Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](OS(C(F)(F)F)(=O)=O)=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccc(Cl)cc2c(=O)n1C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)c2ccc(Cl)cc2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A mixture of ethyl 7-chloro-2-methyl-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydro-3-isoquinolinecarboxylate (2.90 g, 7 mmol), phenylboronic acid (1.02 g, 8.4 mmol) and sodium carbonate (1.85 g, 17.5 mmol) in toluene (20 ml), ethanol (4 ml) and water (4 ml) was stirred under an argon atmosphere at room temperature for 30 min. To the obtained mixture was added tetrakis(triphenylphosphine)palladium (0.46. g, 4 mmol) and the mixture was refluxed under heating under an argon atmosphere for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-2-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylate (1.70 g, 71.1%) as crystals.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C[N:20](C)C=O.N[C:25]1[C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:20][C:27]2[N:26]=[CH:25][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[O:14])[S:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccnc1N
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
In the same manner as that of Example 9, 4,5-diisopropylthiophene-2-carboxylic acid (180 mg, 0.849 mmol) was converted to an acid chloride with thionyl chloride and dimethylformamide. This acid chloride was dissolved in pyridine (4 ml), the solution was added with methyl 2-aminopyridine-3-carboxylate (258 mg, 1.70 mmol) and 4-dimethylaminopyridine (5 mg, 41 μmol), and the mixture was stirred at room temperature for 48 hours. The reaction mixture was treated in a conventional manner, and then the resultant was purified by silica gel chromatography [benzene-ethyl acetate (4:1)] to obtain methyl 6-[(4,5-diisopropylthiophene-2-carbonyl)amino]pyridine-3-carboxylate (98 mg, 33%) as colorless foam, together with the collected starting material (67 mg, 37%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([SH:28])[N:22]=1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[N:22]=1
Reactant: Cc1cc(C)nc(S)n1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: Cc1cc(C)nc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)n1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4,6-dimethyl-2-mercapto-pyrimidine.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:40][CH:26]1[CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]1)[CH2:40][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: CCOC(=O)C1CCC(OCC2CO2)CC1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COC2CCC(C(=O)O)CC2)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=D03A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(ethoxycarbonyl)-cyclohexyloxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>N1C=CC=CC=1.O>[S:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: OCCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reaction time: 16 h

Procedure:
A solution of 3-chloro-1-propanol (1.88 g, 20 mmole) in 20 ml of pyridine was treated at 0° with tosyl chloride (7.6 g, 40 mmole). The solution was warmed to 23°, and stirred 16 hours. The reaction was diluted with 100 mL of H2O and stirred for 90 minutes, and extracted with Et2O. The extracts were washed with 1N HCl, dried, and the solvents thoroughly removed, and gave the titled product, 2.3 g (46%). MS (ESI) 188 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.C(O)=[O:15].O>[Ni].C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:15]
Reactant: O=CO
Reactant: N#Cc1cc(C(F)(F)F)ccc1F
Agent: [Ni]
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc(C(F)(F)F)ccc1F
Reaction time: 8 h

Procedure:
A mixture of 18.7 g (0.0988 mol) of 2-fluoro-5-(trifluoromethyl)benzonitrile (prepared according to G. C. Finger et al., Chem. Comm., 1965, 430), 398 ml of 90% formic acid, 296 ml of water and 17.5 g of Raney nickel is heated for 5 hours at reflux and is then left standing overnight. The mixture is poured into 2.5 liters of water and extraction is carried out with methylene chloride (once 1 l and two times 500 ml). Filtration, washing with water, drying over Na2SO4, filtration and distillation are carried out. Yd.: 10.1 g (53%) B.p.14 =70°-72° C. IR: νc-o =1680 cm-1
