Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.Cl.O1CCOCC1.C(N(CC)CC)C.[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[S:47](Cl)(=[O:49])=[O:48]>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([OH:14])([CH3:13])[C:9]([F:10])([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[N:15]1[CH2:16][CH2:17][N:18]([S:47]([C:43]2[S:42][CH:46]=[CH:45][CH:44]=2)(=[O:49])=[O:48])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(C)(O)C(F)(F)F)cc2Br)CC1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2)c(Br)c1)C(F)(F)F
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
A 250 mL round-bottomed flask was charged with tert-butyl 4-(2-bromo-4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (3.70 g, 8.16 mmol), 25 mL of EtOAc, and 8 mL of 4M HCl in dioxane (32 mmol). After heating at reflux for 30 min, the mixture was cooled and concentrated. The resulting viscous oil was dissolved in 30 mL of CH2Cl2 and triethylamine (3.98 mL, 28.6 mmol). At 0° C., 2-thiophenesulfonyl chloride (1.49 g, 8.16 mmol, Sigma-Aldrich, St. Louis, Mo.) was added at 0° C. After 15 min, the mixture was concentrated then re-dissolved in 5 mL of CH2Cl2, filtered, and purified via column chromatography (120 g of silica, 0 to 50% EtOAc in hexanes) to give 2-(3-bromo-4-(4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (2.75 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1Br)[C:5]([OH:7])=[O:6].[CH3:12][N:13](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:12]#[N:13])[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)ccc1Br
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C(=O)O)cc1N
Temperature: 100 °C
Yield: 67 %

Procedure:
To a solution of 3-amino-4-bromo-benzoic acid (6.0 g, 276 mmol) in dimethyl formamide (30 ml), was added sequentially at ambient temperature zinc cyanide (11.66 g, 99.4 mmol) and tetrakis(triphenylphosphine)palladium (9.57 g, 8.28 mmol). The mixture was heated to 100° C. for 14 hours. The reaction mixture was allowed to cool to ambient temperature before the sequential addition of more zinc cyanide (0.65 g, 5.54 mmol) and tetrakis(triphenylphosphine)palladium (1.9 g, 1.64 mmol) at ambient temperature. The mixture was heated to 100° C. for 1 more hour. The reaction mixture was allowed to cool to ambient temperature and was quenched by addition of a mixture of toluene and aqueous ammonia (1M). The phases were separated and the aqueous layer was extracted with toluene. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:2 to 1:0) to give 3-amino-4-cyano-benzoic acid (2.94 g, 67% yield).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH:39]([CH3:48])[C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([C:40](=[O:41])[CH:39]([CH3:48])[CH3:38])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)C(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-methyl-1-piperazin-1-yl-propan-1-one (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C37H46Cl2N5O3 [(M+H)+] 678.2972, observed 678.2975.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:38][CH2:37][C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([OH:39])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:38][CH2:37][C:36]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([OH:39])[CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(O)(c2ccccc2)C1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(O)(c4ccccc4)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 584 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic 1-((2-bromophenyl)sulfonyl)-3-phenylpyrrolidin-3-ol in Step B. MS (ESI): mass calcd. for C26H23FN4O3S, 490.15; m/z found, 491.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.20 (d, J=9.2, 1H), 8.11 (d, J=1.5, 1H), 8.00 (t, J=8.1, 1H), 7.61 (dd, J=7.5, 6.2, 1H), 7.53 (m, 1H), 7.40-7.34 (m, 3H), 7.34-7.28 (m, 5H), 4.68 (s, 2H), 3.41-3.23 (m, 4H), 3.18 (d, J=10.8, 1H), 2.21-2.11 (m, 1H), 2.10-2.01 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([O:20]CC3C=CC=CC=3)=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2cc(C(=O)OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1ccc2cc(C(=O)O)ccc21
Yield: 111.2 %

Procedure:
The benzyl 1-t-butoxycarbonylmethyl-1H-indole-5-carboxylate (800 mg) obtained above was dissolved in ethanol, then 5% palladium on carbon (160 mg) was added thereto, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (670 mg, Y.:quant.).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[I:10].C([Mg]Cl)(C)C.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[NH4+].