Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][C:13]2[CH:23]=[C:17]3[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]3[C:15](=[O:24])[N:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCc1ccc(Cl)c(Cl)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1ccc(Cl)c(Cl)c1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(3,4-dichlorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:22]=[CH:21][C:20]4[C:16](=[C:17]([CH3:26])[N:18]([CH2:23][CH2:24][OH:25])[N:19]=4)[CH:15]=3)[C:10](=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:33][CH2:34][O:35][CH3:36].O>CN(C)C=O>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:22]=[CH:21][C:20]4[C:16](=[C:17]([CH3:26])[N:18]([CH2:23][CH2:24][O:25][CH2:33][CH2:34][O:35][CH3:36])[N:19]=4)[CH:15]=3)[C:10](=[O:27])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCn1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 4-[(4-chlorobenzyl)oxy]-1-[2-(2-hydroxyethyl)-3-methyl-2H-indazol-5-yl]pyridin-2(1H)-one (30 mg) in N,N-dimethylformamide (2 ml) was added 60% sodium hydride (3.51 mg) at 0° C., and the mixture was stirred at room temperature for 30 min. To the obtained reaction mixture was added (2-bromoethyl)methyl ether (15.3 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (28.1 mg).
Reaction SMILES: C([O:3][C:4](=[O:23])[C@@H:5]([O:20][CH2:21][CH3:22])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:17]([OH:19])=O)([CH3:16])[CH3:15])=[CH:9][CH:8]=1)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[CH2:34][CH2:35][NH2:36].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[CH2:34][CH2:35][NH:36][C:17]([C:14]([CH3:15])([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:20][CH2:21][CH3:22])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=1)[CH3:16])=[O:19]
Reactant: COc1ccc(OC)c(CCN)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)O)cc1)OCC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(OC(C)(C)C(=O)NCCc2cc(OC)ccc2OC)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-ethoxy-propionic acid ethyl ester (EXAMPLE 49, step 2) and 2-(2,5-dimethoxy-phenyl)-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C25H33NO7 [M−H]−: 458.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18](=O)[CH3:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].[ClH:33].Cl>C(O)C>[ClH:33].[ClH:33].[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18](=[N:32][NH:31][C:28]([NH2:30])=[NH:29])[CH3:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)NN
Reactant: CC(=O)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Agent: Cl
Solvent: CCO
Product: CC(=NNC(=N)N)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Temperature: 25 °C
Yield: 125.4 %

Procedure:
A mixture of 1-[5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]ethanone (Example 56) (91 mg, 0.26 mmol), aminoguanidine hydrochloride (30 mg, 0.27 mmol) and 6 N HCl (0.22 mL) in ethanol (10 mL) was heated to reflux under a nitrogen atmosphere for 1.5 h. The reaction mixture was cooled to room temperature, and the desired product precipitated from the solution. The solid was collected by filtration and rinsed with ethanol. After drying, [[1-[5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]ethylidene]amino]guanidine dihydrochloride (82 mg, 65%) was obtained as a yellow solid: EST MS m/z 412 [C24H25N7+H]+; HPLC (Method A) 94.9% (AUC), tR=16.5 min.
Reaction SMILES: [C:1]([C@@H:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[C:1]([C@@H:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]1[S:19]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@H]2C(C)(C)C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC(C)(C)[C@@H]1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from (R)-6-tert-butyl-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (1.35 g, 3.31 mmol), cyclohexene (6.16 g, 75 mmol), and 1.0 M boron tribromide in dichloromethane (20 mL, 20 mmol) according to the procedure and in the same manner as described in Example 12, step b; and yielded, after chromatographic purification and crystallization from a mixture of diethyl ether-hexane, 4-{[(R)-6-tert-butylphenanthridin-5(6H)-yl]sulfonyl}phenol* (1.1 g, 2.8 mmol, 84%) as a homogeneous, colorless, crystalline, single enantiomer*, m.p. 187-189° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[N:10]=[C:2]([Cl:1])[CH:3]=1)[CH3:18]
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Cl)nc(OC)c1
Temperature: 70 °C
Yield: 98 %

