Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S1C=CC=C1CC([NH:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:14]([C:17](=[O:19])[CH3:18])[CH2:15][S:16][C@H:11]12)=O.C(Cl)Cl.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C(OCC)(=O)C.C(=O)(O)[O-].[Na+].CCCCCC.C(O)C(C)C>[NH2:9][CH:10]1[C:36](=[O:37])[N:12]2[C:13]([C:20]([O:22][CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:14]([C:17](=[O:19])[CH3:18])[CH2:15][S:16][C@H:11]12
Reactant: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CC(C)CO
Product: CC(=O)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a slurry of 0.457 g. of benzhydryl 7-(2-thienylacetamido)-3-acetyl-3-cephem-4-carboxylate in 5 ml. of methylene chloride was added .085 ml. of pyridine and 0.205 g. of phosphorous pentachloride. The reaction mixture was allowed to stir for two hours at room temperature. After cooling the reaction mixture briefly in an ice bath 0.425 ml. of isobutanol was added. After allowing the reaction mixture to stir at room temperature for one hour n-hexane was added dropwise causing a precipitate which, after cooling the reaction mixture briefly in an ice bath, was isolated by decanting the supernatant liquid. The product thereby isolated was dissolved in a slurry of ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, washed with aqueous sodium bicarbonate solution and brine and then dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided 0.270 g. (77.9 percent) of title product as a brown froth:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17](=[O:49])[CH2:18][C:19]2[C:23]([CH3:24])=[C:22](/[CH:25]=[C:26]3\[C:27](=[O:47])[NH:28][C:29]4[C:34]\3=[CH:33][C:32]([S:35]([CH2:38][C:39]3[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][C:40]=3[Cl:46])(=[O:37])=[O:36])=[CH:31][CH:30]=4)[NH:21][C:20]=2[CH3:48])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:45][C:44]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:46])[C:39]=1[CH2:38][S:35]([C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:47])/[C:26]/2=[CH:25]\[C:22]1[NH:21][C:20]([CH3:48])=[C:19]([CH2:18][C:17]([NH:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:49])[C:23]=1[CH3:24])(=[O:37])=[O:36]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[2-(2-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetylamino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (from the above reaction) and TFA (1 mL) in DCM (10 mL) was stirred at rt for overnight. The reaction was concentrated and purified to give 590 mg of the titled compound as a yellow solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[C:35]2[C:30](=[C:31](Br)[CH:32]=[CH:33][CH:34]=2)[N:29]=[N:28][C:27]=1[C:37]([NH2:39])=[O:38]>>[NH2:25][C:26]1[C:35]2[C:30](=[C:31]([C:14]3[CH:13]=[CH:12][C:11]4[N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[CH:8]=[N:9][C:10]=4[CH:15]=3)[CH:32]=[CH:33][CH:34]=2)[N:29]=[N:28][C:27]=1[C:37]([NH2:39])=[O:38]
Reactant: CC1(C)OB(c2ccc3c(c2)ncn3C2CCCCC2)OC1(C)C
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Product: NC(=O)c1nnc2c(-c3ccc4c(c3)ncn4C3CCCCC3)cccc2c1N

