Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:64][C@H:65]([C:75]([O:77][CH3:78])=[O:76])[CH2:66][CH2:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71].Cl>CN(C=O)C>[CH3:78][O:77][C:75](=[O:76])[C@@H:65]([NH:64][C:27]([C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@H:8]2[C:6](=[O:7])[NH:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[O:30])[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:19]=1)=[O:29])[CH2:66][CH2:67][C:68]([O:69][C:70]([CH3:71])([CH3:72])[CH3:73])=[O:74]
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1
Reaction time: 24 h

Procedure:
To a solution of 1.50 g 5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carboxylic acid in 22 ml DMF were added 0.60 ml DIPEA, 1.38 g HATU and 923 mg H-Glu(OtBu)-OMe hydrochloride. After stirring for 24 h the solution was concentrated, taken up with dichloromethane and subsequently extracted with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by chromatography on silica using DCM/MeOH 97:3 as eluent. Yield: 2.0 g.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9](OS(C)(=O)=O)[CH2:8][N:7]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17].[C:29]([SH:32])(=[O:31])[CH3:30].CC(C)([O-])C.[K+]>CN(C)C=O>[C:29]([S:32][C@@H:9]1[CH2:8][N:7]([C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)=[O:17])[C@H:6]([CH2:5][O:4][CH2:3][CH2:2][F:1])[CH2:10]1)(=[O:31])[CH3:30]
Reactant: CC(=O)S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCCF)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](COCCF)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C

Procedure:
A solution of (2S,4R)-2-(2-fluoroethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.95 g) in dimethylformamide (5 ml) was added to a mixture of thioacetic S-acid (1.26 ml) and potassium tert-butoxide (1.98 g) in dimethylformamide (25 ml) in a nitrogen stream, and the mixture was heated at 75°-80° C. for 2 hours. The mixture was poured into ice-water (100 ml) and extracted with ethyl acetate (100 ml). The extract was washed with water (100 ml×2) and brine (100 ml), in turn, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (80 g) and eluted with chloroform to give (2S,4S)-4-acetylthio-2-(2-fluoroethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.75 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.Cl[C:12]([O:14][CH2:15][CH2:16][CH3:17])=[O:13].O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([O:14][C:12](=[O:13])[NH:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])[CH2:16][CH3:17]
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CCCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCOC(=O)Nc1c(C)cc(Br)cc1C
Yield: 86 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (4.3 g) and propyl chloroformate (2.70 mL) were mixed in acetonitrile (50 mL) and tetrahydrofuran (20 mL) and the reaction mixture was heated to reflux for 1 hour. Potassium carbonate (4.5 g) was added and the reaction mixture was refluxed for 1 hour and then poured onto crushed ice and saturated aqueous potassium carbonate (50 mL). The product was collected by filtration and washed with water (100 mL) to furnish 5.26 g (86% yield) of the title compound as a solid. LC-MS (m/z) 287 (MH+); tR=3.18, (UV, ELSD) 99%, 95%. 1H NMR (500 MHz, CDCl3): 0.93 (t, 3H), 1.62 (m, 2H), 2.15 (s, 6H), 4.00 (t, 2H), 7.28 (s, 2H), 8.74 (b, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1>>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:9]2[C:4]3[CH:3]=[C:2]([Cl:1])[S:17][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:16][CH2:15]1
Reactant: Clc1cccc(CBr)c1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Product: Clc1cccc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (70 mg, 43%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (110 mg, 0.41 mmol) and 1-(bromomethyl)-3-chlorobenzene (93 mg, 0.45 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.35 (s, 1H), 7.10 (m, 4H), 5.25 (d, 1H), 4.20 (m, 1H), 3.50 (s, 2H), 2.90 (m, 2H), 2.35 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H). MS (ESI) m/z: Calculated: 392.06; Observed: 393.2 (M++1).
