Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:19]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.N>CO.C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C@H:11]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:22]=3)[C@@H:14]3[CH2:15][CH2:16][CH2:17][N:13]3[CH2:12]2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)c1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)cc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 90 %

Procedure:
1-(3,5-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.80 mmol scale, to give 1.10 g (90%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C28H38N2O4, 466.3; m/z found, 467.4 [M+H]+. 1H NMR (MeOH-d4): 7.16 (t, J=7.8, 1H), 6.95 (m, 3H), 6.90 (d, J=7.5, 1H), 6.75 (m, 1H), 6.33 (m, 1H), 3.93 (m, 3H), 3.76 (s, 6H), 3.43 (m, 2H), 3.37 (m, 1H), 2.48 (m, 6H), 2.33 (m, 1H), 2.15 (m, 1H), 1.95 (m, 3H), 1.80 (m, 1H), 1.69 (m, 1H), 1.60 (m, 4H), 1.46 (br s, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](I)[CH:14]=1)=[O:8])[CH3:5].[CH3:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1.CC(O[K])=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([C:28]2[S:27][CH:26]=[N:25][C:24]=2[CH3:23])[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Reactant: Cc1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Solvent: CN(C)C=O
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-c2scnc2C)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 7.9 %

Procedure:
To a stirred solution of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (0.41 g, 1 mmol) and 4-methylthiazole (5 mmol) in 4 ml of DMF was added Pd(PPh3)4 (0.03 mmol) and CH3COOK (0.198 g, 2 mmol). The reaction mixture were heated to 100° C. and stirred for 14 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with n-hexanes/ethyl acetate (1:6) to give 4′-Methyl-5-(4-methyl-thiazol-5-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (30 mg, 80%) as a light yellow solid, MS (M+H)=381.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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[O:6][CH2:5]1.C(NC(C)C)(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([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][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reaction time: 0.17 h

Procedure:
In a 5 mL round-bottomed flask, Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25 mg, 0.068 mmol) was solved in dichloromethane (500 μl) to give a white suspension. N,N-diisopropylamine (26.3 mg, 35.6 μl, 0.204 mmol) was added. and after 10 min stirring, methanesulfonyl chloride (11.7 mg, 7.89 μl, 0.102 mmol) was added and the reaction mixture was stirred over night at room temp. The reaction was quenched with 15 mL of saturated NaHCO3 and extracted with dichloromethane (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as white solid (18 mg, 64.3%), MS (ISP) m/z=410.3 [(M+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[C:16](Br)=[C:15](Br)[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccc(F)c(F)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(F)c(F)c2)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-7-cyano-1-(3,4-difluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 358 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:13]([CH3:23])[N:12]([CH2:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:11]1=[O:33])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:19][CH2:18]2)=[C:13]([CH3:23])[N:12]([CH2:24][C:25]2[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=2[F:31])[C:11]1=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCCc1ccccc1
Reactant: Cc1c(N2CCNCC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(N2CCN(CCc3ccccc3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
To a solution of {(R)-2-[3-(2,6-difluoro-benzyl)-4-methyl-2,6-dioxo-5-piperazin-1-yl-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (2-2) (30 mg, 0.054 mmol) in DMF (1 mL) were added potassium carbonate (15 mg, 0.108 mmol), KI (1.3 mg, 0.0081 mmol), and (2-bromo-ethyl)-benzene (11.0 mg, 0.059 mmol) in the order, followed by stirring at 80° C. for 4 hrs. The solution was diluted in dichloromethane and washed with distilled water. After concentration of the organic layer thus formed, the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 1/1/1) and dried in a vacuum to afford 25 mg of the compound as a colorless oil (yield 70%). 1H NMR (300 MHz, CDCl3) δ 1.35 (9H, s), 2.22 (2H, m), 2.44 (3H, s), 2.49 (2H, m), 2.63 (2H, t), 2.82 (2H, t), 2.88 (2H, m), 3.62 (2H, m), 4.04 (1H, dd), 4.25 (1H, t), 5.01 (1H, m), 5.01-5.36 (2H, dd), 5.84 (1H, m), 6.89 (2H, t), 7.17-7.40 (11H, m)
Reaction SMILES: Br.[CH2:2]([O:6][CH:7]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:8]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([O:11]CC)=O)[CH2:3][CH2:4][CH3:5].[O-:31][C:32]#[N:33].[K+].Cl>C(O)C.O>[CH2:27]([O:26][CH:7]([O:6][CH2:2][CH2:3][CH2:4][CH3:5])[CH:8]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:32](=[O:31])[NH:33][C:9]1=[O:11])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOC(OCCCC)C(NCCCCCCC(=O)OCC)C(=O)OCC
Reactant: N#C[O-]
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCOC(OCCCC)C1C(=O)NC(=O)N1CCCCCCC(=O)OCC
Temperature: 100 °C
Reaction time: 22 h
Yield: 107.8 %

