Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C:42](=O)[CH2:41][CH2:40]4)[CH:37]=[CH:36][C:35]=2[CH:34]=1.O>O1CCCC1>[F:1][C:2]([F:3])=[C:42]1[CH2:41][CH2:40][C@H:39]2[C@H:38]3[C@H:47]([CH2:46][CH2:45][C@:43]12[CH3:44])[C:48]1[CH:35]=[CH:34][C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:50][C:49]=1[CH:36]=[CH:37]3
Reactant: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=O
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H]3c4ccc(OC5CCCCO5)cc4C=C[C@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A solution of 715 mg of difluoromethyldiphenylphosphine oxide in 36 ml of tetrahydrofuran is slowly mixed with 1.42 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 1 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),6-tetraen-17-one in 10 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2.5 hours. For working-up, it is added to water, extracted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. 1.1 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10), 6-tetraene is obtained as colorless crystals.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]/[CH:12]=[CH:13]/[C:14](=[O:16])[CH3:15].C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@@H]23)C=CC=CC=1.CSC.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]/[CH:12]=[CH:13]/[C@H:14]([OH:16])[CH3:15]
Reactant: CC(=O)/C=C/Sc1ccc2ccccc2c1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CSC
Product: C[C@@H](O)/C=C/Sc1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
(E)-4-(2-naphthylthio)-3-buten-2-one (228 mg, 1.0 mmol), (S)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c][1,3,2] oxazaborol (28 mg, 0.1 mmol) and MS4A (500 mg) were dried by a vacuum pump, followed by substituting with an argon gas. Dry toluene (5 ml) and dimethylsulfide (0.22 ml, 3.0 mmol) were added thereto and, after ice cooling, a solution of borane dimethylsulfide complex in toluene (1.07M, 0.65 ml, 0.7 mmol) was dropwise added. After stirring for two hours, an aqueous saturated ammonium chloride solution was added, followed by filtering through a cotton plug.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[OH:25].[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29].N1C=CC=CC=1>ClCCl>[F:26][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[C:14]1[C:23](=[O:24])[NH:22][C:17]2=[N:18][CH:19]=[CH:20][N:21]=[C:16]2[C:15]=1[O:25][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)C(=O)Cl
Reactant: Cn1nc(C(F)(F)F)c(-c2c(O)c3nccnc3[nH]c2=O)c1OC(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)Oc1c(-c2c(C(F)(F)F)nn(C)c2OC(F)F)c(=O)[nH]c2nccnc12

