Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[NH:10][CH:11]1[CH2:15][CH2:14][O:13][C:12]1=O.C([O-])(=[S:19])C.[K+]>COCCOCCOC>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[C:3]=1[NH:10][CH:11]1[CH2:15][CH2:14][S:19][C:12]1=[O:13]
Reactant: CC([O-])=S
Reactant: CCc1cccc(C)c1NC1CCOC1=O
Agent: [K+]
Solvent: COCCOCCOC
Product: CCc1cccc(C)c1NC1CCSC1=O
Temperature: 150 °C
Reaction time: 20 h
Yield: 44.2 %

Procedure:
11 g (0.05 mol) of N-(2-methyl-6-ethylphenyl)amino-tetrahydrofuran-2-one and 6.6 g (0.05 mol) of potassium thioacetate are dissolved in 200 ml of diethylene glycol dimethyl ether and the solution is stirred for 20 hours at 150° C. After cooling, the mixture is poured into ice-water and extracted with methylene chloride. The combined extracts are washed repeatedly with water, dried over sodium sulfate and filtered and the filtrate is concentrated. After distillation under a high vacuum, the residue yields 5.2 g (44.2% of theory) of N-(2-methyl-6-ethylphenyl)-amino-tetrahydrothiophen-2-one. Boiling point 160°-165° C. under 0.45 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[NH:10][C:9]1=S.P(Cl)(Cl)(Cl)(Cl)[Cl:22]>O=P(Cl)(Cl)Cl>[Cl:22][C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1c2cc(F)ccc2[nH]c(=S)n1-c1ccccc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cc(F)ccc2nc(Cl)n1-c1ccccc1Cl

Procedure:
A suspension of 306 mg (1.0 mmol) of 3-(2-chloro-phenyl)-6-fluoro-2-thioxo-2,3-dihydro-1H-quinazolin-4-one in 2.0 mL of POCl3 was treated with 350 mg of PCl5 and the mixture was refluxed for 2.5 hours. The solvent was evaporated and the residues were taken up in ethyl acetate, washed with water and brine, and then the solvent was evaporated to give 2-chloro-3-(2-chloro-phenyl)-6-fluoro-3H-quinazolin-4-one as a solid. This material was dissolved in 15 mL of absolute ethanol and 238 mg (2.20 mmol) of 2-aminomethylpyridine and the mixture was refluxed overnight. The reaction mixture was cooled and the solvent was evaporated. The residue was dissolved in ethyl acetate and washed twice with water. The organic layer was dried with brine and with MgSO4 and evaporated to give a gum which was crystallized from ether to give 190 mg (50%) of the desired product, m.p. 156-158° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)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.C(#N)C>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:22]#[C:23][C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Temperature: 100 °C
Yield: 90 %

Procedure:
(R)-(-)-5'-Bromospiro[1-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine](295 mg, 1 mmol), trimethylsilylacetylene (0.355 mL, 2.5 mmol), tetrakis(triphenylphosphine)palladium (230 mg, 0.2 mmol), triethylamine (2 mL) and anhydrous acetonitrile (2 mL) were combined in a heavy-walled threaded glass tube containing a magnetic stir bar, purged with argon and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 100° C. for 4 hours, cooled to room temperature, dissolved in chloroform (25 mL), washed with saturated aqueous sodium carbonate (2 mL), dried (MgSO4), and evaporated under reduced pressure. Purification by flash chromatography through silica gel (eluting with ammoniated ether/methanol, 9:1) afforded the title compound (280 mg, 0.90 mmol, 90%): chemical ionization MS (m/z, relative intensity) 313 ([MH]+, 30).
Reaction SMILES: B1([C:7]2[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=2)OCCCO1.[Cl:13][C:14]1[CH:15]=[C:16]([C:23]2[CH:27]=[CH:26][N:25]([CH2:28][C@@H:29]([NH:31][C:32]([C:34]3[N:35]=[CH:36][NH:37][CH:38]=3)=[O:33])[CH3:30])[N:24]=2)[CH:17]=[C:18]([F:22])[C:19]=1[C:20]#[N:21].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([C:23]2[CH:27]=[CH:26][N:25]([CH2:28][C@@H:29]([NH:31][C:32]([C:34]3[N:35]=[CH:36][N:37]([C:7]4[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=4)[CH:38]=3)=[O:33])[CH3:30])[N:24]=2)[CH:17]=[C:18]([F:22])[C:19]=1[C:20]#[N:21]
Reactant: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]cn1
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn(-c2cccnc2)cn1
Temperature: 25 °C
Reaction time: 47 h
Yield: 16.57 %

