Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([S:21]([N:24](CC2C=CC(OC)=CC=2OC)[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3ccnn3C)c(Cl)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1Cl
Yield: 77 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (314 mg, 0.51 mmol) prepared in Example 79b, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (183 mg, 77%) as a colorless solid.
Reaction SMILES: [Mg].[CH:2](I)([CH3:4])[CH3:3].CO[C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]>C(OCC)C>[CH:2]([C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11])([CH3:4])[CH3:3]
Reactant: COc1cccc(C#N)c1OC
Reactant: CC(C)I
Agent: [Mg]
Solvent: CCOCC
Product: COc1cccc(C#N)c1C(C)C
Temperature: 0 °C
Yield: 24.9 %

Procedure:
To a mixture of 2.76 g (0.115 mol) of magnesium in 75 mL of diethylether, was slowly added 24.31 g (0.143 mol) isopropyl iodide. The resulting reaction mixture was allowed to react until all of the magnesium was consumed. Then, a solution of 15.0 g (0.92 mol) of 2,3-dimethoxy benzonitrile in 75 mL of diethylether was added over ninety minutes. The resulting reaction mixture was reacted overnight at room temperature and then refluxed for four hours. The resultant reaction mixture was then cooled to 0° C., and the top layer was decanted into saturated ammonium chloride and ice. The resultant layers were separated and the organic layer was washed sequentially with a dilute sodium hydroxide solution, water, and a dilute hydrochloric acid solution, dried over sodium sulfate, filtered and then concentrated to provide an orange oil. This oil was distilled under reduced pressure (5 inch vigreux column; 0.2 mm Hg) to provide 6.25 g of an orange oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:9]#[N:10])=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC#N
Solvent: CC(=O)O
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(C#N)=Cc1ccccc1
Yield: 104.4 %

Procedure:
A solution of 2.55 g of benzaldehyde, 2.46 g of ethyl cyanoacetate, 0.3 ml of acetic acid and 0.3 ml of piperidine in 20 ml of dry benzene was heated under reflux for 16 hours while removing water formed during the reaction by using a molecular sieve. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 4.57 g of 2-cyano-3-phenylpropenoic acid ethyl ester as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1>CO.C(Cl)Cl.O=[Mn]=O>[CH:2]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)=[O:1]
Reactant: O=S(=O)(NCc1ccccn1)c1cccc(CO)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: O=Cc1cccc(S(=O)(=O)NCc2ccccn2)c1
Yield: 75.7 %

Procedure:
3-Hydroxymethyl-N-pyridin-2-ylmethyl-benzenesulfonamide (crude from previous step, 2.87 mmol) and MnO2 (2.9 g, 28.7 mmol) in methanol (0.5 mL) and CH2Cl2 (15 mL) were reacted at 50° C. under N2 overnight. The mixture was concentrated and purified by chromatography on silica gel (50% ethyl acetate and CH2Cl2) to afford the title compound (600 mg, 79% over two steps) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([O:11][C:12](=[O:16])[C:13]#[C:14][CH3:15])[CH3:10].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:9]([O:11][C:12](=[O:16])/[CH:13]=[C:14](/[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])\[CH3:15])[CH3:10]
Reactant: CC#CC(=O)OCC
Reactant: Oc1ccccc1Br
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1Br
Yield: 67.4 %

Procedure:
To a stirred mixture of 2-bromo-phenol (9.02 g, 0.052 mol) and ethyl-2-butynoate (11.7 g, 0.104 mol) in tetrahydrofuran (50 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.05 g, 0.053 mol) slowly. After addition was complete the mixture was stirred at reflux overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated and the residue dried under high vacuum which afforded (E)-3-(2-bromo-phenoxy)-but-2-enoic acid ethyl ester as a yellow oil (10.0 g, 67%) and used without further purification.
Reaction SMILES: C([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)C1C=CC=CC=1.C>CO.[Pd]>[OH:21][C:18]1[CH:17]=[CH:16][C:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)=[CH:20][CH:19]=1
Reactant: Oc1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@H](c2ccc(O)cc2)CC1

