Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.C([O-])(=O)C.[Na+].CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1>C(O)(=O)C.CO>[N:2]1([CH:3]2[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=3)[CH:27]=[CH:31][CH:30]=[CH:29]1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: COC1CCC(OC)O1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)C(n1cccc1)c1ccccc1-2
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To a suspension of 1.4 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 25 ml of acetic acid are added 0.41 g of anhydrous sodium acetate and 0.66 g of 2,5-dimethoxytetrahydrofuran. The mixture is stirred at boiling for 1 hour 30 minutes and, after cooling to 20° C., the solid formed is isolated by filtration, washed twice with 30 ml in total of distilled water and air-dried. The product obtained (2.45 g) is chromatographed on 25 g of neutral silica gel (0.06-0.20 mm) contained in a column 2.4 cm in diameter, eluting with a dichloromethane/methanol mixture (90/10 by volume) and collecting an 18 ml fraction and a 540 ml fraction. After addition of decolorizing charcoal, the latter fraction is filtered and the filtrate is concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 40° C. The product obtained is suspended for 10 minutes in 5 ml of methanol and then isolated by filtration, washed with 1 ml of methanol and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.6 g of 10-(1-pyrrolyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, decomposing without melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 6.12 (t, J=2 Hz, 2H: --H 3 and --H 4 of the pyrrole); 6.61 (s, 1H: --CH-- 10); 6.91 (t, J=2 Hz, 2H: --H 2 and --H 5 of the pyrrole); 7.08 and 7.34 (2 broad s, 1H each: --H of the imidazole); from 7.30 to 7.55 and 7.93 [mt and d respectively (J=7.5 Hz), 3H and 1H: --H 6, --H 7, --H 8 and --H 9]; 12.60 (broad s, 1H: --CONH--)).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:13])[CH3:12])=[CH:3]1.[CH2:14]=O.Cl.[CH3:17][NH:18][CH3:19]>C(O)C.O>[CH3:17][N:18]([CH3:14])[CH2:19][CH2:12][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:13]
Reactant: C=O
Reactant: CNC
Reactant: CC(=O)c1cn(C)c2ccccc12
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)CCC(=O)c1cn(C)c2ccccc12
Yield: 93.6 %

Procedure:
A mixture of 1-(1-methyl-1H-indol-3-yl)-1-ethanone (46.16 g), paraformaldehyde (12.0 g) and dimethylamine hydrochloride (21.65 g) in ethanol (970 ml) was stirred and heated at reflux for 24 h. The mixture was diluted with water (3.5 l) and filtered. The filtrate was basified with 0.88 ammonia solution and extracted with ethyl acetate (3×665 ml). The combined organic extracts were washed with water, dried and evaporated to give title compound (57.24 g) as an oil, λmax (EtOH) 245.5 nm (ε15,820), λmax 303.5 nm (ε15,680), λinf 249.5 nm (ε15,015).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([O:22][C:20](=[O:21])[CH:19]=[CH:18][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][C:13]=1[C:14]([NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:16])([CH3:25])([CH3:24])[CH3:26]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C=Cc1ccc(OCc2ccccc2)cc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.7 %

Procedure:
To a solution of 5-benzyloxy-2-(2-tert-butoxycarbonyl-vinyl)-benzoic acid (1.45 g, 4.09 mmol) in CH2Cl2 (40 mL) was added benzylamine (0.613 g, 5.73 mmol), EDC (1.254 g, 6.54 mmol), and DMAP (1.00 g, 8.18 mmol). The resulting mixture was stirred at room temperature for 12 h, washed with aqueous NH4Cl (50 mL), and extracted with CH2Cl2 (2×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was then purified using silica gel chromatography (hexanes/EtOAc 8/2) to afford the title compound as an oil (720 mg, 40%). 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 4.63 (d, 2H, J=5.5 Hz), 5.09 (s, 2H), 5.97 (br s, 1H), 6.22 (d, 1H, J=15.6 Hz), 7.01 (dd, 1H, J=2.7, 8.6 Hz), 7.10 (d, 1H, J=2.8 Hz), 7.28-7.42 (m, 10H), 7.55 (d, 1H, J=9.0 Hz), 7.88 (d, 1H, J=16.0 Hz).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=1[C:15]([C:17]1[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=1[NH:24][CH:25]=[CH:26][N+:27]([O-:29])=[O:28])=O>C1C=CC=CC=1.O1CCOCC1.C1C=CC=CC=1>[Cl:12][C:13]1[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=1[C:15]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][N:24]=[C:18]2[S:19][C:20]([CH2:22][CH3:23])=[CH:21][C:17]=12
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(NC=C[N+](=O)[O-])s1
Solvent: c1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc2c(-c3ccccc3Cl)c([N+](=O)[O-])cnc2s1
Yield: 89.1 %

