Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[CH2:30][CH2:31]C=C)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[BH4-].[Na+]>C(Cl)Cl.O>[C:42]([O:41][C@@H:35]([C:12]1[C:13]([CH3:34])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:46])([O:4][CH2:1][CH2:2][CH2:3][CH2:31][CH2:30][C:24]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:6][CH2:7]1)[C:36]([O:38][CH2:39][CH3:40])=[O:37])([CH3:44])([CH3:45])[CH3:43]
Reactant: C=CCCc1cc(F)ccc1COCc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCCc1cc(F)ccc1COC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
A mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)-4-fluorobenzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.079 mmol) and Grubb's II catalyst (66.7 mg, 0.079 mmol) in DCM (50 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (2 mL). NaBH4 (2.97 mg, 0.079 mmol) was added and the reaction mixture was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 20% EtOAc/hexane to obtain ethyl (2S)-2-(tert-butoxy)-2-{16-fluoro-4,25-dimethyl-11,24-dioxa-1,5,7,8-tetraazapentacyclo[23.2.2.16,9.02,7.013,18]triaconta-2,4,6(30),8,13(18),14,16-heptaen-3-yl}acetate (36 mg, 0.059 mmol, 75% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.33-7.27 (m, 1H), 6.95 (dd, J=10.3, 2.7 Hz, 1H), 6.85 (td, J=8.3, 2.7 Hz, 1H), 6.56 (s, 1H), 6.07 (s, 1H), 4.78-4.64 (m, 4H), 4.58 (t, J=11.2 Hz, 1H), 4.18-4.11 (m, 2H), 3.90 (t, J=11.0 Hz, 1H), 3.44 (d, J=5.1 Hz, 2H), 3.05 (d, J=11.5 Hz, 1H), 2.95-2.85 (m, 1H), 2.83-2.72 (m, 2H), 2.63 (s, 3H), 2.03-1.88 (m, 2H), 1.84-1.62 (m, 8H), 1.31-1.24 (m, 15H). LCMS (M+1)=611.4.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19]>C(O)C>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]1[CH:8]([C:9]2=[O:14])[CH2:19][CH:18]=[CH:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Solvent: CCO
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12

Procedure:
122 Grams of 5-nitro-1,4-naphthoquinone which contained 10% of the 6-nitro compound, 1,000 grams of ethanol and 48 grams of 1,3-butadiene were placed in an autoclave, followed by reaction at 80° C. for 2.5 hours. After the solution was allowed to cool for precipitating crystals, the crystals were separated by filtration, washed with water and dried to obtain 114 grams of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone. The thus obtained nitro compound was introduced into 2,800 grams of methyl cellosolve, to which was added 1.2 grams of a 5% palladium on carbon catalyst and 120 grams of a 20% aqueous sodium hydroxide solution, followed by feeding hydrogen thereinto for hydrogenation while agitating at room temperature and under normal pressure to absorb hydrogen in an amount of 2 mols per mol of the crude 5-nitro compound. Thereafter, the catalyst was separated by filtration and air was injected to the resultant filtrate for oxidation at room temperature for 3 hours. Then, the methyl cellosolve was distilled off from the reaction solution until crystals were precipitated, followed by allowing to cool. The thus precipitated crystals were separated by filtration, washed with water and dried to obtain 92 grams of 1-aminoanthraquinone containing therein 1% of 2-aminoanthraquinone.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[CH3:33])(=[O:25])=[O:24].[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][NH2:41])[CH:35]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:41][CH2:40][C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)=[O:19])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[CH3:33])(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(C)c1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4cccnc4)cc3)oc2C)c(C)c1
Yield: 23.7 %