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)Cl>[C:18]([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: Oc1ccc2ncccc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of quinolin-6-ol (4.5 g, 31.0 mmol) and pyridine (3.01 ml, 37.2 mmol) in DCM (50 ml) was added acetyl chloride (2.65 ml, 37.2 mmol) at 0° C. The mixture was then stirred at rt for 8 h. The reaction was quenched with saturated NaHCO3 and the mixture was extracted with DCM (30 ml) three times. The combined organic phase was washed with brine and dried over anhydrous MgSO4, filtered and concentrated to give the title compound (5.0 g, 68.9% yield), which was used directly in next step. LCMS (method B): [M+H]+=188, tR=1.64 min.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([Mg]Br)[CH3:14].B(F)(F)F.CCOCC.Cl>C(OCC)C.[Ti+4]>[NH2:2][C:1]1([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccc(C#N)cc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: COC(=O)c1ccc(C2(N)CC2)cc1
Reaction time: 1 h

Procedure:
To the solution of methyl 4-cyanobenzoate (100 g, 620 mmol) in diethyl ether (3 L) was added titanium (IV) isospropoxide (194 g, 682 mmol), followed by dropwise addition of ethylmagnesium bromide 3M solution in diethylether (450 ml, 1.36 mol) at −70° C. The mixture was stirred for 1 h, and then boron trifluoride etherate (157 ml, 1.24 mol) was added at once. After 2 hours, aqueous HCl (5%) was added until the pH showed acidy, then the mixture was filtered. The solid was washed with ethylacetate. The aqueous phase was separated and the organic layer was washed with water. All aqueous layers were collected together, basified with 1M NaOH and extracted with ethylacetate. The organic layer was dried (Na2SO4) and concentrated to afford the title compound (D6) (32.0 g).
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[N:36]1([C:42]2[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:46]3[CH:45]=[CH:44][CH:43]=[C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)[CH:47]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCOc2nccnc2N2CCNCC2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 10.5 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (TMAD; 256 mg, 1.50 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (400 mg, 1.24 mmol; prepared in Example 52, Step 2), 3-(4-morpholinyl)phenol (441 mg, 1.23 mmol) and triphenylphosphine (646 mg, 2.46 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 2.5 h and then concentrated. The residue was purified by repeated chromatography on silica gel using toluene and toluene/EtOAc (8:2) as eluents. Solvents were evaporated and the residue was treated with CH2Cl2/TFA/H2O (1:0.9:0.1; 5 mL) at room temperature for 0.5 h After concentration 5 M NaOH was added followed by extraction with CH2Cl2. The organic phase was dried (K2CO3), filtered, and concentrated. The residue was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give 50 mg (10%) of the title product as on oil. HRMS m/z calcd for C20H27N5O3(M)+385.2114, found 385.2100.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Si:39]([O:46][C:47]1[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])=[CH:53][C:52]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:51][C:48]=1[CH:49]=O)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]>O1CCCC1.CCCCCC.C(OC)(C)(C)C>[C:63]1([C:52]2[CH:51]=[C:48](/[CH:49]=[CH:7]\[C:6]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:4]([O:3][CH3:2])[CH:5]=3)[C:47]([O:46][Si:39]([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:41])[CH3:40])=[C:54]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:57])[CH3:58])[CH:53]=2)[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(-c2ccccc2)cc(C=O)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(/C=C\c2cc(-c3ccccc3)cc(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27.5 %

Procedure:
A suspension of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (0.24 g, 0.46 mmol) in tetrahydrofuran (4 mL) was cooled to 0° C. and butyllithium (0.28 mL of a 1.6 N solution in hexane, 0.46 mmol) was added dropwise. The brick red solution was stirred at 0° C. for 20 min, then a solution of 23 (0.13 g, 0.3 mmol) in tetrahydrofuran (2 mL) was added dropwise. The temperature was allowed to rise to room temperature overnight, than the reaction was diluted with tert-butylmethyl ether (ca 100 mL) and washed with water (ca 50 mL, containing 1 mL 2N HCl) then brine (30 mL). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give a crude which was purified by column (elution with cyclohexane:AcOEt 10:1) to give 0.05 g of 24 still impure with 20% of the E isomer.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1)C1C=CC=CC=1>CCO>[NH2:8][CH:9]1[CH2:13][CH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH2:19][CH3:20])[CH2:10]1
