Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8](=[O:11])[NH:9][CH:10]=1)(=[O:4])=[O:3].C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[Br:17][C:7]1[C:8](=[O:11])[NH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: CS(=O)(=O)c1ccc(=O)[nH]c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1c[nH]c(=O)c(Br)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of Example 288c (0.671 g, 3.87 mmol) and sodium acetate (0.318 g, 3.87 mmol) in acetic acid (8.50 mL) was added bromine (0.201 mL, 3.91 mmol) dropwise as a solution in acetic acid (1.7 mL). The reaction mixture was stirred at 40° C. for 3 hours. Bromine (0.05 mL) was added, and the reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled to ambient temperature and quenched with 100 mL of 10% aqueous sodium thiosulfate. The resulting suspension was filtered, and the solid collected and dried for 16 hours to provide the title compound (0.64 g, 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([OH:15])=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][C:13]([OH:15])=[N:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nnc(O)o2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2nnc(O)o2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a flask, is dissolved 5-(4-nitrophenyl)-1,3,4-oxadiazol-2-ol (4.50 g; 21.72 mmol; 1 eq.) in MeOH (150 ml) under inert atmosphere. Palladium 10% on charcoal (2.31 g; 2.17 mmol; 0.10 eq.) is added and the reaction mixture is stirred 5 minutes at rt. The mixture is then put under atmospheric pressure of hydrogen. The reaction is completed after 2 hours. The mixture is filtrated on celite and rinced with MeOH. The solvents are evaporated under vacuo, affording 5-(4-aminophenyl)-1,3,4-oxadiazol-2-ol as a white powder (2.34 g; 61%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]#N.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[C:13]1[NH:8][C:7]2[C:2](=[N:3][CH:4]=[N:5][CH:6]=2)[N:1]=1
Reactant: COc1ccc(C#N)c(OC)c1
Reactant: Nc1cncnc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc(-c2nc3ncncc3[nH]2)c(OC)c1
Temperature: 120 °C

Procedure:
A mixture of 2 g of 4,5-diamino-pyrimidine, 4 g of 2,4-dimethoxy-benzonitrile, 6 g of p-toluene sulfonic acid hydrate, and 40 ml of benzene was heated, whereby the benzene was distilled off. The residue was heated for 30 minutes at 120° C. After cooling the residue was triturated with 2 N ammonia and extracted with ethyl acetate. The ethyl acetate phase was extracted with 2 N hydrochloric acid, the aqueous phase was neutralized and again extracted with ethyl acetate, and subsequently the organic phase was extracted with 2 N sodium hydroxide solution. When the aqueous phase was neutralized, the product was precipitated and recrystallized from water.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=3)=[CH:15][N:14]2[CH:27]=1.[CH3:28][O:29][CH2:30][CH2:31]Br.[F-].[K+]>CO.CN(C)C=O>[CH3:28][O:29][CH2:30][CH2:31][O:26][CH2:25][C:21]1[CH:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]3[N:14]([CH:27]=[C:11]([C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[N:12]=3)[CH:15]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: OCc1cccc(-c2ccc3nc(-c4ccc5ccccc5c4)cn3c2)c1
Reactant: COCCBr
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COCCOCc1cccc(-c2ccc3nc(-c4ccc5ccccc5c4)cn3c2)c1
Temperature: 80 °C
Yield: 37.7 %

