Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8])[CH:2]=[CH2:3].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(C=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1cc(C=O)ccc1OC

Procedure:
Two equivalents of potassium carbonate are added slowly with stirring to a solution of 4-hydroxybenzaldehyde in acetone. A solution of allyl bromide (1.1 equivalent) in acetone is added and the mixture is refluxed for two hours, filtered to remove inorganic salts and volatiles stripped under reduced pressure. The resulting 4-allyloxybenzaldehyde is then heated for six hours at 220° C. to yield the rearrangement product, 3-allyl-4-hydroxybenzaldehyde. One equivalent of 3-allyl-4-hydroxybenzaldehyde is dissolved in acetone and two equivalents of potassium carbonate are added slowly with stirring followed by a solution of 1.1 equivalents of methyl iodide in acetone. This mixture is refluxed for several hours, filtered and stripped to yield 3-allyl-4-methoxybenzaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](Cl)=[O:24])=[CH:20][CH:21]=2)[C:16]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:15]1)(=O)C.O>N1C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([C:23]([NH:7][C:6]4[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)=[O:24])[CH:18]=3)[NH:14][N:15]=2)=[CH:31][CH:30]=1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution containing 3-nitroaniline (96 mg, 0.694 mmol) in pyridine (5 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (200 mg, 0.631 mmol). The reaction mixture was allowed to stir for 18 hours at ambient temperature. Water (30 mL) was then added and the resulting precipitate was filtered and dried to afford the title compound. This precipitate was taken on directly to the next step for deprotection.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]2=[CH:14][CH:15]=1)([O-:3])=[O:2].[Cl:16][C:17]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:18]=1[CH2:19][CH2:20][NH2:21].CN(C=O)C>C(Cl)Cl>[NH2:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=1[C:8]([NH:21][CH2:20][CH2:19][C:18]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:17]=1[Cl:16])=[O:10]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1cc([N+](=O)[O-])ccc1C(=O)NCCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a stirred solution of 4-nitro-isatoic anhydride (10.0 g, 0.048 mol) in CH2Cl2 (100 mL) was added 2,4-dichlorophenethylamine (10.08 g, 0.053 mol) followed by DMF (10 mL). The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was then dissolved in 1.0 L CH2Cl2 and washed with 1.0 M NaOH. The combined organic layers were concentrated under reduced pressure and purified by silica gel flash chromatography (0-100% EtOAc/hexanes eluent) to give the product (16.5 g, 97% yield) as a yellow solid. HPLC retention time: 3.04 min; Method A; LRMS (ESI) m/z 354 (M+1).
Reaction SMILES: Br.Br.[NH2:3][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[C:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:5]1.C(N(CC)CC)C.[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH:24]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:13](=[O:14])[CH2:12][N:9]1[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[C:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:5][CH:4]([NH:3][C:51]([NH:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:52])[C:10]1=[O:11])([CH3:26])[CH3:25]
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Reactant: O=C=Nc1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3ccccc3)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
According to process A, a solution of 175 mg of 2-(3-amino-2-oxo-5-pyridin-3-yl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide dihydrobromide (0.283 mmol), prepared as in Intermediate 31, in 3 mL of methylene chloride was treated with 98.5 μL of triethylamine (0.706 mmol) and 33.8 μL of phenyl isocyanate (0.311 mmol). After stirring under nitrogen for 20 min., the reaction mixture was diluted with methylene chloride and washed with aqueous potassium carbonate (5% w/v). The phases were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue was triturated with 5 mL of acetonitrile and the resulting slurry was heated to reflux under nitrogen. After stirring for 20 min., the slurry was cooled to ambient temperature, filtered and washed with cold acetonitrile. The product was combined again with 3 mL of acetonitrile and brought to reflux. After stirring for 30 min., the slurry was cooled to ambient temperature, filtered and washed with cold acetonitrile. The product was dried under high vacuum to provide 95 mg of the title compound as a white crystalline solid. 1H NMR (300 MHz, d6-DMSO) -- =9.06 (b, 1H), 8.68 (m, 2H), 7.93 (d, 1H, J=8.0), 7.72 (m, 1H), 7.53 (m, 3H), 7.37 (m, 4H), 7.26 (m, 4H), 7.07 (m, 2H), 6.94 (m, 1H), 5.31 (d, 1H, J=8.3), 4.72 (m, 1H), 4.29 (d, 1H, J=16.4), 4.16 (d, 1H, J=16.4), 3.81 (s, 3H), 0.96 (d, 6H, J=6.1); MS (ESI) [M+H]+ =577.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[OH-].[NH4+:13]>[O-]S([O-])(=O)=O.[Cu+2]>[CH3:11][S:8]([C:6]1[CH:7]=[C:2]([NH2:13])[CH:3]=[N:4][CH:5]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1cncc(Br)c1
Reactant: [NH4+]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [OH-]
