Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:31])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:31])=[O:14])=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To 4-benzyloxy-3-trifluoromethylbenzoic acid (444 mg), toluene (5 mL), N,N-dimethylformamide (2 droplets) and thionyl chloride (0.16 mL) were added, and then the mixture was stirred at 60° C. for 20 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene, and the obtained product was used for the synthesis of (h).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([O:9]C)=[O:8].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17]>>[CH2:17]([N:4]1[CH2:5][CH2:6][C@H:2]([CH3:1])[C@H:3]1[C:7]([OH:9])=[O:8])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCC=O
Reactant: COC(=O)[C@H]1NCC[C@@H]1C
Product: C=CCCCCCN1CC[C@H](C)[C@H]1C(=O)O
Yield: 80 %

Procedure:
Following the procedure described above for Compound 19 Steps 1-2, treatment of methyl (3S)-3-methyl-L-prolinate with hept-6-enal afforded the title compound 125 (80%) as an oil. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 5.78 (m, 1H), 5.03-4.92 (m, 2H), 3.58-3.48 (m, 2H), 3.19-3.01 (m, 2H), 3.07-2.95 (m, 1H), 2.34-2.22 (m, 1H), 2.12-2.00 (m, 3H), 1.69-1.55 (m, 3H), 1.41-1.22 (m, 4H), 1.18 (d, J 8.8, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:15][C:16](=[O:21])[CH2:17][C:18](=O)[CH3:19])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:22]([C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[O:27][CH2:28][C:29]([NH2:31])=O)#[N:23].C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[C:16](=[O:21])[CH:17]=[C:18]([CH3:19])[N:31]=[C:29]2[CH2:28][O:27][C:26]2[CH:25]=[C:24]([CH:34]=[CH:33][CH:32]=2)[C:22]#[N:23])[CH:5]=[C:6]([F:14])[C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(=O)CC(=O)Nc1cc(F)c(N2CCOCC2)c(F)c1
Reactant: N#Cc1cccc(OCC(N)=O)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n(-c2cc(F)c(N3CCOCC3)c(F)c2)c(COc2cccc(C#N)c2)n1
Temperature: 165 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
A mixture of N-(3,5-difluoro-4-morpholinophenyl)-3-oxobutanamide (0.79 g, 2.65 mmol), 2-(3-cyanophenoxy)acetamide (0.93 g, 5.28 mmol) and titanium tetraisopropanolate (6.3 mL) in xylene (25 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 60 mL of toluene and 60 mL of saturated NH4Cl aqueous solution were added. The resulting mixture was stirred at rt overnight and filtered and the filtrate was extracted with DCM (20 mL×4). The combined organic layers were washed with brine (30 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:2) to give the title compound as a yellow solid (0.29 g, 25%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: NC1CCOCC1
Reactant: N#Cc1cnc(N)cc1F
Product: N#Cc1cnc(N)cc1NC1CCOCC1

Procedure:
From intermediate 21 and racemic tetrahydro-2H-pyran-4-amine, reacted in an analogous manner to the preparation of intermediate 49. (UPLC-MS 3) tR 0.36 min; ESI-MS 219.1 [M+H]+.
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[C:10]([CH3:16])[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([S:7][C:8]1[N:9]=[C:10]([CH3:16])[CH:11]=[C:12]([CH2:14][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCNC1
Reactant: CCCCCCSc1nc(C)cc(C=O)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCCCSc1nc(C)cc(CN2CCCC2)n1
Reaction time: 24 h
Yield: 28.2 %

Procedure:
2-Hexylsulfanyl-6-methyl-pyrimidine-4-carbaldehyde (0.1 g, 0.42 mmol) was dissolved in ethanol (1 mL) and acetic acid (0.1 mL). Then pyrrolidine (0.07 mL, 1 mmol) and sodium cyanoborohydride (26 mg, 0.4 mmol) were added slowly at 20° C. and stirring continued for 24 h. The reaction mixture was evaporated to dryness and dissolved in a minimal amount of DMF (0.8 mL) and directly purified by preparative HPLC chromatography on a YMC combiprep ODS-AQ column (75×20 mm iD, S-5 μM, 12 nm) with an acetonitrile-water gradient. One obtained 34.7 mg (28%) of a yellow liquid. MS: m/z=294 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:32][NH:31][CH2:30][CH2:29][C:5]=2[N:6]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:28])=[CH:12][N:13]3[S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:8]=1.[CH3:33][CH:34]([CH3:42])[C:35](=[O:41])[CH2:36][C:37](OC)=[O:38]>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.ClCCl.O>[CH3:1][O:2][C:3]1[C:4]2[CH2:32][N:31]([C:37](=[O:38])[CH2:36][C:35](=[O:41])[CH:34]([CH3:42])[CH3:33])[CH2:30][CH2:29][C:5]=2[N:6]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:28])=[CH:12][N:13]3[S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:8]=1
Reactant: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CNCC2
Reactant: COC(=O)CC(=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: COc1nc(-c2cccc3c2c(C)cn3S(=O)(=O)c2ccc(C)cc2)nc2c1CN(C(=O)CC(=O)C(C)C)CC2
Temperature: 150 °C

