Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:4][CH:3]=1.NC(N)=[O:36].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C@@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]2[N:17]=[C:18]([NH:25][C:26]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[NH:28][N:27]=3)[C:19]3[CH2:24][CH2:23][CH2:22][C:20]=3[N:21]=2)=[O:10])=[CH:6][N+:7]=1[O-:36]
Reactant: NC(N)=O
Reactant: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CCC3)n[nH]1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)[n+]([O-])c3)nc3c2CCC3)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
To a solution of (S)—N-(6-fluoropyridin-3-yl)-1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide (200 mg, 0.44 mmol) and urea-hydrogen peroxide (125 mg, 1.33 mmol) in DCM (10 mL) at 0° C. was added trifluoroacetic anhydride (280 mg, 1.33 mmol). The resulting mixture was allowed to stir at RT overnight. The reaction mixture was concentrated under reduced pressure to afford an oily residue that was diluted with saturated sodium bicarbonate solution (10 mL), and the product was extracted with EtOAc (2×25 mL). The combined organic layer was dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave an oily residue that was purified by reverse phase HPLC to afford 10 mg of (S)-2-fluoro-5-(1-(4-(5-isopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamido)pyridine 1-oxide. 1HNMR (400 MHz, CD3OD) δ (ppm): 1.20 (d, 6H), 2.02-2.18 (m, 4H), 2.21-2.36 (m, 2H), 2.75-2.93 (m, 5H), 3.60-3.70 (m, 1H), 3.77-3.84 (m, 1H), 4.77 (dd, 1H), 6.21 (s, 1H), 7.36-7.41 (m, 1H), 7.50 (s, 1H), 8.81-8.89 (m, 1H). The other enantiomer was obtained using chiral (R) starting material.
Reaction SMILES: [CH2:1]([N:3]([CH2:53][CH3:54])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=2)[C:16]([N:18]([CH2:20][CH2:21][N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[C:27]([OH:29])=O)[CH3:19])=[O:17])=[O:12])=[C:6]([C:33]2[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[CH:36]=[CH:35][N:34]=2)[CH:5]=1)[CH3:2].[CH3:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][NH2:80].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68][CH2:69][CH2:70][O:71][CH2:72][CH2:73][O:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][NH:80][C:27]([C@@H:23]1[CH2:24][CH2:25][CH2:26][N:22]1[CH2:21][CH2:20][N:18]([CH3:19])[C:16](=[O:17])[C:15]1[CH:30]=[CH:31][CH:32]=[C:13]([C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([N:3]([CH2:53][CH3:54])[CH2:1][CH3:2])=[CH:5][C:6]=2[C:33]2[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[CH:36]=[CH:35][N:34]=2)=[O:12])[CH:14]=1)=[O:29]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCC[C@H]3C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a mixture of (S)-1-(2-(3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)-N-methylbenzamido)ethyl)pyrrolidine-2-carboxylic acid (1.32 mmol, 1.12 g), 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (1.38 mmol, 530 mg) and DIEA (9.21 mmol, 1.19 g) in DMF (4 mL) was added HATU (1.45 mmol, 0.551 g). The mixture was stirred at 60° C. for 1 h and purified by prep. HPLC to give a syrup (1.18 g, 62%). MS (ES, m/z): 1110.42 [M+H]+.
