Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].N1C=CC=CC=1>C(#N)C>[Cl:12][CH2:13][CH2:14][C:15]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])=[O:16]
Reactant: O=C(Cl)CCCl
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1ccc(C(=O)O)c(O)c1
Reaction time: 0.33 h

Procedure:
7.5 g of 4-Aminosalicyclic acid was dissolved in 300 ml of acetonitrile at about 60° C. 12 ml of 3-chloropropionyl chloride was added dropwise and followed by addition of 5 ml of pyridine, the resulting mixture was refluxed for three hours. The mixture, which became clear after approximately 20 minutes of refluxing, was cooled and evaporated to dryness under reduced pressure. A gummy oil was dissolved in isopropanol-water and refrigerated for several days. A small amount of solid thus produced was filtered off. The filtrate was evaporated to dryness and approximately 16.8 g of crude 4-(3-chloropropionamido) salicyclic acid was produced. A lens treated with this compound was found to be clear with excellent UV blockage up to about 320 nm. ##STR9##
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.Cl.[O:12]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]1.C(N(CC)CC)C>CCO.O>[I:8][C:7]1[C:2]([NH:17][C@@H:14]2[CH2:15][CH2:16][O:12][CH2:13]2)=[N:3][C:4]([NH2:10])=[N:5][C:6]=1[CH3:9]
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: N[C@@H]1CCOC1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N[C@@H]2CCOC2)c1I
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A mixture of 4-chloro-5-iodo-6-methylpyrimidin-2-amine (7.03 g, 26.08 mmol), (R)-tetrahydrofuran-3-amine hydrochloride (Milestone PharmTech, 3.90 g, 31.3 mmol) and triethylamine (9.236 g, 91.3 mmol) in EtOH (150 mL) and water (50 mL) was refluxed for 2-3 days. The reaction was monitored by LC/MS. After completion, the reaction mixture was cooled to ambient temperature and partitioned between 150 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted by ethyl acetate 3 times. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate afforded (R)-5-iodo-6-methyl-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (4.53 g, 54% yield). MS (EI) for C9H13IN4O: 321.0 (MH+).
Reaction SMILES: [NH2:1][CH:2]([CH:5]([CH3:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:7][C:6]([F:9])([F:8])[CH:5]([CH:2]1[CH2:3][O:4][C:19](=[O:21])[NH:1]1)[CH3:10]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C(N)CO)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C1COC(=O)N1)C(F)(F)F

Procedure:
To a solution of 2-amino-4,4,4-trifluoro-3-methylbutan-1-ol (580 mg, 3.69 mmol) in DCM (13 ml) was added triethylamine (1.132 ml, 8.12 mmol) and added dropwise a solution of triphosgene (329 mg, 1.107 mmol) in 1 mL in DCM (3 ml) over 10 min. The reaction mixture was washed with sat. NH4Cl solution (13 ml) dry, and concentrated in vacuo. Afforded 450 mg (It yellow solid). Used crude in the next step. 1H NMR (400 MHz, CDCl3) b 5.91 (d, J=13.3 Hz, 1H), 4.61-4.34 (m, 1H), 4.22-4.00 (m, 2H), 3.05 (q, J=7.3 Hz, 1H), 2.54-2.14 (m, 1H), 1.34 (t, J=7.3 Hz, 1H), 1.17 (d, J=7.1 Hz, 2H), 1.09 (d, J=7.1 Hz, 1H). MS 183.0507 m/z.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2CCN2CCCCC2)c1
Temperature: 60 °C
Yield: 65.3 %

Procedure:
A mixture of 5-nitroindazole (4.0 g, 24 mmol) and potassium carbonate (10 g 74 mmol) in DMF (60 mL) was stirred for 30 minutes after which 1-(2-chloro-ethyl)-piperidine hydrochloride (6.8 g 37 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (4.3 g, 64% yield). 1H NMR (300 MHz, DMSO-d6) ppm 1.34 (m, 6H), 2.36 (m, 4H), 2.72 (t, J=6.44, 2H), 4.58 (t, J=6.44, 2H), 7.90 (m, 1H), 8.21 (m, 1H), 8.40 (m, 1H), 8.82 (m, 1H); MS (DCI/NH3) m/z 275 [M+H]+.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=O)[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]=12.[Cl:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=O)=[CH:20][CH:19]=1>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([CH2:11][CH3:12])=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][Cl:14])=[CH:19][CH:20]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CCC(=O)c1ccc2nsnc2c1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2nsnc2c1
