Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](O)[CH2:9][CH2:10][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)O)=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O.[C:33]([C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][CH2:10][C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:41]2[C:40]2[CH:42]=[CH:43][C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:38][CH:39]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: O[C@H](CC[C@@H](O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(N2[C@H](c3ccc(Br)cc3)CC[C@H]2c2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of the product from Example 69A (0.60 g, 1.500 mmol) in anhydrous CH2Cl2 (15 mL) at 0° C. was added Et3N (0.627 mL, 4.50 mmol), and the resulting mixture was stirred at 0° C. for 10 min until a homogenous solution was obtained. To the cooled solution was added methanesulfonyl chloride (0.292 mL, 3.75 mmol) dropwise, and the resulting mixture was stirred at 0° C. for 1.5 h until the reaction was complete as determined by TLC (1:1 EtOAc:hexanes). Solvent was removed in vacuo to give a solid, which was dried in vacuo. The solid was dissolved in anhydrous DMF (5 mL), and 4-tert-butylaniline (2.39 mL, 15 mmol) was added. The resulting mixture was stirred at 40° C. for 4 h and then was partitioned between 1N aq. HCl (30 mL) and EtOAc (30 mL). The organic layer was washed with H2O and dried over Na2SO4. The drying agent was filtered off, the solvent was removed in vacuo, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 0-20% EtOAc in hexanes. The title compound was obtained as a colorless solid (0.71 g, 92%). 1H NMR indicated this material was a 87:13 mixture of trans:cis pyrrolidine isomers.
Reaction SMILES: CN1C(=O)CC(=O)N(C)C1=O.C([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][S:23]([CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[N:28]2)=[O:24])=[CH:18][CH:17]=1)C=C>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:27]1([CH2:26][CH2:25][S:23]([CH2:22][C:19]2[CH:18]=[CH:17][C:16]([OH:15])=[CH:21][CH:20]=2)=[O:24])[CH:31]=[CH:30][N:29]=[N:28]1
Reactant: C=CCOc1ccc(CS(=O)CCn2ccnn2)cc1
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Reaction time: 6 h
Yield: 82.5 %

Procedure:
To a solution of 28.46 g (0.182 mol) 1,3-dimethyl-pyrimidine-2,4,6-trione and 1.81 g (1.57 mmol) tetrakis-(triphenylphosphine)-palladium in 600 ml dichloromethane was added dropwise a solution of 17.70 g (60.75 mmol) 1-[2-(4-allyloxy-phenylmethanesulfinyl)-ethyl]-1H-[1,2,3]triazole and stirring was continued for 6 hours at 45° C. It was allowed to cool down over night. The reaction mixture was extracted with three portions of sodium bicarbonate solution, then the aqueous phase was adjusted to pH 1 and extracted three times with ethyl acetate. The organic extract was dried and evaporated to yield 12.6 g (83%) 4-(2[1,2,3] triazol-1-yl-ethanesulfinylmethyl)-phenol as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27](I)=[C:4]2[N:3]=1.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][C:30]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:31]3[CH:30]=[N:29][C:38]4[C:33]([CH:32]=3)=[CH:34][CH:35]=[CH:36][CH:37]=4)=[C:4]2[N:3]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(I)cnn12
Reactant: OB(O)c1ccc2ccccc2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 60 °C

Procedure:
To crude 5-chloro-3-iodo-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-10b, 7.1 g) in DME (120 mL) and H2O (15 mL) were added the quinoline boronic acid (2.4 g, 14.1 mmol), PdCl2(dppf)2 (1.0 g, 1.2 mmol) and K3PO4.H2O (5.4 g, 25.6 mmol). The reaction mixture was heated at 60° C. for 2 hours, at which time LC/MS analysis confirmed full consumption of starting material. On cooling, H2O (40 mL) and EtOAc (100 mL) were added and organics were extracted with EtOAc (4×50 mL), dried (Na2SO4), and concentrated in vacuo to give a brown oil. Gradient column chromatography on silica eluting with 10% to 60% EtOAc/hexanes gave 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-10b) as a light yellow solid (4.1 g, 7.4 mmol, 65% over three steps).
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@@H:10]([O:11]P(OP(OC[C@H]2O[C@@H](N3C(=O)NC(=O)C=C3)[C@H](O)[C@@H]2O)(O)=O)(O)=O)[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@@H:6]1[OH:39])=[O:3].[Na+].[Cl-]>O>[OH:11][CH:10]1[O:9][C@H:8]([CH2:36][OH:37])[C@H:7]([OH:38])[C@H:6]([OH:39])[C@H:5]1[NH:4][C:2]([CH3:1])=[O:3]
Reactant: CC(=O)N[C@H]1[C@@H](OP(=O)(O)OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CO)[C@H](O)[C@@H]1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 18 h

