Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7]Br)[CH:2]=[CH2:3].C([O-])=[O:16].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([Si:4]([CH2:12][CH:13]=[CH2:14])([CH2:9][CH:10]=[CH2:11])[CH2:5][CH2:6][CH2:7][OH:16])[CH:2]=[CH2:3]
Reactant: C=CC[Si](CC=C)(CC=C)CCCBr
Reactant: O=C[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: C=CC[Si](CC=C)(CC=C)CCCO

Procedure:
Triallyl (3-hydroxylpropyl) silane was prepared from triallyl-3-bromopropyl silane prepared in Example 7 via the formyloxypropyl intermediate. A 100 ml flask equipped with stir bar and reflux condenser was charged with 10.0 grams (36 millimoles) of triallyl 3-bromopropyl silane (prepared as described in Example 7), 4.90 grams (72 millimoles) sodium formate (commercially available from Aldrich Chemical Co. of Milwaukee, Wis.) and 0.60 grams of tetrabutyl ammonium bromide (commercially available from Aldrich Chemical Co.). The suspension was stirred at 110° C. for two days. The solution was then filtered and combined with equal volumes of deionized water and cyclohexane (commercially available as Omnisolve from E. Merck of Gibbstown, N.J.). The organic extract was flash chromatographed on silica using first cyclohexane, followed by 80/20 cyclohexane/acetone to collect the triallyl formyloxypropyl silane intermediate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:52][N:53]([CH3:57])[CH2:54][CH2:55][NH2:56]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:56][CH2:55][CH2:54][N:53]([CH3:57])[CH3:52])=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Reactant: CN(C)CCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)CCNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 37 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (250 mg, 0.70 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (292 mg, 0.77 mmol) and N,N-dimethyl ethylene diamine (153 μL, 1.4 mmol); (243 mg, 37% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7 (m, 2H), 8.0 (d, 1H), 7.6-7.8 (m, 4H), 7.4 (m, 2H), 3.3-3.6 (m, 4H), 2.3 (s, 6H), ES-MS (m/z) 349 [M+1]+.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2)(=O)=O.[OH-].[K+]>O1CCCC1.C(O)C.O>[OH:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(OS(C)(=O)=O)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.8 %

Procedure:
Ethyl 7-[(methylsulfonyl)oxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.56 g) was dissolved in a mixture of tetrahydrofuran (10 mL) and ethanol (15 mL). A solution of potassium hydroxide (85%, 0.8 g) in water (10 mL) was added to the mixture at 0° C. The mixture was allowed to warm to room temperature and stirred for 13 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water and 1M hydrochloric acid (14 mL) was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residual solid was washed with diethyl ether to give the title compound (0.93 g, 81%) as a pale orange solid. MS 349 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[N:59]1([CH2:65][CH2:66]O)[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][CH2:65][N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCCN1CCOCC1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(CCN2CCOCC2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), 2-morpholin-4-ylethanol (0.51 mL) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.34 g, 100%).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=3[OH:28])[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:29])[N:5]([CH3:30])[C:4]1=[O:31].[CH2:32](Br)[CH:33]=[CH2:34].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=3[O:28][CH2:34][CH:33]=[CH2:32])[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:29])[N:5]([CH3:30])[C:4]1=[O:31]
Reactant: C=CCBr
Reactant: Cn1c(N2CCN(CCCOc3cc([N+](=O)[O-])ccc3O)CC2)cc(=O)n(C)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1ccc([N+](=O)[O-])cc1OCCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Yield: 77.4 %

Procedure:
1 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 145--free form), 0.31 g of allyl bromide and 0.36 g of potassium carbonate were suspended in 10 ml of dry acetone and heated under reflux for 5 hours. The reaction mixture was poured into 60 ml of water and then extracted three times with 30 ml portions of chloroform. The extract was washed first with a 0.5 N aqueous solution of sodium hydroxide and then with water. The chloroform solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol=20/1, by volume). The resulting oily substance was crystallized from ethanol, thereby obtaining 0.78 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C>[CH2:11]([O:13][C:14]1[CH:19]=[C:18]([C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1)[CH3:12]
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: CCOc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOc1cccc(-c2ccc(C(=O)O)cn2)c1
Temperature: 140 °C
Yield: 24.1 %

