Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[CH:9].I[C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Cu]I.N1CCCC1>[CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCC#CI
Reactant: C#CCCCCCC#C
Agent: [Cu]I
Solvent: C1CCNC1
Product: C#CCCCCCC#CC#CCCCCCCCC
Reaction time: 24 h

Procedure:
Pyrollidine (20 mL) and CuI (0.65 g, 3.42 mmol) were added to a nitrogen flushed reaction vessel. Nona-1,8-diyne (1.58 g, 13.17 mmol) was added via syringe. 1-Iodo-1decyne (2.26 g, 8.53 mmol) was added via syringe dropwise to the solution over ten minutes. The reaction was stirred under nitrogen for 24 h. The reaction mix was then quenched with ammonium chloride (10 mL), separated with diethyl ether, and dried with anhydrous magnesium sulfate. Nonadeca-1,8,10-triyne was then isolated using silica column chromatography with a 1% ether/hexane eluting solution obtaining 1.06 g of an oil. 50% yield; 1H NMR (CDCl3) δ 2.29 (m, 4H, CH2—C≡C), 2.22 (dt, 2H, CH2—C≡C, J=7, 2.7 Hz), 1.97 (t, 1H, H—C≡C, J=2.7 Hz), 1.54 (m, 6H, CH2—C—C≡C), 1.33-1.40 (sextuplet, 2H, CH2—CH2-CH3), 1.27 (m, 10H, C—CH2—C), 0.88 (t, 3H, CH3); 13C NMR (CDCl3) δ: 84.62, 77.99, 77.36, 68.63, 65.76, 65.45, 32.21, 29.54, 29.46, 29.25, 28.72, 28.34, 28.31, 28.23, 23.06, 19.61, 19.52, 14.53; MS (ESI) [M+Na]+calc. 279.2083 found 279.1723 (very unstable to any MS technique). Elemental analysis calc. for C19H28: C, 88.99; H, 11.01. Found: C, 88.80; H, 10.96.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CCNCC
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N(CC)CC)ncn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate, and 73 mg of diethylamine, followed by stirring at a bath temperature of 50° C. for 4 hours. Then, 73 mg of diethylamine was further added, followed by stirring at a bath temperature of 50° C. for 5.5 hours. Then, 146 mg of diethylamine was further added, followed by stirring at a bath temperature of 40° C. for 6 hours. The reaction mixture was left for cooling to room temperature, diluted with ethyl acetate, and washed three times with an aqueous sodium chloride solution. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel thin layer chromatography to give 136 mg of 4-(2-butynyloxy)-6-(N,N-diethylamino)pyrimidine (the present compound (144)).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH2:2]1.[CH2:16]=[CH:17][CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[CH:10]1[C:5]2[C:4]3([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:16][CH:17]=[CH:18][CH2:19][CH:3]3[CH2:2][O:1][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1=CCOc2ccccc21
Reactant: C=CC=C
Solvent: Cc1ccccc1
Product: CCOC(=O)C12CC=CCC1COc1ccccc12
Temperature: 150 °C
Yield: 39.3 %

Procedure:
A solution of the product of Example 15 (20.3 g) was dissolved in toluene (100 ml) and to it was added BHT (0.5 g) and butadiene (73 g) the reaction vessal was pressurized with nitrogen (1900 psi) and heated to 150° C. for 6 days. The resulting syrup (40 g) was partitioned between heptane and acetonitrile. The acetonitrile solution was washed with fresh heptane then evaporated in vacuo. The heptane phase was extracted with fresh acetonitrile which was evaporated to give a further recovery of crude product. The resulting oils were chromatographed on silical gel (eluting with ethyl acetate:heptane (1:60)), to give the title compound as a crystalline solid (10.1 g, 38%), mp 88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH3:13])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].C([O:17]/[C:18](/[CH3:25])=[CH:19]/C(OCC)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](/[CH3:13])=[CH:19]/[C:18](=[O:17])[CH3:25])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)/C=C(\C)OCC
Reactant: CC(=O)c1ccc(CC(C)C)c(Cl)c1
Product: CC(=O)/C=C(\C)c1ccc(CC(C)C)c(Cl)c1
Yield: 61 %

