Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:21][CH2:22][C:23]1([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[Cl:41])[O:27][CH:26]([CH2:28]OS(C)(=O)=O)[CH2:25][O:24]1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:21][CH2:22][C:23]1([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=2[Cl:41])[O:27][CH:26]([CH2:28][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH2:25][O:24]1
Reactant: CS(=O)(=O)OCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1
Reactant: Oc1ccc(N2CCN(Cc3ccccn3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(C2(CBr)OCC(COc3ccc(N4CCN(Cc5ccccn5)CC4)cc3)O2)c(Cl)c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
A mixture of 3.77 g (14 mmol) of 4-(4-hydroxyphenyl)-1(pyrid-2-ylmethyl)piperazine, 200 ml of toluene, 5.88 g (14 mmol) of 2-bromomethyl-2-(2,4-dichlorophenyl)-4-methanesulfonyloxymethyl-1,3-dioxolane, 0.80 g of tetrabutylammonium bromide and 27 ml of 50% strength sodium hydroxide solution was stirred vigorously for 3 hours at 65° C. The phases were subsequently separated at room temperature. The toluene solution was shaken three times with water, dried, filtered and evaporated in vacuo. The residue remaining (8.8 g) was chromatographed on a silica gel S/CH2Cl2 column (diameter 2.6 cm, height 28.0 cm) with elution using CH2Cl2 and CH2Cl2 /C2 5OH mixtures (to a maximum C2H5OH content of 4% by volume). After elution of a preliminary fraction (1.45 g), the fractions which were unary according to TLC were combined and evaporated in vacuo. 6.02 g (=72.4% yield) of 2-bromomethyl-2-(2,4-dichlorophenyl)-4-[4-(4-(pyrid-2-ylmethyl)piperazin-1-yl)phenoxymethyl]-1,3-dioxolane (cis/trans mixture) were obtained as a highly viscous oil, analysis: C27H28BrCl2N3O3 (MW 593.38) calc. C 54.65, H 4.76, Br 13.47, Cl 11.95, N 7.08; found C 53.5, H 4.9, Br 13.1, Cl 13.2, N 6.5%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[CH:12][NH:11][C:10]=2[CH:14]=1)=O)C.O.[NH2:16][NH2:17]>C(O)C>[NH:11]1[C:10]2[CH:14]=[C:6]([C:4]([NH:16][NH2:17])=[O:3])[CH:7]=[CH:8][C:9]=2[N:13]=[CH:12]1
Reactant: NN
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2nc[nH]c2c1
Yield: 88 %

Procedure:
30 g of 1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (0.16 mol) and 150 mL anhydrous ethyl alcohol were added to a three-necked bottle, to which 50 mL of 80% hydrazine hydrate was added. After refluxing for 4 h, the ethyl alcohol was evaporated under reduced pressure and water was added to the residual solution to isolate a solid. After sucking filtration and drying, 24.9 g solid was obtained. Yield: 88%. MS: 177 (M+1).
Reaction SMILES: C[O-].[Na+].[CH:4]1([NH:7][C:8](=[O:21])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([NH:16][C:17](=[O:20])[CH2:18][SH:19])[CH:10]=2)[CH2:6][CH2:5]1.C1(S(O[CH:32]=[C:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[C:34]#[N:35])(=O)=O)C=CC=CC=1>CO>[NH2:35][C:34]1[C:33]([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)=[CH:32][S:19][C:18]=1[C:17]([NH:16][C:11]1[CH:10]=[C:9]([C:8](=[O:21])[NH:7][CH:4]2[CH2:6][CH2:5]2)[CH:14]=[CH:13][C:12]=1[CH3:15])=[O:20]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)CS
Reactant: N#CC(=COS(=O)(=O)c1ccccc1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2ccc(Cl)cc2)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To MeOH (4 mL) at rt was added a 25% (w/w) solution of NaOMe in MeOH followed by addition of N-cyclopropyl-3-(2-mercaptoacetamido)-4-methylbenzamide a (200 mg, 10.8 mmol). After stirring at rt for 15 min, 200 mg (10.6 mmol) of 2-(4-chlorophenyl)-2-cyanovinyl benzenesulfonate (prepared as described in J. Med. Chem., 6(47):1448 (2004)) was added and the resulting solution was warmed to 60° C. for 2 h then allowed to cool to rt and stir for an additional 15 h. The mixture was concentrated under vacuum to remove the MeOH then water (20 mL) was added and the solution was extracted with EtOAc (200 mL). The organic extract was washed with water, brine, then dried over anhyd Na2SO4, filtered, and concentrated under vacuum to afford 300 mg of an orange solid as the crude product. This material was purified by reverse-phase preparative HPLC to afford 50 mg of a light yellow solid as the title compound (Example 209). HPLC Ret time=3.57 min. LCMS [M+H]+ 426.17.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.COC(C1C=NC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2)=CN=1)=O>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:15]2[C:14]([CH2:13][NH:12][C:9]3[N:8]=[N:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=3)=[C:18]([CH3:19])[O:17][N:16]=2)=[N:21][CH:22]=1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(Cl)cn3)noc2C)nn1
Agent: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: Cc1onc(-c2ccc(Cl)cn2)c1CNc1ccc(C(=O)O)nn1
Yield: 91 %

