Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1[CH:24]=O.C[O-].[Li+]>CN(C=O)C.CO>[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:26][C:23]=1/[CH:24]=[CH:2]/[C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(N2CCCC2)cc1C=O
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(N2CCCC2)cc1/C=C/C(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.9 %

Procedure:
A solution 4-acetyl-N-pyridin-2-ylbenzenesulfonamide (Ex-5A, 588 mg, 2.13 mmol) and 2,4-dimethoxy-5-pyrrolidin-1-yl-benzaldehyde (Ex-38B, 500 mg, 2.13 mmol) in DMF (9.3 mL) and MeOH (4.0 mL) was treated with lithium methoxide (243 mg, 6.39 mmol) and stirred for 20 h at room temperature under nitrogen. The reaction mixture was quenched with water (25 mL) and extracted ethyl acetate (3×50 mL). The product precipitated out of the organic phase to give 535 mg (51%) of the title compound as a red solid, mp 124–128° C. 1H-NMR (300 MHz, DMSO-d6) 8.16 (d, 2H, J=8.7), 8.02 (d, 1H, J=15.9 Hz), 7.95 (m, 3H), 7.70 (t, 1H, J=7.80 Hz), 7.61 (d, 1H, J=16.2 Hz), 7.18 (d, 1H, J=8.70 Hz), 7.15 (s, 1H), 6.83 (t, 1H, J=6.0 Hz), 6.66 (s, 1H), 3.84 (s, 6H), 3.13 (m, 4H), 1.18 (m, 4H). HRMS (ESI) Calcd. for C26H27N3O5S: 494.1750 [(M+H)+]; Found: 494.1750.
Reaction SMILES: [Li]CCCC.[CH2:6]([C:13]1[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:22](OC)([O:25]C)[O:23]C.[OH-].[Na+]>C1COCC1.O>[CH2:6]([C:13]1[CH:18]=[C:17]([B:22]([OH:25])[OH:23])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc(Br)cc1Cc1ccccc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(B(O)O)cc1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
8.61 ml (13.8 mmol, 1 eqv) of a 1.6 M solution of n-BuLi in hexanes was added to a solution of 3.82 g (13.8 mmol) 2-Benzyl-4-bromo-anisol (21) in 100 ml dry THF at −78° C. After stirring this mixture for 30 min at −78° C., 4.70 ml (41.4 mmol, 3 eqv) B(OMe)3 was added and the solution was stirred for 24 h at rt. Now 10 ml water and 25 ml of a 10% aq. NaOH-solution were added and stirring was continued for further 60 min. Then the pH was adjusted to 4-5 with 1-N-HCl-solution and most of the solvent was evaporated. The residue was extracted with EtOAc and the comb. org. fractions were dried over MgSO4 and evaporated, which led after drying in high vacuum to 3.33 g (13.8 mmol, 100%) of an orange solid. This crude boronic acid 22 was used without further purification: 1H NMR (500 MHz, CDCl3) δ 3.81 (s, 3H), 3.98 (s, 2H), 6.89 (d, 1H, J=8.20 Hz), 7.10-7.23 (m, 5H), 7.79 (d, 1H, J=1.58 Hz), 7.96 (dd, 1H, J1=8.20 Hz, J2=1.73 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.C(N(CC)CC)C.[CH3:34][N:35]1[C:39]([C:40](Cl)=[O:41])=[CH:38][C:37]([CH3:43])=[N:36]1>O1CCCC1>[CH3:34][N:35]1[C:39]([C:40]([NH:1][C:2]2[CH:26]=[CH:25][CH:24]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:41])=[CH:38][C:37]([CH3:43])=[N:36]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CCOCC4)cn3n2)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CCOCC5)cn4n3)c2)n(C)n1
Yield: 26.9 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]tetrahydro-2H-pyran-4-carboxamide (200 mg, 0.57 mmol), triethylamine (237 mL, 1.70 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (180 mg, 1.13 mmol) and tetrahydrofuran (6.0 mL) as starting materials and in the same manner as in Example 96, the title compound (73 mg, 27%) was obtained as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N+:13]([O-])=[C:12]([CH3:17])[C:11]=2[CH3:18])[O:4][CH2:3]1.C(OC(=O)C)(=[O:22])C.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:17][OH:22])[C:11]=2[CH3:18])[O:4][CH2:3]1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CO
Temperature: 85 °C
Reaction time: 0.75 h
Yield: 39.7 %

Procedure:
