Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([CH:16]([CH2:19][CH3:20])[CH2:17][NH2:18])[CH3:15].Cl[CH:22]([CH3:26])[C:23](O)=[O:24]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:18]([CH2:17][CH:16]([CH2:19][CH3:20])[CH2:14][CH3:15])[C:23](=[O:24])[CH:22]([CH3:26])[S:13]1
Reactant: CC(Cl)C(=O)O
Reactant: CCC(CC)CN
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: CCC(CC)CN1C(=O)C(C)SC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-ethyl-1-butylamine followed by α-chloropropionic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-(2-ethyl-1-butyl)-5-methyl-1,3-thiazolidin-4-one.
Reaction SMILES: CC(O[C:6]([NH:8][C@@H:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]3[CH:35]=2)=[CH:22][CH:21]=1)[CH2:10][CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[O:7])(C)C.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(NC(C)C)(C)C.[Cl:57][C:58]1[CH:59]=[C:60]([CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80])C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>C(Cl)Cl>[Cl:57][C:58]1[CH:59]=[C:60]([C:6]([NH:8][C@@H:9]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[N:27]=[C:28]4[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]4[CH:35]=3)=[CH:24][CH:25]=2)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:7])[CH:75]=[CH:76][C:77]=1[O:78][CH:79]([CH3:81])[CH3:80]
Reactant: CC(C)Oc1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1Cl
Reactant: Cc1cccn2cc(-c3ccc(C[C@@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3)nc12
Agent: CC[SiH](CC)CC
Solvent: CC(C)NC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CCC(=O)O)NC(=O)c4ccc(OC(C)C)c(Cl)c4)cc3)nc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 61 %

Procedure:
To a solution of 1,1-dimethylethyl (4R)-4-(([(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]pentanoate (1.35 g, 2.82 mmol) in CH2Cl2 (14 mL) was added trifluoroacetic acid (10 mL) followed by triethylsilane (2.5 equiv, 7.04 mmol). The reaction was stirred for 45 minutes at room temperature and then concentrated in vacuo. DMF (35 mL) was added to the residue followed by diisopropylamine (14.7 mL, 84.51 mmol) under nitrogen. The reaction was stirred for 5 minutes and pentafluorophenyl 3-chloro-4-[(1-methylethyl)oxy]benzoate (1.1 equiv, 3.10 mmol) was added. The reaction was stirred for 45 minutes and then concentrated in vacuo. Ethyl acetate (50 mL) was added to the residue and it was washed with H2O (30 mL). The aqueous layer was extracted with EtOAc (20 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 25-100% EtOAc/hexanes) provided the title compound as a white foamy solid (61%). ESMS [M+H]+=520.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:13])[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[N:15]([O-])=O.[Na+].[Na+].[C:20]1([S:26]([O-:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[C:20]1([S:26]([N:15]=[N:1][C:2]2[CH:3]=[C:4]([N:9]([CH3:13])[C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Br:8])[CH:7]=2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S([O-])c1ccccc1
Reactant: CC(=O)N(C)c1cc(N)cc(Br)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)N(C)c1cc(Br)cc(N=NS(=O)(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