Reaction SMILES: [Br-:1].[K+].[N+]([O-])(O)=O.[Br:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC(Cl)C>[Br:1][C:13]1[CH:14]=[C:9]([CH2:8][Br:7])[CH:10]=[CH:11][C:12]=1[O:15][CH3:16]
Reactant: [Br-]
Reactant: COc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CC(Cl)Cl
Product: COc1ccc(CBr)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.6 %

Procedure:
To solution of potassium bromide (29.6 g, 248 mmol) in nitric acid (21% by volume, 149 g, 497 mmol), was added dichloroethane (188 mL) and tetrabutylammonium chloride (1.04 g, 3.73 mmol) followed by 4-(bromomethyl)anisol (25.0 g, 124 mmol) in dichloroethane (62 mL), and the reaction was stirred at room temperature for 5 h. The organic layer was separated, washed with water (2×100 mL, 2×150 mL), 2% aqueous potassium carbonate (150 mL), dried over sodium sulfate, and the solvent removed under vacuum. The residue was purified by being run through a flash silica gel plug (10% ethyl acetate in hexanes) to give the title compound (I-42) (9.22 g, 26% yield). 1H NMR (400 MHz, CDCl3) δ: 7.59 (d, 1H), 7.30 (dd, J=8.2, 2.2 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 4.44 (s, 2H), 4.44 (s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>N1C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc(Cl)cc1
Yield: 61.4 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol) and p-chlorobenzoyl chloride (0.72 mL, 5.5 mmol) in pyridine (10 mL) provided 4-chloro-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (1.0 g). Mp 214.0-214.5° C.; Anal. Calcd. for C19H16CINO2: C, 70.05; H, 4.95; N, 4.30; Found: C, 70.10; H, 4.72; N, 4.17.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].CO[C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1>C(OCC)C>[CH3:7][C:6]([CH3:8])=[CH:5][CH2:4][CH2:3][C:11]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=1
Reactant: CC(C)=CCCBr
Reactant: COC1=CC(=O)CC1
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)=CCCC1=CC(=O)CC1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Magnesium turnings 2.1 g (0.086 mole) were added to 50 ml diethyl ether with stirring. 1-Bromo-4-methyl-3-pentene 10 g (0.061 mole) was added dropwise over 30 minutes. The reaction was allowed to warm from 25° C. to 40° C. during the addition and aged for 30 minutes. A solution of 3-Methoxy-2-cyclopenten-1-one, 10 g (0.089 mole) in diethyl ether was added at 25° C. The resulting mixture was aged 30 minutes then quenched with 20% aqueous acetic acid (50 ml). The organic layer was dried over sodium sulfate, filtered and distilled to give 6.6 g (65% yield) of 3-(4-methyl-3-pentenyl)-2-cyclopenten-1-one. The 3-(4-methyl-3-pentenyl)-2-cyclopenten-1-one had a boiling point (Bp) of 117° C. at 5 mmHg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH3:11])[C:5]([C:12]#[N:13])=[C:4]([SH:14])[N:3]=1.Cl[CH2:16][C:17]1[N:18]=[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[S:20][CH:21]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([S:10][CH3:11])[C:5]([C:12]#[N:13])=[C:4]([S:14][CH2:16][C:17]2[N:18]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[S:20][CH:21]=2)[N:3]=1
Reactant: CSc1c(C#N)c(N)nc(S)c1C#N
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1c(C#N)c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
250 mg (1.13 mmol) of 2-amino-6-mercapto-4-(methylthio)pyridine-3,5-dicarbonitrile, 412 mg (1.69 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 378 mg (4.50 mmol) of sodium bicarbonate are combined in 5 ml of DMF and stirred at room temperature for 12 h. A voluminous solid precipitates out, which solid is filtered off using a glass frit, washed three times with water and twice with diethyl ether and dried. This gives a white powder.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:24][CH2:25][CH2:26][OH:27])=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH:55]([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C1CCC(N=C=NC2CCCCC2)CC1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:43]([O:47][C:48]([NH:50][C@@H:51]([CH:55]([CH3:57])[CH3:56])[C:52]([O:27][CH2:26][CH2:25][O:24][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([C:10]3[N:8]4[CH:9]=[C:4]([C@@H:3]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:40])[CH2:29]5)[C:2]([F:1])([F:41])[F:42])[CH:5]=[CH:6][C:7]4=[N:12][N:11]=3)=[N:14]2)=[CH:19][C:18]=1[F:23])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)c(OCCO)cc5n4)n3c2)C(F)(F)F)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