The 4-((5,5-dimethyl-1,3-dioxan-2-yl)methoxy)-2,3-dimethylpyridine 1-oxide (3.1 g, 11.6 mmol) obtained by the step (1c) was mixed with acetic anhydride (9.87 ml, 104 mmol). After the mixture was stirred at 85° C. for 45 minutes, acetic anhydride was removed. The residue was dissolved in methanol (40 ml) and a 5N aqueous sodium hydroxide solution (5.1 ml, 25.5 mmol) was added to the mixture while cooling on ice. The mixture was stirred at room temperature for one hour. Methanol was distilled off and ice water was added to the residue, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resultant mixture was purified by silica gel column chromatography (silica gel: 120 g, elution solvent: ethyl acetate/heptane=1/4 to 4/1) to obtain the title compound (1.23 g, yield: 39.7%) as a light yellow oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:29]=[C:28]([N:30]2[C:34]([NH:35][CH2:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[CH:39]=[CH:40][NH:41]4)=[N:33][N:32]=[N:31]2)[CH:27]=[C:26]([CH3:46])[C:22]=1[C:23]([OH:25])=O.ClN1C(=O)CCC1=O.[CH3:55][O:56][C:57](=[O:66])[CH:58]([P:60]([O:64][CH3:65])([O:62][CH3:63])=[O:61])[NH2:59].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O>ClCCl>[CH3:55][O:56][C:57](=[O:66])[CH:58]([P:60]([O:62][CH3:63])([O:64][CH3:65])=[O:61])[NH:59][C:23](=[O:25])[C:22]1[C:26]([CH3:46])=[CH:27][C:28]([N:30]2[C:34]([NH:35][CH2:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:38]=3[CH:39]=[CH:40][NH:41]4)=[N:33][N:32]=[N:31]2)=[CH:29][C:21]=1[CH3:20]
Reactant: COC(=O)C(N)P(=O)(OC)OC
Reactant: Cc1cc(-n2nnnc2NCc2cccc3[nH]ccc23)cc(C)c1C(=O)O
Agent: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1c(C)cc(-n2nnnc2NCc2cccc3[nH]ccc23)cc1C)P(=O)(OC)OC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (1.31 g, 5 mmol) is added to a suspension of give 2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoic acid (Example 329; 1.81 g, 5 mmol) in dichloromethane (25 mL) at 25° C. The mixture is cooled to 0° C. and N-chlorosuccinimide (0.668 g, 5 mmol) is added. After stirring 15 min at 0° C., the mixture is stirred for an additional 15 min at 25° C. and then a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (3.01 g, 10 mmol) in dichloromethane (5 mL) is added in one portion. The reaction is stirred for 5 h, then the precipitated amine hydrochloride is filtered off, washed with dichloromethane and discarded. The filtrate is washed with 1N hydrochloric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), then is dried (MgSO4) and concentrated under reduced pressure. The residue is chromatographed over silica gel (increasing percentages of ethyl acetate in petroleum ether) and the appropriate fractions are combined and evaporated to yield rac.-N-[2,6-dimethyl-4-[5-[(1H-indol-4-yl)methylamino]tetrazol-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester.
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@:23]([F:29])([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:30])[CH2:19][CH2:20]2)[C@@H:15]([CH3:31])[CH2:14]3)[CH2:11][C@H:10]1[CH3:32])[C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:1]([O:4][C@:5]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@:23]([F:29])([C@@H:24]([OH:28])[CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:30])[CH2:19][CH2:20]2)[C@@H:15]([CH3:31])[CH2:14]3)[CH2:11][C@H:10]1[CH3:32])[C:6](=[O:9])[CH2:7][O:8][C:33](=[O:35])[CH3:34])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@]1(C(=O)CO)[C@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@H](C)C[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C

Procedure:
A solution of 650 mg of 17α-acetoxy-9α-fluoro-11β,21-dihydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione in 6.5 ml of pyridine and 3.2 ml of acetic anhydride is stirred for 2 hours at room temperature and poured on an ice water-sodium chloride solution. The mixture is filtered off and worked up as usual. After crystallization from hexane/ethyl acetate, 430 mg of 17α,21-diacetoxy-9α-monofluoro-11β-hydroxy-6α,16α-dimethyl-4-pregnene-3,20-dione is isolated, mp 194°-195° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH2:13][O:14][CH3:15])[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=1.CCN(C(C)C)C(C)C.[SH:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>O1CCOCC1.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].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>[CH3:15][O:14][CH2:13][O:12][C:4]1[C:5](=[O:11])[N:6]([CH2:8][O:9][CH3:10])[CH:7]=[C:2]([S:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:3]=1
