Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][CH2:21][C:22](O)=[O:23].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(OCC)C>[Cl:20][CH2:21][C:22]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)CCl

Procedure:
A solution of 1-octadecanol 5 (5 0 g, 180 mmol), chloroacetic acid (17.5 g, 180 mmol) and concentrated sulfuric acid (0.1 mL) in 350 mL of toluene was refluxed overnight in a flask equipped with a Dean-Stark trap. The solution was diluted with 500 mL of diethyl ether and extracted twice with a saturated bicarbonate solution (500 mL). The aqueous phase was subsequently extracted with 400 mL of diethyl ether. The combined organic layers were dried with sodium sulfate and evaporated in vacuo yielding a brown solid, which was used without further purification. 1H-NMR (CDCl3) δ=4.20 (t, 2H), 4.07 (s, 2H), 1.68 (q, 2H), 1.30 (m, 30H), 0.89 (t, 3H) ppm. FT-IR: ν=2919, 2851, 1749 (C═O stretch), 1333, 1208 (C—O stretch), 786 cm−1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@H:10]3[CH2:15][CH2:14][C@H:13]([N:16]4[CH2:21][CH2:20][N:19]([CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[Cl:22])[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: c1cc([C@H]2CC[C@H](N3CCNCC3)CC2)cc2c1OCO2
Reactant: ClCc1ccccc1Cl
Product: Clc1ccccc1CN1CCN([C@H]2CC[C@H](c3ccc4c(c3)OCO4)CC2)CC1

Procedure:
The title compound was prepared from trans 1-[4-(1,3-benzodioxol-5-yl)-1-cyclohexyl]piperazine and 2-chlorobenzyl chloride by the method described in example to give the product (89%, mp: 89°-90° C.). Calc'd for C24H29ClN2O2 : C, 69.81%; H, 7.08%; N, 6.79%. Found: C, 69.50%; H, 7.03%; N, 6.71%.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:19]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(OC)cc1C=O)OCC
Yield: 31.2 %

Procedure:
To a stirred suspension containing 2-hydroxy-5-methoxybenzaldehyde (2.0 g, 13.16 mmol) and K2CO3 (2.18 g, 15.79 mmol) in DMF (20 mL), bromoacetaldehyde diethyl acetal (2.43 mL, 15.79 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography. The product was eluted with hexane/EtOAc (4:1) to give the target compound 23 (1.10 g, 31%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 10.49 (1H, s, CHO), 7.33 (1H, d, J=3.30 Hz, ArH), 7.12 (1H, dd, J=5.75 & 3.30 Hz, ArH), 6.97 (1H, d, J=9.05 Hz), 4.87 (1H, t, J=5.25 Hz, CH), 4.09 (2H, d, J=5.25 Hz, CH2), 3.81-3.78 (2H, m, CH2CH3), 3.67-3.64 (2H, m, CH2CH3), 1.26 (6H, t, J=7.05 Hz, 2×CH3).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([N+:23]([O-])=O)=[C:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1>[Fe].Cl>[Br:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1
Reactant: CC(Oc1c([N+](=O)[O-])ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Agent: [Fe]
Agent: Cl
Product: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
3-Bromo-7-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-6-nitrofuro[3,2-c]pyridine (Intermediate 9a) was reacted with iron/HCl as described in Example 2 to give 3-Bromo-7-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine (=racemic Example 2).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[CH2:6]1)#[N:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C([O-])(=O)C.[Na+]>>[C:18]([NH:2][CH2:1][CH2:3][CH2:4][N:5]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[C:8]2[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=2[CH2:6]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC1CC(=O)N(CCC#N)Cc2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)NCCCN1Cc2ccccc2C(C)CC1=O
Reaction time: 4 h
Yield: 74 %