Procedure:
To a solution of DBU (5.1 g) in benzene (50 ml) was added dropwise a solution of 3-(2-chlorobenzoyl)-2-(2-nitroethenylamino)-5-ethylthiophene (5.1 g) in dioxane-benzene (1 : 1, 30 ml}over one hour with stirring under reflux. After refluxing for additional one hour, the mixture was washed with water and dried over MgSO4. The solvent was distilled off and to the residue was added isopropyl ether to obtain 4-(2-chlorophenyl)-2-ethyl-5-nitrothieno[2,3-b]pyridine as crystals (4.3 g, 89.0%). The crystals were recrystallized from isopropyl ether to obtain pale yellow prisms, mp: 72°-73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ncccn2)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ncccn2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
0.64 g of 5-(4-chlorophenyl)-6-methyl-4-(2-pyrimidinyl)-2H-pyridazin-3-one and 10.4 g of phosphorus oxychloride were mixed. The mixture was stirred for 2 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue was added ethyl acetate and ice-cooled sodium bicarbonate water was added. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.56 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.49 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(2-pyrimidinyl)pyridazine (hereinafter, described as compound (6) of the present invention (6).).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[C:9]([CH3:15])[C:8]=2[C:16]=1[O:17][CH3:18])(=O)[CH3:2].C(Cl)(=O)C([Cl:22])=O.CN(C=O)C.[CH3:30][O:31][C:32](=[O:54])[C@@H:33]([NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH:34]([CH3:36])[CH3:35]>N1C=CC=CC=1>[CH3:30][O:31][C:32](=[O:54])[C@@H:33]([NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][C:4]([C:1]([Cl:22])=[CH2:2])=[C:16]([O:17][CH3:18])[C:8]=4[C:9]=3[CH3:15])=[O:14])=[CH:51][CH:52]=2)=[CH:43][CH:42]=1)(=[O:40])=[O:39])[CH:34]([CH3:36])[CH3:35]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1c(C(C)=O)ccc2oc(C(=O)O)c(C)c12
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C=C(Cl)c1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC)C(C)C)cc4)cc3)c(C)c2c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To 75 mg (0.3 mmol) of 5-acetyl-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 1 mL of oxalyl chloride and the mixture was refluxed for 2.5 h in the presence of a catalytic amount of DMF, then the excess oxalyl chloride was removed under vacuum. The residue was dissolved in 1 mL of dichloromethane and was added to a mixture of 163 mg (0.46 mmol) of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester and 2 mL of pyridine in an ice/water bath. The mixture was stirred at room temperature overnight. All the solvents were removed under vacuum. Column chromatography on silica gel gave 36 mg (20% yield) of (S)-2-(4′-{[5-(1-chloro-vinyl)-4-methoxy-3-methyl-benzofuran-2-carbonyl]-amino}-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH3:16]>C1COCC1>[Br-:13].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]2[CH:12]=[CH:11][N:10]([CH2:14][CH2:15][CH3:16])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-n2ccnc2)cc1
Reactant: CCCBr
Solvent: C1CCOC1
Product: CCCn1cc[n+](-c2ccc(C)cc2)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 6.30 mmol (1.00 g) 1-(4-methylphenyl)imidazole and 7.60 mmol (0.930 g, 0.69 ml) 1-bromopropane are dissolved in 5 ml THF and heated for 6 h to 90° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[C:7]([CH2:8][CH2:9][NH2:10])=[CH:6][NH:5]2.Cl.[C:15](OCC)(=O)C.Cl.[OH-].[Na+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:11]([C:7]3[CH2:8][CH2:9][NH:10][CH2:15][C:6]=3[NH:5]2)=[CH:12][CH:13]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2c3c([nH]c2c1)CNCC3
Temperature: 25 °C
Yield: 68 %