Procedure:
To a solution of 4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, prepared as described in Example 17, (300 mg, 0.67 mmol) in toluene (3 mL), in a 2-5 mL microwave vial, was added methyl 4-methyl-3-oxopentanoate (0.28 mL, 2 mmol) followed by DMAP (25 mg, 0.2 mmol). The reaction vessel was then sealed and heated via microwave irradiation at 150° C. for 35 min. The reaction mixture was then cooled to room temperature and diluted with dichloromethane and water. The layers were separated and the organic layer was dried by passing through a phase separator and then concentrated. The resulting residue was purified via silica gel flash chromatography (45-90% ethyl acetate/heptanes) to furnish 1-(4-methoxy-2-(3-methyl-1-tosyl-1H-indol-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpentane-1,3-dione. MS (ESI+) m/z 561.3 (M+H)+.
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[N:20][CH:21]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.CC(O)=O>ClCCCl>[Br:15][C:16]1[CH:17]=[C:18]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)[CH:19]=[N:20][CH:21]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2cncc(Br)c2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sodium triacetoxyl-borohydride (245 mg, 1.16 mmol) was added to the solution of 5-bromo-pyridine-3-amine (100 mg, 0.57 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (127 mg, 0.57 mmol) in 10 ml of 1,2-dichloroethtane (DCE), of HOAc (664, 2 eq. 1.16 mmol) was added, the mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water, and dried over sodium sulfate. The solvent was removed by under reduced pressure to give 200 mg of crude 5-bromo-N-(3-(cyclopentyloxy)-4-methoxybenzyl)pyridin-3-amine, which was used for the next step without further purification.
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][C:9]1[N:10]=[CH:11][C:12]([CH2:15][NH2:16])=[N:13][CH:14]=1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=3)[C:31](O)=[O:32])[C:24]2=[O:37])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:29]=[C:30]([CH:34]=[CH:35][N:36]=3)[C:31]([NH:16][CH2:15][C:12]3[CH:11]=[N:10][C:9]([CH3:8])=[CH:14][N:13]=3)=[O:32])[C:24]2=[O:37])=[CH:38][CH:39]=1
Reactant: Cc1cnc(CN)cn1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: Cc1cnc(CNC(=O)c2ccnc(N3CCN(Cc4ccc(F)cc4)C3=O)c2)cn1
Yield: 39 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (5-methylpyrazin-2-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((5-methylpyrazin-2-yl)methyl)isonicotinamide was obtained as a colorless solid in 39% yield: mp 169-171° C.; 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1H), 8.52 (d, J=0.9 Hz, 1H), 8.39-8.35 (m, 2H), 7.46 (br s, 1H), 7.39-7.37 (m, 1H), 7.29-7.24 (m, 2H), 7.05-6.99 (m, 2H), 4.74 (d, J=5.1 Hz, 2H), 4.44 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.37 (t, J=8.1 Hz, 2H), 2.54 (s, 3H); MS (ES+) m/z 421.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]([NH:12][C:13]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)[CH2:8][O:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:32]=[C:13]([C@@H:15]4[CH2:19][CH2:18][CH2:17][N:16]4[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:12][C:7]=3[CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC1COc2cc(Br)ccc2C1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2c([nH]1)COc1cc(Br)ccc1-2
Temperature: 130 °C
Yield: 57.3 %

