Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=5[CH:32]=O)[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH3:39][O:40][NH2:41]>>[CH3:39][O:40][N:41]=[CH:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[CH:28]1[O:27][N:26]=[C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:5]4[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:38])[F:1])=[N:4]4)[CH2:15][CH2:16]3)[S:21][CH:22]=2)[CH2:29]1
Reactant: CON
Reactant: O=Cc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Product: CON=Cc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1

Procedure:
2-{3-[2-(1-{[3,5-Bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde (150 mg) and O-methylhydroxylamine (24 mg) were reacted analogously to I-40 (step 4). This gave 2-{3-[2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]-4,5-dihydro-1,2-oxazol-5-yl}benzaldehyde 0-methyloxime (169 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[C:16](Cl)(Cl)=[O:17]>>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1)=[C:16]=[O:17]
Reactant: C#CCN1C(=O)COc2ccc(N)cc21
Reactant: O=C(Cl)Cl
Product: C#CCN1C(=O)COc2ccc(N=C=O)cc21

Procedure:
6-Amino-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine is treated with phosgene analogously to the procedure described in Example 103 in order to produce the 3,4-dihydro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine which is used as the starting material in Example 3. 1H-NMR (CDCl3, 400 MHz): 6.98-6.92 ppm (m, 2H), 6.79 ppm (q, 1H), 4.66 ppm (d, 2H), 4.63 ppm (s, 2H), 2.31 ppm (t, 1H).
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCN1CCC(O)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and piperidin-4-ol (38 mg), and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (24 mg, yield 41%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=O.C[SiH](C)O[SiH](C)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:14])([CH3:13])[CH2:3][CH:4]=[CH:5][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)CCC(=O)N1CCCCC1
Agent: C[SiH](C)O[SiH](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)CC=CN1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 250.9 %

Procedure:
4,4-Dimethyl-1-piperidin-1-ylpentan-1-one (508 g) and toluene (1220 mL) were mixed. After an addition of (Ph3P)IrCl(CO) (802 mg) to the mixture, 1,1,3,3-tetramethyldisiloxane (795 mL) was added dropwise to the reaction under water-cooling. The mixture was stirred at RT for 3 hr, then concentrated in vacuo to give the title compound (1171 g) as a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[O:30]=[C:31]1[C:35](=[CH:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[S:34][C:33](=[S:45])[NH:32]1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:41][C:40]3[CH:39]=[CH:38][C:37]([CH:36]=[C:35]4[S:34][C:33](=[S:45])[NH:32][C:31]4=[O:30])=[CH:44][CH:43]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=Cc1ccc(C=C2SC(=S)NC2=O)cc1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C1NC(=S)SC1=Cc1ccc(CNc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 4-(4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 623.8.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[Na].[CH:7]([Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])=[CH2:8].C(O)(=O)C>>[C:1]([C:2]([CH3:4])([CH3:3])[CH2:8][CH2:7][Si:9]([O:14][CH3:15])([O:12][CH3:13])[O:10][CH3:11])#[N:5]
Reactant: C=C[Si](OC)(OC)OC
Reactant: CC(C)C#N
Agent: [Na]
Solvent: CC(=O)O
Product: CO[Si](CCC(C)(C)C#N)(OC)OC
Temperature: 103 °C
Yield: 72.9 %

