Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[OH:17])([CH2:4][CH3:5])([CH3:3])[CH3:2].Br[C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>N1C=CC=CC=1.C(OCC)C.[Cu]Cl>[C:1]([C:6]1[CH:11]=[C:10]([C:12]([CH2:15][CH3:16])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[O:17][C:19]1[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(O)c(C(C)(C)CC)c1
Reactant: COC(=O)c1ccccc1Br
Agent: Cl[Cu]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(Oc2ccccc2C(=O)OC)c(C(C)(C)CC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First, methyl 2,4-di-(tert-amyl)phenoxybenzoate was prepared. To a stirred suspension under argon of sodium hydride (60% dispersion in mineral oil, 1.1 g, 46.5 mmol, washed with ligroin to remove the oil) in pyridine (60 mL) was added dropwise a solution of 2,4-di-(tert-amyl)phenol (12.0 g, 51.2 mmol) in 20 mL of pyridine. The mixture was stirred for 2 h at room temperature and then treated dropwise with a solution of methyl 2-bromobenzoate (10 g, 46.5 mmol) in 10 mL of pyridine. Copper (I) chloride (1.15 g, 11.6 mmol) was added, and the mixture was heated at reflux 16 h and then cooled to ambient. The mixture was diluted with diethyl ether, washed successively with 10% aqueous HCl, water, and brine, and then dried over Na2SO4. The solvent was removed at reduced pressure to deposit dark brown oil. This crude product was purified by column chromatography to give 25.5 g, 78% of theory) of a light brown oil. 1H NMR (CDCl3): δ 0.70 (t, 6H), 1.3 (s, 6H), 1.4 (s, 6H), 1.63 (q, 2H), 1.85 (q, 2H), 3.85 (s, 3H), 6.68 (d, 1H), 6.82 (d, 1H), 7.05 (m, 2H), 7.3 (br s, 1H), 7.35 (t, 1H), 7.9 (dd, 1H).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1.C(OC(=O)C)(=O)C>[OH-].[Na+]>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:16][C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(C=Cc2cccnc2)cc1

Procedure:
p-Tolualdehyde (12.0 g), 3-picoline (8.6 g) and acetic anhydride (10.2 g) were heated at 160°C for 16 hrs. The reaction mixture was then poured hot into 10% NaOH (60 ml). The solid which crystallised was filtered off and subjected to column chromatography with neutral alumina using chloroform as solvent. Mpt. 166°C.
Reaction SMILES: [Br-].[Li+].[Br-].[CH2:4]([O:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Zn+])[CH3:5].Cl[C:16]1[N:25]=[C:24]2[C:19]([CH:20]=[C:21]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23]2)=[CH:18][CH:17]=1.CN1C(=O)N(C)CC1>C1COCC1>[C:32]1([C:21]2[CH:20]=[C:19]3[C:24](=[N:23][C:22]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:25]=[C:16]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([O:6][CH2:4][CH3:5])=[O:14])[CH:17]=[CH:18]3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)CCCCC[Zn+]
Reactant: Clc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCc1ccc2cc(-c3ccccc3)c(-c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture comprising lithium bromide (307 mg, 3.54 mmol) and PEPPSi-iPr catalyst (75 mg, 0.110 mmol) in THF (2 ml) was stirred at room temperature for 15 minutes until a solution formed. (6-Ethoxy-6-oxohexyl)zinc(II) bromide (13.26 ml of a 0.5M solution in THF, 6.62 mmol) was added and the mixture was cooled to 0° C. A solution of 7-chloro-2,3-diphenyl-1,8-naphthyridine (step 1) (350 mg, 1.105 mmol) in THF (3 ml)/DMI (1 ml) was added and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between EtOAc and water and the organic portion was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title product as a yellow oil;
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([C@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: Cl
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-5-methoxyindoline hydrochloride as the starting materials. mp 128–130° C.; 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 1 H), 6.71 (s, 2 H), 4.34–4.24 (m, 2 H), 4.11–3.99 (m, 1 H), 3.75 (s, 3 H), 3.08 (t, J=7.9 Hz, 2 H), 1.93–1.73 (m, 2 H), 1.06–0.99 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.79–0.72 (m, 1 H), 0.54–0.43 (m, 2 H), 0.34–0.24 (m, 1 H); HRMS (ESI) calcd for C19H22N3O2Cl2 (M+H)+: 394.1089; found m/z 394.1088.
Reaction SMILES: FC1C=CC2C(C3CCNCC3)=NOC=2C=1.C([O-])([O-])=O.[K+].[K+].BrCCCO[C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=1.[F:37][C:38]1[CH:65]=[CH:64][C:41]2[C:42]([CH:45]3[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][CH2:53][O:54]C4C=CC(C(=O)C)=CC=4)[CH2:47][CH2:46]3)=[N:43][O:44][C:40]=2[CH:39]=1>C(#N)C>[F:37][C:38]1[CH:65]=[CH:64][C:41]2[C:42]([CH:45]3[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][C:53]([C:28]4[CH:29]=[CH:30][C:31]([C:34](=[O:36])[CH3:35])=[CH:32][CH:33]=4)=[O:54])[CH2:47][CH2:46]3)=[N:43][O:44][C:40]=2[CH:39]=1
Reactant: CC(=O)c1ccc(OCCCBr)cc1
Reactant: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1
Agent: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(C(=O)CCN2CCC(c3noc4cc(F)ccc34)CC2)cc1

