Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH2:23])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH:27]=[C:26]1[S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[NH:23][S:34]([C:26]2[O:25][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:27]=2)(=[O:35])=[O:36])[CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)Nc1cc(CSc2ccc(Cl)cc2N)ccn1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)ccn1
Yield: 55.6 %

Procedure:
Following General Procedure B, the title compound (555 mg, 56%) was prepared from tert-butyl(4-(((2-amino-4-chlorophenyl)thio)methyl)pyridin-2-yl)carbamate(667 mg, 1.827 mmol) and benzofuran-2-sulfonyl chloride (396 mg, 1.827 mmol) in pyridine (10 ml).
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[CH3:16][O:17][CH2:18][C:19]1[N:24]=[C:23]([O:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:22]=[CH:21][CH:20]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][O:25][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:18][O:17][CH3:16])[N:24]=2)[CH2:29][CH2:30]1)#[N:2]
Reactant: COCc1cccc(OCCN2CCNCC2)n1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Product: COCc1cccc(OCCN2CCN(CCCC(C#N)(c3cccs3)C(C)C)CC2)n1

Procedure:
The titile compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 1-(2-(6-methoxymethyl-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Reactant: N
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 300 mg, 50%). mp 181-181° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 6H), 1.72 (t, J=6 Hz, 2H), 4.43 (s, 1H), 4.53 (t, J=6 Hz, 2H), 7.49 (s, 2H), 7.53 (m, 1H), 7.63 (ddd, J=9 Hz, J=9 Hz, J=1.5 Hz, 1H), 7.79 (ddd, J=9 Hz, J=9 Hz, J=3 Hz, 1H), 7.83 (d, J=9 Hz, 1H), 7.95 (d, J=9 Hz, 2H), 8.19 (s, 1H); MS (DCI/NH3) m/z 466 (M+H)+. Anal. calcd. for C21H21F2N2O5S: C, 54.12; H, 4.66; N, 8.81. Found: C, 54.19; H, 4.55; N, 9.03.
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14](=[O:16])[CH3:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[S:27](=[O:30])(=[O:29])[NH2:28].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:14]([N:12]1[C:11]2[CH:10]=[C:9]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[C:19]([S:27]([NH2:28])(=[O:29])=[O:30])[CH:20]=3)=[O:23])[CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)(=[O:16])[CH3:15]
Reactant: CC(=O)n1c2ccccc2c2ccccc21
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)n1c2ccccc2c2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc21
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of 1-carbazol-9-yl-ethanone and 2.43 g of 4-chloro-3-sulfamoyl-benzoyl chloride in methylene chloride (20 mL) is added 2.55 g of aluminum chloride. The mixture is stirred at 50° C. overnight. The solution is then cooled at −78° C., quenched with a 6 N HCl solution and allowed to warm up to room temperature. Methylene chloride is added to dissolve the precipitate and the solution is extracted, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to afford 5-(9-acetyl-9H-carbazole-2-carbonyl)-2-chloro-benzenesulfonamide as yellow foam. MS (m/z): 427 (M+1). HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10→100% CH3CN in 5 min) room temperature=5.35 minutes.
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].B.CSC.Cl>C1COCC1>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)Cc1ccccc1OC
Agent: B
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CCCCCCCNCCc1ccccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
N-Heptyl-2-(2-methoxyphenyl)acetamide (2.00 g, 7.594 mmol) was dissolved in THF (10 ml) and was cooled to zero degrees under argon atmosphere. (Methylthio)methane compound with borane (1:1) (1.442 g, 18.984 mmol) was added and the mixture was refluxed for 5 hours. After the mixture was cooled to room temperature, 5 ml HCl (10%) was gently added and the mixture was stirred overnight. The solvent was removed by evaporation. EtOAc (20 ml) was added and the organic phase was washed with K2CO3 (2M, 2×20 ml). The crude was purified by flash cromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 1.037 g of N-[2-(2-methoxyphenyl)ethyl]heptan-1-amine (yield 54.8%).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:15][CH:16]=1)[CH3:3]
Reactant: CCN(CC)CCCl
Reactant: CCCC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCCC(=O)c1ccc(OCCN(CC)CC)cc1
Yield: 98.8 %