To a stirred solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-7-(2-hydroxyethoxy)quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (Example 123, Step A; 100 mg, 0.169 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (44.1 mg, 0.203 mmol) in DCM (2 mL) was added DMAP (41.4 mg, 0.339 mmol) and DCC (41.9 mg, 0.203 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 4 hours and then poured into water. The mixture was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO3 solution and brine, dried, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (5-95% acetonitrile/water) to give (S)-2-(2-(6-((R)-1-((S)-3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoro quinolin-7-yloxy)ethyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (110 mg, 82%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([CH3:26])=[CH:5][C:4]=1[OH:27].[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42](Cl)(=[O:44])=[O:43].O1CCCC1.Cl>N1C=CC=CC=1>[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42]([NH:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([CH3:26])=[CH:5][C:4]=1[OH:27])(=[O:44])=[O:43]
Reactant: CCCCCCCCCCCCCCCCOc1cc(N)c(O)cc1C
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2OCCOC)c(O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 g of 2-amino-4-hexadecyloxy-5-methylphenol hydrochloride and 18 g of 4-(2-methoxyethoxy)nitrobenzene-3-sulfonyl chloride prepared as described in Step (a) above were added to a mixture of 100 ml of tetrahydrofuran and 10 ml of pyridine and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to a mixture of 300 ml of ice water and 50 ml of concentrated hydrochloric acid with stirring. The crystals thus-precipitated were recovered with filtration, washed with water, air-dried and recrystallized from 100 ml of acetonitrile. Yield: 35 g. Melting Point: 85.5° to 86° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=3)[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[NH:35][C:36](Cl)=[O:37].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][N:26]1[NH:35][C:36](=[O:37])[O:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:16]2
Reactant: O=C(Cl)NN1CCc2ccccc2C1
Reactant: Oc1ccc2c(c1)CN(Nc1ccncc1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NN1CCc2ccccc2C1)Oc1ccc2c(c1)CN(Nc1ccncc1)C2
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a mixture of 2,3-dihydro-2-(4-pyridinylamino)-1H-isoindol-5-ol (1.50 g), triethylamine (1.47 g), and chloroform (15 ml), 1,2,3,4-tetrahydroisoquinolin-2-ylcarbamyl chloride (1.55 g) in chloroform (10 ml) was added dropwise with stirring, under nitrogen, at ambient temperature. The reaction mixture was stirred under reflux for 3 hrs, at ambient temperature overnight and poured into dilute sodium bicarbonate solution. The layers were separated. The aqueous phase was extracted with chloroform, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The residue was chromatographed on silica, eluting with 7% methanol-dichloromethane followed by 185:14:1 dichloromethane-methanol-ammonium hydroxide. The appropriate fractions were collected and evaporated. The residue was recrystallized from ethanol-toluene to give 800 mg (31%) of product, mp 162-163° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:50])=O>ClCCl>[C:1]12([C:11]3[CH:12]=[C:13]([C:24]#[C:25][C:26]4[CH:34]=[CH:33][C:29]([C:30]([Cl:50])=[O:31])=[CH:28][CH:27]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=S(Cl)Cl
Reactant: COCCOCOc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COCCOCOc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
A solution of 3.14 g (6.8 mmol) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl]benzoic acid in 100 ml of anhydrous dichloromethane was introduced into a round-bottomed flask, 1.4 ml (6.8 mmol) of dicyclohexylamine was added and stirring was carried out for one hour. 500 μl (6.8 mmol) of thionyl chloride were then added and stirring was carried out for one hour. Evaporation was carried out to dryness, the residue was taken up in anhydrous ethyl ether, the dicyclohexylamine salt was filtered and the filtrate was evaporated. 3.3 g (100%) of the crude acid chloride were collected, which chloride was used as is in the continuation of the synthesis to follow.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][N:10]([CH2:15][CH2:16][N:17]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:11][C:12]([OH:14])=[O:13])[CH2:5][C:4](=[O:28])[O:3]1.C(N(CC)CC)C.[NH2:36][CH:37]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49].Cl>CN(C)C=O.[OH-].[Na+]>[C:19]([CH2:18][N:17]([CH2:16][CH2:15][N:10]([CH2:11][C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:6]([CH2:7][C:2](=[O:1])[NH:36][CH:37]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[CH2:5][C:4]([OH:28])=[O:3])[CH2:22][C:23]([OH:25])=[O:24])([OH:21])=[O:20]