Procedure:
Under a nitrogen atmosphere, isobutyronitrile (297.4 grams, 4.3 moles) and sodium metal spheres (9.9 grams, 0.43 moles) were added to a flask as described in Example 6. The contents of the flask were heated to 103° C with stirring and vinyltrimethoxysilane (637.8 grams, 4.3 moles) was added. After removing the heat source, the temperature of the flask contents was maintained at 100° C. to 107° C. by the rate of addition of the vinyltrimethoxysilane. After adding all of the vinyltrimethoxysilane, the flask contents were heated to 150° C. for one hour to ensure complete reaction. A sample taken for infra-red analysis showed no signs of any absorption attributable to a vinyl group on silicon. The infra-red spectrum was entirely consistent with the proposed structure and indicated a high state of purity. After cooling to room temperature, 25.8 grams (0.43 moles) of glacial acetic acid was added to neutralize any residual basic material. The reaction product was filtered and vacuum distilled (boiling point, 76° C. to 77° C. at 0.3 mm Hg) to yield 681.4 grams (73% yield after distillation) of 3-cyano-3-methylbutyltrimethoxysilane, as characterized by 1H and 13C NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[N:17]=[CH:16][C:15]2[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:14]=2[CH:13]=1>>[CH:21]1([N:20]2[C:14]3[CH:13]=[C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][N:10]=[C:2]([CH3:1])[CH:3]=4)[N:17]=[CH:16][C:15]=3[C:18]([CH3:25])([CH3:26])[C:19]2=[O:24])[CH2:23][CH2:22]1
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Product: Cc1cc(C(=O)Nc2cc3c(cn2)C(C)(C)C(=O)N3C2CC2)ccn1

Procedure:
Prepared in analogy to example 26 from 2-methylisonicotinic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as off-white foam.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](B(O)O)[CH:3]=[N:2]1.Br[C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:1]1[CH:5]=[C:4]([C:10]2[CH:11]=[C:12]([NH2:13])[CH:14]=[CH:15][CH:16]=2)[CH:3]=[N:2]1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1cn[nH]c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cccc(-c2cn[nH]c2)c1
Temperature: 25 °C
Yield: 26 %

Procedure:
1H-pyrazole-4-boronic acid (0.0976 g, 0.639 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (0-10% MeOH/CH2Cl2). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.024 g in 26% yield.
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])([CH2:7][CH3:8])[C:4](O)=[O:5])[CH3:2].S(Cl)([Cl:13])=O>>[CH2:1]([C:3]([CH2:9][CH3:10])([CH2:7][CH3:8])[C:4]([Cl:13])=[O:5])[CH3:2]
Reactant: CCC(CC)(CC)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCC(CC)(CC)C(=O)Cl

Procedure:
2,2-Diethylbutanoyl chloride was prepared from 2,2-diethylbutanoic acid and thionyl chloride in the usual way.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]([O:29][C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]2=[O:49])(=[O:21])=[O:20])=[CH:15][CH:14]=1>ClCCl>[O:49]=[C:23]1[CH:22]([S:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:12]=[O:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[O:29][C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1C(S(=O)(=O)c2ccc(CO)cc2)CCCCN1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccc(S(=O)(=O)C2CCCCN(OC(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (0.12 ml, 2.0 M in dichloromethane) in dichloromethane (5.0 ml) was added DMSO (0.05 ml) at −78 degree C. dropwise. The mixture was stirred for 15 minutes, at which time, 3-(4-hydroxymethyl-benzenesulfonyl)-1-trityloxy-azepan-2-one (60.5 mg in 2 ml of dichloromethane) from step F was added dropwise. The resulting solution was stirred for 30 minutes and then TEA (0.9 ml) was added in one portion. The reaction mixture was stirred and warmed to 0 degree C. for a period of 15 minutes, at which time, the reaction mixture was diluted with dichloromethane and washed sequentially with water and saturated NaCl solution. The organic phase was then dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude material, which was then purified by a column chromatography (0˜30% EtOAc in hexane). MS: 562.1 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].[CH3:11][CH:12]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:13]([C:15]1[CH:16]=C(O)[CH:18]=[C:19]([CH:21]=1)[OH:20])[CH3:14].Cl>C(O)C>[OH:20][C:19]1[C:18]2[C:9]3[CH2:8][S:7][CH2:6][C:5]=3[C:3](=[O:4])[O:2][C:1]=2[CH:16]=[C:15]([CH:13]([CH:12]([CH3:11])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH3:14])[CH:21]=1
Reactant: COC(=O)C1CSCC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Agent: Cl
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CSC3
Reaction time: 72 h