Procedure:
Treat an ethanol suspension of 2-chloro-6-methoxy-isonicotinic acid (3.75 g, 20 mmol) at 0° C. with thionyl chloride for 30 min. Heat at 70° C. overnight. Cool to room temperature, concentrate, dissolve the residue in ethyl acetate (200 mL), wash the organic layer with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dry (magnesium sulfate) and concentrate to give the title compound (4.2 g, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8](CC)=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].Br[C:31]1[C:39]2[CH:38]=[CH:37][S:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:31]2[C:39]3[CH:38]=[CH:37][S:36][C:35]=3[CH:34]=[CH:33][CH:32]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Reactant: Brc1cccc2sccc12
Product: CCOC(=O)c1c(-c2ccc(-c3cccc4sccc34)cc2)c(C#N)cn1C

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-222 using 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxyphenyl)—1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-97a or 97b) and 4-bromo-benzo(b)thiophene. Purify the material by silica gel chromatography (Chromatotron™) eluting with methylene chloride to provide the title compound a white solid. Mass spectrum (m/e): 415.2 (M*+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:14])[F:13])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25](O)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH:12]([F:13])[F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:31][CH2:30]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.g1) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[CH:10]=O.[OH-].[Na+].Cl>CO.[Pd]>[CH3:6][O:7][C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[CH2:10][NH:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: NCC(=O)O
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCC(=O)O)c(OC)c1

Procedure:
N-(2,4-Dimethoxybenzyl)glycine is prepared by reacting glycine with 2,4-dimethoxybenzaldehyde in the presence of sodium hydroxide, reducing with palladium-on-carbon in methanol and subsequently neutralizing with 2N hydrochloric acid. The aqueous solution obtained is concentrated. 18.6 g of the mixture of N-(2,4-dimethoxybenzyl)glycine and sodium chloride obtained are stirred at 80° and 90°, in each case for 1 hour, together with 60 ml of N,N-dimethylformamide and 10 g (50.6 mmol) of 6-chloroisatoic anhydride. The reaction mixture is evaporated and the residue is heated at 135°-140° for 5 hours in a high vacuum. The crystalline product is boiled in 90 ml of N,N-dimethylformamide, whereupon the mixture is poured into 400 ml of hot water. The mixture is left to cool to room temperature while stirring, then cooled to about 0° in an ice-bath, the product is filtered off under suction, rinsed with water and the material obtained is dissolved in 20 ml of hot N,N-dimethylformamide. After the addition of 150 ml of ethyl acetate the mixture is left to stand in an ice-bath for 1 hour, the product is filtered off under suction, rinsed with cold ethyl acetate and dried at 80° in vacuo. There is obtained 6-chloro-4-(2,4-dimethoxybenzyl)-3,4-dihydro-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 230°-231°.
Reaction SMILES: C(O[N:9]1[C:13](=C=O)[CH:12]([CH2:16][OH:17])[NH:11][C:10]1=[O:18])C1C=CC=CC=1.[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].[OH:25][C:26]1[CH:27]=[CH:28][C:29]2[C:33]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[C:37]([CH3:47])[CH:36]=3)=[C:32]([C:48]3[CH:53]=[CH:52][C:51](OCC4COC(=O)N4)=[CH:50][CH:49]=3)[S:31][C:30]=2[CH:62]=1>C1COCC1>[C:19]([OH:24])(=[O:23])[C:20]([OH:22])=[O:21].[OH:25][C:26]1[CH:27]=[CH:28][C:29]2[C:33]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[C:37]([CH3:47])[CH:36]=3)=[C:32]([C:48]3[CH:53]=[CH:52][C:51]([O:17][CH2:16][CH:12]4[CH2:13][NH:9][C:10](=[O:18])[NH:11]4)=[CH:50][CH:49]=3)[S:31][C:30]=2[CH:62]=1
Reactant: Cc1cc(Cc2c(-c3ccc(OCC4COC(=O)N4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Reactant: O=C=C1C(CO)NC(=O)N1OCc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Cc2c(-c3ccc(OCC4CNC(=O)N4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Yield: 28 %