Procedure:
A mixture of 2-(dibutoxymethyl)glycine ethyl ester (2.0 g) with ethyl 7-bromoheptanoate (1.82 g) was heated under nitrogen in a bath at 100° C. for 3 hours. to give crude ethyl 7-((2,2-dibutoxy-1-ethoxycarbonylethyl)amino)heptanoate hydrobromide. A stirred solution of 3.28 g of this hydrobromide in ethanol (13 ml) was cooled in ice-water and treated with a solution of potassium cyanate (1.34 g) in water (4 ml), followed by 2 N-aqueous hydrochloric acid (3.63 ml); the cooling bath was removed and stirring was continued at room temperature for 22 hours. The ethanol was evaported in vacuo, the residue was shaken with water and ether, and the ethereal solution was separated, washed with water and dried over magnesium sulphate (MgSO4); removal of the ether left an oil which was heated under nitrogen at 100° C. for 3 hours, to give 5-dibutoxymethyl-1-(6-ethoxycarbonylhexyl)hydantoin (2.94 g). This was stirred in ether (6 ml) with water (48 ml) and N-aqueous sodium hydroxide (24.9 ml) at room temperature for 11/2 hours and, after the addition of more ether (50 ml), the aqueous phase was separated, cooled (ice-H2O), stirred with fresh ether and acidified to Congo Red with N-aqueous hydrochloric acid. The ethereal solution of carboxylic acid was thrice washed with water, dried (MgSO4), and evaporated, to leave 1-(6-carboxyhexyl)5-dibutoxymethylhydantoin (2.15 g) as a gum. When 1.89 g of the latter were cooled in ice-water and stirred with concentrated aqueous hydrochloric acid (8.5 ml), the resulting solution gave place spontaneously to a suspension of colourless crystals. The suspension was set at room temperature for 11/2 hours, diluted with water (10 ml) and set aside for 15 minutes; the crystals were then collected, washed with water, dried in vacuo, suspended in ether (3 ml), and collected again, to give 1-(6-carboxyhexyl)hydantoin-5-carboxaldehyde (0.74 g), m.p. 223.5°-225° C. (Found: C. 51.86; H, 6.66; N, 10.62. C11H16N2O5 required, C, 51.56; H, 6.29; N, 10.93%). In dimethyl sulphoxide-d6, this compound exists predominantly as the masked aldehyde, 1-(6-carboxyhexyl)-5-hydroxymethylenehydantoin.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[Br:1][C:12]1[C:13]([O:16][CH3:17])=[N:14][CH:15]=[C:10]([Cl:9])[C:11]=1[CH3:18]
Reactant: COc1cc(C)c(Cl)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c(C)c1Br
Temperature: 50 °C
Reaction time: 20 h
Yield: 97.4 %

Procedure:
20.2 g (114 mmol) of N-bromosuccinimide was charged to a N,N-dimethylformamide (DMF) 15 ml solution of 7.2 g (46 mmol) of 5-chloro-2-methoxy-4-methylpyridine, followed by stirring at 50° C. for 20 hours. A diluted sodium thiosulfate aqueous solution was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and subjected to filtration on the pad of a silica gel cake, and the solvent was distilled off under reduced pressure to obtain 10.6 g (yield: 97%) of 3-bromo-5-chloro-2-methoxy-4-methylpyridine (melting point: 44 to 45° C.).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])[CH2:2][CH3:3].[NH2:14][C:15]1[N:19]([CH2:20][CH2:21][CH3:22])[N:18]=[C:17]([CH3:23])[C:16]=1[C:24]([NH2:26])=[O:25]>N1C=CC=CC=1>[CH3:23][C:17]1[C:16]([C:24]([NH2:26])=[O:25])=[C:15]([NH:14][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[N:19]([CH2:20][CH2:21][CH3:22])[N:18]=1
Reactant: CCCn1nc(C)c(C(N)=O)c1N
Reactant: CCCOc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Product: CCCOc1ccccc1C(=O)Nc1c(C(N)=O)c(C)nn1CCC

