Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([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])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4].[C:50]([O:54][C:55]([NH:57][CH2:58][C:59](O)=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51]>O1CCCC1>[C:50]([O:54][C:55]([NH:57][CH2:58][C:59]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:49])[N:15]([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])[C:16](=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:4])=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CNC(=O)OC(C)(C)C
Yield: 68 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycine. Yield 68%. [α]D =+14.5° (c=0.92, tetrahydrofuran).
Reaction SMILES: [NH2-].[Na+].[C:3]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(OCC)C>[CH2:10]([CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:3]1=[O:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCCCC1
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C1CCCCC1Cc1ccccc1
Yield: 40.2 %

Procedure:
Sodium amide (15.6 g, 0.4 mol) was added portionwise to a solution of cyclohexanone (39.26 g, 1.46 mL, 0.4 mol) in 350 mL of anhydrous diethyl ether. The resulting suspension was heated under reflux for 3 h after which time benzyl chloride (46.8 g, 42.6 mL, 0.37 mol) was rapidly added. The mixture was heated under reflux for a further 5 h, then cooled and poured into cold water. The organics were washed once with a dilute HCI solution, a dilute sodium bicarbonate solution and finally with water. The organic layer was dried, filtered and the ether was removed to give 2-benzylcyclohexanone as an oil (28 g, 40%).
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:42])[CH3:41])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:40]([NH:39][C:36]1[CH:35]=[CH:34][C:33]([S:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:13][CH:12]=2)[C:6]([OH:43])=[O:5])(=[O:31])=[O:32])=[CH:38][CH:37]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)cc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
57 mg (0.09 mmol) of (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield 42 mg. MS (ES+): m/e=559.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:30][N:29]=1.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:28]2[N:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]3[CH:42]=[CH:41][N:40]=[N:39]3)=[CH:30][N:29]=2)[N:18]=1
Reactant: Clc1ncc(CCCCn2ccnn2)cn1
Reactant: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2F)n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(COc2ncc(CCCCn3ccnn3)cn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.100 g, 0.35 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by the addition of sodium tert-butoxide (NaOtBu) (0.041 g, 0.42 mmol). After stirring for 15 min at r.t. 2-chloro-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine (0.075 g, 0.32 mmol) is added slowly and stirred for further 3 h at r.t. Ethyl acetate (20 ml) is added, the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 97:3) 2-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-5-(4-[1,2,3]triazol-1-yl-butyl)-pyrimidine is obtained as a colorless solid. Yield 0.104 g (75%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[CH:37]([N:10]1[CH:11]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)=[N:9]1)([CH3:39])[CH3:38]
Reactant: CC(C)I
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 60 °C

Procedure:
To a solution of 2-[4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline (0.075 g) in dimethyl formamide (2 ml) was added cesium carbonate (0.098 g) and 2-iodo propane (0.030 ml) and the reaction mixture heated at 60° C. for 72 h. The reaction mixture was poured into water and extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated. Purification via Prep TLC eluting with 2% methanol/1% saturated ammonium hydroxide/67% ethyl acetate/30% hexane provided the title compound (60 mg). 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=6.2 Hz, 2H), 8.16 (d, J=8.7 Hz, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.70 (m, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.53 (t, J=7.1 Hz, 1H), 7.38 (d, J=9.1 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 5.38 (s, 2H) 4.51 (m, 1H), 1.54 (d, J=6.6 Hz, 6H); MS: (M+H m/z=421.2).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][C:16]=4[CH:6]2[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3]1)[NH:11][CH:10]=3.[OH-].[K+].[C:23]1(C)[CH:28]=CC(S(OC(C)C)(=O)=O)=C[CH:24]=1>CS(C)=O>[CH3:24][CH:23]([N:11]1[C:12]2[C:17]3[C:9]([CH2:8][C@@H:7]4[C@@H:6]([C:16]=3[CH:15]=[CH:14][CH:13]=2)[CH2:5][CH:4]([C:18]([OH:20])=[O:19])[CH2:3][N:2]4[CH3:1])=[CH:10]1)[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)OC(C)C)cc1
Reactant: CN1CC(C(=O)O)CC2c3cccc4[nH]cc(c34)CC21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1CC(C(=O)O)CN(C)[C@@H]1C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
To a 250 ml, three-neck round bottom flask was added 15.0 g (50.8 mmol) of 92% pure 9,10-dihydrolysergic acid, 18.08 g (277.7 mmol) of 86% pure powdered potassium hydroxide and 150 ml of DMSO. The mixture was stirred for approximately 15 minutes and 14.3 g (66.8 mmol) of p-toluenesulfonic acid, 1-methylethyl ester was added dropwise to the reaction mixture over a period of about 10 minutes. The reaction mixture was stirred at room temperature for approximately 24 hours and poured into 750 ml of ice water. The mixture was washed with 150 ml of ethyl acetate, and the aqueous phase was separated and the pH was adjusted to 5 with glacial acetic acid. The mixture was cooled in the freezer and the precipitated solid was collected by vacuum filtration. The solid was washed with water and dried in vacuo to provide 12.8 g of the title compound. A second crop of 0.82 g of the desired compound was obtained. The purity of the first crop material was 99.6% and the purity of the second crop material was 98.8% as determined by HPLC. Exact mass: theory 312.18378; found 312.18485.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH2:15])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[NH:15][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCc1ccc(N)c(F)c1
Reactant: CCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCC)cc1F

