Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9](N)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C(#N)C.N(OCCCC)=O.[BrH:26]>[Cu]Br>[Br:26][C:9]1[CH:8]=[CH:7][C:6]([C:5]2[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:11][C:10]=1[CH3:12]
Reactant: Br
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1N
Agent: [Cu]Br
Agent: CCCCON=O
Solvent: CC#N
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1Br
Temperature: 25 °C

Procedure:
4′-Chloro-3-methylbiphen-4-ylamine (16.5 g, 0.077 mol) is added to acetonitrile (140 ml) and stirred at room temperature until dissolution is complete. The reaction mixture is cooled to between −5° C. and 0° C., tent-butyl nitrite (90%, 12.4 ml, 0.093 mol) is added dropwise and the reaction mixture is maintained at between −5° C. and 0° C. for 30-40 minutes. The mixture is added slowly to a preheated (50° C.) suspension of copper (I) bromide (5.8 g, 0.04 mol) in hydrobromic acid (5.8 ml) and stirred at 50° C. for 10-15 minutes. The reaction mixture is cooled to room temperature, then poured into ice-cold water and extracted with ethyl acetate (3×300 ml). The organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to yield 4-bromo-4′-chloro-3-methylbiphenyl (11.5 g).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl[C:23]1[N:24]=[CH:25][C:26]([C:29]([O:31][CH3:32])=[O:30])=[N:27][CH:28]=1>CN(C)C=O>[CH3:32][O:31][C:29]([C:26]1[N:27]=[CH:28][C:23]([O:21][C:18]2[CH:19]=[CH:20][C:13]3[CH2:12][CH2:11][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:16][CH2:15][C:14]=3[CH:17]=2)=[N:24][CH:25]=1)=[O:30]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cn1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 58.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil) (6.4 g, 0.16 mol) was added portionwise to a solution of 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) (40 g, 0.15 mol) in dry dimethylformamide (200 ml) cooled to 5° C. over 15 minutes. After 15 minutes, the mixture was allowed to warm to room temperature and stirred for 60 minutes. The mixture was cooled in an ice-water bath and methyl 5-chloro-2-pyrazinecarboxylate (31.2 g, 0.18 mol) was added portionwise. The mixture was allowed to warm to room temperature and stirred for 18 hours. The mixture was poured onto water (500 ml) and ice (500 ml) and stirred until the ice had melted. The resulting solid was collected by filtration, washed with water and dissolved in ethyl acetate (1500 ml). The ethyl acetate layer was washed with brine (200 ml), dried under sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography eluting with a mixture of ethyl acetate:hexane (1:2) to afford the title compound (35.07 g).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:25]([NH:27][C@@H:28]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17])=[O:13])[CH3:11])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[NH:56]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[C@H:57]([C:63]([NH:65][CH2:66][C:67]([OH:69])=O)=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61]>>[NH:56]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[C@H:57]([C:63]([NH:65][CH2:66][C:67]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:25]([NH:27][C@@H:28]([C:39]([O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:20][CH2:21][C:22](=[O:24])[NH2:23])=[O:17])=[O:13])[CH3:11])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:69])=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
Boc-Ile-Ala-Gly-Gln-D-Arg(NO2)-OBzl (3.2 g, 5 m mol) was demasked with respect to the N-masking group, and coupled with Boc-Gln-Gly-OH (1.7 g, 5.5 m mol) in the manner similar to that of Example 1, paragraph 7).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:18]([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH:42]([CH3:45])[C:43]#[N:44]>C1COCC1>[C:43]([CH2:42][CH2:45][C@@:18]1([C:27]([O:29][CH3:30])=[O:28])[CH2:17][CH2:16][C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:14][CH:13]=2)[N:19]1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])#[N:44]
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Reactant: CC(Br)C#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)[C@]1(CCC#N)CC[C@H](c2ccc(OCc3ccccc3)cc2)N1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-{4-[(phenylmethyl)oxy]phenyl}-1,2-pyrrolidinedicarboxylate (D6, 200 mg, 0.49 mmol) in dry THF (2 mL) at −78° C. was added LiHMDS (0.53 mL of a 1M solution in THF, 0.53 mmol). The mixture was allowed to warm to −30° C. and stirred for 30 min at this temperature. Then the yellow slurry was cooled to −78° C. and bromopropionitrile (0.24 mL, 2.92 mmol) was added. The reaction mixture was left under stirring for 2 h and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4), filtered and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1) affording the title compound (107 mg, 52%).
Reaction SMILES: [I-].[CH3:2][Li].[C:4]([C:6]1[C:10]([S:11][C:12]([F:15])([F:14])[F:13])=[C:9]([CH:16]=[O:17])[N:8]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[Cl:29])[N:7]=1)#[N:5].Cl>C(OCC)C>[C:4]([C:6]1[C:10]([S:11][C:12]([F:14])([F:13])[F:15])=[C:9]([CH:16]([OH:17])[CH3:2])[N:8]([C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:27])([F:28])[F:26])=[CH:20][C:19]=2[Cl:29])[N:7]=1)#[N:5]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Reactant: [Li]C
Agent: Cl
Agent: [I-]
Solvent: CCOCC
Product: CC(O)c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Cooper (I) iodide (6.1 g, 0.032 mol) was suspended in anhydrous diethyl ether and cooled to 0° C. Methyllithium (1.6 M in diethyl ether, 40 ml, 0.064 mol) was added via cannula and stirred 10 minutes. A solution of the product of Example 3 (10 g, 0.023 mol) in diethyl ether was added via cannula creating a bright yellow suspension. After 15 minutes, 10% aqueous hydrochloric acid (40 ml) was added while venting the reaction vessel. The remaining suspension was filtered through Celite® and washed with diethyl ether several times. The organic phase was washed with saturated sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Trituration from pentane provided crystals that were purified by silica gel chromatography using ethyl acetate:hexanes. The title compound was isolated as a white solid (7.56 g), m.p. about 123° C.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH2:18])[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH:32]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:36]([O:35][C:33]([N:30]1[CH2:29][CH:28]=[C:27]([C:2]2[CH:3]=[C:4]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH2:18])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[N:5]=[CH:6][N:7]=2)[CH2:32][CH2:31]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: Nc1nc2c(Oc3cc(I)ncn3)cccc2s1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(Oc3cccc4sc(N)nc34)ncn2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(6-iodo-pyrimidin-4-yloxy)-benzothiazol-2-ylamine, (Example 129(b)), (200 mg, 0.54 mmol), 1,1-dimethylethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (200 mg, 0.65 mmol, prepared according Eastwood, P. R. Tetrahedron Lett. 2000, 41, 3705–3708), PdCl2(PPh3)2 (38 mg, 0.050 mmol, Aldrich), and Na2CO3 (86 mg, 0.81 mmol) in DME/EtOH/H2O (2:1:2, 2.0 mL) was stirred and heated by microwave synthesizer at 120° C. for 15 min. The reaction mixture was concentrated in vacuum to dryness. Purification by silica gel chromatography (gradient: 0% to 5.0% MeOH/CH2Cl2) provided the title compound as a light-yellow solid. Mp: 188° C. (decomp.). MS (ESI, pos. ion) m/z: 426 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1.[CH:25](=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:25]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:18])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:16]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)c2ccccc2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2NCc2ccccc2)CC1
Reaction time: 8 h
Yield: 20 %