Reactant: CCOC(=O)CN(CCN(CCN1CC(=O)OC(=O)C1)CC(=O)O)CC(=O)O
Reactant: CCCCCCC(N)CCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCC(CCCCCCCCCCC(=O)O)NC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.33 g (38 mmol) of N3-(2,6-dioxomorpholinoethyl)-N6-(ethoxycarbonylmethyl)-3,6-diazaoctanedioic acid (Example 13a of EP 0 331 616) is suspended in 100 ml of dimethylformamide and mixed in an ice bath with 21.07 ml (152 mmol) of triethylamine and 11.36 g (38 mmol) of 12-aminooctadecanoic acid. After stirring overnight at room temperature, it is concentrated by evaporation in a vacuum, and the residue is absorptively precipitated with 500 ml of diethyl ether. It is suctioned off and the dried reaction product is dissolved in 50 ml of 2 n sodium hydroxide solution. After three hours of stirring, it is neutralized with dilute hydrochloric acid, evaporated to dryness in a vacuum and recrystallized from water. 15.64 g (61% of theory) of a gray powder is obtained.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([OH:22])=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]([Cl:25])=[O:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](OCC(=O)O)(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC(=O)Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
In a 500ml round-bottom flask was mixed {[tert-butyl(diphenyl)silyl]oxy}acetic acid (17g, 54.0mmoles, 1eq), thionyl chloride (11.7g, 0.162moles, 3eq) and dry CH2Cl2(120ml, 0.45M). This mixture was refluxed for 5hours. After cooling to room temperature the volatiles were removed in vacuo. The resulting residue washed twice with toluene and the toluene was subsequently removed in vacuo to remove excess thionyl chloride. This resulted in 18g (100%) of titled compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:26](=[O:28])[CH3:27]
Reactant: c1ccc(CNCCCSc2ccncc2)nc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCCSc1ccncc1)Cc1ccccn1
Yield: 85.6 %

Procedure:
To a solution of 1.62 g (6.24 mmol) of 4-[3-(N-2pyridylmethylamino)propylthio]pyridine and 1.10 ml (7.80 mmol) of triethylamine in 10 ml of methylene chloride, 0.51 ml (7.80 mmol) of acetyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain 1.61 g of the desired compound (yield: 85.6%, yellow oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][N:11]([C@@H:12]([C:13](=[O:14])[NH2:15])[CH2:16][CH:17]([CH3:19])[CH3:18])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of (2R)-2-(4-chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (4.2 grams, 14 mmol) in DMF (50 mL) was added cesium carbonate (13.6 grams, 417 mmol). To this reaction was added 4-(toluene-4-sulfonyloxymethyl)-piperidine 1-carboxylic acid tert-butyl ester (ref.: Gilissen, C.; Bormans, G.; De Groot, T.; Verbruggen, A. J. Labeled Cmpd. Radiopharm. 1999, 42, 1289; 10.4 g, 282 mmol). The reaction was stirred at 70° C. for 18 h. The reaction was then quenched with sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated to a clear oil. The oil was then purified on a Biotage 40S (eluted with 30% EtOAc in hexanes) to afford a white solid (3.0 g, 44%). MS(ESI), (M+H)+502.1; 1H NMR (DMSO-d6, 500 MHz) δ7.86 (dd, 2H, J=2.0, 6.8), 7.65 (dd, 2H, J=2.0, 6.8) 7.37 (br s, 1H), 7.07 (br s, 1H), 4.19 (t, 1H, J=7.6), 3.92 (br s, 2H), 3.35 (dd, 1H, J=15, 6.8), 3.05 (dd, 1H, J=15, 8.1), 1.85 (br s, 1H), 1.50-1.70 (m, 4H), 1.38 (s, 9H), 1.10-1.20 (m, 1H), 0.80-1.00 (m, 3H), 0.82 (d, 6H, J=7.6).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.O[CH2:35][CH2:36][CH2:37][C@@H:38]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:39][C:40]([O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[O:41]>C(Cl)Cl>[Br:1][CH2:35][CH2:36][CH2:37][C@@H:38]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[NH:39][C:40]([O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])=[O:41]
Reactant: CC(C)(C)OC(=O)[C@H](CCCO)NC(=O)OCC[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CCCBr)NC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of N-bromosuccinimide (2.129 g, 11.96 mmol) in DCM (10 ml) was treated with triphenylphosphine (2.93 g, 11.17 mmol) in DCM (10 ml), followed by pyridine (0.387 ml, 4.79 mmol) and tert-butyl 5-hydroxy-N-{[2-(trimethylsilyl)ethoxy]carbonyl}-L-norvalinate (1.33 g, 3.99 mmol) in DCM (5 ml). The resulting black mixture was stirred at room temp for 24 h. The mixture was pre-absorbed onto SiO2 and purified by chromatography (silica gel, 0-5-10-20% Et2O/isohexane) to afford tert-Butyl 5-bromo-N-{[2-(trimethylsilyl)ethoxy]carbonyl}-L-norvalinate Intermediate 5 (1.1 g) as a colourless oil.