Reactant: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Solvent: CCO
Product: CCOC(=O)C1CC(N)CC1CC
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98.9 %

Procedure:
To a vessel containing a slurry of 20% wet Pd(OH)2—C (12.9 g, 92.0 mmol) in EtOH (1.0 L) was added ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (129 g, 352 mmol). The reaction was shaken for about 90 min at about 50° C. at about 30 psi of H2. The resulting mixture was filtered through a nylon membrane and the filtrate was concentrated under reduced pressure to give ethyl 4-amino-2-ethylcyclopentanecarboxylate (64.5 g, 99%) as a yellow syrup: 1H NMR (CDCl3) δ 4.03-3.88 (m, 2H), 3.17 (m, 1H), 2.68 (m, 1H), 2.09-2.02 (m, 2H), 2.02-1.94 (m, 2H), 1.84 (m, 1H), 1.58-1.48 (m, 1H), 1.32-1.18 (m, 1H), 1.09 (m, 3H), 1.03 (m, 2H), 0.78-0.69 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][CH2:25][C:26](O)=[O:27].ClC(OCC(C)C)=O.C(N(CC)CC)C.C(O)(=O)C(O)=O.[CH2:51]([O:53][P:54]([CH2:59][CH2:60][NH2:61])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]>C1COCC1>[CH2:56]([O:55][P:54]([CH2:59][CH2:60][NH:61][C:26](=[O:27])[CH2:25][CH2:24][C:23]([CH3:29])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:18])[CH3:20])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])(=[O:58])[O:53][CH2:51][CH3:52])[CH3:57]
Reactant: CCOP(=O)(CCN)OCC
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CCC(=O)O)C(=O)OC2
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
To a solution of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate (17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. After stirring at 0° C. for 2 hours, diethyl(aminoethyl)phosphonate oxalate (62 mg, 0.26 mmol) was added and stirred at room temperature was continued for one hour. After removal of solvent, the residue was purified by preparative reverse-phase HPLC to afford 37 mg (54%) of the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.15-1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 1.85-1.93 (m,2H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J=7 Hz), 3.48-3.54 (m, 2H), 3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m,2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 6.30 (bs, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 29.91 ppm; MS (m/z) 584 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3C=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:28][N:29]([CH2:37][CH2:38][NH:39][CH3:40])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33].[BH-](OC(C)=O)(OC(C)=O)O[C:43](C)=O.[Na+]>ClCCCl>[CH3:28][N:29]([CH2:37][CH2:38][N:39]([CH3:43])[CH2:40][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][C:7]3[CH:26]=[CH:27][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH:10]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=1)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNCCN(C)C(=O)OC(C)(C)C
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc12
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCN(C)C(=O)OC(C)(C)C)Cc1nn(C2CCCCO2)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of (R/S) 5-(4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (300 mg, 0.82 mmol, 1.00 equiv) and tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (170 mg, 0.90 mmol, 1.11 equiv) in 1,2-dichloroethane (40 mL) was added NaBH(OAc)3 (520 mg). The reaction was stirred at room temperature overnight and then quenched with 50 mL of water. The resulting mixture was extracted with 3×200 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-10% of ethyl acetate in petroleum ether to give 420 mg (95%) of (R/S) tert-butyl methyl(2-(methyl((5-(4-nitrophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methyl)amino)ethyl)carbamate as a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 8.18 (m, 2H), 7.71-7.55 (m, 2H), 7.20-7.09 (m, 1H), 7.05-6.93 (m, 2H), 5.70-5.68 (m, 1H), 4.11-4.09 (m, 1H), 4.06-3.91 (m, 1H), 3.79-3.73 (m, 1H), 3.50-3.33 (m, 1H), 2.79 (s, 3H), 2.57-2.52 (m, 2H), 2.49-2.17 (m, 2H), 2.17-2.05 (m, 1H), 1.80-1.68 (m, 4H), 1.42 (s, 9H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2c(Cl)cccc2C1=O
Solvent: O
Product: O=C1Nc2c(Cl)cccc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
