Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.[OH:19]O.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:12])=[O:19])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1
Reactant: OO
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Temperature: 50 °C

Procedure:
The title compound was prepared by adding the 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (15.20 g, 49.65 mmol), ethanol (130 mL), 30% hydrogen peroxide (aqueous) (130 mL), and 6 N sodium hydroxide (aqueous) (9 mL) to a 2 liter round bottom flask. This mixture was heated at 50° C. for 1 hour, and removed from the heat to allow to cool to room temperature. The pH was adjusted to 3 by adding 6 N hydrochloride solution (aqueous) resulting in a precipitate. This precipitate was filtered and washed with water (15.13 g, 94%): ES-MS (m/z) 324 [M+1]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[C:25]([S:29][CH2:30][C:31](=O)[CH2:32][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH3:28])([CH3:27])[CH3:26].O>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:30]([S:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[C:31]2[CH2:32][C:33]([CH3:39])([CH3:40])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)(C)CC(=O)CSC(C)(C)C
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1-(4-Chlorobenzyl)-1-(4-methoxyphenyl)hydrazine hydrochloride (50 g; 190 mmol), prepared as in step 1, was dissolved in 400 mL toluene and 220 mL acetic acid. Sodium acetate (17.1 g; 210 mmol) was added followed by the addition of ethyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate (49 g; 188 mmol), prepared as in step 2. The reaction was stirred in the dark at room temperature for 4 days. The mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water. Solid sodium bicarbonate was added to the organic extracts and the mixture was filtered. The filtrate was washed with water and brine, dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was taken up in hot ethyl acetate and filtered. The solvent was removed and the product was recrystallized from pentane to give ethyl 3-[1-(4-chlorobenzyl)-3-(1,1-dimethylethylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropionate as a fluffy white solid.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=1.[CH2:11](N(CC)CC)C.C[N:19]=[C:20]=[O:21]>CCOCC>[CH3:11][C:5]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[C:2]([S:1][C:20](=[O:21])[NH2:19])=[N:3][N:4]=1
Reactant: CCCCn1cnnc1S
Reactant: CCN(CC)CC
Reactant: CN=C=O
Solvent: CCOCC
Product: CCCCn1c(C)nnc1SC(N)=O
Reaction time: 8 h
Yield: 57 %

Procedure:
To 6.0 g. (0.0382 mole) of 3-mercapto-4-n-butyl-1,2,4-triazole dissolved in 50 ml. of ether was added 2.5 g. (0.248 mole) of triethylamine and then 2.5 g (0.0438 mole) of methyl isocyanate. The resulting orange-brown solution was allowed to stand overnight. The solid which formed was filtered and washed twice with 50 ml. of ether to give 4.7 g. (57% yield) of 3-methyl-carbamoylmercapto-4-n-butyl-1,2,4-triazole melting at 112°-114° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:11](=[O:12])[N:10]3[C:13](=[O:20])[C:14]([CH:17]([CH3:19])[CH3:18])([CH3:16])[N:15]=[C:9]3[C:6]2=[N:7][CH:8]=1)[CH3:2].Cl.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[NH:10][C:13](=[O:20])[C:14]([CH:17]([CH3:18])[CH3:19])([CH3:16])[N:15]=2)=[C:5]([CH:4]=1)[C:11]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:12])[CH3:2]
Reactant: CCc1cnc2c(c1)C(=O)N1C(=O)C(C)(C(C)C)N=C21
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)NCCCCCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 20.5 h
Yield: 66.4 %