Yield: 9.5 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(benzo[c][1,2,5]thiadiazol-5-yl)propan-1-one (552 mg, 2 mmol) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (384 mg, 2 mmol) to give the desired product (83 mg, 10%, Z/E=1/1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([O:19][CH3:20])=[CH:9][CH:10]=[C:11]3[C:16]=2[NH:15][C:14](=[O:17])[CH:13]=[C:12]3O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:25]>C1(C)C=CC=C(C)C=1>[NH2:25][C:12]1[C:11]2[C:16](=[C:7]([O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([O:19][CH3:20])=[CH:9][CH:10]=2)[NH:15][C:14](=[O:17])[CH:13]=1
Reactant: [NH4+]
Reactant: COc1ccc2c(O)cc(=O)[nH]c2c1OC1CCCC1
Agent: CC(=O)[O-]
Solvent: Cc1cccc(C)c1
Product: COc1ccc2c(N)cc(=O)[nH]c2c1OC1CCCC1
Temperature: 150 °C
Reaction time: 0.03 h

Procedure:
A mixture of 8-(cyclopentyloxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one (350 mg, 1.3 mmol), ammonium acetate (4.0 g, 52 mmol), and anhydrous m-xylene (10 mL) was heated at 150° C. under N2 for 48 h and then allowed to cool to rt. The mixture was concentrated to dryness, diluted with water (25 mL), stirred for 2 min, sonicated for 1 min, and then stirred for 5 min. The free-flowing solid was filtered, washed with water (25 mL), and pumped to dryness to give 4-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one: MS (ESI): 274.9.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:7]#[N:8])[NH:2]2.[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2)[C:21](O)=[O:22])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:7]([C@@H:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[N:2]1[C:21](=[O:22])[C@@H:20]([NH:19][C:17](=[O:18])[O:16][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][C:26]([OH:34])([CH2:27]3)[CH2:25]1)[CH2:31]2)#[N:8]
Reactant: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Reactant: N#C[C@@H]1C[C@@H]2C[C@@H]2N1
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
Path A: (1S,3S,5S)-2-Azabicyclo[3.1.0]hexane-3-carbonitrile or its salts of formula-XIII can be coupled with (2S)-2-{[(benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of formula-XIV to give benzyl N-[(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl]carbamate of Formula-XI in a suitable solvent, for example, tetrahydrofuran, N,N-dimethyl formamide, 1,4-dioxane or ethyl acetate using a coupling agent, for example, 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-(3′-dimethyl amino propyl)carbodiimide (EDAC), 1-propane phosphonic acid cyclic anhydride or N-[(dimethylamino)-1H-1,2,3-trizole[4,5-b]pyridylmethylene]-N-methylmethanaminium hexafluoro phosphate N-oxide (HATU) and optionally, a catalyst, for example, 1-hydroxybenzotriazole (HOBT) or 7-aza-hydroxylbenzotriazole (HOAt) and optionally, with a base, for example, N,N-dimethylamino pyridine (DMAP), triethylamine, N,N-diisopropylethylamine or N-methyl morpholine.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:15][CH2:16][N:17]=3)[C:10]([NH2:14])=[N:11][C:12]=2[CH:13]=1.[CH3:18][C:19]1[S:20][C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=1>>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:9]([CH2:15][CH2:16][N:17]=3)[C:10]([NH:14][C:25]([C:21]3[S:20][C:19]([CH3:18])=[N:23][C:22]=3[CH3:24])=[O:26])=[N:11][C:12]=2[CH:13]=1
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: COc1ccc2c(c1)N=C(N)N1CCN=C21
Agent: Br
