Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[O:36][CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:30](Cl)=[O:31])[CH2:24][CH2:23]1>C(Cl)Cl.C(N(CC)CC)C>[CH:22]1([CH2:25][O:26][C:27]2[CH:28]=[C:29]([C:30]([NH:1][CH:2]3[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]3[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[O:31])[CH:33]=[CH:34][C:35]=2[O:36][CH2:37][CH:38]2[CH2:39][CH2:40]2)[CH2:24][CH2:23]1
Reactant: O=C(Cl)c1ccc(OCC2CC2)c(OCC2CC2)c1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2CC(OC(C)=O)CCC2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
9.5 mmol of (±)-acetic acid (1SR,3RS,4RS)-4-amino-3-(3,4-dimethoxyphenyl)cyclohexyl ester (compound B2) are dissolved in a mixture of 40 ml of methylene chloride and 10 ml of triethylamine and treated with 8.9 mmol of 3,4-dicyclopropylmethoxybenzoyl chloride. After stirring for 1 h at room temperature, the reaction mixture is concentrated and the residue chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate/triethylamine in the ratio 4/4/1 as eluent. After concentration of the corresponding eluate fractions, 1.86 mmol of the title compound are obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)=[O:39]>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][CH2:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]1)=[O:39])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN1CCN(C(=O)CCc2ccccc2O)CC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)Oc1ccccc1CCC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (0.62 mld) and octadecyl isocyanate (1.40 ml) were added to a solution containing 3-(2-hydroxyphenyl)-1-(4-methylpiperazino)-1-propanone (1.00 g) in methylene chloride (10 ml) and stirred for 4 hours at room temperature. The insoluble matters were filtrated out and washed with chloroform. The filtrate and washings were combined and the i mixture was washed with saturated sodium hydrogencarbonate aqueous solution and brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1), thereby yielding the entitled compound (2.05 g) as white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][C:15]=2[NH2:19])[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=1)=[O:4].[NH3:20]>CN(C)C=O>[NH2:20][CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][C:15]=2[NH2:19])[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=1)=[O:4]
Reactant: Nc1cc2cccnc2c2nc(C(=O)CBr)ccc12
Reactant: N
Solvent: CN(C)C=O
Product: NCC(=O)c1ccc2c(N)cc3cccnc3c2n1
Reaction time: 1 h

Procedure:
Bromoacetyl-5-amino-1,10-phenanthroline (4) (Preparation 3; 1.00 g; 3.15 mmol) was dissolved in 50 ml dimethylformamide. Into this solution, was added 0.2 ml concentrated ammonia. The reaction mixture was stirred 1 hr. in the dark. The volume of the reaction mixture then was reduced to 2 ml by evaporation, and the product then was precipitated by addition of 2 ml of ice-cold deionized water. The resulting precipitate was collected by vacuum filtration, was washed with 20 ml ice-cold deionized water, and was washed with 50 ml acetonitrile. Yield: 0.45 g, 32%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-Trifluoromethyl benzene boronic acid. MS (M+H) 421.2
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[NH:13][C:14]1[O:15][CH2:16][C:17](=[O:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1>C(O)C.Cl>[NH:25]1[C:33]2=[N:32][CH:31]=[CH:30][CH:29]=[C:28]2[C:27]([CH:34]=[C:16]2[O:15][C:14]([NH:13][C:7]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2=[O:24])=[CH:26]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccc(C)cc2OCCOC)OCC1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2ccc(C)cc2OCCOC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 43.2 %

Procedure:
To a solution of ethyl 2-{[2-(2-methoxyethoxy)-4-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate (0.015 g, 0.045 mmol) which similarly prepared according to the procedure described in the Example 29, First step and 7-azaindole-3-carboxaldehyde (0.0067 g, 0.046 mmol) in ethanol (0.2 mL), 2M hydrochloric acid in ethanol (0.023 mL, 0.045 mmol) was added at ambient temperature. The mixture was refluxed for 4 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound as solid (0.0090 g, y. 43%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:14][O:15][CH3:16])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[CH3:16][O:15][CH2:14][C@@H:8]([NH2:7])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COC[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@@H](N)CC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((S)-1-methoxymethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (193 mg, 0.787 mmol) in CH2Cl2 (6 mL) was added TFA (0.606 mL, 7.87 mmol). The reaction mixture was stirred at RT for 2 h and concentrated to give the desired material which was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.83 (bs, 3H), 3.50 (m, 1H), 3.35 (m, 1H), 3.35 8s, 3H), 3.28 (m, 1H), 1.48 (dd, 1H), 1.36 (dd, 1H), 0.92 (s, 9H).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[C:10]([CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[OH:19])=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=23)[CH:6]=[CH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=O.[CH:37]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl>[CH:37]1([NH:42][C:3]2[N:8]=[C:7]([C:9]3[C:10]([CH:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[OH:19])=[N:11][N:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=34)[CH:6]=[CH:5][N:4]=2)[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: NC1CCCC1
Reactant: CSc1nccc(-c2c(C(O)c3ccccc3)nn3ccccc23)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OC(c1ccccc1)c1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 36.9 %

