Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:31][CH:30]([CH2:32][C:33](OC)=[O:34])[CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[CH2:32][CH:30]5[CH2:31][O:28][CH2:29]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: COC(=O)CC1COC1
Agent: Cl
Product: O=C(CC1COC1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (99 mg, 92%), MS (ISP) m/z=429.4 [(M+H)+], mp 195° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl 2-(oxetan-3-yl)acetate.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8][C:9]#[N:10].[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)=O>C(O)C>[C:15]1(=[C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5][CH3:4])[C:9]#[N:10])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: COc1ccccc1CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Product: COc1ccccc1C(C#N)=C1CCCCC1
Temperature: 85 °C
Yield: 36.4 %

Procedure:
Sodium methylate (5.40 g, 0.10 mol) is dissolved in ethanol (70 ml) and 2-methoxy benzylcyanide (14.70 g, 0.10 mol) is added over 2 min. Cyclohexanone (9.80 g, 0.10 mol) is added to the white suspension. The resulting mixture is heated to 85° C. (bath) for 4.5 h. Under icecooling, formic acid (5.0 ml) is added dropwise, upon which the mixture turns colourless. Standard aqueous workup as described in example 1, followed by a short path distillation at 0.05 mbar/137-146° C. yields 8.28 g of product (37% yield) as a viscous oil, from which a crystalline byproduct is separated via crystallization from hexane. The mother liquor is concentrated and the residue subjected to a fine distillation at 0.05 mbar/136° C. to yield the product as colourless oil (1.81 g, 8%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6](=[N:7]O)[CH2:5][N:4]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:3]1=[O:17]>CO.[Ni]>[NH2:7][CH:6]1[CH2:5][N:4]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:3](=[O:17])[C:2]1([CH3:1])[CH3:18]
Reactant: C[C@H](c1ccccc1)N1CC(=NO)C(C)(C)C1=O
Agent: [Ni]
Solvent: CO
Product: CC(c1ccccc1)N1CC(N)C(C)(C)C1=O
Reaction time: 16 h
Yield: 123.6 %

Procedure:
To a solution of 8.75 g of 3,3-dimethyl-4-hydroxyimino-1-[1-(R)-phenylethyl]-pyrrolidin-2-one in 300 ml of methanol there was added 20 ml of Raney-nickel, and reduction was carried out under a hydrogen atmosphere at room temperature for 16 hr (H2 pressure: 1 atm). The catalyst was removed by filtration and the solvent of the filtrate was removed under reduced pressure. The residue was purified through column chromatography using a column filled with 300 g of silica gel. From a fraction eluted with a mixture of methanol and chloroform (1:30, v/v), 3.75 g of the less polar isomer of the titled compound was obtained along with 10.2 g of a mixture of the less polar and more polar titled compound.
Reaction SMILES: C[O:2][C:3](=[O:51])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][C@@H:24]2[OH:27])[C@:20]2([CH3:21])[C@@H:15]([CH2:16][C@@H:17]([NH:28][C:29](=[O:49])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:18][CH2:19]2)[CH2:14][C@H:13]3[OH:50])[CH2:10][CH2:9]1)[CH3:7].[OH-].[Na+]>CO>[C:29]([NH:28][C@H:17]1[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:15]([CH2:14][C@@H:13]([OH:50])[C@@H:12]3[C@@H:22]2[CH2:23][C@H:24]([OH:27])[C@@:25]2([CH3:26])[C@H:11]3[CH2:10][CH2:9][C@@H:8]2[C@H:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:51])=[O:2])[CH2:16]1)(=[O:49])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCCCCCCCCC(=O)N[C@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)OC)CC[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCC(=O)N[C@H]1CC[C@@]2(C)[C@@H](C1)C[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)CCC(=O)O)CC[C@@H]12
Reaction time: 24 h
Yield: 142.8 %

Procedure:
0.5 g 3β-arachidylamido-7α,12α-dihydroxy-5β-cholan-24-oic methylester (FIG. 5A-4) were dissolved in 20 ml methanol, treated with 2 ml 1N sodium hydroxide and left for 24 h at room temperature. The methanol was then distilled off, 10 ml water were added and the reaction mixture was extracted with ethyl acetate. The water fraction was then acidified with diluted hydrogen chloride, resulting in a white precipitate which was washed with water, to give 0.7 g of the pure 3β-arachidylamido-7α,12α-dihydroxy-5β-cholan-24-oic acid (FIG. 5A-5).
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[C:4](=O)[C@@H:5]([SH:7])[CH3:6])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH2:1]([N:3]([CH2:9][CH3:10])[CH2:4][C@@H:5]([SH:7])[CH3:6])[CH3:2]
Reactant: CCN(CC)C(=O)[C@H](C)S
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCN(CC)C[C@H](C)S
Temperature: 0 °C
Yield: 64 %