Procedure:
7-(5-Difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-8-hydroxy-5H-pyrido[2,3-b]pyrazin-6-one (Example 2.6) (0.34 g), isobutyryl chloride (0.11 ml), and pyridine (0.10 ml) were stirred in dichloromethane (10 ml) at ambient temperature for 2 hours. The reaction mixture was washed successively with aqueous hydrochloric acid (1M), aqueous sodium hydrogen carbonate (saturated) and water. The organic fraction was dried over sodium sulfate and concentrated to give Compound No. B23 of Table B (0.335 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[CH:4]=[N:3]1)[C:11](=[O:15])[C:10]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2([NH:26]S(C(C)(C)C)=O)[CH2:25][CH2:24][CH2:23]2)=[N:20][CH:21]=1)=[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:8]3.[ClH:39].O1CCOCC1>CO>[ClH:39].[NH2:26][C:22]1([C:19]2[N:20]=[CH:21][C:16]([C:10]3[C:11](=[O:15])[C:12]4[C:7]([O:8][C:9]=3[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:6]3[N:2]([CH3:1])[N:3]=[CH:4][C:5]3=[CH:14][CH:13]=4)=[CH:17][CH:18]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: Cn1ncc2ccc3c(=O)c(-c4ccc(C5(NS(=O)C(C)(C)C)CCC5)nc4)c(-c4ccccc4)oc3c21
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc2ccc3c(=O)c(-c4ccc(C5(N)CCC5)nc4)c(-c4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {1-[5-(1-methyl-6-oxo-8-phenyl-1,6-dihydro-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-7-yl)-pyridin-2-yl]-cyclobutyl}-amide (34 mg, 0.0645 mmol) in MeOH (6 mL) was added a solution of HCl in dioxane (4 M, 0.32 mL, 1.28 mmol). The reaction mixture was stirred at RT for 30 min before evaporating to dryness. The resulting residue was dissolved in a mixture of MeOH (1 mL), water (4 mL) and then chromatographed on a 5 g C18 cartridge {gradient 20 to 60% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound (24.3 mg, 82%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.78 (br s, 3H), 8.41 (dd, J=2.2 and 0.8 Hz, 1H), 8.29 (s, 1H), 7.89-7.81 (m, 3H), 7.75 (d, J=8.3 Hz, 1H), 7.59-7.57 (m, 2H), 7.51-7.41 (m, 3H), 4.41 (s, 3H), 2.60-2.55 (m, 4H), 2.26-2.15 (m, 1H), 2.05-1.94 (m, 1H). LCMS (Method E): =3.22 min, [M+H]+=423.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([CH2:39][C:40]([OH:42])=O)[N:31]=1.Cl.Cl.[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1.CCN(C(C)C)C(C)C>>[Cl:45][C:46]1[C:51]([O:52][CH2:53][CH3:54])=[CH:50][C:49]([N:55]2[CH2:60][CH2:59][N:58]([C:40](=[O:42])[CH2:39][N:32]3[C:33]4=[N:34][CH:35]=[CH:36][CH:37]=[C:38]4[C:30]([C:26]4[NH:25][CH:29]=[CH:28][N:27]=4)=[N:31]3)[CH2:57][CH2:56]2)=[C:48]([F:61])[CH:47]=1
Reactant: CCOc1cc(N2CCNCC2)c(F)cc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Protocol A—the HBTU coupling procedure) A solution of [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]acetic acid (0.30 M, 0.40 mL, 0.12 mmol) was transferred to a vial. 1-(4-Chloro-5-ethoxy-2-fluorophenyl)piperazine dihydrochloride (48 mg, 0.14 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (55 mg, 0.14 mmol) and i-Pr2NEt (0.30 mL) were added to the vial and the mixture was stirred at ambient temperature. After 30 minutes, LC/MS analysis indicated formation of desired product and complete consumption of the carboxylic acid starting material. The mixture was diluted with EtOAc, washed with water (1×) and brine (1×), dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography (1% to 8% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-5-ethoxy-2-fluorophenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ □8.79 (dd, 0.6; H, J=8.4, 1.6 Hz), 8.66 (dd, 0.4; H, J=8.0, 1.6 Hz), 8.57-8.55 (m, 1H), 7.29-7.26 (m, 1H), 7.22-7.16 (m, 1H), 7.09-7.05 (m, 2H), 6.50-6.45 (m, 2H), 5.45 (s, 0.6H), 5.43 (s, 1.4H), 4.07-4.01 (m, 2H), 3.81-3.69 (m, 4H), 3.17-3.13 (m, 1.6H), 3.08-3.02 (m, 2.4H), 1.50-1.42 (m, 3H); LC/MS m/z (M+H)+ 484.4.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]=[C:18]([NH2:20])[NH2:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[CH2:26](N)[CH2:27]N>O.C(O)CCCC>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]1[NH:20][CH2:26][CH2:27][N:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCN
Reactant: NC(N)=Nc1nc2ccccc2n1Cc1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCO
Product: c1ccc(Cn2c(NC3=NCCN3)nc3ccccc32)cc1

