Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].O=[C:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[Si](OCC)(OCC)(OCC)OCC.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:3]2[NH:4][C:12]3[CH:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:15][C:16]=3[C:2]=2[CH:8]=1
Reactant: COc1ccc(N)c(I)c1
Reactant: CCOC(=O)CC1CCCC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OC)cc21
Temperature: 135 °C
Reaction time: 4 h
Yield: 86.6 %

Procedure:
2-Iodo-4-methoxyaniline (2.0 g, 8.03 mmol) and ethyl 2-(2-oxocyclopentyl)acetate (2.05 g, 12.1 mmol) were dissolved in DMF (30 mL) and tetraethyl orthosilicate (2.12 g, 10.4 mmol) and pyridinump-toluenesulfonate (PPTS) (0.081 g, 0.321 mmol) were added. The reaction mixture was heated and stirred at 135° C. for 4 h. After cooling to 120° C., DIEA (3.11 g, 24.09 mmol) and palladium (II) acetate (0.054 g, 0.241 mmol) were added. The reaction mixture was stirred for 3 h and then partitioned between ethyl acetate and water. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant solution was diluted with 50% ethyl acetate in hexanes and filtered through a pad of silica gel. The filtrate was concentrated and purified by silica gel column chromatography to give 1.9 g of ethyl 2-(7-methoxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate containing residual ethyl 2-(2-oxocyclopentyl)acetate. The mixture was dissolved in DCM (80 mL) and cooled to 0° C. Boron tribromide (21.0 mL, 21.0 mmol, 1.0 M in DCM) was added and the reaction was stirred for 1.5 h. Ice water was added and the reaction mixture was allowed to reach room temperature. The aqueous mixture was extracted three times with DCM. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (650 mg). LCMS m/z=260.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.2 Hz, 3H), 2.05-2.14 (m, 1H), 2.50 (dd, J=16.8, 11.2 Hz, 1H), 2.68-2.86 (m, 4H), 3.48-3.58 (m, 1H), 4.16-4.24 (m, 2H), 6.66 (dd, J=8.6, 2.4 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 7.15 (d, J=8.7 Hz, 1H), 8.4 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14])#[N:2].[H][H].[ClH:19]>[Pt]=O.C(O)C.C(OCC)(=O)C>[ClH:19].[NH2:2][CH2:1][CH2:3][C:4]1[N:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)c1cc2n(c1CC#N)CCCC2
Agent: O=[Pt]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cc2n(c1CCN)CCCC2

Procedure:
Methyl 3-(Cyanomethyl)-5,6,7,8-tetrahydroindolizine-2-carboxylate 101e was hydrogenated with platinum oxide catalyst under 50 psi of hydrogen in ethanol and ethyl acetate in the presence of hydrogen chloride overnight at room temperature to give 101f (380 mg, 1.74 mmol) which was used in directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[C:16]=2[N:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>O>[I:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][S:22]([C:17]2[C:16]3[N:15]=[CH:14][CH:13]=[N:12][C:21]=3[CH:20]=[CH:19][CH:18]=2)(=[O:23])=[O:24])[CH:10]=1
Reactant: Nc1cc(I)ccc1C(=O)O
Reactant: O=S(=O)(Cl)c1cccc2nccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
A mixture of 2-amino-4-iodo-benzoic acid (10 g, 38 mmol, 1.0 equiv.) and quinoxaline-5-sulfonyl chloride (8.7 g, 38 mmol) in 100 mL of water was basified with satd. aq. Na2CO3, with stirring, to adjust the pH to 8.0. As the reaction progressed, the pH was maintained at 8.0±0.2 by adding satd. aq. Na2CO3. After 3 h, no further pH changes were observed. The reaction mixture was stirred at rt for another 16 h. Conc. HCl was added to adjust the pH to <2. The precipitated solid was collected by filtration, washed with water and dried to afford the title compound as white solid (17 g, 37.4 mmol, 98%). MS (ESI+): calcd. for C15H10IN3O4S, 455.0; m/z found, 456 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 14.0 (br s, 1H), 11.6 (s, 1H), 9.10 (d, J=1.5, 1H), 9.97 (d, J=1.5, 1H), 8.60 (d, J=7.4, 1H), 8.42 (d, J=8.4, 1H), 8.06 (t, J=7.5, 1H), 7.95 (d, J=1.2, 1H), 7.51 (d, J=8.3, 1H), 7.37 (dd, J=8.3, 1.2, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24](Cl)=[C:23]([Cl:30])[N:22]=1)COCC[Si](C)(C)C)(=[O:11])=[O:10].[C:31]([NH:34][CH2:35][CH2:36][NH2:37])(=[O:33])[CH3:32].C(N(CC)CC)C>C(#N)C>[Cl:30][C:23]1[C:24]([NH:37][CH2:36][CH2:35][NH:34][C:31](=[O:33])[CH3:32])=[N:25][C:26]([O:27][CH3:28])=[C:21]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:10])=[O:11])[N:22]=1
Reactant: CC(=O)NCCN
Reactant: COc1nc(Cl)c(Cl)nc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nc(NCCNC(C)=O)c(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 48 h

