Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH:10]=[CH:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[ClH:15].[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Reactant: CNCCc1ccc(OC)cc1
Product: COc1ccc(CCN(C)CCCN2C=Cc3cc(OC)c(OC)cc3CC2=O)cc1
Product: Cl

Procedure:
This compound was prepared analogous to Example 1(b) by reacting 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane with N-methyl-N-[2-(4-methoxy-phenyl)-ethyl]-amine.
Reaction SMILES: FC1C=CC(CBr)=CC=1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32](=[O:33])[NH:31][N:30]=[CH:29]2)[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:22][C:23]1[CH:27]=[C:26]([N:28]2[C:32](=[O:33])[N:31]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([C:11]([F:21])([F:20])[F:10])=[CH:13][CH:14]=3)[N:30]=[CH:29]2)[S:25][C:24]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)cc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Fc1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)cc1C
Yield: 94 %

Procedure:
Following the procedure as described in Example 29, making variations as required to replace 4-fluorobenzyl bromide with 4-(trifluoromethyl)benzyl bromide to react with ethyl 3-methyl-5-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiophene-2-carboxylate the title compound was obtained as a yellowish solid in 94% yield: 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.95 (s, 1H), 5.07 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); MS (ES+) m/z 412.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([N:26]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:27][CH2:28]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[C:6]([O:10][CH2:28][CH2:27][N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:8][CH:9]=1)[OH:11]
Reactant: COC(=O)c1cccc(O)c1O
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(OCCN(Cc2ccccc2)Cc2ccccc2)c1O

Procedure:
2,3-dihydroxybenzoic acid methyl ester is reacted in the presence of potassium carbonate in acetonitrile with 1.1 equivalents of 1-dibenzylamino-2-chloroethane for 18 hours at 82°. The crude 3-(2-dibenzylaminoethoxy)salicyclic acid methyl ester obtained after working up is put to further use without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]=O)[CH3:2].[H-].[Na+].C[C:9]1(C)[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:18].[CH3:20]I>C1COCC1>[CH3:4][O:3][CH:1]=[C:2]1[C:17]([CH3:9])([CH3:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:18]
Reactant: CC1(C)Cc2ccccc2C1=O
Reactant: CCOC=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C1C(=O)c2ccccc2C1(C)C
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Ethylformate (8.10 g, 110 mmol) in THF (50 ml) was added to the suspension of NaH (55% in mineral oil, 4.80 g, 110 mmol) in THF (50 ml). After stirring for 5 min at RT Dimethylindanone (16.0 g, 100 mmol)in THF (50 ml) was added. Gas evolution started and the temperature of the mixture rose and was controlled with an icebath to not exceed 40° C. After further stirring for 4.5 h at RT, methyl iodide (42.6 g, 300 mmol) was added und stirring continued for 48 h. After quenching with aq. NaHCO3-solution and aqueous workup a dark red oil (20.4 g, 100%) of was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[C:44]([Cl:53])[C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)[C:39]([O:41][CH3:42])=[O:40].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[C:44]([Cl:53])[C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][N:49]1[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1cc(Cl)c(OCC2CCCN2)c(Cl)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (385.8 mg, 0.803 mmol), methyl 3,5-dichloro-4-(2-pyrrolidinyl)methoxybenzoate (244.3 mg, 0.803 mmol), Et3N (0.13 mL, 0.964 mmol) in DMF (4 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:2, v/v) as eluent to afford methyl 3,5-dichloro-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoate as an oil. To a stirred solution of this compound in THF (8 mL) and H2O (2 mL) was added LiOH (57.7 mg, 2.409 mmol), and the mixture was stirred at room temp overnight. The tire was concentrated in vacuo, and the residue was diluted with CHCl3. The solution was washed with 1N HCl, brine, and dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-MeOH—CHCl3 to afford 428.2 mg (91%) 30 as a white crystalline powder. IR (KBr) 1618, 1535, 1454, 1257, 754 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ1.83-2.24 (m, 4H), 2.24 (s, 3H), 3.50-3.58 (m, 4H), 3.84 (s, 3H), 3.98-4.05 (m, 1H), 4.15 (dd, J=2.9, 8.7 Hz, 1H), 4.29 (br m, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.87 (s, 1H), 6.93 (t, J=7.3 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.86 (s, 1H), 7.87 (d, J=9.8 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.49 (s, 1H), 8.58 (s, 1H); MS (FAB) m/z 586 (M++1).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.C(OC(C[N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1)=O)C.Cl.[CH:33]1C=CC=C[CH:34]=1>>[CH:1]1([N:6]2[C:10]3=[N:11][C:33]([CH2:34][C:31]4[NH:27][CH:28]=[CH:29][CH:30]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccccc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)Cn1cccc1
