Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.BrN1C(=[O:21])CCC1=O.C1N2CN3CN(C2)CN1C3>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(C)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 120 °C
Yield: 24 %

Procedure:
Into CCl4 solvent, 2.4 g(13.3 mmol) of the compound produced in Example 1 (Compound 1) and 0.536 g(3.0 mmol) of N-bromosuccinimide were added and refluxed for 24 hours. After cooled down, the reactant was suction-filtrated and the resultant solution was washed with distilled water and then was dried with anhydrous magnesium sulfate. The dried product was dissolved again in chloroform together with 5.34 g(51.2 mmol) of hexamethylenetetraamine and refluxed for 5 hours. After the reactant was cooled down, the solvent was distilled off under reduced pressure and the residue was refluxed severely in acetic acid/H2O(17 mL/17 mL) at 120° C. for 2 hours. Finally, 7 mL of HCl was added to be refluxed. After cooled down, the reactant was extracted with methylene chloride. The solution was distilled off under reduced pressure and the residue was purified through the column chromatography (silica gel, ethyl acetate/n-hexane=1:3) to be dried. Yield; 24%.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([O:6][CH2:7]1)[CH2:4][NH:3]2.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][O:6]3)=[CH:12][CH:11]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Brc1ccc(CN2C[C@@H]3C[C@H]2CO3)cc1
Yield: 76.7 %

Procedure:
(1S,4S)-(+)-2-Aza-5-oxabicyclo[2.2.1]heptane hydrochloride (1.26 g), 4-bromobenzyl bromide (2.32 g) and triethylamine (3.88 ml) were stirred in dimethylformamide (30 ml) for 18 h. The mixture was partitioned between diethyl ether (60 ml) and water (60 ml) and the organic phase was washed further with water (60 ml), dried (MgSO4), concentrated in vacuo and purified by Bondelute® chromatography, eluting with 0-100% ethyl acetate/iso-hexane to give the product as an orange oil (1.91 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2[CH:24]=[C:23]([CH3:25])[S:22][CH:21]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=1.B([C:30]1[CH:41]=[CH:40][C:33]([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])=[CH:32][CH:31]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:36][C@@H:35]([CH2:34][C:33]1[CH:40]=[CH:41][C:30]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[CH:24]=[C:23]([CH3:25])[S:22][CH:21]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=2)=[CH:31][CH:32]=1)[C:37]([OH:39])=[O:38]
Reactant: Cc1cc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cs1
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2ccccc2C(Oc2cc(-c3ccc(C[C@H](N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)cs1
Temperature: 150 °C
Yield: 25.5 %

Procedure:
In a microwave vial, 4-chloro-6-{2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine (30 mg, 0.075 mmol), 4-borono-L-phenylalanine (19 mg, 0.09 mmol), 1 ml of actonitrile and 0.7 ml of water were mixed. 0.3 ml of 1N aqueous sodium carbonate was added to the mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 10.1 mg of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 7.83 (d, J=8.4 Hz, 2H), 7.63 (d, J=7.2 Hz, 1H), 7.34 (m, 4H), 7.26 (m, 1H), 7.12 (d, J=1.2 Hz, 1H), 6.92 (q, J=6.8, 1H), 6.82 (d, J=1.2 Hz, 1H), 6.64 (s, 1H), 4.21 (t, J=5.6 Hz, 1H), 3.29 (m, 1H), 3.20 (m, 1H), 2.47 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.C(OC(CBr)C#N)C1C=CC=CC=1.C(OC(CBr)C(N)=O)C1C=CC=CC=1.[CH2:35]([O:42][CH:43]([CH2:48]Br)[C:44]([O:46][CH3:47])=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1CN2C(=NCCC2)C1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOCC.CCCCCC.O>[CH2:35]([O:42][C:43](=[CH2:48])[C:44]([O:46][CH3:47])=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)C(CBr)OCc1ccccc1
Agent: C1CN=C2CCCN2C1
Agent: Cl
Agent: N#CC(CBr)OCc1ccccc1
Solvent: CO
Solvent: CCCCCC
Solvent: O
Product: C=C(OCc1ccccc1)C(=O)OC
Temperature: -10 °C
Reaction time: 8 h