Procedure:
By essentially following the conditions of Example 2, Part A, the title compound was prepared from 1-benzyloxy-carbonyl-2-oxo-4-hydroxymethylimidazolidine (Saijo et al. Chem. Pharm. Bull. 1980, 28, 1459) and 6-benzyloxy-3-[3-methyl-4-[(1-pyrrolidinyl)methyl]benzyl]-2-(4-hydroxyphenyl)benzo[b]thiophene (Example 8, Part C) in 28% yield following radial chromatography (SiO2; 20% then 25% then 40% THF with 5% TEA in hexanes).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:16])=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[O-]CC.[Na+].Cl[C:22]1([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:27][CH2:26][CH2:25][N:24]2[C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[O:41][C:40]([CH3:42])=[N:39][CH:38]=4)=[C:33]([O:43][CH3:44])[CH:32]=3)=[N:29][N:30]=[C:23]12>C(O)C.[Cl-].[NH4+]>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:4]1[C:3]([O:16][C:22]2([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:27][CH2:26][CH2:25][N:24]3[C:28]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[O:41][C:40]([CH3:42])=[N:39][CH:38]=5)=[C:33]([O:43][CH3:44])[CH:32]=4)=[N:29][N:30]=[C:23]23)=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=1)[CH3:15]
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reactant: CCOC(=O)Cc1cc(F)c(F)c(F)c1O
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1cc(F)c(F)c(F)c1OC1(C(=O)OCC)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
To a mixture of ethyl (3,4,5-trifluoro-2-hydroxyphenyl)acetate (1.77 g) in ethanol (15 mL) was added sodium ethoxide (0.514 g) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 30 min. To the reaction mixture was added ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (3 g), the mixture was stirred at 80° C. overnight under a nitrogen atmosphere, and diluted with saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2 g).
Reaction SMILES: OP([O-])(O)=O.[K+].[I:7][C:8]1[C:9]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][C:10]=2[CH:11]=[N:12][CH:13]=1.[O-:19]Cl=O.[Na+]>O.CS(C)=O>[I:7][C:8]1[C:9]2[O:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][C:10]=2[CH:11]=[N:12][CH:13]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cc2cncc(I)c2o1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc2cncc(I)c2o1
Reaction time: 16 h

Procedure:
A solution of KH2PO4 (81 mg, 0.59 mmol) in H2O (3 mL) was added to a solution of 7-iodofuro[3,2-c]pyridine-2-carbaldehyde (578 mg, 2.12 mmol) in DMSO (16 mL). The stirred mixture was treated carefully with a solution of NaClO2 (335 mg, 2.96 mmol) in H2O (5 mL). After 16 h, more KH2PO4 (81 mg, 0.59 mmol) in H2O (3 mL) and NaClO2 (335 mg, 2.96 mmol) in H2O (5 mL) were added, then stirring was continued for a further 48 h. The precipitated solid was collected, washed with DMSO, H2O, i-PrOH, and EtOAc, and vacuum-dried to furnish the title compound: m/z (ES+)=289.9 [M+H]+.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:25][C:26]([OH:45])([CH2:31][C:32]([C:35]2[C:43]3[O:42][CH2:41][CH2:40][C:39]=3[CH:38]=[C:37]([Cl:44])[CH:36]=2)([CH3:34])[CH3:33])[C:27]([F:30])([F:29])[F:28])(=O)=O)C=CC=CC=1>CO.[OH-].[Na+].[Cl-].[Na+].O>[Cl:44][C:37]1[CH:36]=[C:35]([C:32]([CH3:34])([CH3:33])[CH2:31][C:26]([CH2:25][C:11]2[NH:10][C:18]3[C:13]([CH:12]=2)=[CH:14][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=3)([OH:45])[C:27]([F:29])([F:28])[F:30])[C:43]2[O:42][CH2:41][CH2:40][C:39]=2[CH:38]=1
Reactant: CC(C)(CC(O)(Cc1cc2cc(-c3ccccn3)ccc2n1S(=O)(=O)c1ccccc1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CC(O)(Cc1cc2cc(-c3ccccn3)ccc2[nH]1)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Reaction time: 4 h
Yield: 42.2 %

