Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([NH2:15])[S:14][C:10]=2[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([CH2:30][O:31][C:32]2[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=2)[C:35](O)=[O:36])=[O:29])=[CH:23][CH:22]=1)#[N:20]>CN(C)C(=O)C.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]1[CH2:17][CH2:16][C:11]2[N:12]=[C:13]([NH:15][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[C:32]([O:31][CH2:30][C:28](=[O:29])[NH:27][C:24]4[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=4)[CH:33]=3)[S:14][C:10]=2[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(NC(=O)COc2cccc(C(=O)O)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2nc(N)sc2C1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2nc(NC(=O)c3cccc(OCC(=O)Nc4ccc(C#N)cc4)c3)sc2C1
Temperature: 50 °C
Yield: 75.2 %

Procedure:
Add ((S)-2-amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester (0.10 g, 0.37 mmol) followed by O-(7-aza-benzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (0.13 g, 0.34 mmol) and N,N-diisopropylethyl (0.13 mL, 0.70 mmol) amine to a solution of 3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoic acid (0.10 g, 0.34 mmol) in N,N-dimethylacetamide (3 mL). Heat the mixture to 50° C. for 2 h then cool to room temperature and dilute with water causing a solid to precipitate from solution. Collect the light yellow solid by filtration, wash with water, and dry on the filter pad to provide 0.14 g of ((S)-2-{3-[(4-cyano-phenylcarbamoyl)-methoxy]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1.ClCCl>ClC(Cl)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[S:31]
Reactant: CNC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CNC(=S)c1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 112.8 %

Procedure:
To a solution of methyl 3-[(methylamino)carbonyl]-5-(5-methylpyridin-2-yl)benzoate (2.90 g, 10.2 mmol) in dichloroethane (20 mL) was added 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) (2.27 g, 5.61 mmol) and the mixture heated to 60° C. After 2 h, the reaction was cooled to ambient temperature. Dichloromethane (200 mL) was added, and the mixture washed with 100 mL of saturated aqueous sodium bicarbonate (2×) and brine (100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) to give the title compound (1.9 g). MS 301.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]([NH2:13])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C:11]#[N:13]
Reactant: NC(=O)Cc1cc(F)c(F)cc1Br
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: N#CCc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
The compound (143 mg, 0.572 mmol) of Step 1 was dissolved in THF. Pyridine (0.138 mL, 1.71 mmol) was added thereto, trifluoroacetic anhydride (0.119 mL, 0.858 mmol) was added thereto at −5° C. to 0° C., and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. After diluted with ethyl acetate, the resultant was washed with 1 N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure to thus obtain the title compound without purification.
Reaction SMILES: [ClH:1].[C:2](=[NH:7])([O:4]CC)[CH3:3].[NH2:8][CH2:9][C:10]([NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=[O:11]>C(O)C>[ClH:1].[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[NH:12][C:10]([CH2:9][NH:8][C:9](=[N:8][CH2:3][C:2](=[O:7])[NH:4][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:10])=[O:11]
Reactant: CCOC(C)=N
Reactant: Cc1cccc(C)c1NC(=O)CN
Agent: Cl
Solvent: CCO
Product: CC(=NCC(=O)Nc1c(C)cccc1C)NCC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.85 Grams (0.039 mole) of ethyl acetimidate hydrochloride and 7.0 g of 2-amino-2',6'-dimethylacetanilide were dissolved in 75 ml of anhydrous ethanol and stirred at room temperature for two days. The solid which formed was collected on a filter, recrystallized from ethanol, and dried overnight under vacuum at 60° C. M.P. 240°-241° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([C:8]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[O:9])[CH:7]=1.[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][C:27]#[CH:28])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][C:27]#[C:28][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8](=[O:9])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=1[F:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(c1cc(Cl)ccc1I)c1c(F)cccc1F
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC#Cc1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(5-Chloro-2-iodo-phenyl)-(2,6-difluoro-phenyl)-methanone (2aa) (5.5 g, 14.5 mmol), prop-2-ynyl-carbamic acid tert-butyl ester (2.5 g, 16 mmol)7 PdCl2(PPh3)2 (0.6 g, 0.9 mmol) and Cu(I)I (0.2 g, 0.9 mmol) were suspended in anhydrous CH2Cl2 (50 mL) and the mixture was sparged with nitrogen for 30 min. Diethylamine (8 mL) was added and the solution was stirred at room temperature for 16 h. The solution was concentrated in vacuo and the resulting residue purified by column chromatography (silica gel, 0 to 15% EtOAc/hexanes) to afford 3aa (3.6 g, 61%) as a white solid, MS m/z=406 (M+H).
