Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[N+]([O-])(OCCC(C)C)=O.C(Cl)(Cl)[Cl:28].[OH-].[Na+]>CC#N>[Cl:28][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1nc(N)sc1-c1ccccc1
Reactant: ClC(Cl)Cl
Agent: CC(C)CCO[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)c1nc(Cl)sc1-c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-amino-5-phenylthiazole-4-carboxylate in MeCN was added CuCl2 at 0° C., and the isoamyl nitrate was slowly added dropwise thereto, followed by stirring for 1 hour. To the reaction mixture was added CHCl3, followed by stirring at 0° C. for 2 hours and then at room temperature for 2 hours. The reaction mixture was neutralized by addition of a 1 M aqueous NaOH solution, and filtered through Celite. The filtrate was extracted with EtOAc, and the organic layer was washed with water and brine in this order and then dried over MgSO4. After concentration under reduced pressure, the residue obtained was purified by medium-pressure preparative liquid chromatography (silica gel YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain ethyl 2-chloro-5-phenylthiazole-4-carboxylate as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)c1ccnc(I)c1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2cc(N(C)C)ccn2)c1
Temperature: 90 °C
Yield: 83.6 %

Procedure:
A mixture of 2-iodo-4-dimethylaminopyridine (2.7 g, 11 mmol), 3-methoxyphenylboronic acid (2 g, 13 mmol) and K2CO3 (5.4 g, 39 mmol) in toluene (60 ml) and water (10 ml) were degased with nitrogen for 15 minutes. Pd(PPh3)4 (800 mg, 0.66 mmol) was added and the resulting mixture was heated to 90° C. for 48 hours under nitrogen. After being cooled to room temperature, the aqueous phase was separated and extracted with EtOAc (3×100 ml). The combined organic fractions were washed with brine, dried over MgSO4, filtered and evaporated. The crude compound was purified by column chromatography (SiO2, EtOAc) to afford 2.1 g (84%) of the titled compound as a colorless oil, which solidify upon standing. If some impurities remains, the compound can be purified by following the acidic extraction followed by basic recovery as performed before for 2-phenyl-4-dimethylaminopyridine.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[C:18]1([C@@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: C[C@H](N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@@H](c1ccccc1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 74.4 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 121 mg of (S)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 2 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 240 mg of the desired product as colorless needles. Yield: 74%. m.p. 95-96° C.; [α]20D=−42.2° (C=0.386 AcOEt); MS(EI+) 323(M)+
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[H-].[Na+].[CH3:18][C:19]1([CH3:29])[C:23]([CH3:24])=[CH:22][CH2:21][CH:20]1[CH2:25][C:26](=O)[CH3:27].CC1C(C)(C)C(CC=O)CC=1>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])[C:6]([CH3:7])=[C:26]([CH3:27])[CH2:25][CH:20]1[CH2:21][CH:22]=[C:23]([CH3:24])[C:19]1([CH3:29])[CH3:18])[CH3:1]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CC(=O)CC1CC=C(C)C1(C)C
Agent: CC1=CCC(CC=O)C1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C(C)CC1CC=C(C)C1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.8 %

