Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH2:65]([SH:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:65]([S:72][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:12])=[CH:7][CH:8]=[N:9]2)=[C:4]([CH3:13])[CH:3]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: Cc1cc(Br)cc2nccc(Cl)c12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(SCc2ccccc2)cc2nccc(Cl)c12
Temperature: 60 °C
Yield: 62 %

Procedure:
To a vial charged with 7-bromo-4-chloro-5-methylquinoline (0.048 g, 0.187 mmol) was added Xantphos (0.022 g, 0.037 mmol), Pd2(dba)3 (0.017 g, 0.019 mmol), dioxane (0.748 ml), DIEA (0.065 ml, 0.374 mmol) and benzyl mercaptan. The mixture was purged with argon and heated to 60° C. overnight. The mixture was directly loaded onto a 25 HP silicycle column and purified by ramping EtOAc in heptane (0 to 50%, 10% DCM throughout) to provide product as a light yellow solid (35 mg, 62%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.97 (s, 3H) 4.31 (s, 2H) 7.22-7.26 (m, 1H) 7.27-7.31 (m, 1H) 7.31-7.39 (m, 3H) 7.44 (d, J=6.94 Hz, 2H) 7.82 (d, J=1.96 Hz, 1H) 8.61 (d, J=4.70 Hz, 1H). m/z (ESI) 300.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[O:10][C:5]2=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br-]>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2oc(-c3cccc([N+](=O)[O-])c3)nc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(-c2nc3nc(CBr)ccc3o2)c1
Reaction time: 4 h

Procedure:
In a typical run, 400 mg of 5-methyl-2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridine (1.57 mmol) was suspended in 50 mL of CCl4 along with 280 mg (1.57 mmol) of NBS and 20 mg of benzoyl peroxide. The reaction mixture was stirred under reflux for 4 hours. LC/MS showed about 50% conversion to the desired bromide. After another 2 hours of reflux, no additional change was observed. Another 1 eq of NBS was added and reflux was continued for another 4 hours. LC/MS showed complete conversion. The reaction mixture was concentrated and the resulting crude product was purified by chromatography (Isco, gradient elution, CH2Cl2 to 9:1 CH2Cl2/MeOH) to afford essentially quantitative yield of 5-bromomethyl-2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridine.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>O.C(O)C>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:2][OH:3])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(-c2ccccn2)cc1
Temperature: 80 °C
Yield: 57.5 %

