Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.[N:5]1[CH:6]=[CH:7][N:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15]3)[C:9]=12>CO>[N:5]1[CH:6]=[CH:7][N:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]3)[C:9]=12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3ccnc23)C1
Solvent: CC(=O)Cl
Solvent: CO
Product: N[C@H]1CCN(c2nccn3ccnc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 432.4 %

Procedure:
To a solution of acetyl chloride (114 mL, 1.6 mol) in 290 mL of MeOH at 0° C. was added a solution of (S)-tert-butyl (1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)carbamate (111.7 g, 0.37 mol) in 450 mL of MeOH. The reaction mixture was stirred at room temperature for 2 h then heated at 60° C. for 30 min. The product was filtered, washed with 200 mL of MeOH and dried in a vacuum oven to afforded (S)-1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-amine (101.2 g, 1.6 mol, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([CH3:17])[CH3:16])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:19])[C:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:17])[CH3:16])[CH3:12]
Reactant: O=Cc1cc(F)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(F)cc1C=O
Temperature: 110 °C
Yield: 35.4 %

Procedure:
5-Fluoro-2-hydroxy-benzaldehyde (14 g, 100 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (19.5 g, 100 mmol), K2CO3 (27 g, 196 mmol) and KI (0.97 g, 5.8 mmol) were mixed in DMF (150 mL). Then the reaction mixture was heated at 110° C. for 3 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with aqueous 1N NaOH. Then the organic layer was separated, dried over Na2SO4 and concentrated to give title compound (9 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@:20]([O:51][CH3:52])([NH:21][C:22](=[O:50])[C:23](=[N:29][O:30]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:53])[N:10]2[C:11]=1[C:12]([O:14]C(C)(C)C)=[O:13])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(=O)(O)[O-].[Na+]>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:20]([NH:21][C:22](=[O:50])[C:23](=[N:29][OH:30])[C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)([O:51][CH3:52])[C:19](=[O:53])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CO[C@@]1(NC(=O)C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccco2)C(=O)N2C(C(=O)OC(C)(C)C)=C(COC(C)=O)CS[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@]1(NC(=O)C(=NO)c2ccco2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21

Procedure:
t-Butyl (6R,7S)-3-acetoxymethyl-7-methoxy-7-[2-triphenylmethoxyimino-2-(fur-2-yl)-acetamido]-ceph-3-em-4-carboxylate (syn isomer) (713.3 mg, 0.966 mmole) was treated with trifluoroacetic acid (10 ml) and anisole (5 ml) for a total of 40 mins. and then added slowly to rapidly stirred saturated aqueous sodium bicarbonate (600 ml.). The mixture was extracted with ethyl acetate (2×150 ml), covered with ethyl acetate (200 ml), and adjusted to pH 2 with orthophosphoric acid. The organic layer was combined with the ethyl acetate wash (200 ml) of the aqueous layer, dried, and evaporated to a brown foam. Chromatography on three 40 × 20 cm. preparative-layer plates in chloroform-methanol-formic acid (90:16:2) provided a sample of the title compound as a pale-yellow foam containing ca 21/2mole-equivalents water (i.r. and microanalysis) (137 mg, 0.283 mmole, 29%) paper chromatography Rf 0.26, Rf/Rf cephaloram 0.58, λmax (pH 6 buffer) 272.5 nm (ε 16,400).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[F-].[K+].[I-].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:12]=1
Reactant: COCCCCl
Reactant: O=C1COc2ccc(Br)cc2N1
Agent: [F-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCCN1C(=O)COc2ccc(Br)cc21
Temperature: 100 °C
Reaction time: 40 h