Reaction SMILES: C([O:5][C:6]1[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][C@H:16]([OH:19])[C@H:15]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:14]2)=[N:8][CH:9]=[CH:10][N:11]=1)(C)(C)C.C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][C@H:15]1[C@@H:16]([OH:19])[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[C:6](=[O:5])[NH:11][CH:10]=[CH:9][N:8]=2)[CH2:14]1
Reactant: CC(C)(C)Oc1nccnc1CN1CC[C@H](O)[C@H](COc2ccccc2F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=c1[nH]ccnc1CN1CC[C@H](O)[C@H](COc2ccccc2F)C1
Reaction time: 1 h
Yield: 40.1 %

Procedure:
After dissolving 198 mg of cis-1-(3-tert-butoxy-2-pyrazinylmethyl)-3-(2-fluorophenoxymethyl)piperidin-4-ol in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added while stirring on ice. After 1 hour, aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (68 mg, 40% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=1)=[O:13])[CH2:6]2)#[N:2].C(C1C=C2C(=CC=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=[O:42])C2)#N>>[CH:24]1([CH2:23][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]([N:7]3[CH2:6][C:5]4[C:9](=[CH:10][CH:11]=[C:3]([C:1]([NH2:2])=[O:42])[CH:4]=4)[CH2:8]3)=[O:13])=[CH:16][CH:17]=2)=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: N#Cc1ccc2c(c1)CN(C(=O)Nc1ccc(NC(=O)CC3CCCC3)cc1)C2
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C#N)cc3C2)cc1
Product: NC(=O)c1ccc2c(c1)CN(C(=O)Nc1ccc(NC(=O)CC3CCCC3)cc1)C2

Procedure:
The title compound was prepared as described in Example 132 substituting 5-cyano-N-{4-[(cyclopentylacetyl)amino]phenyl}-1,3-dihydro-2H-isoindole-2-carboxamide for 5-cyano-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.31 (s, 1H), 7.98 (s, 1H), 7.87-7.78 (m, 2H), 7.53-7.38 (m, 5H), 7.36 (brs, 1H), 4.78 (bs, 4H), 2.32-2.13 (m, 3H), 1.82-1.67 (m, 2H), 1.67-1.42 (m, 4H), 1.27-1.10 (m, 2H); MS (ESI(+)) m/e 407 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]1[CH2:29][N:28]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:26](=[O:27])[CH2:25]1.Cl>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:33]4[CH2:34][CH2:35][CH:30]([N:28]5[CH2:29][CH2:24][CH2:25][C:26]5=[O:27])[CH2:31][CH2:32]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCCN1C1CCNCC1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCO
Product: O=C1CCCN1C1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Yield: 22.5 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (400 mg, 1.260 mmol), 4-(N-2-pyrrolidinone)piperidine hydrochloride (493 mg, 4.407 mmol), absolute ethanol (16 ml), activated 3 Å molecular sieves (400 mg), titanium (IV) isopropoxide (1.86 ml, 6.30 mmol) and STAB (2.27 g, 10.71 mmol) were reacted in accordance with the general procedure D. The isolated waxy solid was purified by column chromatography on silica eluting with DCM(95):MeOH(4):NH3(1) to give the title compound as a pale yellow oil (133 mg, 22%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.83-3.71 (m, 3H), 3.52 (dt, 2H), 3.32 (t, 2H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.41-2.30 (m, 6H), 2.18 (dt, 2H), 2.12-1.36 (m, 16H).
Reaction SMILES: CN(CCN(C)C)C.[C:9]1([N:15]2[CH:19]=[CH:18][CH:17]=[CH:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([Li])CCC.[C:25]12([P:35]([C:37]34[CH2:46][CH:41]5[CH2:42][CH:43]([CH2:45][CH:39]([CH2:40]5)[CH2:38]3)[CH2:44]4)Cl)[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>CCCCCC.O>[C:9]1([N:15]2[CH:19]=[CH:18][CH:17]=[C:16]2[P:35]([C:37]23[CH2:38][CH:39]4[CH2:40][CH:41]([CH2:42][CH:43]([CH2:45]4)[CH2:44]2)[CH2:46]3)[C:25]23[CH2:26][CH:27]4[CH2:33][CH:31]([CH2:30][CH:29]([CH2:28]4)[CH2:34]2)[CH2:32]3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(-n2cccc2)cc1
Reactant: ClP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: c1ccc(-n2cccc2P(C23CC4CC(CC(C4)C2)C3)C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
1.6 ml of TMEDA (15 mmol.) are added to a suspension of 1.43 g (10 mmol.) of N-phenylpyrrole in 30 ml of hexane. 6.25 ml of 1.6 molar n-butyllithium solution (10 mmol.) are added at room temperature. The mixture is then heated for 2.5 hours at reflux temperature (solution 1). In another flask, 3.36 g (10 mmol.) of di-1-adamantylchlorophosphane are mixed with 40 ml of hexane and heated to 76° C. (solution 2). The boiling solution 1 is then slowly transferred into solution 2, which is at 76° C., by means of a cannula. The mixture is then boiled for a further 2 hours at reflux, the solution is cooled, and 20 ml of water are added thereto. The organic phase is filtered off over magnesium sulfate. The solution is concentrated in vacuo; 15 ml of toluene are added thereto, and the mixture is heated to 60° C. and then cooled. After one day at room temperature, the product is filtered off. Yield: 3.3 g (75%).