[Cl-]>C1COCC1.CCOCC>[I:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[B:16]([OH:21])[OH:17]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(C)c(I)c(I)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C)c(I)c(B(O)O)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2-diiodo-3,5-dimethylbenzene (0.5 g, 1.40 mmol) in 60 mL in a mixture of THF and Et2O (1:1), was added dropwise at −78° C. isopropylmagnesium chloride (2 M in THF, 0.70 mL, 1.40 mmol). After the mixture was stirred for 2 h at −78° C., B(OiPr)3 (0.96 ml, 4.19 mmol) was added. The solution was warmed to room temperature overnight, then a saturated solution of NH4Cl was added, and the resulting mixture was stirred for 30 min at room temperature. The aqueous layer was extracted with Et2O (50 mL, 3 times), dried over Na2SO4 and concentrated. To the concentrated sample, hexane was added and the resulting precipitate was isolated to provide the products as shown above as non separable mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[N:9]2[C:21]2[CH:22]=[C:23]([N:31](C)[C:32](=O)OC(C)(C)C)[C:24]3[N:25]([C:27]([CH3:30])=[N:28][N:29]=3)[N:26]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:18][CH2:19]4)[C:11]=3[C:10](=[O:20])[N:9]2[C:21]2[CH:22]=[C:23]([NH:31][CH3:32])[C:24]3[N:25]([C:27]([CH3:30])=[N:28][N:29]=3)[N:26]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(N(C)C(=O)OC(C)(C)C)c3nnc(C)n3n1)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc(N2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)nn2c(C)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a stirred solution of tert-butyl (6-(4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-6-oxopyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)(methyl)carbamate (Example 112) (200 mg, 0.364 mmol) in CH2Cl2 (4 mL) was added TFA (0.561 mL, 7.29 mmol) and the resulting mixture was stirred at RT for 2 hr. The reaction was quenched with a saturated aq. NaHCO3 solution and extracted with CH2Cl2. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%) followed by trituration in Et2O to afford the title product (130 mg, 0.290 mmol, 79% yield). tR: 4.73 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 449 [M+H]+ (LC-MS 2); Rf=0.40 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.08 (m, 2H) 1.19-1.26 (m, 2H) 1.90 (s, 3H) 2.45 (s, 3H) 2.85-2.94 (m, 3H) 3.77-3.84 (m, 1H) 6.41 (s, 1H) 7.03 (s, 1H) 7.31-7.36 (m, 2H) 7.37-7.42 (m, 2H) 8.01-8.10 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])#[N:2].[Cl-].C([NH+](CC)CC)C.[N-:19]=[N+:20]=[N-:21].[Na+].O>C1(C)C=CC=CC=1>[NH:2]1[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[N:21][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCC#N
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCCCc1nnn[nH]1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
Methyl 5-cyanopentanoate (4.8 g, 34 mmol) is dissolved in toluene, triethylammonium chloride (14 g, 102 mmol) and sodium azide (6.63, 102 mmol) is added. The mixture is heated to reflux for overnight. The reaction mixture is cooled to room temperature, water is added to extract (3×100 mL) methyl 5-tetrazol-5-ylpentanoate from the organic. To the aqueous phase, concentrate HCl is added to adjust pH to 2. The product is extracted from the aqueous solution with EtOAc (3×50 mL). The organic is combined, dried and concentrated to yield 4.25 g (68%) of methyl 5-tetrazol-5-ylpentanoate.
Reaction SMILES: Cl[CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5].[C:10]([O-:15])(=[O:14])[C:11]([CH3:13])=[CH2:12].[K+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:10]([O:15][CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: CO[Si](CCl)(OC)OC
Reactant: C=C(C)C(=O)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=C(C)C(=O)OC[Si](OC)(OC)OC
Temperature: 90 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
170.7 g (1 mol) of chloromethyltrimethoxysilane, 7.9 g (0.03 mol) of triphenylphosphine and 0.1 g (0.05 mol % based on silane) of phenothiazine are placed in a reaction vessel at 90° C. and 130.4 g (1.05 mol) of potassium methacrylate are added a little at a time over a period of 1 hour. After stirring at 90° C. for another 6 hours, the reaction is complete. After filtration from the potassium chloride formed, the product is distilled by means of a short-path evaporator, giving 193.9 g (95%) of methacryloxymethyl-trimethoxysilane having a purity of 98.4%.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[N:6][C:7]=1Cl.[NH3:29].O1CCOCC1>O>[NH2:29][C:7]1[C:2]([Br:1])=[C:3]([O:18][C:19]2[C:24]([CH3:25])=[CH:23][C:22]([C:26]#[N:27])=[CH:21][C:20]=2[CH3:28])[N:4]=[C:5]([NH:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[N:6]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(Cl)c1Br
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Reaction time: 48 h
Yield: 40.4 %

Procedure:
4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-6-chloro-2-pyrimidinyl]amino]-benzonitrile (0.00250 mol) and NH3/1,4-dioxane 0.5M (0.015 mol) were heated in a pressure vessel at 150° C. for 4 days. The sample was allowed to sit at ambient conditions for 2 days. Water was added slowly to the mixture until a precipitate formed. The mixture was stirred for 2 hours and filtered. The solid was recrystallized from CH3CN to obtain 0.58 g (fraction 1). The filtrate was evaporated (fraction 2). Both fractions were combined and purified by column chromatography, eluting with CH2Cl2. The resulting residue of the desired fraction was recrystallized from CH3CN to yield 0.44 g of 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]-amino]benzonitrile (40.5%). The sample was dried at 80° C. for 16 hours at 0.2 mm Hg (comp. 46).