Reaction SMILES: O.O.O.O.O.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[O-:21].[Na+].C(=O)([O-])[O-].[K+].[K+].[C:32]([C:34]1[O:35][C:36]2[CH:42]=[C:41]([CH2:43]Br)[CH:40]=[CH:39][C:37]=2[N:38]=1)#[N:33]>CC(C)=O.CN(C)C=O>[C:32]([C:34]1[O:35][C:36]2[CH:42]=[C:41]([CH2:43][O:21][C:20]3[CH:22]=[CH:23][CH:24]=[C:18]([O:17][CH2:16][C:7]4[CH:8]=[CH:9][C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[N:6]=4)[CH:19]=3)[CH:40]=[CH:39][C:37]=2[N:38]=1)#[N:33]
Reactant: [O-]c1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1nc2ccc(CBr)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1

Procedure:
To a stirred solution of sodium 3-(2-quinolinylmethyloxy)phenoxide pentahydrate (3.63 g, 10 mmol) in acetone (85 ml) and dimethylformamide (10 ml) at room temperature are added successively potassium carbonate (2.07 g, 15 mmol) and 2-cyano-6-bromomethylbenzoxazole (1.90 g, 8.02 mmol). The resulting solution-suspension is refluxed for 16 hours and concentrated. Water (100 ml) and ethyl acetate (200 ml are added. Extraction with ethyl acetate is followed by washing with water and brine, drying (MgSO4) and evaporation under reduced pressure. The residue is subjected to flash chromatography over silica gel. Elution with 33% ethyl acetate in hexane and concentration of the appropriate fractions provides 2-cyano-6-[3-(2-quinolinylmethyloxy)phenoxymethyl]benzoxazole which is used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[C:4]([F:13])[CH:3]=1.C([Li])CCC.C(O[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[CH:5]=[C:4]([F:13])[C:3]=1[B:23]1[O:27][C:26]([CH3:29])([CH3:28])[C:25]([CH3:31])([CH3:30])[O:24]1
Reactant: COCCOc1cc(F)cc(F)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1,3-difluoro-5-(2-methoxyethoxyl)benzene (1.0 eq) in dry THF (0.2M) under an atmosphere of N2 at −78° C. was added n-butyllithium (1 eq, 1.6M in hexanes) slowly keeping the internal temperature below −65° C. The reaction was stirred for 1 hr at −78° C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3 (sat) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield 2-(2,6-difluoro-4-(2-methoxyethoxyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolαne. 1H NMR (400 MHz, <cdcl3>) δ ppm 6.42 (d, 2 H), 4.10 (m, 2H), 3.74 (m, 2H), 3.44 (s, 3 H), 1.37 (s, 12 H).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].N1CCCCC1>C(O)C>[C:17]([C:19]1[C:20](=[O:21])[NH:22][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:9]2)#[N:18]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C1CC(c2ccccc2)CCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccccc1)CC2

Procedure:
2-Acetyl-4-phenylcyclohexanone, 1.68 g, 0.73 g of cyanoacetamide and a small quantity of piperidine were mixed with 10 ml of ethanol followed by heating to reflux for 2 hours. After cooling, the precipitated crystals were taken out by filtration and purified to give 1.5 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-phenylisoquinoline.
