Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][O:34][CH3:35])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][O:45][Si](C(C)(C)C)(C)C)=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:37])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:36])[CH2:33][O:34][CH3:35])[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][OH:45])=[CH:40][CH:39]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(CO[Si](C)(C)C(C)(C)C)cc3)c3ccccc23)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc(COc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(CO)cc3)c3ccccc23)ccn1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
The pyrazole amine Intermediate N (100 mg, 0.278 mmol) was added portionwise to a stirred suspension of CDI (45.1 mg, 0.278 mmol) in DCM (0.5 mL) over 1 hr and the reaction mixture was stirred at RT for 16 hr. A solution of the naphthylamine, Intermediate M, (47 mg, 0.139 mmol) in DCM (0.5 mL) was added dropwise over 2 hr. After a further 2 hr the mixture was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 12 g, 30-70% EtOAc in isohexane, gradient elution) to yield N-(4-((4-(3-(3-tert-butyl-1-(4-((tert-butyldimethylsilyloxy)methyl)phenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-methoxyacetamide (67) (42 mg, 20%): m/z 723 (M+H)+ (ES+) To a solution of the silyl ether (67) (42 mg, 58 μmol) in THF under nitrogen at −5° C. was added a solution of TBAF (1M in THF, 58 μL, 58 μmol). The mixture was warmed to RT and a second aliquot of TBAF (1M in THF, 58 μL, 58 μmol) was added. After 1 hr the mixture was diluted with EtOAc and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 12 g, 2-6% MeOH in DCM, gradient elution) to provide the title compound (Example 49) (23 mg, 63%): m/z 609 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.28 (9 H, s), 3.37 (3H, s) 4.08 (2H, s), 4.59 (2H, d), 5.32 (1H, t), 5.39 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.29 (1H, dd), 7.48 (2H, m), 7.52 (2H, m), 7.54-7.63 (3H, overlapping m), 7.93 (1H, m), 8.30-8.37 (3H, overlapping m), 8.63 (1H, s), 8.81 (1H, s), 10.02 (1H, br s).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[N+:16]([CH3:19])([O-:18])=[O:17].[F-].C([NH3+])(C)(C)C>C1COCC1.O>[N+:16]([CH2:19][C:8]1([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:10][CH2:9]1)([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C=C1CCC2(CC1)OCCO2
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC1(C[N+](=O)[O-])CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A solution of Methyl 1,4-dioxaspiro[4.5]dec-8-ylideneacetate (4 g, 18.8 mmol) in dry THF (20 mL) was treated by nitromethane (1.5 mL, 28.3 mmol) followed by tertbutylammonium fluoride (18.8 mLot a 1M solution in THF, 0.0188 mol). The resulting mixture was stirred at reflux for 18 h under nitrogen. After cooling to RT, the mixture was diluted with water and extracted with MTBE (3×100 mL). Combined organic layers were washed with 10% sodium bicarbonate solution (20 mL), water (100 mL) and brine (50 mL), dried over sodium sulphate filtered and concentrated. Purification by flash chromatography on silica (Pet.Ether:EtOAc) afforded the title compound as a colorless liquid (2.5 g, 49%). 1H NMR (400 MHz, DMSO) δ 4.7 (s, 2H), 3.94 (s, 4H), 3.69 (s, 3H), 2.57 (s, 2H), 1.74 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)=[O:26])=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cc2ccc(N)cc2)cn1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)cn1

Procedure:
The title compound is prepared from 4-(6-methoxy-pyridin-3-ylmethyl)-phenylamine (Stage 95.1; 300 mg, 1.40 mmol) and 4-methyl-phenyl-isocyanate (0.35 ml, 2.8 mmol) in THF (11 ml) analogously to Example 89: 1H-NMR (DMSO-d6): 8.68 (s, 2 HN), 8.02 (d, 1H), 7.49 (dd, 1H), 7.33 (d, 2H), 7.29 (d, 2H), 7.09 (d, 2H), 7.03 (d, 2H), 6.70 (d, 1H), 3.79 (2s, 5H), 2.21 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Br:12][C:13]1[CH:18]=C[C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=1.O>CO>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:8]([CH:18]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:20][N:19]=2
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: N#CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Brc1ccc2noc(-c3ccccc3)c2c1
Temperature: 50 °C
Yield: 55.1 %

