Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14]=[C:13]([CH3:18])[C:11]3=2)[NH:6][CH:5]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[Cl:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[O:17][CH2:16][CH2:15][N:14]=[C:13]([CH3:18])[C:11]3=2)[N:6]([S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:5]=1
Reactant: CC1=NCCOc2ccc3[nH]cc(Cl)c3c21
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=NCCOc2ccc3c(c(Cl)cn3S(=O)(=O)c3ccccc3)c21
Yield: 21.1 %

Procedure:
Sodium hydride (60% in mineral oil, 38 mg, 0.95 mmol) was added to 10-chloro-1-methyl-3,8-dihydro-4H-[1,4]oxazepino[6,7-e]indole (Intermediate 40, 45 mg, 0.19 mmol) and benzensulfonyl chloride (74 μl, 0.58 mmol) in DMF (3 ml). The reaction mixture was stirred at room temperature for 10 minutes before water was added dropwise. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (15 mg) as a red solid. MS m/z 375 [M+H]+.
Reaction SMILES: N1[CH:5]=[CH:4]N=C1.B([O-])[O-].[C:9](O)([C:11](F)(F)F)=O>CO>[C:11]1([C:5]2[CH:4]=[CH:11][CH:9]=[CH:11][CH:9]=2)[CH:9]=[CH:4][CH:5]=[CH:5][CH:4]=1
Reactant: c1c[nH]cn1
Reactant: O=C(O)C(F)(F)F
Agent: [O-]B[O-]
Solvent: CO
Product: c1ccc(-c2ccccc2)cc1

Procedure:
Example 1-4-d was prepared from 1-4-c and 1b in similar fashion to the preparation of 1d from 1b and 1c. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.99-1.60 (m, 18 H) 1.75-2.11 (m, J=73.24 Hz, 6 H) 2.12-2.32 (m, 2 H) 3.32-3.41 (m, 2 H) 3.56 (s, 2 H) 4.63-5.02 (m, 2 H) 6.98-8.28 (m, 10 H) 11.67-12.33 (m, 2H); LC conditions: Phenomenex Luna 3.0×5.0 mm S10, Solvent A—0.1% TFA in 10% MeOH/90% H2O, Solvent B—0.1% TFA in 90% MeOH/10% H2O, 0 to 100% B over 2 min, Stop time=3 min, Flow rate=4 ml/min, Wavelength=220 nm, LC/MS (M+H)+=625.32. Retention time=1.438 min Additional Biphenyl Analogs were Prepared Similarly.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH2:19]>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:2]2[CH2:3][CH2:4][S:15][C:12]([CH3:13])([CH3:11])[C@@H:7]2[C:6]([OH:5])=[O:19])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CN1CCOCC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O
Solvent: ClCCl
Product: CC1(C)SCCN(S(=O)(=O)c2ccc(F)cc2)[C@H]1C(=O)O
Temperature: 25 °C
Yield: 40 %

Procedure:
To a 0° solution of 1.00 g (3.155 mmol) of 3-(S)-dimethylthexylsilyl-2,2-dimethyl-tetrahydro-2H-1,4thiazine-3-carboxylate (prepared as described in PCT patent application WO9720824) in 20 mL of dichloromethane was added 0.693 mL (6.85 mmol) of 4-methylmorpholine followed by 0.606 g (3.114 mmol) of 4-fluorobenzenesulfonyl chloride. The reaction was allowed to warm to room temperature and then stirred oveniight The reaction mixture was then poured into water and the organic layer was washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in 20 mL of methanol and the solution was heated to reflux for 1 h and then concentrated in vacuo. The residue was then chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide 0.385 g (40%) of the sulfonamide as a white foam. Electrospray Mass Spec 331.8 (M−H)−
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.C1C=CC=CC=1.[CH3:24][C:25]1[O:32][C:30](=[O:31])[CH:29]([C:33]([CH3:35])=[O:34])[C:27](=[O:28])[CH:26]=1>O>[OH:28][C:27]1[CH:26]=[C:25]([CH3:24])[O:32][C:30](=[O:31])[C:29]=1[C:33](=[O:34])[CH:35]=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: Cc1cc(O)c(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)c(=O)o1
Reaction time: 6 h
Yield: 81.6 %