Procedure:
Add hydroxylamine hydrochloride (0.379 g, 5.458 mmol) and a solution of NaOH (0.327 g, 8.187 mmol) in water (2 mL) to a solution of 4-(2-pyridyl)-benzaldehyde (0.5 g, 2.729 mmol) in ethanol (10 mL). Heat the mixture at 80° C. for 2 h. Cool to ambient temperature and remove the solvent in vacuo. Partition the residue between EtOAc and water. Separate and day the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 4:1) to obtain the desired intermediate (311 mg, 58%). GC-MS m/z: 198 (M+).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][S:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[N+:15]([C:18]1[CH:19]=[C:20]([N:24]=[C:25]=[O:26])[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].[N-]=C=O>C1C=CC=CC=1.C(N(CC)CC)C>[N+:15]([C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:26])[O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])[CH:7]=2)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: COC(CSc1cccc(O)c1)OC
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: [N-]=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(CSc1cccc(OC(=O)Nc2cccc([N+](=O)[O-])c2)c1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(2,2-Dimethoxyethylthio)phenol (0.05 mole) dissolved in benzene (10 ml) is charged into a glass reaction flask equipped with a mechanical stirrer. 3-Nitrophenyl isocyanate (0.06 mole) and triethylamine (3 drops) are then added and the resulting mixture is stirred at room temperature for a period of about 6 hours. The mixture is then stripped of solvent and unreacted isocyanate to yield the desired product O-[3-(2,2-dimethoxyethylthio) phenyl] N-3-nitrophenylcarbamate as the residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:27][CH:26]=3)=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.[Br:38]Br.O>CC(O)=O>[Br:38][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][C:9](=[O:13])[C:8]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=1)=[C:7]2[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32](=[O:37])[C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:29][CH:30]=1
Reactant: COc1ccc2c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c(-c3ccc(C(F)(F)F)cc3)c(=O)oc2c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2oc(=O)c(-c3ccc(C(F)(F)F)cc3)c(Cc3ccc(OC(=O)C(C)(C)C)cc3)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
A mixture of 2,2-dimethyl-propionic acid 4-(7-methoxy-2-oxo-3-(4-trifluoromethyl-phenyl)-2H-chromen-4-ylmethyl)-phenyl ester from step C (820 mg, 1.61 mmol) and Br2 (83 μL, 1.61 mmol) in AcOH (15 mL) was stirred at room temperature for 16 h. Another portion of Br2 (80 μL, 1.55 mmol) was added, and stirring was continued for 6 h. The mixture was poured into H2O, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The residual orange solid was crystallized from CH2Cl2/hexane to afford the desired compound as a white solid (710 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 7.67 (s, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 7.07–6.94 (m, 4H), 6.89 (s, 1H), 4.01 (s, 2H), 3.98 (s, 3H), 1.35 (s, 9H); MS (ESI) m/z 588.8 (M+H)+; HPLC tR 7.78 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[Se:20][C:3]=1[C:4]=23.Br.Br[CH2:27][CH2:28][NH2:29].Br>C(O)C>[CH2:14]([N:13]([CH2:16][CH3:17])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:27][CH2:28][NH2:29])=[C:3]3[Se:20][C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:15]
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)[Se]c1ccccc1-2
Reactant: NCCBr
Agent: Br
Solvent: CCO
Product: CCN(CC)CCn1nc2c3c(c(NCCN)ccc31)[Se]c1ccccc1-2
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A mixture of 3.7 g (0.01 mole) of 5-amino-N,N-diethyl-2H[1]benzoselenino[4,3,2-cd]indazole-2-ethanamine, 5.9 g (0.029 mole) of 2-bromoethylamine, hydrobromide, and 25 ml of ethanol is heated under reflux for ten hours. Additional 2-bromoethylamine, hydrobromide (2.0 g) is added and the solution is heated at reflux for 38 hours, then allowed to cool to 25° C. The solids are collected and washed with cold ethanol to give 3.5 g of the dried product as a salt with 2.8 equivalents of hydrogen bromide; mp 268°-270° C. (dec.).
Reaction SMILES: [OH:1][CH:2]1[C:7](OC)([O:8]C)[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1.FC(F)(F)C(O)=O>C1COCC1>[OH:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3]1
Reactant: CCOC(=O)N1CCC(OC)(OC)C(O)C1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(=O)C(O)C1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 117.3 %

Procedure:
Ethyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate from Example 34A (5.00 g, 21.4 mmol) was dissolved in THF (50 mL), and trifluoroacetic acid (15.9 mL, 214 mmol) was added. The mixture was stirred for 3.5 h at rt. The solvent was then removed in vacuo. Twice, toluene was added and again removed in vacuo. The residue was dissolved in dichloromethane, dried over sodium sulfate, and the solvent was removed in vacuo to yield 4.70 g (95%) of an oil, which was used without further purification.
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36](B(O)O)=[C:35]([O:43][CH3:44])[CH:34]=1>CCCCCCC.CCOC(C)=O>[F:32][C:33]1[C:38]([F:39])=[CH:37][C:36]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])=[C:35]([O:43][CH3:44])[CH:34]=1
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1B(O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnccc1-c1cc(F)c(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 4,5-difluoro-2-methoxyphenylboronic acid (CAS RN 870777-32-5) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic separation. Light brown solid (91%). MS (ESI): m/z=251.099 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH:17]([O:20][CH3:21])[O:18][CH3:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:21][O:20][CH:17]([O:18][CH3:19])[CH2:16][NH:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: COC(CNc1ccc(OCc2ccccc2)cc1)OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(CNc1ccc(O)cc1)OC
Reaction time: 3 h

Procedure:
Palladium(II) hydroxide (20% on carbon, 0.5 g) was added to a solution of (4-benzyloxyphenyl)-(2,2-dimethoxyethyl)amine (3.5 g) in ethanol (50 mL) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was shaken for 3 hours. The catalyst was filtered off and the filtrate was concentrated. The crude product was reacted further without purification.
Reaction SMILES: CS(O[C@@H:6]1[C@H:13]2[C@H:9]([CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)[CH2:8][CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[N:21]([C@H:6]1[C@H:13]2[C@H:9]([CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12]2)[CH2:8][CH2:7]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 90 °C

