Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6]1.[CH3:34][O:35][C:36]1[C:37]([NH2:42])=[N:38][CH:39]=[CH:40][CH:41]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:34][O:35][C:36]1[C:37]([NH:42][C:2]2[CH:3]=[C:4]3[C:31](=[CH:32][CH:33]=2)[O:30][CH2:29][C:25]2([CH2:28][O:27][CH2:26]2)[C:5]23[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6]2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: COc1cccnc1N
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cccnc1Nc1ccc2c(c1)C1(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1)C1(COC1)CO2
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (300 mg, 0.571 mmol), 3-methoxypyridin-2-amine (354 mg, 2.86 mmol), tris(dibenzylideneacetone)dipalladium(0) (105 mg, 0.114 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (198 mg, 0.343 mmol), Cs2CO3 (558 mg, 1.71 mmol) and dioxane (15 mL) was stirred for 48 hours at 100° C. The reaction mixture was cooled down to ambient temperature, and partitioned with CHCl3 and water. The organic layer was dried over Na2SO4, and filtered. The filtrate was concentrated at reduced pressure, to give crude di-tert-butyl {6′-[(3-methoxypyridin-2-yl)amino]dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl}imidodicarbonate, which was used for the next reaction without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:35]=[N:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30]>>[Cl:26][C:27]1[CH:35]=[N:34][CH:33]=[CH:32][C:28]=1[C:29]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)=[O:30]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1ccncc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccncc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-chloroisonicotinic acid as starting compounds. The crude product is purified by chromatography (silica gel and DCM/diethyl ether/methanol=10:10:1) to yield the title compound.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:31][C:32]([CH:34]1[CH2:38][CH:37]([N:39]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:36][CH:35]1[CH3:54])=[O:33]>CN(C=O)C>[CH2:47]([N:39]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH:37]1[CH2:38][CH:34]([C:32](=[O:33])[CH2:31][N:20]([C:18]2[N:19]=[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:3])=[O:2])[C:15]3=[N:16][CH:17]=2)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH:35]([CH3:54])[CH2:36]1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NC(=O)OC(C)(C)C)cnc32)cc1
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(N(CC(=O)C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)C(=O)OC(C)(C)C)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A solution of tert-butyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylcarbamate (0.59 g, 1.519 mmol, Example #3 Step E) in DMF (5 mL) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 0.058 g, 1.45 mmol) in DMF (5 mL), at about 0° C. The resulting mixture was stirred at about 0° C. for about 30 min and then added dropwise to a solution of 2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (0.73 g, 1.8 mmol) in DMF (10 mL) at about 0° C. The resulting mixture was stirred at about 0° C. for about 1 h and the solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc (100 mL each). The organic phase was separated, dried over anhydrous MgSO4 and concd under reduced pressure to yield tert-butyl 2-(4-(dibenzylamino)-2-methylcyclopentyl)-2-oxoethyl(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)carbamate (1.04 g, 97%) as a yellow amorphous solid: LC/MS (Table 1, Method a) Rt=3.30 min; MS m/z 708 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18](Cl)=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:17])[F:16])=[CH:6][CH:5]=1)[CH3:2].[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]=1.N1C=CC=CC=1>C1C=CC=CC=1.CCOCC>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:24]=3)=[O:19])[CH2:13][C:12]([F:15])([F:14])[C:11]2([F:16])[F:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C2(C(=O)Cl)CC(F)(F)C2(F)F)cc1
Reactant: OCc1cccc(Oc2ccccc2)n1
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOc1ccc(C2(C(=O)OCc3cccc(Oc4ccccc4)n3)CC(F)(F)C2(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(4-ethoxyphenyl)-2,2,3,3-tetrafluorocyclobutane carbonyl chloride (0.76 gm, 1.54 mmole) in dry benzene (10 ml) was added a solution of 2-hydroxymethyl-6-phenoxypyridine (0.305 g) and pyridine (0.12 g) in dry benzene (15 ml). The mixture was stirred at room temperature for 16 hours then diluted with ether, washed twice with water, dried over Na2SO4 and concentrated in vacuo. Purification by high pressure liquid chromatography gave the ester as a colourless oil. IR (film) λmax 1741, 1606, 1591, 1575, 1500, 1490, 1450 cm-1. N.m.r. (250 MHz) δ (CDCl3) 1.42, t, 3H, J=7 Hz, CH3 ; 2.90-3.08, m, 1H, cyclobutyl H; 3.44-3.64, m, 1H, cyclobutyl H; 4.02, q, 2H, J=7 Hz, CH2CH3 ; 5.10, 5.16, ABq, 2H, J=14.5 Hz, CH2 -O; 6.71-7.64, m, 13H, aromatic H's. Mass spectrum, m/z 476 (M+ +1), 456 (M+ -19).
Reaction SMILES: [AlH4-].[Li+].[Br:3][C:4]1[CH:20]=[CH:19][C:7]2[C:8]3[N:9]=[C:10]([C:16](O)=[O:17])[S:11][C:12]=3[CH2:13][CH2:14][O:15][C:6]=2[CH:5]=1>O1CCCC1>[Br:3][C:4]1[CH:20]=[CH:19][C:7]2[C:8]3[N:9]=[C:10]([CH2:16][OH:17])[S:11][C:12]=3[CH2:13][CH2:14][O:15][C:6]=2[CH:5]=1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 0 °C
Yield: 63.3 %

