Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=NC(OC)=C(C=1)C(O)=O.Cl[C:14]1[CH:15]=[N:16][C:17]([O:35][CH3:36])=[C:18]([CH:34]=1)[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1)=[O:20]>>[CH3:36][O:35][C:17]1[N:16]=[CH:15][CH:14]=[CH:34][C:18]=1[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1)=[O:20]
Reactant: COc1ncc(Cl)cc1C(=O)NCCc1ccc(CC(=O)O)cc1
Agent: COc1ncc(Cl)cc1C(=O)O
Product: COc1ncccc1C(=O)NCCc1ccc(CC(=O)O)cc1

Procedure:
with 5-chloro-2-methoxynicotinic acid, via ethyl 4-[2-(5-chloro-2-methoxynicotinoylamino)-ethyl]-phenylacetae (oil), 4-[2-(5-chloro-2-methoxynicotinoylamino)-ethyl]-phenylacetic acid; m.p. 157°-158° C., after recrystallization from ethanol.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:11]=[N:12][C:13]([F:40])=[CH:14][C:15]=1[C:16]1[C:21]2[S:22][C:23]([C:25]3[C:30]([F:31])=[CH:29][N:28]=[C:27]([NH:32][CH2:33][CH2:34][N:35]4[CH:39]=[CH:38][N:37]=[N:36]4)[N:26]=3)=[CH:24][C:20]=2[CH:19]=[CH:18][CH:17]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1([CH2:34][CH2:33][NH:32][C:27]2[N:26]=[C:25]([C:23]3[S:22][C:21]4[C:16]([C:15]5[C:10]([CH2:9][NH:7][CH3:6])=[CH:11][N:12]=[C:13]([F:40])[CH:14]=5)=[CH:17][CH:18]=[CH:19][C:20]=4[CH:24]=3)[C:30]([F:31])=[CH:29][N:28]=2)[CH:39]=[CH:38][N:37]=[N:36]1
Reactant: CN(Cc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cnc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Combine (6-fluoro-4-{2-[5-fluoro-2-(2-[1,2,3]triazol-1-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophen-7-yl}-pyridin-3-ylmethyl)-methyl-carbamic acid tert-butyl ester (0.30 g, 0.51 mmol) and dry TFA (2.0 mL) and dry DCM (2.2 mL). Stir at RT for 1 h. Evaporate off the solvents. Dilute the resulting residue with DCM and wash with saturated sodium bicarbonate solution, water, and saturated aqueous sodium chloride. Separate the organic layer and dry over magnesium sulfate. Filter and concentrate in vacuo to give the crude product. Purify by column chromatography [0.1% to 2% 2 M ammonia in methanol/DCM] to afford the title compound (0.20 g, 83%). MS (ES) m/z 479 [M+1]+.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11](O)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([Cl:18])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Product: CC(C)(C)c1ccc(OCC(=O)Cl)cc1

Procedure:
Filling in a dry 250 ml flask respectively 57.42 g (0.276 mol) of para-t-butylphenoxyacetic acid synthesized in Example 17 and 80.5 ml of thionyl chloride, the reaction mixture was heated and refluxed for 5-6 hours.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:19])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].C[Si](C)(C)[O:35][NH2:36].C(OCC)C>O1CCCC1>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:36][OH:35])=[O:19])=[C:14]([F:32])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c2)C(=O)O1
Reactant: C[Si](C)(C)ON
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)NO)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
Prepared according to Method D of the General Procedures for Preparation of 5-(S)-(N-Acylaminomethyl)-3-[4′-(4″-(un)substituted amino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from 5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one (0.046 g, 0.1 mmol) and O-trimethylsilylhydroxylamine (0.052 mL, ca. 0.5 mmol) in tetrahydrofuran (1 mL). The synthesis was performed for 2 h at r.t. Diethyl ether (4 mL) was added, the precipitated product washed with diethyl ether, tetrahydrofuran (2×0.5 mL), excess ether, and dried in vacuo. MS: 312 [M+H]+. Rt 2.8 min. 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[N:13]=[C:12]([NH2:24])[N:11]=2)[C:7]([CH3:25])=[CH:6][C:5]=1[O:26][CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[C:40]([O:44][C:45](=[O:51])[NH:46][CH2:47][CH2:48][CH2:49]Br)([CH3:43])([CH3:42])[CH3:41]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:49][CH2:48][CH2:47][NH:46][C:45]([O:44][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:51])[CH:18]=3)[N:13]=[C:12]([NH2:24])[N:11]=2)[C:7]([CH3:25])=[CH:6][C:5]=1[O:26][CH3:27]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)c1cc(-c2cc(Sc3cccc(O)c3)nc(N)n2)c(C)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cc(Sc3cccc(OCCCNC(=O)OC(C)(C)C)c3)nc(N)n2)c(C)cc1OC
Temperature: 25 °C
Reaction time: 37 h
Yield: 92.9 %

