Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:10]([N:15]1C(=O)C2=CC=CC=C2C1=O)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.NN.Cl>C(O)C>[CH3:1][O:2][C@@H:3]([C@@H:10]([NH2:15])[CH2:11][CH:12]([CH3:13])[CH3:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CO[C@H](c1ccccc1)[C@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CO[C@H](c1ccccc1)[C@@H](N)CC(C)C
Temperature: 5 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
The N-[1-(S)-[α-(R)-methoxybenzyl]-3-methyl-butyl]phthalimide (25.6 g, 75.9 mmol.) obtained above was suspended in ethanol (250 mL). To the suspension was added hydrazine hydrate (7.5 mL), and the resulting mixture was heated under reflux for 15 hours. The reaction mixture was chilled in an ice bath, and stirred at 5° C. for one hour after addition of 4N hydrochloric acid (200 mL). The insoluble material was removed by filtration and washed with 4N hydrochloric acid. The filtrate and washings were combined, and placed under reduced pressure to distill off ethanol. The residue was made basic to reach pH approx. 11, by addition of 10N aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The dried extract was placed under reduced pressure to give the titled compound as pale yellow oil (15.5 g, purity: 91%, yield. 81%).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39](Cl)(=[O:41])=[O:40]>N.CO>[CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1[S:39]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc2ccccc2c1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.5 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. Naphthalene-2-sulfonyl chloride (23 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.2 mg). MS m/z 379 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:6]=2[CH:21]=1.[C:25](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>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.O1CCOCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([N:7]2[C:6]3[CH:21]=[C:2]([CH3:25])[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]=3[O:10][C:9]([CH3:12])([CH3:11])[C:8]2=[O:13])=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(Cl)cc2N(c2ccc(F)cc2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C(=O)N2c1ccc(F)cc1
Yield: 5.3 %

Procedure:
To a mixture of 6-chloro-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 50(2); 200 mg), potassium carbonate (236 mg), tetrakis(triphenylphosphine)palladium(0) (66 mg) and dioxane (2 mL) was added trimethylboroxin (80 μL) under argon atmosphere, and the mixture was refluxed under heating for 18 hours. After cooling, the reaction mixture was filtered through a celite pad, and the insolubles were washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=9/1) to give 4-(4-fluorophenyl)-2,2,6-trimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (10 mg) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[C:10]([OH:12])=O)=[CH:4][C:3]=1[F:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:37]([O:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]1[CH:50]([NH2:59])[C:51]1[S:52][C:53]([CH2:57][OH:58])=[C:54]([CH3:56])[N:55]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[C:10]([NH:59][CH:50]([C:51]2[S:52][C:53]([CH2:57][OH:58])=[C:54]([CH3:56])[N:55]=2)[CH:45]2[CH2:46][CH2:47][CH2:48][CH2:49][N:44]2[C:42]([O:41][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:43])=[O:12])=[CH:4][C:3]=1[F:14]
Reactant: Cc1nc(C(N)C2CCCCN2C(=O)OC(C)(C)C)sc1CO