Procedure:
As described for example 112a, 6-{[3-(5-chloro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (405 mg, 1.1 mmol) was converted, instead of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester, to the title compound (346 mg, 92%) which was obtained as an off white solid. MS: m/e=343.9 [M−H]−.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:50]=[CH:49][C:35]5[N:36]=[C:37]([S:39][CH2:40][C:41]6[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=6)[NH:38][C:34]=5[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:60])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:50]=[CH:49][C:35]5[N:36]=[C:37]([S:39]([CH2:40][C:41]6[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=6)=[O:60])[NH:38][C:34]=5[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4nc(SCc5cncn5CCC)[nH]c4c2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4nc(S(=O)Cc5cncn5CCC)[nH]c4c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-[[(1-propylimidazol-5-yl)methyl]sulfanyl]benzimidazol-5-yl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.64 g) was dissolved in methylene chloride (19.2 ml), and a solution of metachloroperbenzoic acid (0.27 g) in methylene chloride (12.8 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and to the mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was allowed to be warmed to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-[[(1-propylimidazol-5-yl)methyl]sulfinyl]benzimidazol-5-yl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 313) (0.21 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:27]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:29]([C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([F:25])[C:27]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:31]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:23][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10]
Reactant: COC(=O)CCCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCC(=O)OC)ccc(C(C)=O)c1O
Yield: 90.4 %

Procedure:
A mixture of 5.0 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.4 g of methyl 6-bromohexanoate and 5.4 g of anhydrous potassium carbonate in 50 ml of anhydrous dimethylformamide was stirred and heated at 75° for 10 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on 125 g of silica gel. Elution with 25% ethyl acetate-hexane gave 7.5 g (90% yield) of 6-(4-acetyl-3-hydroxy-2-propylphenoxy)hexanoic acid methyl ester as an oil.
Reaction SMILES: Cl.[CH:2]12[O:10][CH:6]([CH2:7][NH:8][CH2:9]1)[CH2:5][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CC#N>[CH3:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[CH2:25][N:8]1[CH2:7][CH:6]2[O:10][CH:2]([CH2:3][N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]2)[CH2:9]1
Reactant: CC(C)(C)C(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CN(CC(=O)C(C)(C)C)CC(C1)O2
Temperature: 40 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride (Preparation A; 0.26 g, 1.0 mmol) and K2CO3 (1.45 g, 10.5 mmol) in MeCN (8 mL) was treated with 1-chloropinacolone (0.216 g, 1.6 mmol), and the mixture stirred at 40° C. overnight. The following morning, the temperature was raised to 50° C. for 4 h before the solids were filtered off from the mixture and the filtrate concentrated in vacuo. The crude product was dissolved in DCM and the solution was added to an ion-exchange solid phase extraction plug (10 g CBA (carboxylic acid on silica support)). After 1 h, the plug was washed with DCM (15 mL), after which the product was finally eluted with dichloromethane:MeOH:TEA (90:5:5). The solvents were evaporated to give 0.276 g (85.5%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8](Cl)=[O:9])[S:4][N:3]=1.[NH2:11][CH:12]([CH:15]([CH3:17])[CH3:16])[C:13]#[N:14].C(N(CC)CC)C>ClCCl>[C:13]([CH:12]([NH:11][C:8]([C:5]1[S:4][N:3]=[C:2]([Cl:1])[C:6]=1[Cl:7])=[O:9])[CH:15]([CH3:17])[CH3:16])#[N:14]
Reactant: CC(C)C(N)C#N
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C#N)NC(=O)c1snc(Cl)c1Cl
Reaction time: 4 h
Yield: 55.6 %

