Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].BrCCBr.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1.[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>C1COCC1.O>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][C:16]2([OH:15])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Mg]
Solvent: O
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium (1.2 g) and 1,2-dibromoethane (0.11 mL) in THF (30 mL) was added a solution of 4-fluorobenzyl chloride (6.3 mL) in THF (10 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 1 hr at the same temperature. The reaction mixture was cooled to −78° C., a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g) in THF (10 mL) was added thereto, and the mixture was allowed to warm to room temperature, and stirred for 2 days. To the reaction mixture was added water at 0° C., and then saturated aqueous potassium sodium tartrate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (4.8 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].C(N(C(C)C)C(C)C)C.[CH3:20][O:21][CH2:22][CH2:23][OH:24]>CCOC(C)=O>[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cccc(CBr)c1
Reactant: COCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCc1cccc(C#N)c1
Yield: 81 %

Procedure:
A solution of 3-(bromomethyl)benzonitrile (1 g, 5.1 mmol) in 2-methoxyethanol (10 mL) and n-ethyldiisopropylamine (0.89 mL, 5.1 mmol) was heated under microwave irradiations for 2 hours at 150° C. After this time, reaction mixture was diluted with EtOAc (200 mL), washed with water and brine to give the title compound as a colorless oil (800 mg, 81%). 1H NMR (DMSO-d6, 300 MHz) δ 7.76-7.74 (m, 2H), 7.68-7.65 (m, 1H), 7.59-7.54 (m, 1H), 4.54 (s, 2H), 3.59-3.56 (m, 2H), 3.51-3.47 (m, 2H), 3.25 (s, 3H). HPLC (Method A) Rt 3.09 min (Purity: 82.9%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:15]I.OO.O>CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[C:12]([I:15])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: II
Agent: OO
Solvent: O
Solvent: CO
Product: Nc1ccc(Cc2ccccc2)cc1I
Reaction time: 8 h

Procedure:
To a solution of 4-benzylbenzenamine (3.00 g, 16.4 mmol) in 16 mL MeOH was added iodine (2.49 g, 9.82 mmol) followed by hydrogen peroxide, 30% in water (1.67 mL, 16.4 mmol). The dark solution was allowed to stir overnight. The reaction was partitioned between water/brine and EtOAc. The organic layer was washed 1× brine, dried over MgSO4, filtered, and concentrated. The resulting oil was purified by ISCO (120 g, 0-10% EtOAc/hexanes) to give 4-benzyl-2-iodobenzenamine as a red oil which slowly solidified to a red solid. MS (ESI) m/z: Calculated: 309.0; Observed: 310.0 (M++1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1.COC1C=C(C=CC=1)CCO.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(CCOc2cncc(Cl)n2)c1
Reactant: C1CNCCN1
Agent: COc1cccc(CCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cccc(CCOc2cncc(N3CCNCC3)n2)c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[2-(3-methoxyphenyl)ethoxy]pyrazine (1.12 g, 4.23 mmol; obtained according to the procedure of example 50, step 1, starting from 3-methoxyphenethyl alcohol), piperazine (1.06 g, 12.3 mmol) and K2CO3 (0.585 g, 4.23 mmol). The yield of the title compound was 0.91 g (69%) which was obtained as light beige oil. HRMS m/z calcd for C17H22N4O2 (M)+ 314.1743, found 314.1759. Anal. (C17H22N4O2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]4[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:17](=[O:29])[C:15]4=3)[N:10]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:46]1([S:52](Cl)(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:10]2[C:11]3=[N:12][CH:13]=[C:14]4[C:19](=[O:20])[N:18]([CH2:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:17](=[O:29])[C:15]4=[C:16]3[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:52]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)(=[O:54])=[O:53])[CH:7]=[CH:6][CH:5]=3)=[N:9]2)=[CH:36][CH:35]=1
Reactant: COc1ccc(Cn2nc(-c3cccc(N)c3)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cn2nc(-c3cccc(NS(=O)(=O)c4ccccc4)c3)c3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 17.6 %