Procedure:
A solution of (4-(2-amino-4-nitrophenyl)piperazin-1-yl)(phenyl)methanone (0.4 g, 1.2 mmol) and benzaldehyde (0.18 ml, 1.8 mmol) in 15 ml dichloroethane was stirred for 10 min, followed by the addition of sodium triacetoxyborohydride (0.78 g, 3.68 mmol). The mixture was stirred overnight under argon atmosphere. The reaction was quenched with water and extracted with ethyl acetate (3×20 ml), followed by drying over anhydrous sodium sulfate. N-benzyl-2-(4-benzoylpiperazin-1-yl)-5-nitrobenzenamine (0.1 g, 19%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 3.00-3.60 (d, br, 8H), 4.44 (d, J=5.5 Hz, 2H), 5.04 (t, J=5.5 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.34-7.65 (m, 11H), 7.67 (dd, J=8.6, 2.5 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 48.6, 51.3, 105.5, 113.6, 119.3, 127.6, 127.7, 128.2, 129.1, 129.4, 130.5, 135.9, 138.7, 143.4, 144.3, 146.0, 171.1.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH:24]=[CH:25][C:26](=[O:28])[CH3:27]>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[CH:24]1[CH2:3][C:2](=[O:1])[CH2:27][C:26](=[O:28])[CH2:25]1
Reactant: CC(=O)C=Cc1cc(C)ccc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: Cc1ccc(Cl)c(C2CC(=O)CC(=O)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (4.3 g) was added at room temperature diethyl malonate (10.1 g), and then added little by little 4-(2-chloro-5-methylphenyl)-3-buten-2-one (18.9 g). The mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (33 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (33 ml) for 15 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(2-chloro-5-methylphenyl)cyclohexane-1,3-dione (7.8 g) as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[OH:27])[CH3:2].Cl[CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32]>>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:24])[CH3:25])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[O:27][CH2:29][C@@H:30]([OH:33])[CH2:31][OH:32])[CH3:2]
Reactant: OC[C@H](O)CCl
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1O
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1OC[C@@H](O)CO

