Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([PH:11](=[O:15])[O:12][CH2:13][CH3:14])([O:8][CH2:9][CH3:10])[CH3:7])[CH3:4].Cl[CH2:17][F:18]>C1COCC1>[F:18][CH2:17][P:11]([C:6]([O:5][CH2:3][CH3:4])([O:8][CH2:9][CH3:10])[CH3:7])(=[O:15])[O:12][CH2:13][CH3:14]
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Reactant: FCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)(OCC)P(=O)(CF)OCC
Temperature: -10 °C

Procedure:
Sodium hydride (1.4 g, 57.1 mmol) was suspended in THF (50 mL) in a pressure flask under a nitrogen atmosphere and cooled to −10° C. with stirring. Ethyl (1,1-diethoxyethyl)phosphinate (10.0 g, 47.6 mmol) in THF (20 mL) was added dropwise to the mixture over 10 minutes; the internal temperature was maintained below 0° C. during the addition. On completion of addition, the reaction mixture was allowed to stir at this temperature for 90 minutes. The flask was cooled to −78° C. and chlorofluoromethane gas (9.7 g, 142.8 mmol) was condensed into the reaction mixture. The septum was removed and the flask was sealed with a screw thread stopper. The flask was then allowed to warm to room temperature and then heated at 50° C. for 24 h. The reaction mixture was cooled to 0° C. and cautiously quenched with water (25 mL). Methylene chloride (50 mL) was added to the reaction mixture and the emulsion was filtered through a pad of Celite® (20 g). The aqueous phase was extracted with methylene chloride (2×100 mL), dried over anhydrous magnesium sulfate, and the organic phase was concentrated under reduced pressure affording the crude product as a pale yellow oil (6.93 g). The crude residue was purified by silica gel column chromatography (6×25 cm column) eluting with 20% acetone in hexanes. This procedure afforded ethyl (fluoromethyl)(1,1-diethoxyethyl)phosphinate as a clear, colorless oil (4.4 g, 42%). 1H NMR (300 MHz, CDCl3) δ 4.94-4.54 (m, 2H), 4.32-4.20 (m, 2H), 3.82-3.54 (m, 4H), 1.60-1.44 (m, 3H), 1.40-1.28 (m, 3H), 1.26-1.08 (m, 6H).
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[C:12]([I:47])=[C:13]([C:33]([NH:35][CH2:36][CH:37]([O:43]C(=O)C)[CH2:38][O:39]C(=O)C)=[O:34])[C:14]([I:32])=[C:15]([C:18]([NH:20][CH2:21][CH:22]([O:28]C(=O)C)[CH2:23][O:24]C(=O)C)=[O:19])[C:16]=2[I:17])[C:6]1=[O:48])(=O)C.C[O-].[Na+].[Na]>CO>[OH:43][CH:37]([CH2:38][OH:39])[CH2:36][NH:35][C:33]([C:13]1[C:12]([I:47])=[C:11]([N:7]2[CH2:8][CH2:9][CH2:10][CH:5]([OH:4])[C:6]2=[O:48])[C:16]([I:17])=[C:15]([C:18]([NH:20][CH2:21][CH:22]([OH:28])[CH2:23][OH:24])=[O:19])[C:14]=1[I:32])=[O:34]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(OC(C)=O)C2=O)c1I)OC(C)=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=C(NCC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(N2CCCC(O)C2=O)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 5-[3-(acetyloxy)-2-oxo-1-piperidinyl]-N,N'-bis[2,3-bis(acetyloxy)propyl]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 8c (4 g, 4.3 mmol) in methanol (20 ml) was treated with a solution of sodium methoxide in methanol, prepared from sodium (30 mg, 1.3 mmol) and anhydrous methanol (20 ml), and the mixture was stirred at room temperature for 2 hours. The pH of the solution was adjusted down to 7 by the addition of Dowex-50 (H+) resin. The mixture was filtered and the filtrate was freed of the solvent to obtain the crude product. Purification by low pressure reverse phase column chromatography over the CHP-20P resin furnished analytically pure N,N'-Bis[2,3-dihydroxypropyl)-5-(3-hydroxy-2-oxo-1-piperidinyl)-2,4,6-triiodo-1,3-benzenedicarboxamide as a snow-white glassy solid (2.3 g, 78% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]>CN(C)C=O.N1C=CC=CC=1.O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1c(COc2ccccc2I)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.7 %