Procedure:
A mixture of (2S)-tert-butyl 2-(7-bromo-4-oxochroman-3-ylcarbamoyl)pyrrolidine-1-carboxylate (3.23 g, 7.35 mmol) and ammonium acetate (5.6 g, 73.5 mmol) in xylenes (40 mL) was heated at 130° C. for 2 hours. The reaction was cooled to room temperature. The xylenes were removed under reduced pressure and the residue was diluted with dichloromethane (100 mL). Saturated sodium bicarbonate (200 mL) was added slowly with stirring until gas evolution had subsided. The phases were separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic phases were washed with brine (50 mL) and dried over sodium sulfate. The mixture was filtered and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography with eluant of (10% methanol in ethylacetate) and hexane. The product containing fractions were combined and the solvent was removed under reduced pressure to provide (S)-tert-butyl 2-(7-bromo-3,4-dihydrochromeno[4,3-d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.77 g, 4.21 mmol, 57%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([Cl:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([OH:15])[C:6]([OH:14])=[N:7]2.[CH:16]([CH:18]=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:13][C:10]1[CH:9]=[C:8]2[N:7]=[C:6]([OH:14])[C:5]([OH:15])=[N:4][C:3]2=[C:2]2[C:11]=1[N:12]=[CH:18][CH:16]=[N:1]2
Reactant: O=CC=O
Reactant: Nc1c(Cl)cc2nc(O)c(O)nc2c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1nc2cc(Cl)c3nccnc3c2nc1O
Temperature: 50 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A mixture of 0,5 g (2,24 mmol) 5,6-diamino-7-chloro-2,3-dihydroxyquinoxaline in 20 ml water was added 0,5 ml (3,36 mmol) 40% aqueous glyoxal and 0,35 g (3,36 mmol) sodium carbonate. The reaction mixture was stirred at 50° C. for 3 h. After cooling to 25° C., the precipitate was filtered off. The crude product was stirred with water and added 1N hydrochloric acid to pH 2-3 to give 0,56 g (100%) 6-chloro-2,3-dihydroxypyrazino(2,3-f)quinoxaline, m.p. >300° C. NMR (DMSO-d6): 9.0 (2H,s), 7.73 (1H,s).
Reaction SMILES: [ClH:1].[C:2]1([C@:8]2([OH:36])[CH2:16][CH2:15][C:14]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C@@H:13]3[C@H:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1>[ClH:1].[C:2]1([C@:8]2([OH:36])[CH2:16][CH2:15][C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:13]3[C@H:9]2[CH2:10][NH:11][CH2:12]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O[C@@]1(c2ccccc2)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reaction time: 2 h

Procedure:
A solution of 6.3N hydrochloric acid in 115 cm3 of dioxane is added to a solution of 6.8 g of (3aS, 4S, 7aS )-4,7,7-triphenyl-2-tert-butoxycarbonyl-perhydroisoindol-4-ol in 60 cm3 of dioxane at room temperature. The reaction mixture is stirred at this temperature for 2 hour and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is washed with acetonitrile, filtered off and then dried. 4 g of (3aS, 4S, 7aS )-4,7,7- triphenyl-perhydroisoindol-4-ol hydrochloride are obtained in the form of a white foam.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[C:10]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]([CH3:16])=[CH:12][C:13]=2[CH3:15])[NH:8][CH2:7]1)([OH:3])=[O:2].[CH3:24]COC(C)=O>CCOCC>[CH3:24][O:2][C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[C:10]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:22])[CH3:21])[C:11]([CH3:16])=[CH:12][C:13]=2[CH3:15])[NH:8][CH2:7]1)=[O:3]
Reactant: Cc1cc(C)c2c(c1NC(=O)C(C)(C)C)NCC2CCC(=O)O
Reactant: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)CCC1CNc2c(NC(=O)C(C)(C)C)c(C)cc(C)c21

Procedure:
N-[3-(2—Carboxyethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethyl-propanamide (1.5 g) was dissolved in AcOEt (10 ml) and a solution of CH2N2 in ether was added. AcOEt (100 ml) was added, and after washing with water, the mixture was dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3/MeoH=50/1−10/1) to give 1.0 g of N-[3-(2-methoxycarbonylethyl)-4,6-dimethylindolin-7-yl]-2,2-dimethylpropanamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1.N1C=CC=CC=1.[Br:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClCCl.C(OCC)(=O)C>[Br:23][CH2:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH:5]=[C:4]([O:15][CH3:16])[N:3]=1)=[O:28]
Reactant: O=C(Cl)CCCBr
Reactant: COc1cc(C(=O)OC(C)(C)C)cc(N)n1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)OC(C)(C)C)cc(NC(=O)CCCBr)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of t-butyl 2-amino-6-methoxypyridine-4-carboxylate (D55) (0.263 g) and pyridine (0.12 mL) in dichloromethane (16 mL) under argon, was added 4-bromobutyryl chloride (0.17 mL) dropwise (syringe). The reaction was stirred at room temp for 2.5 h and then diluted with ethyl acetate. The mixture was washed with citric acid solution (10% aq.) and the aqueous layer was re-extracted with ethyl acetate. The combined extracts were washed with aq. bicarbonate, water and brine, dried (MgSO4) and evaporated to give the title compound (D56) as a pale yellow gum (0.47 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C[C@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 87 %

