Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.O=C[C:24]([Cl:27])([Cl:26])[Cl:25].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]([C@@H:10]1[O:15][CH:6]([C:24]([Cl:27])([Cl:26])[Cl:25])[NH:8][C@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12]
Reactant: COC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Reactant: O=CC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1OC(C(Cl)(Cl)Cl)N[C@H]1c1ccccc1
Temperature: 20 °C
Yield: 91 %

Procedure:
A solution of 3.0 g of methyl (2R,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-3-phenylpropionate, of 5 cm3 of chloral and of 0.05 g of pyridinium p-toluenesulphonate in 40 cm3 of anhydrous toluene is heated at reflux with distillation of the solvent. 15 cm3 of solvent are distilled and then 5 cm3 of chloral and 0.05 g of pyridinium p-toluenesulphonate are added. 20 cm3 of solvent are distilled and then 5 cm3 of chloral as well as 30 cm3 of anhydrous toluene are added. 25 cm3 of solvent are distilled and 5 cm3 of chloral and 35 cm3 of anhydrous toluene are added. 25 cm3 of solvent are distilled and then the solution is cooled to a temperature in the region of 20° C. The organic solution is washed with water (2 times 50 cm3), dried over sodium sulphate and concentrated to dryness under reduced pressure at approximately 50° C. The residue obtained is purified by liquid chromatography on silica gel, the eluent being an ethyl acetate/cyclohexane (1/3 by volume) mixture. There are thus obtained, with a yield of 91%, 3.0 g of (4S,5R)-5-methoxycarbonyl-4-phenyl-2-trichloromethyl-1,3-oxazolidine whose characteristics are the following:
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:17])[CH:14]=2)[C:9]1=O)C=CC.[CH3:19][OH:20]>>[O:20]=[CH:19][CH2:4][CH:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)[C:16]1=[O:1]
Reactant: CO
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2cc(Cl)ccc2C1=O
Product: O=CCC1Cc2ccc(Cl)cc2C1=O
Reaction time: 1 h
Yield: 80 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring during 60 minutes through a solution, cooled to -70°, of 11.9 g of (RS)-2-(2-buten-1-yl)-5-chloro-1-indanone in 200 ml of anhydrous dichlomethane and 100 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5.9 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 50 ml of dichloromethane and, after the addition of 12 ml of water and 12 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was crystallized from ethyl acetate/hexane. 8.98 g (80%) of (RS)-2-(2-oxoethyl)-6-chlor-1-indanone were obtained as a white solid with m.p. 66°.
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][CH:8]=1)#[N:2].C([Li])CCC.[CH3:20][N:21]1[C:25]([Cl:26])=[C:24]([C:27](Cl)=[O:28])[C:23]([Cl:30])=[N:22]1.Cl>C1COCC1>[CH3:20][N:21]1[C:25]([Cl:26])=[C:24]([C:27]([OH:28])=[C:3]([C:4]2[N:5]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:7][CH:8]=2)[C:1]#[N:2])[C:23]([Cl:30])=[N:22]1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Reactant: N#CCc1csc(-c2ccccc2)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(Cl)c(C(O)=C(C#N)c2csc(-c3ccccc3)n2)c1Cl
Temperature: -60 °C
Reaction time: 0.33 h
Yield: 63.4 %

Procedure:
0.72 g of 4-cyanomethyl-2-phenylthiazole was dissolved in 10 ml of dry THF, and 4.6 ml of n-butyl lithium (1.56 M hexane solution) was dropwise added thereto at −60° C. or lower in an argon atmosphere. After the resulting product was stirred at −60° C. or lower for 20 minutes, 0.84 g of 1-methyl-3,5-dichloropyrazole-4-carbonyl chloride as dissolved in 3 ml of dry THF was dropwise added thereto at −60° C. or lower. Then, the resulting product was gradually heated, and stirred for 4 hours at room temperature. The reaction mixture was poured into ice water, acidified with diluted hydrochloric acid, extracted with ethyl acetate, and washed with saturated saline. The resulting product was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain the intended product from the fraction eluted with chloroform. The resulting product was crystallized and washed with diethyl ether to obtain 0.86 g of 3-(1-methyl-3,5-dichloropyrazol-4-yl)-2-(2-phenylthiazol-4-yl)-3-hydroxyacrylonitrile.
Reaction SMILES: C(OC([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]2[NH:20][N:21]=[CH:22][C:10]=2[CH2:9]1)=O)(C)(C)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(OCC)(=O)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:20]2[C:11]3[CH2:12][CH:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:8]([S:30]([C:27]4[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=4)(=[O:32])=[O:31])[CH2:9][C:10]=3[CH:22]=[N:21]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1Cc2cn[nH]c2CC1c1ccccc1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)N1Cc2cnn(S(=O)(=O)c3ccc(Cl)cc3)c2CC1c1ccccc1
Temperature: 25 °C