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:66]2[CH:78]=[CH:77][C:76]3[C:75]4[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=4)[C:69](=[O:79])[C:68]=3[CH:67]=2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:80][C:81]1[CH:86]=[CH:85][C:84]([Mg]Br)=[CH:83][CH:82]=1>C1COCC1>[Cl:80][C:81]1[CH:86]=[CH:85][C:84]([C:69]2([OH:79])[C:68]3[CH:67]=[C:66]([O:65][CH2:64][CH:22]4[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]4)[CH:78]=[CH:77][C:76]=3[C:75]3[C:70]2=[CH:71][CH:72]=[CH:73][CH:74]=3)=[CH:83][CH:82]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(=O)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(O)(c2ccc(Cl)cc2)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 40 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
2-(3,4,5-Tris(octadecyloxy)-cyclohexylmethoxy)-9-fluorenone (61.6 mg, 56.1 μmol) was dissolved in dehydrated THF (3 mL), 4-chlorophenyl-magnesium bromide (200 μmol) was added, and the mixture was stirred at 40° C. for 3 hours. After evaporation of the solvent, 0.5N hydrochloric acid (6 mL) was added to the residue to allow crystallization. The crystals were collected by filtration, washed well with hydrochloric acid, water and methanol in this order to give 9-(4-chloro-phenyl)-2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-fluorenol (64.1 mg, 53.0 μmol, 94%).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][C@@H:5]([CH3:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:2].[CH3:12][Mg]Br.C1COCC1.C1(C)C=CC=CC=1>C1COCC1>[OH:2][CH:1]([CH3:12])[CH2:3][CH2:4][C@@H:5]([CH3:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: C[Mg]Br
Reactant: COC(=O)C[C@H](C)CCC=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C[C@H](C)CCC(C)O
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
To a solution of aldehyde from Step 1 (1.03 g, 6.5 mmol) in THF (20 mL) at -70° C. was added 1.4M methyl magnesium bromide in THF-toluene 1:3 (4.66 mL, 6.52 mmol). The mixture was stirred at -70° C. for 45 minutes, quenched with aqueous saturated NH4Cl and allowed to warm up to room temperature. It was diluted with ether, and the organic phase was washed twice with brine, dried over MgSO4 and evaporated down. The residue was chromatographed on silica gel, eluting with a 1:2 mixtue of ethyl acetate and hexane, to afford the desired compound (293 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:3]=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ncccc1B(O)O
Reactant: Cc1cc(Cl)nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)c1
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: COCCOC
Product: COc1ncccc1-c1cc(C)cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)n1
Yield: 37.4 %

Procedure:
To N-(6-chloro-4-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (150 mg, 0.46 mmol) in 1,2-dimethoxyethane (4 mL) was added 2-methoxypyridin-3-ylboronic acid (84 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium (0) (53 mg, 0.046 mmol), and 2 M Na2CO3 (680 μL, 1.4 mmol). The reaction mixture was irradiated in the microwave at 120° C. for 20 minutes. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography eluting with (0-20% ethyl acetate/hexanes) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-4-methyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (69 mg, 38%).