Procedure:
Lithium tetrahydroaluminate (0.363 g, 9.56 mmol) was suspended in tetrahydrofuran (30 mL) and cooled to 0° C. A solution of 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1.04 g, 3.19 mmol) in tetrahydrofuran (1 mL) was then added dropwise over a 10 min period. The resulting reaction mixture was stirred while warming to r.t. for 12 h. LCMS indicated that the reaction was completely converted with a minor uncharacterized impurity present (<5%). The reaction was quenched by diluting with saturated Rochelle's salt solution and EtOAc (1:1, 200 mL). The mixture was stirred very vigorously until the phases separated. The layers were then partitioned and the aqueous layer was extracted with EtOAc (3×). The combined organic portions were dried over MgSO4, filtered and concentrated. The crude residue was purified by ISCO chromatography (40 g column, 0-75% EtOAc/heptane) to provide 0.63 g (63% yield) of (8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-methanol. LC/MS (ESI+): m/z 313.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[CH:13][N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:22][C:13]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:5]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc2ncc3ncn(-c4ccccc4Cl)c3c2c1
Solvent: ClC(Cl)Cl
Product: Clc1ccc2ncc3nc(Br)n(-c4ccccc4Cl)c3c2c1
Temperature: 0 °C

Procedure:
2 g (6.36 mmol) of 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline (Example 25), 6.6 g (37 mmol) N-bromosuccinimide, and 1.32 g (4.45 mmol) FeBr3 (98%; Aldrich) are heated and kept under reflux during 2½ h in 50 ml CHCl3. The cold solution is poured on ca. 300 ml ice-water, where a precipitate is formed. Extraction of the water phase with CH2Cl2 and chromatography of the raw material on silicagel (hexane-ethyl acetate 1:1) gives the desired title compound. mp: 183-192° C.; MS: 392 (M++1); HPLC: tret=12.44 min (Grad 1).
Reaction SMILES: O.[OH-].[Li+].C([O:6][P:7]([CH2:16][CH2:17][CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH3:20])([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:8])C>O.C(O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:19]([CH2:18][CH2:17][CH2:16][P:7]([CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])(=[O:6])[OH:8])[CH3:20])=[CH:27][CH:26]=1
Reactant: CCOC(OCC)P(=O)(CCCN(C)Cc1ccc(Cl)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)P(=O)(O)CCCN(C)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
0.43 g of lithium hydroxide monohydrate in 6 ml of water is added to a solution of 2.0 g of 3-[N-(p-chlorobenzyl)-N-methylamino]propyl(diethoxymethyl)phosphinic acid ethyl ester in 5.5 ml of ethanol, and the mixture is heated at 60° for 25 hours. The reaction mixture is cooled to room temperature, the solvent is removed under reduced pressure, and the evaporation residue is taken up in water and neutralised with phosphoric acid. The suspension formed is concentrated to dryness by evaporation, and the residue is taken up in hot methanol, filtered and concentrated by evaporation again. Crystallisation of the residue from propanol yields 3-[N-(p-chlorobenzyl)-N-methylamino]propyl(diethoxymethyl)phosphinic acid having a melting point of 170°-171.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[NH:13][C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH2:31][CH2:32]Cl)[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:30][CH2:29][N:28]([CH3:27])[CH2:31][CH3:32])[C:12]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CCN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(C)CCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2cc(Cl)ccc21
Yield: 155.8 %