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 1-cyclohexyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 4-amino-8-bromocinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 1.29 (t, J=8 Hz, 1 H), 1.44 (br s, 1 H), 1.52-1.71 (m, 2 H), 1.83 (d, J=12 Hz, 1 H), 1.88-2.08 (m, 3 H), 2.13-2.30 (m, 2 H), 7.58 (d, J=8 Hz, 1 H), 7.66-7.83 (m, 2 H), 7.83-7.96 (m, 2 H), 8.28 (d, J=8 Hz, 1 H), 8.35 (br s, 1 H), 8.62 (s, 1 H); ESI-MS m/z [M+H]+ 387.4.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:7]2.C(N(CC)CC)C.[C:23](=O)([O:39]N1C(=O)CCC1=O)[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>C(#N)C.O>[C:23]([CH:7]1[C:8]2[C:3](=[C:2]([CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][C:6]1([NH2:15])[C:12]([OH:14])=[O:13])([O:24][CH2:25][CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39]
Reactant: Cc1cccc2c1CCC(N)(C(=O)O)C2
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: Cc1cccc2c1CCC(N)(C(=O)O)C2C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
A mixture of racemic 5-methyl-2-aminotetraline-2-carboxylic acid (1.05 g, 5.12 mmole), triethylamine (0.93 ml, 6.67 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 2.24 g, 6.64 mmole) in acetonitrile (30 ml) and water (30 ml) was stirred at room temperature for 2 days. TLC analysis of the reaction indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (520 mg) was added and the mixture was stirred at room temperature for another 24 hours. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH ˜3 with 10% aqueous citric acid solution, and the white emulsion was extracted twice with methylene chloride. The combined organic layers were washed with water, brine and dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 2→5→8% methanol/methylene chloride) to give racemic Fmoc-5-methyl-2-aminotetraline-2-carboxylic acid (1.62 g, 74% yield) as an light brown solid. HRMS (FAB): C27H26NO4 (M+H) calc. 428.1862; observed: 428.1844.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:9]=[C:10](/[CH:15]=C/C(O)=O)[CH:11]=[CH:12][C:13]=1[F:14].CN(C)C=O>ClCCl>[F:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:1][C:2]([Cl:4])=[O:3])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=C(O)/C=C/c1ccc(F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C=Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0-5° C., oxalyl dichloride (25.7 g, 202.36 mmol, 3.00 equiv.) was added to a mixture of (E)-3-(3,4-difluorophenyl)acrylic acid (12.4 g, 67.38 mmol, 1.00 equiv.), N,N-dimethylformamide (1 mL), and dichloromethane (150 mL). The solution was stirred at ambient temperature for about 2 hours, and then concentrated in vacuo to give the title product, which was used in the next step without any further purification.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](N2CCN3C4CCCCC=4C=C3C2=O)=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[N:27]1[CH2:39][CH2:38][N:30]2[C:31]3[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=3[CH:37]=[C:29]2[C:28]1=[O:40])(=[O:3])[CH3:2].Br[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:59]=[C:54]3[CH2:55][O:56][CH2:57][CH2:58][N:53]3[N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[CH:8][C:9]([F:26])=[CH:10][C:11]=1[C:42]1[CH:43]=[C:44]([NH:50][C:51]2[CH:59]=[C:54]3[CH2:55][O:56][CH2:57][CH2:58][N:53]3[N:52]=2)[C:45](=[O:49])[N:46]([CH3:48])[CH:47]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(N2CCn3c(cc4c3CCCC4)C2=O)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCOC3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 52.6 %

Procedure:
A mixture of 2-(acetoxymethyl)-5-fluoro-3-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)phenylboronic acid 210d (150 mg, 0.38 mmol), 5-bromo-3-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-1-methylpyridin-2(1H)-one 110c (122 mg, 0.38 mmol), PdCl2(dppf) (41 mg, 0.056 mmol), K3PO4 (100 mg), and NaOAc (50 mg) in MeCN (10 mL) and H2O (3 mL) was heated at 110° C. in a sealed tube for 2 h. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 149a (120 mg, 53%). MS: [M+H]+ 601.
Reaction SMILES: I[C:2]1[CH:18]=[CH:17][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[C:34]#[CH:35])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.ClCCl.CO.N>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[C:34]#[C:35][C:2]3[CH:18]=[CH:17][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH:10]([C:13]([OH:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc(I)cc2)CC1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)C1CCN(Cc2ccc(C#CC(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 1.1.d. from 2-[1-(4-iodobenzyl)piperidin-4-yl]propan-2-ol and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 45 mg (30% of theory); melting point: 194-195° C.; C30H31ClN2O2 (M=487.04); calc.: molecular ion peak (M+H)+: 487/489; found: molecular ion peak (M+H)+: 487/489; Rf value: 0.3 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH3:7])[N:6]=1.N1C=CC=CC=1.[C:14]1([CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:7][N:5]1[N:4]=[N:3][C:2]([NH:1][C:21](=[O:22])[CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:6]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cn1nnc(N)n1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1
Reaction time: 2 h
Yield: 56 %

Procedure:
To a stirred solution of 5-amino-2-methyl-2H-tetrazole (0.50 g, 5.05 mmol), pyridine (0.48 g, 6.06 mmol) and DMAP (0.06 g, 0.51 mmol) in dichloromethane (30 ml) was added at 0° C. diphenylacetyl chloride (1.16 g, 5.05 mmol). Stirring was continued at RT for 2 h, the reaction mixture was poured into sat. NaHCO3 solution (50 ml) and extracted with dichloromethane (3×50 ml). The combined organic layers were washed with brine (70 ml), dried (Na2SO4) and evaporated. The crude product was crystallized from ethyl acetate/hexane to give the title compound (0.83 g, 56%) as a white solid, m.p. 218° C. (dec.) and MS: m/e=293.1 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8](C(O)=O)=[N:9][CH:10]=1.C1(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:28][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][N:9]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCCCc1ccc(C(=O)O)nc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCCCc1ccc(N)nc1

