Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:30][CH3:31])[CH:25]([CH:27]2[CH2:29][CH2:28]2)[OH:26])[C:5]1=[O:32])C=C.I([O-])(=O)(=O)=O.[Na+].CC[O:42][C:43]([CH3:45])=[O:44]>C(#N)C.O.O.[Ru](Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@@H:24]([CH2:30][CH3:31])[C:25]([CH:27]3[CH2:28][CH2:29]3)=[O:26])[C:5](=[O:32])[C@:4]([CH2:45][C:43]([OH:42])=[O:44])([CH3:1])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)C2CC2)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC[C@@H](C(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 417, Step A; 60 mg, 0.123 mmol) in EtOAc (1 mL), acetonitrile (1 mL) and water (1.5 mL) was added ruthenium chloride hydrate (2.8 mg, 0.012 mmol) and sodium meta-periodate (6.83 μl, 0.123 mmol) (portionwise over 5 minutes). The reaction was stirred at rt for 20 minutes and then partitioned between EtOAc (60 mL) and water (20 mL). The separated aqueous layer was extracted with EtOAc (2×20 mL) and the combined organic extracts were dried over MgSO4, filtered and evaporated in vacuo. Purification by column chromatography (12 g, SiO2, hexanes/IPA, 1:0 to 9:1) gave the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[O:4][CH3:5].[CH2:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O)[CH2:8][CH2:9]C.P(Br)(Br)Br>ClC(Cl)C>[CH3:1][NH:2][C:3](=[O:6])[O:4][C:5]1[CH:9]=[CH:8][CH:7]=[CH:11][C:12]=1[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CNC(=O)OC
Reactant: CCCCc1ccccc1O
Agent: BrP(Br)Br
Solvent: CC(Cl)Cl
Product: CCCCc1ccccc1OC(=O)NC

Procedure:
To a mixture of methyl N-methylcarbamate (0.89 g, 0.01 mole) and 2-sec butylphenol (1.5 g, 0.01 mole) in dichloroethane (10 ml), a solution of phosphorus tribromide (2.7 g, 0.01 mole) in dichloro-ethane (6 ml) was added and the mixture was refluxed for eight hours. It was then worked up and purified as described earlier to give 2-sec butylphenyl N-methylcarbamate of the formula (III).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:37]=[C:36]3[C:32](C4CCNCC=4[N:35]3[CH3:38])=[CH:31][CH:30]=2)[C:25](=[O:43])[CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]3[C:24]4[CH2:25][N:26]([CH2:13][C@@H:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:27][CH2:28][C:23]=4[N:35]([CH3:38])[C:36]=3[CH:37]=2)[C:25](=[O:43])[CH:24]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CBr
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C[C@@H]1CCCN1C(=O)OC(C)(C)C)CC2
Temperature: 60 °C
Yield: 7.9 %

Procedure:
A solution of (S)-tert-butyl-2-(bromomethyl)pyrrolidine-1-carboxylate (0.45 g, 1.7 mmol) in DMSO (1.5 mL) was added to a solution of 4-(benzyloxy)-1-(9-methyl-2,3,4,9,-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridine-2(1H)-one (0.33 g, 0.85 mmol), and Cs2CO3 (1.10 g, 3.4 mmol) in DMSO (2.8 mL), and the resulting solution was heated at 60° C. for 18 h. The reaction mixture was diluted with H2O and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were washed with brine (2×25 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. Purification by flash column chromatography (40 g ISCO column, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 hold 5 column volumes, increased to 0:100:0 over 20 column volumes) provided a clear film. The film was diluted with EtOAc and washed with brine (4×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (19 mg, 3%) as a clear film: ESI MS m/z 569 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]([C:7](=O)[CH3:8])[C:4](=O)[CH3:5])[CH3:2].Cl.[NH:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1)[NH2:12]>>[CH2:1]([C:3]1[C:7]([CH3:8])=[N:12][N:11]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][OH:21])=[CH:17][CH:18]=2)[C:4]=1[CH3:5])[CH3:2]
Reactant: NNc1ccc(CCO)cc1
Reactant: CCC(C(C)=O)C(C)=O
Agent: Cl