Procedure:
A solution of 8 g. (0.034 moles) of 2-(2-cyanoethyl)-5-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one in 220 ml. of acetic anhydride is introduced into a 2-liter autoclave, 12 g. of anhydrous sodium acetate and approximately 5 g. of W-5 -Raney nickel, washed twice with 20 ml. of acetic anhydride, are added thereto. The reaction mixture is brought to a temperature of 50° C. and then stirred for 4 hours under a hydrogen pressure (initial pressure of 3.5 bars). The reaction mixture is filtered, the catalyst is washed with a little acetic anhydride and the solvent is evaporated in vacuo. The residual oil is suspended in water and the pH of the mixture is adjusted to 8 by the addition of aqueous sodium hydroxide solution. It is extracted with chloroform and the organic phase is washed with water and dried over anhydrous sodium sulfate. The syrup obtained after filtration and evaporation of the solvent in vacuo is purified by chromatography on a silica column. 7 g. (74% of theory) of syrupy 2-(3-acetamidopropyl)-5-methyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one are obtained.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[S:17][C:16]3[CH2:15][CH2:14][S:13](=[O:18])[CH2:12][C:11]=3[C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])=[N:4][N:3]=[N:2]1.S(S([O-])=O)([O-])(=O)=[O:24].[Na+].[Na+]>C(O)(=O)C.OO>[NH:1]1[C:5]([NH:6][C:7]([C:9]2[S:17][C:16]3[CH2:15][CH2:14][S:13](=[O:24])(=[O:18])[CH2:12][C:11]=3[C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])=[N:4][N:3]=[N:2]1
Reactant: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CS(=O)CC2
Reactant: O=S([O-])S(=O)(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CS(=O)(=O)CC2
Reaction time: 72 h

Procedure:
To a stirred solution of 0.2 g (0.59 mmol) of 3-isopropoxy-5-oxo-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid (1H-tetrazol-5-yl)amide (from Example 5) in 15 mL of glacial acetic acid was added in one portion 0.19 g of 31.5% aqueous hydrogen peroxide. The reaction mixture stood at 24° C. for 3 days, and then was treated with 10% aqueous sodium metabisulfite. The solvent was removed by evaporation under reduced pressure to give a solid residue. The solid was crystallized from 20 mL of ethylacetate and 1 mL of water to provide 0.115 g of 3-isopropoxy-5,5-dioxo-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid (1H-tetrazol-5-yl) amide, mp 230°-232° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39]O)=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.[NH2:45][C:46]([CH3:51])([CH2:49][OH:50])[CH2:47][OH:48].NC(C)(C)CO>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:45][C:46]([CH2:49][OH:50])([CH3:51])[CH2:47][OH:48])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:43])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(N)(CO)CO
Agent: CC(C)(N)CO
Product: Cc1cc(OCCNC(C)(CO)CO)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 57 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-hydroxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 2-amino-2-methyl-1-propanol, respectively.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].O.[OH-].[Li+].O>CO>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([S:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: COC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(SCCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 8 h

Procedure:
Methyl 3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propanoate (1.0 g, 3 mmole) was added to a clear solution of lithium hydroxide hydrate (0.64 g, 15 mmole) in methanol (15 ml). Water was added until the solution became cloudy and the mixture was then stirred overnight. The mixture was concentrated to about 10 ml and acidified with cold (5° ) 10% hydrochloric acid. The resultant precipitate was collected by filtration, washed with water, and air dried Recrystallization from cyclohexane gave the title compound, m.p. 108°-110°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21]([OH:23])=O)=[CH:10][CH:9]=2)=[O:4].[Cl-].[NH4+].Cl.C([N:44]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl>C1COCC1.O.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:21](=[O:23])[NH2:44])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(C(=O)O)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2ccccc2)c2cc(C(N)=O)ccc2c(=O)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 80.2 %

Procedure:
To a solution of 2-(4-tert-butoxycarbonylbenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3,6-dicarboxylic acid 3-methyl ester (300 mg) in THF (6 ml) were added ammonium chloride (100 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg), 1-hydroxy-1H-benzotriazole monohydrate (180 mg) and triethylamine (1 ml) at room temperature. The reaction mixture was stirred at 40° C. for 12 hrs. Water and 1N-hydrochloric acid were added to acidify the aqueous layer and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crystals were washed with methanol to give the title compound (240 mg).
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO.C(Cl)Cl>[C:11]1([NH:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([N:27]([CH3:28])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Reactant: CCCCCCCCCCl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCN(C)c1ccc(S(=O)(=O)Nc2ccccc2)cc1

