Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:43]([NH:60][CH:58]([C:55]1[CH:56]=[CH:57][C:52]([F:51])=[CH:53][CH:54]=1)[CH3:59])=[O:49]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)c1ccc(F)cc1
Reactant: COc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCCCN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)c(F)c3)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 91.3 %

Procedure:
2-Fluoro-4-{[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy}-aniline (30 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml) to prepare a solution. A solution of triphosgene (17 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 25 min. Next, a solution of 1-(4-fluorophenyl)ethylamine (12 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 5 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (31 mg, yield 73%).
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:14]=1[O:21][CH3:22])[C@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[I-:23].[CH3:24][N+:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH3:35])=[CH:27][CH:26]=1.C([O-])(=O)C.[NH4+].C(Cl)(Cl)Cl.CO>C(O)C>[I-:23].[C@@H:2]1([O:1][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:35][C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N+:25]([CH3:24])=[CH:26][CH:27]=3)=[CH:15][C:14]=2[O:21][CH3:22])[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: Cc1cc[n+](C)c2ccccc12
Reactant: COc1cc(C=O)ccc1O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C=Cc2cc[n+](C)c3ccccc23)ccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h

Procedure:
A suspension of 4-formyl-2-methoxyphenyl β-D-galactopyranoside (1c)(0.20 g, 0.63 mmol), 1,4-dimethylquinolinium iodide (0.18 g, 0.63 mmol) and ammonium acetate (0.15 g, 1.9 mmol) in ethanol (20 ml) was heated at 60°-70° C., with stirring for 1 h when t.l.c. (chloroform-methanol, 5:4) indicated that the aldehyde had been completely converted into the almost non-mobile yellow product. The reaction mixture was cooled, and filtered to give a yellow solid which was washed sequentially with ethanol, acetone and ether to give (23c) as mustard yellow solid (0.33 g, 90%), m.p. 216°-220° C. (decomp.), [α]D -17° (c 1, DMOS)(Found: C, 48.89; H, 5.28; N, 2.36. C25H28INO7.2H2O calc.: C, 48.63; H, 5.22; N, 2.27%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:26])[CH3:25]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](=[O:22])[NH:26][CH2:24][CH3:25])[CH:16]=[CH:17][C:18]=1[Cl:19])[CH:9]1[CH2:11][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)O)ccc1Cl)C1CC1
Reactant: CCN
Solvent: ClCCl
Product: CCNC(=O)Cc1ccc(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1
Reaction time: 1 h
Yield: 63.6 %

Procedure:
To a sol. of {3-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-chloro-phenyl}-acetic acid (4.30 g, 12.6 mmol) in CH2Cl2 (130 mL) was added 1-chloro-N,N-2-trimethylpropenyl amine (1.87 mL, 15.2 mmol), and the mixture was stirred for 60 min. Ethylamine (2M in THF, 25.0 mL, 50.0 mmol) was added, and the mixture was stirred overnight. More CH2Cl2 was added, and the mixture was washed with water and brine, was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 7:3) yielded the title compound (2.94 g, 63%). LC-MS: tR=0.97 min; ES+: 311.28.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:7]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cn1
Yield: 42.5 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (95 mg, 0.41 mmol) and potassium carbonate (75 mg, 0.54 mmol) in anhydrous DCM (1.5 ml) was added dropwise phenyl chloroformate (0.16 ml, 1.24 mmol) as a solution in DCM (1 ml). The crude was purified by silica gel chromatography (DCM/EtOAc 7-60%) to afford phenyl 3-tert-butyl-1-(6-methylpyridin-3-yl)-1H-pyrazol-5-ylcarbamate (61 mg, 42%). 1H NMR (300 MHz, CDCl3) δ 1.34 (s, 9H), 2.63 (s, 3H), 6.47 (s, 1H), 6.83 (d, J=8 Hz, 1H), 6.91-6.93 (m, 3H), 7.12 (s, 1H), 7.21-7.40 (m, 2H), 7.78 (d, J=8 Hz, 1H), 8.68 (d, J=2 Hz, 1H); LC-MS (ESI) m/z 351 (M+H)+.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](=O)[CH3:30])=[CH:28][C:23]=2[CH2:22][CH2:21]1>O1CCCC1>[Br:19][C:15]1[CH:14]=[C:13]([C:29]([C:27]2[CH:26]=[CH:25][C:24]3[O:20][CH2:21][CH2:22][C:23]=3[CH:28]=2)=[CH2:30])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccc2c(c1)CCO2
Reactant: Brc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(c1cccc(Br)c1)c1ccc2c(c1)CCO2
Reaction time: 0.33 h