Procedure:
4-Nitrobenzaldehyde (4.5 g, 29.7 mmol) and then a number of drops of piperidine were added to a benzene (40 ml) solution of dehydroacetic acid (5.00 g, 29.7 mmol) at room temperature, after which refluxing was performed for 6 hours while eliminating water by azeotropy. The majority of the benzene was distilled of directly, and then the distillation taken to dryness under reduced pressure. Following which, when recrystallization was performed from ethanol, 4-hydroxy-6-methyl-3-(4-nitrophenyl)acryloyl-2-pyrone (7.3 g, 82%) was obtained as orange crystals.
Reaction SMILES: Br.[CH3:2][C@@:3]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1.[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)#[N:12]>>[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:4]2[CH2:5][CH2:6][CH2:7][C@@:3]2([CH3:2])[C:8]([OH:10])=[O:9])=[O:18])=[CH:15][CH:14]=1)#[N:12]
Reactant: C[C@@]1(C(=O)O)CCCN1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Br
Product: C[C@@]1(C(=O)O)CCCN1C(=O)c1ccc(C#N)cc1

Procedure:
By reacting 2-methyl-L-proline hydrobromide with p-cyanobenzoyl chloride analogously to Example 2b) there is obtained 1-(p-cyanobenzoyl)-2-methyl-L-proline. MS (EI): 213 (M--COOH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23]OCC[Si](C)(C)C)=[C:18]([O:31][CH3:32])[CH:17]=3)[C:12](=[O:33])[CH:11]=2)=[CH:4][CH:3]=1.[CH3:34]O.Cl.[O:37]1[CH2:42][CH2:41]OCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:42]([OH:37])([CH3:34])[CH3:41])=[C:18]([O:31][CH3:32])[CH:17]=3)[C:12](=[O:33])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: COc1cc(-n2ccc(CSc3ccc(F)cc3)cc2=O)ccc1OCOCC[Si](C)(C)C
Reactant: CO
Agent: Cl
Solvent: ClCCl
Product: COc1cc(-n2ccc(CSc3ccc(F)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((4-fluorophenylthio)methyl)-1-(3-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyridin-2(1H)-one Part A (64 mg, 0.13 mmol) in CH2Cl2 (1.0 mL) and MeOH (1.0 mL) was added 4M HCl/Dioxane (2 mL, 8M mmol). After stirring at RT for 2 h, concentration under vacuum provided the crude phenol as a white solid. LC-MS, [M+H]+=358.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])[CH3:2].N1CCCCC1.[C:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([OH:29])=[O:28]>C1C=CC=CC=1>[C:16]([O:15][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@H:8]1[C:6](=[O:7])/[C:5](/[C:4]([O:3][CH2:1][CH3:2])=[O:20])=[CH:34]/[C:33]1[CH:36]=[CH:37][C:30]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C\c1ccc(C(=O)O)cc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 75.8 %

Procedure:
To a solution of tert-butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (5.0 g, 17.5 mmol) in benzene (50 ml) and piperidine (0.3 ml, 3 mmol) was added 4-carboxybenzaldehyde (2.63 g, 17.5 mmol), and the mixture was refluxed for 3 h. The cooled solution was washed with 0.1 N HCl twice. The aqueous layer was extracted three times with ether. The combined organic phases were dried (Na2SO4) and concentrated to give C as a tan solid (5.54 g, 76% yield). LCMS m/z 416 (M−H), 833 (2M−H).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C:14]([O:30][C@@:31]12[N:38]([CH3:39])[C@@H:35]([CH2:36][CH2:37]1)[CH2:34][CH:33]=[CH:32]2)(=[O:29])[C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)O>C(Cl)(Cl)Cl>[C@@:31]12([OH:30])[N:38]([CH3:39])[C@@H:35]([CH2:36][CH2:37]1)[CH2:34][CH:33]=[CH:32]2.[F:11][C:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]([O-:30])=[O:29]
Reactant: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccccc1)c1ccccc1)CC2
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN1[C@@H]2CC=C[C@@]1(O)CC2
Product: O=C([O-])C(F)(c1ccccc1)c1ccccc1