Procedure:
Method E. Reaction of oxalyl chloride (31 λL, 0.35 mmol) and benzoic acid 44 (92 mg, 0.24 mmol) with subsequent coupling to 3-pyridinylmethylamine (27 λL, 0.26 mmol) gave benzamide 45 (27 mg, 24%) as a clear gum: 1H NMR δ 9.22 (t, J=5.8Hz, 1.H, CONH), 8.57 (d, J=1.5Hz, 1.H, H-2′), 8.47 (dd, J=4.7, 1.5Hz, 1 H, H-6′), 8.00 (d, J=8.4Hz, 2 H, H-2, H-6), 7.88 (d, J=8.4Hz, 2 H, H-3, H-5), 7.74 (br d, J=7.8Hz, 1 H, H-4′), 7.57 (d, J=8.1Hz, 1H, H-5″) 7.37 (dd, J=7.8, 4.7Hz, 1 H, H-5′), 7.27 (br s, 1 H, H-3″), 7.18 (d, J=8.1Hz, 1 H, H-6″), 4.61 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 2.55 (s, 3 H, CH3), 2.34 (s, 3 H, CH3), 2.15 (s, 3 H, CH3); MS m/z 476.6 (MH+, 100%). Anal. calcd for C26H25N3O4S.½CH3CO2CH2CH3: C, 64.72, H, 5.63; N, 8.09. Found: C, 64.72; H, 5.60; N, 7.75%.
Reaction SMILES: CC(CC(O[C@@H:8]1[C@@:12]2([O:14][CH2:13]2)[C@H:11]2[C@H:15](OC(CC(C)C)=O)[O:16][CH:17]=[C:18]([CH2:19][O:20][C:21]([CH3:23])=[O:22])[C:10]2=[CH:9]1)=O)C>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH3:23][C:21]([O:20][CH2:19][C:18]1[C:10]2=[CH:9][CH:8]=[C:12]([CH:13]=[O:14])[C:11]2=[CH:15][O:16][CH:17]=1)=[O:22]
Reactant: CC(=O)OCC1=CO[C@@H](OC(=O)CC(C)C)[C@H]2C1=C[C@H](OC(=O)CC(C)C)[C@]21CO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1cocc2c(C=O)ccc1-2
Reaction time: 0.08 h

Procedure:
Valtrate (1) (9.2 g) was dissolved in 20 ml of chloroform at room temperature. In another flask, 20 g of trifluoroacetic acid was dissolved in 40 ml of chloroform. This second solution then was added to the first solution. The clear solution became dark green/blue after stirring for 5 minutes. Chloroform (60 ml) was added to the reaction mixture, and the reaction mixture was washed with water until a pH of 4 was reached. Sodium chloride with 0.5% NaHCO3 (125 mL) was added to neutralize the mixture. Baldrinal (2, 1.1 g) was collected as a yellow liquid using column chromatography with 8:2 hexanes:ethyl acetate as solvent.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:16]1[C:4](=[O:15])[C:5]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)=[CH:6][NH:7]1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: O=c1c(-n2ccnn2)c[nH]n1-c1ccccn1

Procedure:
250 mg (1.19 mmol) of the compound from Example 3A, 108 mg (0.99 mmol) 2-hydrazinopyridine and 23 mg (99 μmol) camphor-10-sulfonic acid are dissolved in 5 ml anhydrous ethanol and the mixture is heated under reflux overnight. In each case 108 mg (0.99 mmol) 2-hydrazinopyridine are added again a total of four times and the mixture is heated further under reflux until the conversion of the compound from Example 3A is complete. After cooling, the reaction mixture is purified by preparative HPLC several times (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid) and 6 mg (2% of th.) of the title compound are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9]2)([O-:3])=[O:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Commercially available ethyl 7-nitroindole-2-carboxylate (500 mg, 2.14 mmol) was dissolved in a solvent mixture of tetrahydrofuran and water (1:1, 20 mL). Lithium hydroxide hydrate (448 mg, 10.7 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. 1N-hydrochloric acid solution was added, and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([S:5]([CH:8]1[C:12]([S:13]([CH2:16][CH2:17][CH2:18][CH3:19])(=[O:15])=[O:14])=[CH:11][S:10][CH2:9]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([S:5]([C:8]1[C:12]([S:13]([CH2:16][CH2:17][CH2:18][CH3:19])(=[O:14])=[O:15])=[CH:11][S:10][CH:9]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)C1=CSCC1S(=O)(=O)CCCC
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCCCS(=O)(=O)c1cscc1S(=O)(=O)CCCC

