Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C@H:7]([OH:12])[C:8]([O:10][CH3:11])=[O:9])[CH3:4].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=3)[N:21]=[CH:22][C:15]=12.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Cl:29][C:28]1[C:23]([N:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:12][C@@H:7]([CH2:6][O:5][CH2:3][CH3:4])[C:8]([O:10][CH3:11])=[O:9])[C:15]=3[CH:22]=[N:21]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC[C@H](O)C(=O)OC
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)OC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
60% sodium hydride in mineral oil (0.96 g, 24.1 mmol) was added portionwise to (S)-methyl 3-ethoxy-2-hydroxypropanoate (Intermediate G4) (2.97 g, 20.1 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (5.87 g, 22.1 mmol) in tetrahydrofuran (50 mL) was added dropwise over a period of 2 minutes. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 hour. The reaction was cooled to ˜10° C., 1M citric acid (20 mL) added and the mixture was extracted with EtOAc (2×50 mL). The organic extracts were washed with water (25 mL) and saturated brine (25 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 50 to 100% EtOAc in isohexane to give the methyl (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxypropanoate (5.7 g, 70% ee). This was further purified by chiral HPLC on Chiralcel OJ eluting with isohexane/isopropanol/triethylamine (70:30:0.1) at 60 mL/min. to give the enantiomerically pure product (3.8 g, 50%) as a colourless gum. 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.60-3.73 (2H, m), 3.79 (3H, s), 4.00-4.11 (2H, m), 5.85 (1H, dd), 7.45 (1H, dd), 8.00 (1H, dd), 8.42 (1H, s), 8.58 (1H, s), 8.61 (1H, dd), m/z (ESI+) (M+H)+=378; HPLC tR=1.84 min.
Reaction SMILES: [CH2:1]([P:8]([CH2:11][CH:12]([C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:13][CH2:14][C:15]([O:17]CC1C=CC=CC=1)=[O:16])(=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.[Pd]>[CH2:1]([P:8]([CH2:11][CH:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[C:25]([OH:27])=[O:26])([OH:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC(CP(=O)(O)Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: O=C(O)CCC(CP(=O)(O)Cc1ccccc1)C(=O)O
Yield: 56.6 %

Procedure:
Benzyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (0.5 g, 1.0 mmol) in 20 mL of water containing 120 mg of 10% Pd/C was hydrogenated at 40 psi for 6 hours. Filtration through a Celite pad followed by evaporation on high vacuum gave 0.17 g (57%) of 2-[(benzylhydroxyphosphinyl)methyl]-pentanedioic acid (4, R=CH2Ph) as a white solid.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH2:8]I)=[O:2].Cl.[CH3:23][NH:24][CH3:25].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:23][N:24]([CH2:8][CH2:7][CH2:6][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][NH:3][CH:1]=[O:2])[CH3:25]
Reactant: CNC
Reactant: O=CNCC(CCCI)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)CCCC(CNC=O)(c1ccccc1)c1ccccc1
Yield: 67.1 %

Procedure:
A mixture of 5-formylamino-1-iodo-4,4-diphenylpentane (8.5 g), dimethylamine hydrochloride (17.63 g), triethylamine (30.1 ml), and potassium carbonate (3 g) was heated in acetonitrile (250 ml) at 60° C. for 2 hours. This reaction mixture was concentrated to dryness and the group was extracted using ethyl acetate and water. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness. The group was crystallized from ethyl acetate-isopropyl ether to provide the title compound (4.5 g) as white powder.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][CH:19]=[C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CO.C(Cl)Cl>[C:20]1(=[CH:19][CH2:18][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrCC=C1CCCCC1
Reactant: O=S([O-])c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(CC=C1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 38.5 gm of sodium phenyl sulfinate and then 3.85 gm of sodium carbonate were introduced into 116 cc of methanol and 44 gm of freshly prepared 1-bromo-2-cyclohexylidene-ethane were added dropwise over 30 minutes and at room temperature. The reaction mixture was then agitated for 1 hour and 30 minutes at room temperature after which the reaction mixture was poured into 400 cc of ice water. The precipitate formed was vacuum filtered, washed with water and dried. The raw product thus obtained was dissolved at high temperature in a mixture consisting of methylene chloride and methanol. The solution obtained was dried over magnesium sulfate, concentrated to a small volume and admixed with isopropyl ether. The precipitate formed was vacuum filtered and dried to obtain 36.4 gm of (2-cyclohexylidene-ethyl)-phenyl sulfone, having a melting point of 70° C. A sample of this product, crystallized from isopropyl ether, had a melting point of 70° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[NH:10][C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](I)[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:22][CH3:23])[C:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)OC(C)(C)C)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.6 %

