Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:5]2[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.[NH2:29][C:30]1[C:31]([Cl:63])=[C:32]([N:38]2[CH2:43][CH2:42][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:40]([O:52][Si:53]([CH:60]([CH3:62])[CH3:61])([CH:57]([CH3:59])[CH3:58])[CH:54]([CH3:56])[CH3:55])[CH2:39]2)[CH:33]=[C:34]([C:36]#[N:37])[CH:35]=1>>[Cl:63][C:31]1[C:30]([NH:29][C:7]2[N:6]=[C:5]([N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:10]3=[N:11][CH:12]=[C:13]([C:14]#[N:15])[N:9]3[N:8]=2)=[CH:35][C:34]([C:36]#[N:37])=[CH:33][C:32]=1[N:38]1[CH2:43][CH2:42][C@@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C@H:40]([O:52][Si:53]([CH:60]([CH3:62])[CH3:61])([CH:54]([CH3:56])[CH3:55])[CH:57]([CH3:58])[CH3:59])[CH2:39]1
Reactant: CC(C)[Si](O[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Reactant: COc1ccc(CN(c2nc(S(C)(=O)=O)nn3c(C#N)cnc23)C2CC2)cc1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1

Procedure:
tert-butyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate was prepared starting from 4-(cyclopropyl(4-methoxybenzyl)amino)-2-(methylsulfonyl)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 2) and tert-butyl ((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((triisopropylsilyl)oxy)piperidin-4-yl)carbamate using a method analogous to that used to prepare Example 171.
Reaction SMILES: [C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[C:2]1[C:3](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([OH:15])[C:9]([CH3:17])([CH3:16])[CH2:8]1)=[O:5]>[Pd].C(OC(=O)C)(=O)C>[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([O:15][C:7](=[O:6])[CH3:8])[C:9]([CH3:17])([CH3:16])[CH2:8]1)(=[O:5])[C:3]1[C:2](=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([O:32][C:4](=[O:5])[CH3:3])[C:26]([CH3:34])([CH3:33])[CH2:25]1)=[O:22]
Reactant: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Agent: [Pd]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)ON1C(C)(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(OC(C)=O)C(C)(C)C2)CC1(C)C
Yield: 126.5 %

Procedure:
A mixture of 20.0 g (42 mmol) of di-(1-oxyl-2,2,6,6-tetramethyl-piperidin-4-yl) phthalate, 100 ml of acetic anhydride, and 500 mg of 5% Pd on C is hydrogenated in a Paar apparatus (50 psi, ambient temperature, 1 hour). Catalyst is filtered and solvent is evaporated. The residue is dissolved in 150 ml of ethyl acetate. The ethyl acetate solution is washed with 5% aqueous ammonia (2×100 ml), water (100 ml), and saturated sodium chloride (100 ml), then dried over magnesium sulfate and concentrated to obtain a crude solid. The crude product is recrystallized from methanol to obtain 14.9 g (64% yield) of a white crystalline solid, m.p. 172-175° C.
Reaction SMILES: C([O:3][C:4](=[O:25])[C@@H:5]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][C:12]1=[O:24])[CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])C.[OH-].[Li+]>O1CCCC1>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH2:15][N:11]([C@@H:5]([CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:4]([OH:25])=[O:3])[C:12](=[O:24])[CH:13]=1
Reactant: CCOC(=O)[C@H](CC(C)CC)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 5 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid ethyl ester (0.95 g, 2.60 mmol) in tetrahydrofuran (15 mL) was treated with an aqueous 0.5N lithium hydroxide solution (10.4 mL) and stirred at 5° C. for 2 h. The mixture was concentrated in vacuo and the residue was dissolved in water (40 mL) and extracted with diethyl ether. The ether layer was discarded, and the aqueous layer was acidified with 1N aqueous hydrochloric acid (8 mL) and extracted with ethyl acetate. The combined ethyl acetate layers were concentrated in vacuo which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid (839 mg, 96%) as a pale orange solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][CH2:10]Cl)[CH3:8].[CH2:12]([N:16]1[C:20]2[CH:21]=[C:22]([C:25]3[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:27][NH:28][N:29]=3)[CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH2:36])[CH:13]([CH3:15])[CH3:14].[Cl-].[NH4+]>CN(C=O)C>[CH2:7]([O:9][CH2:10][N:28]1[NH:29][C:25]([C:22]2[CH:23]=[CH:24][C:19]3[N:18]=[C:17]([NH2:36])[N:16]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:20]=3[CH:21]=2)=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:27]1)[CH3:8]
Reactant: CCOCCl
Reactant: CC(C)Cn1c(N)nc2ccc(-c3n[nH]nc3-c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOCN1NC(c2ccccc2)=C(c2ccc3nc(N)n(CC(C)C)c3c2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.1 %

