Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([C:19](O)=[O:20])=[CH:18][C:11]=2[N:10]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][C:50]=1[CH3:51])[NH2:47]>CN(C=O)C.O>[CH3:43][C:44]1[CH:45]=[C:46]([NH:47][C:19]([C:17]2[CH:16]=[CH:15][C:12]3[N:13]([CH3:14])[C:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:10][C:11]=3[CH:18]=2)=[O:20])[CH:48]=[CH:49][C:50]=1[CH3:51]
Reactant: Cc1ccc(N)cc1C
Reactant: Cn1c(-c2c(Cl)cccc2Cl)nc2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc3c(c2)nc(-c2c(Cl)cccc2Cl)n3C)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid (100 mg), EDCI (59 mg) and HOBt (42 mg) in DMF (2 mL) was added 3,4-dimethylaniline (38 mg) and the mixture was stirred at room temperature for 18 h. The mixture was poured into water and was extracted with EtOAc. The organic phase was washed with water (3×) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography using EtOAc/CH2Cl2 (1:5) as eluent to give 2-(2,6-dichlorophenyl)-1-methyl-1H-benzoimidazole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a glasslike solid; MS (m/z) 424 (M+1); 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.24 (s, 1H), 8.00 d, J=8.59 Hz, 1H), 7.52-7.39 (m, 6H), 7.10 (d, J=8.08 Hz, 1H), 3.65 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: CO.[C:3]([NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([F:22])=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[C:14]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[N:13]=2)[CH2:8]1)(=[O:5])[CH3:4].[OH-].[Na+]>O.C(OCC)(=O)C>[C:3]([NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([F:22])=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[N:13]=2)[CH2:8]1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)NC1CCN(c2nc(Nc3ccc(F)cc3F)c(C(=O)O)cc2F)C1
Yield: 93 %

Procedure:
In a mixture of 30 ml of tetrahydrofruran, 10 ml of methanol and 4 ml of water was suspended 980 mg of methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and 5.3 ml of 1N aqueous sodium hydroxide solution was added thereto, after which the resulting mixture was subjected to reaction at 65° C. for 3 hours. Subsequently, the reaction mixture was added to a mixture of 50 ml of ethyl acetate and 50 ml of water, and the aqueous layer was separated, after which the pH thereof was adjusted to 2.0 with 1N hydrochloric aicd. The crystals thus deposited were collected by filtration and washed successively with 2 ml of water and 2 ml of ethanol to obtain 880 mg (yield 93.0%) of 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid having a melting point of 232°-234° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[C:4]([CH3:14])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C(Cl)(Cl)(Cl)Cl>[Cl:16][C:7]1[NH:12][C:8](=[O:11])[C:9]2[C:5]([CH:6]=1)=[C:4]([CH3:14])[CH:3]=[C:2]([F:1])[CH:10]=2
Reactant: Cc1cc(F)cc2c1CC(=NO)C2=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(F)cc2c(=O)[nH]c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.1 %

Procedure:
To a solution of 6-fluoro-2-(hydroxyimino)-4-methyl-2,3-dihydro-1H-inden-1-one (800 mg, 4.12 mmol) in anhydrous CCl4 (100 mL) was added PCl5 (1.28 g, 6.18 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated in vacuo and the residue dissolved in anhydrous 1,4-dioxane (100 mL), cooled 0° C., the solution was saturated with HCl gas and allowed to stir RT for 16 h. The reaction mixture was heated at 60° C. for 2 h, cooled to RT and diluted with EtOAc (50 mL), washed with water (25 mL), saturated NaHCO3 solution (25 mL), brine solution (25 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was washed with diethyl ether (10 mL), n-pentane (10 mL) and was dried in vacuo to obtain 3-chloro-7-fluoro-5-methylisoquinolin-1(2H)-one as a pale yellow solid (550 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][C:11]=1[C:19]([OH:21])=O.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C1COCC1>[OH:28][C@@H:26]([CH3:27])[CH2:25][O:24][NH:23][C:19]([C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:16]=[N:17][CH:18]=2)[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: O=C(O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 11 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (130 mg, 0.33 mmol) in THF (1.7 mL) was added (S)-1-aminooxy-propan-2-ol hydrochloride (84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol). After 18 hours stirring at ambient temperature, further (S)-1-aminooxy-propan-2-ol hydrochloride (84 mg, 0.66 mmol), DIPEA (0.23 mL, 1.32 mmol), HOBt (88 mg, 0.66 mmol) and EDCI (126 mg, 0.66 mmol) and THF (1.7 mL) were added. The reaction mixture was stirred at ambient temperature for a further 5 hours. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was then washed with methanol and the desired compound was eluted using a 2M solution of ammonia in methanol. Appropriate fractions were combined and concentrated under reduced pressure and the residue azeotroped with dichloromethane. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 10%, methanol in dichloromethane) to afford the title compound as a yellow solid (17 mg, 11%). LCMS (method A): RT=6.01 min, [M+H]+=471. 1H NMR (DMSO-d6): 8.07 (1H, s), 7.58 (1H, dd, J=10.71, 1.92 Hz), 7.43 (1H, s), 7.38 (1H, d, J=9.31 Hz), 7.31-7.28 (1H, m), 6.89 (1H, d, J=9.31 Hz), 6.35 (1H, t, J=8.68 Hz), 3.69-3.60 (1H, m), 3.45-3.38 (2H, m), 0.96 (3H, d, J=6.35 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][CH:24]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2].[OH-].[Li+]>C(O)C.O1CCCC1.O>[CH:1]([O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][CH:24]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OC(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)OC(=O)c1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
A solution of 6-(4-methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylic acid isopropyl ester (Intermediate 45, 0.019 g, 0.043 mmol) in ethanol (0.3 mL), tetrahydrofuran (0.3 mL) and water (0.3 mL) was treated with 1N lithium hydroxide (0.086 mL, 0.086 mmol) and the resulting reaction mixture was stirred at ambient temperature for 30 minutes. The volatiles were evaporated in vacuo to a residue that was washed with hexane:ethyl acetate (3:1), neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a brown oil (0.015 g, 80%). 1H NMR (300 MHz, CDCl3): δ 7.69 (d, 1H, J=2.4 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.50-7.26 (m, 4H), 5.25 (heptet, 1H), 3.67 (s, 2H), 1.88 (s, 2H), 1.39 (s, 6H), 1.37 (s, 6H), 1.39-1.35 (d, 6H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])[CH3:3]>CO.[H][H]>[CH3:4][C:2]([O:5][C:6]([NH:8][C@H:9]([C:24]([OH:26])=[O:25])[CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O

Procedure:
Boc-Orn--OH (0.51 g) (obtained by catalytically reducing Boc-Orn(Z)--OH in methanol in a stream of hydrogen using 10% Pd-carbon as a catalyst) was dissolved in DMF, and the solution was cooled with ice. TEA (0.61 ml) and PhCOONB (prepared from PhCOOH (0.30 g), HONB (0.47 g) and DCC (0.54 g)) were added thereto, followed by stirring overnight. The reaction solution was concentrated, and the residue was dissolved in AcOEt. The resulting solution was washed with 10% aqueous citric acid. After washing with water, the solution was dried with Na2SO4 and concentrated. Then, ether and dicyclohexylamine (438 μl) were added to the residue to separate out a precipitate, which was collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][C@H:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:10][C:9]=2[CH3:21])=[CH:4][C:3]=1[CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]2[C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:29][O:30][C:26]=2[CH:25]=1.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:21])=[CH:10][C:11]([O:15][C@H:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:12][C:13]=2[CH3:14])=[CH:4][C:3]=1[CH2:22][O:23][C:24]1[CH:37]=[CH:36][C:27]2[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=2[CH:25]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cc(-c4c(C)cc(O[C@H]5CCOC5)cc4C)ccc3F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(O[C@H]2CCOC2)cc(C)c1-c1ccc(F)c(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Reaction time: 12 h
Yield: 67.7 %

Procedure:
