Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=C(O[C@@H]([C@H]2CNC(=O)C2)C)C2N(C)C=NC=2C=1.C[N:22]1[C:27]2[CH:28]=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=[CH:31][C:26]=2[C:25](C)(C)[O:24][C:23]1=[O:43]>>[NH:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH2:25][O:24][C:23]1=[O:43]
Reactant: CN1C(=O)OC(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Product: O=C1Nc2ccccc2CO1

Procedure:
Following general procedure A, starting from (R)-4-((R)-1-((6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (63 mg), and 1,4,4-trimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one (67 mg), 55 mg of 1,4,4-trimethyl-7-(3-methyl-4-4R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-1H-benzo[d][1,3]oxazin-2(4H)-one was synthesized.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[OH:6]>C(OCC)C>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C@H:5]2[CH2:4][O:6]2)=[CH:8][CH:9]=1
Reactant: O[C@H](CCl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Fc1ccc([C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.6 %

Procedure:
1.6 M aqueous sodium hydroxide solution (50 ml) was added to a solution of 2-chloro-(1S)-1-(4-fluorophenyl)ethanol (10.4 g) in diethyl ether (40 ml), and the mixture was stirred at room temperature for 5 hrs. The organic layer was separated and the aqueous layer was extracted with diethyl ether. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give (2S)-2-(4-fluorophenyl)oxirane (8.28 g) as a colorless oil.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:10]([O:14][C:15](=[O:37])[CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][C:24]([N:26]([CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])=[CH:25][C:20]=2[N:19]=[C:18]1[CH2:34][CH2:35][CH3:36])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)C1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)C3CCCCC3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclohexanecarbonyl chloride (48 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H39N3O3+H: 490, observed: 490.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=[O:24])[CH2:19][CH2:18]1.O>CN(C=O)C>[CH2:7]([O:25][C:23]([CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][OH:15])[CH2:18][CH2:19]1)=[O:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C1CCC(CO)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CCC(CO)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (2.61 g, 18.9 mmol) and benzyl bromide (2.24 mL, 18.9 mmol) were added to a solution of 4-hydroxymethyl-cyclohexanecarboxylic acid (cis-trans=2.9:1 mixture) (2.49 g, 15.7 mmol) in DMF (31.5 mL) at room temperature, and the mixture was stirred at 60° C. for one hour. The reaction solution was cooled, and H2O (60 mL) was then added to the reaction solution, followed by extraction with hexane:ethyl acetate (2:1) (300 mL) twice. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 4-hydroxymethyl-cyclohexanecarboxylic acid benzyl ester (cis-trans=3.5:1 mixture) as a colorless oily substance (3.79 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:16][CH2:15]3)[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:17](O)(=[O:24])[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:10]=3)[C:6]3([CH2:16][CH2:15]3)[C:7]2=[O:14])[CH2:12][CH2:13]1
Reactant: Nc1ccc2c(c1)N(C1CC1)C(=O)C21CC1
Reactant: O=C(O)c1ccncc1
Product: O=C(Nc1ccc2c(c1)N(C1CC1)C(=O)C21CC1)c1ccncc1

Procedure:
Prepared in analogy to example 26 from 6′-amino-1′-cyclopropylspiro[cyclopropane-1,3′-indolin]-2′-one and isonicotinic acid. The title compound was obtained as light yellow crystals.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+]=[N-])[CH:46]([O:53][CH:54]([CH3:56])[CH3:55])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([OH:59])[CH2:5][C:4]1=[O:60])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:53][CH:54]([CH3:56])[CH3:55])[CH2:45]2)[CH:7]([CH3:58])[CH:6]([OH:59])[CH2:5][C:4]1=[O:60])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 70 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-azido-3"-isopropyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (22 mg) in 10% aqueous toluene (0.5 ml) was added triphenylphosphine (10.7 mg) and the mixture heated to 70° C. with stirring. After 18 hours, the stir bar was removed and the reaction cooled to room temperature. The mixture was concentrated to 10% volume in vacuo and purified by preparative TLC on silica gel (2% ammonium hydroxide, 5% methanol in methylene chloride) to give the title compound (5.5 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)=O)C>O1CCCC1>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[O:17][CH:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:10][OH:9]
Reactant: CCOC(=O)C1CCCC1OC1CCCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCCC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
A slurry of lithium aluminum hydride (883 mg, 23.27 mmol) in tetrahydrofuran (19.4 mL) cooled to 0° C. was treated with 2-(tetrahydro-pyran-2-yloxy)-cyclopentanecarboxylic acid ethyl ester (4.7 g, 19.59 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was poured onto ice/water. This mixture was filtered through a pad of celite (methylene chloride as eluent). The organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give [2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-methanol (3.25 g, 83.6%) as a clear liquid: EI-HRMS m/e calcd for C11H20O3 (M+) 200.1412 found 200.1412.
Reaction SMILES: C(N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1)C.[C:16]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:26]=2)[CH2:21][CH2:20]1)(=O)[CH3:17]>>[CH2:16]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([S:28]([NH2:31])(=[O:29])=[O:30])[CH:26]=2)[CH2:21][CH2:20]1)[CH3:17]
Reactant: CC(=O)N1CCc2ccc(S(N)(=O)=O)cc21
Agent: CCN1CCc2cc(S(N)(=O)=O)ccc21
Product: CCN1CCc2ccc(S(N)(=O)=O)cc21
Yield: 26.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 53, 1-acetylindoline-6-sulfonamide (Intermediate 60, 200 mg, 0.83 mmol) was converted to the title compound (50 mg, 27%) after purification using preparative HPLC. 1H NMR (CDCl3) δ 7.37 (d, J=7.5 Hz, 1H), 7.21 (d, J=9.7 Hz, 2H), 3.59 (t, J=8.1 Hz, 2H), 3.28 (q, J=8.1 Hz, 2H), 3.10 (t, J=8.1 Hz, 2H), 1.26-1.22 (m, 3H); MS(ESI+) m/z 227.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[O:14][CH3:15])[CH3:2].C(N(CC)C1C=CC=CC=1)C.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>C1(C)C=CC=CC=1>[Cl:10][C:9]1[CH:8]=[C:7]([NH:11][C:29](=[O:30])[O:31][CH:32]([CH3:34])[CH3:33])[CH:6]=[C:5]([NH:12][C:13]([O:14][CH3:15])=[O:16])[C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1c(Cl)cc(N)cc1NC(=O)OC
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1c(Cl)cc(NC(=O)OC(C)C)cc1NC(=O)OC
Temperature: 0 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
Methyl N-(2-ethoxy-3-chloro-5-aminophenyl)carbamate (1.39 g) and N,N-diethylaniline (0.85 g) were dissolved in toluene (15 ml). To the resultant solution was dropwise added isopropyl chloroformate (0.70 g) in 5 minutes under ice-cooling. The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The reside was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-(3-chloro-4-ethoxy-5-methoxycarbonylaminophenyl)carbamate (Compound No. 2) (1.73 g) in a yield of 92.0%. M.P., 140° C.-142° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (38.28 g) and 4-fluoronitrobenzene (26.84 g) in dimethyl sulfoxide (326 ml) was added 60% sodium hydride (7.99 g) under nitrogen atmosphere and with ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (52.384 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21]CC2C=CC=CC=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[OH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1([OH:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: OC1(c2ccccc2OCc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: Oc1ccccc1C1(O)CCNCC1
Reaction time: 6 h
Yield: 108.3 %

Procedure:
In 100 mL of methanol was dissolved 12 g (32 mmol) of 1-benzyl-4-(2-benzyloxyphenyl)-4-piperidinol. To the resulting solution was added 3 g of 20% palladium hydroxide carbon and the resulting mixture was subjected to catalytic reduction at room temperature for 6 hours under 4 atmospheric pressure. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure, whereby 6.7 g (yield: 100%) of 4-(2-hydroxyphenyl)-4-piperidinol was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.Cl.[CH2:27]([N:29]1[CH:33]=[C:32]([NH2:34])[CH:31]=[N:30]1)[CH3:28].CC(C)([O-])C.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([NH:34][C:32]3[CH:31]=[N:30][N:29]([CH2:27][CH3:28])[CH:33]=3)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCn1cc(N)cn1
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Temperature: 140 °C
Yield: 51 %

Procedure:
A mixture of 2-bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (150 mg, 351 μmol), 1-ethyl-1H-pyrazol-4-amine hydrochloride (51.8 mg, 526 μmol), BINAP (10.9 mg, 17.5 μmol), palladium (II) acetate (19.7 mg, 87.7 μmol) and sodium tert-butoxide (101 mg, 1.05 mmol, Eq: 3) in DMF (1 mL) and toluene (500 μL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was diluted with water then extracted into ethyl acetate (3×). The combined organic extracts were washed with brine then dried over magnesium sulfate. Purification by chromatography (silica, 40-80% ethyl acetate in hexanes) gave N-tert-butyl-2-(1-ethyl-1H-pyrazol-4-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (82 mg, 179 μmol, 51%) as a yellow gum. (EI/CI) m/z: 458.4 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1.C(N(CC)CC)C.[CH:32]([S:35](Cl)(=[O:37])=[O:36])([CH3:34])[CH3:33]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:35]([CH:32]([CH3:34])[CH3:33])(=[O:37])=[O:36])[CH2:14][CH2:13]3)=[C:8]([CH3:18])[C:6]=2[N:7]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CN2CCN(S(=O)(=O)C(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Temperature: 25 °C

