Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17](O)[CH2:16]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.ClCCl>[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([O:1][C:2]1[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][C:4]=3[CH:3]=1)[CH2:16]2
Reactant: OC1CN2CCC1CC2
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: c1ccc2c(c1)[nH]c1cc(OC3CN4CCC3CC4)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a 0° C. mixture of 2-hydroxy-9H-carbazole (369 mg, 2.02 mmol; Aldrich), quinuclidin-3-ol (260 mg, 2.05 mmol; Aldrich), and triphenylphosphine (646 mg, 2.47 mmol; Aldrich) in THF (10 mL) was added diethylazodicarboxylate (320 μL, 2.03 mmol; Lancaster). After 1 h, the reaction mixture was allowed to warm to room temperature and was stirred for 3 d. The mixture was diluted with dichloromethane, washed with saturated aq. NaHCO3, dried over MgSO4, and purified by flash chromatography (80 g silica gel, eluting with 1-16% of 10% NH4OH/MeOH in CH2Cl2) to afford the title compound as an oil (350 mg, 1.20 mmol, 59% yield). Trituration of the oil with ethyl acetate produced a solid. 1H NMR (300 MHz, methanol-d4) δ 7.92 (1H, d, J=6 Hz), 7.90 (1H, d, J=8 Hz), 7.37 (1H, d, J=8 Hz), 7.26 (1H, ddd, J=7, 7, 1 Hz), 7.10 (1H, ddd, J=8, 8 ,1 Hz), 6.92 (1H, d, J=2 Hz), 6.78 (1H, dd, J=8, 2 Hz), 4.59 (1H, m), 3.36 (1H, ddd, J=14, 8, 2 Hz), 3.04-2.75 (5H, m), 2.22 (1H, m), 2.11 (1H, m), 1.88-1.65 (2H, m), 1.51 (1H, m). MS (DCl/NH3): m/z 293 (M+1)+. Anal. Calcd. for C19H20N2O.0.1C4H8O2: C, 77.36; H, 6.96; N, 9.30. Found: C, 77.04; H, 7.23; N, 9.45.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[CH:6]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])=[CH2:7].O>C(OCC)(=O)C>[O:13]=[C:9]1[CH2:10][CH2:11][CH2:12][N:8]1[CH:6]([C:5]1[N:4]=[CH:3][NH:2][N:1]=1)[CH3:7]
Reactant: c1nc[nH]n1
Reactant: C=CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(c1nc[nH]n1)N1CCCC1=O
Yield: 63 %

Procedure:
This product is synthesised, in 63% yield, from 1,2,4-triazole and 1-vinyl-2-pyrrolidinone by a similar method described in Example 1. On account of the higher water solubility of this product, ethyl acetate (3×50 ml) is used to extract it from the aqueous phase during washing. The product distils as a pale yellow oil, bp 150°/0.05 mbar.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C@H:10]12[CH2:16][C@H:13]([NH:14][CH2:15]1)[CH2:12][N:11]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[CH2:15][C@@H:10]3[CH2:16][C@H:13]2[CH2:12][N:11]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (20 g, 0.163 mol, 1 equiv.) in CH2Cl2 (340 mL) was added tert-butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (35.7 g, 0.18 mol, 1.1 equiv.), acetic acid (2.8 mL, 0.05 mol, 0.3 equiv.) and sodium triacetoxyborohydride (41.4 g, 0.195 mol, 1.2 equiv.). The reaction was stirred at rt for 16 h. The reaction was quenched with satd. aq. NaHCO3 (3×150 mL) and 1 M NaOH (1×100 mL). The combined aqueous layers were reacidified with 1 M HCl and extracted with CH2Cl2 (2×300 mL). The organic layers were dried, filtered, and concentrated. Purification by column chromatography (5% MeOH/CH2Cl2) yielded product as a white powdery solid (24.4 g, 50%). 1H NMR (500 MHz, CDCl3): 7.16 (d, J=8.5, 2H), 6.74 (d, J=8.5, 2H), 4.37 (s, 0.5H), 4.25 (s, 0.5H), 3.65 (s, 2.5H), 3.52 (s, 0.5H), 3.47 (s, 1H), 3.16 (d, J=10.3, 1H), 2.92 (s, 0.5H), 2.82 (s, 0.5H), 2.72 (s, 0.5H), 2.57 (d, J=9.6, 0.5H), 1.85 (s, 1H), 1.74-1.62 (m, 1H), 1.47 (s, 9H). MS (ESI): mass calcd. for C17H24N2O3, 304.38; m/z found, 305.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[C:12](=[CH:13][C:14]([Br:18])=[CH:15][CH:16]=3)[O:11][CH2:10][C:9]=2[CH:19]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1.CO>[Br:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:19][C:9]=3[CH2:10][O:11]2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc2c(c1)COc1cc(Br)ccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)COc1cc(Br)ccc1-2
Temperature: 25 °C

