Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=3[CH3:30])[CH:14]=[CH:15][C:16]=2[CH3:17])=[O:10])=[CH:4][N:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1.FC(F)(F)C(O)=O.NC1C=CC=CC=1>CC(O)C>[CH3:30][C:21]1[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([NH:38][C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)=[N:7][CH:6]=2)=[O:10])[CH:12]=1)=[O:31]
Reactant: Nc1cccnc1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2C)cc1C(=O)Nc1cnc(Cl)nc1
Solvent: CC(C)O
Solvent: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2C)cc1C(=O)Nc1cnc(Nc2cccnc2)nc1
Temperature: 140 °C

Procedure:
A small microwave reaction vessel was charged with N-(3-(((2-chloro-5-pyrimidinyl)amino)carbonyl)-4-methylphenyl)-2-methyl-3-(trifluoromethyl)benzamide 19 (0.100 g, 0.22 mmol), and pyridin-3-amine (0.10 g, 1.1 mmol) in IPA (1.0 mL). Trifluoroacetic acid (0.034 ml, 0.45 mmol) was added and the vessel was sealed. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 140° C. for 10 min. Monitored the reaction by LCMS and found 50% conversion. Added another 105 mg aniline and 0.05 mL TFA and resumed microwave heating the reaction at 140° C. for 15 min. After about >90% conversion was found by LCMS, the crude reaction mixture was filtered through a Buchner apparatus with micromembrane filter, and the filtrate was washed with copius amounts of MeOH to afford 2-methyl-N-(4-methyl-3-(((2-(3-pyridinylamino)-5-pyrimidinyl)amino)carbonyl)phenyl)-3-(trifluoromethyl)benzamide 20 as an off-white solid after drying. MS m/z found 507.1 [MH+], calc. for C26H21F3N6O2=506.17.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=1)C.[OH-].[Na+]>O1CCCC1>[CH2:16]([O:15][CH:11]([O:12][CH2:13][CH3:14])[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][N:8]=1)[C:4]([OH:18])=[O:3])[CH3:17]
Reactant: CCOC(=O)c1ccnc(C(OCC)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(OCC)c1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-diethoxymethyl-isonicotinic acid ethyl ester (3.0 g, 0.012 mol) in tetrahydrofuran (100 mL) was added IN sodium hydroxide (24 mL, 0.024 mol) and mixture allowed to stir for 2 h at rt. The reaction was concentrated in vacuo to give a pasty solid of 2-diethoxymethyl-isonicotinic acid, which was used in the next step as is.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+]=[N-])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].[N-]=[N+]=[N-].[Na+].[BH4-].[Na+].CCOCC>CO.C(Cl)(Cl)Cl.CC(C)=O.O.Cl[Ni]Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([NH2:22])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [N-]=[N+]=[N-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)=O
Product: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N)(C(=O)OCc3ccccc3)[C@@H]21
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII-1) (200 mg, 0.58 mmol) in MeOH (5.8 mL) and a few drops of chloroform at 0° C. was added NiCl2.6 H2O (661 mg, 2.78 mmol) was dissolved in acetone (45 mL) and H2O (4.5 mL), NaN3 (720 mg, 11.1 mmol) and stirred for 10 min at 0° C. Upon cautious addition of NaBH4 (175 mg, 4.62 mmol) the reaction mixture turned immediately black, stirring was continued at 0° C. for 10 min and then hydrolyzed with water and ether. After additional stirring for 10 min at 0° C., the reaction mixture was extracted with ether, washed with brine (2×50 mL) and dried over Na2SO4 and filtered through celite. The solvent was removed under vacuum, the residue was purified by silica gel column chromatography with ethyl acetate/MeOH 95:5 (+0.6% Et3N) to give (1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VIII) (106 mg, 57%) as a yellow oil. 1H-NMR (250 MHz, CDCl3) □1.25 (3H, t, J=7.1 Hz), 1.75 (1H, t,J=3.5 Hz), 1.97 (1H, m), 2.12 (1H, dd,J=7, 3.5 Hz), 2.14-2.28 (4H, m), 2.33 (1H, dd,J=12.5, 7 Hz), 3.65 (1H, dd, J=8, 7 Hz), 4.10 (2H, q, J=7.1 Hz), 5.22 (1H, d, J=12.5 Hz), 5.27 (1H, d, J=12.5 Hz), 7.38 (5H, m); MS[ISP] 320 (M+H+); □D20 -0.56° (c=0.89, CHCl3).
Reaction SMILES: O[C:2]1([C:26]([F:29])([F:28])[F:27])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[C:4]([C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][S:13][C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:26]([F:28])([F:27])[F:29])[N:3]=[C:4]2[C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][N:16]=2)=[CH:12][CH:11]=1
Reactant: CSc1ccc(N2CC(O)(C(F)(F)F)N=C2c2nnc(-c3ccccc3)s2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(-n2cc(C(F)(F)F)nc2-c2nnc(-c3ccccc3)s2)cc1