Procedure:
Phenylacetonitrile (8.1 g, 69 mmol) was added to a room temperature solution of potassium hydroxide (85%) (74 g, 1.1 mol) in methanol (150 ml). To this was added 4-bromo-1-nitrobenzene (12.7 g, 63 mmol) suspended in methanol (130 ml). An exotherm was noted and the reaction was maintained at 50° C. for 5 hrs. After cooling to room temperature, water (400 ml) was added. The precipitate was collected and washed with water. The crude product (13.15 g) was crystallized from hot methanol (200 ml) to yield yellow needles (9.52 g, mp 113°-116° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].O.[NH2:16][NH2:17]>C(O)C>[NH:16]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12])[NH2:17]
Reactant: NN
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: O
Solvent: CCO
Product: NNc1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 25 °C

Procedure:
2-Chloro-5-nitrobenzenesulphonamide (3.35 g, 14.2 mmole) was dissolved in ethanol (75 ml) with heating and hydrazine hydrate (5 ml. 100 mmole) added. The mixture was refluxed for 45 minutes and then allowed to cool to room temperature. The product cystallised in long needles, 2.4 g. A second crop was obtained on cooling the filtrate in an ice bath, 0.5 g. The combined crops were recrystallised from water (120 ml) to afford pure 2-hydrazino-5-nitrobenzenesulphonamide, m.p. 209°-210° C., 1.85 gm, 60% as orange-yellow needles. TLC analysis (EtOAc:petrol, 1:1) showed one spot (Rf =0.3). Spectroscopic data was consistent with the product.
Reaction SMILES: [CH3:1][C:2]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13]1[N:18]=[C:17]([N:19]2[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]([O:30]CC)=[O:29])[CH:21]=[N:20]2)[CH:16]=[CH:15][CH:14]=1.[OH-:38].[Li+].Cl.[O:41]1CCOCC1>>[C:23]([OH:41])([C:24]([F:27])([F:26])[F:25])=[O:38].[CH3:1][C:2]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[C:13]1[N:18]=[C:17]([N:19]2[C:23]([C:24]([F:25])([F:26])[F:27])=[C:22]([C:28]([OH:30])=[O:29])[CH:21]=[N:20]2)[CH:16]=[CH:15][CH:14]=1
Reactant: [OH-]
Reactant: C1COCCO1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(C)c3OCc3ccc(C)cc3C)n2)c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Product: Cc1ccc(COc2c(C)cccc2-c2cccc(-n3ncc(C(=O)O)c3C(F)(F)F)n2)c(C)c1
Product: O=C(O)C(F)(F)F
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title compound from Example 15 Step C (12.0 mg, 0.023 mmol) in 1,4-dioxane (1.5 mL) was added lithium hydroxide (0.5 mL, 2.0 M in water, 1.00 mmol), and the resulting mixture was stirred at 50° C. After 30 min, the reaction mixture was rendered acidic by addition of aqueous hydrochloric acid, then was diluted with 1,4-dioxane and passed through a 0.45 micron syringe filter. Purification by reverse phase HPLC (40 to 100% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 482.8 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 8.30 (s, 1H), 8.08 (t, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.45 (dd, J=8.0, 1.5 Hz, 1H), 7.35-7.32 (m, 1H), 7.18 (t, J=7.5 Hz, 1H), 6.91-6.86 (m, 3H), 4.52 (s, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 2.06 (s, 3H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[O:15][C:14]([C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][N:17]2[C:18](=[O:32])[N:19]3[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:12]=1.[C:33]([O:37][C:38]([NH:40][C:41](=[N:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])N1C=CC=N1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CO>[C:50]([O:49][C:48]([N:47]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[NH:8][CH2:9][CH2:10][C:11]1[O:15][C:14]([C@@H:16]2[CH2:22][CH2:21][C@@H:20]3[CH2:23][N:17]2[C:18](=[O:32])[N:19]3[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:13][N:12]=1)=[O:54])([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
TEA (77 mg, 0.764 mmol) was added to a 0° C. solution of (2S,5R)-2-(5-(2-aminoethyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one TFA salt from the previous step in MeOH (3.0 mL). Tert-Butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (65 mg, 0.209 mmol) was then added at 0° C. and the reaction mixture was stirred at 0° C. for 4 hrs. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (gradient elution 30%-50% EtOAc/petroleum ether) to give (2S,5R)-2-(5-((2,3-bis(tert-butoxycarbonyl)guanidino)ethyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (80 mg, 70% in 2 steps) as a colorless oil. ESI-MS (EI+, m/z): 586.3 [M+H]+.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:23]1([C:2]2[N:31]3[N:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]3=[N:29][C:3]=2[C:5]2[CH:6]=[CH:7][C:8]([C:11]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:12][CH2:13][CH2:14]3)=[CH:9][CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: COc1ccc(N)nn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Yield: 78 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (0.67 g, 1.50 mmol), 3-amino-6-methoxypyridazine (CAS Registry No. 7252-84-8, 0.23 g, 1.80 mmol, 1.2 eq), N,N-diisopropylethylamine (0.74 mL, 1.50 mmol, 1.0 eq) and powdered activated 3 Å molecular sieves (10 g) in isopropanol (78 mL) was heated at the reflux temperature for 8 h. On cooling, the mixture was filtered through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure to give tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.55 g, 78% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH3:2].[CH:31]([N-:34]C(C)C)(C)[CH3:32].[Li+].BrCC#N.C(OCC)(=O)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:30])[CH:5]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)[CH2:32][C:31]#[N:34])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)CC1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Agent: N#CCBr
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC#N)C1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
Treat a −78° C. solution of [4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-acetic acid ethyl ester (4.71 g, 11.49 mmol) in THF (40 mL) with a 1.6M solution of lithium diisopropylamide in THF (7.18 mL, 14.36 mmol) and stir at −78° C. for 20 minutes under N2. Treat the reaction with bromoacetonitrile (1.71 g, 14.36 mol) and stir at −78° C. for 2 hours. Warm the reaction to room temperature and stir for 2 hours. Quench the reaction with 1N HCl at 0° C. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 25% to 40% ethyl acetate in hexanes gradient to afford 2.62 g (50%) of the titled product. MS (m/z): 450 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[NH2:7][CH2:8][C@H:9]([CH3:37])[O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[C:24]([Cl:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2>>[Cl:36][C:24]1[CH:23]=[C:22]([NH:21][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[CH:20][C:11]=3[O:10][C@@H:9]([CH3:37])[CH2:8][NH:7][C:4](=[O:6])[CH2:3][O:2][CH3:1])[N:16]=[CH:15][N:14]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: COCC(=O)O
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: COCC(=O)NC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 53 %

