Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.C(Cl)Cl>[N:19]1([CH2:18][CH2:17][O:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: ClCCN1CCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COCCN2CCCC2)CC1
Yield: 73.5 %

Procedure:
Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (5 g, 0.023 moles), 1-(2-chloroethyl)pyrrolidine (7.82 g, 0.046 moles) and tetrabutylammonium bromide (0.741 g, 2.3 mmol) were heated in toluene/water (1:1, 60 mL) to 90° C. overnight. The reaction mixture was diluted with DCM (100 mL), washed with water (100 mL), dried over Na2SO4 and concentrated at reduced pressure. The resulting residue was purified by flash chromatography, eluting with a gradient from DCM to 90/10 DCM/methanol to afford tert-butyl 4-(2-pyrrolidin-1-ylethoxymethyl)piperidine-1-carboxylate (5.28 g). LCMS [M+H]+=313.2
Reaction SMILES: [CH3:1][N:2]([CH3:44])[CH2:3][CH2:4][CH2:5][N:6]([C:39]([NH:41][CH2:42][CH3:43])=[O:40])[C:7]([C@@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[N:16](C(OC(C)(C)C)=O)[CH:15]=3)[N:11](C(OC(C)(C)C)=O)[CH2:10]1)=[O:8].Cl.N>ClCCl>[CH3:44][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][N:6]([C:39]([NH:41][CH2:42][CH3:43])=[O:40])[C:7]([C@@H:9]1[CH2:23][C@H:22]2[C@@H:12]([CH2:13][C:14]3[C:24]4[C:17](=[CH:18][CH:19]=[CH:20][C:21]2=4)[NH:16][CH:15]=3)[NH:11][CH2:10]1)=[O:8]
Reactant: CCNC(=O)N(CCCN(C)C)C(=O)[C@@H]1C[C@@H]2c3cccc4c3c(cn4C(=O)OC(C)(C)C)C[C@H]2N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: N
Solvent: ClCCl
Product: CCNC(=O)N(CCCN(C)C)C(=O)[C@H]1CN[C@@H]2Cc3c[nH]c4cccc(c34)[C@H]2C1
Temperature: 35 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To 12.7 g (20.76 mmol) of N-[3-(dimethylamino)propyl]-N-[(ethylamino)carbonyl)-1,6-di(tert-butoxycarbonyl)-ergoline-8β-carboxamide (XVIII, R2=tert-butyl) 230 ml of 4M aqueous hydrochloric acid was added, and the reaction was stirred at 35° C. for 2 hours. The reaction mixture was cooled to ambient temperature, 200 ml of dichloromethane was added and the pH was adjusted to 11 with concentrated aqueous ammonia solution. The organic layer was separated and the aqueous layer was extracted with 2×60 ml of dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate. The dried solution was either subjected to the subsequent step without isolation of the product or it was concentrated in vacuum to give 8.1 g (94.8%) of the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])O)=[C:16]([F:30])[CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)=[C:16]([F:30])[CH:15]=1
Reactant: OC(c1ccc(Cl)cc1F)c1ccc(Cl)cc1F
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3F)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.22 g (4.23 mmol) of the compound from Example 179A in analogy to the synthesis of the compound from Example 278. 97 mg (5% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:31][C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:31]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)c2[nH]c(C3CCCC(NC(=O)OCc4ccccc4)C3)nc2c2ccccc21
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n2Cc2ccccc2)c2ccccc21
Yield: 70 %