Procedure:
To an ice cooled solution of 1-(3-aminophenyl)-3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (synthesized according to General Procedure B) (200 mg) in dichloromethane (6 ml), triethylamine (0.08 ml, 0.59 mmol) was added followed by phenylsulphonyl chloride (0.08 ml, 0.59 mmol). The reaction mixture was warmed to room temperature and stirred for 2-3 hours. After completion of reaction (TLC, LCMS), the reaction mixture was diluted with dichloromethane (15 ml) and was washed with water (10 ml). The dichloromethane layer was dried over sodium sulfate and evaporated under reduced pressure. The crude compound was passed through a plug of silica (eluent 20% ethyl acetate in hexanes) and then purified by reverse phase HPLC on C-18 column to give N-(3-(3-(4-methoxybenzyl)-6,8-dioxo-7-phenethyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridin-1-yl)phenyl)benzenesulfonamide (45 mg, 18%) as a solid. 1HNMR (400 MHz, CDCl3): δ 9.04 (s, 1H), 7.83 (d, J=7.6 Hz, 2H), 7.56-7.20 (m, 14H), 6.84 (d, J=7.6 Hz, 2H), 6.57 (s, 1H), 5.73 (s, 2H), 3.91 (t, J=7.2 Hz, 2H), 3.76 (s, 3H), 2.96 (t, J=7.2 Hz, 2H); LCMS: [M+H] 643.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:23](=[O:24])[N:22]([CH:25]([F:27])[F:26])[C:21]([CH3:28])=[N:20]2)=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][CH:6]=1.[S:29]([CH:33]([CH3:35])[CH3:34])(=[O:32])(=[O:31])[NH2:30]>C(Cl)Cl>[CH3:34][CH:33]([S:29]([NH:30][C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:14]=[C:15]([N:19]3[C:23](=[O:24])[N:22]([CH:25]([F:26])[F:27])[C:21]([CH3:28])=[N:20]3)[C:16]([F:18])=[CH:17][C:2]=2[Cl:1])=[CH:6][CH:7]=1)=[O:12])(=[O:32])=[O:31])[CH3:35]
Reactant: Cc1nn(-c2cc(Oc3ccc(C(=O)Cl)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Reactant: CC(C)S(N)(=O)=O
Solvent: ClCCl
Product: Cc1nn(-c2cc(Oc3ccc(C(=O)NS(=O)(=O)C(C)C)cc3)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 195 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A stirred mixture of 0.59 g (0.0014 mole) of 4-[2-chloro-4-fluoro-5-(4-difluoromethyl -4,5-dihydro-3-methyl-5-oxo-1H-1,2,4 triazol-1-yl)phenoxy]phenyl-carboxylic acid chloride and 0.17 g (0.0014 mole) of 2-sulfamylpropane was heated at 195° C. for approximately 15 minutes. The mixture was cooled and 2 mL of methylene chloride was added. The mixture was allowed to stand at room temperature for approximately 18 hours. A brown solid formed, was collected and triturated with petroleum ether. Recovery of the solid by filtration gave 0.58 g of N-(1-methylethyl)sulfonyl-4-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]phenylcarboxamide as a solid, m.p. 185°-187° C., Compound 130 of Table 1.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[NH:62][C:63](=[O:65])[CH3:64])[CH:53]=[CH:54][CH:55]=1>CN(C=O)C>[C:63]([NH:62][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([NH:49][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:51]=1)(=[O:65])[CH3:64]
Reactant: CC(=O)Nc1ccccc1-c1cccc(N)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
DIEA (0.013 mL, 0.073 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, N-(3′-Amino-biphenyl-2-yl)-acetamide (0.015 g, 0.066 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.007 g of product in 27% yield: LCMS (ESI) m/z 415 (MH+).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:24]=[CH:23][C:13]([O:14][CH2:15][C@@H:16]3[CH2:20]CC(C)(C)[O:17]3)=[C:12]([Br:25])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([O-])(=O)=[O:33])=CC=1>CC(C)=O.O>[C:1]1([S:7]([C:10]2[CH:24]=[CH:23][C:13]([O:14][CH2:15][C@H:16]([OH:17])[CH2:20][OH:33])=[C:12]([Br:25])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)CC[C@@H](COc2ccc(S(=O)(=O)c3ccccc3)cc2Br)O1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(OC[C@H](O)CO)c(Br)c1

Procedure:
A solution of 4-(S)-(4-benzenesulfonyl-2-bromo-phenoxymethyl)-2,2-dimethyl-[3,3]dioxolan (1.07 g, 0.0025 mol) and pyridinum toluene-4-sulfonate (0.38 g, 0.0015 mol) in acetone (20 mL) and water (5 mL) was heated under reflux for 12 hours. The solvent was removed under reduced pressure. The oily residue was dissolved in ethyl acetate (100 mL), washed with cold 10% aqueous hydrochloric acid, saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. Recrystallization of the residue (diethyl ether-hexane) gave 3-(4-benzenesulfonyl-2-bromo-phenoxy)-propane 1-2-(R)-diol as white crystals. Mp. 104.6-105.9° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=2)[CH2:29][CH2:28]3)O1.O1CCOCC1.C([O-])(O)=O.[Na+]>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>[CH3:15][CH:14]([CH3:16])[CH2:13][CH2:12][N:4]1[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=2[C:2]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:46])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=2)[CH2:29][CH2:28]3)=[CH:3]1
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)OC1(C)C
Reactant: CC(C)CCn1cc(Br)c2c(N)ncnc21
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CCn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(C(F)(F)F)c2)c2c(N)ncnc21
Temperature: 100 °C
Yield: 49.8 %

