Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[CH:25]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([C:32](=[O:33])[CH2:31][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)CCc1cccnc1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc2c1c(=O)n(C1CCCN(C(=O)CCc3cccnc3)C1)c1cccc(Cl)c21
Yield: 46.2 %

Procedure:
Add 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol), 3-pyridine propionic acid (20 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.13 mmol), 1-hydroxy-7-azabenzotriazole (18 mg, 0.13 mmol), 4-dimethylamino-pyridine (1 mg, 0.01 mmol), and dimethylformamide (3 mL) to a dry roundbottom flask. Stir the reaction under nitrogen, and add triethylamine (30 μL, 0.22 mmol) dropwise. Stir the solution under nitrogen at room temperature overnight. Concentrate the solution and dissolve in 20% isopropanol/chloroform; wash with 1.0N HCl, saturated aqueous sodium bicarbonate solution, and brine; dry over magnesium sulfate; and concentrate. Purify by flash chromatography on silica gel (eluting with 0.5–3.5% methanol/chloroform) to give 22.9 mg of the title compound as a white solid, 45% yield. 1H NMR: consistent with structure. MS (ion spray) 451 (M+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:43][Si](CC)(CC)CC)[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH2:29][C:30]3[N:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[O:32][N:31]=3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:11][C:10]=1[NH:51][S:52]([CH3:55])(=[O:54])=[O:53])C1C=CC=CC=1.C[Si](I)(C)C.S(=O)(=O)(O)[O-].[Na+]>C(#N)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:43])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([S:26]([CH2:29][C:30]3[N:34]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[O:32][N:31]=3)(=[O:27])=[O:28])=[CH:24][CH:25]=2)=[CH:11][C:10]=1[NH:51][S:52]([CH3:55])(=[O:53])=[O:54]
Reactant: CC[Si](CC)(CC)O[C@@H](CNCCc1ccc(S(=O)(=O)Cc2noc(-c3ccc(OC)cc3)n2)cc1)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: C[Si](C)(C)I
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2nc(CS(=O)(=O)c3ccc(CCNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)cc3)no2)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of the O-protected amino alcohol of Example 26 (0.292 g, 0.362 mmol) in acetonitrile (3 mL) was added 5 equivalents of trimethylsilyl iodide (0.26 mL, 0.1.81 mmol). The reaction mixture was heated to 50° C. for 16 h. TLC shows the absence of starting material, so 1 mL of dilute aqueous sodium bisulfate (Na2S2O5) solution was added to the room temperature reaction mixture and it was stirred vigorously for 15 minutes. The reaction mixture was evaporated in vacuo to dryness and the residue was flash chromatographed (silica gel; dichloromethane/chloroform/methanol: 12/3/2) to afford 0.140 g of the title compound as a light yellow crystalline solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:13])=[C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[N:10]([CH3:28])[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34][O:35][CH2:36]Cl.C(OCC)(=O)C>O1CCCC1.[Cl-].[NH4+]>[C:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([I:13])=[C:11]([N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[N:10]([CH3:28])[N:9]=1)(=[O:3])[CH3:2]
Reactant: COCCOCCl
Reactant: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCN(c1c(I)c(OCCOC(C)=O)nn1C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2-{[5-({[4-(tert-butyl)phenyl]sulfonyl}amino)-4-iodo-1-methyl-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 7) (8 g) in solution in tetrahydrofuran (200 ml) was added sodium hydride (860 mg of a 60% dispersion in oil), at room temperature. The reaction was stirred at room temperature for 0.5 hours and 2-methoxyethoxymethyl chloride (2.7 ml) was added dropwise. The reaction was stirred for an other 0.5 hours and was then diluted with a saturated aqueous solution of ammonium chloride (50 ml) and reduced under reduced pressure. Ethyl acetate (100 ml) was added and the organic layer separated. The organics were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was to purified by chromatography on a suction column packed with silica eluted with ethyl acetate hexane (1:1) to yield the desired product as pale yellow oil (9.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](=O)[C:10]3[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:20]=1.C([OH:23])C.[BH4-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[CH2:11][CH:10]([OH:23])[CH:14]=[C:15]([S:18][CH3:19])[C:16]=3[CH:17]=[CH:9][S:8][C:7]=2[CH:20]=1
Reactant: CCO
Reactant: COc1ccc2c(c1)Sc1ccc(SC)cc1C(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)SC=CC1=C2CC(O)C=C1SC
Reaction time: 1.5 h