Procedure:
A suspension of 3(R,S)-tert-butoxycarbonyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3.645 g, 12.51 mmol), ethyl iodide (2.01 mL, 25.02 mmol) and Cs2CO3 (8.153 g, 25.02 mmol) in acetonitrile (35 mL) was stirred at room temperature for 6 hrs. The reaction mixture was evaporated to dryness, the residue dissolved in water and extracted with DCM. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The solid residue was washed with n-hexane and dried in vacuum. The desired compound (3.50 g, 88%) was obtained as white crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:15]3[CH2:16][NH:17][CH2:18][CH2:19][C:14]=3[NH:13][C:12](=[O:20])[N:11]2[CH:21]=1.[CH:22](=O)[CH2:23][CH2:24][CH3:25].C([BH3-])#N.[Na+].Cl>O.CO>[CH2:22]([N:17]1[CH2:18][CH2:19][C:14]2[NH:13][C:12](=[O:20])[N:11]3[CH:21]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:9]=[C:10]3[C:15]=2[CH2:16]1)[CH2:23][CH2:24][CH3:25]
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Reactant: CCCC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCN1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Reaction time: 6 h

Procedure:
To 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (171 mg, 0.6 mmol) in pH4-5 HCL-methanol (6 mL) at room temperature was added n-butyraldehyde (53 uL, 0.6 mmol) and sodium cyanoborohydride (38 mg, 0.6 mmol). After the reaction mixture was stirred for 6 hours, concentrated HCl was added until the mixture became homogenous. The mixture was then diluted with water (5 mL) and extracted twice with ether. The aqueous layer was made alkaline with aqueous ammonium hydroxide, saturated with sodium chloride, and extracted twice with 10% methanol/ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 9-n-Butyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (Compound 48). Recrystallization from aqueous ethanol gave a white fluffy solid, m.p. 251°-253° C. (d).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: Cc1c[nH]cn1
Reactant: CC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)c1ccc(-n2cnc(C)c2)nc1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
1-(6-chloro-pyridin-3-yl)-ethanone (7.00 g, 45.16 mmol) and 4-methylimidazole (11.11 g, 135.50 mmol) were combined in DMSO (35 ml), before addition of K2CO3. The mixture was heated at 110° C. for 22 h with rapid stirring. The reaction was then cooled to room temperature and poured into ice water (400 ml) with vigorous stirring for 15 min. The resulting precipitate was collected on a filter and washed generously with water. The resulting material was dried in vacuo to yield 19 as a tan solid (6.1 g, 67%). LC/MS: [M+1]+=202.2. C11H11N3O=201.2. 1H NMR (DMSO-d6) 300 MHz δ2.18 (3H, s), 2.63 (3H, s), 7.72 (1H, s), 7.87 (2H, d, J=9.0 Hz), 8.41 (2H, d, J=9.0 Hz), 8.51 (1H, s), 8.98 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[S:16][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][N:19]=1>N1C=CC=CC=1>[C:20]([C:17]1[S:16][C:15]([NH:14][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)=[N:19][CH:18]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)c1cnc(N)s1
Solvent: c1ccncc1
Product: CC(C)(C)c1cnc(NC(=O)c2ccc(Cl)c([N+](=O)[O-])c2)s1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A solution of 4-chloro-3-nitrobenzoyl chloride (1.336 g, 6.681 mmol) in anhydrous pyridine (30 mL) was treated with 2-amino-5-tert-butylthiazole (1.044 g, 6.681 mmol) and the reaction stirred at room temperature under a nitrogen atmosphere. The solvent was removed by rotary evaporation in vacuo and the residue dried on a vacuum pump. The residue was taken up in ethyl acetate (100 mL) and washed with water (4×50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography eluting with 5% ethyl acetate/methylene chloride provided the title compound (1.76 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[S:43](Cl)(=[O:45])=[O:44]>C1COCC1>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[S:43]([NH:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[CH:14][CH:13]=[C:12]3[N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:6]=1)(=[O:45])=[O:44]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(-c2ccc3nccc(N4CCOCC4)c3c2)cnc1Cl)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
(Some starting materials may be obtained from Alfa Aesar, Ward Hills, Mass.) To a flame-dry 50 mL rb flask was added 2-chloro-5-(4-morpholinoquinolin-6-yl)pyridin-3-amine (0.07 g, 0.2 mmol) and THF (8 mL). The reaction mixture was cooled to 0° C. followed by adding sodium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (0.4 mL, 0.4 mmol). After the addition, it was continued to stir at 0° C. under N2. After 30 min, 2,6-dichlorobenzene-1-sulfonyl chloride (0.07 g, 0.3 mmol) was added into the reaction mixture. After the addition, it was continued to stir at 0° C. then slowly warmed up to rt overnight. The reaction was quenched with water. The solvent was concentrated. The residue was partitioned between EtOAc/water. The organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified using SiO2 (12 g) chromatography with DCM:EtOAc:MeOH=70%:26%:4% as the solvent system to afford the desired product as light yellow solid (63.0 mg). MS (ESI pos. ion) m/z: calc'd for C24H19Cl3N4O3S: 548.1; found: 549.4 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.21-3.38 (m, 4 H) 3.93-4.11 (m, 4 H) 6.94 (d, J=4.97 Hz, 1 H) 7.33-7.44 (m, 1 H) 7.45-7.55 (m, 2 H) 7.85 (dd, J=8.77, 2.05 Hz, 1 H) 8.18 (d, J=8.77 Hz, 1 H) 8.25 (d, J=1.90 Hz, 1 H) 8.39-8.50 (m, 2 H) 8.81 (d, J=4.97 Hz, 1 H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]1([C:31]2[N:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:28]3[CH2:29][CH2:30][N:25]([C:31]4[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][N:36]=4)[CH2:26][CH2:27]3)=[O:16])[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Product: N#Cc1ccc(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)nc1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 6-(piperazino)pyridine-3-carbonitrile to give the title compound as a colorless solid. MS: 523.5 ([M+H]+)
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16]O>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 45 %