Product: COc1ccc2c(c1)N=C(NC(=O)c1sc(C)nc1C)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 8-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine hydrobromide (Intermediate I, Step 3) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid as white solid (4.26 g, 77%): HPLC MS RT=2.05 min, MH+=356.1;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:15]([OH:17])=O.[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:15]([C:3]2[CH:4]=[C:5]([C:8]3[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]=2[F:1])=[O:17])[CH:25]=1)[CH3:19]
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)ccc1F
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3)ccc2F)c1

Procedure:
4,4′-Difluoro-biphenyl-3-carboxylic acid (100 mg, 0.43 mmol) was coupled to aniline (60) (82 mg, 0.43 mmol) using Method C to give the title compound.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].O.NN.[OH-].[K+]>C(O)C.C(O)COCCO>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:7][CH2:8]2)=[CH:17][CH:16]=1)[CH3:19]
Reactant: C=CCCC[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Solvent: CCO
Product: C=CCCC[C@H]1CC[C@H](c2ccc(CC)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 0.9 g of p-[trans-4-(4-pentenyl)cyclohexyl]acetophenone in 8 ml of ethanol and 8 ml of diethylene glycol was treated with 350 ml of hydrazine hydrate while gassing with argon and the solution was then heated to reflux (bath temperature 110° C.) while stirring for 1 hour. Subsequently, the mixture was treated with 421 mg of solid potassium hydroxide, the bath temperature was increased to 210° C. and the ethanol was distilled off. After 3 hours at 210° C. the reaction was interrupted and the mixture was partitioned three times in water/petroleum ether. The organic extracts were washed twice with water, dried over magnesium sulphate and evaporated. Chromatographic separation of the residue (0.85 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 0.76 g (90%) of 4-ethyl-1-[trans-4-(4-pentenyl)cyclohexyl]benzene as a colourless oil; m.p. (C--I) -10.6° C.
Reaction SMILES: C([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:12]2[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[C@@H:6]([CH3:32])[CH2:5]1)C=C.C(O)(=O)C1C(=CC=CC=1)S>O1CCCC1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:32][C@H:6]1[CH2:5][NH:4][C@H:9]([CH3:10])[CH2:8][N:7]1[C@@H:11]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1)[C:12]1[CH:24]=[CH:23][C:15]([C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1
Reactant: C=CCN1C[C@H](C)N([C@H](c2ccc(C(=O)N(CC)CC)cc2)c2cccc(O)c2)C[C@H]1C
Agent: O=C(O)c1ccccc1S
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Yield: 103.6 %

Procedure:
A solution of 4-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)-methyl]-N,N-diethylbenzamide (10.89 g, 25 mmol, from Method A) and thiosalicylic acid (4.63 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was stirred with a catalyst solution prepared by dissolution of bis(dibenzylidineacetone)palladium (0.718 g, 1.25 mmol) and 1,4-bis(diphenylphosphino)butane (0.533 g, 1.25 mmol) in tetrahydrofuran (10 mL) at room temperature under nitrogen for 1.5 hours (J. P. Genet, S. Lemaire-Audoire, M. Savignac, Tetrahedron Letters, 36, 1267-1270 (1995)). The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and aqueous sodium carbonate solution. The layers were separated and diethyl ether (250 mL) was added to the organic layer. This was extracted with 5% sodium carbonate solution (2×150 mL). The organic layer was diluted with pentane (500 mL) and extracted with 3 M hydrochloric acid (6×30 mL). The aqueous solution was adjusted to pH 9-10 with saturated aqueous sodium carbonate solution and extracted with methylene chloride (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 4-[(R)-((2S,5R)-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide as a brittle pale yellow foam (10.24 g). The product showed a single peak on HPLC (Zorbax C-8, isocratic 40% 0.01 M NH4OAc in MeOH, 3 min; linear gradient to 100% MeOH, 45 min; isocratic MeOH, 5 min; 1.0 mL/min; δobs=210 nm, Rt=19.24 min). Calc. for C24H33N3O2. 