Procedure:
Compound 52 from the previous step (1.1 g, 3.67 mmol) was dissolved in ethyl acetate (15 ml). HCl (g) was bubbled into the solution for 5 minutes. Solvent was removed under reduced pressure and the residue was re-dissolved in pyridine (15 ml). 4-chlorophenylsulfonyl chloride (1.55 g, 2.2 eq.) was added to the solution at zero degrees. The mixture was stirred at zero degrees and slowly raised to room temperature upon stirring overnight. Ethyl acetate (100 ml) was added to the reaction mixture, and the solution was washed with sat. NaHCO3 (2×25 ml), 10% HCl solution (2×25 ml) and brine (10 ml). Sample dried over (MgSO4), and solvent was removed under reduced pressure. The crude product was purified via flash chromatography, eluted with EtOAc/hexane (15:85) to give a white solid as the mixture of two regioisomers. LCMS 569.9 (M+23)
Reaction SMILES: [N:1]1([C:6]([CH3:11])([CH3:10])[CH2:7][CH2:8][OH:9])[CH:5]=[CH:4][N:3]=[CH:2]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([C:52](=[O:60])[C:53]3[CH:58]=[CH:57][C:56](O)=[CH:55][CH:54]=3)[C@@H:44]([CH3:61])[CH2:43]2)[C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([N:38]([C@H:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[N:45]([C:52](=[O:60])[C:53]3[CH:58]=[CH:57][C:56]([O:9][CH2:8][CH2:7][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)([CH3:11])[CH3:10])=[CH:55][CH:54]=3)[C@@H:44]([CH3:61])[CH2:43]2)[C:39](=[O:41])[CH3:40])=[CH:36][CH:37]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Reactant: CC(C)(CCO)n1ccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)n3ccnc3)cc2)c2ccccc21
Reaction time: 0.08 h
Yield: 46 %

Procedure:
3-Imidazol-1-yl-3-methyl-butan-1-ol was dissolved in benzene at room temperature with PPh3 (0.088 g, 0.33 mmol) added (2S,4R)-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.133 g, 0.30 mmol) and stirred for 5 min. DEAD (0.058 g, 0.33 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by silica gel chromatography (4% MeOH/96% CH2Cl2 to 5% MeOH/95% CH2Cl2 to 6% MeOH/94% CH2Cl2) to afford the product in 46% yield
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].Br[C:13]([F:20])([F:19])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CC(N(C)C)=O>[F:19][C:13]([F:20])([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: CN(C)C(=O)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C)C(=O)C(F)(F)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 33.5 %

Procedure:
A mixture of 2-nitro-5-fluoro-phenol (3.0 g, 19.1 mmol), 2-bromo-2,2-difluoro-N,N-dimethyl-acetamide (3.9 g, 19.1 mmol) and Na2CO3 (2.1 g, 19.8 mmol) in 30 mL of DMAC was heated to 100° C. overnight. The mixture was then poured on 50 mL of H2O and extracted with TBME (2×50 mL). The combined organic layers were washed with 10% NaOH (50 mL) and dried over Na2SO4. The crude product was obtained after evaporation of all volatiles. Purification by chromatography on silica gave the product (1.8 g, 6.4 mmol, 38% yield) as a yellow oil that solidified upon standing.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[O:25]([CH2:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])[CH2:32][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: O=C(Cl)COc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)COc2ccccc2)C(=O)O)cc1
Yield: 77 %