Procedure:
6-Fluorotryptamine (0.71 g) was dissolved in tetrahydrofuran (30 ml), a 4N hydrochloric acid-ethyl acetate solution (1.2 ml) was added dropwise, and the mixture was stirred at room temperature. The solvent was evaporated under reduced pressure. Glyoxylic acid monohydrate (Aldrich Co., 403 mg), a 1N potassium hydroxide solution (3.98 ml) and water (80 ml) were added to the obtained residue, and the mixture was stirred with heating at 80° C. for 1.5 hr. After ice-cooling, the precipitate was collected by filtration and washed with water to give a pale-brown solid. Water (80 ml) and concentrated hydrochloric acid (2 ml) were added to the obtained solid, and the mixture was stirred with heating at 80° C. for 1 hr. Concentrated hydrochloric acid (2 ml) was further added, and the mixture was heated under reflux for 1 hr. The insoluble material was hot filtrated, and the filtrate was adjusted to pH 12 or above with a 6N aqueous sodium hydroxide solution. The precipitated solid was collected by filtration, washed with water, and dried to give 7-fluoro-2,3,4,9-tetrahydro-1H-β-carboline (516 mg, yield 68%).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:10][C:11]([F:26])([F:25])[C:12]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)=[O:13].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:10][C:11]([F:25])([F:26])[C:12]([N:14]([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1)=[O:13]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(Cc1cccc([N+](=O)[O-])c1)C(=O)C(F)(F)F
Reaction time: 15 h
Yield: 61 %

Procedure:
tert-Butyl 2-bromoacetate was added to a solution of 52A (950 mg, 3.8 mmol) in DMF (8 mL) with Cs2CO3 (1.5 g, 4.6 mmol) and stirred 15 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 60% EtOAc in hexanes) to afford 52B (850 mg, 61%) as a clear oil. MS (ESI) m/z 361.3 (M−H)−.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].N(/C(C)(C)C#N)=N\C(C)(C)C#N.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1ccccn1
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)c1ccccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-propylpyridine (2.5 g, 20.63 mmol, purchased from Sigma-Aldrich, St. Louis, Mo.) and (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (1.253 g, 7.63 mmol, purchased from Sigma-Aldrich) in CCl4 (60 mL) at rt was added n-bromosuccinimide (1.93 mL, 22.7 mmol, purchased from Sigma-Aldrich). The mixture was stirred under fluorescent light at rt for 12 hr. The precipitate was removed by filtration of the mixture through a pad of Celite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth), which was washed with CCl4 (10 mL). The filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20% EtOAc/hexanes) provided the title compound as a yellow liquid. Mass Spectrum (ESI) m/z=199.9 and 201.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:25]#[N:26])=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1C(OCC1C=CC=CC=1)=O.O=[C:28]([CH3:35])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[NH2:26][C:25]1[C:3]2[C:2](=[CH:24][CH:23]=[CH:22][C:4]=2[O:5][CH2:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[N:1]=[C:28]([CH3:35])[C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: N#Cc1c(N)cccc1OC[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3)c2c1N

Procedure:
Prepared as in Example 2a from (S)-benzyl 2-((3-amino-2-cyanophenoxy)methyl)pyrrolidine-1-carboxylate (Example 89c) and ethyl 3-oxobutanoate as brown solid. MS 330 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]([CH2:13]Cl)[OH:12].[OH-].[Na+].O(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]1[CH2:13][O:12]1
Reactant: OC(CCl)CCc1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Product: Clc1ccc(CCC2CO2)c(Cl)c1

