Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].OS([O-])(=O)=O.[K+]>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: COC(=O)CBr
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
A suspension of 2.60 g (8.30 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 5A) in 46 ml of THF was treated slowly at −78° C. with 9.30 ml (9.30 mmol) of lithium hexamethyldisilylazide 1M in THF. After 20 min at −78° C., the mixture was warmed to nearly −10° C. to go entirely in solution and cooled to −78° C. just after. Then, a solution of 1.18 ml (12.45 mmol) of methyl bromoacetate in 15 ml of THF was added dropwise. Over night, the solution was naturally warmed to RT, poured on aqueous 10% KHSO4 solution and extracted with EtOAc(3×). The organic phase was dried (Na2SO4) and evaporated to give 3.21 g (quant.) of the titled compound as a light brown solid containing max 5% of methyl bromoacetate. MS: 385.3 (MH+, 2Cl).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:45]=[C:44]2[C:40]([CH:41]=[N:42][N:43]2[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:45]=[C:44]3[C:40]([CH:41]=[N:42][N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCn1ncc2ccc(CCl)cc21
Product: COCCCn1ncc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.390 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy) propoxy]phenyl}piperidine-1-carboxylate and 0.199 g of 6-chloromethyl-1-(3-methoxypropyl)-1H-indazole are reacted. The title compound is obtained as a colourless oil. Rf=0.31 (2:1 EtOAc-heptane); Rt=6.12.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27]>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][OH:27])=[N:12][C:11]1=2)[CH3:14]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Reactant: OC[C@@H]1CCCN1
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC[C@H]3CO)nc21

Procedure:
The title compound, m.p. 238°-240° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and (S)-(+)-2-pyrrolidinemethanol using procedures analogous to those described above, except that the mixture was heated in a pressure bottle at 170° C. for 3 hrs, and the product was crystallized from chloroform/hexane.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([NH2:31])[C:16]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1.[C:32]1(=[O:42])[C:36]2([CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:35][C:34](=O)[O:33]1>C(#N)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=3)[C:34]([CH2:35][C:36]3([C:32]([OH:42])=[O:33])[CH2:40][CH2:39][CH2:38][CH2:37]3)=[N:31][C:15]=2[CH:14]=1
Reactant: O=C1CC2(CCCC2)C(=O)O1
Reactant: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(C(F)(F)F)cc2)CCCC1
Temperature: 80 °C

Procedure:
To a 10 mL round bottomed flask, equipped with a reflux condenser, were added 4-(quinolin-2-ylmethoxy)-N1-(4-(trifluoromethyl)benzyl)benzene-1,2-diamine (53 mg, 0.12 mmol), 2-oxaspiro[4.4]nonane-1,3-dione (19 mg, 0.12 mmol) and acetonitrile (1.3 mL). The flask was heated to 80° C. for 72 hours. The mixture was concentrated and the residue was dissolved in ethanol (2 mL) followed by the slow addition of HCl (0.6 mL, 12 N). The mixture was then heated to 80° C. until the starting material had been consumed. The reaction mixture was cooled to RT, concentrated to dryness and the resulting residue was dissolved in THF (3.4 mL) and methanol (3.4 mL). To this solution was added LiOH (3.6 mL, 1 M aq.) and the reaction was monitored by LCMS until the ester was consumed. The reaction mixture was then partitioned between 1 mL of aqueous NH4Cl and EtOAc. The aqueous layer was further extracted with EtOAc (3×20 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to dryness. The crude residue was purified using reverse phase HPLC to provide the title compound. MS (ESI): mass calcd. for C32H28F3N3O3, 559.21; m/z found, 5602 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.13 (d, J=8.4 Hz, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.58-7.44 (m, 3H), 7.35 (s, 1H), 7.14-6.85 (m, 4H), 5.32 (s, 4H), 3.04 (s, 2H), 2.43-2.14 (m, 2H), 1.75-1.31 (m, 7H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]([NH2:10])[C@H:2]1[OH:11].[C:12]1(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>>[CH2:15]1[CH2:14][C@:13]2([O:11][C@H:2]3[CH2:1][C:9]4[C:4]([C@H:3]3[NH:10]2)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C@@:12]2([O:19][C@H:2]3[CH2:1][C:9]4[C:4]([C@H:3]3[NH:10]2)=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:17][CH2:16]1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: O=C1CCCCC1=O
Product: c1ccc2c(c1)C[C@@H]1O[C@]3(CCCC[C@@]34N[C@@H]3c5ccccc5C[C@@H]3O4)N[C@H]21
Yield: 90 %