Procedure:
To a suspension of 5-hydroxy-4-methoxy-2-nitrobenzoic acid (8.0 g, 37.5 mmol) in methanol was added concentrated sulfuric acid (3 drops) and it was heated at 80° C. overnight. After solvent was removed under reduced pressure, to it was added water and EtOAc. The organic layer was washed with saturated NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure to afford methyl 5-hydroxy-4-methoxy-2-nitrobenzoate as a solid (3.86 g, 45%). 1H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 7.63 (s, 1H), 7.08 (s, 1H), 3.91 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([N+:20]([O-])=O)=[C:18]([NH:23][CH3:24])[N:17]=[C:16]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:29])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([NH2:20])=[C:18]([NH:23][CH3:24])[N:17]=[C:16]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1nc(C(=O)OC)cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNc1nc(C(=O)OC)cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)c1N
Reaction time: 4 h
Yield: 92.2 %

Procedure:
In a dry reaction bottle, 6.54 g (R)-1-[2-methoxycarbonyl-5-nitro-6-methylaminopyridin-4-yl]piperidine-3-carbamic acid tert-butyl ester (16 mmol) was added and dissolved in 200 mL ethanol. 0.65 g 10% Pd—C was added at room temperature. The stirring was continued for 4 h by introducing hydrogen gas. The reaction solution was filtrated, and evaporated to dryness to afford 5.6 g light yellow solid with a yield of 92.3%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][N:14]([CH3:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>>[CH3:13][N:14]([CH3:22])[C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:17][CH:16]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Cc1nc(Nc2ccc(N(C)C)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol), 4-dimethylamino-aniline (136.2 mg, 1.0 mmol) and sodium acetate (98.4 mg, 1.2 mmol) similar to example 20 to give 222 mg (79.9%) of gray solids. 1H NMR (CDCl3): 7.82-7.70 (m, 3H), 7.62 (d, J=9.0 Hz, 2H), 7.45 (t, J=7.5 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 2.97 (s, 6H), 2.66 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].O.Cl[CH2:6][CH2:7][CH:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][C:19]([CH3:21])=[N:20][C:10]=2[O:9]1.[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)(C)C>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:1][N:2]([CH3:3])[CH2:6][CH2:7][CH:8]1[CH2:14][N:13]([CH3:15])[C:12](=[O:16])[C:11]2[CH:17]=[CH:18][C:19]([CH3:21])=[N:20][C:10]=2[O:9]1
Reactant: CNC
Reactant: Cc1ccc2c(n1)OC(CCCl)CN(C)C2=O
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc2c(n1)OC(CCN(C)C)CN(C)C2=O
Reaction time: 72 h