Methyl 2-((S)-6-((4-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy) biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 18e (150 mg, 0.30 mmol) was dissolved in 4.5 mL of a mixture of the solvents tetrahydrofuran, methanol and water (V/V=1:3:0.5), followed by addition of 1M aqueous lithium hydroxide solution (1 mL, 1 mmol). The reaction solution was stirred for 12 hours. The resulting solution was concentrated under reduced pressure. The residue was mixed with 10 mL of water, 2M hydrochloric acid was added dropwise to adjust the pH to 2˜3, and extracted with ethyl acetate (20 mL×2). The combined organic extracts were washed with saturated sodium chloride solution (30 mL), dried with anhydrous magnesium sulphate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by TLC with elution system A to obtain the title compound 2-((S)-6-((4-fluoro-2′,6′-dimethyl-4′-(((S)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid 18 (100 mg, yield 66.7%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1.C(OC([N:35]1[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:35]1[CH:39]=[C:38]([NH:40][C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH2:3][C:2]([F:1])([F:27])[F:26])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:25])[CH:37]=[N:36]1
Reactant: O=C(O)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Reactant: CC(C)(C)OC(=O)n1cc(N)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cn[nH]c1)c1ccc2c(c1)-n1nc(-c3ncnn3CC(F)(F)F)cc1CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure for 126, 2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 4-amino-pyrazole-1-carboxylic acid tert-butyl ester. The intermediate carboxylic acid tert-butyl ester was dissolved in DCM (5 mL) and treated with TFA (2 mL) before the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue triturated in water to give 127 as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.53 (s, 1 H); 8.51 (d, J=2.2 Hz, 1 H); 8.23 (s, 1 H); 7.96 (dd, J=8.5, 2.2 Hz, 1 H); 7.84 (s, 2 H); 7.39 (d, J=8.5 Hz, 1 H); 7.02 (s, 1 H); 5.77 (q, J=8.7 Hz, 2 H); 4.59 (t, J=5.8 Hz, 2 H). 3 Protons obscured by water peak. LCMS: RT=9.11 min, M+H+=445
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:9](=[O:28])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:24][C:23]([C:25]#[C:26][CH3:27])=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)(C)(C)C.[ClH:38]>C(Cl)Cl.O1CCOCC1>[ClH:36].[ClH:38].[NH2:7][CH:8]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:9]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:24][C:23]([C:25]#[C:26][CH3:27])=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:28]
Reactant: CC#Cc1cc2ncnc(N3CCN(C(=O)C(Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC#Cc1cc2ncnc(N3CCN(C(=O)C(N)Cc4ccc(Cl)cc4)CC3)c2s1
Reaction time: 4 h

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-oxo-2-[4-(6-prop-1-ynyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-prop-1-ynyl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 440.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:15])[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:16][CH3:17].[CH3:18]O>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:15])[C:12]([O:14][CH3:18])=[O:13])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(C(=O)C(=O)O)cc([N+](=O)[O-])c1O
Reactant: CO
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.42 g Of 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid are dissolved in 25 ml of dry N,N-dimethylformamide, treated at room temperature with 50 mg of 4-dimethylaminopyridine and 920 mg of dry methanol, subsequently cooled to 0° with an ice-bath and 2.27 g of N,N-dicyclohexylcarbodiimide are added thereto. After 10 minutes the ice-bath is removed and the reaction mixture is stirred for a further 1 hour at room temperature. The mixture is subsequently evaporated. The residue is dissolved in ethyl acetate, whereupon insoluble urea is filtered, the filtrate is washed four times with water, dried over sodium sulfate, filtered and evaporated. There is obtained methyl 4-hydroxy-3-methoxy-5-nitrophenylglyoxylate of m.p. 155°-157° (from methylene chloride/ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[N:16]=[C:15]([S:17][C:18]#[N:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=1>C(O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([S:17][C:18]#[N:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#CSc1nc(Nc2ccc(Cl)c(Cl)c2)ncc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
2.47 g of 3,4-dichloroaniline in 12 ml ethanol are added to 3.00 g of 2-chloro-4-thiocyanato-5-nitro-pyrimidine in 40 ml toluene at ambient temperature. The mixture is stirred for another 16 hours, the solid is suction filtered, washed twice with 30 ml toluene and then once with 30 ml of ethanol and dried.