Procedure:
A stirred solution of 7-ethyl-2-isopropyl-2-methyl-5H-imidazo[1′,2′:1,2]pyrrolo[3,4-b]pyridine-3(2H),5-dione (7.25 g, 26.75 mmol) in anhydrous N,N-dimethylformamide is treated successively with methyl 6-aminocaproate hydrochloride (5.10 g, 28.1 mmol) and triethylamine (3.00 g, 29.6 mmol). The resulting mixture is stirred at room temperature under nitrogen for 20.5 hours. After this period, the reaction mixture is partitioned between water and ethyl acetate. The layers are separated, and the organic layer is washed with water, dried over magnesium sulfate and vacuum filtered through diatomaceous earth. The filtrate is concentrated in vacuo to obtain a white solid. The solid is triturated with 1:1 ether/petroleum ether to give the title product as a white solid (7.40 g, 69%, mp 101-103° C.).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].[CH2:5]1[CH2:10][CH2:9][CH:8]([CH:11]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][CH:13]2[NH:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:7][CH2:6]1>C(#N)C.CO>[CH2:5]1[CH2:6][CH2:7][CH:8]([CH:11]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][CH:13]2[NH:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:10]1.[N+:1]([O-:4])([O-:3])=[O:2]
Reactant: O=[N+]([O-])O
Agent: C1CCC(C(CC2CCCCN2)C2CCCCC2)CC1
Solvent: CC#N
Solvent: CO
Product: O=[N+]([O-])[O-]
Temperature: 0 °C

Procedure:
Nitric acid 65% (0.75 ml) is added to a Perhexiline solution (3.02 g, 10.9 mmole) in acetonitrile and methanol (10 ml), cooled at 0° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[O:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([N:32]2[CH2:37][CH2:36][CH:35]([O:38][C:39](OC3C=CC([N+]([O-])=O)=CC=3)=[O:40])[CH2:34][CH2:33]2)=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[O:16]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([N:32]2[CH2:33][CH2:34][CH:35]([O:38][C:39]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[O:40])[CH2:36][CH2:37]2)=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reactant: NCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCO)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
A solution of triethylamine (65.5 mL, 0.47 mol) and 6-aminohexanol (13.2 g, 0.11 mol) in 300 mL of methylene chloride was added dropwise under nitrogen to a solution of the carbonate (45.0 g, 0.09 mol) produced in Example 3 in 500 mL of methylene chloride at room temperature. After the addition the solution was stirred at room temperature overnight. The reaction was extracted one time with 1N HCl and then multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 47.0 g of an off-white solid. Recrystallization from methylene chloride-diisopropyl ether gave 35.5 g (83%) of the title compound as a white crystalline solid, mp 69-72° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:31]([CH3:33])[CH3:32])=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.[H-].[Na+].Cl.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:31]([CH3:33])[CH3:32])=[CH:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=3)=[O:19])=[CH:15][CH:16]=2)[N:4]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[N:3]=1
Reactant: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2c(N)n[nH]c2n1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2c(N)nn(CCN3CCOCC3)c2n1
Yield: 9.7 %

Procedure:
In analogy to GP 5, reaction of 1-[4-(3-Amino-6-isopropyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (136 mg, 0.3 mmol, 1 eq.) with 39.3 mg NaH, 167 mg 4-(2-Chloro-ethyl)-morpholine hydrochloride (0.9 mmol, 3 eq.), 0.12 mL triethylamine (0.9 mmol, 3 eq.) in 3+3 mL DMF yielded after HPLC purification 16.6 mg of the desired product (10% yield).
Reaction SMILES: C1(SCC(OCC)=O)C=CC=CC=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC[O-].[Na+]>[CH2:21]([S:28][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: SCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: CCOC(=O)CSc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)CSCc1ccccc1

Procedure:
The procedure is as in Example 2 for the preparation of ethyl (phenylthio)acetate starting with ethyl bromoacetate (16.7 g), a 2M ethanolic solution of sodium ethylate (50 cc) and benzylmercaptan (11.7 cc). Ethyl (benzylthio)acetate (19.4 g) is thereby obtained, and is used in the crude state in the subsequent phases.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[S:3])[NH2:2].I[CH3:20]>C1COCC1>[CH:15]1([C:5]2[C:4]([C:1](=[NH:2])[S:3][CH3:20])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:14])[CH:6]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1cc(C(N)=S)c(C2CCC2)cc1C
Reactant: CI
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=N)SC)c(C2CCC2)cc1C
Reaction time: 7 h
Yield: 89 %