Procedure:
To 5-bromo-7-(3-methylbutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (75 mg, 0.265 mmol) and 5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indole (160 mg, 0.371 mmol) were added 1,4-Dioxane (2 mL) and saturated NaHCO3 (1 mL) in a 5 ml sealable vessel. The mixture was then bubbled with N2 gas for 5 minutes then Pd(Ph3P)4 (30.6 mg, 0.026 mmol) was added and the vessel was capped. The reaction was then heated at 100° C. overnight. The reaction was then diluted with water (2 ml) then extracted with EtOAc (3×3 ml). The organics were then combined and washed with brine, dried over MgSO4, filtered and concentrated. The crude was dissolved in 3 mL of DMSO and the product purified by HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 40% ACN/H2O, 0.1% TFA to 65% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organics were combined and washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was transferred to a 40 mL vial with MeCN then water was added and the solution was freeze-dried. to afford 7-(3-methylbutyl)-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (67 mg, 0.132 mmol, 49.8% yield) as a white solid. LC-MS (ES) m/z=508.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.11 (d, J=8.34 Hz, 1H), 7.69 (s, 1H), 7.56-7.66 (m, 3H), 7.33 (s, 2H), 7.24 (d, J=8.34 Hz, 1H), 6.10 (br. s., 2H), 4.27 (t, J=8.46 Hz, 2H), 4.18 (t, J=7.33 Hz, 2H), 4.03 (s, 2H), 3.26 (t, J=8.34 Hz, 2H), 1.69 (q, J=6.99 Hz, 2H), 1.50 (dt, J=6.69, 13.39 Hz, 1H), 0.93 (d, J=6.57 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]1[O:17][N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30]>ClCCl.C(OCC)(=O)C>[OH:12][C:4]1[C:3]([C:13]2[O:17][N:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:14]=2)=[C:2]([O:1][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[C:11]2[C:6]([N:5]=1)=[N:7][CH:8]=[CH:9][N:10]=2
Reactant: O=c1[nH]c2nccnc2c(O)c1-c1cc(C(F)(F)F)no1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)C(=O)Oc1c(-c2cc(C(F)(F)F)no2)c(O)nc2nccnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 8-hydroxy-7-(3-trifluoromethyl-isoxazol-5-yl)-5H-pyrido[2,3-b]pyrazin-6-one (Example 6.5) (0.037 g) and pyridine (0.1 ml) in dichloromethane (2 ml) was added dropwise isobutyryl chloride (0.05 ml). The reaction mixture was stirred at ambient temperature for 6 hours and stored at ambient temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed successively with water, aqueous sodium hydrogen carbonate (saturated) and brine. The organic phase was dried over magnesium sulfate and concentrated to give Compound No. B7 of Table B as a pale yellow solid (0.038 g).
Reaction SMILES: C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:12][CH:13]([CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:33])/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:14][C:15](O)=[O:16].C(OCC)(=O)C>O>[CH3:12][CH:13]([CH2:18][CH2:19]/[CH:20]=[C:21](\[CH3:33])/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:14][CH2:15][OH:16]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CCC(C)CCO
Temperature: 10 °C

Procedure:
To 150 ml. of anhydrous diethyl ether there was added 1.9 g. of lithium aluminum hydride. To the mixture was dropwise added, under stirring and at 10° C., 1.53 g. of the carboxylic acid compound obtained in Example 1. The resulting mixture was then stirred at room temperature for 1 hour, and 1 ml. of ethyl acetate and 1 ml. of water were then added thereto. The mixture was subsequently washed with water and dried. The solvent was removed by evaporation and the resulting residual oil was purified by silica gel column chromatography to obtain 13.8 g. of the desired oily product.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([Sn](C)(C)C)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][N:14]3S(C2C=CC=CC=2)(=O)=O)=[O:8])[N:6]=1.Br[C:33]1[CH:34]=[C:35]([NH:41][C:42](=[O:46])[CH:43]([OH:45])[CH3:44])[C:36]([O:39][CH3:40])=[N:37][CH:38]=1.CN(C=O)C>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.CO>[OH:45][CH:43]([CH3:44])[C:42]([NH:41][C:35]1[CH:34]=[C:33]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)[CH:38]=[N:37][C:36]=1[O:39][CH3:40])=[O:46]
Reactant: Cc1nc(C(=O)Nc2cc([Sn](C)(C)C)cc3c2cnn3S(=O)(=O)c2ccccc2)cs1
Reactant: COc1ncc(Br)cc1NC(=O)C(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NC(=O)C(C)O
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 8.3 %