Procedure:
A solution of 87 parts of 2,4-dichloro-α-(chloromethyl)-benzenepropanol in 144 parts of concentrated sodium hydroxide solution and 350 parts of 2,2'-oxybispropane is stirred overnight at room temperature. The product is extracted with 2,2'-oxybispropane. The extract is washed with water, dried, filtered and evaporated. The oily residue is distilled, yielding [2-(2,4-dichlorophenyl)ethyl]oxirane; bp. 90°-98°C. at 0.01 mm. pressure.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:22]([Cl:23])=[C:21]([Cl:24])[C:20]([Cl:25])=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=O)=[C:4]1[CH3:27])[CH3:2].[CH2:28]([N:30]([CH2:42][CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH3:29].C(O[C:48](=[O:50])[CH3:49])(=O)C>>[CH2:38]([N:37]([CH2:40][CH3:41])[C:33]1[CH:32]=[C:31]([N:30]([CH2:28][CH3:29])[CH2:42][CH3:43])[CH:36]=[CH:35][C:34]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:18])[O:17]1)[CH3:39].[C:48]([NH:37][C:33]1[CH:32]=[C:31]([N:30]([CH3:42])[CH3:28])[CH:36]=[CH:35][C:34]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:17])[O:18]1)(=[O:50])[CH3:49]
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(CC)CC)c1
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3NC(C)=O)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc21

Procedure:
Following a procedure similar to that described in part B of Example 2 above, 4.45 g (0.01 mole) of 2-(1-ethyl-2-methyl-3-indolyl)carbonyl-3,4,5,6-tetrachlorobenzoic acid and 2.20 g (0.01 mole) of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted in the presence of ten ml of acetic anhydride to obtain 3-[2,4-bis(diethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: Ro =R1 =R2 =R3 =Cl; R=R6 =CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; Y1 =H) melting at 100°-103° C. and showing a significant infrared absorption maxima at 1770 cm-1 (C=O; s). A toluene solution of this compound developed an intense blue color when spotted on silica gel.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:16][O-:17].[Na+].Cl>CO.O>[CH3:16][O:17][C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Sc2cccc(F)n2)cc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc(Sc2ccc(O)cc2)n1

Procedure:
A solution of 11.05 grams (0.05 mole) of 4-((6-fluoro-2-pyridyl)thio)phenol (prepared as above in Example VI) and 8.10 grams (0.15 mole) of sodium methoxide in 200 milliliters of methanol was heated at reflux overnight. The resulting solution was acidified with concentrated hydrochloric acid and thereafter diluted with water. The solid 4-((6-methoxy-2-pyridyl)thio)phenol product was recovered by filtration, water washed and dried. The product was recovered in a yield of 10 grams (86 percent of theoretical) and melted at 88.5°-94.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([NH2:20])=[O:19].N1C=CC=CC=1.[CH3:27][O:28][CH2:29][C:30](Cl)=O.[OH-].[Na+]>C1COCC1>[CH3:27][O:28][CH2:29][C:30]1[NH:20][C:18](=[O:19])[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=3)=[N:7][C:2]=2[N:1]=1
Reactant: COCC(=O)Cl
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid amide (0.564 g, 2.0 mmol) in anhydrous THF (10 mL) under N2 atmosphere. Add dropwise pyridine (0.325 mL, 4.0 mmol) and methoxyacetyl chloride (0.365 mL, 4.0 mmol) to the reaction mixture and stir at room temperature overnight. Add 10% aq. NaOH (10 mL) and stir at 50° C. for 3 hours. Concentrate in vacuum, adjust the pH to 6.0 using AcOH, collect the solid by filtration and purify by column chromatography to give 2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one as a white solid.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:21])=[CH:18][CH:17]=1.O>CN(C)C(=O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:20]([C:19]1[CH:28]=[CH:29][C:16]([NH:15][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:17][CH:18]=1)=[O:21]
Reactant: Nc1ccc(C(=O)c2ccccn2)cc1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(C(=O)c2ccccn2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2- hydroxy-2-methylpropanoic acid (1.20 g, 7.6 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.90 g, 7.6 mmol) and the mixture stirred at -10° to -15° C. for 1 hour. 2-(4-Aminobenzoyl)pyridine (1.00 g, 5.0 mmol) was added in one portion and the reaction mixture stirred overnight at room temperature. The reaction mixture was poured into water and the aqueous solution extracted with ethyl acetate (2×50 mL). The combined organics were dried (MgSO4), filtered and the solvent removed in vacuo to yield a brown oil. Flash chromatography (eluted with 5% v/v ethyl acetate in methylene chloride) of the oil, evaporation of the eluent, and trituration with diethyl ether yielded the title propanamide (1.07 g, 63%) as a white solid; mp 151°-154° C. 1H-NHR (250 MHz, d6 -DMSO): 1.58 (s, 3H, CH3), 7.58 (s, 1H, OH), 7.98 (d, 2H, J=8.9 Hz, aromatic), 8.06 (d, 2H, J=9.0 Hz, aromatic), 8.81 (m, 2H, aromatic), 8.97 (d, 1H, J=2.2 Hz, aromatic), 9.39 (s, 1H, aromatic), 10.48 (s, 1H, NH). MS (CI, CH4): 339(M+1).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][Cl:16].O>CS(C)=O>[NH2:3][C:4]1[C:9]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Nc1ncccc1O
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncccc1OCCCCCl
Reaction time: 0.25 h