Procedure:
To a round-bottom flask was added methyl 5-carbamothioyl-4-cyclobutyl-2-methylbenzoate (compound 152.5, 861 mg, 3.27 mmol) in THF (10 mL). Iodomethane (912 mg, 6.42 mmol) was added dropwise and the reaction mixture was stiffed at room temperature for 7 hours. The reaction mixture was concentrated in vacuo and purified by SiO2 flash chromatography (ethyl acetate to ethyl acetate/methanol=95/5) to afford methyl 4-cyclobutyl-5-(imino(methylthio)methyl)-2-methylbenzoate as a yellowish oil (807 mg, 89% yield). m/z (ES+) 278 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 7.67 (s, 1H), 7.40 (s, 1H), 3.88-3.71 (m, 4H), 2.57 (s, 3H), 2.44 (s, 3H), 2.22-2.19 (m, 2H), 2.12 (m, 2H), 1.98-1.86 (m, 1H), 1.82-1.70 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[N-:18]=[C:19]=[O:20].[K+].FC(F)(F)C(O)=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:19](=[O:20])[NH2:18])=[CH:9][CH:8]=1
Reactant: OCc1ccc(OCc2cccc(F)c2)cc1
Reactant: [N-]=C=O
Agent: [K+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCc1ccc(OCc2cccc(F)c2)cc1