Procedure:
The procedure described in Example 1 was repeated using methoxyacetic acid and 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) to give the title compound in 53% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 3.20 (s, 3H), 3.40 (m, 1H), 3.72 (m, 1H), 3.75 (s, 2H), 4.93 (m, 1H), 5.29 (s, 2H), 7.23 (m, 2H), 7.31 (d, 1H), 7.58 (m, 2H), 7.70 (t, 1H), 7.86 (dt, 1H), 7.95 (s, 1H), 8.12 (d, 1H), 8.19 (t, 1H), 8.47 (s, 1H), 8.58 (m, 1H), 9.97 (s, 1H); Mass Spectrum MH+ 508.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.C1N=CN([C:28]([N:30]2[CH:34]=N[CH:32]=[CH:31]2)=[O:29])C=1.N1CC[C@H:37]([OH:40])C1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:28]([N:30]4[CH2:31][CH2:32][C@H:37]([OH:40])[CH2:34]4)=[O:29])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O[C@H]1CCNC1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12)N1CC[C@H](O)C1
Reaction time: 2 h
Yield: 78.1 %

Procedure:
To a DCM (1 mL) solution of (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (25 mg, 0.084 mmol) was added CDI (27 mg, 0.17 mmol) at ambient temperature in one portion. After stirring for two hours, (S)-pyrrolidin-3-ol (15 mg, 0.17 mmol) was added in one portion. The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 40% acetonitrile/water to yield the final product as a solid (27 mg, 78% yield). MS (apci) m/z=412.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.Cl.[NH2:18][C:19]1[C:28]([NH2:29])=[C:27]2[C:22]([CH:23]=[C:24]([C:31]([OH:33])=[O:32])[CH:25]=[C:26]2[OH:30])=[CH:21][CH:20]=1.S(=O)(O)[O-].[Na+]>CCO.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]3[NH:18][C:19]4[CH:20]=[CH:21][C:22]5[C:27](=[C:26]([OH:30])[CH:25]=[C:24]([C:31]([OH:33])=[O:32])[CH:23]=5)[C:28]=4[N:29]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Nc1ccc2cc(C(=O)O)cc(O)c2c1N
Reactant: Cc1ccc(-c2ccc(C=O)o2)cc1C
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2ccc(-c3nc4c(ccc5cc(C(=O)O)cc(O)c54)[nH]3)o2)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To an agitated solution of 5-(3,4-dimethylphenyl)-furan-2-carbaldehyde (0.030 g, 0.15 mmol) in EtOH (0.80 mL) was added 7,8-diamino-1-hydroxy-3-naphthoic acid dihydrochloride (0.029 g, 0.10 mmol) and sodium bisulfite (30 mg) in water (0.20 mL). The solution was heated to 60° C. and agitated overnight. The solution was cooled to room temperature, the tan precipitate was isolated by filtration and washed with water and ethyl acetate to provide the title compound (0.007 g, 15%) MS(ES) m/z 399 [M−H].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH2:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][C:14](=[O:16])[CH3:15]
Reactant: NCCc1ccccc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccccc1C(F)(F)F