Reactant: O=C(O)C(=O)Nc1ccc(Cl)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nc(C(NC(=O)C(=O)Nc2ccc(Cl)c(F)c2)C2CCCCN2C(=O)OC(C)(C)C)sc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(4-chloro-3-fluorophenylamino)-2-oxoacetic acid (3′) (0.3 g, 1.378 mmol), TBTU (0.530 g 1.65 mmol) and TEA (0.166 g, 1.65 mmol) in DCM (20 ml) was stirred at RT for 1 h, then 2-[amino-(5-hydroxymethyl-4-methyl-thiazol-2-yl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (0.470 g, 1.378 mmol) was added and stirring was continued for 6 h. Reaction mixture was washed with 25% aqueous solution of K2CO3 (2×50 ml) and water (50 ml). The product was dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (EtOAc/hexane1/1) to afford tert-butyl 2-((2-(4-chloro-3-fluorophenylamino)-2-oxoacetamido)(5-(hydroxymethyl)-4-methylthiazol-2-yl)methyl)piperidine-1-carboxylate (4′) (0.53 g, 72%) as a white solid; LC-MS (APCI+) m/z: calcd for C24H30ClFN4O5S: 540.16. found: 541 (M+H+).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:19]4[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=4[C:13]4[CH2:21][N:22]([CH3:25])[CH2:23][CH2:24][C:12]3=4)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH:26]([O-])=[O:27].[NH4+]>CO.[Pd]>[CH3:25][N:22]1[CH2:23][CH2:24][C:12]2[N:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[CH2:1][N:2]([CH:26]=[O:27])[CH2:3][CH2:4]4)[C:19]3[CH:18]=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[C:13]=2[CH2:21]1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccc3cnccc3c2)CCN(C)C1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc2c(c1)c1c(n2-c2ccc3c(c2)CCN(C=O)C3)CCN(C)C1
Yield: 27.8 %

Procedure:
To a de-aerated solution of 5-isoquinolin-6-yl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg, 0.10 mmol) in MeOH (5 mL) were added 10% Pd—C (18 mg) and ammonium formate (68 mg, 1.07 mmol). The reaction mixture was refluxed for 15 h and filtered through Celite. The filtrate was concentrated under reduced pressure to afford crude material, which was purified by column chromatography using silica (100:200) and 3% MeOH-DCM to yield 6-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carbaldehyde (10 mg). 1H NMR (HCl salt, CD3OD) d (ppm): 8.2 (s, 1H), 7.41 (s, 1H), 7.3 (s, 1H), 7.25 (m, 2H), 7.1 (d, 1H), 7.03 (d, 1H), 4.7 (d, 1H), 4.4 (d, 1H), 3.8 (m, 3H), 3.57 (m, 3H), 3.17 (s, 3H), 3.0 (m, 4H), 2.4 (s, 3H).
Reaction SMILES: C(C1C=NC(C2C=CC(O[CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:48])([F:47])[C:32]([F:46])([F:45])[O:33][C:34]([F:44])([F:43])[C:35]([F:42])([F:41])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=CC=2)=NC=1)CCCCCCC.[CH2:49]([O:54][C:55]1[CH:56]=[N:57][C:58]([C:61]2[CH:66]=[CH:65][C:64]([OH:67])=[CH:63][CH:62]=2)=[N:59][CH:60]=1)[CH2:50][CH2:51][CH2:52][CH3:53]>CN(C)C=O>[CH2:49]([O:54][C:55]1[CH:60]=[N:59][C:58]([C:61]2[CH:62]=[CH:63][C:64]([O:67][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]([O:30][C:31]([F:47])([F:48])[C:32]([F:45])([F:46])[O:33][C:34]([F:43])([F:44])[C:35]([F:41])([F:42])[O:36][C:37]([F:40])([F:39])[F:38])([F:29])[F:28])=[CH:65][CH:66]=2)=[N:57][CH:56]=1)[CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Reactant: CCCCCOc1cnc(-c2ccc(O)cc2)nc1
Solvent: CN(C)C=O
Product: CCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
The title compound was prepared essentially as in Example 1 by combining 3-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)-1-chloropropane (6.1 g, 28.0 mmol, Example 24) with 5-pentyloxy-2-[4-hydroxyphenyl]pyrimidine (3 g, 11.6 mmol) in dimethylformamide and stirring at 120° C. overnight to provide product boiling at 185-190° C. at 0.3 torr (yield of 5.5 g).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16]C=CC=3)N=2)=[CH:7][CH:6]=1.C(OC1C=CC(C(O)=O)=C([F:42])C=1)C1C=CC=CC=1>>[CH2:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([N:3]([O:2][CH3:1])[CH3:24])=[O:23])=[C:10]([F:42])[CH:9]=1)[C:13]1[CH:22]=[CH:21][CH:20]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1F
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cc1F

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl4-(quinolin-2-ylmethoxy)-benzamide but substituting 4-Benzyloxy-2-fluoro-benzoic acid provided the title compound. MS: (M+H m/z=290.2).
