Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[C:14](=O)[NH:15][CH2:16][CH2:17][C:18]1[N:19]=[C:20]([CH:23]([CH3:25])[CH3:24])[S:21][CH:22]=1)[CH3:2].O=P(Cl)(Cl)Cl>CC#N>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:27])=[C:8]([C:14]2[C:22]3[S:21][C:20]([CH:23]([CH3:25])[CH3:24])=[N:19][C:18]=3[CH2:17][CH2:16][N:15]=2)[CH:9]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C(=O)NCCc1csc(C(C)C)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)COc1ccc(Cl)cc1C1=NCCc2nc(C(C)C)sc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of {4-chloro-2-[2-(2-isopropyl-thiazol-4-yl)-ethylcarbamoyl]-phenoxy}-acetic acid ethyl ester (100 mg, 0.24 mmol, 1 eq.) and POCl3 (0.34 mL, 3.65 mmol, 15 eq.) in MeCN (2 mL) was stirred at 80° C. for 18 hours. The mixture was allowed to cool down to r.t. and concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give ethyl 2-(4-chloro-2-(2-isopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-4-yl)phenoxy)acetate as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH3:11].[Br:12]N1C(=O)CCC1=O>C(#N)C>[Br:12][C:8]1[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1C
Solvent: CC#N
Product: COc1ccc(Br)c(OC)c1C
Yield: 89 %

Procedure:
A solution of 1,3-dimethoxy-2-methylbenzene (1.86 g, 12.2 mmol) and N-bromo-succinimide (2.17 g, 12.2 mmol) in acetonitrile (30 mL) was stirred at 60° C. for 20 h. After most of the solvent was removed in vacuo, extraction in ethyl ether (2×75 mL) with water (2×50 mL) and flash chromatography with silica gel (gradient to 5% ether/hexanes) provided the title compound as a colorless liquid (2.51 g, 89% yield): 1H NMR (300 MHz, CDCl3) δ 2.19 (s, 3H), 3.78 (s, 3H), 3.81 (s, 3H), 6.54 (d, 1H, J=8.8 Hz), 7.32 (d, 1H, J=8.8 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16].Br.[C:19](O)(=O)C>>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:19])=[O:16]
Reactant: COc1ccc(CCCCC(=O)O)c(OC)c1
Reactant: CC(=O)O
Agent: Br
Product: COC(=O)CCCCc1ccc(O)cc1O
Yield: 55 %

Procedure:
A 1 liter 3 neck round-bottomed flask was charged with 35.7 g (150 mmols) of the 5-(2,4-dimethoxyphenyl)-pentanoic acid (4a) and a stir bar. The flask was set into a suitably sized heating mantle supported on a stirring plate with a strong stirring magnet. The flask was fitted with a thermometer, reflux condenser, and argon inlet. Then 400 ml of acetic acid was added via the thermometer port. The mixture was stirred and warmed to dissolve the solid. This was followed by addition of 68 ml (600 mmols) of 48% aqueous hydrobromic acid. The thermometer was replaced and the flask was flushed with argon. With the cooling water on, the flask was heated to reflux. The reflux was maintained for 16 hours, the mixture was cooled and concentrated on a rotary evaporator. 1 L of methanol was added, and HCl was bubbled in for 5 minutes with a sparger, at a moderate rate. The warm solution was allowed to cool and evaporated. The resulting syrup dissolved in 200 ml of ethyl acetate. The solution was washed with 100 ml water, twice with 100 ml of saturated sodium bicarbonate and once with saturated sodium chloride. The organic layer was dried over sodium sulfate and evaporated to a syrup. The crude product was purified on silica eluting with 3:1 to 2:1 hexane-ethyl acetate. Concentration of the pure product fractions afforded 18.5 g (55%) of desired product. 1H NMR (DMSO-d6) δ: 9.01 (s, 1H), 8.92 (s, 1H), 6.75 (d, J=8.2 Hz, 1H), 6.23 (d, J=2 Hz, 1H), 6.10 (dd, J1=2 Hz, J2=8.2 Hz, 1H), 3.56 (s, 3H), 2.37 (t, J=7 Hz, 2H), 2.29 (t, J=7 Hz, 2H), 1.48 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Cl[C:45]1[N:50]=[CH:49][C:48]([N:51]=[S:52]([CH3:57])([N:54]([CH3:56])[CH3:55])=[O:53])=[CH:47][N:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[N:46]=[CH:47][C:48]([N:51]=[S:52]([CH3:57])([N:54]([CH3:55])[CH3:56])=[O:53])=[CH:49][N:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CN(C)S(C)(=O)=Nc1cnc(Cl)nc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: CN(C)S(C)(=O)=Nc1cnc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)nc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-(2-chloropyrimidin-5-yl)-N,N-dimethyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.10 min; Mass spectrum (ESI+): m/z=702 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:19][CH2:20][O:21][CH3:22])[C:6]=2[CH:11]=1
Reactant: COCCBr
Reactant: O=c1[nH]c2cc(Br)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCn1c(=O)sc2ccc(Br)cc21
Reaction time: 24 h