Procedure:
2-(Diethylamino)ethyl chloride hydrochloride (624 mg, 3.65 mmol) was added to a stirred solution of p-hydroxybutyrophenone (200 mg, 1.21 mmol) in anhydrous acetone (6 mL) followed by the addition of potassium carbonate (668 mg, 4.84 mmol). The resulting mixture was heated at reflux for 48 hours. The mixture was diluted with ethyl acetate, washed with water (2×) and sat. brine, dried over sodium sulfate, and concentrated to an oil. Flash silica gel column chromatography, eluting with 1:1 hexanes/ethyl acetate, afforded 21 (315 mg, 98%) as a light yellow oil: MS (ES+) m/z 264.1 (M+H)+.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:8]([NH:10][C@H:11]([C:18](OC)=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].O.[NH2:30][NH2:31]>CO>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:8]([NH:10][C@H:11]([C:18]([NH:30][NH2:31])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: NN
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)NN
Reaction time: 20 h

Procedure:
27.9 g of Boc-Gln-His-OCH3 (Marchiori et al., J. Chem. Soc (C) 1967, 81) are dissolved in 280 ml of highest purity methanol, 28 ml of hydrazine hydrate are added and the mixture is left to stand for 20 hours at 25°C. It is concentrated to dryness in a high vacuum and the residue is recrystallised from methanol-ethyl acetate-petroleum ether. Melting point 187°-189°C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=2)[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:29])=[CH:23][CH:22]=1
Reactant: COC(=O)C(Cc1cccc(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(Cl)cc1
Product: COC(=O)C(Cc1cccc(CCOC(=O)Nc2ccc(Cl)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)benzyl]malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]([NH:40][CH2:41][CH:42]3[CH2:44][CH2:43]3)[S:38][CH:39]=2)=[CH:31][N:30]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]([NH:40][CH2:41][CH:42]3[CH2:44][CH2:43]3)[S:38][CH:39]=2)=[CH:31][N:30]=1
Reactant: NCc1ccc(-c2csc(NCC3CC3)n2)cn1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(-c4csc(NCC5CC5)n4)cn3)c2CC1)C(F)(F)F
Yield: 30.3 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (316 mg, 0.74 mmol) with 2-aminomethyl-5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine (290 mg, 1.11 mmol) in toluene (8 mL). Filter the crude mixture over Celite®, followed by activated charcoal and wash with dichloromethane. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel (12 g) eluting with hexane/(EtOAc with 1% methanol) (20:1 to 3:2 gradient) to obtain 7-chloro-6-{[5-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridin-2-ylmethyl]-amino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (120 mg, 30%). MS (ES+) m/z: 536.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[O-]CC.[Na+]>C(O)C>[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[C:27](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: CCCCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)cccc1OC
Yield: 45.9 %

Procedure:
The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.071 mmol) with 3-methoxy-2-pentyloxybenzaldehyde (333 mg, 1.501 mmol) in presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure of Example 24 to give 261 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.91 (t, J=6.6 Hz, 3H), 1.33-1.42 (m, 4H), 1.50-1.58 (m, 2H), 3.77 (s, 3H), 3.83 (t, J=6.3 Hz, 2H), 6.85-6.90 (m, 2H), 6.96-7.02 (m, 2H), 7.40-7.47 (m, 4H), 7.51-7.90 (m, 1H), 7.95-8.02 (m, 1H), 8.06-8.12 (m, 1H); ESI-MS (m/z) 531.26 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][NH:28][CH2:25][CH2:26][CH3:27])[O:17][N:16]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: CCCN
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(Cl)cc2C1=O
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2cc(Cl)ccc2-3)no1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.3 %