Procedure:
A mixture of the above 2-(1-benzenesulfonyl-5-pyridin-2-yl-1H-indol-2-ylmethyl)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methylpentan-2-ol (30.1 mg, 0.046 mmol, theoretical maximum from above) in 5 mL of methanol and 5 mL of 10% aqueous sodium hydroxide solution was warmed at reflux. After 4 hours, the mixture was diluted with 7 mL of brine and extracted with three 5 mL portions of ethyl acetate. The combined organic layers were washed with three 5 mL portions of saturated aqueous sodium bicarbonate solution, 5 mL of brine, two 5 mL portions of saturated aqueous ammonium chloride solution, 5 mL of brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel preparative TLC using ethyl acetate-hexanes (1:1). The material from the preparative TLC plate when concentrated in vacuo from diethyl ether-hexanes afforded 10 mg (42% yield) of the title compound.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].FC(F)(F)C(O)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][C@H:32]([C:36]4[CH:37]=[N:38][C:39]5[C:44]([CH:45]=4)=[CH:43][CH:42]=[CH:41][CH:40]=5)[C@@H:33]([NH2:35])[CH3:34])=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1.CN(C)C(N(C)C)=N.FC(F)(F)C(OCC)=O>CO>[F:1][C:2]([F:7])([F:6])[C:3]([NH:35][C@@H:33]([CH3:34])[C@H:32]([O:31][C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:22]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=1)[N:23]=[CH:24]2)[C:36]1[CH:37]=[N:38][C:39]2[C:44]([CH:45]=1)=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:4]
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cnc2ccccc2c1
Reactant: O=C(O)C(F)(F)F
Agent: CCOC(=O)C(F)(F)F
Agent: CN(C)C(=N)N(C)C
Solvent: CO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(quinolin-3-yl)propan-2-amine bis(2,2,2-trifluoroacetate) (65 mg, 0.10 mmol) was dissolved in MeOH (1.5 mL), 1,1,3,3-tetramethylguanidine (0.064 mL, 0.51 mmol) and ethyl trifluoroacetate (0.242 mL, 2.03 mmol) was added, the reaction mixture was stirred at r.t. for 2.5 h. Solvent was removed by evaporation and the residual material was purified by HPLC. Fractions was freezedried to give the product as a colourless powder. Yield 35 mg (67%)
Reaction SMILES: CO[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([OH:14])=O.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].Cl.C1C[O:31][CH2:30]C1>>[CH3:30][O:31][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH2:12][OH:14])=[CH:3][C:7]=2[CH:8]=1
Reactant: C1CCOC1
Reactant: COc1c(C(=O)O)oc2ccccc12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Product: COc1ccc2oc(CO)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of 5 methoxybenzofuran-2-carboxylic acid (10.0 gm; 52 mmoles) in THF (300 mL) cooled at -78° C. was added diisobutylaluminium hydride (120 ml, 182 mmoles) via a syringe. The reaction mixture temperature was raised to room temperature and the solution was stirred for 3 hours. The mixture was poured into a saturated solution of ammonium chloride (500 ml) and stirred 15 minutes then was acidified with HCl 6N. This mixture was extracted with ethyl acetate (2×500 ml). The combined organic extract was concentrated in vacuo. The residue was chromatographed on silica gel using 30% ethyl acetate in hexane to yield 5-methoxy-2-hydroxymethylbenzofuran, E8, (6.5 gm, 71%).
Reaction SMILES: [CH3:1][Li].[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH3:21])=[C:12]([C:22]([O:24]CC)=O)[C:11]1=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>C1COCC1.[Cu]I>[CH2:3]([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH3:21])=[C:12]([C:22](=[O:24])[CH3:1])[C:11]1=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCn1c(=O)c(C(=O)OCC)c(OC)c2ccccc21
Reactant: [Li]C
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCCCCCn1c(=O)c(C(C)=O)c(OC)c2ccccc21
Reaction time: 3 h
Yield: 75 %