Procedure:
In analogy to the procedure described in Example 24 b), the reaction of [4-(3-fluoro-benzyloxy)-phenyl]-methanol with potassium isocyanate and trifluoroacetic acid in benzene yielded the carbamic acid 4-(3-fluoro-benzyloxy)-benzyl ester as a white solid; MS: m/e=293 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][OH:16]>>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: OCc1cc(F)cc(F)c1
Product: O=[N+]([O-])c1cnccc1OCc1cc(F)cc(F)c1
Yield: 78 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 3,5-difluorobenzyl alcohol, the titled compound was obtained as a yellow solid. (Yield: 78.0%)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Cl)[N:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>COCCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([CH:18]3[CH2:19][CH2:20][CH2:21][O:17]3)=[O:23])[CH2:25][CH2:26]2)[N:3]=1
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: COCCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
Sixty grams (0.25 tool) of 4-amino-2-chloro-6,7-dimethoxyquinazoline and 56.8 grams (0.308 tool) of N-(2-tetrahydrofuroyl)piperazine were added to a stirred solution of 500 grams of Methyl Cellosolve® (ethylene glycol monomethyl ether) and 37.9 grams of tricthylaminc. The reaction mixture was heated to and maintained at a temperature of between 115° C. to 120° C. for 8 hours, and then allowed to cool to room temperature overnight. The Methyl Cellosolve® was removed by vacuum distillation, the residue was taken up in 1920 ml of 45° C. distilled water, and the temperature of the solution was readjusted to 45° C. The pH was then adjusted to pH 2.5 with concentrated hydrochloric acid and the solution mixed for 1 hour. The solution was then filtered and the pH adjusted to pH 8.3 with filtered ammonia water (28%). After heating for one hour at 65° C., the solution was cooled to 15° C. and held at a temperature of between 15°C. -20° C. for 16 hours. The resulting crystalline product was filtered, washed with cold water (15° C.) and dried in vacuo at 65° C. to yield 84 grams (87%) of anhydrous base.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:23]([OH:25])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.C[N:27]([CH3:30])C=O>>[NH2:27][C@H:30]([C:16]([NH:18][C@H:19]([C:23]([OH:25])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CN(C)C=O
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
9-Fluorenylmethyloxycarbonyl-L-valine esterified to p-alkoxybenzyl alcohol derivitized 2% crosslinked polystyrene (0.25 gm, 0.13 mmol valine) was placed in a solid phase peptide synthesis vessel. Dimethylformamide (5 mL) was added and the slurry was shaken for 30 min. The dimethylformamide was removed and the swollen resin treated twice with 10% piperidine in dimethylformamide (5 mL for 5 min followed by 5 mL for 15 min) to remove the 9-fluorenylmethyloxycarbonyl protecting group. The resin was washed with dimethylformamide (4×5 mL) and reacted with 9-fluorenylmethyloxycarbonyl-L-leucine-N-carboxyanhydride (145 mg, 0.38 mmol) in dimethylformamide (6 mL) for 45 min. The fluorenylmethyloxycarbonyl protecting group was removed as above and the resin washed with dimethylformamide (3×5 mL) and methylene chloride (3×5 mL). The resulting dipeptide was cleaved from the resin by treatment with methylene chloride/trifluoroacetic acid (6 mL, 1/1) for 45 min. The solution was removed and the resin washed with methylene chloride (3×5 mL) and methanol (2×5 mL). The combined solution and washes were evaporated in vacuo to a semi-solid, which was taken up in distilled water and filtered. The aqueous solution was freeze-dried, the resulting solid triturated with ether(3×) to remove resin related contaminants, and dried under reduced pressure to give L-leucyl-L-valine in >90% yield. The identity of the dipeptide was confirmed by HPLC analysis (flow rate=1.5 mL/min, detection at 215 nm, 30% methanol in 0.5 M perchloric acid) by co-elution with a known standard (Retn. time 8.49 minutes). The purity was determined to be >97%, with all contaminants being traceable to the resin. No D-leucyl-L-valine (Retn. time 32 minutes) could be detected (detection limits <0.1%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][CH:29]([NH:32][S:33]([C:36]1[S:37][C:38]([Cl:42])=[C:39]([NH2:41])[CH:40]=1)(=[O:35])=[O:34])[CH2:30][OH:31]>>[Cl:42][C:38]1[S:37][C:36]([S:33](=[O:35])(=[O:34])[NH:32][CH:29]([CH2:28][OH:27])[CH2:30][OH:31])=[CH:40][C:39]=1[NH:41][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cc(S(=O)(=O)NC(CO)CO)sc1Cl
Product: O=C(Nc1cc(S(=O)(=O)NC(CO)CO)sc1Cl)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide (example B.4) according to general procedure II. Yellow solid. MS (ISP) 642.2 [(M−H)−]; mp 225° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C[N:8]([CH:10]=[O:11])C.C(OC(N[C@H](CCCCNC(OC(C)(C)C)=O)C(NCCC(O[C:29]1[CH:30]=[CH:31][C:32]2[C:38]3[C:39]([O:47][CH3:48])=[C:40]([O:45][CH3:46])[C:41]([O:43][CH3:44])=[CH:42][C:37]=3[CH2:36][CH2:35][C@H:34]([NH:49][C:50](=[O:52])[CH3:51])[C:33]=2[CH:53]=1)=O)=O)=O)(C)(C)C>ClCCl>[C:10]([C:29]1[CH:30]=[CH:31][C:32]2[C:38]3[C:39]([O:47][CH3:48])=[C:40]([O:45][CH3:46])[C:41]([O:43][CH3:44])=[CH:42][C:37]=3[CH2:36][CH2:35][C@H:34]([NH:49][C:50](=[O:52])[CH3:51])[C:33]=2[CH:53]=1)(=[O:11])[NH2:8]
Reactant: CN(C)C=O
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1OC)-c1ccc(C(N)=O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
Oxalyl chloride (0.44 g; 3.4 mmol) and DMF (50 μl) were added to a suspension of N-[(5S)-3-carboxy-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (1) under argon atmosphere (1.15 g; 3 mmol) in dichloromethane (10 ml). The mixture was stirred at ambient temperature for 2 hours, evaporated to dryness and redissolved in dichloromethane (20 ml). The solution was cooled at −78° C. and ammonia gas was allowed to bubble through the solution for 5 minutes. The mixture was allowed to warm up and further stirred at ambient temperature for 15 minutes. After evaporation to dryness, the residue was taken up in aqueous sodium hydrogen carbonate/ethyl acetate. The organic phase was separated, evaporated and purified by flash chromatography eluting with ethyl acetate/methanol (95/5) to give N-[(5S)-3-carbamoyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:33][CH:34]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:38]1[CH2:39][CH2:40][N:35]([C:32]2[N:33]=[CH:34][C:29]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(N3CCOCC3)nc2)c2ccc(C=O)cc21
Temperature: 125 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A mixture 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (25 mg, 0.62 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine (22 mg, 0.75 mmol), PdCl2(PPh3)2 (4 mg, 0.006 mmol) and 2M Na2CO3 (0.31 mL, 0.62 mmol) in DME/H2O/EtOH (2.8 mL/0.8 mL/0.4 mL) was sealed and heated with stirring under microwave irradiation at 125° C. for 4 h. Solvent was removed and the crude product was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to yield a bright yellow foam (266 mg, 97%). 1H NMR (400 MHz, CD3OD) δ 10.02 (s, 1H), 8.60 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 7.99 (dd, J=8.9, 2.5 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.64 (dd, J=8.7, 1.1 Hz, 1H), 6.80 (d, J=9.1 Hz, 1H), 5.78 (s, 2H), 3.76 (t, J=4.7 Hz, 4H), 3.61 (t, J=8.0 Hz, 2H), 3.49 (t, J=5.1 Hz, 4H), 0.84 (t, J=8.0 Hz, 2H), −0.12 (s, 9H); MS ESI 439.3 [M+H]+, calcd for [C23H30N4O3Si+H]+ 439.21.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([O:15]CC)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:18](=[O:21])([O-])[O-].[K+].[K+].[OH2:24]>C(O)C>[O:24]1[CH:3]=[CH:2][C:1]([C:18]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:2][CH:3]=2)=[O:21])=[CH:10]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1cccc2ccccc12
Reactant: O
Agent: [K+]
Solvent: CCO
Product: O=C(O)COc1ccc(C(=O)c2ccoc2)c2ccccc12