Product: CCc1c(C)nn(-c2ccc(CCO)cc2)c1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from 3-ethyl-2,4-pentanedione and 2-(4-hydrazinophenyl)ethanol hydrochloride: MS (ESI) m/z 245 [M+H]+, 1H-NMR (CDCl3) δ 7.36-7.26 (4H, m), 3.84 (2H, t, J=6.6 Hz), 2.89 (2H, t, J=6.6 Hz), 2.24 (2H, q, J=7.5 Hz), 2.26 (3H, s), 2.22 (3H, s), 1.12 (3H, t, J=7.5 Hz).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([C:14]1([CH3:17])[CH2:16][CH2:15]1)#[CH:13]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:14]1([C:12]#[C:13][C:2]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH2:16][CH2:15]1
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Reactant: C#CC1(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC1(C#Cc2cc([N+](=O)[O-])ccc2N)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (430 mg, 2.0 mmol) and 1-ethynyl-1-methyl-cyclopropane (630 mg, 8.0 mmol) in triethylamine (20 mL) was added CuI (76 mg, 0.40 mmol) and Pd(PPh3)2Cl2 (140 mg, 0.20 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 h. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2-((1-methylcyclopropyl)ethynyl)-4-nitroaniline (340 mg, 79%). 1H NMR (300 MHz, CDCl3) δ 8.15-8.14 (m, 1H), 7.98-7.95 (m, 1H), 6.63 (d, J=6.9 Hz, 1H), 4.80 (brs, 2H), 1.38 (s, 3H), 1.04-1.01 (m, 2H), 0.76-0.73 (m, 2H).
Reaction SMILES: C([O:3]C(=O)CN(CCC)CCC)C.[CH2:14]([C:17]([C:26]#[N:27])([CH2:23][CH2:24][CH3:25])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH3:16]>>[CH2:21]([O:20][C:18](=[O:19])[C:17]([CH2:23][CH2:24][CH3:25])([CH2:14][CH2:15][CH3:16])[C:26]([NH2:27])=[O:3])[CH3:22]
Reactant: CCCC(C#N)(CCC)C(=O)OCC
Reactant: CCCN(CCC)CC(=O)OCC
Product: CCCC(CCC)(C(N)=O)C(=O)OCC
Yield: 81 %

Procedure:
The synthesis of this compound, which can also be called di-n-propylglycine ethyl ester, was later optimized (P. M. Hardy, l. N. Lingham, Int. J. Peptide Protein Res. 21, 392-405 (1983)). The synthesis of ethyl 2,2-di-n-propylcyanoacetate 2 gave a yield of 81%, while the subsequent reaction to give the 2,2-di-n-propylmalonic acid monoamide ethyl ester 3 gave a yield of 82%. Following further reaction with bromine and NaOH in CHCl3 at low temperature, the N-bromoamide 4 was not isolated, but, following treatment with a 4-fold excess of sodium hydroxide solution, the corresponding isocyanate 6 in a distillative yield of 81% was obtained. The latter was then refluxed with an excess of 3M HCl. Subsequent alkalinization with sodium hydroxide solution gave the amino ester 5 in a yield of 87%. The overall yield of this synthesis was about 47% starting from cyanoacetic ester 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:26])[C:10](=[O:25])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[C:12]=2[C:16](O)=[O:17])[C:7]1=[O:27].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:26])[C:10](=[O:25])[N:11]3[CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[C:16](=[O:17])[C:12]3=2)[C:7]1=[O:27]
Reactant: CNCCCCn1c(C(=O)O)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O

Procedure:
A solution of 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (0.18 g, 0.40 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.08 g, 0.41 mmol), and 1-hydroxy-7-azabenzotriazole (0.07 g, 0.51 mmol), and N-methylmorpholine (0.35 mL, 3.16 mmol) in anhydrous DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. The residue was purified by reverse phase high pressure liquid chromatography. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]#[N:19])[C:6]2[CH:7]=[N:8][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:10]=2[CH:11]=1>N.[Ni]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:5]([CH2:18][NH2:19])[CH:4]=1
Reactant: COc1cc(C#N)c2cnn(C3CCCCO3)c2c1
Agent: [Ni]
Agent: N