Reaction SMILES: C([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:24])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19]([CH2:22][CH3:23])[CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.C(/B(O)O)=C/C>>[ClH:21].[Cl:21][C:20]1[C:13]2[CH2:12][CH2:11][C@@:10]3([CH3:24])[C@@H:15]([CH2:16][NH:8][CH2:9]3)[C:14]=2[CH:17]=[CH:18][C:19]=1[CH2:22][CH3:23]
Reactant: CCc1ccc2c(c1Cl)CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Agent: C/C=C\B(O)O
Product: CCc1ccc2c(c1Cl)CC[C@]1(C)CNC[C@@H]21
Product: Cl

Procedure:
Similar protocols to procedures in example 5-7 (using trans-2-benzyl-6-chloro-7-ethyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole and (Z)-prop-1-enylboronic acid) were employed to afford trans-6-chloro-7-ethyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride, m/z=264.2 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](O)=[O:19])=[CH:13][CH:12]=1.Cl[CH2:22][CH2:23]Cl>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]2[C:4]3[CH:3]=[C:2]([C:6]([O:8][CH3:9])=[O:7])[NH:1][C:5]=3[CH2:23][CH2:22]2)=[CH:13][CH:12]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([C:4]2[CH:3]=[C:2]([C:6]([O:8][CH3:9])=[O:7])[NH:1][CH:5]=2)=[O:19])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc[nH]1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: ClCCCl
Product: COC(=O)c1cc(C(=O)Cc2ccc(Br)cc2)c[nH]1
Product: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(Br)cc1

Procedure:
The title compound was synthesized in six steps. First, methyl 1H-pyrrole-2-carboxylate (1.0 g, 8 mmol, 1 equiv) in DCE (15 mL) was reacted with 4-bromophenylacetic acid (2.06 g, 9.6 mmol, 1.2 equiv) according to General Procedure 1.2.A to afford methyl 4-(2-(4-bromophenyl)acetyl)-1H-pyrrole-2-carboxylate, which was then BOC-protected according to General Procedure 1.2.B to provide 1-tert-butyl 2-methyl 4-(2-(4-bromophenyl)acetyl)-1H-pyrrole-1,2-dicarboxylate, which was next reacted with 2-tert-butoxy-2-oxoethylzinc chloride (3.0 g, 28.2 mL, 0.5M in ether, 14 mmol, 3.5 equiv) according to General Procedure 1.2.C to afford 1-tert-butyl 2-methyl 4-(1-(4-bromophenyl)-4-tert-butoxy-2-hydroxy-4-oxobutan-2-yl)-1H-pyrrole-1,2-dicarboxylate, which was reacted with trifluoroacetic acid (8.25 mL, 0.45 M) and triethylsilane (1.25 g, 1.72 mL, 2.9 equiv) according to General Procedure 1.2.D to provide 4-(4-bromophenyl)-3-(5-(methoxycarbonyl)-1H-pyrrol-3-yl)butanoic acid. This product was then cyclized by reaction with PPA (3.16 g) according to General Procedure 1.2.E to achieve methyl 4-(4-bromobenzyl)-6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate. Reduction with decaborane (0.34 g, 3 mmol, 5 equiv) according to Procedure 5b afforded the title compound, which was purified by purified by column chromatography (Isco CombiFlash) using a 0-30% gradient (EtOAc/Heptane). 0.0998 g. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.03-2.16 (m, 1H) 2.58 (dt, J=12.39, 6.88 Hz, 1H) 2.66 (t, J=6.99 Hz, 2H) 2.76 (d, J=7.39 Hz, 2H) 3.28 (dq, J=7.18, 6.92 Hz, 1H) 3.81 (s, 3H) 6.38 (d, J=1.48 Hz, 1H) 7.07 (d, J=8.31 Hz, 2H) 7.42 (q, J=4.17 Hz, 2H) 8.82 (br. s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1.[H-].[Na+].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=2[F:30])[N:23]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[C:21]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:31])=[CH:27][C:28]=3[F:30])[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:21]=2[CH3:38])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])=[N:6][CH:7]=1
Reactant: COc1ccccc1-c1ncc(Br)cc1N
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ncc(Br)cc1Nc1c(C)c(-c2ccccn2)nc2cc(F)cc(F)c12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A dry flask containing 5-bromo-2-(2-methoxyphenyl)pyridin-3-amine (194.5 mg, 0.7 mmol) in dry DMF (5 mL) was cooled to 0° C., then sodium hydride, 60% dispersion in mineral oil (90.8 mg, 2.27 mmol) was added carefully in portions. The mixture was stirred at 0° C. for 15 min, then 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (308.7 mg, 1.06 mmol) was added in portions. Upon complete addition, the mixture was warmed to 70° C. After 3 h, the reaction was cooled to rt then was carefully treated with 10% sodium carbonate solution. The black mixture was subsequently extracted 5 times with DCM:MeOH (90:10). The organic extraction was then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-35% EtOAc in hexanes) to afford a yellow residue as mostly N-(5-bromo-2-(2-methoxyphenyl)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine that was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:33]#[C:34][CH2:35][CH2:36][CH3:37]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:33]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)#[C:34][CH2:35][CH2:36][CH3:37]