Procedure:
A mixture of 6fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.27 & 14.8 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)phenyl]ethanone (4.5 g, 17.5 mmol) in acetonitrile (60 ml) was heated at reflux for 4 hours. The solvent was removed. The residue was dissolved in dichloromethane (300 ml) and washed with water and brine, then dried over MgSO4. The crude product from the evaporated solution was purified by flash chromatography (SiO2, 60 g; eluted with 1% methanol in dichloromethane, 1 liter). The purest fractions were combined and gave 2.8 g, 48%, of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]ethanone, m.p.=111-112° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17]Cl)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1[NH:19][C:9]2=[N:10][CH:11]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc2cc(OCCCCl)cnc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCCCN3CCCCC3)cnc2[nH]1
Temperature: 25 °C
Yield: 68 %

Procedure:
The suspension consistent of 0.20 g (0.71 mmol) 5-(3-chloro-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, 0.12 g (0.85 mmol) potassium carbonate, 0.12 g (0.71 mmol) potassium iodide and 84 ml (72 μg, 0.85 mmol) piperidine was heated under reflux for 17 hours. After cooling down to room temperature the reaction mixture was poured on water and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was flash-chromatographed on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give 0.16 g (68%) of the desired compound as a light yellow solid.
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)#[N:2].S(Cl)([Cl:14])=O.CC1OC(C)O[CH:19]([CH3:24])O1>[Cl-].[Zn+2].[Cl-]>[C:1]([C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH:19]([Cl:14])[CH3:24])=[O:10])[CH2:7][CH2:8]1)#[N:2]
Reactant: N#C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Reactant: CC1OC(C)OC(C)O1
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(Cl)OC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 90 °C

Procedure:
trans-4-cyanocyclohexanecarboxylic acid (7.7 g; 0.05 mol) and thionyl chloride (8.0 g; 0.066 mol) was mixed and refluxed for 30 min. Excess thionyl chloride was evaporated in vacuum. Paraldehyde (2.5 g; 0.062 mol) and a catalytic amount of zinc chloride were added and the mixture was heated at 90° C. for 11/2 h with stirring. The cooled mixture was extracted with ether, washed with sodium bicarbonate solution, dried and evaporated, the product was distilled at 112° C./1 Pa. Yield 6.5 g of an oil.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([N+:17]([O-])=O)[C:9]=2[NH:20][CH3:21])=[N:6][NH:5][C:4](=[O:22])[CH2:3]1.O.NN>C(O)C.[Ni]>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[C:10]([NH2:17])[C:9]=2[NH:20][CH3:21])=[N:6][NH:5][C:4](=[O:22])[CH2:3]1
Reactant: CNc1c(C2=NNC(=O)CC2C)ccc(C(C)=O)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CNc1c(C2=NNC(=O)CC2C)ccc(C(C)=O)c1N
Temperature: 30 °C

