Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:27]([O-:29])=[O:28])=[C:21]5[C:25]=4[O:24][CH:23]([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8](=[O:31])[C@H:7]2[CH2:32][CH3:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>CO.O1CCCC1>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:27]([OH:29])=[O:28])=[C:21]5[C:25]=4[O:24][CH:23]([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:30])[C:8](=[O:31])[C@H:7]2[CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)[O-])c4c3OC(C)C4)nc2N1C1CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(C)C4)nc2N1C1CCCC1
Reaction time: 12 h
Yield: 94.9 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-methyl-2,3-dihydrobenzofuran-4-carboxylate 30c (100 mg, 0.21 mmol) and 1 M lithium hydroxide solution were dissolved in 50 mL of the mixture solvent of methanol and tetrahydrofuran (V/V=1:1). The reaction solution was stirred for 12 hours followed by the addition of 1 M hydrochloric acid to adjust pH to 6 to 7. The resulting solution was concentrated under reduced pressure. The residue was added dropwise with 1 M lithium hydroxide solution to adjust pH to 3 to 4 and extracted with ethyl acetate (30 mL×3). The combined organic phase was concentrated under reduced pressure to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2-methyl-2,3-dihydrobenzofuran-4-carboxylic acid 30d (90 mg, yield: 95.0%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9]Br>O.C(O)C>[C:11]1([CH:8]([CH3:9])[CH2:7][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(CBr)c1ccccc1
Reactant: C1CNCCN1
Solvent: CCO
Solvent: O
Product: CC(CN1CCNCC1)c1ccccc1

Procedure:
A solution of piperazine (344 g), β-bromoisopropylbenzene (199 g) in water (1 liter) and ethanol (0.35 liter) is refluxed for 24 hours. After cooling, the resulting amine is extracted with 3×0.5 liter methylene chloride. After washing with water and evaporation of the solvent in vacuo, the resulting 2-phenylpropyl piperazine is distilled; b.p.=163°-165° C./15 mm Hg.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCBr)cc1
Yield: 43.9 %

Procedure:
A mixture of 1,2-dibromoethane (3.9 mL, 45 mmol), 4-hydroxybenzaldehyde (1.8 g, 15 mmol) and K2CO3 (10.4 g, 75 mmol) in acetone (40 mLO was heated to reflux for 18 hr. The mixture was cooled, diluted with ethyl acetate (200 mL) and washed with brine (200 mL). Then organic layer was dried (MgSO4), filtered and then concentrated. The resulting residue was subjected to flash chromatography (25% ethyl acetate/hexane) to provide 1.51 g (44%) of 4-(2-bromoethoxy)benzaldehyde.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][CH:7]([CH3:20])[CH2:8][CH:9](C(OCC)=O)[C:10]([O:12]CC)=[O:11])[CH2:4][CH3:5].S(=O)(=O)(O)O.C1C=CC=CC=1>O>[CH2:3]([O:6][CH:7]([CH3:20])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH3:5]
Reactant: CCCOC(C)CC(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCCOC(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
Then, 87 g of 85% KOH was dissolved in 87 ml of water, and 100 g of the above ethyl 4-propoxy-2-ethoxycarbonylvalerate was added at 15°-25° C. in 45 min. The mixture was stirred at 90°-96° C. for 2 hours, and then cooled. While keeping the temperature below 20° C., a solution of 138 g of conc. sulfuric acid in 194 ml of water was added dropwise in 30 min. The mixture was stirred at 90°-95° C. for 3 hours, cooled to room temperature and then subjected to extraction with ether. The ether layer was washed with saturated saline water and then ether was distilled off, followed by vacuum distillation to obtain 47 g of a fraction of 100°-130° C./5 mmHg. Benzene was added to the fraction, and the mixture was washed with 5% NaOH aqueous solution. The aqueous layer was acidified to pH 1 with 6N-hydrochloric acid and subjected to extraction with ether. The ether extract was washed with saturated saline water, and ether was distilled off to obtain 38 g of 4-propoxyvaleric acid.
Reaction SMILES: N(C(C)(C)C#N)=N[C:3](C)(C)C#N.[N:13]([C:24]([C:31]#N)([CH3:30])[CH2:25][CH2:26]C(O)=O)=[N:14][C:15]([C:22]#[N:23])([CH3:21])[CH2:16][CH2:17][C:18](O)=O.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N.C(OO)(C)(C)C.[O-]O.C1(C(C)C)C=CC=CC=1>>[C:24]([N:13]=[N:14][C:15]1([C:22]#[N:23])[CH2:16][CH2:17][CH2:18][CH2:3][CH2:21]1)([CH2:25][CH3:26])([CH3:30])[CH3:31]
Reactant: CC(C#N)(CCC(=O)O)N=NC(C)(C#N)CCC(=O)O
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(C)OO
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Agent: [O-]O
Solvent: CC(C)c1ccccc1
Product: CCC(C)(C)N=NC1(C#N)CCCCC1