Reactant: C#CCCC
Reactant: CCOC(=O)Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CCCC#Cc1cccc(CC(=O)OCC)c1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A mixture of ethyl (3-bromophenyl)acetate (0.3 g, 1.24 mmol) and tetrabutylammonium fluoride hydrate (0.97 g, 3.72 mmol), was treated with PdCl2(PPh3)2 (26 mg, 0.037 mmol; 3 mole %) and 1-pentyne (367 μl, 3.72 mmol) in a sealed tube. The tube was heated at 80° C. for 2 h. The mixture was treated with water, and was extracted with diethyl ether. The organic extract was dried over sodium sulfate, filtered and evaporated in vacuo to give the crude product. Purification on a Biotage™ 25M column (silica), eluting with ethyl acetate/hexane 0:1 to 2:98, gave ethyl (3-(pentyne-1-yl)phenyl)acetate as a pale yellow oil (0.23 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.C1COCC1.CO.[BH4-].[Na+]>O>[Cl:11][C:9]1[CH:8]=[C:7]2[C:3](=[C:2]([Cl:1])[CH:10]=1)[CH2:4][C:5]([CH3:13])=[CH:6]2
Reactant: CC1Cc2c(Cl)cc(Cl)cc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1=Cc2cc(Cl)cc(Cl)c2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 29.3 g (0.136 mol) of 4,6-dichloro-2-methylindan-1-one in 370 ml of a mixture of THF-methanol (2:1, vol.), 11.8 g (0.312 mol) of NaBH4 was added in small portions, while vigorously stirring, over 2 h at 0° C. This mixture was stirred for 12 h at room temperature and then added to 1000 ml of cold water. The organic layer was separated, the aqueous layer was extracted with 3×300 ml of methyl-tert-butyl ether. The combined organic fractions were dried over K2CO3 and then evaporated to dryness. The residue was dissolved in 700 ml of toluene, and 2.0 g of p-TosOH was added. The resulting solution was refluxed for 4 h using a Dean-Stark trap to remove the water formed, and then it was passed through a short Silica Gel 60 column (40-63 um, d 100 mm, l 80 mm, eluent: hexanes). This column was additionally washed with 250 ml of toluene. The combined organic fractions were evaporated to dryness. The product was isolated by flash chromatography on Silica Gel 60 (40-63 um, d 60 mm, l 150 mm). Yield 24.6 g (91%).
Reaction SMILES: [C:1]12([NH:6][C:7]3[C:12]([C:13](O)=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C1C=CC2N(O)N=[N:24]C=2C=1.C(Cl)CCl.[OH-].[NH4+]>C1COCC1.C(#N)C>[C:1]12([NH:6][C:7]3[C:12]([C:13]([NH2:24])=[O:14])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2
Reactant: CSc1ncc(C(=O)O)c(NC23CC(C2)C3)n1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: ClCCCl
Product: CSc1ncc(C(N)=O)c(NC23CC(C2)C3)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirring solution of 4-(bicyclo[1.1.1]pentan-1-ylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (108 g, 0.43 mol) and HOBt (67 g, 0.49 mol) in anhydrous THF (4 L) was added drop-wise a mixture of EDC (94 g, 0.49 mol) in acetonitrile (2 L) at room temperature. After the reaction mixture was stirred for 1 hr at room temperature, aqueous ammonium hydroxide (600 mL, 28-30% concentrated, 10 eq) was added drop-wise over 30 min and then the mixture was heated to gentle reflux for 3 h (60±5° C.). After that all solvents were removed under reduced pressure, the residual paste/solid was diluted with saturated aqueous sodium bicarbonate solution (2 L) and the resulting suspension was filtered to afford the desired compound (100 g, 0.4 mol, 93% yield) as an off-white fluffy solid; MS (ESI): m/z 251.1 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](O)=[O:28])=[O:21])[CH3:18].CCCP(=O)=O.C(OCC)(=O)C.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](=[O:28])[NH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:16]=2)[CH:14]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: Nc1ccc2nc(-c3ccccc3)nn2c1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A mixture of 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (300 mg, 1.43 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (339 mg, 1.71 mmol), propylphosphonic anhydride in ethyl acetate 50% (2.27 g, 2.1 ml, 3.57 mmol) and diisopropylethyl amine (553 mg, 748 μl, 4.28 mmol) in tetrahydrofuran (10 ml) was refluxed for 2.5 days. The mixture was evaporated and the residue was treated with saturated aqueous sodiumhydrogen carbonate and stirred for 30 minutes. The solid was filtered off, washed with water and dried, affording 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (483 mg, 87%) as brown solid. Mp.: 251-254° C. MS: m/z=391.1 (M+H+).