Procedure:
The suspension of 9.87 g of 6-bromo-4H-benzo[1,4]oxazin-3-one [CAS 24036-52-0], 9.40 g of 1-chloro-3-methoxypropane, potassium fluoride on alumina (Fluka 60244), 0.144 g of potassium iodide in 500 ml of acetonitrile is stirred at 100° C. over 40 hours. The reaction mixture is cooled to room temperature and filtered through Hyflo, and the filtrate is concentrated by evaporation to dryness. The title compound is obtained as a slightly yellowish solid from the residue by crystallization from ethyl acetate. Rf=0.43 (1:1 EtOAc-heptane). Rt=4.27 (gradient I). m.p. 193-195° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH3:17])=[C:8]([C:6]2[N:5]=[C:4]([NH2:18])[N:3]=[C:2]([NH:26][C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:7]=2)[CH:13]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1ccc(Cl)cc1
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(Cl)cc2)nc(N)n1
Yield: 45 %

Procedure:
Following the method described in Example 53, 4-chloro-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (45% yield). 1H NMR (DMSO-d6) δ 1.39 (t, 3H, J=6.9 Hz, CH3), 4.14 (q, 2H, J=6.5 Hz, CH2), 6.36 (s, 2H, NH2), 6.78 (s, 1H, Ar), 7.15 (d, 1H, J=8.9 Hz, Ar), 7.32 (d, 2H, J=8.9 Hz, Ar), 7.41 (dd, 1H, J=8.8, 2.8 Hz, Ar), 7.79 (d, 2H, J=8.9 Hz, Ar), 7.91 (d, 1H, J=2.8 Hz), 9.31 (s, 1H, NH).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[H-].[Na+].[CH3:11][O:12][CH2:13]Cl>CN(C=O)C>[CH3:11][O:12][CH2:13][O:7][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:8])[CH:1]=1
Reactant: Cc1cccc(O)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To m-cresol (19.4 mL, 188 mmol) in DMF (1 L) was added NaH (60% disp. in oil, 9.04 g, 0.226 mmol) in several portions. The mixture was stirred at rt for 30 min, chloromethyl methyl ether (11.5 mL, 151 mmol) was added in one portion, and the reaction mixture was stirred at room temperature overnight, partitioned between 1N aq. NaOH and Et2O. The organic phase was washed with 1N aq. NaOH, dried over MgSO4, filtered and concentrated in vacuo, to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.18 (t, 1H), 6.86-6.77 (m, 3H), 5.18 (s, 2H), 3.43 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH2:7][OH:8].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CCOc1ccc(Br)cc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOc1ccc(Br)cc1C=O

Procedure:
5-Bromo-2-ethoxybenzyl alcohol (2.78 g, 12.0 mmol) and pyridinium dichromate (4.51 g, 12.0 mmol) in 120 ml of CH2Cl2 was stirred at RT for 6 h. The mixture was filtered, washed with H2O, 0.5N HCl and brine and dried over Na2SO4. The product was purified by silica gel column chromatography (EtOAc/petroleum ether 10:100) to give 5-bromo-2-ethoxybenzaldehyde.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH:9]=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].N1C=CC=CC=1>C(Cl)Cl>[S:12]([O:10][CH2:9][C:3]1([CH:2]=[O:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)([CH3:11])(=[O:14])=[O:13]
Reactant: O=CC1(CO)CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC1(C=O)CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
To a cold (0° C.) mixture of alcohol 54 (75 g, 0.54 mole) and 65.29 g (0.57 mole) of methanesulfonyl chloride in 80 ml of methylene chloride was added a solution of pyridine (47.96 g, 0.57 mole) in 40 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 h then quenched with water, acidified with conc. HCl and extracted with methylene chloride. The organic layer was washed with water, brine, and dried over sodium sulfate and concentrated under vacuum to give 91.63 g (77.8%) of thick oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([O:12]CC)C.C[O-].[Na+]>CO>[Cl:8][C:5]1[N:4]=[C:3]([O:12][CH3:10])[C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCOCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1Cl
Temperature: 0 °C