Procedure:
2,3-Dichloro-N-(5,6-dichloro-3-methoxy-2-pyrazinyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzenesulphonamide (Example 66 part a) (0.26 g) was dissolved in acetonitrile (1.0 mL) and N-acetylethylenediamine (0.055 mL) and triethylamine (0.19 mL) added. After 48 h, the reaction mixture was concentrated and chromatography on silica gel eluting with ethyl acetate gave the title compound protected with the SEM group, as an oil (0.13 g). The oil was dissolved in dichloromethane (2.0 mL) and boron trifluoride etherate (0.14ml) added. After 2 h, ethyl acetate (20 mL) was added and the mixture washed with 5% aqueous citric acid (5 mL), dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate gave the title compound as a solid (0.031 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][NH2:12])=[C:4]([F:13])[CH:3]=1.[C:14]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O)(=O)[CH3:15].C(O)(=O)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N:11]2[C:14]([CH3:15])=[C:17]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:12]2)=[C:4]([F:13])[CH:3]=1
Reactant: NNc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CC(=O)C1CCCCC1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: Cc1c2c(nn1-c1cc([N+](=O)[O-])c(Cl)cc1F)CCCC2
Yield: 38.2 %

Procedure:
In the same manner as in Example 4 but using 4-chloro-2-fluoro-5-nitrophenylhydrazine (4 g), 2-acetylcyclohexanone (2.8 g), a catalytic amount of acetic acid and xylene (10 ml), there was produced 2.3 g of 2-(4-chloro-2-fluoro-5-nitrophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole. m.p., 143°-144° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:25])[C@@H:10]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[N:26]1[CH:31]=[C:30](B(O)O)[CH:29]=[N:28][CH:27]=1>>[O:25]=[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:30]2[CH:31]=[N:26][CH:27]=[N:28][CH:29]=2)[CH:3]=1)[C@@H:10]([NH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1cncnc1
Reactant: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(Br)c1
Product: CCOC(=O)CN[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2cncnc2)c1
Yield: 41 %

Procedure:
The title compound was prepared from 107.1.B and pyrimidin-5-ylboronic acid according to the procedure described in Example 107.1.C. The crude product was purified to give 108.1.A (85 mg, 41% yield) as colorless crystals. 1H NMR (400 MHz, CDCl3) δ ppm 9.59 (s, 1H), 9.23 (s, 1H), 8.99 (s, 2H), 7.98 (t, J=1.9 Hz, 1H), 7.66-7.62 (m, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.37-7.27 (m, 6H), 4.17-4.12 (m, 2H), 3.51 (dd, J=9.1, 4.1 Hz, 1H), 3.36 (s, 2H), 3.35 (dd, J=14.1, 4.3 Hz, 1H), 2.92 (dd, J=14.1, 9.0 Hz, 1H), 1.22 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9](Cl)=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:5])[CH3:2].CO.[CH2:26]([NH2:28])[CH3:27]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][C:9]([NH:28][CH2:26][CH3:27])=[C:10]([N+:19]([O-:21])=[O:20])[C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Reactant: CCN
Solvent: CO
Solvent: CCN(CC)CC
Product: CCNc1nc(C)c(C(=O)OCC)c(NCCCN(C)C)c1[N+](=O)[O-]

Procedure:
34.5 g. of 6-chloro-4-[[3-(dimethylamino)propyl]amino]-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 Mol.) are dissolved in 200 ml. of methanol. A mixture of 15 g. of triethylamine and 6 g. of ethylamine are added and the solution is refluxed for one hour with stirring. The solvent is distilled off in vacuo and the residue treated with about 100 ml. of water. The aqueous phase is extracted three times with 100 ml. portions of ether, the ether layers are combined, dried over calcium chloride and the solvent distilled off. The resulting yellow oil is recrystallized from ether/ligroin, yield 31 g. (88%), m.p. < 20°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH+:9]([O-])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:22]([C:6]1[N:1]=[C:2]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=[CH:4][CH:5]=1)#[N:23]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)OC(=O)[NH+]([O-])CCc1ccccn1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCCc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.4 %