Procedure:
2-Iodophenol (0.18 g, 0.87 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.2 g, 0.83 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried to yield 280 mg of 2-(2-iodophenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)Cc1ccc2nc(Nc3ccccc3Br)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(Nc3ccccc3Br)oc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
Ethyl 2-(2-bromophenylamino)-6-benzoxazolylacetate (3.82 g, 10.6 mmol) was dissolved in THF-methanol (1:1, 40 ml). To the resulting solution, 1.0M-NaOH (52.0 ml, 52.0 mmol) was added, followed by stirring at room temperature for 1.5 hours. To the residue, which had been obtained by distilling off the solvent under reduced pressure, was acidified with 1.0N-HCl. The crystals thus obtained were collected by filtration under reduced pressure, washed with water and dried overnight under reduced pressure at 60° C., whereby 2-(2-bromophenylamino)-6-benzoxazolylacetic acid (3.40 g, 93%) was obtained as a white crystalline powder.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[C@H:4]([O:5][C:6]([CH:9]=[CH2:10])=[CH:7]2)[CH2:3]1.[SH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([S:11][CH2:10]/[CH:9]=[C:6]2/[CH2:7][N:8]3[C@H:4]([O:5]/2)[CH2:3][C:2]3=[O:1])=[CH:13][CH:14]=1
Reactant: Oc1ccc(S)cc1
Reactant: C=CC1=CN2C(=O)C[C@H]2O1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1C[C@H]2O/C(=C\CSc3ccc(O)cc3)CN12

Procedure:
(5R)-7-Oxo-3-vinyl-4-oxa-1-azabicyclo[3.2.0] hept-2-ene (2.5 mmole) in dry tetrahydrofuran (20 ml) was treated with p-mercaptophenol (650 mg) and benzoyl peroxide (10 mg). The resulting solution was stirred under dry nitrogen while being irradiated using a 200 W bulb placed 1" from the reaction vessel for 1 hour. (The temperature of the solution was 25°-30° during this period). The mixture was diluted with ethyl acetate (100 ml) and was washed with water (3×30 ml) and saturated brine (30 ml). The solution was dried (magnesium sulphate) and the solvent was evaporated under reduced pressure to yield a pale yellow gum. The gum was chromatographed on silica gel using ethyl acetate/petroleum ether (b.p. 60°-80°) to give the title compound as a colourless waxy solid (125 mg), [α]D20 =+138.5° (c 1.0, CHCl3), (Found: M+, 263.0585; C13H 13 NO3S requires 263.0616). νmax (CHCl3): 3200, 1790, 1695, 1600, 1580, 1495 cm-1. δ (CDCl3): 2.62 (1H, d, J 16 Hz), 3.10-3.65 (4H, complex), 4.24 (1H, d, J 14 Hz), 4.39 (1H, t, J 7 Hz), 5.25 (1H, d, J 2 Hz), 6.5-6.8 (3H, m), 7.15-7.35 (2H, m). m/e: 263 (M+, 9%), 138 (100), 126 (25), 125 (23), 96 (42).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[Na+].Cl[CH2:17][C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=1>CN(C=O)C>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([CH2:17][S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)(=[O:11])=[O:10])[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: COc1ccc(S(=O)[O-])cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)Cc2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A suspension of Example 96A (380 mg, 1.6 mmol) in DMF (10 mL) was treated slowly with a solution of 5-(chloromethyl)-1,2,3-trimethoxybenzene (344 mg, 1.6 mmol) in DMF (5 mL), heated to 120° C. for hour, cooled to room temperature, and partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, and the combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/dichloromethane to provide the desired product.