Reaction SMILES: CO[CH:3]([O:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH3:12])[CH:5]=1.[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18].B(F)(F)F.P(=O)([O-])[O-]>ClCl>[CH3:14][O:13][CH:3]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH3:12])[CH:5]=1)[P:15]([O:19][CH2:20][CH3:21])(=[O:22])[O:16][CH2:17][CH3:18]
Reactant: COc1cc(C(OC)OC)ccc1Cl
Reactant: CCOP(OCC)OCC
Agent: ClCl
Agent: FB(F)F
Agent: O=[PH]([O-])[O-]
Product: CCOP(=O)(OCC)C(OC)c1ccc(Cl)c(OC)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of dimethyl acetal 3 (4.3 g, 20 mmol), sieve-dried CH2 Cl2 (20 ml) and triethyl phosphite (4.1 ml, 24 mmol) was stirred under argon at -78° C. Boron trifluoride ethereate (2.95 ml, 24 mmol) was added dropwise at -78° C., the solution was stirred 5 min and stored overnight at -20° C. The next day the reaction was warmed to room temperature and stirred 5 hours to complete phosphonate formation. With vigorous stirring, the reaction was quenched with solid NaHCO3 followed by 40 ml saturated NaHCO3 solution. After gas evolution ceased, 40 ml CH2Cl2 and 20 ml H2O were added, the biphasic mixture was partitioned and the CH2Cl2 phase was recovered, dried over Na2SO4 and evaporated. After pumping in vacuo, the oil was purified on a silica gel plug, eluting with CH2 Cl2 to yield phosphonate 4 as a light yellow oil (6.01 g., 99%).
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][NH:2]1.I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cu]I.CO.CS(C)=O>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[C:1]1=[O:14]
Reactant: O=c1[nH]ccc2[nH]c3ccccc3c12
Reactant: Cc1ccncc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1ccncc1-n1ccc2[nH]c3ccccc3c2c1=O
Temperature: 150 °C
Yield: 5.4 %

Procedure:
2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (I-62a: 500 mg, 2.71 mmol), 3-iodo-4-methylpyridine (892 mg, 4 mmol), 8-hydroxy quinoline (79 mg, 0.542 mmol) and K2CO3 (560 mg, 4.06 mmol) were added to a previously degassed solution of DMSO (10 mL). This was followed by the addition of CuI (103.2 mg, 0.542 mmol) and the resulting reaction mass was heated at 150° C. for 16 hours in a sealed tube. The reaction was monitored by TLC (5% methanol in DCM). The reaction mass was quenched with water, diluted using ethyl acetate and filtered. The filtrate was extracted using ethyl acetate, washed the organic layer with water, brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM), followed by preparative HPLC afforded 40 mg of the product (5.4% yield).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].COC1C=C(C(O)[C:25]([O:27][CH3:28])=[O:26])C=CC=1OC>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]([OH:5])[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)C(O)c1ccc(OC)c(OC)c1
Reactant: COc1cc(F)c(C=O)cc1OC
Product: COC(=O)C(O)c1cc(OC)c(OC)cc1F
Yield: 44 %

Procedure:
139A (1.05 g, 44%) was prepared in 2 steps from 2-fluoro-4,5-dimethoxybenzaldehyde following procedures analogous to those used in the preparation of 137B. LC-MS: 267.11 (M+Na)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][C:28](=[O:30])[CH3:29])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[H-].[Na+].ClCC(=O)C.[NH4+].[Cl-]>CN(C=O)C>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:20][C:21]4[N:26]([CH2:27][C:28](=[O:30])[CH3:29])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(=O)CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: CC(=O)CCl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(=O)CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-1-(2-oxopropyl)-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (60 mg, 0.13 mmol) in dry DMF (2.5 mL) was added sodium hydride (5 mg, 0.14 mmol) at 0° C. under nitrogen. After 1 h at 0° C., chloroacetone (11 □L, 0.14 mmol) was added and the resulting mixture was stirred for two hours at 0° C. A saturated solution of NH4Cl was added while stirring, keeping the temperature below 10° C. The resulting mixture was extracted with dichloromethane (3×) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 100:0 to 55:45) to give the desired product as a white solid (41 mg, 60% yield). 1H NMR (500 MHz, CDCl3): 7.12-7.28 (9H, m), 6.82 (1H,S), 4.95 (2H, s), 4.54 (2H, s), 2.36-2.52 (4H, m), 2.23 (3H, s), 1.98-2.12 (1H, m), 1.69-1.75 (1H, m), 1.47 (9H, br s). 1H NMR (Method A): RT=6.87 min, M+H+=528.