0.1 EtOAc. 0.4 CH2Cl2: % C, 67.96; H, 7.96; N, 9.59. Found: % C, 67.90; H, 8.03; N, 9.54. 1H NMR (CDCl3, 300 MHz): δ7.42 (d, J=8.1 Hz, 2H); 7.2 (d, J=8.3 Hz, 2H); 7.11 (t, J=7.8 Hz, 1H); 6.72 (d, J=8.1 Hz, 1H); 6.65 (s, 1H); 6.59 (d, J=7.6 Hz, 1H); 5.16 (s, 1H); 4.93 (v br s, 2H); 3.51 (br m, 2H); 3.27 (br m, 2H); 3.02-2.97 (m, 1H); 2.92 (d, J=10.5 Hz, 1H); 2.66 (br d, J=8.5 Hz, 2H); 2.60-2.45 (m, 1H); 1.84 (dd, J=11.3, 8.3 Hz, 1H); 1.27-1.15 (m, 3H); 1.10 (d, J=6.1 Hz, 3H overlapping with m, 3H); 1.02 (d, J=6.1 Hz, 3H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].O1CCCC1.C([Li])CCC.[C:18]1([CH2:24][C:25](OC)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC.C(O)(=O)C>[O:26]=[C:25]([CH2:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)Cc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: COP(=O)(CC(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of dimethyl methylphosphonate (62 g.) in 400 ml. of tetrahydrofuran at -74° C. is treated by slow addition of 316 ml. of 1.6 M n-butyllithium in hexane, while maintaining the temperature below -62° C. A solution of phenylacetic acid, methyl ester (37.5 g.) in 100 ml. of tetrahydrofuran is added while maintaining the temperature below -60° C. The mixture is stirred at that temperature for 3 hr. and then allowed to warm to about 25° C. Acetic acid (30 g.) is added and the resulting precipitate removed by filtration. The filtrate is concentrated, taken up in diethyl ether, washed with water and brine, dried over magnesium sulfate and concentrated to the product, 38.74 g. The product is further distilled 140°-155° C./0.4 mm. to yield 19.5 g. of the title compound.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:16][CH:17]=[C:18]([Br:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].C(N)CN>O1CCOCC1.[Cu]I>[Br:20][C:18]1[CH:19]=[C:15]([N:3]2[CH2:4][C@:5]3([CH:10]4[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]4)[CH2:6]3)[O:1][C:2]2=[O:13])[S:16][CH:17]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1csc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1cc(Br)cs1
Yield: 63.2 %

Procedure:
(S)-Spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one (471 mg, 2.58 mmol), 2,4-dibromothiophene (1.875 g, 7.75 mmole), copper (I) iodide (492 mg, 2.58 mmol), potassium carbonate (715 mg, 5.17 mmol) and ethylenediamine (170 μL, 2.58 mmol) in 1,4-dioxane (5 mL) were stirred at 110° C. overnight. The solution was allowed to cool, and then filtered, washed with aqueous ammonium hydroxide and evaporated. The residue was purified by flash chromatography using a gradient of ammoniated methanol in chloroform to give the title compound as a yellow solid (560 mg), m/z 343, 345 (MH+).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH:19]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[NH:21]1[CH2:22][CH2:23][CH:18]([C:15]2[CH:16]=[CH:17][C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:8][CH:7]=4)=[N:13][C:12]=3[CH:14]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3oc(-c4ccc(C(F)(F)F)cc4)nc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(-c2nc3cc(C4CCNCC4)ccc3o2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-{2-[4-(trifluoromethyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.17 mmol) dissolved in DCM (15 ml), cooled to 0° C., trifluoroacetic acid (0.1 ml) was added and stirred the reaction mixture at rt for 3 h. DCM and trifluoroacetic acid was removed on rotavapour to obtain the crude. Crude was washed with petether to obtain 5-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole 2,2,2-trifluoroacetate (90 mg) as an off-white solid. 