Reaction SMILES: [O:1]1[C:11]2[CH:10]=[C:9]([CH2:12][N:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][N:29]4[C:34](=[O:35])[CH:33]=[N:32][C:31]5[N:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:30]4=5)[CH2:23][CH2:22]3)C(=O)OC(C)(C)C)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1>ClCCl.FC(F)(F)C(O)=O>[O:1]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][N:29]4[C:34](=[O:35])[CH:33]=[N:32][C:31]5[N:36]=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:30]4=5)[CH2:25][CH2:26]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cnc2ncc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cnc2ncc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCCO5)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a solution of 87 mg of tert-butyl (3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)(1-(2-(7-methoxy-2-oxopyrido(2,3-b)pyrazin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 2 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and chloroform and water were added thereto. The aqueous layer was separated and adjusted to pH 13.1 with a 20% aqueous sodium hydroxide solution. Chloroform was added thereto, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 54 mg of 1-(2-(4-((3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxypyrido(2,3-b)pyrazin-2(1H)-one as a yellowish brown oily substance.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:22])[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9][CH2:8]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:1][CH2:4][C@@H:5]([OH:22])[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9][CH2:8]1
Reactant: [N-]=[N+]=NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The oil from Step 2 was dissolved in wet tetrahydrofuran (225 mL) and was treated with triphenylphosphine (53.3 g). The reaction was heated at 60° C. and stirred for 4 h. The solvent was removed under vacuum, the residue redissolved into 2N hydrochloric acid (1 L) and the aqueous layer was extracted with ethyl acetate (3×700 mL). The aqueous phase was basified with aqueous 2 N sodium hydroxide solution and extracted with DCM (3×1 L). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by chromatography (8% 7N ammonia in methanol/DCM) to give the title compound as a yellow oil (17 g).
Reaction SMILES: [NH:1]1CC(=O)N[C:2]1=[O:3].[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11].N1CC(=O)NC1=O.N[C@@H](C(O)=O)[C@H](CC)C>>[C:2]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])(=[O:3])[NH2:1]
Reactant: O=C1CNC(=O)N1
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@@H](N)C(=O)O
Product: CC[C@H](C)[C@@H](NC(N)=O)C(=O)O

Procedure:
When this racemization occurs in the presence of a D-hydantoinase, the L-isoleucine hydantoin establishes an equilibrium with the D-allo-isoleucine hydantoin, and the D-allo-isoleucine hydantoin is selectively hydrolyzed by the D-hydantoinase to form the N-carbamoyl-D-allo-isoleucine. As the D-allo-isoleucine hydantoin is depleted from the mixture by D-hydantoinase-catalyzed hydrolysis, the equilibrium between the L-isoleucine hydantoin and the D-allo-isoleucine hydantoin is re-established under the epimerizing conditions, continuously generating additional D-allo-isoleucine hydantoin for stereoselective hydrolysis by the D-hydantoinase enzyme. This continual supply of the hydantoin of D-allo-isoleucine occurs during the course of the reaction until substantially all of the L-isoleucine hydantoin has been converted to N-carbamoyl-D-allo-isoleucine. In this way, the reaction can be carried out to substantial Jun. 7, 2002 completion so that L-isoleucine hydantoin is converted to N-carbamoyl-D-allo-isoleucine. By the term “substantial completion” is meant that at least about 75%, preferably at least about 85%, and most preferably at least about 95%, of the L-isoleucine hydantoin is converted to N-carbamoyl-D-allo-isoleucine. The yield of N-carbamoyl-D-allo-isoleucine produced by the method of the present invention can approach 100% of theoretical, given sufficient reaction time and/or sufficient hydantoinase enzyme. The reaction can be monitored, if desired, by any method known in the art. An example of a method useful for monitoring the extent of reaction in the D-hydantoinase-catalyzed hydrolysis is thin layer chromatography on silica gel. Alternatively, high performance liquid chromatography can be used to monitor the extent of reaction.