Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([NH2:16])[C:11]([NH2:15])=[CH:12][C:13]=3[Cl:14])[CH2:4]2)[CH2:2]1.[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([N:32]=[C:33]=S)[CH:26]=1)([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22](=[O:35])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([NH:32][C:33]2[NH:16][C:10]3[CH:9]=[C:8]([N:5]4[CH2:6][CH2:7][C:3]5([CH2:1][CH2:2]5)[CH2:4]4)[C:13]([Cl:14])=[CH:12][C:11]=3[N:15]=2)[CH:26]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: Nc1cc(Cl)c(N2CCC3(CC3)C2)cc1N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(N4CCC5(CC5)C4)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (130 μL, 0.9 mmol) followed by 4-(5-aza-spiro[2.4]hept-5-yl)-5-chloro-benzene-1,2-diamine (80 mg) were added to (4-chloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (example 1, step (c), 69 mg, 0.2 mmol) in DMF (3 mL). The reaction mixture was stirred at rt overnight, then concentrated and purified by chromatography to give the sub-title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[C:25]([Si:22]([CH3:24])([CH3:23])[O:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2cccc(C(F)(F)F)c2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(C(F)(F)F)c1

Procedure:
Analogous to the procedure described for Compound 1A, Step C, 5-[3-hydroxy-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (1.19 g, 3.95 mmol) was protected with tert-butyidimethylsilyl chloride (893 mg, 6.22 mmol). Purification by medium pressure chromatography eluting with EtOAc provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.47-7.32 (m, 4H), 5.73 (m, 1H), 3.86 (m, 1H), 3.59 (m, 1H), 2.75 (m, 2H), 2.35-2.20 (m, 3H), 1.70-1.40 (m, 5H), 0.81 (s, 9H), −0.05 (d, 3H), −0.3 (d, 3H); MS 416.1 (M+1).
Reaction SMILES: Cl.[CH:2]1[C:10]2[N:9]3[C:11]([C@@H:14]4[C@H:18]([CH3:19])[CH2:17][C@H:16]([NH2:20])[CH2:15]4)=[CH:12][N:13]=[C:8]3[CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]([F:37])([F:36])[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[CH:2]1[C:10]2[N:9]3[C:11]([C@@H:14]4[C@H:18]([CH3:19])[CH2:17][C@H:16]([NH:20][S:32]([CH2:31][CH2:30][C:29]([F:37])([F:36])[F:28])(=[O:34])=[O:33])[CH2:15]4)=[CH:12][N:13]=[C:8]3[CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: C[C@@H]1C[C@H](N)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](NS(=O)(=O)CCC(F)(F)F)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a 2 L flask (1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine hydrochloride (248.0 g, 733 mmol), water (1240 ml), THF (124 ml) and activated carbon (24.12 g) was added and stirred for about 10 min. The resulting mixture was filtered through celite rinsing with a mixture of water (100 mL) and THF (24 mL). Potassium carbonate (668 g, 4836 mmol) and THF (1736 ml) were added and a solution of 3,3,3-trifluoropropane-1-sulfonyl chloride (315 g, 1524 mmol, Matrix) in THF (620 ml) was added over about 1 hr. After cooling to ambient temperature the layers were separated and the aqueous layer extracted with THF (500 mL). The combined organic layers were washed with aqueous ammonium chloride (3×100 mL) and concentrated to approximately 1 L. Water (1770 mL) was added slowly at about 50° C. and the slurry cooled to about 23° C. The solids were collected by filtration, washed with 35% THF in water (750 mL) and dried in a vacuum oven. The crude material was dissolved in MeOH (4.5 L) and treated with activated carbon (28.3 g). After filtering through celite and rinsing with MeOH (500 mL), the solution was concentrated under reduced pressure to approximately 1 L and water (800 mL) was added slowly at about 50° C. then cooled to 35° C. when additional water (360 mL) was added. The product was collected by filtration, washed with 1:1 MeOH:water (2×350 mL) and dried in a vacuum oven to afford N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (215.3 g, 71%) as a white crystalline solid (m.p. 225° C.). 1H NMR (400 MHz, DMSO) δ 11.99 (bs, 1H), 8.30 (s, 1H), 7.40 (bs, 1H), 7.38 (s, 1H), 7.27-7.07 (m, 1H), 6.62 (d, J=3.4 Hz, 1H), 3.75 (dt, J=10.1, 7.8 Hz, 1H), 3.70-3.55 (m, 1H), 3.15-3.02 (m, 2H), 2.61-2.40 (m, 2H), 2.40-2.29 (m, 1H), 2.23 (dd, J=13.3, 6.9 Hz, 1H), 2.16-2.03 (m, 1H), 1.94-1.77 (m, 1H), 1.20-0.99 (m, 1H), 0.17 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[Cl:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[S:24][CH:25]=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[S:24][CH:25]=1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: O=Cc1cccc(-c2nc(Cl)cs2)c1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1cccc(-c2nc(Cl)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with 3-(4-chlorothiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 430.96 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[C:4]([O:19][CH3:20])[CH:3]=1.O=[C:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.CC(O)=O>CO>[Cl:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH:22]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]3)[CH2:14][CH2:15]2)=[O:9])=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCNCC1
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(Cl)c(Cl)cc1CNC(=O)C1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Yield: 19.6 %

