Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.Cl.[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH:47][CH2:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[C:51]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:50]=2)=[CH:42][C:41]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:39]>Cl.CN(C)C=O>[CH3:36][O:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][N:47]([CH2:48][C:49]2[CH:58]=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[C:51]([O:59][CH2:60][C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[CH:50]=2)[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])=[CH:42][C:41]=1[O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:39]
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Reactant: COC(=O)c1ccc(CNCc2ccc(C(=O)OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN(Cc2ccc(C(=O)OC)c(OCc3ccccc3)c2)C(=O)CCCCCNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 76 %

Procedure:
Dissolved N-Cbz-6-aminohexanoic acid (784 mg, 2.96 mmole) into 10 mL of N,N-dimethylformamide and cooled to 0° C. Added triethylamine (1.65 mL, 11.8 mmole), stirred for 10 minutes, then added isobutylchloroformate (385 uL, 2.68 mmole). Stirred for 45 minutes and then added the crude methyl 4-[({[4-(methoxycarbonyl)-3-(phenylmethoxy)phenyl]methyl}-amino)-methyl]-2-(phenylmethoxy)benzoate hydrochloride from the step above (830 mg, 1.48 mmole). Let warm to room temperature and stirred for 3 hours. Diluted the reaction mixture with 1 N HCl and extracted with ethyl acetate. Dried the ethyl acetate layers with brine and anhydrous magnesium sulfate. Filtered, removed solvents in vacuo, and chromatographed on silica gel. Collected 870 mg (76% yield) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:14]COC)[C:6]([CH3:13])=[C:7]([O:9]COC)[CH:8]=1.Cl.O>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6]([CH3:13])=[C:7]([OH:9])[CH:8]=1
Reactant: COCOc1cc(OC)cc(OCOC)c1C
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc(O)c(C)c(O)c1
Yield: 88.3 %

Procedure:
A solution of 9 (314 mg, 1.30 mmol) in MeOH (10.8 mL) at room temperature was treated dropwise with 3 M HCl (3.46 mL, 10.3 mmol), then heated to reflux for 1 hour. Water (11 mL) was added and the solution was extracted with EtOAc (3×15 mL). Combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated to afford 10 as a red amorphous solid (177 mg, 99%): 1H NMR (CDCl3, 500 MHz) 8.17 (s, 1H), 6.09 (d, J=1.6 Hz, 1H), 6.04 (s, 1H), 3.67 (d, J=9.9 Hz, 3H), 2.08 (d, J=4.1 Hz, 3H); 13C NMR (CDCl3, 125 MHz) 60.3, 157.8, 155.4, 108.4, 93.9, 93.8, 55.0, 7.0; IR (film) νmax 3445, 2924, 2853, 2359, 2332, 1653, 1636, 1456, 1080, 1022, 798, 669 cm−1; HRMS (ESI+) m/z: [2M+H]+ calcd for C8H10O3, 309.1338 found, 309.1332.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[C:8]1([N:14]2[C:18]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:17](=[O:24])[NH:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[OH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:21]1[CH2:20][CH2:19][C:18]2([N:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:15][NH:16][C:17]2=[O:24])[CH2:23][CH2:22]1
Reactant: C1CCC2OC2C1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCCCC1O)CC2

Procedure:
The title compound was prepared from cyclohexene oxide and 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one in analogy of the procedure described for the synthesis of (rac,trans)-8-(2-hydroxy-cyclohexyl)-1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one (Example 73c). (rac,trans) 8-(2-Hydroxy-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one was obtained as colorless solid, MS (ISP): 330.3 MH+.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:10]1[O:14][N:13]=[C:12]([NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[C:6]([C:10]1[O:14][N:13]=[C:12]([NH:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[C:11]=1[Cl:4])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)(C)c1cc(NC(=O)C2CC2)no1
Solvent: ClCCl
Product: CC(C)(C)c1onc(NC(=O)C2CC2)c1Cl
Yield: 84.4 %