Procedure:
17.8 G. of 3-methoxy-8-(methylthio)-dibenzo[b,f]thiepin-10(11H)-one is suspended in 150 ml. of ethanol and reacted with 38 g. of sodium borohydride. The reaction mixture is stirred for 90 minutes, and subsequently treated with water and extracted with ether. The organic phase is washed with water, dried over magnesium sulfate and evaporated, whereby there is obtained 10,11-dihydro-3-methoxy-8-(methylthio)-dibenzo[d,f]thiepin-10-ol having a melting point of 122°-124°.
Reaction SMILES: FC1C(F)=CC([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](CCS(C)(=O)=O)[C:16](=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[F:40][C:41]1[CH:46]=[C:45]([F:47])[C:44]([O:48][CH3:49])=[CH:43][C:42]=1B(O)O.[F-].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:40][C:41]1[CH:46]=[C:45]([F:47])[C:44]([O:48][CH3:49])=[CH:43][C:42]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16]
Reactant: COc1cc(B(O)O)c(F)cc1F
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1cnccc1-c1cc(OC)c(F)cc1F
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 69.7 %

Procedure:
To a solution of (4-iodo-pyridin-3-yl)-methyl-amine (100 mg, 0.43 mmol, example 98, intermediate b) in THF (3 mL) and water (1.5 mL) were added 2,4-difluoro-5-methoxyphenyl-boronic acid (231 mg, 0.85 mmol) and potassium fluoride (50 mg, 0.85 mmol) and the reaction mixture was purged with argon for 15 min. Then Pd2(dba)3 (78 mg, 0.09 mmol) and triphenyl phosphine (22 mg, 0.09 mmol) were added to the reaction mixture and the reaction mixture was stirred at 120° C. for 45 min in a microwave oven. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography eluting with a gradient of n-hexane:EtOAc (80:20 to 50:50) to give the desired compound as a yellow liquid (75 mg, 70%). MS (ESI): m/z=251.4 [M+H]+.
Reaction SMILES: [O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[O:1]([CH:8]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)=[CH:15][CH:14]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Oc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(Oc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4.4 g of methyl α-(phenoxy)-α-[p-(p-chlorophenoxy)phenyl]acetate, 27 g of 20% KOH, and 20 ml of methanol is refluxed overnight. After cooling to room temperature, the methanol is removed at reduced pressure. The residue is dissolved in 100 ml of H2O and extracted with 100 ml of ether. The aqueous layer is acidified with concentrated HCl and a yellow oil separates. The mixture is extracted with two 50 ml portions of chloroform. The combined extracts are washed with 50 ml of water and saturated brine and dried over MgSO4. Evaporation of the solvent at reduced pressure affords the product as a white solid, mp 114°-115.5° C, after trituration with petroleum ether.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C@H:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:37]1(B(O)O)[CH2:41][CH2:40][CH2:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([O:25][C@@H:19]([C:9]1[C:8]([CH3:30])=[CH:7][C:5]2[N:6]=[C:2]([C:37]3[CH2:41][CH2:40][CH2:39][CH:38]=3)[S:3][C:4]=2[C:10]=1[O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)C1=CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C3=CCCC3)sc2c1OS(=O)(=O)C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of 32 (100 mg, 0.19 mmol) in toluene (1 mL), ethanol (0.5 mL), water (0.5 mL) was added potassium carbonate (77 mg, 0.56 mmol), cyclopentenylboronic acid (25 mg, 0.22 mmol), and Pd(PPh3)4 (11 mg, 0.0094 mmol). The reaction mixture was stirred at 90° C. for 2 h. The reaction was cooled to rt and diluted with water and EtOAc. The layers were separated, dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 96 mg of 77. 1H-NMR: 400 MHz, (CDCl3) δ: 7.82 (s, 1H), 6.72 (m, 1H), 5.60 (s, 1H), 4.17 (m, 1H), 4.11 (m, 1H), 2.92 (m, 2H), 2.63 (m, 2H), 2.53 (s, 3H), 2.10 (m, 2H), 1.17 (s, 9H), 1.13 (t, J=7 Hz, 3H).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[C:2]#[C:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:32])[CH2:22][NH:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:17][CH:16]=1>C(O)C>[C:28]([O:27][C:25]([NH:24][N:23]([C:2](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:1]([O:10][CH2:11][CH3:12])=[O:9])[CH2:22][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=1)=[O:32])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: COc1ccc(C(=O)CNNC(=O)OC(C)(C)C)cc1
Solvent: CCO
Product: CCOC(=O)C=C(C(=O)OCC)N(CC(=O)c1ccc(OC)cc1)NC(=O)OC(C)(C)C