Procedure:
(S)-N,N-Diethyl-2-mercaptopropionamide (171 g) dissolved in ethyl ether (500 cc) is added dropwise to a suspension of lithium aluminium hydride (42.6 g) in ethyl ether (1500 cc) in the course of 1 hour and 20 minutes. The reaction mixture is then maintained under reflux for 2 hours and 30 minutes and then cooled to a temperature in the vicinity of 0° C. Distilled water (49.8 cc) is then added so that the temperature of the mixture does not exceed 20° C., and 5N sodium hydroxide (36.6 cc) and distilled water (166 cc) are then added. The reaction mixture is filtered, the pH of the filtrate is adjusted to 8 by adding acetic acid (70 cc). The mixture obtained is filtered again, the filtrate is dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the vicinity of 30° C. A yellow oil is obtained, which is purified by distillation under reduced pressure (1.3 kPa). (S)-1-Diethylamino-2-propanethiol (100 g) in the form of a colourless oil [b.p.1.3 kPa=55°- 56° C.; [α]D20 =+39.6° (c=5.6, CH3OH)] is thereby obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[NH2:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([NH:34][CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: NC1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC4CCOCC4)c3)n2)n1
Yield: 87.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.465 g, 0.951 mmol) by treatment with commercially available 4-aminotetrahydropyran [CAS-no. 38041-19-9] (0.192 g, 1.9 mmol) in THF (5 ml) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.460 g, 87%) as an off-white solid. MS (ISP) 554.2 [(M+H)+]; mp 163° C. (dec.).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12](CC1C=CC=CC=1)[CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=1)(=[O:3])[NH2:2]>CO>[C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH:14]([OH:28])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:21][CH:22]=1)(=[O:3])[NH2:2]
Reactant: COCCOc1ccc(OCC(O)CN(CCCCOc2ccc(O)c(C(N)=O)c2)Cc2ccccc2)cc1
Solvent: CO
Product: COCCOc1ccc(OCC(O)CNCCCCOc2ccc(O)c(C(N)=O)c2)cc1

Procedure:
A solution of 25 g of crude 1-[N-[4-(3-carbamoyl-4-hydroxyphenoxy)butyl]benzylamino]-3-[4-(2-methoxyethoxy)phenoxy]propan-2-ol in 250 ml of methanol is hydrogenated and worked up analogously to Example 4. The resulting crystalline crude product is recrystallised from isopropanol and yields 1-[4-(3-carbamoyl-4-hydroxyphenoxy)butylamino]-3-[4-(2-methoxyethoxy)phenoxy]propan-2-ol having a melting point of 122°-124°.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:20][CH2:21][CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26]>CN(C)C=O.ClCCl>[OH:8][C:7]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:20][CH2:21][CH2:22][CH2:23][O:24][N+:25]([O-:27])=[O:26])=[O:11])=[CH:3][C:4]=1[O:5][CH3:6]
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: O=[N+]([O-])OCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C(=O)OCCCCO[N+](=O)[O-])ccc1O
Temperature: 0 °C
Reaction time: 69 h

Procedure:
To a solution of vanillic acid (5.0 g, 29.73 mmol) in N,N-dimethylformamide (50 ml), cesium carbonate (9.68 g, 29.73 mmol) was added. The reaction was cooled at 0° C. and a 20% solution of 1-bromo-4-(nitrooxy)butane in dichloromethane (29.45 g) was added. The reaction was stirred at room temperature for 69 hours. The mixture was poured into a 5% aqueous NaH2PO4 solution and extracted with diethyl ether (3×70 ml) The organic layers were washed with water (70 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage System, Cartridge column FLASH 65+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 95/5 (500 ml), to n-hexane/ethyl acetate 1/1 during 4000 ml, n-hexane/ethyl acetate 1/1 (500 ml)). The product (5.88 g) was obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]2[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=2[N:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:12]=1)(=O)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH2:38])=[O:37])=[CH:31][CH:30]=1>>[Cl:19][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:7]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][C:36]([NH2:38])=[O:37])=[CH:33][CH:34]=3)[C:8]3[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][CH2:20][C:9]=3[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=S1(=O)CCCc2nc(-c3cccc(Cl)c3)nc(OS(=O)(=O)C(F)(F)F)c21
Reactant: NC(=O)Cc1ccc(N)cc1
Product: NC(=O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2S(=O)(=O)CCC3)cc1
Yield: 57.6 %