Reactant: COC(=O)CCS
Reactant: COCOc1cc(Br)cn(COC)c1=O
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: COCOc1cc(SCCC(=O)OC)cn(COC)c1=O
Yield: 84.9 %

Procedure:
A mixture of 5-bromo-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 15) (3.5 g, 12.6 mmol), Pd2(dba)3 (0.46 g, 0.50 mmol), Xantphos (0.58 g, 1.00 mmol) and DIPEA (4.40 ml, 25.2 mmol) in dioxane (60 ml) was degassed and then placed under an atmosphere of nitrogen. To this mixture was added methyl 3-mercaptopropanoate (1.66 g, 13.8 mmol) and the whole was heated under reflux for 3 hours. Upon cooling it was filtered through a pad of celite and ethyl acetate was washed through the pad of celite to recover any remaining compound. The organic filtrate was washed with water and then saturated aqueous sodium chloride solution and the organics were dried (MgSO4), filtered and concentrated under vacuum. The crude residue was purified by column chromatography (SiO2; 0-100% dichloromethane in petrol, then 0-10% methanol in dichloromethane). Product fractions were collected and concentrated in vacuo to give a yellow oil. This oil was purified further by reverse phase column chromatography (SiO2—C18; 5-95% methanol in water with 0.1% formic acid) to give methyl 3-{[5-(methoxymethoxy)-1-(methoxymethyl)-6-oxo-1,6-dihydropyridin-3-yl]sulfanyl}propanoate (3.4 g, 10.7 mmol, 85%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[CH:26][C:25]=3[CH3:32])[C:20](O)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:35][CH:36]([O:51][CH2:52][CH3:53])[C@@H:37]([NH:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[N:49]=[CH:48][CH:47]=[CH:46]2)[CH3:38])[CH3:34].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>ClCCl.C(OCC)(=O)C>[CH2:33]([O:35][CH:36]([O:51][CH2:52][CH3:53])[C@@H:37]([N:39]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[N:49]=[CH:48][CH:47]=[CH:46]2)[C:20](=[O:21])[C@@H:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[CH:26][C:25]=1[CH3:32])[CH3:38])[CH3:34]
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2cccnc12
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.2 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propanoic acid (907 mg, 2.1 mmol) and (S)-1,1-diethoxy-N-(quinolin-8-ylmethyl)propan-2-amine (Compound IX-7)(577 mg, 2.0 mmol) in dichloromethane (10 ml) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (660 mg, 2.1 mmol) and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (50 ml), water (50 ml) and brine (50 ml). The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=1:1) to obtain the title compound (775 mg, 55%).
Reaction SMILES: [Cl-].[C:2]1([PH+:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:21].[Na+].[OH2:23]>>[Br-:21].[O:23]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[CH:7][P+:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Reactant: O
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Product: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution consisting of 2.1 parts of triphenylphosphonium chloride in 50 parts of water is added with stirring to 2 parts of sodium bromide. At the end of about 5 minutes an additional 4 parts of sodium bromide is added the mixture is stirred until precipitation is complete. The precipitate is isolated by filtration, thus affording [(tetrahydro-2H-pyran-2-ylidene)-methyl]triphenylphosphonium bromide. This product is characterized by 60-MHz nuclear magnetic resonance peaks in CDCl3 (deuterated chloroform) at 107 cps (multiplet), 170 cps (multiplet), 228 cps (multiplet), 329 cps (doublet, J≃18 cps) in addition to the aromatic protons, by microanalytic determination of bromide.