0.243 g (0.001 mol) of N-(3-amino-5-bromophenyl)-N-methylacetamide was suspended in 5 ml of water, treated with 0.2 ml (0.002 mol) of HCl (37%) and cooled to 0° C. A solution of 0.069 g (0.001 mol) of NaNO2 in 1 ml of water was added thereto, the mixture was stirred at 0° C. for 5 min. and subsequently at room temperature for 10 min. and finally treated with a solution of 0.25 g (0.0015 mol) of benzenesulphinic acid sodium salt in 5 ml of water. The reaction mixture was treated in an ultrasound bath for 10 min. and subsequently partitioned in water/ethyl acetate. The organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and freed from solvent. The residue was chromatographed on silica gel with 1% MeOH in dichloromethane. There was obtained 0.23 g (58%) of N-[3-[2-(phenylsulphonyl)-diazenyl]-5-bromophenyl]-N-methylacetamide as a brown oil. MS (ISN): me/e=456, 454 (C15H14BrN3O3S- +NaOAc).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[NH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([F:11])[CH:9]=2)[N:4]([C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:19]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:3]=1
Reactant: Clc1ccccc1C(c1ccccc1)c1ccccc1
Reactant: Fc1cnc2[nH]nc(Br)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cnc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 3-bromo-5-fluoro-1H-pyrazolo[3,4-b]pyridine, 4, (0.97 g, 4.49 mmol) and K2CO3 (1.86 g, 13.47 mmol) in DMF (9.7 mL) was cooled to 0° C. Chlorodiphenylmethylbenzene (1.38 g, 4.94 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with 40 mL of ethyl acetate and washed with 30 mL of water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (40% ethyl acetate/hexanes) to afford 1.68 g of the desired product as a white solid: 1H NMR (300 MHz, d6-DMSO) δ 8.45-8.38 (m, 1H), 8.04 (dd, J=8.0, 2.7 Hz, 1H), 7.35-7.16 (m, 15H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, Retention Time=3.03 min, (M+H) 459.46.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:3]=1[C:4]([NH:6][C:7](=[O:24])[NH:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:5].C[N:32](C=O)C.[Cl-].[NH4+].CCN(C(C)C)C(C)C>O>[Cl:1][C:2]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:3]=1[C:4]([NH:6][C:7](=[O:24])[NH:8][C:9]1[C:10]([N:15]2[CH2:16][CH2:17][CH:18]([C:21]([NH2:32])=[O:23])[CH2:19][CH2:20]2)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cccnc1N1CCC(C(=O)O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)C1CCN(c2ncccc2NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 50 mg of 3′-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid, 0.5 ml of DMF, 6.1 mg of ammonium chlorid, 40 μl of Hunig's base and 37.3 mg of Totu was stirred at room temperature for 2 hours. Afterwards, it was diluted with 5 ml of water and the mixture was stirred briefly. The precipitate was filtered of with suction and dried under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[C:16]([NH:19][NH2:20])(=O)[CH3:17]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]3[N:3]([C:16]([CH3:17])=[N:19][N:20]=3)[N:4]=2)=[CH:10][CH:11]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nnc1Cl
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1cc(-c2ccc(Cl)cc2)nn2c(C)nnc12