Procedure:
5-[2-Amino-6-(3-hydroxyphenylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (80 mg, 0.2 mmol) obtained in Step 1 above, cesium carbonate (124 mg, 0.38 mmol), and N,N-dimethylformamide (1.0 ml) were added to a reaction vessel. Then 3-bromopropylcarbamic acid tert-butyl ester (100 mg, 0.42 mmol) was added to the mixture. The mixture was stirred at room temperature for 37 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with a saturated aqueous ammonium chloride solution (50 ml), twice with water (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate) to yield 5-{2-amino-6-[3-(3-tert-butoxycarbonylaminopropoxy)phenylsulfanyl]pyrimidin-4-yl}-2-methoxy-4-methylbenzoic acid methyl ester (103 mg).
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[OH-].[Ca+2:7].[OH-]>>[P:1]([O-:5])([OH:4])([OH:3])=[O:2].[Ca+2:7].[P:1]([O-:5])([OH:4])([OH:3])=[O:2]
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Product: O=P([O-])(O)O

Procedure:
According to an advantageous embodiment of the invention, the method comprises a mixing of phosphoric acid with an aqueous suspension of calcium hydroxide, a formation of a first precipitate of calcium monohydrogenphosphate (DCP), a separation between the first precipitate and an aqueous solution of calcium dihydrogenphosphate (MCP), an addition to this aqueous solution of a strong base and a separation between a second precipitate and a clear solution of calcium dihydrogenphosphate (MCP), forming the said mineral additive.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:19]([O:18][C:13]([C:14]1([CH3:16])[C:9]2=[CH:10][CH:11]=[CH:12][N:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1]1)=[O:17])[CH3:20]
Reactant: Oc1ccccc1-n1cccc1
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1(C)Oc2ccccc2-n2cccc21
Reaction time: 18 h

Procedure:
A solution of the compound of formula 2, N-(2-hydroxyphenyl)pyrrole (18 g), described in Example 1, ethyl pyruvate (13 g) and p-toluenesulfonic acid (1.8 g) in benzene (1.2 1) is stirred and heated at reflux with a Dean-Stark water trap for 30 min. The reaction mixture is allowed to cool and stand at room temperature for 18 hr. The mixture is filtered and the filtrate is washed with 5% NaHCO3, water, saturated brine solution, and then dried (MgSO4). The solvent is evaporated and the remaining material is adsorbed on a silica gel column. Elution with chloroform gives 4-methyl-4H-pyrrolo[2,1-c][1,4]benzoxazine-4-carboxylic acid ethyl ester, νmaxCHCl3 1,735, 1,605, 1,510, 1,345, 1,125, 1,095 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:30][NH2:31]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([NH:30][NH2:31])=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)NN
Temperature: 70 °C
Reaction time: 8 h

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (0.061 g, 2.16 mmol) was dissolved in THF (5 mL) then 1,1′-carbonyldiimidazole (0.390 g, 2.38 mmol) was added and the reaction was heated to 70° C. for 40 minutes. The reaction was then cooled to 0° C. and hydrazine monohydrate (0.220 mL, 4.32 mmol) was added. The reaction was then allowed to slowly warm to room temperature and stirred overnight. Standard aqueous workup afforded the title compound, which was brought to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]1([CH:20]=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>CS(O)(=O)=O>[F:1][C:2]1[C:3](=[O:9])[CH:4]=[C:5]2[C:7](=[CH:8][C:7]3[C:5]([O:6]2)=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:8]=3)[C:20]=1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: Oc1ccc(F)c(O)c1
Agent: CS(=O)(=O)O
Product: O=c1cc2oc3cc(O)c(F)cc3cc-2c(-c2cccc3ccccc23)c1F

Procedure:
Two equivalents of 4-fluororesorcinol (Compound 15) are condensed with one equivalent of naphthalene-1-carboxaldehyde in warm methanesulfonic acid. When the reaction is judged complete by TLC analysis, the intermediate product is precipitated from the reaction solution by the addition of an excess of water. The crude solid is collected on a Büchner funnel, and dried in vacuo. The intermediate is then dissolved in chloroform and treated with an excess of chloramine-T. When the oxidation reaction is complete, as judged by TLC, the volatiles are removed in vacuo and the crude product is purified using flash chromatography to give Compound 57.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:39][CH2:40][CH3:41])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:35](OC)=[O:36])=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].C(OC(OCC)C1C=CC(C2C(C3C=CC(C(OCC)OCC)=CC=3)C(=O)C3C(C(OCC)=O)=CC=CC=3N2)=CC=1)C.O.[NH2:85][NH2:86]>CO>[CH2:40]([O:39][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:85][NH:86][C:35](=[O:36])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:41]
Reactant: CCOC(OCC)c1ccc(C2Nc3cccc(C(=O)OC)c3C(=O)C2c2ccc(C(OCC)OCC)cc2)cc1
Reactant: NN
Agent: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(C(OCC)OCC)cc1)C(c1ccc(C(OCC)OCC)cc1)N2
Solvent: O
Solvent: CO
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(OCC)OCC)cc2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A mixture of methyl 2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate and ethyl 2,3-bis(4-(diethoxymethyl)phenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (240 mg, 0.43 mmol) in hydrazine monohydrate (5 mL) and methanol (5 mL) was stirred at 40° C. for 2 hr. The mixture was cooled to room temperature and filtered to give the 8,9-bis(4-(diethoxymethyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (120 mg, yield 52%) as a light yellow solid. LC-MS (ESI) m/z: 544 (M+1)+. MS (ESI) m/e 381 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCC1CC(c2ccc(Br)cc2)=NO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
[3-(4-Bromophenyl)-4,5-dihydroisoxazol-5-yl]methanol (4.44 g, 17 mmol) was dissolved in a mixture of triethylamine (2.9 ml, 19 mmol) and dichloromethane (100 ml). The resulting solution was cooled to 0° C., then a 1 M solution of tert-butyldimethylsilylchloride (19 ml) in dichloromethane was added dropwise over 5 minutes. 4-Dimethylamino pyridine (0.423 g, 3.4 mmol) was added and the reaction mixture left to stir overnight at room temperature. A second portion of tert-butyldimethylsilylchloride (19 ml) in dichloromethane and triethylamine (2.9 ml, 19 mmol) were added and the reaction mixture left to stir overnight at room temperature. The reaction mixture was concentrated in vacuo then redissolved in dichloromethane (200 ml) and washed with water (200 ml). The dichloromethane layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo onto silica gel (5 ml). This was then subjected to column chromatography (50 g silica gel bond elut: 0% to 50% ethyl acetate/hexanes) to yield 5.405 g (84%) of the desired compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=1)[CH:6]=O.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>CC#N>[CH:17]1([NH:20][CH2:6][C:5]2[CH:8]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:19][CH2:18]1
Reactant: COCCCOc1cc(C=O)cc(OC)c1
Reactant: NC1CC1
Solvent: CC#N
Product: COCCCOc1cc(CNC2CC2)cc(OC)c1

Procedure:
The title compound is synthesized by reductive amination of 3-Methoxy-5-(3-methoxy-propoxy)-benzaldehyde (2.50 g, 11.1 mmol) with cyclopropylamine (855 mg, 15.0 mmol) analogously to the preparation of Example 152. Yellow oil; MS: 266 [M+H]+; tR (HPLC, CombiScreen ODS-AM 50×4.6 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 2.48 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][C:6]2=[O:13])[CH3:2].[CH2:14](N(CC)CC)C.IC>C1COCC1>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:14])[CH2:8][CH2:7][C:6]2=[O:13])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCc1ccc2c(c1)C(=O)CCN2
Solvent: CI
Solvent: C1CCOC1
Product: CCc1ccc2c(c1)C(=O)CCN2C
Temperature: 70 °C
Yield: 30 %

Procedure:
To a solution of 6-ethyl-2,3-dihydroquinolin-4(1H)-one (1.00 g) in THF (25 mL) was added triethylamine (0.64 g) followed by iodomethane (0.89 g). The mixture was refluxed at 70° C. overnight. The solvent was stripped under reduced pressure, and the residue was partitioned between aqueous sodium bicarbonate and dichloromethane. The organics were extracted three times, washed with brine, dried with sodium sulfate, filtered, and concentrated. Chromatography was used to purify the title compound using a 40% ethyl acetate in heptane solvent solution. 0.32 g of the title product were recovered. (30% yield). MS (ESI+) for C12H15NO m/z 190.10 (M+H)+.
Reaction SMILES: C(O[C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:9])=[O:8])(C)C.Cl[Sn](Cl)(Cl)Cl>>[CH2:7]([O:8][C:12]1[CH:13]=[CH:5][C:6]([C:7]([Cl:9])=[O:8])=[CH:10][CH:11]=1)[CH:6]=[CH2:5]
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Product: C=CCOc1ccc(C(=O)Cl)cc1

Procedure:
The procedure is the same as that described for isopropoxy benzoyl chloride. (2 g of the acid chloride was reacted at ambient temperature with 100 mg of SnCl4 for 2 hours and gave a red-brown solid with a dp of 4.4).
Reaction SMILES: O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:22]1([CH:25]=[C:26]2[C:31](=[O:32])[O:30][C:29]([CH3:34])([CH3:33])[O:28][C:27]2=[O:35])[CH2:24][CH2:23]1>O.ClCCl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:22]1([C@H:25]([CH:26]2[C:31](=[O:32])[O:30][C:29]([CH3:33])([CH3:34])[O:28][C:27]2=[O:35])[C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1
Reactant: C#Cc1ccccc1
Reactant: CC1(C)OC(=O)C(=CC2CC2)C(=O)O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC(=O)C([C@H](C#Cc2ccccc2)C2CC2)C(=O)O1
Temperature: 0 °C
Yield: 79.1 %

Procedure:
A solution of copper (II) acetate monohydrate (5.0 mg, 0.025 mmol) in water (0.2 ml) was treated with sodium (L)-ascorbate (10 mg, 0.050 mmol), the mixture was stirred until the mixture was turned bright orange (3 min). Subsequently, (R,M)-3-{[4-(2-diphenylphosphanyl-7-methoxy-naphthalen-1-yl)-phthalazin-1-ylamino]-phenyl-methyl}-pentan-3-ol (1st diastereomer, 16.5 mg, 0.025 mmol) and phenylacetylene (0.275 ml, 2.5 mmol) were added, the resulting mixture was stirred for 10 min at 23° C., cooled to 0° C., stirred for 5 min and treated with 5-(cyclopropylmethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (49 mg, 0.25 mmol). The reaction mixture was stirred vigorously at 0° C. for 51 hrs, diluted with dichloromethane (2 ml) and subjected directly to flash chromatography on silica gel (hexane/dichloromethane 1:3) to give 59 mg of the pure title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]1[N:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[NH2:16][C:13]1[CH:14]=[N:15][C:10]([NH:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NNc1ccc([N+](=O)[O-])cn1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)NNc1ccc(N)cn1
Yield: 99.8 %