Procedure:
A suspension of trans-N-benzyl-4-(4-hydroxyphenyl)cyclohexanamine (7.69 g) and palladium over charcoal (800 mg) in methanol (300 mL) is stirred at a temperature close to 40° C. for 8 h under a pressure of 15 bar of dihydrogene. Filtration over celite and evaporation of the solvent under reduced pressure affords 4.9 g of trans-4-(4-hydroxyphenyl)cyclohexanamine as a white powder. trans-N-benzyl-4-(4-hydroxyphenyl)cyclohexanamine can be prepared as described in WO 01/81295 (Warner-Lambert Company).
Reaction SMILES: [Br:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:5]([NH2:6])=[C:4]([C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:16]=[CH:15][CH:14]=2)[CH:3]=1.CCN(C(C)C)C(C)C.C1N=CN([C:38](N2C=NC=C2)=[O:39])C=1.C(OC(C)C)(C)C.C(OCC)(=O)C>CN1CCCC1=O>[Br:1][C:2]1[C:8]([C:9]([F:11])([F:12])[F:10])=[CH:7][C:5]2[NH:6][C:38](=[O:39])[C:14]3[CH:15]=[N:16][N:17]([CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:13]=3[C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1-c1ccnn1C1CCOCC1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2c2c1cnn2C1CCOCC1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
To a mixture of 3.23 g of 4-bromo-2-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]-5-(trifluoromethyl)aniline and 32 mL of N-methylpyrrolidone were added 2.6 mL of DIPEA and 1.8 g of CDI, followed by stirring at 150° C. for 1.5 hours. After ice-cooling, diisopropyl ether/ethyl acetate (4/1) and ice were added thereto, followed by stirring. The precipitated solid was collected by filtration, and washed with water and diisopropyl ether/ethyl acetate (4/1). The obtained solid was added to diisopropyl ether/ethyl acetate (4/1), and heated, followed by stirring at room temperature for 10 minutes, and the solid was collected by filtration, washed with diethyl ether, and then dried under reduced pressure to obtain 2.95 g of 8-bromo-1-(tetrahydro-2H-pyran-4-yl)-7-(trifluoromethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH3:13])=[CH:5]2.[H-].[Na+].Cl[CH2:17][C:18]1[CH:37]=[CH:36][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.[I-].[Na+].[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C.O1CCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[CH:37]=[CH:36][C:21]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:26][CH:25]=3)=[CH:20][CH:19]=1)[C:6]([CH2:11][CH2:12][CH3:13])=[CH:5]2
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Reactant: CCCc1cc2cc(F)ccc2[nH]1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCc1cc2cc(F)ccc2n1Cc1ccc(COc2ccc(CCC(=O)O)cc2)cc1
Temperature: 0 °C
Yield: 29.8 %

Procedure:
To a solution of 5-fluoro-2-propyl-1H-indole (0.17 g, 0.98 mmol) in N,N-dimethylformamide (6.2 mL) was added sodium hydride (60% in oil, 39 mg, 0.98 mmol) with stirring at 0° C., and the mixture was stirred at the same temperature for 10 min. Methyl 3-(4-([4-(chloromethyl)benzyl]oxy}phenyl)propanoate (0.31 g, 0.98 mmol) and sodium iodide (0.15 g, 0.98 mmol) were added to the obtained mixture and the mixture was stirred at room temperature for 17 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 5% aqueous potassium hydrogensulfate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an oil. Then, a mixture of the obtained oil, 1 N aqueous sodium hydroxide solution (2.0 mL), methanol (5.0 mL) and tetrahydrofuran (10.0 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with 1 N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient cycle A), and the object fractions were collected and concentrated. Water was added to the residue, and the mixture was adjusted to pH 7 with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.13 g, yield 31%) as colorless crystals. MS (APCI−): 444 (M−H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][CH:5]([C:7]([NH:9][C:10]2[C:11]([I:28])=[C:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C:13]([I:22])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C:15]=2[I:16])=[O:8])[CH2:4][O:3]1.[C:30]([O:33][CH2:34][CH2:35]Br)(=[O:32])[CH3:31]>>[C:30]([O:33][CH2:34][CH2:35][N:9]([C:10]1[C:11]([I:28])=[C:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C:13]([I:22])=[C:14]([CH2:17][O:18][C:19](=[O:21])[CH3:20])[C:15]=1[I:16])[C:7]([CH:5]1[CH2:4][O:3][C:2]([CH3:29])([CH3:1])[O:6]1)=[O:8])(=[O:32])[CH3:31]
Reactant: CC(=O)OCc1c(I)c(COC(C)=O)c(I)c(NC(=O)C2COC(C)(C)O2)c1I
Reactant: CC(=O)OCCBr
Product: CC(=O)OCCN(C(=O)C1COC(C)(C)O1)c1c(I)c(COC(C)=O)c(I)c(COC(C)=O)c1I