Procedure:
Following general procedure H, 2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl trifluoromethanesulfonate (0.127 g, 0.29 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.047 g, 0.32 mmol) to afford the title compound (0.074 g, 61%) as a light yellow solid. MW=442.92. 1H NMR (DMSO-d6, 500 MHz) δ 8.79 (s, 1H), 8.24-8.17 (m, 2H), 7.65-7.54 (m, 4H), 7.48 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 6.89 (s, 1H), 3.77-3.71 (m, 2H), 3.41 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 443 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])[CH3:2].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12][CH3:14])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(F)cc1O
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)c1ccc(F)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of compound 4 (19.9 g, 0.109 mol) in acetonitrile (200 mL) was added cesium carbonate (42.0 g, 0.129 mol). The resulting mixture was stirred at rt for 30 min. followed by addition of methyl iodide (13.5 mL, 0.218 mol). The resulting mixture was stirred at rt O/N and filtered through Celite. The solvent was removed under reduced pressure to give crude product 5 (20.0 g, 93%) and used in the next step without further purification. 1H NMR 400 MHz (CDCl3) δ: 7.81-7.78 (m, 1H), 6.60-6.58 (m, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.82 (s, 3H), 1.39 (t, J=7.0 Hz, 3H); MS (ES) m/z: 199 (M+1)′.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](=[O:40])[CH2:38][CH3:39])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([CH2:36][C:37](=[O:40])[CH2:38][CH3:39])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCC(=O)Cc1ccc(O)cc1
Product: CCC(=O)Cc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol (4-hydroxyphenyl)butanone are treated as described in Example 76.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:13][C:14]([Br:18])([Br:17])[CH:15]=O>O>[Br:13][C:14]([Br:18])([Br:17])[CH:15]([C:9]1[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=1)[C:9]1[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=1
Reactant: Oc1ccccc1
Reactant: O=CC(Br)(Br)Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Oc1ccc(C(c2ccc(O)cc2)C(Br)(Br)Br)cc1

Procedure:
A 4-necked 3-L flask, is equipped with a mechanical stirrer, a nitrogen inlet, and thermometer, is charged with 83% sulfuric acid (640 g) and phenol (354 g). To the resulting milky mixture, tribromoacetaldehyde (380 g) in an additional funnel is added dropwise. The reaction temperature is maintained below 30° C. After the addition, the mixture is allowed to stir at the room temperature for 18 hours, before water (640 g) is added. The resulting mixture is filtered and washed with more water to afford 1,1,1-tribromo-2,2-bis(4-hydroxyphenyl)ethane.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:17]=[CH:16][C:15]=3[S:28][C:29]3[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Nc1cc(COc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(COc4ccccc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (0.037 g, 0.205 mmol) was reacted with the product from Example 221d (0.066 g, 0.205 mmol) for 16.5 hours following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.041 g, 34%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.77 (s, 3H) 5.13 (s, 2H) 6.31 (d, J=6.99 Hz, 1H) 6.79 (d, J=8.46 Hz, 2H) 6.88-7.12 (m, 4H) 7.20-7.36 (m, 4H) 7.46-7.56 (m, 2H) 7.81 (d, J=8.82 Hz, 1H) 8.48 (d, J=6.99 Hz, 1H) 9.02 (d, J=8.46 Hz, 1H) 10.01 (s, 1H); MS (ESI+) m/z 466.3 (M+H)+; (ESI−) m/z 464.2 (M−H)−.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[C:8]([C:11]1[C:12]([CH2:35]Br)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[CH:18][C:17]([O:31][CH3:32])=[C:16]([O:33][CH3:34])[CH:15]=2)(=[O:10])[CH3:9].O>CN(C)C=O>[C:8]([C:11]1[C:12]([CH2:35][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[N:13][C:14]2[C:19]([C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=[CH:18][C:17]([O:31][CH3:32])=[C:16]([O:33][CH3:34])[CH:15]=2)(=[O:10])[CH3:9]
Reactant: COc1ccc(-c2c(C(C)=O)c(CBr)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(C(C)=O)c(Cn3cncn3)nc3cc(OC)c(OC)cc23)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
Oily sodium hydride (60%, 0.372 g) was added to a solution of 1H-1,2,4-triazole (0.594 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 15 minutes. Then, 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (3.3 g) was added, and the mixture was stirred at 80° C. for 40 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave 3-acetyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline (1.4 g, 42%). This compound was recrystallized from ethanol to give colorless prisms, mp. 180°-181° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:42]([F:45])([F:44])[F:43])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:7]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26]N(S(C4C=CC(C)=CC=4)(=O)=O)C(=O)[O-])=[CH:21][CH:20]=3)[C:6]=2[CH:41]=1.[OH-:46].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([C:42]([F:43])([F:44])[F:45])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:7]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:46])=[CH:21][CH:20]=3)[C:6]=2[CH:41]=1
Reactant: [OH-]
Reactant: Cc1ccc(S(=O)(=O)N(CCc2ccc(-n3c(CCCc4ccncc4)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)C(=O)[O-])cc1
Agent: [Na+]
Solvent: CCO
Product: OCCc1ccc(-n2c(CCCc3ccncc3)nc3cc(C(F)(F)F)c(Cl)cc32)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 54 %