Procedure:
To an enzymatic reaction mixture (500 μl) containing CH obtained by chemical desulfation of CS and having different non-reducing ends (1 mg, average molecular weight: 10,000, Seikagaku Corporation), UDP-GalNAc (3 μmol) 50 mM Tris-HCl buffer, pH 7.2, 20 mM MnCl2 and 0.15 M NaCl, a K4CP enzyme solution (recombinant enzyme obtained according to the procedure of the example of Japanese Patent Laid-open Publication (KOKAI) No. 2003-199583; corresponding to 37.5 μg protein) was added. A reaction was performed at 30° C. for 18 hours, thermal inactivation was performed for 1 minute in boiling water, the reaction mixture was subjected to ethanol precipitation, and the residue was dissolved again in 200 μl of distilled water. The solution was subjected to gel filtration chromatography in a Superdex 75 HR10/30 column using 0.2 M ammonium acetate as a developing buffer. The solution was loaded at a flow rate of 1 ml/minute, and fractions were collected every 1 minute (1 ml). The obtained fractions were lyophilized, and each of the lyophilized fractions was dissolved again in 10 μl of distilled water. From a part of the solution, 10 μl of a 1 nmole/μl solution was prepared, and the solution was loaded on a small amount of Dowex 50 XW8 (H+ form) gel to prepare a sample for MALDI-TOF-MS.
Reaction SMILES: C(N(CC)CC)C.[C@H:8]12[CH2:14][C@H:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[CH2:15][C:16]1[N:17]([CH3:42])[C:18]2[C:23]([N:24]=1)=[C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[N:21]=[C:20]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH2:40][CH3:41])[N:19]=2.Cl[CH2:44][C:45]([NH2:47])=[O:46]>C(Cl)Cl>[CH2:40]([C:32]1[N:31]([C:20]2[N:19]=[C:18]3[C:23]([N:24]=[C:16]([CH2:15][N:9]4[CH2:10][C@@H:11]5[CH2:14][C@H:8]4[CH2:13][N:12]5[CH2:44][C:45]([NH2:47])=[O:46])[N:17]3[CH3:42])=[C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:21]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1)[CH3:41]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4)n(C)c2n1
Reactant: NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4CC(N)=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
Triethylamine (85 μL, 0.61 mmol) was added to a solution of 8-[(1S,4S)-1-(2,5-diazabicyclo[2.2.1]hept-2-yl)methyl]-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (250 mg, 0.53 mmol) and 2-chloroacetamide (60 mg, 0.64 mmol) in DCM (10 mL). The mixture was stirred at ambient temperature for 24 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 99:1 to 98:2) to afford 597 as a cream solid (175 mg, 62%). LCMS (method I): RT=2.35 min, M+H+=531. 1H NMR (CDCl3, 400 MHz) δ 12.12 (bs, 1 H), 8.01 (m, 1 H), 7.77 (m, 1 H), 7.26 (m, 2 H), 5.62 (bs, 1 H), 4.34 (m, 4 H), 3.92-3.83 (m, 9 H), 3.54 (m, 2 H), 3.37 (q, J=7.4 Hz, 2 H), 3.09 (m, 4 H), 2.93 (m, 2 H), 2.00 (m, 2 H) and 1.42 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:17][OH:18])(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:7]=1[CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)Oc1ccc(OS(C)(=O)=O)c(CO)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(OS(C)(=O)=O)ccc1OS(C)(=O)=O
Reaction time: 0.33 h