Procedure:
5-(2,2,-Dimethyl-1,3-dioxolane-4-carbamido)-2,4,6-triiodo-1,3-di-(acetoxymethyl) benzene was alkylated with 2-bromoethyl acetate according to Example 30a. The crude product, containing some O-alkylated material was used directly in next step.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)[CH:9]=[CH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])=O>C(O)(=O)C>[F:20][C:19]([F:21])([F:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=[CH:9][CH:10]=1
Reactant: Nc1nc[nH]n1
Reactant: CN(C)C=CC(=O)c1ccccc1C(F)(F)F
Solvent: CC(=O)O
Product: FC(F)(F)c1ccccc1-c1ccnc2ncnn12

Procedure:
A mixture of 1.68 g. of 3-amino-1,2,4-triazole and 4.86 g. of 3-dimethylamino-2'-trifluoromethylacrylophenone in 25 ml. of glacial acetic acid refluxed for 16 hours. The resulting mixture is worked up as described in Example 54 to yield the product of the Example, m.p. 149°-151° C.
Reaction SMILES: C[N+:2]([CH2:5][CH2:6][O:7][P:8]([O:11][CH2:12][C@H:13]([O:31][C:32]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][CH3:46])=[O:33])[CH2:14][O:15][C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[O:17])([OH:10])=[O:9])(C)C.C[N+](CCOP(OC[C@H](OC(CCCCCCCCCCCOC)=O)COC(CCCCCCCCCCCOC)=O)([O-])=O)(C)C.C1C2C(COC(ON3C(=O)CCC3=O)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C(OC(=O)CCCCCCCCCCCCC)(=O)CCCCCCCCCCCCC>>[CH3:30][O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:16]([O:15][CH2:14][C@H:13]([O:31][C:32]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][CH3:46])=[O:33])[CH2:12][O:11][P:8]([O:7][CH2:6][CH2:5][NH2:2])([OH:10])=[O:9])=[O:17]
Reactant: COCCCCCCCCCCCC(=O)OC[C@H](COP(=O)(O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCOC
Agent: CCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCC
Agent: COCCCCCCCCCCCC(=O)OC[C@H](COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCOC
Agent: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: C1CCNCC1
Product: COCCCCCCCCCCCC(=O)OC[C@@H](COP(=O)(O)OCCN)OC(=O)CCCCCCCCCCCOC

Procedure:
The preparation of D-AC2 was identical to L-AC2 except D-glycerolphosphocholine, which was obtained from Synthetische Phosphor-Lipide, Biochemisches Labor, Bern CH Switzerland was used. L-PE2 was prepared by reacting glycerolphosphatidylethanolamine (L-a-GPE) with N-(9-Fluorenylmethoxycarbonyloxy) succinimide (FMOC-succinimide) to form L-a-GPE-FMOC followed by diacylation with 12MO anhydride then deprotection of FMOC with piperidine. L-PE1 was prepared by diacylating L-a-GPE-FMOC with myristic anhydride, then PLA2 cleavage to remove the sn-2 chain, then acylation with 12MO anhydride, and finally deprotection with piperidine to remove FMOC. ##STR47##
Reaction SMILES: Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][CH3:15])=[O:13])[C@@H:7]([CH3:16])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][N:36]([CH:38]3[CH2:43][CH2:42][N:41]([C:44](OC(C)(C)C)=O)[CH2:40][CH2:39]3)[CH:37]=2)O1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:3]2[C:2]([C:33]3[CH:34]=[N:35][N:36]([CH:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH:37]=3)=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C@H:7]([CH3:16])[N:8]3[C:12]([O:14][CH3:15])=[O:13])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COC(=O)N1c2ccc(Br)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Product: COC(=O)N1c2ccc(-c3cnn(C4CCN(C)CC4)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C