Procedure:
A 1.6 M solution of n-butyllithium in hexane (22.3 mL, 35.7 mmol, 1.16 eq.) was added dropwise to a solution of 1,3-dibromobenzene (8.0 g, 33.9 mmol, 1.1 eq) in 30 mL of dry tetrahydrofuran at −78° C. under nitrogen, and the mixture was stirred for 20 min. After this time, a solution of 1-(2,3-dihydro-benzofuran-5-yl)-ethanone (5.0 g, 30.8 mmol, 1.0 eq, prepared as shown in Scheme 4) in 20 mL of dry tetrahydrofuran was added over 10 minutes and the resulting solution was further stirred for 45 min. The reaction mixture was examined LCMS which showed complete conversion to the desired product. 20 mL of a saturated aqueous solution of ammonium chloride was added and the cooling bath was removed. The mixture was poured into 100 mL of a 1:1 diisopropyl ether/water mixture. The organic fraction was dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in 10 ml, of acetic acid. 0.3 mL of 98% sulfuric acid were added and the dark solution was stirred at room temperature. After 30 min LCMS showed complete conversion to the desired product. Crushed ice was poured in the reaction mixture which was then extracted with dichloromethane. The organic fraction was collected, washed with water, sodium bicarbonate solution and dried with over sodium sulfate. The crude product was purified by flash chromatography eluting with cyclohexane. 3.5 g of clean product was obtained as colorless liquid (yield: 38%)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([NH2:7])=[O:6])[CH3:4].O=[C:9]([CH3:17])[CH2:10][CH2:11][C:12](OCC)=[O:13]>O>[CH3:4][C@@H:3]1[N:2]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]2([CH3:17])[NH:7][C:5]1=[O:6]
Reactant: CCOC(=O)CCC(C)=O
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Solvent: O
Product: C[C@H]1C(=O)NC2(C)CCC(=O)N12

Procedure:
L-Alaninamide hydrochloride (20.7 g, 0.166 mol) and ethyl 4-oxopentanoate (20 g, 0.13 mol) were reacted together according to the procedure of Example 2 to give the title compound, 4.5 g (19.1%), m.p. 228°-230° (with decomposition), [alpha]D =+50.7° (c=3, H2O). NMR (CDCl3): deltaH =7.95 (bs, 1H, NH); 4.30 (q, J=8 Hz, 1H, CHCH3); 3.00-2.10 (c.a., 4H, CH2CH2); 1.60 (s, 3H, C--CH3 ; 1.45 (d, J=8 Hz, 3H, CH3CH). MS (E.I., 70 eV, 1.5 mA) m/z=168 (M+), 153 (M--CH3 +, 125 (M--CHNO+, 112 (M--C3H4O+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3CCN)[CH2:16][CH2:15][CH2:14][C:13]=2[CH:30]=1)(C(C)(C)C)(C)C.Cl.[N:32]1([CH2:39][CH2:40][O:41][C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=O)=[CH:44][CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.[N:51]1(CCOC(NCCC2C=C(OC)C=CC=2C2CCCC3C=C(O[Si](C(C)(C)C)(C)C)C=CC=3C2)C2C=CC=CC=2)CCCC[CH2:53][CH2:52]1>>[N:32]1([CH2:39][CH2:40][O:41][C:42]2[CH:50]=[CH:49][C:45]([CH2:46][CH2:53][CH2:52][NH:51][C:20]3[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=3[CH:17]3[CH2:16][CH2:15][CH2:14][C:13]4[CH:30]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=4[CH2:18]3)=[CH:44][CH:43]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc(C2CCCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCNC(OCCN2CCCCCC2)c2ccccc2)c1
Reactant: COc1ccc(C2CCCc3cc(O[Si](C)(C)C(C)(C)C)ccc3C2)c(CCN)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)cc1
Agent: Cl
Product: COc1ccc(C2CCCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCC3)cc2)c1

Procedure:
Synthesized from {2-[2-(tert-butyldimethylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-5-methoxyphenyl}ethylamine and 4-(2-azepan-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, [-(2-azepan-1-ylethoxy)benzyl]{2-[2-(tert-butyldimethylsilyloxy)-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl]-5-methoxyphenyl}ethylamine (584 mg) was used according to an analogous synthetic method to Example 325 described below to provide the title compound (426 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([O:15][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 95 %

Procedure:
To a solution of (3S,4S)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate in dichloromethane (0.13 M) was added triethylamine (1.5 equiv.) followed by methanesulfonyl chloride (1.3 equiv.). The reaction was allowed to stir at room temperature for 15 h. The solution was then quenched with saturated NaHCO3, extracted with dichloromethane, dried with sodium sulfate, and concentrated to give the crude product in >95% yield. LCMS (m/z): 428.9/328.9 (MH+), LC Rt=3.81 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][NH2:25])[CH3:2].[CH3:27][S:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH:41]=O)=[CH:34][CH:33]=1)(=[O:30])=[O:29]>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[C:9]2[CH2:23][CH2:24][NH:25][CH2:41][CH2:40][CH2:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:33][CH:34]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Reactant: CS(=O)(=O)Nc1ccc(CCCC=O)cc1
Product: CCOC(=O)Cc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3ccc(NS(C)(=O)=O)cc3)c2c1
Yield: 29 %