Procedure:
The procedure of Example 17 was carried out using nonyl chloride and the product from Step 2 above. mp: 113-116° C.; TLC Rf =0.38 in MeOH/CH2Cl2 ; 1H NMR (CDC13, ppm) δ 7.9 (d, 2H), 7.6 (d, 5H), 7.3 (d, 2H), 7.0 (bs, 1H), 3.0 (s, 3H), 2.0 (t, 2H), 1.4 (m, 12H), 0.9 (t, 3 H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[O:21][C:22](=O)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:11][CH3:12])=[CH:6][CH:5]=1.C(N)[CH2:32][NH2:33].ClCCl>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:32]#[N:33])=[CH:16][C:15]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:11][CH3:12])=[CH:6][CH:5]=1
Reactant: CCN(Cc1ccc(Br)cc1OC(=O)c1ccccc1)c1ccc(C(=O)OC)cc1
Reactant: NCCN
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CCN(Cc1ccc(C#N)cc1OCc1ccccc1)c1ccc(C(=O)OC)cc1
Temperature: 140 °C

Procedure:
A mixture of methyl-4-[N-(2-benzoyloxy-4-bromobenzyl)-N-ethylamino]benzoate (5.64 g) and cuprous cyanide (1.28 g) in N,N-dimethylformamide (100 ml) was stirred and heated at 140° C. for 10 hours in an oil bath. The mixture was allowed to cool and was poured into a solution of ethylenediamine (10 ml) in water (240 ml). The resulting mixture was stirred for 30 minutes and then extracted three times with EtoAc (50 ml each time). The oil obtained on removal of the solvent was subjected to chromatography on silica eluting with dichloromethane to give methyl-4-[N-(2-benzyloxy-4-cyanobenzyl)-N-ethylamino]benzoate, yield 3.9 g.
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([C:13]#[N:14])[C:6]=1[F:15])(=O)C.[N+:16]([O-])([OH:18])=[O:17]>>[F:15][C:6]1[C:5]([OH:4])=[C:10]([O:11][CH3:12])[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[C:13]#[N:14]
Reactant: COc1ccc(C#N)c(F)c1OC(C)=O
Reactant: O=[N+]([O-])O
Product: COc1c([N+](=O)[O-])cc(C#N)c(F)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.8 g of 3-cyano-2-fluoro-6-methoxyphenyl acetate are introduced in three portions at -15° into 5 ml of 96 percent nitric acid, whereupon the mixture is stirred at -10° for 1 hour. Thereupon, the reaction mixture is poured on to 50 g of ice. The mixture is extracted twice with 70 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The thus-obtained residue is dissolved in 50 ml of 1N sodium carbonate solution and 50 ml of methanol, whereupon the solution is stirred at 23° for 1 hour and the methanol is distilled off. The residal aqueous phase is adjusted to pH 2 at 0° with conc. hydrochloric acid and extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated, and the residue is chromatographed on 45 g of silica gel with methylene chloride/methanol (97:3). After recrystallization from ether/hexane there is obtained 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile of m.p. 112°-113°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(CC)CC)C.[C:27]12([CH2:37][NH2:38])[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=[C:2]([NH:38][CH2:37][C:27]23[CH2:36][CH:31]4[CH2:30][CH:29]([CH2:35][CH:33]([CH2:32]4)[CH2:34]2)[CH2:28]3)[N:7]=1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2nc(Cl)nc(NCC34CC5CC(CC(C5)C3)C4)n2)cc1

Procedure:
To a solution of 4,6-dichloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (0.072 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-(1-adamantyl)-methanamine (7.2 mg, 0.072 mmol). The mixture can be microwaved at 120 degrees for 20 minutes. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [OH:1][CH:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:5](=[O:13])[NH:4][C:3]1=[O:14].[CH3:15]I>CO.C[O-]>[OH:1][CH:2]1[N:6]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:5](=[O:13])[N:4]([CH3:15])[C:3]1=[O:14]
Reactant: CI
Reactant: O=C1NC(=O)N(C2CCCCC2)C1O
Agent: C[O-]
Solvent: CO
Product: CN1C(=O)C(O)N(C2CCCCC2)C1=O
Reaction time: 1 h

Procedure:
2.0 g of 5-hydroxy-1-cyclohexylhydantoin were dissolved in 30 ml of methanol containing 600 mg of sodim methoxide. 20 minutes thereafter, 0.7 ml of methyl iodide were added dropwise to the solution and the reaction was continued at 50° C. for 1 hour. The solvent was removed by distillation and the residue was purified by thin layer chromatography on silica gel (ethyl acetate:hexane=1:1). The obtained crude product was recrystallized from benzene to give 500 mg of 5-hydroxy-1-cyclohexyl-3-methylhydantoin (compound 21) in the form of colorless needle crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH2:18][O:19]3)=[CH:14][C:12]=2[N:13]=1>COCCOC>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:8]1[N:9]=[N+:10]([O-:22])[C:11]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH2:18][O:19]3)=[CH:14][C:12]=2[N:13]=1
Reactant: CN(C)CCN
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCCC3
Solvent: COCCOC
Product: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCCC3
Yield: 84.7 %

