Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.Br.Br[CH2:14][CH2:15][CH2:16][NH2:17]>O1CCCC1>[N:3]1([CH2:14][CH2:15][CH2:16][NH2:17])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: NCCCBr
Reactant: c1ccc2[nH]cnc2c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCCn1cnc2ccccc21
Yield: 26.3 %

Procedure:
Prepare a suspension of sodium hydride (812 mg, 20 mmol) in tetrahydrofuran (50 mL). Add benzimidazole (2 g, 16.9 mmol) under nitrogen. Reflux the mixture for 1 hour. At the same time, add 3-bromopropylamine hydrobromide (3.7 g, 16.9 mmol) to a suspension of sodium hydride (676 mg, 16.9 mmol) under nitrogen and reflux the mixture for 1 hour. Combine the two mixtures and reflux for 2 hours. Filter the reaction mixture, concentrate the filtrate to an oil, basify with sodium hydroxide and extract with ethyl acetate (3×50 mL). Concentrate the combined organic layers to an oil. Perform chromatography (silica gel, 9:1 methylene chloride/MeOH) to afford the title compound (780 mg) MS: m/e=176 (MH+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([N+:22]([O-:24])=[O:23])=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:18]=2[CH:31]=1>>[N+:22]([C:20]1[O:21][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][O:1][C:2]3[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=3)=[CH:31][C:18]=2[C:19]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: O=C(O)Cc1cccc(O)c1
Product: O=C(O)Cc1cccc(OCc2ccc3oc([N+](=O)[O-])c(-c4ccccc4)c3c2)c1

Procedure:
Using the method of Example 10 and starting with 3-hydroxyphenylacetic acid and 5-bromomethyl-2-nitro-3-phenylbenzofuran the product obtained is recrystallized from ethanol to provide 3-[(2-nitro-3-phenylbenzofuran-5-yl)methoxy]phenylacetic acid, m.p. 144°-145° C.
Reaction SMILES: [OH:1][CH:2]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2)[C:3]([O:5][CH3:6])=[O:4].[O:17]=C(C12CC3CC(CC(C3)C1)C2)C(OC)=O>>[OH:17][C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([C:2](=[O:1])[C:3]([O:5][CH3:6])=[O:4])([CH2:14]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)C(=O)C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C(O)C12CC3CC(CC(C3)C1)C2
Product: COC(=O)C(=O)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
As shown in Scheme II, in this method, adamantyl bromide (Formula A) is alkylated via zinc chloride catalysis to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula B) is then esterified using acetyl chloride in methanol to produce α-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C). α-Hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula C) is then converted to α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula D) by Swern oxidation. α-Oxotricyclo[3.3.1.13,7]decane-I-acetic acid, methyl ester (Formula D) is then hydroxylated to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid, methyl ester (Formula 1a), which is then hydrolyzed to form 3-hydroxy-α-oxotricyclo[3.3.1.13,7]decane-1-acetic acid (Formula 1).
Reaction SMILES: [CH2:1]([CH2:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=[O:17])[CH3:13].CC[O-].[Na+]>>[CH2:12]([O:14][C:15](=[O:21])[C:16](=[O:17])[CH2:10][C:9](=[O:11])[CH2:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCc1ccccc1
Temperature: 25 °C
Yield: 43.8 %