Procedure:
A mixture of N-(4,5-dichloro-2-methoxybenzyl)piperidine-4-carboxamide (750 mg, 2.37 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (607 mg, 3.55 mmol), AcOH (1 mL) and MeOH (5 mL) was stirred at reflux for 2 h. To this mixture, NaBH3(CN) (0.74 g, 11.85 mmol) was added and the resulting mixture was stirred at 60° C. for 16 h. The mixture was allowed to cool to room temperature and partitioned between NH4Cl aqueous solution and ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (220 mg, 18% yield). ESI-MS m/z: 472.3[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](SC)[N:3]=1.[CH3:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([O:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH3:18])[N:3]=1
Reactant: CC(O)c1ccccn1
Reactant: CSc1nc(N)nc(-c2ccc(C)o2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2nc(N)nc(OC(C)c3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-(5-methyl-furan-2-yl)-6-methylsulfanyl-pyrimidine-5-carbonitrile, (RS)-alpha-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 344 (M+Na+, 20), 322 (M+H+, 100).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:40])[CH2:21][NH:22][C:23]([CH3:39])([CH3:38])[CH2:24][C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.C(O)(=O)C>CO.[Pd]>[OH:40][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[CH2:21][NH:22][C:23]([CH3:38])([CH3:39])[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=1
Reactant: CC(C)(Cc1ccc(OCCCC(=O)O)cc1)NCC(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(Cc1ccc(OCCCC(=O)O)cc1)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
0.70 g (1.28 mmol) of 4-(4-{2-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin -8-yl)-2-hydroxyethylamino]-2-methylpropyl}phenoxy)butyric acid is dissolved in 25 mL methanol and 2 mL acetic acid and hydrogenated in the presence of 150 mg palladium on charcoal (10%) at ambient temperature and normal pressure. The catalyst is filtered off and the filtrate is freed from solvent. The product is obtained by crystallization from a methanol-acetone mixture. Yield: 0.40 g (68%); melting point: 201° C.-204° C.; mass spectroscopy: [M+H]+=459.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:24].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35]>C1(C)C=CC=CC=1>[CH3:22][C:20]([CH3:23])([CH3:21])[CH2:19][CH2:18][CH2:17][CH2:16][C:12]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:24])=[C:4]([C:3]2[NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:35])(=[O:36])[N:37]=2)[C:13]1=[O:14]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CSC(SC)=C1C(=O)c2ccccc2C(C)(CCCCC(C)(C)C)C1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 852.1 %

Procedure:
A solution of Example 35H (0.097 g, 0.249 mmol) and 2-amino-benzenesulfonamide (0.045 g, 0.262 mmol) in toluene (7 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the desired product (0.99 g, 85%).
Reaction SMILES: [NH+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([CH2:9][CH2:10][O:11][P:12](=[O:15])([O-:14])[O-:13])#[N:8].[NH+]1C=CC=CC=1.C(CCOP([O-])([O-])=O)#N.[Ba+2].N1C=CC=CC=1>O>[NH+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]([CH2:9][CH2:10][O:11][P:12](=[O:13])([OH:15])[OH:14])#[N:8]
Reactant: N#CCCOP(=O)([O-])[O-]
Agent: [Ba+2]
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: O
Product: N#CCCOP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
According to the method of Tenor (J. Am. Chem. Soc., p. 159-168, 1961), 2-cyanoethylphosphoric acid pyridinium salt was prepared. Namely, 1.61 g of barium 2-cyanoethylphosphate and 10 g of an ion exchange resin (Dowex 50 (hydrogen ion form)) were suspended in water, stirred at room temperature for 30 minutes, 2 ml of pyridine was added to the supernatant, the mixture was washed with water, and the mixture then concentrated to dryness under a reduced pressure, followed by an addition of pyridine to give 1 mmol/ml of 2-cyanoethylphosphoric acid pyridinium solution.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11][C:12]([C@@H:14]2[CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][C@H:15]2[C:38]([N:40]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]=[CH2:55])[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])=[O:13])[CH2:8][C@H:7]1C=C)=[O:5])[CH3:2]>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C@@:6]12[CH2:8][C@H:7]1[CH:55]=[CH:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][N:40]([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])[C:38](=[O:39])[C@H:15]1[C@@H:14]([CH2:18][C@@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Solvent: ClCCl
Product: CCOC(=O)[C@@]12C[C@H]1C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)[C@@H]1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2

Procedure:
A solution of 38 (158 mg, 0.209 mmol) in dry DCM (25 mL) was bubbled with argon for 5 min. To the stirred solution under argon atmosphere was then added a solution of Hoveyda-Grubbs catalyst 2nd generation (11 mg, 0.018 mmol) in dry DCM (5 mL). The mixture was stirred at reflux under argon atmosphere for 16 h. The solvent was evaporated and purification by HPLC (MeOH/H2O 90:10 with 0.2% triethylamine) yielded the target compound (107 mg, 70%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10][O-:11].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccnc(Cl)c1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc(C)c1Br
Temperature: 100 °C
Reaction time: 12 h

Procedure:
3-bromo-2-chloro-4-methylpyridine (1 g) was added to DMF (5.6 mL). Sodium methoxide (28% solution in methanol, 4.6 mL) was added to the solution, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5% to 30%) to give the title compound (1.1 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:13])[CH3:12])=[CH:8][C:7]([C:15]#[N:16])=[N:6]1)[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[K+].[Br:22]Br>>[CH2:1]([N:5]1[C:9]([CH2:10][C:11]([OH:14])([CH3:12])[CH3:13])=[C:8]([Br:22])[C:7]([C:15]#[N:16])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: BrBr
Reactant: CCCCn1nc(C#N)cc1CC(C)(C)O
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCCCn1nc(C#N)c(Br)c1CC(C)(C)O
Temperature: 0 °C
Yield: 53.5 %

Procedure:
The method described in Part F of Examples 1 through 4 was used to treat 1-butyl-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile (18 g, 81 mmol) with potassium acetate (16.7 g, 171 mmol) and bromine (4.6 mL, 89 mmol). After the acetic acid was removed under reduced pressure, the residue was diluted with dichloromethane (100 mL) and adjusted to pH 12 with the addition of 50% w/w aqueous sodium hydroxide and ice while maintaining the temperature at 0° C. The resulting mixture was extracted with dichloromethane, and the combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (60I cartridge, eluting with 0 to 50% ethyl acetate in hexanes to provide 13 g of 1-butyl4-bromo-5-(2-hydroxy-2-methylpropyl)-1H-pyrazole-3-carbonitrile as a yellow oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 79.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (411 mg, 0.70 mmol) prepared in Example 31a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (241 mg, 79%) as a colorless solid.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([C@H:4]([C@@H:6]([C@@H:8]([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])[OH:3].CO[C:15]1[CH:34]=[CH:33][C:18]([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=1.C(Cl)Cl>N1C=CC=CC=1>[C:19]([O:11][CH2:10][C@H:8]([C@H:6]([C@@H:4]([C@@H:2]([CH2:1][O:12][C:19]([C:18]1[CH:33]=[CH:34][CH:15]=[CH:16][CH:17]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:3])[OH:5])[OH:7])[OH:9])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:18]1[CH:33]=[CH:34][CH:15]=[CH:16][CH:17]=1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O[C@@H]([C@H](O)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a flask containing 1 g of D-mannitol (5.49 mmols) and 3.73 g of 4-methoxytrityl chloride (12.07 mmols) were added 26.7 mL anhydrous DCM. Once all material dissolved 13.35 mL of pyridine was added. The reaction mixture was refluxed for 5 hours then allowed to cool to RT overnight. The reaction was quenched with 25 mL of water then extracted 3 times with 7 mL of DCM buffered with 0.1% triethylamine. The organic fractions were combined then washed 3 times with 7 mL of brine. The DCM layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in a minimum amount of DCM and subjected to silica gel column chromatographic purification (EtOAc/hexanes) to obtain 3.2 g of the desired product (80% yield). 1H-NMR (500 MHz, CDCl3): δ 7.34 (m, 6H, aromatic), 7.24 (m, 24H, aromatic), 6.71 (m, 4H, aromatic), 3.83 (s, 1H, —OH), 3.72 (s, 6H, CH3), 3.687 (broad peak, 4H, CH2), 3.24 (m, 4H, —CH—), 2.88 (s, 1H, —OH), 2.62 (s, 1H, —OH). Mass spec analysis (MALDI-TOF): exact mass: 726.32, obtained: 749.86 [M+Na]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[O:7]=[C:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH2:27][OH:28])=[CH:9]1.CI>C(O)(C)(C)C>[O:7]=[C:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[CH2:27][OH:28])=[C:9]1[CH3:1]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2CO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)(C)O
Product: CC1=C2CC[C@H]3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1=O
Reaction time: 3 h

