Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:24][C:25]3[CH:44]=[CH:43][C:28]([O:29][C:30]4[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=4)=[C:27]([Cl:45])[CH:26]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.O>CO.O1CCCC1.[OH-].[Na+]>[ClH:45].[Cl:45][C:27]1[CH:26]=[C:25]([NH:24][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:44]=[CH:43][C:28]=1[O:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[O:35])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccc(Nc3ncnc4ccn(CCOCCO)c34)cc2Cl)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 193.3 %

Procedure:
tert-Butyl 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy}benzoate (189 mg) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (1 mL), 1N aqueous sodium hydroxide solution (0.6 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and 1N hydrochloric acid/ethyl acetate solution (0.3 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (163 mg) as a white powder.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([F:15])[CH:7]=2)[CH2:3][CH2:2]1.B.C1COCC1.O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[C:8]([F:15])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(OCC2CC2)cc1F
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(OCC2CC2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-2-fluorobenzoic acid (5.00 g, 23.8 mmol) in THF (100 mL) was added dropwise 1 M borane-THF solution (54.7 mL, 54.7 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was slowly added dropwise water (100 mL). To this solution was further added water, and the mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate), and the obtained residue was triturated with hexane to give the title compound (4.08 g, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:13]=2[C:14]([OH:16])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:30])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)[N:11]=[C:12]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[C:13]=2[C:14]([Cl:30])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(C(=O)O)c(-c3ccco3)nn12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(C(=O)Cl)c(-c3ccco3)nn12
Reaction time: 0.5 h
Yield: 105.3 %

Procedure:
To a solution of 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid (358 mg) and N,N-dimethylformamide (1.39 mg) in dichloromethane (3 mL) was added oxalyl chloride (157 mg) at room temperature. After stirring for 30 minutes, the volatile was removed in vacuo, and the residue was azeotroped with toluene three times to afford 4-(3-chlorophenyl)-7-ethyl-2-(2-furyl)pyrrolo[1,2-b]pyridazine-3-carbonyl chloride as an yellow gum (396 mg, 106%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7](F)[C:6]=1[F:14]>CO>[Br:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([O:2][CH3:1])[C:6]=1[F:14]
Reactant: C[O-]
Reactant: O=Cc1ccc(Br)c(F)c1F
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)ccc(Br)c1F
Yield: 93.9 %

Procedure:
Sodium methoxide (28% methanol solution, 69.1 g) was added to a solution of 4-bromo-2,3-difluorobenzaldehyde (52.8 g) in methanol (600 mL) at room temperature. The mixture was refluxed under nitrogen atmosphere for 2 hours and concentrated in vacuo to about 1/4 volume. The mixture was diluted with ethyl acetate and water. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (52.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:29][S:30]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:32])=[O:31].O>CN(C)C(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[ClH:1].[CH2:21]([N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:38]4[CH:39]=[CH:40][C:35]([CH2:34][NH:33][S:30]([CH3:29])(=[O:31])=[O:32])=[CH:36][CH:37]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1)[CH3:22]
Reactant: CS(=O)(=O)NCc1ccc(B(O)O)cc1
Reactant: CCn1ncc(CN2CCN(c3nccnc3Cl)CC2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1ncc(CN2CCN(c3nccnc3-c3ccc(CNS(C)(=O)=O)cc3)CC2)c1C
Product: Cl
Temperature: 70 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
