Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)N(C[CH2:7][CH2:8][CH2:9][NH:10][CH:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:21][CH3:22])[O:13][CH2:12]2)C(=O)C2=CC=CC=C12.[C:29]1(=[O:54])[N:33]([CH2:34][CH2:35]NC2CC3C(=CC=CC=3OC)OC2)[C:32](=[O:49])[C:31]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:30]12>>[CH2:9]([N:10]([CH:11]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[O:21][CH3:22])[O:13][CH2:12]1)[CH2:35][CH2:34][N:33]1[C:29](=[O:54])[C:30]2=[CH:53][CH:52]=[CH:51][CH:50]=[C:31]2[C:32]1=[O:49])[CH2:8][CH3:7]
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Reactant: COc1cccc2c1CC(NCCN1C(=O)c3ccccc3C1=O)CO2
Product: CCCN(CCN1C(=O)c2ccccc2C1=O)C1COc2cccc(OC)c2C1
Yield: 70 %

Procedure:
Using the procedure described in Example 2, but replacing the compound of Example 1 by the compound of Example 5, the expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH:23]=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11][C@H:10]2[CH:23]([OH:24])[C:27]([F:30])([F:29])[F:28])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution (2.6 mL) of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (100 mg) in THF were added a solution (1.0 M, 0.534 mL) of trimethyl(trifluoromethyl)silane (190 mg) and tetrabutylammonium fluoride in THF under ice-cooling, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1 M hydrochloric acid (0.5 ml), and the mixture was further stirred for 3 hr. Distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (91.7 mg).
Reaction SMILES: C(O[CH2:9][N:10](C)[S:11]([CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20](COCC1C=CC=CC=1)[CH:19]=[C:18]2[CH2:33][C@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH3:39])(=[O:13])=[O:12])C1C=CC=CC=1.CS(O)(=O)=O>O.[OH-].[OH-].[Pd+2]>[CH3:9][NH:10][S:11]([CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:33][C@H:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH3:39])(=[O:12])=[O:13]
Reactant: CN1CCC[C@@H]1Cc1cn(COCc2ccccc2)c2ccc(CS(=O)(=O)N(C)COCc3ccccc3)cc12
Agent: [Pd+2]
Agent: CS(=O)(=O)O
Agent: [OH-]
Solvent: O
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
A mixture of (R)-N-Benzyloxymethyl-1-[1-benzyloxymethyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-methylmethanesulfonamide (from step (f), 300 mg, 0.5 mmol) and methanesulfonic acid (60 mg, 0.6 mmol) in water (5 ml) was hydrogenated over Pearlman's catalyst (300 mg) at 60° C. and at 345 kPa (50 psi) for 18 hr. The solution was then filtered through a pad of celite (trade mark) and the filtrate was partitioned between saturated sodium bicarbonate (25 ml) and dichloromethane (3×50 ml). The combined organic extract was then evaporated in vacuo and the residue was dissolved in a mixture of THF and water (1:1) (10 ml). A solution of Triton B (40% w.w. in methanol) (0.2 ml, 0.44 mmol) was then added dropwise and the solution was then refluxed for 2 hr. The solution was then cooled to ambient temperature before being poured into water (10 ml) and extracted with dichloromethane (3×25 ml). The combined organic extracts were evaporated in vacuo to give a yellow film. This was then triturated with IMS (5 ml) and tie solid was filtered in vacuo and dried at 50° C. overnight to yield the title compound (50 mg, 29%) as a white solid. m.p. 209-231° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](Cl)=[O:26])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[Cl-].[NH4+].Cl>C1COCC1>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([N:2]([CH3:3])[CH3:1])=[O:26])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Reactant: CNC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2 M dimethylamine in THF (5 mL) was added to 3-(2′,4′-dichlorobiphenyl-4-ylsulfonamido)benzoyl chloride (350 mg, 0.76 mmol) and the mixture was stirred at room temperature for 3 days. Saturated ammonium chloride (3 mL) was added and the solution acidified to pH 3 with 2 M HCl. The mixture was extracted with EtOAc (3×5 mL) and the organic layer was washed with brine (5 mL), dried over MgSO4, filtered and evaporated to give a yellow glass. This was triturated with acetone and the title compound obtained as a white solid (130 mg).
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:11](=[O:30])[CH2:12][NH:13][C@H:14]([C:16]([N:18]1[CH2:29][CH2:28][CH2:27][C@H:19]1[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:38].N1CCC[C@H]1C(O)=O.CO.C(O)CCC.C(O)(=O)C.O>Cl.C(O)(=O)C>[ClH:38].[C:1]([NH:9][C@@H:10]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:11](=[O:30])[CH2:12][NH:13][C@H:14]([C:16]([N:18]1[CH2:29][CH2:28][CH2:27][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCCCO
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](NCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
1-[N-[(S)-3-(Benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline, 1,1-dimethylethyl ester (740 mg., 1.46 mmole) is dissolved in a solution of hydrogen chloride in acetic acid (1.5N, 10 ml.) and kept at room temperature for 30 minutes. It is then concentrated, taken into water, filtered and lyophilized to obtain 600 mg. of 1-[N-(S)-3-(benzoylamino)-2-oxo-4-phenylbutyl]-L-alanyl]-L-proline, monohydrochloride; m.p. 83°-163°; [α]D25 =-109° (c=1.04, methanol). Rf 0.6 (silica gel; butanol/acetic acid/water, 4:1:1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[C:10](=[O:16])[NH:11][C:12](=S)[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCC2C(=O)NC(SC)=NC=2)C=CC=CC=1.N1C=CC=NC1=O.[CH3:41][C:42]1[NH:46][CH:45]=[N:44][C:43]=1[CH2:47][S:48][CH2:49][CH2:50][NH2:51].[ClH:52]>>[ClH:52].[ClH:52].[CH3:41][C:42]1[NH:46][CH:45]=[N:44][C:43]=1[CH2:47][S:48][CH2:49][CH2:50][NH:51][C:12]1[NH:11][C:10](=[O:16])[C:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][N:13]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: O=c1[nH]c(=S)[nH]cc1CCc1ccccc1
Agent: CSc1ncc(CCc2ccccc2)c(=O)[nH]1
Agent: Cl
Agent: O=c1nccc[nH]1
Product: Cc1[nH]cnc1CSCCNc1ncc(CCc2ccccc2)c(=O)[nH]1