Procedure:
Add cesium carbonate (408 mg, 1.25 mmol) and chloromethyl ethyl ether (0.057 ml, 0.62 mmol) to a solution of 1-isobutyl-2-amino-6-(4-phenyl-2H-[1,2,3]triazol-5-yl)-1H-benzimidazole (208 mg, 0.62 mmol) in DMF (5 tri). Stir for 2 hours at RT, add aqueous ammonium chloride solution (20 ml) and extract with diethyl ether (20 ml). Dry over magnesium sulfate, concentrate and purify (radial silica gel chromatography, eluting with hexane:ethyl acetate 1:1) to provide the title compound as a white solid (32 mg, 13%).
Reaction SMILES: CO.[C:3]([O:7][C:8]([N:10]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([F:44])[CH:38]=1)[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][C:20]2=[O:31])[CH:13]([C:32]([O:34]C)=[O:33])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+]>O>[C:3]([O:7][C:8]([N:10]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[C:39]([F:44])[CH:38]=1)[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][C:20]2=[O:31])[CH:13]([C:32]([OH:34])=[O:33])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)C1CC(N(Cc2ccc(C)c(F)c2)C(=O)OC(C)(C)C)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(N(Cc4ccc(C)c(F)c4)C(=O)OC(C)(C)C)CC3C(=O)O)c2c1
Reaction time: 2.5 h
Yield: 39.7 %

Procedure:
To 5 mL of a methanol solution containing 80 mg of methyl 4-((tert-butoxycarbonyl) (3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate, 0.2 mL of 2 mol/L aqueous sodium hydroxide solution was added at room temperature, and stirred for 2.5 hours. Further, 0.2 mL of 2 mol/L aqueous sodium hydroxide solution and 0.5 mL of water were added, stirred at the sane temperature for 4 hour and 40 min, and allowed to stand overnight. The solvent was removed under reduced pressure, and the reaction mixture was adjusted to pH 7.0 with 2 mol/L hydrochloric acid. To the mixture, water and ethyl acetate were added, the organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 31 mg of 4-((tert-butoxycarbonyl) (3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylic acid as a yellow solid. (2) To 5 mL of an ethyl acetate solution containing 31 mg of 4-((tert-butoxycarbonyl)(3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylic acid, 0.1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 6 hours and 40 min, further, 0.1 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 3.5 hours. The resulting solid was filtered to give 30 mg of 4-((3-fluoro-4-methybenzyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylic acid hydrochloride as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](OS(C)(=O)=O)[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:22]=[N+:23]=[N-:24])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 16 h

Procedure:
(2S,4R)-4-Methanesulfonyloxypyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (11.9 g, 37 mmol) and NaN3 (2 equiv) were mixed in DMSO (160 mL) and stirred at 90° C. for 16 hours. The mixture was cooled then partitioned between water (200 mL) and EtOAc (400 mL). The aqueous layer was discarded, the organics washed with water (200 mL) and saturated aqueous NaCl (200 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (8.5 g, 31 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C11H18N4O4, 270.3. found 271.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20](Br)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1>>[N:11]1([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[N:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: Nc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1

Procedure:
Synthesized using 4-aminophenylboronic acid (173 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. White solid. Yield: 35 mg, 0.14 mmol, 22%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.14 (s, 2H), 6.76 (d, J=8.5 Hz, 2H), 6.92 (s, 1H), 6.93 (brs, 1H), 7.12 (s, 1H), 7.43 (dd, J=8.5, 2.5 Hz, 1H), 7.60 (brs, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.82 (d, J=8.5 Hz, 2H), 8.52 (d, J=1.5 Hz, 1H); MS (ESI): m/z=250.74 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([C:6]([N:8]=[CH:9][N:10](C)C)=O)=[C:4]([F:16])[CH:3]=1.O.[NH2:18]N>C(O)(=O)C>[Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([C:6]2[N:8]=[CH:9][NH:10][N:18]=2)=[C:4]([F:16])[CH:3]=1
Reactant: NN
Reactant: Cc1cc(C(=O)N=CN(C)C)c(F)cc1Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(-c2nc[nH]n2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of 4-bromo-N-((dimethylamino)methylene)-2-fluoro-5-methylbenzamide (24.6 g, 86.2 mmol) in acetic acid (200 mL) was added dropwise hydrazine hydrate (25 mL, 0.70 mol) at 0° C. The reaction mixture was stirred at room temperature overnight. The mixture was filtered washed with water (500 mL×3) and dried under reduced pressure to give the title compound (15 g, 68% yield) as a white solid. MS (ESI) m/z 256.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:26][N:27]2[C:31]([CH3:32])=[CH:30][N:29]=[CH:28]2)[CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:26][N:27]2[C:31]([CH3:32])=[CH:30][N:29]=[CH:28]2)[CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CC(=Cn2cncc2C)c2ccc(F)cc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC(Cn2cncc2C)c2ccc(F)cc2)cc1-c1ccccc1
Reaction time: 22 h