Procedure:
A mixture of potassium-t-butoxide (5 g) in 100 ml t-butanol is heated to reflux. A solution of 3-oxo-17β-(hydroxymethyl)-4-androstene (10 g) in t-butanol is added followed by a solution of methyl iodide (2.7 g) in t-butanol. Heating is continued for 3 hours. The mixture is then cooled, acidified, and extracted with dichloromethane. The dichloromethane solution is washed with brine, dried, and concentrated to yield 3oxo-17β-(hydroxymethyl)-4-methyl-4-androstene.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9](=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>[Pd].CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)[CH:8]=[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:6]=1[OH:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(CCC(=O)O)cc2)C=C(C(C)(C)C)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2ccc(CCC(=O)O)cc2)cc(C(C)(C)C)c1O
Yield: 77.1 %

Procedure:
A mixture of 4.0 g of 3-[4-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenyl]propionic acid, 200 ml of ethanol of 0.1 g of 10% palladium on charcoal catalyst was placed on a Paar apparatus. Hydrogen uptake was complete after 30 minutes. Under a nitrogen atmosphere, the reaction mixture was filtered to remove catalyst. The filtrate was evaporated to give an oil which was coevaporated with hexane to remove all traces of ethanol and then triturated with hexane to give a light orange crystalline solid. This solid was recrystallized from a mixture of ethanol and water to give 3.1 g 3-[N-(3,5-di-tertiary-butyl-4-hydroxyphenyl)-4-aminophenyl]propionic acid, m.p. 140°-142° C. Analysis: Calculated for C23H31NO3 : % C, 74.8; % H, 8.5; % N, 3.8; Found: % C, 74.7; % H, 8.3; % N, 3.9.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:16][C:4]1[CH:3]=[C:2]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccccc1
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccccc3)c12

Procedure:
The title compound, grey solid (52 mg, 74%), MS (ISP) m/z=281.3 [(M+H)+], mp 236.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available phenylboronic acid (39.6 mg, 0.325 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]1.[Cl:21]CCl.CO>>[Cl:21][C:5]1[CH:4]=[C:3]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]2)[CH:2]=[CH:7][C:6]=1[NH2:8]
Reactant: ClCCl
Reactant: CC1CCN(CCNc2ccc([N+](=O)[O-])cc2Cl)CC1
Solvent: CO
Product: CC1CCN(CCNc2ccc(N)c(Cl)c2)CC1

Procedure:
Prepared analogously to Example 3.1.b. from (2-chloro-4-nitrophenyl)-[2-(4-methylpiperidin-1-yl)ethyl]amine. Yield: 7 g (89.3% of theory); C14H22ClN3 (M=267.80); calc.: molecular ion peak (M+H)+: 268/270; found: molecular ion peak (M+H)+: 268/270; Rf value: 0.6 (Alox, dichloromethane/methanol (49:1)).
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21].N12CCN(CC1)CC2.O>CN(C)C=O>[CH:1]1([CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: O=C(CC1CCCCC1)Nc1ccc(O)nc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)Oc1ccc(NC(=O)CC2CCCCC2)cn1)c1ccccc1
Yield: 71.7 %

Procedure:
A solution of 2-cyclohexyl-N-(6-hydroxy-pyridin-3-yl)-acetamide (0.70 g, 3.00 mmol), N -methyl-N-phenylcarbamoyl chloride (0.51 g, 3.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.34 g, 3.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.79 g, 72% yield) as a brown solid.