Procedure:
The solution of 3-Bromo-6H-benzo[c]chromene-8-carboxylic acid methyl ester (160 mg, 0.5 mmol) and sodium hydroxide (1.0 N, 1 ml, 1 mmol) in THF/MeOH (2 ml/2 ml) was heated at 50° C. for 3 hours. The mixture was cooled to 25° C. and was acidified with 2 N HCl (0.6 ml). The solvents were removed under reduced pressure. The mixture was diluted with acetonitrile and water, and was freezer-dried to give 3-Bromo-6H-benzo[c]chromene-8-carboxylic acid as brown powder.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.F[C:20]1[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][CH:25]=1.O>CN(C)C=O>[CH3:3][N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[N:11]=2)[CH2:8][CH2:9]1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: Fc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(c2nn(-c3cccc(C(F)(F)F)c3)c3ccccc23)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a stirred suspension of 4.9 g of a 50% oil dispersion of sodium hydride in 60 ml of dimethylformamide was added dropwise a solution a 10.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 80 ml of hot dimethylformamide. The reaction mixture was stirred for 1 hr and then 15.2 g of 3-fluorobenzotrifluoride was added. The reaction was heated at 90° C. for 22 hrs, cooled and poured into water. The aqueous mixture was extracted with ether. The ethereal extracts were dried over anhydrous magnesium sulfate and concentrated to give an oil. The oil was flash chromatographed (silica gel, diethylamine-ethyl acetate (1:9)). Evaporation of the appropriate fractions followed by recrystallization twice from hexane yielded 2.96 g (18%) of product, mp 103°-105° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.O.[NH2:21][NH2:22]>C(O)C>[CH3:12][C:8]1[NH:22][N:21]=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][C:10]=2[OH:9])[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: Cc1oc2cc(O)ccc2c(=O)c1-c1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1[nH]nc(-c2ccc(O)cc2O)c1-c1ccccc1