Procedure:
The title compound was prepared from 2-n-propoxy-benzoyl chloride (5.33 g, 0.027 mol) and 5-amino-3-methyl-1-n-propylpyrazole-4-carboxamide (Preparation 6; 4.07 g, 0.022 mol) in pyridine (100 ml), following the procedure of Preparation 2, and was obtained as a white solid (5.84 g, 76%). A sample was crystallised from ethyl acetate-hexane, m.p. 111-113° C. Found: C, 62.83; H, 7.09; N, 16.26. C18H24N4O3 requires C, 62.77; H, 7.02; N, 16.27%.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([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)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1>>[O:4]1[C:8]2=[C:9]([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:34](=[O:35])[C:33]5[CH:37]=[CH:38][C:30]([C:29]([F:28])([F:39])[F:40])=[CH:31][CH:32]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound, white solid (117 mg, 93%), MS (ISP) m/z=503.3 [(M+H)+], mp 242.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-trifluoromethyl-benzoic acid.
Reaction SMILES: C([NH:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH3:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>Cl>[CH3:18][N:13]1[C:14]([CH3:16])([CH3:17])[CH2:15][CH:10]([NH2:9])[CH2:11][C:12]1([CH3:20])[CH3:19]
Reactant: CN1C(C)(C)CC(NC(=O)c2ccccc2)CC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1C(C)(C)CC(N)CC1(C)C

Procedure:
750 parts of 4-benzoylamino-1,2,2,6,6-pentamethyl piperidine are dissolved in 1000 parts of concentrated hydrochloric acid and the resulting solution is boiled under reflux for 10 hours. After cooling, sodium hydroxide is added until an alkaline reaction is obtained and the mixture is repeatedly extracted with methylene chloride. The residue obtained after removal of the methylene chloride by evaporation is distilled in vacuo, 300 parts of 1,2,2,6,6-pentamethyl-4-aminopiperidine boiling at 98° C./15 Torr distilling over.
Reaction SMILES: [NH2:1][C:2](=[N:27][N+:28]([O-:30])=[O:29])[NH:3][CH2:4][CH2:5][CH2:6][C@H:7]([C:24](O)=[O:25])[NH:8][C:9](=[O:23])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=1)=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[NH2:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][NH:43][C:24](=[O:25])[C@@H:7]([CH2:6][CH2:5][CH2:4][NH:3][C:2]([NH2:1])=[N:27][N+:28]([O-:30])=[O:29])[NH:8][C:9](=[O:23])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:38][CH:37]=1)=[O:33]
Reactant: NC(=N[N+](=O)[O-])NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCc1ccc(CCC(N)=O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: NC(=O)CCc1ccc(CNC(=O)[C@@H](CCCNC(N)=N[N+](=O)[O-])NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 60 %

Procedure:
Prepared analogously to Example 4b) from (R)-N5 -[amino[nitroimino)methyl]-N2 -(diphenylacetyl)-ornithine, 4-[2-(aminocarbonyl)ethyl]benzenemethanamine and TBTU in a yield of 60% of theory. Colourless crystals, Mp. 139-140° C. (Acetonitrile).
Reaction SMILES: C([O:5]C(NOCC(O)=O)=O)(C)(C)C.C(OCC)(=O)C.[CH:20]1([N:26]=[C:27]=[N:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.ON1C(=O)CCC1=O>C(#N)C>[CH:29]1([NH:28][C:27]([NH:26][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[O:5])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NOCC(=O)O
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyloxycarbonylaminoxy acetic acid was dissolved in ice-cooled ethyl acetate or acetonitrile and treated with N,N′-dicyclohexylcarbodiimide (1.0 equivalent) and N-hydroxysuccinimide (1.0 equivalent). The reaction mixture was stirred at room temperature overnight. The N,N′-dicyclohexylurea formed was removed by filtration and the filtrate was evaporated to dryness in vacuo. The crude Boc-AOA-OSu was either used directly in the next step or purified by recrystallisation from chloroform. Adopted from Kurth et al. J. Med. Chem. 1993, 36, 1255.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]([CH2:16][C:17]1[N:18]=[CH:19][NH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23])[CH2:13][CH2:14]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)Cl>[CH2:5]([N:12]([CH2:16][C:17]1[N:18]=[CH:19][NH:20][C:21]=1[C:22]([O:24][CH3:25])=[O:23])[CH2:13][CH2:14][Cl:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1[nH]cnc1CN(CCO)Cc1ccccc1
Solvent: ClCCl
Product: COC(=O)c1[nH]cnc1CN(CCCl)Cc1ccccc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
Thionyl chloride (0.5 ml, 4 equiv.) was added to a solution of methyl 4-((benzyl(2-hydroxyethyl)amino)methyl)-1H-imidazole-5-carboxylate (1.7 mmol, 1 equiv.) in DCM (10 ml), and the mixture was stirred for 16 h at 45° C. The reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was taken up in acetonitrile, the solvent was removed, and the residue was dried for 24 h in vacuo. The desired product was thus obtained in the form of a white solid. This was used in the following stage without further purification. Yield: quantitative
Reaction SMILES: [N:1]([CH:4]([CH:10]([CH3:18])[C:11]([Cl:17])([F:16])[C:12]([Cl:15])([F:14])[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]([CH:10]([CH3:18])[C:11]([Cl:17])([F:16])[C:12]([Cl:15])([F:14])[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(N=[N+]=[N-])C(C)C(F)(Cl)C(F)(F)Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(N)C(C)C(F)(Cl)C(F)(F)Cl
Yield: 52.9 %