Procedure:
A solution of 20 g. (0.125 mole) of methyl-4-oxo-2,3,4,5-tetrahydrothiophene-3-carboxylate and 32 g. (0.135 mole) of 5-(3-methyl-2-octyl)resorcinol in 200 ml. of absolute ethanol was cooled in an ice-salt bath and saturated with anhydrous hydrogen chloride. The reaction mixture was allowed to stand at room temperature for 72 hours and the solid which formed was removed by filtration. Recrystallization from ethanol gave 16 g. (37%) m.p. 165°-166°. The structure was confirmed by the IR and nmr spectra.
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[N:14]=2)=[CH:9][C:8]=1[O:34][CH3:35])[CH3:5].Cl>C1COCC1.O>[CH3:5][CH:4]([O:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:26]=3[NH:25][CH:24]=[C:23]4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[N:14]=2)=[CH:9][C:8]=1[O:34][CH3:35])[CH3:3]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(OC)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cnc1OC(C)C
Temperature: 90 °C
Yield: 55.2 %

Procedure:
Sodium hydroxide (40 mg) was added to a solution of ethyl 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D38) (280 mg) in THF (3 mL) and water (3 mL). The resulting mixture was heated at 90° C. for 1 hour. Then 0.5 M HCl solution was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E18) (145 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.63 (2H, t), 3.00 (2H, t), 3.96 (3H, s), 5.43 (1H, m), 7.22 (1H, t), 7.27 (1H, d), 7.82 (1H, d), 7.92 (1H, d), 7.95 (1H, d), 8.68 (1H, d), 10.79 (1H, s), 12.10 (1H, br s). MS (ES): C22H22N4O5 requires 422; found 423.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@:8]([CH3:19])([CH:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+:21].[OH-]>CCO>[NH2:21][CH2:18][CH:16]([OH:17])[C@:8]([NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)C1CO1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)C(O)CN

Procedure:
A solution of tert-butyl((1R)-1-methyl-1-oxiran-2-yl-2-phenylethyl)carbamate (986 mg, 3.56 mmol) in EtOH (35 mL) and NH4OH (35 mL) was stirred at 60° C., sealed, for 16 h, concentrated in vacuo and purified by flash chromatography (silica, 0-30% (10% NH4OH/MeOH)/CH2Cl2) to provide tert-butyl ((1R)-3-amino-1-benzyl-2-hydroxy-1-methylpropyl)carbamate as a thick oil. 1H NMR (400 MHz, CD3OD, 1:1 diastereomeric mixture) δ 7.30-7.14 (m, 5H), 4.01 (br d, J=9.2 Hz, 0.5H), 3.54 (dd, J=10.0, 2 Hz, 0.5H), 3.39 (br s, 0.5H), 3.36 (br s, 0.5H), 2.94-2.56 (m, 4H), 1.47 (s, 9H), 1.03 (s, 1.5H), 0.99 (s, 1.5H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@H:7]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CN([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43]N=1)C.O>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(Cl)CCCCCCCCCCCCCCCCC>[C:1]([O:5][C:6](=[O:37])[C@H:7]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:8][C:9](=[O:27])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:25][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:6][CH2:7][CH3:28])[CH2:23][O:24][CH2:41][CH2:46][CH2:45][CH2:44][CH2:43][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:2][CH2:1][CH3:3])=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1ccccn1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NC(=O)CCSCC(O)CO)cc1)C(=O)OC(C)(C)C
Agent: CCCCCCCCCCCCCCCCCCCl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of (4-(6,7-dihydroxy-4-thiaheptanoylamino)benzoyl)glutamic acid di-t-butyl ester as obtained in Reference Example 6 (50 mg) in chloroform (1 ml), triethylamine (0.258 ml), stearyl chloride (0.25 ml) and dimethylaminopyridine (1 mg) were added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the title compound (75 mg, yield 76%) as a wax-like substance.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[C:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:5][N:4]=[CH:3]1.Cl.[H][H]>[Pd].O>[CH3:1][N:2]1[C:6]([CH2:7][CH:8]2[C:20]3[N:19]4[CH:21]=[CH:22][N:23]=[C:18]4[C:17](=[O:24])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)=[CH:5][N:4]=[CH:3]1
Reactant: [H][H]
Reactant: Cn1cncc1C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Agent: [Pd]
Agent: Cl
Solvent: O
Product: Cn1cncc1CC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Yield: 65.2 %