Reaction SMILES: [NH2:1][C:2]([C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH:24]=[CH:25][CH:26]=1)([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([F:20])[CH:11]=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:38]1([N:43]=[C:44]=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39]1.C1COCC1.[OH-].[Li+]>C(Cl)Cl>[CH:38]1([NH:43][C:44](=[O:45])[NH:1][C:2]([C:21]2[CH:22]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:24]=[CH:25][CH:26]=2)([C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[C:12]([F:20])[CH:11]=2)[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C=NC1CCCC1
Reactant: CCOC(=O)CCCCCCc1cccc(C(N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CCCCCCc1cccc(C(Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
To a solution of ethyl 7-(3-(1-amino-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoate (169 mg, 0.33 mmol) in anhydrous DCM (1 mL) was added cyclopentyl isocyanate (22 mg, 0.2 mmol). The reaction mixture was stirred at rt for 18 h. To the reaction mixture was added anhydrous THF (1 mL) and the mixture was stirred at room temperature for additional 1 h. The solvents were evaporated on a rotary evaporator and the residue was dissolved in methanol and purified by preparative HPLC (RT=11.3 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 26-90% MeCN/H2O containing 0.1% TFA over 9 min and hold at 90% for 7 more minutes; 40 mL/min, monitoring at 220 nm). The resulting solid was dissolved in methanol (1 mL) followed by the addition of aqueous lithium hydroxide (1 N, 0.25 mL, 0.25 mmol). The reaction mixture was heated at 36° C. for 18 h. The crude product was purified by preparative HPLC (RT=10.7 min, Waters Sunfire C18 OBD, 19×100 mm eluting with 18-90% MeCN/H2O over 10 min and hold at 90% for 6 additional minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to yield 7-(3-(1-(3-cyclopentylureido)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)phenyl)heptanoic acid (Example 234, 32 mg, 53% yield for 2 steps). LCMS: RT=4.33 min, Purity >95%, [M+H] 599.4 (Sunfire-S5-C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) 7.36 ppm, 1H, s; 7.16-7.24 ppm, 4H, m; 7.10-7.13 ppm, 3H, m; 6.97 ppm, 1H, d, J=7.7 Hz; 6.94 ppm, 1H, s; 6.67 ppm, 2H, d, J=7.1 Hz; 5.58 ppm, 1H, brd, s; 3.87 ppm, 1H, d, J=12.6 Hz; 3.83 ppm, 1H, m; 3.65 ppm, 1H, d, J=12.7 Hz; 2.54, 2H, t, J=7.5 Hz; 2.29 ppm, 2H, t, J=7.4 Hz; 1.73-1.84 ppm, 2H, m; 1.50-1.60 ppm, 8H, m; 1.15-1.36 ppm, 6H, m.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([C:14]#[N:15])=[C:12](F)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH2:20][CH:21]([C:23]1[CH:24]=[CH:25][C:26]([F:35])=[C:27]([NH:29][C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH:28]=1)[CH3:22].CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:13]1[C:12]([NH:20][CH:21]([C:23]2[CH:24]=[CH:25][C:26]([F:35])=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[CH:28]=2)[CH3:22])=[N:11][C:10]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)=[C:17]([F:18])[CH:16]=1)#[N:15]
Reactant: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1F
Reactant: CC(N)c1ccc(F)c(NC(=O)C2CC2)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C#N)c1ccc(F)c(NC(=O)C2CC2)c1
Temperature: 150 °C

Procedure:
To a 10-ml microwave reaction vessel was added 6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2,5-difluoronicotinonitrile (Method 32, 431 mg, 1.65 mmol), N-[5-(1-aminoethyl) -2-fluorophenyl]cyclopropanecarboxamide (Method 69, 550 mg, 2.5 mmol), and DIEA (1.15 ml, 6.6 mmol) in n-butanol (5 ml). The resulting suspension was set to microwave heating (CEM Discover System) at 150° C. for 3 hours. The reaction was concentrated in vacuo and purified by silica gel chromatography (Biotage Horizon System) using a gradient elution of 25-35% EtOAc (20% v/v MeOH) in hexanes to give 267 mg (35% isolated yield) of the title compound. 1H NMR: 11.99 (s, 1H) 9.91 (s, 1H) 9.42 (s, 1H) 7.88 (d, J=6.03 Hz, 1H) 7.59 (d, J=10.55 Hz, 1H) 6.95-7.20 (m, 3H) 5.99 (s, 1H) 5.02-5.21 (m, 1H) 1.89-2.03 (m, 1H) 1.76-1.89 (m, 1H) 1.45 (d, J=7.54 Hz, 3H) 0.87 (t, J=8.67 Hz, 2H) 0.75 (d, J=6.03 Hz, 4H) 0.54-0.66 (m, 2H). MS: Calcd.: 463. Found: [M+H]+ 464.