Procedure:
Under a nitrogen atmosphere, 3,4-bis(butane-1-sulfonyl)dihydrothiophene and chloroform were placed in a reaction vessel to dissolve 3,4-bis(butane-1-sulfonyl)-dihydrothiophene in chloroform. To the solution, thionyl chloride (3.0 equivalents) was added, followed by heating under reflux for 36 hours. A disodium hydrogenphosphate/sodium dihydrogenphosphate buffer which had been adjusted to pH 7 was added to the reaction mixture to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed three times with saturated brine, and was dried over anhydrous sodium sulfate. The solvent was distilled off. The resultant crude product was purified through a silica gel column (hexane:ethyl acetate=2:1) to obtain the reaction product.
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[Cl:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]2)[C:17]([F:28])=[CH:16][N:15]=1>C1COCC1.[Zn]>[Cl:13][C:14]1[N:19]=[C:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][C@:23]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([OH:27])[CH2:22]2)[C:17]([F:28])=[CH:16][N:15]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@]1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Zinc dust (1.61 g, 24.62 mmol) was heated with a heat gun under N2. THF (8.0 mL) was added, then a solution of chloro(trimethyl)silane (0.63 mL, 4.93 mmol) in THF (8.0 mL) was added and stirred for 15 min at room temperature then heated to reflux and cooled. A solution of ethyl 2-bromoacetate (2.73 mL, 24.62 mmol) in THF (6.0 mL) was added slowly to the zinc mixture, then a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (2.00 g, 8.21 mmol) in THF (6.0 mL) was added. The mixture was refluxed for 2 hours then concentrated in vacuo. EtOAc and aqueous saturated NaHCO3 solution were added and the product was extracted with additional EtOAc (3×), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (Hexanes:EtOAc) separated 2 products. Fractions containing the second (minor) peak were combined and concentrated to give 470 mg of 63a. LCMS+: 332.13 at 3.2 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH:19]=[C:20]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc(Br)cnc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Br)cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 6 h
Yield: 68.6 %

Procedure:
To 2,5-dibromo-3-methylpyridine (5.0 g), tetrakis(triphenylphosphine)palladium(0) (1.15 g), and N-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (6.16 g) were added 1,4-dioxane (40 ml) and 2M aqueous solution of sodium carbonate (25 ml), stirred at 90° C. for 6 hours, then tetrakis(triphenylphosphine)palladium(0) (115 mg) was added thereto, and stirred at 90° C. for 1 hour. To the reaction solution was added water, extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 4-(5-bromo-3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (4.83 g) as a pale yellow oil.
Reaction SMILES: COC1C=C([N+]([O-])=O)C=C[C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12]O[CH2:10][CH2:9]1.[H-].[Na+].Cl[C:24]1C=CC([N+]([O-])=O)=C[C:25]=1[O:33]C>CN(C)C=O>[CH3:4][O:5][CH2:6][CH2:7][N:8]1[CH2:9][CH2:10][CH:24]([CH:25]=[O:33])[CH2:12][CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-[2-(2-Methoxy-4-nitro-phenoxy)-ethyl]-morpholine To a solution of (1-(2-hydroxyethyl)-morpholine) (1.94 ml, 16 mmol) in dimethylformamide was added sodium hydride [60% dispersion in oil] (544 mg, 16 mmol). After stirring at room temperature for 10 min, a solution of (1-chloro-2-methoxy-4-nitro-benzene) (3 g, 16 mmol) in dimethylformamide (10 ml) was added dropwise. The reaction mixture was left stirring at room temperature for 16 hours, concentrated, then the residue dissolved in ethyl acetate and washed with water. The organic phase was dried with magnesium sulphate, concentrated and the residue purified by column chromatography on silica gel to afford the title compound; MS(ES+) m/e 283 [M+H]+. Step 2. 3-Methoxy-4-(2-morpholin-4-yl-ethoxy)-phenylamine To a solution of the product of Step 1 (2.3 g, 8.6 mmol) in ethanol (100 ml) was added 10% palladium on charcoal (50 mg). The mixture was then stirred at room temperature under an atmosphere of hydrogen for 16 hours, filtered through celite and concentrated to give the title compound; MS(ES+) m/e 252 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH3:10])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=1)[CH3:10]
Reactant: C1CNCCN1
Reactant: COc1ccccc1C(C)Oc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1C(C)Oc1cncc(N2CCNCC2)n1
Temperature: 90 °C
Yield: 67 %