Procedure:
The reductive amination reaction of [3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-acetic acid ethyl ester and 4-[4-(methanesulfonamido)phenyl]butyraldehyde was accomplished according to the procedure of Example 14.1, Step 14.1B to give the titled compound in 29% yield as a stiff foam; homogenous by TLC in 92.5:7.5 CH2Cl2 --MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=576 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][OH:15])[C:7]2=[O:12].[OH-].[K+].I[CH3:19].O>CS(C)=O.C(OCC)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:13][CH2:14][O:15][CH3:19])[C:7]2=[O:12]
Reactant: CI
Reactant: O=C1c2cccc(Br)c2CCN1CCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: COCCN1CCc2c(Br)cccc2C1=O
Reaction time: 0.5 h

Procedure:
0.39 g of 5-bromo-2-(2-hydroxyethyl)-3,4-dihydroisoquinolin-1(2H)-one is dissolved under an inert atmosphere in 3 cm3 of dimethylsulfoxide at a temperature close to 20° C. 105 mg of finely ground potassium hydroxide are added. The reaction mixture is stirred for 30 min at a temperature close to 20° C., then 0.108 cm3 of iodomethane is introduced. The stirring is continued for 20 h at a temperature close to 20° C. 30 cm3 of water and 30 cm3 of ethyl ether are added. After decanting, the organic phase is washed with 30 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator under reduced pressure (5 kPa). 170 mg of 5-bromo-2-(2-methoxyethyl)-3,4-dihydroisoquinolin-1(2H)-one are obtained in the form of a yellow oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][N:14]2[CH2:18][C@H:17]([CH:19]([CH3:21])[CH3:20])[N:16]([C:22]3[CH:27]=[CH:26][N:25]4[N:28]=[CH:29][C:30]([C:31]5[CH:36]=[CH:35][C:34]([C:37]6[N:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[N:38]=6)=[CH:33][CH:32]=5)=[C:24]4[N:23]=3)[C:15]2=[O:50])(=O)=O)=CC=1.Cl.[F:52][C@@H:53]1[CH2:57][CH2:56][NH:55][CH2:54]1.C(N(C(C)C)C(C)C)C.[OH-].[Na+]>CN(C=O)C>[F:52][C@@H:53]1[CH2:57][CH2:56][N:55]([CH2:12][CH2:13][N:14]2[CH2:18][C@H:17]([CH:19]([CH3:20])[CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][N:25]4[N:28]=[CH:29][C:30]([C:31]5[CH:32]=[CH:33][C:34]([C:37]6[N:41]=[CH:40][N:39]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:48])[CH3:49])[N:38]=6)=[CH:35][CH:36]=5)=[C:24]4[N:23]=3)[C:15]2=[O:50])[CH2:54]1
Reactant: F[C@@H]1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCN2C[C@H](C(C)C)N(c3ccn4ncc(-c5ccc(-c6ncn(COCC[Si](C)(C)C)n6)cc5)c4n3)C2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1CN(CCN2CC[C@@H](F)C2)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 40.2 %