Procedure:
A solution of 3,4-dichloro-5-isothiazolecarboxylic acid chloride (2.1 g) in dichloro-methane (5 ml) was added drop by drop to a solution of 2-amino-3-methyl-butyronitrile (1.2 g) and triethylamine (1.5 g) in dichloromethane (10 ml) under ice cooling. After the addition was completed, the temperature was brought to room temperature, and the mixture was stirred for further 4 hours. The reaction mixture was then washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the remaining residue was purified by silica gel column chromatography (eluent: chloroformn) to obtain N-(1-cyano-2-methyl-propyl)-3,4-dichloro-5-isothiazolecarboxamide (1.5 g) (mp 120-121° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[S:23]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24]1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:25]2[CH:26]=[CH:27][S:23][CH:24]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccsc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccsc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 31 h
Yield: 55.4 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) and commercially available 3-thiophenecarboxylic acid (44 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (82 mg) was added, and the admixture was stirred at room temperature for 31 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 41 mg of the title compound (yield: 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[N:17]#[C:18]Br>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)[C:18]([NH2:17])=[N:16][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)ccc1NCC1CCOCC1
Reactant: N#CBr
Solvent: CCO
Product: Nc1nc2cc(Cl)ccc2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-N1-(tetrahydro-pyran-4-ylmethyl)-benzene-1,2-diamine (1.026 g; 4.261 mmol) is dissolved in ethanol (65 mL) and cyanogen bromide (0.903 g; 8.522 mmol) is added. The reaction is stirred at room temperature overnight. After this time the mixture is concentrated in vacuo to afford title compound as a tan solid which was used without further purification. ESI m/z 266 [M+H]+/264 [M−H]−
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=O)([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[CH3:29]>N1C=CC=CC=1>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:11](=[O:13])[CH2:10][N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])=[CH:24][C:23]=1[CH3:29]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(NC(=O)CN(CC(=O)O)CC(=O)O)ccc1Br
Temperature: 100 °C
Yield: 54.9 %

Procedure:
A slurry of 9.56 g of nitrilotriacetic acid in 80 ml of dry pyridine (dried over molecular sieves) is heated to 55° C. Acetic anhydride (7.66 g) is added and the solution is heated to 100° C. After heating for 0.5 hour, the solution is cooled to 55° C. and 9.30 g of 4-bromo-3-methylaniline is added with a 5 ml pyridine rinse. The solution is heated at 100° C. for 1.0 hour. The reaction is cooled and rotary evaporated to a pasty solid which is dissolved in 120 ml of aqueous ammonium hydroxide (30 ml concentrated ammonium hydroxide/90 ml distilled water). The clear brown solution is extracted with two 100 ml portions of methylene chloride and neutralized to pH 3 with 35 ml of concentrated HCl. The white solid is filtered, washed with three 25 ml portions of cold distilled water, and dried under vacuum for 2.75 hours at 60° C. The crude product (12.9 g) is recrystallized from 360 ml of 50% ethanol to give 9.85 g of product, melting point 206.5°-209.0° C.
Reaction SMILES: C[C:2]1C(B2OC(C)(C)C(C)(C)O2)=C(C)[NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:23][C:24]1[C:28]([C:29]2[CH:30]=[C:31]([C:39]3[C:48]([CH3:49])=[CH:47]C=C4C=3C=CC=N4)[C:32]3[NH:36][C:35](=[O:37])[NH:34][C:33]=3[CH:38]=2)=[C:27]([CH3:50])[O:26][N:25]=1>>[CH3:2][N:3]1[C:39]([C:31]2[C:32]3[NH:36][C:35](=[O:37])[NH:34][C:33]=3[CH:38]=[C:29]([C:28]3[C:24]([CH3:23])=[N:25][O:26][C:27]=3[CH3:50])[CH:30]=2)=[C:48]([CH3:49])[CH:47]=[N:4]1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cnn(C)c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12