Procedure:
A mixture of 1.0 g. of 3-chloro-6-(p-chlorophenyl)-4-methylpyridazine, 0.62 g. of acetic acid hydrazide and 10 ml. of n-butanol is refluxed for 48 hours. The solvent is removed and the residue dissolved in dichloromethane and filtered through magnesol. The solid from the filtrate is recrystallized from dichloromethane-hexane to give 0.6 g. of solid, m.p. 209°-212° C. Recrystallization from dichloromethane-hexane gives the product of the example as light pink colored crystals, m.p. 215°-217° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCN2C(=NCCC2)CC1.[CH2:56]([O:58][C:59](=[O:61])C)C>CO.C1COCC1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:59]([O:58][CH3:56])=[O:61])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: CCOC(C)=O
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Temperature: 110 °C

Procedure:
Alternatively, a suspension of 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 (113 mg, 0.25 mmol), Mo(CO)6 (66 mg, 0.25 mmol), Hermann's palladacycle (trans-di(mu-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II), 23 mg) and tri-tert-butylphosphonium tetrafluoroborate (15 mg) in methanol (0.8 mL) and THF (0.8 mL) in a 10 mL microwave vial was treated with DBU (0.11 mL, 0.75 mmol) and immediately sealed. The whole was heated in a microwave at 110° C. for 20 min, cooled to room temperature and diluted with ethylacetate. The crude suspension was filtered through celite and the eluent concentrated to give a residue that was purified by flash column chromatography (10-100% ethylacetate in hexanes) to give 138 as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 7.69-7.49 (m, 7H), 6.57 (m, 1H), 4.22 (m, 2H), 3.85 (s, 3H), 3.23 (s, 3H, obstructed by water), 3.02 (m, 2H). MS: (ESI+) 428.1
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[CH:6]=[C:7]2C=1NC(=O)[CH2:9][CH2:8]2)[CH3:2].[H-].[Na+].[CH3:19]I.[CH3:21][N:22]([CH3:25])[CH:23]=[O:24]>>[CH3:21][N:22]1[C:25]2[C:7](=[CH:6][C:5]([C:14]([O:16][CH3:19])=[O:15])=[CH:4][C:3]=2[CH2:1][CH3:2])[CH2:8][CH2:9][C:23]1=[O:24]
Reactant: CI
Reactant: CN(C)C=O
Reactant: CCc1cc(C(=O)O)cc2c1NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Product: CCc1cc(C(=O)OC)cc2c1N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 g of 8-ethyl-6-carboxy-3,4-dihydrocarbostyril was gradually added to a solution of 4.2 g of sodium hydride in 50 ml of dimethylformamide with ice-cooling. The mixture was stirred at room temperature for 30 minutes. Thereto was dropwise added a solution of 9.0 ml of methyl iodide in 20 ml of dimethylformamide with ice-cooling. The mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water. The resulting mixture was extracted with methylene chloride. The extract was washed with water and a saturated aqueous sodium chloride solution in this order, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (elutant: methylene chloride/methanol=100/0 to 100/5) to obtain 10.0 g of 1-methyl-8-ethyl-6-methoxycarbonyl-3,4-dihydrocarbostyril as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:11][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[C:18]([Cl:19])[CH:17]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: Clc1ccc(-c2cc(Cl)c3c(n2)CCC3)cc1Cl
Yield: 59 %

Procedure:
Following General Procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with (3,4-dichlorophenyl)boronic acid (0.198 g, 1.04 mmol) to afford the title compound (0.141 g, 94%). MW=298.59. 1H NMR (CD3OD, 300 MHz) δ 8.16 (d, J=2.1 Hz, 1H), 7.90-7.84 (m, 1H), 7.69 (s, 1H), 7.61 (d, J=8.5 Hz, 1H), 3.12 (t, J=7.6 Hz, 2H), 3.05 (t, J=7.6 Hz, 2H), 2.21 (quin, J=7.6 Hz, 2H); APCI MS m/z 297 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.CC(=C)C[N:15]1[C:20]2C=CC=[CH:24][C:19]=2[CH2:18][O:17][C:16]1=[O:25].S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:24][C:19]1([CH2:20][N:15]2[C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=3[CH2:8][O:10][C:16]2=[O:25])[CH2:18][O:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CN1C(=O)OCc2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC1(CN2C(=O)OCc3ccccc32)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.1 %

Procedure:
m-Chloroperbenzoic acid (13.76 g, 55.81 mmol) was added to a solution of 1-(2-methyl-2-propenyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one (7.09 g, 34.88 mmol) in methylene chloride (150 ml), and the mixture was stirred at room temperature for 24 hours. To the mixture, sodium thiosulfate aqueous solution and sodium hydrogencarbonate aqueous solution were added, and the resulting mixture was filtered. The organic layer was separated, washed with sodium hydrogencarbonate aqueous solution, dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford 1-(2-methyl-2-oxiranylmethyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one (5.13 g, 67%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([CH2:20][CH2:21]Cl)[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][OH:24]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([CH2:20][CH2:21][O:24][CH3:23])[N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCc1c[nH]c(-c2ccc(OCc3ccccc3)cc2)n1
Reactant: CO
Product: COCCc1c[nH]c(-c2ccc(OCc3ccccc3)cc2)n1
Reaction time: 15 h
Yield: 94 %