Procedure:
300.0 g (1.27 moles) ethyl 4-benzyloxy-3-oxobutyrate, 300 ml ethanol, and 104.5 mg (0.127 mmol) [RuCl{(R)-segphos}]2(μ-Cl)3 [Me2NH2] were introduced in a nitrogen stream into a 1-L autoclave and flushed with hydrogen, and after introduction of hydrogen at a pressure of 1 MPa, the mixture was heated with stirring. The mixture was reacted at 90 to 95° C. for 7 hours. After the reaction solution was cooled to room temperature, the hydrogen was purged and replaced by nitrogen. The reaction solution was concentrated in a rotary evaporator and the residue was distilled under reduced pressure to give 263.3 g of the title compound (chemical purity, 96.2%; optical purity, 99.1% ee; and yield, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH3:14])[C:11](=[O:15])[NH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]([O:20]CC)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][CH3:14])[C:11](=[O:15])[N:10]([CH2:17][C:18]([OH:20])=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCl
Reactant: CCn1c(-c2ccc(Cl)cc2)c[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1c(-c2ccc(Cl)cc2)cn(CC(=O)O)c1=O

Procedure:
685 mg (3.076 mmol) of 5-(4-chlorophenyl)-1-ethyl-1,3-dihydro-2H-imidazol-2-one from Example 119A are placed in 10 ml acetonitrile, treated with 377 mg (3.076 mmol) of ethyl chloroacetate and 850 mg (6.152 mmol) of potassium carbonate and stirred under reflux overnight. The reaction mixture is evaporated, the residue is partitioned between dichloromethane and water, the organic phase is separated, and this is dried over sodium sulphate and again concentrated. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1→50:1) and thus yields 226 mg (26% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([NH:18][C:19]([S:23][CH3:24])=[N:20]3)=[C:16]([NH2:25])[N:15]=2)=[N:6]1.[C:30](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([S:23][CH3:24])[N:20]3[CH3:30])=[C:16]([NH2:25])[N:15]=2)=[N:6]1
Reactant: CSc1nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2c(N)nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2n1C
Temperature: 70 °C
Reaction time: 48 h
Yield: 24.2 %

Procedure:
100 mg (0.255 mmol) of the compound from example 29 were dissolved in 5 ml of dimethylformamide, and 49 mg (0.357 mmol) of potassium carbonate were added. The mixture was heated to 70° C. for 10 min and, after cooling, 18 μl (0.291 mmol) of iodomethane were added and the mixture was stirred at RT for 48 h. The mixture was concentrated and the residue was taken up in water and acidified with acetic acid. A solid precipitates out, which was filtered off and washed with water. The purification was effected by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 26 mg of the title compound were obtained (24% of theory).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:38])([F:37])[C:8]1[CH:9]=[C:10]([C@H:18]([O:20][C@@H:21]2[C@@H:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[C@H:25]([CH2:35][OH:36])[CH2:24][CH2:23][O:22]2)[CH3:19])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.C(N(CC)CC)C>ClCCl>[F:38][C:7]([F:6])([F:37])[C:8]1[CH:9]=[C:10]([C@H:18]([O:20][C@@H:21]2[C@@H:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[C@H:25]([CH2:35][O:36][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:24][CH2:23][O:22]2)[CH3:19])[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1
Reactant: C[C@@H](O[C@H]1OCC[C@@H](CO)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](O[C@H]1OCC[C@@H](COS(C)(=O)=O)[C@@H]1c1ccc(F)c(F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (50 μl, 0.63 mmol) was added to a mixture of [(2R,3R,4R)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(3,4-difluorophenyl)-tetrahydropyran-4-yl]methanol (Description 15; 235 mg, 0.49 mmol), triethylamine (133 ml, 0.97 mmol), 4-N,N-dimethylaminopyridine (3 mg, 0.02 mmol) and dichloromethane (5 ml) at 0° C. The mixture was stirred for 30 minutes, then quenched with saturated aqueous NaHCO3 and extracted into dichloromethane. The combined organic extracts were dried and concentrated. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[C:27]([C:28]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH2:6]2)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CC1(C)CCC(Nc2ncnc3c(N)cccc23)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CCC(Nc2ncnc3c(NC(=O)c4c(Cl)ccc(CNC(=O)C(C)(C)C)c4F)cccc23)CC1
Yield: 5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-dimethylcyclohexyl)quinazoline-4,8-diamine (Intermediate-15, 100 mg, 0.37 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 212 mg, 0.99 mmol), oxalyl chloride (188 mg, 1.49 mmol), DMF (1 drop) and DIPEA (143 mg, 1.11 mmol) in CH2Cl2 (5 mL) to afford 10 mg of the title product. 1H NMR (300 MHz, CDCl3): δ 9.91 (s, 1H), 8.96 (d, 1H), 8.55 (s, 1H), 7.51-7.44 (m, 3H), 6.11 (br s, 1H), 5.67 (br s, 1H), 4.50 (d, 1H), 4.19 (m, 1H), 1.69-1.60 (m, 4H), 1.38-1.28 (m, 4H), 1.12 (s, 9H), 0.95 (s, 3H), 0.92 (s, 3H); MS (m/z): 540.36 (M)+.