Agent: C[Al](C)C
Agent: Cl
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc[nH]3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.0 g, 4.5 mmol) in benzene (10 ml) in an ice bath was added trimethylaluminum (4.9 ml, 2M in toluene). The reaction mixture was stirred at room temperature for 1 hour, then 1-(ethoxycarbonylmethyl)pyrrole (0.7 g) in benzene (25 ml) was added and the reaction mixture was refluxed overnight. The reaction mixture was cooled, 2N HCl was added and the mixture was extracted with CHCl3 (3×). The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was digested with ether and recrystallized from ether to afford 1-cyclopentyl-3-ethyl-6-(1-pyrrolylmethyl)-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 170°-172° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:4]([OH:13])=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[N:10][CH:9]=[CH:8]2.C(O[N:19]=O)(C)(C)C.C(O)C>O>[Cl-:1].[OH:13][C:4]1[C:3]([N+:2]#[N:19])=[C:12]2[C:7]([CH:8]=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: Cl
Reactant: CC(C)(C)ON=O
Reactant: Nc1c(O)ccc2ccncc12
Solvent: CCO
Solvent: O
Product: N#[N+]c1c(O)ccc2ccncc12
Product: [Cl-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To 8-amino-7-hydroxyisoquinoline HCl salt (4.94 g, 0.025 mol) in ethanolic-HCl at 0° C. is added dropwise a solution of tert-butylnitrite (17.46 ml), ethanol (790 ml) and water (58 ml). Following completion of the addition, the solution is stirred an additional 2 hours at 0° C. The product is precipitated from the reaction mixture by the addition of diethyl ether (2 l). The product is collected by filtration and rinsed with diethyl ether to provide the desired product (2.6 g) in 50% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[Br-].[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Zn+].CCOC(C)=O>C1COCC1.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>[Cl:1][C:2]1[N:3]=[C:4]([Cl:20])[C:5]2[C:10]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(-c2ccccn2)c2c(Cl)nc(Cl)nc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a solution of 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2.25 mmol), as prepared in Example 5, step 1, in THF (11 mL) was added tetrakis(triphenylphosphine)palladium(0) (131 mg, 0.113 mmol) and pyridin-2-ylzinc(II) bromide (9 mL, 4.5 mmol, 0.5 M solution in THF) which was then heated to 65° C. and stirred for 3 hrs. EtOAc (10 mL) was added and the resulting mixture was washed with water (20 mL). The aqueous layer was extracted with EtOAc (three×10 mL), and the combined organic layers were then washed with 1 M aqueous Na2SO3 (20 mL), sat. aqueous NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was then purified via flash chromatography (20%-50% EtOAc/heptane) to give the title compound as a clear oil (378 mg, 43% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59-8.71 (m, 1H) 8.21 (s, 1H) 7.89 (td, J=7.77, 1.89 Hz, 1H) 7.70 (d, J=7.83 Hz, 1H) 7.39 (ddd, J=7.52, 4.86, 1.01 Hz, 1H) 5.67 (s, 2H) 3.50-3.67 (m, 2H) 0.79-0.95 (m, 2H) −0.17-0.00 (m, 9H). m/z (APCI+) for C17H20N4OCl2Si 395.00/397.00 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:12]2[C:11](=[O:13])[C:8]3([CH2:10][CH2:9]3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][Cl:25])[CH3:21].CN(C)C=O>O>[ClH:25].[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][CH2:24][O:1][C:2]1[C:12]2[C:11](=[O:13])[C:8]3([CH2:9][CH2:10]3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: O=C1c2c(O)cccc2OC12CC2
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1cccc2c1C(=O)C1(CC1)O2
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-hydroxyspiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one, (0.176 g.) potassium carbonate (0.276 g.), β-diethylaminoethyl chloride (0.215 g.) and N,N-dimethylformamide (5 ml.) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and distilled to remove the solvent. The residue was purified by column chromatography on silica gel, using chloroform as the eluent. The product was treated with HCl-saturated diethyl ether and the resultant hydrochloride was recrystallized from ethanol-diethyl ether. By the above procedure there was obtained 4-(2-diethylaminoethyloxy)spiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one hydrochloride as colorless needles, m.p. 160°-168° C. Yield 0.221 g.