Procedure:
For example, employing (1R,2S)-cis-1-amino-2-indanol in the acid-promoted reaction with 1,2-cyclohexanedione, bisoxazolidine 1 was obtained in 90% yield and 99% de (FIG. 1B). It was shown that compound 1 was produced with excellent diastereoselectivity and exclusive formation of the (S,S)—N,O-diketal by crystallographic analysis: careful evaporation of a solution of 1 in chloroform gave the single crystal suitable for crystallographic analysis (CDCC602445). (Crystal structure data: C24H26N2O2, monoclinic, space group P21, a=16.9199(16) Å, b=5.5487(5) Å, c=23.585(2) Å, α=90.00°, β=108.5190(10)°, γ=90.00°, V=2099.6(3) Å3, Z=4, ρcalcd=1.367 g cm−3, T=173 K.) It was shown that the ligand possesses a C2-symmetric structure and an averaged separation of 2.35 Å between the nitrogen and oxygen atoms which facilitates bidentate binding to metal ions and organometallic compounds (FIG. 1C). It was envisioned that 1, as well as other bisoxazolidines, would be useful for a variety of asymmetric reactions.
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.Cl[CH2:22][C:23]#[N:24]>C(N(CC)CC)C>[OH:15][C@H:10]1[C@H:9]([NH:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:14][CH2:13][N:12]([CH2:22][C:23]#[N:24])[CH2:11]1
Reactant: N#CCCl
Reactant: O[C@@H]1CNCC[C@H]1NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred and heated (±70° C.) solution of 14.44 parts of trans-4-[(phenylmethyl)amino]-3-piperidinol in 189 parts of N,N-dimethylformamide were added 5.81 parts of chloroacetonitrile. After the addition of 9.7 parts of N,N-diethylethanamine, stirring was continued overnight at 70° C. After evaporation, the residue was taken up in dichloromethane. The organic layer was washed with a sodium carbonate solution in water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 13.1 parts (76.2%) of trans-3-hydroxy-4-[(phenylmethyl)amino]-1-piperidineacetonitrile; mp. 113.2° C. (interm. 16).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:14]2[CH2:19][CH2:18][C@@H:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:27]([NH2:29])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:14]2[CH2:15][CH2:16][C@@H:17]([CH3:20])[CH2:18][CH2:19]2)[CH2:10][C@H:9]1[C:27]#[N:29])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)[C@H]2CC[C@@H](C)CC2)C[C@H]1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of BOC-(2S,4S)-2(aminocarbonyl)-4-[(2,2-dimethylpropanoyl)(cis-4-methylcyclohexyl)amino]pyrrolidine (576 mg, 1.41 mmol) prepared in Step D of Example A7 in DCM (5 ml) was added dropwise TFAA (0.2 ml, 1.41 mmol), and the solution was stirred at rt for 2 h. After the reaction finished, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with brine. The organic solution was dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (514 mg, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Mg].[CH3:11][C:12]1([CH3:19])[CH2:17][CH2:16][C:15](=[O:18])[CH:14]=[CH:13]1>C(OCC)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:15]2([OH:18])[CH2:16][CH2:17][C:12]([CH3:19])([CH3:11])[CH:13]=[CH:14]2)=[CH:4][CH:3]=1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: ClCc1ccc(Cl)cc1
Agent: [Mg]
Solvent: CCOCC
Product: CC1(C)C=CC(O)(Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of 4-chlorobenzyl chloride (266 g, 1.65 mol) in diethyl ether (200 ml) was added slowly to a stirred mixture of magnesium (42 g, 1.73 mol) in diethyl ether (700 ml) to maintain the mixture at reflux. The mixture was warmed for a further 20 minutes after addition was complete. A solution of 4,4-dimethylcyclohex- 2-en-1-one (226 g, 1.82 mol) in diethyl ether (60 ml) was then added dropwise over a period of 30 minutes so as to maintain the mixture at reflux and the mixture stirred overnight. The mixture was then quenched with water (250 ml) and hydrochloric acid (5M, 500 ml), extracted with diethyl ether (3×400 ml), backwashed once with sodium bicarbonate solution (5% w/v) and once with water and then dried with anhydrous magnesium sulphate. The solvent was then flashed off to give 369 g 1-(4-chlorobenzyl)-4,4-dimethylcyclohex-2-en-1-ol as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[CH:3]1.[CH3:12][N:13](CCN(C)C)[CH3:14].C([Li])CCC.CN(C=O)C.[NH4+].[Cl-]>C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH2:12][NH:13][CH3:14]
Reactant: Cc1cccc2ccn(C)c12
Reactant: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CNCc1cc2cccc(C)c2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a solution of 1,7-dimethylindole (2.85 g, 19.6 mmol) and TMEDA (3.3 mL, 21.6 mmol) in diethyl ether (30 mL) at −30° C. under N2 was added n-butyllithium (13.5 mL of a 1.6 M solution in hexanes, 21.6 mmol) dropwise. The resulting orange solution was heated to reflux for 1 h and then DMF (4.6 mL, 58.8 mmol) was added in one portion. The solution was stirred at room temperature overnight. Saturated aqueous NH4Cl solution was added and the mixture was then extracted with ethyl acetate (3×150 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide an orange oil. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) gave the title compound (1.57 g, 46%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.83 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.21 (s, 1H), 7.09-7.02 (m, 2H), 4.39 (s, 3H), 2.79 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34]Cl)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C:45]1=[O:50]>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH:15]([CH3:17])[CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][CH2:34][N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[C:45](=[O:50])[CH2:46]3)=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1
Reactant: CN1CCNCC1=O
Reactant: COc1cc2c(Nc3c(Cl)cc(C#CCOC(C)C)c4c3OCO4)ncnc2cc1OCCCCl
Solvent: CCN(CC)CC
Solvent: COCCO
Product: COc1cc2c(Nc3c(Cl)cc(C#CCOC(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reaction time: 7 h
Yield: 50.3 %