Product: COc1cc(CN)c2cnn(C3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of 6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile (350 mg, 1.36 mmol) in ammonia (2M solution in methanol, 15 mL) was added Raney-Ni (1.17 g, suspension in water). The mixture was stirred under a hydrogen atmosphere (1 atm.) at RT for 16 h and then filtered. The filtrate was concentrated in vacuo to afford crude (6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)methanamine (129, 270 mg, yield: 76%). MS (ESI) m/z: 262.4 [M+1]+.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17]CC2C=CC=CC=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][NH2:28])C1C=CC=CC=1.Cl[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:15][C:14]1[C:9](=[O:8])[C:10]([CH2:26][CH2:27][NH:28][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=2)=[C:11]([CH3:25])[C:12](=[O:17])[C:13]=1[CH3:16]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCN)c(C)c1OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1=C(C)C(=O)C(CCNc2cc(C(F)(F)F)ccn2)=C(C)C1=O
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To a stirring solution of 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl) ethanamine (500 mg, 1.3 mmol) in DMSO (1 mL) was added 2-chloro-4-trifluoromethyl pyridine (256 mg, 2.0 mmol, 1.5 equiv.) and diisopropyl ethyl amine (578 μL, 3.3 mmol, 2.5 equiv.). The resulting solution was stirred at 100° C. for 12 hr, after which time HPLC analysis indicated that the reaction was complete. The mixture was brought to 80° C., water (3 mL) was added, and the resulting suspension was stirred for 30 min. The mixture was subsequently brought to ambient temperature and stirred for an additional 30 min, after which the solids were collected by filtration. After drying in vacuo, 750 mg crude brown solids were obtained containing the desired product. The crude material was taken up in trifluoroacetic acid (6 mL) and treated with thioanisole (393 μL, 3.35 mmol). After stirring at ambient temperature for 1 hour, HPLC analysis indicated that the reaction was complete. Volatiles were removed in vacuo and the residue was taken up in 25 mL ethyl acetate. The organic layer was washed with water, 1 M aqueous sodium bicarbonate, and brine (10 mL each), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude hydroquinone (450 mg) was dissolved in acetonitrile (7 mL) and cooled in an ice-water bath. To the stirring solution was added an aqueous solution of ceric ammonium nitrate (1.46 g, 7.6 mmol in 2 mL) in a dropwise fashion. The reaction was deemed complete by TLC analysis when approximately 90% of the reagent was added. At this point, the mixture was partitioned between ethyl acetate and brine (15 mL each), and the organic layer was removed. The remaining aqueous layer was made basic by addition of 10 mL 1 M aqueous sodium bicarbonate, and extracted with ethyl acetate (15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to produce 500 mg brown oil. Purification by silica gel chromatography (gradient elution 0→35% ethyl acetate in heptane) afforded 2,3,5-trimethyl-6-(2-(4-(trifluoromethyl)pyridin-2-ylamino)ethyl)cyclohexa-2,5-diene-1,4-dione as a bright yellow solid (85 mg). 1H-NMR (400 MHz, CDCl3) 8.15 (d, 1H), 6.76 (m, 2H), 3.49 (m, 2H), 2.86 (t, 2H), 2.08 (s, 3H), 2.01 (s, 6H). M+=338.0.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:12]2[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH2:38]([O:37][C:34]1[CH:35]=[CH:36][C:31]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=3)[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:13]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:32][CH:33]=1)[CH3:39]
Reactant: CCOC(=O)c1c(-c2ccc(OCC)cc2)c2cc(OCc3ccccc3)ccc2n1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(OCC)cc2)c2cc(O)ccc2n1Cc1ccc(F)cc1
Reaction time: 16 h

Procedure:
A solution of ethyl 5-(benzyloxy)-3-(4-ethoxyphenyl)-1-(4-fluorobenzyl)-1H-indole-2-carboxylate (Example 69, 4.7 g, 9.0 mmol) in ethyl acetate (15 mL) was added to a suspension of 10% palladium on charcoal (2.0 g) in ethyl acetate (10 mL). The mixture was placed under an atmosphere of hydrogen (1 atm) and stirred for 16 h. The reaction was filtered through a pad of Celite using ethyl acetate to rinse. Evaporation of the filtrate left 3.5 g (90%) of the desired product. The product had: 1H NMR (300 MHz, acetone-D6) δ 7.98 (s, 1 H), 6.89-7.42 (m, 11 H), 5.81 (s, 2 H), 4.03-4.19 (m, 4 H), 1.41 (t, 3 H), 1.04 (t, 3 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23]([C:27]1[CH:28]=[C:29]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[C:30]([O:53][CH3:54])=[C:31]([NH:33][C:34]([C:36]2[N:37]([CH3:52])[C:38]3[C:43]([CH:44]=2)=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:45][N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[O:35])[CH:32]=1)([CH3:26])([CH3:25])[CH3:24].O>O1CCCC1.C(OCC)(=O)C>[C:23]([C:27]1[CH:28]=[C:29]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[C:30]([O:53][CH3:54])=[C:31]([NH:33][C:34]([C:36]2[N:37]([CH3:52])[C:38]3[C:43]([CH:44]=2)=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:45][N:46]2[CH2:47][CH2:48][N:49]([C:8]([CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:10])[CH2:50][CH2:51]2)=[O:35])[CH:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCNCC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CN1CCCC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)C5CCCN(C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
61 mg 1-methyl-piperidine-3-carboxylic acid are dissolved in 1 ml of tetrahydrofuran, combined with 69 mg carbonyldiimidazole and stirred for 20 minutes at 50° C. The mixture is left to cool to ambient temperature, 150 mg 1-methyl-7-piperazin-1-ylmethyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenyl)-amide are added and then the mixture is stirred for 12 hours at ambient temperature. Then a further 122 mg of 1-methyl-piperidine-3-carboxylic acid in 2 ml of tetrahydrofuran are combined with 138 mg carbonyldiimidazole, the mixture is stirred for 20 minutes at 50° C. and this solution is added to the reaction mixture. It is stirred for 2 hours at 50° C., then divided between water and ethyl acetate, the organic phase is washed with saturated aqueous sodium chloride solution, dried with magnesium sulphate and the solvents are eliminated in vacuo. The residue is chromatographed on silica gel with dichloromethane/(methanol/ammonia 9:1) 99:1 to 90:10. The product thus obtained is purified by preparative HPLC (HPLC method 3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][CH:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:26]=1[NH2:27].CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:21](=[O:23])[NH:27][C:26]1[CH:28]=[CH:29][C:30]([I:32])=[CH:31][C:25]=1[F:24])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)O
Reactant: Nc1ccc(I)cc1F
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)Nc1ccc(I)cc1F
Yield: 91.3 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.673 g, 1.94 mmol), 2-fluoro-4-iodoaniline (0.46 g, 1.94 mmol), EEDQ (0.575 g, 2.32 mmol) and triethylamine (0.408 mL, 2.91 mmol) were heated at reflux in CHCl3 (10 mL) for 22 h. The solution was concentrated and resulting oil partitioned between EtOAc and water. The organic layer was washed with brine and dried over MgSO4. The product was purified by mplc to produce the product as a clear oil (1.0 g, 90%). MS: APCI (AP−): 563.2 (M)−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:21]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=2[CH3:19])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(Nc2nc(Cl)nc3ccsc23)c(C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 23.2 %

Procedure:
To a solution of 2,4-dichlorothieno[3,2-d]pyrimidine (148 mg, 0.73 mmol), TFA (0.17 mL, 2.19 mmol) in TFE (2 mL) was added 2,4,6-trimethylaniline (0.15 mg, 1.1 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography eluting with Hexanes:ethyl acetate (4:1) to afford the product as a white solid (51.4 mg, 23%):
Reaction SMILES: O.C(O)(=O)C.[CH:6]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)([CH3:8])[CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>[Fe].C(O)C>[CH:6]([C:9]1[CH:25]=[CH:24][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(C)c1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CC(C)c1ccc(C(=O)c2ccc(N)cc2)cc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