Procedure:
2-(1-Benzylbenzimidazolyl)guanidine (3.65g, 0.0143 mol) was dissolved in water (600 ml) containing 5N hydrochloric acid (5.5 ml). The solution was cooled to 0° to 5°C and treated portionwise with sodium nitrite (1.0g) each hour for 3 hours. After a further 4 hours the reaction mixture was filtered and the microcrystals so obtained were heated under reflux in amyl alcohol (15 ml) with ethylenediamine (3 ml) for 6 hours. The cooled reaction mixture was evaporated to dryness. The resulting semi-solid was crystallised from amyl alcohol was then recrystallised from ethanol to yield 2-(1-benzylbenzimidazolyl)amino-2-imidazoline (1.0g) as colourless microcrystals m.p. 165°-166°C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12](Cl)([O:14]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:12]([Cl:11])=[O:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc2c(c1)CCNC2
Solvent: ClC(Cl)Cl
Product: O=C(Cl)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Commercially available 1,2,3,4-tetrahydroisoquinoline (50 mg) was dissolved in chloroform (10 ml), and triphosgene (111 mg) was added to the solution. The mixture was stirred at room temperature for 2 hr. The solvent was removed by distillation to give 1,2,3,4-tetrahydro-2-isoquinolinecarbonyl chloride. 1,2,3,4-Tetrahydro-2-isoquinolinecarbonyl isothiocyanate was prepared using this compound as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 1,2,3,4-tetrahydro-2-isoquinolinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 94%).
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].[NH:30]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31]1.C1CCN2C(=NCCC2)CC1>CS(C)=O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[C:20]([CH2:21][CH2:22][CH3:23])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:18][N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][N:30]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31]1
Reactant: O=C(O)C1CCNC1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCC(C(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) and pyrrolidine-3-carboxylic acid (22.81 mg, 0.198 mmol) in DMSO (2 mL) was added DBU (0.030 mL, 0.198 mmol). The reaction mixture was heated at 80° C. for 2 hours. The crude material was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: none; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5, acetonitrile:water with 0.05% TFA; Gradient: 25-100% B over 10 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the product were combined and dried via centrifugal evaporation. The yield of 1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl) pyrrolidine-3-carboxylic acid was 16.3 mg, and its purity was 96%. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.21 (2H, d, J=8.35 Hz), 7.81 (2H, dd, J=8.02, 1.65 Hz), 7.69 (2H, d, J=8.35 Hz), 7.54-7.66 (3H, m), 5.10-5.22 (1H, m), 3.39-3.54 (4H, m), 3.24-3.27 (3H, m), 3.00-3.10 (2H, m), 2.23-2.57 (2H, m), 1.70-1.83 (2H, m), 1.05 (3H, t, J=7.36 Hz). MS (m+1)=489. HPLC Peak RT=2.08 minutes. (Analytical Method C). Purity=96%.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:27]([N:23]1[CH:22]=[C:21]2[C:25]([CH:26]=[C:18]([C:10]3[CH:9]=[C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:2][CH2:3]4)[N:16]4[C:11]=3[C:12]([NH2:17])=[N:13][CH:14]=[N:15]4)[CH:19]=[CH:20]2)=[N:24]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(C3CCCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a solution of 7-azepan-4-yl-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.20 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (17 pt, 0.22 mmol) and N,N-diisopropylethylamine (136 μL, 0.78 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 21 mg (21%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.90 (s, 1 H), 7.78 (dd, 1 H), 7.58 (s, 1 H), 7.28-7.38 (m, 5 H), 7.14 (dd, 1 H), 6.61 (s, 1 H), 5.64 (s, 2 H), 3.19-3.56 (m, 4 H), 2.90 (s, 3 H), 1.66-2.20 (m, 7 H); ES-MS m/z 516.30 [M+H]+, HPLC RT (min) 3.07.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[C:16]([F:17])=[C:15]([O:18][CH:19](F)[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([C:12]2[C:16]([F:17])=[C:15]([O:18][CH2:19][F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2Cl)c(F)c1OC(F)F
Product: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2Cl)c(F)c1OCF

Procedure:
5.8 g (16 mmol) of 2,4-dichloro-5-(5-difluoromethoxy-4-fluoro-1-methyl-1H-pyrazol-3-yl)benzoic acid and 10.4 g (82 mmol) of oxalyl chloride were reacted in the manner described for Precursor 1.1. Yield: 5.2 g.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:21][CH3:22])[O:13][CH2:12]2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.I[CH2:30][CH2:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:30]([N:10]([CH:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:21][CH3:22])[O:13][CH2:12]1)[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]2[C:1]1=[O:28])[CH2:31][CH3:32]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCCCN1C(=O)c2ccccc2C1=O)C1COc2cccc(OC)c2C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
1.5 mmol of the compound prepared in Example 1 is dissolved in 10 ml of dimethylformamide in the presence of 4.4 mmol of 1-iodopropane and 4.4 mmol of potassium carbonate. After 24 hours' stirring at 60° C., the solvent is evaporated off and the crude reaction mixture is taken up with 10 ml of water and extracted with dichloromethane. The organic phase is dried and evaporated and the expected product is obtained after purification by chromatography on a silica column (elution solvent: ether/petroleum ether, 1:99).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[O:32]1[C:40]2[CH:39]=[CH:38][N:37]=[C:36]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[C:35]=2[CH:34]=[CH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:44]4[CH2:45][CH2:46][N:41]([C:36]5[C:35]6[CH:34]=[CH:33][O:32][C:40]=6[CH:39]=[CH:38][N:37]=5)[CH2:42][CH2:43]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: c1cc2occc2c(N2CCNCC2)n1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2nccc3occc23)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-furo[3,2-c]pyridinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=633.03 (M+H+); retention time=0.63 minutes.
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[CH3:8][N:9]([CH3:13])[C:10]([NH2:12])=[O:11]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:12][C:10]([N:9]([CH3:13])[CH3:8])=[O:11])=[O:4]
Reactant: CC(C)(Br)C(=O)Br
Reactant: CN(C)C(N)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)NC(=O)C(C)(C)Br
Reaction time: 4 h