Procedure:
47.6 g (0.20 mol) of triethyl 2-phosphonopropionate was added dropwise under nitrogen to a cooled and stirred suspension of 4.8 g (0.20 mol) of sodium hydride in 300 ml of THF and stirring continued for 30 min. at room temperature. After addition of 30 g (0.18 mol) of 1-(2,2,3-trimethylcyclopent-3-enyl)propan-2-one, prepared from campholenic aldehyde as known per se, and 46 hours of more stirring, the reaction mixture was poured into 400 ml of ice-cold 1N hydrochloric acid and extracted with 2×300 ml of MTBE. The extract was washed with 5×350 ml of brine, dried (MgSO4) and concentrated in vacuo. The distillation at 90-97° C./0.065-0.075 Torr yielded 13 g of the product which was further purified by flash chromatography on silica gel (eluent: hexane/MTBE 15:1) to give 6.4 g (14% yield) of2,3-dimethyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enoic acid ethyl ester.
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])=[C:11]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH:35]([F:37])[F:36])=[C:30]([O:38][CH:39]2[CH2:41][CH2:40]2)[CH:29]=1)C1C=CC=CC=1.Cl.[H][H]>[Pd].C(O)C>[CH:39]1([O:38][C:30]2[CH:29]=[C:28]([C:11]3[NH:10][C:14]4[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=4[C:12]=3[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH:33]=[CH:32][C:31]=2[O:34][CH:35]([F:37])[F:36])[CH2:41][CH2:40]1
Reactant: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=c1[nH]ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(Cc3ccccc3F)c12
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To 330 ml of ethanol solution containing 4.28 g (7.62 mmol) of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-fluorobenzyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 22-(a) were added 1.50 g of 5% palladium-active carbon and 3.8 ml of 2N hydrochloric acid, and then the mixture was stirred under 1 atm hydrogen atmosphere at 50° C. for 1 hour. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, methanol and 28% aqueous ammonia were added to the obtained solid, and the mixture was stirred for 1 hour. Then, the solution was concentrated under reduced pressure, water was added to the obtained concentrate, and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain 2.99 g of the title compound as a white solid. (Yield: 89%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(NC(=O)c2ccccc2CO)cc1
Temperature: 250 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-aminophenyl)phthalimide (332 mg) in tetrahydrofuran (4 mL) is added lithium borohydride (1.0 g) and the mixture is stirred for 1 hour at 250° C. The mixture is poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white foam, which when triturated with diethyl ether provides the desired product as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][O:28][CH2:29][C:30](Cl)=[O:31]>>[CH3:27][O:28][CH2:29][C:30]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:31]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: COCC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and (methyloxy)acetyl chloride.
Reaction SMILES: [Na].[CH3:2][C:3]1[O:9][CH:8]=[CH:7][C:5](=[O:6])[C:4]=1[OH:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO.O>[CH3:2][C:3]1[O:9][CH:8]=[CH:7][C:5](=[O:6])[C:4]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1occc(=O)c1O
Reactant: BrCc1ccccc1
Agent: [Na]
Solvent: CO
Solvent: O
Product: Cc1occc(=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
11.5 g of sodium were dissolved in 300 ml CH3OH and 63g of maltol were added and stirred at room temperature for one hour. 200 ml CH3OH were added and then 102 g benzylbromide were dropped in (30 minutes). Refluxing for 3 hours and distilling off the CH3OH then yielded a residue which was dissolved in 300 ml H2O/300 ml ethyl acetate. The organic phase was washed with water and evaporated. The remaining oil was distilled in vacuo. B.P. (43 mm) =148°-150° C., 81.5 g colorless oil of the title compound was isolated.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33](O)[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH2:39]2)=[CH:26]1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:24][C@H:25]1[CH2:34][C@H:33]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:11][CH3:12])[C@H:32]2[C:27]([CH:28]=[CH:29][C@H:30]([CH3:53])[C@@H:31]2[CH2:36][CH2:37][C@H:38]2[O:43][C:42](=[O:44])[CH2:41][C@H:40]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[CH2:39]2)=[CH:26]1)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: CCC(Oc1ccccc1C(C)=O)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1ccccc1C(C)=O)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 89 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.81 g of (2RS)-2-(2-acetylphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.22 g of the title compound as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:20])[C:16](=O)[CH2:17]Br)[CH3:13].O>CN(C=O)C>[CH2:12]([O:14][C:15]([C:16]1[N:11]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:17]=1)=[O:20])[CH3:13]
Reactant: NC(=S)Nc1ccc(Br)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
(5-Bromo-pyridine-2-yl)-thiourea (1 mmol) is dissolved in DMF (2 ml) and 3-Bromo-2-oxo-propionic acid ethyl ester (1 eq.) is added and stirred 2 h at 70° C. The suspension is diluted with DMF (2 ml). After cooling to RT the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. “A4” is obtained as colourless powder in a yield of 78%; mp. 299.8-300.8° C.; HPLC (method C): 2.01 min; LC-MS (method A): 2.002 min, 327.95 (M+H+);
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[C:16]#[N:17])(=[O:3])[CH3:2].[S:20](Cl)(=[O:23])(=[O:22])[NH2:21]>>[C:1]([O:4][CH2:5][C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:20](=[O:23])(=[O:22])[NH2:21])[C:10]=1[C:16]#[N:17])(=[O:3])[CH3:2]
Reactant: NS(=O)(=O)Cl
Reactant: CC(=O)OCC(C)(C)COc1cccc(N)c1C#N
Product: CC(=O)OCC(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 60 %