Combine 3′-chloro-4-(1-ethyl-5-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.300 g, 0.935 mmol), potassium carbonate (0.310 g, 2.24 mmol), (4-methanesulfonylaminomethylphenyl)boronic acid (0.257 g, 1.12 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.009 mmol) in N,N-dimethylacetamide (1.9 mL). Add water (940 μL), and reflux reaction for 6 hr. Continue to heat at 70° C. for 18 hr. Add (4-methanesulfonylaminomethylphenyl) boronic acid (0.129 g, 0.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.009 mmol) and heat to 115° C. for 6 hr. Continue to stir at ambient temperature over 72 hr. Add DCM and wash with water. Extract water layer three times with DCM. Dry combined organics (magnesium sulfate) and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 to 20:80 methanol:ethyl acetate), to give the free base of the title compound (371 mg, 85%). Dissolve the free base (0.367 g, 0.781 mmol) in acetonitrile (938 μL) and add aq. 1 N HCl solution (938 μL, 0.938 mmol). Shake for 15 min. at ambient temperature. Freeze dry to give the title compound (397 mg, 100%). MS (ES): m/z=470 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C@@H:15]([NH:25][C:26](=[O:44])[CH2:27][N:28]3[C:36]4[C:35]([F:38])([F:37])[CH2:34][CH2:33][C:32]([F:40])([F:39])[C:31]=4[C:30]([CH:41]([F:43])[F:42])=[N:29]3)[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=2)[CH:5]=[CH:4]N=N1.N1(CCN)CC[CH2:57][CH2:56]1.BrC1C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1>>[F:42][CH:41]([F:43])[C:30]1[C:31]2[C:32]([F:39])([F:40])[CH2:33][CH2:34][C:35]([F:38])([F:37])[C:36]=2[N:28]([CH2:27][C:26]([NH:25][C@H:15]([C:13]2[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=[C:9]([NH:8][CH2:7][CH2:6][N:1]3[CH2:57][CH2:56][CH2:4][CH2:5]3)[N:14]=2)[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)=[O:44])[N:29]=1
Reactant: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Reactant: NCCN1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Product: NC(=O)c1cc(-c2cnc(NCCN3CCCC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (27) was prepared according to the method presented for the synthesis of compound 23F of Example 23 starting with 2-(pyrrolidin-1-yl)ethanamine and 23B. 1H NMR (400 MHz, CD3OD) δ 8.67 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 7.41-7.23 (m, 2H), 7.13 (dd, J=10.7, 8.5 Hz, 1H), 6.95-6.48 (m, 2H), 6.35 (d, J=6.2 Hz, 2H), 5.15 (m, 1H), 4.95 (q, J=16.7 Hz, 2H), 3.74 (m, 4H), 3.43 (m, 2H), 3.11 (m, 2H), 3.00-2.88 (m, 2H), 2.70-2.28 (m, 4H), 2.13-1.89 (m, 4H). MS (m/z) 769.29 [M+H]+.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(Cl)c3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 3-chloro-phenylhydrazine according to the method described for example 43. MS: M=427.1 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][C:20]3([CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[O:19][CH2:18][CH2:17]2)=[O:15])[N:13]=1.[Si:27]([O:34][CH2:35][CH2:36][C:37]1[S:41][C:40]([CH2:42][CH:43]=O)=[CH:39][CH:38]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Si:27]([O:34][CH2:35][CH2:36][C:37]1[S:41][C:40]([CH2:42][CH2:43][N:24]2[CH2:25][CH2:26][C:20]3([O:19][CH2:18][CH2:17][N:16]([C:14]([C:12]4[N:13]=[C:9]([CH3:8])[S:10][CH:11]=4)=[O:15])[CH2:21]3)[CH2:22][CH2:23]2)=[CH:39][CH:38]=1)([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(CC=O)s1
Reactant: Cc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: Cc1nc(C(=O)N2CCOC3(CCN(CCc4ccc(CCO[Si](C)(C)C(C)(C)C)s4)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
(2-Methylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 4, step h) (0.25 g) was added to a solution of 2-(5-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)acetaldehyde (0.2 g) (example 4, step g) in a mixture of NMP (5 mL) and acetic acid (0.04 mL). The resulting mixture was stirred for 5 min then sodium triacetoxyborohydride (0.22 g) was added. The mixture was stirred for 1 h and poured into pH 7.2 buffer (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organics were washed with pH 7.2 buffer (50 mL) and brine (50 mL), then dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 4:1:0.05 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine to give the subtitled compound as a yellow oil. Yield 0.23 g.