Procedure:
4-(1,4-dimethyl-1H-pyrazol-5-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one was synthesized using 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and Cs2CO3 in a similar fashion as 6-(3,5-dimethylisoxazol-4-yl)-4-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one (Example 2).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH3:19]O>>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([O:12][CH3:19])=[O:11])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(OCCC(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCOc1ccc(C#N)cc1
Yield: 79 %

Procedure:
A solution of 3.80 g (19.9 mmol) of 3-(4-cyanophenoxy)propanoic acid in 10 ml of methanol is cooled by an ice bath. 3 ml (40 mmol) of thionyl chloride are added drop by drop and then the reaction medium is agitated with solvent reflux for 2 hours. The reaction mixture is then concentrated under reduced pressure and the evaporation residue is purified by silica column chromatography eluting with the help of a dichloromethane/methanol mixture (99/1; v/v). The expected product is obtained in the form of a white solid with a yield of 79%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[N:12]1[C:16]2[C:17](=[O:28])[N:18]([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:19][CH2:20][C:15]=2[C:14]([C:29]([F:32])([F:31])[F:30])=[N:13]1.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][CH2:41][NH2:42].O>C(O)CO>[I:27][C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][C:15]3[C:14]([C:29]([F:32])([F:30])[F:31])=[N:13][N:12]([C:5]4[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=4[C:3]([NH:42][CH2:41][CH2:40][CH:36]4[CH2:37][CH2:38][CH2:39][N:35]4[CH3:34])=[O:2])[C:16]=3[C:17]2=[O:28])=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc(OC)ccc1-n1nc(C(F)(F)F)c2c1C(=O)N(c1ccc(I)cc1)CC2
Reactant: CN1CCCC1CCN
Solvent: OCCO
Solvent: O
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(I)cc2)CC3)c(C(=O)NCCC2CCCN2C)c1
Temperature: 85 °C
Yield: 32 %

Procedure:
The title compound was prepared from 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-benzoic acid methyl ester as obtained in Example 1. The ester (159 mg, 0.278 mmol) was dissolved in ethylene glycol (2 mL) containing 2-(1-methyl-pyrrolidin-2-yl)-ethylamine (400 μL, 2.78 mmol) and heated to 85° C. for 12 h. The reaction was poured into water and extracted with ethyl acetate (3×10 mL). The combined extracts were washed with water (5×10 mL), dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative thin layer chromatography to give 2-[6-(4-iodo-phenyl)-7-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridin-1-yl]-5-methoxy-N-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-benzamide (60 mg, 32%) as a faint yellow solid. MS (ES+) 668.4 (M+H)+(100%). This material (60 mg, 0.089 mmol) was combined with 2-pyridone (17 mg, 0.18 mmol), anhydrous potassium carbonate (49 mg, 0.36 mmol), copper(I) iodide (3.4 mg, 0.018 mmol), 1,10-phenanthroline (3.2 mg, 0.018 mmol), and dry-degassed dimethylsulfoxide (1.0 mL) and heated to 140° C. for 6 h. The mixture was cooled to ambient temperature and diluted with 6N ammonium hydroxide and ethyl acetate. The phases were separated, and the aqueous phase extracted once with ethyl acetate. The combined organic extracts were washed successively with water (2×) and 3N ammonium hydroxide, dried over sodium sulfate, filtered, and evaporated. The residue was purified by preparative HPLC to give the title compound as a colorless solid. MS (ES+) 635.5 (M+H)+(100%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].[I:16]N1C(=O)CCC1=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[I:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CCOC(=O)c1[nH]nc(-c2cccs2)c1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.0 g (4.5 mmol) of 5-thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester was dissolved in 15 ml of dichloromethane and 1.01 g (4.5mmol) of N-iodosuccinimide was added. The resulting solution was stirred at room temperature for 16 h. The solution was washed with aqueous sodium thiosulfate solution. The organic phase was dried with sodium sulfate and filtered. The resulting solution was passed through a short silica gel column, washing with dichloromethane. The solvent was removed under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Na].Br[CH:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=[O:14]>>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][C@H:12]([C:13]([OH:15])=[O:14])[CH:16]([CH3:18])[CH3:17]
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC(C)C(Br)C(=O)O
Agent: [Na]
Product: CC(C)[C@H](Nc1ccc(Cl)cc1F)C(=O)O