Procedure:
100 mg of [3-(2-naphthalen-2-ylimidazo[1,2-a]pyridin-6-yl)phenyl]methanol (Example 2) and 120 mg of 2-bromoethanol methyl ether are dissolved in 5 ml of a 1/1 methanol/dimethylformamide mixture, in a pressure tube, and 1 g of potassium fluoride on alumina is added thereto. The tube is closed and heated for 16 h at 80° C. After cooling, the mineral is removed by filtration and washed with dichloromethane. The filtrate is concentrated under reduced pressure and purified by silica gel chromatography, elution being carried out with a 99/1 dichloromethane/methanol mixture. An oil which crystallizes from 5 ml of diisopropyl ether is obtained. The precipitate is recovered by filtration, washed with diisopropyl ether and dried under reduced pressure. 44 mg of compound are obtained. Mp=80-82° C. 1H NMR (DMSO-d6, δ in ppm): 3.25 (m, 3H) 3.55 (m, 4H); 4.57 (s, 2H); from 7.27 to 7.80 (m, 8H); from 7.82 to 8.16 (m, 4H); 8.52 (m, 2H); 8.89 (m, 1H). M+H=409.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][CH2:25][NH:24][C:23]3=[O:28])[CH2:18][CH2:17]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1NCCCN1C1CCNCC1
Reactant: CC(=O)Nc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(OCC(O)CN2CCC(N3CCCNC3=O)CC2)cc1

Procedure:
A solution of 19.35 g of 1-(p-acetamido-phenoxy)-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 10 ml of abs. ethanol is heated to 95° C. The reaction product crystallises out at boiling heat after about 5 minutes. The crystal broth is diluted with 10 ml of abs. ethanol and heated for a further 5 hours. When the reaction is terminated the batch is evaporated in vacuo and the residue is recrystallised from abs. ethanol/ether to yield the 1-[3-(p-acetamido-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)piperidine, which melts at 218°-221° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3](=[O:11])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[ClH:13].[CH3:14][O:15][C:16]1[C:24]2[O:23][C:22](C)(C)C[C:20]=2[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:43]=[CH:42][C:41]([C:44](N4CCN(C/C=C/C5C=CC=CC=5)CC4)=[O:45])=[CH:40][CH:39]=3)[N:28]=2)=[CH:18][CH:17]=1>>[ClH:13].[CH3:22][O:23][C:24]1[CH:20]=[C:19]([C:27]2[C@@H:36]3[C@@H:31]([CH2:32][CH:33]=[CH:34][CH2:35]3)[C:30](=[O:37])[N:29]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([N:8]4[CH2:7][CH2:6][N:5]([CH2:4][C:3]([N:2]([CH3:12])[CH3:1])=[O:11])[CH2:10][CH2:9]4)=[O:45])=[CH:42][CH:43]=3)[N:28]=2)[CH:18]=[CH:17][C:16]=1[O:15][CH3:14]
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(C/C=C/c5ccccc5)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(c3ccc(C(=O)N4CCN(CC(=O)N(C)C)CC4)cc3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from intermediate product A6 and N,N-dimethyl-2-piperazin-1-yl-acetamide as described for compound 8. M.p. 93–94° C.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.CN(C)C=O.[H-].[Na+].[NH2:14][C:15]1[CH:20]=[C:19](Cl)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>O>[NH2:14][C:15]1[CH:20]=[C:19]([S:1][C:2]2[NH:3][CH:4]=[CH:5][N:6]=2)[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Sc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Sc2ncc[nH]2)ccc1[N+](=O)[O-]

Procedure:
A solution of 2.0 g. 2-mercaptoimidazole in 25 ml. dimethylformamide is treated with 0.85 g. of 57% sodium hydride (in oil suspension). 3.0 G. of 2-amino-4-chloro-1-nitrobenzene is added and the mixture heated overnight at 150°-155°C. The mixture is diluted with water, filtered and the crude product washed with chloroform, recrystallized from aqueous methanol to yield 2-amino-4-(imidazol-2-ylthio)-1-nitrobenzene.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:3].O[N:22]=[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=1)[NH2:24]>>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[O:13][N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:26]=3)[N:22]=2)[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: CS(=O)(=O)c1cccc(C(N)=NO)c1
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1CN(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3cccc(S(C)(=O)=O)c3)no2)cc1CN(C)C