Procedure:
In 30 ml of ethanol, 2.14 g (0.0070 mol) of ethyl 2-azido-3-methyl-4,5-dichloro-4,5,5-trifluoropentanoate and 0.61 g of 5% palladium-containing activated carbon were placed and bubbled with hydrogen gas (at a flow rate of 15 ml/min) for 22 hours. Consequently there was obtained 1.04 g (0.0037 mol, yield of 53% of ethyl 2-amino-3-methyl-4,5-dichloro-4,5,5-trifluoropentanoate having b.p. 71° C./2 mm, nD20 1.4328, νNH2 3398 and 3327 cm-1 and νC=O 1740 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].Cl[CH:22]([F:24])[F:23]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:22]([F:24])[F:23])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCOc1c(Br)ccc(O)c1OC
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1c(Br)ccc(OC(F)F)c1OC
Temperature: -45 °C
Yield: 30 %

Procedure:
To a stirring solution of 4-bromo-2-methoxy-3-(methoxymethoxy)phenol (700 mg, 2.66 mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate (734 mg, 5.32 mmol) cooled to −45° C. and chlorodifluoromethane (gas) was passed for 10 min and the resultant reaction mixture was heated to 80° C. for 2 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were dried over anhy. sodium sulphate and concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-5% ethyl acetate in pet ether) afforded 1-Bromo-4-(difluoromethoxy)-3-methoxy-2-(methoxymethoxy)benzene as a liquid (250 mg, 30%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)=[C:17]([CH:74]=3)[CH2:18][C@H:19]([NH:63][C:64]([O:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])[C:20](=[O:62])[NH:21][C@@H:22]([CH2:40][C@@H:41]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[C:23](=[O:39])[NH:24][C@H:25]([C:29]([O:31]CC3C=CC=CC=3)=[O:30])[CH2:26][C:27]=1[CH:28]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)=[C:17]([CH:74]=3)[CH2:18][C@H:19]([NH:63][C:64]([O:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])[C:20](=[O:62])[NH:21][C@@H:22]([CH2:40][C@@H:41]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[C:23](=[O:39])[NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH2:26][C:27]=1[CH:28]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNC(=O)OCc1ccccc1)C[C@@H]1NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(OCc3ccccc3)c(c2)C[C@@H](C(=O)OCc2ccccc2)NC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNC(=O)OCc1ccccc1)C[C@@H]1NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(OCc3ccccc3)c(c2)C[C@@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
210 mg (0.19 mmol) of the compound from Example 66A are dissolved in 2 ml of THF, and 1 ml each of water and methanol are added. After the addition of 13 mg (0.56 mmol) of lithium hydroxide the mixture is stirred at RT for 12 h. The reaction solution is then diluted with 30 ml of water and adjusted to pH=3 by adding 1N hydrochloric acid. The precipitate is collected by filtration and dried under high vacuum.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH3:26])=[CH:9][C:8]=1[CH3:27])C.[Li+].[OH-]>>[CH2:29]([O:28][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:17][C:16]=2[CH3:26])=[CH:9][C:8]=1[CH3:27])[C:4]([OH:31])=[O:3])[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccccc3)nc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2sc(-c3ccccc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-ethoxy-3-[2-methyl-4-(4-methyl-2-phenyl-thiazol-5-ylmethoxy)-phenyl]-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-[2-methyl-4-(4-methyl-2-phenyl-thiazol-5-ylmethoxy)-phenyl]-propionic acid as colorless oil.