Procedure:
A mixture of 4-hydroxy-1-[4-(methylthio)phenyl]-2-[2-(phenyl)-1,3,4-thiadiazol-5-yl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.5 g, 1.15 mmol) and p-toluenesulfonic acid monohydrate (30 mg) in toluene (50 mL) was heated to reflux for 1 hour. After aqueous work up, 1-[4-(Methylthio)phenyl]-2-[2-(phenyl)-1,3,4-thiadiazol-5-yl]-4-(trifluoromethyl)-imidazole was isolated as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[N:8]1)[CH3:2].[N+:27]([O-])(O)=O.N.Cl>S(=O)(=O)(O)O.C1C=CC=CC=1.[Fe].C(Cl)(Cl)Cl.O>[CH2:25]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH2:27])=[CH:13][CH:14]=2)[C:9]([NH:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[N:8]1)[CH3:26]
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2ccccc12
Reactant: O=[N+]([O-])O
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2ccc(N)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
In 2.58 ml of sulfuric acid was dissolved 1.7 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)indazole. To the solution were added dropwise 0.41 ml of nitric acid(d =1.42) and 0.41 ml of sulfuric acid (specific gravity 1.84) under cooling with ice. The solution was stirred for 2 hours at 5°-10° C. and added to 12.1 ml of ice and water. The pH of the solution was adjusted to at least 11 with an aqueous ammonia solution, and the solution was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure. The residue thus obtained was dissolved in 50 ml of dried benzene. To the solution were added 10 g of iron powder and 2 ml of hydrochloric acid, and the mixture was stirred for 30 minutes at 80° C. To the mixture was added 0.5 ml of water, and the mixture was stirred for 10 hours at 80° C. After cooling, the mixture was filtered, and the benzene layer was extracted three times with 20 ml of 1N hydrochloric acid. The pH of the hydrochloric acid layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 100 g) using chloroform as the developing solvent to give 0.87 g of 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-5-aminoindazole having the following analytical values in a yield of 49 %.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([Se:27][C:28]2[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=2)=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1)=[O:4].[OH-].[Na+]>C1COCC1.C(O)C>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([Se:27][C:28]2[CH:38]=[CH:37][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:15][C:16]2[C:17]([CH3:25])([CH3:26])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1)([OH:4])=[O:2]
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCCCCCCC(=O)OC)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc([Se]c3ccc(C(=O)O)cc3)c(OCCCCCCCC(=O)O)cc21

Procedure:
In a manner similar to that of Example 2, by reaction of 410 mg (0.7 mmol) of ethyl 4-[3-(7-methoxycarbonylheptyloxy)-5,5,8,8-tetramethyl5,6,7,8-tetrahydro-2-naphthylselanyl]benzoate with 280 mg (7 mmol) of sodium hydroxide in a THF/ethanol mixture (5 ml/5 ml), 326 mg (85%) of a white powder are obtained. m.p.: 183° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[C:15]([Cl:20])[CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[C:15]([Cl:20])[CH:14]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Clc1cc(Br)ccc1I
Product: OCc1ccc(-c2ccc(Br)cc2Cl)cc1
Yield: 12 %

Procedure:
In accordance with Example 4-(2), but using [4-(hydroxymethyl)phenyl]boronic acid instead of 4-bromophenylboronic acid, and 4-bromo-2-chloro-1-iodobenzene instead of tert-butyl[2-(4-iodophenyl)ethoxy]dimethylsilane, the title compound (yield 12%) was afforded as a yellow solid.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:20]=[C:19](OC2C=CC=CC=2)[N:18]=1>C(OCC)(=O)C>[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[C:17]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:20]=[C:19]([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[N:18]=1
Reactant: Cc1ccc(-c2nc(Oc3ccccc3)nc(-c3ccc(C)cc3C)n2)c(C)c1
Reactant: Oc1cccc(O)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 150 °C
Reaction time: 4.5 h
Yield: 57 %

Procedure:
A 300 mL three-necked, round-bottomed flask fitted with a magnetic stirrer, an acid trap, a gas inlet and a heat lamp to prevent sublimation is charged with 29.9 g (0.272 mol) of resorcinol and 2.00 g (0.00525 mol) of the product of Example 2. The mixture is heated to 150° C. and hydrogen chloride gas is bubbled slowly through the molten mixture for 25 minutes. The mixture is stirred at this temperature for another 4.5 hours and then allowed to cool to room temperature. Portions of water and toluene are added and the mixture is refluxed till the solids are dissolved. The mixture is allowed to cool to room temperature and the layers separated. The organic layer is washed once with water, twice with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous magnesium sulfate and filtering, the solvent is removed under reduced pressure to afford 1.56 g of crude product. Purification by flash chromatography on silica gel with 3:1 heptane:ethyl acetate gives 1.19 g (57% yield) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11](B(O)O)=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[S:29]([NH:32][CH2:33][CH3:34])(=[O:31])=[O:30]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=3[S:29]([NH:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ncc(B(O)O)cc2F)cn1
Reactant: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Product: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1cnc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using (6-(2-aminopyrimidin-5-yl)-5-fluoropyridin-3-yl)boronic acid and 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H15F4N5O2S, 441.09; m/z found, 442.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.94 (d, J=1.1, 2H), 8.51-8.46 (m, 1H), 8.37-8.31 (m, 1H), 8.03 (dd, J=8.1, 1.9, 1H), 7.81 (dd, J=11.9, 1.8, 1H), 7.68 (d, J=7.9, 1H), 2.86 (q, J=7.3, 2H), 1.02 (t, J=7.2, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][CH:32]([CH3:35])[CH2:33][OH:34]>>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([NH:31][CH:32]([CH3:35])[CH2:33][OH:34])=[O:16])[CH2:6][CH2:5]2
Reactant: CC(N)CO
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NC(C)CO)O2
Yield: 79.4 %

Procedure:
Following the amide coupling procedure described in protocol A, 500 mg 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (2.00 mmol), 365 mg CDI (2.25 mmol) and 165 mg 2-amino-1-propanol (2.2 mmol) produced 488 mg of 6-hydroxy-N-(1-hydroxypropan-2-yl)-2,5,7,8-tetramethylchroman-2-carboxamide as a pale brown foam.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14].C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[C:3]([NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[F:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(Cl)nc1Cl
Reactant: NCc1ccccc1F
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: Nc1cnc(Cl)nc1NCc1ccccc1F
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g (3.1 mmol) of 5-amino-2,4-dichloropyrimidine [D. T. Hurst, Heterocycl. 22, 79 (1984)], 0.35 ml (3.1 mmol) of 2-fluorobenzylamine and 0.46 ml (3.4 mmol) of triethylamine in 8 ml of 1-butanol is heated under reflux for 24 hours. The reaction mixture is then cooled to 0°. The resulting beige-coloured suspension is filtered with suction and the filter cake is washed with cyclohexane and suspended in water for 30 minutes at room temperature with stirring. The suspension is again filtered with suction and the filter cake is dried under a high vacuum at 100° over tetraphosphorus decaoxide. In this manner 5-amino-2-chloro-4-[N-(2-fluorobenzyl)amino]-pyrimidine is obtained in the form of beige-coloured crystals having a melting range of from 224° to 225°.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1)=[CH2:9].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>O>[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][Br:18])=[CH:12][CH:11]=1)=[CH2:9]
Reactant: BrCCCCCCBr
Reactant: C=Cc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(COCCCCCCBr)cc1
Yield: 58 %