Procedure:
The title compound was prepared following the general procedure 3 starting from Intermediate 8 and Intermediate 19 and was isolated as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.59 (t, J=1.7 Hz, 1H), 8.47 (m, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.21 (m, 1H), 8.15 (dd, J=1.9, 7.9 Hz, 1H), 7.92 (t, J=7.9 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.35-7.26 (m, 3H), 7.11 (d, J=7.1 Hz, 1H), 3.35 (s, 3H), 3.19 (brs, 2H), 2.09 (s, 6H), 2.02 (s, 3H). LC/MS (Method B): 448.3 (M+H)+. HPLC (Method A) Rt 3.51 min (Purity: 98.5%).
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH2:11][N:12]=[N+]=[N-])[CH2:8][S:7](=[O:10])(=[O:9])[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[O:9]=[S:7]1(=[O:10])[CH2:8][C:5]([CH2:11][NH2:12])([CH2:4][NH2:1])[CH2:6]1
Reactant: [N-]=[N+]=NCC1(CN=[N+]=[N-])CS(=O)(=O)C1
Agent: [Pd]
Solvent: CO
Product: NCC1(CN)CS(=O)(=O)C1
Yield: 94.7 %

Procedure:
A solution of 3,3-bis-azidomethyl-thietane 1,1-dioxide (1.0 g, 4.63 mmol) in methanol (10 mL) was stirred in the presence of 10% palladium on carbon (0.2 g) under hydrogen atmosphere overnight. The resulting reaction mixture was filtered and the filtrate was concentrated in vacuo to afford 720 mg of the desired product.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.CS(C)=O.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([NH:28][CH3:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O.CCCCCC>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([N:28]([CH2:2][C:3]2[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]3[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=3[CH:4]=2)[CH3:29])=[CH:26][CH:25]=1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: CNc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CN(Cc1cc2cnc(C#N)nc2n1CC(C)(C)C)c1ccc(Cl)cc1
Temperature: 50 °C
Yield: 27 %

Procedure:
To a solution of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (1 mmol) in DMF (or DMSO) (5 ml) are added 4-chloro-N-methylaniline (1.2 mmol) and potassium carbonate (2.4 mmol). The mixture is heated at 50° C. for 13 h. The reaction mixture is diluted with AcOEt, washed with water and brine, dried over sodium sulfate and concentrated. The crude product is purified by HPLC (n-hexane:AcOEt) to give the product in 27% yield. Rf=0.69(n-hexane:AcOEt=1:1). 1H NMR(400 MHz, CDCl3) δ 1.06(s, 9H), 3.03(s, 3H), 4.13(s, 2H), 4.71(s, 2H), 6.40(s, 1H), 6.62-6.69(m, 2H), 7.17-7.23(m, 2H), 8.84(s, 1H).
Reaction SMILES: ClCC([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:11]([CH3:15])[C:10]3[C:16](=O)[CH2:17][CH2:18][C:9]=3[C:8]=2[CH:7]=1)=O.CC([O-])=O.[Na+].Cl.[NH2:26][OH:27]>CCO.O>[OH:27][N:26]=[C:16]1[C:10]2[N:11]([CH3:15])[C:12]3[CH:13]=[CH:14][C:6]([OH:5])=[CH:7][C:8]=3[C:9]=2[CH2:18][CH2:17]1
Reactant: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3cc(O)ccc31)CCC2=NO

Procedure:
7-Chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (8.0 g) was suspended in EtOH (200 ml) and a solution of NaOAc (15.6 g) in water (25 ml) and a solution of hydroxylamine hydrochloride (8.0 g) in water (25 ml) were added and the mixture was refluxed for 3 hours. The mixture was concentrated in vacuo and the residue was recrystallized from 95% EtOH to provide 3-hydroxyimino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol as an off-white solid. The oxime was dissolved in tetrahydrofuran (100 ml), and thereafter acetic anhydride (8.1 g) and 4-dimethylaminopyridine (400 mg) were added and the mixture was stirred under nitrogen at ambient temperature overnight. The mixture was concentrated in vacuo, CH2Cl2 (100 ml) was added and the solution was washed successively with water (50 ml), 5% NaHCO3 (50 ml) and water (50 ml). After drying (Na2SO4), the solvent was removed in vacuo and the product recrystallized from EtOH to provide 3-acetyloximino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl acetate (1.7 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]2=[O:29])[CH2:17][CH2:16]1>>[F:13][C:2]([F:1])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]2=[O:29])[CH2:17][CH2:16]1)=[O:12]
Reactant: O=C1Nc2ccccc2C12CCNCC2
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Product: O=C(Cc1ccccc1C(F)(F)F)N1CCC2(CC1)C(=O)Nc1ccccc12