Procedure:
To a cold (0° C.) solution of {3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanol (294 mg, 0.844 mmol) in dichloromethane (30 mL) was added m-chloroperoxybenzoic acid (218 mg, 1.26 mmol). The reaction mixture was stirred for 1.5 hours at 0° C., then diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, then filtered and concentrated. The resulting solid was heated in cyclopentylamine (2 mL, 20 mmol) at 45° C. for 16 hours. Concentration and flash chromatography (59:1 dichloromethane:methanol) provided {3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}(phenyl)methanol (120 mg, 89%) as a light yellow solid. Rf 0.55 (29:1 dichloromethane:methanol); 1H NMR (CDCl3) δ 8.50 (d, 1H), 8.22 (d, 1H), 7.96 (br, 1H), 7.82 (d, 1H), 7.40 (d, 2H), 7.35–7.17 (m, 4H), 6.85 (t, 1H), 6.78 (d, 1H), 6.20 (s, 1H), 5.12 (s, 1H), 4.29 (m, 1H), 2.05 (m, 2H), 1.79–1.60 (m, 4H), 1.49 (m, 2H); MS m/z 386 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]2)[CH:6]=[C:7]([F:10])[C:8]=1[F:9].CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[F:10][C:7]1[CH:6]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]2[C:30]([O:31][CH3:32])=[O:33])[CH:4]=[C:3]([F:2])[C:8]=1[F:9]
Reactant: COC(=O)C1CCNC(c2cc(F)c(F)c(F)c2)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2cc(F)c(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.2 %

Procedure:
Methyl 2-(3,4,5-trifluorophenyl)piperidine-4-carboxylate hydrochloride (2.75 g, 8.88 mmol) was dissolved into DCM (50 mL), then DIPEA (3.88 mL, 22.20 mmol) was added. Methyl carbonochloridate (0.979 mL, 12.43 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h. The mixture was washed with HCl (0.1 M, 100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(3,4,5-trifluorophenyl)piperidine-1,4-dicarboxylate (2.77 g, 94%) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2([CH3:10])[CH:7]([OH:9])[CH2:8][CH:3]1[CH2:4][CH2:5]2.[O-]Cl.[Na+]>C(O)(=O)C>[C:6]12([CH3:10])[C:2]([CH3:11])([CH3:1])[CH:3]([CH2:4][CH2:5]1)[CH2:8][C:7]2=[O:9]
Reactant: CC1(C)C2CCC1(C)C(O)C2
Agent: [Na+]
Agent: [O-]Cl
Solvent: CC(=O)O
Product: CC12CCC(CC1=O)C2(C)C
Yield: 96.3 %

Procedure:
To a vigorously stirred solution of 600 g (3.89 mol) of (−)-borneol in 1.5 L of glacial acetic acid at 0° C. was added 7.5 L of household bleach (Chlorox™) over a period of 1 h. After 30 min the solid (800 g) was collected by filtration and dissolved in 2 L of hexane. The solution was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated to give 570 g (96%) of camphor.
Reaction SMILES: [CH3:1][NH:2][NH2:3].O=[C:5]([CH2:12][C:13](=O)[CH2:14][CH2:15]C)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].O>C(O)C>[CH3:1][N:2]1[C:12]([CH2:13][CH2:14][CH3:15])=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3]1
Reactant: CNN
Reactant: CCCC(=O)CC(=O)CC(=O)OCC
Solvent: CCO
Solvent: O
Product: CCCc1cc(C(=O)OCC)nn1C
Yield: 7.9 %

Procedure:
10.4 g of methylhydrazine were initially charged in 50 ml of ethanol and, with stirring and external cooling, admixed with a solution of 42.9 g of ethyl 2,4-diketoheptanecarboxylate in 50 ml of ethanol, during which the internal temperature was kept at 5 to 10° C. (time for the dropwise addition: 10 minutes). The solution was stirred at 5 to 10° C. for another 30 minutes, the solvent and the water which had been formed were distilled off and the residue was fractionated under reduced pressure. The desired ethyl 1-methyl-3-n-propyl-pyrazole-5-carboxylate passed over at 125 to 128° C. (13 mm). The yield was 78.3% of theory. By further distillation (166 to 168° C./13 mm), the undesired isomer (=ethyl 1-methyl-5-n-propyl-pyrazole-3-carboxylate) was obtained in a yield of 7.9% of theory. Thus, the isomer ratio was approximately 10:1 in favor of the desired isomer.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Br:23])[CH:22]=1>>[Br:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH:20]=[C:21]([Br:23])[CH:22]=1
Reactant: OB(O)c1cc(Br)cc(Br)c1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Br)cc(Br)c2)cc1