Procedure:
Benzylacetone (1.0 g, 6.75 mmol) and diethyloxalate (0.92 mL, 6.75 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 2.3 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 19. The crude material was purified with 1:1 Hexanes:CH2Cl2 to obtain 0.7348 g (43.9%) of 19. 1H (CD3OD, 400 MHz): δ 7.27-7.12 (5H, m), 4.26 (2H, q, J=7.2 Hz), 2.89 (2H, t, J=7.3 Hz), 2.81 (2H, t, J=7.3 Hz), 1.30 (3H, t, J=7.1 Hz) ppm. Partial 13C (CD3OD, 100 MHz): δ 163.32, 141.74, 129.43, 129.29, 127.16, 126.95, 103.06, 63.34, 43.46, 31.34, 14.24 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 14.24; CH2 carbons: 63.34, 43.46, 31.34; CH carbons: 129.43, 129.29, 127.16, 103.06 ppm. HPLC: 10.279 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]2[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([N+:23]([O-:25])=[O:24])=[C:16]2[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1NCCCCCO
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1NCCCCCCl
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, thionyl chloride (1.7 mL, 23 mmol) was added to a mixture of 5-{[6-(benzyloxy)-3-nitroquinolin-4-yl]amino}pentan-1-ol (5.95 g, 15.6 mmol) and anhydrous dichloromethane (78 mL). The reaction became homogeneous and was heated at reflux for 1.5 hours, at which time a yellow precipitate formed. The volatiles were removed under reduced pressure, and the residue was partitioned between dilute aqueous sodium carbonate (100 mL) and dichloromethane (150 mL). The aqueous layer was washed with dichloromethane (50 mL), and the combined organic solutions were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 6.24 g of 6-benzyloxy-N-(5-chloropentyl)-3-nitroquinolin-4-amine as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[CH:3]=1.C([Li])CCC.CN(C)[CH:17]=[O:18]>CCOCC.C(OCC)(=O)C>[I:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([I:8])[CH:5]=1)[CH:17]=[O:18]
Reactant: Ic1cc(I)cc(I)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=Cc1cc(I)cc(I)c1
Reaction time: 0.25 h

Procedure:
To a slurry of 1,3,5-triiodobenzene (7.5 G, 16.4 mM) in 72 mL of ether at -78° was added n-butyllithium 7.2 mL; 18 mM). After 15 minutes of stirring, 2.8 mL (36 mM) of N,N-dimethylformamide was added dropwise and the reaction mixture was stirred overnight. After diluting with 100 mL of ethyl acetate, the reaction mixture was washed with 3×50 mL of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. Solvent removal gave a crude product, which was chromatographed on silica gel (application in minimum amount of CH2Cl2 ; and elution with 1:9 EtOAc:hexane) to yield 1.3 G of the desired aldehyde as cream colored solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+].Cl>C(O)C.O>[CH:13](=[C:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1)C2
Reaction time: 1 h
Yield: 72.4 %

Procedure:
To a 0° C. mixture of 9.66 g (59.6 mmol) of 6-methoxy-l-indanone and 6.32 g (59.6 mmol) of benzaldehyde in 10 ml ethanol was added 9.66 ml of a 4% KOH in ethanol solution. The reaction was stirred 1 hour and then added to 300 ml water and the pH of the quench adjusted to 2 with 1N hydrochloric acid. The resultant mixture was extracted with 3×300 ml ether, and the extracts combined, dried over MgSO4, evaporated and the residue triturated with ether to yield 10.8 g (72%) of present title compound as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:26]5[N:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: Clc1ncccn1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)C1(CN3CCC(Nc4ncccn4)CC3)CC2c2ccccc21

Procedure:
4-amino-1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (0.500 g, 1.48 mmol, prepared as described in Example 7b) was heated to 100° C. for 5 hours in 1.5 mL N-methylpyrrolidinone with 2-chloropyrimidine (0.212 g, 1.85 mmol, commercial grade purified by extraction into petroleum ether) and triethylamine (0.300 g, 29.6 mmol) under a nitrogen atmosphere. Aqueous method (3 mL, 50% v/v) was added to the warm (50° C.) reaction mixture to give a white precipitate. The solid was collected by filtration and washed with fresh aqueous methanol (5 mL, 50% v/v) to give the title compound as a white solid. The solid was dissolved in methanolic hydrogen chloride, evaporated to dryness on a rotary evaporator, redissolved in a minimum volume of fresh methanol (2 mL) and added at a slow dropwise rate to rapidly stirring ethyl ether (80 mL) to precipitate the hydrochloride salt as a white solid (0.414 g, 0.99 mmol, 67%), mp 212°-214° C.; MS(CI) 417 (M+H); NMR (250 MHz, DMSO-d6): 10.17(br s, 1H), 8.38-8.33(m, 2H), 7.67(br m, 1H), 7.52-7.49(m, 1H, 7.38-7.31(m, 3H), 7.05-6.96(m, 3H), 6.70-6.63(m, 1H), 4.47(s, 1H), 4.35-4.29(m, 2H), 4.16(br m, 1H), 3.57-3.36(m, 4H), 2.76(m, 2H), 2.12-1.90 (m, 4H).
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:10]=2)[O:5][CH:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:3]1.[C:26](=[N:32][Si](C)(C)C)=[N:27][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:15]([C:14]1[CH:13]=[C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:3]/[C:2]/3=[N:32]/[C:26]#[N:27])[CH:19]=[CH:18][CH:17]=1)#[N:16]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC(c2ccccn2)O3)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1/CC(c2ccccn2)Oc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 190.3 %