Procedure:
0.65 gm of 5-methyl-6-(3-nitro-4-acetyl-methylamino-phenyl)-3-oxo-4,5-dihydro-2H-pyridazine were dissolved in 30 ml of ethanol and mixed with 0.5 ml of 80% hydrazine hydrate and 0.5 gm of Raney-nickel. The reaction mixture was heated at 30° C. for 10 minutes. After filtering off of the catalyst, the filtrate was mixed with glacial acetic acid and evaporated in vacuo. The residue was directly processed further.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:11]=1[C:12](O)=[O:13].CCCCCCC>CCOC(C)=O>[F:9][C:10]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:11]=1[C:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:13]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: Cc1ccc(O)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The title compound can also be prepared according to the following method: 4-methylphenol (80.0 g, 739.8 mmol) was added to a suspension of 2,4,5-trifluorobenzoic acid (136.8 g, 776.8 mmol) and 1,1-carbonyldiimidazole (83-85% wt, 163.6 g, 849.7 mmol) in EtOAc (1.20 L) at 40° C. The reaction mixture was stirred at 40° C. for 2 hours, then cooled to 20° C. and washed with water (480 mL), a 0.5 M aqueous solution of sodium hydroxide (2×400 mL) and water (400 mL). The organics were concentrated in vacuo and azeotroped with heptane to give a yellow oil. Heptane (640 mL) was added and the reaction was stirred at room temperature for 16 hours. A seed was used to facilitate the formation of a suspension. The resulting suspension was cooled to 10° C. and filtered. The residue was washed with cold heptane (80 mL) and dried to afford the title compound as an off white solid (147.5 g, 75%):
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:29][OH:30]>N1C=CC=CC=1>[C:20]([N:15]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:19]=2[N:18]=[CH:17][N:16]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][O:8][C:29](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@:4]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([OH:5])[C@@:2]1([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:3])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CO
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(N(C(=O)c4ccccc4)C(=O)c4ccccc4)ncnc32)[C@@](O)(C(=O)c2ccccc2)[C@@]1(O)C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 5.34 g (20 mmole) adenosine (Sigma, dried at 80° C./10-3Torr for 24 h) in 100 ml dry pyridine, 33.74 g (240 mmole) benzoyl chloride was added dropwise. After 20 h stirring at room temperature ("r.t.") the mixture was treated with 16 ml dry MeOH and then extracted with CHCl3 (3×250 ml). The organic phase was washed with water (3×250 ml), dried over Na2SO4, and evaporated to dryness. Final coevaporation was performed with toluene. The residue was dissolved in CHCl3 /MeOH 2/1 by heating, and after cooling to r.t., petrolether (diethylether) was added until the solution became turbid. After standing for 12 h at 0° C. 12.18 g was obtained, and from the mother liquor, 2.66 g of the product were isolated as colorless needles of m.p. 183°-184° C., yield 14.84 g (94%).
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:21](=[N:27]/O)\[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>N1C=CC=CC=1>[F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[O:15])[CH:7]([O:8]/[N:27]=[CH:21]/[C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: O/N=C/c1ccco1
Reactant: CC(=O)OC1NC(=O)NC(=O)C1(F)C(=O)OCC(C)C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1O/N=C/c1ccco1
Temperature: 25 °C
Reaction time: 21 h
Yield: 70 %

Procedure:
In 10 ml of pyridine were dissolved 2.9 g (10 mmol) of isobutyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 2.22 g (20 mmol) of (E)-furfuraldoxime, and 1.01 g (10 mmol) of dried triethylamine was added to the solution, followed by stirring at room temperature for 21 hours. The reaction solution was concentrated under reduced pressure, and 50 ml of ethyl acetate was added to the residue. The organic layer was washed three times with 10-ml portions of water, and the solvent was dried and evaporated under reduced pressure. The residue was recrystallized twice from ethyl acetate-hexane to give 2.39 g of isobutyl 5-fluoro-6-(E)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 167°-168° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([N:15]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:36][C@H:35]([CH2:37][N:38]=[N+]=[N-])[O:34][C:33]3=[O:41])=[CH:28][C:27]=2[F:42])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:43].C1(P([C:57]2[CH:62]=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([N:15]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:36][C@H:35]([CH2:37][NH:38][C:62](=[O:43])[CH3:57])[O:34][C:33]3=[O:41])=[CH:28][C:27]=2[F:42])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N(C(=O)OCc3ccccc3)C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N(C(=O)OCc3ccccc3)C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 0.5 h

