH2:19])=[O:18])=[N:7][C:2]([NH:29][C:27]2[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Reactant: Cn1cc(N)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(Nc2ncc(Cl)c(CCc3ccccc3C(C)(C)C(N)=O)n2)cn1
Temperature: 120 °C
Yield: 18 %

Procedure:
A mixture of 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)-2-methylpropanamide A38 (0.042 g, 0.12 mmol), 1-methyl-1H-pyrazol-4-amine (0.022 g, 0.23 mmol), and p-toluenesulfonic acid monohydrate (0.002 g, 0.012 mmol) in 1,4-dioxane (4.0 mL) was heated in the microwave at 120° C. for 3 hours. After cooling, the volatiles were removed in vacuo and the residue was adsorbed onto silica. Purification by column chromatography (Biotage Isolera, 12 g SiO2, 0-5% MeOH in DCM) gave the title compound 45 as an off-white solid (0.009 g, 18%). LCMS-D: rt 3.29 min; m/z 399 [M+H]+.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:15]3[NH:41][C:18]4=[N:19][CH:20]=[C:21]([NH:23][C:24](=[O:40])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[C:26]=5[F:39])[CH:22]=[C:17]4[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:4][O:3]1.Cl>C1COCC1.CO>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[NH:41][C:18]3=[N:19][CH:20]=[C:21]([NH:23][C:24](=[O:40])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[C:27]([NH:32][S:33]([CH2:36][CH2:37][CH3:38])(=[O:35])=[O:34])[C:26]=4[F:39])[CH:22]=[C:17]3[CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4cccc(OCC5COC(C)(C)O5)c4)cc3c2)c1F
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(-c4cccc(OCC(O)CO)c4)cc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
A solution of N-(2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (22 mg, 36 mmol) in 2:1 THF/MeOH (3 mL) was treated with 1N HCl (1 mL) and the mixture stirred at room temperature for 16 hours. The volatiles were removed via rotary evaporation, and the resulting residue was partitioned between EtOAc and aqueous NaHCO3. The layers were separated, and the organic layer was dried (MgSO4), filtered and concentrated to a solid. The solid was triturated with DCM and collected via vacuum filtration to afford N-(2-(3-(2,3-dihydroxypropoxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (13 mg, 64%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.16 (s, 1H), 10.89 (s, 1H), 9.80 (s, 1H), 8.40-8.33 (m, 2H), 7.58-7.49 (m, 3H), 7.40-7.34 (m, 1H), 7.31-7.24 (m, 1H), 7.00-6.90 (m, 2H), 5.00-4.96 (m, 1H), 4.72-4.67 (m, 1H), 4.12-4.07 (m, 1H), 4.01-3.99 (m, 1H), 3.88-3.81 (m, 1H), 3.52-3.47 (m, 1H), 3.16-3.10 (m, 2H), 1.82-1.74 (m, 2H), 1.04-0.97 (m, 3H); m/z (APCI-pos) M+1=561.2.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([N:10]=[CH:11][CH:12]=2)[CH:5]=[C:6]([O:8]C)[CH:7]=1.Br.[OH-].[Na+]>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:4]([N:10]=[CH:11][CH:12]=2)[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: COc1cc(Br)c2ccnn2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Oc1cc(Br)c2ccnn2c1
Temperature: 150 °C

Procedure:
4-bromo-6-methoxypyrazolo[1,5-a]pyridine (725 mg, 3.19 mmol) was suspended in HBr (12 ml, 106 mmol). The reaction mixture was heated in the Biotage Initiator Series microwave for 1 h at 150° C. The reaction mixture was slowly added via pipete to a solution of 5N NaOH (22.0 ml, 110 mmol) in 100 mL of saturated aqueous sodium bicarbonate at 0° C. The reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated to afford 4-bromopyrazolo[1,5-a]pyridin-6-ol.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)=[O:7])[CH2:3][CH2:2]1.Br[CH2:24][C:25]1[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([CH2:4][NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH2:24][C:25]4[S:29][C:28]([C:30]([O:32][CH3:33])=[O:31])=[CH:27][CH:26]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: COC(=O)c1ccc(CBr)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)cc3)CC2)s1
Yield: 90.9 %

Procedure:
1-(Cyclopropylmethyl)-3-(4-(piperazine-1-carbonyl)phenyl)urea (4.25 mmol, 1.286 g), methyl 5-(bromomethyl)thiophene-2-carboxylate (4.25 mmol, 1 g) and potassium carbonate (12.76 mmol, 1.764 g) were stirred at room temperature in acetonitrile (20 mL) for 18 hours. The reaction mixture was concentrated at reduced pressure and the resulting residue taken up in dichloromethane, washed with water, dried over sodium sulfate and concentrated under vacuum to afford the title compound (1.764 g). MS (ESI) m/z 457.5 [M+H]+
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=O)C.Cl.[Cl:28][CH2:29][C:30]1[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:28].[OH:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:29][C:30]3[N:31]([CH3:35])[CH:32]=[CH:33][N:34]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Reactant: Cn1ccnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1nccn1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
A solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg, 1.06 mmol), (prepared as described for the starting material in Example 1), 2-chloromethyl-1-methylimidazole hydrochloride (354 mg, 2.12 mmol), and potassium carbonate (585 mg) in DMF (15 ml) was heated at 60° C. for 15 hours. After cooling to ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (20 ml) and 2M sodium hydroxide (1 ml) was added. After stirring for 1 hour, the reaction mixture was diluted with water (20 ml) and 2M hydrochloric acid (3 ml) was added. The resulting solid was filtered off, washed with water and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(1-methylimidazol-2-ylmethoxy)quinazoline hydrochloride (150 mg, 29%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10]([CH3:33])=[N:11][C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[CH2:16]2)=[CH:13][CH:14]=1)(C)(C)C.C(O)C.Cl.[OH-].[Na+]>O>[CH3:33][C:10]1[C:9]([CH2:8][NH2:7])=[CH:14][CH:13]=[C:12]([N:15]2[CH2:19][CH2:18][C:17]([C:24]3[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=3)([C:20]([F:22])([F:23])[F:21])[CH2:16]2)[N:11]=1
Reactant: Cc1nc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1CNC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1CN
Temperature: 50 °C
Yield: 77.6 %

Procedure:
t-Butyl({2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-pyridin-3-yl}methyl)carbamate (0.95 g) was added to ethanol (25 ml) and then to the solution was added conc. hydrochloric acid (5 ml) in small portions at room temperature, and then heated at 50° C. for 3 hours. After cooling the mixture to the room temperature, the reaction mixture was diluted with water (100 ml). The pH was adjusted to 11 by using an aqueous solution of sodium hydroxide and the solution was extracted with ethyl acetate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain 1-({2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-3-yl}methanamine (0.6 g).