Procedure:
2-Methyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (150 mg, 0.267 mmol), N-[5-bromo-2-(methyloxy)-3-pyridinyl]-2-hydroxypropanamide (88 mg, 0.321 mmol) and Pd(PPh3)4 (31 mg, 0.027 mmol) were weighed to a microwave vial. DMF (3 ml) was added and the reaction was heated in the microwave at 120° C. for 30 mins, then again at 120° C. for a further for 30 mins. The reaction mixture was passed through a 1 g silica cartridge, pre-conditioned with methanol, washing with methanol. The solvent was evaporated in the blow down. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (Method E). Pure fraction was evaporated to dryness. The residue was dissolved in IPA and 2M NaOH (aq) and left overnight. The reaction was concentrated in vacuo, then neutralised using 2M HCl (aq) and the resultant precipitate was collected by filtration. The material was dissolved in DMSO:methanol (0.7 ml, 1:1, v/v) and purified by MDAP (Method E). Pure fractions were combined and evaporated to dryness to afford the title compound (10 mg).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:12](O)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21]>C(OCC)(=O)C.CCCCCC>[C:1]([O:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCCO
Reactant: C=CCCCCCCCC(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCCCCCCCCOC(=O)CCCCCCCC=C
Yield: 92.7 %

Procedure:
Compound G was prepared from 9-decen-1-ol and 9-decenoic acid following the general procedure already discussed and shown in FIG. 12. Pure compound G was a colorless oil by column chromatography with Ethyl acetate/Hexane=1:50.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])[CH2:5][CH2:6][CH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:23][C:22](=[O:24])[NH:21][S:20]3(=[O:26])=[O:25])=[C:13]([OH:18])[CH:14]=2)[CH2:9]1.[OH-].[Na+]>C1COCC1.CO.O>[OH:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:19]1[CH2:23][C:22](=[O:24])[NH:21][S:20]1(=[O:26])=[O:25])[CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][C:4]([CH3:28])([CH3:27])[C:3]([OH:29])=[O:2])[CH2:17][CH2:16]2
Reactant: COC(=O)C(C)(C)CCCC1CCc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CCCC1CCc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2C1)C(=O)O
Temperature: 80 °C

Procedure:
To a solution of 5-[6-Hydroxy-7-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl]-2,2-dimethylpentanoic acid methyl ester (50 mg, 0.12 mmol) in THF/MeOH/H2O (3:3:1 v/v/v, 1 mL,) is added NaOH (50 mg) and it is heated at 80° C. in microwave for 10 min. The solution is concentrated, dissolved in H2O and neutralized with 1N HCl solution. It is then purified by RP-HPLC to give the title compound as a light yellow solid: 1H NMR(CD3OD) δ1.17 (s, 6H), 1.29-1.35 (m, 5H), 1.39-1.41 (m, 2H), 1.60-1.70 (m, 1H), 1.90-1.94 (m 1H), 2.25-2.35 (m, 1H), 2.71-2.75 (m, 3H), 4.27 (s, 2H), 6.59 (s, 1H), 7.09 (s, 1H); (M−H)−=409.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:22](=O)[CH3:23])[C:15]([O:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)=[O:16].[NH2:25][C:26]([CH3:31])=[CH:27][C:28](=[O:30])[CH3:29]>C(O)C>[C:28]([C:27]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:14]([C:15]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[O:16])=[C:22]([CH3:23])[NH:25][C:26]=1[CH3:31])(=[O:30])[CH3:29]
Reactant: CC(=O)C=C(C)N
Reactant: CC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(=O)OCC1CC1
Solvent: CCO
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
648 mg (1.98 mmol) of cyclopropylmethyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 196 mg (1.98 mmol) of 4-aminopent-3-en-2-one in 10 ml of ethanol and heated under reflux under argon for 24 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. Concentration of the product fractions and crystallization from ethyl acetate result in 327 mg (41% of theory) of the title compound as a white solid.
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[C:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21])#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[F:10][C:9]([F:12])([F:11])[C:6]1[CH:7]=[CH:8][C:3]([C:2]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=[O:21])[O:14][N:13]=2)=[CH:4][CH:5]=1
Reactant: ON=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C#Cc1cccc(C=O)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc(-c2cc(-c3ccc(C(F)(F)F)cc3)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution (20 ml) of 1-[chloro(hydroxyimino)methyl]-4-trifluoromethylbenzene (0.849 g) and 3-ethynylbenzaldehyde (0.521 g) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (1.12 ml) in tetrahydrofuran at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1, volume ratio) and recrystallized from hexane-ethyl acetate to give 3-[3-(4-trifluoromethylphenyl)-5-isoxazolyl]benzaldehyde (0.660 g, yield 52%) as colorless needle crystals. melting point: 151–152° C.