Procedure:
To a solution of the product from Step B (13.6 g, 45.9 mmol) in 100 mL of dichloromethane at 0° C. was added triethylamine (12.8 mL, 92.1 mmol), followed by dropwise addition of methanesulfonyl chloride (4.30 mL, 55.6 mmol). After 20 minutes, the solution was concentrated in vacuo, then partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The product was isolated as a brown solid which was used without further purification.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[O:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[N:28]=[C:29]([CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][C:37]([S:40]([F:45])([F:44])([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[O:30][CH:31]=1.[I-].[K+]>CC(=O)CC>[F:43][S:40]([F:41])([F:42])([F:44])([F:45])[C:37]1[CH:38]=[CH:39][C:34](/[CH:33]=[CH:32]/[C:29]2[O:30][CH:31]=[C:27]([CH2:26][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[O:10][CH:11]=[C:7]([CH2:6][N:1]5[CH:5]=[CH:4][N:3]=[N:2]5)[N:8]=4)=[CH:13][CH:14]=3)[N:28]=2)=[CH:35][CH:36]=1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(-c2nc(Cn3ccnn3)co2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCC(C)=O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(-c4nc(Cn5ccnn5)co4)cc3)co2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A mixture of 97 mg (0.40 mmol) 4-(4-[1,2,3]triazol-1-ylmethyl-oxazol-2-yl)-phenol and 78 mg (0.24 mmol) cesium carbonate in 10 ml butanone was stirred at 60° C. for 30 min, then 140 mg (0.40 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole and 66 mg (0.40 mmol) potassium iodide were added and stirring at 60° C. continued over night. After evaporation, 15 ml water was added and the mixture extracted with three portions of 15 ml ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and water, dried over sodium sulfate and evaporated to yield 89 mg (40%) pure title compound as light yellow solid melting at 172-174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:9]=[C:10]([C:12]3([CH2:15][NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[I:22]N1C(=O)CCC1=O.B(F)(F)F.[O-]S([O-])(=S)=O.[Na+].[Na+]>C([O-])(O)=O.[Na+]>[I:22][C:6]1[N:5]2[N:9]=[C:10]([C:12]3([CH2:15][NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:13][CH2:14]3)[N:11]=[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1cccn2nc(C3(CNC(=O)C(C)C)CC3)nc12
Reactant: O=C1CCC(=O)N1I
Agent: FB(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: COc1ccc(I)n2nc(C3(CNC(=O)C(C)C)CC3)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere N-[1-(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-isobutyramide (0.063 g, 0.22 mmol) was mixed with N-iodosuccinimide (0.15 g, 0.65 mmol). BF3*2H2O (0.47 mL, 7.4 mmol) was added at 0° C. The dark suspension was stirred at rt for 3 h after which it was poured onto a 1:1 solution of saturated Na2S2O3 and saturated NaHCO3 (20 mL). The aqueous phase was extracted with DCM (×2) and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using EtOAc:Toluene 3:1->7:1 as the eluent to afford N-[1-(5-Iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropylmethyl]-isobutyramide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:16])[C:12]=1[C:13](=[O:15])[CH3:14].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Br:41]Br>C(Cl)(Cl)Cl>[Br:41][CH2:14][C:13]([C:12]1[N:11]([CH3:16])[N:10]=[N:9][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1c(-c2ccccc2Cl)nnn1C
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: ClC(Cl)Cl
Product: Cn1nnc(-c2ccccc2Cl)c1C(=O)CBr
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A solution of 1-(4-(2-chlorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)ethanone (1.02 g, 4.33 mmol) was dissolved in chloroform (7 mL) and acetic (0.136 mL) was heated to reflux and then a solution of bromine (0.234 mL, 4.54 mmol) in chloroform (3 mL) was added dropwise within 10 min at and after 1 h bromine (0.09 mL, 1.73 mmol) in chloroform (2 mL) was added and heated under reflux for 1 h. After cooling to room temperature the mixture was poured onto ice-water and the mixture extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 60% ethyl acetate in heptane) afforded the title compound (988 mg, 73%) as an off white solid. MS: m/e=313.9/315.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].F[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:9]([O:8][C:7]([NH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:16]=[CH:15][CH:14]=1)[O:1][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2cccc(CNC(=O)OC(C)(C)C)c2)cc1
Temperature: 100 °C
Yield: 101.7 %

Procedure:
tert-Butyl (3-hydroxybenzyl)carbamate (0.025 g, 0.11 mmol) was dissolved in acetonitrile (1.0 mL) with methyl 4-fluorobenzoate (Aldrich, Cat 120707) (0.034 g, 0.22 mmol) and cesium carbonate (0.073 g, 0.22 mmol) in a sealed tube. The reaction was heated to 100° C. for 2 h. and was complete. The reaction was taken up in ethyl acetate, filtered and concentrated under reduced pressure to give crude methyl 4-(3-((tert-butoxycarbonylamino)methyl)phenoxy)benzoate (0.040 g) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]#[CH:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:24]([CH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([CH2:33][O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[CH:31][CH:30]=1)([O-])=[O:25].C(N(CC)CC)C.C1(N=C=O)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:25][N:24]=[C:27]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=4)=[CH:41][CH:42]=3)[CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)[C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C#Cc1cccnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])CCc1ccc(COc2ccccn2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 5.5 h