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.O1CCCC1>[CH2:12]([O:19][C:20]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1CCCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To an ice cooled solution of nipecotic acid (10.0 g, 77.5 mmol), sodium hydroxide (3.4 g, 85 mmol), and tetrahydrofuran (50 mL) in water (100 mL) was added by simultaneous dropwise addition benzylchloroformate (13.3 mL, 93 mmol) in tetrahydrofuran (50 mL) and sodium hydroxide (3.4 g, 85 mmol) in water (50 mL). Warmed slowly to room temperature. After 24 hours tetrahydrofuran was removed in vacuo and the resulting aqueous mixture acidified with 3 N hydrochloric acid and extracted with dichloromethane (3×). The combined organic portions were dried with anhydrous magnesium sulfate. Filtration followed by evaporation of the filtrate in vacuo gave the titled compound. 1HNMR (CHCl3, 300 MHz) □ 7.45-7.20 (m, 5H); 5.14 (m, 2H); 4.21 (br s, 1H); 3.96 (m, 1H), 3.15 (br s, 1H); 2.93 (m, 1H); 2.51 (m, 1H); 2.09 (m, 1H); 1.80-1.60 (m, 2H); 1.50 (m, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=1.P(Br)(Br)[Br:15]>C(Cl)Cl>[Br:15][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: COCCOc1cccc(CO)c1
Solvent: ClCCl
Product: COCCOc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 171.7 %

Procedure:
To a solution of 27C (18.2 g, 100 mmol) in CH2Cl2 (300 mL) was added PBr3 (4.5 mL, 48 mmol) at 0° C., then the resulting mixture was allowed to warm to RT overnight. The reaction mixture was quenched with saturated NaHCO3 (50 mL) and stirred at RT for an addition 0.5 h. The mixture was extracted with CH2Cl2, and the combined extracted were dried (MgSO4), filtered, and evaporated in vacuum to give the product as a yellow oil (20.2 g, 82%, two steps). 1H NMR (300 MHz, CDCl3): δ 3.45 (s, 1H), 3.75 (t, 2H, J=4.8 Hz), 4.12 (t, 2H, J=4.8 Hz), 4.45 (s, 2H), 6.85-6.99 (m, 3H), 7.21-7.26 (m, 1H). LC-MS: purity >95%, ESI-MS: M/Z 245 (M+H)+, 247 (M+2+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](I)=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH:30]1([C:36]#[CH:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]([C:37]#[C:36][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:14][N:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[C:8]=2[N:9]=[C:10]([Cl:12])[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(I)nn2C1CCCCO1
Reactant: C#CC1CCCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Cl)nc2c1c(C#CC1CCCCC1)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
A solution of 6-chloro-3-iodo-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (1.0 g, 2.30 mmol) and triethylamine (1.92 mL, 13.77 mmol) in THF (7.65 mL) was degassed using argon during 3 min. Cyclohexylacetylene (0.45 mL, 3.44 mmol), copper(I) iodide (0.08 g, 0.46 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.11 mmol) were then added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the residue purified on a silica gel column chromatography using a gradient of ethyl acetate (0-5%) in cyclohexane to afford the title compound as a beige solid (0.93 g, 97%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([CH2:24][CH:25]=[CH:26][CH2:27][P:28]([O:33]CC)([O:30][CH2:31][CH3:32])=[O:29])[CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[OH-].[Li+]>CO.O>[CH2:31]([O:30][P:28]([CH2:27][CH:26]=[CH:25][CH2:24][CH:4]([CH2:5][C:6]([CH3:23])=[CH:7][CH2:8][C:9]1[C:10]([OH:22])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21])[C:3]([OH:36])=[O:2])([OH:33])=[O:29])[CH3:32]
Reactant: CCOP(=O)(CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)OC)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOP(=O)(O)CC=CCC(CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O)C(=O)O
Temperature: 70 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
A mixture of 2-[4-(diethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid methyl ester 4C (25 mg, 0.048 mmol) and lithium hydroxide (200 mg) in a mixture of methanol (3 mL) and water (1 mL) was stirred at 70° C. for 2 hours. The organic solvent was evaporated and the residue acidified with 2N HCl and extracted with ethyl acetate/acetonitrile. The organic extract was concentrated, and the residue was purified by preparative reverse-phase HPLC (acetonitrile and 0.1% aqueous CF3COOH), affording 2-[4-(ethoxy-hydroxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid 4E as an oil (15 mg, 89%); 1H NMR (300 MHz, CD3OD) δ 1.25 (t, J=6.9 Hz, 3H), 1.81 (s, 3H), 2.1-2.6 (m, 8H), 3.40 (d, J=6.6 Hz, 2H), 3.77 (s, 3H), 3.97 (m, 2H), 5.1-5.3 (m, 3H), 5.67 (brs, 2H) ppm.