Procedure:
Diethyl but-2-ynedioate (1.6 equivalents) was added to a stirred solution of crude tert-butyl 2-[2-(4-methoxyphenyl)-2-oxoethyl]hydrazinecarboxylate (2 g) in ethanol at 0° C. The reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated in vacuo to give crude diethyl 2-{2-(tert-butoxycarbonyl)-1-[2-(4-methoxyphenyl)-2-oxoethyl]hydrazinyl}but-2-enedioate (1.3 g). The material was carried through without purification. ESI-MI m/z [M+H]+ 451.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[Cl:8].CCN(C(C)C)C(C)C.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1>CC(O)C>[CH2:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][NH:19][C:6]2[C:7]([Cl:8])=[C:2]([Cl:1])[N:3]=[N:4][CH:5]=2)[CH2:22][CH2:23]1)=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(CNc2cnnc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3,4,5-trichloropyridazine (2.22 g, 12.08 mmol) and DIPEA (4.21 mL, 24.16 mmol) in IPA (25 mL) was added benzyl-4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1, 3.00 g, 12.08 mmol). The resulting reaction solution was stirred at rt for 5 h, then concentrated in vacuo. The residue was dissolved in CH2Cl2 (200 mL), washed with water (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (1–7 (10% NH4OH in MeOH)/99–93 CH2Cl2) to give 4-[(5,6-dichloro-pyridazin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:16].[CH3:18][CH:19](O)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH-].[Na+]>C1COCC1>[CH:13]1([S:10]([C:8]2[CH:7]=[CH:6][C:5]([O:16][CH:19]([CH3:20])[CH3:18])=[C:4]([CH:9]=2)[C:3]([OH:2])=[O:17])(=[O:12])=[O:11])[CH2:15][CH2:14]1
Reactant: CC(C)O
Reactant: COC(=O)c1cc(S(=O)(=O)C2CC2)ccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(=O)(=O)C2CC2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.6 mmol 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester, 3.7 mmol 2-propanol and 0.9 mmol diphenyl-2-pyridylphosphine in 8 ml THF was added 0.9 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 3 h. 4 mmol 5 M aq NaOH solution was then added, and the mixture heated at 60° C. for 1 h. The mixture was then concentrated in vacuo. The residue was resuspended in ethyl acetate and washed twice with 1 M aq NaOH solution. The combined aqueous phases were then acidified to pH 1 by addition of 25% aq HCl and extracted three times with ethyl acetate. The combined organic extracts were then dried with Na2SO4, and concentrated in vacuo to afford the title compound. MS (m/e): 282.9 ([M−H]−, 100%)
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([OH:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][CH2:17][OH:18].[O-][Si]([O-])=O.[Mg+2]>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[NH2:1][C:2]1[C:3]([CH2:16][CH2:17][OH:18])=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:15]
Reactant: Nc1c(CCO)cccc1C(O)c1ccccc1
Agent: [Mn+4]
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: c1ccccc1
Product: Nc1c(CCO)cccc1C(=O)c1ccccc1

Procedure:
A suspension of 7.7 g of 2-amino-3-[hydroxy(phenyl)methyl]benzene ethanol in 250 ml of benzene was treated with 14 g of activated Manganese dioxide and refluxed for 5 hours using a Dean-Stark trap. The hot mixture obtained was then filtered through Celite and the filtrate stripped to yield a dark oil. The oily material was placed on a florisil column and eluted with a benzene-acetone mixture. The isolated product was recrystallized from ethanol-pet. ether (30:60) to give the titled compound as yellow needles, m.p. 107°-108° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([CH2:10][CH3:11])[CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:19](=[O:21])[CH3:20])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: CCc1cc(Br)ccc1CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCc1cc(Br)ccc1CNC(C)=O
Reaction time: 1 h

Procedure:
To 4-bromo-2-ethyl-benzylamine (700 mg, 3.3 mmol) and triethylamine (600 μL, 4.3 mmol) in dichloromethane (5 mL) at room temperature was added acetyl chloride (310 μL, 4.5 mmol). The solution was stirred for 1 h, diluted in water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to an off-white solid (820 mg, 97%). 1H NMR (300 MHz, CDCl3): δ 1.20 (t, J=7.54 Hz, 3 H) 2.00 (s, 3 H) 2.62 (q, J=7.54 Hz, 2 H) 4.38 (d, J=5.46 Hz, 2 H) 5.59 (s, 1 H) 7.09 (d, J=8.10 Hz, 1 H) 7.26–7.31 (m, 1 H) 7.34 (d, J=1.88 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]3=[N:14][C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[CH:16][N:10]3[C:9]2=[O:26])=[CH:4][CH:3]=1>[Ni].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3=[N:14][C:15]([CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=4)=[CH:16][N:10]3[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1cccc(OCc2cn3c(=O)n(-c4ccc(F)cc4)ccc3n2)c1
Agent: [Ni]
Solvent: CO
Product: Cc1cccc(OCc2cn3c(n2)CCN(c2ccc(F)cc2)C3=O)c1
Reaction time: 72 h
Yield: 48.4 %