Procedure:
Of these oil-soluble initiators, the most preferable due to commercial availability are 2,2'-azobis(isobutyronitrile), 4,4'-azobis(4-cyanopentanoic acid), 2,2'-azobis-(2,4-dimethylvaleronitrile), t-butyl hydroperoxide, cumene hydroperoxide, benzoyl peroxide amnd lauroyl peroxide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](=O)[NH:8][CH:9]=1)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:17].P(Cl)(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>>[Cl:17][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc([N+](=O)[O-])cc1C(F)(F)F
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Temperature: 115 °C

Procedure:
A mixture of 5-nitro-3-(trifluoromethyl)pyridin-2(1H)-one 3 (1.50 g, 7.21 mmol), POCl3 (2.76 g, 18.02 mmol) and PCl5 (1.4 g, 10.09 mmol) is heated to about 110-120° C. for 8 hours and then poured into ice water. The mixture is neutralized with solid NaHCO3 and extracted with ethyl acetate (3×40 ml). The combined organic phases is dried over Na2SO4 and all solvents removed under reduced pressure to obtain 2-chloro-5-nitro-3-(trifluoromethyl)pyridine 4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:26][O-:27].[Na+]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[C:7]([O:27][CH3:26])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Agent: [Na+]
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 40a), from 2-(3-nitro-6-fluorophenyl)-5-phenylbenzoxazole (500 mg, 1.5 mmol) and sodium methoxide (161 mg, 3.0 mmol) the subtitle compound was obtained (450 mg, 87%). 1H NMR (DMSO) δ 8.88(d, 1H), 8.48(dd, 1H), 8.12(d, 1H), 7.89(d, 1H), 7.75(m, 3H), 7.53(d, 1H), 7.50(t, 2H), 7.40(d, 1H), 4.11(s, 3H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21](Cl)[N:20]=3)[CH:15]=[CH:16][CH:17]=2)[CH:5]=1.C(N(CC)CC)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:25][C:24]1[CH:23]=[N:22][C:21]2[NH:3][C:4]3[CH:9]=[CH:8][N:7]=[C:6]([CH:5]=3)[CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([NH:18][C:19]=1[N:20]=2)[CH:15]=[CH:16][CH:17]=3
Reactant: Nc1ccnc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1cnc2nc1Nc1cccc(c1)CCc1cc(ccn1)N2
Yield: 35.3 %

Procedure:
To a mixture of N-{3-[2-(4-aminopyridin-2-yl)ethyl]phenyl}-2,5-dichloropyrimidin-4-amine dihydrochloride (90.0 mg, 0.21 mmol) and triethylamine (0.087 mL, 0.62 mmol) in dry 1,4-dioxane (1.8 mL) was added (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (7.2 mg, 0.013 mmol), palladium acetate (1.9 mg, 0.008 mmol) and cesium carbonate (135 mg, 0.42 mmol). The mixture was degassed by bubbling N2 through the solution. The sealed tube was then microwaved at 150° C. for 30 min. The reaction mixture was diluted with THF/MeOH, filtered, and concentrated to give the residue, which was purified by silica gel column chromatography to provide the desired product (24 mg, 36%) as a white powder. LCMS for C17H15ClN5 (M+H)+: m/z=324.0. 1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 9.28 (s, 1H), 8.15 (m, 3H), 7.74 (d, J=1.6 Hz, 1H), 7.27 (dd, J=16.0, 8.0 Hz, 1H), 7.07 (dd, J=12.4, 3.2 Hz, 2H), 6.84 (dd, J=5.6, 2.0 Hz, 1H), 2.93 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][O:24][CH3:25])=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]2([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=2)[CH3:26])=[CH:4][CH:3]=1.[H-].[Na+].[C:39]([O:43][C:44](=[O:47])[CH2:45]Br)([CH3:42])([CH3:41])[CH3:40].O>O1CCCC1>[C:39]([O:43][C:44]([CH2:45][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][O:24][CH3:25])=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]2([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:31][CH:32]=2)[CH3:26])=[CH:4][CH:3]=1)=[O:47])([CH3:42])([CH3:41])[CH3:40]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCc2ccc(O)cc2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCc2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Reaction time: 0.33 h
Yield: 99.5 %