Procedure:
To a suspension of 20 g (500 mmol) of 60% oily sodium hydride in 500 ml of dimethyl sulfoxide, 55.06 g (500 mmol) of 2-amino-3-hydroxypyridine was added at room temperature, followed by stirring for 15 minutes. To this mixture, 57.62 ml (500 mmol) of 1-bromo-4-chlorobutane was added, followed by stirring at 80° C. for 3 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: n-hexane/ethyl acetate=1/1→1/4→1/9). The resulting crude crystal was purified by recrystallization (solvent: chloroform-diethyl ether) to yield 10.35 g (10.3%, white crystal) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2C(=O)C3=CC=CC=C3C2=O)=[CH:4][C:3]=1[O:20][CH3:21].O.NN>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: COc1cc(CN2C(=O)c3ccccc3C2=O)ccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(CN)ccc1Cl
Yield: 96.1 %

Procedure:
To a solution of N-(4-chloro-3-methoxybenzyl)phthalimide (3.00 g) in ethanol (60 mL) was added hydrazine hydrate (2.62 mL), and the mixture was heated for an hour under reflux. The resulting precipitates were faltered off and the filtrate was evaporated in vacuo. The residue was partitioned between chloroform and an aqueous saturated sodium bicarbonate solution. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 4-chloro-3-methoxybenzylamine as a yellow oil (1.64 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:39])[C@H:11]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:12][C:13](=[O:31])[C@H:14]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:15][C:16](=[O:23])[C@H:17]([CH2:19][C:20](=[O:22])[NH2:21])[NH2:18].ClC1C=CC([O:47][C:48](=O)[CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=C(Cl)C=1Cl.C(N1CCOCC1)C>CN(C)C=O>[CH3:8][O:9][C:10](=[O:39])[C@H:11]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH:12][C:13](=[O:31])[C@H:14]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:15][C:16](=[O:23])[C@H:17]([CH2:19][C:20](=[O:22])[NH2:21])[NH:18][C:48](=[O:47])[CH2:49][NH:50][C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)OC(C)(C)C

Procedure:
A solution of asparaginyl-phenylalanyl-phenylalanine methyl ester trifluoroacetate (0.88 g, 1.59 mmole, described by H. U. Immer et al., U.S. Pat. No. 3,917,578, issued Nov. 4, 1975), t-butoxycarbonyl-glycine trichlorophenyl ester (0.56 g, 1.59 mmole) and N-ethylmorpholine (0.203 ml, 1.59 mmole) in dimethylformamide (9 ml) is stirred at 0° C. for 1 hour and at 25° C. for 20 hours. The solution is evaporated and the residue is crystallized from methanol to give the title compound, mp 211°-214° C.