Procedure:
(E)-4-(3-chloro-4-isobutyl-phenyl)-3-pentene-2-one was prepared analogous to Example 52 from 3'-chloro-4'-isobutyl-acetophenone (b.p. 89°-93°C at 0.2 mm Hg) and ethyl (E)-3-ethoxy-crotonate with a yield of 61% of theory (after chromatographic purification on silicagel using petroleum-ether/benzene in a volume ratio of 1:1 as eluant). Colorless oil.
Reaction SMILES: [CH:1](N1[CH2:17][CH:16]([OH:18])C1)([C:8]1C=CC=C[CH:9]=1)[C:2]1[CH:7]=CC=C[CH:3]=1.FC(F)(F)C1C=CC=CC=1C(O)C1C=C[C:27]([O:30]C)=[CH:26]C=1.C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:27]([O:18][CH2:16][CH3:17])(=[O:30])[CH3:26].[CH3:9][CH2:8][CH2:1][CH:2]([CH3:7])[CH3:3]
Reactant: COc1ccc(C(O)c2ccccc2C(F)(F)F)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: CCCC(C)C
Product: CCOC(C)=O

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (7.5 mmol) and 2-(trifluoromethyl)-4′-methoxybenzhydrol (155) (15 mmol) using the procedure described for compound (3). Flash column chromatography [SiO2; ethyl acetate-iso-hexane (10:90→20:80)] afforded a pale yellow gum (2.73 g) which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[F:14][C:15]([F:31])([F:30])[C@H:16]1[CH2:21][NH:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.CCN(C(C)C)C(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([N:20]2[CH2:21][CH:16]([C:15]([F:31])([F:30])[F:14])[CH2:17][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:19]2)=[C:3]2[CH2:13][CH2:12][CH2:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@H](C(F)(F)F)C1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CC(C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 110 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.34 g, 1.7 mmol), cis-tert-butyl [5-(trifluoromethyl)piperidin-3-yl]carbamate (0.50 g, 1.9 mmol) in isopropyl alcohol (1.0 g) and DIPEA (1.0 mL, 5.7 mmol) was stirred at 110° C. for 2 h. The solution was allowed to cool to room temperature, then the mixture was concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus (40 g column, eluting with 0 to 70% EtOAc in hexanes) to give the sub-title compound as a pale yellow powder (0.37 g, 50%). LCMS calc. for C19H26F3N4O4 (M+H)+ m/z=431.2. found: 431.0. The material was subjected to chiral HPLC (Phenomenex Lux® Cellulose 4 column, 21, 2×250 mm, 5 micron particle size; Mobile phase: 7% EtOH in hexanes; Flow rate: 18 mL/min. isocratic; Column loading: 10 mg/injection; Run time: 24 minutes) to give two separated enantiomers of the sub-title compound.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]>>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]([C:7]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=2)=[O:8])=[CH:17][C:12]=1[CH3:11]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: COc1ccccc1C
Product: COc1ccc(C(=O)c2cccc(C)c2)cc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
m-Toluic acid (13.6 g, 0.10 mole) and o-methylanisole (12.2 g, 0.10 mole) are combined in 50 ml of polyphosphoric acid (PPA) and warmed with stirring to 80°C for 2 hours. The cooled reaction mixture is then poured into ice water and extracted into ethyl acetate (200 ml) and washed with 5% sodium hydroxide to give 14.4 g of product (60%), m.p. 62°-4°C, upon removal of the solvent in vacuo.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][C@@H:4]([NH2:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:19][C@@H:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1C(=O)[C@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)[C@H](NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 1,3-dihydro-1-methyl-3(R)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][NH:10][C:11](=[O:30])[C@H:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[C:18]=2[CH3:29])[C@@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35].N1C=CN=C1>CN(C=O)C>[Si:37]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[C:18]=1[CH3:29])[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:32][CH:31]=1)=[O:30])([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O)ccc(C#N)c1C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
The crude material 4-cyano-N′-((2R,3S)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)benzohydrazide (507 mg, 1.14 mmol) was added to DMF (30 mL), followed by addition of TBDMS-Cl (686 mg, 4.55 mmol) and imidazole (619 mg, 9.10 mmol) at 0° C. The solution was allowed to stir at 0° C. for 30 min and then at room temperature for overnight. The reaction was quenched with the addition of 200 mL brine and extracted with EtOAc. The resulting crude material was chromatographed to give the desired product (390 mg) 1H NMR (400 MHz, acetone-d6, δ in ppm): 9.6 (br s), 7.92 (d, J=9 Hz, 2H), 7.8 (d, J=9 Hz, 2H), 7.56 (d, J=9 Hz, 1H), 6.92 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.51 (m, 1H), 4.16 (m, 1H), 2.25 (m, 3H), 1.24 (d, J=6 Hz, 3H), 0.82 (s, 9H), 0.05 (s, 6H), 0.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4]O.