Procedure:
3-Pyridineboronic acid 1,3-propanediol ester (43.7 mg, 0.268 mmol), (S)—N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-imidazole-4-carboxamide (50 mg, 0.134 mmol), anhydrous copper(II) acetate (36.5 mg, 0.201 mmol), pyridine (0.022 ml, 0.268 mmol) and DCM (1 ml) were added into a flask and stirred at RT for 47 h. The reaction mixture was extracted with ethyl acetate, dried, filtered and evaporated. The product was purified by column chromatography. Yield 16.57%. 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 4.28 (dd, 1H), 4.47 (dd, 1H), 4.57-4.67 (m, 1H), 6.64 (d, 1H), 7.48-7.55 (m, 2H), 7.74-7.78 (m, 1H), 7.81 (d, 1H), 7.88 (d, 1H), 7.91-7.94 (m, 2H), 8.27 (d, 1H), 8.72 (d, 1H), 8.79 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[N:20]1([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[N:15][C:16]([N:23]3[CH2:24][CH2:25][N:20]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[CH2:21][CH2:22]3)=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCc1cccc(F)c1)c1ccc(Cl)nn1
Product: O=C(NCCc1cccc(F)c1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(3-fluorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (71% yield). 1H NMR (400 MHz, CDCl3) δ 8.05, 7.93, 7.74, 7.64-7.56, 7.37-7.35, 7.26-7.24, 7.01-6.90, 4.10-4.03, 3.89-3.70, 3.36-3.33, 2.92.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH2:21].CC1C=CC=CC=1C.CC1C=CC(S(O)(=O)=O)=CC=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)N1CCC(=Nc2c(Cl)cccc2Cl)CC1

Procedure:
A mixture of 171 parts of ethyl 4-oxo-1-piperidinecarboxylate, 162 parts of 2,6-dichlorobenzenamine, 800 parts of dimethylbenzene and 1 part of 4-methylbenzenesulfonic acid is stirred and refluxed with water-separator. The reaction mixture is evaporated, yielding 250 parts of ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate as a residue.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=O)[C:24]2=[O:32])=[CH:19][CH:18]=1.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([C:23]2([C:20]3[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=3)[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:24]2=[O:32])=[CH:38][CH:37]=1
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)cc3)no2)CCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.204 g, 1.0 mmol), 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (Example 58D, 0.331 g, 1.0 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.383 g, 2.00 mmol) were stirred together in dichloroethane (5.0 mL) at room temperature for 2 hours under nitrogen. The reaction was then heated to 85° C. and stirred overnight. The reaction mixture was cooled, concentrated, loaded onto a SF25-40 column (Analogix®, Burlington, Wis.) and the product eluted using a gradient of 10% ethyl acetate/hexanes to 70% ethyl acetate over 30 minutes (Flow=30 mL/minute) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.10 (d, J=8.1, 2H), 7.75 (d, J=8.3, 2H), 7.44-7.31 (m, 4H), 7.08-6.94 (m, 4H), 4.90 (s, 2H), 3.57 (t, J=6.5, 2H), 2.84 (t, J=6.5, 2H); MS (DCI) m/z 500.1 (M+H)+.
Reaction SMILES: ClC1N=C2C(C=[CH:7][C:8]([N:12]3[CH:20](OC(OC4C=CC=CC=4)=O)[C:19]4[C:14](=CC=[CH:17][CH:18]=4)[C:13]3=O)=N2)=CC=1.C(#[N:34])C>>[CH2:20]([N:12]1[CH2:8][CH2:7][NH:34][CH2:14][CH2:13]1)[CH2:19][CH:18]=[CH2:17]
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC#N
Product: C=CCCN1CCNCC1