Procedure:
A solution of 200 mg (0.54 mmol) of 8-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 4 ml of N,N-dimethylformamide was treated with 0.136 ml (1.65 mmol) of propylamine and stirred at room temperature under argon for 1.5 hrs. The solution was evaporated and the residue was triturated in 10 ml of water. The aqueous phase was extracted with methylene chloride and the combined extracts were washed twice with water, dried with sodium sulfate, filtered and evaporated. The combined crude products were chromatographed on 30 g of silica gel (ethyl acetate methylene chloride/methanol 9:1). There were obtained 126 mg of 8-chloro-3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as a foam which was converted in acetonitrile with ethereal hydrochloric acid into the hydrochloride. By crystallization from hot acetonitrile there were obtained 102 mg (42%) of 8-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (1:1.8) of m.p. 230°-240° (dec.).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.CN(C=O)C.[NH2:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>O>[Si:1]([O:26][C:22]1[CH:21]=[C:20]([NH2:19])[CH:25]=[CH:24][CH:23]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 250 mL, three-neck, round bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with tert-butyldimethylsilyl chloride (12.5 g, 82.8 mmol), imidazole (7.64 g, 112 mmol), and anhydrous DMF (60 mL). 3-aminophenol (10.0 g, 91.7 mmol) was added to the resulting solution. After stirring for 12 h at ambient temperature, the reaction mixture was poured into water (300 mL). The resulting suspension was extracted with hexanes (3×300 mL), and the extracts were combined, dried over sodium sulfate, and filtered. Concentration of the filtrate followed by column chromatography gave compound 122 as a light yellow oil. 1H NMR (DMSO-d6) δ (ppm), 6.84 (t, 1H, J=7.9 Hz), 6.16 (d, 1H, J=6.7 Hz), 6.10 (m, 1H), 5.97 (d, 1H, J=9.1 Hz), 4.98 (s, 2H), 0.95 (s, 9H), 0.16 (s, 6H); m/z=224 (M+H).
Reaction SMILES: CN(C([O:8][N:9]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([OH:53])=O)[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1.C(N(CC)CC)C.NO.Cl>CS(C)=O>[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:55])[C:31]=1[NH:32][C:33]1[C:42]2[C:37](=[C:38]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][C:51]([NH:9][OH:8])=[O:53])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=2)[O:36][C:35](=[O:54])[CH:34]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)NO
Reaction time: 0.08 h

Procedure:
HATU (25 mg, 0.066 mmol) was added to a solution of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (25 mg, 0.053 mmol, Example 44), triethylamine (0.05 mL, 0.36 mmol), and DMSO (0.5 mL). After 5 min, NH2OH•HCl (10 mg, 0.14 mmol) was added. After an additional 17 h, the mixture was diluted with DMSO (1 mL), filtered through cotton, and the filtrate purified by reverse-phase HPLC (1:9→3:2; acetonitrile:water) to give 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)-N-hydroxyhexanamide: 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 9.51 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 3.96 (t, 2H), 3.92 (s, 3H), 1.96 (t, 2H), 1.67 (m, 2H), 1.54 (m, 2H), 1.43 (m, 2H); MS (ESI): 481.9.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10](=[O:30])[NH:11][CH2:12][C@H:13]([OH:29])[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([F:25])[CH:24]=1)[N:21]([CH2:26][CH3:27])[C:20](=[O:28])[CH2:19]2)([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10](=[O:30])[NH:11][CH2:12][C@@H:13]1[O:29][C:1](=[O:2])[N:15]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([F:25])[CH:24]=2)[N:21]([CH2:26][CH3:27])[C:20](=[O:28])[CH2:19]3)[CH2:14]1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CCN1C(=O)Cc2cc(NC[C@@H](O)CNC(=O)OC(C)(C)C)cc(F)c21
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1C(=O)Cc2cc(N3C[C@H](CNC(=O)OC(C)(C)C)OC3=O)cc(F)c21
Reaction time: 0.5 h

Procedure:
Phosgene (20% solution in toluene, 3.58 ml, 36.7 mmol) is added to (R)-[3-(1-ethyl-7-fluoro-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (1.80 g, 4.89 mmol) and triethylamine (3.38 ml, 24.5 mmol) in dichloromethane (20 ml) at 0° C. and stirred for 30 minutes. The mixture is diluted with dichloromethane, washed with water and brine, dried (Na2SO4) and evaporated to give the title compound as a light brown solid. HPLC r.t. 4.92 min; MS for C19H24FN3O5 m/z 394.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[NH:3][C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]([CH3:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1C
Product: CCOC(=O)C1=C(C)NC(NC(C)=O)=C(C(=O)OCC)C1C