800 parts of water, 250 parts of iron chips and 28 parts of acetic acid are initially introduced, and the mixture is heated to 95° C. and stirred for 1 hour at 95° C. It is then cooled to 90° C., 800 parts of ethanol are added, and 55 parts of 4-isopropyl-4'-nitrobenzophenone are added in a solid form in small portions in the course of 30 minutes. The mixture is heated for 8 hours under reflux, its pH is adjusted to 9 by means of 44 parts of sodium carbonate solution, 600 parts of ethanol are added, heating under reflux is carried out for 15 hours, the mixture is filtered hot and the residue is washed three times with 200 parts each of hot ethanol. Ethanol is distilled off from the combined filtrates and the aqueous bottom is cooled down. The precipitated crystals are then filtered off and dried in vacuo. 45.5 parts of 4-isopropyl- 4'-aminobenzophenone having a melting point of 110° C. are obtained. The valuable dyestuff of the formula VI ##STR7## can be prepared from 4-isopropyl-4'-aminobenzophenone as indicated in German Offenlegungsschrift No. 2,001,821, Table 1, Example 15.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@@H:8]1[C@H:13]([NH2:14])[CH2:12][CH2:11][O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:26]1[N:27]=[N:28][C:29]([C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:30]([NH:32][C:33]2[C:41]3[CH:40]=[CH:39][S:38][C:37]=3[CH:36]=[CH:35][CH:34]=2)[N:31]=1>C1COCC1>[S:38]1[CH:39]=[CH:40][C:41]2[C:33]([NH:32][C:30]3[N:31]=[C:26]([NH:14][C@@H:13]4[CH2:12][CH2:11][O:10][CH2:9][C@@H:8]4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])[N:27]=[N:28][C:29]=3[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:34][CH:35]=[CH:36][C:37]1=2
Reactant: CCOC(=O)c1nnc(Cl)nc1Nc1cccc2sccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(N[C@@H]2CCOC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc2sccc12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl((3R,4R)-4-aminotetrahydro-2H-pyran-3-yl)carbamate (26 mg) and diisopropylethylamine (0.050 ml) were added to a solution of ethyl 3-chloro-5-(benzo[b]thiophen-4-ylamino)-1,2,4-triazine-6-carboxylate obtained in the above-described Step 1 (34 mg) in THF (1 mL), and the reaction solution was stirred at 80° C. for 30 minutes. The solvent was evaporated under vacuum, and the resultant residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain ethyl 5-(benzo[b]thiophen-4-ylamino)-3-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-1,2,4-triazine-6-carboxylate.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH2:18][CH3:19])[C:3](=[O:17])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11](=[O:16])[CH2:12][CH2:13][CH:14]=[CH2:15])=[O:5].[CH2:21]([O:28][C:29]1[CH:34]=[CH:33][C:32](Br)=[CH:31][CH:30]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]([CH3:20])([CH2:18][CH3:19])[C:3](=[O:17])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11](=[O:16])[CH2:12][CH2:13][CH:14]=[CH:15][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:30][CH:31]=1)=[O:5]
Reactant: C=CCCC(=O)C1CCCN1C(=O)C(=O)C(C)(C)CC
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)CCC=Cc1ccc(OCc2ccccc2)cc1
Yield: 60.1 %

Procedure:
A solution of 3,3-dimethyl-1-(2-pent-4-enoylpyrrolidinyl)pentane-1,2-dione (1.73 g; 6.20 mmol), 4-benzyloxybromobenzene (1.80 g; 6.83 mmol), palladium (II) acetate (70 mg; 0.31 mmol), and tri(orthotolyl)phosphine (380 mg; 1.24 mmol) in triethylamine (23 ml) was refluxed overnight. The mixture was concentrated in vacuo and purified on a silica gel column, eluting with a gradient from 10% ethyl acetate/hexane to 20% ethyl acetate/hexane, to obtain 1.72 g (60%) of 3,3-dimethyl-1-(2-{5-[4-(phenylmethoxy)phenyl]pent-4-enoyl}pyrrolidinyl)pentane-1,2-dione as a yellow oil.