Procedure:
Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine was reacted with phenoxyacetyl chloride under the conditions described in example 2. The crude material was purified by flash chromatography (CH2Cl2:MeOH, 19:1 to 9:1) to yield 77% of the desired product.
Reaction SMILES: [C:1]([C-:3]([C:6]#[N:7])[C:4]#[N:5])#[N:2].[K+].CS(O)(=O)=O.[CH:14]([OH:17])([CH3:16])[CH3:15]>>[NH2:2][C:1]([O:17][CH:14]([CH3:16])[CH3:15])=[C:3]([C:6]#[N:7])[C:4]#[N:5]
Reactant: N#C[C-](C#N)C#N
Reactant: CC(C)O
Agent: CS(=O)(=O)O
Agent: [K+]
Product: CC(C)OC(N)=C(C#N)C#N

Procedure:
In the manner of Example V A, 129.2 g of potassium tricyanomethanide and 1000 ml of isopropanol were treated with 65 ml (96 g) of methanesulfonic acid to yield 104 g of 3-amino-2-cyano-3-isopropoxy-2-propenenitrile, which was used as an intermediate without further purification. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:13])(=[O:12])=[O:11])[CH2:7][CH2:6][S:5]2.[OH:14]O>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]2[N:8]([C:9]=1[S:10]([NH2:13])(=[O:11])=[O:12])[CH2:7][CH2:6][S:5]2=[O:14]
Reactant: NS(=O)(=O)c1c(Cl)nc2n1CCS2
Reactant: OO
Solvent: CC(=O)O
Product: NS(=O)(=O)c1c(Cl)nc2n1CCS2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.7 %

Procedure:
To a suspension of 2.0 g of 6-chloro-2,3-dihydroimidazo[2,1-b]thiazole-5-sulfonamide in 20 ml of acetic acid is add 2.2 g of 30% aqueous hydrogen peroxide, followed by stirring for 30 minutes at room temperature and further for 4 hours at 35°-45° C. Stirring is further maintained for 8 hours at room temperature, and the precipitated crystals are collected by filtration, washed with water and then dried to give 1.7 g of the title compound as colorless crystals. mp. 215°-217° C. (decomp.)
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[F:23][C:24]([F:37])([F:36])[S:25]([O:28]S(C(F)(F)F)(=O)=O)(=[O:27])=[O:26].[Cl:38][C:39]1[CH:48]=[C:47]2[C:42]([C:43](O)=[C:44]([C:50]3[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[CH:51]=3)[C:45](=[O:49])[NH:46]2)=[CH:41][C:40]=1[N+:59]([O-:61])=[O:60]>>[Cl:38][C:39]1[CH:48]=[C:47]2[C:42]([C:43]([O:28][S:25]([C:24]([F:37])([F:36])[F:23])(=[O:27])=[O:26])=[C:44]([C:50]3[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[CH:51]=3)[C:45](=[O:49])[NH:46]2)=[CH:41][C:40]=1[N+:59]([O-:61])=[O:60]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Product: Cc1cc(C)cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one (1.0 g in 50 mL dry methylene chloride) was added 0.455 ml diazabicycloundecene and the mixture cooled to -78° C. To this was added trifluoromethanesulfonic anhydride (0.51 mL) dropwise via syringe and the mixture stirred at low temperature. After 1 hour, the reaction was quenched by the addition of saturated ammonium chloride (35 mL) and extracted with ethyl acetate (3×75 mL). The organics were washed with water (50 mL) and brine (50 mL) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:2) gave the title compound (629 mg).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@@H:21]([CH3:46])[C@H:22]([N:28]([CH3:45])[C:29](=[O:44])[C@@H:30]([N:32]([CH3:43])[C:33](=[O:42])[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:31])[C:23]1[O:24]C=CC=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:47].C(Cl)(Cl)(Cl)Cl.CC#N>CC#N.O>[CH2:35]([O:34][C:33]([N:32]([CH3:43])[C@@H:30]([CH3:31])[C:29]([N:28]([C@@H:22]([C@H:21]([CH3:46])[CH2:20][CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:23]([OH:24])=[O:47])[CH3:45])=[O:44])=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O
Reactant: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](c1ccco1)N(C)C(=O)[C@H](C)N(C)C(=O)OCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H](C(=O)O)N(C)C(=O)[C@H](C)N(C)C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of NalO4 (485.0 mg, 2.30 mmol, 6.0 equiv) in H2O/CCl4/CH3CN (3/2/3, 10.4 mL) was added RuCl3 (26.6 mg, 0.13 mmol, 0.34 equiv) and the mixture was stirred vigorously for 15 minutes. To the mixture was then added a solution of 2.18.1g (242.0 mg, 0.38 mmol) in CH3CN (3 mL). After stirring for 15 minutes, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with saturated aqueous NaHSO3 solution, brine, dried over Na2SO4, and concentrated to give product 2.18.1h (242.0 mg) which was used for the next step without further purification. MS m/z (M+1) 619.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O1C=[CH:29][CH:28]=[C:27]1P(C1OC=CC=1)C1OC=CC=1.CN1C(=O)CCC1.C([Sn](CCCC)(CCCC)CCCC)C=C>CCOC(C)=O>[CH2:29]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:28]=[CH2:27]
Reactant: COC(=O)c1cc(Br)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCc1cc(C(=O)OC)cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c1
Temperature: 100 °C
Reaction time: 64 h
Yield: 774.4 %