Procedure:
A mixture of 1 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 0.5 g of 2-(N-methyl-N-ethylamino)ethyl chloride hydrochloride, 0.95 g of potassium carbonate and 20 ml of acetone is treated in the same manner as described in Example 1. The product thus obtained is converted into its hydrochloride and recrystallized from a mixture of chloroform, ethanol and ether. 1.03 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methyl-N-ethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained.
Reaction SMILES: [NH3:1].[C:2]([NH:5][CH:6]([C:12]([CH3:14])=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]>C(O)C>[C:2]([NH:5][C:6](=[C:12]([NH2:1])[CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: N
Reactant: CCOC(=O)C(NC(C)=O)C(C)=O
Solvent: CCO
Product: CCOC(=O)C(NC(C)=O)=C(C)N
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A solution of 0.054 mmol of ammonia in ethanol was added dropwise to 0.054 mol of ethyl 2-acetamidoacetoacetate in 40 ml of ice cold ethanol over a period of 10 minutes. The reaction vessel was tightly capped and allowed to stir overnight at 23° C., after which the solvent was removed at reduced pressure to provide ethyl 2-acetamido-3-aminobut-2-enoate in a 3/1 ratio of two geometrical isomers.
Reaction SMILES: O.[P:2]([Cl:6])(Cl)([Cl:4])=[O:3].[CH2:7]([OH:12])[CH2:8][CH2:9][CH2:10][CH3:11]>C(Cl)(Cl)(Cl)Cl>[P:2]([Cl:6])([Cl:4])(=[O:3])[O:12][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCO
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCOP(=O)(Cl)Cl
Reaction time: 18 h
Yield: 102.9 %

Procedure:
To a tap water cooled solution of 79 g of phosphorous oxychloride in 200 ml of carbon tetrachloride is added dropwise with stirring a solution of 50 g of 1-pentanol in 125 ml of carbon tetrachloride. The temperature rises to 30° C. and stirring is continued for 18 hours. The solvent is evaporated and the syrup evaporated with toluene several times. The residue is distilled from a Kugelrohr still to give 108.7 g of the desired product as a colorless oil, B.P. 85°-90° C./0.3 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].Br[CH2:11][CH:12]1[CH2:17][CH2:16][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(C2C=CC=CC=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C@H:12]2[CH2:17][CH2:16][Si@H:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Cl
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(Cl)c(C)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 4-chloro-3-methylphenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[C:9]=1Br.[C:50]([Sn](CCCC)(CCCC)CCCC)#[N:51]>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.O1CCOCC1>[CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[C:9]=1[C:50]#[N:51]
Reactant: COC(=O)c1ccc(-c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)cc1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2C#N)cc1
Temperature: 160 °C
Reaction time: 2 h

Procedure:
Under Ar, compound, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate (80 mg, 0.1 mmol) was mixed with Pd(PPh3)4 (12 mg, 0.01 mmol, Pd(t-Bu3P)3 (5 mg, 0.01 mmol), cyanotributylstannane (85 uL, 0.3 mmol) and dioxane (3 mL) in sealed tube. The resulting mixture was heated at 160° C. and stirred 2 hrs. After cooled to room temperature, the mixture was filtered through 10% KF on silica gel and washed with EtOAc. After concentration, the crude was used in the next step directly without further purification. HPLC-MS tR=3.18 min (UV254 nm); mass calculated for formula C38H46N6O4Si2 706.3, observed LCMS m/z 707.2 (M+H).
Reaction SMILES: CC1NC(=O)C2C(=CC3CCC(N([C:20]4[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=4)CC#C)C=3C=2)N=1.FC(F)(F)C(O[C:34]1[C:39]([F:40])=[C:38]([F:41])[C:37]([F:42])=[C:36]([F:43])[C:35]=1[F:44])=O>>[N:24]1[CH:25]=[CH:20][CH:21]=[CH:22][C:23]=1[C:26]([O:28][C:34]1[C:35]([F:44])=[C:36]([F:43])[C:37]([F:42])=[C:38]([F:41])[C:39]=1[F:40])=[O:27]
Reactant: C#CCN(c1ccc(C(=O)O)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccn1
Yield: 98 %