Procedure:
To 50 ml of freshly collected dimethylamine was added 5.0 g (0.020 mole) of 2-(2-chloroethyl)-2,3-dihydro-4,8-dimethylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one hydrate[1:1]. The reaction flask was sealed tightly and left standing at room temperature for 3 days. The dimethylamine was evaporated in a stream of air. The residue was taken up in methylene chloride, washed twice with 1N sodium hydroxide and once with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. The syrupy residue was treated with 2 equivalents of fumaric acid in isopropyl alcohol which yield 5.2 g (52%) of white crystals, m.p. 164°-165° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH2:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2)[CH3:15].N1CCCCC1>C(O)C>[CH2:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:11][C:8]1[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=1[CH3:13])[CH3:15]
Reactant: CCc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCc1ccc2c(c1)C(=Cc1[nH]cc(CCC(=O)O)c1C)C(=O)N2
Yield: 32.1 %

Procedure:
4-(2-Carboxyethyl)-2-formyl-3-methylpyrrole (90.6 mg), 80.5 mg 5-ethyl-2-oxindole, and 75 μL of piperidine in 2 mL of ethanol were heated at 95° C. for 5 hours. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N of aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight. The crude solid was purified by a chromatography on a silica gel column eluting with ethyl acetate-hexane-acetic acid to give 52 mg (32%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:5]([O:8]C)=[N:6][CH:7]=1.[Li+].[Cl-]>CN(C=O)C.O>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1
Reactant: COc1cc(OCC2CC2)c(Br)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cc(OCC2CC2)c(Br)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of the title compound from step 1 (450 mg, 1.74 mmol) in DMF (5 mL) was added LiCl (370 mg, 8.72 mmol) and TsORH2O (1.52 g, 8.72 mmol) at room temperature. The mixture was heated to 120° C. and stirred for 1 hour. The mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic phase was washed with saturated brine (2×200 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (380 mg, yield: 88.9%) as yellow solid which used directly for the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 1H), 5.91 (s, 1H), 3.87 (d, J=6.8 Hz, 2H), 1.36-1.22 (m, 1H), 0.71-0.67 (m, 2H), 0.46-0.42 (m, 2H). LCMS: 244.0 (M+1)+; 246.0
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]Br)=[N:13][NH:12][C:11]=1[NH2:20].[NH2:21][C:22]1NN=C(CCCCO)C=1C1SC2C=CC=CC=2N=1.CN.C1COCC1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:21][CH3:22])=[N:13][NH:12][C:11]=1[NH2:20]
Reactant: Nc1[nH]nc(CCCCBr)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCCO)c1-c1nc2ccccc2s1
Agent: CN
Solvent: C1CCOC1
Product: CNCCCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (30 mg) was prepared using 185 mg (0.39 mmol) of 4-benzothiazol-2-yl-5-(4-bromobutyl)-2H-pyrazol-3-ylamine, which was derived from 4-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)-butan-1-ol, and 5 mL of a 2 M solution of methylamine in THF (10 mmol). MS (m/z, ES+): 302.4 (M+1, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[I:14]N1C(=O)CCC1=O>C(O)(=O)C>[I:14][C:10]1[CH:11]=[N:12][C:13]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cccnc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2cc(I)cnc12
Temperature: 62 °C
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A stirred mixture of 8-nitroquinoline (100 g, 0.57 mol) in acetic acid (500 ml) was treated with N-iodosuccinimide (155 g, 0.69 mol) portionwise over 10 minutes, and warmed to 62° C. for 6 h. A further portion of N-iodosuccinimide (25 g, 0.14 mol) was introduced and the mixture stirred for a further 16 h before cooling to ambient temperature. The solvent was removed in vacuo, keeping the temperature below 35° C. The residue was dissolved in dichloromethane (2 L) and washed successively with saturated aqueous sodium bicarbonate solution (2×1 L), 10% aqueous sodium thiosulphate solution (1 L), water (1 L), brine (100 ml), then the organic phase was dried over magnesium sulphate. The mixture was filtered and the solvent removed to give a yellow solid which was recrystallised from ethyl acetate to give the title compound (D3) (168 g, 97%) as a yellow solid;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5](O)=[O:6].O=P(Cl)(Cl)Cl.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:5]([N:22]=[N+:23]=[N-:24])=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(N2CCOCC2)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: [N-]=[N+]=NC(=O)c1ccc(N2CCOCC2)c(F)c1

Procedure:
This compound may be prepared from (14) in a one pot reaction utilizing POCl3 in DMF (Vilsmeier complex) and NaN3 following the literature procedure of Sridhar et al. (Syn. Comm. 2003, 33, 607-611).