Procedure:
A DMF suspension (5 ml) of sodium hydride (50% in oil, 240 mg, 5.0 mmoles) was cooled to 0° C. under an argon atmosphere, and a DMF (1 ml) solution of 1.34 g of 4-vinylbenzyl alcohol (10 mmoles) was added. The reaction mixture was agitated for fifteen minutes, and a DMF solution (3 ml) of 3.66 g of 1,6-dibromohexane (15 mmoles) was added over at least five minutes. The reaction mixture was agitated at room temperature for three hours. Fifteen milliliters of water was added to the reaction solution while cooling using ice, and the solution was agitated for five minutes. The solution was extracted using ethyl acetate (2×40 ml). The combined organic layers were washed using 15 ml of saturated aqueous saline solution and dried using anhydrous sodium sulfate. Upon filtration and concentration, 4.11 g of the residue was purified using silica gel column chromatography (70 g silica gel, 20:1 hexane/Et2O) and 1.72 g of 6-(4-vinylbenzyloxy)bromohexane (5.8 mmoles, 58%) was obtained in the form of an oily substance.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[C:31]([NH:33][NH2:34])=[O:32].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>ClCCl>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:34][NH:33][C:31]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][N:25]=3)=[O:32])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC(=O)c1cnccn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)c1cnccn1
Temperature: -60 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
In a 25 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in dichloromethane (5 mL) and cooled to −60° C. where pyrazine-2-carbohydrazide (0.216 g, 1.1 eq.) was introduced. T3P (50% in EtOAc) (3.39 mL, 4 eq.) was added dropwise followed by DIPEA (0.5 mL, 2 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)—N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)pyrazine-2-carbohydrazide (0.13 g, yield: 19.4%).
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([C:14](=[O:15])[N:13]([CH3:16])[CH2:12][CH:11]2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:13]1[CH2:12][CH:11]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[C:10]2([CH2:23][CH2:24][CH2:25][NH:8][CH2:9]2)[C:14]1=[O:15]
Reactant: CN1CC(c2cccnc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(c2cccnc2)C2(CCCNC2)C1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 2-Methyl-1-oxo-4-pyridin-3-yl-2,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester [from diastereomer 1] (200 mg, 0.58 mmol) in DCM (5 ml) was cooled with an ice bath and TFA (0.70 ml, 8.68 mmol) was added. The resulting solution was stirred for 3 h at 0° C. The reaction mixture was diluted with DCM (20 ml) and quenched at 0° C. with 2M NaOH solution (8 ml). The organic phase was separated, washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2].CCO.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([C@@H:28]([OH:33])[C@H:29]([NH2:32])[CH2:30][OH:31])=[CH:24][CH:23]=1)([O-:21])=[O:20].Cl>CO.O>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C@@H:28]([OH:33])[C@H:29]([NH2:32])[CH2:30][OH:31])=[CH:26][CH:27]=1)([O-:21])=[O:20].[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]1[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C(=O)O
Agent: Cl
Agent: N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC(=O)N1c2ccccc2C[C@H]1C(=O)O
Temperature: 76 °C