Procedure:
In a manner directly analogous to that described in Example 9, ethyl 3-fluoro-4-aminohydrocinnamate is alkylated with hexadecyl bromide to form ethyl 3-fluoro-4-(hexadecylamino)hydrocinnamate. Subsequently, in a manner directly analogous to that described in Example 10, ethyl 3-fluoro-4-(hexadecylamino)hydrocinnamate is hydrolyzed to 3-fluoro-4-(hexadecylamino)hydrocinnamic acid.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([NH2:23])=[CH:21][C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:19]2)[CH:15]=[CH:16][CH:17]=1)C1C=CC=CC=1.O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:23][C:22]1[N:18]([C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][C@H:10]([CH3:28])[CH2:9][OH:8])[N:19]=[C:20]([C:24]([CH3:25])([CH3:27])[CH3:26])[CH:21]=1
Reactant: C[C@H](COCc1ccccc1)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Yield: 78.4 %

Procedure:
A solution of Intermediate 151a (0.37 g, 0.97 mmol) in ethanol (IMS grade, 8 mL) was treated with water (1 mL) and ammonium formate (0.61 g, 9.7 mmol). The mixture was purged with N2 then 10% Pd/C (0.31 g, 0.29 mmol Pd) was added. The mixture was heated to reflux for 16 h then filtered through celite and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and water. The phases were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC, using 0-75% EtOAc in cyclohexane to give the title compound (0.22 g, 79%) as a pink gum. LCMS (Method 3): Rt 2.44 min, m/z 290.3 [MH+].
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>>[CH3:23][C@@H:24]1[CH2:28][CH2:27][N:26]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:25]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: C[C@@H]1CCNC1
Product: C[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-3-methylpyrrolidine (1.2 equiv) to give 141 (2.4 mg, M+1 381.1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([O:22][C:23]4[C:28]5[N:29]=[C:30]([NH2:32])[O:31][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][N:19]=[C:18]([O:22][C:23]4[C:28]5[N:29]=[C:30]([NH:32][C:33](=[O:35])[CH3:34])[O:31][C:27]=5[CH:26]=[CH:25][CH:24]=4)[CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(c1ccc(F)cc1)N1CCN(c2cc(Oc3cccc4oc(N)nc34)ncn2)CC1
Product: CC(=O)Nc1nc2c(Oc3cc(N4CCN(C(C)c5ccc(F)cc5)CC4)ncn3)cccc2o1

Procedure:
4-(6-(4-(1-(4-Fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo[d]oxazol-2-amine (0.06 g, 0.14 mmol, Example 63) was reacted with acetic anhydride under the conditions of Example 1(b) to give the desired product. Mp: 199.8° C. MS (ESI, pos. ion) m/z: 477 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[N:7][CH:8]=1.Cl[S:11]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:12]>N1C=CC=CC=1.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][S:11]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])(=[O:13])=[O:12])[CH:6]=[N:7][CH:8]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: COc1cncc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cncc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-methoxypyridin-3-amine (1 eq) in pyridine (0.4 M) was added methyl 2-(chlorosulfonyl)benzoate (1 eq) and the mixture was stirred overnight at room temperature. The mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (0-8% MeOH/CH2Cl2) to give afford the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 10.56-10.66 (m, 1H) 8.55-8.61 (m, 1H) 7.95-8.01 (m, 1H) 7.86-7.94 (m, 1H) 7.67-7.73 (m, 2H) 7.34-7.40 (m, 1H) 7.02 (s, 1H) 3.83 (s, 3H) 3.73 (s, 3H).
Reaction SMILES: [C:1]([N:11]([C:45]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[N:46]SC)[CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C>[C:1]([N:11]([C:45]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])=[N:46][NH:66][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH2:12][CH2:13][CH2:14][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: NCc1ccccc1
Reactant: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCN(C(=O)OCc2ccccc2)C(=NSC)C(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc([C@@H](C)NC(=O)[C@@H](CCCN(C(=O)OCc2ccccc2)C(=NNCc2ccccc2)C(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 93.2 %