Procedure:
To a solution of 3-(4-oxo-2-(pyridin-2-yl)chroman-6-yl)benzonitrile (50 mg, 0.15 mmol) in DCM (2 mL) was added TiCl4 (1 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.07 mL, 0.31 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (25 g). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layer was dried and concentrated to give crude (Z)—N-(6-(3-cyanophenyl)-2-(pyridin-2-yl)chroman-4-ylidene)cyanamide (100 mg, crude).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29](=[O:31])[CH:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([C:27]2[CH2:28][C:29](=[O:31])[NH:22][C:9]3[CH:10]=[C:11]([C:14]#[C:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(C2=CC(=O)OC(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example G2) and 2,2-dimethyl-6-(3-methoxy-phenyl)-[1,3]dioxin-4-one (Example J11) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (131 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.CN(CCN(C)C)C.[Li]CCCC.[CH3:24][S:25]SC.S(=O)(=O)(O)O>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[S:25][CH3:24]
Reactant: COc1cccc(OC)c1
Reactant: CSSC
Agent: CN(C)CCN(C)C
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cccc(OC)c1SC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,3-dimethoxybenzene (1.94 mL, 15 mmol) and TMEDA (2.35 mL, 15.75 mmol) in ether (40 mL) a under nitrogen atmosphere at 0° C. is added dropwise n-BuLi (9.84 mL, 1.6M in hexane, 15.75 mmol). The mixture is stirred at 0° C. for 30 min then dimethyl disulfide (1.33 mL, 15 mmol) is added and stirring is continued at RT for 30 min. The mixture is poured into dilute sulfuric acid and the ether layer is separated. The aqueous is extracted with ether. The ether solutions are combined and washed with water and brine then dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]([O:19][CH:20]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:18])[C:12]([NH2:15])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>>[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:15][C:12]2[C:11]([NH:16][C:17]([O:19][CH:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[O:18])=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:14][CH:13]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Yield: 72.2 %

Procedure:
Using a similar procedure to that described in Example 48, Part C, N4-(tert-butoxycarbonyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl]-1,2,4-benzenetriamine (380 mg, 0.86 mmol) and 4-chlorobenzoyl chloride (0.12 mL, 0.95 mmol) yielded 360 mg (72%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[NH:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[C:18]1[CH:26]=O>>[NH:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[C:9](=[CH:26][C:18]2[NH:17][C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=2)[C:10](=[O:16])[NH:11]3)[CH2:5][CH2:6]1
Reactant: O=Cc1cc2c([nH]1)CCCC2
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1cc2c([nH]1)CCCC2

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (33 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].C1C(=O)N([Br:27])C(=O)C1.O>CN(C)C=O>[Br:27][C:12]1[S:13][CH:14]=[CH:15][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:6][CH:7]=1
Reactant: CCCCC(CC)Cc1ccc(-c2ccsc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(CC)Cc1ccc(-c2ccsc2Br)cc1
Reaction time: 2 h