Procedure:
8 g (0.03 mol) of diethyl 2-amino-4,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate in 100 ml of acetic anhydride were boiled under reflux for 4 hours. The mixture was concentrated to dryness in vacuo, and the residue was recrystallized from ethanol. Yield: 5.4 g (58% of theory) of m.p.: 105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([Cl:12])[C:3]=1[CH:4]=[O:5].[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[C:6]([Cl:12])[C:3]=1[CH:4]=[O:5])[CH2:10][O:11][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1c(Cl)cc(CO)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
A solution of 500 mg (2.4 mmol) A3 in 5 ml dry dimethyl formamide under nitrogen was cooled in an ice bath and 73 mg (3.0 mmol) sodium hydride was added and the mixture was stirred for 10 minutes. After addition of 410 mg (2.6 mmol) ethyl bromoacetate, the mixture was heated to 110° C. for 8 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with water. The organic layer was dried over sodium sulphate and evaporated to dryness. Purification of the residue by column chromatography on SiGel (heptane/ethyl acetate 4:1) yielded 40 mg (6%) A15.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>>[CH3:10][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1ccc(O)cc1C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(OCOCC[Si](C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 103.3 %

Procedure:
5-hydroxy-2-methylbenzaldehyde (3.4 g) is added portionwise to a stirred suspension of sodium hydride (1.2 g, 60% dispersion in mineral oil). The reaction mixture is stirred at room temperature for 45 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (5 g) is added slowly and stirring continued for a further 3 hours. The mixture is evaporated and the residue partitioned between ethyl acetate (50 mL) and water (150 mL). The organic phase is washed with brine (150 mL) dried over magnesium sulphate and evaporated to give 2-methyl-5-(2-(trimethylsilyl)ethoxymethoxy)benzaldehyde (6.87 g) as a red-brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2Cl.[CH3:16][NH:17][CH:18]([CH3:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:17]([CH:18]([CH3:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[CH3:16]
Reactant: CNC(C)Cc1ccccn1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(N(C)C(C)Cc3ccccn3)c2cc1OC

Procedure:
Reaction of 6,7-dimethoxy-4-chloroquinazoline with 2-(2-[N-methylamino]prop-1-yl)pyridine, according to the procedure of Example I, yielded the title compound, isolated as its dihydrochloride dihydrate, m.p. 242°-5°C.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O.COCCOC.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>[F:14][C:6]1[C:5]([CH3:15])=[C:4]2[C:9]([CH:10]=[C:11]([CH:12]=[O:13])[C:2]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1c(F)ccc2cc(C=O)c(Cl)nc12
Reactant: OB(O)c1cccnc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(F)ccc2cc(C=O)c(-c3cccnc3)nc12
Yield: 92.7 %

Procedure:
Prepared according to the procedure described for Intermediate 1, utilising 2-chloro-7-fluoro-8-methylquinoline-3-carbaldehyde (5.0 g, 22.36 mmol), 3-pyridylboronic acid (3.02 g, 24.6 mmol), tetrakis(triphenylphosphine)palladium(0) (127 mg, 0.11 mmol) and Na2CO3 (3.55 g, 33.54 mmol) in water (30 mL) and DME (60 mL). The title compound (5.52 g, 93%) was obtained as a beige solid. δH (DMSO-d6) 10.13 (s, 1H), 9.08 (s, 1H), 8.95 (dd, J 2.3, 0.8 Hz, 1H), 8.75 (dd, J 4.9, 1.7 Hz, 1H), 8.24 (dd, J 9.0, 6.4 Hz, 1H), 8.16-8.21 (m, 1H), 7.68 (t, J 9.2 Hz, 1H), 7.61 (ddd, J 7.9, 4.0, 0.8 Hz, 1H), 2.66 (d, J 2.4 Hz, 3H). LCMS (ES+) 267 (M+H)+, RT 2.16 minutes.