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 31 using 2-(2-(trifluoromethyl)phenyl)acetic acid and spiro[indoline-3,4′-piperidin]-2-one. LC-MS Method 3 tR=1.089, min, m/z=389; NMR (CDCl3) 1.19 (m, 1H), 1.28 (m, 1H), 1.75 (m, 4H), 3.62 (m, 1H), 3.88 (m, 5H), 6.81 (d, 2H), 6.93 (m, 1H), 7.13 (m, 2H), 7.35 (m, 2H), 7.47 (m, 1H), 7.61 (d, 1H), 8.41 (s, 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1>>[OH:12][C:13]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][CH2:10][OH:11])[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: OCCCc1ccccc1Br
Product: CCOC(=O)N1CCC(O)(c2ccccc2CCCO)CC1

Procedure:
The title compound was prepared according to the procedure described in step 2 of example 74 from 3-(2-bromophenyl)propan-1-ol (J. Am. Chem. Soc. 2003, 125, 3509.) and ethyl 4-oxopiperidine-1-carboxylate:
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17].[OH-].[K+]>C(O)C>[CH3:17][C:16]([CH3:18])=[CH:15][CH2:14][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)=CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=CCON1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.9 %

Procedure:
To a stirring solution of N-hydroxyphthalimide (Aldrich, 1.63 g, 10.0 mmol) in anhydrous ethanol (50 mL) was added 1-bromo-3-methyl-but-2-ene (Aldrich, 1.4 mL, 12.0 mmol) and potassium hydroxide (0.67 g, 12.0 mmol). After the reaction was allowed to stir at 50° C. for 4 hours, it was concentrated in vacuo and then dissolved in ethyl acetate and partitioned with water. The organic layer was washed twice with water, twice with saturated sodium chloride solution, collected and dried over Na2SO4, filtered and concentrated in vacuo, affording a white solid. The collected solid was purified via silica column in 10% methanol in dichloromethane to afford 2-(3-methyl-but-2-enyloxy)-isoindole-1,3-dione (0.53 g, 23%): 1H NMR (400 MHz; DMSO-d6) δ 7.81 (s, 4H), 5.38 (t, 1H, J=1.5), 4.57 (d, 2H, J=7.6). 1.67 (s, 3H), 1.62 (s, 3H); MS (APCI+)=232.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CN(C)C=O>[Br:22][C:20]1[CH:21]=[C:16]2[C:17](=[CH:18][CH:19]=1)[NH:23][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]1)=[CH:15]2
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(Br)ccc2N)CC1
Agent: Cl[Pd]Cl
Solvent: N#Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Br)ccc3[nH]2)CC1
Temperature: 80 °C