Procedure:
Methyl (S)-5-(4-fluorophenoxy)-2-methyl-6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate was synthesized from methyl (S)-6-bromo-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate, and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate according to the procedure outlined above for Example 58. 1H NMR (300 MHz, CDCl3) δ ppm 0.74-1.01 (m, 1H), 1.14 (d, J=6.74 Hz, 3H), 1.47-1.82 (m, 2H), 1.99-2.07 (m, 1H), 2.31 (br s, 1H), 2.44 (dt, J=17.00, 5.72 Hz, 1H), 2.52-2.72 (m, 1H), 2.77 (s, 3H), 3.16 (br s, 1H), 3.27-3.62 (m, 2H), 3.82 (s, 3H), 4.43 (br s, 1H), 4.57-4.84 (m, 2H), 4.85-5.10 (m, 1H), 6.68-6.75 (m, 2H), 6.86-6.98 (m, 2H), 7.27 (s, 1H), 7.41 (d, J=8.50 Hz, 1H), 7.57-7.78 (m, 2H). MS (ESI, pos. ion) m/z 479 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.NC(C1SC=C(C(OCC)=O)N=1)CC(C)C.[C:29]([NH:39][C@H:40]([C:45](O)=[O:46])[CH2:41][CH:42]([CH3:44])[CH3:43])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(N[C@H](C(N[C@H](C(O)=O)CC(C)C)=O)CC(C)C)(OCC1C=CC=CC=1)=O>>[CH2:32]([O:31][C:29]([NH:39][C@@H:40]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:45]([NH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=[O:46])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1csc(CN)n1
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)c1csc(C(N)CC(C)C)n1
Product: CCOC(=O)c1csc(CNC(=O)[C@H](CC(C)C)NC(=O)OCc2ccccc2)n1

Procedure:
Following the of Example 13, except substituting 1-tert-butoxycarbonyl)amino-1-(4-carboethoxythiazol-2yl)methane for (1S)-1-tert-butoxycarbonyl)amino-1-(4carboethoxythiazol-2-yl)-3-methylbutane, and N-Cbz-L-leucine for N-Cbz-L-leucinyl-L-leucine, the title compound was prepared 0.120 g, 32%). MS (MH+): 434.2.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:4])[CH3:5]
Reactant: CC(C)(CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3cccnc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)NC(=O)c1c[nH]c2ncc(Nc3cccnc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
N-(1-Hydroxy-2-methylpropan-2-yl)-2-(pyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32 mg, 70.1 μmol) was dissolved in dichloromethane (1.2 mL) and treated with trifluoroacetic acid (160 mg, 108 μL, 1.4 mmol). The mixture was stirred at room temperature for 16 h. The mixture was concentrated then re-dissolved in dichloromethane (1 mL), methanol (0.5 mL) and ammonium hydroxide (0.2 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with water and filtered. The solid obtained was washed with ether then dried to give N-(1-hydroxy-2-methylpropan-2-yl)-2-(pyridin-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (21 mg, 64.3 μmol, 92%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d) 6 ppm: 12.39 (s, 1H), 9.66 (s, 1H), 8.85 (d, J=2.5, 1 H), 8.21 (m, 1H), 8.16 (dd, J=4.7, 1.6, 1 H), 8.04 (s, 1H), 8.03 (s, 1H), 7.67 (s, 1H), 7.33 (m, 1H), 5.05 (t, J=5.6, 1 H), 3.58 (d, J=5.9, 2 H), 1.36 (s, 6H); MS (EI/CI) m/z: 327.1 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]1[CH:19]=[CH:20][C:21]([OH:51])=[C:22](/[CH:24]=[CH:25]/[CH:26]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][CH:42]=2)[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH:23]=1>CN(C=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:51][CH2:2][CH2:3][CH2:4][N:5]2[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])=[C:22](/[CH:24]=[CH:25]/[CH:26]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][CH:42]=2)[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[CH:23]=1
Reactant: O=C1CCCN1CCCCl
Reactant: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2O)CCc2ccc(C(=O)OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)CCc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
146 mg (0.91 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No. 91152-30-6] and 295 mg (0.91 mmol) of anhydrous cesium carbonate are added to a solution of 215 mg (0.45 mmol) of methyl 4-[(4E)-5-(5-fluoro-2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}pent-4-en-1-yl]benzoate in 5 ml of dry DMF, and the mixture is then stirred at 60° C. for 12 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The residue is purified by preparative HPLC. This gives 165 mg (purity 93%, 0.25 mmol, 56% of theory) of a colorless oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH2:23])#[N:11].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>O1CCCC1>[C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:25](=[O:26])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)#[N:11]
Reactant: N#Cc1ccc2[nH]cc(CCN)c2c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2[nH]cc(CCNC(=O)OCc3ccccc3)c2c1
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
A solution of diisopropylethylamine (6.11 g), in dry tetrahydrofuran (20 ml) was added to a stirred solution of 5-cyano-1H-indole-3-ethanamine (7.3 g) in dry tetrahydrofuran (250 ml). A solution of benzyl chloroformate (7.73 g) in dry tetrahydroguran (20 ml) was then added at room temperature. After stirring for 1.5 h the reaction mixture was partitioned between water (100 ml). The aqueous layer was separated and extracted with ethyl acetate (4×50 ml). The combined organic solutions were washed with water (100 ml), dried (MgSO4) filtered and evaporated to afford an oily solid which was washed with petroleum spirit (b.p. 60°-80°, 100 ml) and then recrystallised from a mixture of ethyl acetate (50 ml) and petroleum spirit (b.p. 60°-80°, 35 ml) to afford the title compound (9.46 g), m.p. 127.5°-129°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:7](=[O:31])[CH2:8][O:9][CH2:10][CH2:11][N:12]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]3[C:14]([N:15]([CH3:30])[C:16](=[O:29])[N:17]([CH3:28])[C:18]3=[O:27])=[CH:13]2)[S:5][CH:6]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]([OH:31])[CH2:8][O:9][CH2:10][CH2:11][N:12]2[C:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:19]3[C:14]([N:15]([CH3:30])[C:16](=[O:29])[N:17]([CH3:28])[C:18]3=[O:27])=[CH:13]2)[S:5][CH:6]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCOCC(=O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCOCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Reaction time: 0.42 h