Procedure:
To a solution of 6-bromo-3-pyridinecarboxylic acid (Sigma-Aldrich; 100 mg, 0.495 mmol) in 1,2-dimethoxyethane (9 ml) was added [3-(ethyloxy)phenyl]boronic acid (Sigma-Aldrich; 247 mg, 1.485 mmol), sodium carbonate (315 mg, 2.97 mmol) pre-dissolved in water (1 ml) and bis(triphenylphosphine)palladium(II)chloride (52.1 mg, 0.074 mmol). The mixture was heated at 140° C. for 30 mins in a microwave reactor (high absorbance). Ethyl acetate and water were added followed by aqueous HCl (5M). The aqueous layer was extracted with more ethyl acetate. The organic layers were evaporated to dryness and purified using a 5 g SAX column which was pre conditioned with MeOH. The column was washed with MeOH (2 column volumes) and then eluted with 0.5M NH3/MeOH. The eluant was evaporated to dryness under reduced pressure to give a yellow solid. Purification by MDAP gave the title compound as a white solid (29 mg);
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([C:15]([OH:17])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:18][C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20]1>>[C:26]1([CH2:25][CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C:15]([CH:13]3[C:14]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[O:6][C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)=[O:17])[CH2:20]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)C1c2ccccc2Oc2ccccc21
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1c2ccccc2Oc2ccccc21

Procedure:
9-Xanthenylcarboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-9-xanthenylcarboxamide.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[C:18]([OH:30])[CH:17]=1.O>CN(C)C(=O)C>[OH:30][C:18]1[CH:17]=[C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH:29]=[CH:28][C:19]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]
Reactant: Nc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccc2)c(O)c1)C(F)(F)F
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.78 g, 4.9 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.59 g, 4.9 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 4-Amino-2-hydroxybenzophenone (0.70 g, 3.3 mmol) was added in one portion and the reaction mixture stirred at room temperature overnight. The mixture was poured into water and the aqueous solution decanted from an oily precipitate which was dissolved in methylene chloride, dried (MgSO4) and concentrated in vacuo to yield a brown oil. Purification by flash column chromatography (5% v/v ethyl acetate/methylene chloride) yielded the title propanamide as a white solid (0.83 g, 71%); mp 173°-175° C. 1H-NMR (250 MHz, CDCl3): 1.74 (s, 3H, CH3) 3.49 (s, 1H, OH) 7.14 (dd, 1H, J=8.7, 2.2 Hz, aromatic) 7.28 (d, 1H, J=2.1 Hz, aromatic),7.46-7.65 (m, 6H, aromatic) 8.49 (s, 1H, NH) 12.3 (s, 1H, phenolic OH). MS (CI, CH4): (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14](C(OC(C)(C)C)=O)[S:15]([N:18]1[C:23]2([CH2:25][CH2:24]2)[CH2:22][N:21]([C:26]2[C:27]3[CH:34]=[CH:33][N:32](C(OC(C)(C)C)=O)[C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][S:15]([N:18]1[C:23]2([CH2:24][CH2:25]2)[CH2:22][N:21]([C:26]2[C:27]3[CH:34]=[CH:33][NH:32][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1CCCN1Cc1ccccc1)S(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(NC[C@@H]1CCCN1Cc1ccccc1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-butyl 4-[8-[[(2S)-1-benzylpyrrolidin-2-yl]methyl-tert-butoxycarbonyl-sulfamoyl]-5,8-diazaspiro[2.5]octan-5-yl]pyrrolo[2,3-d]pyrimidine-7-carboxylate (Intermediate 48) (0.57 mmol) was dissolved in DCM (10 mL) and added TFA (1 mL). The reaction mixture was stirred at rt for 16 h, then added NaHCO3 (15 mL) and extracted with EtOAc (2×25 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using EtOAc and MeOH in heptane as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:19]([OH:21])=O)[C:16]([CH3:18])=[CH:17][C:12]=2[S:11][CH:10]([CH3:22])[C:9]1=[O:23])=[O:4].C(N(C(C)C)C(C)C)C.[CH:33]([NH:36][C@@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]1)([CH3:35])[CH3:34].[Cl-].[Na+]>CN(C)C=O>[CH:33]([N:36]([C:19]([C:15]1[C:16]([CH3:18])=[CH:17][C:12]2[S:11][CH:10]([CH3:22])[C:9](=[O:23])[N:8]([CH2:7][CH2:6][NH:5][C:3]([O:2][CH3:1])=[O:4])[C:13]=2[CH:14]=1)=[O:21])[C@@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:38]1)([CH3:35])[CH3:34]
Reactant: CC(C)N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)NCCN1C(=O)C(C)Sc2cc(C)c(C(=O)O)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCCN1C(=O)C(C)Sc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reaction time: 8 h