Procedure:
According to the procedure described in example 3, step E; [3-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (94 mg, 0.22 mmol) in DMF (3.5 mL) was alkylated with benzyl bromide to give, after work-up and chromatography, [3-(3-benzyl-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (80 mg, 70% yield). 1H-NMR (CDCl3): δ 8.38 (m, 1H), 7.52 (m, 1H), 7.42 (m, 1H), 7.22–7.37 (m, 9H), 7.12 (m, 1H), 5.97 (m, 1H), 5.82 (m, 1H), 5.09 (s, 2H), 3.78 (s, 3H), 3.68 (m, 1H), 2.94 (m, 1H), 2.08 (m, 1H), 1.93 (m, 1H), 1.81 (m, 2H), 1.73 (m, 1H), 1.62 (m, 2H), 1.35 (m, 2H). MS: calculated for C33H31N5O3+H 521.3; found: 521.2.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:28])[CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-])=O)[CH2:14][CH2:13]2)=[O:11])=[CH:3][CH:2]=1>CO.[Pd]>[NH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C:8]([NH:7][C:4]2[CH:5]=[CH:6][C:1]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:2][CH:3]=2)=[O:28])[CH2:13][CH2:14]1
Reactant: O=C(CC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1)Nc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1OC1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a solution of N-biphenyl-4-yl-3-[4-(2-nitro-phenoxy)-piperidin-1-yl]-3-oxo-propionamide (0.09 g, 0.00019 mole) in methanol (10 mL) was added 10% Pd/C (0.015 g) and the resulting mixture was stirred under an atmosphere of hydrogen for 30 minutes. The mixture was then filtered through celite, the celite was washed with methanol and the organic layers were concentrated under reduced pressure. The resulting residue was recrystallized from a mixture of hexane and chloroform to afford 0.025 g (29%) of 3-[4-(2-amino-phenoxy)-piperidin-1-yl]-N-biphenyl-4-yl-3-oxo-propionamide. LC-MS purity: 430.21 (M+1)+, 90.7%, 1H NMR (DMSO-d6): δ 7.7 (m, 6H), 7.4 (m, 2H), 7.3 (m, 1H), 6.8 (m, 1H), 6.6 (m, 2H), 6.5 (m, 1H), 4.6 (bs, 2H), 4.5 (bs, 1H), 3.8 (m, 2H), 3.5 (m, 4H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[CH:16]=[CH:15][C:14]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])[C:16]([N+:1]([O-:3])=[O:2])=[CH:15][C:14]=1[O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: COCCCOc1ccc(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Solvent: CC(=O)O
Product: COCCCOc1cc([N+](=O)[O-])c(/C=C/[N+](=O)[O-])cc1OCc1ccccc1
Reaction time: 6 h

Procedure:
69% Nitric acid (16 mL, 249 mmol) was added to a liquid mixture of (E)-2-(benzyloxy)-1-(3-methoxypropoxy)-4-(2-nitrovinyl)benzene described in Production Example 32-3 (22.6 g, 65.9 mmol) in acetic acid (150 mL) at room temperature. The liquid mixture was stirred at mom temperature for 6 hours. The reaction liquid was transferred into an ice bath, then the precipitate was collected by filteration and washed with water to quantitatively obtain the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:6]=1[Br:15])(=O)C.[ClH:16]>C(O)C>[ClH:16].[Br:15][C:6]1[CH:7]=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1Br
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1ccc(N)c(Br)c1

Procedure:
A solution of 24.33 g (90 mmol) of N-acetyl-2-bromo-4-tert-butyl aniline in 73.5 ml of 95% ethanol and 46 ml of concentrated hydrochloric acid is heated under reflux one hour. Then the mixture is cooled and the product is filtered, washed with cold 95% ethanol and dried. The yield of title compound is 21.75 g (91%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(=O)(=O)(O)O.[CH3:15]O>>[O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:15])=[O:8])[CH2:3]1
Reactant: CO
Reactant: O=C1CCC(C(=O)O)C1
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCC(=O)C1
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 3-oxocyclopentanecarboxylic acid (13.2 g, 103 mmol), MeOH (130 ml) and 98% sulfuric acid (0.1 ml) was heated under reflux with stirring for 1.5 h. The MeOH was evaporated in vacuo. The residue was dissolved in CH2Cl2 (100 ml) and was washed with 1% sodium bicarbonate (50 ml). The solvent was evaporated in vacuo to give the title compound as a liquid, 12.2 g (84% yield); ir (liq.) νmax : 1730-1740 cm-1 ; 1Hmr (CDCl3) δ: 3.71 (s, 3H, OMe), 3.2 (m, 1H, H-1) and 2.5-1.9 ppm (m, 6H, CH2).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1I)[C:8](=[O:11])[O:9][CH3:10].[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)#[N:34].[F-].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33]#[N:34])[C:8](=[O:11])[O:9][CH3:10]
Reactant: N#Cc1ccccc1B(O)O
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1ccccc1C#N