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Li].BrC1C=CC=CC=1OC>CCOCC.CCCCCC>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]c1ccccc1OC
Reactant: C(=Nc1ccncc1)c1ccccc1
Agent: COc1ccccc1Br
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccccc1C(Nc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
2.98 Grams (0.016 mole) of 4-benzylideneaminopyridine in 50 milliliters of dry ether were added dropwise to a stirred solution of 2-methoxyphenyl lithium (prepared from 0.03 mole of butyl lithium and 5.61 grams [0.03 mole] of o-bromoanisole) in a mixture of ether and hexane at 0° C. under nitrogen. The mixture was stirred at room temperature for 2 hours and then poured onto ice. The organic layer was separated and extracted with acid and the acid extracts were combined with the aqueous layer. The combined aqueous medium was basified with 5 N sodium hydroxide and extracted into dichloromethane. After drying over magnesium sulphate, the solvent was removed to leave a solid which yielded 2.3 grams of title compound, m.p. 143°-5° C. The product was converted into its hydrobromide salt, m.p. 196°-198° C., by solution in 2-propanol and addition of hydrogen bromide in dry ether.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([NH:12][C@H:13]1[C@H:18](OS(C)(=O)=O)[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C(OCC)(=O)C>[Cl-].C([N+](CC)(CC)CC)C.CN1CCCC1=O>[N:1]([C@H:18]1[CH2:17][CH2:16][C@H:15]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][C@H:13]1[NH:12][C:10]([O:9][C:5]([CH3:6])([CH3:8])[CH3:7])=[O:11])=[N+:2]=[N-:3]
Reactant: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@H](N=[N+]=[N-])[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 74 h

Procedure:
Sodium azide (357.6 mg) and tetraethylammonium chloride (137.5 mg) were added at room temperature to a solution (2 mL) of ethyl (1S,3R,4R)-3-[(t-butoxycarbonyl)amino]-4-methanesulfonyloxycyclohexanecarboxylate (1.01 g) in N-methyl-2-pyrrolidone, followed by stirring at 60° C. for 74 hours. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with aqueous saturated sodium bicarbonate solution and water, followed by drying over magnesium sulfate anhydrate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane ethyl acetate=4:1), to thereby yield 675.1 mg of the title compound. Spectral data of this compound were found to be identical with those of the compound of Example 5.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(=[O:10])[CH3:9].[CH3:17][C:18]1([CH3:32])[O:22][C@H:21]([C:23]2[C:24]([F:31])=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH:26]=[O:27])[CH2:20][O:19]1.Cl>C1COCC1>[CH3:17][C:18]1([CH3:32])[O:22][C@H:21]([C:23]2[C:24]([F:31])=[C:25]([CH:26]([OH:27])[CH2:9][C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:10])[CH:28]=[CH:29][CH:30]=2)[CH2:20][O:19]1
Reactant: CC1(C)OC[C@@H](c2cccc(C=O)c2F)O1
Reactant: CC(=O)c1cccnc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC1(C)OC[C@@H](c2cccc(C(O)CC(=O)c3cccnc3)c2F)O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
In a stream of argon, anhydrous THF solution containing 0.72 ml of N,N-diisopropylamine was cooled to about −70° C., 3.3 ml of 1.54 M n-butyl lithium-hexane solution was added dropwise thereto, and then the reaction liquid was risen to about −15° C. The reaction liquid was again cooled to about −70° C., mixed with 0.54 ml of 3-acetylpyridine and then stirred at the same temperature for about 30 minutes, and subsequently, 5 ml of anhydrous THF solution containing 1.1 g of 3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorobenzaldehyde was gradually added dropwise thereto. After stirring at −70° C. for about 20 minutes and then at about −30° C. for about 3 hours, this was mixed with an appropriate amount of 0.2 M hydrochloric acid aqueous solution and subjected to several times of extraction operation with ethyl acetate. The organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate, and then the solvent was evaporated and the thus formed residue was isolated and purified by a silica gel column chromatography to obtain 0.77 g (45%) of 3-[3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorophenyl]-3-hydroxy-1-pyridin-3-yl-propan-1-one as a colorless oil from an ethyl acetate-hexane (7:3) eluate. FA: 346