Procedure:
To a solution of (S)-2-(4-isopropyl-2-oxo-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-1-yl)ethyl 4-methylbenzenesulfonate (0.070 g, 0.098 mmol) in DMF was added (R)-3-fluoropyrrolidine hydrochloride (0.044 g, 0.49 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.13 g, 0.98 mmol) and the reaction stirred for 4 days at ambient temperature. The reaction was poured into 1N NaOH and the aqueous layer extracted into EtOAc. The organics were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was chromatographed using EtOAc to 3% MeOH/dichloromethane as eluent to yield (S)-1-(2-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.025 g, 40%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][Si:26]([CH3:76])([CH3:75])[CH2:27][CH2:28][O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][CH2:39][C:40]2[CH:45]=[C:44]([C:46]3[CH:73]=[CH:72][C:49]4[N:50]([C:53]([C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)([C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)[N:51]=[N:52][C:48]=4[CH:47]=3)[CH:43]=[CH:42][C:41]=2[F:74])[CH2:34][CH2:33]1)=[O:31].[F:77][C:78]1[CH:86]=[CH:85][C:81]([C:82](O)=[O:83])=[CH:80][CH:79]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C>[CH3:25][Si:26]([CH3:76])([CH3:75])[CH2:27][CH2:28][O:29][C:30]([N:32]1[CH2:33][CH2:34][CH:35]([N:38]([C:82](=[O:83])[C:81]2[CH:85]=[CH:86][C:78]([F:77])=[CH:79][CH:80]=2)[CH2:39][C:40]2[CH:45]=[C:44]([C:46]3[CH:73]=[CH:72][C:49]4[N:50]([C:53]([C:54]5[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=5)([C:60]5[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=5)[C:66]5[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=5)[N:51]=[N:52][C:48]=4[CH:47]=3)[CH:43]=[CH:42][C:41]=2[F:74])[CH2:36][CH2:37]1)=[O:31]
Reactant: C[Si](C)(C)CCOC(=O)N1CCC(NCc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOC(=O)N1CCC(N(Cc2cc(-c3ccc4c(c3)nnn4C(c3ccccc3)(c3ccccc3)c3ccccc3)ccc2F)C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU was added to a solution of 4-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzylamino]-piperidine-1-carboxylic acid 2-trimethylsilany-1-ethyl ester, 4-fluorobenzoic acid and diisopropylethylamine and the resulting mixture stirred at ambient temperature overnight. The mixture was diluted with ethyl acetate washed with 1 M sodium carbonate solution. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with diethyl ether/hexane, followed by ethyl acetate/hexane) provided 740 mg of product.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[C:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:7]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:6]2[CH:27]=1)#[N:2].[NH2:28]O.Cl.[OH-].[K+].[CH3:33][CH2:34][OH:35]>>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[C:7]1[N:6]2[CH:27]=[C:3]([C:1]3[N:28]=[C:34]([CH3:33])[O:35][N:2]=3)[N:4]=[C:5]2[N:10]=[C:9]([CH3:11])[C:8]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: NO
Reactant: Cc1nc2nc(C#N)cn2c(-c2ccc(Cl)cc2Cl)c1C(=O)OC(C)(C)C
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(-c2cn3c(-c4ccc(Cl)cc4Cl)c(C(=O)OC(C)(C)C)c(C)nc3n2)no1
Temperature: 70 °C
Yield: 68 %

Procedure:
To a stirred solution of tert-butyl 2-cyano-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-6-carboxylate (50 mg, 0.12 mmol) in EtOH (3 mL) was added NH2OH.HCl (10 mg, 0.12 mmol) and KOH (8.5 mg, 0.12 mmol). After heating to 70° C. for 6 h, the reaction was concentrated under reduced pressure. The resulting residue was suspended in H2O and filtered to collect the desired product as a yellow solid (53 mg). This product was dissolved in PhCH3 (3 mL) and DMA-DMA (0.2 mL) was added. The reaction was heated to 90° C. for 2 h and was concentrated and purified by silica gel chromatography to give tert-butyl 5-(2,4-dichlorophenyl)-7-methyl-2-(5-methyl-1,2,4-oxadiazol-3-yl)imidazo[1,2-a]pyrimidine-6-carboxylate (46 mg, 68% for three steps) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br>>[O:17]1[CH2:16][CH:15]1[CH2:13][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=c1[nH]ncc2ccc(O)cc12
Reactant: BrCC1CO1
Product: O=c1[nH]ncc2ccc(OCC3CO3)cc12

Procedure:
7-Hydroxy-1(2H)-phthalazinone was reacted with epibromohydrin in a similar manner to that described in Example 1(iii) to give 7-(2,3-epoxypropoxy)-1(2H)-phthalazinone, which after recrystallisation from ethyl acetate had m.p. 164°-166°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([C:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)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(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([N:29]2[CH2:28][CH:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:31][CH2:30]2)=[O:16])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a dried flask, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropyl-cyclopentanecarboxylic acid (200 mg, 0.7 mmol) and 4-phenyl-1,2,3,6-tetrahydropyridine (160 mg, 0.81 mmol) were suspended in methylene chloride (4 mL) under N2. Triethylamine (0.22 g, 2.2 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.36 g, 0.81 mmol). The reaction was stirred overnight at room temperature and quenched by addition of saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (gradient: 0-45% B over 15 min. Bottle A=hexanes, bottle B=EtOAc) to give 234 mg (80%) of desired product. MS calculated for C25H36N2O3: (M+H) 413; found 413.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][N:13]([CH3:15])[C:11](=[O:12])[CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: CN(C)C(=O)CCl
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C(=O)Cn1cc([N+](=O)[O-])cn1

Procedure:
A suspension of 4-nitro-1H-pyrazole (0.4 g, 3.54 mmol), 2-chloro-N,N-dimethylacetamide (0.546 ml, 5.31 mmol) and potassium carbonate (0.733 g, 5.31 mmol) in 18 ml acetone was refluxed for 6 hours. The cooled suspension was filtered with acetone washes and the concentrated residue was flash chromatographed (50 mm, 3% methanol in CH2Cl2) to afford the title compound.