Procedure:
This compounds was synthesised in the same manner as described above. 7-Hydroxy-2-methyl-3-phenyl-chromen-4-one (0.5 g, 1.70 mmol), hydrazine hydrate (5 ml), ethanol (10 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-(5-Methyl-4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol as an off white solid (0.37 g, 88%); Rf 0.7 Cf SM 0.8 ethyl acetate/hexane (80/20).
Reaction SMILES: [C:1]([C@@H:4]([OH:34])[CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([N:25](C)[C:26](=O)OC(C)(C)C)[CH2:21][CH2:20]4)[C:8]=3[C:7]1=2)(=[O:3])[NH2:2].Cl>ClCCl>[OH:34][C@@H:4]([CH2:5][C@H:6]1[CH2:17][CH2:16][C:15]2[S:14][C:13]3[N:12]=[CH:11][N:10]=[C:9]([O:18][CH:19]4[CH2:20][CH2:21][CH:22]([NH:25][CH3:26])[CH2:23][CH2:24]4)[C:8]=3[C:7]1=2)[C:1]([NH2:2])=[O:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1
Agent: Cl
Solvent: ClCCl
Product: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
Into a 10-mL round-bottom flask was placed a solution of tert-butyl N-(4-[[(3R)-3-[(2S)-2-carbamoyl-2-hydroxyethyl]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (0.9 g, 1.49 mmol, 1.00 equiv) in dichloromethane (10 mL) at 0° C. under nitrogen. Then hydrochloric acid (12 M, 2.0 mL) was added and the resulting solution was stirred for 5 h at 0° C. After completion of the reaction, the solvents were evaporated under reduced pressure. The residue was neutralized with 2 M aqueous sodium bicarbonate and extracted with 3×60 mL of dichloromethane. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 520 mg (crude) of (2S)-2-hydroxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][CH:18]2[CH2:19][CH2:20][CH:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:22][CH2:23]2)[CH:33]=[CH:34][C:35]=1[OH:36]
Reactant: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(O)c(Cl)c4)cc23)CC1
Yield: 33.4 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (65 mg, 0.146 mmol) was reacted with 3-chloro-4-hydroxyphenyl boronic acid (38 mg, 0.219 mmol) to afford the desired product (24 mg, 33%) as a light yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.29 (s, 0.5H), 9.20 (s, 0.5H), 8.38 (s, 1H), 8.12-8.04 (m, 1H), 7.98-7.91 (m, 1H), 7.74 (d, J=2.3 Hz, 0.5H), 7.68 (d, J=2.3 Hz, 0.5H), 7.58-7.48 (m, 1H), 7.06 (dd, J=9.5, 8.5 Hz, 1H), 3.59-3.49 (m, 1H), 3.45-3.15 (m, 4H), 2.98-2.83 (m, 1H), 2.45 (d, J=11.9 Hz, 1H), 2.30-2.19 (m, 2H), 2.11-1.88 (m, 4H), 1.86-1.70 (m, 2H), 1.38 (q, J=7.4 Hz, 6H), 1.27-1.20 (m, 2H), 1.19-1.10 (m, 2H); ESI MS m/z 492 [C29H34ClN3O2+H]+; HPLC 97.5% (AUC), tR=4.53 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH3:19]>CC#N>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution of 3-bromophenylacetic acid (10.0 g, 46.5 mmol) in CH3CN (150 mL) was added K2CO3 (7.39 g, 53.5 mmol) followed by ethyl iodide (5.6 mL, 70.0 mmol). The mixture was heated at reflux for 2.5 h and was cooled to room temperature. The volatiles were removed in vacuo and water was added. The aqueous solution was extracted with EtOAc (3×) and the combined organic extracts were washed with brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide (3-bromo-phenyl)-acetic acid ethyl ester (9.30 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 7.38 (m, 1H), 7.21-7.16 (m, 2H), 4.14 (q, 2H), 3.56 (s, 2H), 1.24 (t, 3H).
Reaction SMILES: [OH:1][C@@:2]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:24])[C:3]([N:5]1[CH2:23][CH2:22][CH2:21][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][NH2:20])=[O:8])=[O:4].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[OH:1][C@@:2]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([CH3:24])[C:3]([N:5]1[CH2:23][CH2:22][CH2:21][C@H:6]1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][CH2:19][NH:20][S:39]([CH3:38])(=[O:41])=[O:40])=[O:8])=[O:4]
Reactant: C[C@](O)(C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CCN)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@](O)(C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CCNS(C)(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-((2R)-2-hydroxy-2-phenylpropanoyl)-N-(2-(2-aminoethyl)-5-chlorobenzyl)-L-prolinamide (90 mg, 0.21 mmol) in CH2Cl2 (2 mL) was added triethylamine (50 microliters, 0.35 mmol) and methanesulfonyl chloride (16 microliters, 0.21 mmol). The mixture was stirred at ambient temperature for 30 min. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated, dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as an amorphous solid (TLC Rf=0.2 (98:2 CH2Cl2:MeOH); HPLC RT=3.05 min, method A; LC-MS m/z=508).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:10]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[CH3:25][N:26]1[CH2:31][CH2:30][CH:29]([NH:32][CH3:33])[CH2:28][CH2:27]1.[OH-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[C:11]([NH:16][CH:17]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:12]=[C:13]([N:32]([CH3:33])[CH:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)[N:14]=2)[CH:5]=[CH:4][C:3]=1[OH:24]
Reactant: CNC1CCN(C)CC1
Reactant: Oc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(N(C)c2nc(Nc3ccc(O)c(Cl)c3)nc(NC3CCCCCC3)n2)CC1
Yield: 14.3 %