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[C:16]([C:17](=O)[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([S:26]([N:29]=C=O)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:1]([C:9]1[O:10][C:11]2[C:16]([C:17](=[N:29][S:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:28])=[O:27])[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cc(=O)c2ccccc2o1
Solvent: CC#N
Product: O=C(c1ccccc1)c1cc(=NS(=O)(=O)c2ccccc2)c2ccccc2o1

Procedure:
Combine 2-Benzoyl-chromone (0.17 g, 0.68 mmol) and benzenesulfonyl isocyanate (1.02 mL, 2.03 mmol) in acetonitrile (7.0 mL). Heat at reflux for 48 hours. Add methanol (5 mL) to quench the reaction. Evaporate in vacuo to obtain a solid. Recrystallize from methanol to give the title compound as a solid: mp, 159°-160° C. Elem. Anal calcd. for C22H15NO4S: C, 67.85; H, 3.88; N, 3.60. Found: C, 67.47; H, 3.70; N, 3.56.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5](Cl)[CH:6]([OH:9])[CH2:7][CH3:8].[C:15]1([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH:6]([OH:9])[CH2:7][CH2:8][N:24]1[CH2:25][CH2:26][N:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22][CH2:23]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCC(O)C(Cl)Oc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: OC(CCN1CCN(c2ccccc2)CC1)COc1ccccc1Cl

Procedure:
A mixture of 35.1 g. (0.15 mole) of 1-(o-chlorophenoxy)-2-hydroxybutyl chloride, 32.6 g. (0.2 mole) of N-phenylpiperazine and 400 ml. of isopropanol was refluxed for 48 hr. The reaction mixture was allowed to stand in a refrigerator overnight and filtered. The filtrate was treated with ethereal hydrogen chloride and the salt precipitated by the addition of ether. The white crystalline solid which formed was dissolved in 0.1 mole of hydrochloric acid and then neutralized with sodium hydroxide producing a crystalline precipitate. This was recrystallized with isopropanol yielding 36 g. of the free base of the product which melted at 100°-101.5° C.
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][N:11]1[C:16](=[O:17])[C:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]([CH3:30])[CH3:29])[CH:22]=2)=[N:14][C:13]([Cl:31])=[C:12]1[CH3:32])C1C=CC=CC=1.Cl>C(O)C.[Pd]>[ClH:31].[Cl:31][C:13]1[N:14]=[C:15]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]([CH3:30])[CH3:29])[CH:22]=2)[C:16](=[O:17])[N:11]([CH2:10][C:9]([OH:33])=[O:8])[C:12]=1[CH3:32]
Reactant: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1c(Cl)nc(NCCc2cccc(CN(C)C)c2)c(=O)n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl-2-[3-chloro-5-(3-[(dimethylamino)methyl]phenethylamino)-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 20) (100 mg, 0.21 mmol) was dissolved in ethanol (10 ml), treated with 10% Pd on carbon catalyst (20 mg), aq HCl (1 m, 0.1 ml) and stirred under a hydrogen atmosphere (20 psi, room temperature, 2 hr). The catalyst was removed by filtration, the solvent evaporated to dryness and the residue azeotroped with CH2Cl2 to give the desired product, slightly impure (white solid, 85 mg). 1H NMR (CD3OD) δ 2.30 (s, 3H), 2.80 (s, 6H), 3.00 (t, 2H), 3.60 (t, 2H), 4.20 (s, 2H), 4.70 (s, 2H), 7.30 (m, 2H), 7.40 (m, 2H). LRMS m/z=379.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])[CH:17]=[CH:16][C:15]=1[S:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=1>C(O)C>[CH3:24][C:22](=[CH2:23])[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: C=C(C)COc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Solvent: CCO
Product: C=C(C)COc1ccc(Sc2ccc(NC(C)=O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 234a (55 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (12 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.76 (s, 3H) 2.02 (s, 3 H), 2.75 (s, 3 H), 4.52 (s, 2 H), 4.98 (s, 1 H), 5.05 (s, 1 H), 6.30 (d, J=7.35 Hz, 1 H), 7.04-7.19 (m, 4 H), 7.36 (s, 1 H), 7.41 (d, J=8.46 Hz, 2 H) 7.78 (d, J=8.82 Hz, 1 H), 8.37 (d, J=6.99 Hz, 1H), 8.94 (d, J=8.46 Hz, 1 H) 9.97 (s, 1 H), 10.99 (s, 1 H), 14.33 (s, 1 H); MS (ESI+) m/z 471(M+H)+.