Procedure:
To a solution of 4-[4-(4-hydroxyphenyl)-1-butyl]-7-methoxymethyloxy-3-(4-methoxymethyloxyphenyl)-3-methylchroman (481 mg, 0.976 mmol) in dry tetrahydrofuran (8 ml) was added sodium hydride (22.7 mg, 1.418 mmol) at room temperature and stirred for 20 minutes. Bromoacetic acid tert-butylester (276.7 mg, 1.418 mmol) was added thereto at the same temperature and stirred for 20 minutes. After the reaction was completed, water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 589 mg (yield: quant.) of the title compound as a colorless oil. The resulting compound was used in the next reaction without purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH3:9])[N:4]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH2:10]([NH:12][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([CH3:9])[N:4]=1)[CH3:11]
Reactant: Cc1cncc(CCl)n1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cncc(C)n1

Procedure:
prepared by reaction of 2-chloromethyl-6-methyl-pyrazine (prepared according to Eiermann U. et al, Chem. Ber., 1990, 123, 523-533) with 2M ethylamine in THF.
Reaction SMILES: [ClH:1].C(O[C:7]([N:9](C)[CH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:14][CH2:13]1)=O)(C)(C)C>O1CCOCC1.CCOCC>[ClH:1].[CH3:7][NH:9][CH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][O:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:14][CH2:13]1
Reactant: CN(CC[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CNCC[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
30 ml of 4N hydrogen chloride solution in dioxan was added to 4.06 g (10.8 mmol) of trans methanesulfonic acid 3-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-cyclohexyl}-propyl ester. After stirring of the reaction mixture for 3 hours at room temperature, it was concentrated under reduced pressure. The residue formed was stirred in ether and the crystals formed were filtered off and washed with ether. After drying under reduced pressure and at and 45° C., 3.12 g (92.4%) trans-methanesulfonic acid 3-[4-(2-methylamino-ethyl)-cyclohexyl]-propyl ester HCl salt could be isolated as colorless crystals, MS: 278 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](O)=[O:25]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24]([NH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])[CH:5]=[CH:6][CH:7]=1)=[O:25]
Reactant: COC(=O)c1cncc(C#Cc2cccc(N)c2)c1
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Product: COC(=O)c1cncc(C#Cc2cccc(NC(=O)c3ccc(F)c(Cl)c3)c2)c1

Procedure:
In a manner similar to that described in Example 1, methyl 5-((3-aminophenyl)ethynyl)nicotinate and 3-chloro-4-fluorobenzoic acid are converted to the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:19][C:20]#[C:21][CH3:22])[C:8](=[N:16][C:17]#[N:18])OC1C=CC=CC=1)=[O:5])[CH3:2].[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:19][C:20]#[C:21][CH3:22])=[N:16][C:17]#[N:18])[CH2:32]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: CC#CCN(CC(=O)OCC)C(=NC#N)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCN(CC(=O)OCC)C(=NC#N)N1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.0 g 1-ethoxycarbonylmethyl-1-(but-2-ynyl)-3-cyano-2-phenyl-isourea are added to a mixture of 10.0 g 3-tert-butoxycarbonylaminopiperidine and 4.8 g potassium carbonate in 50 ml of dimethylformamide. The reaction mixture is stirred for 1 d at ambient temperature and then a further 1.6 g potassium carbonate and 3.0 g 3-tert-butoxycarbonylaminopiperidine are added. After another 3 d at ambient temperature water is added and the mixture is extracted with ethyl acetate. The organic extracts are dried over sodium sulphate, the solvent is removed, and the residue is purified on silica gel (cyclohexane/ethyl acetate 5:1->1:2).
Reaction SMILES: CON(C)[C:4](=[O:19])[CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1>>[CH3:28][C:24]1[CH:23]=[C:22]([C:4](=[O:19])[CH2:5][CH:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Product: Cc1cc(C(=O)CC(c2ccccc2)c2ccccc2)ccn1