Procedure:
(3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl methanesulfonate (1.686 g, 5.71 mmol) from Step C and sodium azide (0.557 g, 8.56 mmol) were combined in N,N-dimethylacetamide (10 mL). The reaction was heated at 90° C. for 15 hours. The reaction was cooled and diluted with 200 mL of ethyl acetate and then quenched with 30 mL water. The organic layer was removed and washed with 2×20 mL of water, then 20 mL of brine. The solvent was removed in vacuo to give (3aS,4R,6aR)-4-azido-2-benzyloctahydrocyclopenta[c]pyrrole: 1H NMR (300 MHz, CDCl3) δ ppm 7.36-7.27 (m, 4H), 7.22 (dd, J=2.9, 5.8, 1H), 3.72-3.61 (m, 1H), 3.54 (s, 2H), 2.76-2.60 (m, 1H), 2.55-2.40 (m, 4H), 2.35 (dd, J=3.5, 9.1, 1H), 2.07-1.86 (m, 2H), 1.72-1.60 (m, 1H), 1.49-1.38 (m, 1H).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8](O)=[C:7]([C:12]#[N:13])[C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].O(Br)[Br:16].[P+3]>CN(C=O)C>[Br:16][C:8]1[CH:9]=[CH:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:14])[C:7]=1[C:12]#[N:13]
Reactant: CCCCn1ccc(O)c(C#N)c1=O
Reactant: BrOBr
Agent: [P+3]
Solvent: CN(C)C=O
Product: CCCCn1ccc(Br)c(C#N)c1=O
Temperature: 110 °C
Yield: 70.9 %

Procedure:
To a solution of intermediate 7 (39 g, 203 mmol) in DMF (600 ml) was added phosphorus(III) oxybromide (116 g, 406 mmol) and the mixture was heated at 110° C. for 1.5 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 10 (36.7 g, 72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]([CH2:17][CH2:18][OH:19])[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH2:31])=[C:25]([CH3:32])[CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:21][O:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH:31][C:14]([C:13]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:9][C:10](=[O:20])[N:11]([CH2:17][CH2:18][OH:19])[CH:12]=2)=[O:16])=[C:25]([CH3:32])[CH:24]=1
Reactant: O=C(O)C1=CN(CCO)C(=O)NC1c1ccc(F)cc1
Reactant: COc1cc(C)c(N)cc1OC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(NC(=O)C2=CN(CCO)C(=O)NC2c2ccc(F)cc2)cc1OC
Yield: 23.5 %

Procedure:
4-(4-Fluoro-phenyl)-1-(2-hydroxy-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid(180 mg), 4,5-dimethoxy-2-methyl-phenylamine (86 mg) and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 265 mg) were dissolved in 10 mL DMF, followed by 0.2 mL di-iso-propylethyl amine. The mixture was heated at 50° for 72 hours, then cooled, diluted with aqueous pH 2 buffer and ethyl acetate, and the layers separated. The organic layer was washed with saturated sodium bicarbonate and brine, then dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed in 3% MeOH/DCM. The fraction containing the product was washed with 10% aqueous HCl, and concentrated in vacuo to yield 52 mg of 4-(4-fluoro-phenyl)-1-(2-hydroxy-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid(4,5-dimethoxy-2-methyl-phenyl)-amide, MS (M+H)=430.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[N:54]=[N:55][CH:56]=[CH:57][CH:58]=1>CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:52][C:53]2[N:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cccnn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Yield: 62.2 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared in Example 38, 625.2 mg, 2.18 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (908.3 mg, 2.39 mmol), N,N-diisopropylethylamine (1.1 mL, 6.53 mmol), and 3-aminopyridazine (310.6 mg, 3.27 mmol) in dry N,N-dimethylformamide (11 mL) was stirred at 25° C. under nitrogen for 72 h. The reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide. The resulting residue was diluted with ethyl acetate (200 mL). The organic layer was washed with a 10% aqueous hydrochloric acid solution and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyridazin-3-yl-propionamide (493.8 mg, 62%) as a white foam: mp 70-71° C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0908.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: BrCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N(CCCCCCCCCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,10-dibromodecane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,10-dibromodecane. The crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a pale yellow solid. Yield: 1.32 g (65%). 1H-NMR (400 MHz, d6-DMSO) δ=1.16-1.40 (m, 14H), 1.76 (tt, J=7.0, 7.0 Hz, 2H), 3.50 (t, J=6.6 Hz, 2H), 3.79 (t, J=7.0 Hz, 2H), 6.61 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 8.95 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:21]#[N:22])([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31]>>[C:21]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])#[N:22]
Reactant: CNCCc1cccc(C(=O)OC)c1
Reactant: CCOC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Product: CCOC(=O)C(C#N)(CCCN(C)CCc1cccc(C(=O)OC)c1)c1ccc(OC)c(OC)c1