Reaction SMILES: O=O.[C:3]([S:6][C@H:7]1[N:10]([C:11](=C(C)C)[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:13])[C:9](=[O:27])[C@@H:8]1[Br:28])(=[O:5])[CH3:4].P(OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(OCC)(=O)C>[C:3]([S:6][C@H:7]1[N:10]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:13])[C:9](=[O:27])[C@@H:8]1[Br:28])(=[O:5])[CH3:4]
Reactant: COc1ccc(COC(=O)C(=C(C)C)N2C(=O)[C@H](Br)[C@H]2SC(C)=O)cc1
Agent: COP(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(COC(=O)CN2C(=O)[C@H](Br)[C@H]2SC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ozonised oxygen was bubbled through a solution of p-methoxybenzyl 2[(3S, 4R)-4-acetylthio-3-bromo-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (Osborne N. F. et al., J. Chem. Soc. Perkin Trans. 1, 1994, 179) (20.16 g, 0.0456 mol) in ethyl acetate (400 ml) at -65° to -70° C. until a permanent blue solution was obtained. Excess ozone was removed by the passage of oxygen, then trimethyl phosphite (53.8 ml, 0.456 mol) was added dropwise. After 15 min. the solution was allowed to warm to room temperature, then stood for 16 hr. The solvents were evaporated and the residue reevaporated twice from toluene, then dissolved in ethyl acetate (300 ml) and stirred vigorously for 1.5 hr. with a solution of p-toluenesulphonic acid (2 g) in water (100 mol). After dilution with water the organic layer was separated and the aqueous layer further extracted with ethyl acetate. The combined extracts were washed successively with saturated aq. sodium hydrogen carbonate and brine, then dried ((MgSO4) and evaporated. Purification by flash chromatography (silica, ethyl acetate-pet. ether) gave the product as a light brown oil, yield 10.6 g (58%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][OH:24].O[C:27]1[CH:28]=[N:29][C:30]([C:33]2[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=2)[CH2:36][N:37]2[C:41]3=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=[C:40]3[O:39][C:38]2=[O:47])=[N:31][CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][O:24][C:27]1[CH:32]=[N:31][C:30]([C:33]2[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=2)[CH2:36][N:37]2[C:41]3=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=[C:40]3[O:39][C:38]2=[O:47])=[N:29][CH:28]=1
Reactant: CN(C)CCO
Reactant: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)c2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(Cc3cccc(-c4ncc(OCCN(C)C)cn4)c3)c2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
100 mg (0.3 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 30 μl (0.3 mmol) of 2-dimethylaminoethanol are added successively to a suspension of 67 mg (0.2 mmol) of 3-[3-(5-hydroxypyrimidin-2-yl)benzyl]-5-methyl-3H-oxazolo[4,5-b]pyridin-2-one in 3 ml of DMF. 69 mg (0.30 mmol) of di-tert-butyl azodicarboxylate are subsequently added. The reaction mixture is shaken at room temperature for 18 hours. A further 100 mg (0.3 mmol) of polymer-bound triphenylphosphine (3 mmol/g) and 69 mg (0.30 mmol) of di-tert-butyl azodicarboxylate are added, and the mixture is shaken at room temperature for 18 h. A further 100 mg (0.3 mmol) of polymer-bound triphenylphosphine (3 mmol/g), 69 mg (0.30 mmol) of di-tert-butyl azodicarboxylate and 30 μl (0.3 mmol) of 2-dimethylaminoethanol are subsequently added, and the mixture is shaken at room temperature for 18 h. The reaction mixture is filtered, the filtrate is evaporated in vacuo, and the residue is purified by column chromatography on silica gel, giving “A109”. The crude product is purified by preparative HPLC; ESI: 406; HPLC: Rt=2.31 min (method B);