Procedure:
5-Bromobenzo[d]thiazol-2(3H)-one (1 g) and potassium carbonate (1.502 g) were stirred in DMF (7 mL) at room temperature and 1-bromo-2-methoxyethane (0.408 mL) was added. The mixture was stirred for 24 h. The mixture was poured onto water and extracted with ethyl acetate. The extracts were washed with dilute hydrochloric acid, water and brine then dried over sodium sulfate and evaporated. Purification by flash silica chromatography eluting with 10% ethyl acetate in isohexane afforded the subtitle compound as a colourless solid (0.73 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:22][CH2:21][CH2:20][C:8]32[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]3)[CH:2]=1.[ClH:23]>ClCCl.Cl>[ClH:23].[ClH:23].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:8]3([CH2:9][CH2:10][NH:11][CH2:12]3)[CH2:20][CH2:21][CH2:22]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCN2c2cccnc2)C1
Agent: Cl
Solvent: ClCCl
Product: c1cncc(N2CCCC23CCNC3)c1
Yield: 72 %

Procedure:
A solution of tert-butyl 6-(3-pyridyl)-2,6-diazaspiro[4.4]nonane-2-carboxylate (100 mg, 0.330 mmol) in dichloromethane (5 mL) was rapidly stirred with 1 mL of 12 M hydrochloric acid at ambient temperature for 1 h, during which time the biphasic mixture became monophasic. The dichloromethane was evaporated, and the residue was dissolved in water (3 mL) and made strongly basic (pH 9) with potassium carbonate. The mixture was saturated with sodium chloride and extracted with chloroform (4×10 mL). The extracts were dried (K2CO3) and concentrated, first by rotary evaporation and then by high vacuum treatment. The viscous brown oil which resulted was 98% pure by GCMS and weighed 50 mg (73%). A sample of this free base (40 mg, 020 mmol) was dissolved in 10 drops of 12 M hydrochloric acid. The water was azeotropically removed by repeated treatment with small volumes of ethanol (˜5 mL) and rotary evaporation. The resulting solid was recrystallized from hot isopropanol to give 40 mg (72%) of fine tan crystals (mp 170-175° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:27][CH3:28])[C:13]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][C@H:16]1[C:24]([OH:26])=O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[F:30][C:31]([F:35])([F:34])[CH2:32][NH:33][C:24]([C@@H:16]1[CH2:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]1[C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:27][CH3:28])=[O:26]
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1c2ccccc2C[C@H]1C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(N-Benzyloxycarbonyl-2(S)-aminobutyryl)-indoline-2(S)-carboxylic acid (0.382 g, 1 mmol) and 2,2,2-trifluoroethylamine hydrochloride (0.207 g, 1.5 mmol) were dissolved in dried dichloromethane (10 ml), and triethylamine (5.5 mmol) was added, followed by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.508 g, 2.0 mmol) under nitrogen at 0° C. The temperature was allowed to rise to room temperature and the mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was concentrated under reduced pressure to give a brown solid which was purified by column chromatography on silica gel using 7:3 petroleum spirit: ethyl acetate as eluent to afford a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([CH2:13][S:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[Li+].[CH3:29][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([CH:13]([CH3:29])[S:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCSC2
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCCSC2C
Reaction time: 1.5 h
Yield: 11.2 %