Procedure:
A solution of 1.15 g 3-{[4-{(5R)-5-azidomethyl-2-oxo-oxazolidin-3-yl}-2-fluoro-phenyl]-benzyloxycarbonyl-amino)-azetidine-1-carboxylic acid benzyl ester (2 mmol), 0.36 ml water (20 mmol) and 0.277 g triphenylphosphine (2.2 mmol) was stirred for 16 h at 50° C. The solvent was evaporated. The residue was dissolved in 5 ml acetic acid and 2 ml acetic anhydride. The solution was stirred for 30 min and evaporated. The residue was purified by chromatography using a 9/1 ethyl acetate/methanol mixture as eluent.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH2:14])[CH2:10][N+:11]([O-:13])=[O:12].[O-:15][C:16]#[N:17].[K+]>O.CO>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([NH:14][C:16]([NH2:17])=[O:15])[CH2:10][N+:11]([O-:13])=[O:12]
Reactant: NC(C[N+](=O)[O-])c1ccccc1Cl
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC(=O)NC(C[N+](=O)[O-])c1ccccc1Cl
Temperature: 40 °C

Procedure:
At RT, 300 mg (about 93% pure, 1.18 mmol) of the compound of Example 25A were initially charged in 12 ml of water/methanol (1:1 v/v), and 287 mg (3.53 mmol) of potassium cyanate were added. The reaction mixture was warmed to 40° C. for 1 h. After cooling to RT, the mixture was directly separated into its components by preparative HPLC [Method 8]. This gave 120 mg (41% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C@@H:16]([CH2:19][N:20]=[N+]=[N-])[CH2:15][CH2:14]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[O:17][C@@H:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2
Reactant: [N-]=[N+]=NC[C@H]1CCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CCc2cccc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82.1 %

Procedure:
To a solution of {[(2R)-8-(2,6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}azide (0.21 g, 0.628 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.628 g, 1.885 mmol) and the reaction mixture stirred at room temperature for 4 days. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under reduced pressure to afford a yellow syrup. Purification by flash chromatography using a solvent gradient of 0.5 to 5% ammonia saturated methanol solution in dichloromethane gave 159 mg (82%) of {[(2R)-8-(2,6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amine as a colorless syrup. The product was dissolved in 2-propanol (1 mL) and diethyl ether (2.5 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.517 mL, 0.517 mmol) was added followed by hexane (2 mL). The resulting white precipitate was filtered to afford 155 mg (72%) of {[(2R)-8-(2,6-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}amine hydrochloride as a white crystalline solid, mp 188–190° C.; [α]D25=−6.74° (c=5.4 mg/0.7 mL MeOH).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][C:9]2[NH:10][CH2:11][CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([N:13]1[CH2:12][CH2:11][N:10]=[C:9]1[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: c1ccc(C(CC2=NCCN2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: CC(=O)N1CCN=C1CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5.0 g of 2-(2,2-diphenyl ethyl)-2-imidazoline and 50 ml of pyridine, 1.1 g of acetyl chloride was dropwise added and the solution stirred at room temperature for about 2 hours. After the reaction, pyridine was removed by distillation. To the resulting residue there was added 100 ml of benzene and the same amount of water, and the solution was well shaken. The benzene layer was separated, washed with water and dried with sodium sulfate. After removing benzene from the solution, the resulting residue was recrystallized from ether to give 1-acetyl-2-(2,2-diphenyl ethyl)-2-imidazoline having a melting point of 104°-106° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.OS([O-])=O.[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1onc(-c2ccccc2)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a chilled solution (-78° C.) of 4-[5-methylthio-3-phenylisoxazol-4-yl]benzenesulfonamide (Example 58) (0.256 g, 0.814 mmol) in dichloromethane (8 mL) was added MCPBA (0.234 g of 60% reagent, 0.814 mmol). After 1 hour, the reaction was warmed to 0° C. and held there for an additional hour. Dichloromethane (30 mL) and a solution of NaHSO3 were added and mixed for 5 minutes. The resulting mixture was extracted with ethyl acetate (20 mL) and the layers separated. The organic phase was washed with NaHSO3 solution and with NaHCO3 solution, dried over MgSO4, filtered and concentrated in vacuo yielding 4-[5-methylsulfinyl-3-phenylisoxazol-4-yl]benzenesulfonamide (0.107 g, 36%) as a pale yellow powder: mp 194°-204° C. 1H NMR (CDCl3 with DMSO6 /300 MHz) 7.98 (d, 2H, 8.46 Hz), 7.53-7.37 (m, 7H), 6.39 (s, 2H), 3.18 (s, 3H). FABLRMS m/z 363 (M+H). FABHRMS m/z 363.0480 (M+H, C16H15N2O4S2 requires 363.0473). Anal. Calc'd for C16H14N2O4S2 : C, 53.03; H, 3.89; N, 7.73. Found: C, 53.24; H, 3.96; N, 7.50.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CC#N>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: C1CNCCNC1
Reactant: Clc1ncc(Br)cn1
Solvent: CC#N
Product: Brc1cnc(N2CCCNCC2)nc1
Yield: 83.9 %