Procedure:
Reaction of 1c with 2d produced 3u. MS found M+H=483. The oxalate salt of 3u was recrystallized from ethyl acetate; mp 89-91° C.
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=2[CH3:30])=[CH:16][C:15]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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>[OH:11][CH2:10][C:3]1[C:2]([C:15]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:21]=3[CH3:30])[CH:18]=[CH:19][C:14]=2[O:13][CH3:12])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1
Reactant: CSc1ncc(Br)c(CO)n1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(B(O)O)c2)c(C)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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3cnc(SC)nc3CO)c2)c(C)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Into a 3000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed [5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methanol (130 g, 560 mmol, 1.00 equiv), [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid (87.5 g, 0.5 equiv), Pd(PPh3)4 (32.3, 28 mmol, 0.05 equiv), Cs2CO3 (365.1 g, 2.00 equiv), water (300 mL), 1,4-dioxane (1200 mL). The resulting solution was stirred for 5 hour at 100° C., then added 2nd batch of [2-methoxy-5-[4-(methoxycarbonyl)-2-methylphenyl]phenyl]boronic acid (50 g, 0.3 equiv). The last batch (37 g, 0.2 equiv) was added after 2 hours. The resulting solution was stirred for 3 h at 100° C. The reaction mixture was cooled to room temperature and diluted with 1000 mL of water. The resulting solution was extracted with 2×1000 mL of ethyl acetate. The organic layers were combined, washed with 1×1000 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:8). This resulted in 81 g (35.7%) of methyl 4-[3-[4-(hydroxymethyl)-2-(methylsulfanyl)pyrimidin-5-yl]-4-methoxyphenyl]-3-methylbenzoate as a yellow solid. LCMS (ES, m/z): 411 [M+H]+. 1H NMR (CDCl3, 300 MHz): δ 8.398 (1H, s), 7.976 (1H, s), 7.916 (2H, d), 7.410 (1H, d), 7.284-7.325 (1H, m), 7.066-7.114 (2H, m), 4.583 (2H, s), 3.954 (3H, s), 3.853 (3H, s), 2.663 (3H, s).
Reaction SMILES: C(N(CC)CC)C.C([SiH](CC)CC)C.[CH3:15][O:16][C:17](=[O:62])[CH:18]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][C:45]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])=[N:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH:39]=1)[O:19][P:20]([C@@H:23]([NH:27]C(OCC1C=CC=CC=1)=O)[CH:24]([CH3:26])[CH3:25])([OH:22])=[O:21]>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][O:16][C:17](=[O:62])[CH:18]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([NH:44][C:45]([NH:54][C:55]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[O:56])=[N:46][C:47]([O:49][C:50]([CH3:52])([CH3:53])[CH3:51])=[O:48])[CH:39]=1)[O:19][P:20]([C@@H:23]([NH2:27])[CH:24]([CH3:26])[CH3:25])([OH:22])=[O:21]
Reactant: COC(=O)C(OP(=O)(O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(OP(=O)(O)[C@@H](N)C(C)C)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reaction time: 0.42 h
Yield: 114.9 %

Procedure:
To a solution of palladium(II) acetate (184 mg, 0.82 mmol) in 13 mL of CH2Cl2 was added triethylamine (0.24 mL, 1.72 mmol) and triethylsilane (1.80 mL, 11.3 mmol). After stirring the resulting black slurry for 25 minutes, 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzyloxycarbonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid methyl ester (2.93 g, 4.23 mmol) in methylene chloride (3 mL) was added. The reaction mixture was stirred at ambient temperature for 5.5 hours at which point the reaction was concentrated in vacuo, dissolved in methanol, and filtered. The filtrate was concentrated in vacuo and placed in vacuo overnight to provide 2.7143 g (116%) of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-amino-2-methylpropyl)-(hydroxy)phosphinoyloxy)ethanoic acid methyl ester as an impure white foam.