Procedure:
Prepared as in Example 215a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl acetate (Example 233b) and sulfamoyl chloride in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.99 (s, 6H), 1.98 (s, 3H), 3.85 (s, 2H), 3.91 (s, 2H), 6.91 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.23 (s, 2H), 7.52 (t, J=8.0 Hz, 1H), 9.45 (s, 1H).
Reaction SMILES: [CH:1]1([C:7]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[CH:24]=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C(C)=CC=CC=1.[C:37]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>O>[C:37]([C:41]1[CH:42]=[CH:43][C:44]([C:45]([C:24]2[N:16]3[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]4[CH:27]=[CH:28][C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:8][CH:9]=4)[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17]3)=[CH:26][CH:25]=2)=[O:46])=[CH:48][CH:49]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)(C)c1ccc(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)cc1
Yield: 6.8 %

Procedure:
A mixture of 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 4 (1.85 g), dry xylene (25 mL) and 4-tert-butylbenzoylchloride (1.97 g) was refluxed overnight. The reaction mixture was poured into water, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and filtered through a short column of Magnesol®. After eluting with several additional volumes of dichloromethane, the combined eluate was refluxed with the gradual addition of hexane until crystallization was noted. Cooling and trituration provided the desired title product (0.18 g) as off-white crystals, m.p. 143–145° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21]([OH:23])=O)=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2].[CH3:34][NH:35][CH3:36]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=3[N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:21]([N:35]([CH3:36])[CH3:34])=[O:23])=[O:17])[CH2:14][CH2:15]2)=[C:6]([F:33])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)O)ccc3N3CCOCC3)CC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C(=O)N(C)C)ccc3N3CCOCC3)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step 2 from 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-morpholin-4-yl-benzoic acid and dimethylamine (44%, yellow solid, MS (m/e): 483.2 (M+H, 100%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].[NH2:27][CH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>>[OH:32][CH:30]([CH3:31])[CH2:29][CH2:28][NH:27][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26]
Reactant: CC(O)CCN
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Product: CC(O)CCNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1

Procedure:
The title compound was prepared using 5-cyano-1-(3-trifluoromethoxy-benzyl)-1H-indole-2-carboxylic acid [prepared from 3-(trifluoromethoxy)benzyl bromide and ethyl 5-cyanoindole-2-carboxylate] and 4-amino-2-butanol in a manner similar to that described in Example 11.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([N:14]1[C:24]2[C:19](=[CH:20][C:21]([N:25]3[CH2:30][CH2:29][N:28]([C:31](=[O:42])[C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=4)[CH2:27][CH2:26]3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:15]1=[O:16])=[O:13])C1C=CC=CC=1>C(O)C.CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][CH:45]=1)[C:12]([N:14]1[C:24]2[C:19](=[CH:20][C:21]([N:25]3[CH2:26][CH2:27][N:28]([C:31](=[O:42])[C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH3:41])[CH:33]=4)[CH2:29][CH2:30]3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][C:15]1=[O:16])=[O:13]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3cccc(OCc4ccccc4)c3)CC2)cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4C(=O)c3cccc(O)c3)CC2)cc1OC
Yield: 78.3 %