Procedure:
A solution of (R)-N5 -(Cbz)-N5 -[methylthio(Cbz-iminomethyl)]-N2 -(diphenylacetyl)-(R)-N-[1-(4-methoxyphenyl)ethyl]ornithine amide (0.25 g, 0.312 mmol; see Example 35(d) above) and benzylamine (0.05 mL; 0.476 mmol) in DMF (5 mL) was stirred overnight at room temperature. The DMF was removed in vacuo and the residue dissolved in EtOAc. The EtOAc solution was washed with KHSO4 solution, 0.5 N NaOH solution and brine, dried over Na2SO4 and concentrated in vacuo to afford 0.25 g of the sub-title compound. The material was used directly in the next step.
Reaction SMILES: C(N(CC)CC)C.C([SiH](CC)CC)C.[CH2:15]([O:20][C:21]([N:23]1[C:27](=[O:28])[CH2:26][CH2:25][CH:24]1[C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:22])[CH2:16][CH2:17][CH:18]=[CH2:19]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:15]([O:20][C:21]([N:23]1[C:27](=[O:28])[CH2:26][CH2:25][CH:24]1[C:29]([OH:31])=[O:30])=[O:22])[CH2:16][CH2:17][CH:18]=[CH2:19]
Reactant: C=CCCCOC(=O)N1C(=O)CCC1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCOC(=O)N1C(=O)CCC1C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
Under nitrogen, to a stirring solution of 240 mg of palladium acetate (1.1 mmol) in 20 mL of de-gassed dichloromethane, was added 460 uL of triethylamine (3.3 mmol), and 5.33 mL of triethylsilane (33 mmol). After stirring at rt for 15 min, 7.3 g of intermediate 17-2 in 25 mL of de-gassed dichloromethane was added in. The resulting solution was stirred at rt overnight. The reaction mixture was passed through a celite pad, and the filtrate was concentrated and purified by flash column chromatography using DCM/MeOH (v/v 9/1) as eluent, giving colorless oil 4.55 g (85%). LC-MS: m/z=240.1 (ES−).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:21]C(C)(C)C)(=[O:20])=[O:19]>ClC(Cl)Cl>[F:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH2:21])(=[O:19])=[O:20]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1SCCF
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1ccccc1SCCF
Reaction time: 18 h

Procedure:
25 ml of trifluoroacetic acid are added at a temperature of 0° C. to a solution of 3.88 g of 2-(2-fluoroethylthio)-N-tert.-butylphenylsulfonamide, obtained in accordance with Example P1, in 25 ml of trichloromethane. After stirring for 18 hours at a temperature of +25° C., the resulting brown reaction mixture is lyophilised. After chromatographic purification of the oily residue with 1) ethyl acetate/petroleum ether (1:1) over silica gel and 2) dichloromethane/acetone (9:1) over silica gel, the resulting fractions are concentrated by evaporation to give 1.5 g (60.5% of the theoretical yield) of crystalline 2-(2-fluoroethylthio)-phenylsulfonamide.
Reaction SMILES: [CH3:1][CH:2]([CH3:35])[C:3]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1.C(Cl)Cl>CO.[Pd]>[CH3:1][CH:2]([CH3:35])[CH:3]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=1
Reactant: CC(C)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 38 h
Yield: 93.8 %

Procedure:
To a stirred solution of 4-(3-methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (87 mg) at r.t. in methanol (4 ml) and CH2Cl2 (1 ml) under an argon atmosphere was added the 10% Pd/C (10 mg). The mixture was then stirred at r.t. under a hydrogen atmosphere for 38 hours. The catalyst was filtered off and washed with MeOH. The filtrate was concentrated to leave 4-(3-methyl-2-phenyl-butyl)-1-trityl-1H-imidazole (82 mg) of an off-white sticky solid which was used in the next step without further purification. MS (ISP): 243.2 ([Trt]+)
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25][N:7]1[C:8]([C:9](=[O:18])[C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]1=[O:19]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2cc(F)cc(F)c2)c(=O)[nH]c1=O
Yield: 59.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (236 mg, yield: 59.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[S:35]>C1COCC1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[S:35])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: Fc1ccccc1N=C=S
Solvent: C1CCOC1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
The compound of example 223 (0.150 g, 0.000443 mol) was taken in THF (3 mL) and 2-fluorophenyl isothiocyanate (0.074 g, 0.000448 mol) was added and stirred at room temperature for 8-10 h. The reaction mixture was concentrated and directly used for preparation of compound of example 257.
Reaction SMILES: [CH:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.[N:7](OS(C)(=O)=O)([CH3:9])[CH3:8].C([Li])CCC>C1COCC1.CCCCCC>[CH3:8][N:7]([C:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH3:9]
Reactant: [Li]C1C=CC=C1
Reactant: CN(C)OS(C)(=O)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [Li]C1(N(C)C)C=CC=C1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 g of cyclopentadienyllithium (0.042 moles) in 30 ml of THF was added slowly at −30° C. to a solution of 5.9 g of compound 6 (0.042 moles) in 20 ml of THF. The mixture was then heated to −20° C. and stirred for 30 min. Hexane was then added and the solution was filtered. 1.8 ml of a 2.3 molar solution of butyllithium (0.042 moles) in hexane were then added at −20° C. to produce a precipitate. The precipitate was filtered off and washed with twice 20 ml of hexane. After drying under vacuum, 2.0 g (40% of the theoretical yield) of compound 7 were obtained in the form of a white powder; cf. Angew. Chem., Int. Ed. Engl. 19, (1980), 1010. 1H NMR (400 MHz, THF): δ=5.34 (bd, J=2.2 Hz, 2H); 5.15 (bd, J 2.2 Hz, 2H); 2.56 (s, 6H).