Procedure:
The colourless gum (E)-ethyl 3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91a) and 3,5-dibromobenzene boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1)[CH2:2][CH3:3].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[O:12]>CC(C)=O>[CH2:15]([O:14][C:10](=[O:13])[CH:11]([OH:12])[N:7]1[CH2:8][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][C:6]1=[O:9])[CH3:16]
Reactant: CCCC1CNC(=O)C1
Reactant: CCOC(=O)C=O
Solvent: CC(C)=O
Product: CCCC1CC(=O)N(C(O)C(=O)OCC)C1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, a mixture of 4-propyl-pyrrolidin-2-one (0.5 g, 3.9 mmol) and ethyl glyoxylate (50% in toluene, 2.4 ml, 11 mmol) in acetone is heated up at 60° C. for 6 h and another portion of ethyl glyoxylate (0.4 ml) is added. After 17 h at 50° C., the reaction mixture is concentrated in vacuo to give the crude hydroxy-(2-oxo-4-propyl-pyrrolidin-1-yl)-acetic acid ethyl ester a19 (2.02 g). It is used in the next step without any further purification.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[NH:13][C:12](=[O:21])[C:11]1=[O:22])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].F[B-](F)(F)F.[O:28]=[N+:29]=[O:30].O>C(Cl)Cl>[CH2:6]([O:5][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:29]([O-:30])=[O:28])=[C:17]([F:20])[CH:18]=2)[NH:13][C:12](=[O:21])[C:11]1=[O:22])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2ccc(F)cc21)OCC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
615 mg of (7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is mixed in 60 ml of methylene chloride with 743 mg of nitronium tetrafluoroborate. The batch is stirred for 2 hours at room temperature. It is mixed with 50 ml of water and, after separation of the organic phase, it is extracted three times with methylene chloride. The collected organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with methylene chloride:ethanol=10:1. 350 mg of (6-nitro-7-fluoro-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)-methanephosphonic acid diethyl ester is obtained.
Reaction SMILES: [Na:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([OH:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28].C([O-])(=O)C.[Na+]>>[Na:1].[C:27]([O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([OH:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][CH:8]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(O)Oc1ccc(C(c2ccc(O)cc2)c2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [Na]
Product: CC(=O)Oc1ccc(C(c2ccc(OS(=O)(=O)O)cc2)c2ccccn2)cc1