Procedure:
A mixture of methyl [3,5-bis(trifluoromethyl)benzyl](2-iodo-5-trifluoromethyl-benzyl)carbamate (29 mg, 0.050 mmol), 2-cyanophenylboronic acid (10.9 mg, 0.074 mmol), potassium fluoride (8.7 mg, 0.149 mmol), 2-dicyclohexylphosphino(biphenyl) ligand (0.7 mg, 0.002 mmol) and a catalytic amount of palladium acetate was stirred in dioxane overnight at 80° C. The title compound was obtained by preparative thin layer chromatography using 20% EtOAc/hexane. 1H NMR (CDCl3, 600 MHz) δ 7.74 (m, 2H), 7.68 (d, J=7.8 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.52 (m, 3H), 7.39 (d, J=7.2 Hz, 1H), 7.24 (m, 1H), 4.30-4.55 (m, 4H), 3.71 (s, 3H). LC-MS (M+1) 561.0 (4.29 min).
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C@H:7]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH:8]([OH:22])[CH2:9][CH2:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(O)=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:15]([O:14][C:12]([NH:11][CH2:10][CH2:9][CH:8]([OH:22])[CH:7]([N:6]1[CH2:5][CH2:4][C:1]1=[O:2])[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CCN[C@H](C(=O)OCc1ccccc1)C(O)CCNC(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(NCCC(O)C(C(=O)OCc1ccccc1)N1CCC1=O)OCc1ccccc1
Yield: 99.8 %

Procedure:
Benzyl N2 -(β-carboxyethyl)-N5 -benzyloxycarbonyl-3-hydroxyornithinate (227 mg, 0.51 mmol) in distilled acetonitrile (50 ml) was heated under reflux with recrystallised 2,2'-dipyridyl disulphide (135 mg, 0.61 mmol) and triphenylphosphine (160 mg, 0.61 mmol) for eight hours. The acetonitrile was removed under vacuum and the residue chromatographed over silica gel (Merck Art. 9385) repeatedly using the following solvents as eluants ether/ethanol (49:1), ethyl acetate/isopropyl alcohol (19:1) and hexane/acetone/ isopropyl alcohol (8:8:1) to yield the slow-moving diastereoisomer of the title compound as an oil (217 mg, 64%) which slowly crystallised m.p. 66°-68° (ethyl acetate/hexane); [Rf 0.22 on thin layer chromatography, silica gel plates (Merck Art. 5719) eluting with dichloromethane/ethyl acetate/ethanol (60:10:1)]. νmax (KBr) 1725, 742, and 698 cm-1 ; δH (CDCl3, 250 MHz) 1.85 (2H, m), 2.98 (2H, t, J 4.2 Hz), 3.40 (4H, m), 4.09 (1H, d, J 3.3H), 4.17 (1H, m), 4.69 (1H, d, J4.1 Hz) (exchanges with D2O), 5.10 (2H, s) 5.22 (3H, m) and 7.36 (10H, m). [Found: C, 64.81; H, 6.12; N, 6.55%; MH+ (p.i. F.A.B. thioglycerol) 427. C23H26N2O7 requires C, 64.77; H, 6.15; N, 6.57%; M, 426].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[S:8][C:4]=2[CH:3]=1.[NH4+].[OH-].O=P(Cl)(Cl)[Cl:16]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([Cl:16])[S:8][C:4]=2[CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(Br)cc2s1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1nc2ccc(Br)cc2s1
Yield: 83 %

Procedure:
A solution of 6-bromobenzothiazolin-2-one (500 mg, 2.2 mmol) in POCl3 (5 mL) was refluxed during 18 h, then poured onto ice. The solution was neutralized to pH 9 by addition of NH4OH, and the resulting solid collected by filtration. Washing with water and drying in vacuo gave 6-bromo-2-chlorobenzothiazole (450 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[K+].[CH2:14]([S:16][CH2:17][CH2:18]Br)[CH3:15]>C(O)C>[CH2:14]([S:16][CH2:17][CH2:18][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[CH3:15]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCSCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCSCCOc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.1 %