Procedure:
A flame-dried 50 ml round bottomed flask was charged with copper (I) iodide (909 rag, 4.78 mmole) and anhydrous THF (20 mL). Methyl lithium (halide-free, 1.4M, 7.2 mL, 10.1 mmole) was added to the white CuI suspension at -78° C. After 0.5 hour the product from step (1) (430 mg. 1.25 mmole) was added drop-wise as a solution in THF (10 mL) to the solution of dimethyllithiocuprate. After 3 hours, the reaction was quenched with saturated ammonium chloride. The product was isolated by acidification of the reaction to pH 5, and extraction (3×) with ethyl acetate. Final purification on Silica-Gel 60 (4:1 hexane:ethyl acetate eluent) gave the title compound in 75% yield. That the expected product was obtained was confirmed by the spectral data: M.S. (E.I.): 315 (M+); NMR (CDCl3): δ8.0 (1H, d), 7.6 (1H, dd), 7.35 (1H, dd), 7.2 (1H, dd), 4.25 (2H, m, CH2N), 3.98 (3H, s, OCH3), 2.65 (3H, s, C(O)CH3), 1.8 (2H, m), 1.35 (8H, m), 0.9 (3H, t, CH3).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]1[CH:39]=[CH:38][C:12]([O:13][CH:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([O:35][CH2:36][CH3:37])[CH:26]=2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([CH2:8][C:9]1[CH:39]=[CH:38][C:12]([O:13][CH:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[C:27]([O:35][CH2:36][CH3:37])[CH:26]=2)[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(Oc2ccc(CC(=O)OC(C)(C)C)cc2)C(=O)OCc2ccccc2)ccc1OC(C)C
Agent: [Pd]
Product: CCOc1cc(C(Oc2ccc(CC(=O)OC(C)(C)C)cc2)C(=O)O)ccc1OC(C)C

Procedure:
A mixture of 13B (85 mg, 0.15 mmol) and Pd/C (cat.) was hydrogenated at 40 psi overnight. The reaction was filtered and concentrated to provide 13C (39 mg, 99%). LC-MS: 482.37 (M+Na)+.
Reaction SMILES: ClCl.BrBr.S([O-])([O-])=O.C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+:57].[Na+:58].[Na+].[Na+].[C:61]1([C:80]([OH:82])=[O:81])[C:70]2[C:69]([C:71]([OH:73])=[O:72])=[CH:68][CH:67]=[C:66]([C:74]([OH:76])=[O:75])[C:65]=2[C:64]([C:77]([OH:79])=[O:78])=[CH:63][CH:62]=1>>[Na:57][Na:58].[C:61]1([C:80]([OH:82])=[O:81])[C:70]2[C:69]([C:71]([OH:73])=[O:72])=[CH:68][CH:67]=[C:66]([C:74]([OH:76])=[O:75])[C:65]=2[C:64]([C:77]([OH:79])=[O:78])=[CH:63][CH:62]=1
Reactant: [Na+]
Agent: BrBr
Agent: ClCl
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Product: [Na][Na]

Procedure:
In the aqueous-alkaline hypohalite oxidation of organic compounds, in particular in the alkaline hypochlorite oxidation of 2,7-dibromodiindanedione (3) to give the tetraalkali metal salt of naphthalene-1,4,5,8-tetracarboxylic acid, the ecological pollution by halogen-containing compounds of the classes CHX3 and CX4, in which X is chlorine, bromine or a combination thereof, is eliminated by carrying out the aqueous-alkaline hypohalite oxidation at a temperature of between 20° and 60° C., preferably 40° to 55° C., in a closed vessel under the autogenous pressure which is established at the corresponding temperature, subjecting the reaction mixture, after the oxidation has ended, to a heat treatment at a temperature of between 90° and 120° C., preferably 90° to 100° C., under the autogenous pressure of 1 to 10 bar, preferably 1 to 5 bar, which is established, in the presence of sulfite, cooling the resulting suspension of the tetrasodium salt of naphthalene-1,4,5,8-tetracarboxylic acid, after the reaction vessel has been let down, to a temperature of below 40° C., preferably to 20° to 30° C., subsequently adjusting the pH to 4.5 to 5 by acidification, isolating the resulting disodium salt of naphthalene-1,4,5,8-tetracarboxylic acid, converting this salt into the tetrasodium salt of naphthalene-1,4,5,8-tetracarboxylic acid in an aqueous alkali metal hydroxide solution and, if appropriate after removal of insoluble impurities, precipitating naphthalene-1,4,5,8-tetracarboxylic acid 1,8-monoanhydride by acidification to a pH of less than 2, preferably less than 1, at a temperature of 80° to 100° C.