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][Br:12]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(CO)c(C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(CBr)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A solution of benzyl alcohol 9 (18.4 g; 135 mmol) and carbon tetrabromide (55.96 g; 169 mmol) in methylene chloride (220 ml) was cooled to 0° C. and treated in dropwise fashion with triphenylphosphine (44.33 g; 169 mmol) in 100 ml of methylene chloride. After the addition was complete the mixture was stirred overnight at room temperature. It was poured into ice-water and partitioned between methylene chloride and water. The organic phase was dried (MgSO4) and concentrated in vacuo. Chromatography of the residue, eluting with 10% ethyl acetate in hexane, gave 26 g (99%) of the product as a yellow liquid. 1HNMR (CDCl3): δ2.31, 2.38 (s, 3H each); 4.51 (s, 2H); 6.99 (m, 2H); 7.18 (d, 1H). IR (neat): 3013, 2972, 2921, 1617, 1507, 1450, 1262, 823 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[C:14]([CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=2)[C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:49][C@@H:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C>O.CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:20]=[C:19]([CH:18]=[C:14]([C:15]([NH:49][C@@H:50]3[C:58]4[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=4)[CH2:52][CH2:51]3)=[O:17])[CH:13]=2)[C:21]([O:23][CH3:24])=[O:22])=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9]
Reactant: CNC(=O)c1nc(-c2cc(C(=O)O)cc(C(=O)OC)c2)cnc1N
Reactant: N[C@H]1CCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1nc(-c2cc(C(=O)N[C@H]3CCc4ccccc43)cc(C(=O)OC)c2)cnc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
A mixture containing 3-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}-5-[(methyloxy)carbonyl]benzoic acid (0.34 g, 1.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.51 g, 1.6 mmol), (S)-(+)-1-aminoindan (0.17 g, 1.3 mmol), diisopropylethylamine (0.6 mL, 3.4 mmol) and DMF (70 mL) were stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted 3' with ethyl acetate and 3× with 5% aqueous lithium chloride, and dried over sodium sulfate. Filtration, concentration, and purification by reverse phase HPLC gave the product as a yellow solid (0.41 g, 90% yield). 1H NMR (400 MHz, d6-DMSO): δ 9.09 (d, 1H), 8.91 (s, 1H), 8.83 (d, 1H), 8.75 (t, 1H), 8.70 (t, 1H), 8.45 (t, 1H), 7.73 (br, 2H), 7.28 (d, 2H), 7.24-7.17 (m, 2H), 5.64-5.58 (q, 1H), 3.91 (s, 3H), 3.04-3.00 (m, 1H), 3.00-2.87 (m, 1H), 2.83 (d, 3H), 2.53-2.51 (m, 1H), 2.06-1.96 (m, 1H). MS (EI) for C24H23N5O4: 446 (MH+).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)C)c1OC(F)F
Temperature: 80 °C
Yield: 21.3 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.75 mmol) and isobutylbromide (102 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 21.2%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10].N1C=CC=CC=1.[CH3:20][Si:21]([CH3:26])([CH3:25])[CH2:22][CH2:23]O.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C(O)=O>CC#N.CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH2:12][CH3:13])[C:9]([O:11][CH2:23][CH2:22][Si:21]([CH3:26])([CH3:25])[CH3:20])=[O:10]
Reactant: C[Si](C)(C)CCO
Reactant: CCC(C(=O)O)c1ccccc1I
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)C(=O)O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCC(C(=O)OCC[Si](C)(C)C)c1ccccc1I
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of the acid of Step 1 (103 g, 0.356 mol), pyridine (58 mL, 0.717 mol) and 2-(trimethylsilyl)ethanol (61.2 mL, 0.427 mol) in CH3CN (270 mL) was added a solution of dicyclohexylcarbodiimide (73.4 g, 0.356 mol) in CH3CN (100 mL). The reaction mixture was stirred at r.t. for 2 h, at which point 5M oxalic acid in DMF solution (11 mL) was added. After stirring for 30 min, the suspension was filtered and the filtrate was diluted with EtOAc, washed with water and dried over MgSO4. The crude product was distilled under reduced pressure to give 109 g of the title compound as a colorless oil (bp 120°-140° C./0.4 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[S:25]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>N1C=CC=CC=1.C(OCC)(=O)C>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:31](=[O:32])[CH2:30][C:27]1[CH:28]=[CH:29][S:25][CH:26]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccsc1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (55 mg, 0.16 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), thiophen-3-ylacetic acid (45 mg, 0.32 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol) were added, and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and washed successively with 5% aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/heptane to give the title compound (51 mg, 68%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[C:13]([OH:15])=O)=[CH:11][C:5]=2[CH2:4][O:3]1.Br.[NH2:19][C@H:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][C:24]([OH:30])=[CH:25][CH:26]=2)[CH2:21]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[CH3:17][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12]([OH:16])[C:13]([NH:19][C@H:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][C:24]([OH:30])=[CH:25][CH:26]=4)[CH2:21]3)=[O:15])=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: N[C@H]1CCc2ccc(O)cc2C1
Reactant: CC1(C)OCc2cc([C@@H](O)C(=O)O)ccc2O1
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)OCc2cc([C@@H](O)C(=O)N[C@H]3CCc4ccc(O)cc4C3)ccc2O1
Yield: 88.9 %