Procedure:
A suspension of E and Z isomers of methyl 4-[2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-prop-2-enyl]-2-phenyl-benzoate (2 g; 4.69 mmol) and 10% Pd/C (0.55 g) in MeOH (25 ml) was hydrogenated for 22 hours. After filtration of the catalyst, the solvent was evaporated to give methyl 4-[2-(4-fluorophenyl)-3-(5-methylimidazol-1-yl)-propyl)-2-phenyl-benzoate as an oil which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([OH:15])=[O:14])=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.IC.[C:18](=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[CH3:18][O:14][C:13]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12]2)[N:6]=1)=[O:15]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)c(OCC2CC2)n1
Yield: 46.7 %

Procedure:
A solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid (Example 9 d, 0.4 g, 1.5 mmol), iodomethane (CAN 16519-98-5, 0.42 g, 3 mmol), sodium carbonate (0.16 g, 1.5 mmol) in DMF (10 mL) was stirred overnight at room temperature. Water was poured into the reaction solution and the resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 20 g, 5% ethyl acetate in petroleum ether) to yield the title compound (0.2 g, 0.7 mmol, 48%) as white solid; MS (EI): m/e=286.0 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CS(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:43][C:44]([F:47])([F:46])[F:45])[C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)cc3c2)CC1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N4CCCCC4)CC2)n3CC(F)(F)F)CC1
Yield: 86 %

Procedure:
The title compound was synthesized in analogy to example 3, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 2) and 2,2,2-trifluoroethyl methanesulfonate, to afford the desired product as a colorless foam (86%). MS (ISP): 613.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:16])[C:14]#[CH:15].C(N(CC)CC)C>C(O)C>[Cl:12][C:11]1[C:2]([NH:16][CH2:13][C:14]#[CH:15])=[N:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: C#CCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: C#CCNc1nc2ccccc2nc1Cl

Procedure:
A mixture of 10 g of 2,3-dichloroquinoxaline, 4.5 ml of propargylamine, 10.5 ml of triethylamine in 50 ml of ethanol is refluxed for 4 h. After evaporating under vacuum the resulting mixture, the residue is chromatographed on SiO2 (eluent: CH2Cl2) thereby obtaining 7.0 g of 2-chloro-3-(propargylamino)quinoxaline (IR (KBr): 3441, 3282, 1518 cm-1). This product is then added with 10 ml of concentrated sulphuric acid and the resulting mixture is stirred at 90° C. for 1 h. After cooling down and cautiously neutralizing with aqueous NaOH, the resulting precipitate is filtered under vacuum, washed, dried, decolorized and recrystallized from dimethylformamide, thereby obtaining 2.4 g of 1-methylimidazo[1,2-a]quinoxaline-4(5H)-one (m.p. >300° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:42])=[C:39]([OH:41])[CH:40]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:41][C:39]2[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1O
Reactant: COc1cnc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cl)n2-c1ccccc1
Product: COc1cnc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Oc1cc(F)ccc1C)n2-c1ccccc1