Procedure:
In close analogy to the procedure described above, 2-(2-trifluoromethyl-phenyl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:25][CH3:26]>CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:25][CH3:26])[C:11]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(NS(=O)(=O)c2ccc(Cl)s2)CC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(C1(C(=O)OC)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 50 °C
Yield: 95 %

Procedure:
A solution of 16 (2 g, 6.7 mmol) in DMF (20 mL) was added with an. K2CO3 (1.5 mol eq, 1.4 g) and, after few minutes, 2-iodoethane (1.2 mol eq, 0.84 ml) was added and the mixture was heated at 50° C. for 4 h. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 17 as a pale yellow oil (2.1 g, 95% yield). 1HNMR (DMSO, 200 MHz) δ 1.18 (m, 2H), 1.25 (t, 3H), 1.37 (m, 2H), 1.98 (s, 3H), 3.45 (m, 2H), 7.28 (d, 1H, J=4), 7.78 (d, 1H, J=3.9)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:20][C:21]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])([CH3:25])[CH2:22][CH:23]=[O:24].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][P:4]([C:9]([F:11])([F:10])[CH:23]([OH:24])[CH2:22][C:21]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])([CH3:25])[CH3:20])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: COc1ccc(F)cc1C(C)(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(F)(F)C(O)CC(C)(C)c1cc(F)ccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
To a solution of the difluoromethylphosphonic acid diethyl ester (1.35 g) in THF (5.0 mL) cooled in a dry ice/acetone bath was added LDA (5.0 mL, 1.5M in cyclohexane) dropwise over 5.0 minutes. After 10.0 minutes, a solution of 3-methyl-3-(2-methoxy-5-fluorophenyl)butyraldehyde (0.94 g) in THF (5.0 mL) was added dropwise. After an additional 20.0 minutes, acetic acid (1 mL) was added and the mixture was warmed to room temperature. The mixture was diluted with ethyl acetate, washed with water, dried, filtered, and evaporated in vacuo. Fractionation of the residue over silica gel (eluent: methylene chloride-ethyl acetate (1:4)) gave the desired [1,1-difluoro-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]phosphonic acid diethyl ester (1.15 g, 40%) as an oil that crystallized on treatment with hexanes.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:43](SCC(COC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)O)CCCCCCCCCCCCCCC.CCI>>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][C:24]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[O:20][CH2:21][CH3:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Solvent: CCI
Product: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC

Procedure:
This compound was prepared in an analogous manner to that of (±)-1-S-hexadecyl-2-O-methyl-3-O-tritylthioglycerol from 10.0 grams (0.02 mole) of (±)-1-S-hexadecyl-3-O-tritylthioglycerol and 3.3 grams (0.03 mole) of CH3CH2I to provide 10.0 grams of crude product as an oil. 1H-NMR (CDCl3): delta, 0.7-1.7[m, 34H, (CH2)14CH3, CH3 --CH2 --O], 2.3-2.8(m, 4H, CH2 --S--CH2), 3.5-3.9[m, 5H, OCH2 --CH3, CHCH2O], 7.1-7.5 [m, 15H, C(C6H5)3 ].
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])C1C=CC=CC=1>[Pd]>[C:21]([O:20][C:18]([CH2:17][CH2:16][N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCN1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Product: CC(C)(C)OC(=O)CCN1CCC[C@H]1C(=O)O
Reaction time: 1 h
Yield: 104.9 %

Procedure:
A solution of Intermediate 84a (1.10 g, 3.29 mmol) in IMS (25.0 mL) was added to palladium on charcoal (10 wt %, 110 mg) and the reaction stirred under H2 for 1 h. The mixture was filtered through Celite and evaporated in vacuo to give the title compound (840 mg, 99%). 1H NMR (300 MHz, d4-MeOD): 1.48 (9H, s), 1.91 (1H, m), 2.02-2.24 (2H, m), 2.41 (1H, m), 2.74 (2H, t, J 7.1), 3.13 (1H, ddd, J 11.1, 10.2, 7.0), 3.32-3.53 (2H, m), 3.72 (1H, ddd, J 11.0, 7.2, 3.5), 3.89 (1H, dd, J 9.5, 5.3).