Procedure:
A mixture of the product from step 1 above (0.93 g, 3.53 mmol) piperazine (0.88 g, 10.2 mmol) and K2CO3 (0.49 g, 3.53 mmol) in acetonitrile (7 mL) was heated in a sealed pyrex flask at 90° C. for 6.5 h. The reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel chromatography (13×4 cm) using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated off and the remaining oil was redissolved in CHCl3, filtered through a short plug of alumina, covered with K2CO3, using CHCl3 as eluent. Solvent removal in vacuo gave 0.74 g (67%) of the title compound as a beige oil. HRMS m/z calcd for C17H22N4O2 (M)+ 314.1743, found 314.1733. Anal. (C17H22N4O2.0.5H2O) C, H, N.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[C@@H:6]([CH3:14])[CH2:5][N:4]([CH2:15][C:16]2[CH:20]=[CH:19][N:18](C(OC(C)(C)C)=O)[N:17]=2)[CH2:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:3][N:4]([CH2:15][C:16]2[CH:20]=[CH:19][NH:18][N:17]=2)[CH2:5][C@H:6]([CH3:14])[N:7]1[C:8](=[O:13])[C:9]([F:10])([F:12])[F:11]
Reactant: C[C@@H]1CN(Cc2ccn(C(=O)OC(C)(C)C)n2)C[C@H](C)N1C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2cc[nH]n2)C[C@H](C)N1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
D8 (2.20 g, 5.63 mmol) was taken up in 25% TFA in DCM (50 ml) and stirred for 4 h at 25° C. The solvent was removed in vacuo and the residue dissolved in DCM (50 ml), washed with saturated NaHCO3, dried (Na2SO4) and concentrated to yield the title compound as an orange foam (1.64 g). δH (CDCl3) 1.43 (6H, d), 2.48 (2H, dd), 2.97 (2H, d), 3.88 (2H, s), 4.15-4.75 (2H, br d), 6.40 (1H, d), 7.64 (1H, d), 8.93 (1H, br s). MS (ES): MH+ 291.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(C(C)C)C(C)C.[CH2:41]([O:43][C:44](=[O:49])[CH2:45][CH:46]([NH2:48])[CH3:47])[CH3:42]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:48][CH:46]([CH3:47])[CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:49])=[O:5]
Reactant: CCOC(=O)CC(C)N
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)Cl)c(F)c3)no2)ccc1-c1ccccc1C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(C)NC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)cc1F
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride, prepared as in example 116 (75 mg; 0.17 mmol) in dry THF, DIEA (103 μl; 0.60 mmol) was added followed by ethyl-3-aminobutyrate (45 mg; 0.34 mmol) and the reaction mixture stirred for 2 h30 at RT. The solvent was then removed under vacuum and the crude material purified by flash chromatography (EtOAc/cHex) to afford the title compound as a colorless oil (82 mg, 89%). 1H NMR: (CDCl3, 300 MHz) δ 8.42 (m, 1H), 8.23 (t, J=8 Hz, 1H), 8.16 (dd, J=1.9, 8 Hz. 1H), 8.09 (dd, J=1.5, 8.1 Hz, 1H), 7.96 (dd, J=1.3, 12.4 Hz, 1H), 7.47 (m, 1H), 7.38-7.22 (m, 5H), 7.12 (m, 1H), 4.62 (m, 1H), 4.21 (m, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.33 (s, 3H), 2.65 (m, 2H), 2.07 (s, 3H), 1.37 (d, J=6.8 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H). UPLC/MS: 532.3 (M+H)+ 530.3 (M−H)−. HPLC (Method A) Rt: 5.52 min (purity: 98.5%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH:4]=[CH:3]1.Cl[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH3:17][N:16]([CH3:18])[C:14](=[O:15])[CH2:13][O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(O)c21
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C(=O)COc1cccc2ccn(C)c12
Yield: 83.2 %