Procedure:
To a solution of 4-{2-[(methoxycarbonyl)amino]ethyl}-2,7-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid (460 mg) in N,N-dimethylformamide (4 ml) were added CIP reagent, N-ethyldiisopropylamine, tert-butyl (3R)-3-(isopropylamino)piperidine-1-carboxylate, and the mixture was stirred overnight. After the reaction was complete, to the mixture was added a saturated aqueous sodium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (284 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26](O)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:64][CH2:65][C@@H:66]([OH:75])[CH2:67][N:68]1[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:64][CH2:65][C@@H:66]([OH:75])[CH2:67][N:68]5[CH2:69][CH2:70][N:71]([CH3:74])[CH2:72][CH2:73]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(C[C@H](O)CN)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@@H](O)CN4CCN(C)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 3 h
Yield: 59.5 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (150 mg, 0.34 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (110 mg, 0.34 mmol) were dissolved in 30 mL of anhydrous dichloromethane, followed by the addition of diisopropylethylamine (0.1 mL, 0.75 mmol) and (2R)-1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 20e (59 mg, 0.34 mmol). The reaction solution was stirred for 3 hours. The resulting solution was added with 30 mL of saturated sodium carbonate solution and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium carbonate solution (50 mL×3), water (50 mL) and saturated sodium chloride solution (50 mL) successively, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(2R)-2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]-2,3-dihydrobenzofuran-4-carboxamide 25 (120 mg, yield: 60.0%) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=2)=[CH:32][CH:31]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=2[C:7]([C:6]2[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:9])=[CH:32][CH:31]=1
Reactant: Cc1cc(Cc2ccc(Br)cc2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C(C)C
Yield: 77.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (1.03 g, 4.35 mmol, RN-117439-59-5), oxalyl chloride (0.417 mL, 4.79 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.560 mL, 4.79 mmol) and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.35 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 1.63 g (77%) of the title compound as a yellow clear oil. 1H NMR (DMSO-d6) δ1.16 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.28 (septet, 2H), 3.74 (s, 3H), 3.83 (s, 2H), 6.98 (d, 2H), 7.41 (dd, 2H), 7.44 (s, 2H).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.Cl[C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+]>CC(O)C>[N:31]1[CH:32]=[CH:33][C:28]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]3)[CH2:10][CH2:9]2)=[CH:29][CH:30]=1
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccncc3)CC2)C1
Temperature: 90 °C