Procedure:
Methyl 3-bromo-5-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}benzoate (Intermediate 104, 300 mg, 0.73 mmol), tris(dibenzylidineacetone)dipalladium (0) (26 mg, 0.03 mmol), trifurylphosphine (14 mg, 0.06 mmol) were weighed into a flask and placed under argon. NMP (3 ml) was added, followed by the dropwise addition of allyltributyl tin (0.25 ml, 0.80 mmol). The mixture was stirred at 100° C. After 64 h, the mixture was diluted with EtOAc and washed sequentially with water followed by brine. The organic phase was dried over MgSO4 and concentrated to dryness. The crude material was purified by chromatography on silica gel using 25% EtOAc/hexanes to give 174 mg of the title product.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].S([O:12][CH3:13])(OC)(=O)=O.[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17](O)=[O:18].O>C(OCC)(=O)C>[CH3:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:16]=1[C:17]([O:12][CH3:13])=[O:18]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(C)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C)cccc1C
Reaction time: 1 h

Procedure:
K2CO3 (10.1 mmol, 1.5 equiv.) and dimethyl sulfate (7.4 mmol, 1.1 equiv.) were added at 25° C. to a solution of 2,6-dimethylbenzoic acid (6.7 mmol, 1 equiv.), and the mixture was stirred for 1 h. The solvent was reduced under reduced pressure, the residue was taken up in ethyl acetate (100 ml), and water (20 ml) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with sat. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The crude product was used in the next stage without being purified further. Yield: quantitative
Reaction SMILES: [OH-:1].[Na+].N1(C(=S)C[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=CC=CC=4)[C:19]=3OC3C(OCC4C=CC=CC=4)=CC=CC=3)=[CH:13][CH:12]=2)CCOCC1.Cl.[CH2:45]([OH:47])[CH3:46]>>[CH2:45]([O:47][C:11]1[CH:12]=[C:25]2[C:20](=[CH:15][CH:16]=1)[CH:19]=[C:18]([O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:13][C:14]([OH:17])=[O:1])=[CH:16][CH:15]=1)[CH:27]=[CH:26]2)[C:46]1[CH:20]=[CH:19][CH:18]=[CH:27][CH:26]=1
Reactant: CCO
Reactant: S=C(Cc1ccc(Oc2ccc3ccccc3c2Oc2ccccc2OCc2ccccc2)cc1)N1CCOCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1ccc(Oc2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Temperature: 100 °C
Yield: 69 %