Procedure:
To E7 (1.00 g, 2.7 mmol) dissolved in THF (25 mL) was added a solution of N-methyl-4-(methylamino)-piperidine (0.45 mL, 3.1 mmol) in THF (5 mL) followed by addition of 2.5 N NaOH (1.1 mL, 2.7 mmol) and 2.5 mL of water. The reaction mixture was stirred and heated at reflux overnight. The reaction mixture was extracted three times using dichloromethane, the combined organic layers were washed with a brine and dried over sodium sulfate. The sample was concentrated and the resulting solid was dried overnight under vacuum. Column chromatography (silica gel, 100% methanol) yielded an off-white solid (138) (177 mg, 14%); mp 68° C.; HPLC: Inertsil ODS 3V C18, 40:30:30 v:v:v [KH2PO4(0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 4.7 min, 99.6% purity; MS (TOF ES+) m/z 460 (M+H, 55.3), 251 (100), 224 (51.1).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[N:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1.[OH-].[Na+]>CO.O>[C:29]1([N:13]2[C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:16]=[C:12]2[O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
171 g of methyl-8-(1,4,5-triphenylimidazol-2-yloxy)-caprylate and 44 g of sodium hydroxide are dissolved in 1,000 ml of methanol and the mixture is stirred at room temperature for about 24 hours. The solvent is then stripped off in vacuo and the residue is taken up in water. The aqueous solution is washed with ether and acidified with dilute hydrochloric acid and the acid precipitated is separated off and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[N:5]([CH2:9][CH3:10])[C:6](=[O:8])[CH3:7].[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:13]([F:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:4]([CH:3]=1)[N:5]([CH2:9][CH3:10])[C:6](=[O:8])[CH3:7]
Reactant: CCN(C(C)=O)c1ccc(F)c(Cl)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCN(C(C)=O)c1cc(Cl)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 61319.6 %

Procedure:
3'-Chloro-N-ethyl-4'-fluoroacetanilide (101 g, 0.468 mmol) is dissolved in conc. sulfuric acid (300 ml). A solution of potassium nitrate (57 g, 0.564 mol) in conc. sulfuric acid (220 ml) is added dropwise thereto at 5°. The solution obtained is stirred overnight, then poured on to ice/water and extracted with ethyl acetate (2×200 ml). The organic phase is washed in succession with water (200 ml), saturated sodium bicarbonate solution (100 ml) and saturated sodium chloride solution (100 ml). The organic phase is treated with active charcoal, filtered and dried over magnesium sulfate. The solvent is distilled off and the residue is recrystallized from ether/n-hexane. There are obtained 74.8 g (61%) of 5'-chloro-N-ethyl-4'-fluoro-2'-nitroacetanilide with a m.p. of 68°.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[C:5]([O:18][CH3:19])[C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH2:20]([NH2:30])[C:21]1[CH:29]=[CH:28][C:27]2[O:26][CH2:25][O:24][C:23]=2[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)C>[CH2:25]1[O:26][C:27]2[CH:28]=[CH:29][C:21]([CH2:20][NH:30][C:2]3[N:11]=[C:10]([O:12][CH3:13])[C:9]4[C:4](=[C:5]([O:18][CH3:19])[C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=4)[N:3]=3)=[CH:22][C:23]=2[O:24]1
Reactant: COc1cc2c(OC)nc(Cl)nc2c(OC)c1OC
Reactant: NCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: COc1cc2c(OC)nc(NCc3ccc4c(c3)OCO4)nc2c(OC)c1OC
Yield: 8.6 %