Procedure:
To a 250 mL round bottom flask equipped with a stir bar was added 1 g 5-chloro-2,4-dichloro-pyrimidine, and 15 mL of diethyl ether. The mixture was cooled to 0° C. in an ice bath and then 1 equivalent of sodium methoxide in methanol (prepared from reacting 120 mg of sodium with 4 mL of methanol at room temperature) was slowly added. The reaction was stirred over night at room temperature and checked by LCMS. The white precipitate was filtered and the solid washed with cold methanol. After drying, 0.98 g of pure 2,5-dichloro-4-methoxypyrimidine was obtained and this material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][C:43]([OH:45])=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:47][NH:48][O:49][CH3:50]>>[CH3:50][O:49][N:48]([CH3:47])[C:43](=[O:45])[CH2:42][C@H:11]1[CH2:10][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CNOC
Agent: Cl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 0.79 g of [(2R,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (from example 25f) are reacted with N,O-dimethylhydroxylamine hydrochloride to afford the title compound as a colourless foam. Rf=0.44 (EtOAc-heptane 5:1); Rt=5.00.
Reaction SMILES: [NH2:1][C@H:2]([CH3:17])[C:3]([NH:5][CH:6]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:4].[N+:18]([C:21]1[CH:51]=[CH:50][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37](=[O:49])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)N2C=CC=N2)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>O1CCCC1>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][O:26][C:27]([N:29]=[C:30]([NH:36][C:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)=[O:49])[NH:1][C@H:2]([CH3:17])[C:3]([NH:5][CH:6]2[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]2)=[O:4])=[O:28])=[CH:50][CH:51]=1)([O-:20])=[O:19]
Reactant: C[C@@H](N)C(=O)NC1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(N=C(NC(=O)OCc1ccc([N+](=O)[O-])cc1)n1cccn1)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: C[C@@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC1CN(C(=O)OC(C)(C)C)C1
Yield: 76.3 %

Procedure:
To a solution of tert-butyl 3-[(2R)-2-amino-2-methylacetylamino]-1-azetidinecarboxylate (443 mg) in anhydrous tetrahydrofuran (20 ml), 4-nitrobenzyl [(4-nitrobenzyloxy)carbonylimino-pyrazol-1-ylmethyl]carbamate (820 mg) was added under ice cooling. The resulting mixture was then treated in a similar manner to that described in Referential Example 16-(1), whereby the title compound (0.860 g) was obtained as an amorphous substance.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]2[C@H:25]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:26][CH2:27][CH2:28][N:21]2[C:20](=[O:36])[CH2:19][CH2:18]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:8]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]2[C@H:25]([C:29]([OH:31])=[O:30])[CH2:26][CH2:27][CH2:28][N:21]2[C:20](=[O:36])[CH2:19][CH2:18]1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)c3ccccc3)C(=O)N12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
TFA (20 ml) was added to an ice cold stirred solution of the t-butyl ester 211e (4.15 g, 10.34 mmol) in dry CH2Cl2 (20 ml). The mixture was kept cold for 1.5 h then left for 2.5 h at rt, concentrated. TFA was removed by repeated concentrations of CH2Cl2\ether and ether solutions of the residue. Finally trituration of the residue with ether afforded 212e 3.05 g (85%) of a white glassy solid: mp 118-126° C.; [α]D24 −70.5° (c 0.1, CH2Cl2). IR (KBr) 3361, 2943, 1737, 1659, 1537, 1426, 1220, 1174; 1H NMR (CDCl3) δ7.80 (2H, m), 7.54-7.33 (4H, m), 8.83 (brs), 5.44 (1H, m), 5.26-5.13 (1H, m), 4.66 (1H, m), 3.59-3.41 (1H, m), 2.97, 2.76 (2H, 2m), 2.36 (2H, m), 1.98 (2H, m), 1.75 (2H, m). MS(ES−, m/z) 344 (M−1, 100%).
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[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][NH:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])=[O:23])=[CH:20][CH:19]=1.[OH-].[K+].C(O)C.Cl>O>[CH3:33][Si:2]([CH3:1])([CH3:32])[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][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:23])=[CH:30][CH:31]=1
Reactant: COC(=O)CCC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCCCCCCCCCCCCCNc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of 5.4 g. of methyl 3-[4-[14-(trimethylsilyl)tetradecylamino]benzoyl]propionate is stirred with 5.4 g. of potassium hydroxide in 100 ml. of 95% ethanol for 3 hours at reflux. The reaction mixture is cooled, diluted with 50 ml. of ethanol and 100 ml. of water, and neutralized with hydrochloric acid. The solution is cooled to room temperature and filtered. The white solid is washed with 50% aqueous ethanol and dried. The product is recrystallized to yield 3-[4-[14-(trimethylsilyl)tetradecylamino]benzoyl]propionic acid as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[Se:10][C:6]=2[N:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[O:17][C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][C:20]=1[C:21]#[N:22].[OH-].[Na+]>CN(C=O)C>[C:23]([C:18]1[O:17][C:16]([NH:15][C:2]2[C:7]3[C:8]4[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=4[Se:10][C:6]=3[N:5]=[CH:4][N:3]=2)=[C:20]([C:21]#[N:22])[CH:19]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(C#N)c(N)o1
Reactant: Clc1ncnc2[se]c3c(c12)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C#N)c(Nc2ncnc3[se]c4c(c23)CCCC4)o1
Yield: 54.7 %