Procedure:
tert-Butyl 2-(2-pyridyl)ethylcarbamate N-oxide (6.2 g, 26 mmol) was dissolved in nitroethane (80 ml), and trimethylsilyl cyanide (7.8 g, 78 mmol) and N,N-dimethylcarbamoyl chloride (5.5 g, 51 mmol) were added thereto. The mixture was stirred at room temperature for 48 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (5.3 g, 83%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH:51]([CH3:53])[CH3:52])[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH:51]([CH3:53])[CH3:52])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CC(C)Nc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To 2.5 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.70 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 600 mg of 2-amino-3,5-difluoro-6-isopropylaminopyridine. The solution was concentrated under reduced pressure. To the residue were added 600 mg of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 20 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 400 ml of distilled water, and the chloroform layer was washed twice with 400 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 620 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[O:5][C:6]([CH3:7])=[C:2]([CH2:1][Cl:18])[N:3]=2)=[CH:9][CH:10]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCl
Temperature: 25 °C

Procedure:
A solution of 4,5-dimethyl-2-(4-bromophenyl)-oxazole oxide (96.6 g, 0.36 mol) in CHCl3 (0.90 L) was treated dropwise with phosphorous oxychloride (61.1 g, 0.40 mol) allowing the reaction to exotherm and then was stirred at reflux for 30 min. The reaction was then cooled to room temperature and washed with water (2×1 L). The combined aqueous washes were back extracted with CH2Cl2 (2×400 mL). The organic layers were dried (MgSO4), and the solvent removed in vacuo to give crude product that was recrystallized from hot hexanes (300 mL), decanting the hot supernate away from a dark oily material. The remaining dark oil was agitated in additional hot hexanes (200 mL) and the combined supernates were cooled to 0° C. to crystallize the product which was isolated by filtration to give 74.2 g (72%) of 2-(4-bromophenyl-4-(chloromethyl)-5-methyloxazole as a lime-green powder: Rf=0.39 in 20% ethyl acetate/hexanes; 1H NMR (500 MHz, CDCl3) 7.88–7.86 (m, 2H), 7.59–7.56 (m, 2H), 4.54 (s, 2H), 2.42 (s, 3H); 13C (125 MHz, CDCl3) 159.2, 146.9, 133.2, 132.0, 127.6, 126.1, 124.7, 37.1, 11.5; IR (KBr) 2970, 1633, 1599, 1481, 1401, 1258, 1117, 1008 cm−1; UV (EtOH)max 281 nm (21349); HRMS (FAB) m/z calculated for C11H1079BrClNO: 285.9634, found 285.9641; Anal. Calculated for C11H9ClBrNO: C, 46.11; H, 3.17; N, 4.89; Cl, 12.37; Br, 27.88. Found C, 46.28; H 3.07; N, 4.81; Cl, 12.36; Br, 27.88.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:44][C:45](=[O:49])[C@H:46]([CH3:48])[NH2:47])C>CCOCC>[CH3:32][Si:29]([CH3:30])([CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:47][C@H:46]([C:45]([OH:49])=[O:44])[CH3:48])=[O:11])=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)CCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCCCC[Si](C)(C)C)cc1)C(=O)O

Procedure:
A solution of 4.64 g. of 4-[N-trifluoroacetyl-14-(trimethylsilyl)tetradecylamino]benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization yields the product as a white, crystalline solid.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[NH:34]1[CH2:38][CH2:37][C@H:36]([CH2:39][OH:40])[CH2:35]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:34]4[CH2:38][CH2:37][C@H:36]([CH2:39][OH:40])[CH2:35]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: OC[C@H]1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@H](CO)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-pyrrolidin-3-yl methanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.72 (1H), 3.66 (m, 2H), 3.49 (m, 2H), 3.32 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.30 (m, 2H). m/z: 438 [M+H]
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:44][CH:43]=1)[C:19]([N:21]([CH2:33][CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[CH:44][CH:43]=1)[C:19]([N:21]([CH2:33][CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccccc1)OCC
Yield: 54.5 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 2-(3-benzylureidooxy)acetic acid (Compound VI-6) (247 mg, 1.0 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (502 mg, 1.0 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2 to 97:3) to obtain the title compound (381 mg, 52%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>C(Cl)Cl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:10][CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
14.1 g. (85 mMol) of the above-obtained p-nitrophenethylamine and 34 ml. (340 mMol) triethylamine are dissolved in 170 ml. methylene chloride and 17.9 g. (85 mMol) p-chlorobenzenesulphonic acid chloride in 170 ml. methylene chloride added dropwise thereto at 0° to 5° C. within the course of 1 hour. After stirring for a further hour at 0° C., the reaction mixture is allowed to warm up to ambient temperature. It is then poured on to ice, mixed with 2N hydrochloric acid and shaken out with methylene chloride. The organic phase is washed neutral, dried over anhydrous magnesium sulphate and evaporated to dryness. The oily residue is chromatographed over silica gel with ligroin/ethyl acetate/glacial acetic acid (1.5:1.0:0.006 v/v/v) as elution agent. There are obtained 10.2 g. (35% of theory) of the desired compound in the form of a colourless oil. 1H-NMR (60 MHz, d6 -DMSO, ppm): δ=2.7-3.1 (m, 5H, CH2, NH); 7.35 and 8.10 (AB system 2d, J=9.5 Hz, 4H); 7.55 and 7.75 (AB system, 2d, J=10 Hz, 4H).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:7]=1)=O.[OH-].[Na+]>>[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:8]2[N:7]=[C:6]([NH2:5])[CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(COc2ccc(C(F)(F)F)cc2)n1