Procedure:
Following the procedure of Example 6, 2-fluoro-4-chloroaniline is reacted with m-phenoxy-α-cyanobenzyl α-bromoisovalerate to give the m-phenoxy-α-cyanobenzyl ester of N-(2-fluoro-4-chlorophenyl)valine, MS m/e 452 (M+). Alternatively 2-fluoro-4-chloroaniline is reacted with the sodium salt of α-bromo-isovaleric acid to give N-(2-fluoro-4-chlorophenyl)valine, which is then esterified using m-phenoxy-α-cyanobenzyl bromide or mesylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[Na].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN1CCCC1=O>[Br:1][C:2]1[CH:7]=[C:6]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1
Reactant: Sc1ccccc1
Reactant: CNc1nc(Br)cc(Br)n1
Agent: [Na]
Solvent: CN1CCCC1=O
Product: CNc1nc(Br)cc(Sc2ccccc2)n1
Yield: 65.3 %

Procedure:
0.33 g (0.00124 mol) of (4,6-dibromopyrimidin-2-yl)-methylamine and 0.33 g (0.00248 mol) of thiophenol sodium salt were stirred in 15 ml of 1-methyl-2-pyrrolidone at 120° C. for 4 hrs. The solvent was removed and the residue was partitioned between water and diethyl ether. The ether phase was washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with diethyl ether/hexane 1:3 and subsequently dried in a high vacuum. There was obtained 0.24 g (65%) of (4-bromo-6-phenylsulphanylpyrimidin-2-yl)-methylamine as white crystals; m.p.: 122-124° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([O:9][CH3:10])[C:5](F)=[CH:6][CH:7]=1.[C:12](#[N:16])[CH:13]([CH3:15])[CH3:14].C[Si](C)(C)[N-][Si](C)(C)C.[K+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([CH3:15])([CH3:14])[C:12]#[N:16])=[C:4]([O:9][CH3:10])[C:3]=1[F:11]
Reactant: CC(C)C#N
Reactant: COc1c(F)ccc(Cl)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C(C)(C)C#N)ccc(Cl)c1F
Temperature: 28 °C
Reaction time: 168 h
Yield: 34.9 %

Procedure:
16.78 g (93.97 mmol) of 3-chloro-2,6-difluoro-anisole is dissolved in 800 ml of toluene. After 25.97 g (375.88 mmol) of isobutyronitrile is added, 283.97 ml (140.95 mmol) of a 0.5 molar solution of potassium hexamethyl disilazide in toluene is added in drops. In this case, the temperature increases to 28° C. The batch is stirred for seven days at 60° C. After mixing with water and ethyl acetate, the reaction mixture is brought to a pH of 4 with 1 M sulfuric acid. After being extracted twice with ethyl acetate, the combined organic extracts are washed with water and saturated NaCl solution and dried. After spinning-in and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 7.46 g (21.4%) of the desired compound is obtained.