Procedure:
To a solution of 4-chloro-5,6,7,8-tetrahydrobenzo[1,2-b]pyrimidino[5,4-d]selenophene (500 mg, 1.83 mmol, from step b of example 1) in DMF (15 mL) was added sequentially 2-amino-5-tert-butylfuran-3-carbonitrile (300 mg, 1.83 mmol) and powdered NaOH (210 mg, 5.49 mmol) at rt. Work-up as described in example 2, gave the product as a yellow color solid (400 mg, 55%), mp 230-232° C. 1H NMR (400 MHz, CDCl3): δ 9.78 (1H, s, H-2), 6.94 (1H, br s, exchangeable with D2O, —NH), 6.35 (1H, s, H-4′), 3.30-3.31 (2H, m, H-8), 2.95 (2H, br s, H-5), 1.90-1.92 (4H, m, H-6,7), 1.38 (9H, s, tert-butyl); 13C NMR (100 MHz, CDCl3): δ 163.2, 161.7, 158.0, 154.0, 144.7, 142.9, 137.1, 133.8, 125.9, 101.4, 97.8, 33.0, 29.0, 28.8, 28.4, 23.1, 22.5; LC-MS (positive ion mode): m/z 399, 401 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH2:25]2)[CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:21][CH:22]([N:24]4[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH2:25]4)[CH2:23]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: O=C1CN(C2CNC2)CCN1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: O=C1CN(C2CN(Cc3ccc4nc(Cl)nc(N5CCOCC5)c4n3)C2)CCN1

Procedure:
4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.201 g) was reacted with 4-(azetidin-3-yl)piperazin-2-one via General Procedure B to afford 0.18 g 4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)piperazin-2-one.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26]([N:34]2[CH2:38][C@H:37]([CH2:39][N:40]3[CH:44]=[C:43]([CH3:45])[N:42]=[N:41]3)[O:36][C:35]2=[O:46])[CH:27]=[CH:28][C:29]=1[Sn](C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:29]3[CH:28]=[CH:27][C:26]([N:34]4[CH2:38][C@H:37]([CH2:39][N:40]5[CH:44]=[C:43]([CH3:45])[N:42]=[N:41]5)[O:36][C:35]4=[O:46])=[CH:25][C:24]=3[F:23])=[CH:18][CH:17]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Reactant: Cc1cn(C[C@H]2CN(c3ccc([Sn](C)(C)C)c(F)c3)C(=O)O2)nn1
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(N5C[C@H](CO[Si](C)(C)C(C)(C)C)OC5=O)cc4)c(F)c3)C(=O)O2)nn1
Yield: 4.3 %