Procedure:
Methylene chloride (20 ml) and sulfuryl chloride (5.40 g) are added to N-(5-t-butyl-3-isoxazolyl)cyclopropanecarboxamide (4.17 g) and refluxed with heating for 1.5 hours. The methylene chloride and the unreacted sulfuryl chloride are evaporated under reduced pressure. The residue is chromatographed on a column of silica gel and recrystallized from benzene to give N-(5-t-butyl-4-chloro-3-isoxazolyl)cyclopropanecarboxamide (4.10 g) as colorless needles melting at 129.5° to 131.0° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]([O:24][CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][C:29]([NH2:32])=[N:28]1)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:32][C:29]2[CH:30]=[CH:31][N:27]([CH2:26][CH2:25][O:24][CH3:21])[N:28]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Reactant: CC(C)OCCn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)N2Cc3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 9, 94 mg, 0.35 mmol) and 1-(2-isopropoxy-ethyl)-1H-pyrazol-3-ylamine (prepared as in US 20080021032, Example 101, 70 mg, 0.41 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.18 g, 0.41 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol) dropwise and the resulting solution stirred at room temperature for 4 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (25 mL), a saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50% ethyl acetate/hexane) to afford (S)-3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (110 mg, 75%) as an off white solid: [α]31D=−50.6°, (c=0.36, chloroform); HR-ES(+) m/e calcd for C24H32N4O3 [M+H]+ 425.2547, observed 425.2547; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.77-2.18 (m, 17H), 3.40-5.25 (m, 8H), 6.39 (d, J=2.11 Hz, 1H), 7.26-7.91 (m, 5H), 10.86 (s, 1H).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:11][C:12]([F:21])([F:22])[O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Yield: 9 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and 4-(trifluoromethoxy)aniline (62.8 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 9.5 mg (32 μmol; 9% yield) of pure desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([NH2:20])=[O:19])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](C(C)C)[C:6]=2[N:17]=1.I[CH2:22][C@@H:23]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:24].BrC(C)C>C(O)=O>[C:28]([O:27][C:26](=[O:32])[NH:25][C@@H:23]([CH3:22])[CH2:24][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:4]=[C:3]([C:18]([NH2:20])=[O:19])[C:2]([NH2:1])=[N:17][C:6]1=2)([CH3:31])([CH3:30])[CH3:29]
Reactant: C[C@@H](CI)NC(=O)OC(C)(C)C
Reactant: CC(C)n1c2ccccc2c2cc(C(N)=O)c(N)nc21
Solvent: CC(C)Br
Solvent: O=CO
Product: C[C@@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=O)OC(C)(C)C

Procedure:
tert-butyl{(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xvi-b) was prepared following the procedure detailed in the synthesis of 13 substituting tert-butyl [(1S)-2-iodo-1-methylethyl]carbamate for 2-bromopropane. HCOOH Standard Conditions. M+H=384. 1H NMR (300 MHz, d6-DMSO): δ 8.71 (s, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.57-7.49 (br s, 2H), 7.31 (dd, J=7.9, 7.3 Hz, 1H), 7.16 (dd, J=7.9, 7.3 Hz, 1H), 6.90 (br d, 1H), 4.27 (dd, J=6.1, 13.4 Hz, 1H), 4.14-3.95 (m, 2H), 1.18 (s, 9H), 1.05 (d, J=6.1 Hz, 3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[CH:5]2.[Cl:21][S:22](O)(=[O:24])=[O:23]>CC#N>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH:6]=[C:5]2[S:22]([Cl:21])(=[O:24])=[O:23]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(F)ccc32)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(S(=O)(=O)Cl)c3cc(F)ccc32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A solution of 5-fluoro-1-(toluene-4-sulfonyl)indole (5.2 g) in dry CH3CN (80 mL) is cooled in an ice-bath and treated drop wise with chlorosulfonic acid (12 mL). The reaction mixture is allowed to warm to rt and stirred for 24 h. The reaction mixture is carefully poured onto ice/water (300 mL). The precipitate is collected by filtration and washed with water to afford 5-fluoro-3-chlorosulfonyl-1-(toluene-4-sulfonyl)-1H-indole (6.8 g, 98%) as a solid. MS: 386 (M−H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:10]([C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=1)[CH3:11]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Yield: 31 %

Procedure:
10 g of 2,6-diacetylpyridine (0.0613 mol), 9.54 g of 2-chloro-4,6-dimethylaniline (0.0613 mol) and 0.6 g of p-toluenesulfonic acid were heated under reflux on a water separator in 400 ml of toluene for 90 min. The solvent was distilled off completely and the residue was recrystallized from 50 ml of isopropanol. 5.66 g (0.019 mol) of 1-{6-[1-(2-chloro-4,6-dimethyl-phenylimino)ethyl]pyridin-2-yl}ethanone were obtained in a yield of 31%.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([C:20]23[CH2:27][CH2:26][C:23]([CH2:28][CH2:29][OH:30])([CH2:24][CH2:25]2)[CH2:22][O:21]3)[CH:10]=[C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:12]=1>C(Cl)Cl>[CH3:1][S:2]([O:30][CH2:29][CH2:28][C:23]12[CH2:24][CH2:25][C:20]([C:9]3[CH:10]=[C:11]([O:13][CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][O:15]4)[CH:12]=[C:7]([F:6])[CH:8]=3)([CH2:27][CH2:26]1)[O:21][CH2:22]2)(=[O:4])=[O:3]
Reactant: OCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Methanesulfonyl chloride (0.100 mL, 1.28 mmol) was added to a solution of 2-(1-(3-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethanol (36G; 0.373 g, 1.06 mmol) and TEA (0.46 mL. 3.19 mmol) in DCM (5 mL) at 0° C. and the reaction was stirred at 0° C. for 2 h and then concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with 1 N aq. HCl and water, sat. aq. NaHCO3, and water again. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo to give the crude title compound (0.456 g, 1.06 mmol, 100% yield) as a clear oil.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.Cl.O.[NH:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH:5]1([CH2:4][N:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1CCN(CC2CC2)CC1
Temperature: 85 °C
Reaction time: 16 h
Yield: 55.3 %