Procedure:
In analogy to example 55, step 2, the title compounds was prepared from N-methoxy-N-methyl-3,3-diphenyl-propionamide and 4-bromo-2-methylpyridine as a colorless oil, MS (ESI+): m/z=302.15 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[OH:8])[CH2:2]1.BrC1C=NC=CC=1.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1O>>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C@H:7]([O:8][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][C:23]([F:22])([F:33])[F:32])[C@@H:3]2[O:4][CH2:5][CH2:6][NH:1][CH2:2]2)[CH:10]=1
Reactant: Oc1ccccc1OC(F)(F)F
Reactant: OC(c1cccnc1)C1CNCCO1
Solvent: Brc1cccnc1
Product: FC(F)(F)Oc1ccccc1O[C@@H](c1cccnc1)[C@H]1CNCCO1

Procedure:
(R)-2-[(S)-Pyridin-3-yl-(2-trifluoromethoxy-phenoxy)-methyl]-morpholine was synthesized via morpholin-2-yl-pyridin-3-yl-methanol from 3-bromopyridine and 2-trifluoromethoxyphenol according to general procedure C and was isolated as a gummy oil. MS (APCI): 355 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C@H:5]([N:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:30]=[N:29][N:28]=2)=[CH:17][CH:16]=1)[C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH:6]=O.N1C=CC=CC=1>O>[OH:3][N:2]=[CH:4][C@@H:5]([N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]2[N:31]([C:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:30]=[N:29][N:28]=2)=[CH:19][CH:20]=1)[C:9](=[O:13])[CH2:10][CH2:11][CH3:12])[CH3:6]
Reactant: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](C)C=NO
Reaction time: 0.25 h
Yield: 77.7 %

Procedure:
Hydroxylamine hydrochloride (25.4 mg, 0.4 mmol) was added to a solution of intermediate (5c) (174 mg, 0.3 mmol), pyridine (3 mL, 37 mmol) and water (1.5 mL, 83 mmol) at room temperature. After 15 minutes, water (10 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated aqueous NaCl (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography gave intermediate (5d) as a white solid (148 mg).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1)[C:4](O)=[O:5].[BH4-].[Na+]>C(O)C.O>[NH2:2][CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([I:14])=[CH:12][CH:13]=1)[CH2:4][OH:5]
Reactant: NC(Cc1ccc(I)cc1)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(CO)Cc1ccc(I)cc1

Procedure:
A mixture of 28.5 g (75.0 mmol) 2-amino-3-(4-iodophenyl)propanoate hydrochloride in 300 mL ethanol and 300 mL water is added to a mixture of 14.2 g (375 mmol) NaBH4 and 600 mL water (gas evolution!) and the resulting mixture is stirred at reflux for 2 h. The ethanol is evaporated in vacuo and the remaining aq. Phase is extracted with DCM (4×). The combined organic layers are dried with Na2SO4 and the solvent is removed in vacuo. The compound is used without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([NH:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CSCCC(N)C(=O)O
Solvent: CC(=O)O
Product: CSCCC(NC(C)=O)C(=O)O