Procedure:
(S)-3-(2-Ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxa-diazol-3-yl}-6-methyl-phenoxy)-propane-1,2-diol is prepared from 2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenol and (S)-3-chloro-1,2-propanediol in analogy to Example 3; LC-MS: tR=1.07 min; [M+1]+=441.37; 1H NMR (CDCl3): δ 1.24 (d, J=6.5 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 2.05 (t, J=5.1 Hz, 1H), 2.41 (s, 3H), 2.51 (s, 3H), 2.73 (d, J=5.5 Hz, 1H), 2.78 (q, J=7.5 Hz, 2H), 2.97 (s, 3H), 3.81-4.00 (m, 4H), 4.12-4.21 (m, 1H), 4.95-5.05 (m, 1H), 7.06 (s, 1H), 7.13 (s, 1H), 7.88 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: O=C(Cn1cc(Cl)cnc1=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-chloropyrimidin-2-one (787 mg) and 2-bromo-4'-nitroacetophenone (1.47 g) in triethylamine (2 ml) and ethanol (40 ml) was stirred at ambient temperature for 1 hr. The reaction mixture was diluted with water and the solid filtered off.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:32][C:31]4[CH2:30][CH2:29][NH:28][CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH2:33]([N:35](CC)CC)C.C([O-])(=O)C.[Na+].N#CBr>C(O)C.ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:32][C:31]4[CH2:30][CH2:29][N:28]([C:33]#[N:35])[CH2:27][C:26]=4[CH:25]=3)=[O:23])[CH2:20][CH2:21]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: CCN(CC)CC
Reactant: O=C(c1cc2c(s1)CCNC2)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: N#CBr
Solvent: CCO
Solvent: ClCCl
Product: N#CN1CCc2sc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In ethanol, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (195 mg), triethylamine (0.2 ml) and sodium acetate (118 mg) were suspended. Cyanogen bromide (114 mg) was added to the resulting suspension, followed by stirring at room temperature for 2 hours. To the residue obtained by concentration of the reaction mixture under reduced pressure, dichloromethane was added. The mixture was washed with water and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane:methanol 100:1), whereby the title compound (51 mg, 28%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[H][H]>[Pt](=O)=O.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)N1CCC(=Nc2c(C)cccc2C)CC1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1

Procedure:
A mixture of 45 parts of ethyl 4-[(2,6-dimethylphenyl)imino]-1-piperidinecarboxylate, 0.3 parts of platinum dioxide in 160 parts of methanol is hydrogenated at normal pressure and at a temperature between 24° and 35° C. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is distilled, to yield 30 parts of the oily free base of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate; bp. 148°-153° C. at 0.01 mm. pressure. From this distillate, the hydrochloride salt is prepared in the usual manner in 1,1'-oxybisethane. The precipitated solid salt is filtered off and dried, yielding 28.5 parts of ethyl 4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate hydrochloride; mp. 195.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Temperature: 92.5 °C
Reaction time: 0.5 h