Procedure:
100 g. 4-hydroxyphenyl-4-sulphoxyphenyl-(2-pyridyl)-methane sodium salt were treated with 400 ml. acetic anhydride and 100 g. anhydrous sodium acetate under conditions similar to those described in Example 4. The reaction mixture was filtered and the filtrate was concentrated at a reduced temperature and under reduced pressure. By subsequently adding excess diethyl ether, there was obtained a crystalline solid which was further purified with appropriate mixtures of ethanol and diethyl ether. A high yield of pure 4-acetoxyphenyl-4-sulphoxyphenyl-(2pyridyl)-methane sodium salt was thus obtained in the form of colourless crystals which melted at 142° - 143°C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.CC(N(C)C)=O.CC(C)([O-])C.[K+].[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([O-:27])=[O:26]>C(OCC)(=O)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O:9][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 16.8 g. (0.1 mole) of 4-hydroxymandelic acid in 300 ml. of dimethylacetamide were added 11.2 g. of potassium t-butoxide with an additional 100 ml. of dimethylacetamide. The mixture was stirred at room temperature until a solution was obtained. p-Nitrobenzyl bromide (21.6 g., 0.1 mole) was added to the solution followed by 100 ml. of additional dimethylacetamide. The reaction mixture was stirred for 24 hours and was diluted with one liter of ethyl acetate. The mixture was washed repeatedly with water and dried over magnesium sulfate. The dried solution was evaporated to yield 25 g. (84 percent yield) of p-nitrobenzyl 4-hydroxymandelate.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10]([N+:11]([O-])=O)=[C:9]([C:14]2[CH:19]=[C:18]([Cl:20])[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:16][C:15]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[NH4+].[Cl-]>C1COCC1.O.[Zn]>[CH2:30]([O:29][C:15]1[CH:16]=[C:17]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]([Cl:20])=[CH:19][C:14]=1[C:9]1[O:8][N:7]=[C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])[C:10]=1[NH2:11])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A solution of 5-(2,4-bis-benzyloxy-5-chloro-phenyl)-4-nitro-isoxazole-3-carboxylic acid ethylamide (1 g, 1.97 mmol) in THF (7 ml) was added to a solution of NH4Cl (2.7 g, 50 mmol) in water (15 ml). Zinc dust (4 g, 61 mmol) was then added portion wise over 15 min with stirring at 0° C. After 30 min at 0° C., the mixture was filtered and the resulting cake was rinsed with MeOH. The combined filtrate were evaporated under vacuo to give 5-[2,4-bis(benzyloxy)-5-chlorophenyl]-4-amino-N-ethylisoxazole-3-carboxamide (820 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:31]([NH:30][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:32])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCOCC2)cc1
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCOCC1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-(tetrahydro-pyran-4-yl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 5 days under reflux conditions to give the title compound as yellow oil. MS: m/e=453.3 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([OH:23])=[O:22])[CH:4]=1.[N+:24]([O-])([O-:26])=[O:25].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([N+:24]([O-:26])=[O:25])[CH:11]=[CH:12][C:13]=3[O:18][CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[C:5]([C:21]([OH:23])=[O:22])[CH:4]=1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(C(=O)O)cc1C2=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc(C(=O)O)cc2c1C(=O)c1c(OC)ccc([N+](=O)[O-])c1C2=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Concentrated sulphuric acid (20 ml) was cooled to 5° C., and 9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene-2-carboxylic acid (1 g) was added portionwise during fifteen minutes, resulting in a deep crimson coloration. Maintaining the cool temperature, potassium nitrate (0.36 g) was added portionwise during 10 minutes. Stirring continued at 5° C. for a further 15 minutes before the mixture was allowed to warm to room temperature. Upon reaching room temperature, the mixture was heated to 40° C. for 1 hour. The material was then poured onto ice/water (100 ml), generating a yellow precipitate. This solid was collected by filtration and washed with water (1×100 ml). Drying in vacuo over silica gel yielded 9,10-dihydro-4,5-dimethoxy-9,10-dioxo-8-nitro-anthracene-2-carboxylic acid as a signal yellow powder, decomposition point 230° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([O:52][CH3:53])([C:13](=[O:51])[NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:19]=[C:18]3[C:43]2[CH:48]=[CH:47][N:46]=[C:45]([O:49][CH3:50])[CH:44]=2)[CH2:9]1)=O)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:50][O:49][C:45]1[CH:44]=[C:43]([C:18]2[C:17]3[C:21](=[CH:22][CH:23]=[C:15]([NH:14][C:13]([C:10]4([O:52][CH3:53])[CH2:11][CH2:12][NH:8][CH2:9]4)=[O:51])[CH:16]=3)[NH:20][N:19]=2)[CH:48]=[CH:47][N:46]=1
Reactant: COc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(NC(=O)C4(OC)CCN(C(=O)OC(C)(C)C)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2n[nH]c3ccc(NC(=O)C4(OC)CCNC4)cc23)ccn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To the stirred solution 3-Methoxy-3-[3-(2-methoxy-pyridin-4-yl)-1-trityl-1H-indazol-5-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester 7BV (2.95 g, 4.16 mmole) in DCM (50 mL) at r.t. was added triethylsilane (1.00 ml, 6.24 mmole) followed by TFA (10 mL). The mixture was stirred at r.t. under dry N2 gas for 4-5 hours. The mixture was evaporated to dryness and co-evaporated with dry toluene (2×75 mL). The resulting crude solid was purified on RediSep 120 g cartridge eluting with 2.5%-6% 2M NH3-MeOH/CH2Cl2 to yield an off-white solid 8BV (1.23 g, 80%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([OH:13])=O)[N:10]=2)[CH:7]=1.[CH3:15][N:16](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:17].F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.CNC>CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:14])=[C:9]([C:11]([N:16]([CH3:17])[CH3:15])=[O:13])[N:10]=2)[CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C(=O)O)nc2ccc(I)cn12
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)N(C)C)nc2ccc(I)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a stirred solution of 6-iodo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (150 mg) in DMF (5 ml) were added HATU (283 mg) and N,N-diisopropylethylamine (0.17 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 30 min. Dimethylamine (2 M in THF, 0.2 ml) was added, and the resultant mixture was stirred at the same temperature for 18 h. The mixture was then concentrated in vacuo and the residue was diluted with DCM (100 ml). The DCM layer was successively washed with saturated aqueous NH4Cl solution (40 ml), saturated aqueous NaHCO3 solution (20 ml), water (30 ml) and brine (50 ml). The DCM layer was then dried m over Na2SO4, and concentrated in vacuo to give the title compound (150 mg) as a brown oil.