Procedure:
A mixture of 3.2 g of 10-[(1-methylimidazol-5-yl)methylene]-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one, 60 ml of 1N hydrochloric acid and 30 ml of water is hydrogenated, at a temperature in the region of 20° C. and at a pressure of 1.7 bar of hydrogen, for 6 hours in the presence of 10% palladium-on-charcoal. The catalyst is removed by filtration under an inert atmosphere and the filtrate is brought to pH=6 with concentrated sodium hydroxide. The white precipitate formed is filtered off, washed with distilled water and dried at 35° C. under vacuum (1 mmHg; 0.13 kPa). 2.1 g of 10-[(1-methylimidazol-5-yl)methyl]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a white solid melting above 260° C. (Analysis, % calculated C: 68.13, H: 4.76, N: 22.07, O: 5.04, % found C: 67.8, H: 4.9, N: 22.5).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[F:28][C:29]1[CH:34]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[C:32]([F:39])=[CH:31][C:30]=1F>C(#N)C>[F:28][C:29]1[CH:34]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[C:32]([F:39])=[CH:31][C:30]=1[O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12]
Reactant: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CS(=O)(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2cc(F)c(S(C)(=O)=O)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 1.3 %

Procedure:
Caesium carbonate (523 mg) was added to a solution of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (234 mg) and 1,2,4-trifluoro-5-(methylsulfonyl)benzene (169 mg) in acetonitrile (5 mL) was added. The mixture was heated in a sealed microwave vial to 160° C. for 7000 seconds and left to cool before being filtered and washed with acetonitrile (10 mL). The filtrate was evaporated in vacuo and chromatographed on silica, eluting with 0 to 10% methanol in ethyl acetate. This gave incomplete resolution so the mixture was purified by preparatory HPLC using a gradient of 5 to 95% acetonitrile in water to afford the desired compound (5.1 mg)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:12]([NH:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1nccc2ccccc12
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CNc2nccc3ccccc23)cc1
Reaction time: 4 h

Procedure:
1-Chloroisoquinoline (1.64 g, 0.01 mol) and benzylamine (2.14 g, 0.02 mol) were mixed at room temperature and heated, with stirring, in an oil-bath at 50° for 4 hours. The mixture was cooled to give a crystalline solid which was equilibrated between methylene chloride (CH2Cl2) and aqueous Na2CO3. The CH2Cl2 fraction was washed with water, dried and evaporated to dryness to give an oil which crystallised on standing (3.0 g). This material was twice re-crystallised from ether/40-60 petroleum ether to give the title compound as buff crystals, m.p. 101°-102°.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[CH:34]=[C:33]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]2=[O:48])[S:32][C:31]=1[C:49]([O:51]CC)=[O:50]>>[CH3:29][C:30]1[CH:34]=[C:33]([N:35]2[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]2=[O:48])[S:32][C:31]=1[C:49]([OH:51])=[O:50]
Reactant: CCOC(=O)c1sc(N2CCN(CCc3ccccc3)C2=O)cc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1cc(N2CCN(CCc3ccccc3)C2=O)sc1C(=O)O
Yield: 78 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 3-methyl-5-(2-oxo-3-phenethylimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 78% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.47-7.17 (m, 5H), 6.25 (s, 1H), 3.83-3.74 (m, 2H), 3.56-3.40 (m, 4H), 2.82 (t, J=7.4 Hz, 2H), 2.38 (s, 3H); MS (ES+) m/z 331.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41]([O:46][CH2:47]Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>CN(C=O)C>[C:41]([O:46][CH2:47][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)(=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: CC(C)C(=O)OCCl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (57 μL, 0.4 mmol) in DMF (1 mL) was added chloromethyl isobutyrate (34 mg, 0.25 mmol) at rt. The reaction was stirred at rt for 16 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) to afford the title compound as a white solid (45 mg, 37.5%). The title compound was characterized by LC-MS and 1H NMR as shown below: