Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:7][O:8][CH:9]([SiH3:12])[O:10][CH3:11]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)CCC>[CH3:7][O:8][CH:9]([SiH2:12][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]([SiH2:12][CH:9]([O:10][CH3:11])[O:8][CH3:7])[CH3:6])[O:10][CH3:11]
Reactant: COC([SiH3])OC
Reactant: C=CCCC=C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CCCCO
Product: COC(OC)[SiH2]CCCCC(C)[SiH2]C(OC)OC

Procedure:
Butanol solution of chloroplatinic acid was added to 41.1 g of 1,5-hexadiene, and to this mixture, 106.2 g of dimethoxymethylsilane was gradually added dropwise. Due to the exothermic nature of the reaction, the speed of the dropwise addition was adjusted so that temperature of the reaction mixture was up to 80° C. After the completion of the dropwise addition, the mixture was distilled at reduced pressure under clean conditions as in the case of Synthetic Example 1 to obtain 1,5-bis(dimethoxymethylsilyl)hexane.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[C:20]1([CH3:34])[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:21]=1>>[C:20]1([CH3:34])[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:30][CH:29]=[N:28][C:27]=2[C:31]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:32])[CH:21]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: Cc1cccc(-c2scnc2C(=O)O)c1
Product: Cc1cccc(-c2scnc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-m-Tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.29 min; [M+H]+=478.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=2)=[CH:24][C:23]=1[F:38]>O1CCCC1.C(N(CC)CC)C>[F:38][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][C:22]=1[NH:21][C:14]([C:11]1([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:12][CH2:13]1)=[O:16])[O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
To a solution of 1-(4-fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (1.45 g) in tetrahydrofuran (14.5 ml) was added dropwise triethylamine (1.13 ml) under a nitrogen atmosphere while cooling in an ice water bath, followed by stirring for 15 min. To the reaction mixture was added thionyl chloride (0.473 ml), followed by stirring at the same temperature for 1.5 hr. To the reaction mixture were added a solution of 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxamide (1.0 g) in tetrahydrofuran (10.5 ml) and triethylamine (1.13 ml) in this order at the same temperature under a nitrogen atmosphere, followed by stirring. The reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was partitioned after addition of ethyl acetate (50 ml) and a 2N aqueous solution of sodium hydroxide (10 ml). The organic layer was washed with a 2N aqueous solution of sodium hydroxide (10 ml, twice), 1N hydrochloric acid (10 ml, three times) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml), and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the residue was filtered (eluent; ethyl acetate) through silica gel column (Fuji Silysia NH). The filtrate was concentrated under reduced pressure, and to the resultant residue (1.28 g) were added ethyl acetate (4 ml) and heptane (4 ml) to suspend. The solid was collected by filtration and dried under aeration to provide the titled compound as a pale pink solid (991.1 mg, 54.1%). The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=3:1). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as a white solid (24.3 mg, 1.33%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[CH:4][CH:3]=1.Br[CH:12]([CH2:21][CH3:22])[C:13](=O)[CH2:14][C:15]([O:17]CC)=[O:16]>>[CH2:21]([C:12]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:13]=1[CH2:14][C:15]([OH:17])=[O:16])[CH3:22]
Reactant: CCOC(=O)CC(=O)C(Br)CC
Reactant: NC(=S)c1ccc(F)cc1
Product: CCc1sc(-c2ccc(F)cc2)nc1CC(=O)O

Procedure:
The title compound was prepared from 6.8 g of 4-fluorothiobenzamide and 7.42 g of ethyl 4-bromo-3-oxo-hexanoate as described in example 2B to give 2.9 grams of intermediate 4B as a solid: 1H NMR (CDCl3, 300 MHz) δ7.96 (dd, 2H, J=8.8, 5.3), 7.11 (t, 2H, J=8.6), 3.61 (s, 2H), 2.69 (q, 2H, J=7.5), 1.27 (t, 3H, J=7.5).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[N:4]([CH2:15][C:16](=[O:18])[CH3:17])[C:3]1=[O:19].[CH2:20]([N:22]([CH2:25][C:26]#[CH:27])[CH2:23][CH3:24])[CH3:21].C(O)(=O)/C=C/C(O)=O>>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:25][C:26]#[C:27][C:16]([OH:18])([CH3:17])[CH2:15][N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:19])[CH3:21]
Reactant: C#CCN(CC)CC
Reactant: CCCn1cnc2c1c(=O)n(CC(C)=O)c(=O)n2C
Agent: O=C(O)/C=C/C(=O)O
Product: CCCn1cnc2c1c(=O)n(CC(C)(O)C#CCN(CC)CC)c(=O)n2C
Yield: 48 %

Procedure:
1-(5-Diethylamino-2-hydroxy-2-methyl-3-pentynyl)-3-methyl-7-propylxanthine was prepared as oily substance in 48% yield using 3-methyl-1-(2-oxopropyl)-7-propylxanthine and N,N-diethyl-2-propynylamine as in Example 6C1). Salt formation with fumaric acid as in Example 7F2) took place in 98% yield. Melting point: 109° C. C23H33N5O7 (MW=491.56 g/mol), base C19H29N5O3 (MW=375.48 g/mol)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)C.CS(C)=O>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][N:3]=2)[CH2:22][CH2:21]1.[ClH:1]
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)ncc2c1=O
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Solvent: CCO
Product: CN1CCN(c2cc3c(cn2)c(=O)c(C(=O)O)cn3C2CC2)CC1
Product: Cl

Procedure:
A suspension of 2.64 g of 7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid and 2.5 g of N-methylpiperazine in 30 ml of ethanol or DMSO (=Dimethylsulfoxide) was heated to the boiling point under reflux for 16 hours or to 135°-140° C. for two hours. The diluent was distilled off in vacuo, the residue was dissolved in 30 ml of 1N NaOH, the solution was filtered and the filtrate was acidified with 10 strength hydrochloric acid. The precipitate was filtered off and washed with water and ethanol. It could be recrystallised from N-dimethylformamide/ethanol. 3.1 g (94% of the theoretical yield) of 7-(4-methylpiperazino)-1-cyclopropyl-4-oxo-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid of melting point 326° C. (hydrochloride) (decomposition) were obtained.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:26]=[N:25][C:24](Cl)=[CH:23][N:22]=1.N12CCCN=C1CCCCC2>CN1C(=O)CCC1.C(OCC)(=O)C>[C:16]([O:15][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:24]3[CH:23]=[N:22][C:21]([Cl:20])=[CH:26][N:25]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: Clc1cnc(Cl)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnc(Cl)cn3)CC2)CC1
Temperature: 110 °C

Procedure:
The tert-butyl 4,4′-bipiperidine-1-carboxylate (1.27 g, 4.7 mmol) and 2,5-dichloropyrazine (670 mg, 4.5 mmol) were dissolved in NMP (5 ml) at room temperature, and 1,8-diazabicyclo[5.4.0]-undec-7-ene (1 mL, 6.8 mmol) added drop-wise. The mixture was heated at 110° C. for 1 h, allowed to cool to r.t. and diluted with 50 mL of ethyl acetate. The solution was washed with water (10 mL ×1), brine (10 mL ×1), dried over magnesium sulfate, filtered, and concentrated in vac. The residue was purified by chromatography on silica gel with 10% acetone:hexanes to yield the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=COC=1)=[C:2]=[S:3].[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH:12]=[CH:11]1.[CH3:17]COCC>>[N:1]([C:4]1[CH:17]=[C:12]2[C:13](=[O:14])[O:15][C:10](=[O:16])[C:11]2=[CH:9][CH:5]=1)=[C:2]=[S:3]
Reactant: O=C1C=CC(=O)O1
Reactant: CCOCC
Reactant: S=C=NCc1ccoc1
Product: O=C1OC(=O)c2cc(N=C=S)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(Isothiocyanatomethyl)furan (0.659 g, 4.734 mmol) and maleic anhydride (0.475 g, 4.844 mmol) were dissolved in ether (17 mL) and stirred at room temperature for 16 hours under a positive pressure. The reaction mixture evaporated to dryness overnight leaving a light colored solid. The solid was triturated with ether (3.0 mL), collected by filtration, washed with ether (8×1.0 mL), and dried to afford the title 4-isothiocyanatophthalic anhydride as off-white crystals in a yield of 0.842 g, (75 percent of theoretical) which melted at 128°-129° C.; 1H NMR (300 MHz, acetone-d6) d 6.58 (br s, 1H), 5.41 (s, 1H), 5.35 (s, 1H), 4.71 (AB q, J=18.4 Hz, 2H), 3.61 (d, J=6.8 Hz, 1H), 3.51 (d, J=6.8 Hz, 1H), 13C NMR (75 MHz, acetone-d6) d 172.1, 172.0, 147.4, 133.6, 128.9, 84.1, 83.5, 51.0 49.7, 43.0; IR (Nujol) 2210, 2135, 1850, 1780, 1760 cm-1; MS m/e 237, 209, 179, 139, 98, 81 (base), 53.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.F[B-](F)(F)F.[O:15]=[N+:16]=[O:17]>C(#N)C.O>[F:1][C:2]1[C:7]([N+:16]([O-:17])=[O:15])=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][CH:3]=1
Reactant: O=[N+]=O
Reactant: Cc1ccc(F)cc1O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1ccc(F)c([N+](=O)[O-])c1O
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
A stirred solution of 5-fluoro-2-methylphenol (640 mg, 5 mmol) in 20 mL of anhydrous acetonitrile was cooled to −30° C. to −40° C. and treated with nitronium tetrafluoroborate (740 mg, 5.5 mmol). After 45 minutes, the reaction mixture was diluted with 100 mL of cold water and extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with three 25 mL portions of water, dried over sodium sulfate, and concentrated in vacuo to give a reddish crystalline solid. Chromatography over SiO2 (5% ethyl acetate in hexanes) gave 0.58 g of the title product as bright yellow solid (68% yield).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH:19]2[CH2:21][CH2:20]2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=1[F:30])=[O:9])=[CH2:2].COC(C1N(C2CC2)C2C=CN=CC=2C=1NC1C=C[C:51]([S:54]C)=CC=1F)=O>>[CH:1]([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[N:18]([CH:19]2[CH2:21][CH2:20]2)[C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:54][CH3:51])=[CH:25][C:24]=1[F:30])=[O:9])=[CH2:2]
Reactant: C=COCCONC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Reactant: COC(=O)c1c(Nc2ccc(SC)cc2F)c2cnccc2n1C1CC1
Product: C=COCCONC(=O)c1c(Nc2ccc(SC)cc2F)c2cnccc2n1C1CC1

Procedure:
This compound was prepared in an analogous fashion to 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]-pyridine-2-carboxylic acid (2-vinyloxy-ethoxy)-amide, using 1-cyclopropyl-3-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester as the starting material. 1H-NMR (500 MHz, CDCl3) δ ppm 9.50 (br s, 1H), 8.60 (d, J=0.88 Hz, 1H), 8.38 (d, J=5.97 Hz, 1H), 7.46 (dd, J=5.98 Hz, 1H), 7.10 (dd, J=11.45 Hz, 1H), 6.89 (dd, J=8.41 Hz, 1H), 6.66 (t, J=8.67 Hz, 1H), 6.42 (dd, J=14.33 Hz, 1H), 6.33 (br s, 1H), 4.29-4.22 (m, 2H), 4.18 (dd, J=14.33 Hz, 1H), 4.04 (dd, J=6.82 Hz, 1H), 3.98-3.90 (m, 2H), 3.61-3.53 (m, 1H), 2.44 (s, 3H), 1.33-1.20 (m, 2H), 1.01-0.96 (m, 2H); LC-MS (method D): [M+H]+=443.3, RT=2.17 min.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28](O)(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.P(Cl)(Cl)([Cl:44])=O>CN(C)C(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([Cl:44])(=[O:30])=[O:29])=[C:23]([CH3:32])[CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(N=Nc2cc(S(=O)(=O)NC(C)(C)C)c(O)c3cccc(NS(C)(=O)=O)c23)cc(C)c1S(=O)(=O)O
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: Cc1cc(N=Nc2cc(S(=O)(=O)NC(C)(C)C)c(O)c3cccc(NS(C)(=O)=O)c23)cc(C)c1S(=O)(=O)Cl
Temperature: 0 °C

Procedure:
To a solution containing 30 g of the naphthol compound obtained in Step (1) above, 250 ml to acetonitrile and 45 ml of phosphorus oxychloride, 15 ml of N,N-dimethylacetamide was added dropwise at a temperature below 60° C. with stirring. The mixture was stirred at 60° C. for 3 hours and poured into 1 l of ice water. The cyrstals thus-precipitated were collected by filtration and washed with 100 ml of acetonitrile.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:14]([C:15]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:16]4[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]4)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:33]([O:38]C)(OC)[O:34]C.Cl>O1CCCC1>[C:5]1([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]([C:22]3[CH:23]=[CH:24][C:25]([B:33]([OH:38])[OH:34])=[CH:26][CH:27]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2c3ccccc3c(-c3ccccc3)c3ccccc23)cc1
Reaction time: 2 h
Yield: 84 %

Procedure:
In a 500 mL three-neck flask were stirred 20 g (49 mmol) of 9-(4-Bromophenyl)-10-phenylanthracene obtained by the above Steps 1(1) to 1(4) and 300 mL of tetrahydrofuran (abbreviation: THF) in a nitrogen atmosphere at −78° C. Then, 34 mL (54 mmol) of n-butyllithium (1.6 mol/L hexane solution) was dropped, and this mixture was stirred for 2 hours at the same temperature. After that, 13 mL (110 mmol) of trimethyl borate was added therein, and the mixture was stirred for 24 hours at room temperature. After the reaction, 200 mL of 1.0 mol/L hydrochloric acid was added therein, and the mixture was stirred for 1 hour at room temperature. After that, an organic layer thereof was washed with water and separated into an organic layer and a water layer, and the obtained water layer was further extracted with ethyl acetate. This extracted solution and the organic layer were mixed and washed with saturated aqueous solution, and magnesium sulfate was added therein, so that moisture was removed. Then, suction filtration was performed so that a filtrate was obtained. The obtained filtrate was concentrated to provide a residue. The obtained residue was recrystallized with a mixed solution of chloroform and hexane, whereby 15 g of a powdery white solid of 4-(10-phenyl-9-anthryl)phenylboronic acid, which was the object of the synthesis, was obtained in a yield of 84% (synthesis scheme (a-5)).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[NH2:8][CH2:9][C@H:10](O)[CH3:11].[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)=[C:18]([CH:22]=1)[C:19](O)=[O:20]>C1(C)C=CC=CC=1>[CH3:11][C@H:10]1[O:3][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[N:8]([C:19](=[O:20])[C:18]2[CH:22]=[C:14]([CH3:13])[CH:15]=[CH:16][C:17]=2[N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)[CH2:9]1
Reactant: CCOC(=O)C=O
Reactant: C[C@@H](O)CN
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1O[C@H](C)CN1C(=O)c1cc(C)ccc1-n1nccn1

Procedure:
By using ethyl glyoxylate (polymer type, a solution of 47% toluene) (0.50 mL, 2.4 mmol), (2R)-1-aminopropan-2-ol (0.18 mL, 2.4 mmol) and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.20 g, 0.98 mmol), the same procedure as in Reference Example 1 was carried out to obtain the title compound (0.14 g) (colorless oil).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].[CH:16]1([NH:24][C:25](=[O:28])[CH2:26]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:26][C:25]([NH:24][CH:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:28])=[CH:7][CH:6]=1
Reactant: O=C(CBr)NC1CCCCCCC1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCC(=O)NC2CCCCCCC2)cc1
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
Bromoacetyl chloride (0.25 mL) was added slowly to a chilled (ice-water-bath) solution of cyclooctylamine (0.763g) in dichloromethane (15 mL) and the mixture was stirred with cooling for 45 minutes, then at room temperature overnight. After water (20 mL) was added, the layers were separated and the dried organic layer (MgSO4) was evaporated to provide 0.7 g of N-cycloocyl-bromoacetamide. A solution of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.605 g) in dimethylformamide (8 mL) under argon was treated with 55% sodium hydride (0.147 g), stirred for 30 minutes and then N-cyclooctyl-bromoacetamide (0.7 g) in dimethylformamide (5 mL) was added. The solution was stirred at room temperature for 18 hours and worked up as in Example 20. The crude material was purified by flash chromatography (ethyl acetate-hexane; 3:7) to yield 0.4 g of 4-[2-(cyclooctylamino)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester as an oil.
Reaction SMILES: N12CCCN=C1CCCCC2.[Si:12]([O:19][CH2:20][C@H:21]1[O:27][C@H:25]([CH3:26])[CH:24]=[CH:23][C@@H:22]1[OH:28])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Cl:29][C:30]([Cl:34])([Cl:33])[C:31]#[N:32]>ClCCl>[Si:12]([O:19][CH2:20][C@H:21]1[O:27][C@H:25]([CH3:26])[CH:24]=[CH:23][C@@H:22]1[O:28][C:31](=[NH:32])[C:30]([Cl:34])([Cl:33])[Cl:29])([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: C[C@@H]1C=C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Reactant: N#CC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C[C@@H]1C=C[C@H](OC(=N)C(Cl)(Cl)Cl)[C@@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.00 ml, 6.83 mmol) was added to a dichloromethane (22 ml) solution of the compound (6.83 mmol) obtained in Step 2 above combined with trichloroacetonitrile (0.82 ml, 8.20 mmol) under ice cooling and the resulting mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was evaporated under reduced pressure and the residue was dissolved in chloroform and added dropwise into n-hexane:ethyl acetate [4:1 (v/v)] mixed solvent. The resulting insoluble matter was removed by filtration through celite and the solvent in the filtrate was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography [n-hexane:ethyl acetate=99:1→10:1 (v/v)] to give 2.1 g (77%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20](O)=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[CH3:31][O:32][C:33](=[O:37])[C@H:34]([CH3:36])[NH2:35]>C(Cl)Cl>[CH3:2][C:1]([CH3:3])([O:5][C:6]([NH:8][CH:9]([C:20]([NH:35][C@@H:34]([C:33]([O:32][CH3:31])=[O:37])[CH3:36])=[O:21])[CH2:10][C:11]1[C:12]([CH3:19])=[CH:13][C:14]([OH:18])=[CH:15][C:16]=1[CH3:17])=[O:7])[CH3:4]
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NC(=O)C(Cc1c(C)cc(O)cc1C)NC(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
Racemic t-butoxycarbonyl 2,6-dimethyltyrosine (3.9 g, 10 mmoles) was dissolved in 30 ml of CH2Cl2 by adding 1.12 ml (10 mmoles) of NMM. After bringing this mixture to reflux it was cooled to -30° C. and 1.32 ml (10 mmoles) of IBCF were added to this stirred solution. The temperature was allowed to rise to -15° C. and then lowered to -50° C. (D) alanine methyl ester hydrochloride (1.54 g, 11 mmoles) was added to the solution followed by 1.3 ml (11 mmoles) of NMM. The mixture was allowed to warm to room temperature and stand for 16 hours. The majority of the CH2Cl2 was removed under reduced pressure. Ethyl acetate (200 ml) was added and this solution was washed twice with 100 ml portions of 0.5 molar KHSO4, once with 100 ml of H2O and dried over MgSO4. Removal of all solvent gave 3.9 g of the mixture of diastereomers. Recrystallization of this material from Skelly B/CH2Cl2 produced 1.6 g (4.2 mmoles) of diastereomer F. Removal of the solvent from the filtrate gave 1.3 g (3.3 mmoles) of diastereomer S contaminated by less than 10% of diastereomer F.
Reaction SMILES: [C-:1]#[C-:2].[Li+].[Li+].N.Br[CH2:7][CH2:8][CH:9]([O:12][CH3:13])[O:10][CH3:11]>>[CH3:11][O:10][CH:9]([O:12][CH3:13])[CH2:8][CH2:7][C:1]#[CH:2]
Reactant: [C-]#[C-]
Reactant: COC(CCBr)OC
Agent: N
Agent: [Li+]
Product: C#CCCC(OC)OC
Reaction time: 2 h