Procedure:
Following the procedure of Example 36 but starting from 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-1-isoindolinone (4.32 g.) and 1-(but-3-en-1-yl)-piperazine (7 g.) in acetonitrile (25 cc.), 3-[4-(but-3-en-1-yl)-1-piperazinyl]-carbonyloxy-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (1.4 g.) melting at 142° C is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.N1C=CC=CC=1.[CH3:39][C:40](OC1C(=O)OC(=O)C1OC(C)=O)=[O:41]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:40]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)(=[O:41])[CH3:39]
Reactant: CC(=O)OC1C(=O)OC(=O)C1OC(C)=O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.6 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydro-3-isoxazolyl]-3-pyridinyl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 200 mg, 0.46 mmol) was suspended in 2 mL of anhydrous dimethylformamide. Anhydrous pyridine (2 mL, 24 mmol), 4-dimethylaminopyridine (DMAP) (20 mg, 0.17 mmol) and di-O-acetyl-L-tartaric anhydride (210 mg, 0.97 mmol) were added and the solution was stirred for 16 hours at room temperature during which the mixture turned black. The reaction was quenched with 1 mL of methanol, the solvents evaporated in vacuo and the product isolated by flash chromatography on silica using a gradient from 0 to 5% methanol in dichloromethane to yield 50 mg (25%) of the title compound as an off white solid.
Reaction SMILES: [OH:1][C@@H:2]([C:13]1[C:14]([CH3:36])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3([C:33]([OH:35])=O)[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>C1COCC1>[OH:1][C@@H:2]([C:13]1[C:14]([CH3:36])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3([C:33]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:35])[CH2:31][CH2:32]3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)[CH2:3][O:4][C@@H:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
1-(4′-{4-[(S)-1-Hydroxy-2-((R)-1-phenyl-ethoxy)-ethyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid (0.022 g, 0.044 mmol) was dissolved in THF (3 mL) and carbonyldiimidazole (0.022 g, 0.14 mmol) was added. After 1.5 hours an additional portion of carbonyldiimidazole (0.011 g) was added. The reaction stirred for 40 minutes then carbonyldiimidazole (0.044 g) was added. The reaction stirred overnight then carbonyldiimidazole (0.044 g) was added and the reaction was heated to 50° C. After heating for 3 hours, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.100 mL, 0.67 mmol) and methanesulfonamide (0.050 g, 0.53 mmol) were added and the reaction was heated to 100° C. The reaction was monitored by analytical LCMS and when it was complete it was cooled and purified on preparatory HPLC to afford the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]([C:21]1[NH:22][CH:23]=[CH:24][N:25]=1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]([C:21]1[N:25]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[O:9][CH3:10])[CH:24]=[CH:23][N:22]=1)[CH3:20]
Reactant: COc1ccccc1CBr
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccccc1Cn1ccnc1C(C)c1cccc(C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(Bromomethyl)-2-methoxybenzene (J. Indian Chem. Soc.; 28, 1951, 277; 150 mg, 0.75 mmol) was added to a suspension of the compound of Example 1 (100 mg, 0.5 mmol) and caesium carbonate (406 mg, 1.2 mmol) in acetone (4 ml), under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered and the filtrate was concentrated in vacuo. To the residue was added water (10 ml) and ethyl acetate (10 ml) and the two layers were separated. The aqueous layer was washed with a further portion of ethyl acetate (10 ml) and the combined organic layers were dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[CH2:38]([P:47](=[O:54])([O:51][CH2:52][CH3:53])[O:48][CH2:49][CH3:50])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12](/[CH:13]=[CH:38]/[P:47](=[O:54])([O:48][CH2:49][CH3:50])[O:51][CH2:52][CH3:53])=[CH:11][N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:9]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 67.7 %