Procedure:
Under N2, Na (0.7 g, 0.029 mol) was added to CH3OH (100 ml) and heated at reflux. After the Na had reacted, a solution of 70 (2.0 g, 0.0064 mol) in CH3OH (75 ml) was added dropwise with stirring. After 15 hours, the suspension was concentrated to dryness to yield 1.85 g (94%) of 71, m.p. 154°-6° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].[N:13]([O-])=O.[Na+].[Sn](Cl)[Cl:18]>Cl>[ClH:18].[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([NH:7][NH2:13])[CH:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: NNc1cccc(OC(F)(F)F)c1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
3-(Trifluoromethoxy)aniline (3.68 ml) was dissolved in 6 M hydrochloric acid (71 ml), and an aqueous solution (4.7 ml) of sodium nitrite (2.08 g) was added dropwise over 20 min at −5° C. Tin (II) chloride (1.954 ml) was dissolved in 6 M hydrochloric acid (25 ml), and the solution was cooled to −5° C., and added quickly to the above-mentioned reaction mixture at −5° C. The mixture was stirred at −5° C. for 2 hr, and the precipitated solid was collected by filtration, washed with 0.1M hydrochloric acid, and dried under reduced pressure to give the title compound (2.72 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[CH:8]2
Reactant: C1CCNC1
Reactant: COc1cccc2c1CCC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1cccc2c1CCC(N1CCCC1)=C2
Yield: 99399.8 %

Procedure:
A mixture of 5-methoxy-2-tetralone (100 g, 0.68 mmol), pyrrolidine (85.7 ml, 1.03 mol) and p-toluenesulfonic acid (100 mg, catalytic) in benzene (1.2L) was heated at reflux under Dean-Stark conditions for 4 h. The mixture was cooled and the solvent evaporated to give the title compound as a brown oil (155 g, 99%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].[Br:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][CH:20]=1>>[Br:1][C:23]1[CH:24]=[C:19]([CH2:18][CH2:17][Br:16])[CH:20]=[CH:21][C:22]=1[NH:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CNc1ccc(CCBr)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CCOC(=O)CNc1ccc(CCBr)cc1Br

Procedure:
Ethyl N-[2-bromo-4-(2-bromoethyl)phenyl]aminoacetate was prepared according to a similar manner to that described in Reference Example 6 using 1 molar equivalent of both N-bromosuccinimide and 0.4M aqueous sodium thiosulfate solution to ethyl N-[4-(2-bromo-ethyl)phenyl]aminoacetate.
Reaction SMILES: ClC(OCC(C)C)=O.[Cl:9][C:10]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:11]=1[C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13].C(N(CC)CC)C.[C:31]1([CH:37]([NH2:39])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH3:38][CH:37]([NH:39][C:16](=[O:18])[CH2:15][NH:14][C:12](=[O:13])[C:11]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:10]=1[Cl:9])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(N)c1ccccc1
Reactant: O=C(O)CNC(=O)c1c(Cl)cccc1Cl
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(NC(=O)CNC(=O)c1c(Cl)cccc1Cl)c1ccccc1
Reaction time: 0.33 h
Yield: 64.9 %

Procedure:
1.05 g of isobutyl chloroformate was slowly dropped at -20° C. under a nitrogen stream onto a solution of 1.74 g of N-(2,6-dichlorobenzoyl)glycine and 0.71 g of triethylamine in 30 ml of anhydrous tetrahydrofuran, and the reaction solution was stirred for 20 minutes. Then, 0.84 g of α-phenylethylamine was added to the solution, which was subsequently stirred for 30 minutes keeping the reaction temperature within the range from -10° C. to -20° C. The reaction solution was then extracted with 60 ml of ethyl acetate. The extract was washed with a 10% w/v aqueous solution of sodium hydroxide, then with 1N aqueous hydrochloric acid, and finally with a saturated aqueous solution of sodium chloride, and was then dried over anhydrous sodium sulfate. The reaction solution was concentrated by evaporation under reduced pressure, and the resulting residue was subjected to silica gel column chromatography for purification to give 1.58 g (yield 67%) of the title product melting at 155° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[I:13]Cl.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([I:13])[C:5]2[O:9][CH2:8][C:7]([CH3:10])([CH3:11])[C:6]=2[CH:12]=1
Reactant: ClI
Reactant: CC1(C)COc2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC1(C)COc2c(I)cc(Br)cc21
Temperature: 0 °C
Yield: 56 %