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([O:20][CH2:21][C:22]#[N:23])[CH:14]=[CH:13]4)=[C:7]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=2[CH:30]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][CH2:21][C:22]5[NH:33][N:32]=[N:31][N:23]=5)[CH:16]=4)[CH:11]=3)=[C:7]([C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])[C:6]=2[CH:30]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OCC#N)ccc3c2)oc2ccc(Cl)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCCC(=O)c1c(-c2ccc3cc(OCc4nnn[nH]4)ccc3c2)oc2ccc(Cl)cc12
Yield: 76.2 %

Procedure:
Following the procedure described in Step 6, of Example 1, the title compound was prepared from [6-(5-Chloro-3-pentanoyl-benzofuran-2-yl)-naphthalen-2-yloxy]-acetonitrile (0.31 g, 0.74 mmol), sodium azide (0.325 g, 5 mmol) and ammonium chloride (0.268 g, 5 mmol) in DMF (20 mL). Trituration with methanol afforded the title compound as a yellow solid (0.26 g), mp 178-180° C. Mass spectrum (+APCl, [M+H]+) m/z 461. 1HNMR (400 MHz, DMSO-d6): δ8.4 (s, 1H), 8.07-7.99 (m, 3H), 7.85 (dd, 1H, J=8.5, 1.7 Hz), 7.77 (d, 1H, J=8.8 Hz),), 7.64 (d, 1H, J=2.2 Hz),), 7.48 (dd, 1H, J=8.8, 2.2 Hz),), 7.38 (dd, 1H, J=8.8, 2.4 Hz), 5.66 (s, 2H), 2.70 (t, 2H, J=7.4 Hz), 1.56-1.48 (m, 2H), 1.15-1.06 (m, 2H), and 0.69 ppm (t, 3H, J=7.5 Hz). Elemental Analysis for C25H21ClN4O3.0.5H2O: Calculated: C, 64.52; H, 4.66; N, 12.04. Found: C, 64.40; H, 4.42; N, 12.07.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]=[C:9]([N:18]3[CH2:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[S:21](=[O:30])(=[O:29])[CH2:20][CH2:19]3)[CH:8]=2)[CH2:4][C@H:3]1[OH:31].C([O-])(=O)C.[Na+].[N:37]#[C:38]Br>CO>[O:29]=[S:21]1(=[O:30])[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH2:24][N:18]([C:9]2[CH:8]=[C:7]([N:5]3[CH2:4][C@H:3]4[C@H:2]([N:1]=[C:38]([NH2:37])[O:31]4)[CH2:6]3)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]=2)[CH2:19][CH2:20]1
Reactant: N#CBr
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H](O)[C@@H](N)C3)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H]4OC(N)=N[C@@H]4C3)c2c1
Reaction time: 8 h

Procedure:
To a mixture of cis-4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol (90 mg 0.20 mmol, prepared in analogy to Example 19-3 in Scheme 7 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and tert-butyl [cis-4-hydroxypyrrolidin-3-yl]carbamate) and sodium acetate (82 mg, 1.0 mmol) in methanol (10 mL) at 0° C. was added cyanogen bromide (105 mg, 1 mmol). The mixture was stirred overnight gradually from 0° C. to room temperature, and then concentrated in vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 464, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J=7.33 Hz, 1 H), 7.98 (d, J=7.58 Hz, 1 H), 7.89 (brs, 1 H), 7.79-7.70 (m, 2 H), 7.66-7.56 (m, 2 H), 6.50 (s, 1 H), 5.89-5.84 (m, 1 H), 5.41 (brs, 2 H), 4.97-5.02 (m, 1 H), 4.63 (brs, 2 H), 4.31 (brs, 1 H), 4.12 (brs, 1 H), 3.77 (brs, 2 H), 3.62-3.42 (b, 2 H), 2.54-2.48 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([OH:12])([CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[C:4]#[CH:5].[Cl:15][O-].[Na+]>C(Cl)Cl>[Cl:15][C:5]#[C:4][C:3]([OH:12])([CH2:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[C:2]([CH3:14])([CH3:13])[CH3:1]
Reactant: [O-]Cl
Reactant: C#CC(O)(Cn1cncn1)C(C)(C)C
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(O)(C#CCl)Cn1cncn1
Yield: 86 %

Procedure:
9.65 (50 mmol) of 4,4-dimethyl-3-hydroxy-3-[(1,2,4-triazol-1-yl)-methyl]-1-pentine in 20 ml of methylene chloride are stirred for 3 days with 400 ml (150 mmol) of a solution of sodium hypochlorite at room temperature. The reaction mixture is then extracted by shaking with methylene chloride. After drying the organic phase and stripping off the solvent in vacuo, there are obtained 9.8 g (43 mmol; 86% of theory) of 1-chloro-4,4-dimethyl-3-hydroxy-3-[(1,2,4-triazol-1-yl)-methyl]-1-pentine having a melting point of 88° C.