Procedure:
3.5 kg of p-anisidine are added to 6.25 kg of diethyl ethoxymethylenemalonate at 14° C., over 85 minutes without cooling of the reaction mass. At the end of addition, the temperature has reached 59° C. The temperature is kept at 59° C. for 30 minutes, and the reaction medium is then heated to 90-95° C. and kept at this temperature for 1 hour. The ethanol formed is then removed by distillation at atmospheric pressure and then under 250 mbar. After cooling to 45° C., 8.4 kg of diethyl 2-[(4-methoxyphenylamino)methylene]malonate are recovered in the form of a brown viscous oil, with a quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C1C=NC2C3N=CC=CC=3C=CC=2C=1.[CH:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: OC1CCCCC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Brc1ccc(OC2CCCCC2)cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To a stirred mixture of 1-bromo-4-iodo-benzene, (1.00 g, 3.53 mmol), o-phenanthroline (255 mg, 1.41 mmol) and cyclohexanol (1.770 g, 17.67 mmol) in toluene (1.500 mL) was added copper(I) iodide (135 mg, 0.707 mmol) and Cs2CO3 (2.879 g, 8.837 mmol). The resulting mixture was then stirred at 120° C. in a sealed tube for 15 hours. The solvent was then removed under reduced pressure and the product was purified by flash chromatography (eluted by hexane). 1H NMR (400 MHz, MeOD) δ1.32-1.65 (m, 6H), 1.77-1.86 (m, 2H), 1.94-2.03 (m, 2H), 4.24-4.37 (m, 1H), 6.81-6.90 (m, 2H), 7.36-7.41 (m, 2H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([C:13](=[N:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(C)C.[Ru+2]>[C:16]1([NH:15][CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:14])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=Nc1ccccc1)c1ccccc1
Agent: [Ru+2]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(Nc1ccccc1)c1ccccc1
Temperature: 60 °C

Procedure:
The reaction was carried out in a multiwell hydrogenation vessel. Dichloro-{1,2-Bis[(2R,5R)-2,5-diphenylphospholano]methane}[(1S,2S)-1,2-diphenylethylenediamine)] ruthenium (II) (2.2 mg, 0.0025 mmol) was suspended in degassed isopropanol (2 ml) in a Schlenk flask under nitrogen. Added potassium tert-butoxide (1M in tert-butanol, 0.025 ml) and heated until a yellow solution was obtained. The glass liner was charged with N-(1-phenylethylidene)aniline (98 mg, 0.50 mmol). Charged to 10 bar nitrogen and vented (×5). Added the precatalyst solution and charged to 10 bar nitrogen and vented (×2). Commenced stirring at 1000 rpm and heated to 60° C. Charged to 10 bar H2 and stirred for 18 h. Cooled to room temperature, vented and evaporated to give phenyl-(1-phenylethyl)amine, conversion>99%, ee 71% (GC, sample derivatised by treatment with acetic anhydride pyridine, Chirasil DEX CB, 25 m×0.25 mm, injector/detector 200° C., helium 20 psi, 140° C. for 20 minutes then ramp at 5° C./min to 200° C., hold for 5 minutes, retention times 23.21 minutes and 23.45 minutes).
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[C@H:40]([C:51]([NH:53][C@H:54]([C:59]([NH:61][C@H:62]([C:67]([NH2:69])=[O:68])[CH2:63][CH2:64][S:65][CH3:66])=[O:60])[CH2:55][CH:56]([CH3:58])[CH3:57])=[O:52])[CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@H:40]([C:51]([NH:53][C@H:54]([C:59]([NH:61][C@H:62]([C:67]([NH2:69])=[O:68])[CH2:63][CH2:64][S:65][CH3:66])=[O:60])[CH2:55][CH:56]([CH3:57])[CH3:58])=[O:52])[CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 97 %

Procedure:
Condensation of BocPro-DPhe-PheNHNH2 (Example 9, 477 mg.) and HTrp-Leu-MetNH2 (510 mg.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-DPhe-Phe-Trp-Leu-MetNH2 in 97% yield. De-t-butoxycarbonylation of BocPro-DPhe-Phe-Trp-Leu-MetNH2 (0.80 g.) using trifluoroacetic acid containing 10% water gave HPro-DPhe-Phe-DTrp-Leu-MetNh2, which was isolated as the amorphous white solid phosphate (1:2) salt tetrahydrate in 32% yield.