Procedure:
15.86 mL (0.086 mol) of bis-(2-methoxyethyl)aminosulfur trifluoride is reacted with 25 g (0.072 mol) of 5f analogously to Example 4, step 4.3 in 480 mL of chloroform. The product is recrystallized from acetone in the form of its hydrochloride. Yield: 18.6 g of white crystals (67% of theory); melting point: 181° C.-182° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:15][CH2:14]1)=[O:12])(C)(C)C.[ClH:38]>C(Cl)Cl.CCOCC.ClCCCl>[ClH:36].[ClH:38].[NH2:7][CH2:8][CH2:9][N:10]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:11]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][N:20]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCN(Cc1ccc(Cl)cc1)C(=O)C1CCN(c2ncnc3ccccc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOCC
Product: NCCN(Cc1ccc(Cl)cc1)C(=O)C1CCN(c2ncnc3ccccc23)CC1
Reaction time: 12 h

Procedure:
Step 5: 1 {2-[(4-Chlorobenzyl)-(1-quinazolin-4-yl-piperidine-4-carbonyl)-amino]-ethyl}-carbamic acid tert-butyl ester (190 mg, 0.36 mmol) was dissolved in DCM (5 mL) followed by the addition of 2.0 M HCl in Et2O (2 mL). After being stirred for 12 hours, the mixture was diluted with DCE and concentrated in vacuo. The resulting white solid was then suspended in MeCN and concentrated in vacuo (repeated twice) to give 1-quinazolin-4-yl-piperidine-4-carboxylic acid (2-amino-ethyl)-(4-chlorobenzyl)-amide dihydrochloride as a white powder (120 mg). 1H NMR (DMSO-d6, 400 MHz) δ 8.83 (m, 1H), 8.51 (bs, 2H), 8.20 (m, 2H), 8.01 (m, 2H), 7.71 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 4.79 (m, 2H), 4.55 (s, 1H), 3.59 (m, 7H), 3.03 (m, 1H), 2.90 (m, 1H), 1.92 (m, 4H). LCMS (APCI+) m/z 424, 426 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH2:46]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A 250 mL three necked round bottom flask equipped with a stir bar, thermocouple and nitrogen in/outlet was charged with 5.0 g (12.7 mmol) of bendamustine hydrochloride, 4.2 g (12.9 mmol, 1.01 eq) of docosyl alcohol, 2.7 g (12.9 mmol, 1.01 eq) of dicyclohexyl carbodiimide (DCC), 50 mL of dichloromethane (MDC) and 0.16 g (1.27 mmol, 0.1 eq) of N,N-dimethylamino pyridine (DMAP). The reaction mixture was stirred at room temperature overnight at which time an HPLC analysis indicated the reaction was complete. Solids were removed by vacuum filtration and the wetcake was washed with 50 mL. Two alternate purification procedures were developed. The filtrate was washed with DI water (2×150 mL), dried over sodium sulfate, filtered and concentrated to dryness in vacuo. The resultant waxy residue was chromatographed on 80 g of silica gel 60, 230-400 mesh eluting with a gradient beginning with 100% MDC, then 0.5% methanol/MDC and finally 1% methanol/MDC collecting 100-150 mL fractions. Fractions containing the desired product were combined and concentrated to dryness in vacuo. The residue was again triturated with 20 mL of MDC and the undesired solids removed by filtration. The filtrate was concentrated in vacuo to yield 3.65 g (5.5 mmol, 43.1%) of the desired product as a waxy white solid with a purity of 95.7 A %. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J=8.72 Hz, 1H), 7.08 (d, J=2.28 Hz, 1H), 6.78 (dd, J=2.36, 8.72 Hz, 1H), 4.05 (t, J=6.76 Hz, 2 H), 3.72 (m, 4H), 3.70 (s, 3H), 3.63 (m, 4H), 2.91 (t, J=7.44 Hz, 2H), 2.49 (t, J=7.08 Hz, 2H), 2.18 (m, 2H), 1.60 (m, 2H), 1.32 (m, 38H), 0.88 (t, J=6.64 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.[CH2:20]1C[O:23][CH2:22][CH2:21]1.Cl.[C:26]([O-])(O)=O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:15]=[C:7]1[NH:8][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[C:6]21[CH2:16][C:17]1[CH:18]=[C:19]3[C:2](=[CH:3][C:4]=1[CH2:5]2)[N:1]=[CH:20][C:21]([CH:22]=[O:23])=[CH:26]3
Reactant: C1CCOC1
Reactant: O=C([O-])O
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=Cc1cnc2cc3c(cc2c1)CC1(C3)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(±)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (125 mg, 0.500 mmol, described in Intermediate 4) and 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane bis(tetrafluoroborate) (266 mg, 0.750 mmol) were suspended in glacial acetic acid and the mixture was heated to reflux for 22 h. The mixture was allowed to cool to ambient temperature before the bulk of the acetic acid was removed in vacuo. THF (3 mL) and 1 N HCl (3 mL, 3 mmol) were added and the mixture was stirred at ambient temperature for 2 h. The mixture was then poured into a separatory funnel containing CHCl3 (50 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous layer was extracted twice with CHCl3 (2×250 mL) and the combined organic layers were dried over Na2SO4. Filtration to remove drying agent gave a solution which was concentrated in vacuo to give a yellow residue. The impure product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:1 to 92:8, to give the title compound. MS: m/z=316 (M+1).
Reaction SMILES: C([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C1C=CC=CC=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23]O>[Pd]>[CH3:23][C:10]([CH3:11])([CH2:15][CH2:14][CH2:13][CH3:12])[C:9]([C:18]1[CH:17]=[C:16]([OH:22])[CH:21]=[CH:20][CH:19]=1)=[O:8]
Reactant: CO
Reactant: Oc1ccccc1
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: [Pd]
Product: CCCCC(C)(C)C(=O)c1cccc(O)c1
Reaction time: 22 h
Yield: 83 %