Procedure:
6-(2-(2-(4-Chlorothiazol-2-yl)-2-oxoethoxy)ethyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (540 mg, 1.177 mmol) was dissolved in MeOH (20 mL) and sodium borohydride (134 mg, 3.53 mmol) was added. The mixture was stirred at room temp. for 25 minutes and the reaction was quenched with sat. NaHCO3(aq) and extracted with chloroform (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound;
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:21][CH2:22][NH2:23]>>[CH3:13][C@H:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([CH3:20])[N:15]1[CH2:21][CH2:22][NH:23][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: CCOC(=O)CN1CCCC1=O
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCCC1=O

Procedure:
A mixture of 17.1 g. of ethyl 2-oxo-1-pyrrolidineacetate (U.S. Pat. No. 3,459,738) and 25.4 g. of cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine (U.S. Pat. No. 3,446,811) is heated at 95°-100° C. for 16 hours. The excess cis-2-(2,6-dimethyl-1-piperidinyl)ethylamine is evaporated at reduced pressure and the residue is fractionated. The product, cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-oxo-1-pyrrolidineacetamide, is obtained as an oil, b.p. 178°-183° C./0.15 mm., which crystallizes on standing; m.p. 93°-94.5° C. after two crystallizations from ethyl acetate-pentane.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O:17]1CCCC1>[Fe]>[F:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=[O:17])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1CCOC1
Reactant: COc1ccc(C=C(C)[N+](=O)[O-])cc1F
Agent: [Fe]
Agent: Cl
Product: COc1ccc(CC(C)=O)cc1F

Procedure:
Concentrated hydrochloric acid (30 ml) was added dropwise, over 45 minutes, to a stirred mixture of iron powder (6 g) and 1-(3-fluoro-4-methoxyphenyl)-2-nitroprop-1-ene (5.7 g) in tetrahydrofuran (100 ml) at reflux. The mixture was heated under reflux for a further two hours, cooled, filtered and evaporated. Water (100 ml) was added to the residue and extracted with dichloromethane. The dried (magnesium sulphate) extracts were evaporated to dryness to give the title compound as an oil.