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[CH3:30][NH:31][CH3:32].Cl.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[CH3:30][N:31]([CH3:32])[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a solution of bromide (204) prepared as described in example 173 (0.12 g, 0.27 mmol) in dimethylacetamide (4 mL) was added the amine, dimethylamine (25 mol eq., 0.85 mL in this case as an 40% aqueous solution). The reaction vessel was sealed and heated at 80° C. with stirring for 18 h, before being diluted with water. The resulting solution was then acidified by the dropwise addition of concentrated hydrochloric acid and the pH was then adjusted to approximately pH=9 by the addition of solid potassium carbonate. The precipitated product was either collected by filtration and washed with water and diisopropyl ether before being dried or extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with methanol/dichloromethane (1:9 to 1:4), followed by trituration in ethyl acetate/hexane gave amine (208) (52 mg, 47%) as a yellow powder, mp 185–189° C. 1H NMR δ [(CD3)2SO] 11.05 (s, 1H), 9.34 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.78 (s, 1H), 7.64 (m, 2H), 7.56 (d, J=8.9 Hz, 1H), 7.47 (m, 3H), 7.14 (dd, J=8.9, 2.4 Hz, 1H), 4.48 (t, J=6.6 Hz, 2H), 2.16 (t, J=6.5 Hz, 2H), 2.08 (s, 6H), 1.90 (m, 2H). Found: C, 71.98; H, 5.67; N, 10.14. C25H23N3O3.1/4H2O requires: C, 71.84; H, 5.67; N, 10.05.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([O:17][CH3:18])=[CH:15][C:14]2[N:13]=[CH:12][C:11]3[N:19]([CH3:32])[C:20](=[O:31])[N:21]([C:22]4[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=4[F:30])[C:10]=3[C:9]=2[CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB(/[CH:43]=[CH:44]/[C:45]2[CH:49]=[CH:48][S:47][CH:46]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O=O>[F:30][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:22]=1[N:21]1[C:10]2[C:9]3[CH:8]=[C:7](/[CH:43]=[CH:44]/[C:45]4[CH:49]=[CH:48][S:47][CH:46]=4)[C:16]([O:17][CH3:18])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:19]([CH3:32])[C:20]1=[O:31])[C:28]#[N:29]
Reactant: CC1(C)OB(/C=C/c2ccsc2)OC1(C)C
Reactant: COc1cc2ncc3c(c2cc1OS(=O)(=O)C(F)(F)F)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: O=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc2ncc3c(c2cc1/C=C/c1ccsc1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
1-(4-Cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yl trifluoromethanesulfonate (119 mg, 240 μmol), 4,4,5,5-tetramethyl-2-[(E)-2-thiophen-3-ylvinyl]-1,3,2-dioxaborolane (142 mg, 602 μmol), tripotassium phosphate (107 mg, 504 μmol) and trans-bis(tricyclohexylphosphine)palladium(II) dichloride (18 mg, 24 μmol) were dissolved in oxygen-free N,N-dimethylformamide (5 ml). The mixture was subsequently heated at 130° C. for 45 min (microwave). The reaction mixture was then filtered with suction, the filtrate was diluted with water and stirred at room temperature for 30 min. The precipitate formed was filtered off with suction and rinsed with water. The residue was chromatographed on flash silica gel (solvent gradient ethyl acetate/0-25% by vol. of ethanol), giving 3-fluoro-4-{7-methoxy-3-methyl-2-oxo-8-[(E)-2-thiophen-3-ylvinyl]-2,3-dihydroimidazo[4,5-c]quinolin-1-yl}benzonitrile (90 mg, 181 μmol) as solid. MS: 457.1 (M+H+), TLC (HPTLC): Rf=0.47 (ethyl acetate/ethanol 2:1, parts by volume).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[N:15]1([CH2:19][C@@H:20]([NH2:32])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)[CH2:18][CH2:17][CH2:16]1>>[N:15]1([CH2:19][C@@H:20]([NH:32][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: N[C@H](CN1CCC1)c1ccc(F)c(C(F)(F)F)c1