Procedure:
The benzyl ether of the desired phenol (26 g) was taken in methanol (150 ml) and this solution was hydrogenated in a Parr apparatus under an atmosphere of hydrogen (45-50 lbs./sq.in.) in the presence of 10% palladium on charcoal (10 g). After 20-24 hours, the suspension was filtered on celite; all methanol was removed to obtain the desired phenol in about 83% yield (15.4 g) as a coloress liquid.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[Cl:10][C:11]1[C:12]([C:13]([N:63]2[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]3[CH:53]=[CH:52][C:51]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[CH:50][CH:49]=3)=[O:47])[CH2:65][CH2:64]2)=[O:15])=[CH:16][CH:17]=[CH:18][N:19]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cccnc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 2-chloro-nicotinic acid (40.5 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 90% EtOAc in hexane as eluent) to afford 39 mg (32.8% yield) of biphenyl-4-carboxylicacid {2-[4-(2-chloro-pyridine-3-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 89.81%, 1H NMR: (DMSO) δ 8.74-8.62 (bs, 1H), 8.56-8.46 (bs, 1H), 8.06-7.92 (d, 3H), 7.84-7.7 (q, 4H), 7.6-7.38 (m, 4H), 4.28-4.12 (d, 2H), 3.78-3.46 (bt, 6H), 3.28-3.18 (bs, 2H).
Reaction SMILES: S[CH:2]([SH:21])[C:3]([CH:5]([OH:20])[C:6]([CH2:18][OH:19])([CH2:16][OH:17])[C:7](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:8])=O.[OH-].[Na+].II.[O-][S:27]([O-])(=S)=O.[Na+].[Na+]>CCO.C(Cl)Cl>[S:21]1[CH2:2][CH2:3][CH2:5][S:27]1.[CH:9](=[C:7]([C:6]([CH2:5][OH:20])([CH2:16][OH:17])[CH2:18][OH:19])[OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S([O-])([O-])=S
Reactant: O=C(C(S)S)C(O)C(CO)(CO)C(O)=Cc1ccccc1
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: C1CSSC1
Product: OCC(CO)(CO)C(O)=Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of dimercaptoacetyl monobenzalpentaerythritol (4.1 mmol) in EtOH (20 ml) is treated with 10 ml of aqueous 1 N NaOH at room temperature for 1 h. The mixture is diluted with CH2Cl2 (100 ml) and then an aqueous solution of 0.1 M iodine (4.5 mmol) is added dropwise. The reaction mixture was stirred for 2 hours at room temperature and 1 mmol of Na2S2O3 (1 M aqueous solution) was added to the reaction mixture. The organic phase was separated, washed with water (3(200 mL), dried with magnesium sulfate, and evaporated at room temperature. The crude product is chromatographed on silica gel (200 mL) using a solvent mixture of hexane and ethyl acetate (40:20) as eluent to give 1,2-dithiolane of monobenzalpentaerythritol. Step 5: Synthesis of 1,2-dithiolane pentaerythritol
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]([N:19]([CH3:21])[CH3:20])=[N:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[N:9][CH:10]=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[C:6]([N:19]([CH3:20])[CH3:21])=[N:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])=[CH:14][CH:13]=2)=[N:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)nc1N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)OCc3ccccc3)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.8 %