5-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole 2,2,2-trifluoroacetate (90 mg, 0.19 mmol) dissolved in DCM (15 ml). To this mixture added TEA (0.1 ml, 0.56 mmol) and stirred the reaction mixture at rt for 30 mins. Reaction mixture cooled to 0° C. and added isopropylchloro formate (46 mg, 0.38 mmol). This mixture was stirred at rt for 30 mins. Work up (DCM/H2O) followed by evaporation of the DCM on rotavapour afforded crude. Crude was purified with combiflash using a gradient mixture of ethylacetate and petether (15:85) as eluent to afford the titled compound (30 mg) as an off-white solid. M.P.: 145-148° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.36 (d, J 8.1, 2H), 7.78 (d, J 8.3, 2H), 7.62 (d, J 1.5, 1H), 7.54 (d, J 8.5, 1H), 7.29-7.21 (m, 1H), 4.96 (septet, 6.2, 1H), 4.31 (bs, 2H), 2.95-2.76 (m, 3H), 1.90 (d, J 12.7, 2H), 1.75-1.63 (m, 2H), 1.27 (d, J 6.2, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CO>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]=[P:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2pc[nH]c12
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCCCn1cpc2ncnc(N)c21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
7-Amino-1H-1,3-azaphospholo[4,5-d]pyrimidine (compound 10, 0.5 g, 3.29 mmol) was suspended in dry DMF to which sodium hydride (160 mg, 4 mmol, 60% dispersion in mineral oil) was added under an argon atmosphere. The mixture was stirred at room temperature for 40 min and 1-bromohexane (0.56 mL, 4 mmol) was added. The reaction was continued for 3 h and the solvent was evaporated. The residue was dissolved in dichloromethane (150 mL) and washed with water (25 mL). Organic layer was separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layer was dried (Na2SO4) and evaporated. The residue was purified by silica gel column (2×15 cm) chromatography eluting with dichloromethane containing 0-4% methanol. The appropriate fractions containing the desired product were evaporated to yield 0.53 g (68%), mp 220-222° C. Ir (KBr): ν690 (=P-C), 1220 (-P=CH), and 3295 (NH2) cm-1. Uv (pH 1): λmax 254 nm (ε23,700), 282 (11,500), and 314 (5200); (MeOH): λmax 266 (ε31,600); (pH 11): λmax 266 nm (ε33,300), and 330 (2200). 31 p nmr (DMSO-d6): 63.21. 1H nmr (DMSO-d6): δ 0.80(t, 3 H, CH3), 1.23 (br s, 6 H, 3CH2), 1.92 (t, 2 H, CH2), 4.24 (t, 2 H, NCH2), 8.15 and 8.23 (2s, 2 H, NH2), 8.44 (d, 1 H, C5H), and 8.86 (d, 1 H, J=58.5 Hz, C2H). Anal. Calcd. for C11H17N4P: C, 55.92; H, 7.25; N, 23.72. Found: C, 55.49; H, 7.31; N, 23.28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: CCNCc1cccc(O)c1
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Product: CCN(Cc1cccc(O)c1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 3-ethylaminomethyl-phenol
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]([OH:35])([CH3:34])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[CH3:34][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[O:35][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@]1(CN2CCN(C(=O)OCc3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 2 h
Yield: 78.8 %

Procedure:
4-Trifluoromethoxybenzyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate prepared in Example 390 (4.3 g, 8.24 mmol) was dissolved in DMF (13 ml). To the solution, sodium hydride (430 mg, 10.7 mmol) was added followed by stirring at the same temperature for 2 hours with cooling on ice-bath. To the reaction mixture, ethyl acetate (4.3 ml) and water (30 ml) were added in this order, and the solution was stirred for 30 minutes. The precipitates were filtered off and washed with water. The solids obtained were recrystallized from ethyl acetate/isopropyl ether and then recrystallized from isopropyl alcohol to afford 4-trifluoromethoxybenzyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (3.15 g, yield 79%) as a white powder.