Reaction SMILES: [CH2:1]([N:4]([C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([Cl:17])[N:11]=1)[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH:2]=[CH2:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:17][C:12]1[N:13]=[CH:14][C:15]2[C:2]([CH3:3])=[CH:1][N:4]([CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[C:10]=2[N:11]=1
Reactant: C=CCN(c1nc(Cl)ncc1Br)C(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(CC)n1cc(C)c2cnc(Cl)nc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of allyl-(5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (2.76 g, 8.7 mmol) in anhydrous DMF (15 mL) is added Pd(OAc)2 (156 mg, 0.69 mmol) and PPh3 (182 mg, 0.69 mmol) and triethylamine (2.4 mL, 17.3 mmol). The reaction mixture is, stirred at 100° C. overnight. The reaction mixture is diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, EtOAC/hexane 1:2) gives 0.95 g of 2-chloro-7-(1-ethyl-propyl)-5-methyl-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26](=[O:31])C(Cl)(Cl)Cl)[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.C1(C)C=CC=CC=1>CN(C)C=O>[CH:16]([CH:15]1[C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:25][C:26](=[O:31])[N:14]1[CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)([CH3:17])[CH3:18]
Reactant: CC(C)C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1NC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)C1c2ccccc2NC(=O)N1C1CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
Into a solution of 6.58 g (13.6 mmol) of 1-benzyl-4-[2-methyl-1-(2-trichloroacetylaminophenyl)propylamino]piperidine in 136 ml of dimethylformamide, 9.42 g (68 mmol) of potassium carbonate were added and stirred at 90° C. for 5 hours. The reaction mixture was cooled to room temperature, and then 0.5% aqueous potassium carbonate solution and ethyl acetate-toluene (1:1) were added thereto and stirred. The separated oil layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform/methanol 100/2) to give 3.65 g (10.0 mmol) of the above-titled compound.
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O[CH2:28][CH:29]([OH:31])[CH3:30].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:28][CH:29]([OH:31])[CH3:30])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(O)CO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(C)O)cc1
Reaction time: 8 h

Procedure:
A solution of 7.2 g. of 4-n-hexadecylaminobenzoic acid, 15.2 g. of 1,2-dihydroxypropane, and 3.9 ml. of boron trifluoride etherate are stirred together, under nitrogen, at 115° C. for 19 hours. The solution is cooled, diluted with methylene chloride, and placed in a freezer overnight. The solid is collected, washed with hexane, and oven-dried to yield a white solid. The solid is recrystallized from hexane and chromatographed on alumina with chloroform. This process yields 2-hydroxypropyl 4-(n-hexadecylamino)benzoate as a white solid, m.p. 91°-93° C.