Procedure:
200 g N-acetyl-indoline-2-carboxylic acid (purity 96.5%) was dissolved in 1760 ml of a mixture containing 90% EtOH, 5% water and 5% MeOH, with heating to 76° C., and with mechanical stirring. 138 g/0.69 eq (1R,2R)-1-(4-nitrophenyl)-2-amino-1,3-propanediol (99.5% chemically pure, [a]20 D =-28.5° (c=0.4, 1N HCl)) was dosed in portions in 30 min. at 73-76° C. After cooling to 70° C., grafting with 1 g S-salt took place, followed by cooling to 15° C. in 3 hours and 30 minutes' subsequent stirring. After filtration over a P4 glass filter, 3 washings with 200 ml EtOH took place. After air-drying, 158.1 g yellow (S)-N-acetyl-indoline-2-carboxylic acid-(1R,2R)-1-(4-nitrophenyl)-2-amino-1,3-propanediol salt was obtained, corresponding to a yield of 40.3%. Enantiomeric excess=99.0% (chiral HPLC).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:36])[NH:13][C@H:14]([CH:33]([CH3:35])[CH3:34])[C:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([OH:23])[C:19]([CH3:32])([CH3:31])[CH2:18]2)=[O:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([Sn](CCCC)(CCCC)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)CCC>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C@@:20]2([OH:23])[CH2:21][CH2:22][N:17]([C:15](=[O:16])[C@H:14]([NH:13][C:12]([C:10]3[CH:9]=[C:4]([CH:3]=[C:2]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:18][C:19]2([CH3:31])[CH3:32])=[CH:25][CH:26]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)cc(-c2ccccn2)c1
Yield: 75.4 %

Procedure:
Methyl 3-bromo-5-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)benzoate (40 mg, 0.069 mmol) was dissolved in toluene (3 mL) at 25° C. then 2-(tributylstannyl)pyridine (76 mg, 0.207 mmol) was added. The reaction was degassed then placed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (4 mg, 3.45 μmol) was added and the reaction heated at reflux for 2 hours. The reaction was concentrated in vacuo to give a dark residue which was then dissolved in MeOH, filtered to remove insoluble material, then purified by LCMS HPLC. The obtained colorless oil was dissolved in EtOAc, dried over sodium sulfate and concentrated in vacuo to give methyl 3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)-5-(pyridin-2-yl)benzoate (30 mg, 0.052 mmol, 75% yield) as a white glass. MS found: (M+H)+=578.34.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:15])([CH3:14])[O:7]2.Cl[C:17]1[C:18]([C:30]([OH:32])=[O:31])=[CH:19][C:20]2[C:25]([C:26]=1[N+:27]([O-:29])=[O:28])=[CH:24][CH:23]=[CH:22][CH:21]=2.C([O-])(=O)C.[K+].CC(O)C>CC([O-])=O.CC([O-])=O.[Cu+2].O.C(N(CC)CC)C>[CH3:14][C:6]1([CH3:15])[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][C:10]([O:12][CH3:13])=[CH:11][C:2]=2[NH:1][C:17]2[C:18]([C:30]([OH:32])=[O:31])=[CH:19][C:20]3[C:25]([C:26]=2[N+:27]([O-:29])=[O:28])=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:7]1
Reactant: O=C(O)c1cc2ccccc2c([N+](=O)[O-])c1Cl
Reactant: COc1cc(N)c2c(c1)OC(C)(C)C=C2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(Nc2c(C(=O)O)cc3ccccc3c2[N+](=O)[O-])c2c(c1)OC(C)(C)C=C2

Procedure:
To 3.3 g of 5-amino-7-methoxy-2,2-dimethylchromene there are added 3 g of the compound obtained in Step 3 above, 3.4 g of potassium acetate, 375 mg of Cu(OAc)2.H2O and 120 ml of 2-propanol containing 3.8 ml of triethylamine. The solution is refluxed for 5 days and is then evaporated under reduced pressure. The residue is taken up in a 1/1 mixture of dichloromethane and 1N aqueous HCl solution. After extraction of the aqueous phase, the combined organic phases are treated in customary manner. Chromatography over silica gel (dichloromethane/methanol: gradient from 0.1 to 1%) allows the expected product to be isolated.