Procedure:
(Formula II, R1=CH3OC(O)—, R2=benzyl). A slow stream of hydrogen chloride gas was passed for 4 h through a solution of 2-benzyloxy-3-bromopropionitrile (16.75 g) in methanol (2.38 g) and ether (66 ml) which was maintained at −10° C. The mixture was allowed to stand at 5° C. overnight, and then ice was added in small portions to the mixture at 0° C. After 20 min of stirring, the mixture was poured into water and the product was extracted with ether, washed with water and aqueous sodium bicarbonate, and dried (MgSO4). After the solvent was removed, the crude product was recrystallized from ether/CH2Cl2 to afford, after a first crop of crystals of 2-benzyloxy-3-bromopropanamide, the required intermediate, methyl 2-benzyloxy-3-bromopropanoate. This bromoester was treated with DBN/potassium carbonate as described above to yield methyl α-benzyloxyacrylate, mp 44.5-45.5° C. (from hexane); 1H NMR δ 3.80 (3H, s), 4.63 (1H, d, J 3 Hz), 4.83 (2H, s), 5.37 (1H, d, J 3Hz), 7.33 (5H, s); IR 1740 cm−1. Ketals of alkyl pyruvates, prepared-according to the directions in The Journal of Organic Chemistry, 1967, 32,1615, also may be converted to α-alkoxyacrylates by an acidic catalyst, as described in Chemische Berichte, 1911, 44, 3514.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O-:16])=O)[CH:7]=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].S(Cl)(Cl)=O.C[N:22](C=O)C>C1COCC1.C(Cl)Cl>[CH3:12][O:11][C:9]([C:8]1[CH:7]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:14]([NH2:22])=[O:16])=[O:10]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(C(=O)[O-])cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(C(N)=O)cc([N+](=O)[O-])c1
Yield: 81 %

Procedure:
A solution of mono-methyl 5-nitroisophthalate (45.0 g, 200 mmol), thionyl chloride (71.4 g, 600 mmol) and DMF through SiO2 (125 μL) in dry THF (100 mL) and dry CH2Cl2 (300 mL) was refluxed overnight. See, FIG. 1C, step 1. The reaction mixture was evaporated in vacuo and then added dry CH2 Cl2 (200 mL) and hexanes (500 mL). Ammonia gas was introduced into the solution and the precipitation was collected on a glass-filter. Id., step 2. The cake was suspended in 1N HCl (500 mL), filtered again and then washed with saturated NaHCO3 aq. (500 mL) and water (500 mL). The product was dried in vacuo to give ivory powder (36.3 g, 81%): 1H NMR (300 MHz, DMSO-d6) δ 8.918 (t, J=1.8 Hz, 1H), 8.816 (t, J=1.2 Hz, 1H), 8.773 (t, J=1.6 Hz, 1H), 8.716 (s, 1H, NH), 7.859 (s, 1H, NH), 3.944 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 164.9, 164.2, 148.1, 136.4, 134.9, 133.8, 133.3, 131.5, 126.4, 126.0, 53.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Cl[CH2:17]/[CH:18]=[CH:19]\[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17]/[CH:18]=[CH:19]\[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][CH:6]=1
Reactant: ClC/C=C\c1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OC/C=C\c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.79 g) in dimethylformamide (30 mL) under argon was treated with 55% sodium hydride (0.432 g), stirred for 15 minutes and treated with (Z)-(3-chloro-1-propenyl)benzene (1.9 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The crude dichloromethane extract was purified by HPLC (dichloromethane-hexane; 4:1 ) and the resulting 1.9 g of analytically pure (Z)-alpha-oxo-4-[(3-phenyl-2-propenyl)oxy]benzeneacetic acid methyl ester failed to crystallize.
Reaction SMILES: C(OC(ON1C2C(=CC([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=CC=2)CC(NC(=O)OC(C)(C)C)C1=O)=O)(C)(C)C.[C:36]1([C:42]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[N:43][C@H:44]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:45][C:46]2[C:51]([N+:52]([O-:54])=[O:53])=[CH:50][CH:49]=[C:48](F)[CH:47]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.ClC1C=CC=CC=1O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][C:48]1[CH:47]=[C:46]([C:51]([N+:52]([O-:54])=[O:53])=[CH:50][CH:49]=1)[CH2:45][C@@H:44]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[N:43]=[C:42]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(Oc3ccccc3Cl)ccc2N(OC(=O)OC(C)(C)C)C1=O
Reactant: CC(C)(C)OC(=O)[C@H](Cc1cc(F)ccc1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1Cl
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H](Cc1cc(Oc2ccccc2Cl)ccc1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
tert-Butyl {1-[(tert-butoxycarbonyl)oxy]-6-(2-chlorophenoxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}carbamate (83) A mixture of tert-butyl N-(diphenylmethylene)-3-fluoro-6-nitro-L-phenylalaninate (which can be prepared according to the general method described in Example 12) (148 mg, 0.33 mmol), 2-chlorophenol (51 mg, 0.40 mmol), and Cs2CO3 (160 mg, 0.50 mmol) in anhydrous MeCN (5 mL) under N2 was heated to 70° C. for 20 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was dissolved in EtOAc (20 mL) and water (20 mL), and the separated aqueous phase was washed with EtOAc (20 mL). The combined organic fractions were washed with saturated aqueous sodium chloride solution (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to yield tert-butyl 3-(2-chlorophenoxy)-N-(diphenylmethylene)-6-nitrophenylalaninate as a brown oil (180 mg). This residue was dissolved in a solution of HCl in dioxane (4 M, 10 mL), and the resulting solution was heated to 100° C. for 1 h. The reaction mixture was concentrated in vacuo to yield 3-(2-chlorophenoxy)-6-nitrophenylalanine (79 mg) as a solid. This product was converted to the title compound following the general procedure described in Example 9. The product was obtained as a gum (51 mg, 48%). LCMS m/z 505.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.56 (br s, 9H), 2.94 (br dd, J=14, 14 Hz, 1H), 3.37 (v br d, J=15 Hz, 1H), 4.48-4.58 (m, 1H), 5.60 (br s, 1H), 6.79 (br s, 1H), 6.88-6.93 (m, 1H), 6.9-7.1 (v br s, 1H), 7.01 (br d, J=8 Hz, 1H), 7.13 (br dd, J=8, 8 Hz, 1H), 7.26 (br dd, J=8, 8 Hz, 1H), 7.47 (br d, J=8 Hz, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([C:11]1[C:15]([C:16]2[C:21]([NH:22][C:23](OCC3C=CC=CC=3)=O)=[CH:20][CH:19]=[C:18]([O:33][CH3:34])N=2)=[CH:14][NH:13][CH:12]=1)=[O:10])[CH3:7].[C:35](=O)(O)[O-].[Na+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:6]([O:8][C:9]([C:11]1[C:15]2[C:16]3[CH:35]=[C:18]([O:33][CH3:34])[CH:19]=[CH:20][C:21]=3[N:22]=[CH:23][C:14]=2[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: O=C([O-])O
Reactant: CCOC(=O)c1c[nH]cc1-c1nc(OC)ccc1NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2cnc3ccc(OC)cc3c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 10 mL aliquot DMF is cooled to 5° C. To this is added 2.26 mL (0.024 mol) of phosphorous oxychloride. The mixture is warmed to room temperature, stirred for 15 minutes and cooked to 5° C. To this solution is added dropwise a solution 3.2 g (0.08 mol) of 4-(benzyloxycarbonylamino-6-methoxy-pyridin-2-yl)-1H-pyrrole-3-carboxylic acid ethyl ester dissolved in 15 mL of DMF. The reaction mixture is warmed to room temperature and stirred for 3 hours. The reaction mixture is carefully poured into 100 mL of saturated sodium bicarbonate. The pH is adjusted to 8 with solid K2CO3 and the mixture extracted with ethyl acetate. The organic extracts are dried (Na2SO4) and evaporated. The residue is chromatographed on 150 g of silica gel using ethyl acetate followed by 10/1 chloroform/methanol as the eluant. Appropriate fractions are combined to yield 1.46 grams of 8-methoxy-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid ethyl ester. 1H NMR (CDCl3) δ 9.10 (s, 1H), 8.35 (d, 1H), 8.10 (s, 1H, 7.2 (s, 1H), 7.05 (d, 1H), 4.4 (q, 2H), 4.10 (s, 3H), 1.40 (t, 3H). Mass spectrum: m/e=260 (p+1). TLC (ethyl acetate) Rf=0.3. Step 8:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[CH2:14][O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1COC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A colourless solution of (2S,4R)-4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (660 g; J. Org. Chem. (2003), 68, 3923-3931) in DCM (6.6 l) was cooled down to 0° C. and treated with TEA (510 ml) and, dropwise, with pivaloyl chloride (378 ml). The reaction mixture was stirred for 24 h at rt. The reaction mixture was cooled to −8° C. and treated with DIPEA (1506 ml). A solution of sulfur trioxide pyridine complex (1036 g) in DMSO (4 l) was added dropwise over 90 min. The reaction mixture was stirred at 0° C. for 1 h and was quenched with the addition of water (41). The aq. layer was extracted with Et2O/Hex (1:1; 2×1 l) and the combined org. layers were concentrated in vacuo. The residue obtained after work up (Et2O/Hex 1:1) was crystallized from Hex (2 l) affording 675 g (74%) of a colourless powder.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=2)=[N:6][N:7]2[CH:12]([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:11][N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Li+].[B-](CC)(CC)CC>C1COCC1>[C:1]([C:4]1[C:5]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([Cl:34])[CH:28]=2)=[N:6][N:7]2[CH:12]([CH2:13][CH3:14])[CH2:11][N:10]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2C(CCOS(C)(=O)=O)C1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1CN(C(=O)OC(C)(C)C)Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-carbamoyl-2-(3-chloro-4-fluorophenyl)-7-(2-((methylsulfonyl)oxy)ethyl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (200 mg, 0.387 mmol) in THF (6 mL) at 0° C. under nitrogen was added 1M THF solution of SUPER-HYDRIDE® (1.934 mL, 1.934 mmol). The reaction mixture was stirred at RT for 1 h and quenched with water. It was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 35-80% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate A98B (128 m g, 78%). MS(ES): m/z=423.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1)#[N:2].Cl>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CCOC(=O)N1CCN(Cc2ccc(F)c(C#N)c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCOC(=O)N1CCN(Cc2ccc(F)c(CN)c2)CC1
Reaction time: 1 h
Yield: 83.4 %

Procedure:
Ethyl 4-(3-cyano-4-fluorobenzyl)piperazine-1-carboxylate (5.9 g, 20.3 mmol, 1.0 equiv.) was dissolved in MeOH (47 mL), to which was added 12 M HCl (2.0 mL, 24.3 mmol, 1.2 equiv) while stirring vigorously. A catalytic amount of palladium on carbon (Aldrich, wet, 10% w/w) was then added as a MeOH slurry. The reaction was placed in a Parr bomb under atmosphere of H2 (55 psi) for 1 hour at room temperature. The reaction mixture was filtered through Celite and concentrated under reduced pressure to provide 5 g of ethyl 4-(3-(aminomethyl)-4-fluorobenzyl)piperazine-1-carboxylate.
Reaction SMILES: C(O[C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.C(N[N:18]([CH2:22][CH3:23])NCC)C>>[CH2:12]([N:13]([CH2:23][CH2:22][NH:18][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])[CH2:6][CH3:4])[CH3:11]
Reactant: CCNN(CC)NCC
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Product: CCN(CC)CCNC(=O)C1CCC2CCC(=O)N21
Temperature: 80 °C

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine-3-carboxylic acid ethyl ester (5.0 g, 0.0254 mol) in N,N-diethylaminoethylamine (23.2 g, 0.2 mol) is stirred at room temperature 24 hours and heated at 80° C. for 24 hours. The solution is concentrated at reduced pressure and distilled to yield N-[N,N-diethylamino-ethyl]hexahydro-5-oxo-1H-pyrrolizine-3-carboxamide
Reaction SMILES: [CH2:1]([C@:8]([OH:28])([CH2:25][CH2:26][OH:27])[C:9]([N:11]1[C@H:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:22][C@H:14]2[O:13][C:12]1([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CCOCC>[CH2:1]([C@@:8]([OH:28])([C:9]([N:11]1[C@H:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH2:22][C@H:14]2[O:13][C:12]1([CH3:23])[CH3:24])=[O:10])[CH2:25][CH:26]=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@@](O)(CCO)Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@@](O)(CC=O)Cc1ccccc1
Yield: 63.6 %