Reaction SMILES: C[Si](C)(C)[O:3][C@H:4]1[C@@H:9]([O:10][Si](C)(C)C)[C@H:8]([O:15][Si](C)(C)C)[CH:7]([CH2:20][O:21][Si](C)(C)C)[O:6][C:5]1=[O:26].Br[C:30]1[CH:31]=[CH:32][C:33]([Cl:55])=[C:34]([CH:54]=1)[CH2:35][O:36][Si:37]([C:50]([CH3:53])([CH3:52])[CH3:51])([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Li][C:57](C)(C)C.CS(O)(=O)=O>O1CCCC1.CO>[Si:37]([O:36][CH2:35][C:34]1[CH:54]=[C:30]([C:5]2([O:26][CH3:57])[C@@H:4]([OH:3])[C@@H:9]([OH:10])[C@H:8]([OH:15])[CH:7]([CH2:20][OH:21])[O:6]2)[CH:31]=[CH:32][C:33]=1[Cl:55])([C:50]([CH3:53])([CH3:52])[CH3:51])([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)[Si](OCc1cc(Br)ccc1Cl)(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)OCC1OC(=O)[C@@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC1(c2ccc(Cl)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)OC(CO)[C@@H](O)[C@H](O)[C@@H]1O
Temperature: -78 °C
Reaction time: 5 h
Yield: 107.4 %

Procedure:
To a solution of (3S,4S,5R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one (3.0 g, 6.5 mmol) and (5-bromo-2-chlorobenzyloxy)(tert-butyl)diphenylsilane (3.7 g, 7.8 mmol) in tetrahydrofuran (105 mL) at −78° C. under nitrogen was added t-BuLi (8.0 mL, 13.7 mmol) dropwise. Reaction was stirred at −78° C. for 5 hours and then a cold (−78° C.) solution of methanesulfonic acid (1.6 mL) in methanol (54 mL) was added to it via cannulation. The cold bath was then removed and the reaction mixture was stirred at room temperature overnight. The reaction solution was quenched with aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic extract was washed with brine, dried over sodium sulfate and concentrated in vacuo to give (3S,4S,5S)-2-(3-((tert-butyldiphenylsilyloxy)methyl)-4-chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (4.0 g, crude, mixture of 2 anomers at 2-position) as a white foam, which was used in the next step without purification.
Reaction SMILES: FC(F)(F)C(O)=O.NN.[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([N:23]([CH2:25][C:26]([O:28]C)=O)[NH2:24])[CH:20]=[CH:21][CH:22]=1)[CH3:11].[O-:30][C:31]#[N:32].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:25][C:26](=[O:28])[NH:32][C:31](=[O:30])[NH:24]2)[CH:20]=[CH:21][CH:22]=1)[CH3:11]
Reactant: N#C[O-]
Reactant: CCOCCCOc1cccc(N(N)CC(=O)OC)c1
Agent: NN
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOCCCOc1cccc(N2CC(=O)NC(=O)N2)c1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
Trifluoroacetic acid (7.32 ml, 95 mmol) was added dropwise to a suspension of the hydrazine (Intermediate 73, 8.94 g, 31.7 mmol) and sodium cyanate (7.21 g, 11 mmol) in toluene (63 ml) at room temperature. After stirring for 30 min the mixture was taken up in chloroform, quenched (NaHCO3), extracted (CHCl3), washed (H2O, sat. NaCl), dried (Na2SO4) and concentrated. The residue was subjected to column chromatography (SiO2, 10% MeOH in CHCl3) to afford the title compound as a pale yellow glass (6.78 g, 66%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:34]/[N:35]=[C:36](/[NH2:38])\[CH3:37].[CH3:39][O:40][C:41]1[C:42]([CH3:69])=[C:43]([C:50]([C:52]2[CH:53]=[C:54]3[C:59](=[CH:60][CH:61]=2)[NH:58][C:57](=[O:62])[N:56]([CH2:63][C:64](OC)=O)[C:55]3=[O:68])=[O:51])[N:44]2[C:49]=1[CH:48]=[CH:47][CH:46]=[CH:45]2>CN(C=O)C.O>[CH3:39][O:40][C:41]1[C:42]([CH3:69])=[C:43]([C:50]([C:52]2[CH:53]=[C:54]3[C:59](=[CH:60][CH:61]=2)[NH:58][C:57](=[O:62])[N:56]([CH2:63][C:64]2[O:34][N:35]=[C:36]([CH3:37])[N:38]=2)[C:55]3=[O:68])=[O:51])[N:44]2[C:49]=1[CH:48]=[CH:47][CH:46]=[CH:45]2