Procedure:
This material was prepared in analogy to example 86 step B] from 2,2-Dimethyl-N-[6-(4-trifluoromethyl-phenoxymethyl)-pyridin-2-yl]-propionamide (0.99 g) and 3M aqueous NaOH (4.68 mL) as an off-white crystalline solid (0.647 g). MS (ESI): 269.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([P:12](=[O:15])([OH:14])[OH:13])([OH:11])[PH2:9]=[O:10])=[CH:4][CH:3]=1.C([Si](C)(C)[O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][C:33]([F:40])=[N:34][C:35]=3Cl)[CH:25]=[CH:26][CH:27]=1)(C)(C)C.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:40][C:33]1[N:32]=[C:31]2[C:36]([N:37]=[CH:38][N:30]2[CH2:29][CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=2)=[C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([P:12](=[O:13])([OH:14])[OH:15])([OH:11])[PH2:9]=[O:10])=[CH:6][CH:7]=2)[N:34]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(CCn2cnc3c(Cl)nc(F)nc32)c1
Reactant: Nc1ccc(C(O)([PH2]=O)P(=O)(O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=[PH2]C(O)(c1ccc(Nc2nc(F)nc3c2ncn3CCc2cccc(O)c2)cc1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.7 %

Procedure:
A sealed pressure flask, flushed with N2, containing a mixture of crude [(4-Amino-phenyl)-hydroxy-phosphinoylmethyl]-phosphonic acid (8.29 mmol), 9-{2-[3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethyl}-6-chloro-2-fluoro-9H-purine (3.37 g, 8.29 mmol), and N,N-diisopropylethylamine (7.2 mL, 41.5 mmol) in 45.0 mL DMSO was heated at 110–120° C. for 13 h. Upon removing excess N,N-diisopropylethylamine (N2 flow, slight heat) the slightly brown solution was cooled to ambient temperature and added ˜500 mL of H2O to produce a milky, off-white solution. Further precipitation occurred upon addition of TFA (final pH=1–2), at which time the mixture was heated (100° C. hot plate) and stirred vigorously for ˜20 min, filtered while hot, then washed with acidified H2O (TFA, pH=1–2; 4×20 mL), EtOH (2×20 mL), and Et2O (4×20 mL). Isolation of a second crop from the concentrated filtrate in the same manner as described above, followed by removal of excess solvent (in vacuo) provided 2.47 g of an off-white solid: m/z 506 (M−H).
Reaction SMILES: C([N:4]([CH:7]([CH3:9])C)[CH2:5]C)(C)C.CS(O[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C@H:28]3[O:32]C(C)(C)[N:30]([C:35](=[O:39])[CH:36]([Cl:38])[Cl:37])[C@@H:29]3[CH2:40][F:41])=[CH:24][CH:23]=2)=[CH:18][N:17]=1)(=O)=O.N1CCC1.Cl>CN(C)C=O>[N:4]1([CH2:15][C:16]2[N:17]=[CH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C@@H:28]([OH:32])[C@H:29]([NH:30][C:35](=[O:39])[CH:36]([Cl:38])[Cl:37])[CH2:40][F:41])=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[CH2:5][CH2:9][CH2:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Agent: C1CNC1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H](CF)[C@H](O)c1ccc(-c2ccc(CN3CCC3)nc2)cc1)C(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
Diisopropylethylamine (296 μL, 1.68 mmol) is added to the product of Example 20, Step 2 (50 mg, 0.11 mmol) and azetidine.HCl salt (146 mg, 1.12 mmol) in dimethylformamide (1 mL) and the mixture heated to 60° C. for 4 hours. The solvent is removed under reduced pressure and the residue dissolved in CH2Cl2 (2 mL). The mixture is cooled to 0° C. and trifluoroacetic acid (2 mL) added. After 1 hour, the solvent is removed under reduced pressure and the crude product purified using reverse phase HPLC to give the title compound (10 mg): m/z (Cl) M−H 425.1.