Procedure:
To an equivalent quantity of lithium acetylide in liquid NH3 55 g (0.3 mol) of 1-bromo-3,3-dimethoxypropane were added in 30 minutes. Subsequently, stirring was continued for a further 2 hours, after which the NH3 was allowed to evaporate and the residue was dissolved in a mixture of ice and water. The mixture was extracted with ether and the combined organic layers were dried and concentrated by evaporation. The residue was distilled under reduced pressure and 11.5 g of 1,1-dimethoxy-4-pentyne were obtained.
Reaction SMILES: [N+](C1C=C[C:7]([O:10][P:11]([CH3:23])(=[O:22])[O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=CC=1)([O-])=O.[N:24]1([CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37]([C:42]2C4C(=CC=C(O)C=4)N[N:43]=2)=[CH:36]3)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1CCN2C(=NCCC2)CC1.CO>ClCCl>[N:24]1([CH2:30][CH2:31][O:32][C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37]([C:42]2[C:15]4[C:16](=[CH:17][CH:18]=[C:13]([O:12][P:11]([CH3:23])(=[O:22])[O:10][CH3:7])[CH:14]=4)[NH:19][N:43]=2)=[CH:36]3)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCOCC5)ccc4[nH]3)c2c1
Reactant: CP(=O)(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COP(C)(=O)Oc1ccc2[nH]nc(-c3cc4cc(OCCN5CCOCC5)ccc4[nH]3)c2c1
Temperature: 25 °C

Procedure:
A suspension of 170 mg of methylphosphonic acid bis-(4-nitrophenyl)ester (prepared according to procedure E) and 189.7 mg of 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-1H-indazol-5-ol in 17 ml of dichloromethane (stabilized with amylene) is stirred at ambient temperature. A solution of 75 μl of DBU in 500 μl of dichloromethane is added dropwise over 10 minutes. Stirring is maintained overnight. 204 μl of methanol are added with 75 μl of DBU. The solution is stirred for 24 hours. The reaction medium is concentrated under vacuum and the crude is then taken up with 25 ml of ethyl acetate and washed with 4 times 25 ml of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The reaction crude is purified by flash chromatography on 5 g of 40-63 μm silica. Eluents: 98/2 then 95/5 dichloromethane/methanol. 95 mg of methylphosphonic acid methyl ester 3-[5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-1H-indazol-5-yl ester are collected.