Procedure:
Fusaric acid (2 g), diphenylphosphoryl azide (2.4 mL) and triethylamine (1.6 mL) in t-butanol (70 mL) were refluxed overnight. The contents were concentrated in vacuo and treated with 25% aqueous HBr (20 mL) for 24 hours. After neutralizing with 50% NaOH, contents were extracted with CH2Cl2, dried (MgSO4) and concentrated in vacuo to give 2-amino-5-(n-butyl)pyridine as an oil (1.1 g).
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCN2C(=NCCC2)CC1.[CH3:62][C:63]([CH3:67])([CH3:66])[C:64]#[CH:65].Cl.[OH-].[NH4+]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:62][C:63]([CH3:67])([CH3:66])[C:64]#[C:65][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)=[CH:9][CH:10]=3)[C:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1
Reactant: NC1=NC2(CO1)c1cc(Cl)ccc1Oc1ccc(-c3cncnc3)cc12
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Temperature: 150 °C
Yield: 49 %

Procedure:
A microwave vial was charged with (racemic)-2′-Chloro-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (prepared in a manner similar to Example 39; 100 mg, 274 μmol), cesium carbonate (134 mg, 411 μmol), bis(triphenylphosphine)palladium(II) chloride (19 mg, 27 μmol) and tri-tert-butylphosphonium tetrafluoroborate (16 mg, 55 μmol). DMF (1 ml), DBU (21 μl, 137 μmol) and 3,3-dimethylbut-1-yne (167 μl, 1371 μmol) were added. The vial was sealed and heated at 150° C. in Biotage microwave oven for 60 min. The mixture was diluted with 5 ml of EtOAc, filtered through Celite and concentrated in vacuo to give brown oil, which was re-dissolved in 7 ml of EtOAc and shaken with 10 ml of 2N HCl. Acidic aqueous layer was basified with 30% ammonium hydroxide and precipitated brown oil was extracted twice with EtOAc. The organic layers were washed with brine, concentrated, dissolved in 1.5 ml of DMF, filtered through Nalgene PTFE 0.2 mkm filter and subjected to preparative reverse phase HPLC (15-90% ACN in 0.1% aq TFA). The fractions containing product were concentrated in vacuo in order to remove ACN, saturated NaHCO3 was added and the mixture was extracted with EtOAc (15 ml). The organic layer was washed with brine, dried over MgSO4 and concentrated to give (rac)-2′-(3,3-dimethylbut-1-ynyl)-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (49% yield).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[CH:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]([C:14]2[C:24]3[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:23]=3[O:22][C:21]3[C:15]=2[CH:16]=[CH:17][C:18]([CH:20]=3)=[O:19])=[C:7]([C:30]([OH:32])=[O:31])[CH:6]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH:5]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([OH:19])=[CH:20][C:21]=3[O:22][C:23]3[C:24]=2[CH:25]=[CH:26][C:27]([CH:28]=3)=[O:29])=[C:7]([C:30]([OH:32])=[O:31])[CH:6]=1.[C:1]([NH2:4])(=[O:12])[C:2]#[CH:3]
Reactant: C#CCN
Agent: O=C(O)c1ccc(C(=O)O)c(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6.8 ul (0.1 mmol) of propargylamine in DMF (1.0 ml) was added to a solution of 22 mg (0.046 mmol) of 6-carboxyfluorescein NHS ester in DMF (1.0 ml) and 0.1M NaHCO3 (0.2 ml) buffer. After overnight stirring at room temperature, the solvent was removed under vacuum. A small amount of reaction mixture was submitted for LC-MS analysis. The crude mixture was purified by Silica gel column chromatography. (DCM: MeOH 9:1). LC-MS analysis confirms that alkenyl FAM is formed. Cal Mass: 414.09. Found Mass: 414.0.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:14]1[O:16][CH:15]1[CH2:17][OH:18]>O.[OH-].[Li+]>[CH2:1]([S:13][CH2:14][CH:15]([OH:16])[CH2:17][OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCS
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCSCC(O)CO