Procedure:
To a mixture of methyl[2-(4-aminobenzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (1.50 g, 4.99 mmol) in pyridine (1.21 mL) and dichloromethane (20 mL) was added benzyl chloroformate (1.07 mL, 7.49 mmol). After stirring for 14 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The remaining residue was chromatographed on silica gel (NH silica gel, hexane/ethyl acetate 2:1) to give methyl[2-(4-{[(benzyloxy)carbonyl]amino}-benzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (1.99 g, 92%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[CH2:11][C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.C(OCC)(=O)C.C(O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]1[N:8]([C:4]2[CH:3]=[C:2]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([S:31][CH3:30])[CH:37]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=[C:10]([C:20]([C:26]([F:27])([F:29])[F:28])([C:22]([F:24])([F:25])[F:23])[OH:21])[CH2:11]1
Reactant: OC(C1=NN(c2cccc(Br)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1cccc(-c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 9.7 %

Procedure:
1-(3-Bromo-phenyl)-5-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (50.0 mg, 0.10 mmol) prepared in Step 2 of Preparation 25, 3-methylthiophenylboronic acid (20.0 mg, 0.15 mmol), Pd(PPh3)4 (11.5 mg, 0.01 mmol), and a 2N sodium carbonate solution (0.5 mL) were added to a mixed solvent of 1,2-dimethoxyethane (2.0 mL) and ethanol (0.5 mL). The reaction mixture was stirred at 90° C. for 2 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 5.3 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][NH:13][CH2:14][CH:15]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:16])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:28][C:29]([CH:31]1[CH2:36][CH:35]([OH:37])[CH2:34][CH:33]([C:38](OCC)=[O:39])[NH:32]1)=O)C>>[O:39]=[C:38]1[NH:16][CH:15]([CH2:17][O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][NH:13][CH2:12][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:11][C:29](=[O:28])[CH:31]2[NH:32][CH:33]1[CH2:34][CH:35]([OH:37])[CH2:36]2
Reactant: CCOC(=O)C1CC(O)CC(C(=O)OCC)N1
Reactant: NC(CNCC(N)COCc1ccccc1)COCc1ccccc1
Product: O=C1NC(COCc2ccccc2)CNCC(COCc2ccccc2)NC(=O)C2CC(O)CC1N2

Procedure:
2,6-Bis(benzyloxymethyl)-1,4,7-triazaheptane (10 mmol), (described in WO-A-89/00557, Example 6 d) and 2,6-bis(ethyloxycarbonyl)-4-hydroxy-piperidine (10 mmol) (described in WO-A-90/08138)is reacted as described in Example 1 a) to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[OH:9].N12CCCN=C1CCCCC2.[CH3:21][CH2:22][CH:23](Br)[C:24](OCC)=[O:25]>CN1CCCC1=O>[Br:1][C:2]1[C:3]2[O:9][CH:23]([CH2:22][CH3:21])[C:24](=[O:25])[NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)CC
Reactant: Nc1cccc(Br)c1O
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCC1Oc2c(Br)cccc2NC1=O
Yield: 71 %

Procedure:
Procedure & NMR Data: 1.5 g (7.9 mmol) of 2-bromo-6-aminophenol, 1.08 ml (0.9 eq, 7.11 mmol) of 1.8-diazabicyclo[5.4.0]undec-7-ene and 3.5 mL of DL-Ethyl 2-bromobutyrate (3 eq, 23.7 mmol)) in 30 mL of 1-Methyl-2-pyrrolidinone were mixed. 1.447 g of P1 were obtained, yield 71%.