Procedure:
Using analogous procedures to those described in Example 12, 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridine-2-carboxylic acid was reacted with pentafluorophenyl trifluoroacetate to give the pentafluorophenyl pyridine-2-carboxylate which was in turn reacted with tri-tert-butyl L-γ-glutamyl-D-glutamate (European Patent Application No. 0509643, Example 1 thereof) to give tri-tert-butyl N-{5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridyl-2-carbonyl -L-γ-glutamyl-D-glutamate in 98% yield which was in turn hydrolysed with aqueous sodium hydroxide solution to give N-{5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]pyridyl-2-carbonyl}-L-γ-glutamyl-D-glutamic acid in 68% yield, m.p. 196° C.;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH2:15])([CH3:14])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(N(CC)CC)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]([C:4]1([CH3:14])[CH2:5][N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:25](=[O:27])[NH:15]1)=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(N)CNc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C1(C)CN(c2ccc(F)cc2)C(=O)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 145.2 %

Procedure:
A solution of 2-amino-3-(4-fluoro-phenylamino)-2-methyl-propionic acid methyl ester (282 mg, 1.25 mmol) in THF (10 mL) was treated with triethylamine (2.00 mL, 14.3 mmol) and cooled to 0° C. under argon. A solution of triphosgene (211 mg, 0.71 mmol) was added to the reaction dropwise and the mixture allowed to reach room temperature. After 1 hour, the mixture was diluted with DCM, washed with 1N HCl and the organic layers concentrated in vacuo. The resulting residue was purified by flash chromatography to afford the product (260 mg, 82%).
Reaction SMILES: [N:1]#[N:2].C(OC([NH:13][C@@H:14]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:15]([OH:30])[CH2:16][C@@:17]1([C:27]([NH2:29])=[O:28])[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]1[C:23]([CH3:26])([CH3:25])[CH3:24])=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:1]#[N:2].[NH2:13][C@@H:14]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:15]([OH:30])[CH2:16][C@@:17]1([C:27]([NH2:29])=[O:28])[CH2:21][C@@H:20]([OH:22])[CH2:19][N:18]1[C:23]([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)N1C[C@H](O)C[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)N1C[C@H](O)C[C@@]1(C[C@@H](O)[C@@H](N)Cc1ccccc1)C(N)=O
Yield: 96 %

Procedure:
0.226 g of N2 -[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-4(R)-hydroxy-L-prolinamide was dissolved in 20 ml of ethanol and hydrogenated over 40 mg of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 0.16 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-4(R)-hydroxy-L-prolinamide as a gum which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])(=O)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:14][O:13][C:11]([C:8]1([C:4]2[CH:3]=[C:2]([B:15]([OH:19])[OH:16])[CH:7]=[N:6][CH:5]=2)[CH2:10][CH2:9]1)=[O:12]
Reactant: COC(=O)C1(c2cncc(Br)c2)CC1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COC(=O)C1(c2cncc(B(O)O)c2)CC1
Temperature: 80 °C

Procedure:
To a vial containing the title compound from Example 71 Step B (0.150 g, 0.586 mmol), bis(pinacolato)diboron (0.178 g, 0.703 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.054 g, 0.059 mmol), tricyclohexylphosphine (0.033 g, 0.117 mmol) and potassium acetate (0.17 g, 1.76 mmol) was added dioxane (5.9 mL). The reaction was heated to 80° C. for 16 hours. It was then cooled to room temperature, passed through a syringe filter and concentrated under reduced pressure to afford the title compound: LCMS m/z 221.63 [M+H]+.
Reaction SMILES: [K+].[K+].[F:3][C:4]([F:22])([S:18]([O-:21])(=[O:20])=[O:19])[C:5]([F:17])([F:16])[C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[S:8]([O-:11])(=[O:10])=[O:9]>O>[F:13][C:7]([F:12])([S:8]([OH:11])(=[O:10])=[O:9])[C:6]([F:15])([F:14])[C:5]([F:16])([F:17])[C:4]([F:3])([F:22])[S:18]([OH:21])(=[O:19])=[O:20]
Reactant: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=S(=O)(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)O

Procedure:
Perfluorobutane-1,4-bis-sulphonate dipotassium salt (15 g, 34.2 mmol) was dissolved in hot water (100 ml). It was added to an ion exchange column of Amberlyst 15 resin, (40×4 cm) which had been previously washed with excess 6N HCl and rinsed with distilled water. The column was then washed slowly with distilled water, and the first 300 ml of aqueous solution collected. The solution was concentrated in vacuum and the residue was dried under reduced pressure at 80° C. to afford perfluorobutane-1,4-bis-sulphonic acid. (11.0 g, 30 mmol, 88%)