Procedure:
5-(2-Phenylethyl)-2-thiouracil (1.8 g) was converted into 5-phenylethyl-2-methylthio-4-pyrimidone (m.p. 160°-161° ex ethanol) by the method described in Example 1(i). Reaction of this pyrimidone (1.5) with 2-(5-methyl-4-imidazolylmethylthio)ethylamine (1.1 g) by the method described in Example 1(ii) gave an oil which was dissolved in 2 N hydrochloric acid, the solution evaporated to dryness and the residue recrystallised from methanol to give 2-[2-(5-methyl-4-imidazolylmethylthio)-ethylamino]-5-(2-phenylethyl)-4-pyrimidone dihydrochloride, m.p. 214°-218°.
Reaction SMILES: C([Cu])#N.[CH2:4]1[O:8][CH:5]1[CH:6]=[CH2:7].[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.CCOCC>[C:9]1([CH2:7]/[CH:6]=[CH:5]/[CH2:4][OH:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CC1CO1
Reactant: Br[Mg]c1ccccc1
Agent: N#C[Cu]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC/C=C/Cc1ccccc1
Temperature: -78 °C

Procedure:
Anhydrous CuCN (4.86 g, 54 mmol) was added to a solution of butadiene monooxide (38 g, 540 mmol) in anhydrous tetrahydrofuran (1.2 L) and the resulting mixture was stirred at −78° C. Commercial phenyl magnesium bromide solution (Aldrich) in ether (65 mmol) was added dropwise over a period of 10 min. The resulting reaction mixture was then allowed to warm to 0° C. and it was continued to stir until the reaction mixture was homogeneous. After this period, the reaction mixture was cooled to −78° C. and 0.58 mole of phenylmagnesium bromide solution in ether was added dropwise for 30 min. The reaction mixture was allowed to warm to 23° C. for 1 h. The reaction was quenched by slow addition of saturated aqueous NH4Cl (120 mL) followed by NH4OH (70 mL), saturated NH4Cl (500 mL) and then H2O (300 mL). The aqueous layer was thoroughly extracted with ethyl acetate (2×300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was distilled under vacuum (0.12 torr) at 95° C. to give trans-4-phenyl-2-butene-1-ol (75.6 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:19]=[N:20]2)=[CH:15][CH:14]=1>CN(C=O)C>[CH3:1][N:2]([CH2:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:19]=[N:20]2)=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: COC(=O)c1cnc2cc(CBr)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2cc(CN(C)c3ccccc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.2 %