Procedure:
57 mg of platinum oxide was added to a solution of 6-(2-t-butoxycarbonylhydrazino)-3-nitropyridine (570 mg) in ethanol (10 ml). The mixture was vigorously stirred in an atmosphere of hydrogen at room temperature for 1 hour. After completion of the reaction, the reaction solution was filtered, and the filtered cake was thoroughly washed with ethanol. The filtrate and the washings were combined, and the solvent was removed by distillation to obtain 502 mg of 3-amino-6-(2-t-butoxycarbonylhydrazino)pyridine as a brown powder.
Reaction SMILES: Cl.[CH:2]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=3)[NH:8][N:7]=2)[CH2:5][CH2:4][CH2:3]1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])[CH3:23].O>CN(C=O)C>[Si:25]([O:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH:2]3[CH2:3][CH2:4][CH2:5]3)=[N:7][NH:8]2)=[CH:13][CH:12]=1)([C:22]([CH3:24])([CH3:23])[CH3:21])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Oc1ccc2c(C3CCC3)n[nH]c2c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](Oc1ccc2c(C3CCC3)n[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyclobutylindazol-6-ol hydrochloride (6.45 g) which can be prepared according to the method described in Reference example 11, etc. and imidazole (5.039 g) were dissolved in DMF (100 mL; manufactured by Kanto Chemical Co., Inc.). Then, TBDPSCl (18.44 mL) was added and the mixture was stirred overnight at room temperature. To the reaction solution, water was added and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (9.93 g).
Reaction SMILES: FC1C=C([CH2:12][C:13](=[O:15])C)C=CC=1S(C)(=O)=O.FC1C=C(C=CC=1S(C)(=O)=O)C=O.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][C:31]=1[O:38][CH3:39]>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][C:13](=[O:15])[CH3:12])=[CH:32][C:31]=1[O:38][CH3:39]
Reactant: COc1cc(C=O)ccc1F
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Agent: CS(=O)(=O)c1ccc(C=O)cc1F
Product: COc1cc(CC(C)=O)ccc1F

Procedure:
The title compound is prepared via an analogous procedure to 1-((3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one (64c) (steps 64b-64c) by replacing 3-fluoro-4-methanesulfonyl-benz-aldehyde in step 64b with 4-fluoro-3-methoxy-benzaldehyde.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]([CH3:10])[C:5](=[O:11])[C:4]=1[C:12](=[O:27])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:16]=1.[Br:28]Br>C(Cl)(Cl)Cl>[Br:28][C:8]1[C:3]([OH:2])=[C:4]([C:12](=[O:27])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:16]=2)[C:5](=[O:11])[N:6]([CH3:10])[C:7]=1[CH3:9]
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(OC)cc(C)n(C)c2=O)c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)COc1cccc(C=CC(=O)c2c(O)c(Br)c(C)n(C)c2=O)c1
Reaction time: 1 h

Procedure:
To a solution of 0.50 g of 4-methoxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 15 ml of chloroform was added dropwise a solution of 70 μl of bromine in 7 ml of chloroform under ice-cooling. After stirred for 1 hour under ice-cooling, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 0.09 g of 5-bromo-4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (1d)] as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[Se:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[Se:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C)[se]1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(C)[se]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
To an ice cold (0-10° C.) solution of methyl 5-methylselenophene-2-carboxylate (5.4 g, 26.6 mmol) in acetic anhydride (15 mL) was added an ice cold mixture of nitric acid (5.5 mL, 61.1 mmol, 70%) and acetic anhydride (10 mL) for 10 min. The reaction mixture was slowly allowed to rt for 1 h and stirred at room temperature (rt) for 16 h. The mixture was poured into ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) as eluents to give the product as an pale yellow color solid (2.3 g, 35%), mp 90-92° C. 1H NMR (400 MHz, CDCl3): δ 8.54 (1H, s), 3.90 (3H, s), 2.90 (3H, s).