Procedure:
A solution of 5-Bromo-2-chloro-pyrimidine (1.0 g, 5.1 mmol), [1,4]Diazepane (1.0 g, 10.2 mmol) in CH3CN (5.0 mL) was stirred at 50° C. for 3 hrs. Filter of the solid and the solution was washed with brine, and concentrated in vacuo to give the title product (1.1 g, 85%) as a brown solid. ESI MS m/z 258 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 2H), 3.77 (m, 4H), 2.97 (q, J=10 Hz, 2H), 2.81 (q, J=15 Hz, 2H), 2.02 (s, 1H) 1.83 (qt, J=15 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(C(C)C)CC)(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:29]
Reactant: CCOC(=O)Cc1ccccc1N
Reactant: O=C(Cl)CCCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccccc1NC(=O)CCCCCl
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of ethyl 2-aminophenylacetate (5.60 g, 0.031 mole) and diisopropylethylamine (7.08 ml, 0.042 mole) in dry THF (75 ml) was treated with 5 chlorovaleryl chloride (4.00 ml, 0.031 mole) and left to stir for 1 h. The reaction mixture was concentrated in vacuo and the residue dissolved in ethyl acetate (200 ml) and washed with 1M HCl (100 ml), dried (Na2SO4) and concentrated in vacuo to afford a beige solid. This was washed with n-pentane/ether (1:1) and dried to afford the title compound as a light beige solid (8.1 g, 91%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]([C:14]2[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=2)[C:17]#[N:18])=[O:13])=[N:4][C:5]([O:10]C)=[N:6][C:7]=1[O:8]C>C(Br)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5](=[O:10])[NH:4][C:3]=1[C:12]([C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:17]#[N:18])=[O:13]
Reactant: COc1nc(OC)c(Br)c(C(=O)c2cc(C)cc(C#N)c2)n1
Agent: CC(=O)Br
Product: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2Br)c1

Procedure:
To a solution of 3-(5-bromo-2,6-dimethoxy-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (0.158 g, 0.436 mmol) in acetyl bromide (2.0 mL) was heated at 65° C. for 24 h. Reaction mixture was concentrated and flash column chromatography (silica gel, 0 to 80% ethyl acetate/hexane) to give a yellow film (0.0802 g, 55%). 1H NMR (300 MHz, CD3OD): δ 8.18 (s, 1H), 8.09 (s, 1H), 7.90 (s, 1H), 2.46 (s, 3H). Mass spectrum: 335.3 (M+H)+.