Procedure:
A mixture of N-[5-chloro-7-(3-isopropoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.22 g, 0.43 mmol), triethylamine (0.29 ml, 2.13 mmol), 1-methylpiperazin-2-one (0.24 g, 2.13 mmol) in 2-methoxyethanol (3 ml) was heated to 80 C for 12 hours and then at 100 C for 7 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 2-8% methanol in dichloromethane to give the product as an light orange solid (0.129 g, 51%). NMR Spectrum: (DMSOd6) 1.18 (d, 6H), 1.98 (m, 2H), 2.52 (t, 2H under DMSO), 2.72 (t, 2H), 2.88 (s, 3H), 3.04 (s, 2H), 3.34 (t, 2H under H2O), 3.83 (m, 1H), 3.97 (s, 3H), 4.22 (t, 2H), 4.42 (s, 2H), 6.17 (s, 2H), 7.15 (s, 1H), 7.21 (s, 1H), 7.83 (s, 1H), 8.34 (s, 1H), 9.52 (s, 1H). Mass Spectrum: M+H+ 596 and M+H− 594.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C2C(=CC=1)OC(C1C=CC=CC=1)CC2=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][C:14]3=[O:27])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=C1CC(c2ccccc2)Oc2ccc(O)cc21
Product: O=C1CC(c2ccccc2)Oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc21

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4one was prepared as described for 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 200 mg of 6-hydroxyflavanone. 1H NMR (400 MHz, d6-DMSO) δ: 9.03 (bs, 1H), 8.64 (d, 1H, J 9.0 Hz), 7.59-7.41 (m, 7H), 7.31 (d, 1H, J 9.0 Hz), 7.23 (d, 1H, 8.8 Hz), 5.75 (dd, 1H, J 12.3, 2.9 Hz), 3.30 (dd, 1H, −16.3, 12.3 Hz), 2.87 (dd, 1H, −16.3, 2.9 Hz).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH2:17]CCO)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH2:9][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: OCCCc1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(CCl)CC(=O)OCCCc1ccccc1
Reaction time: 18 h
Yield: 103.1 %

Procedure:
A solution of ethyl 4-chloroacetoacetate (134 g, 815 mmol) and 3-phenyl-1-propanol (111 mL, 821 mmol) was heated in toluene, with azeotropic removal of ethanol, for 4 h. The solution was allowed to cool with stirring for 18 h and was then concentrated to give the title compound (214 g). Electrospray MS m/z 219 [M−Cl+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]([NH:57][CH2:58][CH2:59][NH2:60])([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[NH:60][CH2:59][CH2:58][NH:57][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:15][CH2:16]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
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: CC(C)(C)OC(=O)NCCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97.4 %