Procedure:
A 250-mL round bottom flask was charged with 3-[4-(2-ethylhexyl)-phenyl]-thiophene (7 g, 0.026 mol), N,N-dimethyl formamide (DMF) (65 mL). The reaction mixture was stirred at ambient temperature for 5 minutes, whereupon a 0.4 M solution of NBS (0.026 mol) in DMF was added and the stirring continued for 2 hours. After addition of water, the mixture was extracted with diethyl ether (3×150 mL). The combined organic layer was dried over anhydrous magnesium sulfate (MgSO4). After the product was filtered, the solvent was removed by rotary evaporation. The crude product was purified using column chromatography on silica gel with hexane as the eluent (Rf=0.35). The compound was dried under vacuum to yield 8.7 g (95%) of slightly yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](O)[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:25])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:25])[C@@H:13]([CH2:17][Br:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@@H](O)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@H](F)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Process A: (3S,4R)-1-Benzyloxycarbonyl-3-bromomethyl-4-hydroxypyrrolidine (2.70 g) was dissolved in dichloromethane (60 mL). While the solution was chilled in an ice water bath, diethylaminosulfur trifluoride (2.30 mL) was added dropwise and the mixture was stirred at room temperature for 20 hours. Following addition of a saturated aqueous solution of sodium bicarbonate (30 mL) in an ice water bath, the dichloromethane layer was separated. The dichloromethane layer was washed sequentially with a saturated aqueous solution of sodium bicarbonate (30 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=2:1) to give (3S,4S)-1-benzyloxycarbonyl-3-bromomethyl-4-fluoropyrrolidine as a yellow-brown tar (2.20 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([Cl:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)c(F)c1

Procedure:
20.9 g (0.1 mol) of 3-fluoro-4-methylbenzenesulphonyl chloride are taken up in 200 ml of carbon tetrachloride and, after addition of 19.6 g (0.11 mol) of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide, the mixture is heated under reflux for 5 hours. After cooling, the solids are filtered off and the filtrate is freed from the solvent. Flash chromatography using petroleum ether/toluene (4:1), 50 μm particle size, gives 12.4 g (44% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:5]([OH:9])[CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12]>>[OH:9][CH:5]([CH:6]([CH3:8])[CH3:7])[C:2]([CH3:10])([CH3:1])[CH2:3][O:4][C:18]1[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)C(O)C(C)(C)CO
Product: CC(C)C(O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 90 %

Procedure:
Prepared as in Example 215c from 2,2,4-trimethylpentane-1,3-diol and 2,6-dinitrobenzonitrile in 90% yield. MS 293 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10](=O)[CH3:11].Cl.[NH2:14][OH:15].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10](=[N:14][OH:15])[CH3:11]
Reactant: NO
Reactant: CC(=O)/C=C/c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1ccccc1Cl)=NO
Yield: 58.1 %

Procedure:
In a 250 ml single neck flask was charged 5.4 g (29.9 mmoles, 1.0 eq.) of (E)-4-(2-chlorophenyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.4 g of 4-(2-chlorophenyl)-3-buten-2-one 2-oxime (E/Z mixture of oximes) as an oil in 58.1% yield.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21])=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:13][CH2:14][C:15]3[NH:22][C:20](=[O:21])[C:19]4[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1ccccc1NC(=O)CCCl
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c(CCn2cnc(-c3ccccc3)c2)nc2ccccc12
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A solution of 4-phenyl-1H-imidazole (500 mg, 3.47 mmol), 2-(3-chloropropanamido)benzamide (1.17 g, 5.21 mmol) and K2CO3 (717 mg, 5.20 mmol) in DMF (50 mL) was stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated. The resulting product was washed with EtOAc and filtered to give the desired product (60 mg). LC-MS: m/z 317 (M+H+).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8])=O.[CH3:18][NH:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:18][N:19]([CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:1][CH2:3][CH2:4][C:5]12[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:6]1[C:7]([NH:9][C:10]2=[O:11])=[O:8]
Reactant: CNCc1cccnc1
Reactant: CC1=C(C)C2C(=O)NC(=O)C2(CCC=O)C=C1
Product: CC1=C(C)C2C(=O)NC(=O)C2(CCCN(C)Cc2cccnc2)C=C1

Procedure:
Prepared from 2-(2-formyl-ethyl)-5,6-dimethyl-phthalimide and 3-(methylamino-methyl)-pyridine analogously to Example 4.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]4[NH:31][N:30]=[N:29][N:24]=4)=[CH:25][CH:26]=3)=[CH:14][CH:15]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(OCC#N)cc3)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(OCc4nnn[nH]4)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-benzyl-2,3-dimethyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.202 g, 0.551 mmol) was reacted with NaN3 (0.179 g, 2.756 mmol) and NH4Cl (0.147 g, 2.756 mmol) in DMF (5 ml) to give the product (0.176 g, 0.430 mmol, 78%) as a yellow solid, dec. 229-232° C.