Procedure:
To a mixture of 3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.43 g, yield 68%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 92-93° C.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]#[C:24][CH3:25]>CN(C)C=O.C(OCC)(=O)C>[CH2:22]([N:11]1[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:23]#[C:24][CH3:25]
Reactant: CC#CCBr
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Chlorotheophylline (4.9 g) and potassium carbonate (5 g) were dissolved in N,N-dimethylformamide (100 ml), and 1-bromo-2-butyne (2.4 ml) was added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected through filtration, and washed with ethyl acetate to give 3.8 g of 7-(2-butynyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (1.8 g) and 1-piperazine carboxylic acid tert-butyl ester (3.7 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over an hydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.6 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20]O)[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:36]([NH:38][CH3:39])=[O:37])[N:8]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=5)=[CH:24][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:59]1(=[O:69])[NH:63][C:62](=[O:64])[C:61]2=[CH:65][CH:66]=[CH:67][CH:68]=[C:60]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][N:63]3[C:59](=[O:69])[C:60]4[C:61](=[CH:65][CH:66]=[CH:67][CH:68]=4)[C:62]3=[O:64])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:36]([NH:38][CH3:39])=[O:37])[N:8]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29]5[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=5)=[CH:24][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCN3C(=O)c4ccccc4C3=O)S(C)(=O)=O)cc2nn1-c1ccc(Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 326.4 %

Procedure:
To a solution of compound (ii) (5 mg, 0.009 mmol), triphenylphosphine (3.6 mg, 0.014 mmol) and phthalimide (2.0 mg, 0.014 mmol) in THF (0.5 mL) was added diisopropyl azodicarboxylate (2.7 μL, 0.014 mmol) at 0° C. After the mixture had been stirred at RT for 3.5 h, more triphenylphosphine (3.6 mg, 0.014 mmol), phthalimide (2.0 mg, 0.014 mmol) and DIAD (2.7 μL, 0.014 mmol) were added and stirring was continued at RT for a further 40 min. The solvent was removed in vacuo and the residue was purified by preparative LCMS (5-50-100% ACN in 0.1% aqueous formic acid) to afford 5-cyclopropyl-6-[3-(1,3-dioxoisoindolin-2-yl)propyl-methylsulfonyl-amino]-2-[4-(4-fluoroanilino)phenyl]-N-methyl-indazole-3-carboxamide (iii) as a white solid (20 mg, 81%).
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:38]=[C:37]4[CH2:39][NH:40][CH2:41][CH2:42][C:36]4=[N:35][C:34]=3[NH:43][CH:44]([CH3:46])[CH3:45])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.C=O>CO>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([F:47])=[C:23]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[N:38]=[C:37]4[CH2:39][N:40]([CH3:2])[CH2:41][CH2:42][C:36]4=[N:35][C:34]=3[NH:43][CH:44]([CH3:45])[CH3:46])[CH2:29][CH2:28]2)=[O:26])[CH:24]=1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CNCC2
Agent: C=O
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(C(=O)c3cc(Cl)ccc3F)CC1)CN(C)CC2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (6.9 mg, 0.033 mmol) was added to a solution of DIPEA (6 μL, 0.033 mmol), (5-chloro-2-fluorophenyl)(1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)methanone TFA salt (8.9 mg, 0.016 mmol) and formaldehyde (1.5 μL, 0.016 mmol) in MeOH (160 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (2.2 mg, 24.1%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.81-1.94 (m, 2H), 1.96-2.05 (m, 2H), 2.85 (t, J=11.5 Hz, 2H), 3.00 (d, J=6.3 Hz, 2H), 3.07 (s, 3H), 3.44-3.53 (m, 4H), 3.71-3.82 (m, 1H), 4.14-4.23 (m, 2H), 4.28-4.37 (m, 1H), 7.28 (dd, J=10.6, 8.8 Hz, 1H), 7.61 (ddd, J=8.8, 4.1, 2.8 Hz, 1H), 7.75 (dd, J=6.1, 2.8 Hz, 1H); ESI-MS m/z [M+H]+ 446.3.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][CH:34]([OH:36])[CH3:35])N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:6]=[N:2][N:3]([CH2:33][CH:34]([OH:36])[CH3:35])[C:4]=2[C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:29][CH:30]=2)=[CH:12][CH:11]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CC(O)CNN
Product: CC(O)Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=6.2 Hz, 2H), 8.23 (d, J=8.7 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.84 (m, 2H), 7.75 (m 2H), 7.57 (t, J=6.6 Hz, 1H), 7.20 (d, J=9.1 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H) 7.00 (dd, J=6.2, 1.7 Hz, 2H), 5.42 (s, 2H), 4.17 (m, 1H), 3.94 (m, 2H), 3.86 (m, 1H), 1.12 (d, J=6.6 Hz, 3H); MS: (M+H m/z=437.3).