Procedure:
1.00 g (3.51 mmol) of 2-chloro-4,6,7,8-tetramethoxyquinazoline, 0.60 g (3.97 mmol) of piperonylamine and 0.60 g of sodium carbonate were mixed with 30 ml of isopropyl alcohol. The obtained mixture was heated under reflux for 24 hours and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to give 0.12 g of the title compound as an oily substance.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.C(C1C=CC(C2N=CC(C(Cl)=O)=C[N:35]=2)=CC=1)CCC.N>O1CCOCC1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([C:17]([NH2:35])=[O:19])=[CH:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2ncc(C(=O)O)cn2)cc1
Reactant: CCCCc1ccc(-c2ncc(C(=O)Cl)cn2)cc1
Agent: N
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: CCCCc1ccc(-c2ncc(C(N)=O)cn2)cc1

Procedure:
8.3 G. of 2-(p-n-butylphenyl)-5-pyrimidinecarboxylic acid are reacted with 50 ml. of thionyl chloride with the exclusion of moisture and worked up in a manner analogous to that given in Example 7. The remaining 2-(p-n-butylphenyl)-5-pyrimidinecarboxylic acid chloride is dissolved in 100 ml. of absolute dioxane and added to a solution of 200 ml. of absolute dioxane saturated with ammonia at room temperature with stirring and further treated in a manner analogous to that described in Example 7. The obtained crude 2-(p-n-butylphenyl)-5-pyrimidinecarboxamide can be sublimed in a high vacuum at 185° C. for purification; melting point 264.0°-266.0° C.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:3]([CH:5]1[CH2:6][CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: COC(=O)C1CC(O)C(CNC(=O)c2ccc(Cl)s2)C1
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Product: O=C(NCC1CC(C(=O)Nc2ccc(-n3ccncc3=O)cc2F)CC1O)c1ccc(Cl)s1

Procedure:
In analogy to example 21C, (1SR,3RS,4SR)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-cyclopentanecarboxylic acid methyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one (prepared from 2-fluoro-4-iodoaniline by reaction with 1H-pyrazin-2-one, Cu(I)I, N,N′-dimethylethylenediamine and cesium carbonate in dioxane at 120° C.) to give 5-chloro-thiophene-2-carboxylic acid {(1RS,2SR,4SR)-4-[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentylmethyl}-amide. Orange solid. MS: 491.3. ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]>>[CH:22]1([O:21][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)OC1CCCC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)OC4CCCC4)cc23)CC1
Yield: 93.5 %

Procedure:
Beginning with 13 mg (0.0567 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 9.27 mg (0.062 mMol) cyclopentyl chloroformate, 18.1 mg (93%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:18]3[CH:22]=[C:21]([C:28]4[CH:29]=[CH:30][C:25]([NH2:24])=[N:26][CH:27]=4)[N:20]=[CH:19]3)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)c1
Product: Nc1ccc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(Cl)cc4)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-chloro-phenyl)-6-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-pyridine (example E.19) (1.35 g, 3.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.792 g, 3.6 mmol) according to the general procedure VI. Obtained as a light yellow solid. (0.750 g, 60%). MS (ISP) 416.3 [(M+H)+] and 418 [(M+2+H)+]; mp 196° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1ccsc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1ccsc1Cl)C2
Temperature: 90 °C
Reaction time: 14 h
Yield: 151 %

Procedure:
A mixture of 7-(2-chlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (147 mg), aminoguanidine hydrochloride (63 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml) was stirred at 90° C. (bath temperature) for 14 hours. The reaction solution was cooled, and precipitated crystals were filtered, washed with ethanol and dried to give 7-(2-chlorothiophen-3-yl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 101) (148 mg) as colorless crystals.