Procedure:
A mixture of 2-(4-{[5-chloro-2-{[4-(4-pyridinyl)butanoyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl acetate (step 3, 220 mg, 0.42 mmol) and 2N NaOH (15 ml) in ethanol (20 ml) was stirred at 40° C. for 7 h. The solvent was removed and the residue was added water (50 ml). The mixture was extracted with ethyl acetate(100 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with dichloromethane:methanol (20:1) to afford 105 mg (54%) of the title compound as pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(N([N:26]=[O:27])C)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([N:26]=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(N=O)CC1

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (26 mmol) in DCM (130 mL) was added, in one portion, Diazald (4 eq.). After stirring at reflux for 12 h, the solution was cooled, concentrated and the residue was purified by flash chromatography (0-20% EtOAc/Heptane) to afford 4-nitrosopiperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].C1C=CC=CC=1>O>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: NCC(O)c1ccccc1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccccc2)cc1

Procedure:
2-Hydroxy-2-phenylethanamine (2.15 g) and 1-(4-carbomethoxyphenyl)propan-2-one (3.0 g) were heated in refluxing benzene (100 ml) under a Dean and Stark head until the theoretical amount of water had been collected. The solvent was replaced by methanol and the mixture was stirred and cooled during the portionwise addition of sodium borohydride (3.0 g). The mixture was stirred for 2 hours, the solvent was evaporated and the residue was partitioned between water and chloroform. The organic extract was dried, evaporated and recrystallised from hexane, mp 82°-84°, (45:55 mixture of diastereoisomers) and from benzene/hexane, mp 121°-122°, (80:20 mixture of diastereoisomers). τ (CDCl3) 8.97 (3H, d, J=6 Hz), 6.85-7.60 (7H, m), 6.15 (3H, s), 5.33 (1H, m), 2.81 (2H, d, J=8 Hz), 2.70 (5H, m), 2.04 (2H, d, J=8 Hz). 13C NMR (d6DMSO)ppm. 20.15, 19.90; 53.82, 53.64; 55.03 54.86; 71.91, 71.73.
Reaction SMILES: [OH:1][C:2](C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:21](=[O:23])(=[O:22])[N:20](CC[Si](C)(C)C)[C:19](=[O:30])[CH2:18]2)=[C:13]([O:31]CC2C=CC=CC=2)[CH:12]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[OH:31][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][N:8]=[C:2]=[O:1])[CH:16]=[CH:15][C:14]=1[N:17]1[S:21](=[O:22])(=[O:23])[NH:20][C:19](=[O:30])[CH2:18]1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C=NCCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
A solution of 5-[4-(2-aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.266 g, 0.46 mmol) (Example 67, step A) and diisopropylethylamine (0.177 mL, 1.02 mmol) in a minimum amount of CH2Cl2 is added dropwise over a period of 30 min to triphosgene (0.051 g, 0.17 mmol) dissolved in CH2Cl2 (10 mL). This solution is used directly in the next step.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[CH3:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH:22]=O)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH:22]2[NH:11][CH2:10][CH2:9][N:4]3[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]23)[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(CCC=O)cc1C
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C)c(C)c1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (344.6 mg; 1.300 mmol) and 3-(3,4-dimethyl-phenyl)-propionaldehyde (211.4 mg; 1.300 mmol) afforded 8-[2-(3,4-dimethyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19]OS(C)(=O)=O)[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:26])([CH3:25])[N:4]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[C-:34]#[N:35].[K+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[C:34]([CH2:19][C:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C@H:7]3[O:6][C:5]([CH3:26])([CH3:25])[N:4]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:3]3[CH2:2][F:1])=[CH:13][CH:12]=2)[O:18][N:17]=1)#[N:35]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CC#N)no3)cc2)OC1(C)C
Yield: 55.8 %

Procedure:
The product of step 1 of Example 10 (200 mg, 0.41 mmol), potassium cyanide (111 mg, 1.65 mmol), and 18-crown-6 (23 mg, 0.08 mmol) in acetonitrile (8 mL) are stirred at room temperature for 16 hours then the mixture is concentrated and purified by column chromatography on silica gel eluting with a gradient of ethyl acetate/heptane to afford the title compound (95 mg). m/z (Cl) 416 [M+H].