Procedure:
In a nitrogen atmosphere, N-methylaniline (383 mg, 3.57 mmol.) was dissolved in DMF (5 mL). Under chilling with ice, 60% sodium hydride (157 mg, 3.93 mmol.) was added to the resulting solution and the mixture was stirred at room temperature for 5 minutes. Under chilling with ice, to this was added dropwise methyl 7-bromomethylquinoline-3-carboxylate (1.0 g, 3.57 mmol.) in dry DMF (10 mL). The resulting mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was extracted with chloroform after addition of water (20 mL). The organic portion was washed successively with water and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1), to give the desired compound as yellow crystalline powder (615 mg, yield: 56%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[C:17]([O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1)[CH3:18])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: Oc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C=C(C)Oc1cccc(C(F)(F)F)c1
Temperature: 130 °C
Yield: 53.3 %

Procedure:
A mixture of 3-trifluoromethyl-phenol (1.09 mL, 8.96 mmol) and ethyl-2-butynoate (2.0 g, 17.83 mmol) in tetrahydrofuran (14 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.37 mmol). The reaction was then heated at 130° C. for 2 h. At this time, the reaction was concentrated in vacuo. The residue dissolved in dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 1N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 1-10% ethyl acetate/hexanes) afforded 3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.31 g, 53%) as a clear, colorless oil: HR-ES-MS m/z calculated for C13H13O3F3 [M+H]+ 275.0890, observed 275.0889; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (t, J=7.1 Hz, 3H), 2.45 (s, 3H), 4.01 (q, J=7.1 Hz, 2H), 4.68 (s, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.57 (br. s., 1H), 7.66-7.75 (m, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:20]2)=[CH:16][CH:15]=1.[CH3:38][C:39]1[O:43][C:42]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=2)=[N:41][C:40]=1[CH2:50]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[OH-].[Li+].Cl>CO.O.O1CCCC1>[CH3:38][C:39]1[O:43][C:42]([C:44]2[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=2)=[N:41][C:40]=1[CH2:50][O:13][C:14]1[CH:37]=[CH:36][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:21]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[N:20]2)=[CH:16][CH:15]=1
Reactant: Cc1oc(-c2ccncc2)nc1CO
Reactant: COC(=O)CCc1cn(Cc2ccc(O)cc2)nc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccncc2)nc1COc1ccc(Cn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
Diethyl azodicarboxylate (40% in toluene, 753 mg) was added dropwise slowly to a mixture of methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (500 mg), [5-methyl-2-(4-pyridyl)-4-oxazolyl]methanol (274 mg), triphenylphosphine (414 mg) and tetrahydrofuran (7 ml) at room temperature. After stirring at room temperature for 4 hours, the reaction solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography, and an oily substance was obtained from the fraction eluted with ethyl acetate-hexane (3:1, volume ratio). A mixture of the oily substance obtained, lithium hydroxide monohydrate (181 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, and 1N hydrochloric acid (4.3 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-[5-methyl-2-(4-pyridyl)-4-oxazolylmethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (470 mg, yield: 68%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 154–155° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C(OCC1N(C[C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)C2C3C=CC=CC=3N=CC=2N=1)C.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]([N:28]2[CH2:29][CH2:30][CH:25]([OH:31])[CH2:26][CH2:27]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CCC(O)CC1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere cyclopropanecarbonyl chloride (0.84 mL, 9.25 mmol) was added dropwise to a chilled mixture of 4-[(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidin-4-ol (3.00 g, 8.81 mmol), triethylamine (1.47 mL, 10.6 mmol) and dichloromethane (90 mL). The reaction mixture was allowed to warm to ambient temperature. After 2 hours the reaction mixture was washed with water. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel eluting with 90/10 dichloromethane/methanol) to provide 3.16 g of 4-[2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]-1-(cyclopropylcarbonyl)piperidin-4-ol as a light orange frothy solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(OCC)(=O)C>ClCCl.CCCCCC>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1C1CCOCC1
Reaction time: 1 h
Yield: 57 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-(tetrahydro-pyran-4-yl)-amide (334) (90 mg, 0.16 mmol) and triphenylphosphine were taken up in dichloromethane (3 ml) at room temperature and diisopropyl azodicarboxylate was added slowly. Stirring was continued for 1 h while silica thin layer chromatography was performed (ethyl acetate:hexane=1:1, Rf=0.6). Dichloromethane (15 ml) was added to the reaction mixture, which was thereafter washed with water (10 ml) and brine (10 ml). The organic part was dried and concentrated under reduced pressure. The obtained residue was purified by nor mal silica gel (100-20 mesh) column chromatography using 30% ethyl acetate in hexane to get 9-benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-(tetrahydro-pyran-4-yl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (335) (50 mg, 60%; 2 steps yield).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:27]=1[C:28]#[N:29]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:32]=[N:33][C:26]([O:25][CH3:24])=[C:27]([CH:30]=5)[C:28]#[N:29])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1C#N