Procedure:
Different quantities of D,L-methionine were dissolved in 100 ml acetic acid the solution warmed in an oil bath and 1.1 equivalence of acetic anhydride were added. After 5 minutes the components were concentrated under vacuum at 100° C. bath temperature. The content of N-Acetyl-D,L-methionyl-D,L-methionine (Ac-Met-Met) was determined by HPLC. the results of these experiments are set forth in the following table.
Reaction SMILES: N[C@H:2]1[C@@H:5]([C:6]#[CH:7])[N:4]([S:8]([OH:11])(=[O:10])=[O:9])[C:3]1=[O:12].C(N(CC)CC)C>CC(C)=O.O>[C:6]([CH:5]1[N:4]([S:8]([OH:11])(=[O:10])=[O:9])[C:3](=[O:12])[CH2:2]1)#[CH:7]
Reactant: C#C[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C#CC1CC(=O)N1S(=O)(=O)O

Procedure:
190 mg (1 mmol) of (3S,4R)-3-amino-4-ethynyl-2-oxo-1-azetidinesulphonic acid, 526 mg (1.1 mmol) of 2-(2-amino-4-thiazolyl)-2-[[(Z)-1-(t-butoxycarbonyl)-1-methylethoxy]imino]-acetic acid 2-benzthiazolyl thioester and 0.280 ml (2 mmol) of triethylamine are stirred at room temperature for 20 hours in 5 ml of acetone/water (4:1). Thereupon, the mixture is concentrated, the residue is taken up in 4 ml of methanol and filtered. The filtrate is chromatographed over reverse-phase silica gel using water/methanol (10:1). After lyophilization there are obtained 213 mg of (3S,4R)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-tert-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-ethynyl-2-oxo-1-azetidinesulphonic acid as an amorphous powder.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]4([CH:31]([OH:33])[CH3:32])[CH2:30][CH2:29][NH:28][CH2:27]4)=[O:25])[CH:21]=3)[N:16]([C:34]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:15]=2)=[CH:10][CH:9]=1.Cl[CH2:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63]2[CH:68]=[CH:67][C:66]([C:69]3[N:74]=[CH:73][CH:72]=[CH:71][N:70]=3)=[CH:65][CH:64]=2)[CH2:59][CH2:58]1)=[O:56]>CN(C=O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:24]([C:26]4([CH:31]([OH:33])[CH3:32])[CH2:30][CH2:29][N:28]([CH2:54][C:55](=[O:56])[N:57]5[CH2:62][CH2:61][N:60]([C:63]6[CH:64]=[CH:65][C:66]([C:69]7[N:70]=[CH:71][CH:72]=[CH:73][N:74]=7)=[CH:67][CH:68]=6)[CH2:59][CH2:58]5)[CH2:27]4)=[O:25])[CH:21]=3)[N:16]([C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[N:15]=2)=[CH:12][CH:13]=1
Reactant: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCNC1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN(CC(=O)N2CCN(c3ccc(-c4ncccn4)cc3)CC2)C1
Reaction time: 8 h

Procedure:
Added Cesium carbonate (60 mg, 0.184 mmol) to a solution of 3-(1-Hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (6N) (60 mg, 0.098 mmol) and 2-chloro-1-[4-(4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (50 mg, 0.158 mmol) in DMF (2 ml) at room temperature, then stirred overnight.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Br[C:20]1[N:25]=[C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:23]=[N:22][CH:21]=1>COCCOC.C(Cl)(Cl)Cl.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>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C:27]4=[O:31])[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: O=C1CCCN1c1cncc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: O=C1CCCN1c1cncc(-c2cnc3[nH]ccc3c2)n1
Temperature: 100 °C

Procedure:
To the starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and 1-(6-bromopyrazin-2-yl)pyrrolidin-2-one (46) (49 mg, 0.205 mmol, 1 eq) in DME (5 mL), was added Pd(PPh3)4 (7.1 mg, 0.00614 mmol, 0.02 eq) Cs2CO3 (133 mg, 0.410 mmol, 2 eq) and degassing and purging under argon for additional 10 min was performed. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 1-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)pyrrolidin-2-one 131 in 9 mg quantity. The compound 131 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.90 (s, 1H), 9.46 (s, 1H), 9.02 (d, J=10.48, 2H), 8.71 (s, 1H), 7.56 (s, 1H), 6.58 (s, 1H)], 4.13 (m, J=7.07, 2H), 2.65 (m, J=8.04, 2H), 2.14 (m, J=192.19, 2H); MS m/z 279.9 (M+H)+.