Reaction SMILES: I[C:2]1[C:10]2[O:9][C:8]3[C:11]([Si:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:12][CH:13]=[CH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Cl:34][C:35]1[CH:36]=[C:37]([C:2]2[C:10]3[O:9][C:8]4[C:11]([Si:15]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[CH:12][CH:13]=[CH:14][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: Ic1cccc2c1oc1c([Si](c3ccccc3)(c3ccccc3)c3ccccc3)cccc12
Reactant: OB(O)c1cccc(Cl)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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cccc(-c2cccc3c2oc2c([Si](c4ccccc4)(c4ccccc4)c4ccccc4)cccc23)c1
Yield: 20.6 %

Procedure:
A solution of (6-iododibenzo[b,d]furan-4-yl)triphenylsilane (5.00 g, 9.05 mmol), (3-chlorophenyl) boronic acid (1.7 g, 11.3 mmol), Pd(PPh3)4 (0.105 g, 0.091 mmol) and K2CO3 (2.502 g, 18.10 mmol) in toluene (75 mL) and water (10 mL) was refluxed under nitrogen for 48 h. The organic layer was separated and the solvent was evaporated. The residue was purified by column chromatography on silica gel with hexane (EtOAc (95/5, v/v) as eluent followed by recrystallization from the same solvent to yield (6-(3-chlorophenyl)dibenzo[b,d]furan-4-yl)triphenylsilane (1.0 g, 21%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([C:14]2[C:22]3[O:21][C:20]([F:24])([F:23])[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[N:11][NH:12][CH:13]=1.[C:25](Cl)(=[O:27])[CH3:26].O>CN(C)C1C=CN=CC=1.C1COCC1>[C:25]([N:12]1[CH:13]=[C:9]([Cl:8])[C:10]([C:14]2[C:22]3[O:21][C:20]([F:24])([F:23])[O:19][C:18]=3[CH:17]=[CH:16][CH:15]=2)=[N:11]1)(=[O:27])[CH3:26]
Reactant: FC1(F)Oc2cccc(-c3n[nH]cc3Cl)c2O1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)n1cc(Cl)c(-c2cccc3c2OC(F)(F)O3)n1
Reaction time: 3 h
Yield: 92.6 %

Procedure:
0.25 g (0.005 mol) of 4-dimethylaminopyridine and 4.25 g (0.042 mol) of triethylamine are added to 11.0 g (0.046 mol) of 4-chloro,3-(2,2-difluorobenzo-1,3-dioxol-4-yl)-1H-pyrazole (prepared as described in patent PH 91-033) dissolved in 100 ml of THF. A solution of 3.6 g (0.046 mol) of acetyl chloride in 50 ml of THF is run dropwise and at 0° C. onto this solution. Stirring is continued for 3 h at room temperature. The reaction mixture is poured into 300 ml of water and extracted with ethyl acetate. After drying the organic phase and concentration under vacuum, the residue is triturated with 50 ml of heptane, filtered and dried. We obtain 12.8 g of 1-acetyl-4-chloro-3-(2,2-difluorobenzo-1,3-dioxol-4-yl)pyrazole melting at 131° C.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH3:4].C(NC(C)C)(C)C.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1>C(#N)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:19][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([C:1]#[C:2][CH2:3][CH3:4])[CH:18]=1
Reactant: Brc1cncc(Br)c1
Reactant: C#CCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CCC#Cc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