Procedure:
Under stirring at 50° C, to a solution of di-tert-butyl(3-ethinyl pyridin-2-yl)imidodicarbonate described in Preparation Example 3-1-1 (2.0 g), 2-(4-(2-nitro-ethyl)-benzyloxy) pyridine described in Preparation Example 1-3-4 (2.44 g), triethylamine (0.086 uL) and tetrahydrofuran (20 mL) was added phenyl isocyanate (2.8 mL) divided into four portions over 5.5 hours. After the additions were finished, stirring was carried out at 50° C for another two hours. NH-silica gel was added to the reaction solution, and the solvent was concentrated under a reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=3:1). The resulting solution was concentrated under a reduced pressure and purified by silica gel chromatography (heptane:ethyl acetate=3:1 then 2:1) to obtain the title compound (2.2 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[C:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[C@@H:25]([CH3:27])O.CO>C(Cl)Cl>[C:30]([O:29][C:24](=[O:28])[C@@H:25]([O:23][C:21]1[CH:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)[CH3:27])([CH3:33])([CH3:32])[CH3:31]
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O[C@@H](C)C(=O)OC(C)(C)C)cc1OCC2
Yield: 62 %

Procedure:
Following the procedures of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 and (+)-tert-butyl d-lactate were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-7% methanol in DCM) to give (S)-2-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy]-propionic acid tert-butyl ester as a yellow solid (70 mg, 62%). LCMS: RT=3.76 min, [M+H]+=440.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NN1CCCCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCCCC2)cn1
Yield: 21 %

Procedure:
As described for example 2b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using N-aminopiperidine instead of N-aminomorpholine to the title compound (27 mg, 21%) which was obtained as a white solid. MS: m/e=393.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].N1C=CC=CC=1.[C:19]12([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=3[O:38][CH3:39])[C:32](Cl)=[O:33])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2.CCCCCC>ClCCl>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]([NH:6][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:29]([C:19]34[CH2:28][CH:23]5[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]5)[CH2:26]3)[CH2:20]4)[CH:30]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: COc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)c([N+](=O)[O-])c1
Yield: 90 %

Procedure:
5.38 g (32 mM) of 2-nitro-4-methoxyaniline and 50 ml of pyridine are introduced into a round-bottomed flask. 9.7 g (32 mM) of 3-(1-adamantyl)-4-methoxybenzoic acid chloride, dissolved in 100 ml of dichloromethane, are then added dropwise. At the end of addition, the mixture is brought to reflux for 12 hours. After having cooled, 100 ml of hexane are added and the precipitate obtained is recovered by filtration and washed with a mixture containing 10% ether and 90% hexane and then with water. After drying, there are obtained 12.5 g (89%) of the expected product. M.p.=208°-210° C.
Reaction SMILES: [CH2:1]([N:4]([C@H:14]1[CH2:19][CH2:18][C@H:17](C2C=CC(CNC)=CC=2)[CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH:2]=[CH2:3].Br[CH2:30][CH2:31][CH2:32][OH:33]>C(Cl)Cl.CO>[CH2:1]([N:4]([C@H:14]1[CH2:15][CH2:16][C@H:17]([C:7]2[CH:8]=[CH:9][C:10]([CH2:30][CH2:31][CH2:32][OH:33])=[CH:11][C:6]=2[CH2:5][NH:4][CH3:1])[CH2:18][CH2:19]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CNC)cc2)CC1
Reactant: OCCCBr
Solvent: ClCCl
Solvent: CO
Product: C=CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(CCCO)cc2CNC)CC1

Procedure:
from trans-N-allyl-N-(4-chlorobenzoyl)-4-(4-methylaminomethylphenyl)cyclohexylamine and 3-bromo-1-propanol. Oil. Rf value: 0.56 (alumina, methylene chloride/methanol=50:1, v:v).
Reaction SMILES: OB(O)[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.Br[C:13]1[N:14]=[C:15]2[C:21]([C:22]([C:24]3([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])=[CH:20][N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:16]2=[N:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:30][C:24]1([C:22]([C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:3]4[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=4)[N:14]=3)[N:19]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[CH:20]=2)=[O:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(Br)nc23)CCCCC1
Reactant: O=C(O)c1ccc(B(O)O)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CC1(C(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4ccc(C(=O)O)s4)nc23)CCCCC1
Yield: 50.6 %

Procedure:
A mixture of 5-(dihydroxyboryl)-2-thiophene-carboxylic acid (1.0 g, 5.4 mmol), [2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-(1-methyl-cyclohexyl)-methanone (2.2 g, 4.9 mmol), potassium carbonate (2.0 g, 15 mmol), and Pd(dppf)Cl2.CH2Cl2 (0.400 g, 0.489 mmol) in 12 mL of 1,4-dioxane and 3 mL of water was stirred at 120° C. in a microwave for 40 min. The resulting red suspension was partitioned between 60 mL of ethyl acetate and 100 mL of water, and the aqueous layer was extracted with three 60 mL portions of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0->50% EtOAc/hexanes) afforded 1.24 g (46%) of 5-[7-(1-methyl-cyclohexanecarbonyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-thiophene-2-carboxylic acid as a brown solid.