Procedure:
An aqueous solution (10 ml) of 50% sodium hydroxide was added to 70% ethanol solution (50 ml) of the 1-(morpholin-4-yl)-2-(4-(6-benzyloxyphenoxy-2-naphthyloxy)phenyl)-ethane-1-thione (3.73 g, 7.94 mmol) obtained by the Reference Example 3 and the mixture was stirred at 100° C. for a night. After completing the reaction, the reaction liquid was added with 6N hydrochloric acid to adjust the pH to about 2, extracted with ethyl acetate, washed with water, dried with magnesium sulfate and concentrated. The obtained crude product was recrystallized from acetonitrile to obtain the subject compound (2.10 g, 5.46 mmol). The result of 1H-NMR was consistent with the above structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[N:12]1([C:18]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:19]=2[C:20](O)=[O:21])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:20]([C:19]1[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:18]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:21])[CH2:6][CH2:5]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCc2cc(Cl)ccc2C1

Procedure:
Prepared in analogy to example 1.1 from 6-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [33537-99-4]) and 2-morpholin-4-yl-5-nitro-benzoic acid (example 2.8).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@@H:18]([CH3:22])[CH2:19][O:20][CH3:21])[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].F[C:24]1[CH:37]=[CH:36][C:27]2[C:28](=[O:35])[N:29]([CH3:34])[C:30]([CH3:33])([CH3:32])[O:31][C:26]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:22][C@H:18]([O:17][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([O:1][C:24]2[CH:37]=[CH:36][C:27]3[C:28](=[O:35])[N:29]([CH3:34])[C:30]([CH3:33])([CH3:32])[O:31][C:26]=3[CH:25]=2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6])[CH2:19][O:20][CH3:21]
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN1C(=O)c2ccc(F)cc2OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OC(C)(C)N(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 12 h
Yield: 30.1 %

Procedure:
A mixture of 3-hydroxy-5-[(1S)-2-methoxy-(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.25 g, 0.82 mmol), 7-fluoro-2,2,3-trimethyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (172 mg, 0.82 mmol) and potassium carbonate (226 mg, 1.64 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 12 hours. The mixture was reduced in vacuo and ethyl acetate (50 mL) added. The mixture was washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo to give a brown oil which was chromatographed on silica, eluting with 0-10% methanol in DCM, to give the desired compound as a white foam (122 mg).
Reaction SMILES: C[O:2][C:3](=[O:19])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1.[Li+:20].[OH-].[ClH:22]>C1COCC1.O>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:5]2[C:6](=[O:9])[CH2:7][CH2:8][C@H:4]2[C:3]([OH:19])=[O:2])=[CH:16][CH:15]=1)#[N:18].[Li+:20].[Cl-:22]
Reactant: Cl
Reactant: COC(=O)[C@@H]1CCC(=O)N1Cc1ccc(C#N)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CN2C(=O)CC[C@H]2C(=O)O)cc1
Product: [Cl-]
Temperature: 25 °C

Procedure:
N-(4-Cyanobenzyl)-L-pyroglutamic acid methyl ester (0.875 g, 0.0034 mol) was dissolved in THF:H2O (3:1) (12 mL) and treated with LiOH (0.294 g, 0.007 mol) with stirring at ambient temperature. After stirring for 3 h, the solution was neutralized with 1N HCl, and concentrated to dryness to give the title compound and 2.1 eq of LiCl which was used without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH:6](O)[CH3:7].[CH2:9]=[O:10].[Cl-:11].[Ca+2].[Cl-].Cl>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:10][CH2:9][Cl:11]
Reactant: COCCOC(C)O
Reactant: C=O
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: COCCOCCOCCl
Temperature: -5 °C
Yield: 57.2 %

Procedure:
Hydrogen chloride gas was bubbled into a mixture containing 24 g (200 mmol) of (2-methoxyethoxy)ethanol, 6.0 g (200 mmol) of paraformaldehyde and 22 g (200 mmol) of powdered calcium chloride with stirring and cooling to -5° C. The HCl was continued for 4 hours as the temperature was allowed to rise gradually to 8° C. Celite was added and the reaction filtered. The filtrate was evaporated leaving 29.8 g of a cloudy oil. The oil was dissolved in methylene chloride and dried over molecular sieves. Evaporation furnished 19.3 g of [2-(2-methoxyethoxy)ethoxy]methyl chloride as an oil which was characterized by nuclear magnetic resonance.