Procedure:
To a suspension of bromomethyl cyclopropane (4 mmol) and 4-piperidone hydrate hydrochloride (4 mmol) in acetonitrile (30 mL) was added sodium carbonate (11 mmol). The reaction mixture was stirred 16 h at 85° C. The resulting suspension was filtered and the solid was washed with acetonitrile. The filtrate was concentrated in vacuo and purified by column chromatography on silica eluting with DCM/2N NH3 in methanol 97:3 to yield 339 mg of the title compound as yellow oil. MS (m/e): 154.2 (MH+, 100%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[H-].[Na+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.O>CN(C)C=O>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](=[O:4])[C:2]([F:14])([F:15])[F:1]
Reactant: BrCCCCCCBr
Reactant: O=C(NCCc1ccccc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(N(CCCCCCBr)CCc1ccccc1)C(F)(F)F
Yield: 63.1 %

Procedure:
2,2,2-Trifluoro-N-(2-phenylethyl)acetamide (21.7 g., 0.1 mole) in dry dimethyformamide (100 ml) was added dropwise with stirring and under nitrogen to sodium hydride (2.4 g ., 0.1 mole, ether washed) in dry dimethylformamide (150 ml). Stirring was continued until a clear solution was obtained and 1,6-dibromohexane (73.2 g., 0.3 moles) was added. The solution was heated at 60°. for 3 hr then poured into water and extracted with ether. The extracts were washed well with water dried and evaporated. Excess dibromohexane was recovered by distillation (b.p. 60°-70°/0.1 mmHg) and the residue was separated on a silica gel column using ether-light petroleum (1:2) as eluant. The major fraction was evaporated to give the title compound as a pale yellow oil (24 g). A sample was distilled to give a colourless viscous liquid, b.p. 146°-152°/0.05 mmHg, (with slight decomposition)
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2C[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Yield: 69.1 %

Procedure:
A solution of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-((S)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.4 g Crude, 3.65 mmol, 1.00 equiv), 2-cyanoacetic acid (0.47 g, 5.48 mmol, 1.50 equiv), HATU (2.08 g, 5.48 mmol, 1.50 equiv), TEA (2.54 ml, 18.25 mmol, 5.00 equiv) in DCM (40 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water, and extracted with DCM. The DCM layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was submitted to flash chromatography (SiO2, PE:EtOAc=2:1 to 1:1) to give 1.28 g (69%) of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: C1(C)C(S([O-])(=O)=[O:8])=CC=CC=1.C1(C)C(S([O-])(=O)=O)=CC=CC=1.[CH2:23]([Sn+2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2]>CN(C)C=O.O>[CH2:23]([Sn:27](=[O:8])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]
Reactant: Cc1ccccc1S(=O)(=O)[O-]
Reactant: CCCC[Sn+2]CCCC
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC[Sn](=O)CCCC