Procedure:
To a stirred solution of ethyl 3-(benzyloxy)-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]thiazepine-2-carboxylate (0.180 g, 0.5 mmol) and iodomethane (0.62 mL, 10 mmol) in THF (5 mL) at −78 C was added 1M solution of LiHMDS (1 mL, 1 mmol) over 2 minutes. After 1.5 h, the reaction mixture was quenched with saturated aq. NH4Cl, diluted with EtOAc (50 mL), dried (Na2SO4), filtered, concentrated and the residue was purified by Prep-HPLC to afford the desired product as orange solid (0.021 g, 11%). 1H NMR (500 MHz, CDCl3) δ: 7.48-7.46 (2H, m), 7.37-7.29 (3H, m), 5.24 (2H, s), 5.15 (1H, dd, J=13.9, 4.4 Hz), 4.33 (2H, q, J=7.0 Hz), 4.18 (1H, q, J=7.0 Hz), 3.62 (1H, dd, J=13.6, 12.1 Hz), 3.14-3.09 (1H, m), 2.77 (1H, dt, J=14.4, 4.2 Hz), 2.34-2.27 (1H, m), 1.91-1.82 (1H, m), 1.62 (3H, d, J=7.0 Hz), 1.30 (3H, t, J=7.0 Hz). HRMS (M+H) calcd for C19H23N2O4S: 375.1379; found: 375.1375.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH:23]=[O:24])([CH3:4])([CH3:3])[CH3:2].CC(=CC)C.[O-:31]Cl=O.[Na+]>C(O)(C)(C)C.O>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:25])=[C:10]([CH:11]=1)[C:23]([OH:31])=[O:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
A solution of 3-(4-benzyloxy-2-formyl-phenyl)-acrylic acid tert-butyl ester (6.70 g, 19.8 mmol) in tert-butanol (150 mL) was treated with 2-methyl-2-butene (50 mL) and cooled to 0° C. A solution of NaClO2 (17.0 g, 188 mmol) and NaH2PO4 (17.0 g, 142 mmol) in H2O (200 mL) was added, and the mixture was stirred at 0° C. for 15 min. The ice bath was removed, and the mixture was stirred at room temperature for 2 h. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified using silica gel chromatography (hexanes/EtOAc 9/1 to 0/10) to afford the title compound as white solid (6.78 g, 96%). 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 5.12 (s, 2H), 6.20 (d, 1H, J=16.2 Hz), 7.13 (dd, 1H, J=3.6, 9.0 Hz), 7.34-7.45 (m, 5H), 7.58 (d, 1H, J=8.8 Hz), 7.64 (d, 1H, J=2.4 Hz), 8.41 (d, 1H, J=16.2 Hz).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[N:11]([C:17]([C:19]1[O:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)=[CH:22][CH:23]=1)=[O:18])[CH2:10][CH2:9]2.[OH-].[Na+]>ClCCl>[N:8]12[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]1)[N:11]([C:17]([C:19]1[O:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:1](=[O:3])[CH3:2])=[CH:26][CH:25]=3)=[CH:22][CH:23]=1)=[O:18])[CH2:10][CH2:9]2
Reactant: Nc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2ccc(C(=O)N3CCN4CCC3CC4)o2)cc1
Reaction time: 4 h