Procedure:
Using essentially the same procedure as Example 28, but starting from (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-(4-iodophenyl)-1,3-oxazolidin-2-one (0.43 g, 1.00 mM) and adding (5R)-3-[3-fluoro-4-(trimethylstannyl)phenyl]-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (0.66 g, 1.50 mM) gave the title compound as a white solid (0.025 g).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1>CC(O)C>[ClH:2].[ClH:1].[F:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)=[C:12]([CH3:17])[CH:11]=1
Reactant: ClCCNCCCl
Reactant: Cc1cc(F)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(F)ccc1N1CCNCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (1.79 g, 10.03 mmol) and 4-fluoro-2-methylaniline (1.26 g, 10.07 mmol) were dissolved in 2-propanol (Volume: 10 mL) and stirred in a closed vial at 100° C. overnight. The reaction mixture was diluted with i-PrOH (10 mL) and cooled to 10° C. The resulting precipitate was filtered and purified using HPLC (10-80% ACN in water, TFA-buffered). The fractions were concentrated in vacuo, suspended in ether (3 mL) and treated with 4N HCl in dioxane (1 mL). The precipitate was filtered and dried in vacuum to afford 1-(4-fluoro-2-methylphenyl)piperazine dihydrochloride (150 mg, 0.561 mmol, 5.60% yield). ESI-MS:m/z 195 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1.[CH2:20]([OH:23])[CH2:21][OH:22]>N1C=CC=CC=1.CCOC(C)=O>[OH:22][CH2:21][CH2:20][O:23][C:2]1[C:3]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][S:5][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Reactant: OCCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2OCCO)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
K-t-BuO (1.24 g, 1 mmol) was added to a mixture of the product obtained in Step 1 (198 g, 6.5 mmol) and ethylene glycol (2.54 ml, 45.5 mmol) in pyridine (15 ml). The reaction mixture was stirred at 100° C. for 6 h and at room temperature overnight. The solution was then poured into ice-water and diluted with EtOAc. The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. The residue %% as purified by chromatography on silica gel eluting hexane/EtOAc (1:1) to give 1.71 g (65%) of title product as an orange oil. MS m/z 331 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-methyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C@@H:13]([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH3:14])[C@@H:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C@@H:7]1[CH2:36][NH2:37])(=O)C.[C:38]1(=O)[CH2:42][CH2:41][C:40](=[O:43])[CH2:39]1>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[F:23][C:21]([F:24])([F:22])[C:19]1[CH:20]=[C:15]([C@H:13]([O:12][C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:5][OH:4])[C@@H:7]([CH2:36][NH:37][C:38]3[CH2:42][CH2:41][C:40](=[O:43])[CH:39]=3)[C@@H:8]2[C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[CH3:14])[CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=1
Reactant: O=C1CCC(=O)C1
Reactant: CC(=O)OC[C@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)[C@@H]1CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H](CO)[C@@H](CNC2=CC(=O)CC2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
To a solution of 0.35 g (0.65 mmol) of [(1S,2R,3R,4S)-2-(aminomethyl)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexyl]methyl acetate (from Step N) in 30 mL dry toluene was added cyclopentane-1,3-dione (0.064 g, 0.65 mmol) and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 1 hr. The solvent was removed under vacuum and the residue was dissolved in 30 mL methanol. Sodium hydroxide (15 mL, 5 N) was added and the resulting mixture was stirred at 50° C. for 2 hr. The methanol and some of water were removed under vacuum. Water (20 mL) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine, dried over Na2SO4 and the solvent was removed under vacuum. The residue was purified by prep. TLC (9:1 ethyl acetate:hexane) to give the title compound (0.12 g). 1H-NMR (CDCl3) δ: 7.70 (1H, s), 7.18 (2H, s), 6.98 (2H, m), 6.93 (2H, m), 5.18 (0.5H, bs), 4.67 (0.5H, bs), 4.22 (1H, m), 3.78 (1H, m), 3.47 (1H, m), 3.27 (1H, m), 3.07 (1H, m), 2.95 (1H, m), 2.30 (1H, t), 2.40-2.20 (5H, m), 1.90 (1H, m), 1.80 (1H, m), 1.70-1.20 (3H, m), 1.33 (3H, d, J=6.4 Hz). MS: (MH)+ 574.1.