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile (Combi-Blocks, San Diego, USA) to give the title compound as a white solid. (HPLC: tR 2.60 min (Method A); M+H=426 MS-ES)
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]3C(=O)C4=CC=CC=C4C3=O)[CH:16]=2)=[C:7]([NH:36][C:37]([NH:39][C:40]2[C:45]([CH:46]([CH3:48])[CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=2[CH:49]([CH3:51])[CH3:50])=[O:38])[C:6]1=[O:52])[CH2:2][CH2:3][CH3:4].O.NN>C(O)C>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:16]=2)=[C:7]([NH:36][C:37]([NH:39][C:40]2[C:41]([CH:49]([CH3:50])[CH3:51])=[CH:42][CH:43]=[CH:44][C:45]=2[CH:46]([CH3:48])[CH3:47])=[O:38])[C:6]1=[O:52])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCN3C(=O)c4ccccc4C3=O)c2)c2cccnc21
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCN)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-phthalimidopropoxy)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (157 mg, 0.22 mmol) in ethanol (10 ml) was added hydrazine monohydrate (100 mg, 2 mmol), and the mixture was stirred at room temperature for 3 hours. The precipitates were removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added methylene chloride, and the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol in chloroform) to give the title compound (58 mg, 0.10 mmol).
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.[CH3:8][C:9]([CH3:33])([CH3:32])[C@H:10]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([O:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[N:19]=1)=[O:17])[C:11](=[O:14])[NH:12][CH3:13]>>[F:2][C:3]1([F:7])[CH2:6][N:5]([C:21]2[CH:22]=[CH:23][C:18]([C:16]([NH:15][C@@H:10]([C:9]([CH3:33])([CH3:32])[CH3:8])[C:11]([NH:12][CH3:13])=[O:14])=[O:17])=[N:19][C:20]=2[O:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)[CH2:4]1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(Br)c(OCC2CCCO2)n1)C(C)(C)C
Reactant: FC1(F)CNC1
Agent: Cl
Product: CNC(=O)[C@@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CCCO2)n1)C(C)(C)C

Procedure:
The title compound was synthesized by addition of 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7) to 5-bromo-6-(tetrahydro-furan-2-ylmethoxy)-pyridine-2-carboxylic acid ((S)-2,2-dimethyl-1-methylcarbamoyl-propyl)-amide (Example 188) in analogy to the procedure described in Example 69 a, MS (EI): m/e=441.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:32]([C:31]([F:30])([F:41])[F:42])=[CH:33][CH:34]=4)[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C

Procedure:
(1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 28 mg, 0.07 mmol) and 4-(trifluoromethyl)benzoic acid (14 mg, 0.07 mmol) were dissolved in DMF (0.265 ml). HBTU (30 mg, 0.08 mmol) and N,N-diisopropyl-ethylamine (0.026 ml, 0.16 mmol) were added and the mixture was stirred over night at r.t. Then it was diluted with acetonitrile and purified by semi-preparative HPLC. Yield 24 mg (59%).