Product: CS(=O)(=O)c1cncc(N)c1
Temperature: 25 °C
Yield: 31 %

Procedure:
A mixture of 3-bromo-5-(methylsulfonyl)pyridine (0.50 g, 2.1 mmol) and CuSO4.(H2O)5 (53 mg, 0.21 mmol) in concentrated ammonium hydroxide (3 mL) was heated in a sealed tube at 170° C. for 16 hours. The reaction was cooled to room temperature and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated to give a brown solid. The solid was purified by column chromatography on silica gel using 0-5% MeOH in dichloromethane to give 5-(methylsulfonyl)pyridin-3-amine (0.11 g, 31% yield) as a tan solid. LC/MS: m/z 173.3 (M+H)+ at 0.21 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[NH2:2][NH2:3].O.NN.C[O:8][C:9]([C@@H:11]1[CH:26]=[C:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][C:18]=3[CH3:28])[N:13]([CH3:14])[CH2:12]1)=O>C(O)CC>[CH3:28][C:18]1[NH:19][C:20]2[C:27]3[C:17]=1[CH2:16][C@@H:15]1[C:25]([C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:26][C@H:11]([C:9]([NH:2][NH2:3])=[O:8])[CH2:12][N:13]1[CH3:14]
Reactant: NN
Reactant: COC(=O)[C@@H]1C=C2c3cccc4[nH]c(C)c(c34)C[C@H]2N(C)C1
Agent: Cl
Solvent: O
Solvent: CCCO
Product: Cc1[nH]c2cccc3c2c1C[C@@H]1C3=C[C@H](C(=O)NN)CN1C
Reaction time: 15 h

Procedure:
15.9 g hydrazine hydrochloride and 18.4 ml hydrazine hydrate are added under stirring to 22.5 g of the product of step (a) in 20 ml n-propanol and the obtained reaction mixture is heated under reflux for 5 hours. The mixture is concentrated, treated with 500 ml H2O, filtered and washed with H2O (fraction A). The mother liquor is extracted with ethyl acetate and the extract evaporated. To the residue (7.5 g) are added 100 ml n-propanol and 20 ml triethylamine and the mixture is stirred and heated at reflux. The reaction is followed by thin layer chromatography. After approximately 15 hours when all of the β-product is converted into the 8α-product, H2O is added and the mixture is filtered. The filter cake is combined with fraction A and recrystallized twice from hot ethanol to afford the heading compound, m.p. 235°-240°, which is the pure α-isomer by NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])[CH:5]=[CH:6][C:7]=1[S:16]([Cl:15])(=[O:18])=[O:17]
Reactant: O=C(Nc1cccc(Br)c1)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: O=C(Nc1ccc(S(=O)(=O)Cl)c(Br)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
The crude N-(3-bromophenyl)-2,2,2-trifluoroacetamide was cooled to 0° C., then chlorosulfonic acid was added dropwise at 0° C. over 10 min. The r×n mix was stirred at 0° C. to rt overnight. LC/MS monitored the r×n. The r×n mix poured into ice-H2O (100 g) to quench the r×n. The sticky gum was washed with H2O and dried in vacuum to give the crude 2-bromo-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=O)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[CH3:30][O:31][NH2:32]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[N:32][O:31][CH3:30])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2=O)C(=O)Nc2cnccn2)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCCC1CC(C(=O)Nc1cnccn1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 32, 99.5 mg, 0.23 mmol) in pyridine (0.69 mL) and methanol (0.69 mL) at 25° C. was treated with methoxyamine hydrochloride (30 mg, 0.35 mmol). The reaction mixture was heated under reflux for 12 h. At this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (75 mL) and was washed with a 1N aqueous sodium hydroxide solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-methoxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (92.7 mg, 87.2%) as a white wax: mp 74-76° C.; FAB-HRMS m/e calcd for C20H23ClN4O4S (M+Na)+ 473.1021. found 473.1024.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1.[CH2:29](O)[CH3:30]>>[CH3:28][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH2:29][CH3:30])[S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CN(C)CCCCOc1ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCO
Product: CCN(c1ccc(OCCCCN(C)C)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 14.1, reaction of N-[4-(4-Dimethylamino-butoxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide 69-2511 with ethanol yielded N-[4-(4-Dimethylamino-butoxy)-phenyl]-N-ethyl-4-trifluoromethyl-benzenesulfonamide, MS: 445 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.ClC1C=CC=CC=1Cl>[CH3:27][O:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:28][CH3:29])[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[C:3]([C:12](=[O:14])[CH3:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(=O)c1cc2ccccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4cc3C(C)=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
1-(3-Hydroxynaphthalen-2-yl)-ethanone (249 mg), 4-chloro-6,7-dimethoxyquinoline (100 mg), and 4-(N,N-dimethylamino)-pyridine (164 mg) were dissolved in 1,2-dichlorobenzene (5 ml) to prepare a solution which was then stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using hexane-acetone to give the title compound (27 mg, yield 16%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]([Si:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:20]2[CH2:19][CH:18]([O:17][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC1CN(C(=O)Cc2ccc(Br)cc2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