Procedure:
1-(3-Benzyloxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (6 g) was dissolved in a mixture of ethanol (100 ml) and DMF (50 ml), and 10% palladium on carbon (1 g) was added thereto. The mixture was hydrogenated at 50° C. After completion of reaction, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent:ethyl acetate:methanol=100:2) to give 1-(3-hydroxybenzoyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (4.0 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:49][C:50]1[CH:51]=[C:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[NH:62][C:63](=[O:65])[CH3:64])[CH:53]=[CH:54][CH:55]=1>CN(C=O)C>[C:63]([NH:62][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=1[C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([NH:49][C:22]([C:17]2[C:18](=[O:21])[O:19][C:20]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:10])=[O:24])[CH:51]=1)(=[O:65])[CH3:64]
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: CC(=O)Nc1ccccc1-c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccccc1-c1cccc(NC(=O)c2cc3cccc(O)c3oc2=O)c1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
DIEA (0.013 mL, 0.073 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.014 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, N-(3′-Amino-biphenyl-2-yl)-acetamide (0.015 g, 0.066 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.007 g of product in 27% yield: LCMS (ESI) m/z 415 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][CH:8]([C:14](=O)[CH3:15])[C:9](OCC)=[O:10].[NH2:17][C:18]([NH2:20])=[S:19]>O1CCCC1.C(O)C>[CH3:7][C:8]1[C:9](=[O:10])[NH:17][C:18](=[S:19])[NH:20][C:14]=1[CH3:15]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C)C(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1[nH]c(=S)[nH]c(=O)c1C
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a stirred solution of potassium tert-butoxide (15.71 g, 0.140 mol) in tetrahydrofuran (200 mL) was added a solution of ethyl 2-methyl-3-oxobutanoate (20.0 g, 0.14 mol) and thiourea (10.55 g, 0.14 mol) in dry ethanol (150 mL). The resulting mixture was refluxed for 15 minutes and cooled down to ambient temperature. The formed precipitate was collected by filtration, washed with tetrahydrofuran (200 mL), and dissolved in water (200 mL). Acetic acid (100 mL) was added in to the resulting solution. The formed precipitate was collected by filtration and dried to yield 17 g (78.5%) of the titled compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.74 (s, 3H) 2.09 (s, 3H) 12.19 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])[CH3:3].[C:11]([C:16](=[CH:22]OCC)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14]>>[C:11]([C:16](=[CH:22][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:2]([OH:1])[CH3:3])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CC(O)c1ccccc1N
Reactant: CCCC(=O)C(=COCC)C(=O)OCC
Product: CCCC(=O)C(=CNc1ccccc1C(C)O)C(=O)OCC
Yield: 96.8 %

Procedure:
2-(1-hydroxyethyl)aniline (30 g, 0.32 mol) and ethyl 2-butyryl-3-ethoxyacrylate (47.3 g, 0.22 mol) were heated together on a rotary evaporator (bath temperature 100° C.) for 1 hour to give ethyl 2-butyryl-3-(2-(1-hydroxyethyl)-phenylamino)acrylate as an oil (65 g, 96%).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].C(O[C:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=1)C.Cl>>[CH:1]([C:9]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CCOC1=CC(=O)CC1
Reactant: CC(C)[Mg]Cl
Agent: Cl
Product: CC(C)C1=CC(=O)CC1
Temperature: 0 °C
Reaction time: 23 h
Yield: 19.7 %

Procedure:
Isopropylmagnesium chloride (5 mL, 10 mmol, 2 M in diethyl ether) was placed in a dry flask and cooled to 0° C. 3-Ethoxycyclopentenone (0.88 g, 7 mmol) was added dropwise to the solution of the Grignard reagent, and the resulting mixture was stirred at room temperature for 23 h. At this point, 1 M HCl (15 mL) was added gradually, the aqueous phase was separated and extracted 3×with diethyl ether. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified first by Kugelrohr distillation (0.1 torr, 120° C.), then by flash chromatography (1:1 pentane:ether) to afford the product as a colorless liquid (0.171 g, 20%). Spectroscopic data were consistent with previously reported data for this compound.7
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cncc(F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ncc(F)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice cooling, 5 g of 5-fluoropyridin-3-ol (44 mmol, 1 equivalent) were dissolved in 43 ml of concentrated sulphuric acid, and, at 0° C., 2.8 ml of concentrated nitric acid were added over a period of 5 min. The reaction was warmed to RT, and stirring was continued overnight. The mixture was added to 100 g of ice and stirred for 30 min. The solid obtained was filtered off and dried under reduced pressure. This gave 5.6 g (81% of theory) of the title compound, which were used without further purification for the next reaction.