Procedure:
5-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran (example 1f) (10 g, 44 mmol) was dissolved in glacial acetic acid (40 mL), iodine monochloride (10.86 g, 66.9 mmol) was added and the reaction mixture was heated at reflux for 72 hours then cooled to 0° C., and 1N NaOH was slowly added until pH=8 followed by Na2CO3 until the solution become colorless. The solution was extracted with ethyl acetate and the organic layer further washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (10% ethyl acetate in hexane) to give 8.7 g of 5-bromo-7-iodo-3,3-dimethyl-2,3-dihydro-benzofuran (56%). 1H NMR (300 MHz; CDCl3): 1.34 (s, 6H), 4.32 (s, 2H), 7.13 (d, J=2 Hz, 1H), 7.58 (d, J=2 Hz, 1H).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][C:17]1[S:21][C:20]([S:22](Cl)(=[O:24])=[O:23])=[CH:19][CH:18]=1.[CH2:26]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:27]>>[CH2:26]([C:28]1[CH:34]=[CH:33][C:31]([N:32]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:22]([C:20]4[S:21][C:17]([CH3:16])=[CH:18][CH:19]=4)(=[O:24])=[O:23])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:30][CH:29]=1)[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: CCc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccc(C)s4)CC3)C2=O)cc1

Procedure:
Off-white solid. MS (ESI): 419.14 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 5-methylthiophene-2-sulphonyl chloride and 4-ethyl-aniline.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]=[CH:9][CH:10]=O)(=[O:4])=[O:3].[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]=[CH:9][CH:10]=[N:15][NH:16][C:17]([NH2:19])=[S:18])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(C=CC=O)c1
Reactant: NNC(N)=S
Product: CS(=O)(=O)c1cccc(C=CC=NNC(N)=S)c1
Yield: 70 %

Procedure:
The compound is prepared according to the method described in example 1A from 3-methylsulfonylcinnamaldehyde (3.8 mmoles) and from thiosemicarbazide (3.8 mmoles). Yield 70%.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C([N-]C(C)C)(C)C.[Li+].IC>O1CCCC1>[F:13][C:14]([F:22])([F:23])[CH2:15][CH:16]([CH3:1])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)CCC(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of diisopropylamine (19.5 mL) in tetrahydrofuran (200 mL) at 0° C. was treated with n-butyllithium (71 mL, 1.5M in hexanes). The resulting solution was stirred for 30 minutes at 0° C., then was cooled to -70° C. A solution of ethyl 4,4,4-trifluorobutyrate (14 mL) in tetrahydrofuran (150 mL) was slowly added to the lithium diisopropylamide solution and the resulting mixture was stirred at -70° C. for 30 minutes. A solution of iodomethane (11.5 mL) in tetrahydrofuran was added in one portion, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with water and evaporated. The residue was dissolved in methylene chloride, washed (10% (w/v) hydrochloric acid, water, and brine), dried (MgSO4), filtered, and evaporated. The resulting pale yellow liquid was purified by distillation to yield ethyl 4,4,4-trifluoro-2-methylbutyrate as a colorless liquid (7.8 g, 46%); bp 125°-128 ° C.; partial NMR: (300 MHz, CDCl3): 1.30 (m, 6H, CH3), CH2CH3), 2.15 (m, 1H, H-C(3)), 2.64 (m, 1H, H-C(3)), 2.72 (m, 1H, H-C(2)), 4.16 (q, 2H, OCH2).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[N:62]=[C:63]=[O:64]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:63]([NH:62][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[F:55])=[O:64])[CH2:49][CH2:48]1
Reactant: O=C=Nc1ccccc1F
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)Nc2ccccc2F)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-fluoro-2-isocyanatobenzene as starting materials in 51% yield. 1H NMR (300 MHz, DMSO-d6): δ 10.04 (s, 1H), 9.41 (m, 2H), 9.02 (s, 1H), 8.25 (m, 4H), 7.65 (s, 1H), 7.30 (m, 2H), 7.05 (m, 4H), 4.09 (m, 2H), 2.98 (m, 4H), 2.83 (m, 2H), 2.32 (m, 2H), 2.02 (m, 1H), 1.75 (m, 2H), 1.21 (m, 2H). LCMS for C31H31ClFN8O2 (M+H)+: m/z=601.2.