Product: NC(=O)c1ccnc2c(N[C@H](CN3CCC3)c3ccc(F)c(C(F)(F)F)c3)ncnc12

Procedure:
Compound 62 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with (S)-2-Azetidin-1-yl-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethylamine to give the title compound as a white solid. LC/MS [390 (M+H)].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@@H:7]([C:12]([OH:14])=O)[CH2:6][CH2:5]2.Cl.Cl.[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[N:23][C:24]([N:27]2[C:31]([CH3:32])=[CH:30][CH:29]=[C:28]2[CH3:33])=[CH:25][CH:26]=1)[OH:20].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:33][C:28]1[N:27]([C:24]2[N:23]=[CH:22][C:21]([C@@H:19]([OH:20])[CH2:18][NH:17][C:12]([C@H:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=4)[O:8]3)=[O:14])=[CH:26][CH:25]=2)[C:31]([CH3:32])=[CH:30][CH:29]=1
Reactant: Cc1ccc(C)n1-c1ccc([C@@H](O)CN)cn1
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1-c1ccc([C@@H](O)CNC(=O)[C@H]2CCc3cc(I)ccc3O2)cn1
Yield: 56 %

Procedure:
A reaction mixture containing (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, 5.39 mmol, 1.0 eq.), (1R)-2-amino-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)-3-pyridinyl]ethanol dihydrochloride (U.S. Pat. No. 6,051,586) (6.47 mmol, 1.2 eq.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 10.8 mmol, 2.0 eq.), 1-hydroxybenzotriazole hydrate (HOBT, 10.8 mmol, 2.0 eq.), and triethylamine (16.2 mmol, 3.0 eq.) in CH2Cl2 (30 mL) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the resulting two-phase mixture was extracted with CH2Cl2. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, concentrated and purified by medium pressure column chromatography (Biotage 40S normal phase silica gel column, CH2Cl2:MeOH=100:4). The product was obtained as a pale yellow foam in 56% yield. MH+=518.2, RT=3.74 min.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16])(=O)C.C[O-].[Na+]>CO>[OH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[CH3:16]
Reactant: COC(=O)c1ccc(COC(C)=O)c(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CO)c(C)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
1.00 g of methyl 4-[(acetyloxy)methyl]-3-methylbenzoate was dissolved in 10 mL of methanol, to which a solution of 0.365 g of sodium methoxide in 7 mL of methanol was added dropwise at 5 to 7° C., and this solution was stirred for 30 minutes at 50° C. The reaction mixture was concentrated under reduced pressure, followed by successive addition of ethyl acetate and water, and then the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 0.79 g of methyl 4-(hydroxymethyl)-3-methylbenzoate as yellow oil.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[N:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=1)(=[O:7])[NH2:8]
Reactant: CCN(CC)c1ccc(Nc2nc(Cl)ccc2C(N)=O)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCN(CC)c1ccc(Nc2nc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccc2C(N)=O)cc1
Temperature: 100 °C
Yield: 55.8 %

Procedure:
A mixture of 6-chloro-2-(4-(diethylamino)phenylamino)nicotinamide (1.669 g, 5.24 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (1.573 g, 7.85 mmol), and DIEA (1.829 mL, 10.47 mmol) in N-methyl-2-pyrrolidinone (10 mL) was heated at 100° C. overnight. The reaction mixture was diluted with ethyl acetate, washed with satd. NaHCO3, water, and concentrated. The resulting residue was purified by MPLC (ISCO, hexane/ethyl acetate, 80 g silica gel column) to give 1.41 g (R)-tert-butyl 1-(5-carbamoyl-6-(4-(diethylamino)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate as a yellow solid. LCMS: (M+H)+=483.3.