Procedure:
2-Bromo-2-methylpropionyl bromide (8.9 g) in dichloromethane (20 ml) was added dropwise at 0° to a stirred suspension of 1,1-dimethylurea (3.4 g) in dichloromethane (25 ml) and triethylamine (16 ml). The mixture was stirred for 4 hr. at 22° and the solvent was evaporated. The residue was stirred with saturated sodium hydrogen carbonate solution (40 ml) and extracted with ethyl acetate (3×20 ml). The ethyl acetate solution was dried and evaporated. The residue was stirred with light petroleum (b.p. 40°-60°, 50 ml) and the remaining solid was filtered off and suspended in sodium hydrogen carbonate solution and extracted into ethyl acetate (2×20 ml). The ethyl acetate solution was dried and evaporated, leaving the urea as a pale brown solid, 1.4 g, m.p. 98°-100°, max (Nujol) 3400, 3370 (NH), 1742, 1685 cm-1 (--CONH.CON--), τ (DMSO d6) 8.06 (--C(Me)2), 7.01 (-N(Me)2), 1.6 (--CONHCO--).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:36]3[N:35]=[C:30]([NH:31][C:32](=[O:34])[NH2:33])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:46]1([N:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:53](Cl)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:12][C@@H:11]([N:23]2[C:36]3[N:35]=[C:30]([NH:31][C:32](=[O:34])[NH2:33])[N:29]=[C:27]([O:28][C:53](=[O:54])[N:52]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(N)=O)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(N)=O)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-carbamoyldeoxyguanosine (1.23 g, 2.29 mmol) was azeotroped with anhydrous pyridine three times and then dissolved in anhydrous pyridine (23 mL). To the resulting solution, diisopropylethylamine (797 μL, 4.58 mmol) and then diphenylcarbamoyl chloride (689 mg, 2.98 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. Then, the reaction was terminated by adding sodium bicarbonate water (5 ml) thereto. The reaction solution was extracted with ethyl acetate (180 mL)/sodium bicarbonate water (150 mL) once and then with ethyl acetate (180 mL)/brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C200) with ethyl acetate/50% to 60% hexane to give 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-carbamoyl-6-O-diphenylcarbamoyldeoxyguanosine (1.53 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([CH2:21]OS(C)(=O)=O)[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH2:21][C:12]1[C:13](=[O:20])[N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[N:15]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:11]=1)[CH3:29]
Reactant: CNC
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Product: COc1ccc(-c2cc(CN(C)C)c(=O)n(CC(C)C)n2)cc1F
Yield: 88.6 %

Procedure:
Following the procedure of Example 7, 6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 88.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[S:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=2[I:16])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[S:13][C:12]([C:14]#[N:15])=[CH:11][C:10]=2[I:16])=[CH:4][CH:3]=1
Reactant: N#Cc1cc(I)c(C(O)c2ccc(Cl)cc2)s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(I)c(Cc2ccc(Cl)cc2)s1
Temperature: 25 °C
Yield: 85 %

Procedure:
A round-bottomed flask was charged with 5-((4-chlorophenyl)(hydroxy)methyl)-4-iodothiophene-2-carbonitrile (1.67 g, 4.45 mmol). After degassed, dichloromethane (8 mL), TFA (4 mL) and triethylsilane (1.1 mL, 6.9 mmol) was added sequentially through syringe. The reaction was further stirred at rt until complete, and then concentrated. The residue was purified by flash chromatography (hexane:CH2CL2=2:1). 1.36 g (85%) of product was obtained as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:14][C:15]=1[F:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[F:16][C:15]1[CH:14]=[CH:13][C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:26])[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][C:10]=1[CH2:9][OH:8]
Reactant: CCOC(=O)C(Cc1ccc(F)c(CO[Si](C)(C)C(C)(C)C)c1)OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(F)c(CO)c1)OC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 116.8 %

Procedure:
1.2 g of Ethyl 3-[3-(t-butyldimethylsilanyloxymethyl)-4-fluorophenyl]-2-isopropoxypropionate was dissolved in 15 ml of tetrahydrofuran, and 3.3 ml of 1.0M tetrabutyl ammonium fluoride in tetrahydrofuran was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography (30% ethyl acetate-hexane), to give 1.0 g of the title compound.