Procedure:
Employing the same formulation as in Example 1, dibutyltin bis-toluenesulfonate (DBTTS) was evaluated, using a solution of this catalyst in dimethylformamide. A portion of this catalyst solution was diluted with 10% water and aged at room temperature for three weeks. From the results reported in Table 2, it is seen that no apparent change in activity occurred in the aged sample. Addition of water to a stannous octoate solution, on the other hand, produces an immediate precipitate of dibutyltin oxide which is relatively inactive as a co-catalyst for urethane production.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[OH:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:33]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:25]([NH2:34])[C:24]=2[N:23]=[C:22]1[CH2:35][CH2:36][CH3:37].[OH-].[Na+]>ClCCl>[NH2:34][C:25]1[C:24]2[N:23]=[C:22]([CH2:35][CH2:36][CH3:37])[N:21]([CH2:20][CH2:19][CH2:18][CH2:17][N:16]([OH:15])[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:33]=2[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:26]=1
Reactant: CC(C)N=C=O
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN(O)C(=O)NC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
Isopropyl isocyanate (0.67 mL, 6.85 mmol) and triethylamine (2.38 mL, 17.1 mmol) were added to a solution of 1-[4-(hydroxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (prepared as described in Parts A-D of Example 43, 2.00 g, 5.71 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours, then 10% aqueous sodium hydroxide (2 equivalents) was added. After the mixture was stirred for 1 hour at room temperature, the layers were separated and the organic layer was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, eluted with 3% methanol in dichloromethane). The appropriate fractions were combined and concentrated under reduced pressure. The resulting solid was slurried in 1:1 saturated aqueous sodium bicarbonate/water and was isolated by filtration, washed with water, and dried overnight in a vacuum oven at 80° C. to provide 0.327 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N-hydroxy-N′-isopropylurea as beige needles, mp 158-160° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C=O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([CH2:18][O:1][C@@H:2]2[CH2:5][C@H:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)=[CH:20][CH:21]=1)#[N:24]
Reactant: CCOC(=O)[C@H]1C[C@@H](O)C1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1C[C@@H](OCc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
To a solution of cis-ethyl 3-hydroxycyclobutanecarboxylate (0.17 g, 1.2 mmol) in DMF (4 mL) was added K2CO3 (0.24 g, 1.8 mmol) followed by 4-(bromomethyl)benzonitrile (0.28 g, 1.4 mmol). The reaction was stirred at about 25° C. for about 16 h. The reaction was partitioned between EtOAc (50 mL) and brine (50 mL). The layers were separated and the organic layer was washed with additional brine (50 mL). The organic layer was then dried over anhydrous Na2SO4, filtered, and concd in vacuo to give cis-ethyl 3-(4-cyanobenzyloxy)-cyclobutanecarboxylate (0.29 g, 95%) as an oil: 1H NMR (DMSO-d6) δ 7.82 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 4.75 (s, 2H), 4.02 (q, J=7.1 Hz, 2H), 3.93 (m, 1H), 2.58-2.45 (m, 1H), 2.41-2.28 (m, 2H), 1.98-1.85 (m, 2H), 1.20-1.08 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CC([O-])(C)C.[K+].[F:36][C:37]1[CH:38]=[C:39]([C@H:47]2[CH2:52][CH2:51][C@H:50]([C@H:53]3[CH2:58][CH2:57][C@H:56]([CH:59]=O)[CH2:55][CH2:54]3)[CH2:49][CH2:48]2)[CH:40]=[CH:41][C:42]=1[C:43]([F:46])([F:45])[F:44]>C(OCC)(=O)C>[F:2][CH2:3][CH2:4][CH:5]=[CH:57][C@H:56]1[CH2:55][CH2:54][C@H:53]([C@H:50]2[CH2:49][CH2:48][C@H:47]([C:39]3[CH:40]=[CH:41][C:42]([C:43]([F:46])([F:44])[F:45])=[C:37]([F:36])[CH:38]=3)[CH2:52][CH2:51]2)[CH2:58][CH2:59]1
Reactant: O=C[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(F)(F)F)c(F)c3)CC2)CC1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FCCC=C[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(F)(F)F)c(F)c3)CC2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (11.2 g, 27.8 millimols) with THF (50 ml) was cooled down to -20° C., followed by adding t-BuOK (3.1 g, 27.8 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (100 ml) solution of trans-4-(trans-4-(3-fluoro-4-trifluoromethylphenyl)cyclohexyl)cyclohexanecarbaldehyde (9.0 g, 25.3 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 2 except that the quantity of ethyl acetate used for extraction was made 400 ml, to obtain raw (trans-4-(trans-4-(4-fluorobutenyl)cyclohexyl)cyclohexyl)-3-fluoro-4-trifluoromethylbenzene (8.9 g).
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])[N:8]=1)([CH3:3])[CH3:2].[NH2:22][C@H:23]([C@@H:31]([OH:51])[CH2:32][C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]1[S:50][CH:49]=[N:48][CH:47]=1)=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C:19]([NH:22][C@H:23]([C@@H:31]([OH:51])[CH2:32][C@@H:33]([NH:41][C:42]([O:44][CH2:45][C:46]2[S:50][CH:49]=[N:48][CH:47]=2)=[O:43])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH:16]([CH3:17])[CH3:18])=[O:13])[N:8]=1)([CH3:2])[CH3:3]
Reactant: CC(C)c1nc(CCOC(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Product: CC(C)c1nc(CCOC(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)[C@@H](O)C[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1

Procedure:
Using the procedure of Example 1U, but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl) methyl)amino)carbonyl)-L-valine with N-((2-(2-isopropyl-4-thiazolyl)ethoxy) carbonyl)valine and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl) methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl) amino)-1,6-diphenyl-3-hydroxyhexane provided, after purification by silica gel chromatography using 99:1 CHCl3 :CH3OH, 50 mg (30%) of the desired compound (Rf 0.3, 95:5 CHCl3 :CH3OH) as a solid, mp 159°-160° C. Mass spectrum: (M+H)+ =722 HRMS. Exact mass calcd for C37H47N5O6S2 : 722.3046. Found: 722.3036.