Procedure:
A solution of 4-amino-3-nitrophenol (17.5 g.) in ethanol (300 ml.) was treated with solid potassium hydroxide (6.38 g.). The mixture was treated with a solution of 2 -bromoethyl ethyl thioether (21.2 g.) in ethanol (100 ml.), and stirred at room temperature for 4 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in chloroform (200 ml.). The chloroform solution was washed with aqueous sodium bicarbonate solution (10% w/v; 200 ml.), dried over magnesium sulphate and evaporated to give 4-[2-(ethylthio)ethoxy]-2-nitroaniline (23.4 g.) in the form of a dark red oil, which was used in the next stage without further purification being necessary.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[CH3:11][C:12]([CH3:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][C:12]([CH3:14])([OH:13])[CH3:11])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC(C)=O
Product: CC(C)(O)Cc1cc(F)cc(F)c1

Procedure:
The target compound is obtained by reacting a Grignard compound, prepared from 25.0 g (121 mmol) of 3,5-difluorobenzyl bromide, with 12.6 mL (171 mmol) of acetone. Yellow oil. Yield: 13.5 g (60%).
Reaction SMILES: C([NH:9][C:10]([NH:22][CH2:23][CH2:24][CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)=[N:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)C1C=CC=CC=1>Cl>[NH:29]1[CH:30]=[C:26]([CH2:25][CH2:24][CH2:23][NH:22][C:10]([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[NH:9])[N:27]=[CH:28]1
Reactant: O=C(NC(=NCCCOc1ccccc1)NCCCc1c[nH]cn1)c1ccccc1
Agent: Cl
Product: N=C(NCCCOc1ccccc1)NCCCc1c[nH]cn1

Procedure:
0.42 g (1 mmol) of N-benzoyl-N'-[3-(imidazol-4-yl) propyl]-N"-(3-phenoxypropyl)-guanidine are heated under reflux in 30 ml of 20% hydrochloric acid for 5 hours. The reaction mixture is worked up by a method analogous to that of
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[C:9]([O:13][C:14](=[O:30])[NH:15][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)([CH2:21][OH:22])[C:17]([F:20])([F:19])[F:18])([CH3:12])([CH3:11])[CH3:10]>C(Cl)Cl>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][O:22][CH2:21][C:16]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)([NH:15][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:30])[C:17]([F:18])([F:19])[F:20])[CH3:8]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(CO)(c1cccc(Br)c1)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)COCC(NC(=O)OC(C)(C)C)(c1cccc(Br)c1)C(F)(F)F

Procedure:
With the use of a syringe pump a solution of 1.87 ml (15.17 mmol) ethyl diazoacetate in 8 ml DCM were added to a stirred solution of 2.01 g (5.23 mmol) [1-(3-bromo-phenyl)-2,2,2-trifluoro-1-hydroxymethyl-ethyl]-carbamic acid tert-butyl ester and 46 mg (0.105 mmol) Rh2(OAc)2 in 34 ml DCM over a period of 3.5 h. After 30 min the mixture was evaporated and chromatographed on silica gel (c-hexane/0-20% TBME) to give the desired product contaminated with a diazo ester oligomer.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][N:24]1[C:29](=[O:30])[N:28]2[CH:31]=[N:32][C:33]([C:34](=[S:42])[NH:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:27]2[N:26]=[N:25]1>C(Cl)(Cl)Cl>[S:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[N:35]=[C:34]1[C:33]1[N:32]=[CH:31][N:28]2[C:29](=[O:30])[N:24]([CH3:23])[N:25]=[N:26][C:27]=12
Reactant: Cn1nnc2c(C(=S)Nc3ccccc3)ncn2c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1nnc2c(-c3nc4ccccc4s3)ncn2c1=O
Reaction time: 1 h
Yield: 9.7 %

Procedure:
Dess Martin periodinane (202 mg, 0.477 mmol) was added in small portions to a solution of 3-methyl-4-oxo-N-phenyl-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (300 mg (as 3:2 mixture with carboxamide), 0.434 mmol) in chloroform (60 mL) and the reaction was monitored by thin layer chromatography. The mixture was stirred for 1 hour and 20 mg of Dess Martin periodinane was added. The mixture was stirred for 30 minutes and the crude product was absorbed on silica and purified by flash chromatography using DCM:MeOH (98:2) as eluent to give the pure title compound as a bright yellow solid (12 mg, 10%). δH (DMSO d6): 8.96 (1H, s), 8.20 (1H, d, J=8.0), 8.15 (1H, d, J=8.0), 7.58 (1H, td, J=7.6, 1.3), 7.50 (1H, td, J=7.6, 1.2), 3.90 (3H, s).
Reaction SMILES: CN(C)S([N:6]1[C:10]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)=[CH:9][N:8]=[CH:7]1)(=O)=O.Cl>>[C:20]1([CH:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C:10]3[N:6]=[CH:7][NH:8][CH:9]=3)=[CH:12]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)S(=O)(=O)n1cncc1C1=CC(c2ccccc2)c2ccccc21
Agent: Cl
Product: C1=C(c2c[nH]cn2)c2ccccc2C1c1ccccc1