Procedure:
A 250 mL round bottom flask was charged with 4-(2-amino-5-bromo-phenylethynyl)-piperidine-1-carboxylic acid tert-butyl ester (5.90 g, 15.6 mmol), dichlorobis(benzonitrile)palladium (II) (1.20 g, 3.13 mmol), and dimethylformamide (175 mL) and the resulting mixture heated to 80° C. for 24 h. The resulting mixture was then concentrated in-vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-80:20 Heptane:EtOAc) to yield tert-butyl 4-(5-bromo-1H-indol-2-yl)piperidine-1-carboxylate. 1H NMR (300 MHz, CDCl3) δ 7.66 (s, 1H), 7.16-7.23 (m, 2H), 6.20 (s, 1H), 2.84-3.02 (m, 5H), 1.97-2.04 (m, 2H), 1.61-1.74 (m, 2H), and 1.48 (s, 9H); MS (ES+) 380 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[C:33](Cl)(=[O:37])[CH2:34][CH2:35][CH3:36]>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([N:17]4[CH2:22][CH2:21][N:20]([C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH2:19][CH2:18]4)[C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CCCC(=O)Cl
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(Cl)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: CCCC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
72 mg of 1-(4-chloro-benzyl)-5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1H-benzoimidazole (0.16 mmol) and 0.033 ml TEA (0.24 mmol) were dissolved in 1.5 ml dichloromethane and treated with 0.0145 ml 0.021 ml butyryl chloride (0.2 mmol). After 1.5 h stirring at rt, the reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 79 mg of a light red solid (94%). MS (ISP) 521.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11](=[O:25])[CH:12]([C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][C:14](=O)[CH3:15])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[CH:13]=[C:14]([CH3:15])[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:17]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:25])[CH3:9]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2ccccc2)c1-c1ccccc1

Procedure:
Aniline (10 mmol, 0.9 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was recrystallized from ethanol (m.p. 130° C.-131.7° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[OH:30][CH2:31][C:32](O)=[O:33].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][N:25]([C:31](=[O:30])[CH2:32][OH:33])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCNC2)c2cnccc12
Reactant: O=C(O)CO
Solvent: CC(=O)OC(C)=O
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCN(C(=O)CO)C2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-16 by using 1-((5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2-hydroxyacetic acid instead of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzimidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and acetic anhydride.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[N:21][CH:22]=4)[N:15]=[C:14]([C:27]([F:30])([F:29])[F:28])[CH:13]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[Cl:31]C1C(C(F)(F)F)=NN(C2C=CC(S(N)(=O)=O)=NC=2)C=1C1C=CC(C2N=CSC=2)=CC=1>>[ClH:31].[S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:18]=[CH:19][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[N:21][CH:22]=4)[N:15]=[C:14]([C:27]([F:28])([F:29])[F:30])[CH:13]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(-c3cscn3)cc2)cn1
Agent: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cncs3)cc2)cn1
Product: Cl

Procedure:
The title compound was prepared according to the procedure of Example 4 using 5-[5-[4-(1,3-thiazol-5-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide, instead of 5-{4-chloro-5-[4-(1,3-thiazol-4-yl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:16](=[O:17])[C:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[C:14]([CH2:33][CH2:34][CH2:35][CH3:36])[N:13]=[C:12]1[CH3:37].IC.[C:40](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:33]([C:14]1[N:13]=[C:12]([CH3:37])[N:11]([CH2:10][C:2]2[N:3]([CH3:40])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[C:16](=[O:17])[C:15]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:20]=1)[CH2:34][CH2:35][CH3:36]
Reactant: O=C([O-])[O-]
Reactant: CCCCc1nc(C)n(Cc2nc3ccccc3[nH]2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCCc1nc(C)n(Cc2nc3ccccc3n2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
A mixture of 4′-{[1-(1H-benzimidazol-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.24 g), iodomethane (0.036 mL), potassium carbonate (0.14 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.25 g, 100%).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O1CCOCC1.C(N(CC)CC)C>C1(C)C=CC=CC=1.O>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:1][NH:2][C:3](=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CCCCOC(=O)NO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)NOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
26.6 Parts of butyl N-hydroxycarbamate and 38.1 parts of p-toluenesulphonylchloride are stirred in 100 parts of dioxan maintained at 0° to 5° C. 20.4 Parts of triethylamine are added during 1 hour keeping the pH at 3 to 6. The mixture is then stirred for 18 hours at 25° C and added to 500 parts of water. The oily precipitate is taken up into 200 parts toluene, and the solution is dried, filtered and evaporated to constant weight at 40° C under reduced pressure to give 52 parts of butyl N-p-toluenesulphonyloxycarbamate as a yellow oil.