Reactant: C/C(N)=N\O
Reactant: COC(=O)Cn1c(=O)[nH]c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(C)c(C(=O)c2ccc3[nH]c(=O)n(Cc4nc(C)no4)c(=O)c3c2)n2ccccc12
Temperature: 90 °C
Yield: 41.3 %

Procedure:
0.14 g (0.37 mmol) of HBTU, 0.21 ml (1.23 mmol) of DIEA and then 0.18 g (1.23 mmol) of (1E)-N′-hydroxyethanimidamide are added, under an inert atmosphere at ambient temperature, to 0.1 g (0.25 mmol) of methyl {6-[(1-methoxy-2-methylindolizin-3-yl)carbonyl]-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl}acetate in 5 ml of DMF. The reaction medium is heated at 90° C. for 24 hours. After hydrolysis with water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The yellow solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.046 g of a yellow solid is obtained.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH2:7][C@@H:8]([CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])\[CH3:4].[CH3:22][O-:23].[Na+]>CO.C(OCC)(=O)C>[CH2:1]([O:23][CH3:22])/[CH:2]=[C:3](/[CH2:5][CH2:6][CH2:7][C@@H:8]([CH2:10][CH2:11][CH2:12][C@@H:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:14])[CH3:9])\[CH3:4]
Reactant: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 95.3 %

Procedure:
10.0 g of phytyl chloride was dropped into a solution of 2.0 g of sodium methoxide dissolved in 70 ml of methanol. The resulting mixture was stirred for 4 hours at 60° C. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue obtained was dissolved in 30 ml of ethyl acetate, and the resulting solution was washed with water. The solution was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to distillation (b.p.: 148°-150° C., 1.5 mmHg) to obtain 9.4 g (yield: 95%) of oily methyl phytyl ether.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)CCC.[NH2:20][C:21]1[O:22][CH2:23][C@:24]2([N:47]=1)[C:37]1[CH:36]=[C:35](Br)[CH:34]=[CH:33][C:32]=1[O:31][C:30]1[C:25]2=[CH:26][C:27]([O:40][CH2:41][C:42]([CH3:46])([CH3:45])[C:43]#[N:44])=[CH:28][C:29]=1[F:39]>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.CN(C=O)C>[NH2:20][C:21]1[O:22][CH2:23][C@:24]2([N:47]=1)[C:37]1[CH:36]=[C:35]([C:6]3[CH:11]=[N:10][CH:9]=[CH:8][N:7]=3)[CH:34]=[CH:33][C:32]=1[O:31][C:30]1[C:25]2=[CH:26][C:27]([O:40][CH2:41][C:42]([CH3:45])([CH3:46])[C:43]#[N:44])=[CH:28][C:29]=1[F:39]
Reactant: CC(C)(C#N)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C#N)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cnccn3)ccc1O2
Temperature: 100 °C

Procedure:
To a flask charged with Pd(PPh3)4 (8.82 mg, 0.034 mmol), 2-(tributylstannyl)pyrazine (248 mg, 0.672 mmol), and (S)-3-(2-amino-2′-bromo-5′-fluoro-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2,2-dimethylpropanenitrile (150 mg, 0.336 mmol) was added 3 ml of DMF. The resulting mixture was heated in the microwave at 100° C. for one hour. The solution was concentrated in vacuo and the derived residue was purified by HPLC (gradient elution 10-90% MeCN/H2O, 0.1% TFA) to afford (S)-3-(2-amino-5′-fluoro-2′-(pyrazin-2-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2,2-dimethylpropanenitrile as a white solid. MS m/z=446.0 [M+H].