Procedure:
To 2-Chloro-7-methyl-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (100 mg) in anhydrous DCM (2 ml) and triethylamine (1.5 equiv., 60 μl) at 0° C. was added isopropylsulfonyl chloride (1.3 equiv., 45.5 μl) and the reaction mixture was allowed to warm up to room temperature overnight. Chloroform/brine extraction and purification on silica gave 2-chloro-7-methyl-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine (105 mg).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=O)C.Cl[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:51]=[CH:50][N:49]([CH2:52][C:53]([OH:56])([CH3:55])[CH3:54])[N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[NH4+]>C(O)CCC.O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]([NH:46][C:47]4[CH:51]=[CH:50][N:49]([CH2:52][C:53]([OH:56])([CH3:54])[CH3:55])[N:48]=4)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)[C:6]=1[CH2:5][OH:4])[N:30]=[CH:29]2)([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: Cn1nc(Cl)cc(Nc2ccn(CC(C)(C)O)n2)c1=O
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CCCCO
Solvent: O
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccn(CC(C)(C)O)n2)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (282 mg, 0.57 mmol), 6-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-3-ylamino)-2-methylpyridazin-3(2H)-one (100 mg, 0.34 mmol), potassium phosphate (178 mg, 0.84 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (16.0 mg, 0.03 mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (9.66 mg, 0.02 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×150 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 10% methanol in dichloromethane) to give 6-tert-butyl-8-fluoro-2-(2-hydroxymethyl-3-{5-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one (119 mg, 60%) as a white solid: MP. 165-170° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91-1.13 (m, 6H) 1.38 (s, 8H) 3.16-3.36 (m, 2H) 3.91 (s, 2H) 4.35-4.65 (m, 4H) 6.20 (d, J=2.27 Hz, 1H) 7.28-7.64 (m, 4H) 7.75 (d, J=13.22 Hz, 1H) 7.82-7.99 (m, 2H) 8.51 (d, J=2.27 Hz, 1H) 9.24 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:16][C:17]1[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:15][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([CH2:2][O:16][C:17]3[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1cccnc1-c1cccc(Cl)c1
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)c(OCc2cccnc2-c2cccc(Cl)c2)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(3-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 2.00 equiv) in CH3CN (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters 2545 UvDector 254 & 220 nm. This resulted in 71 mg (9%) of 5-[[2-(3-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.72 (m, 1H), 8.20 (m, 2H), 7.79 (s, 1H), 7.60 (m, 4H), 6.95 (m, 1H), 5.21 (m, 2H), 3.85 (s, 3H); MS (ESI) m/z 355 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[C:9]2[CH:11]=[C:12]([CH2:14][C:15]([OH:34])([C:30]([F:33])([F:32])[F:31])[CH2:16][C:17]([C:20]3[C:28]4[O:27][CH2:26][CH2:25][C:24]=4[CH:23]=[C:22]([Cl:29])[CH:21]=3)([CH3:19])[CH3:18])[NH:13][C:8]2=[CH:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.CO.O.O.Cl>[Cl:29][C:22]1[CH:21]=[C:20]([C:17]([CH3:19])([CH3:18])[CH2:16][C:15]([OH:34])([C:30]([F:33])([F:31])[F:32])[CH2:14][C:12]2[NH:13][C:8]3[C:9](=[N:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)[CH:11]=2)[C:28]2[O:27][CH2:26][CH2:25][C:24]=2[CH:23]=1
Reactant: COC(=O)c1ccc2[nH]c(CC(O)(CC(C)(C)c3cc(Cl)cc4c3OCC4)C(F)(F)F)cc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CC(O)(Cc1cc2nc(C(=O)O)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
2-[4-(5-Chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-pyrrolo[3,2-b]pyridine-5-carboxylic acid methyl ester (100 mg, 0.2 mmol) was dissolved in 2 mL of THF-MeOH-water (3:1:1). Lithium hydroxide monohydrate (25 mg, 0.6 mmol) was added. The reaction was stirred at room temperature for 4 hours. The mixture was diluted with 5 mL of water and 6 N HCl solution was used to adjust the pH to about 2. The organic was extracted with three 50 mL portions of ethyl acetate, washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give the title compound (13.5 mg, 14% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[O:9][CH3:10].C([Li])CCC.[C:16]1(=[O:20])[CH2:19][CH2:18][CH2:17]1>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2([OH:20])[CH2:19][CH2:18][CH2:17]2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C1CCC1
Reactant: COc1cc(I)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCC2)ccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 12.2 %

Procedure:
To a solution of 2-bromo-5-iodoanisole (400 mg, 1.28 mmol) in tetrahydrofuran (5 mL) at −78° C. was added n-butyl lithium (2.5 M in hexane, 0.62 mL, 1.55 mmol) dropwise over 15 minutes. The reaction mixture was stirred at −78° C. for 30 minutes, then treated with neat cyclobutanone (0.1 mL, 1.3 mmol) dropwise over 10 minutes and stirred at −78° C. for an additional 1.5 hours. The reaction was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature and extracted with ethyl acetate (2×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow oil, which was purified by flash chromatography (12 g silica, 0-50% ethyl acetate/heptane, 27 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a pale yellow oil (40 mg, 12% yield). GCMS 256/258 (M)+; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J=8.29 Hz, 1 H), 7.09 (d, J=1.95 Hz, 1 H), 6.98 (dd, J=8.17, 1.83 Hz, 1 H), 3.94 (s, 3H), 2.51-2.61 (m, 2H), 2.35-2.46 (m, 2 H), 2.02-2.10 (m, 1 H), 1.66-1.79 (m, 1 H).