Reaction SMILES: COC1C=CC(C2CCCC3C=C(OC)C=CC=3C=2)=C(N)C=1.Cl.[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N1(CCOC2C=C[C:56]([CH2:57][NH:58][C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[C:67]3[CH2:73][CH2:72][CH2:71][C:70]4[CH:74]=[C:75]([O:78][CH3:79])[CH:76]=[CH:77][C:69]=4[CH:68]=3)=CC=2)CCCCCC1>>[N:24]1([CH2:31][CH2:32][O:33][C:34]2[CH:42]=[CH:41][C:37]([CH2:38][N:58]([CH2:57][CH3:56])[C:59]3[CH:64]=[C:63]([O:65][CH3:66])[CH:62]=[CH:61][C:60]=3[C:67]3[CH2:73][CH2:72][CH2:71][C:70]4[CH:74]=[C:75]([O:78][CH3:79])[CH:76]=[CH:77][C:69]=4[CH:68]=3)=[CH:36][CH:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Reactant: COc1ccc2c(c1)CCCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCCC3)cc1)=C2
Agent: COc1ccc(C2=Cc3ccc(OC)cc3CCC2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1=Cc2ccc(OC)cc2CCC1

Procedure:
Synthesized from 5-methoxy-2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-azepan-1-ylethoxy)benzyl][5-methoxy-2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenyl]amine (458 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-azepan-1-ylethoxy)benzyl]ethyl[5-methoxy-2-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)phenyl]amine (324 mg). This compound (322 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (280 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1.[H-].[Na+].[CH3:16]I.CO>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:16])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: O=c1[nH]cnc2cc(Cl)nc(Cl)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,7-dichloropyrido[4,3-d]pyrimidin-4(3H)-one (1.73 g, 8.0 mmol) in dry DMF (25 mL) was added NaH (352 mg, 60% in mineral oil, 8.8 mmol) at 0° C. and the resulting mixture was stirred under N2 at 0° C. for 30 min. MeI (0.6 mL, 1.36 g, 9.6 mmol) was added via a syringe and the reaction mixture was stirred at room temperature for 14 hours and was cooled to 0° C. MeOH (2.0 mL) was added slowly and the reaction mixture was stirred for 20 minutes at room temperature and then concentrated under reduced pressure. The resulting residue was partitioned between 10% aqueous NH4Cl solution (80 mL) and EtOAc (40 mL). The aqueous phase was separated and extracted with EtOAc (3×30 mL). The combined EtOAc extracts were washed with brine (8 mL), dried over MgSO4 and evaporated to afford the title compound. 1H NMR (DMSO-d6) δ 3.46 (s, 3H), 7.74 (s, 1H), 8.64 (s, 1H); ESI-MS m/z 230.1 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[C:10](=[O:13])([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19]Br>CN(C=O)C>[CH2:17]([O:13][C:10]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:18][CH2:19][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: BrCCCBr
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCOc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
To a solution of 4-cyanophenol (20.0 g; 0.16 mol) in DMF (350 mL) was added powdered potassium carbonate (34.8g; 0.25 mol) under an atmosphere of argon. This mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 1,3-dibromopropane (8.52 mL; 0.08 mol) via syringe, and the mixture stirred at room temperature for 16 hours. The solvent was removed by high vacuum distillation and the remaining white solid was taken up in 200 mL of EtOAc. HCl (1N in water) was then added and a white precipitate formed. This precipitate was collected by filtration, washed several times with diethyl ether, and then dried under vacuum. A total of 20.2 g of a white solid were obtained (90% yield).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[O:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:7][CH2:6]1.N1C=CC=CC=1.[F:23][C:24]1[C:30]([CH3:31])=[C:29]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)[CH:34]=2)[CH:28]=[CH:27][C:25]=1[NH2:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:23][C:24]1[C:30]([CH3:31])=[C:29]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)[CH:34]=2)[CH:28]=[CH:27][C:25]=1[NH:26][C:12]([N:13]1[CH2:14][CH2:15][N:11]([CH:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)[C:1]1=[O:2])=[O:16]
Reactant: Cc1c(Oc2ccnc(-c3cnn(C)c3)c2)ccc(N)c1F
Reactant: O=C1NCCN1C1CCOCC1
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Oc2ccnc(-c3cnn(C)c3)c2)ccc(NC(=O)N2CCN(C3CCOCC3)C2=O)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
Phosgene (20% in toluene, 0.798 mL, 1.508 mmol) was treated drop-wise with a solution of Example B1 (0.128 g, 0.754 mmol) and pyridine (0.244 mL, 3.02 mmol) in DCM (5 mL), stirred at RT for 10 min, then concentrated to dryness. The residue was dissolved in DCM (5 mL), treated drop-wise with a solution of 2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.15 g, 0.503 mmol) and DIEA (0.527 mL, 3.02 mmol) in DCM (5 mL) stirred at RT for 3 h. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (0.188 g, 76%). 1H NMR (400 MHz, DMSO-d6): δ 10.76 (d, J=2.7 Hz, 1 H), 8.33 (d, J=5.7 Hz, 1 H), 8.24 (s, 1 H), 8.05 (t, J=9.0 Hz, 1 H), 7.95 (d, J=0.7 Hz, 1 H), 7.16 (d, J=2.4 Hz, 1 H), 6.98 (d, J=9.0 Hz, 1 H), 6.57 (dd, J=5.7, 2.4 Hz, 1 H), 3.93-3.83 (m, 6 H), 3.82-3.77 (m, 2 H), 3.46 (t, J=8.2 Hz, 2 H), 3.38 (dd, J=12.6, 10.8 Hz, 2 H), 2.05 (d, J=2.0 Hz, 3 H), 1.71 (m, 2 H), 1.59 (br d, J=12.3 Hz, 2H); MS (ESI) m/z: 495.2 (M+H+).