Reaction SMILES: [Na+].[OH:2][C@@H:3]([C@H:5]1[C:11](=[O:12])[N:10]2[C@@H:6]1[CH2:7][C:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH3:25])=[O:23])=[CH:18][CH:17]=1)=[C:9]2[C:13]([O-:15])=[O:14])[CH3:4].[C:26]([O:32][CH2:33]I)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(OCC)(=O)C>CN(C)C=O>[OH:2][C@@H:3]([C@H:5]1[C:11](=[O:12])[N:10]2[C@@H:6]1[CH2:7][C:8]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:21]=1)=[C:9]2[C:13]([O:15][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:14])[CH3:4]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CNC(=O)c1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt (50 mg) in dry dimethylformamide (1 ml) was cooled with ice, and thereto was added pivaloyloxymethyl iodide (53 mg). The mixture was stirred at the same temperature for 1 hour. To the reaction solution were added ethyl acetate and ice-water, and separated. The organic layer was washed successively with a saturated brine (four times), an aqueous sodium hydrogen carbonate solution, an aqueous sodium thiosulfate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel thin layer chromatography (chloroform/methanol=9/1) to give [(2,2-dimethyl-propanoyl)oxy]methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (27 mg).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(#N)C>[Cl:8][C:7]1[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: CN1CCNCC1
Reactant: Clc1nccnc1Cl
Solvent: CC#N
Product: CN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 74 %

Procedure:
A mixture of 2,3-dichloropyrazine (10.1 g, 68 mmol) and N-methylpiperazine (10.15 g, 100 mmol) in acetonitrile (250 mL) was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was taken up in CHCl3/brine. The dried (MgSO4) organic layer was concentrated and the remaining oil was purified by chromatography on silica gel using CHCl3/MeOH (95:5) as eluent to give 10.7 g (75%) of the title compound as an oil that crystallized upon standing: mp 34-36° C. Anal. (C9H13CIN4) C, H, N.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10]([OH:14])(=[O:13])[CH:11]=O>>[C:10]([CH2:11][N:1]1[CH2:9][CH2:8][N:7]([CH2:11][C:10]([OH:14])=[O:13])[CH2:6][CH2:5][N:4]([CH2:11][C:10]([OH:14])=[O:13])[CH2:3][CH2:2]1)([OH:14])=[O:13]
Reactant: O=CC(=O)O
Reactant: C1CNCCNCCN1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CC1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), glyoxylic acid and H2/Pt.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([N:13]3[CH2:19][CH:18]4[O:20][CH:15]([CH2:16][CH2:17]4)[CH2:14]3)[N:10]=[C:9]([C:21]3[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:28]1([CH3:37])[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1>CN(C1C=CN=CC=1)C>[CH3:37][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([C:9]3[N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:12]=[C:11]([N:13]4[CH2:14][CH:15]5[O:20][CH:18]([CH2:17][CH2:16]5)[CH2:19]4)[N:10]=3)=[CH:22][CH:23]=2)=[O:36])=[CH:30][CH:29]=1
Reactant: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Agent: CN(C)c1ccncc1
Product: Cc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)nc(N4CC5CCC(C4)O5)n3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The titled compound was prepared by starting from 4-[4-morpholin-4-yl-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]aniline (100 mg, 0.27 mmol)-4-tolylisocyanate (60 mg, 0.45 mmol) and DMAP (5 mg) was stirred at room temperature for a period of 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. White solid; mp: 228; Yield 80 mg (80%); (M+H) 502.4