Procedure:
5-(3-Phenyl-3H-inden-1-yl)-1H-imidazole-1-sulfonic acid dimethylamide (158 mg, 0.43 mmol) in 5 ml of a 1.5 M HCl solution was refluxed for 1.5 hr. The reaction mixture was made basic and then extracted with ethyl acetate. The organic phase was washed with water and dried. The solvent was removed under reduced pressure. The crude 4-(3-phenyl-3H-inden-1-yl)-1H-imidazole which was the mixture of isomers (the ratio 75:25) was purified by flash chromatography (elution with dichloromethane-methanol 9.75:0.25).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][S:33]([C:30]4[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=4)(=[O:35])=[O:34])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 33.8 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine (0.35 g, 1.08 mmol) and 4-methoxybenzenesulfonyl chloride (0.25 g, 1.19 mmol) in chloroform (5 ml) was added triethylamine (0.16 ml, 1.19 mmol) and the mixture was stirred at room temperature for 14 hours. The solvent was concentrated under reduced pressure. Water (20 ml) was added into the residue and the product was extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and an aqueous saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 0.18 g (34% yield) of the title compound. Melting point: 206-208° C.
Reaction SMILES: [F:1][C:2]([F:9])=[C:3]([F:8])[Si](C)(C)C.[Si:10]([O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@@:24]3([CH:44]=[CH2:45])[C@H:33]([C@@H:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[O:41])[CH2:35][C@:19]12[CH3:20])[C:32]1[CH:31]=[CH:30][C:29]([O:42][CH3:43])=[CH:28][C:27]=1[CH2:26][CH2:25]3)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>>[Si:10]([O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@@:24]3([CH:44]=[CH2:45])[C@H:33]([C@@H:34]([CH2:36][CH2:37][CH2:38][CH2:39][CH:40]([O:41][Si:10]([CH3:13])([CH3:12])[CH3:11])[C:3]([F:8])=[C:2]([F:9])[F:1])[CH2:35][C@:19]12[CH3:20])[C:32]1[CH:31]=[CH:30][C:29]([O:42][CH3:43])=[CH:28][C:27]=1[CH2:26][CH2:25]3)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC=O)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12
Reactant: C[Si](C)(C)C(F)=C(F)F
Product: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1[C@@H](CCCCC(O[Si](C)(C)C)C(F)=C(F)F)C[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]12

Procedure:
In the reaction with 1,1,2-trifluoro-2-trimethylsilyl ethylene analogously to instructions 1.1, 60 mg of aldehyde 9a yields 77 mg of trimethylsilyl ether 23a as a colorless foam (GC-MS: m/z theor.: 664, pract.: 664) and a mixture of its diastereomers. The latter is used without further purification in the next stage.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([I:27])[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.IC1C=CC(NC(C2C=CC(N3CCC(C(O)=O)CC3)=NC=2)=O)=CC=1C>>[I:27][C:22]1[CH:21]=[C:20]([NH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)=[N:13][CH:14]=2)=[O:28])[CH:25]=[CH:24][C:23]=1[CH3:26]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Agent: Cc1cc(NC(=O)c2ccc(N3CCC(C(=O)O)CC3)nc2)ccc1I
Product: Cc1ccc(NC(=O)c2ccc(N3CCC(C(=O)O)CC3)nc2)cc1I

Procedure:
5′-(3-Iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid was prepared by the hydrolysis of 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester with LiOH monohydrate in a manner similar to the one described in the synthesis of 5′-(4-iodo-3-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid above. HRMS m/z calcd for C19H20N3O3I [M+H]+: 466.0622. Found: 466.0620.