Reaction SMILES: [OH-].[Na+].O.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20]C(=O)C)=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6]1>C(O)C>[CH3:4][N:5]1[CH2:6][CH2:7][N:8]([CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[O:13])[CH2:9][CH2:10]1
Reactant: CC(=O)Nc1ccc(C(=O)CN2CCN(C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(CC(=O)c2ccc(N)cc2)CC1
Temperature: 85 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
1.8 g of sodium hydroxide dissolved in 10 ml of ethanol and 10 ml of water were added to 4.0 g of 2-(4-methylpiperazin-1-yl)-1-(4-acetylamino-phenyl)-ethanone which was obtained in the same manner as in Example 1, and stirred at 85° C for 2 hours in a nitrogen atmosphere. Then, ethanol was distilled off, the deposited oily product was extracted with chloroform, washed with water, dried over anhydrous sodium sulfate and further concentrated to solid to obtain 2.7 g of 2-(4-methylpiperazin-1-yl)-1-(4-amino-phenyl)-ethanone.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1.O>CN(C)C=O>[N:41]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[C:18]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:19][C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:33][CH3:34])[CH:45]=[CH:44][N:43]=[CH:42]1
Reactant: c1c[nH]cn1
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCCl)c(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCCCn3ccnc3)c(OC)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Propyl 3-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-naphthalene-2-carboxylate (compound 325) (110 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Potassium carbonate (317 mg) and imidazole (78 mg) were added to the solution, and the mixture was stirred at 60° C. overnight. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was 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 (97 mg, yield 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[N:16]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:29](B(O)O)[CH3:30].C(Cl)Cl.C1(C)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:25]([C:15]1[CH:14]=[C:13]([NH:12][C:5]2[CH:4]=[CH:3][C:2]([CH2:29][CH3:30])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[N:16]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1cc(Br)ccc1Nc1cc(C(C)(C)C)nn1-c1ccccc1C
Reactant: CCB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCc1ccc(Nc2cc(C(C)(C)C)nn2-c2ccccc2C)c(C(=O)OC)c1
Temperature: 85 °C
Yield: 37.5 %

Procedure:
To a mixture of methyl 5-bromo-2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoate (Example 234, 1.15 g, 4.13 mmol), ethylboronic acid (1.16 g, 15.7 mmol), and Pd(dppf)Cl2.CH2Cl2 (114 mg, 0.16 mmol) was added toluene (20 mL) and dioxane (5 mL). The resulting solution was degassed under nitrogen for 30 min, followed by addition of sodium bicarbonate (2 M aq solution, 15 mL). The mixture was then heated to 85° C. for 16 h. The reaction mixture was allowed to cool to rt. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography using 0 to 10% ethyl acetate in hexanes to afford 606 mg (61%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.17 (s, 1H), 7.68 (s, 1H), 7.22-7.33 (m, 6H), 6.08 (s, 1H), 3.70 (s, 3H), 2.51 (q, 2H), 2.05 (s, 3H), 1.30 (s, 9H), 1.14 (t, 3H). ES-MS m/z 392.2 (MH+); HPLC RT (min) 4.62.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:22][C:23]1[C:24](=[O:30])[NH:25][C:26](=[O:29])[NH:27][CH:28]=1.N1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18]([N:27]2[CH:28]=[C:23]([F:22])[C:24](=[O:30])[NH:25][C:26]2=[O:29])=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3cc(F)c(=O)[nH]c3=O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (75 mg, 0.25 mmol), 5-fluorouracil (75 mg, 0.58 mmol), and 0.5 mL of pyridine in 2.0 mL of THF was stirred at room temperature for 1 h and filtered. The solid was then washed with THF, acetone, methanol, and ether to give 34 mg (36%) of 1-{3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl}-5-fluoro-1H-pyrimidine-2,4-dione as a light yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 12.22 (d, J=4.69 Hz, 1H, CONHCO), 12.19 (s, br, 1H, NH-1′), 8.33 (d, J=6.64 Hz, 1H, H-6″), 7.92–7.94 (m, 1H, H-4), 7.74–7.76 (m, 1H, H-7), 7.71 (s, 1H, H-vinyl), 7.26–7.29 (m, 2H, H-5, 6), 6.16 (s, br, 1H, H-4′), 2.47 (s, 3H, CH3), and 2.35 (s, 3H, CH3).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[C@H:49]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][CH:53]([N:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][C@H:49]3[C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:54][CH2:55]2)=[O:41])=[CH:28][C:29]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H]1CN(C)CCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CN(C)CCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.40 mL (2.88 mmol) triethylamine were added to a mixture of 260 mg (0.46 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 210 mg (0.58 mmol) ethyl(S)-4-methyl-1-piperidin-4-yl-piperazine-2-carboxylate (Example A9f) and 170 mg (0.53 mmol) TBTU in 2.4 mL DMF and the reaction mixture was stirred for 18 h at RT. The reaction mixture was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.