Procedure:
A solution of (S)-2-benzyl-1-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-2,4-dihydroxy-butan-1-one (21g) (0.13 g, 0.34 mmol) in dry CH2Cl2 (5 mL) was added over 1 min to a stirred solution of Dess-Martin periodinate (0.16 g, 0.37 mmol) in dry CH2Cl2 (10 mL). After 30 min the homogeneous mixture was diluted with ether and poured into cold saturated NaHCO3 (10 mL) containing Na2S2O3 (2.2 g). Organic layers were washed with aqueous saturated NaHCO3, brine and dried (MgSO4). The solvents were evaporated below 20° C. to give the title compound (0.082 g, 64%). The residue [MS (ESI+): 380 (M++1)] was immediately used for the next step.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[S:17]1[C:21]2[C:22]([C:26](Cl)=[O:27])=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.Cl>C(Cl)Cl>[C:1]1([S:7]([NH:10][C:26]([C:22]2[C:21]3[S:17][N:18]=[N:19][C:20]=3[CH:25]=[CH:24][CH:23]=2)=[O:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2nnsc12
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc2nnsc12
Reaction time: 8 h

Procedure:
3.2 g of benzenesulfonamide are introduced at from 0°-5° C. into 50 ml of abs. pyridine and, while stirring at that temperature, a solution of 3.9 g of benzo-1,2,3-thiadiazole-7-carboxylic acid chloride in20 ml of methylene chloride is added dropwise. The mixture is stirred overnight and then poured onto ice-water, rendered slightly acidic with hydrochloric acid and extracted with methylene chloride, and the extracts are washed with water, dried and concentrated by evaporation. The residue is dissolved warm in tetrahydrofuran, treated with some silica gel, filtered, concentrated by evaporation and then recrystallised from tetrahydrofuran/hexane. The title compound resulting melts at 231°-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>ClCCl>[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][CH2:11]2)=[O:16])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCC[C@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.1 %

Procedure:
To a solution of cis-tert-butyl 3-(1-(3,4-dichlorophenyl)piperazine-4-carbonyl)cyclohexylcarbamate (640 mg) in dichloromethane (10 mL) was added TFA (10 mL). The resulting solution was allowed to stir at rt. for 2 h. After this time, the solvent was removed by rotary evaporation to provide an oil which was partitioned between dichloromethane and 1 N NaOH. The dichloromethane extract was washed with water, dried over MgSO4 and then evaporated to provide the title compound (590 mg) as an oil.
Reaction SMILES: [C:1]([CH:5]1[CH2:9][O:8][CH:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([O-:17])=O)[C:11]=2[CH3:18])[O:6]1)([CH3:4])([CH3:3])[CH3:2].[K+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:51][C:52]1[C:53](=[O:65])[N:54]([CH:59]2[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]2)[N:55]([CH3:58])[C:56]=1[CH3:57]>CN1C(=O)CCC1.CCOC(C)=O.O>[C:1]([CH:5]1[CH2:9][O:8][CH:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([NH:51][C:52]3[C:53](=[O:65])[N:54]([CH:59]4[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]4)[N:55]([CH3:58])[C:56]=3[CH3:57])=[O:17])[C:11]=2[CH3:18])[O:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)[O-])noc1C1OCC(C(C)(C)C)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1OCC(C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium 5-(4-(tert-butyl)-1,3-dioxolan-2-yl)-4-methylisoxazole-3-carboxylate (43.5 mg, 0.148 mmol) in NMP (0.7 mL) was added HATU (62.0 mg, 0.163 mmol), triethylamine (45.5 μl, 0.326 mmol) and 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate D) (31.0 mg, 0.148 mmol) and the reaction mixture was stirred at room temperature overnight. To the resulting mixture was added water and EtOAc. The organics were washed with brine (×2), dried over MgSO4, filtered and the solvent removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a mixture of diastereoisomers.