To 4-bromophenyl acetylchloride (300 mg, 1.28 mmol) in CH2Cl2 (5 mL) was added 3-(tert-Butyl-diphenyl-silanyloxy)-azetidine (399 mg, 1.28 mmol), DIPEA (670 μL, 3.85 mmol) and the reaction stirred at RT for 2 h. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 80% EtOAc/isohexane to obtain 2-(4-bromo-phenyl)-1-[3-(tert-butyl-diphenyl-silanyloxy)-azetidin-1-yl]-ethanone as a colourless glass (632 mg, 97%).
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH2:19][CH2:20][CH2:21][N:22]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CN(CCCCN1C(=O)c2ccccc2C1=O)CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(CCCCN)CCCCN
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
144 mg (0.33 mmol) of 2.2′-[(methylimino)dibutane-4,1-diyl]bis(1H-isoindole-1.3(2H)-dione) is solubilized in 2 ml of ethanol and 65 μl (0.73 mmol; 2.2 equivalents) of 35% hydrazine hydrate are added to the reaction mixture which is maintained under stirring at 150° C. under microwaves for 30 minutes. The solvents are evaporated off under reduced pressure and the excess hydrazine hydrate is eliminated by co-evaporation with 4 times 15 ml of ethanol. 100 ml of ethanol is added to the reaction mixture which is acidified to pH 1 with a 1N solution of hydrochloric acid in ethyl ether. The reaction medium is concentrated under reduced pressure, then taken up in 50 ml of ethanol and the white precipitate formed is filtered, washed with 3 times 20 ml of water and eliminated. The filtrate is basified to pH 12 with a 2M solution of soda, then concentrated under reduced pressure and used in the following stage without other purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH3:23])[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[C:32]([C:37]([O:39]C(C)(C)C)=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:26]=3)[C:16]=2[CH:44]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH3:23])[N:17]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]4[C:32]([C:37]([OH:39])=[O:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:29][CH:30]=3)[C:16]=2[CH:44]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc2ccc(NC(=O)OCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NC(=O)OCc3ccccc3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-benzyloxycarbonylamino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:17]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]3[N:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:15]([C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:32](=[O:34])[CH3:33])=[CH:24][CH:23]=3)[N:17]([CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:10]=2[N:11]=1)#[N:16]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)Cn1c(Cc2ccc(N)cc2)cc2cnc(C#N)nc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of 6-(4-amino-benzyl)-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.3 mmol) in CH2Cl2 (4 mL), triethylamine(0.36 mmol) and acetyl chloride (0.36 mmol) is added at 0° C. The reaction mixture stirred at room temperature for 1 day. The mixture is quenched with saturated ammonium chloride and extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to crude product. Purification of the residue by silica gel column chromatography affords title compound in 84% yield.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]([OH:18])=[O:17].[CH3:19]O>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]([O:18][CH3:19])=[O:17]
Reactant: CO
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 98 %

Procedure:
Concentrated sulfuric acid (1 mL) was added to a suspension of 5-bromo-1H-indazole-3-carboxylic acid (CXV) (1.30 g, 5.39 mmol) in dry MeOH (50 mL) and heated to reflux for 4 h under argon. The solution was cooled to room temperature and the MeOH was evaporated under vacuum. The residue was dissolved in EtOAc and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated to afford methyl 5-bromo-1H-indazole-3-carboxylate (CXVI) as a white solid (1.35 g, 5.29 mmol, 98% yield). 1H NMR (DMSO-d6) δ ppm 14.13 (s, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.67 (d, J=7.2 Hz, 1H), 7.59 (dd, J=7.2, 1.2 Hz, 1H), 3.92 (s, 3H); ESIMS found for C9H7BrN2O2 m/z 256.0 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([NH2:16])=[N:13][C:12]=2[CH3:17])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:18](N1C=CN=C1)([N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)=[O:19]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[S:15][C:14]([NH:16][C:18]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)=[O:19])=[N:13][C:12]=2[CH3:17])[CH:8]=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(N)sc1-c1ccnc(C(C)(C)C)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(C(C)(C)C)c1
Reaction time: 4 h
Yield: 91.1 %

Procedure:
A mixture of 5-(2-tert-butyl-pyridin-4-yl)-4-methyl-thiazol-2-ylamine (Step 1.2) (1 g, 4.05 mmol) and 1,1′-carbonyldiimidazole (0.984 g, 6.07 mmol, 1.5 eq) in DCM (50 mL) is stirred for 4 h at reflux and allowed to cool. The resulting precipitate is collected by filtration to provide 1.26 g of the title compound as white solid: ESI-MS: 340.2 [M−H]−; tR=2.85 min (System 1).