Procedure:
N,N-Dimethyl-1,2-ethanediamine (0.47 mL, 4.3 mmol) was added to a stirred solution of chloride 240 (341 mg, 1.4 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 241 (343 mg, 83%) as a yellow solid: mp (MeOH/EtOAc) 150-152° C.; 1H NMR δ 7.58 (s, 1H, H-10), 7.30 (s, 1H, H-5), 5.79 (br s, 1H, NH), 4.25 (br dd, J=5.3, 5.2 Hz, 2H, H-8), 3.51-3.56 (m, 2H, CH2N), 2.96 (br t, J=6.0 Hz, 2H, H-6), 2.60 (br t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2], 2.02-2.09 (m, 2H, H-7); 13C NMR δ 158.0, 152.9, 143.6, 135.1, 130.0, 126.1, 104.3, 66.9, 57.6, 45.0 (2), 38.7, 25.9, 21.7. Anal. calcd for C14H19N5O2.½H2O: C, 57.2; H, 6.7; N, 23.8. Found: C, 57.1; H, 6.5; N, 23.9%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2nc(Cl)ncc2F)C1
Temperature: 80 °C

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (0.43 g, 2.59 mmol) and (R)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (0.56 g, 2.59 mmol) in THF (50 mL) was added iPr2NEt (0.45 mL, 2.59 mmol). The reaction mixture was heated at 80° C. at for 8 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (5-30% EtOAc/hexanes) to afford the desired product, 11a.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([OH:7])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.C(CCC(Cl)=O)#N>CN(C=O)C.C1COCC1.C(Cl)Cl>[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([C:5](=[O:7])[CH2:4][CH2:3][C:1]#[N:2])[CH2:26][CH2:25]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: N#CCCC(=O)O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: N#CCCC(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC#N)CC1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a stirred solution at 0° C. of provide 3-cyanopropanoic acid (0.110 g, 1.11 mmol) and DMF (2 drops) in THF (4.0 mL) was added oxalyl chloride (0.144 g, 1.13 mmol) dropwise and the reaction mixture was warmed to room temperature. After 1 h the reaction mixture was concentrated under reduced pressure. To a stirred solution at 0° C. of 1-(2-tert-butylphenyl)piperazine (0.218 g, 1.00 mmol) and triethylamine (0.303 g, 3.00 mmol) in methylene chloride (2.0 mL) was added a solution of the freshly prepared 3-cyanopropanoyl chloride in methylene chloride (2.0 mL) and the reaction mixture was warmed to room temperature. After 2 h the reaction mixture was diluted with methylene chloride (10.0 mL), washed with water (20.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 50% ethyl acetate/heptanes) to provide 4-(4-(2-tert-butyl-phenyl)piperazin-1-yl)-4-oxobutanenitrile (0.170 g, 57%) as an off-white solid, mp 109-110° C.
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[OH:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.[O:32]1CC[CH2:34][CH2:33]1>C(N(CC)CC)C>[C:33]([O:26][C@H:10]1[C@@H:9]([NH:8][C:6](=[O:7])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([NH2:1])=[CH:3][C:4]=2[O:30][CH3:31])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:11]1)(=[O:32])[CH3:34]
Reactant: C1CCOC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7.5 parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-hydroxy-4-piperidinyl]-2-methoxybenzamide in 68 parts of tetrahydrofuran were added dropwise 2.02 parts of N,N-diethylethanamine. After cooling to 0° C., there was dried dropwise a solution of 1.4 parts of acetyl chloride in 9 parts of tetrahydrofurane at a temperature below 0° C. Upon completion, stirring was continued for a while while cooling in an ice-bath. The reaction mixture was allowed to reach slowly room temperature and stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further separated by HPLC using a mixture of trichloromethane, hexane and methanol (48:48:4 by volume) as eluent. The second fraction (B-isomer) was collected and the eluent was evaporated. The residue was suspended in petroleumether. The product was filtered off and dried, yielding 1.7 parts of cis-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[3-(4-fluorophenoxy)propyl]-3-piperidinol acetate (ester); mp. 58.8° C. (compound 232).