Procedure:
15 g of the ester obtained according to (a) are dissolved in 300 ml ethanol; after addition of 7.6 g potassium carbonate in solution in 25 ml water, the mixture is refluxed for 17 hours and the alcohol removed under reduced pressure. The residue is purified by dissolution in water; the final product is extracted from the aqueous phase after acidification. 12 g of the acid which, after recrystallisation from dichloroethane, melts at 177° C. are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.Cl[CH2:23][C:24]1[N:34]=[CH:33][CH:32]=[CH:31][C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]2[N:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:20]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(O)cc1
Reactant: CCOC(=O)c1cccnc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
To a mixture of 4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenol (2.70 g), ethyl 2-chloromethylnicotinate (1.74 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 0.42 g) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 2-[[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenoxy]methyl]nicotinate as a colorless oil (2.45 g, 63%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[N:22][C:23]=3[CH3:27])[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:28]1([CH2:34]C=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:27][C:23]1[N:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[CH:25]=[CH:26][C:17]([NH:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:1][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:9][CH2:10]1)=[N:18]2
Reactant: Cc1nccc2nc(NCCN3CCN(Cc4ccccc4)CC3)ccc12
Reactant: O=CCc1ccccc1
Product: Cc1nccc2nc(NCCN3CCN(CCc4ccccc4)CC3)ccc12

Procedure:
Compound 10 was prepared as described for compound 9, using phenylacetaldehyde in place of benzaldehyde. 1H NMR (CD3OD, 400 MHz) δ 8.20 (d, 1H, J=5.5 Hz), 8.10 (d, 1H, J=7.5 Hz), 7.10-7.40 (m, 6H), 6.85 (d, 1H, J=7.5 Hz), 3.65-3.75 (m, 2H), 2.50-2.90 (m, 17H). LCMS (EI) m/z 376 (M+1).