Procedure:
To a 300-ml flask was added 60.7 grams (0.30 mole) of n-dodecyl mercaptan and 0.63 grams (0.015 mole, 5 mole percent) of lithium hydroxide monohydrate catalyst. The mixture was stirred and heated to 90°-100° C. To this stirred solution was added dropwise over a 4.25 hour period 33.3 grams (0.45 mole) of glycidol. The reaction mixture was stirred and heated at 90°-95° C for an additional 21 hours. The product was isolated by vacuum distillation in a yield of 41.3 grams (50% of theory) boiling at 158°-178° C/0.05-0.15 mm.
Reaction SMILES: N[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4](N)[N:3]=1.N[C:13]1[N:18]=[C:17](N)[CH:16]=[C:15](O)[N:14]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[N:14]1[C:15]2[C:16](=[N:9][C:5]3[CH:4]=[N:3][CH:2]=[N:7][C:6]=3[N:8]=2)[CH:17]=[N:18][CH:13]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: c1ncc2nc3cncnc3nc2n1
Temperature: 113 °C
Reaction time: 20 h

Procedure:
A suspension of 6.20 g of commercial 2,4,6-triamino-5-nitrosopyrimidine (Chemie Uetikon, Lahr, Germany), 5.15 g of commercial 2,4-diamino-6-hydroxypyrimidine (Fluka, Buchs, Switzerland) and 11.52 g of commercial toluene-4-sulfonic acid monohydrate in 110 ml of glacial acetic acid (100%) is stirred for 20 hours at 113° C. The reaction mixture is filtered off over a laminated paper filter while still hot, and the residue is washed with hot water (approx. 60° C.) until the pH of the washing water has reached a value of at least 4. The washed residue, moist with water, is dried in vacuo at 110° C. to yield a greenish-yellow powder of the pyrimido[5,4-g]pteridine salt of formula VI
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1.CI.Cl>O1CCCC1.CCCCCC>[O:13]1[CH2:18][CH2:17][CH:16]([CH:19]([CH3:1])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1
Reactant: CCOC(=O)CC1CCOCC1
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)C1CCOCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
Diisopropylamine (2.8 g) was dissolved in tetrahydrofuran (20 ml). A solution of n-butyllithium in hexane (2.64 N, 11 ml) was added dropwise under nitrogen atmosphere under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was cooled to −78° C. A solution of ethyl 2-(tetrahydro-2H-pyran-4-yl)acetate (4.0 g) in tetrahydrofuran (15 ml) was added dropwise and the mixture was stirred at the same temperature for 15 minutes. Methyl iodide (2.2 ml) was subsequently added dropwise. The mixture was stirred at the same temperature for 10 minutes, and then warmed to room temperature and stirred for 3 hours. A 1 N aqueous hydrochloric acid solution was added under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (4.0 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C[C-]1C(C)=C(C)C(C)=C1C.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[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C(#Cc1ccccc1)c1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: c1ccc(Cn2nnc(-c3ccccc3)c2-c2ccccc2)cc1

Procedure:
Benzyl azide (0.400 g, 3.00 mmol), diphenylacetylene (0.588 g, 3.30 mmol), Cp*RuCl(PPh3)2 (25 mg, 0.031 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 2 hours; yield, 0.75 g (80%). EI-MS: m/z 312 [M+1].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-methoxyphenyl)indole-3-carboxylic acid ethyl ester (176 mg, 0.46 mmol, see step (b) Example 4) and 4-trifluoromethylphenylboronic acid (129 mg, 0.68 mmol) Yield 140 mg (56%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([C:24]([CH3:32])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[NH2:25])[CH2:23][CH2:22]1>>[CH:21]1([C:24]([NH:25][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH3:32])[CH2:23][CH2:22]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: Cc1nc(C(C)(NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3) as starting materials. MS (EI): m/e=434.5 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH3:22][O:23][CH2:24][CH2:25]O>>[CH3:22][O:23][CH2:24][CH2:25][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: COCCO
Product: COCCOc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 58 with 2-methoxyethanol gave 2-(3-(3-(2-methoxyethoxy)phenyl)propyl)isoindoline-1,3-dione as a clear oil. Yield (0.225 g, 19%): 1H NMR (400 MHz, DMSO-d6) δ 7.81-7.84 (m, 2H), 7.67-7.72 (m, 2H), 7.10-7.16 (m, 1H), 6.76-6.80 (m, 2H), 6.67-6.72 (m, 1H), 4.07-4.11 (m, 2H), 3.70-3.76 (m, 4H), 3.45 (s, 3H), 2.55 (t, J=7.6 Hz, 2H), 1.98-2.05 (m, 2H).