But-1-yne (g) was during 5 min gently bubbled through anhydrous acetonitrile cooled in an ice-water bath. The resulting solution contained about 170 mg but-1-yne per mL. The solution of but-1-yne (4.57 mL, 14.36 mmol) and diisopropylamine (3.72 mL, 26.11 mmol) were added sequentially to a mixture of 3,5-dibromopyridine (3.09 g, 13.06 mmol), bis(triphenylphosphine)-palladium(II) chloride (0.458 g, 0.65 mmol) and CuI (0.249 g, 1.31 mmol) in acetonitrile (15 mL) under an argon atmosphere. The resulting mixture was stirred at r.t. overnight, diluted with EtOAc and passed through a short plug of silica. The solvents were evaporated and the residue was purified by flash chromatography on silica (gradient elution 0-20% EtOAc in heptane) to give 2.40 g of the title compound (87% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.17 (t, 4 H), 2.47 (q, 3 H), 8.11 (t, 1 H), 8.57 (d, 1 H), 8.65 (d, 1 H); MS (ES+) m/z 210 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([OH:21])[C@H:11]([NH2:20])[CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:7][C:6]=2[CH:22]=1.C([NH:30][C@@H:31]([C:43](O)=[O:44])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])(OC(C)(C)C)=O>>[C:36]([N:20]([C@@H:11]([CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=2[N:7]=1)[OH:21])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:43](=[O:44])[C@H:31]([NH2:30])[CH2:32][CH2:33][CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]
Reactant: N[C@H](CCc1ccccc1)C(O)c1nc2cc(Cl)ccc2o1
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)(C)OC(=O)NCCC[C@@H](N)C(=O)N(C(=O)OC(C)(C)C)[C@H](CCc1ccccc1)C(O)c1nc2cc(Cl)ccc2o1

Procedure:
(1R)-1-[(RS)-(5-Chloro-2-benzoxazolyl)hydroxymethyl]-3-phenylpropylamine (136 mg) was coupled with N,N′-bis-Boc-D-ornithine to afford the title compound (150 mg) as a glassy solid: mass spectrum (ES+) m/e 35Cl 653.4, 37Cl 655.4 (M+23 (Na)); 1H NMR (400 MHz, CDCl3, 7:3 mixture of diastereomers) δ 1.40 (m, 18H), 1.62 (m, 4H), 1.90 (m, 2H), 2.74 (m, 2H), 3.03-3.23 (m, 2H), 4.09 (m, 0.3H), 4.19 (m, 0.7H), 4.58 (m, 0.7H), 4.69 (m, 0,3H), 5.03 (m, 0.7H), 5.20 (m, 0.3H), 7.11-7.23 (m, 6H), 7.37 (m, 2H), 7.53 (m, 1H), 7.68 (m, 0.3H), and 7.76 (m, 0.7H).
Reaction SMILES: BrCC1C=C(CBr)C=C(CBr)C=1.CCN(CC)CC.C[O:21][C:22]([C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[C:34](S(Cl)(=O)=O)[C:33]([O:40][CH3:41])=[CH:32][C:31]=2[O:42][CH3:43])[CH:27]=[C:26]([C:44]([O:46]C)=[O:45])[N:25]=1)=[O:23].C(NCCO)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.CO.C(Cl)(Cl)Cl.O>[CH3:43][O:42][C:31]1[CH:32]=[C:33]([O:40][CH3:41])[CH:34]=[CH:35][C:30]=1[C:28]1[CH:27]=[C:26]([C:44]([OH:46])=[O:45])[N:25]=[C:24]([C:22]([OH:23])=[O:21])[CH:29]=1
Reactant: COC(=O)c1cc(-c2cc(S(=O)(=O)Cl)c(OC)cc2OC)cc(C(=O)OC)n1
Agent: BrCc1cc(CBr)cc(CBr)c1
Agent: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(C(=O)O)nc(C(=O)O)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.5 g (0.0008 mole) of the amine-hydrochloride 8 in 20 ml of CH2Cl2 was added all at once 1.4 ml (0.01 mole) of Et3N. The mixture was then cooled to 5°-10° C. and 1.4 g (0.0032 mole) of the sulfonyl chloride 39 in 20 ml of CH2Cl2 was slowly added in a dropwise fashion. The reaction was then allowed to stir at room temperature for 30 minutes after which a TLC was taken. Little of the sulfonyl chloride 9 had reacted by TLC so an additional 100 mg of the amine 8 was added and stirring continued overnight. The mixture was then poured into water and extracted with CH2Cl2. The extract was washed with water, dried (Na2SO4) and the solvent removed yielding crude 43. After column chromatography with SiO2 /5%MeOH/CHCl3, 1.55 g (93%) of the desired tetraamide 43 was obtained.