Procedure:
The title compound was prepared from the compound of step 5 (100 mg, 212 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6. Yield: 99.0 mg.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:11]=[C:10]([N:18]([C:17]2[CH:20]=[CH:21][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(C)cc1
Product: Cc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (250 mg, 1.25 mmol) and 4-methyl-N-methylaniline (196 mg, 1.43 mmol) by a procedure similar to example 1b and was isolated as white powder (210 mg, 84%). 1H NMR (CDCl3): 8.69 (d, J=8.4 Hz, 1H), 7.75 (dd, J=8.1 and 7.5 Hz, 1H), 7.39 (d, J=7.8 Hz, 2H), 7.25 (d, J=7.8 Hz, 2H), 7.13 (d, J=8.2 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 3.81 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH:14]([OH:25])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.[CH3:31][O:32][CH2:33]Cl.C(N(CC)C(C)C)(C)C>ClCCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([CH:8]([CH:14]([O:25][CH2:31][O:32][CH3:33])[C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)C(O)c1ccc(C(F)(F)F)cc1
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)C(OCOC)c1ccc(C(F)(F)F)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(tert-butoxycarbonyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propanoate (9.25 g, 24.5 mmol) in DMF (3.78 mL, 49.0 mmol) and 1,2-dichloroethane (20 mL) was added tetra-n-butylammonium iodide (9.51 g, 25.7 mmol), chloromethyl methyl ether (5.59 mL, 73.5 mmol) and N,N-diisopropylethylamine (12.8 mL, 73.5 mmol). The mixture was gradually heated to 45° C. and stirred overnight. The crude product was concentrated in vacuo, diluted with CH2Cl2 and washed three times with water. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography: 16%-20%-25% EtOAc-Hexane. The product was obtained as a white solid. LCMS (API-ES) m/z (%): 322 (M+1-100).
Reaction SMILES: [OH-].[Li+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=O)=[CH:18][CH:17]=1.Cl>C1COCC1>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[O:3][C:4]3[C:5]([C:11](=[O:13])[CH:12]=2)=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=3)=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(=O)c3cc(O)ccc3o2)cc1
Temperature: -1 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (19.7 mmol, 3 equivalents) is added in one portion to a well-stirred solution of 2′,5′-dihydroxyacetophenone (6.4 mmol) in dry THF (5 ml) at −78° C. under an argon atmosphere. The reaction mixture is stirred at −78° C. for one hour and subsequently at −1° C. for two hours. After re-cooling to −78° C., a solution of 4-methoxybenzoyl chloride (6.5 mmol) in THF (10 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied onto a mixture of ice (150 g) and concentrated HCl (5 ml) and extracted with dichloromethane (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (30 ml) and sulfuric acid (0.2 ml) are added to the residue, and the mixture is heated at 95–100° C. under an argon atmosphere for from 30 minutes to one hour. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised from methanol to give 4′-methoxy-6-hydroxyflavone. 1H NMR (500 MHz, d6-DMSO): δ10.08 (br s, OH), 8.02–7.11 (dm, 4H), 7.63 (d, 1H), 7.35 (d, 1H), 7.26 (d, 1H), 6.86 (s, 1H), 3.88 (s, 3H); 13C NMR (62.90 MHz, d6-DMSO): δ176.78 (s), 162.23 (s), 161.93 (s), 154.73(s), 149.24 (s), 127.97 (s), 124.14 (s), 123.44 (s), 122.77 (s), 119.61 (s), 114.46 (s), 107.52 (s), 104.44 (s), 55.43 (s); EI-MS (70 eV) m/e (rel. abund.)=268.0735 (100). The product is colorless and exhibits the UV absorption maximum at λ=322 nm with ε=24790 (in 2-propanol) (cf. FIG. 1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@H:25]4[CH2:28][C@H:27]([C:29]([O:31]CC5C=CC=CC=5)=[O:30])[CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1>CO.[Pd]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C@H:25]4[CH2:28][C@H:27]([C:29]([OH:31])=[O:30])[CH2:26]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@H]1C[C@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H]1C[C@H](n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Reaction time: 8 h

Procedure:
A mixture of trans-benzyl 3-(4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazol-1-yl)cyclobutanecarboxylate (Intermediate 34A; 500 mg; 0.944 mmol) and Pd/C (50 mg) in MeOH (50 mL) was stirred overnight under a hydrogen balloon. The reaction mixture was filtered and the filtrate was concentrated and purified by reverse phase flash chromatography to afford 113 mg (27%) of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:15])=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([CH2:22][CH2:23][C:24](Cl)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([C:5]1[C:6]([NH:15][C:24](=[O:25])[CH2:23][CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc2c(C(C)(C)C)c(N)nn2c1
Reactant: O=C(Cl)CCC1CCCCC1
Product: Cc1cnc2c(C(C)(C)C)c(NC(=O)CCC3CCCCC3)nn2c1

Procedure:
The product from Example 178A and 3-cyclohexylpropionyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-0.93 (m, 2H), 1.09-1.28 (m, 4H), 1.43-1.51 (m, 11H), 1.58-1.73 (m, 5H), 2.24-2.33 (m, 5H), 8.38 (d, J=2.0 Hz, 1H), 8.74 (s, 1H), 9.60 (br s, 1H); MS (DCI) m/z 343 (M+H)+.
Reaction SMILES: [C:1]([C:4]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:5]1[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[C:14]([O:23][CH2:24][CH:25]([CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[OH:26])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:14]([O:23][CH2:24][CH:25]([CH2:27][O:28][C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:26][C:6](=[O:7])[CH:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]1([C:1](=[O:3])[CH3:2])[OH:13])(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCC(=O)OCC(O)COC(=O)CCCCCCC
Reactant: CC(=O)C1(O)C=CC=CC1C(=O)Cl
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OC(=O)C1C=CC=CC1(O)C(C)=O
Yield: 71 %

Procedure:
In analogy with the preceding examples, 2-acetylsalicyloyl chloride is reacted with 1,3-dioctanoylglycerol which, upon work up as before, yields 71% of the desired 1,3-dioctanoyl-2-(2-acetylsalicyloyl)glycerol as an oil.