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[C:8]([CH3:27])=[CH:7][C:5]=2[N:6]=1.OS(O)(=O)=O.[CH3:33]COC(C)=O.C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[C:19]([O:21][CH3:33])=[O:20])[C:8]([CH3:27])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1cc2nc(N)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N)sc2c1-c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of Preparation of (S)-2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetic acid from above in MeOH (25 mL) was added H2SO4 (200 μL). The reaction mixture was stirred at overnight. EtOAc (20 mL) and saturated NaHCO3 solution (50 mL) were added. The layers were separated, dried, filtered, and concentrated in vacuo. The crude mixture was a mixture of the desired (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate and (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate. t-Butyl acetate was added (20 mL) and perchloric acid (500 μL). The mixture was stirred at rt for 3 hr, where all (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-hydroxyacetate was converted to (S)-methyl 2-(2-amino-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate. EtOAc (10 mL) and saturated NaHCO3 solution (50 mL) were added. The layers were separated, dried, filtered, and concentrated in vacuo. LCMS-ESI+: calc'd for C21H23ClN2O3S: 419.1 and 421.1 (M+H+); found: 419.2 and 421.2 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:9]=1[CH:10]=[CH:11][C:12](OCC)=[O:13].[Cl-].[NH4+]>C1COCC1>[Cl:7][C:8]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:9]=1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: CCOC(=O)C=Cc1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Lithium aluminum hydride (98.8 mg, 2.60 mmol) was added to THF (5 mL), and under ice-cold stirring, a solution of ethyl 2,6-dichlorocinnamate (319 mg, 1.30 mmol) in THF (5 mL) was added dropwise. The mixture was then stirred at room temperature for 30 minutes. A small amount of a saturated aqueous solution of ammonium chloride was added to the reaction mixture, followed by drying over anhydrous magnesium sulfate. Subsequent to filtration through Celite, the mixture was concentrated under reduced pressure and further, purified by chromatography on a silica gel column (hexane/ethyl acetate=10/1) to yield the title compound as a pale yellow syrupy substance (yield: 46.9%).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]([NH:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][C:12]=2[O:11][C:10]=1[C:26]([O:28]CC)=[O:27])=[O:7])[CH3:4]>C(O)C>[CH2:3]([O:5][C:6]([NH:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:17][C:12]=2[O:11][C:10]=1[C:26]([OH:28])=[O:27])=[O:7])[CH3:4]
Reactant: CCOC(=O)Nc1c(C(=O)OCC)oc2cc(OCc3ccccc3)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Nc1c(C(=O)O)oc2cc(OCc3ccccc3)ccc12
Yield: 104892.7 %

Procedure:
200 ml of a 10% ethanolic potassium hydroxide solution are added to a solution of 41 g (0.11 mmol) of ethyl 3-[(ethoxycarbonyl)amino]-6-(phenylmethoxy)benzofuran-2-carboxylate in 400 ml of ethanol. The mixture is heated at reflux for 30 minutes and the solvent is then evaporated under reduced pressure. The residue is taken up in water and the solution is acidified with hydrochloric acid to pH 2. 41 g of product are obtained by filtration of the precipitate formed.
Reaction SMILES: C[CH:2](C)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N+]([C:19]1C=CC(O)=CC=1)([O-])=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:19][CH:3]([CH3:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: CC(C)CCCCCCCCCC(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)CCCCCCCCC(=O)O
Reaction time: 12 h

Procedure:
To 11-methyldodecanoic acid (400 mg) and para-nitrophenol (260 mg) dissolved in N,N-dimethylformamide (DMF, 30 ml) was added N,N'-dicyclohexylcarbodiimide (385 mg), and the mixture was stirred for 12 hours. The reaction mixture was filtered and concentrated to give the active ester of 10-methylundecanoic acid. To the active ester (620 mg), after having been dissolved in DMF, were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (710 mg) and triethylamine (2.0 ml), and the mixture was stirred for 12 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK251 in the yield of 236 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].O[N:27]=[C:28]([NH2:33])[CH2:29][CH2:30][O:31][CH3:32]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:33]=[C:28]([CH2:29][CH2:30][O:31][CH3:32])[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COCCC(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C
Product: COCCc1noc(C2CC(c3ccc(C)c(C)c3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (0.58 mmol) of the compound from Example 130A and 136 mg (0.87 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 98 mg (40% of theory)