Procedure:
Acetic acid anhydride (133 mg; 1.3 mmol) solved in dichloromethane (2 ml) was added dropwise to a mixture of (1,4-diaza-bicyclo[3.2.2]non-4-yl)-5-(4-aminophenyl)-furan-2-yl-methanone and dichloromethane (10 ml) at room temperature. The mixture was allowed to stir for 4 hours. Aqueous sodium hydroxide (20 ml; 1M) was added followed by extraction with dichloromethane (3×20 ml). The crude mixture was purified by silica gel chromatography, using a mixture of dichloromethane:methanol (4:1) and 2% methanol as eluent. The product was isolated as the free base. Mp. 113° C. (decomp.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(Cl)Cl.[N:51]1([CH2:57][CH2:58]O)[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>>[N:51]1([CH2:57][CH2:58][O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)[NH:11][C:9]([C:6]2[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=2)=[O:10])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1
Reactant: OCCN1CCOCC1
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCCN2CCOCC2)[nH]n1
Reaction time: 0.17 h
Yield: 14.8 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydr oxy-propionic acid (41.0 mg, 86 μmol), HOBt (70.0 mg, 518 μmol) and EDC (92 μL, 520 μmol) were combined in DCM (0.7 mL, 10 mmol). The resulting solution was stirred for 10 minutes. 4-Morpholineethanol (84 μL, 691 μmol) was added, and the mixture was stirred at room temperature until the reaction was complete (≈2 hours). The mixture was concentrated by rotary evaporation and purified (reverse phase column) to yield the title compound (7.5 mg, purity 98%) as a TFA salt. MS m/z [M+H]+calc'd for C28H31ClFN5O6, 588.19. found 588.1.
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][CH2:6][C:7]([CH:9]=[CH2:10])=[CH2:8])[CH3:3].[CH:12]([O:14]CCCC)=[CH2:13].C([O-])(=O)C.[Na+]>>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C:7]([CH:9]=[CH2:10])=[CH2:8])[CH2:3][CH2:13][CH:12]=[O:14]
Reactant: C=CC(=C)CCCC(C)(C)O
Reactant: C=COCCCC
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CC(=C)CCC=C(C)CCC=O
Yield: 75 %

Procedure:
A mixture of 50 g. of sec.-myrcenol (prepared according to the method described in paragraph b) above), 300 g. of n-butyl vinyl ether, 1 g. of mercuric acetate and 10 g. of sodium acetate were refluxed for 40 hours (120°) under nitrogen. During this heating period 1 g. of additional mercuric acetate was added every 6 hours. The laboratory vessel was connected to a downward directed condenser, and the excess of n-butyl vinyl ether was distilled under ordinary pressure. The residue was distilled under vacuum. A yield of 75% of 4-methyl-8-vinyl-4,8-nonadienal that contained approximately 15% of unreacted alcohol was obtained. This alcohol could be recovered when the above C12 aldehyde was converted to β-sinensal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([OH:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[C:21]([O:23][CH3:24])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)cc2C(=O)O)CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2-Carboxy-4-chloro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.64 g, 1.88 mmol) in toluene:methanol (9:1) was added a trimethylsilyldiazomethane (2.0 M in hexanes) (1.05 mL, 2.07 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (50%). 1H-NMR (CDCL3) δ: 1.45 (9H, s), 2.90-3.00 (4H, m), 3.50-3.60 (4H, m), 3.90 (3H, s), 6.90-7.00 (1H, d), 7.35-7.45 (1H, dd), 7.80 (1H, d).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[CH:8]([CH2:14][O:15][P:16]([O:22][CH2:23][CH:24]=[CH2:25])([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[O:7][C@H:6]1[N:26]1[CH:31]=[C:30]([F:32])[N:29]=[C:28]([C:33]([NH2:35])=[O:34])[C:27]1=[O:36])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[P:16]([O:22][CH2:23][CH:24]=[CH2:25])([O:18][CH2:19][CH:20]=[CH2:21])([O:15][CH2:14][C@@H:8]1[C@@H:9]([OH:10])[C@@H:5]([OH:4])[C@H:6]([N:26]2[CH:31]=[C:30]([F:32])[N:29]=[C:28]([C:33]([NH2:35])=[O:34])[C:27]2=[O:36])[O:7]1)=[O:17]
Reactant: C=CCOP(=O)(OCC=C)OCC1O[C@@H](n2cc(F)nc(C(N)=O)c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOP(=O)(OCC=C)OC[C@H]1O[C@@H](n2cc(F)nc(C(N)=O)c2=O)[C@H](O)[C@@H]1O
Reaction time: 0.08 h
Yield: 180.6 %