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([Cl:15])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3].Cl.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH2:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH:24][C:2]([C:4]2[C:5]([Cl:15])=[C:6]([CH:11]=[CH:12][C:13]=2[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Reactant: NOCc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)c(C(=O)NOCc2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 122.2 %

Procedure:
10.70 g (0.04 mol) of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate in 50 ml of methylene chloride were slowly added dropwise at approximatley 30° C. to a solution of 7.76 g (0.04 mol) of 4-chlorobenzyloxyamine hydrochloride and 4.05 g (0.04 mol) of triethylamine in 200 ml of methylene chloride. After the reaction mixture had been stirred for 12 hours at room temperature, it was washed with dilute phosphoric acid, dried and concentrated. After the residue had been extracted with stirring with diethyl ether, 19.00 g of methyl 3-(4-chlorobenzyloxyaminocarbonyl)-2,4-dichlorobenzoate acid were obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1.N1C=CC=CC=1.Cl>>[F:1][C:2]1[C:7]([CH:8]=[CH:15][C:16]([OH:18])=[O:17])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
20 g (42 mmol) of pentafluoro-benzaldehyde, 21.23 g (2 eq.) of malonic acid, and 0.85 g (0.1 eq.) of piperidine were added to 24 g (3 eq.) of pyridine and stirred at room temperature for about 1 hour. After heating it to 80° C., the mixture was stirred for 12 hours. After the reaction, the resulting solution was cooled down to room temperature and was slowly added with 1M HCl until it was titrated to about pH 4. The resulting powder was filtered and washed with water, and then dried in a vacuum oven. (Yield: 13%)
Reaction SMILES: CN1C(=O)CCC1.[CH2:8]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:18][C:17]([NH2:27])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[N:39]=2)=[CH:31][CH:30]=1>CCOC(C)=O>[CH2:8]([N:15]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:18][C:17]([NH:27][C:37]([C:38]([NH:39][C:35](=[O:36])[C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)([CH3:41])[CH3:40])=[O:42])=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Reactant: CC1(C)N=C(c2ccc(F)cc2)OC1=O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccc(F)cc2)n(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a 5 mL Biotage microwave vial were added NMP (1 ml), 1-benzyl-5-(4-fluorophenyl)-1H-1,2,4-triazol-3-amine (150 mg, 0.559 mmol), 2-(4-fluorophenyl)-4,4-dimethyloxazol-5(4H)-one (116 mg, 0.559 mmol,), under N2. Then it was placed in 100° C. oil bath and stirred for 2.5 h. It was cooled to r.t. and diluted with 2 ml of EtOAc. It was stirred for 10 min that resulted precipitation of the desired product. Then 2 mL of water was added and it was stirred for additional 10 min followed by addition of a couple drops of heptane. The precipitates were collected by filtration and dried under vacuum overnight. This afforded the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 1.50 (s, 6H) 5.40 (s, 2H) 7.08-7.14 (m, 2H) 7.24-7.39 (m, 7H) 7.63-7.71 (m, 2H) 7.96-8.04 (m, 2H) 8.33 (s, 1H) 10.17 (s, 1H). MS (m/z) 476.2 M(+1), tR=1.36, Method A.