Procedure:
(-)-(R)-2-(2,2-Dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)2-hydroxyacetic acid (130 mg), 148 mg of (S)-2-amino-7-hydroxytetralin hydrobromide and 243 mg of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate were dissolved in 1.4 ml of N,N-dimethylformamide, 0.15 ml of triethylamine was added to the solution with stirring under ice-cooling, and the mixture was subjected to 15 hours of reaction. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent: ethyl acetate/acetone=4/1) and then recrystallized from ethyl acetate to give 186 mg of (-)-(2R)-2-(2,2-dimethylbenzo[1,2-d]-1,3-dioxan-6-yl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide having a melting point of 169 to 170° C.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.[CH2:9]([OH:21])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]#[C:16][CH2:17][CH2:18][C:19]#[CH:20].Cl.[CH:23]([OH:30])(O)[C:24]#[C:25][CH2:26][CH2:27][CH3:28]>CO.O=O>[CH2:23]([OH:30])[CH2:24][CH2:25][CH2:26][C:27]#[C:28][C:9]#[C:10][CH2:11][CH2:12][C:3]#[C:4][C:20]#[C:19][CH2:18][CH2:17][C:16]#[C:15][C:14]#[C:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:21]
Reactant: CCCC#CC(O)O
Reactant: C#CCCC#CC#CCCCCO
Reactant: CN(C)CCN(C)C
Agent: Cl
Agent: O=O
Solvent: CO
Product: OCCCCC#CC#CCCC#CC#CCCC#CC#CCCCCO
Reaction time: 1 h

Procedure:
A mixture of 2 parts cuprous chloride, 12 parts methanol, and 4 parts N,N,N',N'-tetramethylethylenediamine was prepared. To this mixture over a period of 15 minutes was added 5,7,11-dodecatriyn-1-ol (produced in Part A above) dissolved in 12 parts methanol, while oxygen was moderately bubbled through the reaction contents. After 1 hour, oxygen flow was stopped and the methanol was distilled leaving a semi-viscous residue. To this was added 100 parts of 3N hydrochloric acid while stirring, causing product to precipitate. It was collected by filtration, washed once with 25 parts 2N hydrochloric acid and several times with water. The solid was dissolved in 200 parts xylene and the solution was refrigerated at -8° C. Subsequent crystallization and filtration yielded 6.0 parts of fluffy product, the above hexayne diol, which turns blue in daylight. The melting point of the material as 101.0° to 104.1° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.Cl.Cl.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([NH:34][C@@H:32]([C:29]2[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[CH3:33])=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)nc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-(thiazol-2-yloxy)benzoic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [C:1]([C:6]1([CH3:14])[CH2:10][C:9]([CH3:11])=[C:8]([OH:12])[C:7]1=[O:13])([O:3]CC)=[O:2].[OH-].[Na+].S(=O)(=O)(O)O>>[C:1]([C:6]1([CH3:14])[CH2:10][C:9]([CH3:11])=[C:8]([OH:12])[C:7]1=[O:13])([OH:3])=[O:2]
Reactant: CCOC(=O)C1(C)CC(C)=C(O)C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(O)C(=O)C(C)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.5 %

Procedure:
4.8 g (24 mmol) of the foregoing 2-carboethoxy-2,4-dimethylcyclopent-4-en-5-olone are treated with 48 ml of 2N sodium hydroxide solution and the mixture is stirred at room temperature for 1.5 hours. For the working-up, the mixture is adjusted to pH 3 with 10% sulphuric acid and extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, concentrated and dried in a high vacuum for 2 hours. There are obtained 3 g (58.5%) of 2-carboxy-2,4-dimethylcyclopent-4-en-5-olone of melting point 98°-105° C., with elimination of carbon dioxide.