7-chloroisatin (0.09 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[N:37]1([C@@H:42]2[CH2:47][CH2:46][CH2:45][CH2:44][C@H:43]2[NH:48][CH3:49])[CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C.C(Cl)[Cl:60]>>[ClH:60].[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([N:48]([CH3:49])[C@@H:43]2[CH2:44][CH2:45][CH2:46][CH2:47][C@H:42]2[N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:12])=[CH:7][CH:8]=1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: ClCCl
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Cc1ccc(C(F)(F)F)cc1)[C@@H]1CCCC[C@H]1N1CCCC1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of 4-trifluoromethylphenyl acetic acid (1.45 g, 7.08 mmol) in 10 mL of dry CH2Cl2 under a nitrogen atmosphere was added 1-hydroxybenzotriazole hydrate (HOBT) (0.95 g, 7.08 mmol) and stirred. The reaction mixture was cooled to 0→45° C. and solid EDCI ([1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl]) (1.35 g, 7.08 mmol) was added and stirred at this temperature for 30 mm. A solution of (±) 3 (1.0 g, 5.48 mmol) in 10 mL of dry CH2Cl2 was added followed by N,N-diisopropylethylamine (Hunig's Base) (0.915 g, 7.08 mmol). The reaction mixture was stirred for 24 h while warming to room temperature. The reaction mixture was then poured onto excess of ice-cold saturated aqueous NaHCO3 solution and stirred for 30 min. After dilution with CH2Cl2, the organic layer was separated, washed with saturated salt solution, and dried over anhydrous Na2SO4. Removal of solvent gave a brown oil which was chromatographed on a silica gel column [solvent system: CH2Cl2:CH3OH:28% NH4OH (99:1:2)] to give the desired product as free base. The hydrochloride salt was prepared from 1M etherial HCl and recrystallized from CH2Cl2:Et2O (1:1) to give (±) 5g HCl as a cream colored solid. 0.68 g (30%); 213-215° C.; 1H NMR (200 MHz, CDCl3) δ 1.02-1.47 (m, 4H), 1.52-2.22 (m, 8H), 2.75-2.90 (m, 2H), 2.94 (s, 3H), 3.07 (m, 1H), 3.37 (m, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.77 (m, 1H), 4.17 (d, J=15.0 Hz, 1H), 4.57 (m, 1H), 7.30 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H). Anal. Calcd for C20H27F3N2O.HCl.0.25H2O: C, 58.68; H, 7.02; N, 6.84. Found: C, 58.68; H, 6.84; N, 6.69.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:6]=2[CH:5]=[CH:4]1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>O1CCCC1>[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28]([N:3]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:13])[C:6]=3[CH:5]=[CH:4]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)c1cccc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)OCc4ccccc4)cccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a suspension of sodium hydride (133 mg) in tetrahydrofuran (5.0 ml) was added dropwise a solution of benzyl indole-4-carboxylate (580 mg) in tetrahydrofuran (5.0 ml) at 0° C. and the mixture was stirred at 0° C. for 1 hour. 4-Toluenesulfonyl chloride (440 mg) was added to the mixture and the solution was stirred at ambient temperature for 1 hour. The reaction was quenched with 1N hydrochloric acid and then the aqueous solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by column chromatography (eluent; n-hexane:ethyl acetate=15:1) to give benzyl 1-(4-toluenesulfonyl)indole-4-carboxylate (560 mg) as a colorless syrup.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=3)[O:16][C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1.Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C)C=O>[Cl:7][C:8]1[C:9]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:21]([CH3:27])[CH:20]=3)[O:16][C:10]=2[N:11]=[C:12]([S:14][CH3:15])[N:13]=1
Reactant: CSc1nc(Cl)c2nc(-c3cc(C)c(O)c(C)c3)oc2n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2nc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)oc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
7.46 g of potassium carbonate were added to a solution of 4.34 g of 4-(7-chloro-5-methylsulfanyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenol in 45 ml of dimethylformamide, and 2.90 g of tert-butyl bromoacetate were then added. The mixture was stirred at 60° C. for 1 h. The cooled reaction mixture was then added to ice water, and the precipitated solid was filtered off with suction and washed with water. The solid was taken up in dichloromethane and dried over sodium sulfate, activated carbon was added and the mixture was filtered and concentrated under reduced pressure. This gave 4.20 g (71%) of the title compound, which was reacted further without any further purification.