Procedure:
General procedure A was followed using N-Boc-isonipecotic acid (0.20 g, 0.86 mmol), HATU (0.43 g, 1.1 mmol), DIPEA (0.76 mL, 4.4 mmol), N-Boc-ethylenediamine (0.18 g, 1.1 mmol) and DMF (4 mL) to furnish the title compound as a beige solid (311 mg, 96%), m.p. 172-174° C.; umax (CHCl3)/cm−1 3022, 2981, 1684, 1671, 1507, 1367, 1241, 1165; m/z (ESI) C18H33N3NaO5 requires 394.2312, found [M+Na]+ 394.2310.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
To a stirred, ice cold solution of 1.8 g of cis-4-hydroxy-cyclohexanecarboxylic acid ethyl ester, and 2.8 mL of triethylamine, in 25 mL of dichloromethane was added 0.85 mL of methane-sulfonyl chloride drop-wise over 10 min. The mixture was allowed to stir for 30 min, then concentrated under reduced pressure and diluted with 50 mL of ether and washed with 25 mL of 10% HCl, 25 mL of water, 25 mL of saturated sodium carbonate. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude mesylate, 2.5 g, was used without further purification: 1H NMR (400 MHz, CDCl3) 4.92 (m, 1H), 4.15 (q, 2H), 3.02 (s, 3H), 2.4 (m, 1H), 2.05 (m, 2H), 1.92 (m, 2H), 1.62-1.4 (complex m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH3:12][NH2:13].[CH3:14][NH2:15].[C-]#N.[K+]>O>[CH3:1][N:2]([CH3:10])[N:3]1[CH2:8][CH2:7][C:6]([NH:15][CH3:14])([C:12]#[N:13])[CH2:5][CH2:4]1
Reactant: CN(C)N1CCC(=O)CC1
Reactant: CN
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: CNC1(C#N)CCN(N(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5.5 g 1-Dimethylamino-piperidin-4-one (prepared as described in Journal of Medicinal & Pharmaceutical Chemistry, 4, 423-36; 1961), 4.2 g methylamine hydrochloride and 4.9 ml methylamine solution (40% in water) are mixed in 35 ml water, then to this mixture a solution of 4 g potassium cyanide in 10 ml water is added. The resulting mixture is stirred at room temperature for 3 days, then extracted with ethyl acetate, the organic layer dried over sodium sulfate, and the solvent evaporated. 5.3 g 1-Dimethylamino-4-methylamino-piperidine-4-carbonitrile is obtained. 1H-NMR (CDCl3): 2.86 ppm (m, 2H), 2.57 ppm (m, 2H), 2.44 ppm (s, 3H), 2.32 ppm (s, 6H), 2.00 ppm (m, 2H), 1.69 ppm (m, 2H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si](C(C)(C)C)(C)C)[CH2:38]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([OH:44])[CH2:38]2)=[CH:10]1
Reactant: CCC(Oc1c(C)cc(C)cc1C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1c(C)cc(C)cc1C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 69.1 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.44 g of ([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2,4,6-trimethylphenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 58, above] and 38.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 694 mg of the desired compound as white crystals, melting at between 134° and 136° C.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][OH:16].[Cl:17][C:18]1[C:23](Cl)=[N:22][CH:21]=[CH:20][N:19]=1>O1CCOCC1>[Cl:17][C:18]1[C:23]([O:16][CH2:15][CH2:14][O:13][C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:3]=2)=[N:22][CH:21]=[CH:20][N:19]=1
Reactant: Clc1nccnc1Cl
Reactant: OCCOc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1nccnc1OCCOc1ccc2ccccc2c1
Temperature: 40 °C
Reaction time: 15 h

Procedure:
Sodium hydride (55% dispersion in mineral oil; 44 mg, 1.0 mmol) was added to a mixture of 2-(2-naphthoxy)ethanol (188 mg, 1.00 mmol) and 2,3-dichloropyrazine (149 mg, 1.00 mmol) in dioxane (0.5 mL), and the reaction mixture was stirred at 40° C. for 15 h. The crude material was used directly in Step 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](OC)(OC)OC.Cl.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][CH:10]=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: COC(OC)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-bromobenzene-1,2-diamine (3 g, 16 mmol) in DMF (22 mL) were added trimethyl orthoformate (44 mL) and conc. HCl (1.5 mL) and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water (200 mL) and adjusted to pH7 with saturated aqueous NaHCO3, extract with ethyl acetate (200 mL). The organic layer was dried over Na2SO4, concentrated to give 5-bromo-1H-benzo[d]imidazole (3.25 g, 100%) as an off-white solid. LCMS: 197 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (t, J=8.8 Hz, 1H), 7.55 (dd, J1=7.6 Hz, J=40 Hz, 1H), 7.79 (d, J=47.2 Hz, 1H), 8.26 (s, 1H), 12.61 (d, J=25.6 Hz, 1H).