Procedure:
To a solution of 1-methyl-1-H-indol-7-ol (Chemstep, CAS: 47577-33-4, 2.2 g, 15 mmol) and 2-chloro-N,N-dimethylacetamide (Fluka, CAS: 2675-89-0, 2.0 g, 17 mmol) in acetone (25 mL) were added potassium carbonate (2.5 g, 18 mmol) and potassium iodide, (0.25 g, 1.5 mmol). The reaction mixture was stirred at reflux for 4 h, quenched with ice/water, and extracted with ethyl acetate. The organics were washed, dried and concentrated. The residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (2.9 g) as a creamy solid. MS (ISP): m/e 233.1 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[N:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:25]([C:33]1[S:34][CH2:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][C@:37]2([C:42]2[CH:47]=[C:46](Br)[CH:45]=[CH:44][C:43]=2[F:49])[N:38]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.O>CN(C=O)C.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>[NH2:25][C:33]1[S:34][CH2:35][C@@H:36]2[CH2:41][CH2:40][CH2:39][C@:37]2([C:42]2[CH:47]=[C:46]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=3)[C:1]#[N:2])[CH:45]=[CH:44][C:43]=2[F:49])[N:38]=1
Reactant: N#Cc1cncc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CCC[C@H]2CS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cncc(-c2ccc(F)c([C@]34CCC[C@H]3CSC(N)=N4)c2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-Cyano-3-pyridinylboronic acid (37.9 mg), tetrakis(triphenylphosphine)palladium and a 1 N sodium carbonate solution (256 μL) were added to a solution of (±)-N,N-bis(tert-butoxycarbonyl) [(4aR*,7aS*)-7a-(5-bromo-2-fluorophenyl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]amine (70.0 mg) in DMF (5 mL). After replacement with nitrogen, the mixture was stirred at 80° C. for two hours. After cooling to room temperature, water was added to the reaction mixture. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (3 mL). Trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for two hours. The reaction mixture was diluted with water, followed by neutralization with a saturated sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH-silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].CO.[OH-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl>O>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][O:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: ClCc1ccccc1Cl
Reactant: O=C(CO)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(COCc1ccccc1Cl)Nc1ccccc1
Reaction time: 2 h

Procedure:
2-Hydroxyacetanilide (15.1 parts) is added to methanol (60 parts). Into this mixture is further added a solution of sodium hydroxide (4.8 parts) in water (14 parts). The resulting mixture is kept at 0° to 5° C. and add dropwise 2-chlorobenzyl chloride (18.3 parts) within 30 minutes, and the reaction is continued for 2 hours at 0° to 5° C., for additional 6 hours at 30° to 40° C. and further for additional 2 hours at 65° C. After completion of the reaction, the reaction mixture is poured into cold water (250 parts) and is then filtered. The filter cake obtained is washed with water and the resulting white cake is dried at 80° C. to yield the intended product (22.3 parts) having melting point 130° to 132° C.