Procedure:
In 4.0 mL of methanol was dissolved 0.23 g of (2R,3R,4R,SR)-4-(acetyloxy)-2-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-5-({[bis(allyloxy)-phosphoryl]oxy}methyl)tetrahydro-3-furanyl acetate. While cooling the solution with ice, 0.17 g of 28% methanol solution of sodium methoxide was added, and stirred for 5 minutes. Then, 0.15 mL of acetic acid was added, and the solvent was removed under reduced pressure. On the other hand, 1.0 g of (2R,3R,4R,5R)-4-(acetyloxy)-2-[3-(aminocarbonyl)-5-fluoro-2-oxo1(2H)-pyrazinyl]-5-({[bis(allyloxy)phosphoryl]oxy}methyl)tetrahydro-3-furanyl acetate was reacted in the same manner as above. Both the reaction mixtures were united and purified by silica gel column chromatography [eluent: chloroform:methanol=40:1]. Thus, 0.35 g of {(2R,3S,4R,5R)-5-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl diallyl phosphate was obtained as a yellow-colored solid product.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)[C:11]=2[CH2:12]O)=[O:6])[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:26][CH2:12][C:11]1[N:10]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:6]
Reactant: BrC(Br)(Br)Br
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CBr)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 149.5 %

Procedure:
To a suspension of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(hydroxymethyl)-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 112 and carbon tetrabromide (630 mg) in dichloromethane (5 ml) was added in small portions triphenylphosphine (598 mg) at 0° C., and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column (ethyl acetate/hexane=4/1 to ethyl acetate) to give the title compound as a white solid (890 mg).
Reaction SMILES: C(S([C:5]1[CH:25]=[C:24](N(CC)CC)[C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH:22]=[O:23])[CH:16]=3)=[N:10][CH2:11][C:12](=S)[NH:13][C:7]=2[CH:6]=1)=O)C.OC[C:33]([NH:35][NH2:36])=O>C(O)CCC>[CH:22]([NH:21][C:17]1[CH:16]=[C:15]([C:9]2[C:8]3[CH:24]=[CH:25][CH:5]=[CH:6][C:7]=3[N:13]3[CH:33]=[N:35][N:36]=[C:12]3[CH2:11][N:10]=2)[CH:20]=[CH:19][CH:18]=1)=[O:23]
Reactant: CCN(CC)c1cc(S(=O)CC)cc2c1C(c1cccc(NC=O)c1)=NCC(=S)N2
Reactant: NNC(=O)CO
Solvent: CCCCO
Product: O=CNc1cccc(C2=NCc3nncn3-c3ccccc32)c1

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-8-(ethylsulfinyl)-6-(diethylamino)-5-(m-formamidophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butylalcohol was refluxed to give 9-(ethylsulfinyl)-7-(diethylamino)-1-hydroxymethyl)-6-(m-formamidophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(I)n[nH]c2c1
Reactant: COC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)NCCCn1nc(I)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.7 %

Procedure:
to a solution of 6-fluoro-3-iodo-1H-indazole (1.5 g) and methyl (3-bromopropyl)carbamate (1.68 g) in N,N-dimethylformamide (5 mL) was added potassium carbonate (1.58 g), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the mixture was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/20→3/2) to give methyl [3-(6-fluoro-3-iodo-1H-indazol-1-yl)propyl]carbamate [REx(102-1)] (836 mg) as a red oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.O>CN(C)C=O>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH:21]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(3,3,3-Trifluoropropyl)malononitrile (407 mg) was dissolved in N,N-dimethylformamide (5 ml), and potassium carbonate (347 mg) was added thereto, and then, a solution of 3-(chloromethyl)pyridine (320 mg) in N,N-dimethylformamide (1 ml) was added dropwise to the mixture, followed by stirring overnight at room temperature. To the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 400 mg of 2-((3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (6)).