Procedure:
Activated Raney nickel (a portion of spatula) was added to a suspension of 6-(4-fluoro-phenyl)-2-m-tolyloxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (70 mg, 0.2 mmol) in MeOH (20 mL). The mixture was hydrogenated at RT under H2 atmosphere for 3 days. The mixture was filtered through a pad of diatomaceous earth and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 50/50 to 75/25). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-(4-fluoro-phenyl)-2-m-tolyloxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (34 mg, 48% yield). 1H NMR (500 MHz, CDCl3) δ ppm 2.33 (s, 3H), 3.29 (t, J=6.6 Hz, 2H), 4.00 (t, J=6.6 Hz, 2H), 5.01 (s, 2H), 6.76-6.88 (m, 3H), 7.09-7.21 (m, 3H), 7.28-7.36 (m, 2H), 7.56 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[N:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[CH2:12][C@H:11]([CH:24]([CH3:26])[CH3:25])[N:10]1[CH2:27][C:28]([O:30]C(C)(C)C)=[O:29]>C(Cl)(Cl)Cl>[O:8]=[C:9]1[N:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[CH2:12][C@H:11]([CH:24]([CH3:26])[CH3:25])[N:10]1[CH2:27][C:28]([OH:30])=[O:29]
Reactant: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H]1CN(c2ccc(C(F)(F)F)nc2)C(=O)N1CC(=O)O
Temperature: 25 °C
Reaction time: 64 h
Yield: 60.6 %

Procedure:
Trifluoroacetic acid (30 mL) was added to a solution of tert-butyl {(55)-2-oxo-5-(propan-2-yl)-3-[6-(trifluoromethyl)pyridin-3-yl]imidazolidin-1-yl}acetate (4.44 g) in chloroform (20 mL), and the mixture was stirred at room temperature for 64 hr. Additional trifluoroacetic acid (9 mL) was added thereto, the resulting mixture was further stirred for 1 hr, and the reaction mixture was then concentrated under reduced pressure. A portion (6.5 g) of the residue was dissolved in diethyl ether, followed by extraction with 6M aqueous sodium hydroxide solution and water. The water layer was washed with diethyl ether and then made acidic using 1M hydrochloric acid. After extraction with chloroform, the organic layer was separated out by phase-separation cartridge, and the solvent was distilled off under reduced pressure to afford the title compound (2.3 g).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41]CC3C=CC=CC=3)=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2]>CO.O1CCCC1.[C].[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
3-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-benzyloxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (2.75 g) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (9 mL). To the solution was added 10% palladium-carbon powder (550 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (2.4 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[S:15][C:14]([C:16]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:18])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1
Product: O=C(NCc1ccccc1)c1cc([N+](=O)[O-])c(Sc2nc3ccccc3s2)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-(1,3-benzothiazol-2-ylsulfanyl)-4-nitro-thiophene-2-carboxylic acid (34 mg, 0.1 mmol) and benzylamine (13.0 mg, 0.12 mmol). The title compound was obtained as a solid (10 mg, 23% yield). MS m/z: 428.08 [M+H]+.
Reaction SMILES: ClC(OCC)=O.CCN(CC)CC.[CH2:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[CH2:26][C@H:25]2[C:27]([OH:29])=O)=[CH:20][CH:19]=1)[CH:15]=[CH2:16].[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[CH2:14]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[CH2:26][C@H:25]2[C:27]([N:30]=[N+:31]=[N-:32])=[O:29])=[CH:20][CH:19]=1)[CH:15]=[CH2:16]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C=CCOc1ccc([C@@H]2C[C@H]2C(=O)N=[N+]=[N-])cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
Ethyl chloroformate (2.72 mL, 28.52 mmol) was added to a solution of Et3N (4.24 mL, 30.42 mmol) and (trans)-2-[4-(allyloxy)phenyl]cyclopropanecarboxylic acid (Intermediate G, 4.15 g, 19.01 mmol) in dry acetone (50 mL) cooled at −10° C., forming a white solid. After 1 h, a solution of NaN3 (2.23 g, 34.23 mmol) in water (10 mL) was added to the reaction and stirred for additional 30 min. The solvent was removed by rotatory evaporation and the residue was dissolved in CH2Cl2 (20 mL); the organic layer was consecutively washed with a mixture of water (200 mL) and HCl (10% aqueous solution, 10 mL) and a mixture of water (200 mL) and NaOH (10% aqueous solution, 10 mL). The organic layer was dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (10% EtOAc/Hexanes), affording 4.10 g of (trans)-2-[4-(allyloxy)phenyl]cyclopropanecarbonyl azide [Rf=0.75 (20% EtOAc/Hexanes), white solid, 89% yield].