Procedure:
tert-Butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (10.403 mmol, 1 eq) and N-ethyl-diisopropylamine (41.608 mmol, 4 eq) were dissolved in 2-propanol (20 ml). 4-Chloropyridine (31.206 mmol, 3 eq) was added and the mixture was heated at 90° C. for 16 h. Saturated sodium bicarbonate solution (50 ml) was added and the phases were separated. The aqueous phase was extracted with ethyl acetate (4×50 ml) and the combined org. phases were washed with saturated sodium chloride solution (50 ml), dried over magnesium sulfate and concentrated. After purification by column chromatography (silica gel, ethyl acetate/methylene chloride/methanol/ammonia (25% aq) (100:100:25:1), the desired product was obtained as a yellow oil. Yield: 1.8 g (55%)
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:8]2[O:12][C:11]([CH2:14]OS(C)(=O)=O)([CH3:13])[CH2:10][C:9]=2[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:3])[CH3:2].[I-:29].[Na+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:8]2[O:12][C:11]([CH2:14][I:29])([CH3:13])[CH2:10][C:9]=2[C:20]=1[C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COS(C)(=O)=O)O2
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CI)O2
Yield: 67.5 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.55 g of 5-acetoxy-4,6-di-t-butyl-2-methanesulfonyloxymethyl-2-methyl-2,3-dihydrobenzofuran and combined with 3.0 g of sodium iodide, and the mixture was heated under reflux for 24 hours. After cooling, water was added and the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 10% ethyl acetate to give 0.4 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran (rotamer mixture) as a colorless oil (yield 68%).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].C1(S([C:25]2[O:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=O)CCCCC1.O>CN1CCCC1=O.CCOCC>[CH2:1]([N:5]([C:25]1[O:26][CH:27]=[C:28]([CH3:30])[N:29]=1)[C:6](=[O:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1coc(S(=O)C2CCCCC2)n1
Reactant: CCCCNC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCCN(C(=O)Cc1ccccc1)c1nc(C)co1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
N-Butyl-phenylacetamide (1.80 g, 0.0094 m) in N-methyl pyrrolidone (10 ml) was stirred at 80° C. under nitrogen during the portionwise addition of a 50% sodium hydride/oil dispersion (0.75 g, 0.0094 m). After the addition, the mixture was warmed to 100° C. and 2-cyclohexylsulphinyl-4-methyloxazole (2.0 g, 0.0094 m) in dry N-methyl pyrrolidone (10 ml) was added. The mixture was stirred at 100° C. for 5 hours and then hydrolysed with water. The solvent was removed in vacuo and the product isolated by column chromatography on silica using ether. Distillation gave the title product as a colourless oil. b.p. 126°-130° C./0.2 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9])N.N([O-])=O.[Na+].[I-:15].[K+].NC(N)=O>C(#N)C.CO.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:15])[CH:6]=[C:7]([Cl:10])[C:8]=1[Cl:9]
Reactant: [I-]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Clc1cc(I)cc(Cl)c1Cl
Temperature: 80 °C

Procedure:
Into a suspension of 25.0 g of 3,4,5-trichloroaniline in 10 mL of acetonitrile, 25 mL of methanol and 100 mL of water, a solution of 9.7 g of sodium nitrite in 25 mL of water was dropped while stirring and ice-cooling the suspension over 20 minutes and after the completion of the dropping, the resultant mixture was stirred at 5 to 6° C. for 30 minutes. Next, the reaction mixture was dropped into 75 mL of an aqueous solution of 23.2 g of potassium iodide which was heated to 80° C. over 20 minutes and after the completion of the dropping, the resultant mixture was continuously stirred at the same temperature further for 1 hour. After the completion of the reaction, 50 mL of an aqueous solution of 7.64 g of urea was added to the reaction mixture and the resultant mixture was left to be cooled down to room temperature while stirring the mixture, followed by diluting the mixture with 400 mL of ethyl acetate. Subsequently, an insoluble substance was filtered off from the mixture by Celite filtration. The organic phase was washed with 300 mL of a saturated sodium hydrogen sulfite aqueous solution and next with 200 mL of water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with hexane to obtain 29.3 g of the objective substance as a light yellow crystal.